CN108689904B - Preparation method and application of chiral heterocyclic tertiary alcohol intermediate - Google Patents

Preparation method and application of chiral heterocyclic tertiary alcohol intermediate Download PDF

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CN108689904B
CN108689904B CN201710255141.1A CN201710255141A CN108689904B CN 108689904 B CN108689904 B CN 108689904B CN 201710255141 A CN201710255141 A CN 201710255141A CN 108689904 B CN108689904 B CN 108689904B
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CN108689904A (en
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朱宁
王海波
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Xuanzhu Biopharmaceutical Co Ltd
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention provides a preparation method of a chiral heterocyclic tertiary alcohol intermediate and a method for preparing a1, 4-dihydropyridine-3, 5-dicarboxylate derivative by using the same. The method of the invention has the advantages of simple and controllable reaction conditions and purification conditions, reduced production cost, improved reaction yield, and suitability for industrial expanded production. Further, according to the process of the present invention, a1, 4-dihydropyridine-3, 5-dicarboxylate derivative can be obtained with high purity and high yield.

Description

Preparation method and application of chiral heterocyclic tertiary alcohol intermediate
Technical Field
The invention belongs to the field of chemical engineering or medicine, and particularly relates to a preparation method of a chiral heterocyclic tertiary alcohol intermediate and a method for preparing a1, 4-dihydropyridine-3, 5-dicarboxylate derivative by using the same.
Background
Dihydropyridine calcium channel blockers, which are drugs for treating cardiovascular diseases since the 70 s of the 20 th century, selectively block Ca in L-type or/and T-type calcium channel by binding to protein receptors2+The internal flow reduces the concentration of Ca2+ in cells, thereby changing the cardiovascular function and playing a role in protecting the heart and the cerebral vessels. The dihydropyridine calcium channel blocker has high blood vessel selectivity, clear blood pressure reducing effect and wide application range, is widely applied clinically and becomes the first choice of blood pressure reducing medicines. The L-type and T-type double calcium channel blockers have the functions of reducing blood pressure, slowing down tachycardia and reducing edema, and have the functions of protecting heart and kidney (Hypertension.2009; 53: 592-594).
Patent application WO2012146067A1 discloses 1, 4-dihydropyridine-3, 5-dicarboxylic acid ester compounds which have a significant antihypertensive effect, can maintain a long-acting antihypertensive effect, and have L-type and T-type dual calcium channel blocking effects, and simultaneously discloses a preparation method of the compounds, wherein example compound 16 has a good antihypertensive effect, and the specific structure is as follows:
Figure BSA0000143440460000011
an important medical intermediate involved in the reaction process is chiral tertiary alcohol pyrrolidine intermediate (VII), the original preparation method is obtained by chiral resolution, the yield is only 16%, the yield of the compound (IX) obtained by further reaction with the intermediate (VIII) is also only 56%, and the preparation method has low yield and is not suitable for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of a medical intermediate, namely a chiral heterocyclic tertiary alcohol intermediate, and further provide a method for preparing a1, 4-dihydropyridine-3, 5-dicarboxylate derivative by using the intermediate obtained by the method.
Specifically, the invention provides the following technical scheme:
1. a process for the preparation of a compound of the formula (VII),
Figure BSA0000143440460000021
the method comprises the following steps: reacting a compound of formula (VI) with a hydroxy activator under basic conditions to give a compound of formula (VII),
Figure BSA0000143440460000022
wherein the hydroxyl activator is selected from one or more of the following: acyl chloride, sulfonyl chloride, anhydride, alcohol, phenol or silane protecting agent, wherein the hydroxyl activating agent can form ester, sulfonate, ether or silicon ether with hydroxyl;
R3、R4each independently selected from the group consisting of: hydrogen, C1-6Alkyl, optionally substituted by 1 to 3Q1Substituted aryl radicals C0-6Alkyl, 3-8 membered cycloalkyl C0-6Alkyl, 3-8 membered heterocyclyl C0-6Alkyl, 5-6 membered heteroaryl C0-6Alkyl, or R3And R4Together form a 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, which is optionally substituted with 1 to 3Q1Substituted, said Q1Selected from the group consisting of: halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or C1-6An alkylamide group;
q is selected from 0, 1, 2 or 3;
n is selected from an integer from 1 to 5.
2. A process for the preparation of a compound of formula (IX) and salts thereof, the compound of formula (VII) prepared by the process for the preparation of a compound of formula (VII) described in 1 is reacted with a compound of formula (VIII) to produce a compound of formula (IX),
Figure BSA0000143440460000023
R3、R4q and n are as defined for 1;
R5and R6Each independently selected from the group consisting of: amino, cyano, and optionally substituted by 1 to 3Q2Substituted C1-6Alkyl radical, C1-4Alkoxy radical C1-3Alkyl radical, C2-6Alkenyl or C2-6Alkynyl, Q2Selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy or C1-6An alkoxy group;
R7selected from optionally substituted 1 to 3Q3Substituted C1-6Alkyl radical, C3-8Cycloalkyl radical C0-6Alkyl, 3-8 membered heterocyclyl C0-6Alkyl or 5-6 membered heteroaryl C0-6Alkyl radical, Q3Selected from the group consisting of: halogen, hydroxy, amino, C1-6Alkyl radical, C1-6Alkoxy, and C substituted by 1 to 3 halogens1-6Alkyl or C1-6An alkoxy group;
R8selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, nitro or C1-6An alkylamide group.
Effects of the invention
By the method, chiral heterocyclic tertiary alcohol intermediates, especially chiral pyrrolidine tertiary alcohol, can be obtained with high selectivity and high yield, so that the yield of the 1, 4-dihydropyridine-3, 5-dicarboxylic ester derivative is improved. In addition, the method of the invention has the advantages of simple and controllable reaction conditions and purification conditions, reduced production cost, improved reaction yield and suitability for industrial expanded production. Further, according to the process of the present invention, a1, 4-dihydropyridine-3, 5-dicarboxylate derivative can be obtained with high purity and high yield.
Detailed Description
[ DEFINITIONS ]
In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula or chemical reaction formula is the standard.
In the present application, unless otherwise indicated, scientific and technical terms used herein have the meanings that are commonly understood by those of skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. Preferably a fluorine atom or a chlorine atom.
"C" according to the invention1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, preferably C1-4Alkyl radicals, e.g. C2-4Alkyl radical, C2-3 alkyl radical, C1-3Alkyl radical, C1-2An alkyl group; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. Said "C" of the present invention1-4Alkyl "means the above examples containing 1 to 4 carbon atoms.
"C" according to the invention0-6Alkyl "represents a linear or branched alkyl group having 0 to 6 carbon atoms, and when the carbon number is 0, represents a bond; preferably C0-4Alkyl radical, C0-3Alkyl radicalMost preferably C0-2An alkyl group.
The 3-8 membered cycloalkyl group in the present invention represents a saturated or partially saturated cyclic group having 3 to 8 carbon atoms and having no aromaticity, and includes "3-8 membered saturated cycloalkyl group" and "3-8 membered partially saturated cycloalkyl group"; for example, a 3-6 membered cycloalkyl group, etc., more preferably a 5-6 membered cycloalkyl group; examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl, and the like.
"C" according to the invention2-6The alkynyl group means a straight chain or branched chain having 2 to 6 carbon atoms and a triple bond, and includes a cyclic alkynyl group, preferably C2-4Alkynyl groups such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl and the like.
The "halo C" of the present invention1-6Alkyl "means one or more" halogen "substituted" C1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "halogen" and "C1-6Alkyl "is as defined above. The "halo C" of the present invention1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.
"C" according to the invention1-6Alkoxy group "," C1-6Alkylamido "is independently" C1-6alkyl-O- "group," C1-6alkyl-C (O) -NH- "group, wherein" C1-6Alkyl "is as defined above. Preferably "C1-4Alkoxy group "," C1-4Alkylamido ".
"C" according to the invention1-4Alkoxy group "," C1-4Alkylamido "is independently" C1-4alkyl-O- "group、“C1-4alkyl-C (O) -NH- "group, wherein" C1-4Alkyl "is as defined above.
The term "3-8 membered heterocyclic group" as used herein means a 3-8 membered saturated or partially saturated cyclic group containing one or more, the same or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein any one of the ring atoms of the heterocyclic group may be oxo-substituted, for example, a 3-6 membered heterocyclic group, etc., more preferably a 5-6 membered heterocyclic group; examples include, but are not limited to, oxiranyl, thietanyl, aziridinyl, oxetanyl, azetidine, thietanyl, oxetanyl, 1, 2-dioxanyl, 1, 2-diazacyclobutyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, oxazolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1, 4-dioxanyl, 1, 3-oxathianyl, 4, 5-dihydroimidazolyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, 4, 5-dihydrothiazolyl, piperidonyl, tetrahydropyridinonyl, dihydropiperidonyl, 4, 5-dihydrooxazolyl, azetidinonyl, 4, 5-dihydrooxazolyl, azetidinyl, and azetidinyl, 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-dioxadienyl, 1, 4-dithiacyclohexadienyl, 1, 4-oxathiadienyl, 1, 4-dioxacyclooctatrienyl, azacycloheptatrienyl, 1, 2-diazacycloheptyltrienyl, 1, 3-diazacycloheptyltrienyl, 1, 4-diazacyclocycloheptatrienyl, azocyclotetraenyl, 1, 4-dihydro-1, 4-diazacyclooctatrienyl, and the like.
