Indian Patents. 252711:"PROCESS FOR PREPARING PRAMIPEXOLE AND INTERMEDIATES USEFUL IN ITS PREPARATION"

Title of Invention	"PROCESS FOR PREPARING PRAMIPEXOLE AND INTERMEDIATES USEFUL IN ITS PREPARATION"
Abstract	The present invention is related to a process for the preparation pramipexole, by making use of a Curtius like rearrangement of novel compounds of formula (I) to amines of formula (VII) is disclosed

Full Text	SUMMARY OF THE INVENTION It has now been found a process for the preparation of pramipexole, which employs novel intermediates and fulfils the requirements for the production in industrial amounts. DETAILED DISCLOSURE OF THE INVENTION The present invention relates to a compound of formula (I), both as a mixture of (R,S) enantiomers, and as the single (R) or (S) enantiomers, or a salt thereof, wherein R is a protected amino group; and the asterisk * indicates the stereogenic carbon atom. A salt of a compound of formula (I) can be a salt with bases or acids, organic or inorganic. Preferred examples of salts with bases are those with inorganic bases, such as sodium, lithium or potassium salts, or salts with primary, secondary or tertiary amines, such as N-methyl-, N,N-dimethyl- and triethyl-ammonium salts, benzylammonium, a-methylbenzylamine, N-methyl- D-gtacamine, cinchonidine or cinchonine salts. Preferred examples of salts with acids are those with hydrochloric, sulfuric, acetic, oxalic or methanesulfonic acids, preferably with an optically active acid, such as tartaric or camphorsulfonic acid. Preferably a compound of formula (I), or a salt thereof, is in the form of the single (R) or (S) enantiomer, in particular as the single (S) enantiomer, typically with at least approx. 96%, more preferably at least approx. 99%, 25 enantiomeric purity. Preferred examples of the compounds of formula (I) are: • (S)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; • (S)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6- carboxylic acid; • (R)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; and • (R)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6- carboxylic acid. A compound of formula (I), as defined above, either as a mixture of 10 (R,S) enantiomers or as single (R) or (S) enantiomer, can be obtained with a process comprising the hydrolysis of an ester of formula (II) or a salt thereof, either as a mixture of (R,S) enantiomers or as single (R) or (S) enantiomer . (ID wherein RI is straight or branched Ci-Cg alkyl, optionally substituted with phenyl; and the asterisk * and R have the meanings defined above; and, if desired, the resolution of tire mixture of (R,S) enantiomers of the compound of formula (I) to yield the single (R) or (S) enantiomer. R] is preferably a CrC4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular ethyl or propyl; or benzyl or phenylethyl. A salt of a compound of formula (II) is for example a salt with a mineral acid, preferably an hydrohalic acid, in particular hydrochloric or hydrobromic acid, or an organic acid, such as acetic, oxalic or methanesulfonic acid, preferably an optically active acid, such as tartaric or camphorsulfonic acid. According to the present invention, a protected amino group R can be, for example, a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group. In an acylamino group, acyl is for example formyl or Ci-C6-CO- alkyl, 5 preferably acetyl, propionyl or pivaloyl, optionally substituted with 1 to 3 halogen atoms, such as chlorine, fluorine, bromine or iodine. In a carbanToyl group, the amino group is linked, for example, to a CrC6 alkoxy-carbonyl group, wherein the alkyl residue is straight or branched, optionally substituted with phenyl. The alkyl residue is preferably a 10 CrC4 alkyl group, optionally substituted with phenyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl or phenylethyl. in particular tert-butyl. In an arylmethylamino group, for example a mono, di- or particularly tri-arylmethylamino group, the aryl moiety is preferably a phenyl group. Said 15 group is for example benzyl-, diphenylmethyl- or trityl-amino; more particularly a 1-methyl-1-phenyl-ethylamino group. A silylamino group is for example a trimethylsilylamino or tert-butyl-dimethylsilylamino group. A protected amino group R is preferably a protected amino group such 20 as an acylamino or arylmethylamino group, in particular acylamino, wherein acyl is formyl, acetyl, propionyl or pivaloyl, the latter three being optionally substituted with 1 to 3 halogen atoms, such as chlorine, fluorine, bromine or iodine. More preferably the R group is acetylamino, propionylamino or pivaloylamino. The hydrolysis of a compound of formula (II) can be carried out by reaction with an alkali hydroxide, for example sodium or potassium hydroxide, in amounts from about 1 to 4 equivalents, preferably from 1.5 to 2.5 equivalents, in a polar protic solvent, for example water or C\|-C4 alkanols, in particular methanol, ethanol, i-propanol, or mixtures thereof; at a temperature ranging from about 0°C to the solvent reflux, preferably from about 10 to 50°C, in particular at approx. 20°C. According to the invention, a mixture of (R,S) enantiomers can contain 5 the two single enantiomers in any ratio to each other. The enantiomeric purity is generally expressed as "enantiomeric excess" and defined, for example, for the (S) enantiomer as (S-R)/(R+S)xlOO wherein S and R are respectively the amounts of the (S) and (R) enantiomers. According to the invention, the expression single (S) or (R) enantiomer means that the enantiomeric purity is usually at least about 96%, preferably at least about 99%. The optional resolution of the mixture of (R,S) enantiomers of a compound of formula (I) into the single (R) or (S) enantiomers can be carried out, for example, by fractional crystallization of the diastereomeric salts of a compound of formula (I) obtained by reaction with optically active, enantiomericaiiy" pure acids or bases. An example is the reaction of the compound of formula (I) with an enantiomerically pure aliphatic or aromatic amine, for example a-methylbenzylamine, N-methyl-D-glucamine, cinchonidine and cinchonine; or with an enantiomerically pure acid, for example tarMric acid or camphorsulfoak acid, in a solvent capable of promoting the formation of the salt and the subsequent precipitation of the desired diastereomer. Examples of said solvents are CrC4 alkanols, such as methanol, ethanol and i-propanol; ketones, such as acetone; ethers such as tetrahydrofuran and dioxane; alkyl esters, such as ethyl acetate; amides, such as dimethylformamide and dimethylacetamide; dimethylsulfoxide; or mixtures thereof or mixtures of one or more of them with water. The temperature can range from room temperature to the solvent reflux temperature. Alternatively, the resolution can be carried out by means of preparative chromatography using a chiral, optically active stationary phase, including the "Simulating Moving Bed" (8MB) technology. A further alternative consists in the enzymatic resolution, either by selective hydrolysis of one stereoisomer of an ester of formula (II) to an acid of formula (I), or by selective esterification of one stereoisomer of an acid of formula (I) to an ester of formula (II). The conversion of a compound of formula (I) into a salt thereof can be obtained with known methods. An object of the invention is also a compound of formula (II), and the salts thereof, as a mixture of (R,S) enantiomers and as the single (R) or (S) eriarLtiomers. Preferably a compound of formula (II), or a salt thereof, is in the form of the single (R) or (S) enantiomer, in particular as the single (S) enantiomer, typically with at least approx. 96%, more preferably at least approx. 99%, enantiomeric purity. US 4,988,699 generally discloses compounds of formula (I) and of formula (II) as (R,S) mixturerta which the R subsiitoent is an amino group optionally substituted with various groups, inter alia lower alkanoyl groups. On the other hand, this patent only describes compounds with unsubstituted amino groups. The following specific acids and esters, as well as the salts thereof, although generrcaily included within die general formula of US 4,988,699, are to be considered novel and are a further object of the invention: • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester; • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; and • 2-prppionylamino-4,5,6,7-tetrahydro-benzothiazote-6-carboxylic acid propyl ester. A compound of formula (II), and the salts thereof, can be obtained by converting the amino group of a compound of formula (III) (Ill) wherein RI and the asterisk * have the meanings reported above, into a protected amino group R as defined above, and optional resolution of the mixture of (R,S) enantiomers of a resulting compound of formula (II) into the single (R) or (S) enantiomers thereof, and/or salification thereof. The conversion of the amino group of a compound of formula (II) to a protected amino group R, preferably in an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group, as well as the salification, can be carried out according to known methods. The protection as an acylamino or carbamoyl group is preferably carried out by reaction with the corresponding anhydride, in particular acetic anhydride, or acyl-chloride or alkoxycarbonyl-chloride, in particular acetyl-chloride or methoxy- or ethoxy-carbonyl-chloride, in a solvent selected for example from acetone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane or toluene; in the presence of a basic agent, preferably triethylamine, diisopropylamine or pyridine. The reaction is carried out from about -15°C to the solvent reflux, preferably between about 0°C and 50°C, in particular at room temperature. The 5 optional resolution of a mixture of (R,S) enantiomers of a compound of formula (II) into the single (R) or (S) enantiomers can be obtained, for example, by reaction with an organic acid, according to the procedures reported above for the resolution of a mixture of (R,S) enantiomers of a compound of formula (I). A compound of formula (III) can be prepared by reaction of a compound of formula 10 (IV), COOR, wherein RI is as defined above, with thiourea. The cyclization reaction is carried out in an organic solvent, for example a C]-C4 alkanol, acetone, tetrahydrofuran, dioxane or mixtures thereof, at a temperature ranging from about 0°C to the solvent reflux temperature, for a time ranging between 1 hour and 8 hours, in particular between 2 hours and 5 hours. The hydrobromide salt of a compound of formula (III) forms first and is then converted to the free base form by suspending it for example in water, Ci-Ce alkanols or acetone, preferably methanol or ethanol; at a temperature ranging from room temperature to the solvent reflux temperature; and adding from 1 to 1.5 equivalents, preferably from 1 to 1.1 equivalents, of an inorganic base, preferably sodium or potassium bicarbonate. Upon filtration, a compound of formula (III) separates as the free base. In particular, a compound of formula (II), as defined above, wherein the protected amino group R is in the form of an acylamino or carbamoyl group, can be prepared by reaction of a compound of formula (IV), as defined above, with a compound of formula (V) 2 2 H (V) wherein R2 is respectively a straight or branched CrC6 alkyl or alkoxy group, optionally substituted with phenyl. R2 is preferably a Ci-C4 alkyl group, optionally substituted with phenyl, such as methyl, e^yl, n-propyl, isopropyl, n-butyl, isobutyl, tert-batyl, benzy! or phenylethyl, in particular methyl. Alternatively, it is preferably a CrC4 alkoxy group, optionally substituted with phenyl, for example methoxy, ethoxy, propoxy or benzyloxy, in particular methoxy. The hydrobromide salt of a compound of formula (II) is first obtained, which is then converted to the free base form. The reaction between a compound of formula (IV) and a compound of formula (V) can be carried out according to the above reported procedure by reaction between a compound of formula (IV) and thiourea. The hydrobromide salt of a compound of formula (II) can be converted to the free base form according to the procedure reported above for the transformation of a hydrobromide -salt of a compound of formula (III) to the free base form. The compounds of formula (IV) and (V) can be prepared with known methods. For example, a compound of formula (IV) can be prepared by monobromination of the corresponding ketone of formula (VI) (VI) wherein R\ is as defined above, with 0.8-1.5 equivalents, preferably 1 equivalent, of bromine in a solvent selected for example from dichloromethane, toluene, acetic acid or a C,-C4 alkanol, in the presence of hydrobromic acid in amounts approx. ranging from 0 to 0.2 equivalents. The 5 reaction is carried out at a temperature ranging from about -15°C to 40°C, preferably from 0°C to 15°C, for a time ranging between 1 hour and 6 hours, preferably between 2 hours and 5 hours. A compound of formula (VI) is commercially available. A compound of formula (I), in particular as the single (S) enantiomer, is 10 particularly useful in the preparation of pramipexole. Said compound is subjected to rearrangement, thereby obtaining intermediates useful in the preparation of pramipexole, according to the synthetic route disclosed in US 4,843,086. Therefore, a further object of the invention is the use of a compound of formula (I), typically as the single (S) enantiomer, in a process for the 15 preparation of pramipexole or a pharmaceutically acceptable salt thereof. In particular, in a process comprising the alkylation of a compound of formula (VII), preferably as the single (S) enantiomer, -Ra (VII) wherein Ra is a free or protected amino group, R3 is hydrogen or a R4-O-CO- group, wherein R4 is straight or branched Ci-C4 alkyl and the asterisk * has the meaning defined above, to obtain a compound of formula (VIII) CH,-CH,-CH 2 «• i2-wi ij SXN^s (VIII) ^ wherein Ra, R3 and the asterisk * are as defined above, and, if necessary, the removal of the primary amino-protecting group and/or of the R4-0-CO- group from the secondary amino group and, if desired, its conversion to a pharmaceutical ly acceptable salt thereof, characterized in that: a) a compound of formula (VII), wherein Ra is a protected amino group and R3 is as defined above, as the single (S) enantiomer, is prepared by rearrangement of a compound of formula (I), as the single (S) enantiomer, via formation of the isocyanate, and subsequent addition of a nucleophilic solvent or subsequent quenching in water in the presence of an acidic agent; or b) a compound of formula (VII), wherein Ra is a free amino group and R3 is hydrogen, as the single (S) enantiomer, is