Preparation method of 2-methyl-L-leucine hydrochloride

Abstract

The invention belongs to the technical field of compounds, and provides a preparation method of 2-methyl-L-leucine hydrochloride. The method comprises the following steps: dissolving 2-amino propionate or hydrochloride thereof, an aldehyde ketone compound and alkali in a first solvent, heating for reaction, reacting with a chiral biphenyl quaternary ammonium salt phase transfer catalyst, performing deprotection reaction, performing catalytic hydrogenation reaction in a hydrogen atmosphere, and finally performing ester hydrolysis reaction to obtain the 2-methyl-L-leucine hydrochloride. The raw materials needed by the method are easy to obtain, the used catalyst and solvent can be used mechanically by 90% or above, the stereoselective chiral biphenyl quaternary ammonium salt phase transfer catalyst is adopted, the ee value of the obtained product can reach 99.5% or above without chiral resolution, the yield is high (even can reach 77.6%), no highly toxic cyanide participates in the preparation process, and the method is safe and environmentally friendly.

Description

Technical Field

[0001] The present invention relates to the technical field of compounds, and more specifically, to a method for preparing 2-methyl-L-leucine hydrochloride. Background Art

[0002] 2-Methyl-L-leucine is a non-natural amino acid. In recent years, as the role of non-natural amino acids in the pharmaceutical field has become increasingly prominent, the synthesis of non-natural amino acids has received increasing attention. The structural formula of 2-methyl-L-leucine hydrochloride is shown in the following formula (VI):

[0003]

[0004] A Chinese patent (publication number CN109369460A) discloses a method for preparing a 2-methyl-L-leucine derivative, but the starting material (2S, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylic acid benzyl ester used is not available in large quantities and is expensive. In addition, the reagents such as bistrimethylsilylamine lithium used have safety risks, making this method unsuitable for large-scale production. The specific synthesis route is as follows:

[0005]

[0006] In addition, the prior art also reports a 2-methyl-L-leucine synthesis process, the raw materials are cheap, and no chiral catalyst is required, but the process route cannot avoid the use of highly toxic cyanides such as sodium cyanide, which is highly polluting, and finally requires multiple chiral separations, and the yield is low (only about 20%). The specific synthesis route is as follows:

[0007]

[0008] Therefore, in view of the problems that the current preparation process of 2-methyl-L-leucine has expensive raw materials, high-risk reagents (such as lithium bis(trimethylsilyl)amide, highly toxic cyanide, etc.), multiple chiral separations, complicated steps and low yield, it is urgent to develop a preparation method of 2-methyl-L-leucine with high yield and high ee value, which has low raw material price and is easy to obtain, few operation steps, simple and easy operation, and no need to use raw materials with high safety risks, with high safety. The prepared 2-methyl-L-leucine can be used in pharmaceuticals, etc. Summary of the invention

[0009] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention proposes a method for preparing 2-methyl-L-leucine hydrochloride. The preparation method provided by the present invention has easy-to-obtain raw materials, low cost, no need to use high-risk reagents (such as lithium bis(trimethylsilyl)amide, highly toxic cyanide, etc.), high safety, high yield (even up to 77.6%), high ee value (without multiple chiral separations, the ee value can be as high as 99.5% or more), and the prepared 2-methyl-L-leucine hydrochloride can be well used in drug preparation, etc.

[0010] A first aspect of the present invention provides a method for preparing 2-methyl-L-leucine hydrochloride.

[0011] Specifically, a method for preparing 2-methyl-L-leucine hydrochloride comprises the following steps:

[0012] (1) dissolving 2-aminopropionic acid ester or its hydrochloride, aldehyde ketone compound and base in a first solvent and heating the mixture to obtain a compound of formula (II);

[0013]

[0014] (2) mixing the compound of formula (II), a chiral biphenyl quaternary ammonium salt phase transfer catalyst, an alkaline solution, and 3-halogenated-2-methylpropylene, heating the mixture to react, separating the layers, taking the organic layer, and removing the solvent to obtain the compound of formula (III);

[0015]

[0016] (3) mixing the compound of formula (III) and the acidic solution, heating the mixture to react, adding a second solvent for extraction, separating the layers, adjusting the pH of the aqueous layer to 7-9, adding a second solvent, extracting the layers, separating the layers, taking the organic layer, and removing the solvent to obtain the compound of formula (IV);

[0017]

[0018] (4) mixing the compound of formula (IV), a catalyst, and a third solvent, introducing hydrogen gas, and performing a hydrogenation reaction to obtain a compound of formula (V);

[0019]

[0020] (5) mixing the compound of formula (V) and a fourth solvent, introducing hydrogen chloride gas or adding hydrochloric acid solution, heating to carry out ester hydrolysis reaction, cooling, crystallizing and filtering to obtain the 2-methyl-L-leucine hydrochloride;

[0021] Among them, in formula (II) to formula (V), R1 is selected from one of methyl, ethyl, isopropyl, propyl, and tert-butyl, R2 is selected from one of phenyl, benzyl, methylphenyl, and halogenated phenyl, and X is selected from one of Cl, Br or I.

