CN114920651A - Synthesis method of (S) -4, 4-dimethyl-2-pentylamine hydrochloride - Google Patents
Synthesis method of (S) -4, 4-dimethyl-2-pentylamine hydrochloride Download PDFInfo
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Abstract
The invention relates to a method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride, which mainly solves the technical problem of expensive raw materials in the synthesis process of the compound. The synthesis method comprises the following steps: (1) reacting pivalaldehyde with (R) -tert-butyl sulfenamide to generate imine, and further adding the imine with a methyl Grignard reagent to generate an amino compound with an advantageous configuration; (2) the protecting group on the amino is removed under the action of acid, and the generated amino hydrochloride is dissociated through Cbz and hydrogenation; (3) free amino compound and L-tartaric acid are salified and crystallized to obtain single-configuration amino compound L-tartrate, and the amino compound L-tartrate is dissociated, added with Boc and treated with acid to obtain pure (S) -4, 4-dimethyl-2-pentylamine hydrochloride. The method avoids raw materials with relatively high cost and without large-scale sources, and greatly reduces the price of the final product.
Description
Technical Field
The invention relates to a method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride.
Background
Chiral amino compounds are often used as a framework structure to construct compounds, and can also be used as a resolution reagent and a chiral auxiliary group. As an important class, the synthesis of chiral amino compounds of alkanes has been studied by many people. Method one German chemical bulletin (Chemische Berichte 1964, 97, 3173-3182) A chiral amino compound is obtained by reducing a carboxylic acid to an alcohol, then converting it to a bromide and finally removing the bromine by hydrogenation, using a chiral amino acid as starting material. WO2014/2053 discloses that alcohols react directly with sodium iodide, zinc powder to give chiral amino compounds. The method has the advantages that the initial raw material is in a single chiral configuration, the chirality is maintained in the reaction process, and the separation and purification are not needed. However, some of the starting materials are expensive and hydrobromic acid or zinc powder is used in the middle, which is corrosive or dangerous. In the second method, the fast chemical report of medicine (J, Med. chem. 2002, 45, 4000-4010) adopts alkyl ketone as the initial material and chiral amine such as alpha-phenylethylamine to generate imine intermediate, and the imine intermediate is reduced to generate a mixture with a dominant configuration, and then the chiral amino compound is obtained by recrystallization and hydrogenation. The method has short route and mild method, but some raw materials are expensive and have low market supply, so that the scale-up production of some chiral amino compounds is limited. Method III journal of organic chemistry in Chemicals J. org. chem. 2006, 71, 6859-one 6862) also used alkyl ketones as starting materials with (R) -tert-butylsulfinamide to give imines. The imine generates a mixture of chiral compounds with advantageous configuration under the action of a special reducing agent and Lewis acid. And finally removing the protecting group by acid to obtain the chiral amino compound. Besides the expensive and low-supply raw materials, the method also needs special reducing agents to obtain better chiral selectivity, which restricts the industrial application of the method. Later synthetic journal (Synthesis 2008, 14, 2283-. The method is simple to operate, but raw materials are not easy to obtain, ether is used for the resolution, and the solvent is flammable and is not suitable for large-scale production. Based on the limitations of the above methods, it is necessary to develop a new route suitable for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride, which not only requires easily available raw materials, but also has relatively simple operation and low risk.
Disclosure of Invention
The invention aims to provide a method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride, which mainly solves the technical problem of expensive raw materials in the synthesis process of the compound.
The technical scheme of the invention is as follows: a method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride is characterized in that: the method comprises the following steps: reacting 3, 3-dimethylbutyraldehyde with (R) -tert-butyl sulfenamide to generate imine, and further adding the imine with a methyl Grignard reagent to generate an amino compound mixture; the protecting group on the amino is removed under the action of acid, and the generated amino hydrochloride is dissociated through Cbz and hydrogenation; free amino compound and L-tartaric acid are salified and crystallized to obtain single-configuration amino compound L-tartrate, and the amino compound L-tartrate is dissociated, added with Boc and treated with acid to obtain pure (S) -4, 4-dimethyl-2-pentylamine hydrochloride.
