Preparation method of (R)-(+)-tert-butylsulfinamide

Abstract

The invention discloses a preparation method of (R)-(+)-tert-butyl sulfinamide. The preparation method comprises the following steps: 1, chlorinating a compound I to obtain a compound II; 2, substituting the compound II to obtain a compound III; 3, carrying out chiral oxidation on the compound III to obtain a compound IV; and 4, carrying out N-deprotection on the compound IV to obtain a compound V. According to the method, tert-butyl mercaptan is taken as a raw material, and the target product (R)-(+)-tert-butyl sulfinamide is obtained through four-step reaction of chlorination, substitution, chiral oxidation and deprotection. The safety risk of materials used in the reaction is low, compared with a traditional route, liquid ammonia is not needed to serve as a solvent for cryogenic reaction, the equipment requirement is low, operation is easy, the three-waste amount is small, the yield is high, the product quality is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, specifically to a method for preparing (R)-(+)-tert-butylsulfinamide using cyclopropionamide as a raw material. Background Technology

[0002] (R)-(+)-tert-butylsulfinamide (TBSA) is a GABA (gamma-aminobutyric acid) analogue and a central nervous system-targeting sedative with anti-anxiety and sedative effects. It can reduce anxiety and stress and promote sleep. Furthermore, it helps improve memory and attention, induces relaxation, and reduces muscle tension. Phynebacterium can also be used to prepare other drugs, such as aspirin and acetaminophen, making it a very important and widely used pharmaceutical product. Its chemical structure is shown in compound I.

[0003] .

[0004] Currently, there are multiple routes for synthesizing (R)-(+)-tert-butylsulfinamide (TBSA). The core route uses tert-butylthiol as the starting material, proceeds to tert-butyl disulfide via a one-step oxidation reaction, and then to chiral tert-butylsulfinic acid tert-butyl thioester via a one-step chiral oxidation reaction. Finally, amino substitution is performed under liquid ammonia / lithium amino acid conditions to prepare the final product. This route is relatively short, uses inexpensive materials, and can be industrialized. However, it involves two oxidation reactions and a cryogenic reaction using liquid ammonia as a solvent. The reaction conditions are harsh, and the equipment requirements are high. In the final cryogenic reaction, tert-butylthiol byproducts are released mixed with ammonia gas, producing a foul odor. It is difficult to recover and separate tert-butylthiol and ammonia gas, resulting in significant pollution. The reaction route is as follows.

[0005] .

[0006] Chinese patent CN108467353A optimizes the above route, attempting to avoid chiral oxidation and cryogenic reactions, and obtains the final product using a chemical resolution method. However, the actual small-scale test results are poor, and the steps are lengthy, offering no advantages for industrialization. The synthetic route is as follows:

[0007] .

[0008] Chinese patent CN101880249A reports the use of prepared N-methyltriphenylamine lithium instead of liquid ammonia / aminolithium to react with (R)-tert-butylsulfinic acid tert-butyl thioester to obtain (R)-tert-butylsulfinamide. This route avoids the final cryogenic reaction with liquid ammonia. However, the preparation of N-methyltriphenylamine lithium still requires a cryogenic reaction with liquid ammonia and the use of n-butyllithium, resulting in high material costs. The route also produces thiols as a byproduct, which have a strong odor and lack industrialization advantages. The reaction route is as follows:

[0009] .

[0010] An article in the journal OPRD titled "Development of Large Scale Asymmetric Process fortert-Butanesulfinamid" describes a commercially viable chiral synthetic method. This route uses chiral ligands, thionyl chloride, and tert-butylmagnesium chloride as starting materials, avoiding the use of the odorous tert-butyl mercaptan, and eliminating the cryogenic reaction of liquid ammonia / lithium amino groups, thus producing no tert-butyl mercaptan byproduct. From an industrialization perspective, this method offers significant advantages. However, the chiral ligands are expensive, and the use of costly LHMDS reagent results in high overall material costs. The synthetic route is as follows:

[0011] .