prepared by rearrangement of a compound of formula (I), as the single (S) enantiomer, via formation of the isocyanate, and subsequent addition of water, to obtain a compound of formula (le) N de) wherein R' has the same meaning as R, and subsequent hydrolysis. An acidic agent is for example a mineral or an organic acid, in 20 particular hydrochloric, sulfuric, formic or acetic acid. A nucleophilic solvent can be for example a CrC4 alkanoi, typically methanol, ethanol or i-propanol. According to process variant a) reported above, quenching in water in the presence of an acidic agent or the addition of a nucleophilic solvent 25 respectively affords a compound of formula (VII) as defined above wherein R3 is hydrogen or R3 is a R4-O-CO- group as defined above. Rearrangement can be effected for example according to the Schmidt, Lessen, Hofmann or Curtius reactions. The sequence of the products formed during the rearrangement reaction is the following: (I) (la) (lb) OCN H Rs°vVx ^x\ e T (Ic) (Id) (VII) in which Y is NHOCOR4, N3 or NH2, wherein R4 is as defined above; R5 is hydrogen or stoight w branched Ci-C4 alkyl; and R and R3 are as defined above. The compounds of formulae (la), (Ib), (Ic) and (Id) can optionally be 15 isolated during the reaction. The compounds of formulae (la), (Ib), (Ic) and (le), either as mixture of (R,S) enantiomers or as the single (R) or (S) enantiomers, are novel compounds and are a further object of the invention. All of the Schmidt, Lessen, Hofmann and Curtius reactions make use of an isocyanate of formula (Ic) as defined above. A compound of formula (Ic) can be prepared according to the Schmidt reaction, treating a compound of formula (I) with hydrazoic acid in the presence of sulfuric acid, to obtain a compound of formula (la), wherein Y is N3 and R is as defined above, which is converted to the corresponding compound of formula (Ic) by heating. Alternatively, a compound of formula (Ic) can prepared according to the Lessen reaction, by reaction of a compound of formula (I) with a halogenating agent, preferably thionyl chloride or oxalyl chloride, and subsequent reaction with an acyl-hydroxylamine, preferably acetyl-hydroxylamine, thereby 5 obtaining the respective acylated hydroxamic acid, i.e. a compound of formula (la) wherein Y is NHOCOR4 and R is as defined above. Treatment of the latter with an alkali hydroxide affords a compound of formula (Ic). Again, a compound of formula (Ic) can be prepared according to the Hofmann reaction, by transforming the carboxylic acid into amide according to known methods, i.e. into a compound of formula (la) wherein Y is NH2 and R is as defined above, then treating it with an alkali hypohalogenite, preferably sodium hypochlorite. Finally, a compound of formula (Ic) can be prepared according to the Curtius reaction, by reaction of a compound of formula (I) with a halogenating agent, preferably thionyl chloride-or oxalyl chloride, and subsequent treatment with sodium azide to obtain the respective acyl-azide of formula (la) wherein Y is N3 and R is as defined above; or directly with diphenylphosphorylazide, in the presence of an organic base, in particular triethylamine, diisopropytethylamine or pyridine. The acyl-azide of formula (la) is converted to the corresponding compound of formula (Ic) by heating. j^ The rearrangement reactions reported above are carried out according to known methods, for example at a temperature approx. ranging from about 10°C to the reflux temperature, for a time ranging between 2 hours and 15 hours, preferably between 5 hours and 10 hours. More particularly, a compound of formula (la), in which Y is N3, is poured in water in the presence of an acidic agent, thereby converting it to a compound of formula (Id) as defined above. An acidic agent is for example a mineral or organic acid, in particular hydrochloric, sulfuric, formic or acetic acid, in amounts ranging from about 2 to about 5 mols, preferably from about 2.5 to about 3.5 mols. The reaction is carried out at a temperature ranging from room temperature to the reaction mixture reflux, preferably from about 50 to about 80°C. When the nucleophilic solvent is for example water, in the 5 resulting compound of formula (Id) R5 is hydrogen. Alternatively, when the nucleophilic solvent is for example a Ci-C* alkanol, in particular methanol, ethanol or i-propanol, in the resulting compound of formula (Id) R5 is alkyl. According to a preferred aspect, the rearrangement reaction to form the acyl-azide of formula (la) in which Y is N3 is carried out according to Curtius in a nucleophilic solvent, as defined above. The reaction proceeds until formation of a compound of formula (Id) wherein R5 is a straight or branched C]-C4 alkyl group, with no need for isolating any intermediate. A compound of formula (Id) in which R5 is hydrogen spontaneously transforms into a compound of formula (VII), wherein Ra is a protected amino group, R is as defined above and R3 is hydrogen. A compound of formula (Id) in which R5 is alkyl is a compound of formula (VII) wherein R3 is a R4-O-CO- group, as defined above and Ra is a protected amino group. Alternatively, when a compound of formula (la), in which Y is N3, is poured in water, or vice versa, a compound of formula (le) 20 -R1 (le) wherein R and R' are as defined above is obtained, which is hydrolysed to a compound of formula (VII) wherein Ra is a free amino group, R3 is hydrogen and the asterisk * has the meaning defined above. The hydrolysis is typically an acidic hydrolysis, for example by treatment with hydrochloric acid according to known methods. The alkylation of a compound of formula (Vll) and, if the case, the removal of the primary amino group protecting group and, if present, of the R4-O-CO- group from the secondary amino group present in a compound of formula (VIII), can be carried out according to US 4,886,812. It has now been found a particularly advantageous process for the conversion of a compound of formula (VII) to a compound of formula (VIII) in which R3 is hydrogen and Ra is as defined above. It should be stressed that a compound of formula (VIII) in which R3 is hydrogen and Ra is -NH2 is pramipexole. Therefore, the invention.provides a process for the preparation of pramipexole or a pharmaceutically acceptable salt thereof, comprising the acylation of a compound of formula (VII), in which R3 is hydrogen and Ra is as defined above, either as a mixture of (R,S) enantiomers or as the single (S) enantiomer, by reaction with propionic anhydride and subsequent reduction of the compound of formula (IX) thus obtained, (IX) wherein Ra is as defined above, by treatment with an alkali metal borohydride and molecular iodine to obtain a compound of formula (VIII) wherein R3 is hydrogen and Ra is as defined above; followed, if necessary, by 20 deprotection of the primary amino group and/or by resolution of the mixture of the (R,S) enantiomers into the single (S) enantiomer and, if desired, by conversion of pramipexole into a pharmaceutically acceptable salt thereof. The acylation is preferably carried out on a compound of formula (VII), as the single (S) enantiomer, in particular having the enantiomeric purity as obtainable according to present invention. The acylation of a compound of formula (VII) with propionic anhydride can be carried out according to known methods. An alkali metal borohydride is for example NaBH4 or KBH4, preferably NaBH4. The amount of alkali metal borohydride used in the reduction, for example NaBH4, is about 1-5 mols per mole of compound of formula (IX), preferably from about 2 to 4 mols, whereas the molar amount of iodine is about 0.5-3 mols per mole of compound of formula (IX), preferably from about 1 to 2. The reduction of a compound of formula (IX) is preferably earned out in an ether solvent, such as tetiakyd+ofuran, dioxane or diethyl ether, in particular tetrahydrofuran. The reaction can be carried out at a temperature ranging from about 0°C to the reflux temperature, preferably at approx. 20-40°C. A pramipexole pharmaceutically acceptable salt is for example an addition salt with an organic or mineral acid, as reported in 15 US 4,886,812, preferably the dihydrochloride, and can be obtained with known procedures. The process of the invention for the preparation of pramipexole is particularly advantageous for the production on an industrial scale. In fact, the resolution of the enantiomers takes place during the first synthetic steps and 20 moreover the discarded enantiomer can be recovered by racemization and recycled. This attains a reduction in the by-products of the more expensive final products and higher yields. The following examples illustrate the invention. Example 1 - 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester hydrobromide [(III), R, = ethyl] A 3 liter reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 1500 ml of ethanol and 200 g of 4-oxo-cyclohexanecarboxylic acid ethyl ester. After cooling to 0°C, 188 g of bromine were dropped therein in about 1 hour. The temperature was raised to 10°C, then to the room one after discolouration. After 1 hour, 89.32 g of thiourea were added in portions to obtain a suspension, that was refluxed to obtain gradual dissolution of the solid. After 4 hours the solution was 5 concentrated to small volume to obtain a solid mass, that was suspended in 800 ml of acetone and refluxed to obtain a solution. The solution was then cooled to room temperature to precipitate a solid, then to 0°C and after 4 hours the solid was filtered, washed twice with 100 ml of cold acetone and dried to obtain 170 g of the title product. 'H-NMR in OMSO: 1.20 ppm (t,3H); 1.79 ppm (m,lH); 2.05 ppm (m,lH); 2.43 ppm (t,2H); 2.70 ppm (m,3H); 4.08 ppm (q,2H); 6.63 ppm (s,2H). Example 2 - 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxyIic acid ethyl ester [(III), R, = ethyl] A 2 liter reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 600 ml of water, 110 g of 2-amino-4.5,6,7- tetrahydro-benzothiazole-6-carboxylic acid ethyl ester hydrobromide [(III), RI = ethyl] and 120 ml of methanol. The mixture was refluxed and hot filtered on a Celite bed. The resulting solution was added with a solution of 32 g of sodium bicarbonate in 300 ml of water (final pH = 7-8). After 2 hours at room temperature, the precipitated white solid was filtered, washed with 100 ml of water and dried to obtain 72 g of the title product. 'H-NMR in DMSO: 1.20 ppm (t,3H); 1.79 ppm (m,lH); 2.05 ppm (m,lH); 2.43 ppm (t,2H); 2.70 ppm (m,3H); 4.08 ppm (q,2H); 6.63 ppm (s,2H). Example 3 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazole-6- carboxylic acid ethyl ester [(II), R, = ethyl, R = -NH-CO-CH3) A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 280 ml of acetonitrile, 71 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(III), Rj = ethyl] and K 38.75 g of acetic anhydride. 38.03 g of triethylamine were dropwise added to the resulting suspension in about 10 minutes. The suspension was refluxed, obtaining complete dissolution at a temperature ranging from 70 to 75°C. After approx. 2 hours 30 minutes the solution was concentrated to dryness, 5 and the residue was crystallized from 450 ml of isopropanol to obtain 74.5 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester. 'H-NMR in DMSO: 1.19 ppm (t,3H); 1.80 ppm (m,lH); 2.09 ppm (s,3H); 2.11 ppm (m,lH); 2.61 ppm (t,2H); 2.82 ppm (m,3H), 4.08 ppm 10 (q,2H). According to the same procedure, the following compounds are obtained: • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester; • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester, • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; and • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester. Example 4 - 2-Acetylamkio-4,5,6,7-tetrahydro-beiizothiazole-6-carboxylic acid ethyl ester hydrobromide [(II), R, = ethyl, R = -NH-CO- CH3] A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 200 ml of methylene chloride, 20 g of 4-oxo-cyclohexanecarboxylic acid ethyl ester, 2 g of 48% hydrobromic acid. The resulting clear solution was cooled to 0°C and dropwise added with 18.88 g of bromine in about 2 hours. Two hours after completion of the addition, 100 ml of water were added and the phases were separated, discarding the aqueous one. 80 ml of water were added and the mixture was neutralized to pH = 7-8 with sodium bicarbonate. The organic phase was separated and was 5 concentrated to one third of the original volume, then added with 150 ml of ethanol and 13.95 g of acetyl thiourea to obtain a suspension. Upon reflux, the solid gradually dissolved to obtain a clear solution. After 3 hours the solution was concentrated to small volume to obtain a solid mass, that was crystallized from 200 ml of i-propanol to obtain 15.9 g of solid. 'H-NMR in DMSO: 1.2 ppm (t,3H); 1.81 ppm (m,lH); 2.09 ppm (m,lH); 2.11 ppm (s,3H); 2.60 ppm (t,2H); 2.81 ppm (m,3H); 4.08 ppm (q,2H). According to the same procedure, the following compounds are obtained, as hydrobromide: • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; and • 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester; • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; and • 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester. Example 5 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazoIe-6- carboxylic acid [(I), R = -NH-CO-CH3] A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 200 ml of water, 30 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(II), RI = ethyl, R = -NH-CO-CH3] and 52.2 g of 30% sodium hydroxide, keeping the temperature below 30°C; during the addition the solid gradually solubilized until complete dissolution. After 2 hours, glacial acetic acid was dropwise added to pH = 4.5-5.5; after approx. 1 hour the precipitated white solid was 5 filtered, washed with 70 ml of water and dried to obtain 24.8 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid. 'H-NMR in DMSO: 1.75 ppm (m,IH); 2.09 ppm (s,3H); 2.11 ppm (m,lH); 2.58 ppm (nUH); 2.78 ppm (m,2H) I3C-NMR in DMSO: 22.48 ppm; 24.72 ppm; 25.04 ppm; 25.5 ppm; 39.37 ppm; 119.77 ppm; 143.4 ppm; 155.27 ppm; 167.99 ppm; 175.69 ppm. According to the same procedure, 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid is obtained. Example 6 - N-(6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide dihydrochloride, [(VII), Ra = -NH-CO-CH3, R3= -H] A 500 ml reactor equipped with mechanical sthrer, thermometer and condenser was loaded with 10 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 146 ml of N,N-dimethylforrnamide, and 4.63 g of triethylamine were added. After that, a solution consisting of 12.57 g of diphenylphosphoryl azide (DPPA) dissolved in 10 ml N,N-dimethylformamide was dropped therein in 2 hours. The reaction mixture gradually solubilized during the addition until complete dissolution. After 5 hours the reaction solution was dropped in 1.3 liters of an aqueous solution containing 14 ml of 37% hydrochloric acid, at 60°C. The mixture was left to cool, then extracted twice with 200 ml of methylene chloride, discarding the organic phase. The aqueous phase was concentrated to a residue, that was crystallized from i-propanol-water to obtain 4.5 g of a white solid. 