WO2008018822A1 - Chemical process for preparation of aromatic cyclopropane esters and amides - Google Patents

Chemical process for preparation of aromatic cyclopropane esters and amides Download PDF

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WO2008018822A1
WO2008018822A1 PCT/SE2007/000706 SE2007000706W WO2008018822A1 WO 2008018822 A1 WO2008018822 A1 WO 2008018822A1 SE 2007000706 W SE2007000706 W SE 2007000706W WO 2008018822 A1 WO2008018822 A1 WO 2008018822A1
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compound
formula
preparing
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PCT/SE2007/000706
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Jean-Paul Dejonghe
Koen Peeters
Marc Renard
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Astrazeneca Ab
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Priority to EP07794102A priority Critical patent/EP2049462A4/en
Priority to JP2009523744A priority patent/JP2010500343A/en
Priority to AU2007282181A priority patent/AU2007282181B2/en
Priority to CA002658953A priority patent/CA2658953A1/en
Priority to MX2009001020A priority patent/MX2009001020A/en
Priority to BRPI0714573-0A priority patent/BRPI0714573A2/en
Publication of WO2008018822A1 publication Critical patent/WO2008018822A1/en
Priority to IL196233A priority patent/IL196233A0/en

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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
    • 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

Abstract

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing said intermediates, to intermediates used in said processes, and to the use of said intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure trans-cyclopropane carboxylic acid derivatives, processes for preparing said carboxylic acid derivatives and their use in preparing pharmaceuticals.

