CN107417515A - A kind of new method for synthesizing Dapagliflozin intermediate - Google Patents
A kind of new method for synthesizing Dapagliflozin intermediate Download PDFInfo
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- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C07C45/46—Friedel-Crafts reactions
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Abstract
The present invention discloses a kind of new method for synthesizing Dapagliflozin intermediate, comprises the following steps：（1）Using dichloromethane as solvent, using pyridine as catalyst, the chlorobenzoic acid of 5 bromine 2 and thionyl chloride are reacted into obtain the chlorobenzoyl chloride of 5 bromine 2；（2）Using dichloromethane as solvent, using solid acid as catalyst, phenetole and the chlorobenzoyl chloride of 5 bromine 2 react to obtain the oxethyl-diphenyl-ketone of 5 bromine, 2 chlorine 4；（3）Using THF as solvent, the oxethyl-diphenyl-ketone concentrate of 5 bromine, 2 chlorine 4 that step 2 obtains first is added, using acetic acid and alchlor as catalyst, sodium borohydride is added and carries out reduction reaction, reaction is added below 25 DEG C of saturated aqueous common salt after terminating and is quenched, and obtains the ethoxy diphenyl methane of 5 bromine, 2 chlorine 4.The present invention has the advantages that raw material is cheap and easy to get, and operation is simple, three-waste free discharge, and reaction yield is high.
Description
Technical field
The invention belongs to Dapagliflozin synthesis technical field, and in particular to a kind of new side for synthesizing Dapagliflozin intermediate
Method.
Background technology
Dapagliflozin is a kind of white 2 inhibitor of sodium glucose co-transporter 2, is a kind of new antidiabetic medicine,
Be useful in diabetes B adult improves glycemic control as auxiliary diet and motion.
The synthetic method of Dapagliflozin is at present：Pair-gram occurs through chloride, with phenetole for the bromo- 2- chlorobenzoic acids of 5- instead
Should, reducing carbonyl obtain the chloro- 4 '-ethoxy diphenyl methane of the bromo- 2- of 5-, then with 2,3,4,6- tetra--O- trimethyl silicane-D- glucopyras
Ester condensation, anomeric carbon etherification of hydroxyl groups in saccharic acid -1,5-, be deprotected the chloro- 5- of 2- (1- methoxy-D-glucopyranos-I- bases) -
4 '-ethoxy diphenyl methane, then with Et3SiH/BF3·OEt2Antidiabetic drug is made in reduction removing methoxyl group, acetic anhydride esterification, hydrolysis
Dapagliflozin, total recovery about 40%.Therefore the chloro- 4- ethoxy diphenyls methane of the bromo- 2- of 5- is the important centre for synthesizing Dapagliflozin
Body.
However, there is very big problem in the method for the chloro- 4- ethoxy diphenyls methane of the bromo- 2- of published synthesis 5-, for example, specially
Profit number is 201410367178.X, and patent name is the synthetic method of Dapagliflozin intermediate, and the patent of invention discloses one kind
The method for synthesizing the chloro- 4- ethoxy diphenyls methane of the bromo- 2- of 5-, comprises the following steps：Step 1, will using dichloromethane as solvent
The bromo- 2- chlorobenzoic acids of compound 5- and oxalyl chloride are reacted under agitation, depressurize steaming vibrating dichloromethane, obtain compound
The concentrate of the bromo- 2- chlorobenzoyl chlorides of 5-；Step 2 is using dichloromethane as solvent, by the bromo- 2- chlorobenzoyls of the compound 5-
Chlorine and phenetole are reacted in the case where alchlor is catalysts conditions, and reaction temperature is -20~-10 DEG C, and the time of reaction is 2
~4 hours, obtain the chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of compound 5-；Step 3, using THF as solvent, by the compound
The chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of 5- carry out reduction reaction with sodium borohydride and aluminum trichloride (anhydrous), obtain the bromo- 2- of 5-
Chloro- 4- ethoxy diphenyls methane.
Wherein, step 1 uses oxalyl chloride, but oxalyl chloride transport inconvenience, and the big requirement of shelter of the big smell of toxicity is high, and price
It is higher, and without catalyst is used, cause yield not high enough, raw material reacts incomplete always；Step 2 uses aluminium chloride conduct
Catalyst, a large amount of waste water and waste gas, post processing trouble can be produced；Step 3, as catalyst, produces more pair using aluminium chloride
Production, and saturated aqueous common salt is quenched reaction and uses organic solvent, i.e. ethyl acetate, the extraction of dichloromethane equal solvent, makes recovery tetrahydrochysene
Furans bothers, and concentration power consumption is big, and solvent cost is high.