[0022] The structural formula of 2-aminopropionic acid ester is shown in the following formula (I):

[0023]

[0024] Wherein, R1 is selected from one of methyl, ethyl, isopropyl, propyl and tert-butyl.

[0025] The reaction route for preparing 2-methyl-L-leucine hydrochloride of formula (VI) in steps (1) to (5) is as follows:

[0026]

[0027] Enantiomeric excess (ee for short): is an evaluation standard for the effect of asymmetric catalytic reactions. ee = ([R]-[S] / [R]+[S]) × 100%, where [R]+[S] = 1. Simply put, the ee value is the percentage of excess of one isomer relative to the other isomer in an enantiomeric mixture.

[0028] The present invention utilizes the compound of formula (I) 2-aminopropionic acid ester or its hydrochloride, aldehyde ketone compound (protective reagent), and base reaction to achieve the effect of protecting the amino group, forming an imine, and obtaining the compound of formula (II), and then under the action of a chiral biphenyl quaternary ammonium salt phase transfer catalyst (referred to as phase transfer catalyst), the temperature is increased in an alkaline solution to obtain the compound of formula (III), and then the temperature is increased in an acidic solution, and the compound of formula (IV) (2S-4,2-dimethyl-2-aminopent-4-enoate) is deprotected, and then catalytic hydrogenation is performed in a hydrogen atmosphere to obtain the compound of formula (V) (2-methyl-L-leucine ester), and finally 2-methyl-L-leucine hydrochloride is obtained by ester hydrolysis reaction. The advantage of the present invention is that the obtained 2-methyl-L-leucine does not undergo chiral resolution, and the ee value can reach more than 99.5%, and there is no participation of high-risk reagents such as highly toxic cyanide in the preparation process, which is safe and environmentally friendly, and more than 90% of the catalyst and alkaline solution are used in the synthesis process, saving resources.

[0029] Preferably, in step (1), the 2-aminoalanine ester or its hydrochloride is at least one of R-2-aminopropionic acid methyl or its hydrochloride, R-2-aminopropionic acid ethyl or its hydrochloride, R-2-aminopropionic acid propyl or its hydrochloride, R-2-aminopropionic acid butyl or its hydrochloride, R-2-aminopropionic acid tert-butyl or its hydrochloride, R-2-aminopropionic acid isopropyl or its hydrochloride, R-2-aminopropionic acid benzyl or its hydrochloride, S-2-aminopropionic acid methyl or its hydrochloride, S-2-aminopropionic acid ethyl or its hydrochloride, S-2-aminopropionic acid propyl or its hydrochloride, S-2-aminopropionic acid butyl or its hydrochloride, S-2-aminopropionic acid tert-butyl or its hydrochloride, S-2-aminopropionic acid isopropyl or its hydrochloride, S-2-aminopropionic acid benzyl or its hydrochloride, and a 2-aminopropionic acid ester or its hydrochloride mixed in any proportion of RS configuration.

[0030] Preferably, in step (1), the first solvent is at least one of toluene, xylene, dichloromethane, hexane, cyclohexane, n-heptane, methyl tert-butyl ether, and isopropyl acetate.

[0031] Preferably, in step (1), the mass of the first solvent is 0.5-50 times the mass of 2-aminopropionic acid ester or its hydrochloride. Further preferably, in step (1), the mass of the first solvent is 2-10 times the mass of 2-aminopropionic acid ester or its hydrochloride.

[0032] Preferably, in step (1), the base is at least one of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate. Further preferably, in step (1), the base is triethylamine and / or diisopropylethylamine.

[0033] Preferably, in step (1), the aldehyde ketone compound is an aromatic aldehyde ketone compound and / or an alkyl aldehyde ketone compound.

[0034] Preferably, in step (1), the aldehyde and ketone compound is at least one of benzaldehyde, p-chlorobenzaldehyde, acetophenone, p-chloroacetophenone, acetaldehyde, acetone, and p-methylbenzaldehyde. Further preferably, in step (1), the aldehyde and ketone compound is benzaldehyde and / or p-chlorobenzaldehyde.

