Preparation method of (2S, 6S)-2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester

Abstract

The invention relates to a preparation method of (2S, 6S)-2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester. Specifically, the invention discloses a method for preparing (2S, 6S)-2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester by using cheap L-threonine as a raw material, and the method has the advantages of simple operation, easily available raw materials, high reaction yield, good purity and easy industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical intermediate preparation, and specifically relates to a method for preparing tert-butyl (2S, 6S)-2,6-dimethyl-1-piperazinecarboxylate. Background Art

[0002] Tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate and its derivatives are important chemical intermediates widely used in pharmaceuticals, pesticides, materials, and other fields, with significant industrial application value. Examples include the psychotropic drug lincain and the floxacin-like drugs sparfloxacin and orbifloxacin.

[0003]

[0004] The literature (J.Org.Chem., Vol.60, No.13, 1995) reports a method for synthesizing (2S,6S)-2,6-dimethyl-1-piperazine or its derivatives. The synthetic route is as follows:

[0005]

[0006] This method requires the use of borane dimethyl sulfide and lithium aluminum hydride to reduce amide, which has high safety risks and production costs, making it unfavorable for industrial production. In addition, when the final product (2S,6S)-2,6-dimethyl-1-piperazine of this synthesis method is further Boc-protected, there are problems with selectivity and overreaction to obtain double Boc protection, resulting in difficult purification and low yield.

[0007] Patent (CN103265498) discloses a synthesis method, and its synthesis route is:

[0008]

[0009] This scheme has a long route and uses sodium borohydride reduction and lithium aluminum hydride reduction of amide, which results in high cost and is not conducive to safe production.

[0010] Therefore, there is an urgent need in the art to develop a method for preparing tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate that is environmentally friendly, has low production cost, low safety risk, high yield and high purity, and is easy to industrialize. Summary of the Invention

[0011] The object of the present invention is to provide a method for preparing tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate which is environmentally friendly, has low safety risks, high reaction yield, good product purity, and is suitable for industrial production.

[0012] The first aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0013] (a) in the presence of an inert solvent and a base, a compound of formula IV undergoes a CN coupling reaction with L-aminopropanol to prepare a compound of formula III having a trans-chiral structure;

[0014] (b) subjecting the compound of formula II prepared from the compound of formula III to a ring-closing reaction in the presence of an inert solvent and a base to prepare the compound of formula I;

[0015]

[0016] in,

[0017] R is selected from the group consisting of toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf).

[0018] In another preferred embodiment, the preparation method of the intermediate compound of formula IV comprises the following steps:

[0019] L-threonine is used as the raw material, and the compound of formula IV is obtained through high-temperature decarboxylation, Cbz protection and TsCl esterification.

[0020]

[0021] In another preferred embodiment, the method for preparing the compound of formula II from the compound of formula III comprises the following steps:

[0022] In an inert solvent, the compound of formula III is subjected to Boc protection, esterification reaction and Cbz protection removal to prepare the compound of formula II;

[0023]

[0024] in,

[0025] R is selected from the group consisting of toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf).

[0026] In another preferred embodiment, the important intermediate is selected from the following group:

[0027]

[0028] in,

[0029] R is selected from the group consisting of toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf);

[0030] R1 is selected from the group consisting of H, Boc;

[0031] R2 is selected from the group consisting of H, Cbz.

[0032] In another preferred embodiment, the inert solvent in steps a and b is selected from the group consisting of alcohol solvents, halogenated alkanes, ether solvents, benzene solvents, acetonitrile, or a combination thereof.

[0033] In another preferred embodiment, the inert solvent in step a is selected from the following group: alcohol solvents such as methanol, ethanol, and isopropanol, halogenated alkanes such as dichloromethane and dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, and 2-methyltetrahydrofuran, acetonitrile, toluene, and xylene benzene solvents, or a combination thereof; preferably dichloromethane.