The "aryl" refers to a 6-10 membered monocyclic or bicyclic aromatic hydrocarbon ring group, such as phenyl, naphthyl, and the like.
The 5-6 membered heteroaryl group in the present invention refers to a cyclic group having aromatic properties and containing at least one heteroatom, wherein the total number of ring atoms is 5-6, the heteroatom is selected from nitrogen, oxygen and sulfur, any ring atom of the heterocyclic group may be oxo, and examples thereof include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, triazinyl, tetrazinyl, pyridyl, and the like.
The hydroxyl activating reagent is a reagent capable of reacting with hydroxyl to form an easy-leaving group, and the formed easy-leaving group can perform nucleophilic reaction with a nucleophilic reagent. The hydroxyl activator includes, but is not limited to, one or more of the following: acyl chloride, sulfonyl chloride, acid anhydride, alcohol, phenol, a halogenating agent and a silane protective agent; the acyl chloride and the anhydride can form ester with hydroxyl; the sulfonyl chloride can form a sulfonic acid ester with a hydroxyl; the alcohol or phenol may form an ether with a hydroxyl group; the halogen in the halogenating agent can replace hydroxyl to form halogenated hydrocarbon; the silane protective agent can form silicon ether with hydroxyl; the term "hydroxyl activating agent" includes aliphatic, alicyclic and aromatic agents, and any activating agent capable of performing the function of the present invention is included in the scope of the present invention.
The organic solvent is at least one selected from aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, glycol derivatives, phenols, nitriles, amides, sulfones, sulfoxides, heteroaromatic hydrocarbons 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, 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 dichloromethane, chloroform, chlorobenzene and dichlorobenzene, the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, tert-hexanol, benzyl alcohol, ethylene glycol and glycerol, the ether solvent is 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, the ketone solvent is selected from at least one of acetone, methyl butyl ketone and methyl isobutyl ketone, the glycol derivative solvent is selected from ethylene glycol monomethyl ether, and propylene oxide, the ester solvent is selected from at least one of methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate, the ketone solvent is selected from at least one of acetone, methyl butyl ketone, methyl glycol monomethyl ether, ethylene glycol monomethyl ether, and propylene glycol monomethyl ether, The solvent comprises at least one of ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether, a phenolic solvent is selected from at least one of phenol and p-cresol, a nitrile solvent is selected from at least one of acetonitrile and propionitrile, an amide solvent is selected from at least one of N, N-dimethylformamide and N, N-dimethylacetamide, a sulfone solvent is selected from at least one of dimethyl sulfone, phenethylsulfone, diethylsulfone, diphenylsulfone and sulfolane, a sulfoxide solvent is selected from at least one of dimethyl sulfoxide, diethylsulfoxide and benzyl sulfoxide, and a heteroaromatic hydrocarbon solvent is selected from pyridine.
The "base" in the present invention is independently selected from at least one of an organic base and an inorganic base.
The "inorganic base" of the present invention refers to an inorganic substance which can give a lone pair of electrons and does not contain carbon element, and is a compound generally generated by metal ions or ammonium ions and hydroxide ions, and specific examples include but are not limited to: sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, ammonium hydroxide, lithium hydroxide as an alkali metal hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide as an alkaline earth metal hydroxide, magnesium hydroxide, barium hydroxide, ammonia water, and the like.
The "organic base" refers to an organic compound having a basic property. The organic base is divided into an alkali metal salt of alcohol selected from at least one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, an alkali metal lithium compound selected from at least one of butyllithium and phenyllithium, an alkali metal lithium compound selected from at least one of lithium diisopropylamide and lithium hexamethyldisilazide, and an amine compound selected from at least one of aliphatic amines such as N, N-diisopropylethylamine, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, ethylenediamine, isopropylamine, dibenzylamine, tert-butylamine and hexyldiamine; alkanolamines, such as at least one of monoethanolamine, diisopropanolamine and N, N-diethylethanolamine, amides, such as at least one of formamide, acetamide, acrylamide, colchicine, camptothecin, N-dimethylformamide and 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-methylaniline, p-chloroaniline, m-ethoxyaniline and m-nitroaniline, naphthalenic amines, such as at least one of 1-naphthylamine, 2-naphthylamine, clavulanic acid, pipecolic acid, R-acid, K-acid and naphthyldiamine, polyethyleneimine, hydroxylamine; preferably aliphatic amines such as at least one of N, N-diisopropylethylamine, dimethylamine, diethylamine, triethylamine and hexamethylenediamine;
the "oxidant" in the present invention means a substance that obtains electrons in a redox reaction or a substance that allows another substance to obtain oxygen or to remove hydrogen; the "pro-oxidant" can be an oxidant per se, or can be an auxiliary component for promoting the action of the oxidant; the "oxidant" or "pro-oxidant" can be divided into non-metal elemental oxidant, oxidant containing metal ions, acidic oxidant and peroxide oxidant;
1) the non-metallic elemental oxidant is selected from at least one of oxygen, chlorine, bromine, iodine and ozone;
2) the metal ion-containing oxidant is at least one selected from manganese compounds, chromium compounds, osmium compounds, lead compounds, iron compounds and cerium compounds; the manganese compound is selected from at least one of potassium permanganate and manganese dioxide; the chromium compound is selected from at least one of sodium dichromate, potassium dichromate and chromium trioxide; the osmium compound is selected from at least one of potassium osmate (VI) dihydrate and osmium tetroxide; the lead compound is selected from lead tetraacetate; the iron compound is at least one selected from potassium ferricyanide, ferric trichloride and ferric nitrate; the cerium compound is at least one of ammonium cerium nitrate and cerium oxide; the metal ion-containing oxidizing agent is not limited to the above specific examples, and any metal ion-containing and oxidizing compound is included in the scope of the present invention.
3) The oxygen acid oxidant is at least one selected from concentrated sulfuric acid, concentrated nitric acid, periodic acid, hypochlorous acid and perchloric acid; the oxoacid oxidizing agent is not limited to the above-mentioned specific examples, and any acid having a certain oxidizing property is included in the scope of the present invention.
4) The peroxide oxidant is selected from inorganic peroxide or organic peroxide compound; the inorganic peroxide is at least one of hydrogen peroxide, sodium peroxide, potassium peroxide, calcium peroxide, zinc peroxide and potassium peroxymonosulfate; the organic peroxide compound is selected from the group consisting of a peroxyalcohol (ROOH), a peroxyether (ROOR '), a diacylperoxide (RCOOCR'), a peroxyacid, a peroxyester (RCOOOR '), a peroxycarbonate (ROOOCOR'), and a ketone peroxide [ R2C(OOH)2]At least one of; r or R' represents any substituent; the peroxyalcohol is selected from at least one of peroxyethanol, tert-butyl peroxide and isopropanol peroxide; the peroxide ether is selected from at least one of peroxy ethyl ether, peroxy di-tert-butyl ether, peroxy isopropyl ether and peroxy tert-butyl ether; the diacyl peroxide is at least one selected from benzoyl peroxide, diisobutyryl peroxide, bis- (2-ethylhexanoyl) peroxide and diacetyl peroxide; the peroxy acid is at least one selected from the group consisting of peroxyformic acid, peroxyacetic acid, peroxybenzoic acid and m-chloroperoxybenzoic acid; the peroxyester is selected from at least one of tert-butyl peroxyacetate, tert-butyl peroxytrifluoroacetate, tert-amyl perbenzoate, tert-butyl peroctoate and tert-amyl peroctoate; the peroxycarbonate is at least one selected from diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate and bis (-phenoxyethyl) peroxydicarbonate; the ketone peroxide is at least one selected from dimethyl ketone peroxide, methyl ethyl ketone peroxide, cyclohexanone peroxide, acetone peroxide and butanone peroxide; the peroxide oxidizing agent is not limited to the specific examples described above, and any peroxide having an oxidizing property is included in the scope of the present invention.
The chiral base catalyst is selected from at least one 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 any derivatives thereof.
The "room temperature" in the invention means about 20 ℃ to 30 ℃, preferably about 25 ℃.
The "catalytic amount" in the present invention refers to the amount of catalyst commonly used in chemical reactions. For example, there may be less than one equivalent in a chemical reaction.
The poor solvent is a solvent which is insoluble or slightly soluble to a compound in a non-heating state and the solubility of the solvent is gradually increased after heating, and can be one solvent or a mixed solution of a plurality of solvents; the solvent includes water and an organic solvent. The poor solvent of the invention includes but is not limited to one or more of aliphatic hydrocarbon solvent, alicyclic hydrocarbon solvent and ester solvent; the aliphatic hydrocarbon 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 ester solvent is selected from at least one of methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate.