[0012] In summary, the existing synthetic process of (R)-tert-butylsulfinamide has various problems, and it is necessary to find a new synthetic route that not only avoids the cryogenic reaction of liquid ammonia / lithium aminohydride and the generation of tert-butylthiol byproducts, but also has low material costs and simple production operation, so as to have good industrialization prospects. Summary of the Invention

[0013] The purpose of this application is to provide a method for preparing (R)-(+)-tert-butylsulfinamide to solve the problems in the background art.

[0014] To achieve the above objectives, this application provides the following technical solution: a method for preparing (R)-(+)-tert-butylsulfinamide, comprising the following reaction steps: Step 1: chlorination of compound I to obtain compound II; Step 2: substitution of compound II to obtain compound III; Step 3: chiral oxidation of compound III to obtain compound IV; Step 4: N-deprotection of compound IV to obtain compound V, the reaction equation being as follows:

[0015] .

[0016] This method uses tert-butylthiol as a raw material and proceeds through four steps—chlorination, substitution, chiral oxidation, and deprotection—to obtain the target product (R)-(+)-tert-butylsulfinamide. The materials used in the reaction pose low safety risks. Compared to traditional routes, it eliminates the need for liquid ammonia as a solvent for cryogenic reactions, requires less equipment, is simple to operate, generates less waste, achieves high yields, and produces high-quality products, making it suitable for industrial production.

[0017] Further, step one includes: compound I undergoes a chlorination reaction with a chlorinating agent in an inert solvent. After the reaction is complete, the solvent is concentrated under reduced pressure to obtain compound II. Step two includes: compound II and hexamethyldisilazane are reacted with an acidifying agent dropwise in a solvent. After the reaction is complete, water is added to quench the reaction, and the mixture is separated. The organic layer is concentrated under reduced pressure to obtain compound III. Step three includes: compound III, a chiral ligand, and VO(acac)₂ are subjected to chiral oxidation by adding an oxidizing agent dropwise in a solvent to obtain compound IV. Step four includes: after the reaction in step three is completed, the reaction is quenched, tetrabutylammonium fluoride is added for deprotection, and after the deprotection reaction is complete, the solvent is concentrated under reduced pressure. Water and an organic solvent are added to extract the product. The organic layer is dried with a desiccant, concentrated under reduced pressure, and then crystallized with an alkane solvent to obtain compound V.

[0018] Furthermore, in step one, the chlorination reagents include: thioyl chloride and NCS, and the inert solvents include: dichloromethane, chloroform, carbon tetrachloride, and dichloroethane. The reaction temperature of the chlorination reaction is -10 to 20 degrees Celsius.

[0019] Furthermore, in step two, the acid-coating agents include triethylamine and pyridine, and the substitution reaction temperature is 20 to 50 degrees Celsius.

[0020] Furthermore, in step three, the chiral ligand is 3,5-di-tert-butylsalicyl(1S,2R)-1-amino-2-indanol, and the oxidizing agents include: 30% hydrogen peroxide and m-chloroperoxybenzoic acid.

[0021] Furthermore, the reaction temperature for step three, chiral oxidation, is between -10 degrees Celsius and 0 degrees Celsius.

[0022] Furthermore, in step four, the alkane solvents used for crystallization include: n-hexane, n-heptane, and cyclohexane, and the reaction temperature for N-deprotection is 20 to 50 degrees Celsius.

[0023] Further, step one includes: adding tert-butyl mercaptan and dichloromethane to the reaction flask, controlling the temperature inside the reaction flask at 10-20 degrees Celsius, adding sulfuryl chloride dropwise, reacting at 10-20 degrees Celsius for 3 hours, and concentrating the solvent under reduced pressure in a 40-degree Celsius water bath to obtain compound II in an oily form.

