CN110183357A - It is a kind of to be used to prepare preparation method of the Sha Ku than bent intermediate - Google Patents
It is a kind of to be used to prepare preparation method of the Sha Ku than bent intermediate Download PDFInfo
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
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Abstract
The present invention discloses a kind of preparation method of midbody compound (R)-tert-butyl (1- ((1,1 '-biphenyl) -4- base) -3- hydroxy propane -2- base) carbamate, and preparation method is as shown in formula.Preparation method step of the invention is brief, improve reaction yield, reaction condition is mild, intermediate obtained in reaction process is largely not required to purify, next step reaction can directly be carried out, be conducive to large batch of synthesis, the Chiral Amine of stereocpecificity be efficiently synthesized using aminopherase, more suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of compound, are exactly that one kind is used to prepare Sha Ku than bent intermediate (R)-
The preparation method of tert-butyl (1- ((1,1 '-biphenyl) -4- base) -3- hydroxy propane -2- base) carbamate.
Background technique
LCZ696 was a kind of economic benefits and social benefits angiotensin receptor enkephalinase inhibitor developed by Novartis Co., Ltd, in 2015
Obtained FDA approval, the treatment for the heart failure patient that exploitation is reduced for ejection fraction on July 7.LCZ696 is by Sha Ku than bent
The compound of (Sacubitril, AHU-377) and Valsartan (Diovan) composition is considered with unique binding mode
The strain of failure heart can be reduced.Wherein husky library can block the mechanism of action of be responsible for reducing blood pressure two kinds of polypeptides, figured silk fabrics than song
It is husky smooth, vasodilation can be improved, stimulation body drains sodium and water.The safety threshold of cardiovascular drugs is high, and
LCZ696 even shows the greater security for surmounting conventional medicine, and industry thinks that the outstanding performance of LCZ696 becomes the medicine
One of the most important progress that past 10 years Heart disease field obtains.Meanwhile over the next several years, cardiovascular field will without appoint
What drug can contend with LCZ696, therefore its prospect in medicine is wide.
Sha Ku is than bent chemical name are as follows: 4- ((2S, 3R) -1- (1,1 '-biphenyl -4- base) -5- ethyoxyl -4- methyl -5- oxo
Pentane -2- base) amino) -4- ketobutyric acid (1), structural formula such as formula 1.(R)-tert-butyl (1- ((1,1 '-biphenyl) -4- base) -
3- hydroxy propane -2- base) carbamate (2) is that synthesis is husky
The compound 2 in formula 2 is seen than bent key intermediate, structure in library.
Document (J.Med.Chem., 1995,38,1689-1700) discloses preparation of the seed sand library than bent intermediate (2)
Method, synthetic route are following (formula 3).
The raw material D-Tyrosine of 3 route of formula is unnatural amino acid, and price is costly；Fluoroform is used in reaction process
Sulphonic acid anhydride, it is not only expensive, and also corrosivity is very strong, and it is more demanding to production operation；Suzuki coupling reaction step needs to use
To expensive palladium catalyst.
Patent WO2014032627 discloses preparation method of the seed sand library than bent intermediate (2), and synthetic route is as follows
(formula 4).
4 route of formula by chiral source introduce chiral centre, although route is shorter, grignard reaction cause be difficult to control, after
Processing operation is complicated.Triphenylphosphine is used in Mitsunobu reaction, and by-product triphenylphosphine oxide is not easy to completely remove.Azo two
Formic acid dialkyl ester is sensitive to light, heat and vibration, and there is a certain security risk.
Patent WO2010081410 discloses preparation method of the seed sand library than bent intermediate (2), and synthetic route is as follows
(formula 5)
5 route of formula is split using traditional method for splitting, and route is tediously long, and yield is lower, and competitiveness is weak.
Patent WO2013026773 discloses preparation method of the seed sand library than bent intermediate (2), and synthetic route is as follows
(formula 6).
6 route of formula constructs chiral centre, the catalyst and ligand price using rhodium catalyst and chiral ligand catalysis reduction
It is expensive and be not easy to obtain, so that 2 synthesis cost of compound is high, and severe reaction conditions (3.0MPa), it is difficult to realize industrialization.
By analyzing the synthetic route of preparation sand library that above-mentioned document is reported than bent intermediate (2), with its chiral centre
Building mode difference from the point of view of there are mainly three types of method.The first is introduced using chiral source.Second method is torn open using traditional
Point-score.The third method restores to obtain by chiral catalyst.The intermediate directly used in its preparation process is not easy to obtain, auxiliary
It helps that reagent dosage is larger or route is cumbersome, is unfavorable for preparing 2 in an economical manner.
Summary of the invention
The present invention provides one kind and can overcome the shortage of prior art, and is used to prepare as shown in Equation 2 prepare in husky library ratio song
The method of mesosome (R)-tert-butyl (1- ((1,1 '-biphenyl) -4- base) -3- hydroxy propane -2- base) carbamate.
