Preparation method of chiral amino alcohol medical intermediate

Abstract

Compared with a chiral resolution preparation method in the prior art, the preparation method provided by the invention has the advantages of mild reaction conditions, simplicity in operation, high reaction yield, high product purity, high chiral purity and convenience in post-treatment, and is suitable for industrial production. # imgabs0 #

Description

A method for preparing a chiral amino alcohol pharmaceutical intermediate Technical Field

[0001] The present invention relates to a method for preparing a pharmaceutical intermediate, in particular to a method for preparing a chiral amino alcohol pharmaceutical intermediate, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] Chiral amino alcohol fragments are widely used as key intermediates or starting materials in pharmaceutical production. For example, Bristol-Myers Squibb's compounds targeting AAK1 all include chiral amino alcohol fragments. In the prior art, chiral amino alcohols are primarily prepared by chiral resolution of racemic amino alcohols (or derivatives).

[0003] Route 1: For the saturated chiral amino alcohol compound 35, the reference J. Med. Chem. 2022, 65, 4457-4480 uses chiral resolution of (S)-36, hydrogenation to remove the Cbz protecting group and reduction of the double bond to yield compound 37, followed by Boc protection and other subsequent operations to yield the saturated amino alcohol 35 (same as A2). This synthetic route utilizes chiral resolution, which is not conducive to cost control and commercial scale-up.

[0004] Route 2: There are currently no patents or literature reports on the unsaturated chiral amino alcohol compound 35. A similar intermediate is reported in WO2005087731A1, but the process utilizes column chromatography and does not provide a method for obtaining the unsaturated chiral amino alcohol. Column chromatography separation and purification is not conducive to cost control and commercial scale-up.

[0005] The above-mentioned existing preparation methods are not conducive to cost control and commercial scale-up production. Based on the broad application prospects of chiral amino alcohols, the inventors have developed a preparation process for chiral amino alcohols and their intermediates. This method has mild reaction conditions, simple operation, high reaction yield, high product purity, high chiral purity, and convenient post-processing, making it suitable for industrial production.

[0006] Summary of the Invention

[0007] The present invention provides a method for preparing an intermediate represented by formula A or a salt thereof, which comprises step d1 of hydrolyzing a compound of formula B-1 under alkaline conditions to remove Cbz protection to obtain an intermediate of formula A:

[0008] In some embodiments, the hydrolysis reagent of the hydrolysis reaction is selected from one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide, potassium tert-amylate, sodium carbonate, cesium carbonate, cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, preferably sodium hydroxide or potassium tert-butoxide, more preferably sodium hydroxide.

[0009] In some embodiments, the solvent for the hydrolysis reaction is selected from one or more of a polar aprotic solvent or a non-polar solvent.

[0010] In some embodiments, the solvent of the hydrolysis reaction is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, ethanol, methanol, and water, preferably at least one of ethanol, tetrahydrofuran, and water, and more preferably at least one of ethanol or water.

[0011] In some embodiments, the reaction temperature of the hydrolysis reaction is 0°C to 90°C, preferably 50°C to 80°C, and more preferably 70±5°C.

[0012] The present invention also provides a method for preparing an intermediate of formula A2 or a salt thereof, which comprises step d2 of subjecting a compound of formula B-1 to a hydrogenation reduction reaction to obtain an intermediate of formula A2:

[0013] In some embodiments, the reducing agent used in the reduction reaction is 5% or 10% Pd / C.

[0014] In some embodiments, the reducing agent used is 10% Pd / C, and the amount used is 1%-50% by mass of the compound of formula B-1, preferably 10%-30%.

[0015] In some embodiments, the solvent used in the reduction reaction is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, ethanol, methanol, and water, preferably one or more of ethanol, methanol, ethyl acetate, or dichloromethane, and more preferably methanol.

[0016] In some embodiments, the reaction temperature of the reduction reaction is 20°C to 60°C, preferably 20°C to 40°C.

[0017] Furthermore, the present invention also provides a method for preparing the intermediate of formula B-1, which comprises step c of reacting a compound of formula C-1 in the presence of an active agent to obtain a mixed acid anhydride, and then reducing the mixed acid anhydride to obtain the intermediate of formula B-1:

[0018] In some embodiments, the active agent is selected from methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, tert-butyl chloroformate, N,N'-dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole, preferably methyl chloroformate or isobutyl chloroformate, more preferably isobutyl chloroformate.

[0019] In some embodiments, the base used in the preparation of the mixed anhydride is selected from potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, diethylamine, preferably triethylamine.