'H-NMR in DMSO: 1.91 ppm (m,lH); 2.17 ppm (s,3H); 2.19 ppm (m,lH); 2.73 pm (m,3H); 3.07 ppm (dd,lH); 3.49 ppm (s,broad,lH); 8.39 ppm (s,broad,2H). 13C-NMR in DMSO: 22.50 ppm; 23.64 ppm; 26.49 ppm; 26.66 ppm; 46.56 ppm; 117.39 ppm; 142.89 ppm; 156.06 ppm; 168.28 ppm. According to the same procedure, starting from (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, (S) N-{6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide dihydrochloride is obtained. Example 7 - (2-Acctylaarino-4^,6,7-tetrahydro-bejizothiazo4-6-yl)-10 carbsmc acid methyl ester hydrochloride [(VII), Ra = -NH-CO-CH3, R3= -CO-O-CH3] A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser is loaded with 5 g of 2-acetylamino-4,5,6.7-tetrahydro-benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 80 ml 15 of N^-dimethyiformamidaet then 2.32 g of trieriiyiamine are added. A solution consisting of 6.3 g of diphenylphosphoryl azide (DPPA) dissolved in 7 ml N,N-dimethylformamide is dropped therein in 2 hours. The reaction mixture gradually solubilizes during the addition until complete dissolution. After 6 hours the reaction solution is dropped in 1 liter of a 20 methanol solution containing 8 ml of 37% hydrochloric acid at 60°C. The mixture is left to cool, then extracted twice with 100 ml of methylene chloride, discarding the organic phase. The aqueous phase is concentrated to a residue that is crystallized from i-propanol-water to obtain 3.6 g of a white solid. According to the same procedure, starting from (S) 2-acetylamino- 4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, (S) (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbammic acid methyl ester hydrochloride is obtained. ^ Example 8 - Resolution of (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxyIic acid [(I), R = -NH-CO-CH3] A 1 liter reactor equipped with mechanical stirrer, thermometer and condenser is loaded with 50 g of 2-acetylamino-4,5,6,7-tetrahydro-5 benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 250 ml of methanol and 50 ml of water. The mixture is heated until dissolution, added with 37.3 g of (SH-)-a-methylbenzylamine then cooled to 25°C. The precipitated product is filtered off, washed with methanol and dried to obtain 42.8 g of a solid^This is suspended in 250 ml of methanol and 50 ml of water, 10 heated to dissolution for 1 hour and cooled to room temperature. The suspended solid is filtered, washed with methanol and dried to obtain 32.3 g of (S)-2-acetylamino-4.5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, having enantiomeric purity > 99.5%. According to the same procedure, (S)-2-propionylamino-4,5,6,7-15 tetrahydro-benzoAiazole-6-carboxylic acid is obtained with enantiomeric purity > 99.5%. Example 9 - Resolution of (R) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ((I), R = -NH-CO-CH3] A 1 liter reactor equipped with mechanical stirrer, thermometer and condenser are loaded with 50 g of 2-acetylamino-4,5,6,7-tetrahydro- benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 250 ml of methanol and 50 ml of water. The mixture is heated until dissolution, added with 37.3 g of (R)-(+)-a-methylbenzylamine, cooled to 25°C, and the precipitated product is filtered off, washed with methanol and dried to obtain 42.8 g of a solid. This is suspended in 250 ml of methanol and 50 ml of water, heated to dissolution for 1 hour and cooled to room temperature. The suspended solid is filtered, washed with methanol and dried to obtain 32.3 g of v (R)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, having enantiomeric purity > 99.5%. According to the same procedure, (R)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid is obtained with enantiomeric 5 purity > 99.5%. Example 10 - N-{6-[3-(2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-ureido]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-acetajaide, [(le), R = -NH-CO-CH3] A 500 ml reactor equipped with mechanical strrrer, thermometer and condenser was loaded with 10 g of 2-acetylamino-4,5,6,7-tetrahydro- benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 146 ml of N,N-dimethylformamide and 4.65 g of triethylamine were added. A solution consisting of 12.52 g of diphenylphosphoryl azide (DPPA) dissolved in 10 ml N,N-dimethylformamide was dropped therein in 2 hours. The reaction mixture gradually solubtlized during the addition until complete • dissolution. After 5 hours, the reaction mixture was dropped in 1.3 liters of an aqueous solution at 60°C. The mixture was left to cool, the separated solid was filtered, washing twice with 50 ml of water to obtain 5.9 g of a white solid. 'H-NMR in OMSO: 1.72 ppm (m,lH); 1.86 ppm (m,lH); 2.07 ppm (s,3H); 2.4 ppm (dd,lH); 2.59 ppm (m,2H); 2.8 ppm (dd,lH); 3.93 ppm (m,lH), 5.96 ppm (d,lH), 11.84 ppm (s,lH). I3C-NMR in DMSO: 22.30 ppm; 23.74 ppm; 26.55 ppm; 26.59 ppm; 44.36 ppm; 118.42 ppm; 144.02 ppm; 156.13 ppm; 157.98 ppm, 169.18 ppm. Example 11 - N-(6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-yI)- amine dihydrochloride, [(VII), Ra = -NH2, R3= -H]. A 1 liter reactor equipped with mechanical stirrer, thermometer and condenser is loaded with 70 g of N-{6-[3-(2-acetylamino-4,5,6,7-tetrahydro- benzothiazol-6-yI)-ureido]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-acetamide, [(le), R = -NH-CO-CH3] suspended in 500 ml of water, and 151 g of 37% hydrochloric acid are added. The mixture is refluxed for 40 hours, then left to cool. The aqueous phase is concentrated to a residue that is crystallized from 5 i-propanol-water to obtain 53 g of a white solid. According to the same procedure, starting from (S)-N-{6-[3-(2- acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-ureido]-4,5,6,7-tetrahydro- benzothiazol-2-yl}-acetamide, [(le), R = -NH-CO-CH3] of enantiomeric purity 96%, (S)-N-(6-aniino-4,5,6,7-tetrahydro-bejizothiazol-2-yI)-amine dihydrochloride is obtained, [(VII), Ra = -NH2, R3= -H] with enantiomeric purity > 97%. 'H-NMR in DMSO: 1.91 ppm (m,lH); 2.17 ppm (s,3H); 2.19 ppm (m,lH); 2.73 ppm (m,3H); 3.07 ppm (dd.lH); 3.49 ppm (s,broad,lH); 8.39 ppm (s,broad,2H). 13C=NMR in DMSO: 22.50 ppm; 23.64 ppm; 26.49 ppm; 26.66 ppm; 46.56 ppm; 117.39 ppm; 142.89 ppm; 156.06 ppm; 168.28 ppm. Example 12 - (S) N-(6-Propienylamino-4,5,6,7-tctrahydro-benzothiazol-2-yl)-amine;[ (IX) Ra = H] A 1 liter reactor equipped with mechanical stirrer, thermometer and condenser is loaded with under nitrogen 43.7 g of (S) N-(6-amino-4,5,6,7- tetrahydro-benzothiazol-2-yl)-amine and 220 ml of methyl ethyl ketone (MEK). Is heated a 28-32°C and approx. 33.6 g of propionic anhydride are dropped therein in 2 hours keeping the temperature at about 28-32°C. The solution is cooled to about 0-5°C and 109 g of 10% aqueous NaOH are added. The aqueous phase is separated; the organic phase is diluted with 60 ml of toluene and concentrated under vacuum at about 40-45°C. Under these conditions, the product starts to crystallize. The suspension is cooled to 0-5°C and left under stirring for an hour. The precipitate is filtered with suction and washed with 10 ml of toluene. 54.2 g of (S) N-(6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2- yl)-amine are obtained. Example 13 - intermediate (VIII) Ra = H; pramipexoie free base A 2 liter reactor under nitrogen is loaded with 53.3 g of, 33.0 g of (S) N-(6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine, 95% sodium borohydride and 260 ml of tetrahydrofuran (THF). A solution of 9$.._7 g of iodine in 160 ml of THF is dropped tbemm in about 3 hours, keeping the temperature at approx. 20-25°C. The reaction mixture is kept under stirring for further 2 hours at about 20-25°C. The reaction mixture is poured into a solution of 60.0 g of 37% HC1 in 260 ml of water. The mixture is heated to 50-55°C and left under stirring for an hour. The complete cleavage of the boran-complexes is checked by HPLC. The mixture is added with 250 g of 50% aqueous NaGHT keeping the temperature at about 20-25°C. After that, 315 ml of toluene are added and the mixture is heated to about 30-35°C. Stirring is interrupted and the two phases are separated. The organic phase are washed, concentrated to a residue and dissolved in 420 ml of ethyl acetate. The solution is concentrated under vacuum at a temperature below 50°C to about 150 ml volume. The resulting suspension is refluxed, then cooled to about 10-15°C, stirred for further 1-2 hours, then filtered with suction and the precipitate is washed twice with 30 ml of ethyl acetate. The product is dried under vacuum at 40°C. 32 g of (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole are obtained. Example 14 - Isopropyl (S)-(2-acetylamino-4,5,6,7-tetrahydro- benzothiazoI-6-yl)-carbamate [(VII), Ra = -NH-CO-CH3, R3= -CO-O-C3H7] A 2000 ml reactor equipped with mechanical stirrer, thermometer and condenser are loaded with 100 g of (S)-2-acetylamino-4,5,6,7-tetrahydro- benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] of 97% enantiomeric purity, suspended in 700 ml of isopropanol; 84.16 g of triethylamine are added. The mixture is refluxed (about 80°C) and a solution consisting of 120.42 g of diphenylphosphoryl azide (DPPA) is dropped therein in 2 hours. 5 After 2 hours, the reaction mixture is cooled to 20-30°C and added with 500 ml of water and 1.6 g of sodium hydroxide. Isopropanol is distilled off under vacuum, then 400 ml of ethyl acetate are added. The mixture is refluxed for 15 minutes, then the hot suspension is filtered through Celite. The solution is cooled to^O-30°C and added with of 1800 ml of waters The phases are separated and the organic phase concentrated to dryness. The residue is taken up with 200 ml of acetonitrile. The suspension is heated at 50°C for 1 hour, then cooled to 20°C and filtered to obtain 75 g of isopropyl (S)- (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamate, with 91% enantiomeric purity. We Claim: 1. A process for the preparation of (S)-2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole (pramipexole), comprising the hydrolysis of a compound of formula (II), which is selected from a racemic mixture of (R,S) enantiomers, a single (R) enantiomer, a single (S) enantiomer, a salt of a racemic mixture of (R,S) enantiomers, a salt of a single (R) enantiomer and a salt of a single (S) enantiomer, (Formula Removed) wherein R is a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group; R1 is straight or branched C1-C6 alkyl, optionally substituted with phenyl; and the asterisk * indicates the stereogenic carbon atom, to obtain a compound of formula (I) (Formula Removed) which is selected from a racemic mixture of (R,S) enantiomers, a single (R) enantiomer, a single (S) enantiomer, a salt of a racemic mixture of (R,S) enantiomers, a salt of a single (R) enantiomer and a salt of a single (S) enantiomer, and wherein R and the asterisk * are as defined above, and, if the desired, recovery of the discarded enantiomer by racemization and its recycling; and a) the rearrangement of a compound of formula (I), as the single (S) enantiomer, via formation of isocyanate, and subsequent addition of a nucleophilic solvent or subsequent quenching in water in the presence of an acidic agent to obtain a compound of formula (VII), as the single (S) enantiomer (Formula Removed) wherein Ra is free or a protected amino group as defined above and R3 is hydrogen or a R4-O-CO- group, wherein R4 is straight or branched C1-C4 alkyl and the asterisk * is as defined above, or b) the rearrangement a compound of a compound of formula (I), as the single (S) enantiomer, via formation of isocyanate, and subsequent addition of water, to obtain a compound of formula (le) (Formula Removed) wherein R' has the same meaning as R defined above, and subsequent hydrolysis to obtain a compound of formula (VII) as the single (S) enantiomer, wherein Ra is a free amino group and R3 is hydrogen; and the subsequent alkylation of a compound of formula (VII) as the single (S) enantiomer, obtained according to above process variants a) or b) (Formula Removed) wherein Ra, R3 is the asterisk * are as defined above, to obtain a compound of formula (VIII) (Formula Removed) wherein Ra, R3 and the asterisk * are as defined above, and the removal of the primary amino-protecting group, if present, and removal of the R4-OR-CO- group from the secondary amino group, if present, and, if desired, its conversion to a pharmaceutically acceptable salt thereof. 2. A process as claimed in claim 1, variant a), wherein quenching in water in the presence of an acidic agent affords a compound of formula (VII), as defined in claim 1, wherein R3 is hydrogen. 3. A process as claimed in claim 1, variant a), wherein the nucleophilic solvent is a C1-C4 alkanol, to obtain a compound of formula (VII), as defined in claim 1, wherein R3 is a R4-O-CO- group, wherein R4 is as defined in claim 1. 4. A process as claimed in claim 1, variant a), wherein the rearrangement reaction is carried out according to Curtius in a nucleophilic solvent, via formation of a compound of formula (la) in which Y is N3 and of a compound of formula (Id) (Formula Removed) wherein R5 is a straight or branched C1-C4 alkyl group, without recovery of the intermediates. 5. A compound as claimed in claim 1, which is selected from a compound of formula (I), of formula (II), wherein the compound is a single (R) enantiomer, single (S) enantiomer, and a salt of a single (R) enantiomer and a single (S) enantiomer, (Formula Removed) wherein R; R1 and the asterisk * are as defined in claim 1. 6. A compound as claimed in claim 5 selected from a compound of formula (I), wherein the compound is a single (S) enantiomer, and a salt of the single (S) enantiomer, which is: (S)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; (S)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; (R)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; or (R)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid. 7. A compound as claimed in claim 1 selected from a compound of formula (I), of formula (II), wherein the compound is a racemic (R,S) mixture, and a salt of racemic (R,S) mixture, which is selected from: 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester; 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; and 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester.

