CN114907242A - Synthesis method of 8-mercapto-6-oxooctanoic acid - Google Patents

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

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CN114907242A
CN114907242A CN202210613120.3A CN202210613120A CN114907242A CN 114907242 A CN114907242 A CN 114907242A CN 202210613120 A CN202210613120 A CN 202210613120A CN 114907242 A CN114907242 A CN 114907242A
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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
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Abstract

The invention discloses a synthesis method of 8-mercapto-6-oxooctanoic acid, belonging to the field of medicine synthesis and preparation. The synthesis method of 8-mercapto-6-oxo octanoic acid is characterized by comprising the following synthesis steps: step 1), taking compound (I) cyclohexanedianhydride as a starting material, and performing nucleophilic addition on the compound (I) with a vinyl Grignard reagent to obtain a compound (II); and 2) reacting the compound (II) with sulfide and sulfur simple substance to perform Michael addition to prepare a compound (III). The synthesis method of 8-mercapto-6-oxooctanoic 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 synthesis method of 8-mercapto-6-oxooctanoic acid.
Background
The lipoic acid has a double-sulfur five-membered ring structure, has high charge density, is easy to generate free radical oxidation, has obvious antioxidant capacity, and can play an antioxidant role through various mechanisms such as free radical scavenging or other antioxidant regeneration. In the medical field, lipoic acid is widely used in the prevention and treatment of diabetes and its related complications; in the field of health care products, lipoic acid is mainly used for eliminating free radicals in vivo, preventing lipid peroxidation, protecting cells from oxidative damage and achieving the purposes of preventing and treating diseases in an auxiliary way. Besides the main purposes, the lipoic acid also has a plurality of potential applications in the aspects of resisting tumors, treating inflammation, ischemia-reperfusion injury, radiation injury, acute and chronic liver diseases and the like.
Lipoic acid, the synthetic scheme of which is numerous, is reviewed in the literature as follows:
in 1957, Donald S.Acker et al adopted adipic acid monoester as a raw material to prepare lipoic acid through 7 steps of reactions such as acyl chlorination, addition, reduction, chlorination, cyclization, hydrolysis and acidification, wherein the yield of the method is only 20.88%.
Figure BDA0003672744640000011
In 1953, m.w. bullock et al prepared lipoic acid by 6 steps of elimination, addition, reduction, hydrolysis, thiol substitution and cyclization starting from 6-carbonyl-8-chlorooctanoate, which was obtained in a yield of 17% starting from monoethyl adipate chloride.
Figure BDA0003672744640000021
In 1954, Lester J.Reed, etc. take 6-carbonyl-8-chlorooctanoate as raw material, and prepare lipoic acid through 4 steps of reduction, chlorination, cyclization, hydrolysis, acidification, etc. The yield of the process is not more than 30 percent, the process needs to react with metallic sodium in a liquid ammonia environment, the reaction is dangerous, deep cooling reaction is needed, and the process is not suitable for large-scale production.
Figure BDA0003672744640000022
In 1957, August Segre et al used cyclohexanone as a raw material, and produced lipoic acid through condensation, coupling, carbonyl protection, reduction, acetylation, deprotection, Baeyer-Villiger oxidation, sulfhydrylation, oxidation and other nine reactions, and the yield of the product is 20%. The whole synthesis route is long, the steps are multiple, the operation is complicated, and the method is not suitable for industrial mass production.
Figure BDA0003672744640000031
In 1999, King and blunt et al, university of Shenyang pharmacy, reported that cyclohexanone was used as a raw material, and that the yield reached 25% by five-step reactions such as condensation, coupling, Baeyer-Villiger oxidation, sulfhydrylation, and oxidation.
Figure BDA0003672744640000032
Chavan et al, using cyclohexanone and ethyl chloroacetate as raw materials, prepare lipoic acid through multiple reactions such as alkylation, elimination, reduction, Cbz protection, oxidation, reduction, methylation, deprotection, Ms protection, cyclization, hydrolysis, etc. The synthesis route is long and the yield is only 15%. The process uses diazomethane and other explosive raw materials, and DIBAL-H also needs to react at the low temperature of-78 ℃, and the series of factors all make the method difficult to carry out industrial production.
