Preparation method of 5, 5 '-dimethyl pyrrolidine-3-alcohol

Abstract

The invention discloses a preparation method of 5, 5 '-dimethyl pyrrolidine-3-alcohol, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: reacting N-benzyl pyrrolidine-3-alcohol serving as a raw material with benzyl halide to generate an intermediate 1; carrying out oxidation reaction on the intermediate 1 under the action of an oxidant to generate an intermediate 2; reacting the intermediate 2 with a methyl Grignard reagent to generate an intermediate 3; generating imine salt from the intermediate 3 in the presence of acid, and then reacting with a methyl Grignard reagent to generate an intermediate 4; the intermediate 4 is subjected to deprotection under the action of Pd / C and hydrogen to generate the product 5, 5 '-dimethyl pyrrolidine-3-alcohol. The raw materials in the method are available in the market, and route reference is provided for synthesis of the compounds through key oxidation, double methylation and other multi-step reactions.

Description

Technical Field

[0001] The invention relates to a preparation method of 5,5'-dimethylpyrrolidin-3-ol, belonging to the technical field of organic synthesis. Background Art

[0002] 5,5'-Dimethylpyrrolidin-3-ol (CAS No: 1784937-75-2) is an important 3-pyrrolidinol compound. As a multifunctional reaction intermediate, 3-pyrrolidinol compounds can participate in a variety of organic reactions to synthesize organic compounds with specific structures and functions. By modifying and transforming the pyrrole ring and hydroxyl group in its molecules, a variety of biologically active compounds can be synthesized, providing strong support for drug research and development and new material development. In the field of drug research and development, 3-pyrrolidinol compounds are also widely used. Due to the particularity of its molecular structure, it can often be used as an active ingredient or key intermediate of certain drugs to participate in the synthesis and modification of drugs. For example, some drugs with pharmacological activities such as anti-inflammatory, antibacterial, and anti-tumor contain structural units of 3-pyrrolidinol or its derivatives. Through in-depth research on its pharmacological effects, it can provide strong support for the development of new drugs.

[0003] 5,5'-dimethylpyrrolidin-3-ol compounds are also used in skin care products, mostly in lotions or as a basic compatibility for moisturizing ingredients, especially in water-in-oil emulsion products, 5,5'-dimethylpyrrolidin-3-ol is an indispensable moisturizing raw material. In addition, 5,5'-dimethylpyrrolidin-3-ol is also used as a humectant, which has the function of absorbing moisture from the surrounding environment and providing a moisturizing effect for the skin.

[0004] There is no report on the synthesis of 5,5'-dimethylpyrrolidin-3-ol. Therefore, it is necessary to conduct in-depth research on the synthesis route of 5,5'-dimethylpyrrolidin-3-ol and provide a simple, safe, stable and economical process route with easy-to-obtain raw materials to meet the growing market demand. Summary of the invention

[0005] In order to solve the above technical problems, the present invention discloses a preparation method of 5,5'-dimethylpyrrolidin-3-ol. N-benzylpyrrolidin-3-ol is used as a raw material to react with a benzyl halide to generate an intermediate 1; intermediate 1 is oxidized under the action of an oxidant to generate an intermediate 2; intermediate 2 reacts with a methyl Grignard reagent to generate an intermediate 3; intermediate 3 generates an imide salt in the presence of an acid, and then reacts with a methyl Grignard reagent to generate an intermediate 4; intermediate 4 is deprotected under the action of Pd / C and hydrogen to generate the product 5,5'-dimethylpyrrolidin-3-ol. The raw materials in the present invention are all available on the market, and after multiple steps of reactions such as key oxidation and dimethylation, a route reference is provided for the synthesis of such compounds.

[0006] The preparation method of 5,5'-dimethylpyrrolidin-3-ol described in the present invention comprises the following steps:

[0007]

[0008] a) N-benzylpyrrolidin-3-ol is used as a raw material and mixed with a base in an organic solvent, and a benzyl halide is added to react to obtain an intermediate 1, i.e., N-benzylpyrrolidin-3-ol protected by alcoholic hydroxyl group;

[0009] Furthermore, in the above technical solution, in step a), the base is selected from sodium hydroxide, potassium hydroxide, sodium ethoxide or sodium tert-butoxide.

[0010] Furthermore, in the above technical solution, in step a), the benzyl halide is selected from benzyl chloride, diphenylmethane or benzyl bromide.

