A method for preparing 4-mercapto-1-octanol

Abstract

The application belongs to the technical field of organic synthesis, and discloses a preparation method of 4-mercapto-1-octanol, which comprises the following steps: mixing propyl octanolide and concentrated hydrochloric acid, heating and refluxing for a set time, and separating an organic phase after cooling; adding thioacetic acid to the organic phase and controlling the temperature at 15-20 DEG C, adding a strong alkali solution thereto, heating to 30-45 DEG C, and keeping for 1-3 h to perform a condensation reaction; after the condensation reaction is completed, adding an acid to adjust the pH value to weak acidity, extracting the reaction system, washing and concentrating the organic phase, redissolving the concentrate in an organic solvent to obtain a mixed solution one; preparing a lithium aluminum hydride solution, slowly adding the mixed solution one to the lithium aluminum hydride solution under low-temperature conditions, performing a reduction reaction at a temperature lower than 20 DEG C after the addition is completed, and keeping for 1-4 h, so that the 4-mercapto-1-octanol is obtained. The raw materials are cheap and easy to obtain, the operation is simple, and the industrial value is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically a method for preparing 4-mercapto-1-octanol. The raw materials for this method are readily available, the cost is low, and the industrialization value is high. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] 4-Mercapto-1-octanol is a novel flavoring compound containing both thiol (-SH) and hydroxyl (-OH) functional groups in its molecular structure. It combines a lipophilic long-chain alkyl group with a polar active group, endowing it with excellent dispersibility and chemical reactivity in various matrices. This compound has an extremely low sensory threshold; even trace amounts can significantly enhance aroma complexity and provide a noticeable flavor-enhancing effect. In beverages and foods, it can significantly improve their mouthfeel, satisfaction, naturalness, and body, thus improving palatability. In perfumes and skincare products, it can significantly improve aroma persistence.

[0004] Currently, the synthesis method of 4-mercapto-1-octanol uses propyloctyl lactone as a raw material, first thiolated with Lawesson's reagent, then transposed with Lewis acid, and finally hydrolyzed and reduced to obtain 4-mercapto-1-octanol. This route uses expensive Lawesson's reagent, which is costly and not suitable for large-scale industrial production. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 4-mercapto-1-octanol. This method uses inexpensive and readily available raw materials and conventional reactions such as hydrolysis, chlorination, condensation, and reduction to obtain a product with high yield and purity. The method has controllable costs, inexpensive raw materials, and higher industrial feasibility.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] A method for preparing 4-mercapto-1-octanol includes the following steps: mixing propyloctyl lactone with concentrated hydrochloric acid, heating and refluxing for a set time, and then separating the organic phase after cooling.

[0008] Add thioacetic acid to the organic phase and control the temperature at 15-20℃. Add a strong alkali solution to the phase, raise the temperature to 30-45℃, and keep it at this temperature for 1-3 hours to carry out the condensation reaction.

[0009] After the condensation reaction is complete, acid is added to adjust the reaction solution to a weakly acidic state. The reaction solution is then extracted, and the extracted organic phase is washed and concentrated. The concentrate is then redissolved with an organic solvent to obtain a mixture.

[0010] Prepare a lithium aluminum hydride solution. Under low temperature conditions, slowly add mixture one to it. After the addition is complete, carry out the reduction reaction at a temperature below 20°C for 1-4 hours to obtain the final product.

[0011] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

[0012] This invention uses inexpensive propyloctyl lactone as a raw material, which is hydrolyzed and chlorinated with hydrochloric acid, then condensed with mercaptoacetic acid under alkaline conditions, and finally reduced to directly obtain 4-mercapto-1-octanol. All raw materials used are inexpensive and readily available, the operation is simple, and the industrialization value is high. Attached Figure Description

[0013] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0014] Figure 1 This is the 1H NMR spectrum of 4-mercapto-1-octanol, the product prepared in Example 1. Detailed Implementation

[0015] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0016] To address the problems of existing technologies that use propyloctyl lactone as a raw material, first thiolated with Lawesson's reagent, then transposed with Lewis acid, and hydrolyzed to obtain 4-mercapto-1-octanol, which uses expensive Lawesson's reagent, resulting in high costs and unsuitability for large-scale industrial production, this invention provides a method for preparing 4-mercapto-1-octanol, comprising the following steps: mixing propyloctyl lactone with concentrated hydrochloric acid, heating under reflux for a set time, cooling, and then separating the organic phase;

[0017] Add thioacetic acid to the organic phase and control the temperature at 15-20℃. Add a strong alkali solution to the phase, raise the temperature to 30-45℃, and keep it at this temperature for 1-3 hours to carry out the condensation reaction.

