阅读说明：本技术 一种哌啶胺的制备方法 (Preparation method of piperidylamine ) 是由 王仲清 孙国栋 胡本全 罗忠华 黄芳芳 于 2019-11-21 设计创作，主要内容包括：本发明涉及一种哌啶胺的制备方法,该方法以化合物02作为原料与三甲基卤化亚砜反应,制得化合物03,化合物03在催化剂作用下反应成环生成化合物04；化合物04在ω-转氨酶和磷酸吡哆醛的作用下反应生成化合物05,化合物05在酸的作用下脱保护基得到化合物06；该方法避免用手性柱拆分或拆分剂拆分,原料便宜易得,步骤短,且分离纯化简单,ee值高,收率高,纯度高,操作安全,利于工业化生产。(The invention relates to a preparation method of piperidine amine, which takes a compound 02 as a raw material to react with trimethyl sulfoxide halide to prepare a compound 03, and the compound 03 reacts to form a ring under the action of a catalyst to generate a compound 04; reacting the compound 04 under the action of omega-transaminase and pyridoxal phosphate to generate a compound 05, and deprotecting the compound 05 under the action of acid to obtain a compound 06; the method avoids chiral column resolution or resolving agent resolution, has the advantages of cheap and easily-obtained raw materials, short steps, simple separation and purification, high ee value, high yield, high purity and safe operation, and is beneficial to industrial production.)

1. A method of preparing compound 03 comprising: reacting compound 02 with trimethyl sulfoxide halide in the presence of a first base in a first solvent to obtain compound 03,

wherein the content of the first and second substances,

R₁is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and 2-nitrobenzenesulfonyl;

R₂is one of methyl, ethyl, n-propyl, isopropyl, tert-butyl and benzyl;

the trimethyl halogenated sulfoxide is at least one of trimethyl iodide sulfoxide, trimethyl bromide sulfoxide and trimethyl chloride sulfoxide.

2. The method according to claim 1, wherein the first solvent is at least one of THF, DMSO, 2Me-THF, DCM, toluene.

3. The method of claim 1, wherein the first base is at least one of sodium hydride, sodium amide, potassium tert-butoxide, sodium tert-butoxide.

4. The method of claim 1, wherein the molar ratio of the first base to compound 02 is from 1:1 to 3: 1; or the molar ratio is 1.5:1-2.5: 1.

5. The method according to claim 1, wherein the molar ratio of trimethyl sulfoxide halide to compound 02 is 1:1 to 3: 1; or the molar ratio is 1.5:1-2.5: 1.

6. The method of claim 1, wherein the reaction temperature of the reaction is-20 ℃ to 80 ℃; or the reaction temperature is 40-60 ℃.

7. The method of claim 1, wherein the reaction time of the reaction is 2h to 24 h; or the reaction time is 5h-20 h; or the reaction time is 10h-15 h.

8. The method of claim 1, comprising reacting compound 03 in a second solvent over a catalyst to form compound 04

9. The process according to claim 8, wherein the second solvent is at least one of DCE, DCM, THF, 2Me-THF, toluene.

10. The process according to claim 8, wherein the catalyst is (1, 5-cyclooctadiene) iridium (I) chloride dimer, (1, 5-cyclooctadiene) methoxyiridium (I) dimer, (1, 5-cyclooctadiene) rhodium (I) chloride dimer, (norbornadiene) rhodium (I) chloride dimer.

11. The method according to claim 8, wherein the molar ratio of the catalyst to the compound 03 is 0.01% to 10%; or the molar ratio is 0.5 to 3 percent.

12. The method of claim 8, wherein the reaction temperature of the reaction is 20 ℃ to 80 ℃; or the reaction temperature is 40-60 ℃.

13. The method of claim 1, comprising reacting compound 03 with a halide in a third solvent to form compound 03-1

Wherein, X is one of fluorine, chlorine, bromine or iodine.

14. The method of claim 13, wherein the halide is hydrogen chloride, hydrogen bromide; or the halide is a mixture of at least one of lithium chloride, sodium bromide, lithium bromide, sodium iodide and potassium iodide and the first acid.

15. The method of claim 14, wherein the first acid is at least one of methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and sulfuric acid.