The dilute acid is used for adjusting the pH value of the solution or neutralizing redundant alkali in the solution or salifying a product and the like, and any dilute acid capable of realizing the invention is included in the scope of the invention, and the dilute acid comprises at least one of 0.1-5% of dilute hydrochloric acid, dilute nitric acid and dilute sulfuric acid.
The dilute alkali or inorganic alkali used in the invention is used for adjusting the pH value of the solution or neutralizing redundant acid in the solution or salifying the product, and the like, and any dilute alkali or inorganic alkali capable of realizing the invention is included in the scope of the invention, and the dilute alkali or inorganic alkali comprises at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.
The reducing inorganic salt of the present invention is used for neutralizing the excessive oxidizing agent in the reaction solution without affecting the yield of the product, and any reducing inorganic salt capable of achieving the present invention is included in the scope of the present invention, and includes, but is not limited to, at least one of sodium sulfite, sodium thiosulfate or sodium dithionite.
More particularly, the present invention relates to and the following:
a process for the preparation of a compound of the formula (VII),
Figure BSA0000143440460000081
the method comprises the following steps: reacting a compound of formula (VI) with a hydroxy activator under basic conditions to give a compound of formula (VII),
Figure BSA0000143440460000082
wherein the hydroxyl activator is selected from one or more of the following: acyl chloride, sulfonyl chloride, anhydride, alcohol, phenol or silane protecting agent, wherein the hydroxyl activating agent can form ester, sulfonate, ether or silicon ether with hydroxyl;
R3、R4each independently selected from the group consisting of: hydrogen, C1-6Alkyl, optionally substituted by 1 to 3Q1Substituted aryl radicals C0-6Alkyl, 3-8 membered cycloalkyl C0-6Alkyl, 3-8 membered heterocyclyl C0-6Alkyl, 5-6 membered heteroaryl C0-6Alkyl, or R3And R4Together form a 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, which is optionally substituted with 1 to 3Q1Substituted, said Q1Selected from the group consisting of: halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or C1-6An alkylamide group;
q is selected from 0, 1, 2 or 3;
n is selected from an integer from 1 to 5.
In another embodiment of the present invention, the compound (VI) is prepared from the compound of formula (II) and the compound of formula (IV),
Figure BSA0000143440460000091
the preparation steps comprise:
reacting a compound of formula (II) with a hydroxy activator under basic conditions to form formula (III),
Figure BSA0000143440460000092
wherein R is1、R2Each independently selected from the group consisting of optionally substituted: : c1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, phenyl, 5-6 membered heteroaryl, phenyl C1-6Alkyl, 5-6 membered heteroaryl C1-6Alkyl radical, C1-6Alkylcarbonyl, phenylcarbonyl, 5-6 membered heteroarylcarbonyl, C1-6Alkylsulfonyl, phenylsulfonyl, 5-to 6-membered heteroarylsulfonyl, phenyl C1-6Alkylsulfonyl, 5-6 membered heteroaryl C1-6Alkylsulfonyl or (C)1-6Alkyl) x (phenyl) ySi, said substituents being selected from the group consisting of optionally substituted by one or more halogens, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or halo C1-6An alkoxy group;
said R2The radical is the residue of a hydroxyl activator;
x and y are each independently an integer selected from 0 to 3, and the sum of x and y is 3, wherein (C)1-6C in alkyl) x (phenyl) ySi1-6The alkyl groups may be the same alkyl group or different alkyl groups;
said R3、R4As defined in claim 1;
reacting the compound of formula (III) with the compound of formula IV to obtain the compound of formula (V),
Figure BSA0000143440460000093
removing R of formula (V)1And (c) reacting the compound of formula (VI) with a base to obtain the compound of formula (VI).
In another embodiment of the present invention, the compound of formula (II) is prepared by the following steps,
Figure BSA0000143440460000101
the compound of formula (II) is obtained by catalytic oxidation of the compound of formula (I) under the action of chiral base catalyst.
In another embodiment of the present invention, R1、R2Each independently selected from the group consisting of optionally substituted: c1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, phenyl C1-4Alkyl radical, C1-4Alkylcarbonyl, phenylcarbonyl, C1-4Alkylsulfonyl, phenylsulfonyl, phenyl C1-4Alkylsulfonyl or (C)1-4Alkyl) x (phenyl) ySi, said substituents being selected from one or more of halogen, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy or halo C1-4An alkoxy group;
said R2The group is the residue of a hydroxy activator;
x and y are each independently an integer selected from 0 to 3, and the sum of x and y is 3, wherein (C)1-4C in alkyl) x (phenyl) ySi1-6The alkyl groups may be the same alkyl group or different alkyl groups.
In another embodiment of the invention, R3And R4Each independently selected from hydrogen, optionally substituted with 1 to 3Q1Substituted phenyl, benzyl, pyridyl, pyrimidinyl, furanyl, thienyl, thiazolyl, pyrrolyl, imidazolyl or oxazolyl, and R3And R4When the catalyst is not hydrogen at the same time,
Q1selected from fluorine, chlorine, hydroxyl, 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 invention, n is selected from 2 or 3.
In another embodiment of the invention, R1Selected from the group consisting of optionally substituted: phenyl, phenyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, phenylcarbonyl, phenylsulfonyl, phenyl C1-4Alkylsulfonyl or (C)1-4Alkyl) x (phenyl) ySi, said substituents being selected from one or more halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, methoxy, ethoxy, propoxy, tert-butoxy, halomethoxy or haloethoxy substitution; x and y are each independently an integer selected from 0 to 3, and the sum of x and y is 3.
In another embodiment of the invention, R2Selected from the group consisting of optionally substituted: c1-4Alkylcarbonyl, phenylcarbonyl, C1-4Alkylsulfonyl, phenylsulfonyl, phenyl C1-4Alkylsulfonyl, said substituents 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, R1Selected from the group consisting of optionally substituted: phenyl, benzyl, ethoxymethyl, propoxymethyl, tert-butoxymethyl, phenylcarbonyl, phenylsulfonyl, phenylmethylsulfonyl, Et3Si、i-Pr3Si、t-BuMe2Si or t-BuPh2Si, said substituents being selected from one or more of fluoro, chloro, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy or trifluoromethoxy.
In another embodiment of the present invention, R2Selected from the group consisting of optionally substituted: formyl, acetyl, phenylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or phenylmethylsulfonyl, said substituents being selected from one or more of fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxyEthoxy, propoxy, tert-butoxy or trifluoromethoxy.
In another embodiment of the invention, the compound of formula VII has the structure shown below as formula VII':
Figure BSA0000143440460000111
in another embodiment of the present invention, in step a, the chiral base catalyst, the oxidant and/or the pro-oxidant and the base are added into the mixed solution of water and the organic solvent, the temperature is reduced, the compound of formula (I) is added, the temperature is maintained for reaction, and the compound of formula (II) is obtained after the treatment. Preferably, the temperature of the reduced temperature in the step A is-25 ℃ to 10 ℃. The reaction time is preferably 4 to 15 hours. Preferably, the molar ratio of the compound of formula (I) to the base is 1:1 to 1: 10. Preferably, the oxidant is selected from catalytic amount, and the molar ratio of the compound shown in the formula (I) to the co-oxidant is 1: 1-1: 10. Preferably, the molar ratio of the compound of the formula (I) to the chiral base catalyst is 50: 1-120: 1. In another embodiment of the invention, in the step a, the chiral base catalyst, the oxidant containing metal ions and/or the pro-oxidant, and the inorganic base are added into the mixed solution of water and alcohol, the temperature is reduced to-5 ℃ to 5 ℃, the compound of formula (I) is added, the temperature is maintained for reaction for 6h to 10h, and the compound of formula (II) is obtained after treatment. Preferably, the molar ratio of the compound of formula (I) to the inorganic base is 1:2 to 1: 5. The preferable oxidant containing the metal ions is a catalytic amount of osmium compound, the pro-oxidant containing the metal ions is an iron compound, and the molar ratio of the compound shown in the formula (I) to the pro-oxidant is 1: 1-1: 5. Preferably, the molar ratio of the compound of the formula (I) to the chiral base catalyst is 80: 1-100: 1. In another embodiment of the present invention, step a further comprises the following steps: after the reaction is finished, adding aqueous solution of reducing inorganic salt to quench the reaction, extracting the ester solvent, washing and drying the organic phase by using dilute acid and saturated sodium chloride aqueous solution in turn, and concentrating to obtain the compound shown in the formula (II).