Figure BDA0003672744640000041
Maitreyee Bezbarua et al use 2-nitrocyclohexanone as a raw material to prepare 6, 8-dihydroxymethyl octanoate through 5 steps of alkylation, ring opening, methylation, fermentation reduction, demethylation and the like, the yield is only 18%, and industrial production cannot be really developed.
Figure BDA0003672744640000042
In 1989, Aravamdan et al used acetoacetate and 4-iodobutyronitrile as raw materials and prepared them by 7-step reactions such as alkylation, enzymatic 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-butyl lithium, sodium hydrogen and the like are used, so the process is extremely easy to explode and dangerous, and is not suitable for industrial production.
Figure BDA0003672744640000051
In 1995, Adger et al, starting from ethyl 2-cyclohexanone acetate, catalyzed the (R) -enantiomer by a monooxygenase enzyme (MO2) to give a selective Baeyer-Villiger oxidation, which gave a yield of 34% under optimal conditions. Then (R) -alpha-lipoic acid is prepared by ring opening, Mitsunobu, hydrolysis, Ms protection, cyclization, hydrolysis and other reactions. The method has the advantages of expensive raw materials, low yield, high cost and unsuitability for industrial production.
Figure BDA0003672744640000052
The existing synthetic routes have the defects of long steps, need to use expensive reagents, relate to flammable and explosive dangerous reagents or production processes, need special production equipment, cause 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, which is simple in reaction, low in cost, and ultimately easy to industrially produce.
Disclosure of Invention
The technical problem to be solved by the invention is as follows:
the synthesis method of the 8-mercapto-6-oxooctanoic acid, which has the advantages of easily obtained raw materials, higher yield, better quality, simple and convenient operation and suitability for industrial production, is developed;
finally, the synthetic method for preparing the lipoic acid can also achieve the requirements of high quality, high yield and simple and convenient operation, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the specific synthetic process is as follows:
a method for synthesizing 8-mercapto-6-oxo octanoic acid comprises the following synthesis steps:
step 1), performing nucleophilic addition on compound (I) cyclohexanedianhydride serving as a starting material and a vinyl Grignard reagent to obtain a compound (II);
step 2), enabling the compound (II) to act with sulfide and sulfur simple substance, and carrying out Michael addition to prepare a compound (III);
the reaction equations for steps 1) to 2) are as follows:
Figure BDA0003672744640000061
as a further improvement of the scheme, in the step 1), compound (I) cyclohexanedianhydride is used as a starting material, and undergoes nucleophilic addition with a vinyl grignard reagent under the catalysis of a cuprous reagent to prepare compound (II), the compound (I) and the vinyl grignard reagent react in a solvent at a reaction temperature of-80 to 20 ℃, and the compound (II) or a solution thereof is obtained through aftertreatment.
As a further improvement of the 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 cyclohexanedianhydride 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 the 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 the sulfide and the elemental sulfur in an autoclave at an internal temperature of 60-200 ℃, and the compound (II) or the solution thereof is prepared by post-treatment, wherein the molar ratio of the compound (II) to the sulfide to the elemental sulfur is 1: 1.0-10.0: 0.01 to 1.0.
As a further improvement of the above scheme, in the step 2), the sulfide is any one or more of sodium sulfide, potassium sulfide, sodium hydrogen sulfide and potassium hydrogen sulfide.
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 cyclohexanedianhydride 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 scheme, in the step 2), the reaction temperature is 100-150 ℃, and the molar ratio of the compound (II), the sulfide and the elemental sulfur is 1: 1.0-2.0: 0.1 to 0.3.