[0034] In another preferred embodiment, the inert solvent in step b is selected from the following group: alcohol solvents such as methanol, ethanol, isopropanol, and n-butanol, halogenated alkanes such as dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, and 2-methyltetrahydrofuran, acetonitrile, toluene, and xylene benzene solvents, or a combination thereof; preferably n-butanol.

[0035] In another preferred embodiment, the base in step a is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, or a combination thereof; preferably pyridine.

[0036] In another preferred embodiment, the base in step b is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, or a combination thereof; preferably diisopropylethylamine.

[0037] In another preferred embodiment, the amount of the base used in step a is 1.0-20.0 times the equivalent of the compound represented by formula IV, preferably 3.0-4.0 times the equivalent.

[0038] In another preferred embodiment, the amount of the base used in step b is 1.0-20.0 times the equivalent of the compound represented by formula II, preferably 3.0-4.0 times the equivalent.

[0039] In another preferred embodiment, the reaction temperature of step a is 0-80°C, preferably 50-60°C.

[0040] In another preferred embodiment, the reaction temperature of step b is 0-80°C, preferably 50-60°C.

[0041] In another preferred embodiment, the reaction time of step a is 2-24 hours, preferably 18-20 hours.

[0042] In another preferred embodiment, the reaction time of step b is 2-24 hours, preferably 18-20 hours.

[0043] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0044] After extensive and in-depth research, the inventors unexpectedly discovered that a compound of Formula IV undergoes a Walden inversion through a CN coupling reaction with L-aminopropanol, resulting in a trans-chiral compound of Formula III. This compound of Formula II can then be subjected to a ring-closure reaction to produce a compound of Formula I with a -Boc group in high yield and high purity. This method, which does not require the use of strong reducing agents, is environmentally friendly, has low safety risks, contains few impurities, and is amenable to industrial production. Based on this foundation, the inventors completed the present invention.

[0045] the term

[0046] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0047] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0048] As used herein, the terms "the method of the present invention", "the preparation method of the present invention" and "the industrial preparation method of the present invention" can be used interchangeably to refer to the method described in the first aspect of the present invention.

[0049] The compound of formula I described in the present invention is (2S,6S)-2,6-dimethyl-1-piperazinecarboxylic acid tert-butyl ester, and its structural formula is as follows:

[0050]

[0051] The important intermediates of the present invention are selected from the following groups:

[0052]

[0053] wherein R, R1, and R2 are as defined above.

[0054] In another preferred embodiment, in the compound, R, R1 and R2 are corresponding groups in the specific compound of the present invention.

[0055] As used herein, the structure of the protecting group -Cbz is

[0056] The structure of the protecting group -Boc is

[0057] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0058] Preparation method

[0059] Typically, the preparation method of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0060] The present invention provides a method for preparing tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate, comprising the following steps:

[0061]

[0062] (a-1) Using L-threonine as raw material, compound IV-1 is generated by high temperature decarboxylation;

[0063] (a-2) Compound IV-1 obtained in step a-1 is protected with Cbz to obtain compound IV-2;

[0064] (a-3) Compound IV-2 obtained in step a-2 is esterified with TsCl to obtain compound IV;

[0065] (a) Compound IV obtained in step a-3 is subjected to a CN substitution reaction to obtain compound III;

[0066] (b-1) Compound III obtained in step a is subjected to Boc protection to obtain compound II-1;

[0067] (b-2) Compound II-1 obtained in step b-1 is subjected to an esterification reaction to obtain compound II-2;

[0068] (b-3) Compound II-2 obtained in step b-2 is subjected to Cbz removal to obtain compound II;

[0069] (b) Compound II obtained in step b-3 is subjected to ring closure to obtain the final product Compound I.

[0070] Specifically, the steps of the preparation method of the present invention are as follows:

[0071] Step a-1: This step is a decarboxylation reaction. In an inert solvent, L-threonine undergoes a decarboxylation reaction at high temperature to prepare a compound of formula IV-1.

