CN111018663A - Nepitastat important intermediate and enzyme catalytic synthesis method thereof - Google Patents
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Abstract
The invention discloses an important nepicastat intermediate and an enzymatic synthesis method thereof, and particularly relates to (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalene-2-ol, wherein the raw material of the synthesis method is 3, 5-difluorophenylacetic acid, the raw material I, the 3, 5-difluorophenylacetic acid and oxalyl chloride react to generate corresponding acyl chloride, the acyl chloride is cyclized by aluminum trichloride in dichloroethane and ethylene to generate an intermediate III, ketone is reduced by sodium borohydride in methanol to obtain an intermediate IV, the alcohol is catalyzed by adding vinylacetate in acetonitrile to obtain an intermediate V, and the ester is hydrolyzed in the methanol to obtain a final product VI. The invention has the advantages that the synthesis method has lower cost and simple operation process, the enzyme catalysis method is adopted, the catalysis efficiency of the enzyme is higher, the enzyme has high specificity, and the filtered enzyme can be recycled after the reaction of the enzyme is terminated.
Description
Technical Field
The invention relates to the technical field of treatment of post-traumatic stress disorder, in particular to an important nepicastat intermediate and an enzymatic synthesis method thereof.
Background
According to the statistics of American Psychiatric Association (APA), the population of American post-traumatic stress disorder (PTSD) has an overall prevalence of 1-14%, 8% on average, a lifetime risk of developing 3-58%, and about 2 times that of men. The german study showed an overall risk of disease of only 1.3% for the population, whereas the ale and liya study showed a risk of up to 37.4% and the suicide risk for PTSD patients was also higher than that of the general population by up to 19%. In general, the risk of PTSD development varies from population to population or from individual to individual as well as from stress event to stress event. Studies have shown that after a traffic accident, about 25% of children, whether injured or not, suffer from PTSD, and that injuries to teenagers lacking parental care are more susceptible to this disease. The childhood suffers physical or sexual abuse, PTSD is suffered in 10-55% of patients after adult, and the symptoms of 50-75% of children PTSD patients can be continued to adult. In adolescent criminals, the prevalence of PTSD is 4 times that of normal adolescents, with women being 2 times that of men. Brimes studied 8 casualty survivors and found 4 acute stress disorders a week after trauma, 3 PTSD a month later, and 2 comorbid depressive disorders. Another study of 3000 hospitalized soldiers in gulf war found that 13% of soldiers had PTSD. Goenjian et al investigated 582 victims, 74% PTSD and 22% depressive disorders after earthquake in the sbacak region of the united states in 1988. Conlon et al studied 40 hospitalized patients with minor trauma after traffic accident, about 75% of patients complained strong mental suffering after one week, 19% diagnosed PTSD after 3 months, with time prevalence of 9%, early mental suffering severity, old age, trauma severity of patients after traffic accident, etc. are the main influencing factors of PTSD. PTSD exhibits distinct physiological and psychological symptoms and its complexity is manifested in the development of disorders often associated with mental disorders such as depression, drug abuse, memory and cognitive problems, and other physiological and mental health problems. Such disorders may also be accompanied by impairment of an individual's ability to play a role in social and family life, including occupational instability, marital problems and dissimilarities, household disorders, and difficulties in educating children. Nepicastat hydrochloride is a compound which is very effective in treating PTSD (PTSD), but in the prior art, nepicastat hydrochloride has high cost and high synthesis difficulty.
Disclosure of Invention
The invention aims to solve the problems and designs an important nepicastat intermediate and an enzyme catalytic synthesis method thereof.
The technical scheme of the invention is that the nepicastat important intermediate and the enzymatic synthesis method thereof are used for realizing the above purpose, the raw material required by the synthesis step comprises 3, 5-difluorophenylacetic acid, and the synthesis step comprises the following steps:
and S1, dissolving the raw material I in dichloromethane, carrying out ice water bath on the obtained solution A, simultaneously dropwise adding a reagent into the solution A, stirring overnight at room temperature, and carrying out vacuum drying on the obtained product by using a concentrated oil pump to obtain the corresponding intermediate II.
