CN108689904A - The preparation method and applications of chiral heterocycle tertiary alcohol intermediates - Google Patents

Abstract

The present invention provides a kind of preparation method and its method for being used to prepare Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylate derivatives of chiral heterocycle tertiary alcohol intermediates.Method through the invention so that reaction condition and purification condition are simply controllable, reduce production cost, and reaction yield improves, and is suitable for industrial expanding production.Also, by means of the invention it is also possible to high-purity, obtain Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylate derivatives in high yield.

Description

Preparation method and application of chiral heterocyclic tertiary alcohol intermediate

technical field

The invention belongs to the field of chemical industry or medicine, and specifically relates to a preparation method of a chiral heterocyclic tertiary alcohol intermediate and a method for preparing 1,4-dihydropyridine-3,5-dicarboxylate derivatives.

Background technique

Dihydropyridine calcium ion channel blockers are drugs used to treat cardiovascular diseases since the 1970s, which selectively block L-type or/and T-type calcium ion channels by binding to protein receptors Influx of Ca ²⁺ in the blood can reduce the concentration of Ca2+ in the cells, thereby changing the cardiovascular function and protecting the heart and cerebrovascular. Dihydropyridine calcium channel blockers have a high degree of vascular selectivity, clear antihypertensive effect, and a wide range of applications. They are widely used in clinical practice and have become the first choice of antihypertensive drugs. L-type and T-type dual calcium ion channel blockers can not only lower blood pressure, but also slow down tachycardia, reduce the occurrence of edema, and have heart and kidney protection (Hypertension.2009; 53:592-594).

Patent application WO2012146067A1 discloses a class of 1,4-dihydropyridine-3,5-dicarboxylate compounds, which have significant antihypertensive effect and can maintain long-term antihypertensive effect and have L-type and T-type type double calcium ion channel blocking effect, and the preparation method of this type of compound is also disclosed in the application documents, wherein the embodiment compound 16 has a good antihypertensive effect, and the specific structure is:

An important pharmaceutical intermediate involved in this reaction process is the chiral tertiary alcohol pyrrolidine intermediate (VII). The original preparation method is to obtain by chiral resolution, and its productive rate is only 16%. VIII) The yield of compound (IX) obtained by further reaction is only 56%. The yield of this preparation method is too low to be suitable for industrial production.

Contents of the invention

The technical problem to be solved by the present invention is to provide a preparation method of a pharmaceutical intermediate, that is, a chiral heterocyclic tertiary alcohol intermediate, and further provide a method for preparing 1,4-dihydropyridine-3 from an intermediate obtained by the method, Method of 5-dicarboxylate derivatives.

Specifically, the present invention provides the following technical solutions:

1. A method for preparing a compound of the following formula (VII),

The method comprises: reacting the compound of formula (VI) with a hydroxyl activator to obtain the compound of formula (VII) under basic conditions,

Wherein, the hydroxyl activator is selected from one or more of the following: acid chloride, sulfonyl chloride, acid anhydride, alcohol, phenol or silane protecting agent, and the hydroxyl activator can form ester, sulfonate, Ether or silicon ether;

R ₃ and R ₄ are independently selected from the following groups: hydrogen, C _1-6 alkyl, aryl C _0-6 alkyl optionally substituted by 1 to 3 Q ¹ , 3-8 membered ring Alkyl C _0-6 alkyl, 3-8 membered heterocyclyl C _0-6 alkyl, 5-6 membered heteroaryl C _0-6 alkyl, or R ₃ and R ₄ together form a 3-8 membered ring Alkyl, 3-8 membered heterocyclic group, which is optionally substituted by 1 to 3 Q ¹ , said Q ¹ is selected from the following group: halogen, hydroxyl, cyano, nitro, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl amido;

q is selected from 0, 1, 2 or 3;

n is an integer selected from 1 to 5.

2. The method for preparing the compound of the following formula (IX) and its salts, the compound of the formula (VII) prepared by the preparation method of the compound of the formula (VII) described in 1 reacts with the compound of the formula (VIII) to prepare the compound of the formula (IX) compound,

R ₃ , R ₄ , q and n are as defined in 1;

R ₅ and R ₆ are each independently selected from the following group: amino, cyano, and C _1-6 alkyl optionally substituted by 1 to 3 Q ² , C _1-4 alkoxy C _{1- 3} alkyl, C _2-6 alkenyl or C _2-6 alkynyl, Q ² is selected from the following group of groups: halogen, hydroxyl, amino, cyano, carboxyl or C _1-6 alkoxy;

R is selected from C _1-6 alkyl, C _3-8 cycloalkyl C _0-6 alkyl, 3-8 membered heterocyclyl C _0-6 alkyl optionally substituted by ¹ to 3 Q ³ or 5-6 membered heteroaryl C _0-6 alkyl, Q ³ is selected from the following group: halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, and 1 to 3 C _1-6 alkyl or C _1-6 alkoxy substituted by halogen;

R ₈ is selected from the following group of groups: hydrogen, halogen, hydroxyl, cyano, nitro or C _1-6 alkyl amido.

Invention effect

Through the method of the present invention, chiral heterocyclic tertiary alcohol intermediates can be obtained with high selectivity and high yield, especially chiral pyrrolidine tertiary alcohol, thereby improving 1,4-dihydropyridine-3,5-dicarboxylic acid Yield of ester derivatives. In addition, through the method of the present invention, the reaction conditions and purification conditions are simple and controllable, the production cost is reduced, the reaction yield is increased, and it is suitable for expanding industrial production. Furthermore, by the method of the present invention, 1,4-dihydropyridine-3,5-dicarboxylate derivatives can be obtained with high purity and high yield.

Detailed ways

【definition】

In the specification and claims of this application, the compounds are named according to the chemical structural formula. If the naming of the compound is inconsistent with the chemical structural formula when referring to the same compound, the chemical structural formula or chemical reaction formula shall prevail.

In this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

The "halogen" in the present invention refers to fluorine atom, chlorine atom, bromine atom and iodine atom. Preferred are fluorine atoms and chlorine atoms.

The "C _1-6 alkyl" in the present invention means a linear or branched alkyl group containing 1-6 carbon atoms, preferably a C _1-4 alkyl group, such as a C _2-4 alkyl group, a C _2- 3 alkyl, C _1-3 alkyl, C _1-2 alkyl; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl , 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methyl Pentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethyl Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl Wait. The "C _1-4 alkyl" in the present invention refers to the above-mentioned embodiments containing 1-4 carbon atoms.

The "C _0-6 alkyl" in the present invention means a straight chain or branched chain alkyl group containing 0 to 6 carbon atoms, and when the carbon number is 0, it means a bond; preferably C _0-4 alkyl, C _0-3 alkyl, most preferably C _0-2 alkyl.

The 3-8 membered cycloalkyl group in the present invention means a saturated or partially saturated and non-aromatic cyclic group containing 3-8 carbon atoms, including "3-8 membered saturated cycloalkyl group" and " 3-8 membered partially saturated cycloalkyl"; such as 3-6 membered cycloalkyl etc., more preferably 5-6 membered cycloalkyl; examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-diene, cyclohexa- 1,4-diene, cycloheptenyl, cyclohepta-1,3-dienyl, cyclohepta-1,4-dienyl, cyclohepta-1,3,5-trienyl, cyclooctene Cyclooctyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctyl tetraenyl, etc.

The "C _2-6 alkynyl group" in the present invention refers to a straight chain or branched chain with 2 to 6 carbon atoms containing a triple bond, and also includes a cyclic alkynyl group, preferably a C _2-4 alkynyl group, Such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, cyclopropynyl, cyclobutynyl, cyclopentynyl Alkynyl, cyclohexynyl, etc.

The "halogenated C _1-6 alkyl" in the present invention refers to a group derived from one or more "halogen" replacing one or more hydrogen atoms on the "C _1-6 alkyl", the "halogen" and "C _1-6 alkyl" are as defined above. The "halogenated C _1-4 alkyl" in the present invention refers to the specific examples containing 1-4 carbon atoms in the above examples.

"C _1-6 alkoxy" and "C _1-6 alkylamido" in the present invention refer to "C _1-6 alkyl-O-" group, "C _1-6 alkyl- C(O)-NH-" group, wherein "C _1-6 alkyl" is as defined above. "C _1-4 alkoxy" and "C _1-4 alkylamido" are preferred.

"C _1-4 alkoxy" and "C _1-4 alkylamido" in the present invention refer to "C _1-4 alkyl-O-" group, "C _1-4 alkyl- C(O)-NH-" group, wherein "C _1-4 alkyl" is as defined above.

The "3-8 membered heterocyclic group" in the present invention refers to a 3-8 membered saturated or partially saturated cyclic group containing one or more, the same or different heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur, any ring atom of the heterocyclic group can be oxo, such as a 3-6 membered heterocyclic group, etc., more preferably a 5-6 membered heterocyclic group; examples include but are not limited to oxirane group, thiiridine group, aziridine group, oxetanyl group, azetidine, thietanyl group, oxetane, 1,2-dioxetane 1,2-diazetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, oxazolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, Piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-oxathione, 4, 5-dihydroimidazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, 4,5-dihydrothiazolyl, piperidonyl, tetrahydropyridonyl, dihydropiperidine Keto, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H-1,2-oxazinyl, 4H-1,2 -Oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3 -Thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, 1,4-dioxo Heterocyclohexadienyl, 1,4-dithianyl, 1,4-oxathianyl, 1,4-dioxahexatrienyl, azepine Trienyl, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine tetraenyl , 1,4-dihydro-1,4-diazacyclooctatrienyl, etc.

The "aryl" in the present invention refers to 6-10 membered monocyclic or bicyclic aromatic hydrocarbon ring groups, such as phenyl, naphthyl and the like.