[0035] Preferably, in step (1), the temperature of the temperature-raising reaction is -15-100°C, and / or the time of the temperature-raising reaction is 0.5-12h. Further preferably, in step (1), the temperature of the temperature-raising reaction is 10-30°C, and / or the time of the temperature-raising reaction is 3-5h.

[0036] Preferably, in step (1), after the temperature-raising reaction, water is added, and after quenching, the liquids are separated to obtain the compound of formula (II).

[0037] Preferably, in step (2), the chiral biphenyl quaternary ammonium salt phase transfer catalyst has the structural formula shown below:

[0038]

[0039] Preferably, in step (2), the mass of the chiral biphenyl quaternary ammonium salt phase transfer catalyst is 0.01-200% of the mass of the compound of formula (II). Further preferably, in step (2), the mass of the chiral biphenyl quaternary ammonium salt phase transfer catalyst is 0.5-10% of the mass of the compound of formula (II).

[0040] Preferably, in step (2), the 3-halogenated 2-methylpropene is at least one of 3-chloro-2-methylpropene, 3-bromo-2-methylpropene and 3-iodo-2-methylpropene. Further preferably, in step (2), the 3-halogenated 2-methylpropene is 3-bromo-2-methylpropene.

[0041] Preferably, in step (2), the molar amount of the 3-halogenated 2-methylpropene is 0.8-5 times the molar amount of the compound of formula (II). Further preferably, in step (2), the molar amount of the 3-halogenated 2-methylpropene is 1-3 times the molar amount of the compound of formula (II).

[0042] Preferably, in step (2), the alkaline solution is at least one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and an aqueous potassium carbonate solution. Further preferably, in step (2), the alkaline solution is an aqueous sodium hydroxide solution and / or an aqueous potassium hydroxide solution.

[0043] Preferably, in step (2), the mass concentration of the alkali in the alkaline solution is 5-55%. Further preferably, in step (2), the mass concentration of the alkali in the alkaline solution is 30-55%.

[0044] Preferably, in step (2), the molar amount of the base in the alkaline solution is 3-20 times the molar amount of the compound of formula (II). Further preferably, in step (2), the molar amount of the base in the alkaline solution is 5-12 times the molar amount of the compound of formula (II).

[0045] Preferably, in step (2), the temperature of the temperature-raising reaction is -15-80°C, and / or the time of the temperature-raising reaction is 0.5-32h. Further preferably, in step (2), the temperature of the temperature-raising reaction is -15 to -10°C, and / or the time of the temperature-raising reaction is 8-16h.

[0046] Preferably, in step (2), after the separation, the aqueous layer is added with part of the alkaline solution and the catalyst and then used.

[0047] Preferably, in step (2), the solvent is removed by reducing the solvent.

[0048] Preferably, in step (3), the acid is at least one of acetic acid, propionic acid, hydrochloric acid, sulfuric acid, phosphoric acid and citric acid.

[0049] Preferably, in step (3), the mass concentration of the acid is 1-50%. Further preferably, in step (3), the mass concentration of the acid is 5-20%.

[0050] Preferably, in step (3), the molar amount of the acid is 1-20 times the molar amount of the compound of formula (III). Further preferably, in step (3), the molar amount of the acid is 1-6 times the molar amount of the compound of formula (III).

[0051] Preferably, in step (3), the second solvent is at least one of toluene, xylene, dichloromethane, hexane, cyclohexane, n-heptane, methyl tert-butyl ether, isopropyl acetate and ethyl acetate.

[0052] Preferably, in step (3), the mass of the second solvent is 0.5-20 times the mass of the compound of formula (III). Further preferably, in step (3), the mass of the second solvent is 2-8 times the mass of the compound of formula (III).

[0053] Preferably, in step (3), the temperature of the temperature-raising reaction is -5-80°C, and / or the time of the temperature-raising reaction is 0.5-16h. Further preferably, in step (3), the temperature of the temperature-raising reaction is 5-50°C, and / or the time of the temperature-raising reaction is 3-6h.

[0054] Preferably, in step (3), the second solvent is added to extract the generated aldehyde and ketone compounds. The solvent layer is desolventized to recover the second solvent and the aldehyde and ketone compounds.

[0055] Preferably, in step (4), the third solvent is at least one of methanol, ethanol, ethyl acetate, isopropyl acetate, toluene, xylene, tetrahydrofuran and isopropanol.