[0072]

[0073] Wherein, the inert solvent is selected from the following group: tetraethylene glycol dimethyl ether, ethylene glycol, 1,3-propylene glycol and other high boiling point solvents, or a combination thereof.

[0074] Preferably, the inert solvent is tetraethylene glycol dimethyl ether.

[0075] The reaction temperature is 160-200°C, preferably 170-180°C.

[0076] The reaction time is 2-10 hours, preferably 3-5 hours.

[0077] Step a-2: The Cbz protection methods and conditions in this step are conventional in the art. Cbz-Cl is added dropwise to the compound of Formula IV-1 in an inert solvent or water in the presence of a base. After the reaction, the layers are separated and the solvent is concentrated to yield the compound of Formula IV-2.

[0078]

[0079] The inert solvent is selected from the following group: halogenated alkanes such as dichloromethane and dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran, acetonitrile, toluene, xylene and benzene solvents, or a combination thereof.

[0080] Preferably, the inert solvent is dichloromethane.

[0081] The base is selected from the following group: organic bases commonly used in organic synthesis such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, and commonly used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, and sodium phosphate.

[0082] Preferably, the base is potassium carbonate.

[0083] The equivalent weight of the Cbz-Cl is 1.0-20.0 times the equivalent weight of the compound of formula IV-1.

[0084] Preferably, the equivalent weight of the Cbz-Cl is 1.0-2.0 times the equivalent weight of the compound of formula IV-1.

[0085] The equivalent of the base is 1.0-20.0 times the equivalent of the compound of formula IV-1.

[0086] Preferably, the equivalent of the base is 1.0-2.0 times the equivalent of the compound of formula IV-1.

[0087] The reaction temperature is 20-80°C, preferably 20-30°C.

[0088] The reaction time is 2-20 hours, preferably 2-3 hours.

[0089] Step a-3: The esterification method and conditions in this step are conventional methods and conditions in the art. Compound IV-2 is added dropwise to a base in an inert solvent with TsCl. After the reaction, the mixture is washed with acid and alkali, the solvent is concentrated, and crystallization is performed to obtain compound IV.

[0090]

[0091] The inert solvent is selected from the following group: halogenated alkanes such as dichloromethane and dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran, acetonitrile, toluene, xylene and benzene solvents, or a combination thereof.

[0092] Preferably, the inert solvent is dichloromethane.

[0093] The base is selected from the following group: organic bases commonly used in organic synthesis such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, and commonly used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, and sodium phosphate.

[0094] Preferably, the base is triethylamine.

[0095] The equivalent of TsCl is 1.0-20.0 times the equivalent of the compound of formula IV-2.

[0096] Preferably, the equivalent of TsCl is 1.0-2.0 times the equivalent of the compound of formula IV-2.

[0097] The equivalent of the base is 1.0-20.0 times the equivalent of the compound of formula IV-2.

[0098] Preferably, the equivalent of the base is 1.0-2.0 times the equivalent of the compound of formula IV-2.

[0099] The reaction temperature is 0-80°C, preferably 20-30°C.

[0100] The reaction time is 2-24 hours, preferably 20-24 hours.

[0101] Step a: The CN coupling method and conditions in this step are conventional methods and conditions in the art. Compound IV and L-aminopropanol are added to an inert solvent in the presence of a base and heated for reaction. After completion of the reaction, the layers are separated by extraction, washed with water and then with an alkali solution, and the solvent is concentrated to obtain the compound of Formula III.

[0102]

[0103] The inert solvent is selected from the following group: alcohol solvents such as methanol, ethanol, and isopropanol; halogenated alkanes such as dichloromethane and dichloroethane; ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, and 2-methyltetrahydrofuran; benzene solvents such as acetonitrile, toluene, and xylene; or a combination thereof.

[0104] Preferably, the inert solvent is acetonitrile.