Full Text

SUMMARY OF THE INVENTION
It has now been found a process for the preparation of pramipexole,
which employs novel intermediates and fulfils the requirements for the
production in industrial amounts.
DETAILED DISCLOSURE OF THE INVENTION
The present invention relates to a compound of formula (I), both as a
mixture of (R,S) enantiomers, and as the single (R) or (S) enantiomers, or a
salt thereof,

wherein R is a protected amino group; and the asterisk * indicates the
stereogenic carbon atom.
A salt of a compound of formula (I) can be a salt with bases or acids,
organic or inorganic. Preferred examples of salts with bases are those with
inorganic bases, such as sodium, lithium or potassium salts, or salts with
primary, secondary or tertiary amines, such as N-methyl-, N,N-dimethyl- and
triethyl-ammonium salts, benzylammonium, a-methylbenzylamine, N-methyl-
D-gtacamine, cinchonidine or cinchonine salts. Preferred examples of salts
with acids are those with hydrochloric, sulfuric, acetic, oxalic or
methanesulfonic acids, preferably with an optically active acid, such as
tartaric or camphorsulfonic acid.
Preferably a compound of formula (I), or a salt thereof, is in the form of the single (R) or (S) enantiomer, in particular as the single (S) enantiomer, typically with at least approx. 96%, more preferably at least approx. 99%, 25 enantiomeric purity.
Preferred examples of the compounds of formula (I) are:

• (S)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid;
• (S)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-
carboxylic acid;
• (R)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid; and
• (R)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-
carboxylic acid.
A compound of formula (I), as defined above, either as a mixture of 10 (R,S) enantiomers or as single (R) or (S) enantiomer, can be obtained with a process comprising the hydrolysis of an ester of formula (II) or a salt thereof, either as a mixture of (R,S) enantiomers or as single (R) or (S) enantiomer

. (ID
wherein RI is straight or branched Ci-Cg alkyl, optionally substituted with phenyl; and the asterisk * and R have the meanings defined above;
and, if desired, the resolution of tire mixture of (R,S) enantiomers of the
compound of formula (I) to yield the single (R) or (S) enantiomer.
R] is preferably a CrC4 alkyl group, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl or tert-butyl, in particular ethyl or propyl; or benzyl or phenylethyl.
A salt of a compound of formula (II) is for example a salt with a
mineral acid, preferably an hydrohalic acid, in particular hydrochloric or
hydrobromic acid, or an organic acid, such as acetic, oxalic or
methanesulfonic acid, preferably an optically active acid, such as tartaric or
camphorsulfonic acid.