[0020] In some embodiments, the solvent for the step c reaction is selected from a polar aprotic solvent or a polar protic solvent.

[0021] In some embodiments, the solvent for the reaction in step c is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, water, methanol, and ethanol, preferably tetrahydrofuran.

[0022] In some embodiments, the solvent is selected from water or a mixture of water and a polar solvent.

[0023] In some embodiments, the polar solvent is selected from tetrahydrofuran, methanol, or ethanol.

[0024] In some embodiments, the reducing agent used in the step (c) reaction is selected from sodium borohydride and lithium borohydride, preferably sodium borohydride.

[0025] In some embodiments, the additive used in the step (c) reaction is selected from methanol, ethanol or water, preferably methanol or water, more preferably water.

[0026] In some embodiments, the molar ratio of Formula B-1: isobutyl chloroformate: triethylamine: sodium borohydride is 1.0:(1.0-3.0):(1.0-4.0):(1.0-6.0), preferably the molar ratio is 1.0:(1.3-2.5):(1.5-3.0):(2.0-4.0), and more preferably the molar ratio is 1.0:(1.3-1.7):(1.5-2.0):(2.5-3.0).

[0027] In some embodiments, the reaction temperature in step c is 20°C to 40°C.

[0028] Furthermore, the present invention also provides a method for preparing the intermediate of formula C-1, comprising step b of reacting a compound of formula D-1 in the presence of an alkaline reagent to obtain the intermediate of formula C-1:

[0029] The R is selected from H, halogen, C1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The cycloalkyl group is substituted with a substituent.

[0030] In some embodiments, R in Formula D-1 is selected from H.

[0031] In some embodiments, the alkaline reagent in step b is selected from one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide, potassium tert-amylate, sodium carbonate, cesium carbonate, cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, preferably lithium hydroxide.

[0032] In some embodiments, the solvent used in the step b reaction is selected from one or more of amide solvents, alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, sulfone solvents or water, preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, n-butanone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran and water, more preferably at least one of tetrahydrofuran or water.

[0033] In some embodiments, the reaction temperature in step b is -10°C to 50°C, preferably 0°C to 30°C.

[0034] Furthermore, the present invention also provides a method for preparing a compound of formula D-1, comprising step a) reacting a compound of formula E-1 with a compound of formula F-1 in the presence of an alkaline reagent to obtain a compound of formula D-1:

[0035] The R is selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The cycloalkyl group is substituted with a substituent.

[0036] In some embodiments, R in formula F-1, D-1 is selected from H.

[0037] In some embodiments, the alkaline reagent in step a reaction is selected from one or more of sodium hydrogen, lithium diisopropylamide, lithium amide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium bicarbonate, sodium carbonate, dipotassium hydrogen phosphate, potassium bicarbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium hydride, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine, and 1,8-diazabicycloundec-7-ene, preferably lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide or potassium bistrimethylsilylamide, more preferably lithium bistrimethylsilylamide, i.e., LiHMDS.

[0038] In some embodiments, the solvent used in the reaction of step a is selected from polar aprotic solvents.

[0039] In some embodiments, the polar aprotic solvent used in the reaction of step a is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, acetone, n-butanone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or toluene, preferably tetrahydrofuran or 2-methyltetrahydrofuran, more preferably tetrahydrofuran.

[0040] In some embodiments, the molar ratio of Formula F-1:Formula E-1:LiHMDS is 1.0:(1.0-2.0):(0.5-2.0), preferably the molar ratio is 1.0:(1.25-1.75):(1.0-1.5), and more preferably the molar ratio is 1.0:(1.3-1.5):(1.1-1.5).

[0041] In some embodiments, the reaction temperature of step a is -70°C to 10°C, preferably -50°C to -10°C, and more preferably -40°C to -20°C.

[0042] In some embodiments, any preparation method described in the present invention includes a combination of any two steps or multiple steps (such as three, four, five, six, etc.).

[0043] In addition, the present invention also provides a salt compound of formula A' or formula A2',

[0044] wherein HX is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, benzoic acid, phosphorous acid, formic acid, oxalic acid, malonic acid, sulfuric acid, hydroiodic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, succinic acid, L-tartaric acid or L-malic acid.

[0045] In one embodiment, the HX is benzoic acid.

[0046] At the same time, the present invention also provides an intermediate compound of formula A-1:

[0047] Unless otherwise stated, the terms used in this specification and claims have the following meanings.

[0048] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0049] "Halogen" refers to F, Cl, Br or I.