The content of the invention
To solve the problems, such as that prior art is present, the present invention provides a kind of new method of synthesis Dapagliflozin intermediate this hair
It is bright that there is the advantages that raw material is cheap and easy to get, and operation is simple, three-waste free discharge, and reaction yield is high.
To achieve the above object, the technical solution adopted by the present invention is：
A kind of new method for synthesizing Dapagliflozin intermediate, comprises the following steps：
Step 1, using dichloromethane as solvent, using pyridine as catalyst, the bromo- 2- chlorobenzoic acids of 5- and thionyl chloride are existed
Back flow reaction under conditions of heating, is detected to reaction with TLC and finished, and be concentrated under reduced pressure dichloromethane, that is, obtains the bromo- 2- chlorobenzenes first of 5-
Acyl chlorides concentrate；
Step 2, using dichloromethane as solvent, solid acid catalyst is added into reactor, phenetole is added dropwise at room temperature, dripped
2h is stirred after adding end, then the bromo- 2- chlorobenzoyl chlorides concentrates of 5- of dropwise addition step 1 acquisition, under 30 DEG C of temperature conditionss
3-4h is reacted, filters, concentrate after completion of the reaction, produce the chloro- 4- oxethyl-diphenyl-ketones concentrates of the bromo- 2- of 5-；
Step 3, using THF as solvent, first add the chloro- 4- oxethyl-diphenyl-ketones concentrations of the bromo- 2- of 5- that step 2 obtains
Liquid, acetic acid is then added, and alchlor is added portionwise, addition finishes is added portionwise sodium borohydride progress at a temperature of 30 DEG C
Reduction reaction, reaction are added below 25 DEG C of saturated aqueous common salt after terminating and are quenched, and are stirred 30min, split-phase are stood, by tetrahydrofuran phase
Concentration, tetrahydrofuran recycle, and crude product ethanol crystallization, suction filtration dries, and produces the chloro- 4- ethoxy diphenyls first of the bromo- 2- of 5-
Alkane.
Preferably, the preparation method of solid acid is in the step 2：Tetraethyl orthosilicate, deionized water, hydrochloric acid are added
Enter into reactor, the concentrated sulfuric acid is added in above-mentioned pastel, stirring 2h to slowly solid, shape by stirring 30min into pasty state
Into flexible silica gel shape block, 5h is dried under conditions of 100 DEG C, is crushed, that is, solid acid catalyst is made.
Preferably, the mass ratio of the tetraethyl orthosilicate, deionized water, hydrochloric acid and the concentrated sulfuric acid is 5：4：1：4.
Preferably, the concentration of the hydrochloric acid is 0.05mol/L.
Preferably, the temperature of back flow reaction is 40 DEG C in the step 1, reaction time 3.5h.
Preferably, the reaction mol ratio of the bromo- 2- chlorobenzoic acids of 5-, thionyl chloride and pyridine is 1 in the step 1：1~
2：40~50.
Preferably, in the step 2, the molar reactive ratio of the bromo- 2- chlorobenzoyl chlorides of 5- and phenetole is 1:1~1.5.
Preferably, in the step 2, the reaction mol ratio of solid acid catalyst and the bromo- 2- chlorobenzoyl chlorides of 5- is 1:40
~50.
Preferably, in the step 3, the bromo- 2- of 5- chloro- 4- oxethyl-diphenyl-ketones, sodium borohydride, acetic acid and tri-chlorination
The molal quantity ratio of aluminium is 1:1~2：8~10：1~2.
Beneficial effects of the present invention are：
The raw material cheap and simple that uses of step one of the present invention is easy to get, and a small amount of catalyst makes simple to operate, and reaction is clean.
Using there is thionyl chloride to make solvent in current more document, but catalyst is used, cause yield not high enough, raw material is anti-always
Should be incomplete.Also have using oxalyl chloride, but oxalyl chloride transport inconvenience, the big requirement of shelter of the big smell of toxicity is high, and price is higher.
