CN114907242B - Synthesis method of 8-mercapto-6-oxooctanoic acid - Google Patents

Synthesis method of 8-mercapto-6-oxooctanoic acid Download PDF

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CN114907242B
CN114907242B CN202210613120.3A CN202210613120A CN114907242B CN 114907242 B CN114907242 B CN 114907242B CN 202210613120 A CN202210613120 A CN 202210613120A CN 114907242 B CN114907242 B CN 114907242B
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compound
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cuprous
mercapto
sulfide
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CN114907242A (en
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钱伟
冯宇
许燕萍
高莉燕
王植鹏
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CHENGDA PHARMACEUTICALS CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/083—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a synthetic method of 8-mercapto-6-oxo-octanoic acid, belonging to the field of medicine synthesis and preparation. The synthesis method of the 8-mercapto-6-oxo octanoic acid is characterized by comprising the following synthesis steps: step 1), nucleophilic addition of a compound (I) cyclohexane anhydride serving as a starting material and a vinyl Grignard reagent to prepare a compound (II); step 2), the compound (II) reacts with sulfide and sulfur simple substance, and Michael addition is carried out to prepare the compound (III). The synthesis method of 8-mercapto-6-oxo-octanoic acid has the characteristics of low cost, simple operation, suitability for industrial production and the like.

Description

Synthesis method of 8-mercapto-6-oxooctanoic acid
Technical Field
The invention relates to the technical field of medicine and intermediate synthesis, and relates to a method for synthesizing 8-mercapto-6-oxo-octanoic acid.
Background
The lipoic acid has a disulfide five-membered ring structure, has high charge density and is easy to generate free radical oxidation, thus having remarkable antioxidation capability and playing an antioxidation role through various mechanisms such as free radical removal or other antioxidant regeneration. In the medical field, lipoic acid is widely used for preventing and treating diabetes and related complications thereof; in the field of health products, lipoic acid is mainly used for removing free radicals in vivo, preventing lipid peroxidation, protecting cells from oxidative damage, and achieving the purposes of preventing and assisting in treating diseases. In addition to the above main uses, lipoic acid has a variety of potential applications in anti-tumor, treatment of inflammation, ischemia reperfusion injury, radiation injury, and acute and chronic liver diseases.
Lipoic acid has a large number of synthetic schemes, and the literature is reviewed as follows:
in 1957, donald s. acker et al used adipic monoester as a raw material and prepared lipoic acid through 7 steps of reaction such as acyl chlorination, addition, reduction, chlorination, cyclization, hydrolysis and acidification, wherein the yield of the route is only 20.88%, sodium disulfide is used in the cyclization reaction of the method, and the reaction is easy to generate a polymer, so that the quality of the product is reduced, and the reaction yield is affected.
In 1953, M.W. Bullock et al used 6-carbonyl-8-chlorooctanoate as a starting material to perform 6 steps of elimination, addition, reduction, hydrolysis, mercapto substitution, cyclization and the like to prepare lipoic acid, wherein the yield of lipoic acid is 17% from adipic acid monoethyl ester acyl chloride.
In 1954, lester J.Reed et al prepared lipoic acid from 6-carbonyl-8-chlorooctanoate by 4 steps of reduction, chlorination, cyclization, hydrolysis, acidification, etc. The process yield is not more than 30%, and the process needs to react with metal sodium in a liquid ammonia environment, so that the reaction is dangerous, needs a cryogenic reaction and is not suitable for large-scale production.
In 1957, august Segre et al used cyclohexanone as the starting material and produced lipoic acid by nine steps of condensation, coupling, carbonyl protection, reduction, acetylation, deprotection, baeyer-Villiger oxidation, sulfhydrylation, oxidation and the like, with a product yield of 20%. The whole synthesis route is longer, the steps are more, the operation is complicated, and the method is not suitable for industrialized mass production.
In 1999, wang Dun et al, university of Shenyang pharmacy, reported that the yield was 25% from cyclohexanone as the starting material by five steps of condensation, coupling, baeyer-Villiger oxidation, sulfhydrylation and oxidation.