[0011] Furthermore, in the above technical solution, in step a), the organic solvent is selected from DMSO, DMF or DMAc.

[0012] Furthermore, in the above technical solution, in step a), the molar ratio of N-benzylpyrrolidin-3-ol, base and benzyl halide is 1:1.2-1.4:1.2-1.4.

[0013] b): adding iodine to 2-methyltetrahydrofuran and mixing, adding intermediate 1 to the above solution, dropping sodium bicarbonate aqueous solution, then dropping hydrogen peroxide, adding saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution after the reaction is completed, extracting with dichloromethane, and distilling under reduced pressure to obtain intermediate 2;

[0014] Furthermore, in the above technical solution, in step b), the molar ratio of the intermediate 1, iodine, sodium bicarbonate and hydrogen peroxide is 1:1.0-1.5:2.5-3.5:1.0-1.5.

[0015] c): Intermediate 2 is mixed in tetrahydrofuran (THF), methyl Grignard reagent (3.0M in THF) is slowly added, followed by dilute acid hydrolysis, and intermediate 3 is extracted;

[0016] Furthermore, in the above technical solution, in step c), the molar ratio of the intermediate 2 to the methyl Grignard reagent is 1:1.1-1.2.

[0017] d): Intermediate 3 is mixed in toluene, tetrafluoroboric acid or perchloric acid is added for dehydration reaction, filtered after the reaction is completed, and recrystallized from ethanol to obtain intermediate 4;

[0018] e): Intermediate 4 is mixed in tetrahydrofuran (THF), methyl Grignard reagent is slowly added, and then dilute acid is added for hydrolysis, and intermediate 5 is extracted;

[0019] Furthermore, in the above technical solution, in step e), the molar ratio of the intermediate 4 to the methyl Grignard reagent is 1:1.2-1.3.

[0020] f): The intermediate 5 is mixed in an organic solvent, and Pd / C is added for catalytic hydrogenation to carry out a deprotection reaction, followed by concentration and reduced pressure distillation to obtain the product 5,5'-dimethylpyrrolidin-3-ol.

[0021] Furthermore, in the above technical solution, in step f), the organic solvent is selected from methanol, ethanol or isopropanol.

[0022] The present invention has the following beneficial effects:

[0023] 1. The present invention adopts a new multi-step route with good feasibility.

[0024] 2. The oxidation step of the present invention uses iodine and hydrogen peroxide to oxidize pyrrolidone, and the reaction yield reaches 82%, providing a route reference for the synthesis of such compounds.

[0025] 3. The present invention adopts two methyl Grignard reagent reactions to convert the carbonyl group into dimethyl, which has a novel route and good feasibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the HNMR spectrum of 5,5'-dimethylpyrrolidin-3-ol obtained in Example 1. Specific embodiments

[0027] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0028] Synthesis of 5,5'-Dimethylpyrrolidin-3-ol

[0029] Example 1

[0030] Under nitrogen protection, 17.7 g (0.1 mol) of N-benzylpyrrolidin-3-ol, 8.8 g (0.13 mol) of sodium ethoxide and 55 mL of DMSO were mixed, the temperature was raised to 50-55°C, 16.5 g (0.13 mol) of benzyl chloride was slowly added dropwise, and the temperature was maintained at 50-55°C after the addition was completed, and the reaction was carried out for 6 hours, and the temperature was lowered to room temperature, 1 M hydrochloric acid was added to adjust the pH to 8-9, 60 mL of toluene was added to extract twice, the toluene layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 1, 24.3 g, with a yield of 91%. LC-MS [M+H] + =268.5

[0031] Under nitrogen protection, 8.3 g (0.065 mol) of iodine was added to 124.5 mL of 2-methyltetrahydrofuran and mixed, and intermediate 1 (13.4 g, 0.05 mol) was added, and then sodium bicarbonate (12.6 g dissolved in 50 mL of water) aqueous solution was added dropwise, and the reaction was carried out at room temperature for 1.5 hours, and then 30% hydrogen peroxide 7.4 g (0.065 mol) was added dropwise, and the temperature was raised to 65-70°C, and the reaction was carried out for 6 hours. After sampling GC to detect that there was no residual raw material, 50 mL of saturated sodium thiosulfate aqueous solution was then added to neutralize 50 mL of saturated sodium bicarbonate aqueous solution, and 100 mL of dichloromethane was extracted twice, and the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 2, 11.5 g, with a yield of 82%. LC-MS [M+H] + =282.5