The 5-6 membered heteroaryl group in the present invention refers to an aromatic cyclic group containing at least one heteroatom and a total of 5 to 6 ring atoms, and the heteroatoms are selected from nitrogen, oxygen and Sulfur, any ring atom of the heterocyclic group can be oxo, examples include but not limited to pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazole base, thiadiazolyl, pyrimidinyl, triazinyl, tetrazinyl, pyridyl, etc.

The "hydroxyl activating reagent" in the present invention refers to a reagent capable of reacting with a hydroxyl group to form an easily leaving group, and the formed easily leaving group can undergo a nucleophilic reaction with a nucleophile. The hydroxyl activator includes but is not limited to one or more of the following: acid chlorides, sulfonyl chlorides, acid anhydrides, alcohols, phenols, halogenating agents, silane protecting agents; the acid chlorides and acid anhydrides can form esters with hydroxyl groups; The sulfonyl chloride can form sulfonate with hydroxyl; the alcohol or phenol can form ether with hydroxyl; the halogen in the halogenation reagent can replace hydroxyl to form halogenated hydrocarbon; the silane protecting agent can form with hydroxyl Silicone ether; the "hydroxyl activating reagent" includes aliphatic, alicyclic and aromatic reagents, that is, all activating reagents that can realize the functions of the present invention are included in the scope of the present invention.

The "organic solvent" described in the present invention is independently selected from aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, glycol derivatives, phenols At least one of carbons, nitriles, amides, sulfones, sulfoxides, heteroaromatics and mixtures thereof. Wherein, the aromatic hydrocarbon solvent is selected from at least one of benzene, toluene and xylene, the aliphatic hydrocarbon solvent is selected from at least one of pentane, hexane, heptane and octane, and the alicyclic hydrocarbon solvent is selected from At least one of cyclopentane and cyclohexane, the halogenated hydrocarbon solvent is selected from at least one of methylene chloride, chloroform, chlorobenzene and dichlorobenzene, and the alcohol solvent is selected from methanol, ethanol, isopropanol, At least one of tert-butanol, tert-amyl alcohol, tert-hexanol, benzyl alcohol, ethylene glycol and glycerol, and ether solvents are selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and propylene oxide The ester solvent is selected from at least one of methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate, and the ketone solvent is selected from acetone, methyl butyl ketone and methyl isobutyl At least one of ketones, glycol derivative solvents selected from at least one of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether One, the phenolic solvent is selected from at least one of phenol and p-cresol, the nitrile solvent is selected from at least one of acetonitrile and propionitrile, and the amide solvent is selected from N,N-dimethylformamide and N , at least one of N-dimethylacetamide, the sulfone solvent is selected from at least one of dimethyl sulfone, phenethyl sulfone, diethyl sulfone, diphenyl sulfone and sulfolane, and the sulfoxide solvent is selected from two At least one of methyl sulfoxide, diethyl sulfoxide and benzyl sulfoxide, and the heteroaromatic solvent is selected from pyridine.

The "base" in the present invention is independently selected from at least one of organic bases and inorganic bases.

The "inorganic base" in the present invention refers to an inorganic substance that can donate a lone pair of electrons and usually does not contain carbon elements. It is generally a compound formed by a metal ion or an ammonium ion and a hydroxide ion. Specific examples include but not Limited to: sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, ammonium hydroxide, lithium hydroxide as alkali metal hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, as alkaline earth metal hydroxide Calcium hydroxide, magnesium hydroxide, barium hydroxide, ammonia water, etc.

The "organic base" refers to an organic compound with basicity. Organic bases are divided into alkali metal salts of alcohols, alkyl metal lithium compounds, amino metal lithium compounds and amine compounds, and the alkali metal salts of alcohols are selected from lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide , sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, the alkyl metal lithium compound is selected from at least one of butyllithium and phenyllithium, and the amino metal lithium compound is selected from diiso At least one of lithium propylamide and lithium hexamethyldisilazide, the amine compounds are selected from fatty amines, such as N,N-diisopropylethylamine, methylamine, ethylamine, dimethylamine , diethylamine, triethylamine, ethylenediamine, isopropylamine, dibenzylamine, tert-butylamine, and hexamethylenediamine; alcohol amines, such as monoethanolamine, diisopropanolamine, and N,N-diethylamine At least one of ethanolamine, amides, such as at least one of formamide, acetamide, acrylamide, colchicine, camptothecin, N,N-dimethylformamide and dimethylacetamide, Alicyclic amines, such as at least one of cyclohexylamine, diethylenetriamine, hexamethylenetetramine, morpholine and piperazine, aromatic amines, such as aniline, diphenylamine, benzidine, o-phenyl At least one of diamine, p-phenylenediamine, p-methylaniline, p-chloroaniline, m-ethoxyaniline and m-nitroaniline, naphthalene-based amines, such as 1-naphthylamine, 2-naphthylamine, carat At least one of Fusic acid, Tuccinic acid, R acid, K acid and naphthalene diamine, polyethyleneimine, hydroxylamine; preferred fatty amines, such as N, N-diisopropylethylamine, dimethylamine, At least one of diethylamine, triethylamine and hexamethylenediamine;

The "oxidant" in the present invention refers to a substance that obtains electrons in a redox reaction or a substance that allows another substance to obtain oxygen or dehydrogenate; Auxiliary components for oxidants to play a role; the "oxidants" or "pro-oxidants" can be divided into non-metal elemental oxidants, metal ion-containing oxidants, acid oxidants, and peroxide oxidants;

1) The non-metal elemental oxidant is selected from at least one of oxygen, chlorine, bromine, iodine, and ozone;

2) The metal ion-containing oxidizing agent is selected from at least one of manganese compounds, chromium compounds, osmium compounds, lead compounds, iron compounds, and cerium compounds; and the manganese compounds are selected from potassium permanganate and manganese dioxide Described chromium compound is selected from at least one in sodium dichromate, potassium dichromate, chromium trioxide; Described osmium compound is selected from potassium osmate (VI) dihydrate, osmium tetroxide at least one of; the lead compound is selected from lead tetraacetate; the iron compound is selected from at least one of potassium ferricyanide, ferric chloride, ferric nitrate; the cerium compound is selected from cerium nitrate At least one of ammonium and cerium oxide; the metal ion-containing oxidizing agent is not limited to the above specific examples, and any compound containing metal ions and having oxidizing properties is included in the scope of the present invention.

3) The oxyacid oxidizing agent is selected from at least one of concentrated sulfuric acid, concentrated nitric acid, periodic acid, hypochlorous acid, and perchloric acid; the oxyacid oxidizing agent is not limited to the above-mentioned specific examples, and any Oxidizing acids are included within the scope of this invention.

4) The peroxide oxidant is selected from inorganic peroxides or organic peroxygen compounds; the inorganic peroxide is selected from hydrogen peroxide, sodium peroxide, potassium peroxide, calcium peroxide, zinc peroxide, peroxide At least one of monopotassium hydrogensulfate; the organic peroxy compound is selected from the group consisting of alcohol peroxide (ROOH), ether peroxide (ROOR'), diacyl peroxide (RCOOOOCR'), peroxyacid, peroxy At least one of ester (RCOOOR'), peroxycarbonate (ROCOOOOCOR') and ketone peroxide [R ₂ C(OOH) ₂ ]; R or R' represents any substituent; the peroxyalcohol At least one selected from peroxyethanol, tert-butanol peroxide, and isopropanol peroxide; At least one of oxidized tert-butyl ethers; the diacyl peroxide is selected from the group consisting of benzoyl peroxide, diisobutyryl peroxide, di-(2-ethylhexanoyl) peroxide, diacetyl At least one of peroxides; said peroxy acid is selected from at least one of peroxyformic acid, peracetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid; said peroxyester is selected from peroxy At least one of tert-butyl acetate, tert-butyl peroxytrifluoroacetate, tert-amyl perbenzoate, tert-butyl perbenzoate, tert-butyl peroctoate, tert-amyl peroctoate; the peroxycarbonic acid The ester is selected from at least one of diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, bis(-phenoxyethyl) peroxydicarbonate; the ketone peroxide is selected from dimethyl at least one of ketone peroxide, methyl ethyl ketone peroxide, cyclohexanone peroxide, acetone peroxide, butanone peroxide; are all included within the scope of the present invention.

The chiral base catalyst described in the present invention is selected from the group consisting of quinine, quinine monohydrochloride dihydrate, cinchonine, cinchonidine, dihydroquinine (DHQ), quinidine, dihydroquinidine (DHQD ), hydrogenated quinine 1,4-(2,3-naphthyridine) diether ((DHQ)2PHAL), hydrogenated quinidine 1,4-(2,3-naphthyridine) diether (( DHQD) 2PHAL) and at least one of any derivatives thereof.

The "room temperature" in the present invention refers to about 20°C-30°C, preferably about 25°C.

The "catalytic amount" mentioned in the present invention refers to the amount of catalyst commonly used in chemical reactions. For example, it can be less than one equivalent in a chemical reaction.

The "poor solvent" in the present invention refers to a solvent that is insoluble or slightly soluble to compounds in a non-heated state, and its solubility gradually increases after heating. It can be a solvent or a mixture of multiple solvents; the solvent includes water and Organic solvents. The poor solvent of the present invention includes but not limited to one or more in aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, ester solvents; aliphatic hydrocarbon solvents are selected from pentane, hexane, heptane and octane At least one of them, the alicyclic hydrocarbon solvent is selected from at least one of cyclopentane and cyclohexane, and the ester solvent is selected from methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate at least one of the

The dilute acid of the present invention is used to adjust the pH value of the solution or neutralize the excess alkali in the solution or to make the product into a salt, etc. All dilute acids that can realize the present invention are included within the scope of the present invention, so The dilute acid includes but not limited to at least one of 0.1%-5% dilute hydrochloric acid, dilute nitric acid and dilute sulfuric acid.

