Title of Invention

"PROCESS FOR THE PREPARATION OF OXO-OXAZOLINE OR ALLOAMINO ACID DERIVATIVES"

Abstract A method for producing a compound represented by the general formula (I-A) or the general formula (I-B), comprising the following steps wherein R1 is an optionally substituted lower alkyl, and the like; R3 is a lower alkyl or an optionally substituted aralkyl. and the like; R3 is a lower alkyl, characterized in that a compound represented by the general formula (II-A) or the general formula(II-B) is treated with thionyl chloride.
Full Text TECHNICAL FIELD
The present invention relates to a method for producing oxo-oxazoline derivatives using a simple and inexpensive method.
BACKGROUND ART
Oxo-oxazollne derivatives are critical intermediates for compounds (WO98/08867) which are TRH (thyrotropin releasing hormone) derivatives represented by the following general formula (VIII):
(Formula Removed ) wherein R* is a hydrogen atom or optionally substituted lower alkyl; Y is an optionally substituted alkyl.
Further, compounds represented by the following general formulas (III-A), (III-B), (IV-A), or (IV-B):
(Formula Removed )
wherein R1 is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl, and derivatives thereof, are useful as tools for combinatorial ohemistry.
Conventionally, as a method for producing oxo-oxazoline derivatives having a lower alkyloxycarbonyl group or a carboxyl group, a method of cyclizing a starting material while retaining its stereochemistry, and a method using cyclization reaction without reference to stereoselectivity are known.
An example of the method of cyclizing a starting material while retaining its stereochemistry is the following:
(Formula Removed )
(Tetrahedron, 48, 2507, 1992). In this reaction, L-allo-threonlne used as a starting material is allowed to react with phosgene and potassium hydroxide in toluene at 0°C for one hour, thereby obtaining a cyclized product which retains its stereochemisty. Unfortunately, this method encounters a problem in industrialization since the method employs L-allo-threonlne which is more expensive than its natural type, and phosgene which is toxic to the human body.
An example of the cycllzatlon method without reference to stereoselectivity is the following:
(Formula Removed )
(Japanese Laid-Open Publication No. 60-34955). In this reaction, a starting material is allowed to react with potassium carbonate in water at 60°c for 1.5 hours to obtain a oyclized product. It iB believed that the stereochemistry of the material is maintained in view of the mechanism of this method. Therefore, it is considered that allo-threonine needs to be used as a starting material in order to obtain a cis-form oycllzed product.
Although a resultant cyolized product Is an oxo-oxazollne derivative which does not have a lower alkyloxycarbonyl group or a cerboxyl group, the following method is known:
(Formula Removed )
(Bull. Chem. Soc. Japan., 44, 2515, 1971). In this reaction, a starting material is allowed to react in thionyl chloride at 60°C for 24 hours without solvent, thereby obtaining a cyclized product at a yield of 65%. In this method, similar to the method of the present invention, the position of an ethyl group is inverted after the reaotion. However, the