In another embodiment of the present invention, in step B-1, the hydroxy activator is added to a mixture of the compound of formula (II), a base and an organic solvent, and then the mixture is reacted under certain conditions to obtain (III) after treatment. Preferably, the temperature at which the hydroxyl activator is added to the mixture is from-25 ℃ to 20 ℃. The reaction temperature is preferably from-10 ℃ to 10 ℃. The reaction time is preferably 0.5 to 2 hours. Preferably, the molar ratio of the compound of formula (II) to the base is 1:0.5 to 1: 5. Preferably, the molar ratio of the compound of formula (II) to the hydroxy activator is 1:1 to 1:3. In another embodiment of the invention, in step B-1, sulfonyl chloride is added into a mixed solution of the compound of formula (II), aliphatic amine and halogenated hydrocarbon solvent at the temperature of-15 ℃ to-5 ℃, and then the mixture is reacted for 0.5h to 1.5h at the temperature of-5 ℃ to obtain the compound of formula (III) after treatment. Preferably, the molar ratio of the compound of formula (II) to the base is 1:1 to 1:2. Preferably, the molar ratio of the compound of formula (II) to the sulfonyl chloride is 1:1 to 1: 1.5. In another embodiment of the present invention, the step B-1 further comprises the following steps: after the reaction is finished, adding a proper amount of water, stirring for about 0.5-1h, standing for layering, washing the organic phase with dilute acid, dilute alkali and saturated sodium chloride aqueous solution in turn, drying and concentrating to obtain the product. In the preparation step, the selectivity of the hydroxyl activating reagent to different hydroxyl groups can be controlled by controlling the proportion of the fed materials and the reaction temperature.
In another embodiment of the present invention, in step B-2, the compound of formula (III) and the compound of formula (IV) are dissolved in an organic solvent, heated and reacted under stirring to obtain the compound of formula (V). The reaction temperature is preferably 50 ℃ to 100 ℃. The reaction time is preferably 1 to 10 hours. Preferably, the molar ratio of the compound of formula (III) to the compound of formula IV is 1:1 to 1: 5. In another embodiment of the invention, in the step B-2, the compound of formula (III) and the compound of formula IV are dissolved in an alcohol solvent, heated to 60 to 90 ℃ under stirring for 2 to 5 hours, and then treated to obtain the 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, the step B-2 further comprises the steps of: after the reaction is finished, concentrating the reaction solution, adding a halohydrocarbon solvent to dissolve the product, washing the product by using dilute acid, dilute alkali and saturated sodium chloride aqueous solution in sequence, drying and concentrating to obtain a crude product; ② adding one or more poor solvents of the compound shown in the formula (V) to wash and purify to obtain the product.
In another embodiment of the present invention, in step B-3, the compound of formula (V) is dissolved in an organic solvent, cooled while stirring, added with an aqueous solution of an oxidizing agent, reacted under certain conditions, and treated to obtain the compound of formula (VI). Preferably, the temperature is lowered to a temperature of-20 ℃ to 0 ℃. The reaction temperature is preferably from-10 ℃ to 10 ℃. The reaction time is preferably 0.1 to 2 hours. Preferably, the molar ratio of the compound of formula (V) to the oxidizing agent is 1:0.5 to 1: 5. In another embodiment of the invention, in step B-3, the compound of formula (V) is dissolved in a nitrile solvent, the temperature is reduced to-15 ℃ to-5 ℃ under stirring, an aqueous solution containing a metal ion oxidant is added, the reaction is carried out for 0.1h to 1.5h at-5 ℃ to obtain the compound of formula (VI) after treatment. Preferably, the molar ratio of the compound of formula (I) to the metal ion-containing oxidant is 1:1 to 1:3. In another embodiment of the present invention, the step B-3 further comprises the steps of: adding aqueous solution of reducing inorganic salt to quench reaction after the reaction is finished, concentrating the reaction solution, adding mixed solution of halogenated hydrocarbon and water, stirring, filtering, standing and layering to obtain an organic phase; salifying and purifying, extracting an organic phase with dilute acid, regulating the pH value of the obtained water phase with inorganic base to 8-11, extracting with an ester solvent, washing the obtained organic phase with saturated saline solution in sequence, drying and concentrating to obtain a product; preferably, the obtained product can be repeatedly subjected to salifying purification so as to obtain a product with higher purity.
In another embodiment of the present invention, in step C, the hydroxy activator is added to the mixture of the compound of formula (VI), the base and the organic solvent, and then reacted at room temperature until the reaction is completed, and the compound of formula (VII) is obtained after treatment. It is preferred that the reaction temperature in step C is from-25 ℃ to 20 ℃. Preferably, the molar ratio of the compound of formula (VI) to the base is 1:1 to 1: 6. Preferably, the molar ratio of the compound of formula (VI) to the hydroxy activator is 1:1 to 1:3. In another embodiment of the present invention, in step C, sulfonyl chloride is added to the mixture of the compound of formula (VI), aliphatic amine and halogenated hydrocarbon solvent at-5 ℃ to 5 ℃, and then reacted at room temperature until the reaction is finished, and the compound of formula (VII) is obtained after treatment. Preferably, the molar ratio of the compound of formula (VI) to the base is 1:2 to 1: 4. Preferably, the molar ratio of the compound of formula (VI) to sulfonyl chloride is 1:1 to 1:2. In another embodiment of the present invention, step C further comprises the steps of: firstly, after the reaction is finished, adding a proper amount of water, stirring for about 0.5-1h, standing for layering, washing an organic phase with saturated saline solution, drying, and concentrating to obtain a crude product; ② adding one or more poor solvents of the compound shown in the formula (VII) and purifying by recrystallization to obtain the product.
In another embodiment of the present invention, a process for preparing a compound of formula (VII), comprising the steps of:
(1) reacting a catalytic amount of potassium osmate dihydrate, potassium ferricyanide, (DHQ)2PHAL and potassium carbonate are dissolved in a mixture of water and tert-butanol, the temperature is reduced to 0 ℃ and a solution of the compound of formula (I ') in tert-butanol is added, the molar ratio of the compound of formula (I ') to potassium ferricyanide is 1:3 to 1:3.5, the molar ratio of potassium osmate dihydrate to potassium ferricyanide is 1: 50 to 1: 500, preferably about 1: 300, and the compound of formula (I ') is mixed with (DHQ)2PHAL is 1:90-1:100, the molar ratio of the compound of the formula (I ') to potassium carbonate is 1:3-1:3.5, the reaction is kept at 0 ℃ for 8 hours, then sodium sulfite is added to quench the reaction, ethyl acetate is used for extraction, the organic phase is washed by 0.5% diluted hydrochloric acid and saturated sodium chloride in turn, and the mixture is dried and concentrated to obtain the compound of the formula (II');
Figure BSA0000143440460000131
(2) dissolving a compound shown in a formula (II ') and triethylamine in dichloromethane, cooling to-10 ℃, adding a dichloromethane solution of methanesulfonyl chloride, wherein the molar ratio of the compound shown in the formula (II') to the methanesulfonyl chloride is 1:1, the molar ratio of the compound shown in the formula (II) to the triethylamine is 1: 1-1: 1.5, and then reacting at 0 ℃ for 1-1.5 h, and finishing the reaction; adding water, stirring, standing for layering, sequentially washing the organic phase with 0.5% diluted hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, drying, and concentrating to obtain compound of formula (III');
Figure BSA0000143440460000132
(3) dissolving a compound shown in a formula (III ') and a compound shown in a formula (IV ') in an ethanol solvent, wherein the molar ratio of the compound shown in the formula (III ') to the compound shown in the formula (IV ') is 1:2, heating and refluxing for 3-4 h under stirring, evaporating the solvent under reduced pressure, adding dichloromethane, washing with 0.5% diluted hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride aqueous solution in sequence, drying, concentrating, adding a mixed solvent of n-heptane and ethyl acetate (n-heptane: ethyl acetate is 10: 1), stirring to precipitate a solid, and filtering to obtain a compound shown in a formula (V ');
Figure BSA0000143440460000141
(4) dissolving a compound shown in a formula (V ') in an acetonitrile solvent, cooling to-10 ℃ under stirring, adding an aqueous solution of ammonium ceric nitrate, wherein the molar ratio of the compound shown in the formula (V') to the ammonium ceric nitrate is 1:2-1:2.5, reacting for 0.5h at 0 ℃, adding saturated sodium sulfite to quench the reaction, evaporating the solvent under reduced pressure, adding a mixed solution of dichloromethane and water, stirring, filtering by using kieselguhr, standing and layering to obtain an organic phase; extracting the obtained organic phase by using 2% diluted hydrochloric acid, regulating the pH value of the obtained water phase to 9-10 by using sodium bicarbonate, extracting the water phase by using ethyl acetate, washing by using saturated saline solution, drying, adding 1-1.5eq of diluted hydrochloric acid/1, 4-dioxane solution, and separating out to obtain a product;
Figure BSA0000143440460000142
(5) at the temperature of 0 ℃, adding methylsulfonyl chloride into a dichloromethane solution of a compound of a formula (VI ') and triethylamine, wherein the molar ratio of the compound of the formula (VI') to the triethylamine is 1: 3; reacting the compound shown in the formula (VI') with sulfonyl chloride at a molar ratio of 1: 1-1: 1.5 at room temperature for 8 hours, adding water for washing, standing for layering, washing an organic phase with saturated saline solution, drying, and concentrating to obtain a crude product; dissolving the crude product in 3 times of n-heptane solution, heating to 60 deg.C, cooling the supernatant to 25 deg.C, separating out solid, filtering, and drying to obtain compound of formula (VII')
Figure BSA0000143440460000143
In another embodiment of the present invention, said formula I' is prepared by the following steps,
step (1)
Figure BSA0000143440460000144
Reacting the compound shown in the formula 1 with MSCI under alkaline conditions to obtain a compound shown in a formula 2; the preferred base is triethylamine; the preferred reaction solvent is dichloromethane;
step (2)
Figure BSA0000143440460000151
Reacting the compound shown in the formula 2 with a compound shown in a formula 3 under a basic condition to obtain a compound shown in a formula (I'); the preferred base is potassium tert-butoxide; the preferred reaction solvent is THF.