[0018] After the condensation reaction is complete, acid is added to adjust the reaction solution to a weakly acidic state. The reaction solution is then extracted, and the extracted organic phase is washed and concentrated. The concentrate is then redissolved with an organic solvent to obtain a mixture.

[0019] Prepare a lithium aluminum hydride solution. Under low temperature conditions, slowly add mixture one to it. After the addition is complete, carry out the reduction reaction at a temperature below 20°C for 1-4 hours to obtain the final product.

[0020] The specific process route is as follows:

[0021]

[0022] When gamma-octyl lactone is mixed with concentrated hydrochloric acid and heated under reflux, the hydrolysis and chlorination of gamma-octyl lactone occur, yielding an organic phase of compound II. Reflux provides the energy required for the reaction, promoting the ring-opening hydrolysis and chlorination of the lactone ring, thus accelerating the reaction process. Reflux maintains the reaction system at a higher temperature, preventing incomplete reactions due to insufficient temperature and improving the conversion rate of raw materials. Reflux also allows volatile reactants to condense and reflux, maintaining a stable concentration in the reaction system and ensuring the efficient formation of the target product.

[0023] Compound II reacts with thioacetic acid under strongly alkaline conditions to form potassium thioacetate, which increases its nucleophilic substitution activity. Then, a condensation reaction occurs to obtain compound III. After the condensation reaction is complete, acid is added to adjust the system to a weakly acidic state, maintaining the state of the carboxylic acid groups in the system, making them easy to extract and separate, and preventing the increased water solubility after salt formation, which would cause yield loss.

[0024] Compound III undergoes a reduction reaction with lithium aluminum hydride (LDH), yielding compound IV. LDH is a strong reducing agent; its reaction with a mixture containing carboxyl and thioacetate groups is vigorous. Low temperatures effectively control the reaction rate, preventing side reactions caused by localized overheating and avoiding the decomposition of LDH at high temperatures to generate hydrogen gas, thus posing a safety risk. This improves the selectivity of the reduction reaction and the yield of the target product.

[0025] In some embodiments, the mass ratio of octyl lactone to concentrated hydrochloric acid is 1:1.5-3, preferably 1:2-2.5.

[0026] Preferably, the concentration of the concentrated hydrochloric acid is 30-35%, where % is a mass percentage.

[0027] More preferably, the concentration of the concentrated hydrochloric acid is 31-33%.

[0028] In some embodiments, after adding a strong alkali solution, the pH value of the reaction system is 5-6 in the condensation reaction.

[0029] In some embodiments, after the condensation reaction is complete, acid is added to adjust the pH value to 3-5, preferably 4.

[0030] In some embodiments, the organic solvent used for extraction is dichloroethane, chloroform, or ethyl acetate. Considering both cost and solubility characteristics, dichloroform is the most suitable choice.

[0031] Preferably, the organic solvent used for extraction is dichloromethane.

[0032] In some embodiments, the organic phase is washed with saturated sodium chloride.

[0033] In some embodiments, when the concentrate is reconstituted using an organic solvent, the organic solvent is diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, or dimethoxyethane, preferably tetrahydrofuran.

[0034] In some embodiments, the solvent for the lithium aluminum hydride solution is tetrahydrofuran.

[0035] In some embodiments, after the reduction reaction is complete, an aqueous solution of ammonium chloride is added for quenching. After quenching, the mixture is allowed to stand and separate into layers. Then, the liquid is separated and the aqueous phase is collected.

[0036] Preferably, the method further includes the step of extracting the aqueous phase after separation with methyl tert-butyl ether, removing the solvent, combining the crude products, and distilling to obtain the final product.

[0037] More preferably, during the distillation, the fraction collected is at 92-94°C and 10-12 mmHg.

[0038] The present invention will be further described below with reference to the embodiments.