According to the present invention, a protected amino group R can be, for example, a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group.
In an acylamino group, acyl is for example formyl or Ci-C6-CO- alkyl, 5 preferably acetyl, propionyl or pivaloyl, optionally substituted with 1 to 3 halogen atoms, such as chlorine, fluorine, bromine or iodine.
In a carbanToyl group, the amino group is linked, for example, to a CrC6 alkoxy-carbonyl group, wherein the alkyl residue is straight or branched, optionally substituted with phenyl. The alkyl residue is preferably a 10 CrC4 alkyl group, optionally substituted with phenyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl or phenylethyl. in particular tert-butyl.
In an arylmethylamino group, for example a mono, di- or particularly tri-arylmethylamino group, the aryl moiety is preferably a phenyl group. Said 15 group is for example benzyl-, diphenylmethyl- or trityl-amino; more particularly a 1-methyl-1-phenyl-ethylamino group.
A silylamino group is for example a trimethylsilylamino or tert-butyl-dimethylsilylamino group.
A protected amino group R is preferably a protected amino group such 20 as an acylamino or arylmethylamino group, in particular acylamino, wherein acyl is formyl, acetyl, propionyl or pivaloyl, the latter three being optionally substituted with 1 to 3 halogen atoms, such as chlorine, fluorine, bromine or iodine. More preferably the R group is acetylamino, propionylamino or pivaloylamino.
The hydrolysis of a compound of formula (II) can be carried out by
reaction with an alkali hydroxide, for example sodium or potassium hydroxide, in amounts from about 1 to 4 equivalents, preferably from 1.5 to 2.5 equivalents, in a polar protic solvent, for example water or C|-C4 alkanols,

in particular methanol, ethanol, i-propanol, or mixtures thereof; at a temperature ranging from about 0°C to the solvent reflux, preferably from about 10 to 50°C, in particular at approx. 20°C.
According to the invention, a mixture of (R,S) enantiomers can contain 5 the two single enantiomers in any ratio to each other. The enantiomeric purity is generally expressed as "enantiomeric excess" and defined, for example, for the (S) enantiomer as (S-R)/(R+S)xlOO wherein S and R are respectively the amounts of the (S) and (R) enantiomers. According to the invention, the expression single (S) or (R) enantiomer means that the enantiomeric purity is
usually at least about 96%, preferably at least about 99%.
The optional resolution of the mixture of (R,S) enantiomers of a compound of formula (I) into the single (R) or (S) enantiomers can be carried out, for example, by fractional crystallization of the diastereomeric salts of a compound of formula (I) obtained by reaction with optically active,
enantiomericaiiy" pure acids or bases. An example is the reaction of the compound of formula (I) with an enantiomerically pure aliphatic or aromatic amine, for example a-methylbenzylamine, N-methyl-D-glucamine, cinchonidine and cinchonine; or with an enantiomerically pure acid, for example tarMric acid or camphorsulfoak acid, in a solvent capable of
promoting the formation of the salt and the subsequent precipitation of the desired diastereomer. Examples of said solvents are CrC4 alkanols, such as methanol, ethanol and i-propanol; ketones, such as acetone; ethers such as tetrahydrofuran and dioxane; alkyl esters, such as ethyl acetate; amides, such as dimethylformamide and dimethylacetamide; dimethylsulfoxide; or mixtures
thereof or mixtures of one or more of them with water. The temperature can range from room temperature to the solvent reflux temperature. Alternatively, the resolution can be carried out by means of preparative chromatography using a chiral, optically active stationary phase, including the "Simulating

Moving Bed" (8MB) technology. A further alternative consists in the
enzymatic resolution, either by selective hydrolysis of one stereoisomer of an
ester of formula (II) to an acid of formula (I), or by selective esterification of
one stereoisomer of an acid of formula (I) to an ester of formula (II).
The conversion of a compound of formula (I) into a salt thereof can be
obtained with known methods.
An object of the invention is also a compound of formula (II), and the salts thereof, as a mixture of (R,S) enantiomers and as the single (R) or (S) eriarLtiomers.
Preferably a compound of formula (II), or a salt thereof, is in the form
of the single (R) or (S) enantiomer, in particular as the single (S) enantiomer, typically with at least approx. 96%, more preferably at least approx. 99%, enantiomeric purity.
US 4,988,699 generally discloses compounds of formula (I) and of
formula (II) as (R,S) mixturerta which the R subsiitoent is an amino group optionally substituted with various groups, inter alia lower alkanoyl groups. On the other hand, this patent only describes compounds with unsubstituted amino groups. The following specific acids and esters, as well as the salts thereof, although generrcaily included within die general formula of
US 4,988,699, are to be considered novel and are a further object of the invention:
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid;
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid;
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
methyl ester;

• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
ethyl ester;
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
propyl ester;
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid methyl ester;
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid ethyl ester; and
• 2-prppionylamino-4,5,6,7-tetrahydro-benzothiazote-6-carboxylic
acid propyl ester.
A compound of formula (II), and the salts thereof, can be obtained by converting the amino group of a compound of formula (III)

(Ill)
wherein RI and the asterisk * have the meanings reported above,
into a protected amino group R as defined above, and optional resolution of the mixture of (R,S) enantiomers of a resulting compound of formula (II) into the single (R) or (S) enantiomers thereof, and/or salification thereof.
The conversion of the amino group of a compound of formula (II) to a
protected amino group R, preferably in an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group, as well as the salification, can be carried out according to known methods. The protection as an acylamino or carbamoyl group is preferably carried out by reaction with the
corresponding anhydride, in particular acetic anhydride, or acyl-chloride or alkoxycarbonyl-chloride, in particular acetyl-chloride or methoxy- or ethoxy-carbonyl-chloride, in a solvent selected for example from acetone,

acetonitrile, tetrahydrofuran, dioxane, dichloromethane or toluene; in the presence of a basic agent, preferably triethylamine, diisopropylamine or pyridine. The reaction is carried out from about -15°C to the solvent reflux, preferably between about 0°C and 50°C, in particular at room temperature. The 5 optional resolution of a mixture of (R,S) enantiomers of a compound of formula (II) into the single (R) or (S) enantiomers can be obtained, for example, by reaction with an organic acid, according to the procedures reported above for the resolution of a mixture of (R,S) enantiomers of a compound of formula (I). A compound of formula (III) can be prepared by reaction of a compound of formula 10 (IV),

COOR,
wherein RI is as defined above, with thiourea. The cyclization reaction is carried out in an organic solvent, for example a C]-C4 alkanol, acetone, tetrahydrofuran, dioxane or mixtures thereof, at a temperature ranging from
about 0°C to the solvent reflux temperature, for a time ranging between 1 hour and 8 hours, in particular between 2 hours and 5 hours. The hydrobromide salt of a compound of formula (III) forms first and is then converted to the free base form by suspending it for example in water, Ci-Ce alkanols or acetone, preferably methanol or ethanol; at a temperature ranging from room
temperature to the solvent reflux temperature; and adding from 1 to 1.5 equivalents, preferably from 1 to 1.1 equivalents, of an inorganic base, preferably sodium or potassium bicarbonate. Upon filtration, a compound of formula (III) separates as the free base.
In particular, a compound of formula (II), as defined above, wherein the
protected amino group R is in the form of an acylamino or carbamoyl group,

can be prepared by reaction of a compound of formula (IV), as defined above, with a compound of formula (V)
2
2 H (V)
wherein R2 is respectively a straight or branched CrC6 alkyl or alkoxy
group, optionally substituted with phenyl.
R2 is preferably a Ci-C4 alkyl group, optionally substituted with phenyl,
such as methyl, e^yl, n-propyl, isopropyl, n-butyl, isobutyl, tert-batyl, benzy!
or phenylethyl, in particular methyl. Alternatively, it is preferably a CrC4
alkoxy group, optionally substituted with phenyl, for example methoxy,
ethoxy, propoxy or benzyloxy, in particular methoxy.
The hydrobromide salt of a compound of formula (II) is first obtained, which is then converted to the free base form.
The reaction between a compound of formula (IV) and a compound of
formula (V) can be carried out according to the above reported procedure by
reaction between a compound of formula (IV) and thiourea. The hydrobromide
salt of a compound of formula (II) can be converted to the free base form
according to the procedure reported above for the transformation of a
hydrobromide -salt of a compound of formula (III) to the free base form.
The compounds of formula (IV) and (V) can be prepared with known
methods. For example, a compound of formula (IV) can be prepared by monobromination of the corresponding ketone of formula (VI)

(VI)

wherein R\ is as defined above, with 0.8-1.5 equivalents, preferably 1 equivalent, of bromine in a solvent selected for example from dichloromethane, toluene, acetic acid or a C,-C4 alkanol, in the presence of hydrobromic acid in amounts approx. ranging from 0 to 0.2 equivalents. The 5 reaction is carried out at a temperature ranging from about -15°C to 40°C, preferably from 0°C to 15°C, for a time ranging between 1 hour and 6 hours, preferably between 2 hours and 5 hours. A compound of formula (VI) is commercially available.
A compound of formula (I), in particular as the single (S) enantiomer, is 10 particularly useful in the preparation of pramipexole. Said compound is subjected to rearrangement, thereby obtaining intermediates useful in the preparation of pramipexole, according to the synthetic route disclosed in US 4,843,086.
Therefore, a further object of the invention is the use of a compound of formula (I), typically as the single (S) enantiomer, in a process for the 15 preparation of pramipexole or a pharmaceutically acceptable salt thereof.
In particular, in a process comprising the alkylation of a compound of formula (VII), preferably as the single (S) enantiomer,

-Ra
(VII)
wherein Ra is a free or protected amino group, R3 is hydrogen or a
R4-O-CO- group, wherein R4 is straight or branched Ci-C4 alkyl and the asterisk * has the meaning defined above,
to obtain a compound of formula (VIII)
CH,-CH,-CH
2 «• i2-wi ij
SXN^s
(VIII)
^

wherein Ra, R3 and the asterisk * are as defined above, and, if
necessary, the removal of the primary amino-protecting group and/or of the
R4-0-CO- group from the secondary amino group and, if desired, its
conversion to a pharmaceutical ly acceptable salt thereof, characterized in
that:
a) a compound of formula (VII), wherein Ra is a protected amino group
and R3 is as defined above, as the single (S) enantiomer, is prepared by
rearrangement of a compound of formula (I), as the single (S) enantiomer, via
formation of the isocyanate, and subsequent addition of a nucleophilic solvent
or subsequent quenching in water in the presence of an acidic agent; or
b) a compound of formula (VII), wherein Ra is a free amino group and
R3 is hydrogen, as the single (S) enantiomer, is prepared by rearrangement of
a compound of formula (I), as the single (S) enantiomer, via formation of the
isocyanate, and subsequent addition of water, to obtain a compound of
formula (le)

N
de)
wherein R' has the same meaning as R, and subsequent hydrolysis. An acidic agent is for example a mineral or an organic acid, in 20 particular hydrochloric, sulfuric, formic or acetic acid.
A nucleophilic solvent can be for example a CrC4 alkanoi, typically methanol, ethanol or i-propanol.
According to process variant a) reported above, quenching in water in the presence of an acidic agent or the addition of a nucleophilic solvent 25 respectively affords a compound of formula (VII) as defined above wherein R3 is hydrogen or R3 is a R4-O-CO- group as defined above.