The specific technical scheme is as follows: a method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride is characterized in that: the method comprises the following steps:
(1) reacting 3, 3-dimethylbutyraldehyde with (R) -tert-butylsulfinamide to produce N- (3, 3-dimethylbutenyl) -2-methylpropane-2-sulfinamide a: dissolving 3, 3-dimethylbutyraldehyde in tetrahydrofuran, sequentially adding (R) -tert-butyl sulfinamide and anhydrous copper sulfate, stirring at room temperature overnight, and carrying out aftertreatment to obtain a compound a: n- (3, 3-dimethylbutenyl) -2-methylpropane-2-sulfinamide;
(2) and (3) reacting the compound a with methyl magnesium bromide to generate a compound b: (R) -N- ((S) -4, 4-dimethylpentan-2-yl) -2-methylpropan-2-sulfinamide and compound b': (R) -N- ((R) -4, 4-dimethylpentan-2-yl) -2-methylpropane-2-sulfinamide: dissolving a in tetrahydrofuran, adding a methyl magnesium bromide solution at 0-5 ℃, then heating to room temperature, stirring overnight, and carrying out post-treatment after the reaction to obtain a mixture of a compound b and a compound b';
(3) deprotection of a mixture of compound b and compound b': dissolving the mixture of the compound b and the compound b' in ethanol, adding hydrochloric acid/dioxane solution, stirring for 3 hours at room temperature, spin-drying the solvent, and pulping by using petroleum ether/dichloromethane to obtain a compound c: (S) -4, 4-dimethyl-2-pentylamine hydrochloride and compound c': a mixture of (R) -4, 4-dimethyl-2-pentylamine hydrochloride salts;
(4) reacting a mixture of compound c and compound c' with Cbz-OSu to produce compound d: cbz- (S) -4, 4-dimethyl-2-pentylamine and compound d': a mixture of Cbz- (R) -4, 4-dimethyl-2-pentylamine: dissolving a mixture of a compound c and a compound c 'in tetrahydrofuran/water, adding sodium bicarbonate and Cbz-OSu, stirring at room temperature for 3 hours, and performing post-treatment after the reaction to obtain a mixture of a compound d and a compound d';
(5) hydrogenating the mixture of compound d and compound d' to form compound e: (S) -4, 4-dimethyl-2-pentylamine and compound e': (R) -4, 4-dimethyl-2-pentylamine: dissolving the mixture of the compound d and the compound d 'in methanol, adding palladium carbon, hydrogenating at room temperature for 3 hours, and carrying out post-treatment after the reaction is finished to obtain a mixture of a compound e and a compound e';
(6) salifying the mixture of the compound e and the compound e' and L-tartaric acid, and recrystallizing to obtain a compound f: (S) -4, 4-dimethyl-2-pentylamine L-tartrate: dissolving a mixture of a compound e and a compound e' in ethanol, adding L-tartaric acid, stirring for half an hour to precipitate in a salt form, and then recrystallizing to obtain a compound f: (S) -4, 4-dimethyl-2-pentylamine L-tartrate;
(7) reaction of compound f with Boc anhydride yields compound g: boc- (S) -4, 4-dimethyl-2-pentylamine: dissolving the compound f in tetrahydrofuran/water, adding sodium bicarbonate and Boc anhydride, stirring at room temperature for 3 hours, and performing post-treatment after the reaction is finished to obtain a compound g;
(8) deprotection of compound g: dissolving the compound g in dichloromethane, adding hydrochloric acid/dioxane solution, stirring at room temperature for 3 hours, and spin-drying the solvent to obtain a final product c: (S) -4, 4-dimethyl-2-pentylamine hydrochloride.
