CN107880011B - The synthetic method of Lu Makatuo key intermediate - Google Patents
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Abstract
The present invention relates to the synthetic methods of Lu Makatuo key intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid.With 2,2- difluoro piperonyl cyclonene is starting material, 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid is made including Friedel-Crafts reaction, grignard reaction, dehydration, catalytic hydrogenation, substitution reaction, cyclization reaction, hydrolysis.Method of the invention is without harsh reaction condition, and simple to operation, agents useful for same is easy to get, and avoids using hypertoxic material Cymag, improves reaction yield, is suitble to industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to Lu Makatuo intermediate 1- (2,2- difluoro benzos [D] [1,3]
Dioxole -5- base) cyclopropane-carboxylic acid synthetic method.
Background technique
Cystic fibrosis (CF) is a kind of genetic disease for seriously threatening life, is adjusted by CF transmembrane conductance
(CFTR) gene mutation causes.Lu Makatuo (lumacaftor) is cftr gene corrector, and CFTR albumen can be helped to reach
Cell surface.By Lu Makatuo and the compound medicine formed according to Kato (ivacaftor) is cut down, in July, 2015 by U.S.'s food
It is listed with Drug Administration (FDA) approval in the U.S., trade name Orkambi.The medicine is by Vertex drugmaker, the U.S.
Research and development are first drugs ratified for treating cystic fibrosis in the world.Lu Makatuo chemical structural formula is as follows:
It is related to key intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxy in the synthesis technology of Lu Makatuo bulk pharmaceutical chemicals
Heterocyclic pentene -5- base) cyclopropane-carboxylic acid synthesis.Patent WO2009/73757, WO2014/14841 and patent
CN101356170 discloses a kind of conjunction of 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid
At method, it is as follows to chemically react route:
For this method with 5- fluoro- 1, the 3- benzo dioxazole of bromo- 2,2- bis- for starting material, closing palladium in four (triphenylphosphines) is to urge
Under conditions of agent and carbon monoxide, methanol reaction generate 2,2- difluoro methyl piperate；2,2- difluoro methyl piperate is through hydrogen
Change the reduction of aluminium lithium and generates (2,2- difluoro benzo [D] [1,3] dioxole -5- base) methanol；The latter reacts with thionyl chloride
Generate chloromethyl compound；The chloromethyl compound occurs displacement with Cymag and reacts, and generates (2,2- difluoro benzos [D] [1,3]
Dioxole -5- base) acetonitrile；Cyclization reaction occurs under alkaline condition for the latter and the bromo- 2- chloroethanes of 1-, generate 1- (2,
2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropanecarbonitrile；1- (2,2- difluoro benzo [D] [1,3] dioxane
Amylene -5- base) cyclopropanecarbonitrile hydrolyzed in sodium hydrate aqueous solution generate 1- (2,2- difluoro benzo [D] [1,3] dioxane penta
Alkene -5- base) cyclopropane-carboxylic acid.
The synthetic method has the disadvantage that (1) reaction raw materials price height, is unfavorable for controlling cost；(2) four (three are used
Phenylphosphine) conjunction palladium be catalyst, dosage is larger, expensive, it is difficult to recycle；(3) it needs to use toxic articles Cymag and inflammable
Explosive material lithium aluminium hydride reduction does not meet the development trend of current medical chemistry safety and environmental protection, it is difficult to industrialized production.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of Lu Makatuo intermediate 1- (2,2- difluoro benzos [D]
[1,3] dioxole -5- base) cyclopropane-carboxylic acid synthetic method.
Term explanation:
Type I compound: 2,2- difluoro piperonyl cyclonenes have structure shown in formula I；
II compound of formula: ethyl oxalyl chloride or Methyl oxatyl chloride have structure shown in formula II；
III compound of formula: 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- glyoxylic acid ethyl ester or 2-
(2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- glyoxalic acid methylester has structure shown in formula III；
Grignard Reagent shown in formula IV: (2- (benzyloxy) ethyl) magnesium bromide；
V compound of formula~formula, Ⅸ compound: there is structure shown in V~formula of formula Ⅸ.