[0056] Preferably, in step (4), the mass of the third solvent is 0.5-50 times the mass of the compound of formula (IV). Further preferably, in step (4), the mass of the third solvent is 2-5 times the mass of the compound of formula (IV).

[0057] Preferably, in step (4), the catalyst is at least one of Raney nickel, platinum carbon and palladium carbon.

[0058] Preferably, in step (4), the mass of the catalyst is 0.05-200% of the mass of formula (IV). Further preferably, in step (4), the mass of the catalyst is 1-20% of the mass of formula (IV).

[0059] Preferably, in step (4), the temperature of the hydrogenation reaction is 0-100°C, and / or the time of the hydrogenation reaction is 0.5-8h. Further preferably, in step (4), the temperature of the hydrogenation reaction is 15-50°C, and / or the time of the hydrogenation reaction is 2-4h.

[0060] Preferably, in step (4), hydrogen is introduced until the pressure reaches 0.01-2 MPa. Further preferably, in step (4), hydrogen is introduced until the pressure reaches 0.1-0.8 MPa.

[0061] Preferably, in step (4), after mixing the compound of formula (IV), the catalyst and the third solvent, the nitrogen is replaced three times, stirring is started, and hydrogen is introduced.

[0062] Preferably, in step (4), after the hydrogenation reaction, the catalyst is recovered by filtration, and the third solvent is removed under reduced pressure to obtain a compound of formula (V).

[0063] Preferably, in step (5), the fourth solvent is at least one of ethyl acetate, methanol, ethanol, dichloromethane, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, toluene and xylene.

[0064] Preferably, in step (5), the mass of the fourth solvent is 0.5-50 times the mass of the compound of formula (V). Further preferably, in step (5), the mass of the fourth solvent is 3-10 times the mass of the compound of formula (V).

[0065] Preferably, in step (5), the molar amount of the hydrogen chloride gas is 0.1-20 times the molar amount of the compound of formula (V). Further preferably, in step (5), the molar amount of the hydrogen chloride gas is 1-6 times the molar amount of the compound of formula (V).

[0066] Preferably, in step (5), the mass concentration of the solute in the hydrochloric acid solution is 10-37%.

[0067] Preferably, in step (5), the temperature of the ester hydrolysis reaction is 0-120°C, and / or the time of the ester hydrolysis reaction is 0.5-24h. Further preferably, in step (5), the temperature of the ester hydrolysis reaction is 20-60°C, and / or the time of the ester hydrolysis reaction is 3-6h.

[0068] Preferably, in step (5), the crystallization temperature is -15-50°C. Further preferably, in step (5), the crystallization temperature is -15-30°C.

[0069] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0070] The present invention uses 2-aminopropionic acid ester or its hydrochloride as a starting material, firstly dissolves it with an aldehyde or ketone compound (protective reagent) and a base in a first solvent, and reacts at a high temperature to form an imine, so as to protect the amino group, thereby preparing a compound of formula (II); then reacts with a chiral biphenyl quaternary ammonium salt phase transfer catalyst, an alkaline solution, and 3-halogenated-2-methylpropylene at a high temperature, separates the liquids, takes an organic layer, and removes the solvent to obtain a compound of formula (III); then adds an acidic solution to react at a high temperature (for deprotection), adds a second solvent for extraction, separates the liquids, and The pH of the aqueous layer is adjusted to 7-9, a second solvent is added, extraction is performed, the liquids are separated, the organic layer is taken, and the solvent is removed to obtain a compound of formula (IV) (2S-4,2-dimethyl-2-aminopent-4-enoate); a catalyst and a third solvent are added, and a hydrogenation reaction is performed in a hydrogen atmosphere to obtain a compound of formula (V) (2-methyl-L-leucine ester); finally, the compound is mixed with a fourth solvent, hydrogen chloride gas is introduced or a hydrochloric acid solution is added to perform an ester hydrolysis reaction, the temperature is lowered, crystallization is performed and filtration is performed to obtain 2-methyl-L-leucine hydrochloride. The raw materials required for the method of the invention are easily available and low in price, thus reducing the production cost. The catalysts and solvents used can be reused at a rate of more than 90%, thus saving resources. A stereoselective chiral biphenyl quaternary ammonium salt phase transfer catalyst is also used, and the obtained product can reach an ee value of more than 99.5% without undergoing chiral separation, and has a high yield (even up to 77.6%). In addition, no highly toxic cyanide or other high-risk reagents are involved in the preparation process, so the method is safe and environmentally friendly. The prepared 2-methyl-L-leucine hydrochloride can be well applied to drug preparation, etc., and is suitable for large-scale production. DETAILED DESCRIPTION