S2 cyclization reaction: dissolving the intermediate II in dichloroethane, slowly adding aluminum trichloride into the obtained solution B, stirring to dissolve the aluminum trichloride, then reducing the temperature to a certain temperature to obtain a reaction system A, adding dried ethylene gas into the reaction system A, detecting while adding the ethylene gas until the intermediate II cannot be detected, stopping adding the ethylene gas, continuing stirring at room temperature overnight, and performing post-treatment to obtain an intermediate III.
S3 reduction reaction: dissolving the intermediate III in methanol, adding sodium borohydride into the obtained solution C to obtain a reaction system B, reacting the reaction system B for a certain time after the temperature of the reaction system B is slightly increased, quenching the reaction system B after the reaction is finished, and performing post-treatment to obtain an intermediate IV.
S4 enzymatic reaction: dissolving the intermediate IV in acetonitrile, adding esterifying enzyme and vinyl acetate into the obtained solution D, putting the obtained reaction system C into an oven, controlling the temperature of the oven to enable the reaction system C to react in the oven for a period of time, obtaining the reaction system D after the reaction is finished, filtering the reaction system D, recovering the filtered enzyme, recycling the enzyme, and post-treating and purifying the filtered product to obtain the intermediate V.
S5 hydrolysis reaction: dissolving the intermediate V in methanol, adding lithium hydroxide into the obtained solution E to obtain a reaction system E, then allowing the reaction system E to perform self reaction for a certain time until the intermediate V cannot be detected, terminating the reaction, and performing post treatment to obtain a final product VI, wherein the final product VI is (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalene-2-ol.
Wherein the reagent in S1 in the synthesis step is preferably oxalyl chloride; in the synthesis step, the temperature in S2 is preferably reduced to below-10 ℃, and the ethylene gas is dried by sulfuric acid; in the synthesis step S3, adding the sodium borohydride by a fractional addition method, wherein the reaction time is preferably 5 hours; in the S4 step, the oven temperature is preferably controlled to be 55-60 ℃, and the reaction time is preferably 50 hours; in S5 in the synthesis step, the reaction time is preferably overnight.
The invention has the beneficial effects that the invention provides an important intermediate for synthesizing nepicastat named as (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalene-2-ol and a synthetic step synthesized by an enzyme catalysis method, wherein the intermediate is prepared by reacting raw materials I3, 5-difluorophenylacetic acid and oxalyl chloride:
the intermediate II is cyclized with ethylene through aluminum trichloride in dichloroethane to generate an intermediate III:
reduction of the ketone in methanol with sodium borohydride affords intermediate IV:
adding alcohol into acetonitrile, adding vinyl acetate and esterase to catalyze and obtain an intermediate V:
hydrolysis of the ester in methanol gives the final product VI:
i.e. (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalen-2-ol. The synthesis method has the advantages of low cost, simple operation process and low synthesis difficulty, the enzyme catalysis method is adopted, the catalysis efficiency of the enzyme is high, the enzyme has high specificity during catalysis, and the filtered enzyme can be recycled after the enzyme reaction participating in the reaction is terminated.
Drawings
FIG. 1 is a schematic of the synthetic route of the present invention;
FIG. 2 is a schematic diagram of the synthetic route of the synthetic step S1 according to the present invention;
FIG. 3 is a schematic diagram of the synthetic route of the synthetic step S2 according to the present invention;
FIG. 4 is a schematic diagram of the synthetic route of the synthetic step S3 according to the present invention;
FIG. 5 is a schematic diagram of the synthetic route of the synthetic step S4 according to the present invention;
FIG. 6 is a schematic diagram of the synthesis route of the synthesis step S5 according to the present invention.