Technical scheme is as follows:
A kind of Lu Makatuo intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid
Synthetic method, with 2,2- difluoro piperonyl cyclonene be starting material, comprising steps of
(1) under the conditions of Aluminium Trichloride as Catalyst, in solvent, 2,2- difluoro pepper cycle compound and formula shown in formula I
Friedel-Crafts reaction, III compound represented of production occur for II compound represented；
(2) in solvent, (2- (benzyloxy) ethyl) magnesium bromide of Grignard Reagent shown in III compound of formula and formula IV occurs to add
At reaction, V compound of production；
(3) V compound of formula is using p-methyl benzenesulfonic acid as catalyst, and dehydration production occurs for reflux in toluene solvant
Compound shown in VI；
(4) in solvent, in the presence of palladium carbon catalyst, compound shown in formula VI and hydrogen carry out catalytic hydrogenation,
Carbon-carbon double bond is reduced, while taking off benzyl, compound shown in production VII；
(5) in solvent, under phosphorus trichloride or phosphorus tribromide effect substitution reaction, hydroxyl occur for compound shown in formula VII
Replaced by chlorine or bromine, compound shown in production VIII；
(6) in solvent, in the presence of a base, compound shown in formula VIII occur cyclization reaction, compound shown in production Ⅸ；
(7) compound shown in formula Ⅸ hydrolyzes in sodium hydrate aqueous solution, generates Lu Makatuo intermediate 1- (2,2- difluoros
Benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid；
R represents methyl or ethyl in the above structural formula；X represents chlorine or bromine.
Preferred according to the present invention, in step (1), the solvent is methylene chloride or carbon tetrachloride；Reaction temperature is 0-
10℃；Mole dosage formula II is 1.1 times of amounts of formula I, and alchlor is 1.1 times of amounts of formula I；
Preferred according to the present invention, in step (2), the solvent is tetrahydrofuran or ether, reaction temperature 10-30
℃；
Preferred according to the present invention, in step (2), the Grignard Reagent (2- (benzyloxy) ethyl) magnesium bromide is by 2- benzyl
Oxygroup bromoethane and magnesium chips are prepared in tetrahydrofuran solvent；Mole dosage magnesium chips is 1.2 times of 2- benzyloxy bromoethane
Amount, formula IV are 1.0 times of amounts of formula III；
Preferred according to the present invention, in step (3), reaction temperature is 90-110 DEG C；Mole dosage catalyst is to toluene sulphur
Acid is 0.05 times of amount of formula V；
Preferred according to the present invention, in step (4), the solvent is methanol or ethyl alcohol；Reaction temperature is 40-60 DEG C；Hydrogen
Atmospheric pressure is 0.5-0.6mPa；10% palladium charcoal of quality dosage catalyst is the 5% of formula VI；
Preferred according to the present invention, in step (5), the solvent is methylene chloride, and reaction temperature is 10-20 DEG C；Mole
Dosage phosphorus trichloride or phosphorus tribromide are 1.1 times of amounts of formula VII；
Preferred according to the present invention, in step (6), the solvent is n,N-Dimethylformamide or N- crassitude
Ketone；The alkali is potassium carbonate；Reaction temperature is 100-120 DEG C；Mole dosage potassium carbonate is 1.2 times of amounts of formula VIII；
Preferred according to the present invention, in step (7), the solvent is methanol or ethyl alcohol；Reaction temperature is 10-30 DEG C；It rubs
Your dosage sodium hydroxide is 1.5 times of amounts of formula Ⅸ.
It needs to separate post-processing with the product of last step, presses the prior art.Preferred post-processing approach is shown in reality
Apply example.