Subhash P.Chavan et al used cyclohexanone and ethyl chloroacetate as raw materials and prepared lipoic acid through multiple steps of alkylation, elimination, reduction, cbz protection, oxidation, reduction, methylation, deprotection, ms protection, cyclization, hydrolysis and the like. The synthetic route is long and the yield is only 15%. The process uses explosive raw materials such as diazomethane, and the DIBAL-H needs to react at the low temperature of-78 ℃, and the series of factors make the method difficult to realize industrial production.
Maitreyee Bezbarua et al prepared methyl 6, 8-dihydroxyoctoate by 5 steps of reaction such as alkylation, ring opening, methylation, fermentation reduction and demethylation by using 2-nitrocyclohexanone as a raw material, and the yield is only 18%, so that industrial production cannot be truly carried out.
In 1989, aradamudan et al used acetoacetate and 4-iodobutyronitrile as raw materials and prepared by 7 steps of reactions such as alkylation, enzyme-catalyzed asymmetric hydrogenation, reduction, alcoholysis, ms protection, cyclization and hydrolysis. The process has long steps, the raw material 4-iodobutyronitrile is expensive, and the raw materials such as n-butyllithium, sodium hydrogen and the like are used, so that the method is extremely easy to burn and explode, is dangerous and is not suitable for industrial production.
In 1995, adger et al used ethyl 2-cyclohexanone acetate as a starting material and catalyzed (R) -enantiomer by monooxygenase (MO 2) to produce a selective Baeyer-Villiger oxidation reaction with a yield of 34% under optimal conditions. Then the (R) -alpha-lipoic acid is prepared through the reactions of ring opening, mitsunobu, hydrolysis, ms protection, cyclization, hydrolysis and the like. The raw materials in the route are expensive, the yield is low, the cost is high, and the method is not suitable for industrial production.
The existing synthetic routes have the defects of longer steps, high-price reagents, flammable and explosive hazardous reagents or production processes, special production equipment, serious environmental pollution and the like, and are not beneficial to large-scale industrial production.
Therefore, there is an urgent need for a method for preparing lipoic acid that is simple in reaction, low in cost, and ultimately easy for industrial production.
Disclosure of Invention
The invention aims to solve the technical problems that:
the 8-mercapto-6-oxo-octanoic acid synthesis method is easy to obtain raw materials, high in yield, good in quality, simple and convenient to operate and suitable for industrial production;
finally, the synthetic method for preparing the lipoic acid can also reach the requirements of high quality, high yield, simple and convenient operation and industrial production.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the specific synthesis process is as follows:
the synthesis method of the 8-mercapto-6-oxo-octanoic acid comprises the following synthesis steps:
step 1), nucleophilic addition of a compound (I) cyclohexane anhydride serving as a starting material and a vinyl Grignard reagent to prepare a compound (II);
step 2), the compound (II) reacts with sulfide and sulfur simple substance, and Michael addition is carried out to prepare a compound (III);
the reaction equations of steps 1) to 2) are as follows:
as a further improvement of the scheme, in the step 1), the compound (I) is used as a starting material and is subjected to nucleophilic addition with a vinyl Grignard reagent under the catalysis of a cuprous reagent to prepare the compound (II), the compound (I) and the vinyl Grignard reagent react in a solvent at the reaction temperature of-80-20 ℃, and the compound (II) or a solution thereof is obtained through post-treatment.
As a further improvement of the above scheme, in the step 1), the solvent is any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and dioxane.
As a further improvement of the scheme, in the step 1), the molar ratio of the cyclohexanedicarboxylic anhydride to the vinyl Grignard reagent is 1:0.9-3.0, and the vinyl Grignard reagent is any one or more of vinyl magnesium chloride, vinyl magnesium bromide and vinyl magnesium iodide.
As a further improvement of the above scheme, in step 1), the cuprous reagent is any one or more of cuprous iodide, cuprous chloride, cuprous bromide and cuprous acetate.
