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

The preparation method and applications of chiral heterocycle tertiary alcohol intermediates Download PDF

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CN108689904A
CN108689904A CN201710255141.1A CN201710255141A CN108689904A CN 108689904 A CN108689904 A CN 108689904A CN 201710255141 A CN201710255141 A CN 201710255141A CN 108689904 A CN108689904 A CN 108689904A
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CN108689904B (en
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朱宁
王海波
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Xuanzhu Biopharmaceutical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/12—Oxygen or sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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

The preparation method and applications of chiral heterocycle tertiary alcohol intermediates
Technical field
The invention belongs to chemical industry or field of medicaments, and in particular to the preparation method of chiral heterocycle tertiary alcohol intermediates and its use In the method for preparing Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylate derivatives.
Background technology
Dihydropyridine calcium ion channel blocker has been used to treat the drug of angiocardiopathy since being the 1970s, Its by with protein receptor binding, selectively block Ca in L-type or/and T- type calcium channels2+Interior stream is reduced intracellular Ca2+ concentration plays a protective role to the heart, the cerebrovascular to change cardiovascular function.Dihydropyridine calcium ion channel blocking Agent has the cardioselective of height, and antihypertensive effect is clear, applied widely, is clinically widely used, it has also become preferred Antihypertensive drugs.L-type and the dual calcium ion channel blocker of T- types not only have the effect that reduces blood pressure, but also can slow down tachycardia, drop Low oedema occurs, and has heart, Renoprotective Effect (Hypertension.2009;53:592-594).
Patent application WO2012146067A1 discloses a kind of Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic acids ester type compound, should Class compound antihypertensive effect significantly and can maintain long-acting antihypertensive effect and there is L-type and the dual calcium channel of T- types to block Effect, while the preparation method of this kind of compound is also disclosed in application documents, wherein embodiment compound 16 has good Antihypertensive effect, concrete structure are:
The i.e. chiral tertiary alcohol pyrrolidines intermediate (VII) of the important medicine intermediate arrived involved in the reaction process, Former preparation method is obtained by chiral resolution, and yield is only 16%, and with further being obtained by the reaction of intermediate (VIII) The yield for closing object (IX) is also only 56%, and preparation method yield is too low is not suitable for industrial production for this.
Invention content
Technical problem to be solved by the present invention lies in provide a kind of i.e. chiral heterocycle tertiary alcohol intermediates of medicine intermediate Preparation method, it is further provided a kind of intermediate using obtained by this method prepares Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester and spreads out The method of biology.
Specifically, the present invention provides following technical scheme:
1, the method such as following formula (VII) compound is prepared,
The method includes:Make formula (VI) compound that formula (VII) be obtained by the reaction under alkaline condition with hydroxy activating reagent Compound,
Wherein, the hydroxy activating reagent is selected from one of the following or a variety of:Acyl chlorides, sulfonic acid chloride, acid anhydrides, alcohol, phenol or Silane protectant, the hydroxy activating reagent can form ester, sulphonic acid ester, ether or silicon ether with hydroxyl;
R3,R4Separately it is selected from following one group of group:Hydrogen, C1-6Alkyl, optionally by 1 to 3 Q1Substituted aryl C0-6 Alkyl, 3-8 member naphthenic base C0-6Alkyl, 3-8 circle heterocyclic ring bases C0-6Alkyl, 5-6 unit's heteroaryls C0-6Alkyl or R3With R4Shape together At 3-8 members naphthenic base, 3-8 circle heterocyclic ring bases, optionally by 1 to 3 Q1Replaced, the Q1Selected from following one group of group:Halogen Element, hydroxyl, cyano, nitro, amino, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamidoalkyl;
Q is selected from 0,1,2 or 3;
N is selected from 1 to 5 integer.
2, the method such as following formula (IX) compound and its salt, the preparation method institute of formula (VII) compound described in 1 are prepared Formula (VII) compound obtained is reacted with formula (VIII), is prepared into formula (IX) compound,
R3,R4, q and n such as 1 defined;
R5And R6It is each independently selected from following one group of group:Amino, cyano, and optionally by 1 to 3 Q2Substituted C1-6 Alkyl, C1-4Alkoxy C1-3Alkyl, C2-6Alkenyl or C2-6Alkynyl, Q2Selected from following one group of group:Halogen, hydroxyl, amino, cyanogen Base, carboxyl or C1-6Alkoxy;
R7Selected from optionally by 1 to 3 Q3Substituted C1-6Alkyl, C3-8Naphthenic base C0-6Alkyl, 3-8 circle heterocyclic ring bases C0-6Alkyl Or 5-6 unit's heteroaryls C0-6Alkyl, Q3Selected from following one group of group:Halogen, hydroxyl, amino, C1-6Alkyl, C1-6Alkoxy, and The C replaced by 1 to 3 halogen1-6Alkyl or C1-6Alkoxy;
R8Selected from following one group of group:Hydrogen, halogen, hydroxyl, cyano, nitro or C1-6Alkylamidoalkyl.
Invention effect
By means of the invention it is also possible to which highly selective and high yield obtain chiral heterocycle tertiary alcohol intermediates, especially The chiral pyrrolidine tertiary alcohol, to improve the yield of Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylate derivatives.In addition, through the invention Method so that reaction condition and purification condition are simply controllable, reduce production cost, and reaction yield improves, and are suitable for industrial expand Big production.Also, by means of the invention it is also possible to high-purity, obtain Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester in high yield Derivative.
Specific implementation mode
[Definition]
In the description and claims of this application, compound is in accordance with chemical structural formula and names, if It indicates that the name of compound is not inconsistent with chemical structural formula when same compound, is subject to chemical structural formula or chemical equation.
In this application, unless otherwise stated, Science and Technology noun used herein has art technology The normally understood meaning of personnel institute.However, for a better understanding of the present invention, be provided below part relational language definition and It explains.In addition, working as the definition of term provided herein and explaining with the normally understood meaning of those skilled in the art not When consistent, with the definition of term provided herein and it is construed to accurate.
" halogen " of the present invention refers to fluorine atom, chlorine atom, bromine atom, iodine atom.Preferably fluorine atom, chlorine are former Son.
" C of the present invention1-6Alkyl " indicates the alkyl containing 1-6 carbon atom of linear chain or branched chain, preferably C1-4Alkane Base, such as C2-4Alkyl, C2-3 alkyl, C1-3Alkyl, C1-2Alkyl;Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- first Base propyl, 1- methyl-propyls, 1,1- dimethyl ethyls, n-pentyl, 3- methyl butyls, 2- methyl butyls, 1- methyl butyls, 1- second Base propyl, n-hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2,2- Dimethylbutyl, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- ethyls Butyl, 1,2- dimethyl propyls etc.." C of the present invention1-4Alkyl " refers to containing 1-4 carbon atom above-described embodiment.
" C of the present invention0-6Alkyl " indicates the linear or branched alkyl group containing 0 to 6 carbon atom, when carbon number is 0 When, indicate a key;It is preferred that C0-4Alkyl, C0-3Alkyl, most preferably C0-2Alkyl.
It is that 3-8 members naphthenic base of the present invention indicates the saturation containing 3-8 carbon atom or fractional saturation and do not have The cyclic group of armaticity, including " 3-8 members saturated cyclic alkyls " and " 3-8 member fractional saturations naphthenic base ";Such as 3-6 member naphthenic base Deng more preferable 5-6 members naphthenic base;The example include but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cycloheptyl alkyl, Cyclooctane base, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group, hexamethylene -1,3- diene, hexamethylene -1, 4- diene, cycloheptenyl, cycloheptyl -1,3- dialkylene, cycloheptyl-Isosorbide-5-Nitrae-dialkylene, cycloheptyl -1,3,5- trialkenyls, cyclo-octene base, ring Octyl- 1,3- dialkylenes, ring octyl- Isosorbide-5-Nitrae-dialkylene, ring octyl- 1,5- dialkylenes, 1,3,5- trialkenyl of ring octyl-, cyclooctatetraenyl etc..
" C of the present invention2-6Alkynyl " refers to the linear chain or branched chain that the carbon atom number containing three keys is 2~6, is also wrapped Include cricoid alkynyl, preferably C2-4Alkynyl, as acetenyl, propinyl, 2- butynyls, valerylene base, 3- pentynyls, 2- hexin bases, 3- hexin bases, cyclopropyne base, cyclobutynyl, ring pentynyl, hexamethylene alkynyl etc..
" halogenated C of the present invention1-6Alkyl " refers to one or more " halogen " substitution " C1-6One or more on alkyl " Group derived from hydrogen atom, " halogen " and " C1-6Alkyl " is as defined hereinabove." halogenated C of the present invention1-4Alkane Base " refers to the specific example containing 1-4 carbon atom in examples detailed above.
" C of the present invention1-6Alkoxy ", " C1-6Alkyl amido " refers respectively to " C1-6Alkyl-O- " groups, " C1-6 Alkyl-C (O)-NH- " groups, wherein " C1-6Alkyl " is as defined hereinabove.It is preferred that " C1-4Alkoxy ", " C1-4Alkyl amido ".
" C of the present invention1-4Alkoxy ", " C1-4Alkyl amido " refers respectively to " C1-4Alkyl-O- " groups, " C1-4 Alkyl-C (O)-NH- " groups, wherein " C1-4Alkyl " is as defined hereinabove.
" 3-8 circle heterocyclic rings base " of the present invention refer to containing one or more, identical or different heteroatomic 3~8 yuan it is full And/or fractional saturation cyclic group, the hetero atom are selected from nitrogen, oxygen and sulphur, any annular atom of the heterocycle is from can be by Oxo, such as 3-6 circle heterocyclic ring bases etc., more preferable 5-6 circle heterocyclic rings base;The example includes but not limited to Oxyranyle, thia ring Propyl, aziridine base, oxetanyl, azetidine, Thietane base, oxetanes, 1,2- dioxies Azetidinyl, 1,2- diazetidines base, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, oxazolidine radicals, pyrazolidine Base, imidazolidinyl, thiazolidinyl, THP trtrahydropyranyl, piperidyl, piperazinyl, morpholinyl, Isosorbide-5-Nitrae-dioxane base, 1,3- Dioxane base, 1,3- thioxane base, 4,5- glyoxalidine base, 4,5- pyrazolines base, 2,5- dihydro-thiophenes Base, 4,5- dihydro-thiazolyls, piperidone base, tetrahydropyridine ketone group, dihydro piperidone base, 4,5- dihydro-oxazoles base, 4,5- dihydros Isoxazolyl, 2,3- dihydro-isoxazoles base, 2H-1,2- oxazinyls, 4H-1,2- oxazinyls, 6H-1,2- oxazinyls, 4H-1,3- Evil Piperazine base, 6H-1,3- oxazinyls, 4H-1,4- oxazinyls, 4H-1,3- thiazinyls, 6H-1,3- thiazinyls, 2H- pyranoses, 2H- pyrroles It mutters -2- ketone groups, 3,4- dihydro -2H- pyranoses, Isosorbide-5-Nitrae-Dioxin base, Isosorbide-5-Nitrae-dithiins base, Isosorbide-5-Nitrae-oxygen Thia cyclohexadienyl, Isosorbide-5-Nitrae-dioxane sarohornene base, azepine cycloheptatriene base, 1,2- diazas cycloheptatriene base, 1,3- Diaza cycloheptatriene base, Isosorbide-5-Nitrae-diaza cycloheptatriene base, azepine cyclooctatetraenyl, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-diazocine Trialkenyl etc..