[0071] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0072] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0073] Example 1

[0074] A method for preparing 2-methyl-L-leucine hydrochloride comprises the following steps:

[0075] (1) Synthesis of compound of formula (II)

[0076] Put 140 g of S-2-aminopropionic acid methyl ester hydrochloride, 120 g of benzaldehyde and 450 mL of xylene into a 2000 mL reactor with stirring and a thermometer, control the temperature at 25-30°C, add 220 g of triethylamine dropwise, and complete the addition within 20 min. Keep the reaction at 25-30°C for 3 h, add 300 mL of water, stir for 0.5 h, separate the liquids, and obtain a xylene solution containing the compound of formula (II) in the upper layer.

[0077] (2) Synthesis of compound of formula (III)

[0078] Add the xylene solution containing the compound of formula (II) obtained in step (1), 1.5g of chiral biphenyl quaternary ammonium salt phase transfer catalyst, 700g of 32% sodium hydroxide aqueous solution, and 200g of 3-bromo-2-methylpropylene into a 2000mL reactor with mechanical stirring and a thermometer, start stirring, control the temperature at -15 to -10°C, and react for 12h. Stop stirring and let stand to separate. Separate the liquid, the upper organic phase is the xylene solution containing the compound of formula (III), desolventize and recover xylene to obtain the compound of formula (III). The lower layer is the alkaline water phase, and contains the catalyst for the next batch.

[0079] (3) Synthesis of compound of formula (IV)

[0080] The compound of formula (III) obtained in step (2) and 2500g of 10% citric acid aqueous solution are placed in a 5L reactor with mechanical stirring and a thermometer. Stirring is started, and the reaction is kept at 35-40°C for 4 hours. 500mL of dichloromethane is added to extract and recover benzaldehyde. After 30 minutes, stirring is stopped and the mixture is allowed to stand for stratification. The lower dichloromethane layer is separated and distilled to recover dichloromethane and benzaldehyde. After the upper aqueous phase is adjusted to pH 8-9 with sodium bicarbonate, 500mL of dichloromethane is added to extract for 30 minutes, stirring is stopped, the mixture is allowed to stand for stratification, and the lower organic phase is separated to obtain a dichloromethane solution containing the compound of formula (IV).

[0081] (4) Synthesis of the compound of formula (V)

[0082] The dichloromethane solution containing the compound of formula (IV) obtained in step (3) is desolventized and the solvent dichloromethane is recovered to obtain the compound of formula (IV). The obtained compound of formula (IV), 600 mL of ethanol, and 2 g of palladium carbon are put into a hydrogenation kettle. After nitrogen replacement three times, the temperature is controlled at 40°C, the hydrogen pressure is maintained at 0.6 MPa, and the reaction is carried out for 2 hours. After the reaction is completed, the platinum carbon is filtered and recovered to obtain a methanol solution containing the compound of formula (V).

[0083] (5) Synthesis of the compound of formula (VI)

[0084] The ethanol solution containing the compound of formula (V) obtained in step (4) is depressurized and desolventized to recover ethanol to obtain the compound of formula (V). The compound of formula (V), 450 mL of tetrahydrofuran, and 108 g of concentrated hydrochloric acid with a mass fraction of 37% are put into a reaction kettle with a stirrer and a thermometer, and the stirring is turned on. The temperature is controlled at 55-60°C and the reaction is carried out for 5 hours. The temperature is slowly lowered to 0°C, and the crystals are filtered to obtain 137 g of 2-methyl-L-leucine hydrochloride compound of formula (VI), with a yield of 75%, a purity of 99.1%, and an ee value of 99.62%.

[0085] The above-mentioned synthetic route is as follows:

[0086]

[0087] Example 2

[0088] A method for preparing 2-methyl-L-leucine hydrochloride comprises the following steps:

[0089] (1) Synthesis of compound of formula (II)

[0090] Put 181.7 g of tert-butyl R-2-aminopropionate hydrochloride, 138.1 g of p-methylbenzaldehyde and 500 mL of toluene into a 2000 mL reactor with a stirrer and a thermometer, control the temperature at 15-20°C, add 150 g of triethylamine dropwise, and complete the addition within 20 min. Keep the reaction at 15-20°C for 5 h, add 300 mL of water, stir for 0.5 h, separate the liquids, and obtain a toluene solution containing the compound of formula (II) in the upper layer.