Rearrangement can be effected for example according to the Schmidt, Lessen, Hofmann or Curtius reactions.
The sequence of the products formed during the rearrangement reaction is the following:

(I) (la) (lb)
OCN
H Rs°vVx
^x\ e

T
(Ic) (Id) (VII)
in which Y is NHOCOR4, N3 or NH2, wherein R4 is as defined above; R5 is hydrogen or stoight w branched Ci-C4 alkyl; and R and R3 are as defined above.
The compounds of formulae (la), (Ib), (Ic) and (Id) can optionally be 15 isolated during the reaction. The compounds of formulae (la), (Ib), (Ic) and (le), either as mixture of (R,S) enantiomers or as the single (R) or (S) enantiomers, are novel compounds and are a further object of the invention.
All of the Schmidt, Lessen, Hofmann and Curtius reactions make use of an isocyanate of formula (Ic) as defined above.
A compound of formula (Ic) can be prepared according to the Schmidt
reaction, treating a compound of formula (I) with hydrazoic acid in the presence of sulfuric acid, to obtain a compound of formula (la), wherein Y is N3 and R is as defined above, which is converted to the corresponding compound of formula (Ic) by heating.

Alternatively, a compound of formula (Ic) can prepared according to the Lessen reaction, by reaction of a compound of formula (I) with a halogenating agent, preferably thionyl chloride or oxalyl chloride, and subsequent reaction with an acyl-hydroxylamine, preferably acetyl-hydroxylamine, thereby 5 obtaining the respective acylated hydroxamic acid, i.e. a compound of formula (la) wherein Y is NHOCOR4 and R is as defined above. Treatment of the latter with an alkali hydroxide affords a compound of formula (Ic).
Again, a compound of formula (Ic) can be prepared according to the
Hofmann reaction, by transforming the carboxylic acid into amide according
to known methods, i.e. into a compound of formula (la) wherein Y is NH2 and
R is as defined above, then treating it with an alkali hypohalogenite,
preferably sodium hypochlorite.
Finally, a compound of formula (Ic) can be prepared according to the
Curtius reaction, by reaction of a compound of formula (I) with a halogenating
agent, preferably thionyl chloride-or oxalyl chloride, and subsequent treatment
with sodium azide to obtain the respective acyl-azide of formula (la) wherein
Y is N3 and R is as defined above; or directly with diphenylphosphorylazide,
in the presence of an organic base, in particular triethylamine,
diisopropytethylamine or pyridine. The acyl-azide of formula (la) is converted
to the corresponding compound of formula (Ic) by heating.
j^
The rearrangement reactions reported above are carried out according to known methods, for example at a temperature approx. ranging from about 10°C to the reflux temperature, for a time ranging between 2 hours and 15 hours, preferably between 5 hours and 10 hours.
More particularly, a compound of formula (la), in which Y is N3, is
poured in water in the presence of an acidic agent, thereby converting it to a compound of formula (Id) as defined above. An acidic agent is for example a mineral or organic acid, in particular hydrochloric, sulfuric, formic or acetic

acid, in amounts ranging from about 2 to about 5 mols, preferably from about 2.5 to about 3.5 mols. The reaction is carried out at a temperature ranging from room temperature to the reaction mixture reflux, preferably from about 50 to about 80°C. When the nucleophilic solvent is for example water, in the 5 resulting compound of formula (Id) R5 is hydrogen. Alternatively, when the nucleophilic solvent is for example a Ci-C* alkanol, in particular methanol, ethanol or i-propanol, in the resulting compound of formula (Id) R5 is alkyl.
According to a preferred aspect, the rearrangement reaction to form the
acyl-azide of formula (la) in which Y is N3 is carried out according to Curtius
in a nucleophilic solvent, as defined above. The reaction proceeds until
formation of a compound of formula (Id) wherein R5 is a straight or branched
C]-C4 alkyl group, with no need for isolating any intermediate.
A compound of formula (Id) in which R5 is hydrogen spontaneously
transforms into a compound of formula (VII), wherein Ra is a protected amino
group, R is as defined above and R3 is hydrogen. A compound of formula (Id)
in which R5 is alkyl is a compound of formula (VII) wherein R3 is a R4-O-CO-
group, as defined above and Ra is a protected amino group.
Alternatively, when a compound of formula (la), in which Y is N3, is poured in water, or vice versa, a compound of formula (le) 20

-R1
(le)
wherein R and R' are as defined above is obtained, which is hydrolysed
to a compound of formula (VII) wherein Ra is a free amino group, R3 is
hydrogen and the asterisk * has the meaning defined above. The hydrolysis is
typically an acidic hydrolysis, for example by treatment with hydrochloric
acid according to known methods.

The alkylation of a compound of formula (Vll) and, if the case, the
removal of the primary amino group protecting group and, if present, of the
R4-O-CO- group from the secondary amino group present in a compound of
formula (VIII), can be carried out according to US 4,886,812.
It has now been found a particularly advantageous process for the
conversion of a compound of formula (VII) to a compound of formula (VIII) in which R3 is hydrogen and Ra is as defined above. It should be stressed that a compound of formula (VIII) in which R3 is hydrogen and Ra is -NH2 is pramipexole. Therefore, the invention.provides a process for the preparation
of pramipexole or a pharmaceutically acceptable salt thereof, comprising the acylation of a compound of formula (VII), in which R3 is hydrogen and Ra is as defined above, either as a mixture of (R,S) enantiomers or as the single (S) enantiomer, by reaction with propionic anhydride and subsequent reduction of the compound of formula (IX) thus obtained,

(IX)
wherein Ra is as defined above, by treatment with an alkali metal borohydride and molecular iodine to obtain a compound of formula (VIII) wherein R3 is hydrogen and Ra is as defined above; followed, if necessary, by 20 deprotection of the primary amino group and/or by resolution of the mixture of the (R,S) enantiomers into the single (S) enantiomer and, if desired, by conversion of pramipexole into a pharmaceutically acceptable salt thereof.
The acylation is preferably carried out on a compound of formula (VII),
as the single (S) enantiomer, in particular having the enantiomeric purity as
obtainable according to present invention. The acylation of a compound of

formula (VII) with propionic anhydride can be carried out according to known methods.
An alkali metal borohydride is for example NaBH4 or KBH4, preferably
NaBH4. The amount of alkali metal borohydride used in the reduction, for
example NaBH4, is about 1-5 mols per mole of compound of formula (IX),
preferably from about 2 to 4 mols, whereas the molar amount of iodine is
about 0.5-3 mols per mole of compound of formula (IX), preferably from
about 1 to 2. The reduction of a compound of formula (IX) is preferably
earned out in an ether solvent, such as tetiakyd+ofuran, dioxane or diethyl
ether, in particular tetrahydrofuran. The reaction can be carried out at a
temperature ranging from about 0°C to the reflux temperature, preferably at
approx. 20-40°C.
A pramipexole pharmaceutically acceptable salt is for example an addition salt with an organic or mineral acid, as reported in 15 US 4,886,812, preferably the dihydrochloride, and can be obtained with known procedures.
The process of the invention for the preparation of pramipexole is particularly advantageous for the production on an industrial scale. In fact, the resolution of the enantiomers takes place during the first synthetic steps and 20 moreover the discarded enantiomer can be recovered by racemization and recycled. This attains a reduction in the by-products of the more expensive final products and higher yields.
The following examples illustrate the invention.
Example 1 - 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester hydrobromide [(III), R, = ethyl]
A 3 liter reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 1500 ml of ethanol and 200 g of 4-oxo-cyclohexanecarboxylic acid ethyl ester. After cooling to 0°C, 188 g of

bromine were dropped therein in about 1 hour. The temperature was raised to 10°C, then to the room one after discolouration. After 1 hour, 89.32 g of thiourea were added in portions to obtain a suspension, that was refluxed to obtain gradual dissolution of the solid. After 4 hours the solution was 5 concentrated to small volume to obtain a solid mass, that was suspended in 800 ml of acetone and refluxed to obtain a solution. The solution was then cooled to room temperature to precipitate a solid, then to 0°C and after 4 hours the solid was filtered, washed twice with 100 ml of cold acetone and dried to obtain 170 g of the title product.
'H-NMR in OMSO: 1.20 ppm (t,3H); 1.79 ppm (m,lH); 2.05 ppm (m,lH);
2.43 ppm (t,2H); 2.70 ppm (m,3H); 4.08 ppm (q,2H); 6.63 ppm (s,2H).
Example 2 - 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxyIic acid ethyl ester [(III), R, = ethyl]
A 2 liter reactor equipped with mechanical stirrer, thermometer and
condenser was loaded with 600 ml of water, 110 g of 2-amino-4.5,6,7-
tetrahydro-benzothiazole-6-carboxylic acid ethyl ester hydrobromide [(III),
RI = ethyl] and 120 ml of methanol. The mixture was refluxed and hot filtered
on a Celite bed. The resulting solution was added with a solution of 32 g of
sodium bicarbonate in 300 ml of water (final pH = 7-8). After 2 hours at room
temperature, the precipitated white solid was filtered, washed with 100 ml of
water and dried to obtain 72 g of the title product.
'H-NMR in DMSO: 1.20 ppm (t,3H); 1.79 ppm (m,lH); 2.05 ppm (m,lH); 2.43 ppm (t,2H); 2.70 ppm (m,3H); 4.08 ppm (q,2H); 6.63 ppm (s,2H).
Example 3 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazole-6- carboxylic acid ethyl ester [(II), R, = ethyl, R = -NH-CO-CH3)
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 280 ml of acetonitrile, 71 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(III), Rj = ethyl] and