Description

Chemical process for preparation of aromatic cyclopropane esters and amides
The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing said intermediates, to intermediates used in said processes, and to the use of said intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure trans-cyclopropane carboxylic acid derivatives, processes for preparing said carboxylic acid derivatives and their use in preparing pharmaceuticals.
The compound [15-(Ia, 2a, 3β (15*,2i?*),5β)]-3-[7-[2-(3,4-difluorophenyl)- cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-(f|pyrimidin-3-yl)-5-(2- hydroxyethoxy)-cyclopentane-l,2-diol (Compound A), and similar such compounds, are disclosed in WO 00/34283 and WO 99/05143. These compounds are disclosed as P2x (which is now usually referred to as P2Yi2) 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 the following advantages: diastereoselecivity, enantioselectivity, high yield, potential for manufacturing (e.g. reagents and procedures suitable for large scale production, non-hazardous reagents,less waste).
According to a first aspect of the present invention there is provided a compound of formula IV
Figure imgf000002_0001
IV
Wherein R is an alkyl group. Suitable values of R include, for example, (l-6C)alkyl such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl. A particular value for R is ethyl.
The compound of formula IV may be prepared from a compound of formula II
Figure imgf000003_0001
According to a further aspect of the present invention there is provided a process for preparing a compound of formula II from a compound of formula I.
Figure imgf000003_0002
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 H.
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.
The compound of formula IV may be prepared by treating a compound of formula III
Figure imgf000004_0001
III with a compound of formula :
Figure imgf000004_0002
Wherein R1 and R2 are independently selected from alkyl such as (Cl-όC)alkyl. A preferred agent 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 800C5 conveniently 40 to 60° e.g. 40° C. The reaction may conveniently be carried out in the presence of a base. Examples of suitable bases include 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 the compound of formula IV via the compound of formula III, without isolation of the compound of formula III.
Figure imgf000005_0001
in
In a particular embodiment of the present invention, the compound of formula II is converted to the 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 0C.
The present invention also provides a process for preparing a compound of formula VII which comprises treating the compound of formula IV with ammonia in the presence of a suitable base. Suitable bases include 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.
Figure imgf000005_0002
VII
The 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° C5 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. The invention will now be further illustrated with reference to the following examples.
Example 1
Preparation of 2-chloro-l-(3,4-difluorophenyl)ethanone Aluminium trichloride (210.2 g) was added to 1,2-difluorobenzene (200.0 g) at room temperature. The obtained slurry was heated to 50 0C5 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 0C. After the addition the reaction mixture was heated to 60 0C and the layers separated. The organic layer was washed twice with a 20 w/v% sodium chloride solution (200.0 niL). 2-Chloro-l- (3,4-difluorophenyl) ethanone (270.2 g) was obtained by vacuum distillation of the organic layer.
Spectral data: 1H-NMR of2-chloro-l-(3,4-difluorophenyl)ethanone in CDCl3, 300 mHz
Figure imgf000006_0001
13 C-NMR o 2-chloro-l- 3,4-di luoro hen l ethanone in CDCl3, 75 MHz
Figure imgf000006_0002
Example 2
Preparation of 2-chloro-l-S-(3,4-difluorophenyl)ethanol 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 dimethylsulfϊde (22.3 g) was added over 15 minutes maintaining the temperature between 35 and 45 0C. This mixture was stirred for 60 minutes at 40 °C, then a solution of 2-chloro-l-(3,4-difiuorophenyl)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 0C, 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 0C. After the addition the mixture was cooled to 20 0C, then stirred at this temperature for 30 minutes. The obtained solution was then distilled, under reduced pressure at maximum 45 °C, till the residual Methanol and trimethoxyborane was less than 2 wt%. The obtained solμtion 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 till less than 0.4 wt% water. After correction with toluene a 33 wt% solution of 2-chloro-l-S-(3,4-difluorophenyl)ethanol was obtained (214.4 g theoretical yield).
The product in solution was characterized by mass spectroscopy
Figure imgf000007_0001
Example 3
Preparation of ethyl (lR,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxylate
Sodium hydride (13.4 g) was suspended in toluene (119.9 mL ) and the resulting slurry heated to 40 0C, 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 0C. When the addition was complete the reaction mixture was stirred for an additional 60 minutes at 40 0C, then 90.9 g of a 33 wt% solution of 2-chloro-l-S-(3,4- difluorophenyl)ethanol in toluene was added over a period of 35 minutes allowing the temperature to raise to maximum 60 0C. Once the addition was complete the obtained mixture was stirred for an additional 14 hours at 60 0C, then water (155.8 mL) was added and the phases separated at 60 °C. The toluene solution containing ethyl (lR,2R)-trans 2- (3,4-difluorophenyl) cyclopropyl carboxylate was used as such in the next step.
The roduct in solution was characterized by mass spectroscopy (EI):
Figure imgf000008_0001
Example 4
Preparation of (lR,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxamide Starting from 2-chloro-l-S-(3,4-difluorophenyl)ethanol (30.9 g), ethyl (lR,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 0C in a closed reactor, then 2 bar NH3-pressure was applied. During a period of 4 hours the temperature was maintained at 60 0C and the pressure at 2 bar, then the reactor was cooled to room temperature and vented. The reaction mixture was heated to 60 0C and water (277.2 mL) dosed over 1 hour, the temperature was maintained at 60 0C. The resulting solution was cooled to room temperature, then filtered and washed with 1/1 metbanol/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 (lR,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxamide (22.8 g) was obtained.
Spectral data:
1HNMR o lR,2R-trans 2-3,4-diluoro hen l c clo ro l carboxamide
Figure imgf000009_0001
13CNMR of (lR,2R)-trans 2-(3,4-difluorophenyl) cyclopropyl carboxamide
Figure imgf000009_0002
Example 5
Preparation of (IR, 2S)2~(3,4-difluorophenyl)-cyclopropane amine
(lR,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 20-25 °C. A 26 wt% solution of aqueous NaOCl (89.5 g) was dosed over a period of 30 minutes maintaining the temperature below 33 0C. Once the addition was finished the reaction mixture was stirred for an additional 3 hours at 30 to 33 0C. The resulting mixture was then heated to 60 0C and stirred at this temperature for an additional 20 minutes. After cooling to 5 0C the pH of the reaction mixture was corrected with HCl 37 wt% (99.1 g) till a pH of 8.5-9.5. iPrOAc (153.3 mL) and MeOH (85.0 niL) 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). And the combined organic phases were diluted till a concentration of 5 wt%. The obtained solution contains (IR, 2S)2-(3,4-difluorophenyl)-cyclopropane amine (18.0 g in 360.4 g solution).
The roduct in solution was characterized by mass spectroscopy (APCI)
Figure imgf000010_0001

