A method for synthesizing 2-(R)-hydroxymethylmorpholine-n-tert-butyl ester

Abstract

The application belongs to the technical field of medical intermediate synthesis, and relates to a synthesis method of 2-(R)-hydroxymethyl morpholine-N-methyl tert-butyl ester. The synthesis method comprises the following steps: taking D-glyceraldehyde and N-benzyl amino ethanol as raw materials, and performing reduction amination, hydroxyl sulfonate preparation, de-propanal protection, intramolecular ring closure under alkaline conditions, isomer purification and protection group switching to obtain 2-(R)-hydroxymethyl morpholine-N-methyl tert-butyl ester. The synthesis method can obtain 2-(R)-hydroxymethyl morpholine-N-methyl tert-butyl ester through a synthesis process which is low in cost, easy to operate, high in efficiency and yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a synthesis method of 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate. BACKGROUND

[0002] For the synthesis of 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate, two patents with publication numbers WO 200812457 and WO2016091776 disclose a six-step synthesis route of 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate from 2-ethanolamine and (R) benzyl glycidol as raw materials:

[0003]

[0004] The ring closure step of the patent has a relatively low yield due to the instability of the sulfate inner salt under alkaline conditions, and the total yield is 34%, so the production cost is relatively high.

[0005] In addition, patent WO 2012160392 discloses a method for synthesizing 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate from (S)-epichlorohydrin and benzyl amino ethanol as raw materials through two times of epoxide ring opening and hydrogenation debenzylization. At present, this method is the main method for large-scale production. However, (S)-epichlorohydrin is a 6.1 toxic substance, and some people are allergic to this compound.

[0006]

[0007] Patent WO 2009044162 discloses a synthesis method of 2-(S)-hydroxymethylmorpholine-N-tert-butyl carbamate and 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate, respectively using (S)-3-amino-1,2-propanediol or (R)-3-amino-1,2-propanediol and chloroacetyl chloride as raw materials, through four steps of amidation, ring closure and amide reduction, and upper protection group to obtain the target compound. The yield of the two steps of ring closure and amide reduction is relatively low, both less than 55%, so the total yield of 2-(S)-hydroxymethylmorpholine-N-tert-butyl carbamate and 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate is 11-12%.

[0008] Synthesis of 2-(S)-hydroxymethylmorpholine-N-tert-butyl carbamate:

[0009]

[0010] Synthesis of 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate:

[0011] SUMMARY

[0012] In view of the deficiencies of the prior art, the present application provides a synthesis method of 2-(R)-hydroxymethylmorpholine-N-carboxylic acid tert-butyl ester, which can obtain 2-(R)-hydroxymethylmorpholine-N-carboxylic acid tert-butyl ester through a synthesis process with low cost, easy operation, high efficiency and high yield.

[0013] The technical scheme provided by the present application is as follows:

[0014] The present application provides a synthesis method of 2-(R)-hydroxymethylmorpholine-N-carboxylic acid tert-butyl ester, comprising the following steps:

[0015] 2-(R)-hydroxymethylmorpholine-N-carboxylic acid tert-butyl ester is obtained by using D-glyceraldehyde acetonide and N-benzyl amino ethanol as raw materials, through reductive amination, hydroxyl sulfonate preparation, de-propanal protection, intramolecular ring closure under alkaline conditions, isomer purification and protection group switching.

[0016] Further, the reductive amination comprises the following steps:

[0017] D-glyceraldehyde acetonide and N-benzyl amino ethanol are dissolved in an organic solvent, and a first stirring reaction is carried out under the condition that the reaction liquid system is slightly acidic, then a reducing agent is added to the reaction liquid to carry out a second stirring reaction, the reaction solution is quenched with an aqueous base solution, and the organic phase is obtained by extraction with an extraction solvent, and the concentrated solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentane-4-yl)methyl)amino)ethyl-1-ol is obtained by concentration.

[0018] Further, in the reductive amination:

[0019] The organic solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran and 2-methyltetrahydrofuran;

[0020] And / or, the reducing agent is selected from any one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium borohydride acetate;

[0021] And / or, the molar ratio of D-glyceraldehyde acetonide to N-benzyl amino ethanol is 1:0.75-2.0;

[0022] And / or, the mass-volume ratio of D-glyceraldehyde acetonide to organic solvent is 1:6-15 g / mL;

[0023] And / or, the slightly acidic reaction liquid system is realized by adding glacial acetic acid or BF3•Et2O;

[0024] And / or, the molar ratio of D-glyceraldehyde acetonide to reducing agent is 1:2-3;

[0025] and / or, the temperature of the first stirring reaction and the second stirring reaction is 5-40℃;

[0026] and / or, the time of the first stirring reaction is 1-2 h, and the time of the second stirring reaction is 15-20 h;

[0027] and / or, the aqueous base solution is selected from any one or more of saturated aqueous sodium bicarbonate solution, 5wt% aqueous sodium carbonate solution, 5wt% aqueous potassium carbonate solution;

[0028] and / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, toluene.

[0029] In a preferred embodiment, in the reductive amination:

[0030] the organic solvent is dichloromethane;

[0031] and / or, the reducing agent is sodium borohydride in acetic acid;

[0032] and / or, the molar ratio of D-glyceraldehyde acetonide to N-benzyl aminoethanol is 1:0.95;

[0033] and / or, the mass to volume ratio of D-glyceraldehyde acetonide to organic solvent is 1:8 g / mL;

[0034] and / or, the molar ratio of D-glyceraldehyde acetonide to sodium borohydride in acetic acid is 1:2;

[0035] and / or, the temperature of the first stirring reaction and the second stirring reaction is 20-25℃;

[0036] and / or, the time of the first stirring reaction is 1-2 h, and the time of the second stirring reaction is 16 h;

[0037] and / or, the aqueous base solution is saturated aqueous sodium bicarbonate solution;

[0038] and / or, the extraction solvent is dichloromethane.

[0039] Further, the preparation of the hydroxyl group into a sulfonate ester comprises the following steps:

[0040] The concentrated solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol is mixed with a base in an organic solvent, and then methanesulfonyl chloride is added dropwise to the reaction solution for stirring reaction, the reaction solution is quenched with an aqueous base, and then extracted with an extraction solvent, the organic phase is concentrated, and then crystallized by adding a crystallization solvent, and then filtered to obtain (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl methanesulfonate.

[0041] Further, in the preparation of the hydroxyl group into a sulfonate:

[0042] The organic solvent is selected from any one or more of dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran;

[0043] And / or, the base is selected from any one or more of triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate;

[0044] And / or, the molar ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol to the base is 1:1.2-3.0;

[0045] And / or, the molar ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol to methanesulfonyl chloride is 1:1.2-3.0;

[0046] And / or, the mass-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol to the organic solvent is 1:3-5 g / mL;

[0047] And / or, the temperature for stirring reaction is 0-20℃;

[0048] And / or, the time for stirring reaction is 6-25 h;

[0049] And / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, toluene;

[0050] And / or, the crystallization solvent is selected from one or more of n-heptane, methyl tert-butyl ether, toluene.