K
38.75 g of acetic anhydride. 38.03 g of triethylamine were dropwise added to the resulting suspension in about 10 minutes. The suspension was refluxed, obtaining complete dissolution at a temperature ranging from 70 to 75°C. After approx. 2 hours 30 minutes the solution was concentrated to dryness, 5 and the residue was crystallized from 450 ml of isopropanol to obtain 74.5 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester.
'H-NMR in DMSO: 1.19 ppm (t,3H); 1.80 ppm (m,lH); 2.09 ppm (s,3H); 2.11 ppm (m,lH); 2.61 ppm (t,2H); 2.82 ppm (m,3H), 4.08 ppm 10 (q,2H).
According to the same procedure, the following compounds are obtained:
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
methyl ester;
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
propyl ester;
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid methyl ester,
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid ethyl ester; and
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid propyl ester.
Example 4 - 2-Acetylamkio-4,5,6,7-tetrahydro-beiizothiazole-6-carboxylic acid ethyl ester hydrobromide [(II), R, = ethyl, R = -NH-CO-
CH3]
A 500 ml reactor equipped with mechanical stirrer, thermometer and
condenser was loaded with 200 ml of methylene chloride, 20 g of 4-oxo-cyclohexanecarboxylic acid ethyl ester, 2 g of 48% hydrobromic acid. The resulting clear solution was cooled to 0°C and dropwise added with 18.88 g of

bromine in about 2 hours. Two hours after completion of the addition, 100 ml of water were added and the phases were separated, discarding the aqueous one. 80 ml of water were added and the mixture was neutralized to pH = 7-8 with sodium bicarbonate. The organic phase was separated and was 5 concentrated to one third of the original volume, then added with 150 ml of ethanol and 13.95 g of acetyl thiourea to obtain a suspension. Upon reflux, the solid gradually dissolved to obtain a clear solution. After 3 hours the solution was concentrated to small volume to obtain a solid mass, that was crystallized from 200 ml of i-propanol to obtain 15.9 g of solid.
'H-NMR in DMSO: 1.2 ppm (t,3H); 1.81 ppm (m,lH); 2.09 ppm (m,lH);
2.11 ppm (s,3H); 2.60 ppm (t,2H); 2.81 ppm (m,3H); 4.08 ppm (q,2H).
According to the same procedure, the following compounds are obtained, as hydrobromide:
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
methyl ester; and
• 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid
propyl ester;
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid methyl ester;
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid ethyl ester; and
• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic
acid propyl ester.
Example 5 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazoIe-6- carboxylic acid [(I), R = -NH-CO-CH3]
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 200 ml of water, 30 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(II), RI = ethyl,

R = -NH-CO-CH3] and 52.2 g of 30% sodium hydroxide, keeping the temperature below 30°C; during the addition the solid gradually solubilized until complete dissolution. After 2 hours, glacial acetic acid was dropwise added to pH = 4.5-5.5; after approx. 1 hour the precipitated white solid was 5 filtered, washed with 70 ml of water and dried to obtain 24.8 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid.
'H-NMR in DMSO: 1.75 ppm (m,IH); 2.09 ppm (s,3H); 2.11 ppm (m,lH); 2.58 ppm (nUH); 2.78 ppm (m,2H)
I3C-NMR in DMSO: 22.48 ppm; 24.72 ppm; 25.04 ppm; 25.5 ppm;
39.37 ppm; 119.77 ppm; 143.4 ppm; 155.27 ppm; 167.99 ppm; 175.69 ppm.
According to the same procedure, 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid is obtained.
Example 6 - N-(6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide dihydrochloride, [(VII), Ra = -NH-CO-CH3, R3= -H]
A 500 ml reactor equipped with mechanical sthrer, thermometer and
condenser was loaded with 10 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 146 ml of N,N-dimethylforrnamide, and 4.63 g of triethylamine were added. After that, a solution consisting of 12.57 g of diphenylphosphoryl azide (DPPA)
dissolved in 10 ml N,N-dimethylformamide was dropped therein in 2 hours. The reaction mixture gradually solubilized during the addition until complete dissolution. After 5 hours the reaction solution was dropped in 1.3 liters of an aqueous solution containing 14 ml of 37% hydrochloric acid, at 60°C. The mixture was left to cool, then extracted twice with 200 ml of methylene
chloride, discarding the organic phase. The aqueous phase was concentrated to a residue, that was crystallized from i-propanol-water to obtain 4.5 g of a white solid.

'H-NMR in DMSO: 1.91 ppm (m,lH); 2.17 ppm (s,3H); 2.19 ppm (m,lH); 2.73 pm (m,3H); 3.07 ppm (dd,lH); 3.49 ppm (s,broad,lH); 8.39 ppm (s,broad,2H).
13C-NMR in DMSO: 22.50 ppm; 23.64 ppm; 26.49 ppm; 26.66 ppm; 46.56 ppm; 117.39 ppm; 142.89 ppm; 156.06 ppm; 168.28 ppm.
According to the same procedure, starting from (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, (S) N-{6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide dihydrochloride is obtained.
Example 7 - (2-Acctylaarino-4^,6,7-tetrahydro-bejizothiazo4-6-yl)-10 carbsmc acid methyl ester hydrochloride [(VII), Ra = -NH-CO-CH3, R3= -CO-O-CH3]
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser is loaded with 5 g of 2-acetylamino-4,5,6.7-tetrahydro-benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 80 ml 15 of N^-dimethyiformamidaet then 2.32 g of trieriiyiamine are added. A solution consisting of 6.3 g of diphenylphosphoryl azide (DPPA) dissolved in 7 ml N,N-dimethylformamide is dropped therein in 2 hours. The reaction mixture gradually solubilizes during the addition until complete dissolution. After 6 hours the reaction solution is dropped in 1 liter of a 20 methanol solution containing 8 ml of 37% hydrochloric acid at 60°C. The mixture is left to cool, then extracted twice with 100 ml of methylene chloride, discarding the organic phase. The aqueous phase is concentrated to a residue that is crystallized from i-propanol-water to obtain 3.6 g of a white solid.
According to the same procedure, starting from (S) 2-acetylamino-
4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, (S) (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbammic acid methyl ester hydrochloride is obtained.

^
Example 8 - Resolution of (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxyIic acid [(I), R = -NH-CO-CH3]
A 1 liter reactor equipped with mechanical stirrer, thermometer and condenser is loaded with 50 g of 2-acetylamino-4,5,6,7-tetrahydro-5 benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 250 ml of methanol and 50 ml of water. The mixture is heated until dissolution, added with 37.3 g of (SH-)-a-methylbenzylamine then cooled to 25°C. The precipitated product is filtered off, washed with methanol and dried to obtain 42.8 g of a solid^This is suspended in 250 ml of methanol and 50 ml of water, 10 heated to dissolution for 1 hour and cooled to room temperature. The suspended solid is filtered, washed with methanol and dried to obtain 32.3 g of (S)-2-acetylamino-4.5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, having enantiomeric purity > 99.5%.
According to the same procedure, (S)-2-propionylamino-4,5,6,7-15 tetrahydro-benzoAiazole-6-carboxylic acid is obtained with enantiomeric purity > 99.5%.
Example 9 - Resolution of (R) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ((I), R = -NH-CO-CH3]
A 1 liter reactor equipped with mechanical stirrer, thermometer and
condenser are loaded with 50 g of 2-acetylamino-4,5,6,7-tetrahydro-
benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 250 ml
of methanol and 50 ml of water. The mixture is heated until dissolution, added
with 37.3 g of (R)-(+)-a-methylbenzylamine, cooled to 25°C, and the
precipitated product is filtered off, washed with methanol and dried to obtain
42.8 g of a solid. This is suspended in 250 ml of methanol and 50 ml of water,
heated to dissolution for 1 hour and cooled to room temperature. The
suspended solid is filtered, washed with methanol and dried to obtain 32.3 g of

v
(R)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid, having enantiomeric purity > 99.5%.
According to the same procedure, (R)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid is obtained with enantiomeric 5 purity > 99.5%.
Example 10 - N-{6-[3-(2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-ureido]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-acetajaide, [(le), R = -NH-CO-CH3]
A 500 ml reactor equipped with mechanical strrrer, thermometer and
condenser was loaded with 10 g of 2-acetylamino-4,5,6,7-tetrahydro-
benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] suspended in 146 ml
of N,N-dimethylformamide and 4.65 g of triethylamine were added. A
solution consisting of 12.52 g of diphenylphosphoryl azide (DPPA) dissolved
in 10 ml N,N-dimethylformamide was dropped therein in 2 hours. The
reaction mixture gradually solubtlized during the addition until complete
•
dissolution. After 5 hours, the reaction mixture was dropped in 1.3 liters of an
aqueous solution at 60°C. The mixture was left to cool, the separated solid
was filtered, washing twice with 50 ml of water to obtain 5.9 g of a white
solid.
'H-NMR in OMSO: 1.72 ppm (m,lH); 1.86 ppm (m,lH); 2.07 ppm
(s,3H); 2.4 ppm (dd,lH); 2.59 ppm (m,2H); 2.8 ppm (dd,lH); 3.93 ppm
(m,lH), 5.96 ppm (d,lH), 11.84 ppm (s,lH).
I3C-NMR in DMSO: 22.30 ppm; 23.74 ppm; 26.55 ppm; 26.59 ppm;
44.36 ppm; 118.42 ppm; 144.02 ppm; 156.13 ppm; 157.98 ppm, 169.18 ppm.
Example 11 - N-(6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-yI)-
amine dihydrochloride, [(VII), Ra = -NH2, R3= -H].
A 1 liter reactor equipped with mechanical stirrer, thermometer and
condenser is loaded with 70 g of N-{6-[3-(2-acetylamino-4,5,6,7-tetrahydro-