[0105] The base is selected from the following group: organic bases commonly used in organic synthesis such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, and commonly used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, and sodium phosphate.

[0106] Preferably, the base is pyridine.

[0107] The equivalent of the base is 1.0-20.0 times the equivalent of the compound of formula IV.

[0108] Preferably, the equivalent weight of the base is 2.0-3.0 times the equivalent weight of the compound of formula IV.

[0109] The equivalent of the L-aminopropanol is 1.0-20.0 times the equivalent of the compound of formula IV.

[0110] Preferably, the equivalent weight of the L-aminopropanol is 1.5-2.5 times the equivalent weight of the compound of formula IV.

[0111] The reaction temperature is 0-80°C, preferably 50-60°C.

[0112] The reaction time is 2-24 hours, preferably 18-20 hours.

[0113] Step b-1: The Boc protection method and conditions in this step are conventional in the art. Compound III is treated in an inert solvent in the presence of a base and a catalyst, and Boc2O is added dropwise. After the reaction is complete, water is added, the layers are separated, and the solvent is concentrated to obtain compound II-1.

[0114]

[0115] The inert solvent is selected from the following group: halogenated alkanes such as dichloromethane and dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran, acetonitrile, toluene, xylene and benzene solvents, or a combination thereof.

[0116] Preferably, the inert solvent is dichloromethane.

[0117] The base is selected from the following group: organic bases commonly used in organic synthesis such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, and commonly used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, and sodium phosphate.

[0118] Preferably, the base is triethylamine.

[0119] The catalyst is DMAP.

[0120] The equivalent of Boc2O is 1.0-20.0 times the equivalent of the compound represented by formula III.

[0121] Preferably, the equivalent of Boc2O is 1.0-1.2 times the equivalent of the compound represented by formula III.

[0122] The equivalent weight of the base is 1.0-20.0 times the equivalent weight of the compound represented by formula III.

[0123] Preferably, the equivalent weight of the base is 1.0-2.0 times the equivalent weight of the compound represented by Formula III.

[0124] The equivalent weight of the catalyst is 0.01-0.1 times the equivalent weight of the compound represented by formula III.

[0125] Preferably, the equivalent weight of the catalyst is 0.02-0.04 times the equivalent weight of the compound represented by formula III.

[0126] The reaction temperature is 20-80°C, preferably 20-30°C.

[0127] The reaction time is 2-20 hours, preferably 16-20 hours.

[0128] Step b-2: The esterification method and conditions in this step are conventional in the art. The compound of Formula II-1 is added dropwise to an inert solvent in the presence of a base, followed by acid and alkali washing. The solvent is concentrated and crystallized to obtain the compound of Formula II-2.

[0129]

[0130] Wherein, R is selected from the following group: toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), trifluorosulfonyl (Tf).

[0131] The inert solvent is selected from the following group: halogenated alkanes such as dichloromethane and dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran, acetonitrile, toluene, xylene and benzene solvents, or a combination thereof.

[0132] Preferably, the inert solvent is dichloromethane.

[0133] The base is selected from the following group: organic bases commonly used in organic synthesis such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, and commonly used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, and sodium phosphate.

[0134] Preferably, the base is triethylamine.

[0135] The equivalent of the RCl or (RO)2O is 1.0-20.0 times the equivalent of the compound of formula II-1.

[0136] Preferably, the equivalent of RCl or (RO)2O is 1.0-2.0 times the equivalent of the compound of formula II-1.

[0137] The equivalent of the base is 1.0-20.0 times the equivalent of the compound of formula II-1.

[0138] Preferably, the equivalent weight of the base is 1.0-2.0 times the equivalent weight of the compound of formula II-1.

[0139] The reaction temperature is 0-80°C, preferably 20-30°C.

[0140] The reaction time is 2-24 hours, preferably 20-24 hours.

