CN108440349B - Preparation method of chiral optical pure p-toluenesulfinamide - Google Patents

Preparation method of chiral optical pure p-toluenesulfinamide Download PDF

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CN108440349B
CN108440349B CN201810450631.1A CN201810450631A CN108440349B CN 108440349 B CN108440349 B CN 108440349B CN 201810450631 A CN201810450631 A CN 201810450631A CN 108440349 B CN108440349 B CN 108440349B
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toluenesulfinamide
preparation
chiral
chloride
optically pure
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CN108440349A (en
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李华
高峰
曾赛兰
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SHANGHAI TIANYE CHEMICAL Co.,Ltd.
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Shanghai Tianye Chemical Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02Sulfinic acids; Derivatives thereof
    • C07C313/06Sulfinamides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02Sulfinic acids; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

Abstract

The invention discloses a preparation method of chiral optical pure p-toluenesulfinamide, which comprises the steps of carrying out acyl chlorination on sodium p-toluenesulfinate and an acyl chlorination reagent to obtain p-toluenesulfinane chloride, then carrying out separation and dissociation on the p-toluenesulfinane chloride and hydrazine hydrate to obtain p-toluenesulfinane hydrazide, and then carrying out splitting dissociation on the p-toluenesulfinane and the p-toluenesulfinane by using a DBTA resolving agent, and finally obtaining the enantiomorph pure p-toluenesulfinamide after zinc-acetic acid cracking. The method has the advantages of simple and stable process operation, high yield and environmental friendliness, and compared with the existing process, the method has the advantages of cheap and easily-obtained raw materials, greatly reduces the production cost of the existing chiral optical pure p-toluenesulfinamide, and is favorable for industrial mass production.

Description

Preparation method of chiral optical pure p-toluenesulfinamide
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of chiral optical pure p-toluenesulfinamide.
Background
P-toluenesulfinamide, known as p-toluenesulfinamide in english, has the molecular formula: C7H9 NOS. The compound comprises R-type and S-type configurations, and the English names are (R) -p-toluenesulfinamide and (S) -p-toluenesulfinamide respectively. Since the first synthesis in the middle of the last century, it is used as one of the key chiral sources of chiral amine drugs and intermediates thereof. Especially, the chiral auxiliary group is wide in academia, is an important chemical as a chiral auxiliary group, and has important significance in chiral synthesis and chiral drug synthesis. Most drugs or drug intermediates today have amine groups and chiral optically pure p-toluenesulfinamide is a flexible source of diastereomers in asymmetric syntheses in many reports.
Both (R) -p-toluenesulfinamide and (S) -p-toluenesulfinamide are reported in the literature, wherein the synthetic route is as follows:
route one: the reaction equation is as follows:
using racemic p-toluenesulfinamide to synthesize N-p-toluenesulfinamide, using alpha-chymotrypsin to perform resolution treatment for 24 hours, obtaining (R) -p-toluenesulfinamide from the mixture, and then obtaining (S) -N-p-toluenesulfinamide by HCl treatment.
In the above method, N-p-toluenesulfonylamide is synthesized from racemic p-toluenesulfinamide and subjected to resolution treatment with alpha-chymotrypsin for 24 hours. The method has the advantages of long resolution time, difficult purification, high price of the alpha-chymotrypsin, difficult scale-up production and poor economic benefit.
Aiming at the (S) -p-toluenesulfinamide literature report, the synthetic process route is as follows:
the method comprises the following steps of taking sodium p-toluenesulfinate as a raw material to react with thionyl chloride to generate p-toluenesulfinate chloride, reacting the intermediate with L-menthol to generate corresponding chiral ester, and finally performing ammonolysis by LiHMDS to obtain (S) -p-toluenesulfinamide, wherein the reaction equation is as follows:
in the method, the LiHMDS is high in price, the proportion of the solvent is large, and the method is only effective for (S) -p-toluenesulfinamide and is not beneficial to large-scale production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method which is simple, convenient and stable to operate, high in yield, environment-friendly, low in production cost and suitable for industrial scale production of chiral optical p-toluenesulfinamide.
The invention provides a preparation method of chiral optical pure p-toluenesulfinamide. The reaction equation is as follows:
the technical scheme is realized by the following steps:
the first step is the synthesis of p-toluenesulfinic chloride.
Adding sodium p-toluenesulfonate into an organic solvent, and dropwise adding an acyl chlorination reagent at 0 ℃ to react completely to obtain p-toluenesulfinic chloride. Wherein the reaction temperature is selected from 0 ℃ to 70 ℃.
And the second step of synthesizing p-toluenesulfonyl hydrazide.
Adding p-toluenesulfinic chloride into hydrazine hydrate at 0 ℃ to react to obtain toluenesulfinalsylhydrazine, wherein the reaction temperature is selected from 0 ℃ to 30 ℃.
And thirdly, carrying out salt formation resolution and dissociation on the toluene sulfinyl hydrazide.
Adding p-toluenesulfinalshydrazide into an organic solvent, dropwise adding a tartaric acid resolving agent solution at 30 ℃, refluxing for 3 hours after the dropwise adding is finished, and slowly cooling to obtain chiral p-toluenesulfinalshydrazide complex salt. Wherein the reaction temperature is selected from 0 ℃ to 66 ℃. Then the chiral optical pure p-toluenesulfonyl hydrazide is obtained by dissociation.
And step four, synthesizing chiral optical pure p-toluenesulfinamide.
Adding chiral optically pure p-toluenesulfinil hydrazine into acetic acid and dichloromethane, adding zinc powder at 40-45 deg.c to react at 20-45 deg.c to obtain chiral optically pure p-toluenesulfinil amide.
Further, in the above technical scheme, the acyl chlorination reagent in the first step is selected from oxalyl chloride and thionyl chloride. The molar ratio of the sodium p-toluenesulfinate to the oxalyl chloride and the thionyl chloride is as follows: 1:1.1-1.25:1.5-1.8.
Further, in the above technical scheme, the organic solvent in the first step of reaction is selected from toluene, methyl tert-butyl ether, dichloromethane and benzene. The mass ratio of the sodium p-toluenesulfinate to the toluene, the methyl tert-butyl ether, the dichloromethane and the benzene is 1:5-7:6-8:7-10: 6-8.
Further, in the above technical solution, the derivative series resolving agent in the fourth step is selected from tartaric acid, DBTA and DTTA. When in splitting, 1 equivalent or 0.5 equivalent of a splitting agent is adopted to split respectively.
Wherein DBTA is Dibenzoyl-L-tartanic acid (DBTA) for short; DTTA is Di-p-toluoyl-tartaric acid (Di-p-toluoyl-tartaric acid) for short; both resolving agents include their hydrate forms.
Further, in the above technical scheme, the product EE obtained in the third step is more than 98%.
Further, in the above technical scheme, the product obtained in the fourth step is recrystallized by butyl acetate to obtain a pure product with purity of more than 99% and EE of more than 99%.
The invention has the beneficial effects that:
compared with the prior synthesis method, the invention has the following beneficial effects:
1) the invention has simple synthetic route, easily obtained raw materials, avoids using combustible raw materials such as LiMSDS or expensive raw materials such as biological enzyme, greatly facilitates the industrial scale-up production and saves the cost.
2) The p-toluenesulfonyl hydrazide obtained by the method not only improves the alkalinity, but also improves the yield. The product is easy to purify, and the reaction condition is mild.
3) The method avoids cryogenic reaction through the improvement of the resolution, and has simple operation and high atom utilization rate. The solvent and the resolving agent can be recycled and reused, the yield of the product is greatly improved, and the method is more suitable for industrial amplification.
Detailed Description
The invention is further illustrated by the following specific examples.
These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally carried out under conventional conditions.
The starting materials or reagents used in the following examples of the present invention are commercially available unless otherwise specified.
The average room temperature described in the following examples of the present invention is 20-35 ℃. Unless otherwise indicated herein, it is to be understood that,
the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers and used without treatment. The reaction was analyzed by TLC, GC, HPLC and the end of the reaction was judged by the consumption of starting material.
Example 1
The first step is as follows: synthesis of p-toluenesulfinic chloride.
(1) 267g of toluene, 53.4g of sodium p-toluenesulfinate and 0.1g N, N-dimethylformamide are put into a dry and clean 500mL four-mouth bottle by using an addition funnel, 57.5g of thionyl chloride is dripped at room temperature, the reaction is carried out for 4 hours at 55-65 ℃, the sampling GC or HPLC detection after derivatization is carried out, the raw material is less than 0.3 percent, the concentration is carried out under reduced pressure, 150g of toluene is used for replacing once, and 50g of toluene is added for dilution for standby. The external standard yield is 94%.
(2) 267g of benzene, 53.4g of sodium p-toluenesulfinate and 0.1g N, N-dimethylformamide are put into a dry and clean 500mL four-neck flask by using an addition funnel, 57.5g of thionyl chloride is dripped at room temperature, the reaction is carried out for 4 hours at 55-65 ℃, the sampling GC or HPLC detection after derivatization is carried out, the raw material is less than 0.3 percent, the concentration is carried out under reduced pressure, 150g of benzene is used for replacing once, and 50g of benzene is added for dilution for standby. The external standard yield is 93 percent.
(3) A clean dry 500mL four-necked flask is charged with 260g of methyl tert-butyl ether, 44.5g of sodium p-toluenesulfinate and 0.04g of pyridine by using an addition funnel, 16.5g of oxalyl chloride is added dropwise at 0 ℃, after the reaction is carried out for 2 hours at 35-40 ℃, the rest 20g of oxalyl chloride is added dropwise at 0 ℃, after the reaction is carried out for 2 hours at 35-40 ℃, the raw material is sampled and detected by GC or HPLC after derivatization, the concentration is carried out under reduced pressure, 150g of toluene is used for replacing once, and 45g of toluene is added for dilution for standby. The external standard yield is 89%.
(4) 330g of dichloromethane, 44.5g of sodium p-toluenesulfinate and 0.04g of pyridine are put into a dry and clean 500mL four-neck flask by using an addition funnel, 16.5g of oxalyl chloride is dropwise added at 0 ℃, after the reaction is carried out for 2 hours at 35-40 ℃, the rest 20g of oxalyl chloride is dropwise added at 0 ℃, after the reaction is carried out for 2 hours at 35-40 ℃, the raw material is sampled and detected by GC or HPLC after derivatization, the raw material is less than 0.3 percent, the concentration is carried out under reduced pressure, 150g of toluene is used for replacing once, and 45g of toluene is added for dilution for standby. The external standard yield is 91%.
The second step is that: and (3) synthesizing p-toluenesulfonyl hydrazide.
(1) 50g of 80% hydrazine hydrate and 85g of water are put into a clean 500mL four-necked bottle by using an addition funnel, 45g of the p-toluenesulfinic chloride solution diluted by toluene in the first step (3/4) is added dropwise, the temperature is controlled to be between-5 ℃ and 15 ℃, after the dropwise addition is finished, the reaction is carried out for 2 hours at the temperature of between 20 and 25 ℃, the sampling TLC detection is carried out, the mixture is kept stand, the toluene on the upper layer is partitioned, the water phase on the lower layer is centrifuged, and 37g of p-toluenesulfinate hydrazide is obtained, wherein the yield is 89. The p-toluenesulfonyl hydrazide is easy to deliquesce and needs to be stored at low temperature.
(2) 70g of 80% hydrazine hydrate and 104g of water are put into a clean 500mL four-mouth bottle by using an addition funnel, 50g of the p-toluenesulfinaloyl chloride solution diluted by benzene in the first step (2) is dripped into the bottle at the temperature of between 5 ℃ below zero and 15 ℃, after the dripping is finished, the reaction is carried out for 2 hours at the temperature of between 20 and 25 ℃, the sampling is carried out by TLC (thin layer chromatography) detection, the bottle is kept stand, the upper layer of toluene is partitioned, the lower layer of water phase is centrifuged, 45g of p-toluenesulfinaldehyde is obtained, and the. The p-toluenesulfonyl hydrazide is easy to deliquesce and needs to be stored at low temperature.
The third step: resolving and dissociating the p-toluenesulfiniyl hydrazine into salt.
(1) 140g of MTBE and 29g of p-toluenesulfonylhydrazide are added into a clean 500mL four-neck flask, 32.9g (0.5eq) of solution of D-DTTA dissolved in 150g of MTBE is dripped, the dripping temperature is controlled to be 30-45 ℃, after the dripping is finished, the reflux and heat preservation are carried out for 3 hours, the gradient is slowly cooled to 5-10 ℃, the filtration is carried out, the cold MTBE is leached, the wet product is recrystallized by 140g of MTBE, the filtration and the drying are carried out, 31.3g of resolution product is obtained, EE is 98.6 percent, and the yield is 33 percent. The resulting mixture was hydrolyzed with 4N aqueous hydrochloric acid to adjust pH to 3-4, MTBE-extracted D-DTTA was recovered and used, and the aqueous phase was adjusted with aqueous NaOH to adjust pH to 9-10, followed by extraction with dichloromethane to give 8.4g of (r) -p-toluenesulfonylhydrazide (EE 99.1%, and the dissociation yield was 87.5%).
(2) 130mL of 1, 2-dichloroethane and 29g of p-toluenesulfinalshydrazide are added into a clean 500mL four-mouth bottle, 30.5g (0.5eq) of solution of L-DBTA dissolved in 120mL of 1, 2-dichloroethane is added dropwise, the dropwise addition temperature is controlled to be 30-45 ℃, after the dropwise addition is finished, the temperature is kept for 3 hours at 63 ℃, the temperature is gradually reduced to 15-20 ℃, the filtration is carried out, the 1, 2-dichloroethane at 10 ℃ is used for leaching, and the product is dried, so that 34.2g of resolution product is obtained, wherein EE is 97.9 percent, and the yield is 38 percent. The resulting mixture was hydrolyzed with 4N aqueous hydrochloric acid to adjust pH to 3-4, MTBE-extracted D-DBTA was recovered and used, and the aqueous phase was adjusted with aqueous NaOH to adjust pH to 9-10, and extracted with dichloromethane to give 9.8g of(s) -p-toluenesulfonylhydrazide (EE 98.6%, yield of dissociation 89%).
(3) 150g of methanol, 3g of water and 32g of p-toluenesulfinalshydrazide are added into a clean 500mL four-mouth bottle, a solution of 28.2g (1eq) of D-Tartaric acid dissolved in 140g of methanol is dropwise added, the dropwise adding temperature is controlled to be 30-45 ℃, after the dropwise adding is finished, the temperature is kept at 65 ℃ for 3 hours, the temperature is gradually reduced to 0-10 ℃ in a gradient manner, the temperature is reduced to be 0-10 ℃, the wet product EE is filtered, after the wet product EE is dissolved and dissociated by NaOH, dichloromethane is extracted and concentrated, the obtained product is subjected to primary splitting through the above operation, 18.6g of split product is obtained, the EE is 99.3%, and the yield is 31%. Hydrolysis was performed with an aqueous NaOH solution, and methylene chloride was extracted to obtain 8.3g of (r) -p-toluenesulfonylhydrazide, EE ═ 99.6%, and the dissociation yield was 83%.
(4) Adding the salifying mother liquor filtered in the fourth step (3) into a clean 500mL four-mouth bottle, concentrating to dryness, adding a small amount of ethyl acetate for pulping, filtering to obtain 42.1g of solid, hydrolyzing by using a NaOH aqueous solution, extracting by using dichloromethane to obtain 20.1g of p-toluenesulfinate hydrazide, adding 100g of methanol and 1g of water, dropwise adding a solution of 17.7g (1eq) of L-Tartaric acid dissolved in 90g of methanol, controlling the dropwise adding temperature to be 30-45 ℃, keeping the temperature at 64 ℃ for 3 hours after the dropwise adding is finished, slowly cooling to 0-10 ℃ in a gradient manner, filtering, leaching by using 10g of 0 ℃ methanol, drying the product to obtain 23.8g of split product, and obtaining the yield of 63%. Hydrolysis was performed with an aqueous NaOH solution, and methylene chloride was extracted to obtain 10.7g of(s) -p-toluenesulfonylhydrazide, EE ═ 99.3%, and the dissociation yield was 85%.
The fourth step: synthesis of chiral optically pure p-toluenesulfinamide.
(1) 70g of acetic acid, 51g of (R) -p-toluenesulfinalshydrazide, 58.5g of zinc powder and 160mL of dichloromethane are added into a clean 500mL four-mouth bottle, the mixture is slowly heated to 40-45 ℃ and reacted for 9-11 hours, TLC and HPLC (high performance liquid chromatography) are sampled, the raw materials are less than 2%, the mixture is filtered, filtrate is poured into 120mL of water, 75g of dichloromethane is added for extraction each time, the total extraction is carried out for 3 times, organic phase is enriched, 30% NaOH is added for adjusting the pH value to be 7-8, the organic phase is layered, 30g of saturated sodium chloride aqueous solution is used for washing for 1 time, magnesium sulfate is dried and filtered, the filtrate is concentrated to be not smooth liquid at 25-30 ℃ under reduced pressure, butyl acetate is replaced, 251g of butyl acetate is added for recrystallization, temperature reduction and filtration are carried out, 32.1g of (R) -p-toluenesulfinamide is obtained, the HPLC purity is 99.3%, EE is 99.1%.
(2) Adding 70g of acetic acid, 51g of (S) -p-toluenesulfinalsylhydrazide (the product obtained by the method 2 in the third step), 60.5g of zinc powder and 160mL of dichloromethane into a clean 500mL four-neck flask, slowly heating to 40-45 ℃, reacting for 9-11 hours, sampling TLC, detecting by HPLC, wherein the raw material is less than 2%, filtering, pouring the filtrate into water containing 120mL, adding 75g of dichloromethane each time for extraction, co-extracting for 3 times, enriching the organic phase, adding 30% NaOH to adjust the pH value to be 7-8, layering, washing the organic phase for 1 time by using saturated sodium chloride aqueous solution 30g, drying by magnesium sulfate, filtering, concentrating the filtrate under reduced pressure at 25-30 ℃ until the filtrate is not distilled, replacing butyl acetate, adding 243g of butyl acetate for recrystallization, cooling and filtering to obtain 35.7g of (S) -p-toluenesulfinamide, the HPLC purity is 99.7%, and the EE is 99.6%, the yield is 77%, and HNMR is consistent with the literature.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.

Claims (7)

1. A method for preparing chiral optical pure p-toluenesulfinamide is characterized by comprising the following steps: 1) adding an acyl chloride reagent into an organic solvent to react with sodium p-toluenesulfinate to obtain p-toluenesulfinate chloride; 2) dripping into hydrazine hydrate to obtain p-toluenesulfonyl hydrazide; 3) adopting a DBTA resolving agent to carry out salifying resolution dissociation; 4) chiral optically pure p-toluenesulfinamide is obtained by zinc/acetic acid reduction.
2. The process for the preparation of chiral optically pure p-toluenesulfinamide according to claim 1, wherein: the acyl chlorination reagent is oxalyl chloride or thionyl chloride.
3. The process for the preparation of chiral optically pure p-toluenesulfinamide according to claim 1, wherein: the organic solvent is selected from the group consisting of toluene, methyl tert-butyl ether, dichloromethane, and benzene.
4. The process for the preparation of chiral optically pure p-toluenesulfinamide according to claim 2, characterized in that: the molar ratio of the sodium p-toluenesulfinate to the oxalyl chloride to the thionyl chloride is 1:1.1-1.25: 1.5-1.8.
5. The process for the preparation of chiral optically pure p-toluenesulfinamide according to claim 3, wherein: the mass ratio of the sodium p-toluenesulfinate to the toluene, the methyl tert-butyl ether, the dichloromethane and the benzene is 1:5-7:6-8:7-10: 6-8.
6. The process for the preparation of chiral optically pure p-toluenesulfinamide according to claim 1, wherein: when in resolution, 1 equivalent or 0.5 equivalent of resolving agent is adopted for resolution.
7. The process for the preparation of chiral optically pure p-toluenesulfinamide according to claim 1, wherein: the product is recrystallized by butyl acetate to further improve the purity, wherein the mass ratio of the product to the butyl acetate is 1: 6.5-7.
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