" aryl " of the present invention refers to 6~10 unit monocycles or di-aromatics cyclic group, such as phenyl, naphthalene etc..
5-6 unit's heteroaryls of the present invention refer at least contain there are one hetero atom, annular atom sum be 5~6 and Cyclic group with armaticity, the hetero atom are selected from nitrogen, oxygen and sulphur, and any annular atom of the heterocycle can be by Oxo, the example include but not limited to pyrrole radicals, furyl, thienyl, imidazole radicals, pyrazolyl, oxazolyl, oxadiazolyls, thiophene Oxazolyl, thiadiazolyl group, pyrimidine radicals, triazine radical, tetrazine base, pyridyl group etc..
" hydroxy activated reagent " of the present invention is the reagent for referring to form it into easy leaving group with hydroxyl reaction, Necleophilic reaction can be occurred with nucleopilic reagent by being formed by easy leaving group.The hydroxy activating reagent is including but not limited to following In it is one or more:Acyl chlorides, sulfonic acid chloride, acid anhydrides, alcohol, phenol, halide reagent, silane protectant;The acyl chlorides, acid anhydrides can be with Hydroxyl forms ester;The sulfonic acid chloride can form sulphonic acid ester with hydroxyl;The alcohol or phenol can form ether with hydroxyl;The halogen Change the halogen in reagent and may replace hydroxyl formation halogenated hydrocarbons;The silane protectant can form silicon ether with hydroxyl;" the hydroxyl Base activating reagent " includes aliphatic, alicyclic and aromatic reagent, i.e., all activation examinations that can realize function of the present invention Agent is all contained in the scope of the invention.
" organic solvent " of the present invention is separately selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbon Class, alcohols, ethers, esters, ketone, diol, derivatives class, phenols, nitrile, amides, sulfone class, sulfoxide type, heteroaryl hydro carbons and it At least one of mixture.Wherein, aromatic hydrocarbon solvent is selected from least one of benzene, toluene and dimethylbenzene, fat Hydrocarbon solvent is selected from least one of pentane, hexane, heptane and octane, and alicyclic hydrocarbon type solvent is in pentamethylene and hexamethylene At least one, halogenated hydrocarbon solvent is selected from least one of dichloromethane, chloroform, chlorobenzene and dichloro-benzenes, alcohols solvent choosing From at least one of methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, tert-pentyl alcohol, tertiary hexanol, benzyl alcohol, ethylene glycol and glycerine, ether Class solvent is selected from least one of tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE) and propylene oxide, and esters solvent is selected from acetic acid first At least one of ester, ethyl acetate, repefral and propyl acetate, ketones solvent are selected from acetone, methyl butyl At least one of ketone and methyl iso-butyl ketone (MIBK), diol, derivatives class solvent are selected from glycol monoethyl ether, ethylene glycol monoethyl ether, second At least one of glycol monobutyl ether, glycol dimethyl ether and ethylene glycol diethyl ether, phenol solvent are selected from phenol and p-cresol At least one of, nitrile solvents are selected from least one of acetonitrile and propionitrile, and amide solvent is selected from N, N- dimethyl formyls At least one of amine and n,N-dimethylacetamide, sulfone class solvent be selected from dimethyl sulfone, benzene second sulfone, diethyl sulfone, diphenyl sulfone and At least one of sulfolane, sulfoxide type solvents are selected from least one of dimethyl sulfoxide (DMSO), diethyl sulfoxide and benzyl, Heteroaryl hydrocarbon solvent is selected from pyridine.
" alkali " of the present invention is separately selected from least one of organic base and inorganic base.
" inorganic base " of the present invention is the inorganic matter for referring to provide lone pair electrons, be typically free of carbon, The compound generally generated with hydroxide ion by metal ion or ammonium ion, specific example include but not limited to:Sodium hydride, Sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, ammonium hydroxide, lithium hydroxide, sodium hydroxide, hydrogen as alkali metal hydroxide Potassium oxide, cesium hydroxide, the calcium hydroxide as alkaline earth metal hydroxide, magnesium hydroxide, barium hydroxide, ammonium hydroxide etc..
" organic base " refers to the organic compound with alkalinity.Organic base is divided into the alkaline metal salt of alcohol, alkyl gold Belong to lithium compound, ammonobase lithium compound and aminated compounds, the alkaline metal salt of the alcohol is selected from tert-butyl alcohol lithium, the tert-butyl alcohol At least one of sodium, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, the metal alkyl lithium compound are selected from At least one of butyl lithium and phenyl lithium, the ammonobase lithium compound are selected from two silicon of lithium diisopropylamine and hexamethyl At least one of lithium amide, the aminated compounds is selected from fatty amines, such as n,N-diisopropylethylamine, methylamine, ethamine, two At least one of methylamine, diethylamine, triethylamine, ethylenediamine, isopropylamine, dibenzyl amine, tert-butylamine and hexamethylene diamine;Alcamines, Such as monoethanolamine, diisopropanolamine (DIPA) and N, at least one of N- diethyl ethylene diamines, amides, such as formamide, acetamide, third At least one of acrylamide, colchicin, camptothecine, n,N-Dimethylformamide and dimethylacetylamide, alicyclic ring amine, such as At least one of cyclohexylamine, diethylenetriamines, hexa, morpholine and piperazine, aromatic amine, such as aniline, hexichol In amine, benzidine, o-phenylenediamine, p-phenylenediamine, open-chain crown ether, parachloroanilinum, m-oxethyl aniline and meta nitro aniline At least one, naphthalene system amine, such as at least one in naphthalidine, 2- naphthylamines, Kerafyrm acid, tobias acid, R acid, K acid and naphthylenediamine Kind, polyethyleneimine, azanol;Preferred fat amine, as n,N-diisopropylethylamine, dimethylamine, diethylamine, triethylamine and oneself two At least one of amine;
" oxidant " of the present invention refers to obtaining the substance of electronics in redox reaction or making another substance It obtains oxygen or sloughs the substance of hydrogen;" pro-oxidant " itself can be oxidant, can also be to promote oxidant hair Wave the auxiliary element of effect;" oxidant " or " pro-oxidant " can be divided into non-metal simple-substance oxidant, metal ion Oxidant, acidic oxidation agent, peroxide oxidant;
1) the non-metal simple-substance oxidant described in is selected from least one of oxygen, chlorine, bromine gas, iodine, ozone;
2) the metal ion oxidant described in is selected from manganese compound, chromium compound, osmium compound, lead compound, iron Close at least one of object, cerium compound;The manganese compound is selected from least one of potassium permanganate, manganese dioxide;Institute The chromium compound stated is selected from least one of sodium dichromate, potassium bichromate, chromium trioxide;The osmium compound is selected from osmic acid At least one of potassium (VI) dihydrate, osmium tetroxide;The lead compound is selected from lead tetra-acetate;The iron compound Selected from least one of the potassium ferricyanide, ferric trichloride, ferric nitrate;The cerium compound is in ammonium ceric nitrate, cerium oxide At least one;The metal ion oxidant is not limited to above-mentioned specific example, every containing metal ion and have The compound of oxidisability is included within the scope of the present invention.
3) the oxygen-containing acid oxidant is selected from least one of the concentrated sulfuric acid, concentrated nitric acid, periodic acid, hypochlorous acid, perchloric acid; The oxygen-containing acid oxidant is not limited to above-mentioned specific embodiment, and every acid with certain oxidisability is included in model of the present invention Within enclosing.
4) peroxide oxidant is selected from inorganic peroxide or organic per-compounds;The inorganic peroxygen Object is selected from least one of hydrogen peroxide, sodium peroxide, potassium peroxide, calper calcium peroxide, zinc peroxide, potassium hydrogen peroxymonosulfate; The organic per-compounds are selected from peroxidating alcohol (ROOH), peroxidating ether (ROOR '), diacyl peroxide (RCOOOOCR '), peroxy acid, peroxy esters (RCOOOR '), peroxycarbonates (ROCOOOOCOR ') and Tong Guoyanghuawu [R2C (OOH)2]At least one of;R or R ' represents any substituent group;The peroxidating alcohol was selected from oxyethanol, the tertiary fourth of peroxidating At least one of alcohol, peroxidating isopropanol;The peroxidating ether is selected from ethyl peroxide, peroxidation di-t-butyl, peroxidating At least one of isopropyl ether, tert-butyl peroxide ether;The diacyl peroxide is selected from benzoyl peroxide, two isobutyls At least one of acyl peroxide, two-(2- ethyl hexanoyls) peroxide, diacetyl peroxide;The peroxy acid is selected from At least one of peroxyformic acid, Peracetic acid, benzoyl hydroperoxide, metachloroperbenzoic acid;The peroxy esters are selected from peroxide second It is tert-butyl acrylate, the peroxy trifluoroacetic acid tert-butyl ester, benzylhydroperoxide tert-pentyl ester, t-butyl perbenzoate, tert-butyl peroctoate, excessively sad At least one of tert-pentyl ester;The peroxycarbonates are selected from di-isopropyl peroxydicarbonate, two ring of dicetyl peroxydicarbonate At least one of own ester, dicetyl peroxydicarbonate two (- benzene oxygen ethyl) ester;The ketone peroxide is selected from dimethyl peroxidating At least one of ketone, methyl ethyl ketone peroxide, cyclohexanone peroxide, acetone peroxide, methylethyl ketone peroxide;The peroxide Oxidant is not limited to above-mentioned specific example, and every peroxide with oxidisability is included within the scope of the invention.