The reaction formula is as follows:
the beneficial effects of the invention are: the compound a obtained in the step (1) of the invention is an important intermediate for synthesizing an amino compound with a dominant configuration. Lewis acids such as titanium tetraethoxide and the like are commonly used for catalyzing the reaction, but the post-treatment is troublesome. The method uses inorganic anhydrous copper sulfate as water absorbent to promote reaction. It should be noted that the method is only suitable for alkane aldehyde or ketone compounds, and aromatic aldehydes have poor activity and low reaction yield. The amino compound b and the compound b' generated in the step (2) have advantageous configurations in a ratio of 87: 13, and lay a foundation for later purification. And (6) performing salt formation crystallization by using L-tartaric acid to finally obtain the amino compound with a single configuration. In research and development, salt formation crystallization experiments are carried out on various chiral acids, D-tartaric acid, L-dibenzoyl tartaric acid, D-dibenzoyl tartaric acid, L-camphorsulfonic acid, D-camphorsulfonic acid and various solvents, and finally research shows that the combination of the L-tartaric acid and the ethanol can not only ensure that the chiral purity of the final compound reaches more than 99%, but also ensure that the yield is higher (62%). The advantages of the invention are as follows:
(1) by the method, cheap and easily-obtained raw materials can be selected to synthesize (S) -4, 4-dimethyl-2-pentylamine hydrochloride; (2) because the chiral raw material is used, the later chiral control is better, and the yield is greatly improved; (3) the method has the advantages of relatively simple process and convenient operation, does not use complex reaction and dangerous reagents in the middle, and can be used for large-scale production after process optimization.
Drawings
FIG. 1 is an HPLC chart of a mixture of compound c and compound c' of the present invention.
FIG. 2 is a HPLC chart of the product of the present invention.
FIG. 3 is a nuclear magnetic spectrum of the product of the present invention.
Detailed Description
Example 1: preparation of (S) -4, 4-dimethyl-2-pentylamine hydrochloride
(1) Preparation of N- (3, 3-dimethylbutenyl) -2-methylpropane-2-sulfinamide:
50g of 3, 3-dimethylbutyraldehyde was weighed and placed in a 1L three-necked reaction flask, and 300mL of tetrahydrofuran was added thereto. 60.5g of (R) -tert-butylsulfinamide and 120g of anhydrous copper sulfate were added thereto, and the mixture was stirred at room temperature overnight. Filtration, washing of the filtrate with ethyl acetate, spin-drying of the filtrate and purification of the crude product over short column gave 93g of N- (3, 3-dimethylbutenyl) -2-methylpropane-2-sulfinamide.
(2) Preparation of a mixture of (R) -N- ((S) -4, 4-dimethylpentan-2-yl) -2-methylpropan-2-sulfinamide and (R) -N- ((R) -4, 4-dimethylpentan-2-yl) -2-methylpropan-2-sulfinamide:
42.6g of N- (3, 3-dimethylbutenyl) -2-methylpropane-2-sulfinamide are dissolved in 200mL of tetrahydrofuran, and the solution is cooled to 0-5 ℃ under nitrogen protection, followed by dropwise addition of 210 mL of methylmagnesium bromide solution (3M in tetrahydrofuran). The reaction was stirred at room temperature overnight. The reaction solution was slowly poured into a mixture of 1M aqueous hydrochloric acid and ice water, and extracted three times with ethyl acetate. The combined extracts were washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried by spinning to give 45g of a crude product of a mixture of (R) -N- ((S) -4, 4-dimethylpentan-2-yl) -2-methylpropane-2-sulfinamide and (R) -N- ((R) -4, 4-dimethylpentan-2-yl) -2-methylpropane-2-sulfinamide. The crude product was used directly in the next reaction.
(3) Preparation of a mixture of (S) -4, 4-dimethyl-2-pentylamine hydrochloride and (R) -4, 4-dimethyl-2-pentylamine hydrochloride:
a mixture of (R) -N- ((S) -4, 4-dimethylpentan-2-yl) -2-methylpropan-2-sulfinyl and (R) -N- ((R) -4, 4-dimethylpentan-2-yl) -2-methylpropan-2-sulfinamide (45 g) was dissolved in 90mL of ethanol, and 60mL of a hydrochloric acid/dioxane solution was added, followed by stirring at room temperature for 3 hours. The solvent was removed by rotary drying and the solid was slurried twice with 90ml of petroleum ether/dichloromethane (vol. 10: 1) to give 34g of crude (S) -4, 4-dimethyl-2-pentylamine hydrochloride/R) -4, 4-dimethyl-2-pentylamine hydrochloride mixture, which was used directly in the next reaction. The HPLC profile of the mixture is shown in FIG. 1.
