Method for preparing mercapto primary alcohol compound

Abstract

The invention relates to a method for preparing a mercapto primary alcohol compound, and belongs to the technical field of perfume synthesis. The method comprises the following steps: carrying out nucleophilic addition reaction on a substance as shown in a formula (I) and thiocyanate in a molar ratio of 1: (1-2) to obtain intermediates as shown in a formula (II) and a formula (III), and carrying out reduction reaction on the intermediates as shown in a formula (IV) and a formula (V) in a molar ratio of 1: (2-4) and a reducing agent to obtain products as shown in a formula (IV) and a formula (V). # imgabs0 #; in the formula (I), R is selected from-CH3,-CH2CH3,-(CH2) 2CH3 or-(CH2) 4CH3.

Description

Technical Field

[0001] The invention belongs to the technical field of fragrance synthesis, relates to the technical field of synthesis of primary alcohols containing mercapto groups, and specifically relates to a method for preparing primary mercapto alcohol compounds. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] The unique tropical flavor of tropical fruits is very popular among consumers. The source of the tropical flavor is mainly volatile sulfur compounds (VCS), of which thiol compounds are an important part. Typical thiol compounds in nature are often found in the volatile components of coffee, grapefruit and beef soup. Among them, 3-thiol-1-ol alkyl compounds and 4-thiol-1-ol alkyl compounds have very obvious tropical fruit aroma.

[0004] The current synthesis method is shown below. .

[0005] It is mainly through the thiolation of aliphatic 3-alkyl substituted lactone compounds, and then catalytic reduction to obtain 3-mercapto-1-ol alkyl compounds and 4-mercapto-1-ol alkyl compounds. This synthesis method has the following disadvantages: 1. The raw material is aliphatic alkyl lactone, which is expensive and has high production cost; 2. The catalyst is hydrobromic acid aqueous solution, which is a corrosive strong acidic fuming liquid; 3. The reaction time is long and the yield is low; 4. A large amount of ether waste will be generated during the post-treatment process, which increases the difficulty of treatment; 5. Ether has a low boiling point, is volatile and has high toxicity, which increases the difficulty of storage and transportation. Summary of the invention

[0006] In view of the deficiencies in the prior art, the purpose of the present invention is to provide a method for preparing a primary mercapto alcohol compound, which uses 1-hydroxy-3-olefin as a basic raw material, undergoes nucleophilic addition with thiocyanate, and then undergoes hydrogenation reduction to obtain a product; the method has the characteristics of readily available raw materials, low price, mild reaction conditions, simple post-treatment method, and high product yield.

[0007] In order to achieve the above object, the technical solution of the present invention is: A method for preparing a primary mercapto alcohol compound comprises: A substance represented by formula (I) and thiocyanate are subjected to a nucleophilic addition reaction at a molar ratio of 1:(1-2) to obtain intermediates represented by formula (II) and formula (III), and the intermediates are subjected to a reduction reaction with a reducing agent to obtain products represented by formula (IV) and formula (V); ; ; ; ; ; wherein R is selected from -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3 or -(CH2)4CH3.

[0008] The beneficial effects of the present invention are: In the method of the present invention, the raw materials are easily available and inexpensive; the reaction conditions are mild, and no corrosive raw materials or volatile toxic substances are involved; the post-treatment method is simple and does not produce a large amount of ether waste, and the product yield is high. DETAILED DESCRIPTION

[0009] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0010] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0011] A method for preparing a primary mercapto alcohol compound comprises: A substance represented by formula (I) and thiocyanate are subjected to a nucleophilic addition reaction at a molar ratio of 1:(1-2) to obtain intermediates represented by formula (II) and formula (III), and the intermediates are subjected to a reduction reaction with a reducing agent to obtain products represented by formula (IV) and formula (V); ; ; ; ; ; wherein R is selected from -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3 or -(CH2)4CH3.

