US20110137056A1 - Chemical Process For Preparation Of Intermediates - Google Patents
Chemical Process For Preparation Of Intermediates Download PDFInfo
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- US20110137056A1 US20110137056A1 US12/956,133 US95613310A US2011137056A1 US 20110137056 A1 US20110137056 A1 US 20110137056A1 US 95613310 A US95613310 A US 95613310A US 2011137056 A1 US2011137056 A1 US 2011137056A1
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- 0 *OC(=O)[C@@H]1CC1C1=CC(F)=C(F)C=C1 Chemical compound *OC(=O)[C@@H]1CC1C1=CC(F)=C(F)C=C1 0.000 description 18
- JBWIJKZPCPUWBR-UHFFFAOYSA-N CC1CC1C1=CC(F)=C(F)C=C1 Chemical compound CC1CC1C1=CC(F)=C(F)C=C1 JBWIJKZPCPUWBR-UHFFFAOYSA-N 0.000 description 5
- YODCHFWWRFXLGD-UHFFFAOYSA-N CCC(O)C1=CC(F)=C(F)C=C1 Chemical compound CCC(O)C1=CC(F)=C(F)C=C1 YODCHFWWRFXLGD-UHFFFAOYSA-N 0.000 description 5
- XJXVTLRKVJBWFN-UHFFFAOYSA-N FC1=C(F)C=C(C2CC2)C=C1 Chemical compound FC1=C(F)C=C(C2CC2)C=C1 XJXVTLRKVJBWFN-UHFFFAOYSA-N 0.000 description 4
- UNJRFWWCCAHSRB-UHFFFAOYSA-N FC1=C(F)C=C(C2CO2)C=C1 Chemical compound FC1=C(F)C=C(C2CO2)C=C1 UNJRFWWCCAHSRB-UHFFFAOYSA-N 0.000 description 4
- PYEJQVYISBUGDU-UHFFFAOYSA-N NC(=O)C1CC1C1=CC(F)=C(F)C=C1 Chemical compound NC(=O)C1CC1C1=CC(F)=C(F)C=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 description 3
- RYOLLNVCYSUXCP-UHFFFAOYSA-N OC(CCl)C1=CC(F)=C(F)C=C1 Chemical compound OC(CCl)C1=CC(F)=C(F)C=C1 RYOLLNVCYSUXCP-UHFFFAOYSA-N 0.000 description 3
- VMEDAWUIKFAFJQ-UHFFFAOYSA-N O=C(CCl)C1=CC(F)=C(F)C=C1 Chemical compound O=C(CCl)C1=CC(F)=C(F)C=C1 VMEDAWUIKFAFJQ-UHFFFAOYSA-N 0.000 description 2
- RYOLLNVCYSUXCP-MRVPVSSYSA-N O[C@H](CCl)c(cc1)cc(F)c1F Chemical compound O[C@H](CCl)c(cc1)cc(F)c1F RYOLLNVCYSUXCP-MRVPVSSYSA-N 0.000 description 2
- FSZOBSMJJFHVCQ-UHFFFAOYSA-N CCC(=O)C1=CC(F)=C(F)C=C1 Chemical compound CCC(=O)C1=CC(F)=C(F)C=C1 FSZOBSMJJFHVCQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
- C07C67/26—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran with an oxirane ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/753—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of polycyclic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
- C07D301/26—Y being hydrogen
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals.
- the present invention concerns enantiomerically pure trans-cyclopropane carboxylic acid derivatives, processes for preparing the carboxylic acid derivatives and their use in preparing pharmaceuticals.
- the present invention provides processes for preparing a compound of formula IV
- R is an alkyl group, comprising: treating a compound of formula III
- R 1 and R 2 are, independently, alkyl.
- the present invention also provides processes for preparing a compound of formula IV
- R is an alkyl group, comprising: a) reducing a compound of formula I
- R 1 and R 2 are, independently, selected from alkyl.
- R is an alkyl group, comprising: a) treating the compound of formula II
- R 1 and R 2 arc, independently, selected from alkyl.
- the present invention also provides processes for preparing a compound of formula VII
- the present invention also provides a compound of formula II
- R is an alkyl group
- suitable values of R include, but arc not limited to, for example, (C 1-6 )alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl. In some embodiments, R is ethyl.