[0050] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0051] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0052] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0053] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0054] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3-8 membered monocycle, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system. The carbocyclyl can be attached to the aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be optionally monocyclic, bridged, or spirocyclic. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, and a naphthalene ring. "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0055] The term "substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro ring, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-Ra, -O-(CH2) m -C(=O)-Ra, -(CH2) m -C(=O)-NRbRc, -(CH2) m S(=O) n Ra, -(CH2)m -alkenyl-Ra, ORd or -(CH2) m -alkynyl-Ra (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NRbRc, wherein Rb and Rc are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or bicyclic groups.

[0056] The salt of a compound refers to a salt obtained by reacting a free acid with an inorganic base or an organic base, or a salt obtained by reacting a free base with an inorganic acid or an organic acid.

[0057] "Alcohol solvent" refers to a solvent containing hydroxyl groups in its molecular structure. Non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, sec-pentanol, 3-pentanol, isopentanol, tert-pentanol, n-hexanol and cyclohexanol.

[0058] "Ether solvent" refers to a solvent with an ether bond in its molecular structure. Non-limiting examples include tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, diisopropyl ether, ethyl butyl ether, dibutyl ether, diamyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and anisole.

[0059] "Aromatic hydrocarbon solvents" refer to solvents containing 0-3 heteroatoms (heteroatoms selected from O, S or N) and aromatic rings in their molecular structure. Non-limiting examples include benzene, pyridine, toluene, ethylbenzene, xylene, chlorobenzene and o-dichlorobenzene.

[0060] “Halogenated alkane solvents” refer to alkane solvents containing halogens (fluorine, chlorine, bromine, iodine) in their molecular structure. Non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, carbon tetrachloride, pentachlorohexane, 1-chlorobutane, and bromoform.

[0061] "Alkane solvent" refers to a solvent containing only alkanes in its molecular structure, and non-limiting examples include n-hexane, n-heptane, n-octane, n-pentane, cyclohexane, and cycloheptane.

[0062] "Ester solvents" refer to solvents containing carboxylic acid esters in their molecular structure. Non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetoacetate, isoamyl acetate, isopropyl acetate, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, sec-butyl acetate, butyl formate, propyl formate, n-amyl formate, and diethyl carbonate.

[0063] "Ketone solvents" refer to solvents containing a ketone carbonyl group in their molecular structure. Non-limiting examples include acetone, butanone, acetophenone, methyl isobutyl ketone, 2,6-dimethyl-2,5-heptadien-4-one, 3,5,5-trimethyl-2-cyclohexenone, and mesityl oxide.

[0064] "Nitrile solvent" refers to a solvent containing a cyano group in its molecular structure, non-limiting examples of which include acetonitrile, propionitrile, butyronitrile, and benzyl cyanide.

[0065] "Amide solvents" refer to solvents containing amides in their molecular structure, non-limiting examples of which include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, hexamethylphosphoramide, and N-methylpyrrolidone.

[0066] A "polar aprotic solvent" refers to a solvent that does not contain hydrogen atoms directly attached to electronegative atoms and does not have hydrogen bonding capability. Non-limiting examples include acetone, dimethyl sulfoxide, HMF (hydroxymethylfurfural), crown ethers, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone.

[0067] "Polar protic solvents" refer to solvents capable of hydrogen bonding (because they contain at least one hydrogen atom directly attached to an electronegative atom (e.g., an OH or NH bond)), non-limiting examples of which include methanol, water, ethanol, ammonia, acetic acid, and the like.

[0068] "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, including instances where the event or circumstance occurs or does not occur.

[0069] The reaction process of the present invention is tracked by HPLC, HNMR or thin layer chromatography to determine whether the reaction is completed.

[0070] In the present invention, the internal temperature refers to the temperature of the reaction system.

[0071] In the present application, "V" or "V / M" refers to the volume of the reaction solvent relative to the mass of 1 eq of the raw material fed to the step.

[0072] In this application, the actual amount of raw materials or the actual amount of products obtained is: if the content is marked, the amount of raw materials or product = the weight of raw materials or products × content; if the content is not marked, it is calculated based on the content as 100%.

[0073] Definitions of Abbreviations and Key Terms:

[0074] Technical effects of the present invention

[0075] The preparation method of the chiral amino alcohol pharmaceutical intermediates of Formula A and Formula A2 provided by the present invention has the advantages of mild reaction conditions, simple operation, high reaction yield, high product purity, high chiral purity, convenient post-processing, and suitability for industrial production compared to the chiral resolution preparation methods in the prior art. DETAILED DESCRIPTION

[0076] The present invention is further described in detail below with reference to the embodiments, but the present invention is not limited thereto. Any equivalent replacements in the art made according to the disclosure of the present invention shall fall within the scope of protection of the present invention.