The dilute alkali or inorganic alkali described in the present invention is used to adjust the pH value of the solution or neutralize the excess acid in the solution or to make the product into a salt, etc. All the dilute alkali or inorganic alkali that can realize the present invention are included in the present invention. Within the scope of the invention, the dilute base or inorganic base includes but not limited to at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate.

The reducing inorganic salts described in the present invention are used to neutralize excess oxidants in the reaction solution and do not affect the yield of the product. All reducing inorganic salts that can realize the present invention are included within the scope of the present invention. The described Reducing inorganic salts include, but are not limited to, at least one of sodium sulfite, sodium thiosulfate, or sodium dithionite.

More specifically, the present invention relates to the following:

The preparation method of following formula (VII) compound,

The method comprises: reacting the compound of formula (VI) with a hydroxyl activator to obtain the compound of formula (VII) under basic conditions,

Wherein, the hydroxyl activator is selected from one or more of the following: acid chloride, sulfonyl chloride, acid anhydride, alcohol, phenol or silane protecting agent, and the hydroxyl activator can form ester, sulfonate, Ether or silicon ether;

R ₃ and R ₄ are independently selected from the following groups: hydrogen, C _1-6 alkyl, aryl C _0-6 alkyl optionally substituted by 1 to 3 Q ¹ , 3-8 membered ring Alkyl C _0-6 alkyl, 3-8 membered heterocyclyl C _0-6 alkyl, 5-6 membered heteroaryl C _0-6 alkyl, or R ₃ and R ₄ together form a 3-8 membered ring Alkyl, 3-8 membered heterocyclic group, which is optionally substituted by 1 to 3 Q ¹ , said Q ¹ is selected from the following group: halogen, hydroxyl, cyano, nitro, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl amido;

q is selected from 0, 1, 2 or 3;

n is an integer selected from 1 to 5.

In another embodiment of the present invention, the compound (VI) is prepared from the compound of the formula (II) and the compound of the formula (IV) through the following steps,

Described preparation step comprises:

The compound of formula (II) is reacted with a hydroxyl activator under basic conditions to form formula (III),

Among them, R ₁ and R ₂ are independently selected from the following groups that may be substituted: C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, phenyl, 5-6 Heteroaryl, phenyl C _1-6 alkyl, 5-6 membered heteroaryl C _1-6 alkyl, C _1-6 alkylcarbonyl, phenylcarbonyl, 5-6 membered heteroarylcarbonyl, C _{1 -6} alkylsulfonyl, phenylsulfonyl, 5-6 membered heteroarylsulfonyl, phenyl C _1-6 alkylsulfonyl, 5-6 membered heteroaryl C _1-6 alkylsulfonyl or ( C _1-6 alkyl) x (phenyl) ySi, the substituents are selected from optionally replaced by one or more halogen, nitro, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;

_The R2 group is the residue of a hydroxyl activator;

x, y are independently selected from 0 to 3 integers, and the sum of x and y is 3, wherein the C _1-6 alkyl in (C _1-6 alkyl) x (phenyl) ySi can be the same Alkyl groups can also be different alkyl groups;

The R ₃ and R ₄ are as defined in claim 1;

Formula (III) is reacted with formula IV compound to prepare formula (V),

Formula (V) removes the R ₁ group to obtain the compound of formula (VI).

In another embodiment of the present invention, the compound of formula (II) is prepared through the following steps,

The compound of formula (II) is obtained by catalytic oxidation of the compound of formula (I) under the action of a chiral base catalyst.

In another embodiment of the present invention, R ₁ and R ₂ are independently selected from the following groups optionally substituted: C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, Phenyl, phenyl C _1-4 alkyl, C _1-4 alkylcarbonyl, phenylcarbonyl, C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl C _1-4 alkylsulfonyl or ( C _1-4 alkyl) x (phenyl) ySi, the substituent is selected from one or more halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy Or halogenated C _1-4 alkoxy;

_The R2 group is the residue of a hydroxyl activator;

x, y are independently selected from 0 to 3 integers, and the sum of x and y is 3, wherein the C _1-6 alkyl in (C _1-4 alkyl) x (phenyl) ySi can be the same Alkyl groups can also be different alkyl groups.

_In another embodiment of the present invention, _R and R are each independently selected from hydrogen, phenyl, benzyl, pyridyl, pyrimidinyl, furyl, thienyl optionally substituted by ¹ to 3 Q , thiazolyl, pyrrolyl, imidazolyl or oxazolyl, and _R3 and _R4 are not simultaneously hydrogen,

Q is selected from fluorine, chlorine, hydroxy, amino, methyl, ethyl, isopropyl, tert ^- butyl, methoxy, ethoxy or trifluoromethyl.

In another embodiment of the present invention, q is selected from 1, 2 or 3.

In another embodiment of the present invention, n is selected from 2 or 3.

In another embodiment of the present invention, R ₁ is selected from the following groups optionally substituted: phenyl, phenyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, benzene Carbonyl, benzenesulfonyl, phenyl C _1-4 alkylsulfonyl or (C _1-4 alkyl) x (phenyl) ySi, the substituents are selected from one or more of halogen, methyl, ethyl radical, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, methoxy, ethoxy, propoxy, tert-butoxy, halomethoxy or haloethoxy Substitution; x, y are independently selected from 0 to 3 integers, and the sum of x and y is 3.

In another embodiment of the present invention, R ₂ is selected from the following groups optionally substituted: C _1-4 alkylcarbonyl, phenylcarbonyl, C _1-4 alkylsulfonyl, phenylsulfonyl, benzene C _1-4 alkylsulfonyl group, the substituent is selected from one or more halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, Methoxy, ethoxy, propoxy, tert-butoxy, halomethoxy or haloethoxy.

In another embodiment _of the present invention, R is selected from the following groups optionally substituted: phenyl, benzyl, ethoxymethyl, propoxymethyl, tert-butoxymethyl, phenylcarbonyl , benzenesulfonyl, phenylmethylsulfonyl, Et ₃ Si, i-Pr ₃ Si, t-BuMe ₂ Si or t-BuPh ₂ Si, the substituents are selected from one or more of fluorine, chlorine, methyl, Ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy or trifluoromethoxy.

_In another embodiment of the present invention, R is selected from the following groups optionally substituted: formyl, acetyl, phenylcarbonyl, methylsulfonyl, ethylsulfonyl, benzenesulfonyl or phenylmethylsulfonyl, The substituent is selected from one or more of fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert butoxy or trifluoromethoxy.

In another embodiment of the present invention, the compound shown in formula VII has the structure shown in the following formula VII':

In another embodiment of the present invention, in step A, the chiral base catalyst, oxidant and/or pro-oxidant and base are added to the mixed solution of water and organic solvent, the temperature is lowered, the compound of formula (I) is added, and the temperature is maintained to carry out After reaction and treatment, the compound of formula (II) is obtained. Preferably, the cooling temperature in step A is -25°C to 10°C. Preferably the reaction time is 4h-15h. It is preferred that the molar ratio of the compound of formula (I) to the base is 1:1 to 1:10. Preferably, the oxidizing agent is selected from a catalytic amount, and the molar ratio of the compound of formula (I) to the pro-oxidizing agent is 1:1-1:10. Preferably, the molar ratio of the compound of formula (I) to the chiral base catalyst is 50:1-120:1. In another embodiment of the present invention, in step A, the chiral base catalyst, metal ion-containing oxidant and/or co-oxidant, and inorganic base are added to the mixed solution of water and alcohol, and the temperature is lowered to -5°C to 5°C, Add the compound of formula (I), keep the temperature and react for 6h-10h, and obtain the compound of formula (II) after treatment. It is preferred that the molar ratio of the compound of formula (I) to the inorganic base is 1:2 to 1:5. The preferred metal ion-containing oxidizing agent is a catalytic amount of H2O compound, the metal ion-containing pro-oxidant is an iron compound, and the molar ratio of the compound of formula (I) to the pro-oxidant is 1:1 to 1:5. Preferably, the molar ratio of the compound of formula (I) to the chiral base catalyst is 80:1-100:1. In another embodiment of the present invention, step A further includes the following steps: after the reaction is completed, add an aqueous solution of reducing inorganic salts to quench the reaction, extract with an ester solvent, and use dilute acid and saturated aqueous sodium chloride solution in sequence for the organic phase After washing and drying, concentrate to obtain the compound of formula (II).

In another embodiment of the present invention, in step B-1, the hydroxyl activator is added to the mixed solution of the compound of formula (II), base and organic solvent, and then reacted under certain conditions to obtain ( III). Preferably, the temperature at which the hydroxyl activator is added to the mixed solution is -25°C to 20°C. Preferably, the reaction temperature is -10°C to 10°C. Preferably, the reaction time is 0.5h to 2h. It is preferred that the molar ratio of the compound of formula (II) to the base is 1:0.5 to 1:5. It is preferred that the molar ratio of the compound of formula (II) to the hydroxyl activator is 1:1 to 1:3. In another embodiment of the present invention, in step B-1, under the condition of -15°C to -5°C, add sulfuryl chloride to the mixture of the compound of formula (II), aliphatic amine, and halogenated hydrocarbon solvent, Then react at -5°C to 5°C for 0.5h to 1.5h, and after treatment, the compound of formula (III) is obtained. It is preferred that the molar ratio of the compound of formula (II) to the base is 1:1 to 1:2. It is preferred that the molar ratio of the compound of formula (II) to sulfonyl chloride is 1:1 to 1:1.5. In another embodiment of the present invention, step B-1 further includes the following steps: ① After the reaction is completed, add an appropriate amount of water and stir for about 0.5-1h. Wash with saturated sodium chloride aqueous solution, dry, and concentrate to obtain the product. In this preparation step, the selectivity of the hydroxyl activating reagent to different hydroxyl groups can be controlled by controlling the ratio of the feeding amount and the reaction temperature.