benzothiazol-6-yI)-ureido]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-acetamide, [(le), R = -NH-CO-CH3] suspended in 500 ml of water, and 151 g of 37% hydrochloric acid are added. The mixture is refluxed for 40 hours, then left to cool. The aqueous phase is concentrated to a residue that is crystallized from 5 i-propanol-water to obtain 53 g of a white solid.
According to the same procedure, starting from (S)-N-{6-[3-(2-
acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-ureido]-4,5,6,7-tetrahydro-
benzothiazol-2-yl}-acetamide, [(le), R = -NH-CO-CH3] of enantiomeric purity
96%, (S)-N-(6-aniino-4,5,6,7-tetrahydro-bejizothiazol-2-yI)-amine
dihydrochloride is obtained, [(VII), Ra = -NH2, R3= -H] with enantiomeric purity > 97%.
'H-NMR in DMSO: 1.91 ppm (m,lH); 2.17 ppm (s,3H); 2.19 ppm (m,lH); 2.73 ppm (m,3H); 3.07 ppm (dd.lH); 3.49 ppm (s,broad,lH); 8.39 ppm (s,broad,2H).
13C=NMR in DMSO: 22.50 ppm; 23.64 ppm; 26.49 ppm; 26.66 ppm;
46.56 ppm; 117.39 ppm; 142.89 ppm; 156.06 ppm; 168.28 ppm.
Example 12 - (S) N-(6-Propienylamino-4,5,6,7-tctrahydro-benzothiazol-2-yl)-amine;[ (IX) Ra = H]
A 1 liter reactor equipped with mechanical stirrer, thermometer and
condenser is loaded with under nitrogen 43.7 g of (S) N-(6-amino-4,5,6,7-
tetrahydro-benzothiazol-2-yl)-amine and 220 ml of methyl ethyl ketone
(MEK). Is heated a 28-32°C and approx. 33.6 g of propionic anhydride are
dropped therein in 2 hours keeping the temperature at about 28-32°C. The
solution is cooled to about 0-5°C and 109 g of 10% aqueous NaOH are added.
The aqueous phase is separated; the organic phase is diluted with 60 ml of
toluene and concentrated under vacuum at about 40-45°C. Under these
conditions, the product starts to crystallize. The suspension is cooled to 0-5°C

and left under stirring for an hour. The precipitate is filtered with suction and washed with 10 ml of toluene.
54.2 g of (S) N-(6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-
yl)-amine are obtained.
Example 13 - intermediate (VIII) Ra = H; pramipexoie free base
A 2 liter reactor under nitrogen is loaded with 53.3 g of, 33.0 g of (S)
N-(6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine, 95%
sodium borohydride and 260 ml of tetrahydrofuran (THF). A solution of 9$.._7 g of iodine in 160 ml of THF is dropped tbemm in about 3 hours, keeping
the temperature at approx. 20-25°C. The reaction mixture is kept under stirring for further 2 hours at about 20-25°C. The reaction mixture is poured into a solution of 60.0 g of 37% HC1 in 260 ml of water. The mixture is heated to 50-55°C and left under stirring for an hour. The complete cleavage of the boran-complexes is checked by HPLC. The mixture is added with 250 g of
50% aqueous NaGHT keeping the temperature at about 20-25°C. After that, 315 ml of toluene are added and the mixture is heated to about 30-35°C. Stirring is interrupted and the two phases are separated. The organic phase are washed, concentrated to a residue and dissolved in 420 ml of ethyl acetate.
The solution is concentrated under vacuum at a temperature below 50°C
to about 150 ml volume. The resulting suspension is refluxed, then cooled to about 10-15°C, stirred for further 1-2 hours, then filtered with suction and the precipitate is washed twice with 30 ml of ethyl acetate. The product is dried under vacuum at 40°C. 32 g of (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole are obtained.
Example 14 - Isopropyl (S)-(2-acetylamino-4,5,6,7-tetrahydro-
benzothiazoI-6-yl)-carbamate [(VII), Ra = -NH-CO-CH3, R3= -CO-O-C3H7]
A 2000 ml reactor equipped with mechanical stirrer, thermometer and condenser are loaded with 100 g of (S)-2-acetylamino-4,5,6,7-tetrahydro-

benzothiazole-6-carboxylic acid [(I), R = -NH-CO-CH3] of 97% enantiomeric purity, suspended in 700 ml of isopropanol; 84.16 g of triethylamine are added. The mixture is refluxed (about 80°C) and a solution consisting of 120.42 g of diphenylphosphoryl azide (DPPA) is dropped therein in 2 hours. 5 After 2 hours, the reaction mixture is cooled to 20-30°C and added with 500 ml of water and 1.6 g of sodium hydroxide. Isopropanol is distilled off under vacuum, then 400 ml of ethyl acetate are added. The mixture is refluxed for 15 minutes, then the hot suspension is filtered through Celite. The solution is cooled to^O-30°C and added with of 1800 ml of waters The phases are
separated and the organic phase concentrated to dryness. The residue is taken up with 200 ml of acetonitrile. The suspension is heated at 50°C for 1 hour, then cooled to 20°C and filtered to obtain 75 g of isopropyl (S)- (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamate, with 91% enantiomeric purity.

We Claim:
1. A process for the preparation of (S)-2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole (pramipexole), comprising the hydrolysis of a compound of formula (II), which is selected from a racemic mixture of (R,S) enantiomers, a single (R) enantiomer, a single (S) enantiomer, a salt of a racemic mixture of (R,S) enantiomers, a salt of a single (R) enantiomer and a salt of a single (S) enantiomer,
(Formula Removed)
wherein R is a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group; R1 is straight or branched C1-C6 alkyl, optionally substituted with phenyl; and the asterisk * indicates the stereogenic carbon atom, to obtain a compound of formula (I)
(Formula Removed)
which is selected from a racemic mixture of (R,S) enantiomers, a single (R) enantiomer, a single (S) enantiomer, a salt of a racemic mixture of (R,S) enantiomers, a salt of a single (R) enantiomer and a salt of a single (S) enantiomer, and wherein R and the asterisk * are as defined above, and, if the desired, recovery of the discarded enantiomer by racemization and its recycling; and a) the rearrangement of a compound of formula (I), as the single (S) enantiomer, via formation of isocyanate, and subsequent addition of a nucleophilic solvent or
subsequent quenching in water in the presence of an acidic agent to obtain a compound of formula (VII), as the single (S) enantiomer
(Formula Removed)
wherein Ra is free or a protected amino group as defined above and R3 is hydrogen or a R4-O-CO- group, wherein R4 is straight or branched C1-C4 alkyl and the asterisk * is as defined above, or b) the rearrangement a compound of a compound of formula (I), as the single (S) enantiomer, via formation of isocyanate, and subsequent addition of water, to obtain a compound of formula (le)
(Formula Removed)
wherein R' has the same meaning as R defined above, and subsequent hydrolysis to obtain a compound of formula (VII) as the single (S) enantiomer, wherein Ra is a free amino group and R3 is hydrogen; and the subsequent alkylation of a compound of formula (VII) as the single (S) enantiomer, obtained according to above process variants a) or b)
(Formula Removed)
wherein Ra, R3 is the asterisk * are as defined above, to obtain a compound of formula (VIII)
(Formula Removed)
wherein Ra, R3 and the asterisk * are as defined above, and the removal of the primary amino-protecting group, if present, and removal of the R4-OR-CO- group from the secondary amino group, if present, and, if desired, its conversion to a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1, variant a), wherein quenching in water in the presence of an acidic agent affords a compound of formula (VII), as defined in claim 1, wherein R3 is hydrogen.
3. A process as claimed in claim 1, variant a), wherein the nucleophilic solvent is a C1-C4 alkanol, to obtain a compound of formula (VII), as defined in claim 1, wherein R3 is a R4-O-CO- group, wherein R4 is as defined in claim 1.
4. A process as claimed in claim 1, variant a), wherein the rearrangement reaction is carried out according to Curtius in a nucleophilic solvent, via formation of a compound of formula (la)

in which Y is N3
and of a compound of formula (Id)
(Formula Removed)
wherein R5 is a straight or branched C1-C4 alkyl group, without recovery of the intermediates.
5. A compound as claimed in claim 1, which is selected from a compound of formula
(I), of formula (II), wherein the compound is a single (R) enantiomer, single (S)
enantiomer, and a salt of a single (R) enantiomer and a single (S) enantiomer,
(Formula Removed)
wherein R; R1 and the asterisk * are as defined in claim 1.
6. A compound as claimed in claim 5 selected from a compound of formula (I), wherein
the compound is a single (S) enantiomer, and a salt of the single (S) enantiomer,
which is:
(S)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; (S)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; (R)-2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; or (R)-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid.
7. A compound as claimed in claim 1 selected from a compound of formula (I), of
formula (II), wherein the compound is a racemic (R,S) mixture, and a salt of racemic
(R,S) mixture, which is selected from:
2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid; 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester;
2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester; 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid methyl ester; 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester; and 2-propionylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl ester.

Documents:

5374-DELNP-2006-Abstract-(16-02-2012).pdf

5374-delnp-2006-abstract.pdf

5374-delnp-2006-assignment.pdf

5374-DELNP-2006-Claims-(16-02-2012).pdf

5374-delnp-2006-claims.pdf

5374-DELNP-2006-Correspondence Others-(11-01-2012).pdf

5374-DELNP-2006-Correspondence Others-(16-02-2012).pdf

5374-delnp-2006-correspondence-others.pdf

5374-delnp-2006-description(complete).pdf

5374-DELNP-2006-Form-1-(16-02-2012).pdf

5374-delnp-2006-form-1.pdf

5374-DELNP-2006-Form-2-(16-02-2012).pdf

5374-delnp-2006-form-2.pdf

5374-DELNP-2006-Form-3-(11-01-2012).pdf

5374-delnp-2006-form-3.pdf

5374-delnp-2006-form-5.pdf

5374-DELNP-2006-GPA-(16-02-2012).pdf

5374-delnp-2006-pct-304.pdf

5374-delnp-2006-pct-request.pdf

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Patent Number

252711

Indian Patent Application Number

5374/DELNP/2006

PG Journal Number

22/2012

Publication Date

01-Jun-2012

Grant Date

28-May-2012

Date of Filing

18-Sep-2006

Name of Patentee

DIPHARMA S.P.A

Applicant Address

XXIV MAGGIO 40, I-33036 MERETO DITOMBA, ITALY

Inventors:

#	Inventor's Name	Inventor's Address
1	CASTALDI, GRAZIANO	VIA LIVIA GALLINA, 5,I-28072 BRONIA, ITALY,
2	DIPHARMA S.P.A	VIA XXIV MAGGIO 40, 1-33036 MERETO DI TOMBA, ITALY
3	BOLOGNA, ALBERTO	VIA ENRICO MARTINI, 62-L, I-26013 CREMA, ITALY
4	ALLEGRINI, PIETRO	VIA GORIZIA 1, I-20097 SAN DONATO MILANESE, ITALY
5	RAZZETTI, GABRIELE	VIA G. PUCCINI, 60,I-20099 SESTO S. GIOVANNI, ITALY
6	LUCCHINI, VITTORIO	VIA DON CANDIANI, 3, I-20097 SAN DONATO MILANESE, ITALY

PCT International Classification Number

C07D 277/82

PCT International Application Number

PCT/EP2005/002641

PCT International Filing date

2005-03-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2005A000126	2005-01-28	Italy
2	MI2004A000531	2004-03-19	Italy
3	MI2004A000531	2005-03-11	Italy