Chirality base catalyst of the present invention is selected from by quinine, quinine mono-hydrochloric salts dihydrate, cinchonine, Xin Keni Fourth, hydroquinine (DHQ), quinindium, dihydrochinidin (DHQD), hydroquinine Isosorbide-5-Nitrae-(2,3- benzodiazine) diether ((DHQ) 2PHAL), at least one in hydroquinidine Isosorbide-5-Nitrae-(2,3- benzodiazine) diether ((DHQD) 2PHAL) and its arbitrary derivative Kind.
" room temperature " of the present invention refers to 20 DEG C -30 DEG C or so, preferably 25 DEG C or so.
" catalytic amount " of the present invention refers to common catalytic amount in chemical reaction.For example, it may be chemical reaction In, it is less than an equivalent.
" poor solvent " of the present invention refers to insoluble to compound under non-heated state or slightly soluble, is dissolved after heating Spend the solvent that gradually increases, can a kind of solvent or multi-solvents mixed liquor;The solvent includes water and organic solvent.This The invention poor solvent includes but not limited to fat hydrocarbon solvent, alicyclic hydrocarbon type solvent, one kind in esters solvent or more Kind;Fat hydrocarbon solvent is selected from least one of pentane, hexane, heptane and octane, alicyclic hydrocarbon type solvent be selected from pentamethylene and At least one of hexamethylene, esters solvent is in methyl acetate, ethyl acetate, repefral and propyl acetate At least one.
Diluted acid of the present invention is pH value for adjusting solution or neutralizes alkali extra in solution or for making product At salt etc., all to realize that the diluted acid of the present invention is included within the scope of the invention, the diluted acid includes but not limited to 0.1%- At least one of 5% dilute hydrochloric acid, dust technology, dilute sulfuric acid.
Diluted alkaline or inorganic base of the present invention are pH value for adjusting solution or neutralize acid or use extra in solution In make product at salt etc., it is all to realize that the diluted alkaline of the present invention or inorganic base are included within the scope of the invention, the diluted alkaline or Inorganic base includes but not limited at least one of sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate.
Reducing inorganic salt of the present invention is not influence for oxidant extra in neutralization reaction liquid and product Yield, all to realize that the reducing inorganic salt of the present invention is included within the scope of the invention, reducing inorganic salt packet Include but be not limited at least one of sodium sulfite, sodium thiosulfate or sodium dithionite.
More specifically for, the present invention relates to and lower content:
The preparation method of following formula (VII) compounds,
The method includes:Make formula (VI) compound that formula (VII) be obtained by the reaction under alkaline condition with hydroxy activating reagent Compound,
Wherein, the hydroxy activating reagent is selected from one of the following or a variety of:Acyl chlorides, sulfonic acid chloride, acid anhydrides, alcohol, phenol or Silane protectant, the hydroxy activating reagent can form ester, sulphonic acid ester, ether or silicon ether with hydroxyl;
R3,R4Separately it is selected from following one group of group:Hydrogen, C1-6Alkyl, optionally by 1 to 3 Q1Substituted aryl C0-6 Alkyl, 3-8 member naphthenic base C0-6Alkyl, 3-8 circle heterocyclic ring bases C0-6Alkyl, 5-6 unit's heteroaryls C0-6Alkyl or R3With R4Shape together At 3-8 members naphthenic base, 3-8 circle heterocyclic ring bases, optionally by 1 to 3 Q1Replaced, the Q1Selected from following one group of group:Halogen Element, hydroxyl, cyano, nitro, amino, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamidoalkyl;
Q is selected from 0,1,2 or 3;
N is selected from 1 to 5 integer.
In another embodiment of the present invention, (VI) compound is passed through by formula (II) compound and formula (IV) compound Following steps are prepared,
The preparation process includes:
Formula (II) compound is reacted into the formula of being formed (III) with hydroxy activating reagent under alkaline condition,
Wherein, R1,R2It is independently selected from optionally substituted following groups::C1-6Alkyl, C1-6Alkoxy C1-6Alkane Base, phenyl, 5-6 unit's heteroaryls, phenyl C1-6Alkyl, 5-6 unit's heteroaryls C1-6Alkyl, C1-6Alkyl-carbonyl, phenylcarbonyl group, 5-6 members Heteroarylcarbonyl, C1-6Alkyl sulphonyl, phenyl sulfonyl, 5-6 unit's heteroaryls sulfonyl, phenyl C1-6Alkyl sulphonyl, 5-6 members Heteroaryl C1-6Alkyl sulphonyl or (C1-6Alkyl) x (phenyl) ySi, the substituent group is selected from optionally by one or more halogen Element, nitro, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy or halogenated C1-6Alkoxy;
The R2Group is the residue of hydroxy activating reagent;
X, y is independently selected from 0 to 3 integer, and the summation of x and y is 3, wherein (C1-6Alkyl) in x (phenyl) ySi C1-6Alkyl, which can be identical alkyl, can also be different alkyl;
The R3,R4As defined in claim 1;
Formula (III) is reacted into the formula of being prepared into (V) with formula IV compound,
Formula (V) sloughs R1Group and formula (VI) compound.
In another embodiment of the present invention, the formula (II) compound is prepared by following steps,
By formula (I) compound formula (II) compound is obtained by catalysis oxidation under the action of chiral base catalyst.
In another embodiment of the present invention, R1,R2It is independently selected from optionally substituted following groups:C1-4Alkane Base, C1-4Alkoxy C1-4Alkyl, phenyl, phenyl C1-4Alkyl, C1-4Alkyl-carbonyl, phenylcarbonyl group, C1-4Alkyl sulphonyl, phenyl Sulfonyl, phenyl C1-4Alkyl sulphonyl or (C1-4Alkyl) x (phenyl) ySi, the substituent group be selected from one or more halogens, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy or halogenated C1-4Alkoxy;
The R2Group is the residue of hydroxy activating reagent;
X, y is independently selected from 0 to 3 integer, and the summation of x and y is 3, wherein (C1-4Alkyl) in x (phenyl) ySi C1-6Alkyl, which can be identical alkyl, can also be different alkyl.
In another embodiment of the present invention, R3And R4It is each independently selected from hydrogen, optionally by 1 to 3 Q1Substituted benzene Base, benzyl, pyridyl group, pyrimidine radicals, furyl, thienyl, thiazolyl, pyrrole radicals, imidazole radicals Huo oxazolyls, and R3And R4It is different When be hydrogen,
Q1Selected from fluorine, chlorine, hydroxyl, amino, methyl, ethyl, isopropyl, tertiary butyl, methoxyl group, ethyoxyl or fluoroform Base.
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, R1Selected from optionally substituted following groups:Phenyl, phenyl C1-4Alkyl, C1-4Alkoxy C1-4Alkyl, phenylcarbonyl group, benzenesulfonyl, phenyl C1-4Alkyl sulphonyl or (C1-4Alkyl) x (phenyl) ySi, institute The substituent group stated be selected from one or more halogens, methyl, ethyl, propyl, isopropyl, tertiary butyl, halogenated methyl, halogenated ethyl, Methoxyl group, ethyoxyl, propoxyl group, tert-butoxy, halogenated methoxy or halo ethyoxyl substitution;X, y is independently selected from 0 and arrives 3 integer, and the summation of x and y is 3.
In another embodiment of the present invention, R2Selected from optionally substituted following groups:C1-4Alkyl-carbonyl, phenyl Carbonyl, C1-4Alkyl sulphonyl, phenyl sulfonyl, phenyl C1-4Alkyl sulphonyl, the substituent group are selected from one or more halogen Element, methyl, ethyl, propyl, isopropyl, tertiary butyl, halogenated methyl, halogenated ethyl, methoxyl group, ethyoxyl, propoxyl group, tertiary fourth oxygen Base, halogenated methoxy or halo ethyoxyl.
In another embodiment of the present invention, R1Selected from optionally substituted following groups:Phenyl, benzyl, methylamino ethoxy Base, propoxy methyl, t-butoxymethyl, phenylcarbonyl group, benzenesulfonyl, benzene mesyl, Et3Si,i-Pr3Si,t- BuMe2Si or t-BuPh2Si, the substituent group are selected from one or more fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tertiary fourth Base, trifluoromethyl, methoxyl group, ethyoxyl, propoxyl group, tert-butoxy or trifluoromethoxy.
In another embodiment of the present invention, R2Selected from optionally substituted following groups:Formoxyl, acetyl group, benzene Base carbonyl, mesyl, ethylsulfonyl, benzenesulfonyl or benzene mesyl, the substituent group be selected from one or more fluorine, Chlorine, methyl, ethyl, propyl, isopropyl, tertiary butyl, trifluoromethyl, methoxyl group, ethyoxyl, propoxyl group, tert-butoxy or trifluoro Methoxyl group.
In another embodiment of the present invention, Formula VII compound represented have following Formula VII ' shown in structure:
In another embodiment of the present invention, in step A, by chiral base catalyst, oxidant and/or pro-oxidant and Alkali is added in the mixed liquor of water and organic solvent, and formula (I) compound is added in cooling, and temperature is kept to be reacted, and formula is obtained after processing (II) compound.The temperature that cools down in preferably step A is -25 DEG C~10 DEG C.Preferably the reaction time is 4h~15h.It is excellent Choosing be the molar ratio of formula (I) compound and alkali is 1: 1~1: 10.Preferably oxidant is selected from catalytic amount, formula (I) compound Molar ratio with pro-oxidant is 1: 1~1: 10.Preferably formula (I) compound and the molar ratio of chiral base catalyst is 50: 1 ~120: 1.In another embodiment of the present invention, in step A, by chiral base catalyst, metal ion oxidant and/or Pro-oxidant, inorganic base are added in the mixed liquor of water and alcohol, are cooled to -5 DEG C~5 DEG C, and formula (I) compound is added, and keep temperature 6h~10h is reacted, formula (II) compound is obtained after processing.Preferably formula (I) compound and the molar ratio of inorganic base is 1: 2~1: 5.Preferred metal ion oxidant is the hungry compound of catalytic amount, and the pro-oxidant of metal ion is iron compound, formula (I) compound and the molar ratio of pro-oxidant are 1: 1~1: 5.Preferably mole of formula (I) compound and chiral base catalyst Than being 80: 1~100: 1.In another embodiment of the present invention, further comprise the steps in step A:Reaction terminates Afterwards, reaction, esters solvent extraction is quenched in the aqueous solution that reducing inorganic salt is added, and organic phase uses diluted acid, saturated sodium-chloride successively Aqueous solution washs drying, is concentrated to give formula (II) compound.