[0077] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0078] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0079] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SC-A18 100 × 4.6 mm, 3.5 μM);

[0080] Example 1: Preparation of Compound A and its Benzoate

[0081] The preparation route of compound A is as follows:

[0082] Step 1: Preparation of D-1(2R,4S)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylic acid benzyl ester

[0083] benzyl(2R,4S)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylate

[0084] At room temperature (20±5°C) and under high-purity nitrogen, to a dry three-necked round-bottom flask, add 0.650 kg of F-1 (1.5 eq.), 7 L of THF (7V), and 4 L of 1M / L LiHMDS (1.25 eq.) in sequence. Cool to -30±10°C, and add a solution of 1.000 kg of E-1 (1.0 eq.) in 3 L of THF (3V) dropwise under controlled temperature (a significant exotherm occurs). After the addition is complete, maintain the internal temperature at -30±10°C and stir for 1.5-2 hours. Samples were taken and sent to IPC-1. The reaction was complete. Post-treatment: 10 L of water (10V) was added dropwise, controlling the temperature not to exceed 25°C. After the addition, maintain the temperature at 10-20°C and stir for 0.5 h. Allow to stand for phase separation. The aqueous phase was back-extracted once with 5 L of MTBE (5V), and the organic phases were combined and concentrated under reduced pressure at JT = 45 ± 5 ° C and a vacuum degree of 70-200 mbar until almost no liquid outflowed, to obtain 1.158 kg of a yellow oil with a purity of 98.8%, a content of 83.8%, and a content yield of 83%.

[0085] LC-MS: m / z = 366.6 [M+H] +

[0086] 1 H NMR(400MHz,DMSO-d6)δ7.46-7.37(m,7H),7.22-7.16(m,2H),6.83-6.81(d,1H),6.48-6.44(m,1H),5.18-5 .40(t,1H),5.00-4.90(m,2H),4.74-4.60(m,1H),3.21-3.17(d,1H),2.46-2.41(m,1H),1.77-1.64(m,6H).

[0087] Step 2: Preparation of C-1

[0088] (S)-2-(((Benzyloxy)carbonyl)amino)-2,4-dimethylpent-4-enoic acid

[0089] (S)-2-(((benzyloxy)carbonyl)amino)-2,4-dimethylpent-4-enoic acid

[0090] At room temperature (20°C), 2.5 L of THF (2 V) and 1.158 kg of D-1 (1.0 eq, 2.65 mol) were added to a dry three-necked round-bottom flask. The temperature was lowered to 0°C, and a LiOH solution (95.20 g of LiOH, 1.5 eq dissolved in 2.5 L of water) was added dropwise. The temperature was controlled at 0-10°C. After the addition was complete, the temperature was raised to 35-40°C and the reaction was allowed to proceed overnight. Post-treatment at room temperature was performed by extracting twice with 5 L of n-hexane (to remove some of the benzaldehyde, which was not completely washed off). The aqueous phase was collected, the pH was adjusted to 3-4, and the product was extracted again with 5 L of EA (5 V). The organic phase was collected and dried over anhydrous sodium sulfate (the product contained water, which affected the next reaction). The organic phase was spin-dried to give 882 g of a yellow oil with a purity of 90.5%, a content of 69.3%, and a content yield of 83%.

[0091] LC-MS: m / z = 278.2 [M+H] +

[0092] 1 H NMR(400MHz,DMSO-d6)δ12.60(s,1H),7.36-7.29(m,5H),5.03-5.02(d,2H),4.85-4.8 4(t,1H),4.69(s,1H),2.68-2.64(d,1H),2.51-2.48(d,1H),1.67(s,3H),1.34(s,3H).

[0093] Step 3: Preparation of B-1

[0094] Benzyl (S)-(1-hydroxy-2,4-dimethylpent-4-en-2-yl)carbamate

[0095] benzyl(S)-(1-hydroxy-2,4-dimethylpent-4-en-2-yl)carbamate

[0096] At room temperature, 8.7 L THF (10 V) and 875 g C-1 (1.0 eq, 2.18 mol) were added to a 50 L reactor. The temperature was lowered to IT = 0 to 5 ° C. 446 g isobutyl chloroformate (1.5 eq, 3.27 mol) was added and the temperature was controlled at 0 to 5 ° C. 375 g TEA (1.7 eq, 3.71 mol) was added dropwise. A white solid precipitated. After the addition was completed, the temperature was controlled at IT = 0 to 5 ° C. and stirred for at least 1-1.5 h. The sample was taken for central control. If the central control was qualified, 10 L water and 8 L EA were added for extraction. The organic phase was concentrated and dried through a column PE:EA 50:1-20:1 to obtain 438.57 g of the intermediate as a colorless oil.