[0012] The reaction route is as follows: .

[0013] In the nucleophilic addition reaction, taking cuprous thiocyanate as an example, the reaction mechanism is as follows: ; The nucleophilic reaction mechanism involving cuprous thiocyanate includes: cuprous thiocyanate acts as a nucleophilic reagent, the substance represented by formula (I) acts as an electrophilic substrate, the lone electron pair provided by the nucleophilic reagent attacks the electrophilic substrate, a nucleophilic addition reaction occurs, and the substances represented by formula (II) and formula (III) are generated.

[0014] Optionally, the thiocyanate is potassium thiocyanate, sodium thiocyanate or cuprous thiocyanate.

[0015] Optionally, the thiocyanate is cuprous thiocyanate.

[0016] Optionally, the molar ratio of the substance represented by formula (I) to thiocyanate is 1:1.2.

[0017] Optionally, the temperature of the nucleophilic addition reaction is 0-80° C., and the reaction time is 0.5-6 h.

[0018] Optionally, the temperature of the nucleophilic addition reaction is 40° C. and the reaction time is 2 h.

[0019] Optionally, the reaction solvent of the nucleophilic addition reaction is one or more of cyclohexane, n-hexane, n-heptane, toluene or chlorobenzene.

[0020] Optionally, the reducing agent is one or more of hydrogen, zinc powder, NaBH4 or LiAlH4.

[0021] Optionally, the molar ratio of the intermediate to the reducing agent is 1:(2-4).

[0022] Optionally, when the reducing agent is LiAlH4, the molar ratio of the intermediate to the reducing agent is 1:2.4.

[0023] Optionally, the temperature of the reduction reaction is -5~25°C, and the reaction time is 2~6h; different reducing agents correspond to different temperatures and times. If there are more intermediates as reaction substrates, the time is increased accordingly, and the final time is determined according to the reaction state detected by TLC.

[0024] Optionally, the reaction solvent of the reduction reaction is diethyl ether, methyl tert-butyl ether or tetrahydrofuran.

[0025] Example 1 When R in the substance represented by formula (I) is -(CH2)3CH3, the substance is 3-octen-1-ol (CAS No. 20125-84-2).

[0026] A three-necked flask was used as a reaction container, 30 mL of cyclohexane was added as a reaction solvent for nucleophilic addition reaction, 10 g (0.078 mol) of 3-octen-1-ol was added thereto, and the mixture was stirred at room temperature for 15 min, and N2 was replaced three times; 11.47 g (0.0936 mol) of cuprous thiocyanate was dissolved in 10 mL of ethanol to obtain a mixed solution, and the mixed solution was slowly added dropwise to the three-necked flask at room temperature.

[0027] After the dropwise addition, the temperature was raised to 40°C, stirred and refluxed for 2 hours, the temperature was lowered, and the reaction solution was spin-dried to obtain 9.2 g (0.049 mol) of a mixed solution of intermediate A of 3-thiocyanatooctane-1-ol and 4-thiocyanatooctane-1-ol, the molar ratio of 3-thiocyanatooctane-1-ol to 4-thiocyanatooctane-1-ol was 6.5:2, and the conversion rate was 63%; the intermediate A was dissolved in methyl tert-butyl ether for later use.

[0028] A three-necked flask was used as the reaction vessel, 100 mL of methyl tert-butyl ether was added as the reaction solvent for the reduction reaction, 2.4 N (equivalent, here refers to the molar ratio of the added substance to the intermediate A) of LiAlH4 was added thereto under stirring, and 10 g (0.053 mol) of intermediate A in 30 mL of methyl tert-butyl ether solution was added dropwise over 15 min.

[0029] The reaction temperature was controlled at 0-10°C; the reaction progress was monitored by TLC after the dropwise addition. After the reaction was completed, the reaction solution was stirred at room temperature for 2.5 hours, then cooled to 0°C, and 3 N (equivalent, here refers to the molar ratio of the added substance to the intermediate A) HCl aqueous solution (mass fraction 10%) was slowly added dropwise, and stirred for 10 minutes after the dropwise addition.