starting material is not an amino acid derivative, and the relationship between the amino group and the hydroxy 1 group of the etarting material is different from that of a starting material used in the method of the present invention. Moreover, since the reaction is conducted in thionyl chloride, the yield is as low as 65%.
Similar to the method of the present invention, a cyclization reaction with inversion is known:
(Formula Removed )
(Heterooycl. Commun., 2, 55, 1996). An example in which trifluoroacetic anydride is used in the first step is disclosed. Although In the method of the present invention, the yield of a cyclization reaction Is as high as 83%, the yield of the cyclization reaction disclosed in the above-described publication is as low as 40% in both a method using tosyl chloride and a method using trifluoroacetic anydride. Moreover, the method of the present invention is superior in regard to simplicity of reaction.
DISCLOSURE OF THE INVENTION
The objective of the present invention is to provide a method for producing oxo-oxazoline derivatives in a simple, inexpensive and stereoselective manner. The oxo-oxazoline
derivatives are useful as intermediates for pharmaceuticals and tools for combinatorial chemistry. Moreover, the oxo-oxazollne derivatives in an open-circular form are also useful as tools for combinatorial chemistry.
The inventors found a method for producing oxo-oxazoline derivatives in a stereoselective manner, which is suitable for large-scale synthesis.
That is, the present invention relates to I) A method for the production of a compound represented by a general formula (I-A) or a general formula (I-B), comprising the step of treating a compound represented by a general formula (II-A) or a general formula (II-B) with thlonyl chloride as follows:
(Formula Removed ) wherein R1 is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl; Ra is a lower alkyl, an optionally substituted aralkyl. or an optionally substituted heteroarylalkyl; and R3 is a lower alkyl.
More specifically, the present invention relates to following II) to X).
II) A method for the production according to I), wherein
the compound represented by the general formula (II-A) or
the general formula (II-B) is allowed to react with 1.0 to
5.0 equivalents of thionyl chloride in a solvent of toluene,
ethyl acetate, cyclohexane, or acetonitrile at 30°C to reflux
temperature.
III) A method for the production according to I), wherein the compound represented by the general formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 3.0 equivalents of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at 60°C to 80°C.
IV) A method for the production of a compound represented by a general formula (III-A) or a general formula (III-B), comprising the step of subjecting a compound represented by a general formula (I-A) or a general formula (I-B) obtained by a method according to any of I) to III) to a hydrolysis as follows:
(Formula Removed ) wherein R1 and R1 are as described above.
V) A method for the production of a compound represented