[0051] In a preferred embodiment, in the preparation of the hydroxyl group into a sulfonate:

[0052] The organic solvent is dichloromethane;

[0053] And / or, the base is triethylamine;

[0054] and / or, the molar ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4- yl)methyl)amino)ethyl-1-ol to the base is 1:1.5;

[0055] and / or, the molar ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4- yl)methyl)amino)ethyl-1-ol to the methane sulfonyl chloride is 1:1.5;

[0056] and / or, the mass-volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4- yl)methyl)amino)ethyl-1-ol to the organic solvent is 1:5 g / mL;

[0057] and / or, the temperature of the stirring reaction is 0~5℃;

[0058] and / or, the time of the stirring reaction is 16h;

[0059] and / or, the extraction solvent is dichloromethane;

[0060] and / or, the crystallization solvent is n-heptane.

[0061] Further, the de-propylidene protection comprises the following steps:

[0062] dissolving the (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl methanesulfonate in an organic solvent, then dropping an aqueous solution of an acid into the reaction solution for stirring reaction, concentrating and removing the solvent at 30~40℃, and extracting and separating with an extraction solvent, and concentrating the organic phase to obtain (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methanesulfonate.

[0063] Further, in the de-propylidene protection:

[0064] the organic solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran, acetone, 1,4-dioxane;

[0065] and / or, the aqueous solution of the acid is selected from any one or more of 5wt% dilute hydrochloric acid, 5wt% dilute sulfuric acid, 30wt% acetic acid, 10wt% methanesulfonic acid, 5wt% p-toluenesulfonic acid;

[0066] and / or, the mass-volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4- yl)methyl)amino)ethyl methanesulfonate to the aqueous solution of the acid is 1:0.3~2.0 g / mL;

[0067] and / or, the mass volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4- yl)methyl)amino)ethyl methanesulfonate to the organic solvent is 1:3-5 g / mL;

[0068] and / or, the temperature of the stirring reaction is 0-20 °C;

[0069] and / or, the time of the stirring reaction is 1-12 h;

[0070] and / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, toluene;

[0071] and / or, the mass volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4- yl)methyl)amino)ethyl methanesulfonate to the extraction solvent is 1:10-20 g / mL.

[0072] In one preferred embodiment, the de-propylidene protection comprises:

[0073] the organic solvent is methanol;

[0074] and / or, the aqueous acid is 5 wt% hydrochloric acid;

[0075] and / or, the mass volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4- yl)methyl)amino)ethyl methanesulfonate to the 5 wt% hydrochloric acid is 1:2 g / mL;

[0076] and / or, the mass volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4- yl)methyl)amino)ethyl methanesulfonate to the organic solvent is 1:5 g / mL;

[0077] and / or, the temperature of the stirring reaction is 10-20 °C;

[0078] and / or, the time of the stirring reaction is 3 h;

[0079] and / or, the extraction solvent is ethyl acetate;

[0080] and / or, the mass volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4- yl)methyl)amino)ethyl methanesulfonate to the ethyl acetate is 1:14-15 g / mL;

[0081] and / or, the concentration temperature is 35-38 °C.

[0082] Further, the intramolecular ring closure under basic conditions comprises the following steps:

[0083] (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate is dissolved in an organic solvent, and a base is added to the reaction solution to perform a first stirring reaction and a second stirring reaction, the reaction solution is quenched with deionized water, and the organic phase is extracted with an extraction solvent, and the organic phase is concentrated to obtain a concentrated solution of (R)-4-benzylmorpholine-2-methanol;

[0084] The purification of the isomer includes the following steps:

[0085] The (R)-4-benzylmorpholine-2-methanol is dissolved in an organic solvent, Boc anhydride is added, and then Pd / C catalyst is added to the reaction solution, followed by nitrogen replacement, hydrogen replacement, stirring reaction, filtration of the catalyst after the reaction is completed, addition of n-heptane at 5-10°C for beating, suction filtration, and drying to obtain 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate.

[0086] The protection group switching includes the following steps:

[0087] The (R)-4-benzylmorpholine-2-methanol is dissolved in an organic solvent, Boc anhydride is added, and then Pd / C catalyst is added to the reaction solution, followed by nitrogen replacement, hydrogen replacement, stirring reaction, filtration of the catalyst after the reaction is completed, addition of n-heptane at 5-10°C for beating, suction filtration, and drying to obtain 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate.

[0088] Further, in the intramolecular ring closure under basic conditions:

[0089] The organic solvent is selected from any one or more of N,N-dimethylformamide, tetrahydrofuran, toluene, and 1,4-dioxane;

[0090] And / or, the base is selected from any one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, and potassium tert-butoxide;

[0091] And / or, the molar ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate to base is 1:2.0-5.0;

[0092] And / or, the mass-volume ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate to organic solvent is 1:3-10 g / mL;

[0093] And / or, the temperature of the first stirring reaction and the second stirring reaction is 0-100°C;

[0094] and / or, the reaction time of the first stirring reaction is 1-2 h, and the reaction time of the second stirring reaction is 3-20 h;

[0095] and / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, toluene;

[0096] and / or, the mass-volume ratio of the (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate to the extraction solvent is 1:30-45 g / mL;

[0097] In the purification of the isomers:

[0098] and / or, the base is selected from any one or more of triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate;

[0099] and / or, the molar ratio of the (R)-4-benzylmorpholine-2-methanol to the base is 1:0.6-1.8;

[0100] and / or, the diacid anhydride is succinic anhydride or phthalic anhydride;

[0101] and / or, the molar ratio of the (R)-4-benzylmorpholine-2-methanol to the diacid anhydride is 1:0.2-0.8;

[0102] and / or, the alkali solution is selected from any one or more of ammonia, potassium carbonate, sodium carbonate, cesium carbonate;

[0103] and / or, the concentration of the alkali solution is 1.5-5.0 wt%;

[0104] and / or, the alkali hydrolysis solution is selected from any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide;

[0105] and / or, the concentration of the alkali hydrolysis solution is 10-60 wt%;

[0106] and / or, the extraction solvent is selected from any one or more of dichloromethane, methyl tert-butyl ether, toluene;

[0107] and / or, the mass-volume ratio of the (R)-4-benzylmorpholine-2-methanol to the extraction solvent is 1:5-15 g / mL;

[0108] and / or, the temperature of the first stirring reaction and the second stirring reaction is 0-30°C;

[0109] and / or, the reaction time of the first stirring reaction is 3-20 h, and the reaction time of the second stirring reaction is 2-6 h.

[0110] In one preferred embodiment, the intramolecular cyclization under basic conditions is carried out in the presence of an organic solvent.

