WO2012142983A1 - Optically active salts of (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahydro-3ah- cyclopenta-[d] [1,3]dioxol-4-ol and a method of their preparation - Google Patents

Optically active salts of (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahydro-3ah- cyclopenta-[d] [1,3]dioxol-4-ol and a method of their preparation Download PDF

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Publication number
WO2012142983A1
WO2012142983A1 PCT/CZ2012/000036 CZ2012000036W WO2012142983A1 WO 2012142983 A1 WO2012142983 A1 WO 2012142983A1 CZ 2012000036 W CZ2012000036 W CZ 2012000036W WO 2012142983 A1 WO2012142983 A1 WO 2012142983A1
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Prior art keywords
preparation
salt
solution
mandelic
compounds
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PCT/CZ2012/000036
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French (fr)
Inventor
Petr Lustig
Ludmila Hejtmankova
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Zentiva, K.S.
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Priority to HU1300734A priority Critical patent/HUP1300734A2/en
Publication of WO2012142983A1 publication Critical patent/WO2012142983A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C07C59/50—Mandelic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Diastereomeric salts of the compound of formula I with D-(-)-mandelic and R-(-)-3- chloromandelic acid, a method of for the preparation thereof and their use in the synthesis of the drug ticagrelor.

Description

Optically active salts of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta-[d] [l,3]dioxol-4-ol and a method of their preparation
Technical Field
The invention relates to diastereomeric salts of the compound of formula I with D-(-)- mandelic and R-(-)-3-chloromandelic acid, a method for the preparation thereof and their use in the synthesis of the drug ticagrelor.
Figure imgf000003_0001
Background Art
The application WO 2009/064249 describes preparation of a salt of the compound I with dibenzoyl-L-tartaric acid by crystallization from a water - ethanol mixture. Several methods are mentioned, either with isolation of a racemic intermediate which is a mixture of the compound I and the undesired stereoisomer la
Figure imgf000003_0002
or without isolation of this intermediate. A racemic mixture of the compounds I and la is obtained by hydrogenation of a racemate consisting of the two antipodes with the corresponding configuration of asymmetrical centres:
Figure imgf000004_0001
The patent EP 1 289 992 B l describes preparation of the hydrochloride of the compound I, consisting in depfotection of the imidocarbonate group in the environment of hydrochloric acid. The same method of preparation is also mentioned in the applications WO 00/34283 and WO 99/05142.
Preparation of salts of the compound I in these documents starts with the compound II.
Figure imgf000004_0002
The compound II is prepared from the compound III
Figure imgf000004_0003
(III)
in such a way that the O-acetate group is replaced with a substituted amino group by the Tsuji- Trost reaction under catalysis of tetrakis triphenyl phosphine palladium, followed by hydroxylation of the double bond.
Disclosure of Invention
The invention provides diastereomeric salts of the compound I with D-(-)-mandelic and R-(-)- 3-chloromandelic acid, a method for the preparation thereof and their use for the preparation of the compound I with high purity, serving as an intermediate for the production of the drug ticagrelor. The invention further provides a method for the preparation of ticagrelor, comprising preparation of a diastereomeric salt of the compound I with D-(-)-mandelic or R- -)-3 -chloromandelic acid in accordance with the invention,
Figure imgf000005_0001
wherein R is H or CI.
Detailed description of the invention
The method according to the invention comprises mixing of a solution of the racemic mixture of the compounds I and la with a solution of D-(-)-mandelic or R-(-)-3 -chloromandelic acid at a temperature from 0 °C to the boiling point of the solvent used, preferably while hot, and isolation of the solid salt. The term "while hot" is to be understood as meaning the same or higher temperature as compared to the boiling point of the selected solvent at the normal pressure, reduced by 15 K. An especially preferable approach is mixing a solution of the racemic mixture of the compounds I and la with a solution of D-(-)-mandelic or R-(-)-3- chloromandelic acid at a temperature which is the same or higher as compared to the value of the boiling point of the selected solvent at the normal pressure, reduced by 5 K. Isolation of the solid salt from the mother liquor is done in usual ways, e.g. by means of pressure filtration, aspiration, or centrifugation, while the isolated solid phase may be freed from residues of the mother liquor by washing with a suitable solvent if necessary. A preferable embodiment of the invention consists in isolation of the solid salt according to the invention in a crystalline state. A suitable temperature for crystallization of the salt is a temperature lower than 35 °C with most solvents; a preferable temperature is a temperature lower than 25°C.