In another embodiment of the present invention, in step B-2, the compound of formula (III) and compound of formula (IV) are dissolved in an organic solvent, heated and reacted under stirring conditions, and the compound of formula (V) is obtained after treatment. Preferably, the reaction temperature is 50°C to 100°C. Preferably, the reaction time is 1 h to 10 h. Preferably, the molar ratio of the compound of formula (III) to the compound of IV is 1:1-1:5. In another embodiment of the present invention, in step B-2, the compound of formula (III) and compound IV are dissolved in an alcoholic solvent, heated to 60-90°C under stirring conditions for 2h-5h, and after treatment, A compound of formula (V). Preferably, the molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1 to 1:2.5. In another embodiment of the present invention, step B-2 further includes the following steps: ① After the reaction is completed, concentrate the reaction solution, add a halogenated hydrocarbon solvent to dissolve the product, and use dilute acid, dilute alkali, and saturated aqueous sodium chloride solution successively to Washing, drying, and concentration to obtain a crude product; ② adding one or more poor solvents of the compound of formula (V) to wash and purify the product.

In another embodiment of the present invention, in step B-3, the compound of formula (V) is dissolved in an organic solvent, the temperature is lowered under stirring, the aqueous solution of oxidizing agent is added, and the reaction is carried out under certain conditions, and the formula ( VI) Compounds. Preferably, the cooling temperature is -20°C to 0°C. Preferably, the reaction temperature is -10°C to 10°C. Preferably, the reaction time is 0.1h to 2h. It is preferred that the molar ratio of the compound of formula (V) to the oxidizing agent is 1:0.5-1:5. In another embodiment of the present invention, in step B-3, dissolve the compound of formula (V) in a nitrile solvent, stir and cool down to -15°C to -5°C, add an aqueous solution containing a metal ion oxidizing agent, and React at -5°C to 5°C for 0.1h to 1.5h, and get the compound of formula (VI) after treatment. It is preferred that the molar ratio of the compound of formula (I) to the metal ion-containing oxidizing agent is 1:1 to 1:3. In another embodiment of the present invention, step B-3 further includes the following steps: ① After the reaction is finished, add an aqueous solution of reducing inorganic salt to quench the reaction, concentrate the reaction solution, add a mixed solution of halogenated hydrocarbon and water, and Stir, filter, and stand to separate to obtain the organic phase; ②Salt purification, the organic phase is extracted with dilute acid, the obtained aqueous phase is adjusted to PH=8-11 with an inorganic base, and then extracted with an ester solvent, and the obtained organic phase is successively saturated with Wash with salt water, dry, and concentrate to obtain the product; the preferred product can be repeatedly subjected to salt-forming purification to obtain a product with higher purity.

In another embodiment of the present invention, in step C, the hydroxyl activator is added to the mixed solution of the compound of formula (VI), base and organic solvent, and then reacted at room temperature until the reaction is completed, and the formula (VII) is obtained after treatment compound. Preferably, the reaction temperature of step C is -25°C to 20°C. It is preferred that the molar ratio of the compound of formula (VI) to the base is 1:1 to 1:6. It is preferred that the molar ratio of the compound of formula (VI) to the hydroxyl activator is 1:1 to 1:3. In another embodiment of the present invention, in step C, under the condition of -5°C to 5°C, add sulfonyl chloride to the mixed solution of the compound of formula (VI), aliphatic amine, and halogenated hydrocarbon solvent, and then React until the end of the reaction, and obtain the compound of formula (VII) after treatment. It is preferred that the molar ratio of the compound of formula (VI) to the base is 1:2 to 1:4. It is preferred that the molar ratio of the compound of formula (VI) to sulfonyl chloride is 1:1-1:2. In another embodiment of the present invention, step C further includes the following steps: ① After the reaction is completed, add an appropriate amount of water and stir for about 0.5-1h, after standing for stratification, the organic phase is washed with saturated brine, dried, and concentrated to obtain crude product; ② adding one or more poor solvents of compounds of formula (VII) to obtain the product through recrystallization and purification.

In another embodiment of the present invention, the method for preparing the compound of formula (VII) comprises the following steps:

(1) Dissolve a catalytic amount of potassium osmate dihydrate, potassium ferricyanide, (DHQ) ₂ PHAL, and potassium carbonate in a mixture of water and tert-butanol, cool to 0°C, and add the compound of formula (I') tert-butanol solution, the molar ratio of formula (I') compound and potassium ferricyanide is 1: 3-1: 3.5, wherein the mol ratio of potassium osmate dihydrate and potassium ferricyanide is 1: 50-1: 500, preferably about 1:300, the molar ratio of the compound of formula (I') to (DHQ) ₂ PHAL is 1:90-1:100, the molar ratio of the compound of formula (I') to potassium carbonate is 1:3-1 : 3.5, keep 0 DEG C to react for 8 hours, then add sodium sulfite to quench the reaction, extract with ethyl acetate, wash the organic phase with 0.5% dilute hydrochloric acid and saturated sodium chloride successively, dry, and concentrate to obtain the compound of formula (II');

(2) Dissolve the compound of formula (II') and triethylamine in dichloromethane, lower the temperature to -10°C, add the methylene chloride solution of methanesulfonyl chloride, the moles of the compound of formula (II') and methanesulfonyl chloride Ratio is 1: 1, and the mol ratio of formula (II) compound and triethylamine is 1: 1～1: 1.5, reacts 1～1.5h under 0 ℃ then, and reaction completes; The phase was washed successively with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, dried and concentrated to obtain the compound of formula (III');

(3) Dissolve the compound of formula (III') and compound IV' in ethanol solvent, the molar ratio of compound of formula (III') and compound IV' is 1:2, heat and reflux under stirring for 3-4h, evaporate under reduced pressure Remove the solvent, add dichloromethane, wash with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated aqueous sodium chloride successively, dry, concentrate, add a mixed solvent of n-heptane and ethyl acetate (n-heptane: ethyl acetate Ester=10:1), stirred to precipitate a solid, and filtered to obtain the compound of formula (V');

(4) Dissolve the compound of formula (V') in acetonitrile solvent, stir and cool down to -10°C, add the aqueous solution of ammonium cerium nitrate, the molar ratio of compound of formula (V') to ammonium cerium nitrate is 1:2-1: 2.5, react at 0°C for 0.5h, add saturated sodium sulfite to quench the reaction, evaporate the solvent under reduced pressure, add a mixture of dichloromethane and water and stir, filter with diatomaceous earth, and stand to separate to obtain an organic phase; The organic phase was extracted with 2% dilute hydrochloric acid, and the obtained aqueous phase was adjusted to PH=9-10 with sodium bicarbonate, then the aqueous phase was extracted with ethyl acetate, washed with saturated brine, dried, and then added with 1-1.5eq dilute hydrochloric acid /1,4-dioxane solution, the product is separated out;

(5) Under the condition of 0°C, add methanesulfonyl chloride to the dichloromethane solution of the compound of formula (VI') and triethylamine, and the molar ratio of the compound of formula (VI') to triethylamine is 1:3 ; The molar ratio of the compound of formula (VI') to sulfonyl chloride is 1:1～1:1.5, reacted at room temperature for 8h, added water and washed, left to stand for layering, the organic phase was washed with saturated brine, dried, and concentrated to obtain a crude product; Dissolve the crude product in 3 times the volume of n-heptane solution, heat to 60°C, then cool the supernatant to 25°C, solid precipitates, filter, and dry to obtain the compound of formula (VII')

In another embodiment of the present invention, said formula I' is prepared by the following steps,

step 1)

The compound of formula 1 is reacted with MSCI under alkaline conditions to obtain the compound of formula 2; the preferred base is triethylamine; the preferred reaction solvent is methylene chloride;

step (2)

The compound of formula 2 is reacted with the compound of formula 3 under alkaline conditions to obtain the compound of formula (I'); the preferred base is potassium tert-butoxide; the preferred reaction solvent is THF.

The method for preparing the following formula (IX) compound and its salt, the compound of formula (VII) prepared by the preparation method of the compound of formula (VII) described above in the present invention is reacted with formula (VIII) to prepare formula (IX) or its salt compounds,

R ₃ , R ₄ , q and n are as defined in claim 1;

R ₅ and R ₆ are each independently selected from the following group: amino, cyano, and C _1-6 alkyl optionally substituted by 1 to 3 Q ² , C _1-4 alkoxy C _{1- 3} alkyl, C _2-6 alkenyl or C _2-6 alkynyl, Q ² is selected from the following group of groups: halogen, hydroxyl, amino, cyano, carboxyl or C _1-6 alkoxy;

R is selected from C _1-6 alkyl, C _3-8 cycloalkyl C _0-6 alkyl, 3-8 membered heterocyclyl C _0-6 alkyl optionally substituted by ¹ to 3 Q ³ or 5-6 membered heteroaryl C _0-6 alkyl, Q ³ is selected from the following group: halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, and 1 to 3 C _1-6 alkyl or C _1-6 alkoxy substituted by halogen;

R ₈ is selected from the following group of groups: hydrogen, halogen, hydroxyl, cyano, nitro or C _1-6 alkyl amido.

In another embodiment of the present invention, _R3 and R4 are each independently selected from hydrogen, phenyl optionally substituted by ¹ to ₃ Q1, benzyl, pyridyl, pyrimidinyl, furyl, thienyl , thiazolyl, pyrrolyl, imidazolyl or oxazolyl, and _R3 and _R4 are not hydrogen at the same time,

^Q is selected from fluorine, chlorine, hydroxy, amino, methyl, trifluoromethyl or methoxy.

In another embodiment of the present invention, _R5 and R6 are each independently selected from _C1-4 alkyl optionally substituted by ₁ to ^{3 Q2} selected from fluorine, chlorine, amino, methoxy base or ethoxy.