[0111] The organic solvent is N,N-dimethylformamide;

[0112] The base is potassium tert-butoxide;

[0113] The molar ratio of (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methanesulfonate to base is 1:2.5;

[0114] The mass-volume ratio of (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methanesulfonate to organic solvent is 1:8 g / mL;

[0115] The temperature of the first stirring reaction is 5-10°C, and the temperature of the second stirring reaction is 45-50°C;

[0116] The reaction time of the first stirring reaction is 1 h, and the reaction time of the second stirring reaction is 20 h;

[0117] The extraction solvent is ethyl acetate;

[0118] The mass-volume ratio of (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methanesulfonate to extraction solvent is 1:30 g / mL;

[0119] In the purification of the isomer:

[0120] The base is triethylamine;

[0121] The molar ratio of (R)-4-benzylmorpholine-2-methanol to base is 1:1.5;

[0122] The diacid anhydride is succinic anhydride;

[0123] The molar ratio of (R)-4-benzylmorpholine-2-methanol to succinic anhydride is 1:0.8;

[0124] The base solution is 2.5 wt% ammonia water;

[0125] The basic hydrolysis solution is 10 wt% sodium hydroxide;

[0126] The extraction solvent is dichloromethane;

[0127] The mass-volume ratio of (R)-4-benzylmorpholine-2-methanol to extraction solvent is 1:7.5 g / mL;

[0128] And / or, the temperature of the first stirring reaction is 20-25℃, and the temperature of the second stirring reaction is 0-5℃.

[0129] And / or, the reaction time of the first stirring reaction is 16h, and the reaction time of the first stirring reaction is 2-3h.

[0130] Further, in the protection group switching reaction:

[0131] The organic solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran, and ethyl acetate;

[0132] And / or, the Pd / C catalyst is D10H5A or D10H5B;

[0133] And / or, the mass-volume ratio of (R)-4-benzylmorpholine-2-methanol to the organic solvent is 1:5-10g / mL;

[0134] And / or, the hydrogen pressure is 0.5-1.0 MPa;

[0135] And / or, the temperature of the stirring reaction is 50-80℃;

[0136] And / or, the reaction time of the stirring reaction is 18-25h.

[0137] In a preferred embodiment, in the protection group switching reaction:

[0138] The organic solvent is methanol;

[0139] And / or, the mass-volume ratio of (R)-4-benzylmorpholine-2-methanol to methanol is 1:10g / mL;

[0140] And / or, the Pd / C catalyst is D10H5B;

[0141] And / or, the hydrogen pressure is 0.75-1.0 MPa;

[0142] And / or, the temperature of the stirring reaction is 55-60℃;

[0143] And / or, the stirring reaction time is 20h;

[0144] And / or, the concentration temperature is 35-40℃.

[0145] Beneficial effects

[0146] The present application uses D-glyceraldehyde acetonide and N-benzyl amino ethanol as raw materials, and obtains the target compound through reductive amination, hydroxyl preparation of sulfonate, de-propanal protection, intramolecular cyclization, isomer purification, and protection group switching. The linear total yield is 35.2%.

[0147] The two-step reaction of the first step reductive amination and the third step ketal deprotection does not need to be separated and purified directly using the reaction solution for feeding the subsequent reaction, which is proved to be effective, thereby simplifying the synthesis process. The second step must be separated and treated, and a crystallization purification point is set. The crude product of 6 obtained by intramolecular cyclization in the fourth step contains 20-30% of a seven-membered ring isomer, which is removed by chemical impurities to ensure the product quality. The linear total yield is 35.2%. BRIEF DESCRIPTION OF DRAWINGS

[0148] Figure 1 is a high-performance liquid chromatogram of 2-(R)-hydroxymethyl morpholine-N-carboxylic acid tert-butyl ester in the embodiment of the application. DETAILED DESCRIPTION

[0149] The application will be further described below. The following examples are only used to more clearly illustrate the technical solutions of the application, and cannot be used to limit the protection scope of the application.

[0150] The embodiment of the application provides a synthesis method of 2-(R)-hydroxymethyl morpholine-N-carboxylic acid tert-butyl ester, including the following steps.

[0151] D-glyceraldehyde acetonide and N-benzyl amino ethanol are used as raw materials to obtain 2-(R)-hydroxymethyl morpholine-N-carboxylic acid tert-butyl ester through reductive amination, preparation of a hydroxyl sulfonate, deprotection of a propylidene group, intramolecular cyclization under alkaline conditions, purification of isomers, and switching of a protecting group.

[0152] The synthesis route is as follows:

[0153]

[0154] In application, the reductive amination includes the following steps:

[0155] D-glyceraldehyde acetonide and N-benzyl amino ethanol are dissolved in an organic solvent, and a first stirring reaction is performed under a slightly acidic condition of the reaction solution system. A reducing agent is added to the reaction solution for a second stirring reaction. The reaction solution is quenched by using an aqueous base solution, and is extracted by using an extraction solvent. The organic phase is concentrated to obtain a concentrated solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolanyl-4-yl)methyl)amino)ethyl-1-ol.

[0156] In addition, in the reductive amination:

[0157] The organic solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, preferably dichloromethane; the reducing agent is selected from any one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride or sodium borohydride acetate, preferably sodium borohydride acetate; the molar ratio of D-glyceraldehyde acetonide to N-benzyl amino ethanol is 1:0.75-2.0, preferably 1:0.95; the mass-volume ratio of D-glyceraldehyde acetonide to the organic solvent is 1:6-15 g / mL, preferably 1:8 g / mL; the slightly acidic reaction liquid system is achieved by adding glacial acetic acid or BF3·Et2O; the molar ratio of D-glyceraldehyde acetonide to the reducing agent is 1:2-3, preferably 1:2; the temperature of the first stirring reaction and the second stirring reaction is 5-40°C, preferably 20-25°C; the reaction time of the first stirring reaction is 1-2 h, and the time of the second stirring reaction is 15-20 h, preferably the time of the second stirring reaction is 16 h; the aqueous alkali solution is selected from any one or more of saturated sodium bicarbonate aqueous solution, 5wt% sodium carbonate aqueous solution, 5wt% potassium carbonate aqueous solution, preferably saturated sodium bicarbonate aqueous solution; the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, toluene, preferably dichloromethane.

[0158] Specifically, after the reduction amination is completed, the mixture is simply washed with water, extracted, and the extracted organic phase is concentrated to half to one-third of the volume. Then, the residual liquid is added with alkali and methane sulfonyl chloride for further reaction, that is, 2-(R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol is obtained without separation and purification, which is directly used as a raw material for further substitution, thereby simplifying the synthesis process.

[0159] In use, the preparation of the sulfonate from the hydroxyl group comprises the following steps:

[0160] The concentrated solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol is mixed with alkali in an organic solvent, and then methane sulfonyl chloride is added dropwise into the reaction liquid for stirring reaction. The reaction solution is quenched with an aqueous alkali solution, and then extracted with an extraction solvent. The organic phase is concentrated, and then crystallized by adding a crystallization solvent. After filtration, (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methane sulfonate is obtained.