The step two of the present invention uses solid acid catalyst, has post processing simply, no waste water, no waste gas, without useless solid
Advantage, and operation is simple and easy, self-control solid acid catalyst raw material is simple easy, can reuse.
The step three of the present invention has advantages below：(1) acetic acid of catalytic amount makes reaction more clean thorough, reduces secondary
Production, easy crystallization；(2) saturated aqueous common salt is quenched reaction and does not have to reuse organic solvent, i.e. ethyl acetate, dichloromethane equal solvent
Extraction, reaction solution can be easier recovery tetrahydrofuran with saline solution split-phase, decrease the expense of other solvents, concentrate
Energy consumption has been greatly reduced in step.
Embodiment
To be easy to understand the technical means, the inventive features, the objects and the advantages of the present invention, with reference to
Embodiment, the present invention is expanded on further, but the present invention includes but is not limited to the embodiment.
The reaction equation of the present invention is as follows：
Embodiment 1
Step 1: the bromo- 2- chlorobenzoic acids (100g, 0.43mol) of 5- are dissolved in 500ml dichloromethane, 1g pyrroles are added
Pyridine be catalyzed, at room temperature be added dropwise thionyl chloride (60.5g, 0.51mol), be warming up to 40 DEG C flow back 3.5 hours, using TLC detect to
Reaction finishes, and be concentrated under reduced pressure dichloromethane, that is, the bromo- 2- chlorobenzoyl chlorides crude product 104g (yield 97%) of 5- is obtained, without progress
Purifying is directly used as in next step；
Step 2: using 500ml dichloromethane as solvent, by solid acid catalyst 10g (under attached solid acid preparation method) plus
Enter reactor, add phenetole (50g, 0.41mol) at room temperature, 2h is stirred after completion of dropwise addition, be then added dropwise what step 1 obtained
Enter the bromo- 2- chlorobenzoyl chlorides concentrates of 5-, 3-4h is reacted at a temperature of 30 DEG C, filtering and concentrating obtains 5- after reaction finishes
The bromo- chloro- 4- oxethyl-diphenyl-ketones 120.67g (yield 87%) of 2-；
Step 3: using THF as solvent, the chloro- 4- oxethyl-diphenyl-ketones concentrates of the bromo- 2- of 5- are first added, add catalytic amount
Acetic acid (2.5g, 0.042mol) and alchlor (46.8g, 0.355mol) is added portionwise, addition finish 30 DEG C in batches plus
Enter sodium borohydride (16g, 0.426mol), reaction is added below 25 DEG C of saturated aqueous common salt after terminating and is quenched, and is stirred 30min, is stood
Split-phase, tetrahydrofuran is mutually concentrated, tetrahydrofuran recycles, and crude product ethanol crystallization, suction filtration dries, and it is 5- to obtain compound
The bromo- chloro- 4- ethoxy diphenyls methane 97.75g (yield 85%) of 2-.
Embodiment 2
Step 1: the bromo- 2- chlorobenzoic acids (100g, 0.43mol) of 5- are dissolved in 500ml dichloromethane, 1g pyrroles are added
Pyridine be catalyzed, at room temperature be added dropwise thionyl chloride (76.1g, 0.645mol), be warming up to 40 DEG C flow back 3 hours, using TLC detect to
Reaction finishes, and be concentrated under reduced pressure dichloromethane, that is, obtains the bromo- 2- chlorobenzoyl chlorides crude product 102.5g (yield 95%) of 5-, do not have into
Step purifying is directly used as in next step；
Step 2: using 500ml dichloromethane as solvent, by solid acid catalyst 10g (under attached solid acid preparation method) plus
Enter reactor, add phenetole (59.6g, 0.49mol) at room temperature, 2h is stirred after completion of dropwise addition, step 1 is then added dropwise and obtains
Enter the bromo- 2- chlorobenzoyl chlorides concentrates of 5-, react 4h at a temperature of 30 DEG C, filtering and concentrating obtains 5- after reaction finishes
The bromo- chloro- 4- oxethyl-diphenyl-ketones 123.7g (yield 90%) of 2-；
Step 3: using THF as solvent, first add the chloro- 4- oxethyl-diphenyl-ketones of the bromo- 2- of 5- (123.7g,
0.366mol), add the acetic acid (2.5g, 0.042mol) of catalytic amount and alchlor (48.6g, 0.366mol) be added portionwise,
Addition is finished and sodium borohydride (16g, 0.426mol) is added portionwise at 40 DEG C, and reaction is added below 25 DEG C of saturated aqueous common salt after terminating
It is quenched, stirs 30min, stand split-phase, tetrahydrofuran is mutually concentrated, tetrahydrofuran recycles, crude product ethanol crystallization, filters
Dry, it is the chloro- 4- ethoxy diphenyls methane 104.3g (yield 88%) of the bromo- 2- of 5- to obtain compound.