- the compound of formula IV may be prepared from a compound of formula II
- the compound of formula I is reduced to the compound of formula II.
- the reduction is carried out using a suitable reducing agent.
- suitable reducing agents will include those which are able to reduce the carbonyl group in the compound of formula I to the hydroxyl group of formula II and give an enantiometric excess of the compound of formula II with the stereo chemistry shown in formula II.
- suitable conditions include, for example, catalytic reduction or use of a transition metal with chiral ligand.
- a particular example of a suitable reducing agent is oxazaborolidine which may be formed by mixing trimethoxy borane and S-diphenylprolinol, followed by addition of borane dimethylsulphide. This is generally carried out in an inert solvent such as toluene.
- the temperature is conveniently maintained at a temperature in the range 25 to 45° C., for example 35 to 40° C.
- the compound of formula I is treated with the reducing agent so formed. This is generally carried out in an inert solvent such as toluene.
- the temperature is conveniently maintained at a temperature in the range 25 to 45° C., for example 35 to 40° C.
- a compound of formula IV may be prepared by treating a compound of formula III
- R 1 and R 2 are, independently, selected from alkyl such as (C 1-6 )alkyl.
- a suitable 25 compound of formula 3 is triethyl phosphonoacetate.
- the reaction is generally carried out in an inert solvent such as toluene.
- the reaction is generally carried out at a temperature in the range 30 to 80° C., conveniently 40 to 60° C., e.g. 40° C.
- the reaction may conveniently be carried out in the presence of a base.
- suitable bases include, but are not limited to, sodium hydride and alkali metal (for example potassium or sodium) alkoxides (for example t-butoxide). Specific examples are potassium and sodium t-butoxide.
- the compound of formula III may be prepared by treating the compound of formula II with a base, such as an alkali metal hydroxide, for example sodium hydroxide. This is conveniently carried out in a suitable solvent such as water.
- a base such as an alkali metal hydroxide, for example sodium hydroxide.
- the compound of formula II may be converted to a compound of formula IV via the compound of formula III,
- the compound of formula II is converted to a compound of formula IV by treating the compound of formula II with a base, such as sodium hydride. This is generally carried out in an inert solvent such as toluene. This is treated with triethyl phosphonoacetate. This is generally carried out at a temperature in the range 30 to 80° C., conveniently 40 to 60° C., e.g. 40° C.
- the present invention also provides processes for preparing a compound of formula VII
- Suitable bases include, but are not limited to, alkali metal alkoxides such as potassium methoxide or sodium methoxide.
- An agent such as methyl formiate may also be present.
- the reaction is generally carried out in a suitable solvent such as an alcohol in a suitable solvent. In one embodiment, the reaction is carried out in toluene and methanol.
- a compound of formula IV may be treated with the base and then treated with ammonia.
- the reaction is under pressure during the treatment with ammonia.
- An example of a suitable pressure is 2 to 10 bar.
- the reaction may be carried out at an elevated temperature, such as 40 to 70° C., for example at about 60° C.
- the present invention is also directed to compounds of formula IV and VII.
- the present invention also provides novel intermediates of formula II, III, or VII.
- Aluminium trichloride (210.2 g) was added to 1,2-difluorobenzene (200.0 g) at room temperature. The obtained slurry was heated to 50° C., then chloroacetyl chloride (198.0 g) was added over 50 minutes. The reaction mixture was stirred for an additional 60 minutes, then added slowly to a mixture of ice (786.0 g), water (196.0 g) and 37 wt % hydrochloric acid (297.0 g), during the addition the temperature was kept below 60° C. After the addition, 20 the reaction mixture was heated to 60° C. and the layers separated. The organic layer was washed twice with a 20 w/v% sodium chloride solution (200.0 mL). 2-Chloro-1-(3,4-difluorophenyl)ethanone (270.2 g) was obtained by vacuum distillation of the organic layer.