[0141] Step b-3: The hydrogenation reaction method and conditions in this step are conventional methods and conditions for hydrogenation reactions in this field. The compound represented by Formula II-2 is hydrogenated in an inert solvent in the presence of a catalyst. After the reaction is completed, the compound is simply filtered and the solvent is concentrated to obtain the compound of Formula II.

[0142]

[0143] Wherein, R is selected from the following group: toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), trifluorosulfonyl (Tf).

[0144] The inert solvent is selected from the following group: C1-C8 alcohol solvents, ester solvents, ether solvents, or a combination thereof.

[0145] In another preferred embodiment, the alcohol solvent is selected from the following group: methanol, ethanol, isopropanol, isobutanol, n-butanol, or a combination thereof; the ester solvent is selected from the following group: ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, or a combination thereof; the ether solvent is selected from the following group: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, or a combination thereof.

[0146] Preferably, the inert solvent is methanol or ethanol.

[0147] The catalyst is selected from the group consisting of Raney nickel, Pd / C, Ru / C, Rh / C, or a combination thereof.

[0148] Preferably, the catalyst is Pd / C.

[0149] The amount of the inert solvent used is 1-20 times that of the compound of formula II-2.

[0150] Preferably, the amount of the inert solvent is 10 times that of the compound of formula II-2.

[0151] The hydrogen pressure is 0.1-2.0 MPa, preferably 0.3 MPa.

[0152] The hydrogen reaction temperature is 20-80°C, preferably 40-50°C.

[0153] Step b: The methods and conditions in this step are conventional methods and conditions in the art. Compound II is added to an inert solvent under nitrogen protection and the presence of a base. After the reaction, the mixture is washed with water and then with an alkali solution, the solvent is concentrated, and crystallization is performed to obtain the compound of Formula I.

[0154]

[0155] The inert solvent is selected from the following group: alcohol solvents such as methanol, ethanol, isopropanol, and n-butanol, halogenated alkanes such as dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, and 2-methyltetrahydrofuran, benzene solvents such as acetonitrile, toluene, and xylene, or a combination thereof.

[0156] Preferably, the inert solvent is n-butanol.

[0157] The base is selected from the following group: organic bases commonly used in organic synthesis such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, and commonly used inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, and sodium phosphate.

[0158] Preferably, the base is diisopropylethylamine.

[0159] The equivalent of the base is 1.0-20.0 times the equivalent of the compound of formula II.

[0160] Preferably, the equivalent weight of the base is 3.0-4.0 times the equivalent weight of the compound of formula II.

[0161] The reaction temperature is 0-80°C, preferably 50-60°C.

[0162] The reaction time is 2-24 hours, preferably 18-20 hours.

[0163] The present invention also provides a method for preparing L-aminopropanol, the specific steps of which are as follows:

[0164] L-aminopropanol was prepared from L-alanine methyl ester by reduction with a reducing agent.

[0165]

[0166] The main advantages of the present invention are:

[0167] 1. The present invention provides a method for preparing tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate using L-threonine as a raw material. The raw material is cheap and has a great cost advantage.

[0168] 2. In step a of the method of the present invention, chirality inversion occurs, unexpectedly obtaining a compound of formula III having a trans chiral structure.

[0169] 3. The present invention can prepare the product compound of formula I in high yield through the ring closure reaction described in step b, without the need for difficult purification.

[0170] 4. The method of the present invention is simple to operate, has a high product yield (the yield of each step is 79% to 99%) and good purity, produces less three wastes, has relatively mild reaction conditions, and is easy to industrialize.

[0171] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0172] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0173] In the present invention, the structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. LCMS measurements are performed using a Waters 2695 liquid chromatography-mass spectrometer (MS model: Micromass ZQ).

[0174] HPLC determination was performed using an Agilent 1100 high pressure liquid chromatograph (ZORBAX SP-C18 250×4.6 mm column, Eclipse Plus-C18 250×4.6 mm column).