[0039] Example 1

[0040] The synthetic route for 4-mercapto-1-octanol is as follows:

[0041]

[0042] The specific preparation method is as follows:

[0043] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 200.8g (1.76mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate 125.1g of the lower organic phase (Formula II).

[0044] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 206 g (0.74 mol) of 20% potassium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and kept at that temperature for 2 h. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 132.7 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated liquid to prepare a mixed solution of THF.

[0045] Add 200g THF and 23.1g (0.61mol) lithium aluminum hydride to a 2000ml three-necked flask. Control the temperature at 0-5℃ and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature at T≤20℃ and slowly add 560g of 10% (% is mass percentage) ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0046] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 87.7 g of the fraction collected at 92-94℃ (10-12 mmHg) was obtained, yielding 76.9% and purity 99.2%. Figure 1 As shown, 1 HNMR(400MHz, CDCl3)δ4.05-4.09(t,1H),3.46-3.51(m,2H),3.04-3.06(d,1H),2.54-2 .64(m,1H),1.58-1.68(m,4H),1.45-1.58(m,4H),1.25-1.34(m,2H),0.88-0.91(t,3H).

[0047] Example 2

[0048] The preparation method of 4-mercapto-1-octanol is as follows:

[0049] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 160.6g (1.4mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate the lower organic phase (Formula II).

[0050] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 206 g (0.74 mol) of 20% potassium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and kept at that temperature for 2 h. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 112.6 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated liquid to prepare a mixed solution of THF.

[0051] Add 200g THF and 23.1g (0.61mol) lithium aluminum hydride to a 2000ml three-necked flask, control the temperature at 0-5℃, and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature T≤20℃ and slowly add 560g of 10% ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0052] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 80.4 g of the fraction was collected at 92-94℃ under 10-12 mmHg, with a yield of 70.4% and a purity of 98.9%.

[0053] Example 3

[0054] The preparation method of 4-mercapto-1-octanol is as follows:

[0055] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 240.9g (2.1mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate the lower organic phase (Formula II).

[0056] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 206 g (0.74 mol) of 20% potassium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and kept at that temperature for 2 hours. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 120.5 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated liquid to prepare a mixed solution of THF.

[0057] Add 200g THF and 23.1g (0.61mol) lithium aluminum hydride to a 2000ml three-necked flask, control the temperature at 0-5℃, and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature T≤20℃ and slowly add 560g of 10% ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0058] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 85.9 g of the fraction was collected at 92-94℃ under 10-12 mmHg, with a yield of 75.3% and a purity of 99.1%.

[0059] Example 4

[0060] The preparation method of 4-mercapto-1-octanol is as follows:

[0061] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 200.8g (1.76mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate 125.1g of the lower organic phase (Formula II).

[0062] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 147 g (0.74 mol) of 20% sodium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and the reaction was maintained for 2 h. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 132.7 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated solution to prepare a mixed THF solution.

[0063] Add 200g THF and 23.1g (0.61mol) lithium aluminum hydride to a 2000ml three-necked flask, control the temperature at 0-5℃, and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature T≤20℃ and slowly add 560g of 10% ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0064] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 81.4 g of the fraction was collected at 92-94℃ under 10-12 mmHg, with a yield of 71.3% and a purity of 99.0%.

[0065] Example 5

[0066] The preparation method of 4-mercapto-1-octanol is as follows:

[0067] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 200.8g (1.76mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate 125.1g of the lower organic phase (Formula II).

[0068] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 260 g (0.37 mol) of 15% sodium carbonate aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and kept at this temperature for 2 hours. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 132.7 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated liquid to prepare a mixed solution of THF.

[0069] Add 200g THF and 23.1g (0.61mol) lithium aluminum hydride to a 2000ml three-necked flask, control the temperature at 0-5℃, and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature T≤20℃ and slowly add 560g of 10% ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0070] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 77.8 g of the fraction was collected at 92-94℃ under 10-12 mmHg, with a yield of 68.2% and a purity of 99.1%.

[0071] Example 6

[0072] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 200.8g (1.76mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate the lower organic phase (Formula II).

[0073] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 206 g (0.74 mol) of 20% potassium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and kept at that temperature for 2 h. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 132.7 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated liquid to prepare a mixed solution of THF.