Detailed Description
In order to make the present invention more clear to those skilled in the art, the following will specifically describe the synthetic steps of the present invention:
s1: 1.72kg of starting material I (1 equivalent) 3, 5-difluorophenylacetic acid of the formula:
dissolving in 17L (10 times volume) of dichloromethane, subjecting the obtained solution a to ice-water bath while dropping 2.5kg of oxalyl chloride (2 equivalents) into the solution a, stirring overnight at room temperature, concentrating the obtained product by oil pump vacuum drying to obtain 2.1kg of intermediate II as acid chloride, having the formula:
s2 cyclization reaction: dissolving 2.1kg of intermediate II (1 equivalent) in 21L dichloroethane, after the intermediate II is completely dissolved, slowly adding 2.6kg of aluminum trichloride (2 equivalents) into the obtained solution B, stirring to dissolve the aluminum trichloride, then reducing the temperature to below-10 ℃ to obtain a reaction system A, adding ethylene gas dried by sulfuric acid into the reaction system A, detecting while adding the ethylene gas until the intermediate II is not detected, stopping adding the ethylene gas, continuing stirring at room temperature overnight, and carrying out aftertreatment to obtain 1.6kg of intermediate III which is tetrone, wherein the structural formula is as follows:
in the step, the acyl chloride is cyclized with ethylene by aluminum trichloride in dichloroethane to generate an intermediate III, and the reaction yield is 88%.
S3 reduction reaction: dissolving 1.6kg of intermediate III (1 equivalent) in 16L of methanol, after the intermediate III is completely dissolved, adding 0.34kg of sodium borohydride (1 equivalent) into the obtained solution C to obtain a reaction system B, after the temperature of the reaction system B is slightly raised, allowing the reaction system B to perform self reaction for 5 hours, after the reaction is ended, quenching the reaction system B after the reaction is ended, and performing post-treatment to obtain 1.56kg of intermediate IV, wherein the structural formula of the intermediate IV is as follows:
in the step, ketone is reduced in methanol by sodium borohydride to obtain an intermediate IV, and the reaction yield is 96.3%.
S4 enzymatic reaction: dissolving 1.56kg of intermediate IV (1 equivalent) in 15.6L of acetonitrile, adding 0.031kg of esterifying enzyme (0.05 equivalent) and 0.36kg of vinyl acetate (0.5 equivalent) into the obtained solution D after complete dissolution, putting the obtained reaction system C into an oven, controlling the temperature of the oven to be between 55 and 60 ℃, allowing the reaction system C to react in the oven for 50 hours, obtaining the reaction system D after the reaction is ended, filtering the obtained reaction system D, recovering the filtered enzyme for recycling, and post-treating and purifying the filtered product to obtain 0.86kg of intermediate V, wherein the structural formula is as follows:
in the step, alcohol is added into acetonitrile, vinyl acetate is added for catalysis to obtain an intermediate V, and the reaction yield is 45%.
S5 hydrolysis reaction: dissolving 0.86kg (1 equivalent) of intermediate V in 8.6L of methanol, after complete dissolution, adding 0.46kg (5 equivalents) of lithium hydroxide into the obtained solution E to obtain a reaction system E, then allowing the reaction system E to react for a certain time until the intermediate V is not detected, terminating the reaction, and carrying out aftertreatment to obtain 0.64kg of a final product VI (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalene-2-ol, wherein the structural formula is as follows:
in the step, the ester is hydrolyzed in methanol to obtain a final product VI, the reaction yield is 91 percent, and the optical purity (ee value) of the (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalene-2-alcohol is more than 99 percent.
The technical solutions described above only represent the preferred technical solutions of the present invention, and some possible modifications to some parts of the technical solutions by those skilled in the art all represent the principles of the present invention, and fall within the protection scope of the present invention.
Claims (8)
1. An important nepicastat intermediate and an enzymatic synthesis method thereof are characterized in that the enzymatic synthesis steps are as follows:
and S1, dissolving the raw material I in dichloromethane, carrying out ice water bath on the obtained solution A, simultaneously dropwise adding a reagent into the solution A, stirring overnight at room temperature, and carrying out vacuum drying on the obtained product by using a concentrated oil pump to obtain the corresponding intermediate II.