In another embodiment of the present invention, in step B-1, by hydroxy activating reagent be added formula (II) compound, alkali with It in the mixed liquor of organic solvent, is then reacted under certain conditions, obtains (III) after processing.Preferably hydroxyl is lived It is -25 DEG C~20 DEG C that agent, which is added to the temperature in mixed liquor,.Preferably reaction temperature is -10 DEG C~10 DEG C.Preferably Reaction time is 0.5h~2h.Preferably formula (II) compound and the molar ratio of alkali is 1: 0.5~1: 5.Preferably formula (II) compound and the molar ratio of hydroxy activating reagent are 1: 1~1: 3.In another embodiment of the present invention, step B-1 In, under conditions of -15 DEG C~-5 DEG C, by sulfonic acid chloride addition formula (II) compound, the mixed liquor of fatty amine, halogenated hydrocarbon solvent In, 0.5h~1.5h is then reacted under conditions of -5 DEG C~5 DEG C, obtains formula (III) compound after processing.Preferably formula (II) compound and the molar ratio of alkali are 1: 1~1: 2.Preferably formula (II) compound and the molar ratio of sulfonic acid chloride is 1: 1~1 :1.5.In another embodiment of the present invention, further comprise the steps in step B-1:1. after reaction, adding appropriate Water stir about 0.5-1h, after stratification, organic phase is washed with diluted acid, diluted alkaline, saturated sodium-chloride water solution successively, dry, dense Contract to obtain product.The ratio and the hydroxy activated reagent pair of controlling reaction temperature of control inventory can be passed through in this preparation process The selectivity of different hydroxyls.
In another embodiment of the present invention, in step B-2, formula (III) compound and formula (IV) compound are dissolved in In organic solvent, heating reaction under agitation obtains formula (V) compound after processing.Preferably reaction temperature be 50 DEG C~ 100℃.Preferably the reaction time is 1h~10h.Preferably formula (III) compound and the molar ratio of IV compounds is 1: 1 ~1: 5.In another embodiment of the present invention, in step B-2, it is molten that formula (III) compound with IV compounds is dissolved in alcohols In agent, it is heated to 60~90 DEG C of reaction 2h~5h under agitation, formula (V) compound is obtained after processing.Preferably formula (III) The molar ratio of compound and formula (IV) compound is 1: 1~1: 2.5.In another embodiment of the present invention, in step B-2 into One step includes the following steps:1. halogenated hydrocarbon solvent dissolved product is added in after reaction, concentration of reaction solution, diluted acid, dilute is used successively Alkali, saturated sodium-chloride water solution washing, it is dry, it is concentrated to give crude product;2. the bad molten of one or more formulas (V) compound is added Agent washing purifies to obtain product.
In another embodiment of the present invention, in step B-3, formula (V) compound is dissolved in organic solvent, under stirring Cool down, the aqueous solution of oxidant is added, is reacted under certain condition, formula (VI) compound is obtained after processing.Preferably Be cooling temperature be -20 DEG C~0 DEG C.Preferably reaction temperature is -10 DEG C~10 DEG C.Preferably the reaction time be 0.1h~ 2h.Preferably formula (V) compound and the molar ratio of oxidant is 1: 0.5~1: 5.In another embodiment of the present invention, In step B-3, formula (V) compound is dissolved in nitrile solvents, -15 DEG C~-5 DEG C are cooled under stirring, metal ion is added The aqueous solution of oxidant reacts 0.1h~1.5h under the conditions of -5 DEG C~5 DEG C, and formula (VI) compound is obtained after processing.Preferably Formula (I) compound and the molar ratio of metal ion oxidant are 1: 1~1: 3.In another embodiment of the present invention, step Further comprise the steps in B-3:1. reaction is quenched in the aqueous solution that reducing inorganic salt after reaction, is added, concentration is anti- Liquid is answered, mixed liquor and the stirring of halogenated hydrocarbons and water, filtering is added, stratification obtains organic phase;2. being purified at salt, organic phase is with dilute Acid extraction, gained water phase modulates PH=8~11 with inorganic base, then is extracted with esters solvent, and gained organic phase is successively with saturation food Salt water washing, it is dry, it is concentrated to give product;Preferred products obtained therefrom may be repeated into salt and purify, to obtain the higher production of purity Product.
In another embodiment of the present invention, in step C, formula (VI) compound, alkali is added in hydroxy activating reagent and is had In the mixed liquor of solvent, then reaction terminates until reacting at room temperature, obtains formula (VII) compound after processing.Preferably The reaction temperature of step C is -25 DEG C~20 DEG C.Preferably formula (VI) compound and the molar ratio of alkali is 1: 1~1: 6.It is preferred that Be the molar ratio of formula (VI) compound and hydroxy activating reagent be 1: 1~1: 3.In another embodiment of the present invention, it walks In rapid C, under conditions of -5 DEG C~5 DEG C, by sulfonic acid chloride addition formula (VI) compound, the mixed liquor of fatty amine, halogenated hydrocarbon solvent In, then reaction terminates until reacting at room temperature, obtains formula (VII) compound after processing.Preferably formula (VI) compound with The molar ratio of alkali is 1: 2~1: 4.Preferably formula (VI) compound and the molar ratio of sulfonic acid chloride is 1: 1~1: 2.In the present invention Another embodiment in, further comprise the steps in step C:1. after reaction, add suitable quantity of water stir about 0.5-1h, After stratification, organic phase saturated common salt water washing is dry, is concentrated to give crude product;2. one or more formulas (VII) change is added The poor solvent for closing object obtains product by recrystallization purifying.
In another embodiment of the present invention, the method for preparing formula (VII) compound, includes the following steps:
(1) by two hydration potassium osmates, the potassium ferricyanide, (DHQ) of catalytic amount2PHAL, potassium carbonate are dissolved in water and the tert-butyl alcohol In mixed liquor, it is cooled to 0 DEG C, the t-butanol solution of formula (I ') compound, mole of formula (I ') compound and the potassium ferricyanide is added Than being 1: 3-1: 3.5, wherein the molar ratio of two hydration potassium osmates and the potassium ferricyanide is 1: 50-1: 500, preferably 1: 300 or so, formula (I ') compound and (DHQ)2The molar ratio of PHAL is 1: 90-1: 100, and the molar ratio of formula (I ') compound and potassium carbonate is 1: 3- 1: 3.5, it is kept for 0 DEG C react 8 hours, sodium sulfite is then added, reaction, ethyl acetate extraction is quenched, organic phase is used successively 0.5% dilute hydrochloric acid, saturated sodium-chloride washing, it is dry, it is concentrated to give formula (II ') compound;
(2) formula (II ') compound, triethylamine are dissolved in dichloromethane, are cooled to -10 DEG C, the two of methylsufonyl chloride is added The molar ratio of chloromethanes solution, formula (II ') compound and methylsufonyl chloride is 1: 1, mole of formula (II) compound and triethylamine Than being 1: 1~1: 1.5,1~1.5h is then reacted at 0 DEG C, reaction finishes;Add water to stir, is then allowed to stand layering, organic phase is successively It is washed with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride, it is dry, it is concentrated to give formula (III ') compound;
(3) formula (III ') compound and IV ' compounds are dissolved in alcohol solvent, formula (III ') compound and IV ' chemical combination The molar ratio of object is 1: 2, stirs lower 3~4h of heating reflux reaction, removes solvent under reduced pressure, dichloromethane is added, successively with 0.5% Dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride water solution washing, the mixed of normal heptane and ethyl acetate is added in dry, concentration Bonding solvent (normal heptane: ethyl acetate=10: 1), solid is precipitated in stirring, filters to obtain formula (V ') compound;
(4) formula (V ') compound is dissolved in acetonitrile solvent, is cooled to -10 DEG C under stirring, the water-soluble of ammonium ceric nitrate is added Liquid, the molar ratio 1: 2-1: 2.5 of formula (V ') compound and ammonium ceric nitrate react 0.5h under the conditions of 0 DEG C, and saturation sulfurous acid is added Reaction is quenched in sodium, removes solvent under reduced pressure, and mixed liquor and the stirring of dichloromethane and water, diatomite filtering is added, and stratification obtains Organic phase;Gained organic phase is extracted with 2% dilute hydrochloric acid, and gained water phase modulates PH=9~10 with sodium bicarbonate, then with acetic acid second Ester aqueous phase extracted, it is dry with saturated common salt water washing, then 1-1.5eq dilute hydrochloric acid/Isosorbide-5-Nitrae-dioxane solution is being added, it is precipitated Obtain product;
(5) under conditions of 0 DEG C, by methylsufonyl chloride addition formula (VI ') compound, the dichloromethane solution of triethylamine In, the molar ratio of formula (VI ') compound and triethylamine is 1: 3;Formula (VI ') compound and the molar ratio of sulfonic acid chloride are 1: 1~1: 1.5,8h is reacted at room temperature, adds stratification after water washing, organic phase saturated common salt water washing is dry, is concentrated to give crude product; Crude product being dissolved in the n-heptane solution of 3 times of volumes, be heated to 60 DEG C, supernatant is then cooled to 25 DEG C, solid is precipitated, Filtering, dry formula (VII ') compound
In another embodiment of the present invention, the Formulas I ' it is prepared by following steps,
Step (1)
2 compound of formula is obtained by the reaction in 1 compound of formula with MSCI under alkaline condition;Preferred alkali is triethylamine; Preferred reaction dissolvent is dichloromethane;
Step (2)
Formula (I ') compound is obtained by the reaction in 2 compound of formula with 3 compound of formula under alkaline condition;Preferably alkali is Potassium tert-butoxide;Preferred reaction dissolvent is THF.
Prepare the method such as following formula (IX) compound and its salt, the preparation of previously described formula (VII) compound of the present invention Formula (VII) compound obtained by method is reacted with formula (VIII), is prepared into formula (IX) or its salt compound,
R3,R4, q and n it is as defined in claim 1;
R5And R6It is each independently selected from following one group of group:Amino, cyano, and optionally by 1 to 3 Q2Substituted C1-6 Alkyl, C1-4Alkoxy C1-3Alkyl, C2-6Alkenyl or C2-6Alkynyl, Q2Selected from following one group of group:Halogen, hydroxyl, amino, cyanogen Base, carboxyl or C1-6Alkoxy;
R7Selected from optionally by 1 to 3 Q3Substituted C1-6Alkyl, C3-8Naphthenic base C0-6Alkyl, 3-8 circle heterocyclic ring bases C0-6Alkyl Or 5-6 unit's heteroaryls C0-6Alkyl, Q3Selected from following one group of group:Halogen, hydroxyl, amino, C1-6Alkyl, C1-6Alkoxy, and The C replaced by 1 to 3 halogen1-6Alkyl or C1-6Alkoxy;
R8Selected from following one group of group:Hydrogen, halogen, hydroxyl, cyano, nitro or C1-6Alkylamidoalkyl.