[0091] (2) Synthesis of compound of formula (III)

[0092] Add the toluene solution containing the compound of formula (II) obtained in step (1), 1.3g of chiral biphenyl quaternary ammonium salt phase transfer catalyst, 1400g of 30% potassium hydroxide aqueous solution, and 195g of 3-bromo-2-methylpropene into a 3000mL reactor with mechanical stirring and a thermometer, start stirring, control the temperature at -5 to -10°C, and react for 14h. Stop stirring and let stand to separate. Separate the liquid, the upper organic phase is the toluene solution of the compound of formula (III), desolventize and recover toluene, and obtain the compound of formula (III). The lower layer is the alkaline aqueous phase, and contains the catalyst for the next batch.

[0093] (3) Synthesis of compound of formula (IV)

[0094] The compound of formula (III) obtained in step (2) and 4000g of 10% citric acid aqueous solution are placed in a 10L four-necked flask with mechanical stirring and a thermometer. Stirring is started, and the reaction is kept at 35-40°C for 4 hours. 600mL of ethyl acetate is added to extract and recover p-methylbenzaldehyde. After 30 minutes, stirring is stopped, and the stratification is allowed to stand, and the upper ethyl acetate layer is separated. The ethyl acetate layer is decompressed to recover ethyl acetate and benzaldehyde. After the lower aqueous phase is adjusted to pH 8-9 with sodium bicarbonate, 600mL of ethyl acetate is added to extract for 30 minutes, stirring is stopped, and the stratification is allowed to stand, and the upper organic phase is separated to obtain an ethyl acetate solution containing the compound of formula (IV).

[0095] (4) Synthesis of the compound of formula (V)

[0096] The ethyl acetate solution containing the compound of formula (IV) obtained in step (3) is desolventized to recover the solvent ethyl acetate to obtain the compound of formula (IV). The obtained compound of formula (IV), 500 mL of methanol, and 5 g of platinum carbon are put into a hydrogenation kettle. After nitrogen replacement three times, the temperature is controlled at 30°C, the hydrogen pressure is maintained at 0.1 MPa, and the reaction is carried out for 3 hours. After the reaction is completed, the platinum carbon is filtered and recovered to obtain a methanol solution containing the compound of formula (V).

[0097] (5) Synthesis of the compound of formula (VI)

[0098] The methanol solution containing the compound of formula (V) obtained in step (4) is depressurized and desolventized to recover methanol to obtain the compound of formula (V). The compound of formula (V), 500 mL of ethyl acetate, and 108 g of 37% concentrated hydrochloric acid are put into a reactor equipped with a stirrer and a thermometer, the stirring is turned on, and the temperature is controlled at 55-60°C for 5 hours. The temperature is slowly lowered to 0°C, and the crystals are filtered to obtain 131 g of 2-methyl-L-leucine hydrochloride compound of formula (VI), with a yield of 72%, a purity of 99.3%, and an ee value of 99.64%.

[0099] The above-mentioned synthetic route is as follows:

[0100]

[0101] Example 3

[0102] A method for preparing 2-methyl-L-leucine hydrochloride comprises the following steps:

[0103] (1) Synthesis of compound of formula (II)

[0104] Put 145.2 g of racemic tert-butyl 2-aminopropionate, 160 g of p-chlorobenzaldehyde and 4500 mL of DCM (dichloromethane) into a 1000 mL reactor equipped with a stirrer and a thermometer, control the temperature at 20-25°C, add 120 g of triethylamine dropwise, and complete the addition within 20 min. Keep the reaction at 20-25°C for 4.5 h, add 300 mL of water, stir for 0.5 h, separate the liquids, and obtain a dichloromethane solution containing the compound of formula (II) in the lower layer.

[0105] (2) Synthesis of compound of formula (III)

[0106] The dichloromethane solution containing the compound of formula (II) obtained in step (1), 0.2g of chiral biphenyl quaternary ammonium salt phase transfer catalyst, 140g of 40% potassium hydroxide aqueous solution, 1260g of the lower alkaline aqueous phase recovered in step (2) of Example 2, and 196g of 3-bromo-2-methylpropene were added to a 3000mL reactor with mechanical stirring and a thermometer, stirring was started, the temperature was controlled at -5 to -10°C, and the reaction was carried out for 15h. Stirring was stopped and the layers were allowed to stand. The upper organic phase was a dichloromethane solution containing the compound of formula (III), and dichloromethane was recovered by desolventizing to obtain the compound of formula (III). The lower layer was an alkaline aqueous phase, and contained a catalyst for the next batch.