[0030] The phases were separated, and the aqueous phase was extracted with 3×30 mL of methyl tert-butyl ether. The organic phases were combined and spin-dried to obtain 8.8 g (0.052 mol) of a mixed solution of 3-mercapto-1-octanol and 4-mercapto-1-octanol. The molar ratio of 3-mercapto-1-octanol to 4-mercapto-1-octanol was 5.5:2, and the conversion rate was 98%.

[0031] The mixed solution was distilled to obtain 5.8 g (0.035 mol) of 3-mercapto-1-octanol with a mass yield of 58% and 1.83 g (0.011 mol) of 4-mercapto-1-octanol with a mass yield of 18.3%.

[0032] The product was subjected to mass spectrometry and nuclear magnetic resonance analysis, and the results were consistent with 3-mercapto-1-octanol and 4-mercapto-1-octanol.

[0033] Among them, the analytical test results of 3-mercapto-1-octanol include: The results of mass spectrometry detection (EI, 70 eV) were: m / z 55 (100); 41 (86); 57 (50); 61 (46); 81 (34) (148a (11) present) The results of H NMR spectrum are as follows: 1 H NMR (CDCl3, 400MHZ): δ 8.38 (s, 1H), 3.80 (t, J = 6.0Hz, 2H), 2.38-2.23 (m, 1H), 2.28-1.25 (m, 11H), 0.88 (t, J = 7.2Hz, 3H).

[0034] The test results for 4-Mercapto-1-octanol include: The results of mass spectrometry detection MS (EI, 70eV) were: m / z 162(4), 144(17), 103(34), 101(22), 87(55), 74(14), 69(100), 68(21), 67(21), 55(41), 43(14), 41(35).

[0035] The results of H NMR spectrum are as follows: 1 H NMR (CDCl3, 400MHZ): δ 8.06 (s, 1H), 4.18 (t, J = 6.0Hz, 2H), 2.82-2.73 (m, 1H), 1.96-1.25 (m, 11H), 0.91 (t, J = 7.2Hz, 3H).

[0036] This shows that the target product was successfully prepared in this example.

[0037] Example 2 A three-necked flask was used as a reaction container, 30 mL of cyclohexane was added as a reaction solvent for nucleophilic addition reaction, 10 g (0.078 mol) of 3-octen-1-ol was added thereto, and the mixture was stirred at room temperature for 15 min, and N2 was replaced three times; 9.56 g (0.078 mol) of cuprous thiocyanate was dissolved in 10 mL of ethanol to obtain a mixed solution, and the mixed solution was slowly added dropwise to the three-necked flask at room temperature.

[0038] After the dropwise addition, the temperature was raised to 40°C, stirred and refluxed for 3 h, the temperature was lowered, and the reaction solution was spin-dried to obtain 7.7 g (0.041 mol) of a mixed solution of intermediate A of 3-thiocyanatooctane-1-ol and 4-thiocyanatooctane-1-ol, the molar ratio of 3-thiocyanatooctane-1-ol to 4-thiocyanatooctane-1-ol was 7:1, and the conversion rate was 53%; the intermediate was dissolved in methyl tert-butyl ether for later use.

[0039] A three-necked flask was used as the reaction vessel, 100 mL of methyl tert-butyl ether was added as the reaction solvent for the reduction reaction, 2.4 N (equivalent concentration) of LiAlH4 was added thereto under stirring, and 10 g (0.053 mol) of intermediate A in 30 mL of methyl tert-butyl ether solution was added dropwise over 15 min.

[0040] The reaction temperature was controlled at 0-10°C. After the reaction was completed, the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was then cooled to 0°C, and a 3N HCl aqueous solution (mass fraction 10%) was slowly added dropwise. After the reaction was completed, the solution was stirred for 10 minutes.