In another embodiment of the present invention, R3And R4It is each independently selected from hydrogen, optionally by 1 to 3 Q1Substituted benzene Base, benzyl, pyridyl group, pyrimidine radicals, furyl, thienyl, thiazolyl, pyrrole radicals, imidazole radicals Huo oxazolyls, and R3And R4It is different When be hydrogen,
Q1Selected from fluorine, chlorine, hydroxyl, amino, methyl, trifluoromethyl or methoxyl group.
In another embodiment of the present invention, R5And R6It is each independently selected from optionally by 1 to 3 Q2Substituted C1-4Alkane Base, Q2Selected from fluorine, chlorine, amino, methoxy or ethoxy.
In another embodiment of the present invention, R7Selected from optionally by 1 to 3 Q3Substituted C1-4Alkyl, Q3Selected from fluorine, Chlorine, methyl, methoxyl group.
In another embodiment of the present invention, R8Selected from hydrogen, chlorine 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 formula (IX) compound or its salt has structure as follows:
Without prejudice to the field on the basis of common sense, above-mentioned each condition can be combined arbitrarily to get of the present invention each preferable Example.
In preparation method of the present invention, the drying includes but not limited to following drying means:Constant pressure and dry, decompression are dry Dry, spray drying, fluidized drying, freeze-drying, infrared drying, microwave drying, hygroscopic desiccation etc..Those skilled in the art can To select one or more drying modes according to the property of the product, carried out according to the humidity of product one or many dry It is dry.
Raw material or reagent of the present invention are commercially available in addition to special instruction.
In the present invention, using the well-known method of organic synthesis field technical staff, the present invention can be detached and purified Compound and intermediate.The example of the conventional method of separation and purifying compound may include but be not limited to:It is carried in solid Chromatographic isolation is carried out on body (for example, silica gel, aluminium oxide or silica derived from alkyl silane), is tied again under high or low temperature Brilliant (optionally being pre-processed with activated carbon), TLC separation distill at a variety of pressures, vacuum sublimation, grinding, for example, below Described method:″Vogel′s Textbook of Practical Organic Chemistry", 5th edition (1989), Furniss et al., pub.Longman Scientific&Technical, Essex CM20 2JE, England.
Asymmetry catalysis synthetic method prepares formula (VII) compound through the invention, can improve yield at least 46%, and stereoselectivity is high, ee values > 95%.
Raw material that is less toxic, cheap, being easy to get or examination are used in the method for the present invention for preparing formula (VII) compound Agent, manufacturing cost is lower, and per kilogram cost is only 40% or so of chiral resolution cost, and cost substantially reduces;Meanwhile it making The cost of standby Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic acids ester type compound (Formula IX ') is greatly reduced.
Isosorbide-5-Nitrae-dihydropyridine -3,5- bis- that formula (the VII ') compound prepared by the method for the invention is further prepared Carboxylic acid ester compound (Formula IX ') it is up-to-standard, no new impurity occurs.
Preparation method of the present invention has more efficiency, and each step reaction condition is mild, easy to control, and product can pass through extraction The simple operations such as take, crystallize purified:Its integrated artistic is simple, easy to operate.
The present invention develops a novel method for constructing the pyrrolidines with the chiral tertiary alcohol, and stereoselectivity is high, not Come the value that is widely used.
Description of the drawings
Attached drawing 1 is the high-efficient liquid phase chromatogram of chiral intermediate.
Embodiment
Mode by the following examples is described in further detail the above of the present invention, but therefore not incite somebody to action this Invention is limited among the embodiment described range.All technologies realized based on the above of the present invention belong to the present invention's Range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to product manual Selection.
Embodiment 1 (S) -1- (preparations (compound VII ') of 3 alcohol of (3,3- diphenyl propyl) -3- methylpyrrolidin-
1, the preparation of -1 base methanesulfonates of 3 alkene of 3- methyl butyl-
- 1 alcohol (1kg, 11.61mol) of 3 alkene of 3- methyl butyl-, triethylamine (1762g, 17.42mol), two are added in reaction kettle Chloromethanes (10L), is cooled to 0 DEG C under stirring, methylsufonyl chloride (1596g, 13.92mol) is added dropwise, controlling reaction temperature exists 10 DEG C are reacted 16 hours hereinafter, warming naturally to 25 DEG C after adding, and reaction is completed.It is slowly added to water (5L), is stirred 20 minutes, it is quiet Layering is set, water phase is discarded, organic phase is washed with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution successively, anhydrous slufuric acid Sodium is dried, and filtering, 45 DEG C remove solvent under reduced pressure and obtain crude title compound, direct plunges into next step.
2, ((- 1 base of 3 alkene of 3- methyl butyl-) oxygroup prepares synthesis to 1- methoxyl groups -4-
- 1 base methanesulfonates (1209g, 9.74mol) of 3 alkene of 3- methyl butyl-, THF (12L) are added in reaction kettle, stirring is lower to be added Enter potassium tert-butoxide (1025g, 9.13mol), be heated to 60 DEG C react 1 hour, be slowly added to 4- metoxyphenols (1kg, 6.09mol), 60 DEG C are kept after adding to react 16 hours, reaction is completed.25 DEG C are cooled to, pad diatomite filtering, filtrate concentrates, DMF (10L) lysate is added, adds water (1L) and stirs 10 minutes, with mixed solvent (normal heptane: ethyl acetate=10: 1) Extraction three times, merges organic phase, and washing twice, then with saturated sodium-chloride water solution is washed, and anhydrous sodium sulfate drying is steamed after filtering Do to obtain title compound (yield 70%).
3, the preparation of (S) -4- (4- methoxyphenoxies) -2- methybutane -1,2- glycol
Two hydration potassium osmates (3.9g), (DHQ) are added in reaction kettle2PHAL (42.7g), the potassium ferricyanide (5481g) and carbon Water (30L) and the tert-butyl alcohol (5L) is added in sour potassium (2302g), is cooled to 0 DEG C, and 1- methoxyl groups -4- ((3 alkene -1 of 3- methyl butyl- is added dropwise Base) oxygroup) benzene (1kg) t-butanol solution (5L), add holding 0 DEG C react 8 hours, reaction terminates.Anhydrous sulfurous acid is added Sodium (237g), keep 0 DEG C stir 1 hour, be added ethyl acetate extraction three times, merge organic phase, successively with 0.5% dilute salt Acid, saturated sodium-chloride washing, organic phase are dried with anhydrous sodium sulfate, and title compound (yield 90%, e.e values is concentrated under reduced pressure to obtain > 95%).
4, the preparation of (S) -2- hydroxyls -4- (4- methoxyphenoxies) -2- methyl butyl methanesulfonates
In reaction kettle be added (S) -4- (4- methoxyphenoxies) -2- methybutanes -1,2- glycol (1kg, 4.42mol), Triethylamine (537g, 5.30mol), dichloromethane (12L), -10 DEG C are cooled under stirring, be added dropwise methylsufonyl chloride (532g, Dichloromethane solution (2L) 4.64mol) keeps 0 DEG C and reacts 1 hour after adding, reaction finishes.Water (5L) is added and stirs 20 points Clock, stratification, successively with 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride, anhydrous sodium sulfate drying subtracts organic phase Pressure is evaporated off solvent and obtains title compound (yield 96%).
5, the system of (S) -1- ((3,3- diphenyl propyl) amino) -4- (4- methoxyphenoxies) -2- methybutane -2- alcohol It is standby
Be added in reaction kettle (S) -2- hydroxyls -4- (4- methoxyphenoxies) -2- methyl butyls methanesulfonates (1kg, 3.28mol), 3,3-1- diphenyl propanes -1- ammonia (1389g, 6.57mol), absolute ethyl alcohol (15L), are heated to 80 DEG C under stirring Back flow reaction 3~4 hours, reaction are completed.It removes solvent under reduced pressure, dichloromethane (10L) dissolved product is added, successively with 0.5% Solvent is evaporated off after filtering in dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying Crude product is obtained, mixed solvent (10L, normal heptane: ethyl acetate=10: 1) stirring 2 hours, and product is precipitated, natural after filtering is added Dry to obtain title compound (yield 75%).
6, the preparation of (S) -4- ((3,3- diphenyl propyl) amino) -3- methylpropane -1,3- glycol
(S) -1- ((3,3- diphenyl propyl) amino) -4- (4- methoxyphenoxies) -2- methyl fourths are added in reaction kettle Alkane -2- alcohol (1kg, 2.38mol), acetonitrile (10L), -10 DEG C are cooled under stirring, be added dropwise ammonium ceric nitrate (2744g, Aqueous solution (5L) 5.00mol), control temperature at 0 DEG C hereinafter, keeping thermotonus 30min, complete by reaction during being added dropwise. Be added saturated aqueous sodium sulfite quench (1L) go out reaction, remove acetonitrile under reduced pressure, the mixed liquor of dichloromethane and water be added (respectively 30min, pad diatomite filtering 5L) are stirred, filter cake is washed with dichloromethane (2L), merging filtrate, stratification, and organic phase is used 2%HCl is extracted three times, discards organic phase, water phase NaHCO3PH=9~10 are adjusted to, then water phase is extracted with ethyl acetate three times, Merge organic phase, uses saturated common salt water washing, anhydrous sodium sulfate to dry successively, after filtering, be added with stirring the HCl/ of 1.2eq Dioxane solution, product are precipitated, and filter to obtain title compound (yield 65%).
7, (S) -1- (preparations of 3 alcohol of (3,3- diphenyl propyl) -3- methylpyrrolidin-
In reaction kettle be added (S) -4- ((3,3- diphenyl propyl) amino) -3- methylpropanes -1,3- glycol (1kg, 3.19mol), triethylamine (968g, 9.57mol), dichloromethane (10L), are cooled to 0 DEG C, MsCl are added dropwise under stirring (548g, 4.78mol) warms naturally to 25 DEG C and reacts 8 hours after adding, add water (5L) stirring after the completion of HPLC display reactions 30min, stratification, organic phase use saturated common salt water washing, anhydrous sodium sulfate to dry, crude product are evaporated to obtain after filtering successively. The normal heptane of 3 times of volumes is added, is heated to 60 DEG C and stirs 1 hour, supernatant is poured into another container and stirred by stratification Lower Temperature fall, 60 DEG C of the normal heptane that layer oily matter adds 1 times of volume extract again, and supernatant merges with first time, Product is precipitated in temperature-fall period, and temperature continues stirring 2 hours, filtering after being down to 25 DEG C, and filter cake is washed with normal heptane, is dried in vacuo It is persistently vacuumized with vacuum pump 8 hours 40 DEG C in case, under -0.1MPa, obtains title compound (yield 46%, ee > 95%).Point Minor:C20H25NO molecular weight:295.43 mass spectrum (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).