Claims

Claims
1. A process for preparing a compound of formula IV
Figure imgf000011_0001
IV wherein R is an alkyl group, which comprises treating a compound of formula III
Figure imgf000011_0002
0 III
with a compound of formula 3
Figure imgf000011_0003
s wherein R1 and R2 are independently selected from alkyl.
2. A process as claimed in claim 1 wherein the compound of formula 3 is triethyl phosphonoacetate. Q 3. A process as claimed in claim 1 or 2 which includes the step of preparing the compound of formula III, which step comprises treating a compound of formula II
Figure imgf000011_0004
II with a base.
4. A process for preparing a compound of formula IV
Figure imgf000012_0001
IV which process comprises
(a) reducing a compound of formula I
Figure imgf000012_0002
to give a compound of formula II
Figure imgf000012_0003
II
(b) treating the compound of formula II with a base to give a compound of formula III
Figure imgf000012_0004
III
(c) treating a compound of formula III with a compound of formula 3
Figure imgf000012_0005
such as triethyl phosphonoacetate.
5. A process for preparing a compound of formula IV
Figure imgf000013_0001
IV comprising a) the compound of formula II
Figure imgf000013_0002
II is converted to the compound of formula IV by treating the compound of formula II with a base such as sodium hydride, b) treating the product of step a) with a compound of formula 3
Figure imgf000013_0003
such as triethyl phosphonoacetate.
6. A process as claimed in any one of the preceeding claims which also includes a step of converting the compound of formula IV to a compound of formula VII
Figure imgf000013_0004
vπ
7. A process as claimed in claim 6 wherein the compound of formula IV is treated with ammonia in the presence of a suitable base.
8. A process as claimed in any one of claims 1-6 wherein R, R1 and R2 are independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.
9. A process for preparing a compound of formula VII
Figure imgf000014_0001
VII comprising treating the compound of formula IV
Figure imgf000014_0002
IV with ammonia in tibe presence of a suitable base.
10. A process as claimed in claim 9 wherein the base is sodium methoxide.
11. A process as claimed in claim 9 wherein the base is potassium methoxide.
12. A compound of formula II, III or VII.
PCT/SE2007/000706 2006-08-05 2007-08-02 Chemical process for preparation of aromatic cyclopropane esters and amides WO2008018822A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP07794102A EP2049462A4 (en) 2006-08-05 2007-08-02 Chemical process for preparation of aromatic cyclopropane esters and amides
JP2009523744A JP2010500343A (en) 2006-08-05 2007-08-02 Chemical production of aromatic cyclopropane esters and amides
AU2007282181A AU2007282181B2 (en) 2006-08-05 2007-08-02 Chemical process for preparation of aromatic cyclopropane esters and amides
CA002658953A CA2658953A1 (en) 2006-08-05 2007-08-02 Chemical process for preparation of aromatic cyclopropane esters and amides
MX2009001020A MX2009001020A (en) 2006-08-05 2007-08-02 Chemical process for preparation of aromatic cyclopropane esters and amides.
BRPI0714573-0A BRPI0714573A2 (en) 2006-08-05 2007-08-02 process for preparing a compound and compound
IL196233A IL196233A0 (en) 2006-08-05 2008-12-28 Chemical process for preparation of aromatic cyclopropane esters and amides

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GB0615619.4 2006-08-05
GBGB0615619.4A GB0615619D0 (en) 2006-08-05 2006-08-05 Chemical process for preparation of intermediates

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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)
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WO2010030224A1 (en) 2008-09-09 2010-03-18 Astrazeneca Ab A process for preparing [1s- [1-alpha, 2-alpha, 3-beta (1s*, 2r*) 5-beta] ] -3- [7- [2- (3, 4-dif luorophenyl) -cyclopropylamino] - 5- (propylthio) -3h-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -5- (2- hydroxyethoxy) cyclopentane-1, 2-diol and to its intermediates
CN102356075A (en) * 2009-01-23 2012-02-15 里格尔药品股份有限公司 Compositions and methods for inhibition of the jak pathway
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EP2589587A1 (en) 2011-11-04 2013-05-08 Chemo Ibérica, S.A. Synthesis of nitrogen substituted cyclopropanes
EP2628721A1 (en) 2012-02-20 2013-08-21 LEK Pharmaceuticals d.d. Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid
EP2644590A1 (en) 2012-03-30 2013-10-02 LEK Pharmaceuticals d.d. Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts
WO2013144295A1 (en) 2012-03-30 2013-10-03 Sandoz Ag Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts
WO2015162630A1 (en) 2014-04-25 2015-10-29 Anlon Chemical Research Organization Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis.
WO2016116942A1 (en) 2015-01-20 2016-07-28 Anlon Chemical Research Organization Novel pharmaceutical compounds comprising ticagrelor with salts of aspirin
CN106854158A (en) * 2016-12-08 2017-06-16 淮阴工学院 The synthetic method and its intermediate of a kind of ticagrelor intermediate
CN106905182A (en) * 2017-01-12 2017-06-30 淮阴工学院 The synthetic method and its intermediate of a kind of ticagrelor intermediate
CN107118141A (en) * 2017-04-18 2017-09-01 淮阴工学院 The synthetic method and its intermediate of a kind of ticagrelor intermediate
EP3617181A1 (en) 2018-08-30 2020-03-04 Arevipharma GmbH Synthesis of trans-2-phenylcyclopropylamine or a salt or solvate thereof
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor

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GB0615619D0 (en) * 2006-08-05 2006-09-13 Astrazeneca Ab Chemical process for preparation of intermediates
GB0615620D0 (en) 2006-08-05 2006-09-13 Astrazeneca Ab A process for the preparation of optically active intermediates
EP2560939A2 (en) 2010-04-20 2013-02-27 Actavis Group Ptc Ehf Novel process for preparing phenylcyclopropylamine derivatives using novel intermediates
WO2012063126A2 (en) 2010-11-09 2012-05-18 Actavis Group Ptc Ehf Improved processes for preparing pure (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahdro-3ah-cyclopenta[d] [1,3]-dioxol-4-ol and its key starting material
MX2013007115A (en) 2010-12-20 2014-02-10 Actavis Group Ptc Ehf Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof.
US20140206867A1 (en) 2011-06-15 2014-07-24 Actavis Group Ptc Ehf Process for Preparing Cyclopentylamine Derivatives and Intermediates Thereof
WO2013150495A2 (en) 2012-04-05 2013-10-10 Dr. Reddy's Laboratories Limited Preparation of ticagrelor
CN103664697B (en) * 2012-09-07 2016-12-21 博瑞生物医药（苏州）股份有限公司 For preparing the chemical method of aromatic ring propionitrile and cyclopropylamine
CN102863341B (en) * 2012-10-22 2014-05-07 南通大学 Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative
CN103087011A (en) * 2013-02-04 2013-05-08 北京科技大学 Method for preparing (S)-3,4-difluorophenyl oxirane through hydrolytic kinetic resolution
WO2014206187A1 (en) 2013-06-24 2014-12-31 苏州明锐医药科技有限公司 Preparation method of ticagrelor and intermediates thereof
CN104974017B (en) * 2014-04-09 2017-11-17 上海医药工业研究院 The preparation method of (1R, 2S) 2 (3,4 difluorophenyl) cyclopropylamine D mandelates
US10011605B2 (en) 2014-06-18 2018-07-03 Flamma Spa Process for the preparation of triazolo[4,5-D] pyrimidine cyclopentane compounds
CN104326922B (en) * 2014-11-03 2016-08-17 成都百裕制药股份有限公司 The preparation method of ticagrelor intermediate (1R, 2S)-2-(2,3-difluorophenyl) cyclopropylamine
TWI579259B (en) * 2014-12-17 2017-04-21 日名國際藥品有限公司 Method of preparing (1r,2s)-2-(3,4-difluorophenyl)-3-r substituted-cyclopropylamine
CN105671099A (en) * 2016-01-26 2016-06-15 中国科学院成都生物研究所 Method for preparing optical pure difluorophenyl ethylene oxide
CN107686447A (en) * 2017-08-25 2018-02-13 许昌恒生制药有限公司 A kind of preparation method of ticagrelor intermediate
CN108083997A (en) * 2017-11-14 2018-05-29 南通常佑药业科技有限公司 A kind of preparation method of chiral aryl cyclopropyl amine derivatives
CN110437092B (en) * 2019-07-11 2022-06-10 泓博智源(开原)药业有限公司 Preparation method of ticagrelor key intermediate aromatic cyclopropane amide
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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092263A1 (en) * 2000-06-02 2001-12-06 Astrazeneca Ab Novel triazolo pyrimidine compounds

Family Cites Families (15)