by a general formula (IV-A) or a general formula (IV-B), comprising the step of subjecting a compound represented by a general formula (III-A) or a general formula (III-B) obtained by a method according to IV) to a hydrolysis as follows:
(Formula Removed ) wherein R1 is as described above.
VI) A method for the production of a compound represented by a general formula (I-A) or a general formula (I-B), comprising the step of protecting the amino group of a compound represented by a general formula (V-A) or a general formula (V-B) with R2OC(-O)-, wherein R2 is as desoribed above, esterlfylng the carboxyl group thereof, and treating with thionyl chloride as follows:
(Formula Removed )
wherein R1 and R3 are as described above.
VII) A method for production of a compound represented by
a general formula (VI):
(Formula Removed )
wherein R1 Is as described above, and Y Is an optionally substituted alley 1, comprising the step of subjecting a compound represented by a general formula (III-A) or a general formula (III-B) obtained by a method according to IV) to a peptide bond formation.
VIII) A method for the production according to IV), wherein
R1 is phenyl, 5-lmldazolyl, methyl/ isopropyl, ethynyl, or
1-propynyl.
IX) A method for the production according to IV), wherein
R3 is a lower alkyl, an aralkyl, or a heterbarylalkyl.
X) A method for the production according to IV), wherein
R2 is an aralkyl.
XI) A method for the production according to IV), wherein
R1 is methyl and R2 is benzyl.
"Halogen" as used herein refers to fluorine, chlorine, bromine, and iodine. Chlorine and bromine are preferable.
The term "lower alkyl" as herein used alone or in combination with other words comprises C1-C6 straight chained or branched alkyl. Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and t-butyl, and the like. Methyl and ethyl are preferable.
"Alkynyl" as used herein comprises C2-C9 straight or branched ohaln monovalent hydrocarbon group having one or two or more triple bonds. The alkynyl may have a double bond. Examples of the alkynyl include ethynyl, l-propynyl, 2-propynyl, 6-heptynyl, 7-octynyl, and0-nonyl, and the like. Ethynyl and 1-propynyl are preferable.
The term "aryl" as herein used alone or in combination with other words comprises a monocyclic or condensed ring aromatic hydrocarbon. Examples of the aryl include phenyl, 1-naphthyl, 2-naphthyl, anthryl, and the like.
"Aralkyl" as used herein comprises the above-described "lower alkyl" substituted with the above-described "aryl", where the substitution may be carried out at any possible position. Examples of the aralkyl include benzyl, phenylethyl (e.g., 2-phenylethyl, and the like),
phenylpropyl (e.g., 3-phenylpropyl, and the like), naphthylmethyl (e.g., 1-naphthylmethyl, 2-naphthylmethyl, and the like), and anthrylmethyl (e.g., 9-anthrylmethyl. and the like), and the like. Benzyl, and the like are preferable.
"Heteroaryl" as used herein comprises a 5 to 6-membered aromatic ring including one or more atoms arbitrarily selected from oxygen atom, sulfur atom or nitrogen atom within the ring. Heteroaryl may be fused with cyoloalkyl, aryl, or other heteroaryl at any possible position. Regardless whether the heteroaryl is monocyclic or fused cyclic, the heteroaryl can bind at any possible position.
Examples of the heteroaryl include pyrrolyl (e. g., 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), imldazolyl (e.g., 4-imidazolyl. 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-lsothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl). pyrazinyl (e.g., 2-pyrazinyl), pyrimldinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadlazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indoli z inyl (e.g., 2-lndoliz iny1, 6-indollzlnyl), isoindolyl (e.g., 2-ieolndolyl). indolyl (e.g., 1-indolyl, 2-indolyl. 3-Indolyl), indazolyl (e.g., 3-indazolyl), purinyl (e.g., 8-purlnyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl (e.g., 3-isoquinolyl), qulnolyl (e.g.. 2-qulnolyl, 5-qulnolyl), phthalazinyl (e.g.,
- *r-
1-phthalazinyl), naphthyrldlnyl (e.g., 2-naphthyrldlnyl), quinolanyl (a.g.,2-quinolanyl), quinazolinyl (e.g., 2-quinazolinyl). clnnolinyl (e.g., 3-clnnolinyl), pteridinyl (e.g., 2-pteridinyl), carbazolyl (e.g.. 2-oarbazolyl, 4-carbazolyl), phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl). dibenzofuranyl (e.g., 1-dibenzofuranyl, 2-dibenzofuranyl), benzimldazolyl (e.g., 2-benzimidazolyl), benziaoxazolyl (e.g., 3-benziaoxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadlazolyl), benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), and benzothlenyl (e.g., 2-benzothienyl). As "heteroaryl" of R1, lmldazolyl and the like are prefarable.
"Heteroarylalkyl" as used herein comprises the above-described "lower alkyl" substituted with the above-described "heteroaryl" , where such a substitution may be carried out at any possible position.
"Optionally substituted lower alkyl" at R1 as used herein comprises the above-described "lower alkyl" which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthlo (e.g., methylthio), oyoloalkyl (e.g.. eyclopropyl, oyolobutyl. cyclopentyl, cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxyoarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, oyqno, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituent include lower alkyloxy, halogen.
and the Ilka. Examples of the "optionally substituted lower alkyl" Include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and trifluoromethyl, and the like. An unsubstituted lower alkyl Is preferable.
"Optionally substituted alkyl" at Y as used herein
comprises the above-described "alkyl" which may have one
or more substituents at any possible positions, such as
hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto,
alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl,
cyclobutyl. cyclopentyl, and cyolohexyl), halogen (e.g.,
fluorine, chlorine, bromine, and iodine), carboxy, carbamoyl,
alkyloxycarbonyl (e.g., methoxyoarbonyl and
ethoxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl),
nitro, cyano, SOpR* (p is an mtegnr of 1 to 3, R is hydrogen
or alkyl), PO(OH)2 or P(0)OH which may be substituted with
alkyl, substituted or unsubstituted amino (e.g., methyl amino,
dimethyl amino, and carbamoyl amino), optionally substituted
aryl (e.g., phenyl and tolyl), optionally substituted
heteroaryl, optionally substituted nonaromatic
heterocyclic group, aryloxy, acyloxy, acyloxycarbonyl,
alkylcarbonyl, nonaromatic heterocyclic carbonyl,
heterocyclic imino, hydrazine hydroxyamino, alkyloxyomlno,
