CN109608431A - A kind of preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- - Google Patents
A kind of preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- Download PDFInfo
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- CN109608431A CN109608431A CN201811514229.1A CN201811514229A CN109608431A CN 109608431 A CN109608431 A CN 109608431A CN 201811514229 A CN201811514229 A CN 201811514229A CN 109608431 A CN109608431 A CN 109608431A
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- sulfanilamide
- thiophene
- chloro
- preparation
- acetyl bromide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
Abstract
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method for preparing the chloro- 2- thiophene sulfanilamide of brinzolamide intermediate 3- acetyl bromide -5-.This method comprises the following steps: using the chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- as raw material, N- bromo-succinimide is brominated reagent, and temperature control is heated to raw material fully reacting, crystallization after concentrated solvent；Centrifugation obtained solid is added to the water mashing, dries to obtain the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- after being centrifuged again.Operation of the present invention is easy, and production Green environmental protection, resulting product yield is higher, is more suitable for large-scale production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, are related to the synthetic technology of medicine intermediate, and in particular to a kind of cloth woods
Help the preparation method of the chloro- 2- thiophene sulfanilamide of amine intermediate 3- acetyl bromide -5-.
Background technique
The chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- is the key intermediate for synthesizing brinzolamide, CAS 160982-11-
6, molecular formula C6H5BrClNO3S2, structural formula is as follows:
。
Brinzolamide is a kind of carbonic anhydrase inhibitor, is researched and developed by Ai Erkang.April in 1998 1 U.S. Huo food and medicine
Management board's approval obtains European Drug Administration approval, obtains Japanese pharmaceutical product medical instrument on October 8th, 2002 on March 9th, 2000
Comprehensive organ's approval listing.Brinzolamide reduces the generation of bicarbonate ion by the carbonic anhydrase of inhibition eye ciliary process, with
It reduces the conveying of sodium and water afterwards to reduce secretion of aqueous humor, eventually reduces intra-atrial pressure at the moment.The medicine is suitable for reducing angle of release
The intraocular pressure of type glaucoma or ocular hypertension.Intraocular pressure after can also be used for prevention and treatment laser surgey increases.It can be used as to β-resistance
Stagnant dose invalid, or has the monotherapy drug using the patient of contraindication, or the synergistic treatment medicine as beta-Blocking agent.
The synthetic method of the chloro- 2- thiophene sulfanilamide of document report 3- acetyl bromide -5-, mostly with bromine, pyridinium tribromide, N-
Bromo-succinimide, C5H6Br2N2O2, hydrobromic acid and hydrogen peroxide, copper bromide etc. are brominated reagent synthesis.But each brominated reagent is anti-
It should have some disadvantages:
(1) although bromine price is lower, there are strong pungent smell and strong corrosive；Transport needs special dangerous material
Transport vehicle, preservation are also required to fluid-tight.And be more toxic, it is unfavorable for safety in production operation, for the health of operating staff
It is unfavorable.
(2) pyridinium tribromide and C5H6Br2N2O2 price are higher, and because reactivity is higher, can generate a certain amount of two
Bromo-derivative influences the purity of finished product；And be respectively necessary for addition strong acid and carry out catalysis reaction, operation needs to divide when strong acid uses
It is outer careful, it is not easy to operate.
(3) bromo-reaction is carried out with the mixed solution of hydrobromic acid and hydrogen peroxide, side reaction is more, leads to products obtained therefrom yield
It is lower.
(4) it is brominated reagent with copper bromide, 50 times of mixed solvent is needed to be reacted；Quantity of solvent is greatly for production environmental protection
It is unfavorable.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of systems of chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-
Preparation Method.This method uses N- bromo-succinimide for brominated reagent and the chloro- 2- thiophene sulfanilamide reaction preparation of 3- acetyl group -5-
The chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, avoiding bromine, hydrobromic acid, pyridinium tribromide and C5H6Br2N2O2 and copper bromide makes
With the risk for production, the pollution to environment is reduced；The preparation method meets environmentally protective production technology, is easy to real
Existing industrialized production.
The present invention is realized by following technical solutions:
A kind of preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, includes the following steps:
Suitable solvent is added in the chloro- 2- thiophene sulfanilamide of 3- acetyl group -5-, adds the suspended of N- bromo-succinimide and solvent
Liquid adds rear temperature control heating and thermal insulation reaction until raw material disappears, and reduced pressure removes crystallization after solvent, obtains crude product after centrifugation；
Crude product is beaten after deionized water is added, and is centrifuged after the crystallization that cools down again, gained wet product dries to obtain the chloro- 2- of 3- acetyl bromide -5-
Thiophene sulfanilamide.
Reaction equation is as follows:
。
In the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the solvent is ethyl acetate, second
One or more of sour methyl esters, propyl acetate, butyl acetate, acetonitrile, methylene chloride, N,N-dimethylformamide.Preferably
Ethyl acetate.
In the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the chloro- 2- thiophene of 3- acetyl group -5-
The weight ratio of pheno sulfanilamide (SN) and ethyl acetate is 1:3-20；It is preferred that 1:4-8.
