CN113801096B - Preparation method of dexlansoprazole - Google Patents

Preparation method of dexlansoprazole Download PDF

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CN113801096B
CN113801096B CN202011001004.3A CN202011001004A CN113801096B CN 113801096 B CN113801096 B CN 113801096B CN 202011001004 A CN202011001004 A CN 202011001004A CN 113801096 B CN113801096 B CN 113801096B
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reaction
dexlansoprazole
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solvent
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CN113801096A (en
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洪旭明
胡海文
楼逍龙
孟佳瑛
邹涛
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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    • C07F13/005—Compounds without a metal-carbon linkage
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/70—Complexes comprising metals of Group VII (VIIB) as the central metal
    • B01J2531/72—Manganese
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention relates to a preparation method of dexlansoprazole, which uses sodium hypochlorite with low price, environmental friendliness and high safety as an oxidant to replace traditional oxidants such as cumene hydroperoxide and m-chloroperoxybenzoic acid, so that excessive oxidation reaction is reduced, and aftertreatment pressure is reduced. In addition, the method uses a new catalyst system to replace a condition-sensitive L- (+) -diethyl tartrate/titanium isopropoxide catalyst system, and the catalyst system has milder reaction conditions and higher catalytic efficiency. The total yield is improved from 33.3% to 76% compared with the literature method due to the effective control of side reactions.