formyl, and the like. Examples of the "optionally
substituted alkyl" include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
cyclopropyl, cyclopentyl, cyclohexyl, benzyl,
hydroxymethyl, tert-butylcarbonyloxymethyl,
morpholinomethyl, plperldlnomethyl,
N-methyl-l-piperazinylmethyl, ethylcarbonylmethyl, and morpholinocarbonylmethyl, acetyloxymethyl, and the like. An unsubstituted alkyl Is preferable, particularly methyl.
"Optionally substituted aryl" as used herein comprises the above-described "aryl" which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthlo (e.g., methylthio), cycloalkyl (e.g., cyclopropyl. cyclobutyl, cyclopentyl, and oyalohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxyoarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituent include lower alkyloxy and halogen, and the like. Examples of the "optionally substituted aryl" include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and the like. An unsubstltuted aryl is preferable.
"Optionally substituted heteroaryl" as used herein comprises the above-described "heteroaryl" which may have one or more substituents at any possible positions, suoh as hydroxy, alkyloxy (e.g.. methoxy and ethoxy), mercapto. alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxyoarbonyl (e.g., phenyloxyoarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituents include lower alkyloxy, halogen, and the like. Examples of the "optionally substituted heteroaryl" include 2-chloroimldazole-5-yl, 4-chloroimidazole-5-yl, and the like. An unsubstltuted heteroaryl is preferable. ,
"Optionally substituted aralkyl" as used herein
comprises the above-described "aralkyl" which may have one or more substltuents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio}, cycloalkyl (e.g., cyclopropyl, cyclobutyl, oyclopentyl and cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxyoarbonyl (e.g., phenyloxycarbonyl), nitro, oyano, aryloxy, aoyloxy, acyloxyoarbonyl, alkylcorbonyl, and the like. Preferable examples of the substltuents include lower alkyloxy. halogen, and the like. Examples of the "optionally substituted aralkyl" include furyl, thienyl, pyridyl, 5-chlorofuryl, 5-thienyl, 3-ohloropyrldyl, and the like. An unsubstituted aralkyl is preferable.
BEST MODE FOR CARRYING OUT THE INVENTION
The production method of the present invention will be described in detail in which a starting material is one optically active substance. When the other material is used, similar reactions can be carried out. When a starting material has a substltuent which is an obstacle to a reaction in first to sixth steps shown below, the starting material may be protected in advance In accordance with a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley 6 Sons), and the like, and deprotected in an appropriate stage.
(Formula Removed ) wherein R1, R2, R3, and Y are as described above.
(First step)
In the first step, R2OC(=O)-Hal, wherein Hal is halogen, [RaOC(-0) ]2O, and the like are caused to react with a compound represented by a general formula (V-A) to obtain a compound (VII-A) in which an amino group is protected by R2OC(«0)-. This step can be carried out in aooordance with a method described In Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), and the like.
For example, a compound represented by a general formula (V-A) Is caused to react with 1.0 equivalent to 3.0 equivalents, preferably 1.0 equivalent to 1.5 equivalents, of R2OC(=0)-Hal, wherein Hal is halogen, and 2.0 equivalents to 6.0 equivalents; preferably 2.0 equivalents to 3.0 equivalents, of an organlobase (e.g..
trlethylamlne. and the like) or an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodiumtcarbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and the like), in a mixed solvent, such as water-toluene, water-dioxane, water-acetone, and the like, or a solvent, such as water, dioxane, and the like at -20°C to 50°C. preferably 0°C to 20°C for 0.5 to 3 hours to obtain a compound represented by a general formula (VII-A).
In the above-described IV), "step of protecting an amino group with R2OC(=o)-" refers to this first step.
(Second step)
In the second step, the carboxyl group of a compound represented by a general formula (VII-A) is esterlfied to obtain a compound represented by a general formula (II-A). This step can be carried out by a commonly used esterif ication.
For example, a compound represented by the general formula (VII-A) is dissolved In a solvent, such as methanol, ethanol, lsopropyl alcohol, and the like, and allowed to react with 1 equivalent to 5 equivalents, preferably 1 equivalent to 2 equivalents, of a halogenating agent, such as thionyl chloride, hydrochloric acid, phosphorus oxychloride, and the like, at -20°C to 50"C, preferably 0°C to 25°C, one hour to 24 hours, preferably one hour to 3 hours to obtain a compound represented by a general formula (II-A).
In the above-described IV), "step of esterifying a carboxyl group" refers to this second step.
(Third step)
The third step Is a cyclisation reaction in whioh the stereochemistry of R1 is reversed.
For example, a compound represented by a general formula (I-A) aan be obtained in accordance with 1) to 3) described below. 1) a compound represented by a general formula (II-A) Is dissolved in a solvent, such as toluene, ethyl acetate, cyclohexaner aoetonitrlle, and the like, preferably toluene. The amount of the solvent is preferably 1 V to 50 V, particularly 1 V to 10 V, where use of 1 ml of a solvent with respect to 1 g of a starting material is referred to as 1 V. 2} 1.0 equivalent to 20 equivalents, preferably 1.0 equivalent to 2.0 equivalents, of thionyl ohlorlde are added at 25*C to 80'C, preferably 25°C to SO'C. Thionyl chloride can be used as a solvent. 3) The reaction solution is stirred at 25°C to 80°C, preferably 60°C to 80°C. for 5 hours to 48 hours, preferably 6 hours to 12 hours.
In this reaction, the closer the equivalent value of thionyl chloride is to 1.0 and the higher the "V" value of the amount of the solvent, the proportion of the els-form of the Intended compound was increased (the proportion of the trans-form was deoreased).
The yield of the total compounds of cis-form and trans-form is not substantially affected by the equivalent value of thionyl chloride and the amount of the solvent.
In the above-described IV), "step of treating with thionyl chloride" refers to this third step.
(Fourth step)
In the fourth step, an ester compound represented
by the general formula (I-A) is hydrolyzed to carboxylic acid. This step con be carried out by a commonly used hydrolysis.