[0161] In addition, in the preparation of the sulfonate from the hydroxyl group:

[0162] The organic solvent is selected from any one or more of dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and preferably dichloromethane; the base is selected from any one or more of triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, and preferably triethylamine; the molar ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol to the base is 1:1.2-3.0, and preferably 1:1.5; the molar ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol to methane sulfonyl chloride is 1:1.2-3.0, and preferably 1:1.5; the mass-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl-1-ol to the organic solvent is 1:3-5 g / mL, and preferably 1:5 g / mL; the temperature for stirring the reaction is 0-20 °C, and preferably 0-5 °C; the time for stirring the reaction is 6-25 h, and preferably 16 h; the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and toluene, and preferably dichloromethane; and the crystallization solvent is selected from any one or more of n-heptane, methyl tert-butyl ether, and toluene, and preferably n-heptane.

[0163] Specifically, the preparation of the hydroxyl sulfonic acid ester includes a post-treatment step:

[0164] The temperature of the reaction liquid system is controlled to be 5-10 °C, water is added to the reaction liquid to quench, stirred for half an hour, layered, and the organic phase is washed with water. The solvent of the organic phase is concentrated and removed, and the mixture is stirred at 0-5 °C for 12-15 h after being replaced twice with 5-8 volumes of n-heptane. Filtration is performed, the filter cake is washed with 5 °C n-heptane, and vacuum drying is performed to obtain (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl methanesulfonate light yellow solid with a purity of 97.6 %, and a two-step cumulative yield of 81.2 %.

[0165] In use, the de-propylidene protection includes the following steps:

[0166] (R)-2-(benzyl((2,2-dimethyl-1,3-oxan-4-yl)methyl)amino)ethyl methanesulfonate is dissolved in an organic solvent, an aqueous acid solution is added dropwise to the reaction liquid to stir, the solvent is concentrated and removed at 30-40 °C, and extraction is performed with an extraction solvent to separate the liquid, the organic phase is concentrated, and (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methanesulfonate is obtained.

[0167] In addition, in the de-propylidene protection:

[0168] The organic solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran, acetone, 1,4-dioxane, preferably methanol; the aqueous acid solution is selected from any one or more of 5wt% dilute hydrochloric acid, 5wt% dilute sulfuric acid, 30% acetic acid, 10% methanesulfonic acid, 5% p-toluenesulfonic acid, preferably 5wt% hydrochloric acid; the mass-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate to the aqueous acid solution is 1:0.3-2.0 g / mL, preferably 1:2 g / mL; the mass-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate to the organic solvent is 1:3-5 g / mL, preferably 1:5 g / mL; the stirring reaction temperature is 0-20°C, preferably 10-20°C; the stirring reaction time is 1-12 h, preferably 3 h; the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, toluene; the mass-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate to the extraction solvent is 1:10-20 g / mL, preferably 1:14-15 g / mL; the concentration temperature is 35-38°C.

[0169] Specifically, in the depropylidation reaction, (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate is dissolved in 5 volumes of methanol, 1 volume of 5wt% dilute hydrochloric acid is added, and stirring is maintained at 5-10°C for 3 h; 15 volumes (relative to the mass of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate) of ethyl acetate are added to the reaction solution, stirring is maintained for 15-30 min, the solution is separated, and the organic phase is concentrated at a temperature of 35-38°C;

[0170] In use, the intramolecular ring closure comprises the following steps:

[0171] (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate is dissolved in an organic solvent, a base is added to the reaction solution to perform a first stirring reaction and a second stirring reaction, the reaction solution is quenched with deionized water, and the solution is extracted with an extraction solvent, the organic phase is concentrated, and a concentrated solution of (R)-4-benzylmorpholine-2-methanol is obtained;

[0172] The purification of the isomers comprises the following steps:

[0173] The first stirring reaction is carried out by adding a base to a concentrated solution of (R)-4-benzylmorpholine-2-methanol, and the second stirring reaction is carried out by adding a dianhydride to the reaction solution, to obtain a dianhydric monoester of (R)-4-benzylmorpholine-2-methanol; the dianhydric monoester of (R)-4-benzylmorpholine-2-methanol is washed into an aqueous phase by using a lye, and the aqueous phase is hydrolyzed by using a basic hydrolysis solution; the reaction solution is acidified and extracted by using an extraction solvent; the organic phase is concentrated to obtain pure (R)-4-benzylmorpholine-2-methanol;

[0174] The protection group switching comprises the following steps:

[0175] (R)-4-benzylmorpholine-2-methanol is dissolved in an organic solvent, Boc anhydride is added, a Pd / C catalyst is added to the reaction solution, nitrogen is replaced, hydrogen is replaced, stirring is carried out, the catalyst is filtered off after the reaction is completed, n-heptane is added at 35-45°C to carry out beating, and the product is obtained by filtration and drying.

[0176] In addition, in the intramolecular ring closure:

[0177] The organic solvent is selected from any one or more of N,N-dimethylformamide, tetrahydrofuran, toluene, and 1,4-dioxane, and preferably N,N-dimethylformamide; the base is selected from any one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, and potassium tert-butoxide, and preferably potassium tert-butoxide; the molar ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate to the base is 1:2.0-5.0, and preferably 1:2.5; the mass-volume ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate to the organic solvent is 1:3-10 g / mL, and preferably 1:8 g / mL; the temperature of the first stirring reaction and the second stirring reaction is 0-100°C, and preferably the temperature of the first stirring reaction is 5-10°C and the temperature of the second stirring reaction is 45-50°C; the reaction time of the first stirring reaction is 1-2 h, and the reaction time of the second stirring reaction is 3-20 h, and preferably the reaction time of the first stirring reaction is 1 h and the reaction time of the second stirring reaction is 20 h; the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and toluene, and preferably ethyl acetate; the mass-volume ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate to the extraction solvent is 1:30-45 g / mL, and preferably 1:30 g / mL;

[0178] In the purification of the isomer:

[0179] The base is selected from any one or more of triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, preferably triethylamine; the molar ratio of (R)-4-benzylmorpholine-2-methanol to base is 1:0.6-1.8, preferably 1:1.5; the diacid anhydride is succinic anhydride or phthalic anhydride; the molar ratio of (R)-4-benzylmorpholine-2-methanol to diacid anhydride is 1:0.2-0.8, preferably 1:0.8; the base solution is selected from any one or more of aqueous ammonia, potassium carbonate, sodium carbonate, cesium carbonate, the concentration of the base solution is 1.5-5.0 wt%, preferably 2.5 wt% aqueous ammonia; the basic hydrolysis solution is selected from any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, the concentration of the basic hydrolysis solution is 10-60 wt%, preferably 10 wt% sodium hydroxide; the extraction solvent is selected from any one or more of dichloromethane, methyl tert-butyl ether, toluene, preferably dichloromethane; the mass-volume ratio of (R)-4-benzylmorpholine-2-methanol to extraction solvent is 1:5-15 g / mL, preferably 1:7.5 g / mL; the temperature of the first stirring reaction and the second stirring reaction is 0-30 °C, preferably the temperature of the first stirring reaction is 20-25 °C and the temperature of the second stirring reaction is 0-5 °C; the reaction time of the first stirring reaction is 3-20 h and the reaction time of the second stirring reaction is 2-6 h, preferably the reaction time of the first stirring reaction is 16 h and the reaction time of the first stirring reaction is 2-3 h.

