CN109293627A - A kind of recovery method of Ketotifen intermediate mother liquor - Google Patents

A kind of recovery method of Ketotifen intermediate mother liquor Download PDF

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Publication number
CN109293627A
CN109293627A CN201811411088.0A CN201811411088A CN109293627A CN 109293627 A CN109293627 A CN 109293627A CN 201811411088 A CN201811411088 A CN 201811411088A CN 109293627 A CN109293627 A CN 109293627A
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China
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thiophene
benzo
methoxyl group
recovery method
mother liquor
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CN109293627B (en
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张露
黄健升
徐云超
何琦
涂国良
梁尊俊
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Southern China Chemical Co Ltd
Zhejiang Huahai Pharmaceutical Co Ltd
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Southern China Chemical Co Ltd
Zhejiang Huahai Pharmaceutical Co Ltd
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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
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C07D333/80—Seven-membered rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Abstract

The present invention provides one kind -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor recovery method, this method includes that will contain 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor dissolves in organic solvent, heating, reducing agent is added into reaction solution to be reacted, heat filtering after reaction is concentrated to dryness and recrystallisation solvent crystallization is added, the 10- methoxyl group -4H- benzo [4 of high-purity can be obtained, 5] cycloheptatriene [1,2-b] thiophene -4- ketone.This method has been able to achieve the effectively recycling to 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor, and reaction process is easily controllable, without complicated special equipment；In addition each impurity in mother liquor is converted through reduction reaction, can be isolated and purified by simple method for crystallising.