[0107] (3) Synthesis of compound of formula (IV)

[0108] Put the compound of formula (III) obtained in step (2) and 1000g of 10% hydrochloric acid aqueous solution into a 2L four-necked flask with mechanical stirring and a thermometer. Turn on stirring and keep the reaction at 35-40℃ for 4h. Add 600mL of toluene, extract and recover p-chlorobenzaldehyde, stop stirring after 30min, and let stand to separate. Separate the upper toluene layer, and recover toluene and p-chlorobenzaldehyde under reduced pressure. After adjusting the pH of the lower aqueous phase to 7-8 with sodium bicarbonate, add 600mL of toluene and extract for 30min, stop stirring, let stand to separate, and separate the upper organic phase to obtain a toluene solution containing the compound of formula (IV).

[0109] (4) Synthesis of the compound of formula (V)

[0110] The toluene solution containing the compound of formula (IV) obtained in step (3) is desolventized to recover the solvent toluene to obtain the compound of formula (IV). The obtained compound of formula (IV), 500 mL of ethyl acetate and 20 g of Raney nickel are put into a hydrogenation kettle. After nitrogen replacement three times, the temperature is controlled at 20°C, the hydrogen pressure is maintained at 0.6 MPa, and the reaction is carried out for 3.5 hours. After the reaction is completed, the Raney nickel is filtered and recovered to obtain an ethyl acetate solution containing the compound of formula (V).

[0111] (5) Synthesis of the compound of formula (VI)

[0112] The ethyl acetate solution containing the compound of formula (V) obtained in step (4) was placed in a reaction kettle equipped with a stirrer and a thermometer, the stirring was turned on, the temperature was controlled at 25-30°C, 75 g of hydrogen chloride gas was introduced, and the reaction was kept at 25-30°C for 5 hours. The temperature was slowly lowered to 0°C, and the crystals were filtered to obtain the compound of formula (VI), i.e., 141 g of 2-methyl-L-leucine hydrochloride, with a yield of 77.6%, a purity of 99.1%, and an ee value of 99.55%.

[0113] The above reaction route is as follows:

[0114]

[0115] Comparative Example 1

[0116] A method for preparing 2-methyl-L-leucine hydrochloride comprises the following steps:

[0117] (1) Synthesis of compound of formula (II)

[0118] Put 181.7 g of tert-butyl R-2-aminopropionate hydrochloride, 138.1 g of p-methylbenzaldehyde and 500 mL of toluene into a 2000 mL reactor with a stirrer and a thermometer, control the temperature at 15-20°C, add 150 g of triethylamine dropwise, and complete the addition within 20 min. Keep the reaction at 15-20°C for 5 h, add 300 mL of water, stir for 0.5 h, separate the liquids, and obtain a toluene solution containing the compound of formula (II) in the upper layer.

[0119] (2) Synthesis of compound of formula (III)

[0120] Add the toluene solution containing the compound of formula (II) obtained in step (1), 1.3 g of tetrabutylammonium bromide, 1400 g of 30% potassium hydroxide aqueous solution, and 195 g of 3-bromo-2-methylpropene into a 3000 mL reactor with mechanical stirring and a thermometer, start stirring, control the temperature at -5 to -10°C, and react for 14 hours. Stop stirring and let stand to separate. Separate the liquid, the upper organic phase is the toluene solution of the compound of formula (III), desolventize and recover toluene, and obtain the compound of formula (III). The lower layer is an alkaline aqueous phase, and contains a catalyst for the next batch.

[0121] (3) Synthesis of compound of formula (IV)

[0122] The compound of formula (III) obtained in step (2) and 4000g of 10% citric acid aqueous solution are placed in a 10L four-necked flask with mechanical stirring and a thermometer. Stirring is started, and the reaction is kept at 35-40°C for 4 hours. 600mL of ethyl acetate is added to extract and recover p-methylbenzaldehyde. After 30 minutes, stirring is stopped, and the layers are allowed to stand to separate, and the upper ethyl acetate layer is separated. The ethyl acetate layer is decompressed to recover ethyl acetate and benzaldehyde. After the lower aqueous phase is adjusted to pH 8-9 with sodium bicarbonate, 600mL of ethyl acetate is added to extract for 30 minutes, stirring is stopped, and the layers are allowed to stand to separate, and the upper organic phase is separated to obtain an ethyl acetate solution containing the compound of formula (IV).

[0123] (4) Synthesis of the compound of formula (V)

[0124] The ethyl acetate solution containing the compound of formula (IV) obtained in step (3) is desolventized to recover the solvent ethyl acetate to obtain the compound of formula (IV). The obtained compound of formula (IV), 500 mL of methanol, and 5 g of platinum carbon are put into a hydrogenation kettle. After nitrogen replacement three times, the temperature is controlled at 30°C, the hydrogen pressure is maintained at 0.1 MPa, and the reaction is carried out for 3 hours. After the reaction is completed, the platinum carbon is filtered and recovered to obtain a methanol solution containing the compound of formula (V).