[0180] In the protection group switching:

[0181] The organic solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran, ethyl acetate, preferably methanol; the Pd / C catalyst is D10H5A or D10H5B, preferably D10H5B; the mass-volume ratio of (R)-4-benzylmorpholine-2-methanol to organic solvent is 1:5-10 g / mL, preferably 1:10 g / mL; the hydrogen pressure is 0.5-1.0 MPa, preferably 0.75-1.0 MPa; the temperature of the stirring reaction is 50-80 °C, preferably 55-60 °C; the reaction time of the stirring reaction is 18-25 h, preferably 20 h; the concentration temperature is 35-40 °C.

[0182] Specifically, in the ring closure reaction, (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methane sulfonate is dissolved in 8 volumes of N,N-dimethylformamide solution, 2.5 equivalents of potassium tert-butoxide are slowly added at 5-10 °C, and then slowly warmed to 40-55 °C and stirred for 16-20 h. The system is quenched with 12 v of deionized water, extracted with ethyl acetate three times (10 v*3), the obtained organic phase is concentrated to half the volume (12-14 v), and (R)-4-benzylmorpholine-2-methanol ethyl acetate solution is obtained.

[0183] In the isomer purification, the temperature of the above-mentioned ethyl acetate concentrated solution of (R)-4-benzylmorpholine-2-methanol was controlled to be constant, 1.5 eq of triethylamine was added for stirring reaction, dianhydride was added to the reaction solution, and the temperature of the reaction solution system was controlled to be constant at 0-5°C, and stirring reaction was carried out for 2-3 h. The reaction solution was washed with alkaline water (ammonia water), the water phase was extracted with ethyl acetate to remove impurities, the water phase was hydrolyzed with sodium hydroxide alkaline, and the pH was adjusted to 7-8 with hydrochloric acid, and then the product (R)-4-benzylmorpholine-2-methanol was extracted with dichloromethane. The purity can reach more than 96%.

[0184] In the protecting group switching, (R)-4-benzylmorpholine-2-methanol was dissolved in 5-10 volumes of methanol and added to a high-pressure hydrogenation kettle, 1.0 eq of Boc anhydride was added, Pd / C catalyst was added to the reaction solution, replaced with nitrogen, and then replaced with hydrogen, the hydrogen pressure was maintained at 0.5-1 MPa, the internal temperature was maintained at 55-65°C, and stirring reaction was carried out for 20 h. After the reaction was completed, the catalyst was filtered off, concentrated, and the product 2-(R)-hydroxymethylmorpholine-N-tert-butyl carbamate was obtained by slurry.

[0185] Example 1

[0186] This example details the synthesis of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolan-4-yl)methyl)amino)ethyl-1-ol.

[0187] The synthesis method of the present application comprises the following steps:

[0188]

[0189] Reductive amination reaction:

[0190] In a 250 mL three-necked flask, D-glyceraldehyde acetonide (10.0 g, 76.8 mmol) and N-benzyl aminoethanol (12.0 g, 79.4 mmol, 1.03 eq.) were added, dichloromethane (100 mL, 10 v) was added, and the temperature of the reaction solution system was controlled to be constant at 20-25°C. Sodium borohydride (32.5 g, 153.8 mmol, 2.0 eq.) was slowly added to the reaction solution in batches under nitrogen atmosphere, the temperature of the reaction solution system was controlled to be constant at 20-25°C, and stirring reaction was carried out for 16 h.

[0191] In use, the reductive amination synthesis reaction of this example includes post-treatment.

[0192] After the reaction is completed, saturated sodium bicarbonate solution (50 mL) is added to the reaction system and stirred for half an hour. The reaction mixture is moved into a separatory funnel; the aqueous phase is extracted with dichloromethane 40 mL twice; the dichloromethane in the organic phase is removed by concentration, and the residue is dried under vacuum (16-18 mBa) for 5 h to obtain 19.3 g of thick oil, a crude product of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol.

[0193] The purity of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol obtained in this example is 93.1%, and the yield is 94.6%.

[0194] In this example, the product is obtained by directly concentrating and drying dichloromethane, but this process is not suitable for production scale-up.

[0195] Example 2

[0196] This example details the synthesis process of a dichloromethane solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol.

[0197] The synthesis method of the present application comprises the following steps:

[0198]

[0199] Reductive amination reaction:

[0200] In a 500 mL three-necked flask, D-glyceraldehyde acetonide (26.0 g, 199.8 mmol) and N-benzylaminoethanol (28.7 g, 189.8 mmol, 0.95 eq.) are added, dichloromethane (210 mL, 8 v) is added, and the reaction liquid system is controlled to be constant at 20-25°C, acetic acid (2.4 g, 40.0 mmol, 0.2 eq.) is added and stirred, under a nitrogen atmosphere, sodium borohydride (84.7 g, 400.0 mmol, 2.0 eq.) is slowly added to the reaction liquid in 12 batches, the reaction liquid system is controlled to be constant at 20-25°C, and stirring is carried out for 16 h.

[0201] In use, the reductive amination reaction of this example includes post-treatment.

[0202] After the reaction is completed, saturated sodium bicarbonate solution (130 mL) is added to the reaction system and stirred for half an hour. The reaction mixture is transferred to a separatory funnel; the aqueous phase is extracted with dichloromethane twice at 110 mL each time; the dichloromethane in the organic phase is concentrated to about 150 mL of residual liquid to obtain a dichloromethane solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol (186.8 g). The next step is used directly.

[0203] The (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol obtained in this example is not isolated and purified and detected.

[0204] Example 3

[0205] This example details the synthesis process of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate.

[0206] The synthesis method of the present application comprises the following steps:

[0207]

[0208] Substitution reaction:

[0209] 100 mL reaction bottle is added (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl-1-ol (4.5 g, 17.0 mmol), dissolved in dichloromethane (36 mL, 8 v), under nitrogen atmosphere and control the reaction liquid system temperature constant at 0-5℃, add triethylamine (2.6 g, 25.4 mmol, 1.5 eq), stir the reaction, then drop methanesulfonyl chloride (2.9 g, 25.4 mmol, 1.5 eq) into the reaction liquid, and control the reaction liquid system temperature constant at 0-5℃, stir the reaction for 16 h.

[0210] In use, the substitution reaction of this example includes post-treatment.

[0211] Quench with aqueous sodium bicarbonate solution (27 mL, 6 v), separate, extract the aqueous phase with dichloromethane (18 mL*2, 4 v*2), concentrate the combined organic phase to 13.5-18 mL (3-4 v), add n-heptane (36 mL, 8 v) to the system and concentrate to about 20 mL (4-5 v), cool the residual liquid, stir at 0-5℃ for 2 h, filter, rinse with 5 mL of n-heptane, and dry to obtain 3.2 g of (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate.

[0212] detected by 1H NMR: 1H NMR (400 MHz, DMSO) δ 7.30-7.25 (m, 5H), 3.88 (m, 1H), 3.61 (m, 6H), 3.30 (s, 3H), 2.55 (m, 3H), 2.35 (m, 1H), 1.25 (s, 6H).