- Trimethoxy borane (2.7 g) was added at room temperature to a stirred solution of S-diphenylprolinol (4.7 g) in toluene (128.6 mL). After stirring this mixture for 90 minutes at 40° C. borane dimethylsulfide (22.3 g) was added over 15 minutes maintaining the temperature between 35 and 45° C. This mixture was stirred for 60 minutes at 40° C., then a solution of 2-chloro-1-(3,4-difluorophenyl)ethanone (70.0 g) in toluene (184.1 mL) was dosed over a period of 120 minutes maintaining the temperature between 35 and 45° C.
- the product in solution was characterized by mass spectroscopy (APCI).
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- Epoxy Compounds (AREA)
Abstract
The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure trans-cyclopropane carboxylic acid derivatives, processes for preparing the carboxylic acid derivatives and their use in preparing pharmaceuticals.
Description
- This application claims priority to Great Britain Application No. 0615619.4 filed 5 Aug. 5, 2006, which is incorporated herein by reference in its entirety.
- The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure trans-cyclopropane carboxylic acid derivatives, processes for preparing the carboxylic acid derivatives and their use in preparing pharmaceuticals.
- The compound [1S-(1α, 2α, 3β(3S*,2R*),5 β)]-3-[7-[2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol (Compound A), and similar such compounds, are disclosed in WO 00/34283 and WO 99/05143. These compounds are disclosed as P2T (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as, inter alia, inhibitors of platelet activation, aggregation or degranulation.
- We have now found an advantageous process for preparing enantiomerically pure trans-cyclopropane carboxylic acid derivatives which may be used in the preparation of Compound A. The process offers advantages such as, for example: diastereoselecivity, enantioselectivity, high yield, potential for manufacturing (e.g. reagents and procedures suitable for large scale production, non-hazardous reagents, less waste).
- The present invention provides processes for preparing a compound of formula IV
- wherein R is an alkyl group, comprising: treating a compound of formula III
- with a compound of formula 3
- wherein R1 and R2 are, independently, alkyl.
- The present invention also provides processes for preparing a compound of formula IV
- wherein R is an alkyl group, comprising: a) reducing a compound of formula I
- to give a compound of formula II
- b) treating the compound of formula II with a base to give a compound of formula III
- and c) treating the compound of formula III with a compound of formula 3
- wherein R1 and R2 are, independently, selected from alkyl.
-
- The present invention also provides processes for preparing a compound of formula IV
- wherein R is an alkyl group, comprising: a) treating the compound of formula II
- with a base; and b) treating the product of a) with a compound of formula 3
- wherein R1 and R2 arc, independently, selected from alkyl.
- The present invention also provides processes for preparing a compound of formula VII
- comprising treating the compound of formula IV
- with ammonia in the presence of a suitable base.
- The present invention also provides a compound of formula II
- or formula III
- or formula VII
- According to a first aspect of the present invention there is provided one or more compounds of formula IV
- wherein R is an alkyl group.
- For any of the embodiments described herein, suitable values of R include, but arc not limited to, for example, (C1-6)alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl. In some embodiments, R is ethyl.
- The compound of formula IV may be prepared from a compound of formula II
- According to a further aspect of the present invention there is provided processes for preparing one or more compounds of formula II from a compound of formula I.
- The compound of formula I is reduced to the compound of formula II. The reduction is carried out using a suitable reducing agent. Suitable reducing agents will include those which are able to reduce the carbonyl group in the compound of formula I to the hydroxyl group of formula II and give an enantiometric excess of the compound of formula II with the stereo chemistry shown in formula II. Examples of suitable conditions include, for example, catalytic reduction or use of a transition metal with chiral ligand.
- A particular example of a suitable reducing agent is oxazaborolidine which may be formed by mixing trimethoxy borane and S-diphenylprolinol, followed by addition of borane dimethylsulphide. This is generally carried out in an inert solvent such as toluene. The temperature is conveniently maintained at a temperature in the range 25 to 45° C., for example 35 to 40° C.
- The compound of formula I is treated with the reducing agent so formed. This is generally carried out in an inert solvent such as toluene. The temperature is conveniently maintained at a temperature in the range 25 to 45° C., for example 35 to 40° C.
- A compound of formula IV may be prepared by treating a compound of formula III
- with a compound of formula 3
- wherein R1 and R2 are, independently, selected from alkyl such as (C1-6)alkyl. A suitable 25 compound of formula 3 is triethyl phosphonoacetate.