Compound as shown in Equation 2 2-(R)-tert-butyl (1- ((1,1 '-biphenyl)-4- base)-3- hydroxy propane-of the invention
2- yl) carbamate preparation method, the reaction mechanism mechanism of reaction such as formula 7, it may be assumed that
(1) be starting material with compound 4- Phenylbenzoic acid 25, with acyl halide reagent or under alkaline condition with chlorine
Formic acid esters reacts in non-protonic solvent obtains compound 26, in which: the acyl halide reagent is halogenation sulfoxide or grass
Appointing in carboxylic acid halides or phosphorus oxychloride or phosphorus pentachloride or mesyl chloride or aryl sulfonyl chloride or trifluoromethanesulfchloride chloride
It is a kind of；R is halogen or sulfonate group or methyl carbonic acid ester group or alkylcarbonic acid ester group or aryl less than six carbon
Carbonate group；The alkali is triethylamine or diisopropyl ethyl amine or N-methylmorpholine or pyridine or triethylene two
Amine (DABCO) the either 11 carbon -7- alkene (DBU) of 1,8- diazabicyclo [5,4,0] or 1,5- diazabicyclo [4,3,0]
Nonyl- 5- alkene (DBN) either any one of 4-dimethylaminopyridine or tetramethylethylenediamine: the non-protonic solvent is
Any combination of any or above-mentioned solvent of methylene chloride or methyl tertiary butyl ether(MTBE) or toluene；
(2) through micro passage reaction Wollf rearrangement reaction is occurred into for the methyl tertiary butyl ether(MTBE) of compound 26 and diazomethane
Obtain compound 27；
(3) anti-in non-protonic solvent with chloro-formate by compound 27 and acyl halide reagent or under alkaline condition
Compound 28 should be obtained, the alkaline condition refers to triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine or three
Ethylene diamine (DABCO), the 11 carbon -7- alkene (DBU) of 1,8- diazabicyclo [5,4,0], 1,5- diazabicyclo [4,3,0]
Nonyl- 5- alkene (DBN) alkaline condition that either any one of 4-dimethylaminopyridine or tetramethylethylenediamine are constituted；
(4) through micro passage reaction Wollf rearrangement reaction is occurred into for compound 28 with diazomethane again and obtains the conjunction of chlorine assimilation
Object 29；
(5) compound 29 is converted under alkaline condition and obtains compound 30, in which: the alkali is alkali metal hydroxide
Object or alkaline earth metal hydroxide or alkali metal formate or alkaline-earth metal formates or alkali metal acetate or alkaline-earth metal
Any one of acetate；
(6) compound 30 is obtained into compound 12 through aminopherase enzymic catalytic reaction highly-solid selectively；
(7) compound 12 is reacted under alkaline condition to obtain compound 2 with di-tert-butyl dicarbonate, the alkali is alkali
Metal carbonate, alkali metal hydrogencarbonate, alkali metal hydroxide, alkaline earth metal hydroxide, pyridine, triethylamine, diisopropyl
Any one of base ethylamine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethylethylenediamine.
Preferably, the Sha Ku that is used to prepare of the invention is than the preparation method of bent midbody compound 2:
Step (1) is into (5): the acyl halide reagent is thionyl chloride, and the alkyl for being less than six carbon includes: first
Any one of base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and tert-butyl, R be halogen or sulfonate group or
Methyl carbonic acid ester group is chlorine, ethyl carbonate ester group or different less than the alkylcarbonic acid ester group of six carbon or arylcarbonic acid ester group
Butylcarbonate base it is any, the alkali be triethylamine, diisopropyl ethyl amine or N-methylmorpholine it is any；
The conversion in polar solvent obtains the polar solvent of compound 30 and is compound 29 under alkaline condition in step (5)
N,N-Dimethylformamide, N-Methyl pyrrolidone, low alkyl group alcohols solvent or water, alkali be sodium hydroxide, potassium hydroxide,
Any one of barium hydroxide, potassium carbonate, sodium formate or sodium acetate.
It is preferably, of the invention that be used to prepare Sha Ku more excellent than in its step (7) in the preparation method of bent midbody compound 2
The alkali of choosing is potassium carbonate or sodium hydroxide.