In the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the chloro- 2- thiophene of 3- acetyl group -5-
The molar ratio of pheno sulfanilamide (SN) and N- bromo-succinimide is 1:1-5.
Preferably, in the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the 3- acetyl group -5-
The molar ratio of chloro- 2- thiophene sulfanilamide and N- bromo-succinimide is 1:1-3.
In the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the reaction of the heating and thermal insulation reaction
Temperature is 40-80 DEG C.
In the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the chloro- 2- thiophene of 3- acetyl group -5-
The weight ratio of pheno sulfanilamide (SN) and deionized water is 1:5-20.
In the preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, the crude product is beaten with deionized water
Temperature is 30-80 DEG C；
The preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, steps are as follows:
The chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- is added in ethyl acetate, N- bromo-succinimide and ethyl acetate are added
Suspension, add the reaction of rear temperature control heating and thermal insulation until raw material disappears, be concentrated under reduced pressure after removing solvent in 0-10 DEG C of crystallization, from
Crude product is obtained after the heart；Crude product is warming up to 40-50 DEG C of mashing after deionized water is added, then is cooled to 0-10 DEG C of centrifugation, gained wet product
Drying obtains the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-.
The preparation method of the above-mentioned chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, detailed step are as follows:
120kg ethyl acetate is squeezed into the 500L reaction kettle of dried and clean, is added with stirring the chloro- 2- of 24kg3- acetyl group -5-
Thiophene sulfanilamide is warming up to 60 ~ 70 DEG C；The suspension solution of dropwise addition 21.3kgN- bromo-succinimide and 85.2kg ethyl acetate, 1
It finishes within ~ 2 hours.Thin layer monitor raw material end of reaction, concentration remove solvent in 0 ~ 10 DEG C crystallization 3 hours, crude product is obtained after centrifugation；
240kg deionized water is added in crude product, is warming up to 40 ~ 50 DEG C and is beaten 1 hour, is cooled to 0 ~ 10 DEG C of centrifugation, gained wet product and dries
To the chloro- 2- thiophene sulfanilamide 28.61kg of off-white color 3- acetyl bromide -5-.
The beneficial effects of the present invention are:
(1) in the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- of the invention, using N- bromo-succinimide as
Brominated reagent, the use for avoiding bromine have reached the condition of environmentally protective production, have alleviated the harm to human body, eliminate fortune
Risk in defeated and production process.
(2) in the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- of the invention, with N- bromo-succinimide
For brominated reagent, reaction condition is mild, easy to operate.
(3) in the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- of the invention, by the way that N- bromo fourth two is added dropwise
Imido ethyl acetate suspension solution, makes the selectivity of product have guarantee, has also been removed document report center pillar chromatographic runs.
Specific embodiment
The present invention will be further explained combined with specific embodiments below, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
Embodiment 1
192kg ethyl acetate is squeezed into the 500L reaction kettle of dried and clean, is added with stirring the chloro- 2- of 24kg3- acetyl group -5-
Thiophene sulfanilamide is warming up to 70 ~ 80 DEG C；The suspension solution of 35.6kgN- bromo-succinimide and 142.4kg ethyl acetate is added dropwise,
It finishes within 1 ~ 2 hour.Thin layer monitors raw material end of reaction, concentration remove solvent in 0 ~ 10 DEG C crystallization 3 hours, obtained after centrifugation thick
Product；150kg deionized water is added in crude product, is warming up to 40 ~ 50 DEG C and is beaten 1 hour, is cooled to 0 ~ 10 DEG C of centrifugation, the drying of gained wet product
Obtain the off-white color 3- acetyl bromide chloro- 2- thiophene sulfanilamide 29.06kg of -5-, molar yield 91.2%, liquid phase purity 95.6%.
Embodiment 2
120kg ethyl acetate is squeezed into the 500L reaction kettle of dried and clean, is added with stirring the chloro- 2- of 24kg3- acetyl group -5-
Thiophene sulfanilamide is warming up to 60 ~ 70 DEG C；The suspension solution of dropwise addition 21.3kgN- bromo-succinimide and 85.2kg ethyl acetate, 1
It finishes within ~ 2 hours.Thin layer monitor raw material end of reaction, concentration remove solvent in 0 ~ 10 DEG C crystallization 3 hours, crude product is obtained after centrifugation；
240kg deionized water is added in crude product, is warming up to 60 ~ 70 DEG C and is beaten 1 hour, is cooled to 0 ~ 10 DEG C of centrifugation, gained wet product and dries
To the off-white color 3- acetyl bromide chloro- 2- thiophene sulfanilamide 28.61kg of -5-, molar yield 89.8%, liquid phase purity 96.8%.