- The reaction is generally carried out in an inert solvent such as toluene. The reaction is generally carried out at a temperature in the range 30 to 80° C., conveniently 40 to 60° C., e.g. 40° C. The reaction may conveniently be carried out in the presence of a base. Examples of suitable bases include, but are not limited to, sodium hydride and alkali metal (for example potassium or sodium) alkoxides (for example t-butoxide). Specific examples are potassium and sodium t-butoxide.
- The compound of formula III may be prepared by treating the compound of formula II with a base, such as an alkali metal hydroxide, for example sodium hydroxide. This is conveniently carried out in a suitable solvent such as water.
- The compound of formula II may be converted to a compound of formula IV via the compound of formula III,
- without isolation of the compound of formula III.
- In a particular embodiment of the present invention, the compound of formula II is converted to a compound of formula IV by treating the compound of formula II with a base, such as sodium hydride. This is generally carried out in an inert solvent such as toluene. This is treated with triethyl phosphonoacetate. This is generally carried out at a temperature in the range 30 to 80° C., conveniently 40 to 60° C., e.g. 40° C.
- The present invention also provides processes for preparing a compound of formula VII
- which comprises treating a compound of formula IV with ammonia in the presence of a suitable base. Suitable bases include, but are not limited to, alkali metal alkoxides such as potassium methoxide or sodium methoxide. An agent such as methyl formiate may also be present. The reaction is generally carried out in a suitable solvent such as an alcohol in a suitable solvent. In one embodiment, the reaction is carried out in toluene and methanol.
- A compound of formula IV may be treated with the base and then treated with ammonia. Preferably, the reaction is under pressure during the treatment with ammonia. An example of a suitable pressure is 2 to 10 bar. The reaction may be carried out at an elevated temperature, such as 40 to 70° C., for example at about 60° C.
- The present invention is also directed to compounds of formula IV and VII.
- The present invention also provides novel intermediates of formula II, III, or VII.
- Any of the embodiments described herein can be combined with any of the other embodiments described herein.
- In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.
- Aluminium trichloride (210.2 g) was added to 1,2-difluorobenzene (200.0 g) at room temperature. The obtained slurry was heated to 50° C., then chloroacetyl chloride (198.0 g) was added over 50 minutes. The reaction mixture was stirred for an additional 60 minutes, then added slowly to a mixture of ice (786.0 g), water (196.0 g) and 37 wt % hydrochloric acid (297.0 g), during the addition the temperature was kept below 60° C. After the addition, 20 the reaction mixture was heated to 60° C. and the layers separated. The organic layer was washed twice with a 20 w/v% sodium chloride solution (200.0 mL). 2-Chloro-1-(3,4-difluorophenyl)ethanone (270.2 g) was obtained by vacuum distillation of the organic layer.
- Spectral data:
- 1H-NMR of 2-chloro-1-(3,4-difluorophenyl)ethanone in CDCl3, 300 mHz
-
δ (ppm) H Pattern 4.7 ClCH2 S 7.3 Ph H-5 d × d × d × d 7.8 Ph H-6 M Ph H-2 - 13C-NMR of 2-chloro-1-(3,4-difluorophenyl)ethanone in CDCl3, 75 MHz
-
δ (ppm) Assignment 45.7 ClCH2CO 118.4 Ph C-2 and C-5, small JF-C visible 126.2 Ph C-6, small JF-C visible 131.6 Ph C-1, small JF-C visible 149.1-156.3 Ph C-3 and C-4, large JF-C visible 189.3 ClCH2COPh - Trimethoxy borane (2.7 g) was added at room temperature to a stirred solution of S-diphenylprolinol (4.7 g) in toluene (128.6 mL). After stirring this mixture for 90 minutes at 40° C. borane dimethylsulfide (22.3 g) was added over 15 minutes maintaining the temperature between 35 and 45° C. This mixture was stirred for 60 minutes at 40° C., then a solution of 2-chloro-1-(3,4-difluorophenyl)ethanone (70.0 g) in toluene (184.1 mL) was dosed over a period of 120 minutes maintaining the temperature between 35 and 45° C. After the completion of the addition, the reaction mixture was stirred for another 60 minutes at 40° C., then cooled to 10° C. Methanol (69.7 g) was added over a period of 20 minutes controlling the gas formation and the temperature to a maximum of 35° C. After the addition the mixture was cooled to 20° C., it was stirred at this temperature for 30 minutes. The obtained solution was then distilled, under reduced pressure at maximum 45° C., until the residual methanol and trimethoxyborane was less than 2 wt %. The obtained solution in toluene was then washed four times with a 10 wt % aqueous HOAc (280.0 mL) at 45 to 55° C. and the obtained water layer back extracted with toluene (140.0 mL). Both organic layers were combined and washed with water (140.0 mL). The resulting organic layer was azeotroped until less than 0.4 wt % water. After correction with toluene, a 33 wt % solution of 2-chloro-1-S-(3,4-difluorophenyl)ethanol was obtained (214.4 g theoretical yield).