A method for preparing a compound of the following formula (IX) and a salt thereof, a compound of the formula (VII) prepared by the preparation method of the compound of the formula (VII) described above in the invention is reacted with a compound of the formula (VIII) to prepare a compound of the formula (IX) or a salt thereof,
Figure BSA0000143440460000152
R3、R4q and n are as defined in claim 1;
R5and R6Each independently selected from the group consisting of: amino, cyano, and optionally substituted by 1 to 3Q2Substituted C1-6Alkyl radical, C1-4Alkoxy radical C1-3Alkyl radical, C2-6Alkenyl or C2-6Alkynyl, Q2Selected from the group consisting of: halogenElement, hydroxy, amino, cyano, carboxy or C1-6An alkoxy group;
R7selected from optionally substituted 1 to 3Q3Substituted C1-6Alkyl radical, C3-8Cycloalkyl radical C0-6Alkyl, 3-8 membered heterocyclyl C0-6Alkyl or 5-6 membered heteroaryl C0-6Alkyl radical, Q3Selected from the group consisting of: halogen, hydroxy, amino, C1-6Alkyl radical, C1-6Alkoxy, and C substituted by 1 to 3 halogens1-6Alkyl or C1-6An alkoxy group;
R8selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, nitro or C1-6An alkylamide group.
In another embodiment of the invention, R3And R4Each independently selected from hydrogen, optionally substituted with 1 to 3Q1Substituted phenyl, benzyl, pyridyl, pyrimidinyl, furanyl, thienyl, thiazolyl, pyrrolyl, imidazolyl or oxazolyl, and R3And R4When the catalyst is not hydrogen at the same time,
Q1selected from fluorine, chlorine, hydroxyl, amino, methyl, trifluoromethyl or methoxy.
In another embodiment of the invention, R5And R6Each independently selected from optionally substituted 1 to 3Q2Substituted C1-4Alkyl radical, Q2Selected from fluorine, chlorine, amino, methoxy or ethoxy.
In another embodiment of the invention, R7Selected from optionally substituted 1 to 3Q3Substituted C1-4Alkyl radical, Q3Selected from fluorine, chlorine, methyl and methoxy.
In another embodiment of the invention, R8Selected from hydrogen, chlorine or nitro.
In another embodiment of the invention, q is selected from 0, 1, 2 or 3.
In another embodiment of the invention, n is selected from 1, 2 or 3.
In another embodiment of the invention, the compound of formula (IX) or a salt thereof has the structure shown below:
Figure BSA0000143440460000161
the above conditions can be combined arbitrarily to obtain the preferred embodiments of the present invention without departing from the common general knowledge in the field.
In the preparation method of the invention, the drying includes but is not limited to the following drying methods: drying under normal pressure, drying under reduced pressure, spray drying, boiling drying, freeze drying, infrared drying, microwave drying, moisture absorption drying, etc. One skilled in the art can select one or more drying modes according to the properties of the product, and perform one or more drying modes according to the humidity of the product.
The starting materials or reagents described herein are commercially available, unless otherwise specified.
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 a solid support (e.g., silica gel, alumina or silica derivatized with alkylsilanes), recrystallization at high or low temperatures (optionally pretreated with activated carbon), thin layer chromatography, distillation at various pressures, vacuum sublimation, trituration, e.g., as described below: "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Furniss et al, pub. Longman Scientific & Technical, Essex CM 202 JE, England.
The compound of formula (VII) prepared by the method of asymmetric catalytic synthesis can improve the yield to at least 46% and has high stereoselectivity, and the ee value is more than 95%.
The method for preparing the compound shown in the formula (VII) uses low-toxicity, cheap and easily-obtained raw materials or reagents, has lower preparation cost, has the cost per kilogram which is only about 40 percent of the chiral resolution cost, and greatly reduces the cost; meanwhile, the cost for preparing the 1, 4-dihydropyridine-3, 5-dicarboxylic acid ester compound (formula IX') is greatly reduced.
The 1, 4-dihydropyridine-3, 5-dicarboxylic acid ester compound (formula IX ') further prepared from the compound of formula (VII') prepared by the method is qualified in quality and has no new impurities.
The preparation method has higher efficiency, the reaction conditions of each step are mild and easy to control, and the product can be purified by simple operations such as extraction, crystallization and the like: the whole process is simple and the operation is convenient.
The invention develops a novel method for constructing pyrrolidine with chiral tertiary alcohol, has high stereoselectivity and wide application value in the future.
Drawings
FIG. 1 is a high performance liquid chromatogram of a chiral intermediate.
Examples
The present invention is further described in detail by way of the following examples, which are not intended to limit the scope of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1 preparation of (S) -1- ((3, 3-Diphenylpropyl) -3-methylpyrrolidin-3-ol (Compound VII')
Figure BSA0000143440460000171
1. Preparation of 3-methylbut-3-en-1-yl methanesulfonate
Figure BSA0000143440460000172
Adding 3-methylbut-3-en-1-ol (1kg, 11.61mol), triethylamine (1762g, 17.42mol) and dichloromethane (10L) into a reaction kettle, cooling to 0 ℃ under stirring, dropwise adding methylsulfonyl chloride (1596g, 13.92mol), controlling the reaction temperature below 10 ℃, naturally heating to 25 ℃ after the addition, reacting for 16 hours, and finishing the reaction. Water (5L) was slowly added, stirred for 20 minutes, allowed to stand for layering, the aqueous phase was discarded, the organic phase was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure at 45 ℃ to give a crude title compound, which was directly put into the next step.
2. Synthesis of 1-methoxy-4- ((3-methylbut-3-en-1-yl) oxy
Figure BSA0000143440460000181
3-methylbut-3-en-1-yl methanesulfonate (1209g, 9.74mol) and THF (12L) were added to the reaction vessel, potassium tert-butoxide (1025g, 9.13mol) was added with stirring, heated to 60 ℃ for 1 hour, 4-methoxyphenol (1kg, 6.09mol) was slowly added, and after the addition, the reaction was carried out for 16 hours while maintaining 60 ℃, and the reaction was completed. The temperature was reduced to 25 ℃, celite pad filtration was performed, the filtrate was concentrated, DMF (10L) was added to dissolve the product, water (1L) was added and stirred for 10 minutes, extraction was performed three times with a mixed solvent (n-heptane: ethyl acetate ═ 10: 1), the organic phases were combined, washed twice with water, washed with a saturated aqueous sodium chloride solution, 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
Figure BSA0000143440460000182
Osmate dihydrate potassium (3.9g), (DHQ) was added to the reaction kettle2PHAL (42.7g), potassium ferricyanide (5481g) and potassium carbonate (2302g), water (30L) and tert-butanol (5L) were added, the temperature was reduced to 0 ℃, a solution (5L) of 1-methoxy-4- ((3-methylbut-3-en-1-yl) oxy) benzene (1kg) in tert-butanol was added dropwise, and the reaction was completed by maintaining the temperature at 0 ℃ for 8 hours. Anhydrous sodium sulfite (237g) was added, stirring was maintained at 0 ℃ for 1 hour, ethyl acetate was added to extract three times, the organic phases were combined, washed successively with 0.5% dilute hydrochloric acid and saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (yield 90%, e).e value > 95%).
4. Preparation of (S) -2-hydroxy-4- (4-methoxyphenoxy) -2-methylbutyl methanesulfonate
Figure BSA0000143440460000183
Adding (S) -4- (4-methoxyphenoxy) -2-methylbutane-1, 2-diol (1kg, 4.42mol), triethylamine (537g, 5.30mol) and dichloromethane (12L) into a reaction kettle, cooling to-10 ℃ under stirring, dropwise adding a dichloromethane solution (2L) of methylsulfonyl chloride (532g, 4.64mol), keeping the temperature at 0 ℃ after the addition, reacting for 1 hour, and finishing the reaction. Water (5L) was added thereto, the mixture was stirred for 20 minutes, the mixture was allowed to stand for separation, and the organic phase was dried with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to give the title compound (yield: 96%).
5. Preparation of (S) -1- ((3, 3-diphenylpropyl) amino) -4- (4-methoxyphenoxy) -2-methylbutan-2-ol
Figure BSA0000143440460000191
Adding (S) -2-hydroxy-4- (4-methoxyphenoxy) -2-methylbutyl methanesulfonate (1kg, 3.28mol), 3-1-diphenylpropane-1-ammonia (1389g, 6.57mol) and absolute ethyl alcohol (15L) into a reaction kettle, heating to 80 ℃ under stirring, and carrying out reflux reaction for 3-4 hours to complete the reaction. The solvent was evaporated under reduced pressure, dichloromethane (10L) was added to dissolve the product, and the product was washed with 0.5% dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, a mixed solvent (10L, n-heptane: ethyl acetate: 10: 1) was added thereto, and stirred for 2 hours to precipitate the product, and the product was filtered and naturally dried to obtain the title compound (yield 75%).