Description

Preparation method of dexlansoprazole
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of dexlansoprazole.
Background
Dexlansoprazole (Dexlansoprazole) is a new esophagitis treatment drug developed by wutian pharmaceutical company of japan, approved by the U.S. FDA to be marketed in 1/30.2009, and is a single enantiomer of lansoprazole, a proton pump inhibitor, used for treating heartburn and various degrees of erosive esophagitis associated with non-erosive gastroesophageal reflux disease, and has higher bioavailability and fewer side effects than lansoprazole. The structural formula is shown as the formula (I):
Figure BDA0002694314680000011
CN1117747C discloses a method for preparing optically pure lansoprazole, which uses an optically pure binaphthol compound as a chiral auxiliary agent, adopts a resolution method to prepare a crude product, and then prepares the relatively stable white powdery optically pure lansoprazole in an alkaline solution or water/a small amount of organic solvent.
WO2010035283A2 discloses a preparation method of dexlansoprazole formed by condensation of chloromethyl compound 1 and benzomercaptoimidazole to obtain thioether 2, oxidizing the thioether with cumene hydroperoxide to obtain compound 3, and finally reacting the compound with trifluoroethanol under the action of potassium tert-butoxide. In the final step of the method, trifluoroethanol may react with methylsulfonyl, which causes more trifluoroethanol to be consumed:
Figure BDA0002694314680000012
CN106543146A discloses a method for preparing dexlansoprazole by using a compound 4 as a starting material and performing three reactions of chlorination, nucleophilic substitution and asymmetric oxidation:
Figure BDA0002694314680000013
CN102108077B discloses that R-2- (((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl) benzimidazole is used as a raw material to prepare dexlansoprazole through asymmetric oxidation and trifluoroethanol substitution under the condition of sodium hydroxide. However, water is generated in the reaction process, and the presence of water is extremely unfavorable for the reaction, so that incomplete reaction of raw materials is caused, the sulfone impurities are large, great pressure is brought to subsequent refining, impurities such as sulfone analogues need to be removed by a column chromatography method, the process period is prolonged, and the production cost is increased;
Figure BDA0002694314680000021
the chiral construction of the dexlansoprazole is a key step, the main methods comprise chiral resolution, asymmetric oxidation and the like, and literature comparison shows that the existing asymmetric oxidation method is mostly applied, but in the process of asymmetric oxidation, if the reaction conditions are improperly controlled, impurities such as sulfone impurities A, N-oxide B and the like can be generated, the impurities are difficult to remove by conventional purification methods such as recrystallization and the like, the impurities are usually removed by chromatography, and the cost of the impurity removal method is too high;
Figure BDA0002694314680000022
in summary, researchers have further investigated enantioselective oxidation processes in order to reduce the materials involved in the process and at the same time optimize the yield. On the basis of ensuring the yield and the purity of the product, the preparation process of the dexlansoprazole with lower preparation cost and environmental friendliness is researched.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a controllable asymmetric oxidation method, a Salen complex catalytic system is used as a chiral catalyst, sodium hypochlorite is used as an oxidant, the reaction conditions of the reaction system are milder, the content of excessive oxidation impurities is obviously reduced, and the pressure of post-treatment is reduced.
The method of the invention comprises the following steps:
Figure BDA0002694314680000023
the method comprises the following steps: the compound II is oxidized with sodium hypochlorite under the action of a chiral catalyst to generate a crude product of the compound I,
step two: recrystallizing the crude product of the compound I by using an organic solvent to obtain the compound I with high chiral purity.
As a specific embodiment, in step one said chiral catalyst is selected from compound III or IV, preferably compound IV.
Figure BDA0002694314680000031
As a specific embodiment, the reaction solvent in the first step is one selected from ethyl acetate, acetonitrile and acetone, preferably acetonitrile.
As a specific embodiment, the molar ratio of compound II to sodium hypochlorite fed in step one is 1:1.2; the molar consumption of the catalyst is 0.05-0.2 time of that of the compound II.
As a specific embodiment, the reaction temperature in step one is 0 to 30 ℃, preferably 15 to 25 ℃.
As a specific embodiment, in the second step, the recrystallization solvent is a mixed solution of one of tetrahydrofuran, methanol, ethanol and ethyl acetate and water, and preferably a mixed solvent of tetrahydrofuran and water.
The invention has the beneficial effects that: sodium hypochlorite which is cheap, environment-friendly and high in safety is used as an oxidant to replace traditional oxidants such as cumene hydroperoxide and m-chloroperoxybenzoic acid, so that excessive oxidation reaction is reduced, and aftertreatment pressure is reduced. A new catalyst system is used to replace a condition-sensitive L- (+) -diethyl tartrate/titanium isopropoxide catalyst system, and the catalyst system has mild reaction conditions and high catalytic efficiency. Due to the effective control of side reaction, the pressure of post-treatment and refining is reduced, and the total yield is improved from 33.3% to 76% compared with the method in the literature.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The following examples are provided for understanding the method and core idea of the present invention, and it will be apparent to those skilled in the art that any possible changes or substitutions may be made without departing from the spirit of the present invention. The experimental method of the present invention, in which no specific condition is specified, is usually a conventional condition or a condition suggested by a manufacturer of raw materials or goods; the reagent of which the source is not indicated is usually a conventional reagent commercially available.
The term "chiral ligand" as used in the examples herein refers to the chiral structure of catalysts III and IV when not bound to manganese, and is available from conventional commercial sources; further, the structures of chiral ligands corresponding to catalysts III and IV of the present application are shown in IIIa and IVb, respectively:
Figure BDA0002694314680000041
example 1
