CN107880011A - The synthetic method of Shandong agate Kato key intermediate - Google Patents
The synthetic method of Shandong agate Kato key intermediate Download PDFInfo
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- CN107880011A CN107880011A CN201711201390.9A CN201711201390A CN107880011A CN 107880011 A CN107880011 A CN 107880011A CN 201711201390 A CN201711201390 A CN 201711201390A CN 107880011 A CN107880011 A CN 107880011A
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- 0 *OC(C(CCOCc1ccccc1)(c(cc1O2)ccc1OC2(F)F)O)=O Chemical compound *OC(C(CCOCc1ccccc1)(c(cc1O2)ccc1OC2(F)F)O)=O 0.000 description 4
- FWOHDAGPWDEWIB-UHFFFAOYSA-N BrCCOCc1ccccc1 Chemical compound BrCCOCc1ccccc1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 description 1
- BWAHMRJCENGCBD-UHFFFAOYSA-N CCOC(C(CCO)C(C1)C=CC(O2)=C1OC2(F)F)=O Chemical compound CCOC(C(CCO)C(C1)C=CC(O2)=C1OC2(F)F)=O BWAHMRJCENGCBD-UHFFFAOYSA-N 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N CCOC(C(Cl)=O)=O Chemical compound CCOC(C(Cl)=O)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- BKKDDQPNQCBVBU-UHFFFAOYSA-N COC(CCOCc1ccccc1)(C([O]1CC1)=O)c1ccc2OC(N)(N)Oc2c1 Chemical compound COC(CCOCc1ccccc1)(C([O]1CC1)=O)c1ccc2OC(N)(N)Oc2c1 BKKDDQPNQCBVBU-UHFFFAOYSA-N 0.000 description 1
- DGCOGZQDAXUUBY-UHFFFAOYSA-N FC1(Oc2ccccc2O1)F Chemical compound FC1(Oc2ccccc2O1)F DGCOGZQDAXUUBY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
The present invention relates to the synthetic method of Shandong agate Kato key intermediate 1 (base of 2,2 difluoro benzo [D] [1,3] dioxole 5) cyclopropane-carboxylic acid.With 2,2 difluoro piperonyl cyclonenes are initiation material, 1 (base of 2,2 difluoro benzo [D] [1,3] dioxole 5) cyclopropane-carboxylic acid is made including Friedel-Crafts reaction, grignard reaction, dehydration, catalytic hydrogenation, substitution reaction, ring-closure reaction, hydrolysis.Reaction condition of the method for the present invention without harshness, simple to operation, agents useful for same is easy to get, and avoids using hypertoxic material Cymag, improves reaction yield, is adapted to industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to Shandong agate Kato intermediate 1- (2,2- difluoro benzos [D] [1,3]
Dioxole -5- bases) cyclopropane-carboxylic acid synthetic method.
Background technology
Cystic fibrosis (CF) is a kind of genetic disease of serious threat life, is adjusted by CF transmembrane conductance
(CFTR) gene mutation causes.Shandong agate Kato (lumacaftor) is cftr gene corrector, and CFTR albumen can be helped to reach
Cell surface.By Shandong agate Kato and the compound medicine formed according to Kato (ivacaftor) is cut down, in July, 2015 by U.S.'s food
With Drug Administration (FDA) approval in U.S.'s listing, trade name Orkambi.The medicine is by Vertex drugmakers of the U.S.
Research and development, it is first medicine ratified for treating cystic fibrosis in the world.Shandong agate Kato chemical structural formula is as follows：
It is related to key intermediate 1- (2,2- difluoros benzo [D] [1,3] dioxies in the synthesis technique of Shandong agate Kato bulk drug
Heterocyclic pentene -5- bases) cyclopropane-carboxylic acid synthesis.Patent WO2009/73757, WO2014/14841 and patent
CN101356170 discloses a kind of conjunction of 1- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid
It is as follows into method, chemical reaction route：
This method, for initiation material, closes palladium to urge with fluoro- 1, the 3- benzos dioxazoles of bromo- 2, the 2- bis- of 5- in four (triphenylphosphines)
Under conditions of agent, and carbon monoxide, methanol reaction generation 2,2- difluoro methyl piperates；2,2- difluoro methyl piperates are through hydrogen
Change aluminium lithium reduction generation (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) methanol；The latter reacts with thionyl chloride
Generate chloromethyl compound；With Cymag displacement reaction occurs for the chloromethyl compound, generates (2,2- difluoro benzos [D] [1,3]
Dioxole -5- bases) acetonitrile；Ring-closure reaction occurs in the basic conditions for the latter and the bromo- 2- chloroethanes of 1-, generation 1- (2,
2- difluoros benzo [D] [1,3] dioxole -5- bases) cyclopropanecarbonitrile；1- (2,2- difluoros benzo [D] [1,3] dioxanes
Amylene -5- bases) cyclopropanecarbonitrile hydrolyzed in sodium hydrate aqueous solution generation 1- (2,2- difluoros benzo [D] [1,3] dioxanes
Amylene -5- bases) cyclopropane-carboxylic acid.