Structural identification tests (HPLC chromatogram experiment)
Chromatographic condition:It takes this product accurately weighed, add flowing phased soln and the solution containing 0.3mg in 1mL is made, as examination Product solution is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), with amylose-tri- [3, 5- xylyl An Jijiasuanzhis ]As filler (4.6 × 250mm, 5 μm of AD-H);Mobile phase is n-hexane-absolute ethyl alcohol- Diethylamine (90: 10: 0.05);Flow velocity is 0.6mL/min;Column temperature is 30 DEG C;Detection wavelength is 214nm.Precision measures test sample 10 μ L of solution inject liquid chromatograph, record chromatogram.Theoretical cam curve must not be less than 3000.
Experimental result:
See the high-efficient liquid phase chromatogram of 1 chiral intermediate of attached drawing
The retention time and respective configuration of 6 chiral intermediate of table
2 3- of embodiment ((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) 5- methyl (S) -2,6- bis- The preparation of methyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester (compound IX ') and its salt
1,3- ((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) 5- methyl (S) -2,6- dimethyl -4- The preparation of (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester (crude product)
By (R) -5- (methoxycarbonyl) -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylates (304g, 1.02mol) is dissolved in dichloromethane solution (3.4L), and DMF (34mL) is added, is cooled to -10 DEG C, oxalyl chloride is slowly added dropwise (155.8g, 1.23mol), control temperature are reacted 4 hours at 0 DEG C or less, and TLC monitoring reactions are completed.By (S) -1- ((3,3- bis- Phenyl propyl) -3- methylpyrrolidin- 3 the dichloromethane solution (600mL) of alcohol (302g, 1.02mol) be slowly added to, control temperature Degree reacts 1 hour at 0 DEG C or less, and the reaction was complete for TLC monitorings, uses water, 1% dilute hydrochloric acid, 5% aqueous sodium carbonate, 5% food successively Salt water washing, organic phase are dried with anhydrous sodium sulfate, and filtering removes solvent under reduced pressure and obtains 3- ((S) -1- (3,3- diphenylprops Base) -3- methylpyrrolidin- 3- yls) 5- methyl (S) -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- bis- Carboxylate crude product (624g) is directly used in next step.
2, potassium (S) -3- ((((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) oxygroup) carbonyl) -5- The preparation of (methoxycarbonyl) -2,6- dimethyl -4- (3- nitrobenzophenones) -4H- pyridine -1- compounds
By 3- ((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) 5- methyl (S) -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester (623.7g, 1.02mol) is dissolved in the tert-butyl alcohol (4L), is heated to 50 DEG C stirring is uniformly dissolved for 1 hour, and normal heptane (800mL) is added, continue to be added at stirring 10 minutes, 50 DEG C potassium tert-butoxide (172g, 1.53mol), rear Temperature fall is added, solid is precipitated, and filtering is washed with poor solvent (petroleum ether or normal heptane), obtains potassium (S)- 3- ((((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) oxygroup) carbonyl) -5- (methoxycarbonyl) -2,6- Dimethyl -4- (3- nitrobenzophenones) -4H- pyridine -1- compounds.
Molecular formula:C36H38ClKN3O6Molecular weight:647.8 mass spectrums (m/z):648.2(M+H+)
Potassium element is analyzed:K, 6.42%.
3,3- ((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) 5- methyl (S) -2,6- dimethyl -4- The preparation of (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester hydrochloride
By potassium (S) -3- ((((S) -1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls) oxygroup) carbonyl) -5- (methoxycarbonyl) -2,6- dimethyl -4- (3- nitrobenzophenones) -4H- pyridine -1- compounds are dissolved in absolute methanol (500mL), It adds dichloromethane (4L) to be uniformly dissolved, successively with 2% dilute hydrochloric acid, water washing, then washs three with 5% aqueous sodium carbonate It is secondary, then washed to acidity with 1% dilute hydrochloric acid, organic phase is evaporated, and obtains grease (360g).Methanol (1L) is added to dissolve, uses hole Filtrate is added dropwise in quickly 1% dilute hydrochloric acid (10L) of stirring (200rpm) by the micro-pore-film filtration that 0.45 micron of diameter, Product is precipitated, filtering, filter cake pure water washing to filtrate pH=7, anhydrous calcium chloride drying, vacuum drying chamber (50 DEG C ,- It is dried 24 hours under 0.09MPa) and obtains product (301g).
Specific rotation is+105.23 ° of (temperature:20 DEG C, concentration:2mg/mL, MeOH dissolve).
Molecular formula:C36H40ClN3O6Molecular weight:646.2 mass spectrums (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 (16)

1. preparing the method such as following formula (VII) compound, which is characterized in that
The method includes:Make formula (VI) compound that formula (VII) chemical combination be obtained by the reaction under alkaline condition with hydroxy activating reagent Object,
Wherein, the hydroxy activating reagent is selected from one of the following or a variety of:Acyl chlorides, sulfonic acid chloride, acid anhydrides, alcohol, phenol, halogenation examination Agent or silane protectant, the hydroxy activating reagent can form ester, sulphonic acid ester, ether, alkyl halide or silicon ether with hydroxyl;
R3,R4Separately it is selected from following one group of group:Hydrogen, C1-6Alkyl, optionally by 1 to 3 Q1Substituted aryl C0-6Alkane Base, 3-8 member naphthenic base C0-6Alkyl, 3-8 circle heterocyclic ring bases C0-6Alkyl, 5-6 unit's heteroaryls C0-6Alkyl or R3With R4It is formed together 3-8 members naphthenic base, 3-8 circle heterocyclic ring bases, optionally by 1 to 3 Q1Replaced, the Q1Selected from following one group of group:Halogen, Hydroxyl, cyano, nitro, amino, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamidoalkyl;
Q is selected from 0,1,2 or 3;
N is selected from 1 to 5 integer.
2. preparation method as described in claim 1, which is characterized in that wherein described formula (VI) compound is changed by formula (II) Object is closed to be prepared by following steps with formula (IV) compound,
The preparation process includes:
Formula (II) compound is reacted into the formula of being formed (III) with hydroxy activating reagent under alkaline condition,
Wherein, R1,R2It is independently selected from optionally substituted following groups:C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, benzene Base, 5-6 unit's heteroaryls, phenyl C1-6Alkyl, 5-6 unit's heteroaryls C1-6Alkyl, C1-6Alkyl-carbonyl, phenylcarbonyl group, 5-6 member heteroaryls Base carbonyl, C1-6Alkyl sulphonyl, phenyl sulfonyl, 5-6 unit's heteroaryls sulfonyl, phenyl C1-6Alkyl sulphonyl, 5-6 member heteroaryls Base C1-6Alkyl sulphonyl or (C1-6Alkyl)x(phenyl)ySi, the substituent group are selected from one or more halogens, nitro, C1-6Alkane Base, halogenated C1-6Alkyl, C1-6Alkoxy or halogenated C1-6Alkoxy;
The R2Group is the residue of hydroxy activating reagent;
X, y is independently selected from 0 to 3 integer, and the summation of x and y is 3;
The R3,R4, q, n it is as defined in claim 1;
Formula (III) is reacted into the formula of being prepared into (V) with formula IV compound,
Formula (V) sloughs R1Group and formula (VI) compound.
3. preparation method as claimed in claim 2, which is characterized in that wherein described formula (II) compound passes through following steps It is prepared,
By formula (I) compound formula (II) compound is obtained by catalysis oxidation under the action of chiral base catalyst.
4. such as claim 2-3 any one of them preparation methods, which is characterized in that
R1,R2It is independently selected from optionally substituted following groups:C1-4Alkyl, C1-4Alkoxy C1-4Alkyl, phenyl, phenyl C1-4Alkyl, C1-4Alkyl-carbonyl, phenylcarbonyl group, C1-4Alkyl sulphonyl, phenyl sulfonyl, phenyl C1-4Alkyl sulphonyl or (C1-4 Alkyl)x(phenyl)ySi, the substituent group are selected from one or more halogens, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy or Halogenated C1-4Alkoxy;
The R2Group is the residue of hydroxy activating reagent;
R3And R4It is each independently selected from hydrogen, optionally by 1 to 3 Q1Substituted phenyl, benzyl, pyridyl group, pyrimidine radicals, furyl, Thienyl, thiazolyl, pyrrole radicals, imidazole radicals Huo oxazolyls, and R3And R4It is asynchronously hydrogen,
Q1Selected from fluorine, chlorine, hydroxyl, amino, methyl, ethyl, isopropyl, tertiary butyl, methoxyl group, ethyoxyl or trifluoromethyl;
Q is selected from 1,2 or 3;
N is selected from 2 or 3;
X, y is independently selected from 0 to 3 integer, and the summation of x and y is 3.
5. preparation method as claimed in claim 4, which is characterized in that
R1Selected from optionally substituted following groups:Phenyl, phenyl C1-4Alkyl, C1-4Alkoxy C1-4Alkyl, phenylcarbonyl group, benzene sulphur Acyl group, phenyl C1-4Alkyl sulphonyl or (C1-4Alkyl)x(phenyl)ySi, the substituent group are selected from one or more halogens, first Base, ethyl, propyl, isopropyl, tertiary butyl, halogenated methyl, halogenated ethyl, methoxyl group, ethyoxyl, propoxyl group, tert-butoxy, halogen Replace for methoxyl group or halo ethyoxyl;
R2Selected from optionally substituted following groups:C1-4Alkyl-carbonyl, phenylcarbonyl group, C1-4Alkyl sulphonyl, phenyl sulfonyl, Phenyl C1-4Alkyl sulphonyl, the substituent group are selected from one or more halogens, methyl, ethyl, propyl, isopropyl, tertiary fourth Base, halogenated methyl, halogenated ethyl, methoxyl group, ethyoxyl, propoxyl group, tert-butoxy, halogenated methoxy or halo ethyoxyl;
X, y is independently selected from 0 to 3 integer, and the summation of x and y is 3.