For example, a compound represented by the general formula (I-A} is dissolved in a solvent, such as water, and the like, and 0.1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, of aold (e.g., hydrochloric acid, sulfuric acid, and the like) are added to the solution at 0'C to 100°C. preferably 25°C to 80°C. The resultant solution is allowed to react at 25°C to 100°C, preferably 50°C to 80°C for 1 hour to 5 hours to obtain a compound represented by a general formula (III-A). This step oan be carried out under basic conditions.
(Fifth step)
In the fifth step, a aompound represented by the general formula (III-A) is hydrolyzed to obtain alio-amino acid derivatives represented by a general formula (IV-A).
For example, a compound represented by the general formula (III-A) is dissolved in a solvent, such as water, and 0.1 equivalent to 20 equivalents, preferably 1 equivalent to 10 equivalents, of acid (e.g., hydrochloric aold, sulfuric acid, and the like) are added to the solution at 0'c to 100°C, preferably 25°C to 80°C. The resultant solution is allowed to react at 25°C to 100°C, preferably 80°C to 100°C for 1 hour to 48 hours to obtain a compound represented by the general formula (IV-A).
(Sixth step) (peptide bond formation)
Three amino acid derivatives are subjected to two
peptide bond formation to synthesize a compound (VI) (WO98/08867). A compound represented by the general formula (I-A) obtained by the above-desoribed method is used to synthesize the compound (VI) in the following two methods (method A and method B).
Method A
(Formula Removed ) wherein R4 la the protecting group of a carboxyl group, R5 is the protecting group of an amino group, and Rl and Y are as described above.
Method A - First step
The carboxyl group of 3-(4-thiazole)alanine synthesized in accordance with a method described In Synth. Commun., 20, 22, 3507 (1990) and Chem. Pharm. Bull., 38. 1, 103 (1990), is protected as an ester, such as methyl ester, benzyl ester, t-butyl e6ter, diphenymethyl ester, and the like, resulting in a compound represented by a general formula (VIII). This compound and a compound represented by the general formula (III-A) are subjected to a peptide bond formation.
When the carboxyl group is protected as dipheny lmethyl ester, the protecting reaction can be carried out as follows. 3-(4-thiazole)alanine is dissolved in a mixed solvent of an alcohol solvent, such as methanol, ethanol, and the like and a solvent, such as tetrahydrof uran, dloxane, and the like. 1 to 3 equivalents, preferably 1 to 2 equivalents, of dipheny1 dlazomethane are added to the solution at 0 to 50°C. preferably 20 to 40°C for 10 minutes to 1 hour, preferably 20 to 40 minutes. The resultant solution is allowed to react at the same temperature for 30 minutes to 3 hours, preferably 1 to 2 hours while being stirred.
The peptide bond formation is described in "Peputido Gosei [Peptide Synthesis]" (Nobuo Izumlya, Maruzen), and the like, and can be carried out by such a commonly used peptide bond formation method.
As commonly used peptide bond formation methods, a method employing a condensing agent, such as N.N-dicyclohexylcarbodiimide (DCC). and the like, an azide
method, an acid chloride method, an acid anhydride method, an active ester method, and the like. When a starting material has a substituent (amino, carboxy. hydroxyl, and the like) which is an obstacle to the peptide formation, the substituent can be protected in advance in accordance with a method described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), and the like, and the protecting group is removed at a desired stage.
A compound represented by the general formula (VIII) and a compound represented by the general formula (III-A) are dissolved in a solvent, such as N,N-dimethylformamide. tetrahydrofuran, acetonitrile, and the like. An N,N-dimethylformamide solution of a base, such as trlethylamine, and the like, and dicyclohexyloarbodiimide (DCC), is added to that solution at -10 to 10°c, preferably in ice bath. 1-hydroxybenzotriazole may be added. The resultant solution is stirred at 10 to 50°C, preferably 20 to 30°C, for one hour to one day, preferably 5 to 10 hours, followed by typical subsequent processes. Thus, a compound represented by a general formula (IX) can be obtained.