The synthetic method has the following disadvantages：(1) reaction raw materials price is high, is unfavorable for control cost；(2) four (three are used
Phenylphosphine) conjunction palladium is catalyst, dosage is larger, expensive, it is difficult to reclaims；(3) toxic articles Cymag and inflammable is needed to use
Explosive material lithium aluminium hydride reduction, the development trend of current medical chemistry safety and environmental protection is not met, it is difficult to industrialized production.
The content of the invention
In view of the shortcomings of the prior art, the invention provides a kind of Shandong agate Kato intermediate 1- (2,2- difluoro benzos [D]
[1,3] dioxole -5- bases) cyclopropane-carboxylic acid synthetic method.
Term explanation：
Type I compound：2,2- difluoro piperonyl cyclonenes, there is the structure shown in formula I；
The compound of formula II：Ethyl oxalyl chloride or Methyl oxatyl chloride, there is the structure shown in formula II；
The compound of formula III：2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- glyoxylic acid ethyl esters or 2-
(2,2- difluoro benzo [D] [1,3] dioxole -5- bases) -2- glyoxalic acid methylesters, there is the structure shown in formula III；
RMgBr shown in formula IV：(2- (benzyloxy) ethyl) magnesium bromide；
The compound of V compound of formula~formula Ⅸ：With the structure shown in V~formula of formula Ⅸ.
Technical scheme is as follows：
A kind of Shandong agate Kato intermediate 1- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid
Synthetic method, with 2,2- difluoros piperonyl cyclonene for initiation material, including step：
(1) under the conditions of Aluminium Trichloride as Catalyst, in solvent, 2,2- difluoros piperonyl cyclonene (formula I) and ethyl oxalyl chloride are made
Or Friedel-Crafts reaction, generation 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- occur for Methyl oxatyl chloride (formula II)
Base) -2- glyoxylic acid ethyl esters or 2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- glyoxalic acid methylester (formulas
Ⅲ)；
(2) in solvent, RMgBr shown in the compound of formula III and formula IV (2- (benzyloxy) ethyl) magnesium bromide occurs to add
Into reaction, the compound of production V；
(3) compound of formula V is using p-methyl benzenesulfonic acid as catalyst, the backflow generation dehydration production in toluene solvant
Compound shown in VI；
(4) in solvent, in the presence of palladium carbon catalyst, compound shown in formula VI carries out catalytic hydrogenation with hydrogen,
Carbon-carbon double bond is reduced, while takes 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
Substituted by chlorine or bromine, compound shown in production VIII；
(6) in solvent, in the presence of a base, compound shown in formula VIII occur ring-closure reaction, compound shown in production Ⅸ；
(7) compound shown in formula Ⅸ hydrolyzes in sodium hydrate aqueous solution, generates Shandong agate Kato intermediate 1- (2,2- difluoros
Benzo [D] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid；
R represents methyl or ethyl in above structural formula；X represents chlorine or bromine.