As a further improvement of the scheme, in the step 2), the compound (II) reacts with sulfide and elemental sulfur in an autoclave at an internal temperature of 60-200 ℃, and the compound (III) or a solution thereof is obtained by post-treatment, wherein the molar ratio of the compound (II), the sulfide and the elemental sulfur is 1:1.0 to 10.0:0.01 to 1.0.
As a further improvement of the above scheme, in step 2), the sulfide is any one or more of sodium sulfide, potassium sulfide, sodium hydrosulfide and potassium hydrosulfide.
As a further improvement of the scheme, the vinyl Grignard reagent in the step 1) is vinyl magnesium bromide, and the molar ratio of the cyclohexanedicarboxylic anhydride to the vinyl Grignard reagent is 1:1.0-1.2.
As a further improvement of the scheme, the cuprous reagent in the step 1) is cuprous iodide, and the molar ratio of the cyclohexanedicarboxylic anhydride to the cuprous reagent is 1:0.05-0.2.
As a further improvement of the above scheme, the reaction temperature in step 2) is 100 to 150 ℃, and the molar ratio of the compound (II), sulfide and elemental sulfur is 1:1.0 to 2.0:0.1 to 0.3.
The method for synthesizing lipoic acid provided by the invention has the following advantages:
1) The synthetic method of the 8-mercapto-6-oxo-octanoic acid has the advantages that the route is relatively simple, the raw materials are commercial materials, the raw materials are relatively cheap, no complex special operation is caused, and the synthetic method is suitable for industrial production;
2) The 8-mercapto-6-oxo-octanoic acid is prepared through the steps 1) and 2), and a new synthesis scheme is provided for the synthesis and preparation of lipoic acid;
3) The 8-mercapto-6-oxo-octanoic acid is prepared by the method, and the 8-mercapto-6-oxo-octanoic acid is prepared by the product 8-mercapto-6-oxo-octanoic acid, and the synthetic route has the advantages of easily available raw materials, higher yield, higher quality of the prepared product, simple operation and suitability for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described below with reference to examples:
example 1:
into the reaction flask, 128.1g of cyclohexane anhydride (1 mol,1 eq), 600mL of tetrahydrofuran and 19.0g of cuprous iodide (0.1 mol,0.1 eq) were charged, cooled to-20℃and 600mL of 2M vinylmagnesium bromide (1.2 mol,1.2 eq) was added dropwise to the reaction solution, and the reaction was continued for 1 hour. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is washed once with sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, the distillation is carried out under reduced pressure until no fraction is generated, and the crude product of the compound (II) is obtained and is directly put into the next reaction.
Taking the whole batch of the crude product of the compound (II), putting the batch into an autoclave, adding 288.2g of sodium sulfide nonahydrate solid (1.2 mol,1.2 eq), 0.64g of elemental sulfur (0.02 mol,0.02 eq) and 1000mL of water, heating to 110-120 ℃ and reacting for 5 hours. After the reaction is finished, cooling to room temperature, acidifying to pH 3-4 by adopting hydrochloric acid, extracting for 3 times by adopting tetrahydrofuran, merging organic phases, distilling until no fraction exists basically, adding 500g of methanol to obtain a methanol solution of the compound (III), and directly putting into the next reaction.
The methanol solution of the compound (III) in the previous step is cooled to-5 ℃, 37.8g of sodium borohydride (1.0 mol,1.0 eq) is added in portions, and after the addition is completed, the mixture is stirred for 1h. After the reaction, adding an ammonium chloride aqueous solution to quench the reaction. Distilled off methanol, added with tetrahydrofuran and sodium chloride aqueous solution, stirred for 30min, and layered. Extracting the water layer with tetrahydrofuran for 3 times, combining the organic phases, distilling under reduced pressure to a certain volume to obtain a compound (IV), and directly putting into the next reaction.