[0097] Add 438.57g of the intermediate and 4.5L of THF to a 10L four-necked flask, cool to 5±5℃, add 115g of NaBH4 (2.5eq,), control the temperature at 5±5℃, and add 500ml of tap water (1V) dropwise over 4 to 6 hours. Bubbles will be generated. After the water is added, stir for 0.5h, take samples for central control, and if the central control is qualified, perform post-processing.

[0098] Room temperature post-treatment: control the temperature IT = 10 ± 10 ° C and add 2.5 L of 10% ammonium chloride (5V) dropwise. After the addition, raise the temperature to IT = 25 ± 5 ° C, stir for at least 2-3 h, let it stand, and separate the phases (if any solids remain, filter first and then separate the phases). The aqueous phase is extracted again with DCM (5V). The organic phases are combined and concentrated at JT = 45 ± 5 ° C until there is no fraction to give 434 g of a colorless oil with a purity of 98.5%, a content of 92.6%, and a content yield of 70%.

[0099] LC-MS: m / z = 264.2 [M+H] +

[0100] Step 4: Preparation of Compound A

[0101] (S)-2-Amino-2,4-dimethylpent-4-en-1-ol

[0102] (S)-2-amino-2,4-dimethylpent-4-en-1-ol

[0103] At 25±5°C, add 4.5L EtOH / H2O=10 / 1 (10V) solution to a 50L reactor, control the temperature at 25±5°C, and add 434g A4 (1.0 eq, 1.52 mol), temperature controlled at 30±10°C, 182.4 g of sodium hydroxide (3.0 eq.) was added, the temperature was raised to IT = 70±5°C, and the mixture was stirred for at least 20 h. IPC was sampled (if unqualified, 1 V of water and 1.0 eq. of NaOH were added and the mixture was stirred for another 5 h). The mixture was cooled to 20±5°C, filtered under reduced pressure, and rinsed with ethanol (3 V). The filtrate was concentrated at JT = 50±5°C until there was no fraction. Water (2 V) was added to the residual liquid at 25±5°C, the temperature was controlled at 25±5°C, and 10% HCl aqueous solution was added dropwise to adjust the pH to 3-5. The phases were separated based on the pH, and the aqueous phase was retained. The aqueous phase was extracted twice with methyl tert-butyl ether (5 V). The aqueous phase was retained, sodium hydroxide solution was added to adjust the pH to 11-13, and 2-methyltetrahydrofuran was added for extraction. The organic phase was washed once with saturated sodium chloride aqueous solution and concentrated to obtain 209 g of HSK41167 oil with a purity of 89.3%, a content of 75%, and a content yield of 80%.

[0104] LC-MS: m / z = 130.2 [M+H] +

[0105] 1 H NMR (400MHz, DMSO-d6) δ4.82-4.81(t,1H),4.67-4.66(d,1H),3.15-3.09(t,2H),2.00(s,2H),1.78(s,3H),0.91(s,3H).

[0106] Step 5: Preparation of benzoate salt of compound A

[0107] (S)-2-Amino-2,4-dimethylpent-4-en-1-ol

[0108] (S)-2-amino-2,4-dimethylpent-4-en-1-ol

[0109] To a 2L reaction flask, 0.58L of DCM (10V) solution was added at 25±5°C. The temperature was controlled at 25±5°C, and 58g of A (1.0eq, 0.44mol) was added to dissolve the system. 57g of benzoic acid (1.05eq.) solid was added in batches. During the process, solid (non-benzoic acid) precipitated from the system. After the addition was completed, the system was stirred for 2h. The system was filtered under reduced pressure and rinsed with 50ml of DCM. The solid was dried in an oven at 50 degrees to obtain 52g of an off-white product with a yield of 45% and a purity of 99%.

[0110] LC-MS: m / z = 130.1 [M+H] +

[0111] 1 H NMR(400MHz,DMSO-d6)δ7.91-7.88(m,2H),7.43-7.33(m,3H),4.91-4.90(m,1H),4.79(m,1H),3.40-3 .33(dd,2H,J=12Hz),2.31-2.18(d,1H,J=12Hz),2.21-2.18(d,1H,J=12Hz),1.17(s,3H),1.10(s,3H).