S2 cyclization reaction: dissolving the intermediate II in dichloroethane, slowly adding aluminum trichloride into the obtained solution B, stirring to dissolve the aluminum trichloride, then reducing the temperature to a certain temperature to obtain a reaction system A, adding dried ethylene gas into the reaction system A, detecting while adding the ethylene gas until the intermediate II cannot be detected, stopping adding the ethylene gas, continuing stirring at room temperature overnight, and performing post-treatment to obtain an intermediate III.
S3 reduction reaction: dissolving the intermediate III in methanol, adding sodium borohydride into the obtained solution C to obtain a reaction system B, reacting the reaction system B for a certain time after the temperature of the reaction system B is slightly increased, quenching the reaction system B after the reaction is finished, and performing post-treatment to obtain an intermediate IV.
S4 enzymatic reaction: dissolving the intermediate IV in acetonitrile, adding esterifying enzyme and vinyl acetate into the obtained solution D, putting the obtained reaction system C into an oven, controlling the temperature of the oven to enable the reaction system C to react in the oven for a period of time, obtaining the reaction system D after the reaction is finished, filtering the reaction system D, recovering the filtered enzyme, recycling the enzyme, and post-treating and purifying the filtered product to obtain the intermediate V.
S5 hydrolysis reaction: dissolving the intermediate V in methanol, adding lithium hydroxide into the obtained solution E to obtain a reaction system E, then allowing the reaction system E to perform self reaction for a certain time until the intermediate V cannot be detected, terminating the reaction, and performing post treatment to obtain a final product VI, wherein the final product VI is (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalene-2-ol.
2. The nepicastat important intermediate and the enzymatic synthesis method thereof according to claim 1, wherein the structural formula of the (R) -5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalen-2-ol is as follows:
3. the nepicastat important intermediate and the enzymatic synthesis method thereof according to claim 1, wherein the raw material I comprises 3, 5-difluorophenylacetic acid, and the structural formula of the raw material I is as follows:
4. the method for the enzymatic synthesis of nepicastat important intermediate and nepicastat according to claim 1, wherein the reagent in S1 in the synthesis step is preferably oxalyl chloride.
5. The method for the enzymatic synthesis of nepicastat important intermediate and the nepicastat important intermediate according to claim 1, wherein the temperature in the synthesis step S2 is preferably reduced to below-10 ℃, and the ethylene gas is dried by sulfuric acid.
6. The method for the catalytic synthesis of nepicastat important intermediate and the nepicastat enzyme according to claim 1, wherein in the synthesis step S3, the sodium borohydride is added in a fractional addition manner, and the reaction time is preferably 5 hours.
7. The method for the enzymatic synthesis of nepicastat important intermediate and the nepicastat important intermediate according to claim 1, wherein in the step of synthesizing, in S4, the oven temperature is preferably controlled to be 55-60 ℃, and the reaction time is preferably 50 hours.
8. The method for the enzymatic synthesis of nepicastat important intermediate and nepicastat according to claim 1, wherein in the step of synthesizing, in S5, the reaction time is preferably 18 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527108A (en) * | 2021-09-16 | 2021-10-22 | 斯芬克司药物研发（天津）股份有限公司 | Process for preparing optically pure 5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalen-2-amine and salts thereof |
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| US5438150A (en) * | 1994-04-26 | 1995-08-01 | Syntex (U.S.A.) Inc. | Process for making 1-benzocycloalkyl-1,3-dihydroimidazole-2-thione derivatives |
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Patent Citations (4)
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| US5438150A (en) * | 1994-04-26 | 1995-08-01 | Syntex (U.S.A.) Inc. | Process for making 1-benzocycloalkyl-1,3-dihydroimidazole-2-thione derivatives |
| WO2010124089A2 (en) * | 2009-04-22 | 2010-10-28 | Synosia Therapeutics, Inc. | Methods for treating dependence |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527108A (en) * | 2021-09-16 | 2021-10-22 | 斯芬克司药物研发（天津）股份有限公司 | Process for preparing optically pure 5, 7-difluoro-1, 2,3, 4-tetrahydronaphthalen-2-amine and salts thereof |
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