Method A - Second step
A deprotectlng reaction can be carried out by a commonly used deprotectlng reaction (Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons)). For example, when R4 is dlphenylmethyl, a compound represented by a general formula (IX) can be added'to anisole and trif luoro acetic acidat-10 to 10°C, preferably in ice bath. Themixture is stirred at the same temperature for 5 to 30 minutes, preferably 10 to 20 minuses. After the mixture is warmed to 20 to 40°C, the mixture can be stirred for 1 to 4 hours, preferably 2 to 3 hours.
The resultant deprotected substance can be reacted with a pyrrolidine derivative synthesized by a method described in Tetrahedron, 27, 2599 (1971) through a peptide bond formation similar to method A - first step, thereby obtaining a compound represented by the general formula (VI).
Method B - First step
The amino group of 3-(4-thiazole)alanine synthesized In accordance with a method described in Synth. Commun., 20, 22. 3507 (1990) and Chem. Pharm. Bull., 38, 1, 103 (1990), is protected by a protecting group for an amino group, such as t-butyloxycarbonyl. benzyloxyaarbonyl, 9-fluorenylmethoxycarbonyl, phthaloyl, trifluoroaoetyl, and the like to obtain a compound represented by a general formula (X). This compound and a pyrrolidine derivative synthesized by a method described in Tetrahedron, 27, 2599 (1971) are subjected to a peptide bond formation.
When t-butyloxycarbonyl is used for the protection, the protecting reaction can be carried out as follows. 3-(4-thlazole)alanine is dissolved in a solvent, suoh as dioxane, tetrahydrof uran, acetonitrile, and the like. Boc20 is added to the solution at 0 to 50'C, preferably 10 to 30°C, and stirred for 1 to 5 hours, preferably 2 to 4 hours.
A peptide bond formation can be carried out in a manner similar to that of the above-described method A - First step.
Method B - Second step
A deprotecting reaction for an amino group can be carried out as follows. When the protecting group is t-butyloxycartaonyl. a compound represented by a general
formula (XI) is dissolved in a solvent, such as ethyl acetate, and the like, l to 4 N hydrochloric acid-ethyl acetate solution is added to that solution at -10 to 30°C. preferably in ice. The resultant mixture is stirred at the same temperature for 1 to 5 hours, preferably 2 to 3 hours.
The resultant deprotected substance can be subjected to a peptide bond formation similar to that of method A -First step, thereby obtaining a compound represented by the general formula (VI).
In the production method, a compound represented by the general formula (V-A) or (V-B) is preferably L- threonine or D-threonine (R1 = methyl). Further, compounds represented by the general formulas (VII-A). (VII-B), (II-A), (II-B), (I-A), (I-B). (III-A), (III-B). (IV-A), (IV-B), and (VI) are also preferably compounds derived from L- threonine or 0-threonine.
As Ra, benzyl is preferable. As R3 and Y, methyl is preferable.
In Examples, the following abbreviations are used.
Me:methyl
Z:benzyloxycarbonyl
Examples Example 1
(Formula Removed ) Potassium hydroxide (54.77 g) and a compound (1) (L-threonine) (100.0 g) were dissolved in water (1000 ml). To the solution was added potassium carbonate (139.23 g). The resultant solution was cooled below 10°C. Toluene (180 ml) solution of Z-Cl (157.5 g) was dropped into the solution at 10±5°C for about one hour while the solution was vigorously stirred. The stirring was further continued for about 1.5 hours at the same temperature. Thereafter, the resulting reaction mixture was extracted with toluene (120 ml). The aqueous layerwas washed with toluene (200 ml). Each toluene layer was extracted with water (50 ml) again. The aqueous layers were combined. To the resultant aqueous layer was added 25% hydrochloric acid (about 294 g) to adjust the pH to 2. 0±0.5, followed by extraotion with ethyl acetate (800 ml). The organic layer was washed with 10% brine (400 ml). Each aqueous layer was extracted with ethyl acetate (200 ml) again. Thereafter, the organic layers were combined. The organic layer was evaporated. Adding ethyl acetate (1000 ml} to the residue and condensing were repeated twice. Further, methanol (500 ml)'was added, followed by evaporation. Thereafter methanol was added to adjust the volume to about 440 ml. To the resultant methanol solution of compound (2) was dropped thlonyl chloride (109.9 g) at 10±l0°c, followed by stirring at 20±10°C for 2.5 hours. The reaction mixture was dropped into a slurry of sodium
