Title of Invention

METHOD FOR PRODUCING {N-[1-(S)-CARBOLKOXY-3-PHENYLPROPYL]-S-ALANYL-2S, 3AR, 7AS-OCTAHYDROINDOL-2-CARBOXYLIC ACID} COMPOUNDS

Abstract The invention relates to a method for producing optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid} and the pharmaceutically acceptable salts thereof. To this end, a racemic mixture of optionally substituted trans-octahydroindol-2-carboxylic acid is reacted with the N-carboxyanhydride of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine}, which is optionally substituted on the phenyl ring, in an appropriate inert solvent, and the obtained optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid}, preferably trandolapril, is subsequently isolated, as well as polymorphous forms A and B of trandolapril.
Full Text - 1 - P1323/trandolapril
Method for producing {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid} compounds
The present invention relates to a method for preparing {N- [1- (S) -carbalkoxy-3-phenylpropy.l] -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid} compounds and in particular the compound {N-[1-S-carbethoxy-3-phenyl-propyl]-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid}, which is also known under the name trandolapril. Trandolapril is an active ingredient which, owing to inhibition of angiotensin converting enzyme (ACE), has blood pressure-lowering properties and is employed in particular for the treatment of high blood pressure and heart failure. Trandolapril corresponds to the formula (I):

EP 0 084 164 discloses the synthesis of trandolapril by esterifying trans-octahydroindole-2-carboxylic acid with a protective group and subsequently reacting with {N-[1-(S)- ethoxycarbonyl-3-phenylpropyl]-L-alanine in a peptide coupling. The resulting product is then fractionated into the diastereomers by chromatography, after which trandolapril is obtained by eliminating the protective group from the appropriate diastereomer. In this case, the octahydroindole-2-carboxylic acid has the trans configuration and is employed as benzyl or tert-butyl

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ester in the racemic form or as enantiopure compound in the peptide coupling. EP 0 088 341 and the publication J. Med. Chem. 1987, 30, 992-998 describe analogous syntheses of trandolapril diastereomers. These start from octahydro-indole-2-carboxylic ester in the cis configuration and employ for the peptide coupling besides dicyclohexyl-carbodiimide or hydroxybenzotriazole also carbonyl-diimidazole. It is particularly disadvantageous in said syntheses that in each case trans-octahydroindole-2-carboxylic acid must be provided with a protective group, and a previous racemate separation of the racemic trans-octahydroindole-2-carboxylic, acid employed as coupling component is necessary.
EP 0 215 335 describes a method for preparing {N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline} by reacting the N-carboxyanhydride of {N-[1-(S)-ethoxy-carbonyl-3-phenylpropyl]-L-alanine} with L-proline. It is found in this case that the reaction of N-carboxyanhydrides has no general applicability for controlled and reproducible preparation of heteropeptides and is applicable only to the invention claimed in EP 0 215 335.
The following definitions apply in the present text:
"ECAPPA" means {N- [1- (S)-ethoxycarbonyl-3-p_henyl£ropyl]-L-
alanine}.
"NCA" means an N-carboxyanhydride.
"ECAPPA-NCA" means the N-carboxyanhydride of ECAPPA.
"rac." means "racemic".
"rac. trans-octahydroindole-2-carbOxylic acid" means a
racemic mixture of trans-octahydroindole-2-carboxylic
acid.