Lu Makatuo intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane first of the present invention
The synthetic method of acid, starting material 2,2- difluoro piperonyl cyclonene (formula I) is under conditions of alchlor is catalyst, with oxalyl chloride list
Friedel-Crafts reaction occurs for ethyl ester or Methyl oxatyl chloride (formula II), generates 2- (2,2- difluoro benzo [D] [1,3] dioxole-
5- yl) -2- glyoxylic acid ethyl ester or 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- glyoxalic acid methylester (formula
Ⅲ)；Addition reaction, production occur for (2- (benzyloxy) ethyl) magnesium bromide of Grignard Reagent shown in compound shown in formula III and formula IV
Compound shown in V；Compound shown in formula V occurs dehydration in reflux in toluene and generates using p-methyl benzenesulfonic acid as catalyst
Compound shown in formula VI；For compound shown in formula VI using palladium charcoal as catalyst, hydrogen is generation catalytic hydrogenation under conditions of hydrogen source
Reaction, carbon-carbon double bond is reduced, while taking off benzyl, compound shown in production VII；Compound shown in formula VII is in phosphorus trichloride
Or the lower generation substitution reaction of phosphorus tribromide effect, hydroxyl are replaced by chlorine or bromine, compound shown in production VIII；Chemical combination shown in formula VIII
Cyclization reaction, compound shown in production Ⅸ occur under conditions of potassium carbonate does alkali for object；Compound shown in formula Ⅸ is in hydroxide
It is hydrolyzed in sodium water solution, generates Lu Makatuo intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) ring
Propane formic acid；The compound is the key intermediate for preparing Lu Makatuo, can be used for preparing Lu Makatuo.
Synthesis road involved in the above-mentioned preparation method of the present invention is as follows:
Wherein R represents methyl or ethyl；X represents chlorine or bromine.
Beneficial effects of the present invention:
The raw materials used in the present invention is cheap and easy to get, at low cost；Reaction condition is simple to operation；Reaction selectivity is high, by-product
Few, stable reaction is controllable, products obtained therefrom purity is high, high income, and purity can reach 98.5% or more, total recovery be up to 57.2% with
On；Present invention reaction, which avoids, uses hypertoxic material Cymag and inflammable explosive article lithium aluminium hydride reduction, environmentally protective, is conducive to industry
Metaplasia produces.
Specific embodiment
The present invention will be further explained with reference to the examples below, but not limited to this.Yield is all in all embodiments
Molar yield.
Embodiment 1:2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- glyoxylic acid ethyl ester (formula III, R
=ethyl) preparation
Addition methylene chloride 300ml in tri- mouthfuls of reaction flasks of 1L, 2,2- 47.4 grams of difluoro piperonyl cyclonenes, 44 grams of anhydrous aluminum chloride,
It is cooled to 0-10 DEG C after system is stirred, 45 grams of ethyl oxalyl chlorides and 200ml dichloro is slowly added dropwise
The mixed liquor of methane drips off for about 1 hour.Continue extremely to detect raw material fully reacting in stirring 1-2 hours after dripping off.Reaction system is fallen
Enter and is quenched in 250ml ice water.Liquid separation, organic phase are washed with 200ml, and 200ml saturated sodium bicarbonate aqueous solution is washed；It is eventually adding nothing
Aqueous sodium persulfate is dry.Organic phase solvent evaporated methylene chloride, obtains 74.8 grams of light yellow oil, yield 96.6%, liquid-phase pure
Degree 95%.
Embodiment 2:(2- (benzyloxy) ethyl) magnesium bromide (formula IV) preparation
Anhydrous tetrahydro furan 300ml is added in tri- mouthfuls of reaction flasks of 1L, 12 grams and 3 iodine of magnesium chips are warming up to 60-65 DEG C, drop
Add 96.8 grams of 2- benzyloxy bromoethane and the mixed liquor of tetrahydrofuran 200ml, controls rate of addition, the initiation of attentive response.Entirely
Portion drip off after then at 60-65 DEG C keep the temperature 20 minutes, obtain black transparent solution, it is standby to be cooled to room temperature under nitrogen protection later
With.The concentration for being titrated the Grignard Reagent is 0.85mol/L.