[0041] The phases were separated, and the aqueous phase was extracted with 3×30 mL of methyl tert-butyl ether. The organic phases were combined and spin-dried to obtain 8.2 g (0.050 mol) of a mixed solution of 3-mercapto-1-octanol and 4-mercapto-1-octanol. The molar ratio of 3-mercapto-1-octanol to 4-mercapto-1-octanol was 7:2, and the conversion rate was 94%.

[0042] The mixed solution was distilled, and the analytical results were the same as those in Example 1. The results were as follows: 6 g (0.037 mol) of 3-mercapto-1-octanol was obtained, with a mass yield of 60%; and 1.2 g (0.0073 mol) of 4-mercapto-1-octanol was obtained, with a mass yield of 12%.

[0043] Example 3 A three-necked flask was used as a reaction container, 30 mL of cyclohexane was added as a reaction solvent for nucleophilic addition reaction, 10 g (0.078 mol) of 3-octen-1-ol was added thereto, and the mixture was stirred at room temperature for 15 min, and N2 was replaced three times; 19.1 g (0.156 mol) of cuprous thiocyanate was dissolved in 20 mL of ethanol to obtain a mixed solution, and the mixed solution was slowly added dropwise to the three-necked flask at room temperature.

[0044] After the dropwise addition, the temperature was raised to 40°C, stirred and refluxed for 0.5 h, the temperature was lowered, and the reaction solution was spin-dried to obtain 8.5 g (0.045 mol) of a mixed solution of intermediate A of 3-thiocyanatooctane-1-ol and 4-thiocyanatooctane-1-ol, the molar ratio of 3-thiocyanatooctane-1-ol to 4-thiocyanatooctane-1-ol was 6:4, and the conversion rate was 58%. The intermediate was dissolved in methyl tert-butyl ether for later use.

[0045] A three-necked flask was used as the reaction vessel, 100 mL of methyl tert-butyl ether was added as the reaction solvent for the reduction reaction, 2.4 N (equivalent concentration) of LiAlH4 was added thereto under stirring, and 10 g (0.053 mol) of intermediate A in 30 mL of methyl tert-butyl ether solution was added dropwise over 15 min.

[0046] The reaction temperature was controlled at 0-10°C. After the reaction was completed, the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was then cooled to 0°C, and a 3N HCl aqueous solution (mass fraction 10%) was slowly added dropwise. After the reaction was completed, the solution was stirred for 10 minutes.

[0047] The phases were separated, and the aqueous phase was extracted with 3×30 mL of methyl tert-butyl ether. The organic phases were combined and spin-dried to obtain 8.4 g (0.051 mol) of a mixed solution of 3-mercapto-1-octanol and 4-mercapto-1-octanol. The molar ratio of 3-mercapto-1-octanol to 4-mercapto-1-octanol was 6:4, and the conversion rate was 95.5%.

[0048] The mixed solution was distilled to obtain 4.4 g (0.037 mol) of 3-mercapto-1-octanol with a mass yield of 44% and 2.7 g (0.016 mol) of 4-mercapto-1-octanol with a mass yield of 27%.

[0049] Example 4 A three-necked flask was used as a reaction container, 30 mL of cyclohexane was added as a reaction solvent for nucleophilic addition reaction, 10 g (0.078 mol) of 3-octen-1-ol was added thereto, and the mixture was stirred at room temperature for 15 min, and N2 was replaced three times; 9.04 g (0.093 mol) of potassium thiocyanate was dissolved in 10 mL of ethanol to obtain a mixed solution, and the mixed solution was slowly added dropwise to the three-necked flask at room temperature.