Description

A kind of recovery method of Ketotifen intermediate mother liquor
Technical field
The present invention relates to one kind-the 4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquors Recovery method belongs to chemical pharmacy field.
Technical background
Ketotifen Fumarate is a kind of potent oral Anaphylactic mediator sustained-release agent, has histamine H1-receptor antagonism and inhibition Allergic reaction medium release action, not only anti-allergic effects are stronger, and duration of efficacy is longer, therefore to the various bronchuses of prevention The curative effect of asthma attack and extrinsic asthma compares intrinsic asthma more preferably.
10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone is the pass for synthesizing Ketotifen Fumarate Key intermediate, structure are shown in formula I:
Document Helvetica Chimica Acta, 1976,59 (3), P866-877 disclose the Ketotifen intermediate Synthetic method: potassium hydroxide is added after reacting dissolved clarification, finally obtains product 10- for the methanol solution by heating dibromide Methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone, yield 80%, 164-166 DEG C of product fusing point, but do not have There is the purity of open product.
Chinese patent CN108417532B discloses dibromide and mixes with anhydrous methanol, after being stirred at reflux 2-6h, to reaction Solid K is added in liquid2O/MgO base catalyst continues back flow reaction 2-6h, filters after reaction, is cooled to 0 DEG C of stirring analysis Crystalline substance, filtering, filter cake spent glycol monomethyl ether recrystallization obtain 10- methoxyl group -4H- benzo [4,5] cycloheptyl three of content >=97% Alkene [1,2-b] thiophene -4- ketone, yield 59.59%.
Document Collect Czech Chem Commun, 1989,54,2443-2469 disclose according to document Helvetica Chimica Acta, 1976,59 (3), the synthetic method of P866-877 obtain 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone, in addition to target product in mother liquor, while generate there are also a large amount of impurity As, impurity B, impurity C, impurity The impurity of D, generation are non-reusable, and the impurity generated cannot recycle compound I by purification process in mother liquor, cause Atom utilization is lowly generated with a large amount of three wastes.But the prior art is disclosed the recovery method of the mother liquor not yet, therefore develops The recovery method of one kind -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone is of great significance.
Summary of the invention
The object of the present invention is to provide one kind-the 4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- The recovery method of ketone mother liquor.
The present inventor surprisingly has found after study, can recycle the 10- methoxyl group -4H- of high-purity by the following method Benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone:
The recovery method of one kind -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor, tool Body step are as follows: will be containing 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor in organic solvent Dissolution, heating are added reducing agent into reaction solution and are reacted, and heat filtering, is concentrated to dryness addition recrystallisation solvent after reaction 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone of high-purity can be obtained in crystallization.
It is further preferred that the organic solvent is selected from methyl tertiary butyl ether(MTBE), ethylene glycol monoethyl ether, ethyl acetate, four Hydrogen furans, dioxane, toluene, methanol, ethyl alcohol；More preferably methyl tertiary butyl ether(MTBE) and ethylene glycol monoethyl ether；
It is further preferred that the reaction temperature is 30-100 DEG C；
It is further preferred that the recrystallisation solvent is selected from glycol monoethyl ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE), 1, 4- dioxane.
It is further preferred that the reducing agent is palladium carbon/hydrogen, palladium carbon/hydrazine hydrate, iron powder/organic acid, zinc powder/have Machine acid, magnesium powder/organic acid, nickel acetate/sodium hydride, further preferred palladium carbon/hydrogen, zinc powder/organic acid.
It is further preferred that the organic acid be formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, it is more excellent Select acetic acid.
It is further preferred that-the 4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1, the 2-b] thiophene -4- ketone mother liquor It is 125:1~10:1, more preferably 30:1~15:1 with palladium carbon mass ratio.
It is further preferred that the Hydrogen Vapor Pressure is 0.1~1.0Mpa, more preferable 0.4~0.6Mpa.
It is further preferred that the concentration of hydrazine hydrate is 40%~80% ,-the 4H- of methoxyl group containing 10- benzo [4,5] ring Heptantriene [1,2-b] thiophene -4- ketone mother liquor and hydrazine hydrate mass ratio are 2:1~1:1.
It is further preferred that-the 4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1, the 2-b] thiophene -4- ketone mother liquor It is 4:1:0.8~1:1 with iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid, nickel acetate/sodium hydride mass ratio: 0.8。
Iron powder/the organic acid, zinc powder/organic acid, magnesium powder/organic acid, nickel acetate/sodium hydride can divide 2~10 inferior Amount investment, dosing intervals were at 0.5~6 hour.
Technical solution of the present invention has the advantages that:
1. technical solution of the present invention will be by that will contain 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene - Impurity D in 4- ketone mother liquor is converted to 10- methoxyl group -4H- benzo [4,5] cycloheptyl three through reduction reaction in the effect of reducing agent Alkene [1,2-b] thiophene -4- ketone.It realizes to 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor Effectively recycling, significantly improve the benefit of 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone With rate, production cost is reduced, and reaction process is easily controllable, without complicated special equipment, meets industrialized production.
2. the impurity A in mother liquor, impurity B are difficult through simple purification process and 10- methoxyl group -4H- benzo originally [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone separates.But the present inventor has found impurity A, impurity B in the course of the research Impurity C can be converted to through reduction reaction in the effect of reducing agent, and impurity C and 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone can be separated by simple crystallization mode, so that obtaining the very high 10- methoxyl group -4H- benzo of purity [4,5] cycloheptatriene
[1,2-b] thiophene -4- ketone is possibly realized, the purification process and easy to operate, high income.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is furture elucidated, is merely to illustrate the present invention rather than limits this hair Bright range.
Measure the HPLC analysis method of purity and external standard content:
Chromatographic column: Shim-pack VP-ODS 150*4.6mm, 5 μm or comparable chromatographic column
Mobile phase: methanol/water=70/30 (%V/V)
Flow velocity: 1.5mL/min column temperature: 25 DEG C of runing times: 25 minutes；Detection wavelength: 230nm.
Embodiment 1:
According to document Helvetica Chimica Acta, 1976,59 (3), P866-877, the preparation method preparation 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone, specific as follows:
120.0g dibromide (compound II) and 1200mL methanol are added in reaction flask, is warming up to reflux, reaction 7 is small When, 44.0g potassium hydroxide is then added, continues back flow reaction 7 hours, is cooled to 0 DEG C, stirs 3 hours, filtering, and use 500mL Washing, obtains 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone 53.6g, yield 68.6%.Filtrate Concentration is precipitated solid, filtering, and is eluted with 100mL water, and drying obtains the -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene The solid mother liquor 25.8g of [1,2-b] thiophene -4- ketone.The solid mother liquor quality are as follows: compound I 58.2%, impurity A 5.5%, Impurity B 10.5%, impurity C 8.6%, impurity D 13.4%.
Embodiment 2:
By the resulting -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone solid mother liquor of example 1 25g is dissolved in 150mL THF, adds suitable reducing agent, temperature reaction, contact plate follows reaction process, to the end of reacting Afterwards, then heat filtering is concentrated to dryness, glycol monoethyl ether recrystallization is added, after filtering, obtains compound I.
The resulting yield of different reducing agents and purity are shown in Table one:
Table one:
Serial number Reducing agent Reducing agent dosage Reaction temperature Reaction time Yield Yieldb Purity
1 Pd/Ca,H2 1.2g, 0.5Mpa 55℃ 25h 11.3g 45.2% 97.1%
2 Pd/C, hydrazine hydrate 3.7g, 25.0g 55℃ 18h 10.1g 40.4% 96.6%
3 Nickel acetate/sodium hydride 8.5g, 6.8g 45℃ 8h 8.2g 32.8% 95.7%
4 Zinc powder/acetic acid 20.0g 16.0g 65℃ 6h 9.5g 38.0% 97.2%
5 Iron powder/acetic acid 20.0g 16.0g 75℃ 16h 8.0g 32.0% 92.0%
Remarks: Pd/CaMiddle Pd content is 7%, water capacity 60~70%.
Yield b=yield/mother liquor gross mass * 100%
Embodiment 3:
By the resulting -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone solid mother liquor of example 1 25g is dissolved in the solvent of 150ml, and 1.2g Pd/C is added, is passed through 0.5Mpa hydrogen, is warming up to 55 DEG C, contact plate is and then reacted Glycol monoethyl ether recrystallization, filtering, dryingization is added to after reaction, then heat filtering is concentrated to dryness in process Close object I.
The yield and purity that different reaction dissolvents obtains are shown in Table two:
Table two:
Serial number Reaction dissolvent Reaction time Yield Yield Purity
1 Ethyl acetate 6.5h 9.5g 38.0% 93.3%
2 Glycol monoethyl ether 6h 12.6g 50.4% 97.6%
3 THF 9h 11.3g 45.2% 97.1%
4 Methanol 8h 6.5g 26.0% 89.3%
5 Toluene 7.5h 8.0g 32.0% 82.0%
One kind-the 4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor proposed by the present invention Recovery method be described by embodiment, related technical personnel obviously can not depart from the content of present invention, spirit and Recycling in range to the -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor as described herein Method is modified or appropriate changes and combinations, to realize the technology of the present invention.In particular, it should be pointed out that all similar replaces Change and change apparent to those skilled in the art, they are considered as including in spirit of the invention, range In content.