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It has now been found that it is possible to prepare trandolapril reproducibly in high yield without interfering side reactions by reacting rac. trans-octa-hydroindole-2-carboxylic acid (i.e. without protective group) with the N-carboxyanhydride of {N-[1-(S) -ethoxy-carbonyl-3-phenylpropyl]-L-alanine}, and subsequently to obtain trandolapril from the reaction mixture directly in very pure form by crystallization. Separation of diastereomers by chromatography is unnecessary. In this connection, rac. trans-octahydroindole-2-carboxylic acid specifically means a racemic mixture of (2S, 3aR, 7aS)-octahydroindole-2-carboxylic acid and (2R, 3aS, 7aR)-octa-hydroindole-2-carboxylic acid. Analogous statements apply in each case to the claimed substituted compounds.
The present invention provides a simple way of using rac. traus-octahydroindole-2-carboxylic acid (without use of protective groups) and E(bAPPA-NCA as starting materials for preparing trandolapril, without the need for a previous racemate separation of rac. trans-octahydroindole-2-carboxylic acid. It is surprising that trandolapril can be obtained directly from the racemate in such pure form by crystallization. Moreover, the reaction according to the invention proceeds without further racemization and allows aqueous workup of the reaction mixture, i.e. the ECAPPA-NCA reaction mixture used in the peptide coupling, to destroy excess reagents such as, for example, triphosgene and byproducts, as is described hereinafter.
The present invention also provides a method permitting separation of diastereomers A1 and B1 (see scheme 1 below)

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by crystallization so that no intermediate purification is necessary until the desired diastereomer is isolated by crystallization. It is possible in this connection for the diastereomers to be separated by crystallization either after salt formation (e.g. as hydrochloride, see method 1 below) or preferably without additional conversion into a salt (see method 2 below). To date, chromatographic methods which are technically difficult to apply have been described for separating corresponding diastereomeric compounds.
Subsequent to the crystallization of the product, elutriation under mild conditions in a suitable medium such as, for example, acetone/water or in acetone is sufficient. The yields of the elutriations are very high and afford the final product in high purity. Overall, the process of the invention is distinguished by technical easy and fast performability.
It has moreover been found that specifically trandolapril crystallizes in two different polymorphic forms and that these different forms also exhibit different properties such as, for example, different bioavailabilities, solubilities and dissolution rates, resulting in appropriate advantages in the production of different administration forms.

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The compounds used according to the invention correspond to the following chemical formulae:

The present invention is defined in the claims. The present invention relates in particular to a method for preparing optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid) and pharmaceutically acceptable salts thereof, which is characterized in that a racemic mixture of optionally substituted trans-octahydroindole-2-carboxylic acid is reacted with the N-carboxyanhydride of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine}, which is optionally substituted on the phenyl ring, in a suitable inert solvent, and subsequently the resulting optionally substituted {N-[1-S-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid) is isolated.
The compound is preferably isolated by crystallization. The compound {N-[1-S-carbethoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid) (trandolapril) is preferably prepared.

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The procedure for isolating the compound by crystallization may be such that the resulting diastereomer mixture is converted into a suitable salt, for example in to the hydrochloride, the desired diastereomeric salt is crystallized and then the desired compound, e.g. trandolapril, is liberated therefrom. This method is referred to herein as method 1 (depicted in scheme 1). The compound obtained in this way can subsequently be converted into a suitable salt.

The desired diastereoisomer is preferably crystallized directly from the reaction mixture, i.e. without previous salt formation, so that trandolapril or a derivative of this compound is obtained directly. This preferred method is referred to herein as method 2. The compound prepared in this way can subsequently be converted into a suitable

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salt. The preparation referred to as method 2 follows scheme 1, but the compound referred to as diastereomer A1 is crystallized directly without salt formation.
Optionally substituted trans-octahydroindole-2-carboxylic acid and racemic mixtures thereof are known per se. The unsubstituted carboxylic acid and racemic mixtures thereof is preferably used. The preparation of the N- = carboxyanhydride of {N-[1-(S)-ethoxycarbonyl-3-
phenylpropyl]-L-alanine} is likewise known.
The preparation of optionally substituted [N-(1-S-carbalkoxy-3-phenylpropyl)-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid] compounds preferably means those compounds in which "carbalkoxy" (identical to "alkoxycarbonyl") means carbethoxy, carbopropoxy and carbobutoxy, preferably carbethoxy, and the 3-phenylpropyl radical is optionally substituted on the phenyl by methyl, ethyl, propyl or butyl, preferably in the ortho or para position. The 3-phenylpropyl radical is preferably unsubstituted.
Pharmaceutically acceptable salts of this optionally

substituted {N-[1-(S)-cafbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid} are in particular those with hydrochloric acid, oxalic acid, tartaric acid, methylsulfonic acid (mesylate), benzenesulfonic acid (besylate), and the other salts
described in the literature.
Optionally substituted trans-octahydroindole-2-carboxylic acid and racemic mixtures thereof, and the preparation of {N-[1-(S)-ethoxycarbonyl-3-phenylpropyi]-L-aianine} are