6. Preparation of (S) -4- ((3, 3-diphenylpropyl) amino) -3-methylpropane-1, 3-diol
Figure BSA0000143440460000192
Adding (S) -1- ((3, 3-diphenylpropyl) amino) -4- (4-methoxyphenoxy) -2-methylbutane-2-ol (1kg, 2.38mol) and acetonitrile (10L) into a reaction kettle, cooling to-10 ℃ under stirring, dropwise adding an aqueous solution (5L) of ammonium ceric nitrate (2744g, 5.00mol), controlling the temperature below 0 ℃ in the dropwise adding process, keeping the temperature for reaction for 30min, and finishing the reaction. Adding saturated sodium sulfite aqueous solution to quench (1L) for reaction, distilling under reduced pressure to remove acetonitrile, adding mixed solution of dichloromethane and water (each 5L), stirring for 30min, filtering with diatomaceous earth, washing filter cake with dichloromethane (2L), mixing filtrates, standing for layering, extracting organic phase with 2% HCl for three times, discarding organic phase, and extracting aqueous phase with NaHCO3Adjusting the pH to 9-10, extracting the aqueous phase with ethyl acetate for three times, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, adding 1.2eq of HCl/dioxane solution while stirring to precipitate the product, and filtering to obtain the title compound (yield 65%).
7. Preparation of (S) -1- ((3, 3-diphenylpropyl) -3-methylpyrrolidin-3-ol
Figure BSA0000143440460000193
Adding (S) -4- ((3, 3-diphenylpropyl) amino) -3-methylpropane-1, 3-diol (1kg, 3.19mol), triethylamine (968g, 9.57mol) and dichloromethane (10L) into a reaction kettle, cooling to 0 ℃ under stirring, dropwise adding MsCl (548g, 4.78mol), naturally heating to 25 ℃ after the addition is finished, reacting for 8 hours, adding water (5L) after the reaction is finished by HPLC (high performance liquid chromatography), stirring for 30 minutes, standing for layering, washing an organic phase with saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a crude product. Adding 3 times volume of n-heptane, heating to 60 deg.C, stirring for 1 hr, standing for layering, pouring the supernatant into another container, stirring, naturally cooling, adding 1 time volume of n-heptane into the lower layer of oily substance, extracting at 60 deg.C, mixing the supernatant with the first time, separating out the product during cooling, cooling to 25 deg.C, stirring for 2 hr, filtering, washing the filter cake with n-heptane, vacuum drying at 40 deg.C under-0.1 MPaVacuum was continued for 8 hours on a vacuum pump to afford the title compound (46% yield, ee > 95%). The molecular formula is as follows: c20H25Molecular weight of NO: 295.43 Mass Spectrometry (m/z): 296.2(M + H)+)
1H-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 are as follows: weighing the product, dissolving with mobile phase to obtain 1mL solution containing 0.3mg as sample solution, and measuring by high performance liquid chromatography (0512 in the four parts of the 2015 edition of Chinese pharmacopoeia) with amylose-tris [3, 5-xylyl carbamate ] as filler (4.6 × 250mm, 5 μm AD-H); the mobile phase is n-hexane-absolute ethyl alcohol-diethylamine (90: 10: 0.05); the flow rate is 0.6 mL/min; the column temperature is 30 ℃; the detection wavelength was 214 nm. Precisely measuring 10 μ L of the test solution, injecting into a liquid chromatograph, and recording chromatogram. The theoretical plate number must not be less than 3000.
The experimental results are as follows:
see figure 1 high performance liquid chromatogram of chiral intermediate
TABLE 6 Retention time and corresponding configuration of chiral intermediates
Figure BSA0000143440460000201
Example 23 preparation of- ((S) -1- (3, 3-Diphenylpropyl) -3-methylpyrrolidin-3-yl) 5-methyl (S) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (Compound IX') and salts thereof
1. Preparation of 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 (crude)
Figure BSA0000143440460000211
(R) -5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylate (304g, 1.02mol) was dissolved in dichloromethane solution (3.4L), DMF (34mL) was added, the temperature was reduced to-10 ℃ and oxalyl chloride (155.8g, 1.23mol) was slowly added dropwise, the temperature was controlled below 0 ℃ for 4 hours and the completion of the reaction was monitored by TLC. Slowly adding a dichloromethane solution (600mL) of (S) -1- ((3, 3-diphenylpropyl) -3-methylpyrrolidin-3 alcohol (302g, 1.02mol), controlling the temperature below 0 ℃ for 1 hour, monitoring the reaction by TLC for completion, washing with water, 1% diluted hydrochloric acid, 5% aqueous sodium carbonate solution and 5% common salt water in sequence, drying an organic phase with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a crude product (624g) of 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, was used directly in the next step.
2. Preparation of 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
Figure BSA0000143440460000212
Dissolving 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) in tert-butyl alcohol (4L), heating to 50 ℃, stirring for 1 hour to dissolve uniformly, adding n-heptane (800mL), stirring for 10 minutes, adding potassium tert-butoxide (172g, 1.53mol) at 50 ℃, naturally cooling after adding, separating out a solid, filtering, washing with a poor solvent (petroleum ether or n-heptane) to obtain potassium (S) -3- (((((S) -1- (3, 3-diphenylpropyl) -3-methylpyrrolidin-3-yl) oxy) carbonyl) -5- (methoxy) carbonyl Alkylcarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -4H-pyridine-1-compound.
The molecular formula is as follows: c36H38ClKN3O6Molecular weight: 647.8 Mass Spectrometry (m/z): 648.2(M + H +)
And (3) potassium element analysis: k, 6.42 percent.
3. Preparation of 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 hydrochloride
Figure BSA0000143440460000221
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 was dissolved in anhydrous methanol (500mL), dichloromethane (4L) was added to dissolve uniformly, and the mixture was washed with 2% dilute hydrochloric acid and water in this order, then washed three times with 5% aqueous sodium carbonate solution, then washed with 1% dilute hydrochloric acid until acidic, and the organic phase was evaporated to dryness to give an oil (360 g). Adding methanol (1L) for dissolution, filtering with a microporous membrane with the pore diameter of 0.45 micron, dropwise adding the filtrate into 1% diluted hydrochloric acid (10L) which is rapidly stirred (200rpm), separating out the product, filtering, washing a filter cake with purified water until the pH value of the filtrate is 7, drying the filtrate with anhydrous calcium chloride, and drying the filtrate in a vacuum drying oven (50 ℃, -0.09MPa) for 24 hours to obtain the product (301 g).
The specific rotation was +105.23 ° (temperature: 20 ℃, concentration: 2mg/mL, MeOH dissolved).
The molecular formula is as follows: c36H40ClN3O6Molecular weight: 646.2 Mass Spectrometry (m/z): 610.6(M + H)+)
1H-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 (11)

1. A process for the preparation of a compound of formula (VII),
the method comprises the following steps: reacting a compound of a formula (II) with a hydroxyl activating agent under alkaline conditions to form a compound of a formula (III), reacting the compound of the formula (III) with a compound of a formula (IV) to prepare a compound of a formula (V),
removing R of formula (V)1To obtain the compound of the formula (VI),
reacting the compound of the formula (VI) with a hydroxyl activating agent under alkaline conditions to obtain a compound of a formula (VII);
Figure FDA0003572686820000011
wherein the hydroxyl activator is selected from one or more of the following: acid chloride, sulfonyl chloride, acid anhydride, alcohol, phenol, halogenating agent or silane protecting agent, wherein the hydroxyl activating agent can form ester, sulfonate, ether, alkyl halide or silyl ether with hydroxyl;
R1、R2each independently selected from the group consisting of optionally substituted: c1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, phenyl, 5-6 membered heteroaryl, phenyl C1-6Alkyl, 5-6 membered heteroaryl C1-6Alkyl radical, C1-6Alkylcarbonyl, phenylcarbonyl, 5-6 membered heteroarylcarbonyl, C1-6Alkylsulfonyl, phenylsulfonyl, 5-6 membered heteroarylsulfonyl, phenyl C1-6Alkylsulfonyl, 5-6 membered heteroaryl C1-6Alkylsulfonyl or (C)1-6Alkyl radical)x(phenyl group)ySi, the substituent is selected from one or more of halogen, nitro and C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or halo C1-6An alkoxy group;
R3、R4each independently selected from the group consisting of: hydrogen, C1-6Alkyl, optionally substituted by 1 to 3Q1Substituted aryl radicals C0-6Alkyl, 3-8 membered cycloalkyl C0-6Alkyl, 3-8 membered heterocyclyl C0-6Alkyl, 5-6 membered heteroaryl C0-6Alkyl, or R3And R4Together form a 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, which is optionally substituted with 1 to 3Q1Substituted, said Q1Selected from the group consisting of: halogen, hydroxy, cyano, nitro, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or C1-6An alkylamide group;
q is selected from 0, 1, 2 or 3;
n is an integer from 1 to 5;
x and y are respectively and independently integers from 0 to 3, and the sum of x and y is 3;
the alkaline condition is selected from inorganic base or fatty amine; the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; the aliphatic amine is triethylamine.