(4) Preparation of a mixture of Cbz- (S) -4, 4-dimethyl-2-pentylamine and Cbz- (R) -4, 4-dimethyl-2-pentylamine:
a mixture (34 g) of (S) -4, 4-dimethyl-2-pentylamine hydrochloride and (R) -4, 4-dimethyl-2-pentylamine hydrochloride was dissolved in 50mL of water, washed twice with 20mL of ethyl acetate, and 50mL of tetrahydrofuran, 52g of sodium hydrogencarbonate and 51g of Cbz-OSu were added to the aqueous phase in this order and stirred at room temperature for 3 hours. The reaction system was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate and the solvent was dried by rotary drying to obtain 47g of a crude mixture of Cbz- (S) -4, 4-dimethyl-2-pentylamine and Cbz- (R) -4, 4-dimethyl-2-pentylamine. The crude product was used directly in the next reaction.
(5) Preparation of a mixture of (S) -4, 4-dimethyl-2-pentylamine and (R) -4, 4-dimethyl-2-pentylamine:
a mixture of Cbz- (S) -4, 4-dimethyl-2-pentylamine and Cbz- (R) -4, 4-dimethyl-2-pentylamine (47 g) was dissolved in methanol (150 mL), and palladium on charcoal (4 g) was added thereto, followed by hydrogenation at room temperature under normal pressure for 3 hours. After completion of the reaction, celite was added and the filtrate was spin-dried to obtain 16g of a crude mixture of (S) -4, 4-dimethyl-2-pentylamine and (R) -4, 4-dimethyl-2-pentylamine. The crude product was used directly in the next reaction.
(6) Preparation of (S) -4, 4-dimethyl-2-pentylamine L-tartrate:
16g of a mixture of (S) -4, 4-dimethyl-2-pentylamine and (R) -4, 4-dimethyl-2-pentylamine is dissolved in 200mL of ethanol, 20.8g of L-tartaric acid is added, and the mixture is stirred for half an hour to precipitate salts. Heating the reaction system to 90 ℃ to dissolve, slowly cooling to 35 ℃ to precipitate solid, filtering the solid, and recrystallizing the filter cake with 200mL of ethanol to obtain 20g of (S) -4, 4-dimethyl-2-pentylamine L-tartrate.
(7) Preparation of Boc- (S) -4, 4-dimethyl-2-pentylamine:
20g of (S) -4, 4-dimethyl-2-pentylamine L-tartrate was dissolved in 50mL of water, 50mL of tetrahydrofuran, 26g of sodium hydrogencarbonate and 16.5g of Boc anhydride were added, and the mixture was stirred at room temperature for 3 hours. The reaction system was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate and the solvent Boc- (S) -4, 4-dimethyl-2-pentylamine crude product 14g was spin dried. The crude product was used directly in the next reaction.
(8) Preparation of (S) -4, 4-dimethyl-2-pentylamine hydrochloride:
boc- (S) -4, 4-dimethyl-2-pentylamine (14 g) was dissolved in methylene chloride (30 mL), and a hydrochloric acid/dioxane solution (20 mL) was added, followed by stirring at room temperature for 3 hours. The solvent was dried by evaporation to give 7.9g of (S) -4, 4-dimethyl-2-pentylamine hydrochloride. The HPLC chart of the product is shown in FIG. 2, and the NMR chart of the product is shown in FIG. 3.
Claims (8)
1. A method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride is characterized in that: the method comprises the following steps: 3, 3-dimethylbutyraldehyde and (R) -tert-butyl sulfenamide react to generate imine, and the imine is further added with a methyl Grignard reagent to generate an amino compound mixture with a dominant configuration; the protecting group on the amino group is removed under the action of acid, and the generated amino hydrochloride is dissociated through Cbz and hydrogenation; salt-forming crystallization is carried out on the free amino compound and the L-tartaric acid to obtain amino compound L-tartrate with single configuration, and pure (S) -4, 4-dimethyl-2-pentylamine hydrochloride is obtained through free, Boc and acid treatment.