[0175] Unless otherwise stated, the following examples were carried out under normal pressure.

[0176] Example 1

[0177]

[0178] Tetraethylene glycol dimethyl ether (700 ml), L-threonine (100 g), and 2-cyclohexenone (5 g) were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 170-180°C and stirred for 3-5 hours until the system became clear and no gas was generated. After completion of the reaction, the mixture was concentrated under reduced pressure and distilled to obtain the product (50.4 g) with an 80% yield and a purity of 98.1% as determined by GC.

[0179] MS (ESI+) m / z: 76 [M+H + ].

[0180] Example 2

[0181]

[0182] To a reactor equipped with a stirrer and temperature controller, dichloromethane (500 mL), water (500 mL), the compound of formula IV-1 (100 g), and potassium carbonate (202 g) were added dropwise at a temperature of 0-10°C. Cbz-Cl (230 g) was added dropwise. After the addition, the mixture was stirred at a temperature of 10-20°C for 4 hours. After the reaction was complete, the liquids were separated, and the organic phase was washed with 5% citric acid and 5% sodium bicarbonate. The organic phase was concentrated to dryness under reduced pressure to obtain the compound (236 g) with a yield of 85% and a purity of 89.7% as determined by HPLC.

[0183] MS (ESI+) m / z: 210 [M+H+].

[0184] Example 3

[0185]

[0186] Under nitrogen, dichloromethane (500 mL), triethylamine (96.5 g), the compound of formula IV-2 (100 g), and trimethylamine hydrochloride (6 g) were added to a reactor equipped with a stirring and temperature control device. A solution of TsCl (164 g) in dichloromethane (300 mL) was added dropwise at a temperature of 0-10°C. After the addition, the mixture was stirred and reacted for 16 hours at a temperature of 10-20°C. After the reaction was completed, 500 ml of water was added for separation. The organic phase was washed twice with 5% sodium bicarbonate, concentrated to dryness under reduced pressure, and recrystallized from ethanol to obtain the compound (158 g) with a yield of 91%. The purity was 98.9% as determined by HPLC.

[0187] MS (ESI+) m / z: 364 [M+H+].

[0188] Example 4

[0189]

[0190] Under nitrogen, L-aminopropanol (20.6 g), acetonitrile (600 mL), and pyridine (30.5 g) were added to a reactor equipped with a stirrer and temperature controller. The temperature was controlled at 60-65°C. 100 g of the compound of formula IV (50 g) was added portionwise. After addition, the mixture was allowed to react at 60-65°C for 20 h. After completion of the reaction, dichloromethane (500 mL) and water (500 mL) were added, and the layers were separated. The aqueous phase was extracted once with dichloromethane, and the organic phase was concentrated to dryness to obtain the compound (29 g) with a yield of 79% and a purity of 97.6% as determined by HPLC.

[0191] MS (ESI+) m / z: 267 [M+H + ].

[0192] Example 5

[0193]

[0194] To a reactor equipped with a stirrer and temperature controller, add dichloromethane (500 mL), compound III (60 g), triethylamine (27.3 g), and DMAP (4 g). Add Boc2O (54 g) dropwise at a temperature of 0-10°C. After addition, stir and react for 4 hours at a temperature of 10-20°C. After completion of the reaction, concentrate to dryness under reduced pressure to obtain the compound (80.8 g) with a yield of 98%. The purity, as determined by HPLC, was 97.0%.

[0195] MS (ESI+) m / z: 367 [M+H+].

[0196] Example 6

[0197]

[0198] Under nitrogen protection, dichloromethane (500 mL), triethylamine (19 g), and the compound of formula II-1 (36 g) were added to a reactor equipped with a stirring and temperature control device. A solution of TsCl (26.6 g) in dichloromethane (300 mL) was added dropwise at a temperature of 0-10°C. After the addition, the mixture was stirred at a temperature of 10-20°C for 16 hours. After the reaction was completed, water was added to quench the reaction. The organic phase was washed twice with 5% sodium bicarbonate, concentrated to dryness under reduced pressure, and then recrystallized from ethanol to obtain compound II-2 (47.8 g) with a yield of 92%. The purity was 98.9% as determined by HPLC.