* Cited by examiner, † Cited by third party
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
DE3546372A1 (en) * 1985-12-31 1987-07-02 Basf Ag NEW PHENYLACETALDEHYDE AND METHOD FOR PRODUCING PHENYLACETALDEHYDE
DE3729226A1 (en) * 1987-09-02 1989-03-23 Basf Ag METHOD FOR PRODUCING PHENYL-SUBSTITUTED EPOXIES
DE3909142A1 (en) 1989-03-21 1990-10-04 Basf Ag METHOD FOR PRODUCING AMINES
DE69432576T2 (en) * 1993-02-15 2004-03-18 Daicel Chemical Industries, Ltd., Sakai Process for the preparation of optically active epoxides
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
TWI290549B (en) * 2000-06-02 2007-12-01 Astrazeneca Ab Process for the preparation of cyclopropyl carboxylic acid ester and derivatives
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
GB0615620D0 (en) * 2006-08-05 2006-09-13 Astrazeneca Ab A process for the preparation of optically active intermediates
GB0615619D0 (en) * 2006-08-05 2006-09-13 Astrazeneca Ab Chemical process for preparation of intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092263A1 (en) * 2000-06-02 2001-12-06 Astrazeneca Ab Novel triazolo pyrimidine compounds

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARMSTRONG A. ET AL.: "Stereocontrolled Synthesis of 3-(trans-2-Aminocyclopropyl)alanine, a Key Component of Belactosin A", ORGANIC LETTERS, vol. 5, no. 13, 2003, pages 2331 - 2334, XP003018631 *
BARBIERI C. ET AL.: "Chemo-enzymatic synthesis of (R)- and (S)-3,4-dichlorophenylbutanolide intermediate in the synthesis of sertraline", TETRAHEDRON: ASYMMETRY, vol. 10, 1999, pages 3931 - 3937, XP003018632 *
See also references of EP2049462A4 *
SINGH A.K. ET AL.: "Development of a Practical, Safe, and High-Yielding Process for the Preparation of Enantiomerically Pure trans-Cyclopropane Carboxylic Acid", ORGANIC PROGRESS RESEARCH & DEVELOPMENT, vol. 6, 2002, pages 618 - 620, XP003018633 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030224A1 (en) 2008-09-09 2010-03-18 Astrazeneca Ab A process for preparing [1s- [1-alpha, 2-alpha, 3-beta (1s*, 2r*) 5-beta] ] -3- [7- [2- (3, 4-dif luorophenyl) -cyclopropylamino] - 5- (propylthio) -3h-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -5- (2- hydroxyethoxy) cyclopentane-1, 2-diol and to its intermediates
CN102356075A (en) * 2009-01-23 2012-02-15 里格尔药品股份有限公司 Compositions and methods for inhibition of the jak pathway
CN103003231A (en) * 2010-06-30 2013-03-27 阿特维斯集团公司 Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor
EP2589587A1 (en) 2011-11-04 2013-05-08 Chemo Ibérica, S.A. Synthesis of nitrogen substituted cyclopropanes
CN104411676A (en) * 2012-02-20 2015-03-11 力奇制药公司 Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid
EP2628721A1 (en) 2012-02-20 2013-08-21 LEK Pharmaceuticals d.d. Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid
WO2013124280A1 (en) 2012-02-20 2013-08-29 Lek Pharmaceuticals D.D. Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid
EP2644590A1 (en) 2012-03-30 2013-10-02 LEK Pharmaceuticals d.d. Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts
WO2013144295A1 (en) 2012-03-30 2013-10-03 Sandoz Ag Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts
CN102775314A (en) * 2012-08-03 2012-11-14 江苏富泽药业有限公司 Preparation method of trans-(1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine
CN103073525A (en) * 2013-02-04 2013-05-01 北京科技大学 Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide
WO2015162630A1 (en) 2014-04-25 2015-10-29 Anlon Chemical Research Organization Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis.
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
WO2016116942A1 (en) 2015-01-20 2016-07-28 Anlon Chemical Research Organization Novel pharmaceutical compounds comprising ticagrelor with salts of aspirin
CN106854158A (en) * 2016-12-08 2017-06-16 淮阴工学院 The synthetic method and its intermediate of a kind of ticagrelor intermediate
CN106854158B (en) * 2016-12-08 2019-06-14 淮阴工学院 A kind of synthetic method and its intermediate of ticagrelor intermediate
CN106905182A (en) * 2017-01-12 2017-06-30 淮阴工学院 The synthetic method and its intermediate of a kind of ticagrelor intermediate
CN107118141A (en) * 2017-04-18 2017-09-01 淮阴工学院 The synthetic method and its intermediate of a kind of ticagrelor intermediate
EP3617181A1 (en) 2018-08-30 2020-03-04 Arevipharma GmbH Synthesis of trans-2-phenylcyclopropylamine or a salt or solvate thereof

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US7863469B2 (en) 2011-01-04
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