Embodiment 3:4- (benzyloxy) -2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- hydroxyl fourth
The preparation of acetoacetic ester (formula V, R=ethyl)
1L tri- is added in 51.6 grams of 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- glyoxylic acid ethyl esters
In mouth flask, tetrahydrofuran 400ml is added, controls 10-30 DEG C of temperature and (2- (benzyloxy) ethyl) prepared by embodiment 2 is added dropwise
The tetrahydrofuran solution 250ml of magnesium bromide.Continue stirring 1 hour after dripping, liquid phase detects raw material 2- (2,2- difluoro benzos
[D] [1,3] dioxole -5- base) -2- glyoxylic acid ethyl ester is less than 2%.Reaction system is poured into the salt of 200ml 1mol/L
It is quenched in acid.Liquid separation, water phase are extracted with 500ml ethyl acetate, merge organic phase, and organic phase is washed with 300ml saturated common salt, had
Machine is mutually concentrated under reduced pressure dry, obtains 85 grams of light brown grease, yield 109%, liquid phase purity 92%.
Embodiment 4:4- (benzyloxy) -2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- butenoic acid
The preparation of ethyl ester (formula VI, R=ethyl)
By 80 grams of 4- (benzyloxy) -2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- hydroxybutyric acid
Ethyl ester is added in 1L three-necked flask, and 400ml toluene is added, and 4 grams of p-methyl benzenesulfonic acids are warming up to and flow back and gradually separate reaction life
At water.Reaction time about 8-10 hours, liquid phase detected raw material less than 1%.Reaction system is cooled to 20 DEG C hereinafter, pouring into
In 200ml saturated sodium bicarbonate aqueous solution, it is sufficiently stirred.Liquid separation, the dry toluene of organic phase decompression contracting, obtains light brown grease
81.5g, yield 102%, liquid phase purity 89%.
Embodiment 5:2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -4 hydroxybutyric acid ethyl ester (formula
VII, R=ethyl) preparation
By 80g4- (benzyloxy) -2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -2- butenoic acid second
Ester is added to 1L autoclave, and 600ml dehydrated alcohol, 5 gram of 10% palladium charcoal is added.Sealing autoclave is replaced 3 times with nitrogen,
Drive remaining air in autoclave away.Leading to hydrogen to pressure later is 0.5-0.6mPa, is warming up to the reaction of 40-60 degree.Reaction needs
12-16 hours.Cooling down later, reaction system is extruded with nitrogen, filtered under nitrogen palladium charcoal, filtrate, which is directly depressurized to contract, does,
Obtain 56.6 grams of light brown grease.Yield 92.3%, liquid phase purity 93%.
Embodiment 6:2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -4- bromobutyrate (formula VIII, R
=ethyl, X=bromine) preparation
56 grams of 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -4 hydroxybutyric acid ethyl esters are added to
In 500ml there-necked flask, 350ml methylene chloride is added, cools to 10-20 DEG C, is added dropwise 57.7 grams of phosphorus tribromide.Continue to stir after adding
1-2 hours are mixed to fully reacting.System is poured into 200ml ice water, with saturated aqueous sodium carbonate tune aqueous pH values to 8.Point
Liquid, the organic phase dry dry solvent of retraction of anhydrous sodium sulfate, obtains 59.4 grams of brown oil.Yield 86.9%, liquid phase purity
93%.
Embodiment 7:1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) ethylene-acetic acid ethyl ester (formula Ⅸ,
R=ethyl) preparation
57 grams of 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) -4- bromobutyrates, are added to
In 500ml three-necked flask, 200mlN, dinethylformamide is added, 22.5 grams of potassium carbonate are gradually heated to 100-120 DEG C instead
It answers 8-10 hours.System is cooled to room temperature, is poured into 500ml water, is extracted with ethyl acetate 2 times, each 250ml；It is associated with
Machine phase is washed 2 times, each 200ml, then is washed once with 200ml saturated common salt.After organic phase anhydrous sodium sulfate drying directly
It is evaporated, obtains 35.9 grams of brown oil.Yield 82%, liquid phase purity 91%.