Solvents for the preparation of salts according to the invention include organic solvents not containing strong acidic or basic groups, able to dissolve the two constituents forming the resulting salt at least while hot. Suitable solvents include aliphatic or cyclic ketones with three to six carbon atoms such as acetone, butanone or cyclohexanone, esters with two to six carbon atoms such as methyl acetate, ethyl acetate or butyl acetate, nitriles with two to six carbon atoms such as acetonitrile or propionitrile. Especially suitable solvents are Ci-C6 aliphatic alcohols, e.g. methanol, ethanol, n-propanol, 2-propanol, n-butanol. For crystallization or precipitation of the solid salt according to the invention a mixture of two solvents can also be used, such that, e.g., the racemic mixture of compounds I and la can be dissolved in a different solvent than the acid. The method according to the invention makes it possible to obtain the compound I in a purity comparable to hitherto findings, but in a higher yield. This especially relates to the salt of D-(-)-mandelic acid. In the case of R-(-)-3-chloromandelic acid the result is comparable to the hitherto findings as regards the optical quality of the product and slightly better as regards the yield.
Working Examples
Example 1
Method for the preparation of D-(-)-mandelate of compound I
10.3 g of the racemic mixture of the compounds I and la were dissolved in 25 ml of ethanol and D-(-)-mandelic acid was dissolved in 15 ml of ethanol, both at the boil. The resulting solutions were mixed in the molar ratio of the base to the corresponding acid of 1 : 1 while warm. The mixture was cooled to the room temperature, at which a crystalline product precipitated.
The precipitated solid substance was aspirated and washed with 2 x 5 ml of ethanol. The product was first dried at the room temperature and then in a vacuum drier at 50 °C.
9.5 g of a product (49 %) was obtained with a purity characterized by the enantiomeric excess (ee) of 97 %, m. p.: 190 to 193 °C, which was further used for the synthesis of ticagrelor. The purity was determined by the gas chromatography (GC) method with the standardized quality evaluation procedure. Example 2
Method for the preparation of R-(-)-3-chloromandelate of compound I
12.3 g of the racemic mixture of the compounds I and la were dissolved in 25 ml of ethanol at the boil. R-(-)-3-chloromandelice acid (11.8 g) was dissolved in 15 ml of ethanol at the boil. The prepared hot solutions were mixed in the molar ratio of the base to the acid of 1 : 1 . The mixture was cooled to the room temperature under stirring, at which the crystalline product precipitated.
This solid substance was aspirated and washed with 3 x 5 ml of ethanol. The product was first dried at the room temperature and then in a vacuum drier at 50 °C.
9.1 g of a product (40 %) was obtained with a purity characterized by the enantiomeric excess (ee) of 98.6 %, m. p.: 186 to 188 °C, which was further used for the synthesis of ticagrelor. The purity was determined by the gas chromatography (GC) method with the standardized quality evaluation procedure.
It has been verified that using the salts according to the invention with the purity of at least 96 % ee makes it possible to obtain, in any of the further steps of the synthesis of ticagrelor, the final product containing less than 0.15 % of the isomeric impurity IV with a configuration derived from the undesired diastereoiso ier la, without the necessity to use chromatographic purification.
Figure imgf000007_0001
The salts of compound I with D-(-)-mandelic and R-(-)-3-chloromandelic acid in the purities mentioned in Examples 1 and 2 were used for the preparation of ticagrelor, which is illustrated in Scheme 1. The salts of the compound I with the said acids are marked I * HA therein.
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
ticagrelor
SCHEME 1
Abbreviations used:
CBz = benzyloxycarbonyl,
MIBK methyl isobutyl ketone,
DIPEA diisopropylethylamine.
The total yield of the method described in Scheme 1 was 16 %. The quality of the obtained product was determined using the liquid chromatography method and amounted to 99.5 % with the content of impurity IV lower than 0.1 %. The method of preparation of ticagrelor according to Scheme 1 did not require the use of chromatographic purification in any of the steps of its synthesis.