[0074] Add 200g THF and 19g (0.5mol) lithium aluminum hydride to a 2000ml three-necked flask, control the temperature at 0-5℃, and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature at T≤20℃ and slowly add 560g of 10% ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0075] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 74.7 g of the fraction was collected at 92-94 °C under 10-12 mmHg, with a yield of 65.5% and a purity of 98.5%.

[0076] Example 7

[0077] Add 100g (0.7mol) of propyloctyl lactone (Formula I) and 200.8g (1.76mol) of 32% concentrated hydrochloric acid to a 1000ml three-necked flask, heat to reflux for 5h, cool to room temperature, and separate the lower organic phase (Formula II).

[0078] The organic phase was transferred to a reaction flask, and 50.8 g (0.67 mol) of thioacetic acid was added. The temperature was controlled at T = 15-20℃. 206 g (0.74 mol) of 20% potassium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was raised to 40℃ and kept at that temperature for 2 h. A small amount of concentrated hydrochloric acid was added to adjust the pH to 4. 200 ml of dichloromethane was added for extraction twice. The organic phase was washed once with saturated sodium chloride and concentrated to obtain 132.7 g of pale yellow liquid (Formula III). 150 g of tetrahydrofuran (THF) was added to the concentrated liquid to prepare a mixed solution of THF.

[0079] Add 200g THF and 26.6g (0.7mol) lithium aluminum hydride to a 2000ml three-necked flask, control the temperature at 0-5℃, and slowly add the THF mixture dropwise. After the addition is complete, continue stirring the reaction for 3h. Then, control the temperature at T≤20℃ and slowly add 560g of 10% ammonium chloride aqueous solution to quench the reaction. Allow the mixture to stand and separate into layers.

[0080] The aqueous phase was extracted twice with methyl tert-butyl ether (MTBE), the solvent was removed, the crude products were combined, and the fraction was distilled. 86.0 g of the fraction was collected at 92-94℃ under 10-12 mmHg, with a yield of 75.4% and a purity of 99.2%.

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the preparation of 4-mercapto-1-octanol, characterized in that: The method comprises the following steps: mixing propyl octalactone with concentrated hydrochloric acid, heating and refluxing for a set time, and separating the organic phase after cooling; the mass ratio of propyl octalactone to concentrated hydrochloric acid is 1:2-3; Sulfacetic acid is added to the organic phase while the temperature is controlled at 15-20℃, and a strong alkali solution is added thereto, and the temperature is raised to 30-45℃, and the condensation reaction is carried out for 1-3h; After the condensation reaction is completed, an acid is added to adjust the reaction solution to be weakly acidic, the reaction solution is extracted, the extracted organic phase is washed and concentrated, the concentrate is redissolved with an organic solvent to obtain a mixed solution one; A lithium aluminum hydride solution is prepared, and the mixed solution one is slowly added thereto under low temperature, and the reduction reaction is carried out at a temperature lower than 20℃ for 1-4h, and the product is obtained.

2. The process for the preparation of 4-mercapto-1-octanol according to claim 1, characterized in that: The concentration of the concentrated hydrochloric acid is 30-35% by mass.

3. The method of claim 1, wherein: In the condensation reaction, the pH value of the reaction system is 5-6 after the strong alkali solution is added.

4. The method of claim 1, wherein: The organic solvent used in the extraction is dichloromethane, dichloroethane, trichloromethane or ethyl acetate.

5. The method of claim 1, wherein: The organic phase is washed with saturated sodium chloride.

6. The method of claim 1, wherein: When the concentrate is redissolved with an organic solvent, the organic solvent is diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether or dimethoxyethane.

7. The process for the preparation of 4-mercapto-1-octanol according to claim 6, characterized in that: The solvent of the lithium aluminum hydride solution is diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether or dimethoxyethane.

8. The method of claim 1, wherein: After the reduction reaction is completed, an aqueous ammonium chloride solution is added for quenching, and the mixture is left to separate into two layers after quenching, and then the liquid-liquid separation is carried out to collect the aqueous phase.

9. The process for the preparation of 4-mercapto-1-octanol according to claim 8, characterized in that: The aqueous phase after the liquid-liquid separation is extracted with methyl tert-butyl ether, and after the solvent is removed, the crude product is combined and rectified, and the fraction at 10-12mmHg and 92-94℃ is collected, and the product is obtained.

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