[0213] The purity of (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4-yl)methyl)amino)ethyl methanesulfonate obtained in this example is 98.2%, and the yield is 54.9%.

[0214] Example 4

[0215] This example details the synthesis of (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4-yl)methyl)amino)ethyl methanesulfonate.

[0216] The synthesis method of the present application comprises the following steps:

[0217]

[0218] Substitution reaction:

[0219] Into a 1000 mL reaction flask was added a solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4-yl)methyl)amino)ethyl-1-ol (186.8 g, containing (R)-2-(benzyl((2,2-dimethyl-1,3-oxazolidin-4-yl)methyl)amino)ethyl-1-ol calculated at 49.5 g, 187.0 mmol) dissolved in dichloromethane (250 mL, 5 v), under a nitrogen atmosphere and with the reaction system temperature controlled at 0-5°C, triethylamine (28.6 g, 279.4 mmol, 1.5 eq.) was added, the reaction was stirred, and methanesulfonyl chloride (32.0 g, 280.0 mmol, 1.5 eq.) was added dropwise to the reaction solution, with the reaction system temperature controlled at 0-5°C, and the reaction was stirred for 16 h.

[0220] In use, the substitution reaction of this example includes post-treatment.

[0221] The reaction solution was quenched with aqueous sodium bicarbonate solution (300 mL, 6 v), and the solution was separated and the aqueous phase was extracted with dichloromethane (200 mL*2, 4 v*2). The combined organic phase was concentrated to about 200 ml (about 4 v), and n-heptane (400 mL, 8 v) was added to the system and then concentrated to about 200 ml (about 4 v). The residual solution was cooled and stirred at 0~5℃ for 2 h, and then filtered, rinsed with 50 mL of n-heptane, and dried to obtain (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate.

[0222] In this example, (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate 52.6 g was obtained, with a purity of 97.6%, and a cumulative yield of 81.2% for two steps.

[0223] Example 5

[0224] This example describes the synthesis of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate.

[0225] The synthesis method of the present application comprises the following steps:

[0226]

[0227] Hydrolytic deprotection reaction:

[0228] (R)-2-(benzyl((2,2-dimethyl-1,3-oxolane-4-yl)methyl)amino)ethyl methanesulfonate (5.6 g, 1.0 eq.) was added to a 100 mL reaction bottle, and methanol (28 mL, 5 v) was added, and the reaction solution was controlled to have a constant temperature of about 10 degrees. The reaction was stirred, and then 5wt% hydrochloric acid aqueous solution (11.2 mL, 2 v, 2 eq.) was added dropwise to the reaction solution, and the reaction solution was controlled to have a constant temperature of 10~20℃. The reaction was stirred for 3 h.

[0229] In use, the hydrolytic deprotection reaction of this example includes post-treatment.

[0230] At 30℃, the methanol was removed by concentration, and then the extraction liquid was extracted with ethyl acetate three times (28 mL*3). The extraction liquid was concentrated to obtain (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate.

[0231] In this example, (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate 4.9 g was obtained, with a purity of 95.7% and a yield of 95.0%.

[0232] Example 6

[0233] This embodiment details the synthesis process of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate.

[0234] The synthesis method of the present application comprises the following steps:

[0235]

[0236] Hydrolytic deprotection reaction:

[0237] (R)-2-(benzyl((2,2-dimethyl-1,3-oxolanyl-4-yl)methyl)amino)ethyl methanesulfonate (40 g) and methanol (200 mL, 5 v) were added to a 1000 mL reaction bottle, and the reaction liquid system was controlled to be constant at about 10°C, and the reaction was stirred. Then 5wt% hydrochloric acid aqueous solution (80.0 mL, 2 v, 2 eq.) was added dropwise into the reaction liquid, and the reaction liquid system was controlled to be constant at 10-20°C, and the reaction was stirred for 3 h.

[0238] In application, the hydrolytic deprotection reaction of this embodiment includes post-treatment.

[0239] 30°C, the methanol was removed by concentration, and then extracted with ethyl acetate three times (200 mL*3), and the extract was concentrated to obtain (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate 33.9 g, yield 95%.

[0240] This embodiment obtained (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate 33.9 g, purity 95.3%, yield 95.9%.

[0241] Example 7

[0242] This embodiment details the synthesis process of (R)-4-benzylmorpholine-2-methanol.

[0243] The synthesis method of the present application comprises the following steps:

[0244]

[0245] Intramolecular ring closure:

[0246] In a 100 mL reaction flask, (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate (4.5 g, 14.8 mmol) was dissolved in DMF (36 mL, 8v) and the reaction system was controlled to be constant at 5-10 °C, and the reaction was stirred. Then, potassium tert-butoxide (3.7 g, 32.6 mmol, 2.2 eq.) was slowly added to the reaction solution (exothermic), and the reaction system was controlled to be constant at 5-10 °C. After the addition was completed, the temperature was kept constant for half an hour, and then slowly increased to 35-45 °C. The reaction was stirred for 15-20 h.

[0247] In use, the intramolecular cyclization reaction of this embodiment includes post-treatment.

[0248] Water (54 mL, 12 v) was used to quench the system, and ethyl acetate was used to extract three times (45 mL*3, 10 v*3). The obtained organic phase was concentrated to dryness to obtain crude (R)-4-benzylmorpholine-2-methanol. The crude product was separated by silica gel column chromatography to obtain 1.6 g of target (R)-4-benzylmorpholine-2-methanol with a purity of 96.7% and a yield of 52.3%. At the same time, 0.6 g of by-product was obtained, which was identified as a seven-membered ring isomer.

[0249] The purification method of this embodiment is silica gel column chromatography, which is not suitable for large-scale production process.

[0250] Example 8

[0251] This embodiment details the synthesis process of (R)-4-benzylmorpholine-2-methanol.

[0252] The synthesis method of the present application comprises the following steps:

[0253]

[0254] Intramolecular cyclization:

[0255] In a 250 mL reaction flask, (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate (10.0 g, 33.0 mmol) was dissolved in DMF (80 mL, 8v) and the reaction system was controlled to be constant at 5-10 °C, and the reaction was stirred. Then, potassium tert-butoxide (9.3 g, 82.4 mmol, 2.5 eq.) was slowly added to the reaction solution (exothermic), and the reaction system was controlled to be constant at 5-10 °C. After the addition was completed, the temperature was kept constant for 1 hour, and then slowly increased to 45-50 °C. The reaction was stirred for 20 h.

[0256] In use, the intramolecular cyclization reaction of this embodiment includes post-treatment.

[0257] The reaction system was quenched with water (120 mL, 12 v) and extracted with ethyl acetate three times (100 mL*3, 10 v*3). The obtained organic phase was concentrated to a volume of about 150 mL to obtain an ethyl acetate solution of (R)-4-benzylmorpholine-2-methanol 135.4 g.