In another embodiment of the present invention, R ₇ is selected from C _1-4 alkyl optionally substituted by 1 to ^{3 Q 3 selected} from fluorine, chlorine, methyl, methoxy.

In another embodiment of the present invention, _R8 is selected from hydrogen, chloro or nitro.

In another embodiment of the present invention, q is selected from 0, 1, 2 or 3.

In another embodiment of the present invention, n is selected from 1, 2 or 3.

In another embodiment of the present invention, the compound of formula (IX) or its salt has the following structure:

On the basis of not violating common knowledge in the field, the above conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

In the preparation method of the present invention, the drying includes but not limited to the following drying methods: normal pressure drying, reduced pressure drying, spray drying, boiling drying, freeze drying, infrared drying, microwave drying, moisture absorption drying and the like. Those skilled in the art can select one or more drying methods according to the properties of the product, and perform one or more dryings according to the humidity of the product.

Unless otherwise specified, the raw materials or reagents described in the present invention are commercially available.

In the present invention, the compounds and intermediates of the present invention can be isolated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to: chromatography on solid supports (e.g., silica gel, alumina, or silica derivatized with alkylsilanes), recrystallization at high or low temperatures ( Optional pretreatment with activated carbon), thin layer chromatography, distillation at various pressures, vacuum sublimation, trituration, for example, as described in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989) , Furniss et al., pub. Longman Scientific & Technical, Essex CM20 2JE, England.

By preparing the compound of formula (VII) through the asymmetric catalytic synthesis method of the present invention, the yield can be increased to at least 46%, and the stereoselectivity is high, and its ee value is more than 95%.

In the method for preparing the compound of formula (VII) described in the present invention, low-toxicity, cheap and easy-to-obtain raw materials or reagents are used, and its preparation cost is lower, and its cost per kilogram is only about 40% of the cost of chiral resolution , the cost is greatly reduced; at the same time, the cost of preparing 1,4-dihydropyridine-3,5-dicarboxylate compounds (formula IX') is also greatly reduced.

The quality of the 1,4-dihydropyridine-3,5-dicarboxylate compound (formula IX') further prepared from the compound of formula (VII') prepared by the method of the present invention is qualified, and no new impurities appear.

The preparation method described in the invention is more efficient, the reaction conditions of each step are mild and easy to control, and the product can be purified through simple operations such as extraction and crystallization: the overall process is simple and the operation is convenient.

The present invention develops a novel method for constructing pyrrolidine with chiral tertiary alcohol, which has high stereoselectivity and has wide application value in the future.

Description of drawings

Accompanying drawing 1 is the high performance liquid chromatogram of chiral intermediate.

Example

The above-mentioned content of the present invention will be further described in detail below by means of examples, but the present invention is not limited to the scope of the examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

The preparation of embodiment 1 (S)-1-((3,3-diphenylpropyl)-3-methylpyrrolidin-3 alcohol (compound VII')

1, the preparation of 3-methylbut-3 en-1 base mesylate

Add 3-methylbut-3-en-1 alcohol (1kg, 11.61mol), triethylamine (1762g, 17.42mol), dichloromethane (10L) into the reaction kettle, stir and cool down to 0°C, add formaldehyde dropwise Sulfonyl chloride (1596g, 13.92mol), the reaction temperature was controlled below 10°C, after the addition was completed, the temperature was naturally raised to 25°C for 16 hours, and the reaction was completed. Slowly add water (5L), stir for 20 minutes, let stand to separate layers, discard the water phase, and wash the organic phase successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and reduce to 45°C. The solvent was removed by pressure evaporation to obtain the crude product of the title compound, which was directly put into the next step.

2. Preparation and synthesis of 1-methoxy-4-((3-methylbut-3-en-1 base)oxy group

Add 3-methylbut-3en-1-yl methanesulfonate (1209g, 9.74mol) and THF (12L) into the reaction kettle, add potassium tert-butoxide (1025g, 9.13mol) under stirring, and heat to 60°C for reaction After 1 hour, 4-methoxyphenol (1 kg, 6.09 mol) was added slowly, and after the addition was completed, the mixture was kept at 60° C. for 16 hours, and the reaction was completed. Cool down to 25°C, filter with diatomaceous earth, concentrate the filtrate, add DMF (10L) to dissolve the product, add water (1L) and stir for 10 minutes, and extract three times with a mixed solvent (n-heptane:ethyl acetate=10:1) , the organic phases were combined, washed twice with water, then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain the title compound (yield 70%).

3. Preparation of (S)-4-(4-methoxyphenoxy)-2-methylbutane-1,2-diol

Potassium osmate dihydrate (3.9g), (DHQ) ₂ PHAL (42.7g), potassium ferricyanide (5481g) and potassium carbonate (2302g) were added to the reaction kettle, water (30L) and tert-butanol (5L) were added , cool down to 0°C, dropwise add 1-methoxy-4-((3-methylbut-3-1-yl)oxy)benzene (1kg) in tert-butanol solution (5L), keep 0 °C for 8 hours, and the reaction is complete. Add anhydrous sodium sulfite (237g), keep stirring for 1 hour at 0°C, add ethyl acetate to extract three times, combine the organic phases, wash with 0.5% dilute hydrochloric acid and saturated sodium chloride successively, dry the organic phases with anhydrous sodium sulfate, reduce Concentrate under reduced pressure to obtain the title compound (90% yield, ee>95%).

4. Preparation of (S)-2-hydroxy-4-(4-methoxyphenoxy)-2-methylbutyl methanesulfonate

Add (S)-4-(4-methoxyphenoxy)-2-methylbutane-1,2-diol (1kg, 4.42mol), triethylamine (537g, 5.30mol) into the reaction kettle , dichloromethane (12L), stirring and lowering the temperature to -10°C, adding methylenesulfonyl chloride (532g, 4.64mol) in dichloromethane solution (2L) dropwise, keeping at 0°C for 1 hour after the addition, and the reaction was complete . Add water (5L) and stir for 20 minutes, let stand and separate layers, and the organic phase is successively dried with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride, and anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to obtain the title compound (yield 96%).

5. Preparation of (S)-1-((3,3-diphenylpropyl)amino)-4-(4-methoxyphenoxy)-2-methylbutan-2-ol

Add (S)-2-hydroxyl-4-(4-methoxyphenoxy)-2-methylbutyl methanesulfonate (1kg, 3.28mol), 3,3-1-diphenylpropane to the reaction kettle - 1-Ammonia (1389g, 6.57mol), absolute ethanol (15L), heated to 80°C for 3-4 hours under reflux under stirring, and the reaction was completed. Evaporate the solvent under reduced pressure, add dichloromethane (10L) to dissolve the product, wash with 0.5% dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution successively, dry over anhydrous sodium sulfate, filter and evaporate the solvent to obtain a crude product , adding a mixed solvent (10 L, n-heptane:ethyl acetate=10:1) and stirring for 2 hours, the product precipitated, filtered and air-dried to obtain the title compound (yield 75%).

6. Preparation of (S)-4-((3,3-diphenylpropyl)amino)-3-methylpropane-1,3-diol

Add (S)-1-((3,3-diphenylpropyl)amino)-4-(4-methoxyphenoxy)-2-methylbutan-2-alcohol (1kg , 2.38mol), acetonitrile (10L), stirring and lowering the temperature to -10°C, adding an aqueous solution (5L) of cerium ammonium nitrate (2744g, 5.00mol) dropwise, controlling the temperature below 0°C during the dropping process, and keeping the temperature for reaction 30min, the reaction is complete. Add saturated sodium sulfite aqueous solution (1 L) to quench the reaction, distill off acetonitrile under reduced pressure, add dichloromethane and water mixture (5 L each) and stir for 30 min, filter with diatomaceous earth, and wash the filter cake with dichloromethane (2 L). Combine the filtrates, let stand to separate the layers, extract the organic phase three times with 2% HCl, discard the organic phase, adjust the aqueous phase to pH=9-10 with _NaHCO3 , then extract the aqueous phase three times with ethyl acetate, combine the organic phases, and Wash with saturated brine, dry over anhydrous sodium sulfate, filter, add 1.2eq of HCl/dioxane solution with stirring, the product precipitates, and filter to obtain the title compound (65% yield).

7. Preparation of (S)-1-((3,3-diphenylpropyl)-3-methylpyrrolidin-3 alcohol

(S)-4-((3,3-diphenylpropyl)amino)-3-methylpropane-1,3-diol (1kg, 3.19mol), triethylamine (968g, 9.57mol), dichloromethane (10L), stirring and lowering the temperature to 0°C, adding MsCl (548g, 4.78mol) dropwise, after the addition was completed, the temperature was naturally raised to 25°C and reacted for 8 hours, HPLC showed that the reaction was completed, and water (5L) was added Stir for 30 minutes, let stand to separate layers, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and evaporate to dryness to obtain a crude product. Add 3 times the volume of n-heptane, heat to 60°C and stir for 1 hour, let stand to separate layers, pour the supernatant into another container, stir and lower the temperature naturally, add 1 times the volume of n-heptane 60 Extract again at ℃, the supernatant is combined with the first time, the product precipitates during the cooling process, the temperature is lowered to 25 ℃, continue to stir for 2 hours, filter, wash the filter cake with n-heptane, and put it in a vacuum drying oven at 40 ℃, -0.1 The vacuum pump was continuously evacuated at MPa for 8 hours to obtain the title compound (yield 46%, ee>95%). Molecular formula: C ₂₀ H ₂₅ NO Molecular weight: 295.43 Mass spectrum (m/z): 296.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO) δ: 7.30-7.36(m, 8H), 7.17-7.21(m, 2H), 4.48(s, 1H), 3.99-4.02(t, 1H), 2.49-2.51(m , 2H), 2.41-2.49(m, 2H), 2.34-2.38(m, 2H), 2.22-2.25(m, 2H), 2.11-2.19(m, 2H), 1.61-1.74(m, 2H), 1.27 (s, 3H).