[0032] Under nitrogen protection, intermediate 2 (14.1 g, 0.05 mol) and 42.2 mL of tetrahydrofuran were mixed, the reaction temperature was controlled at 0-10°C, 19.2 mL of methylmagnesium chloride Grignard reagent (3.0 M in THF) was slowly added, and after the addition was completed, the reaction was continued at 0-10°C for 2 hours, then the temperature was raised to room temperature and the reaction was continued for 2 hours. After sampling GC to detect that there was no residual raw material, 0.1 M hydrochloric acid was added for hydrolysis, 50 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 3, 10.4 g, with a yield of 70%. LC-MS [M+H] + =298.4

[0033] Under nitrogen protection, in a reaction flask equipped with a water separator, intermediate 3 (14.9 g, 0.05 mol), B(C6F5)3 (0.4 g) and 110 mL of toluene were added, and 40% fluoroboric acid aqueous solution (11.5 g, 0.052 mol) was added, and the temperature was raised to reflux for reaction for 8 hours, and the temperature was lowered to room temperature and concentrated. The remaining reactants were added to 120 mL of ethanol, heated to reflux and recrystallized to obtain intermediate 4, 8.3 g, with a yield of 45%; 1HNMR(400MHz,DMSO-d6):7.11-7.33(m,10H),4.42(s,2H),3.46(m,1H),2.71( s,2H),2.26-2.33(m,2H),1.65-1.84(d,1H),1.52-1.62(d,1H),1.18(s,3H).

[0034] Under nitrogen protection, intermediate 4 (14.1 g, 0.05 mol) and 42.2 mL of tetrahydrofuran were mixed, the reaction temperature was controlled at 0-10°C, 20.8 mL of methylmagnesium chloride Grignard reagent (3.0 M in THF) was slowly added, and after the addition was completed, the reaction was continued at 0-10°C for 5 hours, then the temperature was raised to room temperature and the reaction was continued for 5 hours, 0.1 M hydrochloric acid was added for hydrolysis, 50 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 5, 7.4 g, with a yield of 50%. LCMS [M+H] + =296.5

[0035] Under nitrogen protection, intermediate 5 (14.8 g, 0.05 mol) and 44.3 g ethanol were added to the autoclave, and 0.7 g Pd / C (10% Pd, 50% water) was added. The nitrogen was replaced 3 times, the temperature was raised to 60-65°C, H2 was introduced, the pressure was maintained at 0.2 MPa, and the reaction was carried out for 8 hours. After sampling GC to detect that there was no residual raw material, the temperature was lowered, filtered, and the filtrate was concentrated and distilled under reduced pressure to obtain the product 5,5'-dimethylpyrrolidin-3-ol, 5.3 g, with a yield of 92%. GC purity was 99.3%. 1 HNMR (400MHz, CDCl3): 4.43(m,1H),3.06-3.10(m,1H),2.91-2.94(m,1H),1.78-1.92(m,3H),1.56-1.60(d,1H),1.31(s,3H),1.13(s,3H).

[0036] Example 2

[0037] Under nitrogen protection, 17.7 g (0.1 mol) of N-benzylpyrrolidin-3-ol, 5.2 g (0.13 mol) of sodium hydroxide and 55 mL of DMF were mixed, the temperature was raised to 50-55 ° C, and 20.5 g (0.12 mol) of benzyl bromide was slowly added dropwise. After the addition was completed, the temperature was maintained at 50-55 ° C, and the reaction was continued for 5 hours. The temperature was lowered to room temperature, 1 M hydrochloric acid was added to adjust the pH to 8-9, and 60 mL of toluene was added to extract twice. The toluene layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 1, 22.7 g, with a yield of 85%;

[0038] Under nitrogen protection, iodine 6.4g (0.05mol) was added to 124.5mL 2-methyltetrahydrofuran and mixed, intermediate 1 (13.4g, 0.05mol) was added, and then sodium bicarbonate (12.6g dissolved in 50mL water) aqueous solution was added dropwise, and the reaction was carried out at room temperature for 1.5 hours, followed by dropwise addition of 30% hydrogen peroxide 8.5g (0.075mol), and the temperature was raised to 65-70°C, and the reaction was carried out for 8 hours. After sampling GC to detect that there was no residue of raw materials, 50mL saturated sodium thiosulfate aqueous solution was then added to neutralize 50mL saturated sodium bicarbonate aqueous solution, and 100mL dichloromethane was added to extract twice, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 2, 10.8g, with a yield of 77%;