Claims (10)

  1. The recovery method of one kind 1. the -4H- of methoxyl group containing 10- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor, specifically Step are as follows: will be molten in organic solvent containing 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor Solution, heating are added reducing agent into reaction solution and are reacted, after reaction heat filtering, be concentrated to dryness and recrystallisation solvent knot is added 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone of high-purity can be obtained in crystalline substance.
  2. 2. recovery method according to claim 1, which is characterized in that the organic solvent be selected from methyl tertiary butyl ether(MTBE), Ethylene glycol monoethyl ether, ethyl acetate, tetrahydrofuran, dioxane, toluene, methanol, ethyl alcohol；More preferably methyl tertiary butyl ether(MTBE) and Ethylene glycol monoethyl ether.
  3. 3. recovery method according to claim 1, which is characterized in that the reaction temperature is 30 DEG C~100 DEG C.
  4. 4. recovery method according to claim 1, which is characterized in that the recrystallisation solvent be selected from glycol monoethyl ether, Tetrahydrofuran, methyl tertiary butyl ether(MTBE), 1,4- dioxane.
  5. 5. recovery method according to claim 1, which is characterized in that the reducing agent is palladium carbon/hydrogen, palladium carbon/water Close hydrazine, iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid, nickel acetate/sodium hydride, further preferred palladium carbon/hydrogen, zinc Powder/organic acid.
  6. 6. recovery method according to claim 5, which is characterized in that the organic acid is formic acid, acetic acid, trifluoro second Acid, methanesulfonic acid, p-methyl benzenesulfonic acid, preferably acetic acid.
  7. 7. recovery method according to claim 5, which is characterized in that-the 4H- of methoxyl group containing 10- benzo [4, the 5] cycloheptyl Triolefin [1,2-b] thiophene -4- ketone mother liquor and palladium carbon mass ratio are 125:1~10:1, more preferably 30:1~15:1.
  8. 8. recovery method according to claim 5, which is characterized in that the Hydrogen Vapor Pressure is 0.1~1.0Mpa, more preferably 0.4~0.6Mpa.
  9. 9. recovery method according to claim 5, which is characterized in that the concentration of hydrazine hydrate is 40%~80%, is contained 10- methoxyl group -4H- benzo [4,5] cycloheptatriene [1,2-b] thiophene -4- ketone mother liquor and hydrazine hydrate mass ratio are 2:1~1:1.
  10. 10. recovery method according to claim 5, which is characterized in that-the 4H- of methoxyl group containing 10- benzo [4, the 5] ring Heptantriene [1,2-b] thiophene -4- ketone mother liquor and iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid, nickel acetate/sodium hydride Mass ratio be 4:1:0.8~1:1:0.8.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2625642A1 (en) * 1975-06-18 1977-01-13 Sandoz Ag NEW BENZOCYCLOHEPTATHIOPHEN DERIVATIVES, THEIR PRODUCTION AND USE AS A MEDICINE
CN104817532A (en) * 2015-03-04 2015-08-05 浙江工业大学 10-methoxy-4H-benzo[4,5]cycloheptatriene[1,2-b]thiazol-4-one preparation method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2625642A1 (en) * 1975-06-18 1977-01-13 Sandoz Ag NEW BENZOCYCLOHEPTATHIOPHEN DERIVATIVES, THEIR PRODUCTION AND USE AS A MEDICINE
CN104817532A (en) * 2015-03-04 2015-08-05 浙江工业大学 10-methoxy-4H-benzo[4,5]cycloheptatriene[1,2-b]thiazol-4-one preparation method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOLLINGER, PIETRO等: "(Benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)acetic acids: novel non-ulcerogenic antiinflammatory agents", 《HELVETICA CHIMICA ACTA》 *
WALDVOGEL, ERWIN等: "Studies on synthetic drugs. The 9- and 10-oxo derivatives of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophenes", 《HELVETICA CHIMICA ACTA》 *

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