2. The process according to claim 1, wherein the compound of formula (II) is prepared by the following steps,
Figure FDA0003572686820000021
the compound of formula (II) is obtained by catalytic oxidation of the compound of formula (I) under the action of a chiral base catalyst;
the chiral base catalyst is at least one selected from quinine, cinchonine, dihydroquinine and hydrogenated quinine 1,4- (2, 3-naphthyridine) diether.
3. The production method according to claim 1 or 2,
R1、R2each independently selected from the group consisting of optionally substituted: c1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, phenyl C1-4Alkyl radical, C1-4Alkylcarbonyl, phenylcarbonyl, C1-4Alkylsulfonyl, phenylsulfonyl, phenyl C1-4Alkylsulfonyl or (C)1-4Alkyl radical)x(phenyl group)ySi, said substituents being selected from one or more of halogen, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy or halo C1-4An alkoxy group;
R3and R4Each independently selected from hydrogen, optionally substituted with 1 to 3Q1Substituted phenyl, benzyl, pyridyl, pyrimidinyl, furanyl, thienyl, thiazolyl, pyrrolyl, imidazolyl or oxazolyl, and R3And R4When the catalyst is not hydrogen at the same time,
Q1selected from fluoro, chloro, hydroxy, 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 each independently an integer selected from 0 to 3, and the sum of x and y is 3.
4. The method according to claim 3,
R1selected from the group consisting of optionally substituted: phenyl, phenyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, phenylcarbonyl, phenylsulfonyl, phenyl C1-4Alkylsulfonyl or (C)1-4Alkyl radical)x(phenyl group)ySi, said substituents being selected from one or more halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, methoxy, ethoxy, propoxy, tert-butoxy, halomethoxy or haloethoxy substitutions;
R2selected from the group consisting of optionally substituted: c1-4Alkylcarbonyl, phenylcarbonyl, C1-4Alkylsulfonyl, phenylsulfonyl, phenyl C1-4Alkylsulfonyl, said substituents selected from one or more halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, halomethyl, haloethyl, methoxy, ethoxy, propoxy, tert-butoxy, halomethoxy, or haloethoxy;
x and y are each independently an integer selected from 0 to 3, and the sum of x and y is 3.
5. The method according to claim 4,
R1selected from the group consisting of optionally substituted: phenyl, benzyl, ethoxymethyl, propoxymethyl, tert-butoxymethyl, phenylcarbonyl, phenylsulfonyl, phenylmethylsulfonyl, Et3Si、i-Pr3Si、t-BuMe2Si or t-BuPh2Si, said substituents being selected from one or more of fluoro, chloro, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy or trifluoromethoxy;
R2selected from the group consisting of optionally substituted: formyl, acetyl, phenylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or phenylmethylsulfonyl, said substituents being selected from one or more of fluoro, chloro, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy or trifluoromethoxy.
6. The method of claim 2, comprising the steps of:
step A: adding a chiral base catalyst, an oxidant and/or an auxiliary oxidant and alkali into a mixed solution of water and an organic solvent, cooling, adding a compound of a formula (I), keeping the temperature for reaction, and treating to obtain a compound of a formula (II);
step B-1: adding a hydroxyl activating agent into a mixed solution of a compound of a formula (II), alkali and an organic solvent, reacting under a certain condition, and treating to obtain (III);
step B-2: dissolving a compound of a formula (III) and a compound of a formula (IV) in an organic solvent, heating and reacting under the condition of stirring, and treating to obtain a compound of a formula (V);
in the step B-3: dissolving the compound shown in the formula (V) in an organic solvent, cooling while stirring, adding an aqueous solution of an oxidant, reacting under a certain condition, and treating to obtain a compound shown in the formula (VI);
step C: adding a hydroxyl activating agent into a mixed solution of a compound of a formula (VI), alkali and an organic solvent, reacting at room temperature until the reaction is finished, and treating to obtain a compound of a formula (VII);
the organic solvent in the step A is an alcohol solvent, and the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol or tert-amyl alcohol; the alkali is inorganic alkali, and the inorganic alkali is selected from sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate; the oxidant and the pro-oxidant are respectively and independently metal ion-containing oxidants; the metal ion-containing oxidizing agent is selected from an osmium compound or an iron compound;
the organic solvent in the step B-1 is a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent is selected from dichloromethane or chloroform; the alkali is fatty amine, and the fatty amine is triethylamine;
the organic solvent in the step B-2 is an alcohol solvent, and the alcohol solvent is selected from ethanol, methanol, isopropanol, tert-butanol or tert-amyl alcohol;
the organic solvent in the step B-3 is selected from nitrile solvents selected from acetonitrile or propionitrile; the oxidant is an oxidant containing metal ions, the oxidant containing metal ions is a cerium compound, and the cerium compound is selected from ammonium cerium nitrate or cerium oxide;
the organic solvent in the step C is a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent is selected from dichloromethane or chloroform; the alkali is fatty amine, and the fatty amine is triethylamine.
7. The preparation method according to claim 6, wherein the temperature of the cooling in the step A is-25 ℃ to 10 ℃, the reaction time is 4h to 15h, and the molar ratio of the compound of the formula (I) to the alkali is 1:1 to 1: 10; the oxidant is selected from catalytic amount, and the molar ratio of the compound shown in the formula (I) to the pro-oxidant is 1: 1-1: 10; the molar ratio of the compound of the formula (I) to the chiral base catalyst is 50: 1-120: 1; the temperature of adding the hydroxyl activating agent in the step B-1 into the mixed solution is-25 ℃ to 20 ℃, the reaction temperature is-10 ℃ to 10 ℃, the reaction time is 0.5h to 2h, and the molar ratio of the compound in the formula (II) to the alkali is 1:0.5 to 1: 5; the molar ratio of the compound of the formula (II) to the hydroxyl activator is 1: 1-1: 3; the reaction temperature in the step B-2 is 50-100 ℃, the reaction time is 1-10 h, and the molar ratio of the compound of the formula (III) to the compound of the formula (IV) is 1: 1-1: 5; the temperature reduction in the step B-3 is-20 ℃ to 0 ℃, the reaction temperature is-10 ℃ to 10 ℃, the reaction time is 0.1h to 2h, and the molar ratio of the compound of the formula (V) to the oxidant is 1:0.5 to 1: 5; the reaction temperature of the step C is-25-20 ℃, and the molar ratio of the compound of the formula (VI) to the alkali is 1: 1-1: 6; the molar ratio of the compound of formula (VI) to the hydroxyl activator is 1: 1-1: 3.
8. The method according to claim 7, wherein the step of preparing the composition,
in the step A, adding a chiral base catalyst, an oxidant containing metal ions and/or an auxiliary oxidant and an inorganic base into a mixed solution of water and alcohol, cooling to-5 ℃, adding a compound of formula (I), keeping the temperature for reaction for 6-10 h, and treating to obtain a compound of formula (II); the molar ratio of the compound of formula (I) to the inorganic base is 1:2-1: 5; the metal ion-containing oxidant is a catalytic amount of osmium compound, the metal ion-containing pro-oxidant is an iron compound, and the molar ratio of the compound in the formula (I) to the pro-oxidant is 1: 1-1: 5; the molar ratio of the compound shown in the formula (I) to the chiral base catalyst is 80: 1-100: 1; said osmium compound is selected from potassium osmate (VI) dihydrate or osmium tetraoxide; the iron compound is selected from potassium ferricyanide, ferric trichloride or ferric nitrate;
in the step B-1, adding sulfonyl chloride into a mixed solution of a compound in a formula (II), aliphatic amine and a halogenated hydrocarbon solvent at the temperature of-15 to-5 ℃, reacting for 0.5 to 1.5 hours at the temperature of-5 to 5 ℃, and treating to obtain a compound in a formula (III); the molar ratio of the compound of the formula (II) to the fatty amine is 1: 1-1: 2; the molar ratio of the compound of the formula (II) to sulfonyl chloride is 1: 1-1: 1.5;
in the step B-2, dissolving the compound of the formula (III) and the compound of the formula (IV) in an alcohol solvent, heating to 60-90 ℃ under the condition of stirring, reacting for 2-5 h, and treating to obtain a compound of the formula (V); the molar ratio of the compound of the formula (III) to the compound of the formula (IV) is 1: 1-1: 2.5;
in the step B-3, dissolving the compound shown in the formula (V) in a nitrile solvent, cooling to-15 to-5 ℃ under stirring, adding an aqueous solution containing a metal ion oxidant, reacting for 0.1 to 1.5 hours at-5 to 5 ℃, and treating to obtain the compound shown in the formula (VI); the molar ratio of the compound shown in the formula (I) to the oxidant containing the metal ions is 1: 1-1: 3;
in the step C, adding sulfonyl chloride into a mixed solution of a compound in a formula (VI), aliphatic amine and a halogenated hydrocarbon solvent at the temperature of-5 ℃, then reacting at room temperature until the reaction is finished, and treating to obtain a compound in a formula (VII); the molar ratio of the compound of formula (VI) to the fatty amine is 1:2-1: 4; the molar ratio of the compound of formula (VI) to sulfonyl chloride is 1: 1-1: 2.