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known per se. Preparation of the N-carboxyanhydride (NCA) of ECAPPA is likewise known. ECAPPA-NCA is prepared for example by reacting ECAPPA with a carbonyl compound which comprises suitable leaving groups, such as carbonyldi-imidazole, trichloromethyl chloroformate, phosgene, diphosgene or triphosgene, preferably with triphosgene.
The method of the invention starts with the preparation of the N-carboxyanhydride in an inert organic solvent at about 0-40oC. This entails heating {N-[1-(S)-alkoxy-carbonyl-3-phenylpropyl]-L-alanine), which is optionally substituted on the phenyl ring, in methylene chloride or another suitable solvent, in the presence of a carbonyl compound which comprises suitable leaving groups, preferably triphosgene, with formation of the NCA. The solvent and the unreacted carbonyl compound are subsequently preferably removed. The remaining product can then be reacted with rac. octahydroindole-2-carboxylic acid to give the diastereomer mixture (A1 and B1, see scheme 1). The desired diastereomer A1, preferably trandolapril, can then be crystallized from the mixture as salt, e.g. as hydrochloride, preferably without conversion into a salt.
Reaction of the NCA of {N-(1-(S)-alkoxycarbonyl-3-phenyl-propyl]-L-alanine) with rac. octahydroindole-2-carboxylic acid to give the diastereomer mixture A1 and B1 preferably takes place at a temperature in the range from about -20oC to room temperature, preferably in the range from about -20oC to 0oC, with the NCA of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine) preferably being added to a suspension of rac. tran5-octahydroindole-2-carboxylic acid in a mixed aqueous solvent system. The molar ratio of the

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NCA, preferably of ECAPPA-NCA, to rac. trans-octahydro-indole-2-carboxylic acid is preferably in the range from 1:1 to 1:1.6, preferably;about 1:1.3. Moreover, the acid value (pH) is kept preferably in the basic range, preferably in the range from pH 9 to pH 10, during the reaction, which is achieved by simultaneous addition of an inorganic or organic basically reacting compound.
Examples of such inorganic 6r organic basically reacting compounds are alkali metal hydroxides, alkali metal carbonates or alkali metal bicarbonates,-preferably of sodium or potassium, or secondary or tertiary amines such as, for example, dialkylamines such as dimethylamine, diethylamine, trialkylamines such as trimethylamine, triethylamine, tripropylamine or tributylamine. It is also possible to use for example pyridine or quaternary ammonium hydroxides.
Mixed aqueous solvent systems are preferably mixtures of water and of a water-miscible organic solvent such as, for example, acetone, dioxane or tetrahydrofuran. Acetone is preferred.
After the reaction is complete, the organic solvent is distilled off, resulting initially in an aqueous solution which is then taken up with a water-immiscible organic solvent, for example in an organic ester such as, for example, methyl acetate, ethyl acetate, prbpyl acetate, preferably ethyl acetate!. This entails initially the aqueous and the organic phase being brought with ah acid, e.g. by adjusting the aqueous phase with an inorganic acid to an acid value (pH) in the range of pH = 4.5-6.0 and subsequent shaking of the two phases, to this acid value,