2. The method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 1, wherein: the specific reaction steps are as follows:
(1) dissolving 3, 3-dimethylbutyraldehyde in tetrahydrofuran, sequentially adding (R) -tert-butyl sulfinamide and anhydrous copper sulfate, stirring at room temperature overnight, and carrying out aftertreatment to obtain a compound a: n- (3, 3-dimethylbutenyl) -2-methylpropane-2-sulfinamide;
(2) dissolving the compound a in tetrahydrofuran, adding methyl magnesium bromide solution at 0-5 ℃, then heating to room temperature, stirring overnight, and carrying out post-treatment after the reaction to obtain a compound b: (R) -N- ((S) -4, 4-dimethylpentan-2-yl) -2-methylpropane-2-sulfinamide and compound b': a mixture of (R) -N- ((R) -4, 4-dimethylpentan-2-yl) -2-methylpropan-2-sulfinamide;
(3) dissolving the mixture of the compound b and the compound b' in ethanol, adding hydrochloric acid/dioxane solution, stirring at room temperature for reaction, spin-drying the solvent, and pulping by petroleum ether/dichloromethane to obtain a compound c: (S) -4, 4-dimethyl-2-pentylamine hydrochloride and compound c': a mixture of (R) -4, 4-dimethyl-2-pentylamine hydrochloride salts;
(4) dissolving a mixture of a compound c and a compound c' in tetrahydrofuran/water, adding sodium bicarbonate and Cbz-OSu, stirring at room temperature for reaction, and carrying out post-treatment after the reaction is finished to obtain a compound d: cbz- (S) -4, 4-dimethyl-2-pentylamine and compound d': a mixture of Cbz- (R) -4, 4-dimethyl-2-pentylamine;
(5) dissolving a mixture of a compound d and a compound d' in methanol, adding palladium carbon, carrying out hydrogenation reaction at room temperature, and carrying out post-treatment after the reaction to obtain a compound e: (S) -4, 4-dimethyl-2-pentylamine and compound e': a mixture of (R) -4, 4-dimethyl-2-pentylamine;
(6) dissolving the mixture of the compound e and the compound e' in ethanol, adding L-tartaric acid, stirring to precipitate, and then recrystallizing to obtain a compound f: (S) -4, 4-dimethyl-2-pentylamine L-tartrate;
(7) dissolving the compound f in tetrahydrofuran/water, adding sodium bicarbonate and Boc anhydride, stirring at room temperature for reaction, and performing post-treatment after the reaction to obtain a compound g: boc- (S) -4, 4-dimethyl-2-pentylamine;
(8) dissolving the compound g in dichloromethane, adding hydrochloric acid/dioxane solution, stirring at room temperature for reaction, and spin-drying the solvent to obtain a final product c: (S) -4, 4-dimethyl-2-pentylamine hydrochloride; the reaction formula is as follows:
3. the method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 2, wherein: the reaction time of the step (3) is 3 hours.
4. The method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 2, wherein: the reaction time in the step (4) is 3 hours.
5. The method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 2, wherein: the reaction time in step (5) was 3 hours.
6. The method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 2, wherein: and (6) reacting for half an hour.
7. The method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 2, wherein: the reaction time in step (7) was 3 hours.
8. The method for synthesizing (S) -4, 4-dimethyl-2-pentylamine hydrochloride according to claim 2, wherein: the reaction time in step (8) was 3 hours.
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| GUANGCHENG LIU等: "Synthesis of Enantiomerically Pure N-tert-Butanesulfinyl Imines (tert-Butanesulfinimines) by the Direct Condensation of tert-Butanesulfinamide with Aldehydes and Ketones", J. ORG. CHEM., vol. 64, no. 4, pages 1278 - 1284, XP002712272, DOI: 10.1021/JO982059I * |
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