The synthetic method of the lipoic acid provided by the invention has the following advantages:
1) the invention route in the synthetic method of 8-mercapto-6-oxo octanoic acid is relatively simple, the raw materials are commercial materials, and the raw materials are relatively cheap, have no complex special operation, and are suitable for industrial production;
2) the 8-mercapto-6-oxooctanoic acid is prepared through the steps 1) and 2), and a new synthesis scheme is finally provided for the synthesis and preparation of the lipoic acid;
3) the 8-mercapto-6-oxooctanoic acid is prepared by the method, and then the 8-mercapto-6-oxooctanoic acid is prepared by the product 8-mercapto-6-oxooctanoic acid.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described with reference to the following embodiments:
example 1:
Figure BDA0003672744640000071
128.1g of cyclohexanedianhydride (1mol, 1eq), 600mL of tetrahydrofuran and 19.0g of cuprous iodide (0.1mol, 0.1eq) were added to a reaction flask, the temperature was reduced to-20 ℃, 600mL of 2M vinylmagnesium bromide (1.2mol, 1.2eq) was added dropwise to the reaction solution, and the reaction was allowed to proceed for 1 hour with incubation. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is continuously washed once by sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, reduced pressure distillation is carried out until no fraction is produced, and a crude product of the compound (II) is obtained and directly put into the next reaction.
And (3) putting the whole batch of the crude product of the compound (II) into a high-pressure kettle, adding 288.2g of sodium sulfide nonahydrate solid (1.2mol, 1.2eq), 0.64g of sulfur simple substance (0.02mol, 0.02eq) and 1000mL of water, heating to 110-120 ℃, and reacting for 5 hours. After the reaction is finished, cooling to room temperature, acidifying with hydrochloric acid until the pH value is 3-4, extracting with tetrahydrofuran for 3 times, combining organic phases, distilling until no fraction is generated, adding 500g of methanol to obtain a methanol solution of a compound (III), and directly putting the methanol solution into the next reaction.
Figure BDA0003672744640000081
And cooling the methanol solution of the compound (III) in the last step to-5 ℃, adding 37.8g of sodium borohydride (1.0mol,1.0eq) in batches, and stirring for 1h after the addition is finished. After the reaction, an aqueous ammonium chloride solution was added to quench the reaction. Distilling to remove methanol, adding tetrahydrofuran and sodium chloride water solution, stirring for 30min, and layering. The water layer is extracted by tetrahydrofuran for 3 times, organic phases are combined, reduced pressure distillation is carried out to a certain volume, and a compound (IV) is obtained and directly put into the next reaction.
76.12g of thiourea (1.0mol,1.0eq) and 438.0g of 20% hydrochloric acid (2.4mol, 2.4eq) were added to a reaction flask, the temperature was raised to 60 ℃, the compound (IV) solution obtained in the previous step was slowly added dropwise to the reaction solution, and after completion of the dropwise addition,the temperature is increased to 80 ℃ for reaction for at least 10 hours. After the reaction, 586.7g of 30% liquid caustic soda (4.4mol, 4.4eq) was added, and the mixture was kept at 50 ℃ for hydrolysis reaction for at least 2 hours. After the reaction is finished, adjusting the pH value to 3-4 by using hydrochloric acid, extracting for 3 times by using chloroform, combining organic phases, and washing for 1 time by using half-saturated saline solution. After distillation to no fraction, the residue was purified by molecular distillation to prepare 125.2g of compound (V) in a four-step reaction yield of 60.1%, with the following nuclear magnetic data: 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)。
adding 104.2g of the compound (V) (0.5mol,1.0eq) into a reaction bottle, adding 1000g of 2% sodium hydroxide aqueous solution, adjusting the pH to 8.8-9.2, adding 0.08g of ferric sulfate, controlling the reaction temperature to be 20-30 ℃, slowly introducing oxygen into the reaction system, and reacting for more than 3 hours. And after the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adjusting the pH to 1-2 by using hydrochloric acid, and stirring for 2 hours. Filtration, drying of the filter cake, recrystallization from ethyl acetate and n-heptane, filtration and drying gave 77.4g of product compound (VI) in 75.0% 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)。
example 2:
Figure BDA0003672744640000091
128.1g of cyclohexanedianhydride (1mol, 1eq), 600mL of tetrahydrofuran and 19.0g of cuprous iodide (0.1mol, 0.1eq) were added to a reaction flask, cooled to-10 ℃, 525mL of 2M vinylmagnesium bromide (1.05mol, 1.05eq) was added dropwise to the reaction mixture, and the reaction was allowed to proceed for 1 hour with incubation. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is continuously washed once by sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, reduced pressure distillation is carried out until no fraction is produced, and a crude product of the compound (II) is obtained and directly put into the next reaction.