- The product in solution was characterized by mass spectroscopy (EI):
-
M/z Identification 175.6 M+—H2O 143.6 M+—CH2Cl - Sodium hydride (13.4 g) was suspended in toluene (119.9 mL) and the resulting slurry heated to 40° C. Then a solution of triethyl phosphonoacetate (38.4 g) in toluene (60.0 mL) was added over a period of 60 minutes keeping the temperature between 40 and 45° C. When the addition was complete, the reaction mixture was stirred for an additional 60 minutes at 40° C. Then 90.9 g of a 33 wt % solution of 2-chloro-1-S-(3,4-difluorophenyl)ethanol in toluene was added over a period of 35 minutes allowing the temperature to raise to maximum 60° C. Once the addition was complete, the obtained mixture was stirred for an additional 14 hours at 60° C. Then water (155.8 mL) was added and the phases separated at 60° C. The toluene solution containing ethyl (1R,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxylate was used as such in the next step.
- The product in solution was characterized by mass spectroscopy (EI):
-
m/z Identification 226.3 M+. 198.3 M+.—H2C═CH2 180.4 M+.—HOCH2CH3 153.7 F2PhCH2CH2CH2 +. 127.4 F2Ph+. - Starting from 2-chloro-1-S-(3,4-difluorophenyl)ethanol (30.9 g), ethyl (1R,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxylate was prepared as in example 3. The solvent was distilled and to the resulting oil methanol (109.0 mL), methyl formiate (7.2 g) and 30 wt % sodium methoxide in methanol (11.5 g) were added at room temperature. The mixture was heated to 60° C. in a closed reactor. Then 2 bar NH3-pressure was applied. During a period of 4 hours, the temperature was maintained at 60° C. and the pressure at 2 bar. Then the reactor was cooled to room temperature and vented. The reaction mixture was heated to 60° C. and water (277.2 mL) dosed over 1 hour, the temperature was maintained at 60° C. The 25 resulting solution was cooled to room temperature, then filtered and washed with 1/1 methanol/water (69.3 mL), then with water (49.5 mL) and finally with DiPE (49.5 mL). The resulting crystals were dried at 50° C. in a vacuum oven. After drying, (1R,2R)-trans 2(3,4-difluorophenyl) cyclopropyl carboxamide (22.8 g) was obtained.
- Spectral data:
- 1H NMR of (1R,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxamide
-
δ (ppm) H Pattern 1.2 CH (from CH2) d × d × d 1.6 CH (from CH2) d × d × d and CH—CONH2 2.5 CH—Ph d × d × d 5.8 NH2 6.8-7.1 3 × Ph—H M - 13C NMR of (1R,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxamide
-
δ (ppm) Assignment 16.7 CH2 25.0 C—CONH2 or C—Ph 26.1 C—Ph or C—CONH2 115.3 Ph C-2, 2JF-C: 17.6 Hz 117.6 Ph C-5, 2JF-C: 17.4 Hz 122.7 Ph C-6, 3JF-C: 6.0 Hz and 4JF-C: 3.5 135-155 Ph C-4 and C-3 174.3 CONH2 - (1R,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxamide (25.0 g) and 157.4 g of a 30 wt % solution of NaOH were mixed and heated to 20 to 25° C. A 26 wt % solution of aqueous NaOCl (89.5 g) was dosed over a period of 30 minutes maintaining the temperature below 33° C. Once the addition was finished, the reaction mixture was stirred for an additional 3 hours at 30 to 33° C. The resulting mixture was then heated to 60° C. and stirred at this temperature for an additional 20 minutes.