[0024] Step 2 includes: adding compound II and hexamethyldisilazane to dichloromethane, adding triethylamine dropwise at a controlled temperature of 0-10 degrees Celsius, reacting after the addition is complete, reacting at 0-10 degrees Celsius for 2 hours, quenching the reaction with water dropwise, allowing the mixture to stand and separate, and concentrating the organic layer under reduced pressure in a 40-degree Celsius water bath to obtain compound III;

[0025] Step 3 includes: adding compound III, the chiral ligand, and VO(acac)2 to acetone, controlling the internal temperature from -10°C to 0°C, adding 30% hydrogen peroxide dropwise to the reaction, with the addition time mainly controlled by temperature, maintaining the temperature from -10°C to 0°C for 3-5 hours after the addition is complete, adding sodium sulfite aqueous solution to quench the reaction, adding tetrabutylammonium fluoride, raising the temperature to 30-50°C and maintaining the temperature for 3-5 hours, concentrating most of the acetone under reduced pressure in a 50°C water bath, adding ethyl acetate to extract the product, drying the ethyl acetate layer with anhydrous sodium sulfate to remove water, concentrating the ethyl acetate under reduced pressure, adding n-heptane, raising the temperature to 30-40°C and stirring for 1-2 hours, lowering the temperature to 0-10°C to crystallize, filtering to obtain (R)-(+)-tert-butylsulfinamide wet product, and drying the wet product under reduced pressure at 30-35°C to obtain the finished product.

[0026] This invention has at least the following beneficial effects:

[0027] 1. The raw materials used in this preparation method are simple and readily available, with ample market supply and low material costs;

[0028] 2. This preparation method does not involve the cryogenic reaction of liquid ammonia / lithium amino acid, has low equipment requirements, produces no tert-butyl mercaptan byproduct, generates no odorous waste gas, and does not require the treatment of large amounts of ammonia and tert-butyl mercaptan mixed gas, resulting in a small amount of waste.

[0029] 3. The synthesis route of this preparation method is simple, the reaction conversion rate is high, the total yield of the route exceeds 40%, and the average yield per step exceeds 80%, which has industrialization advantages;

[0030] 4. The final product obtained by this preparation method has a chemical purity of over 99.5% and isomers of less than 0.1%. Attached Figure Description

[0031] Figure 1 The liquid phase detection spectrum of (R)-(+)-tert-butylsulfinamide prepared in Example 1 of this invention;

[0032] Figure 2 The liquid phase detection spectrum of (R)-(+)-tert-butylsulfinamide prepared in Example 2 of this invention. Detailed Implementation

[0033] The technical solutions in the embodiments of this application are described clearly and completely below. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0034] Example 1

[0035] A method for preparing (R)-(+)-tert-butylsulfinamide, the reaction route is as follows:

[0036] ,

[0037] Step 1: Add 100g of tert-butyl mercaptan and 500ml of dichloromethane to a 1000ml three-necked flask. Control the internal temperature at 10℃ and add 157.4g (1.05eq.) of thioyl chloride dropwise. After the addition is complete, react at 10℃ for 5h. Take a sample to detect GC. Concentrate the reaction solution under reduced pressure in a 30℃ water bath to remove the solvent, and obtain 140.5g of pale yellow oily compound II with a GC purity of 97.0%.

[0038] Step 2: Add 140.5g of compound II, 188g (1.05 eq.) hexamethyldisilazane, and 700ml dichloromethane to a 2000ml three-necked flask. Maintain the internal temperature at 2℃. Add 134.6g (1.2 eq.) triethylamine dropwise. After the addition is complete, react at 2℃ for 2 hours. Quench the reaction with 500ml of water. Allow the mixture to stand and separate the layers. Store the organic layer temporarily. Extract the aqueous layer once with 300ml of dichloromethane. Combine the dichloromethane layers and wash once with 300ml of water. Concentrate the dichloromethane layer under reduced pressure in a 40℃ water bath to remove the solvent, yielding 158.5g of a pale yellow oily compound III with an HPLC purity of 92%.