Further, of the invention to be used to prepare in preparation method of the Sha Ku than bent midbody compound 2: in step (3) and
(4) preparation of the t-butyl methyl ether solution of diazomethane in are as follows: by methyl tertiary butyl ether(MTBE) and diethylene glycol dimethyl ether in ice water
It under bath is cooling, is stirred evenly after methyl-nitroso-urea is added, then the hydrogen for being 30% by the solution of methyl-nitroso-urea and weight ratio
Potassium oxide solution is prepared by weight 3:1 through micro passage reaction, and the t-butyl methyl ether solution of diazomethane is obtained, by chemical combination
The solution of object 26 and the t-butyl methyl ether solution of diazomethane prepare diazonium compound through micro passage reaction by weight 1:1,
It flows into water, is slowly heated to 60 DEG C, is stirred to react 1 hour, stratification, organic phase is concentrated under reduced pressure, and dichloro is added in residue
Methane under ice-water bath is cooling, is added dropwise thionyl chloride, removes cryostat after dripping off, be warming up to back flow reaction 2 hours, be cooled to room temperature
The solution of compound 28 is obtained, then by the t-butyl methyl ether solution of the solution of compound 28 and diazomethane by weight 1:1
Diazonium compound is prepared through micro passage reaction, is flowed into hydrochloric acid, ice-water bath is cooling, is stirred to react 1 hour.Stratification, it is organic
It is mutually concentrated under reduced pressure, residue directly casts single step reaction.
It is being previously described for preparing in preparation method of the husky library than bent midbody compound 2, alkali used in step (5) is
Sodium hydroxide；It is used to prepare in preparation method of the Sha Ku than bent midbody compound 2, alkali used in step (7) is potassium carbonate.
Preferably, of the invention to be used to prepare in preparation method of the Sha Ku than bent midbody compound 2: in step (3) and
(4) preparation of the t-butyl methyl ether solution of diazomethane in are as follows: by methyl tertiary butyl ether(MTBE) and diethylene glycol dimethyl ether in ice water
It under bath is cooling, is stirred evenly after methyl-nitroso-urea is added, then the hydrogen for being 30% by the solution of methyl-nitroso-urea and weight ratio
Potassium oxide solution is prepared by weight 3:1 through micro passage reaction, and the t-butyl methyl ether solution of diazomethane is obtained, by chemical combination
The solution of object 26 and the t-butyl methyl ether solution of diazomethane prepare diazonium compound through micro passage reaction by weight 1:1,
It flows into water, is slowly heated to 60 DEG C, is stirred to react 1 hour, stratification, organic phase is concentrated under reduced pressure, and dichloro is added in residue
Under ice-water bath is cooling, triethylamine is added dropwise in methane, and ethyl chloroformate is added dropwise in temperature control -5~0 DEG C, and it is small to drip off rear insulated and stirred reaction 1
When, filtering obtains the solution of compound 28, and the t-butyl methyl ether solution of the solution of compound 28 and diazomethane is by weight
1:1 prepares diazonium compound through micro passage reaction, flows into hydrochloric acid, and ice-water bath is cooling, is stirred to react 1 hour, stratification has
Machine is mutually concentrated under reduced pressure, and n,N-Dimethylformamide, sodium formate are added in the residue after concentration, is heated to 90 DEG C, is stirred to react 5
Hour, it is cooled to room temperature, 100mL hydrochloric acid is added, continues to be heated to 100 DEG C of stirrings 1 hour, be cooled to room temperature, solid is precipitated and produces
Object, filtering obtain compound 30, and polyethylene glycol is added in compound 30, stir 10 minutes, the phosphate-buffered of pH=8.0 is added
Liquid, isopropylamine, phosphopyridoxal pyridoxal phosphate and transaminase, 45 DEG C insulated and stirred 20 hours.With sodium hydroxide solution tune pH to 10 or more, mistake
Crude product is filtered to obtain, second alcohol and water is added in crude product, and system is warming up to 45~50 DEG C, stirs 30min, and di-tert-butyl dicarbonate is added dropwise in temperature control
And sodium hydroxide solution, control system pH=9~10, drip off rear insulation reaction 3 hours.Ethyl alcohol is recovered under reduced pressure, is cooled to room temperature,
Filtering, obtains product 2.