Preparation of catalyst III/IV: the chiral ligand (0.5 mol) was dissolved in absolute ethanol, and Mn (OAc) dissolved therein was added thereto 4 The reaction was performed under reflux for 4 hours. Cooling the reaction liquid to room temperature, then adding 1.5mol of lithium chloride, stirring for 2 hours at 25 ℃, and filtering to obtain the product. Washing with ethanol and distilled water for several times, and drying to obtain solid.
Preparing a sodium hypochlorite solution: dissolving 100g of sodium hypochlorite in water, adding 300ml of water, stirring and dissolving, and adjusting the pH value of the system to 11-12 for later use.
The method comprises the following steps: taking compound II (35.3 g, 0.1mol), catalyst IV (9.51g, 0.015mol) and acetonitrile 220g, stirring, controlling the temperature at 20 ℃, adding a prepared sodium hypochlorite solution (8.2g, 0.11mol), stirring for reacting for 2-3 hours, after the reaction is finished, adjusting the pH of the system to be about 9.0 by using a glacial acetic acid solution, filtering the catalyst, then adding 220mL of purified water, cooling to 5 ℃, stirring for crystallizing for 3 hours, and performing suction filtration to obtain a crude product 35g, the purity is 97.2%, and the ee value is: 98.5%, oxidized impurity a:0.4%, oxidized impurity B:0.5 percent.
Step two: taking 35g of crude dexlansoprazole, adding 350mL of tetrahydrofuran, stirring and heating to 45 ℃, keeping the temperature and stirring for 30 minutes until the system is completely dissolved, adding activated carbon for decolorization, performing heat filtration, slowly cooling the filtrate to 20 ℃, dropwise adding 525g of purified water, cooling to 5 ℃ after the addition, performing crystallization for 2 hours, filtering, and drying to obtain 30g of pure I, wherein the yield is 85.7%, the purity is 99.2%, and the ee value is: 99.5 percent. The yield of the two steps is about 76%.
Example 2
The method comprises the following steps: taking compound II (35.3 g, 0.1mol), catalyst III (9.69g, 0.015mol) and acetonitrile 220g, stirring, controlling the temperature at 20 ℃, adding a sodium hypochlorite solution (8.2g, 0.11mol) prepared in advance, stirring for reacting for 2-3 hours, after the reaction is finished, adjusting the pH of a system to be about 9.0 by using a glacial acetic acid solution, filtering out the catalyst, then adding 220mL of purified water, cooling to 5 ℃, stirring for crystallizing for 3 hours, and performing suction filtration to obtain a crude product 34.8g, wherein the purity is 96.8 percent, and the ee value is: 98.8%, oxidized impurity a:0.5%, oxidized impurity B:0.5 percent.
Step two: taking 34g of crude dexlansoprazole, adding 340mL of tetrahydrofuran, stirring and heating to 45 ℃, keeping the temperature and stirring for 30 minutes until the system is completely dissolved, adding activated carbon for decolorization, performing heat filtration, slowly cooling the filtrate to 20 ℃, dropwise adding 525g of purified water, cooling to 5 ℃ after the addition, performing crystallization for 2 hours, filtering, and drying to obtain 30g of pure I, wherein the yield is 88.2%, the purity is 99.1%, and the ee value is: 99.4 percent.
Example 3
The method comprises the following steps: taking compound II (35.3 g, 0.1mol), catalyst IV (9.51g, 0.015mol) and acetonitrile 220g, stirring, controlling the temperature at 20 ℃, adding a prepared sodium hypochlorite solution (8.2g, 0.11mol), stirring for reacting for 2-3 hours, after the reaction is finished, adjusting the pH of the system to be about 9.0 by using a glacial acetic acid solution, filtering the catalyst, then adding 220mL of purified water, cooling to 5 ℃, stirring for crystallizing for 3 hours, and performing suction filtration to obtain a crude product 35g, the purity is 97.2%, and the ee value is: 98.5%, oxidized impurity a:0.4%, oxidized impurity B:0.5 percent.
Step two: taking 35g of crude dexlansoprazole, adding 350mL of methanol, stirring and heating to 55 ℃, keeping the temperature and stirring for 30 minutes until the system is completely dissolved, adding activated carbon for decolorization, performing heat filtration, slowly cooling the filtrate to 20 ℃, dropwise adding 525g of purified water, cooling to 5 ℃ after the addition, performing crystallization for 2 hours, filtering, and drying to obtain 28g of pure product I, wherein the yield is 80%, the purity is 99.5%, and the ee value is: 99.5 percent.
Example 4 comparative example-Using the method of CN106866630B (which reports a complicated post-treatment in examples 1[0043] - [0051], a two-step total yield of 32.3%)
The method comprises the following steps: taking compound II (35.3 g,0.1 mol) and 176mL of toluene, heating to reflux and keeping for about 60 minutes, cooling the reaction mass to room temperature under the protection of nitrogen, adding 0.3g of water and 15.8g of L- (+) -diethyl tartrate, heating to 60-65 ℃, keeping the temperature for about 15 minutes, adding 10.2g of titanium isopropoxide in 10-15 minutes, keeping the temperature for reaction for about 50 minutes, cooling to room temperature, adding 8.4g of diisopropylethylamine, adding 21.8g of cumene hydroperoxide in about 30 minutes, and keeping the reaction for about 3.5 hours. After the reaction was completed, the reaction solution was washed three times with a sodium thiosulfate solution to remove the aqueous layer. The temperature is raised to 30-35 ℃, 45g of water is added, 89mL of methyl tert-butyl ether is added within 10-15 minutes, 177mL of cyclohexane is added within 10-15 minutes, and the mixture is stirred for no more than 40 minutes. Filtered, washed with 35mL of methyl tert-butyl ether and dried for about 1.5 hours. 177mL of acetone is added into the filter cake, stirring is carried out for about 10 minutes, 530mL of water is added within 30-45 minutes, stirring is carried out for about 30 minutes, filtering is carried out, and 30.1g of crude dexlansoprazole is dried, wherein the yield is 81.5%.
And (3) adding 30g of crude dexlansoprazole and 150mL of acetone into a reaction bottle at room temperature, stirring, and adding 0.7mL of ammonia water solution and 1.73g of activated carbon. Filtering, rinsing with acetone, and collecting filtrate to a reaction bottle. 0.7mL of aqueous ammonia solution was added, the mixture was filtered, 300mL of methylene chloride was added to the filter cake, the mixture was stirred and then allowed to stand, and the bottom organic layer was separated and dried over sodium thiosulfate. The organic solvent was distilled off, 30mL of acetone was added, the solvent was distilled off, and after cooling to room temperature, 30mL of acetone was added and stirred to dissolve completely. 300mL of n-heptane was added, the temperature was raised to 40 to 45 ℃ and then the mixture was filtered and left to stand for about 30 minutes. Filtration, washing with n-heptane, and drying of dexlansoprazole 10g, yield 33.3%.