The preparation of embodiment 8:1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid
300ml water is added in 500ml three-necked flask, and 8.9 grams of sodium hydroxide stirring and dissolvings are added.Cool to 30 DEG C with
Under, it is slowly added to 30 grams of 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) ethylene-acetic acid ethyl ester and 50ml
Then the solution of methanol reacts 2 hours at 10-30 DEG C.System is extracted 2 times with toluene, each 150ml；Then water phase reagent
Salt acid for adjusting pH is to 4-5, then is cooled to 0-10 DEG C of stirring 1h；Solid filters, and filter cake is washed on a small quantity, dries to obtain off-white powder
21.8 grams.Yield 81.1%, purity 98.5%.
ESI-MS 241.6(M-1)；1H-NMR(300MHz,DMSO)δ12.60(s,1H),7.36(d,1H),7.22(d,
1H),7.13(dd,1H),1.46(m,2H),1.14(m,2H).
Claims (9)
1. a kind of Lu Makatuo intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid
Synthetic method, with 2,2- difluoro piperonyl cyclonene for starting material, comprising steps of
(1) under the conditions of Aluminium Trichloride as Catalyst, in solvent, 2,2- difluoro pepper cycle compound shown in formula I and II institute of formula
Friedel-Crafts reaction, III compound represented of production occur for the compound shown；
(2) in solvent, it is anti-that addition occurs for (2- (benzyloxy) ethyl) magnesium bromide of Grignard Reagent shown in III compound of formula and formula IV
It answers, V compound of production；
(3) V compound of formula is using p-methyl benzenesulfonic acid as catalyst, and VI institute of dehydration production occurs for reflux in toluene solvant
Show compound；
(4) in solvent, in the presence of palladium carbon catalyst, compound shown in formula VI and hydrogen carry out catalytic hydrogenation, carbon carbon
Double bond is reduced, while taking off benzyl, compound shown in production VII；
(5) in solvent, under phosphorus trichloride or phosphorus tribromide effect substitution reaction occurs for compound shown in formula VII, and hydroxyl is by chlorine
Or bromine replaces, compound shown in production VIII；
(6) in solvent, in the presence of a base, compound shown in formula VIII occur cyclization reaction, compound shown in production Ⅸ；
(7) compound shown in formula Ⅸ hydrolyzes in sodium hydrate aqueous solution, generates Lu Makatuo intermediate 1- (2,2- difluoro benzos
[D] [1,3] dioxole -5- base) cyclopropane-carboxylic acid；
R represents methyl or ethyl in the above structural formula；X represents chlorine or bromine.
2. synthetic method as described in claim 1, which is characterized in that in step (1), including any of the following conditions or more
:
A1) solvent is methylene chloride or carbon tetrachloride；
A2) reaction temperature is 0-10 DEG C；
A3) mole dosage formula II is 1.1 times of amounts of formula I, and alchlor is 1.1 times of amounts of formula I.
3. synthetic method as described in claim 1, which is characterized in that in step (2), including any of the following conditions or more
:
B1) solvent is tetrahydrofuran or ether；
B2) reaction temperature is 10-30 DEG C.
4. synthetic method as described in claim 1, which is characterized in that in step (2), including any of the following conditions or more
:
C1 Grignard Reagent (2- (benzyloxy) ethyl) magnesium bromide described in) is molten in tetrahydrofuran by 2- benzyloxy bromoethane and magnesium chips
It is prepared in agent；
C2) mole dosage magnesium chips is 1.2 times of amounts of 2- benzyloxy bromoethane；
C3) mole dosage formula IV is 1.0 times of amounts of formula III.