Claims

Claims
A salt of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta- [d][l ,3]dioxol-4-ol I of the general formula
Figure imgf000010_0001
wherein R = H or CI.
The salt according to claim 1 , which is in a crystalline state.
A method for the preparation of the salt according to claims 1 or 2, characterized a solution of the racemic mixture of compounds I and la
Figure imgf000010_0002
is mixed with a solution of D-(-)-mandelic or R-(-)-3-chloromandelic acid at a temperature from 0 °C to the boiling point of the solvent and the produced solid salt is isolated.
The method according to claim 3, characterized in that the solvent is selected from the group consisting of Ci to C6 aliphatic alcohols.
The method according to claims 3 or 4, characterized in that the mixing of the solution of the racemic mixture of compounds I and la with the solution of D-(-)-mandelic or R-(-)-3-chloromandelic acid is carried out at the same or higher temperature as compared to the value of the boiling point of the selected solvent at the normal pressure, reduced by 15 .
6. The method according to claims 3 or 4, characterized in that the mixing of the solution of the racemic mixture of compounds I and la with the solution of D-(-)-mandelic or R-(-)-3-chloromandelic acid is carried out at the same or higher temperature as compared to the value of the boiling point of the selected solvent at the normal pressure, reduced by 5 K.
7. The use of a salt according to any one of claims 1 and 2 for the preparation of
ticagrelor.
8. The use according to claim 7, wherein the salt according to claims 1 or 2 has a purity characterized by an enantiomeric excess of at least 97 %.
9. A method for the preparation of ticagrelor, characterized in that it comprises use of a salt obtained by the method according to any one of the claims 3 to 6.
PCT/CZ2012/000036 2011-04-19 2012-04-19 Optically active salts of (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahydro-3ah- cyclopenta-[d] [1,3]dioxol-4-ol and a method of their preparation WO2012142983A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513221A (en) * 2013-09-26 2015-04-15 上海科胜药物研发有限公司 Preparation method of ticagrelor intermediate with optical activity
CN113461656A (en) * 2021-08-11 2021-10-01 常州制药厂有限公司 Preparation method of ticagrelor key chiral intermediate isomer impurity TGAD2
CN113461655A (en) * 2021-08-11 2021-10-01 常州制药厂有限公司 Preparation method of ticagrelor key chiral intermediate isomer impurity TGAD1

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999005142A1 (en) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO2000034283A1 (en) 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
EP1289992A1 (en) 2000-06-02 2003-03-12 AstraZeneca AB New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound
WO2009064249A1 (en) 2007-11-15 2009-05-22 Astrazeneca Ab A process for the preparation of (3ar,4s, 6r, 6as)-6-amino-2, 2- dimethyltetrahydro-3ah-cyclopenta[d] [1,3] dioxol-4-ol dibenzoyl-l-tartrate and to products of said process

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999005142A1 (en) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO2000034283A1 (en) 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
EP1289992A1 (en) 2000-06-02 2003-03-12 AstraZeneca AB New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound
WO2009064249A1 (en) 2007-11-15 2009-05-22 Astrazeneca Ab A process for the preparation of (3ar,4s, 6r, 6as)-6-amino-2, 2- dimethyltetrahydro-3ah-cyclopenta[d] [1,3] dioxol-4-ol dibenzoyl-l-tartrate and to products of said process

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOZHUSHKOV S I ET AL: "Convenient and inexpensive synthesis of (1R,2R)-trans-1-amino-6-nitroindan-2-ol", ADVANCED SYNTHESIS AND CATALYSIS, WILEY, WEINHEIM, DE, vol. 347, 1 January 2005 (2005-01-01), pages 255 - 265, XP002444253, ISSN: 1615-4169, DOI: 10.1002/ADSC.200404296 *
SPRINGTHORPE ET AL: "From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 17, no. 21, 1 November 2007 (2007-11-01), pages 6013 - 6018, XP022267216, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2007.07.057 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513221A (en) * 2013-09-26 2015-04-15 上海科胜药物研发有限公司 Preparation method of ticagrelor intermediate with optical activity
CN113461656A (en) * 2021-08-11 2021-10-01 常州制药厂有限公司 Preparation method of ticagrelor key chiral intermediate isomer impurity TGAD2
CN113461655A (en) * 2021-08-11 2021-10-01 常州制药厂有限公司 Preparation method of ticagrelor key chiral intermediate isomer impurity TGAD1

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