16. The method of claim 14, wherein the third solvent is at least one of DCM, EA, THF, dioxane, toluene.

17. The method of claim 14, comprising reacting compound 03-1 in a fourth solvent in the presence of a third base to form compound 04-1

Wherein the third base is at least one of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine and diisopropylethylamine.

18. The method of claim 17, wherein the fourth solvent is at least one of methanol, ethanol, acetone, tetrahydrofuran, dichloromethane, toluene; or the fourth solvent is at least one of triethylamine and diisopropylethylamine.

19. The method of claim 17, wherein the molar ratio of the third base to compound 03-1 is from 0.8:1 to 3:1, or from 1:1 to 1.8: 1.

20. A method of making compound 05 comprising: contacting compound 04 with amino donor in cosolvent and buffer in the presence of omega-transaminase and pyridoxal phosphate to obtain compound 05

R₁Is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and nitrobenzenesulfonylAnd (4) seed preparation.

21. The process according to claim 20, wherein said compound 04 is contacted with said amino donor in the presence of ω -transaminase and pyridoxal phosphate in said co-solvent and buffer solution, and reacted at 25 ℃ -60 ℃ at pH 8.5-11 to give said compound 05.

22. The method of claim 20, wherein the amino donor is at least one of isopropylamine, alanine, n-propylamine, 1-phenylethylamine, glycine, or their hydrochloride salts.

23. The method of claim 20, wherein the co-solvent is dimethylsulfoxide or ethanol or a combination thereof.

24. The method of claim 20, comprising deprotecting compound 05 in a fifth solvent and a second acid to produce compound 06 by adjusting pH with a fourth base

The fifth solvent is at least one of ethanol, methanol, ethyl acetate and dichloromethane;

the second acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid and trifluoroacetic acid;

the fourth alkali is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

25. A compound represented by formula compound 03, compound 03-1, or compound 06:

wherein R is₁Is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and nitrobenzenesulfonyl;

x is one of fluorine, chlorine, bromine or iodine.

Technical Field

The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of piperidinamine.

Background

Piperidine amine is an important pharmaceutical intermediate, and is commonly used for synthesizing pharmaceutically active compounds, such as PF-06651600.

PF-06651600 is a potent, selective inhibitor of JAK3, previously approved by FDA breakthrough therapy for the treatment of alopecia areata. Currently, it is subjected to a phase 3 clinical trial for the treatment of moderate to severe alopecia areata, while continuing the trial for the treatment of Rheumatoid Arthritis (RA), Crohn's Disease (CD) and Ulcerative Colitis (UC); the structure of PF-06651600 is shown by the following formula:

in the prior art, 5-methyl-3-aminopyridine is used as a raw material, for example, WO2010048012 discloses that a metal rhodium catalyst is used to reduce a pyridine ring into a piperidine ring; WO2016112298 discloses the use of PtO₂As a catalyst to reduce the pyridine ring. However, the metal catalyst is expensive, generally uses hydrogen for reduction, and is heated and hydrogenated under high pressure for a long time, and the reaction conditions are harsh. E.g. using PtO₂The generated platinum black is flammable and dangerous to produce. In the prior art, the multi-step reaction needs column chromatography purification and is difficult to be produced in an enlarged way. In the prior art, (R) -N-3, 5-dinitrobenzoyl phenylglycine is used as a resolving agent, which is expensive and is a document (Organic Process Research)&Development (2019) records that the resolving agent has violent exothermic phenomenon in use, and has potential safety hazard due to poor control in production.

Therefore, a new intermediate is urgently needed to be found, or a new method for preparing the piperidine amine intermediate of PF-06651600 is researched to obtain a preparation method which is simple and convenient to operate, avoids chiral resolution loss yield, is cheap and easy to obtain raw materials, has short steps, is simple to separate and purify, has a high ee value, a high yield and a high purity, and is environment-friendly, so that the compound PF-06651600 is better prepared.

Disclosure of Invention

The invention provides a preparation method of piperidine amine, in the method, a compound 02 can be used as a raw material to react with trimethyl sulfoxide halide to prepare a compound 03, and the compound 03 reacts to form a ring under the action of a catalyst to generate a compound 04; and reacting the compound 04 under the action of omega-transaminase and pyridoxal phosphate to generate a compound 05, and deprotecting the compound 05 under the action of acid to obtain a compound 06.