Structure Confirmation Test (HPLC Chromatography Experiment)

Chromatographic conditions: get this product to be accurately weighed, add mobile phase to dissolve and make a solution containing 0.3mg in 1mL, as the test solution, measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512), use direct Amylopectin-tris[3,5-xylylcarbamate] was used as filler (4.6×250mm, 5μm AD-H); mobile phase was n-hexane-absolute ethanol-diethylamine (90:10:0.05 ); the flow rate is 0.6mL/min; the column temperature is 30°C; the detection wavelength is 214nm. Precisely measure 10 μL of the test solution, inject it into the liquid chromatograph, and record the chromatogram. The number of theoretical plates shall not be less than 3000.

Experimental results:

See the high performance liquid chromatogram of accompanying drawing 1 chiral intermediate

Table 6 Retention times and corresponding configurations of chiral intermediates

Example 2 3-((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)5-methyl(S)-2,6-dimethyl - Preparation of 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (compound IX') and salts thereof

1. 3-((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)5-methyl(S)-2,6-dimethyl- Preparation of 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (crude product)

(R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (304g, 1.02 mol) was dissolved in dichloromethane solution (3.4L), DMF (34mL) was added, the temperature was lowered to -10°C, oxalyl chloride (155.8g, 1.23mol) was slowly added dropwise, and the temperature was controlled below 0°C for 4 hours, monitored by TLC The reaction is complete. Add (S)-1-((3,3-diphenylpropyl)-3-methylpyrrolidin-3 alcohol (302g, 1.02mol) in dichloromethane solution (600mL) slowly, and control the temperature at 0 React for 1 hour below ℃, TLC monitors that the reaction is complete, wash with water, 1% dilute hydrochloric acid, 5% sodium carbonate aqueous solution, 5% saline successively, dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain 3- ((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)5-methyl(S)-2,6-dimethyl-4-(3 The crude -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (624 g) was used directly in the next step.

2. Potassium (S)-3-((((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)oxy)carbonyl)-5-( Preparation of methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-4H-pyridine-1-compound

3-((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)5-methyl(S)-2,6-dimethyl-4 -(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (623.7g, 1.02mol) was dissolved in tert-butanol (4L), heated to 50°C and stirred for 1 hour to dissolve Evenly, add n-heptane (800mL), continue to stir for 10 minutes, add potassium tert-butoxide (172g, 1.53mol) at 50°C, cool down naturally after the addition, solid precipitates, filter, use a poor solvent (petroleum ether or n-heptane Alkane) washing, potassium (S)-3-((((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)oxy)carbonyl)- 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-4H-pyridine-1-compound.

Molecular formula: C ₃₆ H ₃₈ ClKN ₃ O ₆ Molecular weight: 647.8 Mass spectrum (m/z): 648.2 (M+H+)

Potassium analysis: K, 6.42%.

3. 3-((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)5-methyl(S)-2,6-dimethyl- Preparation of 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

Potassium (S)-3-((((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl)oxy)carbonyl)-5-(methyl Oxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-4H-pyridine-1-compound was dissolved in anhydrous methanol (500mL), then dichloromethane (4L) was added to dissolve Evenly, washed with 2% dilute hydrochloric acid, water successively, then washed three times with 5% sodium carbonate aqueous solution, and then washed with 1% dilute hydrochloric acid until acidic, and the organic phase was evaporated to dryness to obtain an oily substance (360 g). Add methanol (1L) to dissolve, filter with a microporous membrane with a pore size of 0.45 microns, add the filtrate dropwise to rapidly stirring (200rpm) 1% dilute hydrochloric acid (10L), the product precipitates, filter, and wash the filter cake with pure water The filtrate was dried with anhydrous calcium chloride until pH = 7, and dried in a vacuum oven (50°C, -0.09MPa) for 24 hours to obtain the product (301g).

The specific rotation is +105.23° (temperature: 20°C, concentration: 2mg/mL, dissolved in MeOH).

Molecular formula: C ₃₆ H ₄₀ ClN ₃ O ₆ Molecular weight: 646.2 Mass spectrum (m/z): 610.6 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO) δ: 9.11(d, 1H), 8.03-7.94(m, 2H), 7.62-7.48(m, 2H), 7.33-7.27(m, 8H), 7.20-7.16(m , 2H), 4.89(d, 1H), 4.00-3.96(m, 1H), 3.76-3.52(m, 2H), 3.61-3.52(s, 3H), 3.20-2.91(m, 4H), 2.54-2.42 (m, 2H), 2.28-2.26 (s, 6H), 2.25-1.93 (m, 2H), 1.34 (d, 3H).

Claims (16)