6. preparation method as claimed in claim 5, which is characterized in that
R1Selected from optionally substituted following groups:Phenyl, benzyl, ethoxyl methyl, propoxy methyl, t-butoxymethyl, benzene Base carbonyl, benzenesulfonyl, benzene mesyl, Et3Si,i-Pr3Si,t-BuMe2Si or t-BuPh2Si, the substituent group are selected from One or more fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tertiary butyl, trifluoromethyl, methoxyl group, ethyoxyl, propoxyl group, uncle Butoxy or trifluoromethoxy;
R2Selected from optionally substituted following groups:Formoxyl, acetyl group, phenylcarbonyl group, mesyl, ethylsulfonyl, benzene sulfonyl Base or benzene mesyl, the substituent group be selected from one or more fluorine, chlorine, methyl, ethyl, propyl, isopropyl, tertiary butyl, Trifluoromethyl, methoxyl group, ethyoxyl, propoxyl group, tert-butoxy or trifluoromethoxy.
7. preparation method as described in any one of claims 1-3, it is characterised in that include the following steps:
Step A:By chiral base catalyst, oxidant and/or pro-oxidant and alkali are added in the mixed liquor of water and organic solvent, drop Formula (I) compound is added in temperature, and temperature is kept to be reacted, and formula (II) compound is obtained after processing.
Step B-1:Hydroxy activating reagent is added in the mixed liquor of formula (II) compound, alkali and organic solvent, then in certain item It is reacted under part, obtains (III) after processing;
Step B-2:Formula (III) compound and formula (IV) compound are dissolved in organic solvent, under agitation heating reaction, Formula (V) compound is obtained after processing;
In step B-3:Formula (V) compound is dissolved in organic solvent, is cooled down under stirring, the water-soluble of oxidant is then added Liquid is reacted under certain condition, and formula (VI) compound is obtained after processing;
Step C:Hydroxy activating reagent is added in the mixed liquor of formula (VI) compound, alkali and organic solvent, is then reacted at room temperature Until reaction terminates, formula (VII) compound is obtained after processing.
8. preparation method as claimed in claim 7, cooling temperature is preferably -25 DEG C~10 DEG C in wherein step A, the reaction time The molar ratio of preferably 4h~15h, formula (I) compound and alkali is preferably 1: 1~1: 10;Preferably oxidant is selected from catalysis The molar ratio of amount, formula (I) compound and pro-oxidant is preferably 1: 1~1: 10;Formula (I) compound is rubbed with chiral base catalyst You are than preferably 50: 1~120: 1;The hydroxy activating reagent of step B-1 is added at preferably -25 DEG C~20 DEG C of the temperature of mixed liquor It carries out, reaction temperature is preferably -10 DEG C~10 DEG C, and the reaction time is preferably 0.5h~2h, and formula (II) compound and alkali rub You are than preferably 1: 0.5~1: 5;Formula (II) compound and the molar ratio of hydroxy activating reagent are preferably 1: 1~1: 3;In step B-2 Reaction temperature be preferably 50 DEG C~100 DEG C, the reaction time is preferably 1h~10h, formula (III) compound and formula (IV) compound Molar ratio be preferably 1: 1~1: 5;Cooling temperature in step B-3 is preferably -20 DEG C~0 DEG C, and reaction temperature is preferably -10 DEG C~10 DEG C, the reaction time is preferably 0.1h~2h, and the molar ratio of formula (V) compound and oxidant is preferably 1: 0.5~1: 5; It is carried out at preferably -25 DEG C~20 DEG C of the reaction temperature of step C, the molar ratio of formula (VI) compound and alkali is preferably 1: 1~1: 6; Formula (VI) compound and the molar ratio of hydroxy activating reagent are preferably 1: 1~1: 3.
9. preparation method as claimed in claim 8, which is characterized in that
In each step, the organic solvent separately be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, Alcohols, ethers, esters, ketone, diol, derivatives class, phenols, nitrile, amides, sulfone class, sulfoxide type, heteroaryl hydro carbons and they At least one of mixture, wherein aromatic hydrocarbon solvent is selected from least one of benzene, toluene and dimethylbenzene, aliphatic hydrocarbon Class solvent is selected from least one of pentane, hexane, heptane and octane, and alicyclic hydrocarbon type solvent is in pentamethylene and hexamethylene At least one, halogenated hydrocarbon solvent are selected from least one of dichloromethane, chloroform, fluorobenzene and dichloro-benzenes, and alcohols solvent is selected from At least one of methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, tert-pentyl alcohol, tertiary hexanol, benzyl alcohol, ethylene glycol and glycerine, ethers Solvent is selected from least one of tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE) and propylene oxide, and esters solvent is selected from acetic acid first At least one of ester, ethyl acetate, repefral and propyl acetate, ketones solvent are selected from acetone, methyl butyl At least one of ketone and methyl iso-butyl ketone (MIBK), diol, derivatives class solvent are selected from glycol monoethyl ether, ethylene glycol monoethyl ether, second At least one of glycol monobutyl ether, glycol dimethyl ether and ethylene glycol diethyl ether, phenol solvent are selected from phenol and p-cresol At least one of, nitrile solvents are selected from least one of acetonitrile and propionitrile, and amide solvent is selected from N, N- dimethyl formyls At least one of amine and n,N-dimethylacetamide, sulfone class solvent be selected from dimethyl sulfone, benzene second sulfone, diethyl sulfone, diphenyl sulfone and At least one of sulfolane, sulfoxide type solvents are selected from least one of dimethyl sulfoxide (DMSO), diethyl sulfoxide and benzyl, Heteroaryl hydrocarbon solvent is selected from pyridine;
In each step, the alkali is separately selected from least one of organic base and inorganic base, and the inorganic base difference is only On the spot it is selected from sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxide At least one of caesium, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide and ammonium hydroxide;
The alkaline metal salt, metal alkyl lithium compound, ammonobase lithiumation that the organic base is separately selected from alcohol close At least one of object and aminated compounds, the alkaline metal salt of the alcohol be selected from tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, At least one of sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, the metal alkyl lithium compound are selected from butyl lithium and phenyl At least one of lithium, the ammonobase lithium compound in lithium diisopropylamine and hexamethl disilamine base lithium extremely Few one kind, the aminated compounds are selected from fatty amines, as n,N-diisopropylethylamine, methylamine, ethamine, dimethylamine, diethylamine, At least one of triethylamine, ethylenediamine, isopropylamine, dibenzyl amine, tert-butylamine and hexamethylene diamine;Alcamines, such as monoethanolamine, two Isopropanolamine and N, at least one of N- diethyl ethylene diamines, amides, such as formamide, acetamide, acrylamide, colchicum At least one of alkali, camptothecine, n,N-Dimethylformamide and dimethylacetylamide, alicyclic ring amine, such as cyclohexylamine, two sub- second At least one of base triamine, hexa, morpholine and piperazine, aromatic amine, such as aniline, diphenylamines, benzidine, adjacent benzene At least one of diamines, p-phenylenediamine, open-chain crown ether, parachloroanilinum, m-oxethyl aniline and meta nitro aniline, naphthalene system amine Class, such as at least one of naphthalidine, 2- naphthylamines, Kerafyrm acid, tobias acid, R acid, K acid and naphthylenediamine, polyethyleneimine, hydroxyl Amine;Preferred fat amine, such as at least one of n,N-diisopropylethylamine, dimethylamine, diethylamine, triethylamine and hexamethylene diamine;
In each step, the oxidant or pro-oxidant are independently selected from non-metal simple-substance oxidant, metal ion At least one of oxidant, acidic oxidation agent, peroxide oxidant;
1) the non-metal simple-substance oxidant described in is selected from least one of oxygen, chlorine, bromine gas, iodine, ozone;
2) metal ion oxidant described in be selected from manganese compound, chromium compound, osmium compound, lead compound, iron compound, At least one of cerium compound;The manganese compound is selected from least one of potassium permanganate, manganese dioxide;The chromium Compound is selected from least one of sodium dichromate, potassium bichromate, chromium trioxide;The osmium compound is selected from potassium osmate (VI) At least one of dihydrate, osmium tetroxide;The lead compound is selected from lead tetra-acetate;The iron compound is selected from iron At least one of potassium cyanide, ferric trichloride, ferric nitrate;The cerium compound in ammonium ceric nitrate, cerium oxide at least It is a kind of;
3) the oxygen-containing acid oxidant is selected from least one of the concentrated sulfuric acid, concentrated nitric acid, periodic acid, hypochlorous acid, perchloric acid;
4) peroxide oxidant is selected from least one of inorganic peroxide or organic per-compounds;The nothing Machine peroxide in hydrogen peroxide, sodium peroxide, potassium peroxide, calper calcium peroxide, zinc peroxide, potassium hydrogen peroxymonosulfate extremely Few one kind;The organic per-compounds are selected from peroxidating alcohol, peroxidating ether, diacyl peroxide, peroxy acid, peroxide At least one of ester, peroxycarbonates and ketone peroxide;The peroxidating alcohol was selected from oxyethanol, the tertiary fourth of peroxidating At least one of alcohol, peroxidating isopropanol;The peroxidating ether is selected from ethyl peroxide, peroxidation di-t-butyl, peroxidating At least one of isopropyl ether, tert-butyl peroxide ether;The diacyl peroxide is selected from benzoyl peroxide, two isobutyls At least one of acyl peroxide, two-(2- ethyl hexanoyls) peroxide, diacetyl peroxide;The peroxy acid is selected from At least one of peroxyformic acid, Peracetic acid, benzoyl hydroperoxide, metachloroperbenzoic acid;The peroxy esters are selected from peroxide second It is tert-butyl acrylate, the peroxy trifluoroacetic acid tert-butyl ester, benzylhydroperoxide tert-pentyl ester, t-butyl perbenzoate, tert-butyl peroctoate, excessively sad At least one of tert-pentyl ester;The peroxycarbonates are selected from di-isopropyl peroxydicarbonate, two ring of dicetyl peroxydicarbonate At least one of own ester, dicetyl peroxydicarbonate two (- benzene oxygen ethyl) ester;The ketone peroxide is selected from dimethyl peroxidating At least one of ketone, methyl ethyl ketone peroxide, cyclohexanone peroxide, acetone peroxide, methylethyl ketone peroxide;
The chiral base catalyst is selected from by quinine, quinine mono-hydrochloric salts dihydrate, cinchonine, cinchonidine, dihydro Kui Rather, quinindium, dihydrochinidin, hydroquinine Isosorbide-5-Nitrae-(2,3- benzodiazine) diether, hydroquinidine Isosorbide-5-Nitrae-(2,3- diazas Naphthalene) at least one of diether and its arbitrary derivative.