[0258] Isomer purification:

[0259] The concentrated solution of (R)-4-benzylmorpholine-2-methanol was added to triethylamine (5.0 g, 49.5 mmol, 1.5 eq.), and the internal temperature was controlled to be constant at 20-25°C. The reaction was stirred for 16 h. Succinic anhydride (2.64 g, 26.4 mmol, 0.8 eq.) was then added to the reaction solution, and the internal temperature of the reaction system was controlled to be constant at 0-5°C. The reaction was stirred for 2-3 h. The reaction solution was washed with alkaline water (2.5 wt% ammonia water 25 mL, 2.5 v), and the aqueous phase was washed with ethyl acetate (20 mL, 2 v). The aqueous phase was hydrolyzed with sodium hydroxide, neutralized with hydrochloric acid to 7-8, extracted with dichloromethane (30 mL*3), and the combined organic phase was concentrated to obtain pure (R)-4-benzylmorpholine-2-methanol 3.0 g, with a yield of 44.0% and a purity of 96.6%.

[0260] In this embodiment, the purification is performed by acid-base treatment, avoiding the use of silica gel column chromatography.

[0261] Example 9

[0262] This embodiment details the synthesis process of (R)-4-benzylmorpholine-2-methanol.

[0263] The synthesis method of the present application comprises the following steps:

[0264]

[0265] Intramolecular ring closure:

[0266] In a 500 mL reaction flask, (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethyl methanesulfonate (23.1 g, 76.4 mmol) was dissolved in DMF (185 mL, 8 v), and the internal temperature of the reaction solution was controlled to be constant at 5-10°C. The reaction was stirred, and potassium tert-butoxide (21.4 g, 190.4 mmol, 2.5 eq.) was slowly added to the reaction solution in batches (exothermic), and the internal temperature of the reaction solution was controlled to be constant at 5-10°C. After the addition was completed, the temperature was maintained for 1 h, and then slowly increased to 45-50°C. The reaction was stirred for 20 h.

[0267] In use, the intramolecular ring closure reaction of this embodiment includes post-treatment.

[0268] The reaction system was quenched with water (280 mL, 12 v), extracted with ethyl acetate three times (230 mL*3, 10 v*3), and the obtained organic phase was concentrated to a volume of about 350 mL to obtain an ethyl acetate solution of (R)-4-benzylmorpholine-2-methanol 317.4 g.

[0269] Isomer purification:

[0270] The concentrated solution of (R)-4-benzylmorpholine-2-methanol was added to triethylamine (11.6 g, 114.2 mmol, 1.5 eq), and the internal temperature was controlled to be constant at 20-25°C, and the reaction was stirred for 16 h. Then succinic anhydride (6.1 g, 60.1 mmol, 0.8 eq.) was added to the reaction solution, and the internal temperature of the reaction system was controlled to be constant at 0-5°C, and the reaction was stirred for 2-3 h. The reaction solution was washed with alkaline water (2.5 wt% ammonia water 58 mL, 2.5 v), and the aqueous phase was washed with ethyl acetate (45 mL*2, 2 v*2). The aqueous phase was hydrolyzed with sodium hydroxide, neutralized with hydrochloric acid to 7-8, extracted with dichloromethane 80 mL*3, and the combined organic phase was concentrated to obtain pure (R)-4-benzylmorpholine-2-methanol 7.2 g, with a yield of 45.7% and a purity of up to 96.6 A%.

[0271] In this embodiment, (R)-4-benzylmorpholine-2-methanol 7.2 g was obtained with a yield of 45.7% and a purity of up to 96.6%.

[0272] In this embodiment, the purification was carried out by acid-base treatment, avoiding the use of silica gel column chromatography.

[0273] Example 10

[0274] This embodiment details the synthesis process of 2-(R)-hydroxymethylmorpholine-N-tert-butyl ester.

[0275] The synthesis method of the present application comprises the following steps:

[0276]

[0277] Hydrogenation reaction:

[0278] In a 200 mL hydrogenation reactor, (R)-4-benzylmorpholine-2-methanol (7.0 g, 33.8 mmol) was dissolved in methanol (70 mL, 10 v), Boc anhydride (7.4 g, 33.8 mmol) was added, and then Pd / C catalyst (0.7 g, 0.1 eq.) was added to the reaction solution, replaced with nitrogen, and then replaced with hydrogen, and the internal temperature was controlled to be constant at 55-60°C, and the reaction was stirred for 20 h.

[0279] In application, the hydrogenation reaction of this embodiment includes post-treatment.

[0280] After the hydrogenation was completed, the reaction solution was filtered through 10 g of diatomite to remove the catalyst, and the filtrate was concentrated at 40 °C to dryness. Then, n-heptane (30 mL, 4.3 v) was added, and the mixture was stirred at 5-10 °C for 2 h, filtered and dried to obtain 2-(R)-hydroxymethylmorpholine-N-tert-butyl ester.

[0281] In this example, 2-(R)-hydroxymethylmorpholine-N-tert-butyl ester was obtained in a yield of 95.2% and a purity of 97.8% (HPLC). Figure 1

[0282] The above only describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several improvements and modifications without departing from the technical principles of the present application, and these improvements and modifications should also be considered as the protection scope of the present application.​

Claims

1. A method for synthesizing tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylic acid, characterized in that, Includes the following steps: 2-(R)-hydroxymethylmorpholine-N-carboxylic acid tert-butyl ester was obtained by reductive amination, preparation of sulfonate ester by hydroxylation, depropionation protection, intramolecular cyclization under alkaline conditions, purification of isomers and switching of protecting groups. The reductive amination includes the following steps: D-glyceraldehyde acetal and N-benzylaminoethanol were dissolved in an organic solvent and stirred for the first reaction under slightly acidic conditions. Then, a reducing agent was added to the reaction solution for the second stirring reaction. The reaction solution was quenched with an alkaline aqueous solution and extracted with an extraction solvent. The organic phase was concentrated to obtain a concentrated solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl-1-ol. The preparation of sulfonates from hydroxyl groups includes the following steps: The concentrated solution of (R)-2-(benzyl((2,2-dimethyl-1,3-oxepane-4-yl)methyl)amino)ethyl-1-ol was mixed with an alkali in an organic solvent. Methanesulfonyl chloride was then added dropwise to the reaction solution and stirred. The reaction solution was quenched with an alkaline aqueous solution and extracted with an extraction solvent. The organic phase was concentrated and crystallized with a crystallization solvent. After filtration, (R)-2-(benzyl((2,2-dimethyl-1,3-oxepane-4-yl)methyl)amino)ethylmethanesulfonate was obtained. The depropionylene protection includes the following steps: (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl methanesulfonate was dissolved in an organic solvent, and then an aqueous solution of acid was added dropwise to the reaction mixture while stirring. The mixture was concentrated at 30-40°C to remove the solvent, and then extracted with an extraction solvent. The organic phase was concentrated to obtain (R)-2-(benzyl((2,3-dihydroxy-propyl)amino)ethyl methanesulfonate; The intramolecular cyclization under alkaline conditions includes the following steps: (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethylmethanesulfonate was dissolved in an organic solvent. Then, a base was added to the reaction solution for the first and second stirring reactions. The reaction solution was quenched with deionized water and extracted with an extraction solvent. The organic phase was concentrated to obtain a concentrated solution of (R)-4-benzylmorpholine-2-methanol. The purification of the isomer includes the following steps: A base was added to the concentrated solution of (R)-4-benzylmorpholine-2-methanol for the first stirring reaction, and then dianhydride was added to the reaction solution for the second stirring reaction to obtain the dianhydride monoester of (R)-4-benzylmorpholine-2-methanol. The dianhydride monoester of (R)-4-benzylmorpholine-2-methanol was washed with an alkaline solution into an aqueous phase, and the aqueous phase was hydrolyzed with an alkaline hydrolysis solution. The reaction solution was acidified and extracted with an extraction solvent. The organic phase was concentrated to obtain pure (R)-4-benzylmorpholine-2-methanol. The switching of the protection base includes the following steps: (R)-4-benzylmorpholine-2-methanol was dissolved in an organic solvent, Boc anhydride was added, and then Pd / C catalyst was added to the reaction solution. Nitrogen gas was used for purging, followed by hydrogen gas purging. The reaction was stirred and the catalyst was filtered off after the reaction was completed. The solution was concentrated to dryness at 35-45℃, and then n-heptane was added and the solution was slurried at 5-10℃. The solution was then filtered and dried to obtain tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylate.