hydrogencarbonate (211.6 g) in water (1320 ml) over about 30 minutes. The resultant slurry was stirred at 5°C for one hour. Thereafter, crystals were collected by filtration and dried, to obtain 206.3 g of compound (3) (yield 92%).
Melting point: 91°C
lH NMR (CD30D) δ 1.19 (d, J-6.38, 3H), 3.73(6, 3H), 4.21-4.31 (m, ZH), 5.11 (S, 2H), 7.30-7.38 (m. 5H)
Example 2
(Formula Removed ) A solution of a compound (3) (50.0 g) and thionyl chloride (24.48 g) in toluene (250 ml) was stirred at 80°C for 8 hours and thereafter was cooled to room temperature. The reaction mixture was extracted with water (150 ml). The aqueous layer was washed with toluene (25 ml). Each toluene layer was extracted with water (50 ml) again. Thereafter, the aqueous layers were combined. 36% hydrochlorio acid (18.94 g) was added to the resultant aqueous layer. The aqueous layer was stirred at 80°C for one hour and thereafter the water was evaporated. Water (100 ml) was added to the residue, followed by condensation. Adding aoetonitrlle (200 ml) to the residue and condensing were repeated three times. Acetonitrile was added to adjust the volume to about 50 ml. The resultant slurry was stirred at 0±5°C for one hour. Thereafter, crystals were collected by filtration and dried. Thus ,17.4 g of compound (5) was obtained (yield 64%).
Malting points 165"C
1H NMR (CD3OD) δ 1.38 (d, J=6.52, 3H), 4.40 (d, J=8.64, 1H), 4.96 (dq, J-6.54, J=8.66, 1H) [α] D" -19.5° (C=l.Q, H2O)
Example 3
(Formula Removed ) A solution of a compound (3) (3.0 g) and thionyl ahloride (1.47 g) in toluene (15 ml) was stirred at 80°C for 8 hours and thereafter was cooled to room temperature. The reaation mixture was extracted with water (9 ml). The aqueous layer was washed with toluene (1.5 ml). Each toluene layer was extracted with water (3 ml) and water (1.5 ml). The aqueous layers were combined. The resultant aqueous layer was condensed, thereby obtaining 1.48 g of aompound (4) as oil (yield 83%).
1H NMR (CD3OD) δ 1.31(d, J-6.48, 3H). 3.79(s, 3H), 4.46(d. J-8.52, 1H), 4.96(dq, J=6.48, J«8.52, 1H)
Example 4
(Formula Removed ) Methanol (5 ml) was added to compound (4) (1.0 g) and cooled in ice. 20% aqueous sodium hydroxide solution (2.5 g) was added to the solution, which was in turn stirred in loe hath for 30 minutes. 98% sulfuric acid (0.62 g) was added to the solution. Thereafter, precipitated crystals were filtered out and the filtrate was condensed. Adding acetonltrlle (5 ml) to the residue and condensing were repeated four times. Acetonltrlle (8ml) was added to the resultant residue. The solution was dried oyer anhydrous sodium sulfate (2.2 g). The sodium sulfate was filtered out and the filtrate was condensed. The resultant slurry was stirred in ice bath for 30 minutes. Thereafter, crystals were collected by filtration and dried, thereby obtaining 0.50 g of compound (5) (yield 55%).
Example 5
(Formula Removed )
36% hydrochloric acid (10.5 g) was added to oompound (5) (3.00 g). The solution was refluxed under stirring for 15 hours. Thereafter, water was evaporated and water (10ml) was added to the residue, thereafter condensing. The residual oil matter was dissolved in water (10 ml). Aqueous lithium hydroxide solution was added to the solution to be adjusted to pH 6, followed by evaporation of water. Methanol (8 ml) was added to the resultant solid, followed by stirring at room temperature for one hour, thereafter subjected to filtration and dried. Thus. 2.25 g of compound (6) (L-allo-threonine) was obtained (yield 91%).
lH NMR (D2O) 6 1.20 (d. J-6.30. 3H), 3.83 (d, J-3.90, 1H), 4.36 Idq. J-3.90, J=6.60, 1H) [α] D30 +9.07° (C=2.0, H20)
INDUSTRIAL APPLICABILITY
According to the production method of the present invention, oxo~oxazollne derivatives and alloamino acid derivatives can be produced in a stereoselective and inexpensive manner.