And (3) putting the whole batch of the crude product of the compound (II) into a high-pressure kettle, adding 360.3g of sodium sulfide nonahydrate solid (1.5mol,1.5eq), 0.64g of sulfur simple substance (0.02mol, 0.02eq) and 1000mL of water, heating to 110-120 ℃, and reacting for 5 hours. After the reaction is finished, cooling to room temperature, acidifying with hydrochloric acid until the pH value is 3-4, extracting with tetrahydrofuran for 3 times, combining organic phases, distilling until no fraction is generated, adding 500g of methanol to obtain a methanol solution of a compound (III), and directly putting the methanol solution into the next reaction.
Figure BDA0003672744640000092
And cooling the methanol solution of the compound (III) in the last step to-5 ℃, adding 41.6g of sodium borohydride (1.1mol, 1.1eq) in batches, and stirring for 1h after the addition is finished. After the reaction, an aqueous ammonium chloride solution was added to quench the reaction. Distilling to remove methanol, adding tetrahydrofuran and sodium chloride aqueous solution, stirring for 30min, and layering. The water layer is extracted by tetrahydrofuran for 3 times, organic phases are combined, reduced pressure distillation is carried out to a certain volume, and a compound (IV) is obtained and directly put into the next reaction.
76.12g of thiourea (1.0mol,1.0eq) and 1534.8g of 20% hydroiodic acid (2.4mol, 2.4eq) were added to a reaction flask, the temperature was raised to 60 ℃, the solution of the compound (IV) obtained in the above step was slowly added dropwise to the reaction solution, and after completion of the dropwise addition, the temperature was raised to 80 ℃ for reaction for at least 10 hours. After the reaction, 586.7g of 30% liquid caustic soda (4.4mol, 4.4eq) was added, and the mixture was kept at 50 ℃ for hydrolysis reaction for at least 2 hours. After the reaction is finished, adjusting the pH value to 3-4 by using hydrochloric acid, extracting for 3 times by using chloroform, combining organic phases, and washing for 1 time by using half-saturated saline solution. After distillation to no fraction, the residue was purified by molecular distillation to give 131.7g of compound (V) in 63.2% yield in four steps with the following nuclear magnetic data: 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 the compound (V) (0.5mol,1.0eq) was added to a reaction flask, 1000g of a 2% aqueous solution of sodium hydroxide was added, the pH was adjusted to 8.8 to 9.2, 0.08g of ferric chloride was added, the reaction temperature was controlled to 20 to 30 ℃, oxygen was slowly introduced into the reaction system, and the reaction was carried out for 3 hours or more.And after the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adjusting the pH to 1-2 by using hydrochloric acid, and stirring for 2 hours. Filtration, drying of the filter cake, recrystallization from ethyl acetate and n-heptane, filtration and drying gave 78.9g of the product compound (VI) in 76.5% 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 3:
Figure BDA0003672744640000101
128.1g of cyclohexanedianhydride (1mol, 1eq), 600mL of tetrahydrofuran and 19.0g of cuprous iodide (0.1mol, 0.1eq) were added to a reaction flask, the temperature was reduced to-20 ℃, 600mL of 2M vinylmagnesium chloride (1.2mol, 1.2eq) was added dropwise to the reaction solution, and the reaction was allowed to proceed for 1 hour with incubation. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is continuously washed once by sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, reduced pressure distillation is carried out until no fraction is produced, and a crude product of the compound (II) is obtained and directly put into the next reaction.
And (3) putting the whole batch of the crude product of the compound (II) into an autoclave, adding 288.2g of sodium sulfide nonahydrate solid (1.2mol, 1.2eq), 1.6g of sulfur simple substance (0.05mol, 0.05eq) and 1000mL of water, heating to 130-140 ℃, and reacting for 4 hours. After the reaction is finished, cooling to room temperature, acidifying with hydrochloric acid until the pH value is 3-4, extracting with tetrahydrofuran for 3 times, combining organic phases, distilling until no fraction is produced, adding 500g of ethanol to obtain an ethanol solution of a compound (III), and directly putting the ethanol solution into the next reaction.