- After cooling to 5° C., the pH of the reaction mixture was corrected with HC137 wt % (99.1 g) until a pH of 8.5-9.5 was achieved. iPrOAc (153.3 mL) and MeOH (85.0 mL) were added, followed by water (33.8 mL), after stirring and decantation the phases were separated. The obtained water layer was extracted twice with iPrOAc (75.0 and 55.0 mL respectively). The combined organic phases were diluted until a concentration of 5 wt % was achieved. The obtained solution contains (1R, 2S)2-(3,4-difluorophenyl)-cyclopropane amine (18.0 g in 360.4 g solution).
- The product in solution was characterized by mass spectroscopy (APCI).
-
m/z Identification 210.6 MH+ + CH3CN 169.9 MH+ 153.2 MH+ − NH3 - Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, U.S. and non-U.S. patents, patent application publications, international patent application publications, and the like) cited in the present application is incorporated herein by reference in its entirety.
Claims (21)
2. A process according to claim 1 wherein the compound of formula 3 is triethyl phosphonoacetate.
3. A process according to claim 1 wherein R, R1, and R2 are, independently, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.
5. A process according to claim 4 wherein the compound of formula IV is treated with ammonia in the presence of a suitable base.
7. A process for preparing a compound of formula IV
wherein R is an alkyl group, comprising:
a) reducing a compound of formula I
8. A process according to claim 7 wherein the compound of formula III is triethyl phosphonoacetate.
9. A process according to claim 7 wherein R, R1 and R2 are, independently, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.
11. A process according to claim 10 wherein the compound of formula IV is treated with ammonia in the presence of a suitable base.
13. A process according to claim 12 wherein the base is sodium hydroxide.
14. A process according to claim 12 wherein R, R1 and R2 are, independently, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.
15. A process according to claim 12 wherein the compound of formula 3 is triethyl phosphonoacetate.
17. A process according to claim 16 wherein the compound of formula IV is treated with ammonia in the presence of a suitable base.
19. A process according to claim 18 wherein the base is sodium methoxide.
20. A process according to claim 18 wherein the base is potassium methoxide.
Priority Applications (1)
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US12/956,133 US20110137056A1 (en) | 2006-08-05 | 2010-11-30 | Chemical Process For Preparation Of Intermediates |
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GBGB0615619.4A GB0615619D0 (en) | 2006-08-05 | 2006-08-05 | Chemical process for preparation of intermediates |
GB0615619.4 | 2006-08-05 | ||
US11/833,263 US7863469B2 (en) | 2006-08-05 | 2007-08-03 | Chemical process for preparation of intermediates |
US12/956,133 US20110137056A1 (en) | 2006-08-05 | 2010-11-30 | Chemical Process For Preparation Of Intermediates |
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US11/833,263 Continuation US7863469B2 (en) | 2006-08-05 | 2007-08-03 | Chemical process for preparation of intermediates |
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US20110137056A1 true US20110137056A1 (en) | 2011-06-09 |
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US11/833,263 Expired - Fee Related US7863469B2 (en) | 2006-08-05 | 2007-08-03 | Chemical process for preparation of intermediates |
US12/956,133 Abandoned US20110137056A1 (en) | 2006-08-05 | 2010-11-30 | Chemical Process For Preparation Of Intermediates |