9. The method according to claim 8, wherein the step of preparing the composition,
the step A further comprises the following steps: after the reaction is finished, adding reducing inorganic salt to quench and react, extracting an ester solvent, washing an organic phase with dilute acid and saturated sodium chloride aqueous solution in turn, drying and concentrating to obtain a compound in a formula (II);
the step B-1 further comprises the following steps: firstly, after the reaction is finished, adding a proper amount of water, stirring for about 0.5-1h, standing for layering, washing the organic phase with dilute acid, dilute alkali and saturated sodium chloride aqueous solution in turn, drying and concentrating to obtain a product;
the step B-2 further comprises the following steps: after the reaction is finished, concentrating the reaction solution, adding a halohydrocarbon solvent to dissolve the product, washing the product by using dilute acid, dilute alkali and saturated sodium chloride aqueous solution in sequence, drying and concentrating to obtain a crude product; adding one or more poor solvents of the compound shown in the formula (V) to wash and purify to obtain a product;
the step B-3 further comprises the following steps: firstly, after the reaction is finished, adding reductive inorganic salt to quench the reaction, concentrating the reaction solution, adding a mixed solution of halogenated hydrocarbon and water, stirring, filtering, standing and layering to obtain an organic phase; salifying and purifying, extracting an organic phase with dilute acid, adjusting the pH of the obtained water phase to 8-11 with inorganic base, extracting with an ester solvent, washing the obtained organic phase with saturated saline solution in sequence, drying and concentrating to obtain a product; the obtained product can be subjected to repeated salifying purification;
the step C further comprises the following steps: firstly, after the reaction is finished, adding a proper amount of water, stirring for about 0.5-1h, standing for layering, washing an organic phase with saturated saline solution, drying, and concentrating to obtain a crude product; ② adding one or more poor solvents of the compound shown in the formula (VII) and purifying by recrystallization to obtain the product.
10. The production method as claimed in claim 9,
the poor solvent is selected from one or more of aliphatic hydrocarbon solvent, alicyclic hydrocarbon solvent and ester solvent; the aliphatic hydrocarbon 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 ester solvent is selected from at least one of methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate;
the dilute acid is at least one of 0.1-5% dilute hydrochloric acid, dilute nitric acid and dilute sulfuric acid;
the dilute alkali or inorganic alkali is at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate;
the reducing inorganic salt is at least one of sodium sulfite, sodium thiosulfate or sodium dithionite.
11. A process for the preparation of a compound of formula (VII'), characterized in that it comprises the following steps:
(1) reacting a catalytic amount of potassium osmate dihydrate, potassium ferricyanide, (DHQ)2Dissolving PHAL and potassium carbonate in a mixture of water and tert-butyl alcohol, cooling to 0 deg.C, adding tert-butyl alcohol solution of compound of formula (I ') at a molar ratio of compound of formula (I ') to potassium ferricyanide of 1:3-1:3.5, and reacting compound of formula (I ') with (DHQ)2PHAL is 1:90-1:100, the molar ratio of the compound of the formula (I ') to potassium carbonate is 1:3-1:3.5, the reaction is kept at 0 ℃ for 8 hours, then sodium sulfite is added for quenching reaction, ethyl acetate is used for extraction, organic phase is washed by 0.5% diluted hydrochloric acid and saturated sodium chloride in sequence, and the mixture is dried and concentrated to obtain the compound of the formula (II');
Figure FDA0003572686820000051
(2) dissolving a compound shown in a formula (II ') and triethylamine in dichloromethane, cooling to-10 ℃, adding a dichloromethane solution of methanesulfonyl chloride, wherein the molar ratio of the compound shown in the formula (II') to the methanesulfonyl chloride is 1:1, and the molar ratio of the compound shown in the formula (II) to the triethylamine is 1: 1-1: 1.5, and then reacting at 0 ℃ for 1-1.5 h, and finishing the reaction; adding water, stirring, standing for layering, sequentially washing the organic phase with 0.5% diluted hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, drying, and concentrating to obtain compound of formula (III');
Figure FDA0003572686820000061
(3) dissolving a compound shown as a formula (III ') and a compound shown as an IV ' in an ethanol solvent, wherein the molar ratio of the compound shown as the formula (III ') to the compound shown as the IV ' is 1:2, heating and refluxing for 3-4 h under stirring, evaporating the solvent under reduced pressure, adding dichloromethane, washing with 0.5% diluted hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride aqueous solution in sequence, drying, concentrating, adding a mixed solvent of n-heptane and ethyl acetate, stirring to precipitate a solid, and filtering to obtain a compound shown as a formula (V ');
Figure FDA0003572686820000062
(4) dissolving a compound shown in a formula (V ') in an acetonitrile solvent, cooling to-10 ℃ under stirring, adding an aqueous solution of ammonium ceric nitrate, wherein the molar ratio of the compound shown in the formula (V') to the ammonium ceric nitrate is 1:2-1:2.5, reacting for 0.5h at 0 ℃, adding saturated sodium sulfite to quench the reaction, evaporating the solvent under reduced pressure, adding a mixed solution of dichloromethane and water, stirring, filtering by using kieselguhr, standing and layering to obtain an organic phase; extracting the obtained organic phase with 2% dilute hydrochloric acid, adjusting the pH value of the obtained water phase to 9-10 with sodium bicarbonate, extracting the water phase with ethyl acetate, combining the organic phases, washing with saturated saline solution, drying, adding 1-1.5 equivalent of dilute hydrochloric acid/1, 4-dioxane solution, and separating out to obtain a product;
Figure FDA0003572686820000063
(5) adding methylsulfonyl chloride into a dichloromethane solution of a compound of formula (VI ') and triethylamine at 0 ℃, wherein the molar ratio of the compound of formula (VI') to the triethylamine is 1: 3; reacting the compound shown in the formula (VI') with sulfonyl chloride at a molar ratio of 1: 1-1: 1.5 at room temperature for 8 hours, adding water for washing, standing for layering, washing an organic phase with saturated saline solution, drying, and concentrating to obtain a crude product; dissolving the crude product in n-heptane solution, heating to 60 deg.C, stirring for a certain time, cooling the supernatant to 25 deg.C, precipitating solid, filtering, drying to obtain compound of formula (VII'),
Figure FDA0003572686820000071
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007284402A (en) * 2006-04-19 2007-11-01 Univ Of Tokyo Lysophosphatidyl-threonine and derivative thereof
CN101573332A (en) * 2006-11-09 2009-11-04 弗·哈夫曼-拉罗切有限公司 Arylsulfonyl pyrrolidines as 5-HT6 inhibitors
WO2010132873A2 (en) * 2009-05-15 2010-11-18 Northwestern University Chiral pyrrolidine core compounds en route to inhibitors of nitric oxide synthase
WO2012146067A1 (en) * 2011-04-29 2012-11-01 山东亨利医药科技有限责任公司 1,4-dihydropyridine -3,5-dicarboxylate derivatives, preparation methods and uses thereof
CN104203915A (en) * 2012-04-25 2014-12-10 霍夫曼-拉罗奇有限公司 (3,4-dichloro-phenyl)-((s)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride and manufacturing processes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007284402A (en) * 2006-04-19 2007-11-01 Univ Of Tokyo Lysophosphatidyl-threonine and derivative thereof
CN101573332A (en) * 2006-11-09 2009-11-04 弗·哈夫曼-拉罗切有限公司 Arylsulfonyl pyrrolidines as 5-HT6 inhibitors
WO2010132873A2 (en) * 2009-05-15 2010-11-18 Northwestern University Chiral pyrrolidine core compounds en route to inhibitors of nitric oxide synthase
WO2012146067A1 (en) * 2011-04-29 2012-11-01 山东亨利医药科技有限责任公司 1,4-dihydropyridine -3,5-dicarboxylate derivatives, preparation methods and uses thereof
CN103649075B (en) * 2011-04-29 2016-05-25 山东轩竹医药科技有限公司 Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylate derivatives and preparation and application thereof
CN104203915A (en) * 2012-04-25 2014-12-10 霍夫曼-拉罗奇有限公司 (3,4-dichloro-phenyl)-((s)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride and manufacturing processes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Phytophthoraα1性信息素C(9)～C(16)片段的合成;罗兵等;《应用化工》;20090731;第38卷(第7期);第998-1003、1016页 *
Synthesis and Antileishmanial Activity of Lipidic Amino Alcohols;Elaine S. Coimbra et al.;《Chem Biol Drug Des》;20091101;第75卷;第233-235页 *

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