Embodiment 3
Step 1: the bromo- 2- chlorobenzoic acids (100g, 0.43mol) of 5- are dissolved in 500ml dichloromethane, 1g pyrroles are added
Pyridine is catalyzed, and thionyl chloride (101.5g, 0.86mol) is added dropwise at room temperature, is warming up to 40 DEG C and is flowed back 5 hours, is detected using TLC to anti-
It should finish, be concentrated under reduced pressure dichloromethane, that is, obtains the bromo- 2- chlorobenzoyl chlorides crude product 103g (yield 96%) of 5-, pure without progress
Change is directly used as in next step；
Step 2: using 500ml dichloromethane as solvent, by solid acid catalyst 10g (under attached solid acid preparation method) plus
Enter reactor, add phenetole (50g, 0.41mol) at room temperature, 1h is stirred after completion of dropwise addition, be then added dropwise what step 1 obtained
Enter the bromo- 2- chlorobenzoyl chlorides concentrates of 5-, 5h is reacted at a temperature of 35 DEG C, filtering and concentrating obtains 5- bromines after reaction finishes
The chloro- 4- oxethyl-diphenyl-ketones 113.7g (yield 82%) of -2-；
Step 3: using THF as solvent, first add the chloro- 4- oxethyl-diphenyl-ketones of the bromo- 2- of 5- (113.7g,
0.336mol), add the acetic acid (2.5g, 0.042mol) of catalytic amount and alchlor (46.8g, 0.355mol) be added portionwise,
Addition finishes and sodium borohydride (12.6g, 0.336mol) is added portionwise at 35 DEG C, reaction added after terminating 25 DEG C of saturated aqueous common salt with
Under be quenched, stir 30min, stand split-phase, tetrahydrofuran is mutually concentrated, tetrahydrofuran recycle, crude product ethanol crystallization, take out
Filter is dried, and it is the chloro- 4- ethoxy diphenyls methane 97.98g (yield 90%) of the bromo- 2- of 5- to obtain compound.
The preparation method of solid acid in embodiment 1-3 is as follows：
By 100g tetraethyl orthosilicates, 80g deionized waters, 20g 0.05mol/L hydrochloric acid is added in reactor, stirring
The 80g concentrated sulfuric acids are added in above-mentioned pastel, 2h is to slowly solid for stirring, forms flexible silica gel by 30min into pasty state
Shape block, 5h is dried at 100 DEG C, crushes and solid acid catalyst is made.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (9)
1. a kind of new method for synthesizing Dapagliflozin intermediate, it is characterised in that comprise the following steps：
Step 1, using dichloromethane as solvent, using pyridine as catalyst, the bromo- 2- chlorobenzoic acids of 5- and thionyl chloride are being heated
Under conditions of back flow reaction, detected to reaction and finished with TLC, be concentrated under reduced pressure dichloromethane, that is, obtains the bromo- 2- chlorobenzoyl chlorides of 5-
Concentrate；
Step 2, using dichloromethane as solvent, solid acid catalyst is added into reactor, phenetole is added dropwise at room temperature, knot is added dropwise
2h is stirred after beam, the bromo- 2- chlorobenzoyl chlorides concentrates of 5- that step 1 obtains then are added dropwise, react 3- under 30 DEG C of temperature conditionss
4h, filter, concentrate after completion of the reaction, produce the chloro- 4- oxethyl-diphenyl-ketones concentrates of the bromo- 2- of 5-；
Step 3, using THF as solvent, the chloro- 4- oxethyl-diphenyl-ketones concentrates of the bromo- 2- of 5- that step 2 obtains first are added, so
After add acetic acid, and alchlor is added portionwise, addition, which finishes, to be added portionwise sodium borohydride at a temperature of 30 DEG C and reduced
Reaction, reaction are added below 25 DEG C of saturated aqueous common salt after terminating and are quenched, and stir 30min, stand split-phase, and tetrahydrofuran is mutually dense
Contracting, tetrahydrofuran recycle, and crude product ethanol crystallization, suction filtration dries, and produces the chloro- 4- ethoxy diphenyls methane of the bromo- 2- of 5-.