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US11/833,263 Expired - Fee Related US7863469B2 (en) | 2006-08-05 | 2007-08-03 | Chemical process for preparation of intermediates |
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US (2) | US7863469B2 (en) |
EP (1) | EP2049462A4 (en) |
JP (1) | JP2010500343A (en) |
KR (1) | KR20090045920A (en) |
CN (1) | CN101495442A (en) |
AR (1) | AR062148A1 (en) |
AU (1) | AU2007282181B2 (en) |
BR (1) | BRPI0714573A2 (en) |
CA (1) | CA2658953A1 (en) |
CL (1) | CL2007002267A1 (en) |
GB (1) | GB0615619D0 (en) |
IL (1) | IL196233A0 (en) |
MX (1) | MX2009001020A (en) |
MY (1) | MY147871A (en) |
TW (1) | TW200812958A (en) |
WO (1) | WO2008018822A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120136167A1 (en) * | 2006-08-05 | 2012-05-31 | Astrazeneca Ab | Processes For The Preparation Of Optically Active Intermediates |
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CN111233673B (en) * | 2020-02-26 | 2022-08-16 | 苏州元兴生物医药有限公司 | Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method |
CN115894496A (en) * | 2021-09-30 | 2023-04-04 | 上海贝美医药科技有限公司 | Preparation method of ticagrelor and intermediate thereof |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4411925A (en) * | 1980-01-21 | 1983-10-25 | Pfizer Inc. | Branched amides of L-aspartyl-d-amino acid dipeptides |
US4590292A (en) * | 1985-06-10 | 1986-05-20 | Ciba-Geigy Corporation | Process for the manufacture of cyclopropylamine |
US4933477A (en) * | 1987-09-02 | 1990-06-12 | Basf Aktiengesellschaft | Preparation of phenyl-substituted epoxides |
US5225602A (en) * | 1985-12-11 | 1993-07-06 | Basf Aktiengesellschaft | Phenylacetaldehydes and the preparation of phenylacetaldehydes |
US5672504A (en) * | 1993-02-15 | 1997-09-30 | Daicel Chemical Industries, Ltd. | Process for enriching an R,S!-1,2-epoxide in one enantiomer by using microbes to convert one enantiomer to the other or to preferentially open the epoxide ring |
US6552217B2 (en) * | 2000-08-01 | 2003-04-22 | Eastman Chemical Company | Process for the preparation of alkyl 1-methylcyclopropanecarboxylate |
US6683216B1 (en) * | 2002-11-06 | 2004-01-27 | Eastman Chemical Company | Continuous process for the preparation of amines |
US20080071114A1 (en) * | 2006-08-05 | 2008-03-20 | Astrazeneca Ab | Processes For The Preparation Of Optically Active Intermediates |
US7863469B2 (en) * | 2006-08-05 | 2011-01-04 | Astrazeneca Ab | Chemical process for preparation of intermediates |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3909142A1 (en) | 1989-03-21 | 1990-10-04 | Basf Ag | METHOD FOR PRODUCING AMINES |
DE4315623A1 (en) | 1993-05-11 | 1994-11-17 | Hoechst Ag | Process for the preparation of amines |
DE4400328A1 (en) * | 1994-01-07 | 1995-07-13 | Huels Chemische Werke Ag | Process for the preparation of cyclopropanecarboxamide |
DE19523868A1 (en) | 1995-06-30 | 1997-01-02 | Huels Chemische Werke Ag | Cyclopropanamine prodn. by Hofmann degradation of cyclopropane-carboxamide |
DE19547635A1 (en) * | 1995-12-20 | 1997-06-26 | Bayer Ag | Process for the preparation of cyclopropanecarboxamides |
GB0013488D0 (en) * | 2000-06-02 | 2000-07-26 | Astrazeneca Ab | Chemical compound |
AR028110A1 (en) * | 2000-06-02 | 2003-04-23 | Astrazeneca Ab | NEW PROCESS |
-
2006
- 2006-08-05 GB GBGB0615619.4A patent/GB0615619D0/en not_active Ceased
-
2007
- 2007-07-27 TW TW096127556A patent/TW200812958A/en unknown
- 2007-07-30 AR ARP070103364A patent/AR062148A1/en not_active Application Discontinuation
- 2007-08-02 MX MX2009001020A patent/MX2009001020A/en active IP Right Grant
- 2007-08-02 CN CNA2007800287758A patent/CN101495442A/en active Pending
- 2007-08-02 MY MYPI20090411A patent/MY147871A/en unknown