According to currently preferred, in step (1), the solvent is dichloromethane 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；
According to currently preferred, in step (2), the solvent is tetrahydrofuran or ether, reaction temperature 10-30
℃；
According to currently preferred, in step (2), described RMgBr (2- (benzyloxy) ethyl) magnesium bromide is by 2- benzyls
Epoxide bromoethane and magnesium chips are prepared in tetrahydrofuran solvent；Mole dosage magnesium chips is 1.2 times of 2- benzyloxy bromoethanes
Amount, formula IV are 1.0 times of amounts of formula III；
According to currently preferred, 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；
According to currently preferred, in step (4), the solvent is methanol or ethanol；Reaction temperature is 40-60 DEG C；Hydrogen
Atmospheric pressure is 0.5-0.6mPa；The palladium charcoal of quality dosage catalyst 10% is the 5% of formula VI；
According to currently preferred, in step (5), the solvent is dichloromethane, and reaction temperature is 10-20 DEG C；Mole
Dosage phosphorus trichloride or 1.1 times of amounts that phosphorus tribromide is formula VII；
According to currently preferred, in step (6), the solvent is DMF or N- crassitudes
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；
According to currently preferred, in step (7), the solvent is methanol or ethanol；Reaction temperature is 10-30 DEG C；Rub
Your dosage sodium hydroxide is 1.5 times of amounts of formula Ⅸ.
Need to separate post processing with the product of last step, by prior art.Preferable post-processing approach is shown in reality
Apply example.
Shandong agate Kato intermediate 1- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) cyclopropane first of the present invention
The synthetic method of acid, initiation material 2,2- difluoros piperonyl cyclonene (formula I) is under conditions of alchlor is catalyst, with oxalyl chloride list
Ethyl ester or Methyl oxatyl chloride (formula II) generation Friedel-Crafts reaction, generation 2- (2,2- difluoro benzo [D] [1,3] dioxole-
5- yls) -2- glyoxylic acid ethyl esters or 2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- glyoxalic acid methylester (formulas
Ⅲ)；Addition reaction, production occur for RMgBr shown in compound shown in formula III and formula IV (2- (benzyloxy) ethyl) magnesium bromide
Compound shown in V；Using p-methyl benzenesulfonic acid as catalyst, in reflux in toluene dehydration generation occurs for compound shown in formula V
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 takes off benzyl, compound shown in production VII；Compound is in phosphorus trichloride shown in formula VII
Or the lower generation substitution reaction of phosphorus tribromide effect, hydroxyl are substituted by chlorine or bromine, compound shown in production VIII；Chemical combination shown in formula VIII
Ring-closure reaction, compound shown in production Ⅸ occur under conditions of potassium carbonate does alkali for thing；Compound is in hydroxide shown in formula Ⅸ
Hydrolyzed in sodium water solution, generate Shandong agate Kato intermediate 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- bases) ring
Propane formic acid；The compound is to prepare the key intermediate of Shandong agate Kato, available for preparation Shandong agate Kato.
Involved synthesis road is as follows in the above-mentioned preparation method of the present invention：
Wherein R represents methyl or ethyl；X represents chlorine or bromine.
Beneficial effects of the present invention：
The present invention is raw materials used cheap and easy to get, and cost is low；Reaction condition is simple to operation；Reaction selectivity is high, accessory substance
Few, stable reaction is controllable, and products obtained therefrom purity is high, high income, and purity can reach more than 98.5%, 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, green, is advantageous to industry
Metaplasia is produced.
Embodiment
With reference to embodiment, the present invention is described further, 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- bases) -2- glyoxylic acid ethyl esters (formula III, R
=ethyl) preparation
Addition dichloromethane 300ml in tri- mouthfuls of reaction bulbs of 1L, 2,2- 47.4 grams of difluoro piperonyl cyclonenes, 44 grams of anhydrous Aluminum chloride,
0-10 DEG C is cooled to after system is stirred, 45 grams of ethyl oxalyl chlorides and 200ml dichloros is slowly added dropwise
The mixed liquor of methane, drip off within about 1 hour.Continue to stir 1-2 hours after dripping off to the reaction of detection raw material completely.Reaction system is fallen
Enter and be quenched in 250ml frozen water.Liquid separation, organic phase are washed with 200ml, and 200ml saturated sodium bicarbonate aqueous solutions are washed；It is eventually adding nothing
Aqueous sodium persulfate is dried.Organic phase solvent evaporated dichloromethane, obtain 74.8 grams of light yellow oil, yield 96.6%, liquid-phase pure
Degree 95%.