In a first aspect, the present invention provides a method for preparing piperidinamine, comprising reacting compound 02 with trimethyl sulfoxide halide in a first solvent in the presence of a first base to obtain compound 03,

wherein the content of the first and second substances,

R₁is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and 2-nitrobenzenesulfonyl;

R₂is one of methyl, ethyl, n-propyl, isopropyl, benzyl and tert-butyl;

the trimethyl halogenated sulfoxide is at least one of trimethyl iodide sulfoxide, trimethyl bromide sulfoxide and trimethyl chloride sulfoxide.

In some embodiments, the first solvent is at least one of THF, DMSO, 2Me-THF, DCM, toluene.

In some embodiments, the first base is at least one of sodium hydride, sodium amide, potassium tert-butoxide, sodium tert-butoxide, facilitating better preparation of a product of high yield and purity.

In some embodiments, the molar ratio of the first base to compound 02 is from 1:1 to 3: 1; in some embodiments, the molar ratio of the first base to compound 02 is from 1.5:1 to 2.5: 1.

In some embodiments, the molar ratio of trimethyl sulfoxide halide to compound 02 is from 1:1 to 3: 1; in some embodiments, the molar ratio of trimethyl sulfoxide halide to compound 02 is 1.5:1 to 2.5:1, which facilitates better preparation of the resulting product.

In some embodiments, the reaction temperature of the reaction is from-20 ℃ to 80 ℃; in some embodiments, the reaction temperature of the reaction is from 40 ℃ to 60 ℃.

In some embodiments, the reaction is for a reaction time of 2h to 24 h; in some embodiments, the reaction is for a reaction time of 5h to 20 h; in some embodiments, the reaction time for the reaction is from 10h to 15 h.

In a second aspect, the present invention provides a method for preparing piperidinamine, comprising the further reaction of compound 03 in a second solvent under the action of a catalyst to produce compound 04

R₁Is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and 2-nitrobenzenesulfonyl.

In some embodiments, the second solvent is at least one of DCE, DCM, THF, 2Me-THF, toluene.

In some embodiments, the catalyst is (1, 5-cyclooctadiene) iridium (I) chloride dimer, (1, 5-cyclooctadiene) methoxyiridium (I) dimer, (1, 5-cyclooctadiene) rhodium (I) chloride dimer, (norbornadiene) rhodium (I) chloride dimer, having the structure shown in the following formula:

the catalyst is favorable for better catalyzing and obtaining the compound 04 with high ee value, high yield and high purity.

In some embodiments, the molar ratio of the catalyst to compound 03 is from 0.01% to 10%; in some embodiments, the molar ratio of the catalyst to compound 03 is between 0.5% and 3%.

In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 80 ℃; in some embodiments, the reaction temperature of the reaction is from 40 ℃ to 60 ℃.

In a third aspect, the present invention provides a process for preparing piperidinamine, which comprises reacting compound 03 with a halide in a third solvent to form compound 03-1

Wherein the content of the first and second substances,

r1 is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and 2-nitrobenzenesulfonyl;

x is one of fluorine, chlorine, bromine or iodine.

In some embodiments, the halide is hydrogen chloride, hydrogen bromide; in some embodiments, the halide is a mixture of at least one of lithium chloride, sodium bromide, lithium bromide, sodium iodide, potassium iodide and a first acid.

In some embodiments, the first acid is at least one of methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid.

In some embodiments, the third solvent is at least one of DCM, EA, THF, dioxane, toluene.

In a fourth aspect, the present invention provides a process for preparing piperidinamine, which comprises reacting compound 03-1 in a fourth solvent in the presence of a third base to form compound 04-1

Wherein, X is one of fluorine, chlorine, bromine or iodine.

In some embodiments, the third base is at least one of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, diisopropylethylamine.

In some embodiments, the fourth solvent is at least one of methanol, ethanol, acetone, tetrahydrofuran, dichloromethane, toluene; in some embodiments, the fourth solvent is at least one of triethylamine, diisopropylethylamine. The liquid organic base is directly used as a solvent, which is favorable for preparing the compound 04-1 more conveniently.