[0112] Example 2: Preparation of Compound A2 and Salt A2'

[0113] Step 1: Prepare A2

[0114] (S)-2-Amino-2,4-dimethylpentan-1-ol (Compound A2)

[0115] (S)-2-amino-2,4-dimethylpentan-1-ol

[0116] To a 50 ml single-necked flask at room temperature, 3.00 g of B-1 (1.0 eq, 0.0114 mol), 30 ml of methanol (10 V), and 0.60 g of 10% Pd / C (20% M) were added. The mixture was replaced with H2 three times. The temperature was raised to IT = 45 ± 5 ° C. The reaction was carried out for 12 h. Sampling was performed for intermediate control. If the intermediate control was qualified, Pd / C was removed by filtration. The methanol was concentrated to dryness and PE:EA 20:1-DCM:MeOH 10:1 was separated by column chromatography to obtain 0.82 g of the product as a colorless oil in a yield of 55%.

[0117] LC-MS: m / z = 132.1 [M+H] +

[0118] 1 H NMR (400MHz, DMSO-d6) δ3.07(s,2H),1.78-1.68(m,2H),1.21-1.11(m,2H),0.92-0.88(m,9H).

[0119] Step 2: Preparation of Benzoate A2'

[0120] (S)-2-Amino-2,4-dimethylpentan-1-ol benzoate (Compound A2')

[0121] (S)-2-amino-2,4-dimethylpentan-1-ol benzoic acid

[0122] To a 2L reaction flask was added 0.58L of DCM (10V) solution at 25±5°C. The temperature was controlled at 25±5°C, and 5.0g of A2 (1.0eq, 38mmol) was added to dissolve the system. 4.89g of benzoic acid (1.05eq, 40.04mmol) solid was added in batches. During the process, solid (non-benzoic acid) precipitated from the system. After the addition was completed, the mixture was stirred for 2h. The system was filtered under reduced pressure and rinsed with 50ml of DCM. The solid was dried in an oven at 50°C to obtain 7.22g of an off-white product with a yield of 75% and a purity of 99%.

[0123] LC-MS: m / z = 132.1 [M+H] +

[0124] Example 3: Preparation of Compound A-1

[0125] Na2CO3 (1.5eq.) and methyl tert-butyl ether (5V) were added to the aqueous phase, (Boc)2O (2.0eq.) was added dropwise, and the mixture was stirred for at least 20h. The sample was taken for central control. After the central control was qualified, the mixture was filtered, the phases were separated, and the aqueous phase was extracted once with methyl tert-butyl ether (5V). The organic phases were combined, JT = 45±5°C, concentrated to ~1.8w, and n-heptane (3V) was added to the residual liquid. The mixture was concentrated to ~1.8w. n-heptane (10V) was added to the residual liquid, and the temperature was slowly lowered to IT = 5±5°C, stirred for at least 0.5h, cooled to IT = -8±2°C, stirred for at least 2h, filtered, and the filter cake was rinsed with n-heptane (2V). The filter cake was naturally dried for 12h to obtain the product HPLC: 99.7%, yield 73%.

[0126] LCMS m / z=230.10[M+H] +

[0127] 1 H NMR(400MHz,DMSO-d6)δ6.08(s,1H),4.81-4.80(m,1H),4.66-4.63(m,2H),3.38-3.30 (m,2H),4.49-4.44(m,1H),2.26-2.22(m,1H),1.72(s,3H),1.40(s,9H),1.08(s,3H).

[0128] Example 4: Preparation of D-1

[0129] Preparation method: Prepared according to the method of the first step of Example 1. The reaction results of different base systems and conditions are shown in Table 1 below.

[0130] Table 1 Reaction results under different reaction systems and conditions

[0131] Note: Solvent volume: The volume of the solvent is the multiple of the mass of the F1 feed.

[0132] Conclusion: A reaction temperature of -30 ± 10°C is optimal; LiHMDS provides the best reaction results, followed by NaHMDS, while KHMDS and LDA are less effective as bases. A molar ratio of F-1:E-1:base of 1.0:1.5:1.25 results in a high proportion of product D-1 and a good reaction. The addition method significantly influences the reaction; it is best to add LiHMDS first, followed by F1.

[0133] Example 5: Preparation of C-1

[0134] The preparation was carried out according to the method of the second step of Example 1. The reaction results under different conditions are shown in Table 2.