We Claim:
1. A process for preparation of a compound represented by the general formula (I-A) or the general formula (I-B), comprising the step of treating a compound represented by the general formula (II-A) or the general formula (II-B) with thionyl chloride characterize in that in presence of a solvent such as herein described;
(Formula Removed ) wherein R1 is an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl; R2 is a lower alkyl, an optionally substituted aralkyl, or an optionally substituted heteroarylalkyl; and R3 is a lower alkyl.
2. The process as claimed in claim 1, wherein the compound represented by the general
formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 5.0 equivalent
of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at
30° C to reflux.
3. The process as claimed in claim 1, wherein the compound represented by the general
formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 3.0 equivalent
of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane or acetonitrile at
60°C to 80° C.

Documents:

in-pct-2002-00226-del-abstract.pdf

in-pct-2002-00226-del-claims.pdf

in-pct-2002-00226-del-correspondence-(po).pdf

in-pct-2002-00226-del-correspondence-others.pdf

in-pct-2002-00226-del-description (complete).pdf

in-pct-2002-00226-del-form-1.pdf

in-pct-2002-00226-del-form-13.pdf

in-pct-2002-00226-del-form-19.pdf

in-pct-2002-00226-del-form-2.pdf

in-pct-2002-00226-del-form-3.pdf

in-pct-2002-00226-del-form-5.pdf

in-pct-2002-00226-del-gpa.pdf

in-pct-2002-00226-del-petition-137.pdf

in-pct-2002-00226-del-petition-138.pdf


Patent Number 248687
Indian Patent Application Number IN/PCT/2002/00226/DEL
PG Journal Number 32/2011
Publication Date 12-Aug-2011
Grant Date 04-Aug-2011
Date of Filing 25-Feb-2002
Name of Patentee SHIONOGI & CO., LTD
Applicant Address 1-8, DOSHOMACHI-3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-0045, JAPAN.
Inventors:
# Inventor's Name Inventor's Address
1 MOKOTO KOBAYASHI C/O SHIONOGI & CO., LTD., 1-3, KUISE TERAJIMA 2-CHOME, AMAGASAKI-SHI, HYOGO 660-0813, JAPAN.
2 HARUO KOIKE C/O SHIONOGI & CO., LTD., 1-3, KUISE TERAJIMA 2-CHOME, AMAGASAKI-SHI, HYOGO 660-0813, JAPAN.
3 MASAHIKO NAGAI C/O SHIONOGI & CO., LTD., 12-4, SAGISU 5-CHOME, FUKUSHIMA-KU, OSAKA-SHIM, OSAKA 553-0002, JAPAN.
PCT International Classification Number C07D 263/20
PCT International Application Number PCT/JP00/05753
PCT International Filing date 2000-08-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 11/242647 1999-08-20 Japan