Claims (8)

1. A preparation method of dexlansoprazole is characterized by comprising the following steps: the compound II and sodium hypochlorite are subjected to oxidation reaction to generate a compound I under the action of a catalyst, and the reaction is as follows:
Figure FDA0003978349730000011
further recrystallizing the compound I by using an organic solvent to obtain a compound I; wherein the catalyst is selected from compounds III or IV,
Figure FDA0003978349730000012
2. the method according to claim 1, wherein the solvent for the oxidation reaction is selected from one of ethyl acetate, acetonitrile, and acetone.
3. The process of claim 2, wherein the solvent for the oxidation reaction is acetonitrile.
4. The method according to claim 1, wherein the molar ratio of compound II to sodium hypochlorite is 1; the molar dosage of the catalyst is 0.05 to 0.2 time of that of the compound II.
5. The method of claim 1, wherein the oxidation reaction is carried out at a reaction temperature of 0 to 30 ℃.
6. The method of claim 5, wherein the oxidation reaction is carried out at a reaction temperature of 15 to 25 ℃.
7. The method according to claim 1, wherein the recrystallization solvent is a mixed solution of water and one selected from tetrahydrofuran, methanol, ethanol and ethyl acetate.
8. The method according to claim 7, wherein the recrystallization solvent is a mixed solvent of tetrahydrofuran and water.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101372484A (en) * 2008-10-29 2009-02-25 北京工商大学 Asymmetric synthesis method of chiral benzimidazole compound
CN102245594A (en) * 2008-10-14 2011-11-16 力奇制药公司 Process for the preparation of enantiomerically enriched proton pump inhibitors
CN104203938A (en) * 2012-01-21 2014-12-10 朱比兰特生命科学有限公司 Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers
CN104387368A (en) * 2014-12-11 2015-03-04 扬子江药业集团四川海蓉药业有限公司 Method for preparing dexilant
CN106946849A (en) * 2017-03-28 2017-07-14 乐普药业科技有限公司 A kind of R-lansoprazole and preparation method thereof and purposes
CN107964005A (en) * 2017-11-10 2018-04-27 扬子江药业集团江苏海慈生物药业有限公司 A kind of preparation method of Lansoprazole

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102245594A (en) * 2008-10-14 2011-11-16 力奇制药公司 Process for the preparation of enantiomerically enriched proton pump inhibitors
CN101372484A (en) * 2008-10-29 2009-02-25 北京工商大学 Asymmetric synthesis method of chiral benzimidazole compound
CN104203938A (en) * 2012-01-21 2014-12-10 朱比兰特生命科学有限公司 Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers
CN104387368A (en) * 2014-12-11 2015-03-04 扬子江药业集团四川海蓉药业有限公司 Method for preparing dexilant
CN106946849A (en) * 2017-03-28 2017-07-14 乐普药业科技有限公司 A kind of R-lansoprazole and preparation method thereof and purposes
CN107964005A (en) * 2017-11-10 2018-04-27 扬子江药业集团江苏海慈生物药业有限公司 A kind of preparation method of Lansoprazole

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