Figure BDA0003672744640000111
And (3) cooling the ethanol solution of the compound (III) in the last step to-5 ℃, adding 21.8g of lithium borohydride (1.0mol,1.0eq) in batches, and stirring for 1h after the addition is finished. After the reaction, an aqueous ammonium chloride solution was added to quench the reaction. Distilling to remove ethyl, adding tetrahydrofuran and sodium chloride water solution, stirring for 30min, and layering. The water layer is extracted by tetrahydrofuran for 3 times, organic phases are combined, reduced pressure distillation is carried out to a certain volume, and a compound (IV) is obtained and directly put into the next reaction.
76.12g of thiourea (1.0mol,1.0eq) and 1534.8g of 20% hydroiodic acid (2.4mol, 2.4eq) were added to a reaction flask, the temperature was raised to 60 ℃, the solution of the compound (IV) obtained in the above step was slowly added dropwise to the reaction solution, and after completion of the dropwise addition, the temperature was raised to 80 ℃ for reaction for at least 10 hours. After the reaction, 822.8g of 30% aqueous potassium hydroxide solution (4.4mol, 4.4eq) was added, and the mixture was kept at 50 ℃ for hydrolysis reaction for at least 2 hours. After the reaction is finished, adjusting the pH value to 3-4 by using hydrochloric acid, extracting for 3 times by using chloroform, combining organic phases, and washing for 1 time by using half-saturated saline solution. After distillation to no fraction, the residue was purified by molecular distillation to give 122.5g of compound (V) in 58.8% yield in four steps with the following nuclear magnetic data: 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)。
adding 104.2g of the compound (V) (0.5mol,1.0eq) into a reaction bottle, adding 1402.5g of 2% potassium hydroxide aqueous solution, adjusting the pH to 8.8-9.2, adding 0.2g of ferric bromide, controlling the reaction temperature to be 20-30 ℃, slowly introducing oxygen into the reaction system, and reacting for more than 3 hours. And after the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adjusting the pH to 1-2 by using hydrochloric acid, and stirring for 2 hours. Filtration, drying of the filter cake, recrystallization from ethyl acetate and n-heptane, filtration and drying gave 75.5g of 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:
Figure BDA0003672744640000121
128.1g of cyclohexanedianhydride (1mol, 1eq), 600mL of 2-methyltetrahydrofuran and 14.3g of cuprous bromide (0.1mol, 0.1eq) were charged into a reaction flask, cooled to-20 ℃, 550mL of 2M vinylmagnesium chloride (1.1mol, 1.1eq) was added dropwise to the reaction mixture, and the mixture was allowed to react for 1 hour with heat preservation. After the reaction, the reaction solution is quenched by hydrochloric acid, filtered and layered. The organic phase layer is continuously washed once by sodium chloride aqueous solution, the internal temperature is controlled below 50 ℃, reduced pressure distillation is carried out until no fraction is produced, and a crude product of the compound (II) is obtained and directly put into the next reaction.
And (3) putting the whole batch of the crude product of the compound (II) into a high-pressure kettle, adding 336.2g of sodium sulfide nonahydrate solid (1.4mol, 1.4eq), 0.64g of sulfur simple substance (0.02mol, 0.02eq) and 1000mL of water, heating to 110-120 ℃, and reacting for 5 hours. After the reaction is finished, cooling to room temperature, acidifying with hydrochloric acid until the pH value is 3-4, extracting with 2-methyltetrahydrofuran for 3 times, combining organic phases, distilling until no fraction is generated, adding 500g of methanol to obtain a methanol solution of a compound (III), and directly putting the methanol solution into the next reaction.
Figure BDA0003672744640000122
And cooling the methanol solution of the compound (III) in the last step to-5 ℃, adding 53.9g of potassium borohydride (1.0mol,1.0eq) in batches, and stirring for 1h after the addition is finished. After the reaction, an aqueous ammonium chloride solution was added to quench the reaction. Distilling to remove methanol, adding 2-methyltetrahydrofuran and sodium chloride water solution, stirring for 30min, and layering. The water layer is extracted for 3 times by adopting 2-methyltetrahydrofuran, organic phases are combined, reduced pressure distillation is carried out to a certain volume, and a compound (IV) is obtained and is directly put into the next reaction.