1. A method for preparing a compound of the following formula (VII), characterized in that, The method comprises: reacting the compound of formula (VI) with a hydroxyl activator to obtain the compound of formula (VII) under basic conditions, Wherein, the hydroxyl activator is selected from one or more of the following: acid chlorides, sulfonyl chlorides, acid anhydrides, alcohols, phenols, halogenating agents or silane protecting agents, and the hydroxyl activators can form esters, sulfonyl esters, ethers, alkyl halides or silicon ethers; R ₃ and R ₄ are independently selected from the following groups: hydrogen, C _1-6 alkyl, aryl C _0-6 alkyl optionally substituted by 1 to 3 Q ¹ , 3-8 membered ring Alkyl C _0-6 alkyl, 3-8 membered heterocyclyl C _0-6 alkyl, 5-6 membered heteroaryl C _0-6 alkyl, or R ₃ and R ₄ together form a 3-8 membered ring Alkyl, 3-8 membered heterocyclic group, which is optionally substituted by ¹ to ³ Q1, said Q1 is selected from the following group: halogen, hydroxyl, cyano, nitro, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl amido; q is selected from 0, 1, 2 or 3; n is an integer selected from 1 to 5. 2. The preparation method according to claim 1, wherein said compound of formula (VI) is prepared from a compound of formula (II) and a compound of formula (IV) through the following steps, Described preparation step comprises: The compound of formula (II) is reacted with a hydroxyl activator under basic conditions to form formula (III), Wherein, R ₁ and R ₂ are independently selected from the following groups optionally substituted: C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, phenyl, 5-6 membered hetero Aryl, phenyl C _1-6 alkyl, 5-6 membered heteroaryl C _1-6 alkyl, C _1-6 alkylcarbonyl, phenylcarbonyl, 5-6 membered heteroarylcarbonyl, C _{1- 6} alkylsulfonyl, phenylsulfonyl, 5-6 membered heteroarylsulfonyl, phenyl C _1-6 alkylsulfonyl, 5-6 membered heteroaryl C _1-6 alkylsulfonyl or (C _1-6 alkyl) _x (phenyl) _y Si, the substituent is selected from one or more halogen, nitro, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 Alkoxy or halogenated C _1-6 alkoxy; _The R2 group is the residue of a hydroxyl activator; x and y are independently selected from integers from 0 to 3, and the sum of x and y is 3; The R ₃ , R ₄ , q, and n are as defined in claim 1; Formula (III) is reacted with formula IV compound to prepare formula (V), Formula (V) removes the R ₁ group to obtain the compound of formula (VI). 3. The preparation method according to claim 2, wherein said compound of formula (II) is prepared through the following steps, The compound of formula (II) is obtained by catalytic oxidation of the compound of formula (I) under the action of a chiral base catalyst. 4. the preparation method as described in any one of claim 2-3, is characterized in that, R ₁ and R ₂ are independently selected from the following groups optionally substituted: C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, phenyl, phenyl C _1-4 alkane base, C _1-4 alkylcarbonyl, phenylcarbonyl, C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl C _1-4 alkylsulfonyl or (C _1-4 alkyl) _x (benzene Base) _y Si, the substituent is selected from one or more halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy or halogenated C _1-4 alkoxy base; _The R2 group is the residue of a hydroxyl activator; _R and R _are each independently ^selected from hydrogen, phenyl, benzyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, or _Oxazolyl , and _R3 and R4 are not hydrogen at the same time, Q is selected from fluorine, chlorine, hydroxyl, amino, methyl, ethyl, isopropyl, tert ^- butyl, methoxy, ethoxy or trifluoromethyl; q is selected from 1, 2 or 3; n is selected from 2 or 3; x and y are independently selected from integers from 0 to 3, and the sum of x and y is 3. 5. preparation method as claimed in claim 4, is characterized in that, R ₁ is selected from the following groups optionally substituted: phenyl, phenyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, phenylcarbonyl, benzenesulfonyl, phenyl C _1-4 alkylsulfonyl or (C _1-4 alkyl) _x (phenyl) _y Si, the substituents are selected from one or more halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, methoxy, ethoxy, propoxy, tert-butoxy, halomethoxy or haloethoxy substitution; R is selected from the following groups optionally substituted _: C _1-4 alkylcarbonyl, phenylcarbonyl, C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl C _1-4 alkylsulfonyl, The substituent is selected from one or more of halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, methoxy, ethoxy, propoxy radical, tert-butoxy, halomethoxy or haloethoxy; x and y are independently selected from integers from 0 to 3, and the sum of x and y is 3. 6. preparation method as claimed in claim 5, is characterized in that, R is selected from the following groups optionally substituted: phenyl, benzyl, ethoxymethyl, propoxymethyl, tert _- butoxymethyl, phenylcarbonyl, benzenesulfonyl, phenylmethylsulfonyl , Et ₃ Si, i-Pr ₃ Si, t-BuMe ₂ Si or t-BuPh ₂ Si, the substituents are selected from one or more fluorine, chlorine, methyl, ethyl, propyl, isopropyl , tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy or trifluoromethoxy; R is selected from the following groups optionally substituted _: formyl, acetyl, phenylcarbonyl, methylsulfonyl, ethylsulfonyl, benzenesulfonyl or benzenemethylsulfonyl, and the substituents are selected from one or more fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy or trifluoromethoxy. 7. The preparation method according to any one of claims 1-3, characterized in that it comprises the steps of: Step A: Add the chiral base catalyst, oxidant and/or pro-oxidant and base into the mixture of water and organic solvent, lower the temperature, add the compound of formula (I), keep the temperature for reaction, and obtain the compound of formula (II) after treatment. Step B-1: adding a hydroxyl activator to the mixture of the compound of formula (II), base and organic solvent, and then reacting under certain conditions to obtain (III) after treatment; Step B-2: dissolving the compound of formula (III) and compound of formula (IV) in an organic solvent, heating and reacting under stirring conditions, and obtaining the compound of formula (V) after treatment; In step B-3: dissolving the compound of formula (V) in an organic solvent, cooling down with stirring, then adding an aqueous solution of an oxidizing agent, reacting under certain conditions, and obtaining the compound of formula (VI) after treatment; Step C: adding the hydroxyl activator to the mixture of the compound of formula (VI), alkali and organic solvent, and then reacting at room temperature until the reaction is completed, and the compound of formula (VII) is obtained after treatment. 8. The preparation method according to claim 7, wherein the cooling temperature in step A is preferably -25°C to 10°C, the reaction time is preferably 4h to 15h, and the molar ratio of the compound of formula (I) to the base is preferably 1:1 ～1: 10; It is preferred that oxidizing agent is selected from catalytic amount, and the mol ratio of formula (I) compound and prooxidant is preferably 1: 1～1: 10; The mol ratio of formula (I) compound and chiral base catalyst is preferably 50:1～120:1; the hydroxyl activator in step B-1 is preferably added to the mixed solution at a temperature of -25°C to 20°C, the reaction temperature is preferably -10°C to 10°C, and the reaction time is preferably 0.5h ～2h, the molar ratio of formula (II) compound and base is preferably 1: 0.5～1:5; The molar ratio of formula (II) compound and hydroxyl activator is preferably 1:1～1:3; In step B-2 The reaction temperature is preferably 50°C to 100°C, the reaction time is preferably 1h to 10h, and the molar ratio of the compound of formula (III) to the compound of formula (IV) is preferably 1:1 to 1:5; the cooling in step B-3 The temperature is preferably -20°C to 0°C, the reaction temperature is preferably -10°C to 10°C, the reaction time is preferably 0.1h to 2h, and the molar ratio of the compound of formula (V) to the oxidizing agent is preferably 1:0.5 to 1:5; The reaction temperature of step C is preferably carried out at -25°C to 20°C, the molar ratio of the compound of formula (VI) to the base is preferably 1:1 to 1:6; the molar ratio of the compound of formula (VI) to the hydroxyl activator is preferably 1 :1～1:3. 9. preparation method as claimed in claim 8, is characterized in that, In each step, the organic solvents are independently selected from aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, glycol derivatives, phenolic At least one of nitriles, amides, sulfones, sulfoxides, heteroaromatics, and mixtures thereof, wherein the aromatic hydrocarbon solvent is selected from at least one of benzene, toluene, and xylene, and the aliphatic hydrocarbon The solvent is selected from at least one of pentane, hexane, heptane and octane, the alicyclic hydrocarbon solvent is selected from at least one of cyclopentane and cyclohexane, and the halogenated hydrocarbon solvent is selected from methylene chloride , at least one of chloroform, fluorobenzene and dichlorobenzene, the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, tert-hexanol, benzyl alcohol, ethylene glycol and glycerin At least one ether solvent is selected from at least one of tetrahydrofuran, ether, methyl tert-butyl ether and propylene oxide, and the ester solvent is selected from methyl acetate, ethyl acetate, dimethyl phthalate and at least one of propyl acetate, the ketone solvent is selected from at least one of acetone, methyl butyl ketone and methyl isobutyl ketone, and the glycol derivative solvent is selected from ethylene glycol monomethyl ether, At least one of ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether, the phenolic solvent is selected from at least one of phenol and p-cresol, and the nitrile solvent At least one selected from acetonitrile and propionitrile, the amide solvent selected from at least one of N,N-dimethylformamide and N,N-dimethylacetamide, the sulfone solvent selected from dimethyl sulfone , at least one of phenylethyl sulfone, diethyl sulfone, diphenyl sulfone and sulfolane, the sulfoxide solvent is selected from at least one of dimethyl sulfoxide, diethyl sulfoxide and benzyl sulfoxide, hetero Aromatic solvents are selected from pyridine; In each step, the bases are independently selected from at least one of organic bases and inorganic bases, and the inorganic bases are independently selected from sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, lithium hydroxide , sodium hydroxide, potassium hydroxide, cesium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide and ammonia water; The organic bases are independently selected from at least one of alkali metal salts of alcohols, alkyl metal lithium compounds, amino metal lithium compounds and amine compounds, and the alkali metal salts of alcohols are selected from tert-butanol At least one of lithium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, the alkyl metal lithium compound is selected from at least one of butyllithium and phenyllithium , the amino metal lithium compound is selected from at least one of lithium diisopropylamide and lithium hexamethyldisilamide, and the amine compound is selected from fatty amines, such as N, N-diisopropyl ethyl At least one of amine, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, ethylenediamine, isopropylamine, dibenzylamine, tert-butylamine and hexamethylenediamine; alcohol amines, such as monoethanolamine, di At least one of isopropanolamine and N,N-diethylethanolamine, amides such as formamide, acetamide, acrylamide, colchicine, camptothecin, N,N-dimethylformamide and At least one of dimethylacetamide, alicyclic amines, such as at least one of cyclohexylamine, diethylenetriamine, hexamethylenetetramine, morpholine and piperazine, aromatic amines, Such as at least one of aniline, diphenylamine, benzidine, o-phenylenediamine, p-phenylenediamine, p-methylaniline, p-chloroaniline, m-ethoxyaniline and m-nitroaniline, naphthalene-based amines, such as At least one of 1-naphthylamine, 2-naphthylamine, Krafft acid, Turbic acid, R acid, K acid and naphthalene diamine, polyethyleneimine, hydroxylamine; preferably fatty amines, such as N, N- At least one of diisopropylethylamine, dimethylamine, diethylamine, triethylamine and hexamethylenediamine; In each step, the oxidizing agent or pro-oxidizing agent is independently selected from at least one of non-metal elemental oxidizing agent, metal ion-containing oxidizing agent, acidic oxidizing agent and peroxide oxidizing agent; 1) The non-metal elemental oxidant is selected from at least one of oxygen, chlorine, bromine, iodine, and ozone; 2) The metal ion-containing oxidizing agent is selected from at least one of manganese compounds, chromium compounds, osmium compounds, lead compounds, iron compounds, and cerium compounds; and the manganese compounds are selected from potassium permanganate and manganese dioxide Described chromium compound is selected from at least one in sodium dichromate, potassium dichromate, chromium trioxide; Described osmium compound is selected from potassium osmate (VI) dihydrate, osmium tetroxide at least one of; the lead compound is selected from lead