Alternatively, of the invention is used to prepare preparation method of the Sha Ku than bent midbody compound 2 using following measure: in step
Suddenly in (3) and (4) t-butyl methyl ether solution of diazomethane preparation are as follows: by methyl tertiary butyl ether(MTBE) and diethylene glycol dimethyl ether
In the case where ice-water bath is cooling, stirred evenly after methyl-nitroso-urea is added, then be by the solution of methyl-nitroso-urea and weight ratio
30% potassium hydroxide solution is prepared by weight 3:1 through micro passage reaction, and the methyl tertiary butyl ether(MTBE) for obtaining diazomethane is molten
Liquid prepares the t-butyl methyl ether solution of the solution of compound 26 and diazomethane by weight 1:1 through micro passage reaction
Diazonium compound flows into water, is slowly heated to 60 DEG C, is stirred to react 1 hour, stratification, and organic phase is concentrated under reduced pressure, residue
Methylene chloride is added, under ice-water bath is cooling, N-methylmorpholine is added dropwise, isobutyl chlorocarbonate is added dropwise in temperature control -10~-5 DEG C, after dripping off
Insulation reaction 30 minutes, the solution of compound 28 is obtained by filtration, by the methyl tertbutyl of the solution of compound 28 and diazomethane
Ethereal solution prepares diazonium compound through micro passage reaction by weight 1:1, flows into hydrochloric acid, and ice-water bath is cooling, and it is small to be stirred to react 1
When, stratification, organic phase is concentrated under reduced pressure, and water and potassium hydroxide are added into the residue after concentration, is heated to slightly boiled, stirring
Reaction 8 hours, is cooled to room temperature, is extracted with dichloromethane, separate organic phase, recrystallized after concentration with methyl tertiary butyl ether(MTBE), obtained
To compound 30, compound 30 and polyethylene glycol stir 10 minutes, the phosphate buffer, isopropylamine, phosphoric acid of pH=8 are added
Pyridoxal and transaminase, 45 DEG C insulated and stirred 20 hours, then with sodium hydroxide solution tune pH to 10 or more, filter to obtain crude product,
Upper step, which is obtained by filtration in crude product, is added water and ethyl alcohol, is warming up to 40~50 DEG C, stirs 30min dissolved clarification, and triethylamine is added dropwise, slowly drops
To room temperature, di-tert-butyl dicarbonate is added dropwise, drips off rear insulation reaction 5 hours, ethyl alcohol is recovered under reduced pressure, is cooled to room temperature, filters, obtain
Product 2.
Relative to it has been reported that husky library than the synthetic method of bent intermediate (2), method and step provided by the invention is brief,
Reaction yield is improved, reaction condition is mild, and intermediate obtained in reaction process is largely not required to purify, and can directly carry out down
Single step reaction is conducive to large batch of synthesis, and the Chiral Amine of stereocpecificity is efficiently synthesized using aminopherase, is more suitable for
In industrialized production.
Specific embodiment
The present invention explains with reference to embodiments.
Embodiment one: in synthetic route as shown in Equation 7, acyl halide reagent is thionyl chloride, and R is chlorine atom；Compound
29 are converted into alkali used in compound 30 as sodium hydroxide.
The preparation of compound 26
Compound 25 (19.8g, 0.1mol) is added in 500mL there-necked flask, 100mL toluene is added, under ice-water bath is cooling,
It is added dropwise thionyl chloride (14.3g, 0.12mol).Cryostat is removed after dripping off, back flow reaction is warming up to 5 hours, is cooled to room temperature, and is protected
It deposits stand-by.
The preparation of compound 27
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 26 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into water, be slowly heated to 60 DEG C, be stirred to react 1 hour.Stratification, organic phase decompression are dense
Contracting, residue directly cast single step reaction.
The preparation of compound 28
Compound 27 (21.2g, 0.1mol) is added in 500mL there-necked flask, 100mL methylene chloride is added, ice-water bath is cold
But it under, is added dropwise thionyl chloride (14.3g, 0.12mol).Cryostat is removed after dripping off, and is warming up to back flow reaction 2 hours, is cooled to room
Temperature saves stand-by.
The preparation of compound 29
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 28 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into hydrochloric acid, ice-water bath is cooling, is stirred to react 1 hour.Stratification, organic phase are concentrated under reduced pressure,
Residue directly casts single step reaction.
The preparation of compound 30
Into the residue after above-mentioned concentration be added 100mL water, be added sodium hydroxide (8g, 0.2mol), be heated to it is slightly boiled,
It is stirred to react 8 hours, is cooled to room temperature, the extraction of 200mL methylene chloride is added, separates organic phase, uses methyl tertbutyl after concentration
Ether recrystallization, obtains compound 30 (17g, yield 75%).
The preparation of compound 12
Compound 30 (10g, 0.044mol) and 15mL polyethylene glycol 400 are added into reaction flask, stirs 10 minutes, is added
200mL phosphate buffer (pH=8.0), isopropylamine (3.1g), phosphopyridoxal pyridoxal phosphate (0.75g), transaminase (2.0g), 45 DEG C of guarantors
Temperature stirring 20 hours.With 2.0M sodium hydroxide solution tune pH to 10 or more, crude product is filtered to obtain, the next step is directly used in.
The preparation of compound 2
Crude product is obtained by filtration in upper step to be added in 250mL there-necked flask, 100mL methylene chloride and 30mL water is added.System liter
Temperature stirs 30min dissolved clarification to 45~50 DEG C, and potassium carbonate (17g, 0.13mol) is added and is slowly dropped to room temperature, two dimethyl dicarbonates are added dropwise
Butyl ester (11g, 0.048mol), drips off rear insulation reaction 3 hours.Normal pressure recycles methylene chloride, is cooled to room temperature, and filters, must produce
Object 12.6g, yield 84%.
Embodiment two: in synthetic route as shown in Equation 7, acyl halide reagent is oxalyl chloride, R chlorine atom；29 turns of compound
Turning to alkali used in compound 30 is sodium formate.
The preparation of compound 26
Compound 25 (19.8g, 0.1mol) is added in 500mL there-necked flask, 100mL methylene chloride is added, ice-water bath is cold
But it under, is added dropwise oxalyl chloride (13.7g, 0.12mol).Cryostat is removed after dripping off, reaction 4 hours is warmed to room temperature, is cooled to room temperature, and is protected
It deposits stand-by.
The preparation of compound 27
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 26 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into water, be slowly heated to 60 DEG C, be stirred to react 1 hour.Stratification, organic phase decompression are dense
Contracting, residue directly cast single step reaction.
The preparation of compound 28
Compound 27 (21.2g, 0.1mol) is added in 500mL there-necked flask, 200mL methyl tertiary butyl ether(MTBE), ice water is added
Under bath is cooling, it is added dropwise oxalyl chloride (13.7g, 0.12mol).Cryostat is removed after dripping off, and is warmed to room temperature reaction 4 hours, is cooled to room
Temperature saves stand-by.
The preparation of compound 29
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 28 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into hydrochloric acid, ice-water bath is cooling, is stirred to react 1 hour.Stratification, organic phase are concentrated under reduced pressure,
Residue directly casts single step reaction.
The preparation of compound 30
Be added 100mLN into the residue after above-mentioned concentration, dinethylformamide, be added sodium formate (13.6g,
0.2mol), 90 DEG C are heated to, is stirred to react 5 hours, room temperature is cooled to, 100mL hydrochloric acid is added, continues to be heated to 100 DEG C of stirrings
It 1 hour, is cooled to room temperature, solid product is precipitated, filtering obtains compound 30 (18g, yield 80%).
The preparation of compound 12
Compound 30 (10g, 0.044mol) and 15mL polyethylene glycol 400 are added into reaction flask, stirs 10 minutes, is added
200mL phosphate buffer (pH=8.0), isopropylamine (3.1g), phosphopyridoxal pyridoxal phosphate (0.75g), transaminase (2.0g), 45 DEG C of guarantors
Temperature stirring 20 hours.With 2.0M sodium hydroxide solution tune pH to 10 or more, crude product is filtered to obtain, the next step is directly used in.
The preparation of compound 2
Crude product is obtained by filtration in upper step to be added in 250mL there-necked flask, 70mL ethyl alcohol and 30mL water is added.System is warming up to 45
~50 DEG C, 30min is stirred, di-tert-butyl dicarbonate (11g, 0.048mol) and 30% sodium hydroxide solution, control is added dropwise in temperature control
System pH=9~10, drip off rear insulation reaction 3 hours.Ethyl alcohol is recovered under reduced pressure, is cooled to room temperature, filters, obtains product 11.8g, receives
Rate 82%.
Embodiment three: in synthetic route as shown in Equation 7, acyl halide reagent is phosphorus oxychloride, and R is chlorine atom；Compound
29 are converted into alkali used in compound 30 as potassium hydroxide.
The preparation of compound 26
Compound 25 (19.8g, 0.1mol) is added in 500mL there-necked flask, 100mL methylene chloride is added, ice-water bath is cold
But it under, is added dropwise phosphorus oxychloride (18.4g, 0.12mol).Cryostat is removed after dripping off, is warmed to room temperature reaction 2 hours, is saved stand-by.
The preparation of compound 27
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 26 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into water, be slowly heated to 60 DEG C, be stirred to react 1 hour.Stratification, organic phase decompression are dense
Contracting, residue directly cast single step reaction.
The preparation of compound 28
Compound 27 (21.2g, 0.1mol) is added in 500mL there-necked flask, 200mL methyl tertiary butyl ether(MTBE), ice water is added
Under bath is cooling, it is added dropwise phosphorus oxychloride (18.4g, 0.12mol).Cryostat is removed after dripping off, be warmed to room temperature reaction 2 hours, save to
With.
The preparation of compound 29
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 28 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into hydrochloric acid, ice-water bath is cooling, is stirred to react 1 hour.Stratification, organic phase are concentrated under reduced pressure,
Residue directly casts single step reaction.
The preparation of compound 30
100mL water is added into the residue after above-mentioned concentration, is added potassium hydroxide (11.2g, 0.2mol), is heated to micro-
Boiling, is stirred to react 8 hours, is cooled to room temperature, and the extraction of 200mL methylene chloride is added, separates organic phase, methyl- tert fourth is used after concentration
Base ether recrystallization, obtains compound 30 (15.8g, yield 70%).
The preparation of compound 12
Compound 30 (10g, 0.044mol) and 15mL polyethylene glycol 400 are added into reaction flask, stirs 10 minutes, is added
200mL phosphate buffer (pH=8.0), isopropylamine (3.1g), phosphopyridoxal pyridoxal phosphate (0.75g), transaminase (2.0g), 45 DEG C of guarantors
Temperature stirring 20 hours.With 2.0M sodium hydroxide solution tune pH to 10 or more, crude product is filtered to obtain, the next step is directly used in.
The preparation of compound 2
Crude product is obtained by filtration in upper step to be added in 250mL there-necked flask, 70mL water and 30mL ethyl alcohol is added.It is warming up to 40~50
DEG C, stir 30min dissolved clarification, be added dropwise triethylamine (18g, 0.18mol), be slowly dropped to room temperature, be added dropwise di-tert-butyl dicarbonate (11g,
0.048mol), rear insulation reaction is dripped off 5 hours.Ethyl alcohol is recovered under reduced pressure, is cooled to room temperature, filters, obtains product 12.8g, yield
87%.
Example IV: in synthetic route as shown in Equation 7, carboxylic acid does alkali in triethylamine, reacts to obtain with ethyl chloroformate
Active ester, R are ethyl carbonate ester group；It is sodium formate that compound 29, which is converted into alkali used in compound 30,.
The preparation of compound 26
Compound 25 (19.8g, 0.1mol) is added in 500mL there-necked flask, 200mL methyl tertiary butyl ether(MTBE), ice water is added
It under bath is cooling, is added dropwise triethylamine (20.2g, 0.2mol), temperature control -5~0 DEG C, is added dropwise ethyl chloroformate (16.3g, 0.15mol).
It drips off rear insulated and stirred to react 1 hour, filtering, filtrate cryo-conservation is stand-by.
The preparation of compound 27
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 26 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into water, be slowly heated to 60 DEG C, be stirred to react 1 hour.Stratification, organic phase decompression are dense
Contracting, residue directly cast single step reaction.
The preparation of compound 28
Compound 27 (21.2g, 0.1mol) is added in 500mL there-necked flask, 200mL methyl tertiary butyl ether(MTBE), ice water is added
It under bath is cooling, is added dropwise triethylamine (20.2g, 0.2mol), temperature control -5~0 DEG C, is added dropwise ethyl chloroformate (16.3g, 0.15mol).
It drips off rear insulated and stirred to react 1 hour, filtering, filtrate cryo-conservation is stand-by.
The preparation of compound 29
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 28 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into hydrochloric acid, ice-water bath is cooling, is stirred to react 1 hour.Stratification, organic phase are concentrated under reduced pressure,
Residue directly casts single step reaction.
The preparation of compound 30
Be added 100mLN into the residue after above-mentioned concentration, dinethylformamide, be added sodium formate (13.6g,
0.2mol), 90 DEG C are heated to, is stirred to react 5 hours, room temperature is cooled to, 100mL hydrochloric acid is added, continues to be heated to 100 DEG C of stirrings
It 1 hour, is cooled to room temperature, solid product is precipitated, filtering obtains compound 30 (18g, yield 80%).
The preparation of compound 12
Compound 30 (10g, 0.044mol) and 15mL polyethylene glycol 400 are added into reaction flask, stirs 10 minutes, is added
200mL phosphate buffer (pH=8.0), isopropylamine (3.1g), phosphopyridoxal pyridoxal phosphate (0.75g), transaminase (2.0g), 45 DEG C of guarantors
Temperature stirring 20 hours.With 2.0M sodium hydroxide solution tune pH to 10 or more, crude product is filtered to obtain, the next step is directly used in.
The preparation of compound 2
Crude product is obtained by filtration in upper step to be added in 250mL there-necked flask, 70mL ethyl alcohol and 30mL water is added.System is warming up to 45
~50 DEG C, 30min is stirred, di-tert-butyl dicarbonate (11g, 0.048mol) and 30% sodium hydroxide solution, control is added dropwise in temperature control
System pH=9~10, drip off rear insulation reaction 3 hours.Ethyl alcohol is recovered under reduced pressure, is cooled to room temperature, filters, obtains product 11.8g, receives
Rate 82%.
Embodiment five: in synthetic route as shown in Equation 7, carboxylic acid does alkali in N-methylmorpholine, anti-with isobutyl chlorocarbonate
Active ester should be obtained, R is isobutyl group base carbonate group；It is potassium hydroxide that compound 29, which is converted into alkali used in compound 30,.
The preparation of compound 26
Compound 25 (19.8g, 0.1mol) is added in 500mL there-necked flask, 200mL methylene chloride is added, ice-water bath is cold
But it under, is added dropwise N-methylmorpholine (21.2g, 0.21mol).Temperature control -10~-5 DEG C dropwise addition isobutyl chlorocarbonate (20.5g,
0.15mol), it drips off rear insulation reaction 30 minutes, filters, filtrate cryo-conservation is stand-by.
The preparation of compound 27
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 26 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into water, be slowly heated to 60 DEG C, be stirred to react 1 hour.Stratification, organic phase decompression are dense
Contracting, residue directly cast single step reaction.
The preparation of compound 28
Compound 25 (19.8g, 0.1mol) is added in 500mL there-necked flask, 200mL methylene chloride is added, ice-water bath is cold
But it under, is added dropwise N-methylmorpholine (21.2g, 0.21mol).Temperature control -10~-5 DEG C dropwise addition isobutyl chlorocarbonate (20.5g,
0.15mol), it drips off rear insulation reaction 30 minutes, filters, filtrate cryo-conservation is stand-by.
The preparation of compound 29
250mL methyl tertiary butyl ether(MTBE) and 90mL diethylene glycol dimethyl ether are added in 500mL there-necked flask, ice-water bath is cooling
Under, it is added methyl-nitroso-urea (30g, 0.29mol), stirs 10 minutes, cryo-conservation, for use.By the molten of methyl-nitroso-urea
Liquid and 30% potassium hydroxide solution (50g, 0.89mol) prepare the first of diazomethane through micro passage reaction by weight 3:1
Base tertbutyl ether solution.
By the t-butyl methyl ether solution of the solution of above compound 28 and diazomethane by weight 1:1 through microchannel plate
It answers device to prepare diazonium compound, flows into hydrochloric acid, ice-water bath is cooling, is stirred to react 1 hour.Stratification, organic phase are concentrated under reduced pressure,
Residue directly casts single step reaction.
The preparation of compound 30
100mL water is added into the residue after above-mentioned concentration, is added potassium hydroxide (11.2g, 0.2mol), is heated to micro-
Boiling, is stirred to react 8 hours, is cooled to room temperature, and the extraction of 200mL methylene chloride is added, separates organic phase, methyl- tert fourth is used after concentration
Base ether recrystallization, obtains compound 30 (15.8g, yield 70%).
The preparation of compound 12
Compound 30 (10g, 0.044mol) and 15mL polyethylene glycol 400 are added into reaction flask, stirs 10 minutes, is added
200mL phosphate buffer (pH=8.0), isopropylamine (3.1g), phosphopyridoxal pyridoxal phosphate (0.75g), transaminase (2.0g), 45 DEG C of guarantors
Temperature stirring 20 hours.With 2.0M sodium hydroxide solution tune pH to 10 or more, crude product is filtered to obtain, the next step is directly used in.
The preparation of compound 2
Crude product is obtained by filtration in upper step to be added in 250mL there-necked flask, 70mL water and 30mL ethyl alcohol is added.It is warming up to 40~50
DEG C, stir 30min dissolved clarification, be added dropwise triethylamine (18g, 0.18mol), be slowly dropped to room temperature, be added dropwise di-tert-butyl dicarbonate (11g,
0.048mol), rear insulation reaction is dripped off 5 hours.Ethyl alcohol is recovered under reduced pressure, is cooled to room temperature, filters, obtains product 12.8g, yield
87%.
Claims (8)
- The compound as shown in formula I (R)-tert-butyl 1. (1- ((1,1 '-biphenyl) -4- base) -3- hydroxy propane -2- base) carbamic acid The preparation method of ester, the reaction mechanism mechanism of reaction such as formula 3, it may be assumed that(1) be starting material with compound 4- Phenylbenzoic acid 25, with acyl halide reagent or under alkaline condition with chloro-carbonic acid Ester reacts in non-protonic solvent obtains compound 26, in which: the acyl halide reagent is halogenation sulfoxide, oxalyl halogen, three Any one of chlorethoxyfos, phosphorus pentachloride, mesyl chloride, aryl sulfonyl chloride or trifluoromethanesulfchloride chloride；R is halogen or sulphonic acid ester Base or methyl carbonic acid ester group or alkylcarbonic acid ester group or arylcarbonic acid ester group less than six carbon；The alkali is three second Amine, diisopropyl ethyl amine, N-methylmorpholine, pyridine or triethylene diamine (DABCO), 1,8- diazabicyclo [5,4,0] 11 carbon -7- alkene (DBU), 1,5- diazabicyclo [4,3,0] nonyl- 5- alkene (DBN) either 4-dimethylaminopyridine or tetramethyl Any one of base ethylenediamine: the non-protonic solvent is any of methylene chloride or methyl tertiary butyl ether(MTBE) or toluene Any combination of kind or above-mentioned solvent；(2) through micro passage reaction Wollf rearrangement reaction is occurred for the methyl tertiary butyl ether(MTBE) of compound 26 and diazomethane to obtain Compound 27；(3) compound 27 is reacted in non-protonic solvent with acyl halide reagent or under alkaline condition with chloro-formate To compound 28, the alkaline condition refers to triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine or triethylene Diamines (DABCO), the 11 carbon -7- alkene (DBU) of 1,8- diazabicyclo [5,4,0], 1,5- diazabicyclo [4,3,0] nonyl- 5- Alkene (DBN) alkaline condition that either any one of 4-dimethylaminopyridine or tetramethylethylenediamine are constituted；(4) through micro passage reaction Wollf rearrangement reaction is occurred into for compound 28 with diazomethane again and obtains chlorine ketone compound 29；(5) compound 29 is converted under alkaline condition and obtains compound 30, in which: the alkali be alkali metal hydroxide or Alkaline earth metal hydroxide or alkali metal formate or alkaline-earth metal formates or alkali metal acetate or alkaline-earth metal acetic acid Any one of salt；(6) compound 30 is obtained into compound 12 through aminopherase enzymic catalytic reaction highly-solid selectively；(7) compound 12 is reacted under alkaline condition to obtain compound 2 with di-tert-butyl dicarbonate, the alkali is alkali metal Carbonate, alkali metal hydrogencarbonate, alkali metal hydroxide, alkaline earth metal hydroxide, pyridine, triethylamine, diisopropyl second Any one of base amine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethylethylenediamine.