[0039] Step 3: Weigh 79.25g of Compound III, 1.3g of chiral ligand, and 0.94g of VO(acac)2 and add them to 300ml of acetone. Control the internal temperature at 3 degrees Celsius. Add 60g of 30% hydrogen peroxide dropwise to the reaction mixture, controlling the addition time primarily by temperature. After the addition is complete, maintain the temperature at 3 degrees Celsius for 5 hours. Quench the reaction by adding sodium sulfite aqueous solution. Add 140g of tetrabutylammonium fluoride, raise the temperature to 40 degrees Celsius, and maintain the temperature for 3 hours. Concentrate under reduced pressure in a 50-degree Celsius water bath to remove most of the acetone. Add 240ml of ethyl acetate to extract the product. Dry the ethyl acetate layer with anhydrous sodium sulfate to remove water. Concentrate under reduced pressure to remove ethyl acetate. Add 170ml of n-heptane, raise the temperature to 35 degrees Celsius, and stir for 2 hours. Cool to 5 degrees Celsius to crystallize. Filter to obtain (R)-(+)-tert-butylsulfinamide wet product. Dry the wet product under reduced pressure at 30 degrees Celsius to obtain 42g of the finished product with a purity of 99.3% and a chiral purity of 99.5%. The liquid chromatography chromatogram of (R)-(+)-tert-butylsulfinamide prepared in this embodiment is as follows: Figure 1 As shown.

[0040] Example 2

[0041] Step 1: Add 100g of tert-butyl mercaptan and 600ml of dichloromethane to a 1000ml three-necked flask. Control the internal temperature at 10℃ and add 157.4g (1.05eq.) of thioyl chloride dropwise. After the addition is complete, react at 0℃ for 6h. Take a sample to detect GC. Concentrate the reaction solution under reduced pressure in a 30℃ water bath to remove the solvent, and obtain 142g of a pale yellow oily compound II with a GC purity of 96.3%.

[0042] Step 2: Add 142g of compound II, 190g (1.05 eq.) hexamethyldisilazane, and 700ml dichloromethane to a 2000ml three-necked flask. Control the internal temperature at 4℃, and add 136g (1.2 eq.) triethylamine dropwise. After the addition is complete, react at 4℃ for 1h. Quench the reaction with 500ml of water, allow to stand, and separate the layers. Temporarily store the organic layer, and extract the aqueous layer once with 300ml of dichloromethane. Combine the dichloromethane layers and wash once with 300ml of water. Concentrate the dichloromethane layer under reduced pressure in a 40℃ water bath to remove the solvent, yielding 163.2g of a pale yellow oily compound III with an HPLC purity of 92.6%.

[0043] Step 3: Weigh 81.6g of Compound III, 1.5g of chiral ligand, and 1.06g of VO(acac)2 and add them to 320ml of acetone. Control the internal temperature at 5°C. Add 65g of 30% hydrogen peroxide dropwise to the reaction mixture, controlling the addition time primarily by temperature. After the addition is complete, maintain the reaction temperature at 5°C for 5 hours. Quench the reaction by adding sodium sulfite aqueous solution. Add 147g of tetrabutylammonium fluoride, raise the temperature to 35°C, and maintain the reaction temperature for 5 hours. Concentrate most of the acetone under reduced pressure in a 50°C water bath. Add 240ml of ethyl acetate to extract the product. Dry the ethyl acetate layer with anhydrous sodium sulfate to remove water. Concentrate the ethyl acetate under reduced pressure. Add 170ml of n-heptane, raise the temperature to 40°C, and stir for 2 hours. Cool to 2°C to crystallize. Filter to obtain (R)-(+)-tert-butylsulfinamide wet product. Dry the wet product under reduced pressure at 32°C to obtain 42.6g of the finished product with a purity of 99.4% and a chiral purity of 99.6%. The liquid chromatography chromatogram of (R)-(+)-tert-butylsulfinamide prepared in this embodiment is as follows: Figure 2 As shown.

[0044] Example 3

[0045] Step 1: Add 100g of tert-butyl mercaptan and 600ml of dichloromethane to a 1000ml three-necked flask. Control the internal temperature at 3℃ and add 157.4g (1.05eq.) of thioyl chloride dropwise. After the addition is complete, react at 3℃ for 4h. Take a sample to detect GC. Concentrate the reaction solution under reduced pressure in a 35℃ water bath to remove the solvent, and obtain 144g of pale yellow oily compound II with a GC purity of 95.7%.

[0046] Step 2: Add 144g of compound II, 191g (1.05 eq.) hexamethyldisilazane, and 700ml dichloromethane to a 2000ml three-necked flask. Control the internal temperature at 5℃, and add 136g (1.2 eq.) triethylamine dropwise. After the addition is complete, react at 5℃ for 2 hours. Add 500ml of water to quench the reaction, allow to stand, and separate the layers. Store the organic layer temporarily, and extract the aqueous layer once with 300ml of dichloromethane. Combine the dichloromethane layers and wash once with 300ml of water. Concentrate the dichloromethane layer under reduced pressure in a 40℃ water bath to remove the solvent, yielding 161g of a pale yellow oily compound III with an HPLC purity of 93.8%.

[0047] Step 3: Weigh 80.5g of Compound III, 1.5g of chiral ligand, and 1.07g of VO(acac)2 and add them to 340ml of acetone. Control the internal temperature at 3°C. Add 65g of 30% hydrogen peroxide dropwise to the reaction mixture, controlling the addition time primarily by temperature. After the addition is complete, maintain the reaction temperature at 3°C ​​for 5 hours. Quench the reaction by adding sodium sulfite aqueous solution. Add 147g of tetrabutylammonium fluoride, raise the temperature to 35°C, and maintain the reaction temperature for 5 hours. Concentrate under reduced pressure in a 50°C water bath to remove most of the acetone. Add 240ml of ethyl acetate to extract the product. Dry the ethyl acetate layer with anhydrous sodium sulfate to remove water. Concentrate under reduced pressure to remove ethyl acetate. Add 170ml of n-heptane, raise the temperature to 40°C, and stir for 3 hours. Cool to 2°C to crystallize. Filter to obtain (R)-(+)-tert-butylsulfinamide wet product. Dry the wet product under reduced pressure at 32°C to obtain 43.3g of the finished product with a purity of 99.5% and a chiral purity of 99.5%.

[0048] Unless otherwise specified, the methods used in this invention are conventional methods in the art.

[0049] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for preparing (R)-(+)-tert-butylsulfinamide, characterized in that, The synthesis route is as follows: ； The reaction steps include: Step 1: Compound I is chlorinated to obtain compound II; Step 2: Compound II is substituted to obtain compound III; Step 3: Compound III is chirally oxidized to give compound IV; Step 4: Compound IV is N-deprotected to obtain compound V.

2. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 1, characterized in that, Step one includes: Compound I undergoes a chlorination reaction with a chlorinating agent in an inert solvent. After the reaction is complete, the solvent is concentrated under reduced pressure to obtain Compound II.

3. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 1 or 2, characterized in that, Step two includes: reacting compound II and hexamethyldisilazane with an acidifying agent added dropwise in a solvent; quenching with water after the reaction is complete; separating the liquids; and concentrating the organic layer under reduced pressure to obtain compound III.

4. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 1 or 2, characterized in that, Step 3 includes: adding an oxidizing agent dropwise to compound III, a chiral ligand, and VO(acac)2 in a solvent to perform chiral oxidation and obtain compound IV.

5. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 4, characterized in that, Step four includes: quenching the reaction after the reaction in step three, adding tetrabutylammonium fluoride for deprotection, concentrating the solvent under reduced pressure after the deprotection reaction is complete, adding water and organic solvent to extract the product, drying the organic layer with a desiccant, concentrating it under reduced pressure, and then adding an alkane solvent to crystallize and obtain compound V.

6. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 2, characterized in that, In step one, the chlorination reagents include: thioyl chloride and NCS, and the inert solvents include: dichloromethane, chloroform, carbon tetrachloride, and dichloroethane. The reaction temperature of the chlorination reaction is -10 to 20 degrees Celsius.

7. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 3, characterized in that, In step two, the acid-coating agents include triethylamine and pyridine, and the substitution reaction temperature is 20 to 50 degrees Celsius.

8. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 4, characterized in that, In step three, the chiral ligand is 3,5-di-tert-butylsalicyl(1S,2R)-1-amino-2-indanol, and the oxidizing agents include hydrogen peroxide and m-chloroperoxybenzoic acid.

9. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 4, characterized in that, The reaction temperature for step three, chiral oxidation, is from -10 degrees to 0 degrees.

10. The method for preparing (R)-(+)-tert-butylsulfinamide according to claim 1, characterized in that, In step four, the alkane solvents used for crystallization include n-hexane, n-heptane, and cyclohexane, and the reaction temperature for N-deprotection is 20 to 50 degrees Celsius.

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