[0039] Under nitrogen protection, intermediate 2 (14.1 g, 0.05 mol) and 42.2 mL of tetrahydrofuran were mixed, the reaction temperature was controlled at 0-10 ° C, 20.0 mL of methyl magnesium chloride Grignard reagent (3.0 M in THF) was slowly added, and after the addition was completed, the reaction was continued at 0-10 ° C for 2 hours, then the temperature was raised to room temperature and the reaction was continued for 2 hours. After sampling GC to detect that there was no residual raw material, 0.1 M hydrochloric acid was added for hydrolysis, and 50 mL of dichloromethane was added for extraction twice. The organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 3, 10.1 g, with a yield of 68%;

[0040] Under nitrogen protection, in a reaction flask equipped with a water separator, intermediate 3 (14.9 g, 0.05 mol), B(C6F5)3 (0.4 g) and 110 mL of toluene were added, and 40% fluoroboric acid aqueous solution (12.0 g, 0.054 mol) was added, and the temperature was raised to reflux for reaction for 8 hours, and 120 mL of ethanol was added, and the mixture was heated to reflux and then recrystallized to obtain intermediate 4, 7.9 g, with a yield of 43%;

[0041] Under nitrogen protection, intermediate 4 (14.1 g, 0.05 mol) and 42.2 mL of tetrahydrofuran were mixed, the reaction temperature was controlled at 0-10 ° C, 21.7 mL of methyl magnesium chloride Grignard reagent (3.0 M in THF) was slowly added, and after the addition was completed, the reaction was continued at 0-10 ° C for 5 hours, then the temperature was raised to room temperature and the reaction was continued for 5 hours, 0.1 M hydrochloric acid was added for hydrolysis, 50 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 5, 6.9 g, with a yield of 47%;

[0042] Under nitrogen protection, intermediate 5 (14.8 g, 0.05 mol) and 44.3 g methanol were added to the autoclave, and 0.5 g Pd / C (10% Pd, 50% water) was added. The nitrogen was replaced 3 times, the temperature was raised to 55-60°C, H2 was introduced, and the pressure was maintained at 0.2 MPa. The reaction was carried out for 10 hours. After sampling GC to detect that there was no residual raw material, the temperature was lowered, filtered, and the filtrate was concentrated and distilled under reduced pressure to obtain the product 5,5'-dimethylpyrrolidin-3-ol, 5.0 g, with a yield of 87%. GC purity was 99.1%.

[0043] Example 3

[0044] Under nitrogen protection, 17.7 g (0.1 mol) of N-benzylpyrrolidin-3-ol, 7.8 g (0.14 mol) of potassium hydroxide and 50 mL of DMAc were mixed, the temperature was raised to 40-45 ° C, and 15.2 g (0.12 mol) of benzyl chloride was slowly added dropwise. After the addition was completed, the temperature was maintained at 40-45 ° C, and the reaction was carried out for 7 hours. The temperature was lowered to room temperature, 1 M hydrochloric acid was added to adjust the pH to 8-9, and 60 mL of toluene was added to extract twice. The toluene layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 1, 23.5 g, with a yield of 88%;

[0045] Under nitrogen protection, iodine 9.5g (0.075mol) was added to 124.5mL 2-methyltetrahydrofuran and mixed, intermediate 1 (13.4g, 0.05mol) was added, and then sodium bicarbonate (12.6g dissolved in 50mL water) aqueous solution was added dropwise, and the reaction was carried out at room temperature for 1.5 hours, followed by dropwise addition of 30% hydrogen peroxide 5.7g (0.05mol), and the temperature was raised to 70-75°C, and the reaction was carried out for 8 hours. After sampling GC to detect that there was no residue of raw materials, 50mL saturated sodium thiosulfate aqueous solution was then added to neutralize 50mL saturated sodium bicarbonate aqueous solution, and the mixture was extracted twice with 100mL dichloromethane, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 2, 11.1g, with a yield of 79%;

[0046] Under nitrogen protection, intermediate 2 (14.1 g, 0.05 mol) and 42.2 mL of tetrahydrofuran were mixed, the reaction temperature was controlled at 0-10 ° C, 18.3 mL of methyl magnesium chloride Grignard reagent (3.0 M in THF) was slowly added, and after the addition was completed, the reaction was continued at 0-10 ° C for 2.5 hours, and then the temperature was raised to room temperature and the reaction was continued for 2.5 hours. After sampling GC to detect that there was no residual raw material, 0.1 M hydrochloric acid was added for hydrolysis, and 50 mL of dichloromethane was added for extraction twice. The organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 3, 9.7 g, with a yield of 65%;