Embodiment 2：The preparation of (2- (benzyloxy) ethyl) magnesium bromide (formula IV)
Anhydrous tetrahydro furan 300ml is added in tri- mouthfuls of reaction bulbs of 1L, 12 grams and 3 iodine of magnesium chips, is warming up to 60-65 DEG C, drop
Add 96.8 grams of 2- benzyloxies bromoethane and tetrahydrofuran 200ml mixed liquor, control rate of addition, the initiation of attentive response.Entirely
Portion drip off after then at 60-65 DEG C be incubated 20 minutes, obtain black transparent solution, it is standby to be cooled to room temperature under nitrogen protection afterwards
With.Concentration through titrating the RMgBr is 0.85mol/L.
Embodiment 3：4- (benzyloxy) -2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- hydroxyl fourths
The preparation of acetoacetic ester (formula V, R=ethyls)
51.6 grams of 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- bases) -2- glyoxylic acid ethyl esters, add 1L tri-
In mouth flask, tetrahydrofuran 400ml is added, (2- (benzyloxy) ethyl) prepared by embodiment 2 is added dropwise in 10-30 DEG C of control temperature
The tetrahydrofuran solution 250ml of magnesium bromide.Continue stirring 1 hour, liquid phase detection raw material 2- (2,2- difluoro benzos after dripping
[D] [1,3] dioxole -5- bases) -2- glyoxylic acid ethyl esters be less than 2%.Reaction system is poured into 200ml 1mol/L salt
It is quenched in acid.Liquid separation, aqueous phase are extracted with 500ml ethyl acetate, merge organic phase, and organic phase is washed with 300ml saturated common salts, 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- difluoros benzo [D] [1,3] dioxole -5- bases) -2- butenoic acids
The preparation of ethyl ester (formula VI, R=ethyls)
By 80 grams of 4- (benzyloxy) -2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- hydroxybutyric acids
Ethyl ester is added in 1L three-necked flasks, is added 400ml toluene, 4 grams of p-methyl benzenesulfonic acids, is warming up to and flows back and gradually separate reaction
The water of generation.About 8-10 hours in reaction time, liquid phase detection raw material are less than 1%.Reaction system is cooled to less than 20 DEG C, poured into
In 200ml saturated sodium bicarbonate aqueous solutions, 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- difluoros benzo [D] [1,3] dioxole -5- bases) -4 hydroxybutyric acid ethyl ester (formula
VII, R=ethyl) preparation
By 80g4- (benzyloxy) -2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- butenoic acid second
Ester is added to 1L autoclaves, adds 600ml absolute ethyl alcohols, 5 gram of 10% palladium charcoal.Sealing autoclave, with nitrogen displacement 3 times,
Drive the air of residual in autoclave away.It is 0.5-0.6mPa to lead to hydrogen to pressure afterwards, is warming up to the reaction of 40-60 degree.Reaction needs
12-16 hours.Cooling afterwards, 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- bases) -4- bromobutyrates (formula VIII, R
=ethyl, X=bromines) preparation
56 grams of 2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -4 hydroxybutyric acid ethyl esters are added to
In 500ml there-necked flasks, 350ml dichloromethane is added, cools to 10-20 DEG C, 57.7 grams of phosphorus tribromide is added dropwise.Continue to stir after adding
It is complete to reaction to mix 1-2 hours.System is poured into 200ml frozen water, aqueous pH values are adjusted to 8 with saturated aqueous sodium carbonate.Point
Liquid, the organic phase dry solvent of anhydrous sodium sulfate drying retraction, 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- bases) ethylene-acetic acid ethyl ester (formula Ⅸ,
R=ethyls) preparation
57 grams of 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- bases) -4- bromobutyrates, are added to
In 500ml three-necked flasks, 200mlN is added, dinethylformamide, 22.5 grams of potassium carbonate, is gradually heating to 100-120 DEG C instead
Answer 8-10 hours.System is cooled to room temperature, poured into 500ml water, is extracted with ethyl acetate 2 times, each 250ml；It is associated with
Machine phase, wash 2 times, each 200ml, then with the washing of 200ml saturated common salts once.After organic phase anhydrous sodium sulfate drying directly
It is evaporated, obtains 35.9 grams of brown oil.Yield 82%, liquid phase purity 91%.