Embodiment 3
120kg acetonitrile is squeezed into the 500L reaction kettle of dried and clean, is added with stirring the chloro- 2- thiophene of 24kg3- acetyl group -5-
Sulfanilamide (SN) is warming up to 70 ~ 80 DEG C；The suspension solution of 21.3kgN- bromo-succinimide and 85.2kg acetonitrile is added dropwise, adds within 1 ~ 2 hour
Finish.Thin layer monitor raw material end of reaction, concentration remove solvent in 0 ~ 10 DEG C crystallization 3 hours, crude product is obtained after centrifugation；Crude product is added
192kg deionized water is warming up to 40 ~ 50 DEG C and is beaten 1 hour, is cooled to 0 ~ 10 DEG C of centrifugation, gained wet product and dries to obtain off-white color
The chloro- 2- thiophene sulfanilamide 28.71kg of 3- acetyl bromide -5-, molar yield 90.1%, liquid phase purity 96.3%.
Claims (10)
1. a kind of preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-, includes the following steps:
Suitable solvent is added in the chloro- 2- thiophene sulfanilamide of 3- acetyl group -5-, adds the suspended of N- bromo-succinimide and solvent
Liquid adds rear temperature control heating and thermal insulation reaction until raw material disappears, and reduced pressure removes crystallization after solvent, obtains crude product after centrifugation；
Crude product is beaten after deionized water is added, and is centrifuged after the crystallization that cools down again, gained wet product dries to obtain the chloro- 2- of 3- acetyl bromide -5-
Thiophene sulfanilamide.
2. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 1, which is characterized in that described
Solvent be ethyl acetate, methyl acetate, propyl acetate, butyl acetate, acetonitrile, methylene chloride, in N,N-dimethylformamide
One or more.
3. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 2, which is characterized in that described
Solvent be ethyl acetate.
4. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 3, which is characterized in that described
The chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- and ethyl acetate weight ratio be 1:3-20.
5. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 1, which is characterized in that described
The chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- and N- bromo-succinimide molar ratio be 1:1-5.
6. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 5, which is characterized in that described
The chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- and N- bromo-succinimide molar ratio be 1:1-3.
7. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 1, which is characterized in that described
Heating and thermal insulation reaction reaction temperature be 40-80 DEG C.
8. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 1, which is characterized in that described
The chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- and deionized water weight ratio be 1:5-20.
9. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 1, which is characterized in that described
Crude product with deionized water be beaten temperature be 30-80 DEG C.
10. the preparation method of the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5- according to claim 1, which is characterized in that step
It is rapid as follows:
The chloro- 2- thiophene sulfanilamide of 3- acetyl group -5- is added in ethyl acetate, N- bromo-succinimide and ethyl acetate are added
Suspension, add the reaction of rear temperature control heating and thermal insulation until raw material disappears, be concentrated under reduced pressure after removing solvent in 0-10 DEG C of crystallization, from
Crude product is obtained after the heart；Crude product is warming up to 40-50 DEG C of mashing after deionized water is added, then is cooled to 0-10 DEG C of centrifugation, gained wet product
Drying obtains the chloro- 2- thiophene sulfanilamide of 3- acetyl bromide -5-.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0617038A1 (en) * | 1993-02-18 | 1994-09-28 | Alcon Laboratories, Inc. | Preparation of carbonic anhydrase inhibitors |
| WO2008062463A2 (en) * | 2006-10-13 | 2008-05-29 | Usv Limited | Improved process for the preparation of (r)-(+)-4-(ethyiamino)-3,4-dihydro-2-(3- methoxypropyl)-2h-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-l,l-dioxide |
| WO2010103550A2 (en) * | 2009-03-13 | 2010-09-16 | Indoco Remedies Limited | Process for the preparation of intermediates |
| CN106632001A (en) * | 2016-12-28 | 2017-05-10 | 山东诚汇双达药业有限公司 | Preparation method of 4-(bromoacetyl) pyridine hydrobromide |
-
2018
- 2018-12-11 CN CN201811514229.1A patent/CN109608431A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0617038A1 (en) * | 1993-02-18 | 1994-09-28 | Alcon Laboratories, Inc. | Preparation of carbonic anhydrase inhibitors |
| WO2008062463A2 (en) * | 2006-10-13 | 2008-05-29 | Usv Limited | Improved process for the preparation of (r)-(+)-4-(ethyiamino)-3,4-dihydro-2-(3- methoxypropyl)-2h-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-l,l-dioxide |
| WO2010103550A2 (en) * | 2009-03-13 | 2010-09-16 | Indoco Remedies Limited | Process for the preparation of intermediates |
| CN106632001A (en) * | 2016-12-28 | 2017-05-10 | 山东诚汇双达药业有限公司 | Preparation method of 4-(bromoacetyl) pyridine hydrobromide |
Non-Patent Citations (3)
| Title |
|---|
| N. CHIDANANDA等: "Hantzsch and Schiff’s reaction: synthesis, in vitro cytotoxic and antimicrobial activity of [1,3,4]oxadiazoline and [1,3]thiazole derivatives", 《MED CHEM RES》 * |
| RAYMOND E. CONROW等: "Enantioselective Synthesis of Brinzolamide (AL-4862), a New Topical Carbonic Anhydrase Inhibitor. The "DCAT Route" to Thiophenesulfonamides", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 贾海浪: "布林佐胺重要中间体及其类似物的合成", 《中国优秀硕士学位论文数据库 工程科技I辑》 * |
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Application publication date: 20190412 |