- 2007-08-02 CA CA002658953A patent/CA2658953A1/en not_active Abandoned
- 2007-08-02 JP JP2009523744A patent/JP2010500343A/en active Pending
- 2007-08-02 KR KR1020097003039A patent/KR20090045920A/en not_active Application Discontinuation
- 2007-08-02 WO PCT/SE2007/000706 patent/WO2008018822A1/en active Application Filing
- 2007-08-02 AU AU2007282181A patent/AU2007282181B2/en not_active Ceased
- 2007-08-02 BR BRPI0714573-0A patent/BRPI0714573A2/en not_active IP Right Cessation
- 2007-08-02 EP EP07794102A patent/EP2049462A4/en not_active Withdrawn
- 2007-08-03 US US11/833,263 patent/US7863469B2/en not_active Expired - Fee Related
- 2007-08-03 CL CL200702267A patent/CL2007002267A1/en unknown
-
2008
- 2008-12-28 IL IL196233A patent/IL196233A0/en unknown
-
2010
- 2010-11-30 US US12/956,133 patent/US20110137056A1/en not_active Abandoned
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4411925A (en) * | 1980-01-21 | 1983-10-25 | Pfizer Inc. | Branched amides of L-aspartyl-d-amino acid dipeptides |
US4590292A (en) * | 1985-06-10 | 1986-05-20 | Ciba-Geigy Corporation | Process for the manufacture of cyclopropylamine |
US5225602A (en) * | 1985-12-11 | 1993-07-06 | Basf Aktiengesellschaft | Phenylacetaldehydes and the preparation of phenylacetaldehydes |
US4933477A (en) * | 1987-09-02 | 1990-06-12 | Basf Aktiengesellschaft | Preparation of phenyl-substituted epoxides |
US5672504A (en) * | 1993-02-15 | 1997-09-30 | Daicel Chemical Industries, Ltd. | Process for enriching an R,S!-1,2-epoxide in one enantiomer by using microbes to convert one enantiomer to the other or to preferentially open the epoxide ring |
US6552217B2 (en) * | 2000-08-01 | 2003-04-22 | Eastman Chemical Company | Process for the preparation of alkyl 1-methylcyclopropanecarboxylate |
US6683216B1 (en) * | 2002-11-06 | 2004-01-27 | Eastman Chemical Company | Continuous process for the preparation of amines |
US20080071114A1 (en) * | 2006-08-05 | 2008-03-20 | Astrazeneca Ab | Processes For The Preparation Of Optically Active Intermediates |
US7790927B2 (en) * | 2006-08-05 | 2010-09-07 | Astrazeneca Ab | Processes for the preparation of optically active intermediates |
US20100331575A1 (en) * | 2006-08-05 | 2010-12-30 | Astrazeneca Ab | Processes For The Preparation Of Optically Active Intermediates |
US7863469B2 (en) * | 2006-08-05 | 2011-01-04 | Astrazeneca Ab | Chemical process for preparation of intermediates |
US8026396B2 (en) * | 2006-08-05 | 2011-09-27 | Astrazeneca Ab | Processes for the preparation of optically active intermediates |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120136167A1 (en) * | 2006-08-05 | 2012-05-31 | Astrazeneca Ab | Processes For The Preparation Of Optically Active Intermediates |
US8278475B2 (en) * | 2006-08-05 | 2012-10-02 | Astrazeneca Ab | Processes for the preparation of optically active intermediates |
Also Published As
Publication number | Publication date |
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AU2007282181B2 (en) | 2012-04-19 |
CL2007002267A1 (en) | 2008-04-04 |
EP2049462A4 (en) | 2012-06-13 |
IL196233A0 (en) | 2009-09-22 |
CN101495442A (en) | 2009-07-29 |
US7863469B2 (en) | 2011-01-04 |
KR20090045920A (en) | 2009-05-08 |
WO2008018822A1 (en) | 2008-02-14 |
JP2010500343A (en) | 2010-01-07 |
MY147871A (en) | 2013-01-31 |
US20080132719A1 (en) | 2008-06-05 |
BRPI0714573A2 (en) | 2013-06-04 |
TW200812958A (en) | 2008-03-16 |
AR062148A1 (en) | 2008-10-15 |
CA2658953A1 (en) | 2008-02-14 |
EP2049462A1 (en) | 2009-04-22 |
AU2007282181A1 (en) | 2008-02-14 |
MX2009001020A (en) | 2009-02-05 |
GB0615619D0 (en) | 2006-09-13 |
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