76.12g of thiourea (1.0 mol,1.0 eq) and 438.0g of 20% hydrochloric acid (2.4 mol,2.4 eq) were added to a reaction flask, the temperature was raised to 60℃and the compound (IV) solution obtained in the above step was slowly added dropwise to the reaction solution, and the reaction was carried out at 80℃for at least 10 hours after the completion of the dropwise addition. After the reaction was completed, 586.7g of 30% liquid alkali (4.4 mol,4.4 eq) was added, and the reaction was carried out by hydrolysis at 50℃for at least 2 hours. After the reaction, hydrochloric acid is adopted to adjust the pH value to 3-4, chloroform is adopted to extract for 3 times, the organic phases are combined, and half-saturated saline water is adopted to wash for 1 time. After distillation to no fraction, the residue was purified by molecular distillation to give 125.2g of compound (V), four-step reaction yield 60.1%, and nuclear magnetic data as follows: 1 H NMR(CDCl 3 ,400MHz) δ:2.93(m,1H),2.71(m,2H),2.38(t,2H),1.95-1.42(m,8H),1.35(t,1H),1.30(d,1H)。
104.2g of compound (V) (0.5 mol,1.0 eq) is added into a reaction bottle, 1000g of 2% sodium hydroxide aqueous solution is added, the pH is regulated to 8.8-9.2, 0.08g of ferric sulfate is added, the reaction temperature is controlled to be 20-30 ℃, oxygen is slowly introduced into the reaction system, and the reaction is carried out for more than 3 hours. After the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adopting hydrochloric acid to adjust the pH value to 1-2, and stirring for 2 hours. Filtering, drying the filter cake to dryness, recrystallizing with ethyl acetate and n-heptane, filtering, and drying to obtain 77.4g of product compound (VI), and collectingThe rate was 75.0%. The nuclear magnetic data are as follows: 1 H-NMR(CDCl 3 ,400MHz):δ＝11.3ppm (s,1H)；3.58(m,1H)；3.18(t,2H)；2.48(m,2H)；1.3-2.30(m,8H)。
example 2:
into the reaction flask, 128.1g of cyclohexane anhydride (1 mol,1 eq), 600mL of tetrahydrofuran and 19.0g of cuprous iodide (0.1 mol,0.1 eq) were charged, cooled to-10℃and 525mL of 2M vinylmagnesium bromide (1.05 mol,1.05 eq) was added dropwise to the reaction solution, and the reaction was continued for 1 hour. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is washed once with sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, the distillation is carried out under reduced pressure until no fraction is generated, and the crude product of the compound (II) is obtained and is directly put into the next reaction.
Taking the whole batch of the crude product of the compound (II), putting the batch into an autoclave, adding 360.3g of sodium sulfide nonahydrate solid (1.5 mol,1.5 eq), 0.64g of elemental sulfur (0.02 mol,0.02 eq) and 1000mL of water, heating to 110-120 ℃ and reacting for 5 hours. After the reaction is finished, cooling to room temperature, acidifying to pH 3-4 by adopting hydrochloric acid, extracting for 3 times by adopting tetrahydrofuran, merging organic phases, distilling until no fraction exists basically, adding 500g of methanol to obtain a methanol solution of the compound (III), and directly putting into the next reaction.
The methanol solution of the compound (III) in the previous step is cooled to-5 ℃, 41.6g of sodium borohydride (1.1 mol,1.1 eq) is added in portions, and after the addition is completed, the mixture is stirred for 1h. After the reaction, adding an ammonium chloride aqueous solution to quench the reaction. Distilled off methanol, added with tetrahydrofuran and sodium chloride aqueous solution, stirred for 30min, and layered. Extracting the water layer with tetrahydrofuran for 3 times, combining the organic phases, distilling under reduced pressure to a certain volume to obtain a compound (IV), and directly putting into the next reaction.