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followed by separation from the aqueous phase and concentration of the organic phase. This organic phase now comprises the desired reaction product as diastereomer A1. mixed with diastereomer B1, as shown in scheme 1. Selective crystallization of the resulting product, preferably trandolapril, from, the organic phase can now be undertaken.
The selective crystallization,is preferably carried out at a temperature in the range from -5°C to +30°C. Since the organic phase comprises the desired reaction product as diastereomer A1 mixed with diastereomer B1, usually in the ratio of about 1:1, it is necessary to separate diastereomer A1 from diastereomer B1. This is surprisingly possible by crystallization.
It has been found that on crystallization of trandolapril, both as hydrochloride (by method 1) and as free compound (by method 2), the water content of the solvent plays a crucial role. Thus, in method 1, a water content of the organic solvent of preferably in the range of 2-4% by weight, preferably of 2.5-3.5% by weight and preferably of about 3% by weight, is used. In this case, the desired diastereomer A1 crystallizes in high purity, while diastereomer B1 remains substantially in solution. The separation at lower water contents is poor or nonexistent,. Losses of yield are to be expected with.higher water contents.
In method 2, a water content of the organic solvent of preferably in the range of 0.05-4.0% by weight, preferably of 1.5-3.0% by weight, is used. In this case, the desired diastereomer A1 crystallizes in surprisingly high purity,

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while diastereomer B1 remains substantially in solution. Losses of yield are to be expected with higher water contents, but are not critical.
The solvent preferably used is an organic ester such as, for example, methyl acetate, ethyl acetate, propyl acetate, preferably ethyl acetate.
This crystallization usually results in diastereomer A1 in a purity in the range from 88.0% by weight to 98% by weight, the remaining 2-12% by weight consisting predominantly of ECAPPA and diastereomer B1. Further purification of the product obtained by crystallization can take place by recrystallization or, preferably, by elutriation in an organic solvent or in a mixture of such a solvent with water. Preferred solvents or solvent mixtures are: acetone/water, acetone, acetone/MTBE (methyl tert-butyl ether), ethyl acetate and ethyl acetate/MTBE. The purities of diastereomer A1 obtained with acetone/ water at a temperature in the range from 0°C to room temperature are virtually 100% in this case.
In method 1, diastereomer A1 is isolated by first converting the diastereomer mixture into a suitable salt, and then subjecting it to crystallization. Examples of salts suitable for this purpose are the hydrochloride, sulfate, phosphate, and other salts known per se. The hydrochloride is preferably used. This entails initially the aqueous and the organic phase being brought with an acid, e.g. by adjusting the aqueous phase with an inorganic acid to an acid value (pH) in the range of pH -4.5-6.0 and subsequent shaking of the two phases, to this acid value, followed by separation from the aqueous phase.

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The organic phase, preferably ethyl acetate, now comprises the desired reaction product as diastereomer A1 mixed with diastereomer B1. The hydrochloride is prepared by passing HC1 gas into the organic phase at 0-20°C, whereupon the hydrochloride is formed. The evaporation of the organic phase results in an oily crude product which is taken up in one of the solvents mentioned, such as acetone with the described water content, and crystallized. Thus, for example, trandolapril hydrochloride is crystallized from acetone/MTBE (methyl tert-butyl ether).
Trandolapril is liberated from the hydrochloride preferably in a mixture of water and a water-miscible organic solvent (e.g. acetone), a pH - 4.0-6.0 being adjusted by adding a base. Sodium bicarbonate is preferably used as base. Crystallization of the product may start even during addition of the base at 0-25°C. Further purification of the final product (trandolapril) is possible by recrystallization or, preferably, by elutriation in an organic solvent, possibly mixed with water.
Besides the method described above, the present invention also relates to two novel crystalline forms of trandolapril. It has been found that two different crystalline forms, referred to as form A and form B herein, can be obtained on crystallization of trandolapril.
Crystalline form A is characterized by the following IR and XRD data (tables 1 and 2) and by the ORTEP representation of the corresponding crystal structure analysis (figure 1 and table 3).