。
A kind of 2. new method for synthesizing Dapagliflozin intermediate according to claim 1, it is characterised in that the step 2
The preparation method of middle solid acid is：Tetraethyl orthosilicate, deionized water, hydrochloric acid are added in reactor, stirring 30min into
Pasty state, the concentrated sulfuric acid is added in above-mentioned pastel, stirring 2h to slowly solid, forms flexible silica gel shape block,
5h is dried under conditions of 100 DEG C, is crushed, that is, solid acid catalyst is made.
A kind of 3. new method for synthesizing Dapagliflozin intermediate according to claim 2, it is characterised in that the positive silicic acid
Tetra-ethyl ester, deionized water, the mass ratio of hydrochloric acid and the concentrated sulfuric acid are 5：4：1：4.
4. a kind of new method for synthesizing Dapagliflozin intermediate according to claim 2, it is characterised in that the hydrochloric acid
Concentration is 0.05mol/L.
A kind of 5. new method for synthesizing Dapagliflozin intermediate according to claim 1, it is characterised in that the step 1
The temperature of middle back flow reaction is 40 DEG C, reaction time 3.5h.
A kind of 6. new method for synthesizing Dapagliflozin intermediate according to claim 1, it is characterised in that the step 1
The reaction mol ratio of the bromo- 2- chlorobenzoic acids of middle 5-, thionyl chloride and pyridine is 1：1~2：40~50.
A kind of 7. new method for synthesizing Dapagliflozin intermediate according to claim 1, it is characterised in that the step 2
In, the molar reactive ratio of the bromo- 2- chlorobenzoyl chlorides of 5- and phenetole is 1:1~1.5.
A kind of 8. new method for synthesizing Dapagliflozin intermediate according to claim 1, it is characterised in that the step 2
In, the reaction mol ratio of solid acid catalyst and the bromo- 2- chlorobenzoyl chlorides of 5- is 1:40~50.
A kind of 9. new method for synthesizing Dapagliflozin intermediate according to claim 1, it is characterised in that the step 3
In, the chloro- 4- oxethyl-diphenyl-ketones of the bromo- 2- of 5-, sodium borohydride, the molal quantity ratio of acetic acid and alchlor are 1:1~2：8~
10：1~2.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111662166A (en) * | 2020-05-28 | 2020-09-15 | 吴赣药业（苏州）有限公司 | Preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
| CN114315534A (en) * | 2021-12-31 | 2022-04-12 | 山东鲁宁药业有限公司 | Preparation method of dapagliflozin intermediate |
| CN114369021A (en) * | 2022-01-28 | 2022-04-19 | 黑龙江立科新材料有限公司 | Preparation method and application of 2-chloro-5-bromobenzoyl chloride |
| CN115073271A (en) * | 2022-06-08 | 2022-09-20 | 苏州敬业医药化工有限公司 | Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol |
| CN115650826A (en) * | 2022-10-25 | 2023-01-31 | 江苏阿尔法药业股份有限公司 | Preparation method of novel dapagliflozin intermediate |
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Cited By (9)
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|---|---|---|---|---|
| CN111662166A (en) * | 2020-05-28 | 2020-09-15 | 吴赣药业（苏州）有限公司 | Preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
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| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
| CN114315534A (en) * | 2021-12-31 | 2022-04-12 | 山东鲁宁药业有限公司 | Preparation method of dapagliflozin intermediate |
| CN114369021A (en) * | 2022-01-28 | 2022-04-19 | 黑龙江立科新材料有限公司 | Preparation method and application of 2-chloro-5-bromobenzoyl chloride |
| CN114369021B (en) * | 2022-01-28 | 2023-12-19 | 黑龙江立科新材料有限公司 | Preparation method and application of 2-chloro-5-bromobenzoyl chloride |
| CN115073271A (en) * | 2022-06-08 | 2022-09-20 | 苏州敬业医药化工有限公司 | Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol |
| CN115650826A (en) * | 2022-10-25 | 2023-01-31 | 江苏阿尔法药业股份有限公司 | Preparation method of novel dapagliflozin intermediate |
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