To the reaction flask was added 76.12g thiourea (1.0 mol, 1).0 eq) and 1534.8g of 20% hydroiodic acid (2.4 mol,2.4 eq), heating to 60 ℃, slowly adding dropwise the compound (IV) solution obtained in the above step into the reaction solution, heating to 80 ℃ for reaction for at least 10 hours after the dropwise addition is completed. After the reaction was completed, 586.7g of 30% liquid alkali (4.4 mol,4.4 eq) was added, and the reaction was carried out by hydrolysis at 50℃for at least 2 hours. After the reaction, hydrochloric acid is adopted to adjust the pH value to 3-4, chloroform is adopted to extract for 3 times, the organic phases are combined, and half-saturated saline water is adopted to wash for 1 time. After distillation to no fraction, the residue was purified by molecular distillation to give 131.7g of compound (V), four-step reaction yield 63.2%, and nuclear magnetic data as follows: 1 H NMR (CDCl 3 ,400MHz)δ:2.93(m,1H),2.71(m,2H),2.38(t,2H),1.95-1.42(m,8H), 1.35(t,1H),1.30(d,1H)。
104.2g of compound (V) (0.5 mol,1.0 eq) is added into a reaction bottle, 1000g of 2% sodium hydroxide aqueous solution is added, the pH is regulated to 8.8-9.2, 0.08g of ferric chloride is added, the reaction temperature is controlled to be 20-30 ℃, oxygen is slowly introduced into the reaction system, and the reaction is carried out for more than 3 hours. After the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adopting hydrochloric acid to adjust the pH value to 1-2, and stirring for 2 hours. After filtration and drying of the filter cake to dryness, recrystallization from ethyl acetate and n-heptane, filtration and drying gave 78.9g of the product compound (VI) in a yield of 76.5%. The nuclear magnetic data are as follows: 1 H-NMR(CDCl 3 ,400MHz):δ＝11.3ppm (s,1H)；3.58(m,1H)；3.18(t,2H)；2.48(m,2H)；1.3-2.30(m,8H)。
example 3:
into the reaction flask, 128.1g of cyclohexane anhydride (1 mol,1 eq), 600mL of tetrahydrofuran and 19.0g of cuprous iodide (0.1 mol,0.1 eq) were added, the temperature was lowered to-20℃and 600mL of 2M vinyl magnesium chloride (1.2 mol,1.2 eq) was added dropwise to the reaction solution, followed by thermal insulation reaction for 1 hour. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is washed once with sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, the distillation is carried out under reduced pressure until no fraction is generated, and the crude product of the compound (II) is obtained and is directly put into the next reaction.
Taking the whole batch of the crude product of the compound (II), putting the batch into an autoclave, adding 288.2g of sodium sulfide nonahydrate solid (1.2 mol,1.2 eq), 1.6g of elemental sulfur (0.05 mol,0.05 eq) and 1000mL of water, heating to 130-140 ℃ and reacting for 4 hours. After the reaction is finished, cooling to room temperature, acidifying to pH 3-4 by adopting hydrochloric acid, extracting for 3 times by adopting tetrahydrofuran, merging organic phases, distilling until no fraction exists basically, adding 500g of ethanol to obtain an ethanol solution of the compound (III), and directly putting into the next reaction.
The ethanol solution of the compound (III) in the previous step is cooled to-5 ℃, 21.8g of lithium borohydride (1.0 mol,1.0 eq) is added in portions, and after the addition is completed, the mixture is stirred for 1h. After the reaction, adding an ammonium chloride aqueous solution to quench the reaction. Distilling off B, adding tetrahydrofuran and sodium chloride aqueous solution, stirring for 30min, and layering. Extracting the water layer with tetrahydrofuran for 3 times, combining the organic phases, distilling under reduced pressure to a certain volume to obtain a compound (IV), and directly putting into the next reaction.