2. The method for synthesizing tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylic acid according to claim 1, characterized in that, In the reductive amination: The organic solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran; And / or, the reducing agent is selected from any one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, and sodium borohydride acetate; And / or, the molar ratio of D-glyceraldehyde acetal to N-benzylaminoethanol is 1:0.75~2.0; And / or, the mass-to-volume ratio of the D-glyceraldehyde acetal to the organic solvent is 1:6~15 g / mL; And / or, the slightly acidic nature of the reaction solution system is achieved by adding glacial acetic acid or BF3•Et2O; And / or, the molar ratio of the D-glyceraldehyde acetal to the reducing agent is 1:2~3; And / or, the temperature for the first and second stirring reactions is 5~40℃; And / or, the first stirring reaction takes 1-2 hours, and the second stirring reaction takes 15-20 hours; And / or, the alkaline aqueous solution is selected from any one or more of the following: saturated sodium bicarbonate aqueous solution, 5 wt% sodium carbonate aqueous solution, and 5 wt% potassium carbonate aqueous solution; And / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and toluene.

3. The method for synthesizing tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylic acid according to claim 1, characterized in that, In the preparation of sulfonates by the hydroxyl groups: The organic solvent is selected from any one or more of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran; And / or, the base is selected from any one or more of triethylamine, diisopropylethylamine, potassium carbonate, and sodium carbonate; And / or, the molar ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl-1-ol to base is 1:1.2~3.0; And / or, the molar ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl-1-ol to methanesulfonyl chloride is 1:1.2~3.0; And / or, the mass-to-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl-1-ol to the organic solvent is 1:3~5 g / mL; And / or, the temperature for stirring the reaction is 0~20℃; And / or, the stirring reaction time is 6~25h; And / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and toluene; And / or, the crystallization solvent is selected from any one or more of n-heptane, methyl tert-butyl ether, and toluene.

4. The method for synthesizing tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylic acid according to claim 1, characterized in that, In the aforementioned depropionization protection: The organic solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran, acetone, and 1,4-dioxane; And / or, the aqueous solution of the acid is selected from any one or more of 5 wt% dilute hydrochloric acid, 5 wt% dilute sulfuric acid, 30 wt% acetic acid, 10% methanesulfonic acid, and 5 wt% p-toluenesulfonic acid; And / or, the mass-to-volume ratio of the (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl methanesulfonate to the aqueous solution of acid is 1:0.3~2.0 g / mL; And / or, the mass-to-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl methanesulfonate to organic solvent is 1:3~5 g / mL; And / or, the temperature for stirring the reaction is 0~20℃; And / or, the stirring reaction time is 1 to 12 hours; And / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and toluene; And / or, the mass-to-volume ratio of (R)-2-(benzyl((2,2-dimethyl-1,3-oxacyclopentan-4-yl)methyl)amino)ethyl methanesulfonate to the extraction solvent is 1:10~20 g / mL.

5. The method for synthesizing tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylic acid according to claim 1, characterized in that, In the intramolecular cyclization under the alkaline conditions: The organic solvent is selected from any one or more of N,N-dimethylformamide, tetrahydrofuran, toluene, and 1,4-dioxane; And / or, the base is selected from any one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, and potassium tert-butoxide; And / or, the molar ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethylmethanesulfonate to base is 1:2.0~5.0; And / or, the mass-to-volume ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethylmethanesulfonate to organic solvent is 1:3~10 g / mL; And / or, the temperature of the first stirring reaction and the second stirring reaction is 0~100℃; And / or, the reaction time for the first stirring reaction is 1-2 hours, and the reaction time for the second stirring reaction is 3-20 hours; And / or, the extraction solvent is selected from any one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and toluene; And / or, the mass-to-volume ratio of (R)-2-(benzyl((2,3-dihydroxypropyl)amino)ethylmethanesulfonate to the extraction solvent is 1:30~45 g / mL; During the purification of the isomer: And / or, the base is selected from any one or more of triethylamine, diisopropylethylamine, potassium carbonate, and sodium carbonate; And / or, the molar ratio of (R)-4-benzylmorpholine-2-methanol to the base is 1:0.6~1.8; And / or, the dianhydride is succinic anhydride or phthalic anhydride; And / or, the molar ratio of (R)-4-benzylmorpholine-2-methanol to dianhydride is 1:0.2~0.8; And / or, the alkaline solution is any one or more of ammonia, potassium carbonate, sodium carbonate, and cesium carbonate; And / or, the concentration of the alkaline solution is 1.5~5.0 wt%; And / or, the alkaline hydrolysate is selected from any one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; And / or, the concentration of the alkaline hydrolysate is 10~60 wt%; And / or, the extraction solvent is selected from any one or more of dichloromethane, methyl tert-butyl ether, and toluene; And / or, the mass-to-volume ratio of (R)-4-benzylmorpholine-2-methanol to the extraction solvent is 1:5~15 g / mL; And / or, the temperature of the first stirring reaction and the second stirring reaction is 0~30℃; And / or, the reaction time for the first stirring reaction is 3 to 20 hours, and the reaction time for the second stirring reaction is 2 to 6 hours.

6. The method for synthesizing tert-butyl 2-(R)-hydroxymethylmorpholine-N-carboxylic acid according to claim 1, characterized in that, During the switching of the protecting base: The organic solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran, and ethyl acetate; And / or, the Pd / C catalyst is D10H5A or D10H5B; And / or, the mass-to-volume ratio of (R)-4-benzylmorpholine-2-methanol to the organic solvent is 1:5~10 g / mL; And / or, the hydrogen pressure is 0.5~1.0 MPa; And / or, the temperature of the stirred reaction is 50~80℃; And / or, the reaction time for the stirring reaction is 18~25h.

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