[0135] Table 2 Reaction conditions screening

[0136] Conclusion: Table 2 shows that when 1.5 eq. LiOH was added in THF / H2O (2V / 2V) and the reaction was carried out at room temperature overnight, the raw material was completely reacted and the purity was 88.9%.

[0137] Example 6: Preparation of B-1

[0138] Prepared according to the method of the third step of Example 1, the reaction results under different conditions are shown in Table 3-1 and Table 3-2:

[0139] Table 3-1 Reaction Condition Screening

[0140] Conclusion: When THF was used as solvent for condition screening, isobutyl chloroformate / NaBH4 / water had the best effect.

[0141] Referring to the preparation method of the third step of Example 1, the reaction results under different conditions are shown in Table 3-2

[0142] Table 3-2 Reaction results under different reduction systems and conditions

[0143] Conclusion: Table 3-2 shows that the isobutyl chloroformate / NaBH4 / water reduction system works best. The molar ratio of isobutyl chloroformate:TEA:NaBH4:water of 1.5:1.7:2.5:1 (V / M) worked best, with a raw material residue of 5.6% and a product ratio of 71.3%.

[0144] Example 7: Preparation of Compound A

[0145] Prepared according to the method of the fourth step of Example 1, the reaction results under different conditions are shown in Table 4-1, Table 4-2 and Table 4-3:

[0146] Table 4-1 Reaction results under different conditions

[0147] Note: “IMP-1” means impurity 1, and “IMP-2” means impurity 2.

[0148] As shown in Table 4-1, IMP-1 is obtained by removing Cbz with acid, while a large amount of IMP-2 is obtained by hydrogenation.

[0149] Fragment B-2 was first synthesized under alkaline conditions and then hydrolyzed to obtain A.

[0150] Table 4-2 Reaction results under different conditions

[0151] As shown in Table 4-2, the intermediate B-2 is obtained by alkali removal. NaOH is better than t-BuOK.

[0152] The hydrolysis reaction of B-2 was investigated:

[0153] Table 4-3 Hydrolysis reaction results under different conditions

[0154] Table 4-3 shows that at IT = 70 ± 5°C, the optimal conditions for conversion to A are EtOH / H2O = 10 / 1 as solvent and 3.0 eq. NaOH as base. Furthermore, B-1 can be directly converted to A under this system.

Claims

1. A method for preparing an intermediate represented by formula A or a salt thereof, comprising step d1 of subjecting a compound of formula B-1 to a hydrolysis reaction under alkaline conditions to remove the Cbz protection to obtain the intermediate of formula A:

2. The preparation method according to claim 1, wherein the hydrolysis reagent for the hydrolysis reaction is selected from one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide, potassium tert-pentoxide, sodium carbonate, cesium carbonate, cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, preferably sodium hydroxide or potassium tert-butoxide, and more preferably sodium hydroxide.

3. The preparation method according to claim 1 or 2, wherein the solvent for the hydrolysis reaction is selected from one or more of polar aprotic solvents or nonpolar solvents.

4. The preparation method according to claim 3, wherein the solvent for the hydrolysis reaction is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, ethanol, methanol, water, preferably at least one of ethanol, tetrahydrofuran, water, and more preferably at least one of ethanol or water.

5. The preparation method according to any one of claims 1-4, wherein the reaction temperature of the hydrolysis reaction is 0 °C to 90 °C, preferably 50 °C to 80 °C, and more preferably 70 ± 5 °C.

6. A method for preparing an intermediate represented by formula A2 or a salt thereof, comprising step d2 of subjecting a compound of formula B-1 to a hydrogenation reduction reaction:

7. The preparation method according to claim 6, wherein the reducing agent for the reduction reaction is 5% or 10% Pd / C.

8. The preparation method according to claim 7, wherein the Pd / C is 10% Pd / C, and the dosage is 1% - 50% of the mass of the compound of formula B-1, preferably 10% - 30%.

9. The preparation method according to any one of claims 6-8, wherein the solvent for the reduction reaction is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, ethanol, methanol, water, preferably one or more of ethanol, methanol, ethyl acetate or dichloromethane, and more preferably methanol.

10. The preparation method according to any one of claims 6-9, wherein the reaction temperature of the reduction reaction is 20 °C to 60 °C, preferably 20 °C to 40 °C.

11. A method for preparing an intermediate represented by Formula B-1 or a salt thereof, which comprises step c of reacting a compound of Formula C-1 in the presence of an active reagent to obtain a mixed anhydride, and then reducing the mixed anhydride to obtain the intermediate of Formula B-1:

12. The preparation method according to claim 11, wherein the active reagent is selected from methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, tert-butyl chloroformate, N,N'-dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole, preferably methyl chloroformate or isobutyl chloroformate, and more preferably isobutyl chloroformate.