76.12g of thiourea (1.0 mol,1.0 eq) and 1534.8g of 20% hydroiodic acid (2.4 mol,2.4 eq) were added to the reaction flask, the temperature was raised to 60℃and the solution of the compound (IV) obtained in the above step was slowly added dropwise to the reaction solution, and the reaction was carried out at 80℃for at least 10 hours after the completion of the dropwise addition. After the completion of the reaction, 822.8g of 30% aqueous potassium hydroxide (4.4 mol,4.4 eq) was added, and the hydrolysis reaction was carried out at 50℃for at least 2 hours. After the reaction, hydrochloric acid is adopted to adjust the pH value to 3-4, chloroform is adopted to extract for 3 times, the organic phases are combined, and half-saturated saline water is adopted to wash for 1 time. After distillation to no fraction, the residue was purified by molecular distillation to prepare 122.5g of compound (V), 58.8% in four-step reaction yield, and the nuclear magnetic data were as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.93(m,1H),2.71(m,2H),2.38(t,2H),1.95-1.42(m, 8H),1.35(t,1H),1.30(d,1H)。
into a reaction flask, 104.2g of Compound (V) (0.5 mol,1.0 eq) was charged, and 1402.5g of 2% aqueous potassium hydroxide solution was added to adjust the pH to 8.8About 9.2 g of ferric bromide is added, the reaction temperature is controlled to be 20-30 ℃, oxygen is slowly introduced into the reaction system, and the reaction is carried out for more than 3 hours. After the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adopting hydrochloric acid to adjust the pH value to 1-2, and stirring for 2 hours. After filtration and drying of the filter cake to dryness, recrystallization from ethyl acetate and n-heptane, filtration and drying gave 75.5g of the product compound (VI) in 73.2% yield. The nuclear magnetic data are as follows: 1 H-NMR(CDCl 3 ,400MHz):δ＝11.3ppm (s,1H)；3.58(m,1H)；3.18(t,2H)；2.48(m,2H)；1.3-2.30(m,8H)。
example 4:
128.1g of cyclohexane anhydride (1 mol,1 eq) and 600mL of 2-methyltetrahydrofuran and 14.3g of cuprous bromide (0.1 mol,0.1 eq) were added to the reaction flask, the temperature was lowered to-20℃and 550mL of 2M vinyl magnesium chloride (1.1 mol,1.1 eq) was added dropwise to the reaction solution, and the reaction was continued for 1 hour. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is washed once with sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, the distillation is carried out under reduced pressure until no fraction is generated, and the crude product of the compound (II) is obtained and is directly put into the next reaction.
Taking the whole batch of the crude product of the compound (II), putting the batch into an autoclave, adding 336.2g of sodium sulfide nonahydrate solid (1.4 mol,1.4 eq), 0.64g of elemental sulfur (0.02 mol,0.02 eq) and 1000mL of water, heating to 110-120 ℃ and reacting for 5 hours. After the reaction is finished, cooling to room temperature, acidifying to pH 3-4 by adopting hydrochloric acid, extracting for 3 times by adopting 2-methyltetrahydrofuran, merging organic phases, distilling until no fraction is basically generated, adding 500g of methanol to obtain a methanol solution of the compound (III), and directly putting into the next reaction.
The methanol solution of the compound (III) in the previous step was cooled to-5 to 5℃and 53.9g of potassium borohydride (1.0 mol,1.0 eq) was added in portions, followed by stirring for 1 hour. After the reaction, adding an ammonium chloride aqueous solution to quench the reaction. Methanol was distilled off, 2-methyltetrahydrofuran and aqueous sodium chloride solution were added, stirred for 30min, and the layers were separated. The aqueous layer is extracted for 3 times by adopting 2-methyltetrahydrofuran, the organic phases are combined, reduced pressure distillation is carried out to a certain volume, and the compound (IV) is obtained and directly put into the next reaction.