[0199] MS (ESI+) m / z: 521 [M+H+].

[0200] Example 7

[0201]

[0202] Methanol, the compound of formula II-2 (30 g), and wet Pd / C (3 g) were added to a hydrogenation reactor. The reaction was carried out at a hydrogen pressure of 10 atm and a reaction temperature of 50°C for 24 h. After the reaction, the Pd / C was filtered off and the product was concentrated to dryness to obtain the compound (22.0 g) with a yield of 99%.

[0203] MS (ESI+) m / z: 387 [M+H + ].

[0204] Example 8

[0205]

[0206] Under nitrogen, n-butanol (200 mL), DIPEA (10.5 g), and the compound of Formula II (10 g) were added to a reactor equipped with a stirrer and temperature controller. The temperature was raised to 110-120°C and stirred for 12 hours. After completion of the reaction, 10% aqueous sodium carbonate solution and ethyl acetate were added with stirring to separate the layers. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were concentrated to dryness under reduced pressure and recrystallized from toluene to obtain the compound of Formula I (4.7 g) in a yield of 84%.

[0207] MS (ESI+) m / z: 215 [M+H+].

[0208] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: (a) in the presence of an inert solvent and a base, a compound of formula IV undergoes a CN coupling reaction with L-aminopropanol to prepare a compound of formula III having a trans-chiral structure; (b) subjecting the compound of formula II prepared from the compound of formula III to a ring-closing reaction in the presence of an inert solvent and a base to prepare the compound of formula I; in, R is selected from the group consisting of toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf).

2. The preparation method according to claim 1, wherein The preparation method of the intermediate compound of formula IV comprises the following steps: L-threonine is used as the raw material, and the compound of formula IV is obtained through high-temperature decarboxylation, Cbz protection and TsCl esterification.

3. The preparation method according to claim 1, wherein The method for preparing a compound of formula II from a compound of formula III comprises the following steps: In an inert solvent, the compound of formula III is subjected to Boc protection, esterification reaction and Cbz protection removal to prepare the compound of formula II; in, R is selected from the group consisting of toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf).

4. The preparation method according to claim 1, wherein The important intermediate is selected from the following group: in, R is selected from the group consisting of H, toluenesulfonyl (Ms), methanesulfonyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf); R1 is selected from the group consisting of H, Boc; R2 is selected from the group consisting of H, Cbz.

5. The preparation method according to claim 1, wherein The inert solvent in steps a and b is selected from the group consisting of alcohol solvents, halogenated alkanes, ether solvents, benzene solvents, acetonitrile, or a combination thereof.

6. The preparation method according to claim 1, wherein The base in step a is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2,6-lutidine, DMAP, DABCO, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, or a combination thereof; preferably pyridine.

7. The preparation method according to claim 1, wherein The base in step b is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-picoline, 2,6-lutidine, DMAP, DABCO, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, or a combination thereof; preferably diisopropylethylamine.

8. The preparation method according to claim 1, wherein The amount of the base used in step a is 1.0-20.0 times the equivalent of the compound represented by formula IV, preferably 3.0-4.0 times the equivalent; and / or The amount of the base used in step b is 1.0-20.0 times the equivalent of the compound represented by formula II, preferably 3.0-4.0 times the equivalent.

9. The preparation method according to claim 1, wherein The reaction temperature of step a is 0-80°C, preferably 50-60°C; and / or The reaction temperature of step b is 0-80°C, preferably 50-60°C.

10. The preparation method according to claim 1, wherein The reaction time of step a is 2-24 hours, preferably 18-20 hours; and / or The reaction time of step b is 2-24 hours, preferably 18-20 hours.

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