tetraacetate; the iron compound is selected from at least one of potassium ferricyanide, ferric chloride, ferric nitrate; the cerium compound is selected from cerium nitrate At least one of ammonium and cerium oxide; 3) The oxyacid oxidant is selected from at least one of concentrated sulfuric acid, concentrated nitric acid, periodic acid, hypochlorous acid, and perchloric acid; 4) The peroxide oxidant is selected from at least one of inorganic peroxides or organic peroxygen compounds; the inorganic peroxide is selected from hydrogen peroxide, sodium peroxide, potassium peroxide, calcium peroxide, At least one of zinc peroxide and potassium monopersulfate; the organic peroxy compound is selected from peroxyalcohol, peroxyether, diacyl peroxide, peroxyacid, peroxyester, peroxycarbonate and at least one of ketone peroxides; the peroxide alcohol is selected from at least one of peroxyethanol, tert-butanol peroxide, and isopropanol peroxide; the peroxide ether is selected from peroxyethyl ether , at least one of di-tert-butyl peroxide, isopropyl peroxide, t-butyl peroxide; the diacyl peroxide is selected from benzoyl peroxide, diisobutyryl peroxide , two-(2-ethylhexanoyl) peroxide, at least one of diacetyl peroxide; said peroxyacid is selected from peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, m-chloroperoxy At least one of benzoic acid; the peroxyester is selected from tert-butyl peroxyacetate, tert-butyl peroxytrifluoroacetate, tert-amyl perbenzoate, tert-butyl perbenzoate, tert-butyl peroctoate , at least one of tert-amyl peroctoate; the peroxycarbonate is selected from diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, di(-phenoxyethyl) peroxydicarbonate At least one of esters; the ketone peroxide is selected from at least one of dimethyl ketone peroxide, methyl ethyl ketone peroxide, cyclohexanone peroxide, acetone peroxide, butanone peroxide; The chiral base catalyst is selected from quinine, quinine monohydrochloride dihydrate, cinchonine, cinchonidine, dihydroquinine, quinidine, dihydroquinidine, hydrogenated quinine 1,4 - at least one of (2,3-naphthyridine) diether, hydroquinidine 1,4-(2,3-naphthyridine) diether and any derivative thereof. 10. The preparation method as claimed in claim 9, characterized in that, In step A, the chiral base catalyst, metal ion-containing oxidant and/or co-oxidant, and inorganic base are added to the mixed solution of water and alcohol, the temperature is lowered to -5°C to 5°C, the compound of formula (I) is added, and the temperature is maintained for reaction 6h～10h, after treatment, the compound of formula (II) is obtained; preferably the molar ratio of the compound of formula (I) to the inorganic base is 1:2～1:5; the preferred metal ion-containing oxidizing agent is a catalytic amount of osmium compound containing The pro-oxidant of metal ion is iron compound, and the mol ratio of formula (I) compound and pro-oxidant is 1: 1～1: 5; Preferably the mol ratio of formula (I) compound and chiral base catalyst is 80: 1～ 100:1; In step B-1, under the condition of -15°C to -5°C, add sulfonyl chloride to the mixture of the compound of formula (II), aliphatic amine, and halogenated hydrocarbon solvent, and then under the condition of -5°C to 5°C Down reaction 0.5h～1.5h, formula (III) compound is obtained after treatment; Preferably the molar ratio of formula (II) compound and aliphatic amine is 1:1～1:2; Preferably formula (II) compound and The mol ratio of sulfonyl chloride is 1: 1～1: 1.5; In step B-2, the compound of formula (III) and compound IV are dissolved in an alcoholic solvent, heated to 60°C-90°C under stirring conditions for 2h-5h, and the compound of formula (V) is obtained after treatment; preferably The molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1～1:2.5; In step B-3, dissolve the compound of formula (V) in a nitrile solvent, stir and cool down to -15°C to -5°C, add an aqueous solution containing a metal ion oxidant, and react at -5°C to 5°C for 0.1 h～1.5h, the formula (VI) compound is obtained after treatment; preferably the molar ratio of the formula (I) compound and the metal ion-containing oxidizing agent is 1:1～1:3; In step C, under the condition of -5°C to 5°C, sulfonyl chloride is added to the mixed solution of the compound of formula (VI), aliphatic amine, and halogenated hydrocarbon solvent, and then react at room temperature until the reaction is completed, and after treatment, the formula (VII) compound; It is preferred that the mol ratio of formula (VI) compound and aliphatic amine is 1: 2～1: 4; It is preferred that the mol ratio of formula (VI) compound and sulfonyl chloride is 1: 1～1: 2 . 11. The preparation method as claimed in claim 10, characterized in that, Step A further includes the following steps: after the reaction is completed, adding a reducing inorganic salt to quench the reaction, extracting with an ester solvent, washing the organic phase with dilute acid and saturated aqueous sodium chloride solution, drying, and concentrating to obtain the compound of formula (II); Step B-1 further includes the following steps: ① After the reaction is completed, add an appropriate amount of water and stir for about 0.5-1h. After standing for stratification, the organic phase is washed with dilute acid, dilute alkali, and saturated aqueous sodium chloride solution, dried, and concentrated get the product; Step B-2 further includes the following steps: ① After the reaction is completed, concentrate the reaction solution, add a halogenated hydrocarbon solvent to dissolve the product, wash with dilute acid, dilute alkali, and saturated aqueous sodium chloride solution successively, dry, and concentrate to obtain a crude product; ② Adding one or more poor solvents of the compound of formula (V) to wash and purify the product; Step B-3 further includes the following steps: ① After the reaction is completed, adding a reducing inorganic salt to quench the reaction, concentrating the reaction solution, adding a mixed solution of halogenated hydrocarbon and water and stirring, filtering, and standing for stratification to obtain an organic phase; ②Salt formation and purification, the organic phase is extracted with dilute acid, the obtained aqueous phase is adjusted to pH = 8-11 with an inorganic base, and then extracted with an ester solvent, the obtained organic phase is sequentially washed with saturated saline, dried, and concentrated to obtain the product; preferably The resulting product can be subjected to multiple salt-forming purifications; Step C further includes the following steps: ①After the reaction is completed, add an appropriate amount of water and stir for about 0.5-1h. After standing for stratification, the organic phase is washed with saturated brine, dried, and concentrated to obtain a crude product; The poor solvent of the compound of formula (VII) is purified by recrystallization to obtain the product. 12. The preparation method as claimed in claim 11, characterized in that, Described poor solvent is selected from one or more in aliphatic hydrocarbon solvent, alicyclic hydrocarbon solvent, ester solvent; Aliphatic hydrocarbon solvent is selected from at least one in pentane, hexane, heptane and octane The alicyclic hydrocarbon solvent is selected from at least one of cyclopentane and cyclohexane, and the ester solvent is selected from at least one of methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate kind; The dilute acid is selected from at least one of 0.1%-5% dilute hydrochloric acid, dilute nitric acid, and dilute sulfuric acid; Described dilute alkali or inorganic alkali is selected from at least one in sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate; The reducing inorganic salt is at least one selected from sodium sulfite, sodium thiosulfate or sodium dithionite. 13. The method for preparing the compound of formula (VII) according to any one of claims 1-12, characterized in that it comprises the following steps: (1) Dissolve a catalytic amount of potassium osmate dihydrate, potassium ferricyanide, (DHQ) ₂ PHAL, and potassium carbonate in a mixture of water and tert-butanol, cool to 0°C, and add the compound of formula (I') tert-butanol solution, the molar ratio of formula (I') compound to potassium ferricyanide is 1:3-1:3.5, and the molar ratio of formula (I') compound to (DHQ) ₂ PHAL is 1:90-1 : 100, the mol ratio of formula (I') compound and salt of wormwood is 1: 3-1: 3.5, keeps 0 ℃ of reaction 8 hours, then adds sodium sulfite to quench reaction, ethyl acetate extracts, and organic phase is used successively with 0.5% Wash with dilute hydrochloric acid and saturated sodium chloride, dry, and concentrate to obtain the compound of formula (II'); (2) Dissolve the compound of formula (II') and triethylamine in dichloromethane, lower the temperature to -10°C, add the methylene chloride solution of methanesulfonyl chloride, the moles of the compound of formula (II') and methanesulfonyl chloride Ratio is 1: 1, and the mol ratio of formula (II) compound and triethylamine is 1: 1～1: 1.5, reacts 1～1.5h under 0 ℃ then, and reaction completes; The phase was washed successively with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, dried and concentrated to obtain the compound of formula (III'); (3) Dissolve the compound of formula (III') and compound IV' in ethanol solvent, the molar ratio of compound of formula (III') and compound IV' is 1:2, heat and reflux under stirring for 3-4h, evaporate under reduced pressure Remove the solvent, add dichloromethane, wash with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated aqueous sodium chloride successively, dry, concentrate, add a mixed solvent of n-heptane and ethyl acetate (n-heptane: ethyl acetate Ester=10:1), stirred to precipitate a solid, and filtered to obtain the compound of formula (V'); (4) Dissolve the compound of formula (V') in acetonitrile solvent, stir and cool down to -10°C, add the aqueous solution of ammonium cerium nitrate, the molar ratio of compound of formula (V') to ammonium cerium nitrate is 1:2-1: 2.5, react at 0°C for 0.5h, add saturated sodium sulfite to quench the reaction, evaporate the solvent under reduced pressure, add a mixture of dichloromethane and water and stir, filter with diatomaceous earth, and stand to separate to obtain an organic phase; The organic phase was extracted with 2% dilute hydrochloric acid, the resulting aqueous phase was adjusted to pH=9-10 with sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and then added with 1 -1.5eq dilute hydrochloric acid/1,4-dioxane solution, the product is separated out; (5) Under the condition of 0°C, add methanesulfonyl chloride to the dichloromethane solution of the compound of formula (VI') and triethylamine, and the molar ratio of the compound of formula (VI') to triethylamine is 1:3 ; The molar ratio of the compound of formula (VI') to sulfonyl chloride is 1:1～1:1.5, reacted at room temperature for 8h, added water and washed, left to stand for layering, the organic phase was washed with saturated brine, dried, and concentrated to obtain a crude product; The crude product was dissolved in n-heptane solution, heated to 60°C and stirred for a certain period of time, then the supernatant was cooled to 25°C, solid precipitated, filtered, and dried to obtain the compound of formula (VII'), 14. the method for preparing following formula (IX) or its salt, it is characterized in that, the formula (VII) compound prepared by the preparation method of the formula (VII) compound described in claim 1 reacts with formula (VIII), prepares A compound of formula (IX) or a salt thereof, R ₃ , R ₄ , q and n are as defined in claim 1; R ₅ and R ₆ are each independently selected from the following group: amino, cyano, and C _1-6 alkyl optionally substituted by 1 to 3 Q ² , C _1-4 alkoxy C _{1- 3} alkyl, C _2-6 alkenyl or C _2-6 alkynyl, Q ² is selected from the following group of groups: halogen, hydroxyl, amino, cyano, carboxyl or C _1-6 alkoxy; R is selected from C _1-6 alkyl, C _3-8 cycloalkyl C _0-6 alkyl, 3-8 membered heterocyclyl C _0-6 alkyl optionally substituted by ¹ to 3 Q ³ or 5-6 membered heteroaryl C _0-6 alkyl, Q ³ is selected from the following group: halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, and 1 to 3 C _1-6 alkyl or C _1-6 alkoxy substituted by halogen; R ₈ is selected from the following group of groups: hydrogen, halogen, hydroxyl, cyano, nitro or C _1-6 alkyl amido. 15. preparation method as claimed in claim 14, is characterized in that, _R and R are each independently selected from hydrogen, phenyl optionally substituted by ¹ to ₃ Q, benzyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl or _Oxazolyl , and _R3 and R4 are not hydrogen at the same time, ^Q1 is selected from fluorine, chlorine, hydroxyl, amino, methyl, trifluoromethyl or methoxy; R and R are each independently selected from C _1-4 alkyl optionally substituted by ₁ to ₃ Q ² selected from fluorine, chlorine, amino, methoxy or ethoxy ^; R is selected from C _1-4 alkyl optionally substituted by ^{1 to 3 Q 3 selected} _from fluorine, chlorine, methyl, methoxy; R _is selected from hydrogen, chlorine or nitro; q is selected from 0, 1, 2 or 3; n is selected from 1, 2 or 3. 16. The preparation method according to claim 15, characterized in that, the compound of formula (IX) or its salt has the structure shown below: