CN109293627B - Recovery method of ketotifen intermediate mother liquor - Google Patents

Recovery method of ketotifen intermediate mother liquor Download PDF

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CN109293627B
CN109293627B CN201811411088.0A CN201811411088A CN109293627B CN 109293627 B CN109293627 B CN 109293627B CN 201811411088 A CN201811411088 A CN 201811411088A CN 109293627 B CN109293627 B CN 109293627B
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cycloheptatriene
benzo
methoxy
mother liquor
reaction
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CN109293627A (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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Linhai Huanan Chemical Co ltd
Zhejiang Huahai Pharmaceutical Co Ltd
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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 invention provides a method for recovering mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone, which comprises the steps of dissolving the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone in an organic solvent, heating, adding a reducing agent into reaction liquid for reaction, carrying out thermal filtration after the reaction is finished, concentrating until the reaction is dry, adding a crystallization solvent for crystallization, and obtaining the high-purity 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone. The method can realize the effective recycling of the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone mother liquor, and the reaction process is easy to control without complex special equipment; in addition, each impurity in the mother liquor is converted through reduction reaction and can be separated and purified through a simple crystallization method.

Description

Recovery method of ketotifen intermediate mother liquor
Technical Field
The invention relates to a method for recovering a mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone, belonging to the field of chemical pharmacy.
Technical Field
The ketotifen fumarate is a powerful oral allergy medium release inhibitor, has histamine H1 receptor antagonism and anaphylactic reaction medium release inhibition effects, has strong antiallergic effect and long-lasting drug effect, and has better curative effect on prevention of various bronchial asthma attacks and exogenous asthma than endogenous asthma.
The 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone is a key intermediate for synthesizing ketotifen fumarate, and the structure of the intermediate is shown as a formula I:
Figure BDA0001878517600000011
the document Helvetica Chimica Acta, 1976, 59(3), P866-877 discloses a synthesis method of the ketotifen intermediate: the product 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one is finally obtained by heating a methanol solution of dibromide, adding potassium hydroxide after the reaction is clear, the yield is 80 percent, the melting point of the product is 164-.
Figure BDA0001878517600000012
Chinese patent CN108417532B discloses that dibromide is mixed with anhydrous methanol, stirred and refluxed for 2-6h, and then solid K is added into the reaction solution 2 Continuously carrying out reflux reaction for 2-6H by using an O/MgO alkali catalyst, filtering after the reaction is finished, cooling to 0 ℃, stirring for crystallization, filtering, and recrystallizing a filter cake by using ethylene glycol monomethyl ether to obtain 10-methoxy-4H-benzo [4,5] with the content of more than or equal to 97 percent]Cycloheptatriene [1,2-b ]]Thiophen-4-one in 59.59% yield.
The literature Collect Czech Chem Commun, 1989, 54, 2443-2469 discloses that 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-B ] thiophen-4-one is obtained according to the synthetic method of the literature Helvetica Chimica Acta, 1976, 59(3), P866-877, the mother liquor is not only the target product, but also a large amount of impurities A, B, C and D are generated, the generated impurities can not be reused, and the generated impurities can not be used for recovering the compound I in the mother liquor by a purification method, so that the atom utilization rate is low and a large amount of three wastes are generated. However, the prior art has not disclosed a method for recovering the mother liquor, so that the development of a method for recovering 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone is of great significance.
Figure BDA0001878517600000021
Disclosure of Invention
The invention aims to provide a method for recovering a mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone.
The present inventors have surprisingly found that 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one can be recovered in high purity by the following method:
a method for recovering mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone comprises the following specific steps: dissolving mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone in an organic solvent, heating, adding a reducing agent into the reaction liquid for reaction, carrying out thermal filtration after the reaction is finished, concentrating until the reaction is dry, adding a crystallization solvent for crystallization, and obtaining the high-purity 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone.
Further preferably, the organic solvent is selected from methyl tert-butyl ether, ethylene glycol monoethyl ether, ethyl acetate, tetrahydrofuran, dioxane, toluene, methanol, ethanol; more preferably methyl tert-butyl ether and ethylene glycol monoethyl ether;
further preferably, the reaction temperature is 30-100 ℃;
further preferably, the crystallization solvent is selected from the group consisting of ethylene glycol monomethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane.
More preferably, the reducing agent is palladium carbon/hydrogen, palladium carbon/hydrazine hydrate, iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid, nickel acetate/sodium hydride, and more preferably palladium carbon/hydrogen, zinc powder/organic acid.
Further preferably, the organic acid is formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, more preferably acetic acid.
Further preferably, the mass ratio of the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-one-containing mother liquor to palladium carbon is 125: 1-10: 1, and more preferably 30: 1-15: 1.
Further preferably, the hydrogen pressure is 0.1 to 1.0MPa, more preferably 0.4 to 0.6 MPa.
Further preferably, the concentration of the hydrazine hydrate is 40-80%, and the mass ratio of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone to the hydrazine hydrate is 2: 1-1: 1.
Further preferably, the mass ratio of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-one to iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid and nickel acetate/sodium hydride is 4:1: 0.8-1: 1: 0.8.
The iron powder/organic acid, the zinc powder/organic acid, the magnesium powder/organic acid and the nickel acetate/sodium hydride can be added in equal amount for 2-10 times, and the feeding interval is 0.5-6 hours.
The technical scheme of the invention has the following advantages and positive effects:
1. the technical scheme of the invention is that the impurity D in the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone is converted into 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone through reduction reaction under the action of a reducing agent. The method realizes the effective recycling of the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone mother liquor, obviously improves the utilization rate of the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone, reduces the production cost, is easy to control the reaction process, does not need complex special equipment, and accords with industrial mass production.
2. The impurities A and B in the original mother liquor are difficult to separate from 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-B ] thiophene-4-ketone by a simple purification method. However, in the research process, the inventor finds that the impurity A and the impurity B can also be converted into the impurity C through reduction reaction under the action of a reducing agent, and the impurity C and the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-B ] thiophen-4-one can be separated through a simple crystallization mode, so that the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-B ] thiophen-4-one with high purity can be obtained.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention.
HPLC analytical method for determination of purity and external standard content:
a chromatographic column: shim-pack VP-ODS 150 x 4.6mm, 5 μm or equivalent chromatography column
Mobile phase: methanol/water 70/30 (% V/V)
Flow rate: 1.5mL/min column temperature: 25 ℃ run time: 25 minutes; detection wavelength: 230 nm.
Example 1:
the preparation of 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one was carried out according to the method described in the document Helvetica Chimica Acta, 1976, 59(3), P866-877, as follows:
adding 120.0g of dibromide (compound II) and 1200mL of methanol into a reaction bottle, heating to reflux, reacting for 7 hours, then adding 44.0g of potassium hydroxide, continuing to reflux and react for 7 hours, cooling to 0 ℃, stirring for 3 hours, filtering, and washing with 500mL of water to obtain 53.6g of 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone, wherein the yield is 68.6%. The filtrate was concentrated to precipitate a solid, which was then filtered, rinsed with 100mL of water, and dried to obtain 25.8g of a mother solution containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one as a solid. The solid mother liquor comprises the following components in percentage by mass: 58.2 percent of compound I, 5.5 percent of impurity A, 10.5 percent of impurity B, 8.6 percent of impurity C and 13.4 percent of impurity D.
Example 2:
25g of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone solid obtained in example 1 is dissolved in 150mL of THF, a proper amount of reducing agent is added, the temperature is raised for reaction, the reaction process is followed by a point plate, after the reaction is finished, hot filtration is carried out, then concentration is carried out till dryness, ethylene glycol monomethyl ether is added for recrystallization, and after filtration, the compound I is obtained.
The yields and purities obtained with the different reducing agents are shown in table one:
table one:
serial number Reducing agent Amount of reducing agent Reaction temperature Reaction time Yield of the product Yield of b Purity of
1 Pd/C a ,H 2 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％
Remarking: Pd/C a The content of Pd in the product is 7%, and the moisture content is 60-70%.
Yield b ═ yield/total mother liquor mass 100%
Example 3:
dissolving 25g of solid mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone obtained in example 1 in 150ml of solvent, adding 1.2g of Pd/C, introducing 0.5Mpa hydrogen, heating to 55 ℃, carrying out reaction process by a point plate, carrying out heat filtration after the reaction is finished, then concentrating to dryness, adding ethylene glycol monomethyl ether for recrystallization, filtering, and drying to obtain a compound I.
The yields and purities obtained for the different reaction solvents are shown in table two:
a second table:
serial number Reaction solvent Reaction time Yield of the product Yield of Purity of
1 Ethyl acetate 6.5h 9.5g 38.0％ 93.3％
2 Ethylene glycol monomethyl 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％
The recovery method of a mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one proposed by the present invention has been described by way of example, and it is obvious to those skilled in the art that the recovery method of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one described herein can be modified or properly modified and combined to realize the technology of the present invention without departing from the content, spirit and scope of the present invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.

Claims (11)

1. A method for recovering mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone comprises the following specific steps:
dissolving mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone in an organic solvent, heating, adding a reducing agent into the reaction liquid for reaction, carrying out heat filtration after the reaction is finished, concentrating until the reaction is dry, adding a crystallization solvent for crystallization, and obtaining 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-ketone;
the organic solvent is selected from methyl tert-butyl ether, ethylene glycol monoethyl ether, ethyl acetate, tetrahydrofuran, dioxane, toluene, methanol and ethanol;
the reducing agent is palladium carbon/hydrogen, palladium carbon/hydrazine hydrate, iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid, nickel acetate/sodium hydride;
the crystallization solvent is selected from ethylene glycol monomethyl ether, tetrahydrofuran, methyl tert-butyl ether and 1, 4-dioxane;
the reaction temperature is 30-100 ℃.
2. The recovery method according to claim 1, wherein the organic solvent is methyl tert-butyl ether and ethylene glycol monoethyl ether.
3. The recycling method according to claim 1, wherein the reducing agent is palladium on carbon/hydrogen, zinc powder/organic acid.
4. The recovery method according to claim 1 or 3, wherein the organic acid is formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid.
5. The recovery method according to claim 1 or 3, wherein the mass ratio of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one to palladium-carbon is 125: 1-10: 1.
6. The recovery method according to claim 1 or 3, wherein the hydrogen pressure is 0.1 to 1.0 MPa.
7. The recovery method according to claim 1, wherein the mass concentration of the hydrazine hydrate is 40-80%, and the mass ratio of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one to the hydrazine hydrate is 2: 1-1: 1.
8. The recovery method according to claim 1, wherein the mass ratio of the mother liquor containing 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophen-4-one to iron powder/organic acid, zinc powder/organic acid, magnesium powder/organic acid and nickel acetate/sodium hydride is 4:1: 0.8-1: 1: 0.8.
9. A recovery process as claimed in claim 4, characterized in that the organic acid is acetic acid.
10. The recovery method according to claim 5, wherein the mass ratio of the 10-methoxy-4H-benzo [4,5] cycloheptatriene [1,2-b ] thiophene-4-one-containing mother liquor to palladium carbon is 30: 1-15: 1.
11. The recycling method according to claim 6, wherein the hydrogen pressure is 0.4 to 0.6 MPa.
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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
(Benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)acetic acids: novel non-ulcerogenic antiinflammatory agents;Bollinger, Pietro等;《Helvetica Chimica Acta》;19900808;第73卷(第5期);1197-1204 *
Studies on synthetic drugs. The 9- and 10-oxo derivatives of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophenes;Waldvogel, Erwin等;《Helvetica Chimica Acta》;19761231;第59卷(第3期);866-877 *

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