[0050] After the dropwise addition, the temperature was raised to 60°C, stirred and refluxed for 6 hours, cooled, and the reaction solution was spin-dried to obtain 3.3 g (0.018 mol) of a mixed solution of intermediate A of 3-thiocyanatooctane-1-ol and 4-thiocyanatooctane-1-ol, the molar ratio of 3-thiocyanatooctane-1-ol to 4-thiocyanatooctane-1-ol was 9:2, and the conversion rate was 23%.

[0051] Example 5 A three-necked flask was used as a reaction container, 30 mL of cyclohexane was added as a reaction solvent for nucleophilic addition reaction, 10 g (0.078 mol) of 3-octen-1-ol was added thereto, and the mixture was stirred at room temperature for 15 min, and N2 was replaced three times; 7.55 g (0.093 mol) of sodium thiocyanate was dissolved in 10 mL of ethanol to obtain a mixed solution, and the mixed solution was slowly added dropwise to the three-necked flask at room temperature.

[0052] After the dropwise addition, the temperature was raised to 60°C, stirred and refluxed for 6 hours, cooled, and the reaction solution was spin-dried to obtain 4.1 g (0.022 mol) of a mixed solution of intermediate A of 3-thiocyanatooctane-1-ol and 4-thiocyanatooctane-1-ol, the molar ratio of 3-thiocyanatooctane-1-ol to 4-thiocyanatooctane-1-ol was 7:2, and the conversion rate was 28%.

[0053] Example 6 According to the method in Example 1, 30 mL of methyl tert-butyl ether solution of intermediate A was obtained. After hydrogen replacement three times, hydrogen was continuously introduced and reacted at room temperature. Samples were taken every 2 hours to monitor the reaction progress.

[0054] After the reaction was completed, the reaction solution was cooled to 0°C; 3N HCl aqueous solution (mass fraction 10%) was slowly added dropwise, and stirred for 10 minutes after the dropwise addition was completed.

[0055] The phases were separated, the aqueous phase was extracted with 3×30 mL of methyl tert-butyl ether, and the organic phases were combined and spin-dried to obtain 6.2 g (0.038 mol) of a mixed solution of 3-mercapto-1-octanol and 4-mercapto-1-octanol. The molar ratio of 3-mercapto-1-octanol to 4-mercapto-1-octanol was 6:2, and the conversion rate was 73%.

[0056] Example 7 According to the method in Example 1, 30 mL of methyl tert-butyl ether solution of intermediate A was obtained.

[0057] A three-necked flask was used as a reaction vessel, 100 mL of methyl tert-butyl ether was added as a reaction solvent for the reduction reaction, 2N zinc powder was added thereto under stirring, and 10 g (0.053 mol) of intermediate A in 30 mL of methyl tert-butyl ether solution was added dropwise over 15 min.

[0058] After hydrogen replacement three times, hydrogen was continuously introduced, the reaction was carried out at 10°C, sampling was performed every 2 hours, and the reaction progress was monitored by TLC detection; after the reaction was completed, the reaction solution was cooled to 0°C; 3N HCl aqueous solution (mass fraction 10%) was slowly added dropwise, and the mixture was stirred for 10 minutes after the dropwise addition was completed.

[0059] The phases were separated, and the aqueous phase was extracted with 3×30 mL of methyl tert-butyl ether. The organic phases were combined and spin-dried to obtain 8.1 g (0.050 mol) of a mixed solution of 3-mercapto-1-octanol and 4-mercapto-1-octanol. The molar ratio of 3-mercapto-1-octanol to 4-mercapto-1-octanol was 6.5:2, and the conversion rate was 94%.

[0060] Example 8 According to the method in Example 1, 30 mL of methyl tert-butyl ether solution of intermediate A was obtained.

[0061] A three-necked flask was used as the reaction vessel, 100 mL of methyl tert-butyl ether was added as the reaction solvent for the reduction reaction, 2.4 N NaBH4 was added thereto under stirring, and 10 g (0.053 mol) of intermediate A in 30 mL of methyl tert-butyl ether solution was added dropwise over 15 min.