13. The preparation method according to claim 11 or 12, wherein the base used in the preparation process of the mixed anhydride is selected from potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, diethylamine, preferably triethylamine.

14. The preparation method according to any one of claims 11-13, wherein the solvent for the reaction in step c is selected from polar aprotic solvents or polar protic solvents.

15. The preparation method according to claim 14, wherein the solvent is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, water, methanol, ethanol, preferably tetrahydrofuran.

16. The preparation method according to claim 14, wherein the solvent is selected from water or a mixture of water and a polar solvent.

17. The preparation method according to claim 16, wherein the polar solvent is selected from tetrahydrofuran, methanol or ethanol.

18. The preparation method according to any one of claims 11-17, wherein the reducing agent used in the reaction of step (c) is selected from sodium borohydride and lithium borohydride, preferably sodium borohydride.

19. The preparation method according to any one of claims 11-18, wherein the additive used in the reaction of step (c) is selected from methanol, ethanol or water, preferably methanol or water, more preferably water.

20. The preparation method according to claim 18 or 19, wherein the molar ratio of formula B-1: isobutyl chloroformate: triethylamine: sodium borohydride is 1.0: (1.0 to 3.0): (1.0 to 4.0): (1.0 to 6.0), preferably the molar ratio is 1.0: (1.3 to 2.5): (1.5 to 3.0): (2.0 to 4.0), and more preferably the molar ratio is 1.0: (1.3 to 1.7): (1.5 to 2.0): (2.5 to 3.0).

21. The preparation method according to any one of claims 11-20, wherein the temperature of the reaction in step c is 20°C to 40°C.

22. A method for preparing an intermediate represented by formula C-1 or a salt thereof, which comprises step b of reacting a compound of formula D-1 in the presence of a basic reagent to obtain an intermediate of formula C-1: R is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group, and the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 substituted by a cycloalkyl substituent.

23. The preparation method according to claim 22, wherein R in formula D-1 is selected from H.

24. The preparation method according to claim 22 or 23, wherein the basic reagent is selected from one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide, potassium tert-amylate, sodium carbonate, cesium carbonate, cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, preferably lithium hydroxide.

25. The preparation method according to any one of claims 22-24, wherein the solvent used in the reaction is selected from one or more of amide solvents, alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, sulfone solvents or water, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, n-butyl ketone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran and water, and more preferably at least one of tetrahydrofuran or water.

26. The preparation method according to any one of claims 22-25, wherein the temperature of the reaction is -10°C to 50°C, preferably 0°C to 30°C.

27. A method for preparing an intermediate represented by formula D-1 or a salt thereof, which comprises step a of reacting a compound of formula E-1 and a compound of formula F-1 in the presence of a basic reagent to obtain an intermediate of formula D-1: R is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group, and the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl.

28. The preparation method according to claim 27, wherein R in formula F-1 and D-1 is selected from H.

29. The preparation method according to claim 27 or 28, wherein the basic reagent is selected from one or more of sodium hydride, lithium diisopropylamide, lithium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bicarbonate, sodium carbonate, dipotassium hydrogen phosphate, potassium bicarbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium hydride, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, more preferably lithium bis(trimethylsilyl)amide, i.e., LiHMDS.

30. The preparation method according to any one of claims 27-29, wherein the solvent used in the reaction is selected from polar aprotic solvents.

31. The preparation method according to claim 30, wherein the polar aprotic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or toluene, preferably tetrahydrofuran or 2-methyltetrahydrofuran, more preferably tetrahydrofuran.

32. The preparation method according to any one of claims 29-31, wherein the molar ratio of formula F-1: formula E-1: LiHMDS is 1.0: (1.0-2.0): (0.5-2.0), preferably the molar ratio is 1.0: (1.25-1.75): (1.0-1.5), more preferably the molar ratio is 1.0: (1.3-1.5): (1.1-1.5).

33. The preparation method according to claims 27-32, wherein the temperature of the reaction is -70°C to 10°C, preferably -50°C to -10°C, more preferably -40°C to -20°C.

34. A salt-type compound of formula A' or formula A2' Wherein HX is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, benzoic acid, phosphorous acid, formic acid, oxalic acid, malonic acid, sulfuric acid, hydroiodic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, succinic acid, L-tartaric acid or L-malic acid, preferably benzoic acid.

35. An intermediate compound of formula A-1:

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