5. synthetic method as described in claim 1, which is characterized in that in step (3), including any of the following conditions or more
:
D1) reaction temperature is 90-110 DEG C；
D2) mole dosage catalyst p-methyl benzenesulfonic acid is 0.05 times of amount of formula V.
6. synthetic method as described in claim 1, which is characterized in that in step (4), including any of the following conditions or more
:
E1) solvent is methanol or ethyl alcohol；
E2) reaction temperature is 40-60 DEG C；
E3) Hydrogen Vapor Pressure is 0.5-0.6mPa；
E4) 10% palladium charcoal of quality dosage catalyst is the 5% of formula VI.
7. synthetic method as described in claim 1, which is characterized in that in step (5), including any of the following conditions or more
:
F1) solvent is methylene chloride；
F2) reaction temperature is 10-20 DEG C；
F3) mole dosage phosphorus trichloride or phosphorus tribromide are 1.1 times of amounts of formula VII.
8. synthetic method as described in claim 1, which is characterized in that in step (6), including any of the following conditions or more
:
G1) solvent is N,N-dimethylformamide or N-Methyl pyrrolidone；
G2) alkali is potassium carbonate；
G3) reaction temperature is 100-120 DEG C；
G4) mole dosage potassium carbonate is 1.2 times of amounts of formula VIII.
9. synthetic method as described in claim 1, which is characterized in that in step (7), including any of the following conditions or more
:
H1) solvent is methanol or ethyl alcohol；
H2) reaction temperature is 10-30 DEG C；
H3) mole dosage sodium hydroxide is 1.5 times of amounts of formula Ⅸ.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102892764A (en) * | 2010-03-25 | 2013-01-23 | 弗特克斯药品有限公司 | Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide |
| CN105130949A (en) * | 2015-09-02 | 2015-12-09 | 阜新奥瑞凯新材料有限公司 | Preparation method for 1-(2,2-difluoro-benzo[D][1,3]dioxol-5-yl)-cyclopropanecarbonitrile |
| CN105153105A (en) * | 2015-08-15 | 2015-12-16 | 浙江永宁药业股份有限公司 | Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate |
| CN106432209A (en) * | 2015-08-11 | 2017-02-22 | 苏州晶云药物科技有限公司 | New crystal form of lumacaftor, and preparation method thereof |
| CN106749156A (en) * | 2016-12-02 | 2017-05-31 | 浙江永宁药业股份有限公司 | The preparation method of benzo [1,3 d] dioxole and its intermediate |
| CN107892693A (en) * | 2017-11-14 | 2018-04-10 | 安徽诺全药业有限公司 | A kind of preparation method of ticagrelor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622595A (en) * | 2014-11-21 | 2016-06-01 | 重庆朗天制药有限公司 | Novel preparation method of azilsartan medoxomil sylvite and its intermediate |
-
2017
- 2017-11-27 CN CN201711201390.9A patent/CN107880011B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102892764A (en) * | 2010-03-25 | 2013-01-23 | 弗特克斯药品有限公司 | Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide |
| CN106432209A (en) * | 2015-08-11 | 2017-02-22 | 苏州晶云药物科技有限公司 | New crystal form of lumacaftor, and preparation method thereof |
| CN105153105A (en) * | 2015-08-15 | 2015-12-16 | 浙江永宁药业股份有限公司 | Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate |
| CN105130949A (en) * | 2015-09-02 | 2015-12-09 | 阜新奥瑞凯新材料有限公司 | Preparation method for 1-(2,2-difluoro-benzo[D][1,3]dioxol-5-yl)-cyclopropanecarbonitrile |
| CN106749156A (en) * | 2016-12-02 | 2017-05-31 | 浙江永宁药业股份有限公司 | The preparation method of benzo [1,3 d] dioxole and its intermediate |
| CN107892693A (en) * | 2017-11-14 | 2018-04-10 | 安徽诺全药业有限公司 | A kind of preparation method of ticagrelor |
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