[0062] After closing the reaction at 10°C, sample the mixture every 2 hours and monitor the progress of the reaction by TLC. After the reaction, stir the mixture at room temperature for 2.5 hours and then cool the reaction mixture to 0°C. Slowly add 3N HCl aqueous solution (mass fraction 10%) and stir the mixture for 10 minutes after closing the reaction.

[0063] The phases were separated, and the aqueous phase was extracted with 3×30 mL of methyl tert-butyl ether. The organic phases were combined and spin-dried to obtain 7.4 g (0.045 mol) of a mixed solution of 3-mercapto-1-octanol and 4-mercapto-1-octanol. The molar ratio of 3-mercapto-1-octanol to 4-mercapto-1-octanol was 5.82, and the conversion rate was 86%.

[0064] In the above examples, Example 1, Example 2 and Example 3 show the effect of the difference in the molar ratio of 3-octen-1-ol and thiocyanate on the reaction conversion rate, specifically: the reaction conversion rate when 0.078 mol of 3-octen-1-ol is respectively matched with 0.0936 mol, 0.078 mol and 0.156 mol of cuprous thiocyanate; Example 1, Example 4 and Example 5 show the effects of different thiocyanate types on the reaction conversion rate, specifically: thiocyanic acid ketone, sodium thiocyanate, potassium thiocyanate, among which thiocyanic acid ketone is the best thioagent.

[0065] Example 1, Example 6, Example 7 and Example 8 respectively demonstrate the effects of different types of reducing agents on the reaction conversion rate, specifically: the reaction conversion rate when LiAlH4 is used as the reducing agent, hydrogen is used as the reducing agent, zinc powder and hydrogen are used as the reducing agent, and NaBH4 is used as the reducing agent.

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a primary mercapto alcohol compound, characterized in that: The substance represented by formula (I) in a molar ratio of 1:(1-2) is subjected to a nucleophilic addition reaction with thiocyanate to obtain intermediates represented by formula (II) and formula (III), and the intermediates in a molar ratio of 1:(2-4) are subjected to a reduction reaction with a reducing agent to obtain products represented by formula (IV) and formula (V); ; ; ; ; ; wherein R is selected from -CH3, -CH2CH3, -(CH2)2CH3 or -(CH2)4CH3.

2. The method for preparing a primary mercapto alcohol compound according to claim 1, wherein The thiocyanate is potassium thiocyanate, sodium thiocyanate or cuprous thiocyanate.

3. The method for preparing a primary mercapto alcohol compound as claimed in claim 2, wherein: The thiocyanate is cuprous thiocyanate.

4. The method for preparing a primary mercapto alcohol compound according to claim 1, wherein The molar ratio of the substance represented by formula (I) to thiocyanate is 1:1.

2.

5. The method for preparing a primary mercapto alcohol compound as claimed in claim 1, characterized in that The temperature of the nucleophilic addition reaction is 0-80° C., and the reaction time is 0.5-6 h.

6. The method for preparing a primary mercapto alcohol compound according to claim 5, wherein: The temperature of the nucleophilic addition reaction is 40° C. and the reaction time is 2 h.

7. The method for preparing a primary mercapto alcohol compound according to claim 1, wherein The reaction solvent of the nucleophilic addition reaction is one or more of cyclohexane, n-hexane, n-heptane, toluene or chlorobenzene.

8. The method for preparing a primary mercapto alcohol compound according to claim 1, wherein The reducing agent is one or more of hydrogen, zinc powder, NaBH4 or LiAlH4.

9. The method for preparing a primary mercapto alcohol compound according to claim 1, wherein When the reducing agent is LiAlH4, the molar ratio of the intermediate to the reducing agent is 1:2.

4.

10. The method for preparing a primary mercapto alcohol compound according to claim 1, wherein The temperature of the reduction reaction is -5 to 25°C, and the reaction time is 2 to 6 hours.

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