In some embodiments, the molar ratio of the third base to compound 03-1 is from 0.8:1 to 3:1, and in some embodiments, the molar ratio of the third base to compound 03-1 is from 1:1 to 1.8: 1.

In a fifth aspect, the present invention provides a process for preparing piperidinamine, which comprises contacting compound 04 with an amino donor in the presence of ω -transaminase and pyridoxal phosphate in a cosolvent and a buffer to obtain compound 05

R₁Is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and nitrobenzenesulfonyl.

In some embodiments, the compound 04 is contacted with the amino donor in the presence of a co-transaminase and pyridoxal phosphate in the co-solvent and buffer solution, and reacted at 25 ℃ to 60 ℃ at a pH of 8.5 to 11 to provide the compound 05.

In some embodiments, the amino donor is at least one of isopropylamine, alanine, n-propylamine, 1-phenylethylamine, glycine, or their hydrochloride salts.

In some embodiments, the co-solvent is dimethylsulfoxide or ethanol, or a combination thereof.

In a sixth aspect, the present invention provides a method for preparing piperidinamine, comprising deprotecting compound 05 in a fifth solvent and under a second acid, and adjusting pH with a fourth base to obtain compound 06

R₁Is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and nitrobenzenesulfonyl.

In some embodiments, the fifth solvent is at least one of ethanol, methanol, ethyl acetate, dichloromethane.

In some embodiments, the second acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid.

In some embodiments, the fourth base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

In a seventh aspect, the present invention provides a compound represented by formula 03, 03-1 or 06:

wherein the content of the first and second substances,

r1 is one of Boc, Cbz, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, methylsulfonyl, phenylsulfonyl and nitrobenzenesulfonyl;

x is one of fluorine, chlorine, bromine or iodine.

The preparation method of the piperidine amine provided by the invention avoids chiral column resolution or resolving agent resolution, has the advantages of cheap and easily-obtained raw materials, short steps, simple separation and purification, high ee value, high yield, high purity and safe operation, and is beneficial to industrial production.

In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.

In the description herein, references to the description of the terms "some embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

In the present invention, the expression "compound 01" and "compound represented by formula (01)" means the same compound.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

In the present invention, mmol means mmol, h means hour, g means g, ml means ml, eq means equivalent, M means mol/L, THF means tetrahydrofuran, 2Me-THF means 2-methyltetrahydrofuran, MeOH means methanol, EtOH means ethanol, CH means₃CN represents acetonitrile, DCM represents dichloromethane, DMF represents N, N-dimethylformamide, DMSO represents dimethyl sulfoxide, PE represents petroleum ether, EA represents ethyl acetate, Boc₂O represents di-tert-butyl dicarbonate, CbzCl represents benzyl chloroformate, TLC represents thin-layer chromatography, LCMS represents liquid chromatography-mass spectrometry, NaOH represents sodium hydroxide, Ms represents methanesulfonyl, Ts or Tos represents p-toluenesulfonyl, NH₄Cl represents ammonium chloride, NaHCO₃Denotes sodium bicarbonate, Na₂CO₃Representing sodium carbonate, DME glyme, TEA triethylamine and MeMgBr methyl magnesium bromide.

EXAMPLE 1 preparation of Compound 01-1

Adding compound 00-1(20.0g, 1.0eq) into DCM (100mL) at room temperature, slowly dropwise adding a solution of methoxycarbonyl methylene triphenylphosphine (42.5g, 1.1eq) dissolved in DCM (150mL) at 0 ℃ under the protection of nitrogen, reacting the reaction system at room temperature for about 20h after the addition is finished, controlling the reaction, finishing the reaction, concentrating the reaction solution under reduced pressure, and performing column chromatography separation and purification (PE: EA is 10: 1-PE: EA is 8:1) to obtain 22.66g of a colorless oily liquid of compound 01-1, wherein the purity is as follows: 99.10 percent and 85.5 percent of yield; analyzing data:

LCMS+H⁺：130.2,174.2。

EXAMPLE 2 preparation of Compound 02-1

Adding the compound 01-1(12.0g, 1.0eq) and 10% Pd/C (0.12g, 10% Wt) into a methanol (100mL) medium at room temperature, replacing with hydrogen, reacting for 5h at room temperature, controlling, finishing the reaction, filtering, and concentrating the filtrate under reduced pressure to obtain 11.82g of a compound 02-1 white solid product with purity: 99.02 percent; yield: 98 percent; analyzing data:

LCMS+H⁺：132.20,176.20；

¹H NMR(400MHz,CDCl₃)δ4.38(s,1H),3.67(s,4H),2.37(t,J＝7.6Hz,2H),1.86–1.64(m,2H),1.44 (s,9H),1.14(d,J＝6.6Hz,3H)。

EXAMPLE 3 preparation of Compound 03-2

Adding potassium tert-butoxide (12.35g, 1.65eq) into a THF (110mL) medium at room temperature, adding trimethyl sulfoxide iodide (23.44g, 1.6eq) in batches within 5min under nitrogen protection at room temperature and stirring, heating to 65 ℃ after the addition is finished, reacting for 2h, transferring to room temperature, slowly dropwise adding a solution of the compound 02-1 dissolved in THF (15mL) under nitrogen protection, reacting for 20h at room temperature, performing LCMS (liquid crystal display system) control, finishing the reaction, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography (EA: EtOH 2:1) to obtain 16.1g of a compound 03-2 white solid product with purity: 99.3%, yield: 83 percent; analyzing data:

LCMS+H⁺：292.20；

¹H NMR(400MHz,CDCl₃)δ4.61(s,1H),4.39(s,1H),3.70–3.54(m,1H),3.40(s,6H),2.24(dd,J＝11.5, 7.2Hz,2H),1.76–1.64(m,2H),1.43(s,9H),1.13(d,J＝6.5Hz,3H)；

¹³C NMR(151MHz,CDCl₃)δ190.26,155.45,78.85,69.52,46.55,42.24,37.26,32.71,28.48,21.55。

EXAMPLE 4 preparation of Compound 04-2

Catalyst (1, 5-cyclooctadiene) iridium (I) chloride dimer ([ Ir (COD) Cl) was added at room temperature]₂) (45mg, 0.1 mmol%) was added to DCE (400mL) medium, the mixture was stirred at 65 ℃ under nitrogen protection, after preheating for 10min, a solution of compound 03-2(13.1g, 1.0eq) dissolved in DCE (200mL) was slowly added dropwise, the reaction was continued at 65 ℃ after completion of the addition, LCMS was used for neutralization after 18h, the reaction was terminated, the mixture was cooled to room temperature and concentrated under reduced pressure, and column chromatography purification (PE: EA ═ 8:1 to PE: EA ═ 5:1) gave 6.9g of compound 04-2 as a white solid product with purity: 98.2%, yield: 72 percent; analyzing data:

LCMS+H⁺：114.30,158.20；

¹H NMR(400MHz,CDCl₃)δ4.40(d,J＝18.4Hz,1H),4.29(s,1H),3.58(d,J＝18.8Hz,1H),2.42(dd,J ＝7.4,5.9Hz,2H),2.21(dt,J＝19.7,5.9Hz,1H),1.66–1.56(m,1H),1.47(s,9H),1.24(d,J＝6.4Hz,3H)；

¹³C NMR(101MHz,CDCl₃)δ207.91,154.51,80.35,49.76,46.69,36.01,28.37,27.81,18.31。

EXAMPLE 5 preparation of Compound 05-1

Adding isopropylamine hydrochloride (16mL, 4M, pH 8.5) and triethanolamine hydrochloride (11mL, 0.1M, pH 8.5) buffer solution into a 100mL single-mouth bottle at room temperature, stirring at room temperature, adding omega-transaminase powder (1.5g), PLP (0.1g) and DMSO (15mL), heating to 45 ℃, dropwise adding a solution of a compound 04-1(5.0g, 1.0eq) dissolved in DMSO (15mL), controlling the pH to be 9-10, and carrying out heat preservation reaction for 14 hours; after the reaction is finished, cooling to room temperature, filtering, adding ethyl acetate and water for extraction and washing. Vacuum concentrating to remove organic layer to obtain compound 05-1 colorless oily substance 4.9g, purity 99.13%, yield 89.6%; analyzing data:

LCMS+H⁺：115.3,159.3。

EXAMPLE 6 preparation of Compound 06-1

Adding the compound 05-1(4.0g, 1.0eq) into 6mol/L hydrochloric acid aqueous solution (20ml) at room temperature, stirring, heating to reflux, and reacting for 14 h; after the reaction is finished, cooling to 10 ℃, adding sodium hydroxide to adjust the pH value of 7-8, adding dichloromethane to extract and evaporate to dryness to obtain 2.04g of a compound 06-1 faint yellow oily substance with purity: 99.05%, ee value 99.1%, yield 96.01%; analyzing data:

LC-MS:M+H＝115.2；

¹H NMR(400MHz,DMSO-d6):δ8.24(brs,2H),5.25(brs,2H),4.43(m,1H),4.19(d,J＝8.11Hz,1H),2.97 (m,2H),1.78(m,2H),1.50(m,2H),1.11(d,J＝7.0Hz,3H)；

¹³C NMR(100MHz,DMSO-d6):δ43.05,40.34,36.23,24.56,21.75,17.55。

EXAMPLE 7 preparation of Compound 03-1

Compound 03-02(16g, 55 mm) was added at room temperatureol), THF (20mL), ethyl acetate in HCl (20mL) was added to a three-necked flask, N₂Reacting at room temperature for 10min under protection, transferring to 70 ℃ for reaction, after reacting for 2h, stopping the reaction after the raw materials react, evaporating the organic solvent under reduced pressure, and purifying by column chromatography to obtain (DCM: MeOH ═ 8:1) compound 03-1-1 as colorless oily product 6.6g, purity: 98.1%, ee value 99.20%, yield 80.2%; analyzing data:

LC-MS:M+H＝150.1。

EXAMPLE 8 preparation of Compound 04-1

Adding the compound 03-1-1(6g, 1.0eq, 40mmol), acetonitrile (20mL), triethylamine (6.06g, 1.5eq, 60mmol) into a reaction bottle at room temperature, reacting at 70 ℃ overnight, stopping the reaction after the reaction of the raw materials is finished, cooling to room temperature, adding H₂Quenching with O (10mL), EtOA extraction 2 times, drying of the organic phase with anhydrous sodium sulfate, and purification by column chromatography (EA: PE ═ 1:1) afforded compound 04-1 as a colorless oily product 4.01g, purity: 99.12%, ee value 99.15%, yield 88%; analyzing data:

LC-MS:M+H＝114.1。

EXAMPLE 9 preparation of Compound 04-2

At room temperature, compound 04-1(2g, 1.0eq, 17.7mmol), DCM (20mL) were added to the reaction flask, and temperature was controlled at 20 deg.C for addition of (Boc)₂O (4.6g, 1.2eq, 21.2mmol), at which temperature after overnight reaction, the starting material reacted, stopped, and the organic solvent column chromatography purification (EA: PE ═ 8:1) was evaporated under reduced pressure to afford compound 04-2 as a white solid, 3.6g, purity: 98.56%, ee value 99.02%, yield 95%; analyzing data:

LCMS+H⁺：114.30,158.20。

EXAMPLE 10 preparation of Compounds 04-3

Dissolving compound 04-1(1.8g, 1.0eq, 16mmol) in THF (10mL) in a 100mL two-necked flask at room temperature, dissolving NaOH (1.28g, 2.0eq, 32mmol) in 10mL water, adding benzyl chloroformate (3.26g, 1.2eq, 19.2mmol) at 0 ℃, reacting for 16h at room temperature after completion of the addition, stopping the reaction, extracting with ethyl acetate 30mL × 2, separating, washing the organic phase once with 2NHCl (10mL) and saturated saline (10mL), drying over anhydrous sodium sulfate, and purifying (EA: PE ═ 6: 1) to obtain compound 04-3 as a colorless oily product with purity of 3.5 g: 99.05%, ee value 99.10% and yield 90%; analyzing data:

LCMS+H⁺：248.20。

while the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.