114.2g of thiourea (1.5 mol,1.5 eq) and 809.0g of 20% hydrobromic acid (2.0 mol,2.0 eq) were added to a reaction flask, the temperature was raised to 60℃and the solution of the compound (IV) obtained in the above step was slowly added dropwise to the reaction solution, and the reaction was carried out at 80℃for at least 10 hours after the completion of the dropwise addition. After the completion of the reaction, 822.8g of 30% aqueous potassium hydroxide (4.4 mol,4.4 eq) was added, and the hydrolysis reaction was carried out at 50℃for at least 2 hours. After the reaction, hydrochloric acid is adopted to adjust the pH value to 3-4, chloroform is adopted to extract for 3 times, the organic phases are combined, and half-saturated saline water is adopted to wash for 1 time. After distillation to no fraction, the residue was purified by molecular distillation to give 117.3g of compound (V), four-step reaction yield 56.3%, and nuclear magnetic data as follows: 1 H NMR (CDCl 3 ,400MHz)δ:2.93(m,1H),2.71(m,2H),2.38(t,2H),1.95-1.42(m,8H), 1.35(t,1H),1.30(d,1H)。
104.2g of compound (V) (0.5 mol,1.0 eq) is added into a reaction bottle, 1000g of 2% sodium hydroxide aqueous solution is added, the pH is regulated to 8.8-9.2, 0.20g of ferric chloride is added, the reaction temperature is controlled to be 20-30 ℃, oxygen is slowly introduced into the reaction system, and the reaction is carried out for more than 3 hours. After the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adopting hydrochloric acid to adjust the pH value to 1-2, and stirring for 2 hours. After filtration and drying of the cake to dryness, recrystallization from ethyl acetate and n-heptane, filtration and drying gave 80.5g of the product compound (VI) in 78.0% yield. The nuclear magnetic data are as follows: 1 H-NMR(CDCl 3 ,400MHz):δ＝11.3ppm (s,1H)；3.58(m,1H)；3.18(t,2H)；2.48(m,2H)；1.3-2.30(m,8H)。

Claims (5)

1. a synthesis method of 8-mercapto-6-oxo-octanoic acid, which is characterized by comprising the following synthesis steps:
step 1), nucleophilic addition of a compound (I) cyclohexane anhydride serving as a starting material and a vinyl Grignard reagent to prepare a compound (II);
step 2), the compound (II) reacts with sulfide and sulfur simple substance, and Michael addition is carried out to prepare a compound (III);
the reaction equation of steps 1) to 2) is as follows:
；
in the step 1), the compound (I) is taken as an initial raw material, and is subjected to nucleophilic addition with a vinyl Grignard reagent under the catalysis of a cuprous reagent to prepare a compound (II), the compound (I) and the vinyl Grignard reagent react in a solvent at the reaction temperature of-80-20 ℃, and the compound (II) or a solution thereof is obtained through post-treatment;
in the step 2), the compound (II) reacts with sulfide and elemental sulfur in an autoclave at an internal temperature of 60-200 ℃, and the compound (III) or a solution thereof is prepared by post-treatment, wherein the molar ratio of the compound (II), the sulfide and the elemental sulfur is 1:1.0 to 10.0:0.01 to 1.0;
in the step 1), the molar ratio of the cyclohexane anhydride to the vinyl Grignard reagent is 1:0.9-3.0, wherein the vinyl Grignard reagent is any one or more of vinyl magnesium chloride, vinyl magnesium bromide and vinyl magnesium iodide;
in the step 1), the cuprous reagent is any one or more of cuprous iodide, cuprous chloride, cuprous bromide and cuprous acetate;
in the step 2), the sulfide is any one or more of sodium sulfide, potassium sulfide, sodium hydrosulfide and potassium hydrosulfide.
2. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1, wherein in step 1), the solvent is any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane.
3. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1, wherein the vinyl grignard reagent in the step 1) is vinyl magnesium bromide, and the molar ratio of the cyclohexane anhydride to the vinyl grignard reagent is 1:1.0-1.2.
4. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1, wherein the cuprous reagent in step 1) is cuprous iodide, and the molar ratio of the cyclic anhydride to the cuprous reagent is 1:0.05-0.2.
5. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1, wherein in the step 2), the reaction temperature is 100-150 ℃, and the molar ratio of the compound (II), sulfide and elemental sulfur is 1:1.0 to 2.0:0.1 to 0.3.
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