[0047] Under nitrogen protection, in a reaction flask equipped with a water separator, intermediate 3 (14.9 g, 0.05 mol), B(C6F5)3 (0.6 g) and 110 mL of toluene were added, and 70% aqueous perchloric acid solution (7.4 g, 0.052 mol) was added, and the temperature was raised to reflux for reaction for 5 hours, and 145 mL of ethanol was added, and the mixture was heated to reflux and then recrystallized to obtain intermediate 4, 12.9 g, with a yield of 68%;

[0048] Under nitrogen protection, intermediate 4 (14.1 g, 0.05 mol) and 42.2 mL of tetrahydrofuran were mixed, the reaction temperature was controlled at 0-10°C, 20.0 mL of methylmagnesium chloride Grignard reagent (3.0 M in THF) was slowly added, and after the addition was completed, the reaction was continued at 0-10°C for 6 hours, then the temperature was raised to room temperature and the reaction was continued for 6 hours, 0.1 M hydrochloric acid was added for hydrolysis, 50 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain intermediate 5, 6.6 g, with a yield of 45%;

[0049] Under nitrogen protection, intermediate 5 (14.8 g, 0.05 mol) and 44.3 g isopropanol were added to the autoclave, and 0.9 g Pd / C (10% Pd, 50% water) was added. The nitrogen was replaced 3 times, the temperature was raised to 65-70°C, H2 was introduced, the pressure was maintained at 0.2 MPa, and the reaction was carried out for 8 hours. After sampling GC to detect that there was no residual raw material, the temperature was lowered, filtered, and the filtrate was concentrated and distilled under reduced pressure to obtain the product 5,5'-dimethylpyrrolidin-3-ol, 5.1 g, with a yield of 89%. GC purity was 99.1%.

[0050] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 5,5'-dimethylpyrrolidin-3-ol, characterized in that: The steps include: a): N-benzylpyrrolidin-3-ol is used as a raw material and mixed with a base in an organic solvent, and a benzyl halide is added to react to obtain an intermediate 1; b): adding iodine to 2-methyltetrahydrofuran and mixing, adding intermediate 1 to the above solution, dropping sodium bicarbonate aqueous solution, then dropping hydrogen peroxide, adding saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution after the reaction is completed, extracting with dichloromethane, and distilling under reduced pressure to obtain intermediate 2; c): Mix the intermediate 2 in tetrahydrofuran, slowly add methyl Grignard reagent, then add dilute acid for hydrolysis, and extract to obtain the intermediate 3; d): Intermediate 3 is mixed in toluene, tetrafluoroboric acid or perchloric acid is added for dehydration reaction, filtered after the reaction is completed, and recrystallized from ethanol to obtain intermediate 4; e): Mix the intermediate 4 in tetrahydrofuran, slowly add methyl Grignard reagent, then add dilute acid for hydrolysis, and extract to obtain the intermediate 5; f): The intermediate 5 is mixed in an organic solvent, and Pd / C is added for catalytic hydrogenation to carry out a deprotection reaction, followed by concentration and reduced pressure distillation to obtain the product 5,5'-dimethylpyrrolidin-3-ol.

2. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step a), the base is selected from sodium hydroxide, potassium hydroxide, sodium ethoxide or sodium tert-butoxide.

3. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step a), the benzyl halide is selected from benzyl chloride, diphenylmethane chloride or benzyl bromide.

4. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step a), the organic solvent is selected from DMSO, DMF or DMAc.

5. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step a), the molar ratio of N-benzylpyrrolidin-3-ol, base and benzyl halide is 1:1.2-1.4:1.2-1.

4.

6. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step b), the molar ratio of the intermediate 1, iodine, sodium bicarbonate and hydrogen peroxide is 1:1.0-1.5:2.5-3.5:1.0-1.

5.

7. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step c), the molar ratio of the intermediate 2 to the methyl Grignard reagent is 1:1.1-1.

2.

8. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step e), the molar ratio of the intermediate 4 to the methyl Grignard reagent is 1:1.2-1.

3.

9. The method for preparing 5,5'-dimethylpyrrolidin-3-ol according to claim 1, characterized in that: In step f), the organic solvent is selected from methanol, ethanol or isopropanol.

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