Embodiment 8：The preparation of 1- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid
300ml water is added in 500ml three-necked flasks, adds 8.9 grams of sodium hydroxide stirring and dissolvings.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- bases) ethylene-acetic acid ethyl esters and 50ml
The solution of methanol, then reacted 2 hours at 10-30 DEG C.System is extracted 2 times with toluene, each 150ml；Then aqueous phase reagent
Salt acid for adjusting pH is to 4-5, then is cooled to 0-10 DEG C of stirring 1h；Solid is filtered, 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 Shandong agate Kato intermediate 1- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid
Synthetic method, with 2,2- difluoros piperonyl cyclonene for initiation material, including step：
(1) under the conditions of Aluminium Trichloride as Catalyst, in solvent, 2,2- difluoros piperonyl cyclonene (formula I) and ethyl oxalyl chloride or grass are made
Friedel-Crafts reaction occurs for monomethyl ester chloride (formula II), generates 2- (2,2- difluoro benzo [D] [1,3] dioxole -5- bases) -2-
Glyoxylic acid ethyl ester or 2- (2,2- difluoros benzo [D] [1,3] dioxole -5- bases) -2- glyoxalic acid methylesters (formula III)；
(2) in solvent, it is anti-that addition occurs for RMgBr shown in the compound of formula III and formula IV (2- (benzyloxy) ethyl) magnesium bromide
Should, the compound of production V；
(3) compound of formula V is using p-methyl benzenesulfonic acid as catalyst, the institute of backflow generation dehydration production VI in toluene solvant
Show compound；
(4) in solvent, in the presence of palladium carbon catalyst, compound shown in formula VI carries out catalytic hydrogenation, carbon carbon with hydrogen
Double bond is reduced, while takes 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 substitution, compound shown in production VIII；
(6) in solvent, in the presence of a base, compound shown in formula VIII occur ring-closure reaction, compound shown in production Ⅸ；
(7) compound shown in formula Ⅸ hydrolyzes in sodium hydrate aqueous solution, generates Shandong agate Kato intermediate 1- (2,2- difluoro benzos
[D] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid；
R represents methyl or ethyl in above structural formula；X represents chlorine or bromine.
2. synthetic method as claimed in claim 1, it is characterised in that in step (1), including any one of following condition or more
：
A1) solvent is dichloromethane 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 claimed in claim 1, it is characterised in that in step (2), including any one of following condition or more
：
B1) solvent is tetrahydrofuran or ether；
B2) reaction temperature is 10-30 DEG C.
4. synthetic method as claimed in claim 1, it is characterised in that in step (2), including any one of following condition or more
：
C1 RMgBr (2- (benzyloxy) ethyl) magnesium bromide described in) is molten in tetrahydrofuran by 2- benzyloxies bromoethane and magnesium chips
It is prepared in agent；
C2) mole dosage magnesium chips is 1.2 times of amounts of 2- benzyloxy bromoethanes；
C3) mole dosage formula IV is 1.0 times of amounts of formula III.
5. synthetic method as claimed in claim 1, it is characterised in that in step (3), including any one of following condition 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 claimed in claim 1, it is characterised in that in step (4), including any one of following condition or more
：
E1) solvent is methanol or ethanol；
E2) reaction temperature is 40-60 DEG C；
E3) Hydrogen Vapor Pressure is 0.5-0.6mPa；
E4) the palladium charcoal of quality dosage catalyst 10% is the 5% of formula VI.
7. synthetic method as claimed in claim 1, it is characterised in that in step (5), including any one of following condition or more
：
F1) solvent is dichloromethane；
F2) reaction temperature is 10-20 DEG C；
F3) mole dosage phosphorus trichloride or 1.1 times of amounts that phosphorus tribromide is formula VII.
8. synthetic method as claimed in claim 1, it is characterised in that in step (6), including any one of following condition or more
：
G1) solvent is N,N-dimethylformamide or 1-METHYLPYRROLIDONE；
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 claimed in claim 1, it is characterised in that in step (7), including any one of following condition or more
：
H1) solvent is methanol or ethanol；
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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| CN109456177A (en) * | 2018-11-26 | 2019-03-12 | 深圳市第二人民医院 | The synthetic method of the bromo- 2- chlorobenzoyl chloride of Dapagliflozin intermediate 5- |
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| 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 |
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| 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 |
| 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 |
| 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 |
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| 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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| CN109456177A (en) * | 2018-11-26 | 2019-03-12 | 深圳市第二人民医院 | The synthetic method of the bromo- 2- chlorobenzoyl chloride of Dapagliflozin intermediate 5- |
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