[0125] (5) Synthesis of the compound of formula (VI)

[0126] The methanol solution containing the compound of formula (V) obtained in step (4) is depressurized and desolventized to recover methanol to obtain the compound of formula (V). The compound of formula (V), 500 mL of ethyl acetate, and 108 g of concentrated hydrochloric acid with a mass fraction of 37% are put into a reactor with a stirrer and a thermometer, and the stirring is turned on. The temperature is controlled at 55-60°C and the reaction is carried out for 5 hours. The temperature is slowly lowered to 0°C, and the crystals are filtered to obtain 101 g of 2-methyl-L-leucine hydrochloride compound of formula (VI), with a yield of 55.5%, a purity of 99.2%, and an ee value of 3.6%.

[0127] Compared with Example 2, in Comparative Example 1, the chiral biphenyl quaternary ammonium salt phase transfer catalyst in step (2) is replaced by an equal amount of tetrabutylammonium bromide. The yield and ee value of the final product 2-methyl-L-leucine hydrochloride compound of formula (VI) are greatly reduced, and the obtained 2-methyl-L-leucine hydrochloride is difficult to be used in subsequent applications, especially in drug preparation.

Claims

1. A method for preparing 2-methyl-L-leucine hydrochloride, characterized in that: The steps include: (1) dissolving 2-aminopropionic acid ester or its hydrochloride, aldehyde ketone compound and base in a first solvent and heating the mixture to obtain a compound of formula (II); (2) mixing the compound of formula (II), a chiral biphenyl quaternary ammonium salt phase transfer catalyst, an alkaline solution, and 3-halogenated-2-methylpropylene, heating the mixture to react, separating the layers, taking the organic layer, and removing the solvent to obtain the compound of formula (III); (3) mixing the compound of formula (III) and the acidic solution, heating the mixture to react, adding a second solvent for extraction, separating the layers, adjusting the pH of the aqueous layer to 7-9, adding a second solvent, extracting the layers, separating the layers, taking the organic layer, and removing the solvent to obtain the compound of formula (IV); (4) mixing the compound of formula (IV), a catalyst, and a third solvent, introducing hydrogen gas, and performing a hydrogenation reaction to obtain a compound of formula (V); (5) mixing the compound of formula (V) and a fourth solvent, introducing hydrogen chloride gas or adding hydrochloric acid solution to carry out ester hydrolysis reaction, cooling, crystallizing and filtering to obtain the 2-methyl-L-leucine hydrochloride; Among them, in formula (II) to formula (V), R1 is selected from one of methyl, ethyl, isopropyl, propyl, and tert-butyl, R2 is selected from one of phenyl, benzyl, methylphenyl, and halogenated phenyl, and X is selected from one of Cl, Br or I.

2. The preparation method according to claim 1, characterized in that: In step (1), the aldehyde and ketone compound is an aromatic aldehyde and ketone compound and / or an alkyl aldehyde and ketone compound.

3. The preparation method according to claim 1, characterized in that: In step (1), the temperature of the temperature-raising reaction is -15-100°C, and / or the time of the temperature-raising reaction is 0.5-12h.

4. The preparation method according to claim 1, characterized in that: In step (2), the structural formula of the chiral biphenyl quaternary ammonium salt phase transfer catalyst is as follows:

5. The preparation method according to claim 1, characterized in that: In step (2), the temperature of the temperature-raising reaction is -15-80°C, and / or the time of the temperature-raising reaction is 0.5-32h.

6. The preparation method according to claim 1, characterized in that: In step (3), the temperature of the temperature-raising reaction is -5-80°C, and / or the time of the temperature-raising reaction is 0.5-16h.

7. The preparation method according to claim 1, characterized in that: In step (4), the catalyst is at least one of Raney nickel, platinum carbon, and palladium carbon.

8. The preparation method according to claim 1, characterized in that: In step (4), the temperature of the hydrogenation reaction is 0-100° C., and / or the time of the hydrogenation reaction is 0.5-8 h.

9. The preparation method according to claim 1, characterized in that: In step (4), hydrogen is introduced until the pressure reaches 0.01-2 MPa.

10. The preparation method according to claim 1, characterized in that: In step (5), the temperature of the ester hydrolysis reaction is 0-120° C., and / or the time of the ester hydrolysis reaction is 0.5-24 h.

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