10. preparation method as described in claim 9, which is characterized in that
In step A, by the mixed of chiral base catalyst, metal ion oxidant and/or pro-oxidant, inorganic base addition water and alcohol It closes in liquid, is cooled to -5 DEG C~5 DEG C, formula (I) compound is added, keep thermotonus 6h~10h, formula (II) chemical combination is obtained after processing Object;Preferably formula (I) compound and the molar ratio of inorganic base is 1: 2~1: 5;Preferred metal ion oxidant is catalysis The osmium compound of amount, the pro-oxidant of metal ion are iron compound, and the molar ratio of formula (I) compound and pro-oxidant is 1: 1~1: 5;Preferably formula (I) compound and the molar ratio of chiral base catalyst is 80: 1~100: 1;
In step B-1, under conditions of -15 DEG C~-5 DEG C, it is molten that formula (II) compound, fatty amine, halogenated hydrocarbons is added in sulfonic acid chloride In the mixed liquor of agent, 0.5h~1.5h is then reacted under conditions of -5 DEG C~5 DEG C, obtains formula (III) compound after processing;It is excellent Choosing be the molar ratio of formula (II) compound and fatty amine is 1: 1~1: 2;Preferably formula (II) compound and sulfonic acid chloride is rubbed Your ratio is 1: 1~1: 1.5;
In step B-2, formula (III) compound and IV compounds are dissolved in alcohols solvent, are heated to 60 DEG C under agitation ~90 DEG C of reaction 2h~5h, obtain formula (V) compound after processing;Preferably formula (III) compound and formula (IV) compound is rubbed Your ratio is 1: 1~1: 2.5;
In step B-3, formula (V) compound is dissolved in nitrile solvents, -15 DEG C~-5 DEG C are cooled under stirring, is added and contains metal The aqueous solution of ion-oxygen agent reacts 0.1h~1.5h under the conditions of -5 DEG C~5 DEG C, and formula (VI) compound is obtained after processing;It is preferred that Be formula (I) compound and the molar ratio of metal ion oxidant is 1: 1~1: 3;
In step C, under conditions of -5 DEG C~5 DEG C, formula (VI) compound, fatty amine, halogenated hydrocarbon solvent is added in sulfonic acid chloride In mixed liquor, then reaction terminates until reacting at room temperature, obtains formula (VII) compound after processing;Preferably formula (VI) is changed The molar ratio for closing object and fatty amine is 1: 2~1: 4;Preferably formula (VI) compound and the molar ratio of sulfonic acid chloride is 1: 1~1: 2。
11. preparation method as described in claim 10, which is characterized in that
Further comprise the steps in step A:After reaction, reducing inorganic salt is added, reaction, esters solvent extraction is quenched It takes, organic phase is washed with diluted acid, saturated sodium-chloride water solution successively, dry, is concentrated to give formula (II) compound;
Further comprise the steps in step B-1:1. after reaction, add suitable quantity of water stir about 0.5-1h, after stratification, Organic phase is washed with diluted acid, diluted alkaline, saturated sodium-chloride water solution successively, dry, is concentrated to give product;
Further comprise the steps in step B-2:1. halogenated hydrocarbon solvent dissolving production is added in after reaction, concentration of reaction solution Product are washed with diluted acid, diluted alkaline, saturated sodium-chloride water solution successively, dry, are concentrated to give crude product;2. one or more formulas are added (V) the poor solvent washing of compound purifies to obtain product;
Further comprise the steps in step B-3:1. reducing inorganic salt, which after reaction, is added, is quenched reaction, concentration is anti- Liquid is answered, mixed liquor and the stirring of halogenated hydrocarbons and water, filtering is added, stratification obtains organic phase;2. being purified at salt, organic phase is with dilute Acid extraction, gained water phase is adjusted to pH=8~11 with inorganic base, then is extracted with esters solvent, and gained organic phase is successively with saturation food Salt water washing, drying, are concentrated to give product;Preferred products obtained therefrom can carry out repeatedly purifying at salt;
Further comprise the steps in step C:1. after reaction, adding suitable quantity of water stir about 0.5-1h, after stratification, have Machine mutually uses saturated common salt water washing, dry, is concentrated to give crude product;2. the bad molten of one or more formulas (VII) compound is added Agent obtains product by recrystallization purifying.
12. preparation method as described in claim 11, which is characterized in that
The poor solvent is one or more in fat hydrocarbon solvent, alicyclic hydrocarbon type solvent, esters solvent;Aliphatic hydrocarbon Class solvent is selected from least one of pentane, hexane, heptane and octane, and alicyclic hydrocarbon type solvent is in pentamethylene and hexamethylene At least one, esters solvent in methyl acetate, ethyl acetate, repefral and propyl acetate at least one Kind;
The diluted acid is selected from least one of dilute hydrochloric acid, dust technology, dilute sulfuric acid of 0.1%-5%;
The diluted alkaline or inorganic base is selected from least one of sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate;
The reducing inorganic salt is selected from least one of sodium sulfite, sodium thiosulfate or sodium dithionite.
13. the method for preparing formula (VII) compound such as claim 1-12 any one of them, which is characterized in that including following Step:
(1) by two hydration potassium osmates, the potassium ferricyanide, (DHQ) of catalytic amount2PHAL, potassium carbonate are dissolved in the mixed liquor of water and the tert-butyl alcohol In, it is cooled to 0 DEG C, is added the t-butanol solution of formula (I ') compound, the molar ratio of formula (I ') compound and the potassium ferricyanide is 1: 3-1: 3.5, formula (I ') compound and (DHQ)2The molar ratio of PHAL is 1: 90-1: 100, and formula (I ') compound and potassium carbonate rub You are kept for 0 DEG C react 8 hours, sodium sulfite are then added, reaction, ethyl acetate extraction, organic phase is quenched than being 1: 3-1: 3.5 It is washed successively with 0.5% dilute hydrochloric acid, saturated sodium-chloride, it is dry, it is concentrated to give formula (II ') compound;
(2) formula (II ') compound, triethylamine are dissolved in dichloromethane, are cooled to -10 DEG C, the dichloromethane of methylsufonyl chloride is added The molar ratio of alkane solution, formula (II ') compound and methylsufonyl chloride is 1: 1, and the molar ratio of formula (II) compound and triethylamine is 1 : 1~1: 1.5,1~1.5h is then reacted at 0 DEG C, reaction finishes;Add water to stir, be then allowed to stand layering, organic phase is used successively 0.5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride washing, it is dry, it is concentrated to give formula (III ') compound;
(3) formula (III ') compound and IV ' compounds are dissolved in alcohol solvent, formula (III ') compound and IV ' compounds Molar ratio is 1: 2, stirs lower 3~4h of heating reflux reaction, removes solvent under reduced pressure, dichloromethane is added, successively with 0.5% it is dilute Hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride water solution washing, dry, concentration, the mixing that normal heptane and ethyl acetate is added are molten Agent (normal heptane: ethyl acetate=10: 1), solid is precipitated in stirring, filters to obtain formula (V ') compound;
(4) formula (V ') compound is dissolved in acetonitrile solvent, is cooled to -10 DEG C under stirring, the aqueous solution of ammonium ceric nitrate, formula is added (V ') compound and the molar ratio of ammonium ceric nitrate 1: 2-1: 2.5 react 0.5h under the conditions of 0 DEG C, and saturated sodium sulfite is added and quenches It goes out reaction, removes solvent under reduced pressure, mixed liquor and the stirring of dichloromethane and water is added, diatomite filtering, stratification obtains organic Phase;Gained organic phase is extracted with 2% dilute hydrochloric acid, and gained water phase modulates PH=9~10 with sodium bicarbonate, then is extracted with ethyl acetate Water intaking phase, merge organic phase, it is dry with saturated common salt water washing then molten 1-1.5eq dilute hydrochloric acid/Isosorbide-5-Nitrae-dioxane is added Product is precipitated to obtain in liquid;
(5) under conditions of 0 DEG C, by methylsufonyl chloride be added formula (VI ') compound, triethylamine dichloromethane solution in, formula (VI ') compound and the molar ratio of triethylamine are 1: 3;Formula (VI ') compound and the molar ratio of sulfonic acid chloride are 1: 1~1: 1.5, room Temperature is lower to react 8h, adds stratification after water washing, organic phase saturated common salt water washing is dry, is concentrated to give crude product;It will slightly produce Product are dissolved in, and in n-heptane solution, are heated to 60 DEG C and are stirred certain time, and supernatant is then cooled to 25 DEG C, and solid is precipitated, Filtering, dry formula (VII ') compound,
14. preparing the method such as following formula (IX) or its salt, which is characterized in that the system of formula (VII) compound described in claim 1 Formula (VII) compound obtained by Preparation Method is reacted with formula (VIII), is prepared into formula (IX) compound or its salt,
R3,R4, q and n it is as defined in claim 1;
R5And R6It is each independently selected from following one group of group:Amino, cyano, and optionally by 1 to 3 Q2Substituted C1-6Alkane Base, C1-4Alkoxy C1-3Alkyl, C2-6Alkenyl or C2-6Alkynyl, Q2Selected from following one group of group:Halogen, hydroxyl, amino, cyano, Carboxyl or C1-6Alkoxy;
R7Selected from optionally by 1 to 3 Q3Substituted C1-6Alkyl, C3-8Naphthenic base C0-6Alkyl, 3-8 circle heterocyclic ring bases C0-6Alkyl or 5-6 Unit's heteroaryl C0-6Alkyl, Q3Selected from following one group of group:Halogen, hydroxyl, amino, C1-6Alkyl, C1-6Alkoxy, and by 1 to The C of 3 halogens substitution1-6Alkyl or C1-6Alkoxy;
R8Selected from following one group of group:Hydrogen, halogen, hydroxyl, cyano, nitro or C1-6Alkylamidoalkyl.
15. preparation method as claimed in claim 14, which is characterized in that
R3And R4It is each independently selected from hydrogen, optionally by 1 to 3 Q1Substituted phenyl, benzyl, pyridyl group, pyrimidine radicals, furyl, Thienyl, thiazolyl, pyrrole radicals, imidazole radicals Huo oxazolyls, and R3And R4It is asynchronously hydrogen,
Q1Selected from fluorine, chlorine, hydroxyl, amino, methyl, trifluoromethyl or methoxyl group;
R5And R6It is each independently selected from optionally by 1 to 3 Q2Substituted C1-4Alkyl, Q2Selected from fluorine, chlorine, amino, methoxyl group or second Oxygroup;
R7Selected from optionally by 1 to 3 Q3Substituted C1-4Alkyl, Q3Selected from fluorine, chlorine, methyl, methoxyl group;
R8Selected from hydrogen, chlorine or nitro;
Q is selected from 0,1,2 or 3;
N is selected from 1,2 or 3.
16. preparation method as claimed in claim 15, which is characterized in that described formula (IX) compound or its salt has as follows Shown in structure:
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