114.2g of thiourea (1.5mol,1.5eq) and 809.0g of 20% hydrobromic acid (2.0mol, 2.0eq) were added to a reaction flask, the temperature was raised to 60 ℃, the solution of the compound (IV) obtained in the above step was slowly added dropwise to the reaction solution, and after completion of the dropwise addition, the temperature was raised to 80 ℃ for reaction for at least 10 hours. After the completion of the reaction, 822.8g of a 30% aqueous solution of potassium hydroxide (4.4mol, 4.4eq) was added and the hydrolysis reaction was carried out at 50 ℃ for at least 2 hours. After the reaction is finished, adjusting the pH value to 3-4 by using hydrochloric acid, extracting for 3 times by using chloroform, combining organic phases, and washing for 1 time by using half-saturated saline solution. Distilling until no fraction is obtained, purifying the residual liquid by molecular distillation to obtain 117.3g of Compound (V), 56.3% yield in a four-step reaction, NMR 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 the compound (V) (0.5mol,1.0eq) was added to a reaction flask, 1000g of a 2% aqueous solution of sodium hydroxide was added, the pH was adjusted to 8.8 to 9.2, 0.20g of ferric chloride was added, the reaction temperature was controlled to 20 to 30 ℃, oxygen was slowly introduced into the reaction system, and the reaction was carried out for 3 hours or more. And after the reaction is finished, filtering, cooling the filtrate to 0-10 ℃, adjusting the pH to 1-2 by using hydrochloric acid, and stirring for 2 hours. Filtration, drying of the filter cake, 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 (10)

1. the synthesis method of 8-mercapto-6-oxo octanoic acid is characterized by comprising the following synthesis steps:
step 1), performing nucleophilic addition on compound (I) cyclohexanedianhydride serving as a starting material and a vinyl Grignard reagent to obtain a compound (II);
step 2), enabling the compound (II) to act with sulfide and sulfur simple substance, and carrying out Michael addition to prepare a compound (III);
the reaction equations of steps 1) to 2) are as follows:
Figure FDA0003672744630000011
2. the synthesis method of 8-mercapto-6-oxooctanoic acid according to claim 1, wherein in step 1), compound (I) cyclohexane dianhydride is used as a starting material, and undergoes nucleophilic addition with vinyl Grignard reagent under catalysis of cuprous reagent to obtain compound (II), the compound (I) and the vinyl Grignard reagent react in a solvent at a reaction temperature of-80 to 20 ℃, and the compound (II) or a solution thereof is obtained through post-treatment.
3. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 2, wherein in the step 1), the solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane.
4. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 2, wherein in the step 1), the molar ratio of the cyclohexanedianhydride 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.
5. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 2, wherein in the step 1), the cuprous reagent is any one or more of cuprous iodide, cuprous chloride, cuprous bromide and cuprous acetate.
6. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1, wherein in the step 2), the compound (II) reacts with sulfide and elemental sulfur at an internal temperature of 60 to 200 ℃ in an autoclave, and the compound (III) or a solution thereof is obtained by post-treatment, wherein the molar ratio of the compound (II) to the sulfide to the elemental sulfur is 1: 1.0-10.0: 0.01 to 1.0.
7. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 6, wherein in the step 2), the sulfide is any one or more of sodium sulfide, potassium sulfide, sodium hydrogen sulfide, and potassium hydrogen sulfide.
8. 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 cyclohexanedianhydride to the vinyl Grignard reagent is 1:1.0 to 1.2.
9. The method for synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1, wherein the cuprous reagent in the step 1) is cuprous iodide, and the molar ratio of the cyclohexanedianhydride to the cuprous reagent is 1:0.05 to 0.2.
10. The method of synthesizing 8-mercapto-6-oxooctanoic acid according to claim 1,
in the step 2), the reaction temperature is 100-150 ℃, and the molar ratio of the compound (II), the sulfide and the elemental sulfur is 1: 1.0-2.0: 0.1 to 0.3.
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