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Table 1. IR absorption bands of polymorphic form A of trmdotaprt
Wavelength (cm )
48(m) 1407(m) 1247(m)
3280(m) 1474(sh) 1236(m)
3083(w) 1457(S) 1207(sh)
3028(w) 1434(s) 1104(t)
2994(sh) 1307(m) 1174(sh)
2973(w) 1367(s) 1100 (sh)
2943(m) 1358(sh) 1102 (m)
2881(w) 1340 (w) 1004(m)
2S49(w) 1338 (w) 1024(m)
1736(s) 1319(m) 038 (m)
1705(sh) 1311(m) 705 (m)
1655(S) 1299 (w) 737(m)
1601(w) 1281 (m) 800(m)

Tabte 2. XRO data of polymorphic form A of trandoiaprt
Angt*2thata(*) Lattice tpadng d(A) Relative Intensity W—(%)
7.34 12.07 31
8.88 0.00 8
10 88 8.33 1
11.68 763 3
12.3 7.24 20
1254 7.1 6
12.88 602 12
14.58 6.12 18
15 68 5.71 10
16.44 5.45 18
17 5.27 100
17.82 5.04 12
16.2 4.04 11
18.64 4.82 43
10.76 4.56 10
21.08 4.20 30
21.36 4.23 37
21.52 42 38
221 4.1 25
22.0 3.06 18
23.14 3.92 6
23.54 3.86 7
24.28 3.75 25
25.08 3.64 18
25.04 3.52 18
26.68 3.43 20
27.78 3.31 20
20.38 3.14 16
Not*: As to known, the ******* may vary owing to todure efects

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Figure 1. Crystal structure of trandolapril (stereo-ORTEP representation)


Table 3. Crystal data and structural parameters of trandotapntIdentfflcsbon oode trando Empirical formula C24 K34 N2 05


Formula wilgrit 430.53
Temperature 160(2) K
Wavelength 0.71073 A
Crystal system, epece group orthorhombtc. P2,2,2,
Unit cell dknenelorw • ¦7.6078(11) A a-90 dag.
6-15 1017(13) A B-90daa.
c-20.131(3) A Y- 90 dag.
Volume 2312.8(5) A*
Z. CafcuMed density 4. 1.236 Mg/mJ
Abeorptton coefficient 0.086 mm'1
F(000) 926
Crystal ate oa. 0.3 x 0.05 x 0.02 mm
1 iWla rVBI HJr QHa OOHKBOn 2.70 to 24AS dag.
LJmMnQ Irtdtoaa (Kh£6. 0Ste17, 02*22
RaOacbont ooaaclad / uniqua 1629 /1829 [Rflnt) • 0.0000]
ComptatanaM to thata - 24.85 79.90%
Raflnamant mathod FiaVmatrbt laaat*aojuaraa on F
uaca / Tmtmwnct i paramawrs 1829/0/283
QoodnaMoMfconF^ 0.645
Final R MOM [t>2a)gma(0] R1-0.0733, wR2-0.1796
R InotoM (al data) R1 - 0.1469. w*2 - 0.24O5
AbaoMa atructur* pvamatar -2(5)
Laroatt oitT paak and note 0218 and -0241 •>-*

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The second crystalline form (form B) of trandolapril is characterized by the following IR and XRD data (tables 4 and 5):

Table 4. IRabecfptonbanofrc/pocymorphfcformBoftwctolaprt
WaveleituUi (cm
J3&(m1 I497(m) 1186(»)
3300(th) 1455 3004{w) 1444

Documents:

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Patent Number 242372
Indian Patent Application Number 1385/KOLNP/2006
PG Journal Number 35/2010
Publication Date 27-Aug-2010
Grant Date 24-Aug-2010
Date of Filing 23-May-2006
Name of Patentee AZAD PHARMACEUTICALS INGREDIENTS AG
Applicant Address FRIEDBERGSTRASSE 68, CH-8200 SCHAFFHAUSEN
Inventors:
# Inventor's Name Inventor's Address
1 POGUTTER, MIRKO SPIEGELGUTSTRASSE 45, CH-8200 SCHAFFHAUSEN
2 BICHSEL, HANS-ULRICH SALEN-REUTENEN, CH-8507 HORHAUSEN
3 BADER, THOMAS BUCHZELGSTRASSE 78, CH-8053 ZURICH
4 RUDOLF, FELIX OBERSTADT 46, CH-8200 SCHAFFHAUSEN
PCT International Classification Number C07D 209/42
PCT International Application Number PCT/CH2004/000688
PCT International Filing date 2004-11-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2038/03 2003-11-28 Switzerland