- 2. being used to prepare preparation method of the Sha Ku than bent midbody compound 2 as described in claim 1, it is characterised in that:Step (1) is into (5): the acyl halide reagent is thionyl chloride, and the alkyl for being less than six carbon includes: methyl, second Any one of base, n-propyl, isopropyl, normal-butyl, isobutyl group and tert-butyl, R are halogen or sulfonate group or methyl Carbonate group or alkylcarbonic acid ester group less than six carbon or arylcarbonic acid ester group are chlorine, ethyl carbonate ester group or isobutyl group Carbonate group it is any, the alkali be triethylamine, diisopropyl ethyl amine or N-methylmorpholine it is any；The polar solvent that the conversion in polar solvent obtains compound 30 under alkaline condition of compound 29 is N, N- in step (5) Dimethylformamide, N-Methyl pyrrolidone, low alkyl group alcohols solvent or water, alkali are sodium hydroxide, potassium hydroxide, hydrogen-oxygen Change any one of barium, potassium carbonate, sodium formate or sodium acetate.
- 3. according to claim 1 or 2 be used to prepare preparation method of the Sha Ku than bent midbody compound 2, feature exists Preferred alkali is potassium carbonate or sodium hydroxide in step (7).
- 4. according to claim 3 be used to prepare preparation method of the Sha Ku than bent midbody compound 2, it is characterised in that: The preparation of the t-butyl methyl ether solution of diazomethane in step (3) and (4) are as follows: by methyl tertiary butyl ether(MTBE) and diethylene glycol two Methyl ether stirs evenly after methyl-nitroso-urea is added in the case where ice-water bath is cooling, then by the solution and weight ratio of methyl-nitroso-urea It is prepared by weight 3:1 through micro passage reaction for 30% potassium hydroxide solution, obtains the methyl tertiary butyl ether(MTBE) of diazomethane Solution, by the t-butyl methyl ether solution of the solution of compound 26 and diazomethane by weight 1:1 through micro passage reaction system Standby diazonium compound, flows into water, is slowly heated to 60 DEG C, is stirred to react 1 hour, stratification, and organic phase is concentrated under reduced pressure, remaining Methylene chloride is added in object, under ice-water bath is cooling, thionyl chloride is added dropwise, removes cryostat after dripping off, is warming up to back flow reaction 2 hours, It is cooled to room temperature to obtain the solution of compound 28, then the t-butyl methyl ether solution of the solution of compound 28 and diazomethane is pressed Weight ratio 1:1 prepares diazonium compound through micro passage reaction, flows into hydrochloric acid, and ice-water bath is cooling, is stirred to react 1 hour.It stands Layering, organic phase are concentrated under reduced pressure, and residue directly casts single step reaction.
- 5. according to claim 4 be used to prepare preparation method of the Sha Ku than bent midbody compound 2, it is characterised in that Alkali used in step (5) is sodium hydroxide.
- 6. according to claim 5 be used to prepare preparation method of the Sha Ku than bent midbody compound 2, it is characterised in that Alkali used in step (7) is potassium carbonate.
- 7. according to claim 3 be used to prepare preparation method of the Sha Ku than bent midbody compound 2, it is characterised in that: The preparation of the t-butyl methyl ether solution of diazomethane in step (3) and (4) are as follows: by methyl tertiary butyl ether(MTBE) and diethylene glycol two Methyl ether stirs evenly after methyl-nitroso-urea is added in the case where ice-water bath is cooling, then by the solution and weight ratio of methyl-nitroso-urea It is prepared by weight 3:1 through micro passage reaction for 30% potassium hydroxide solution, obtains the methyl tertiary butyl ether(MTBE) of diazomethane Solution, by the t-butyl methyl ether solution of the solution of compound 26 and diazomethane by weight 1:1 through micro passage reaction system Standby diazonium compound, flows into water, is slowly heated to 60 DEG C, is stirred to react 1 hour, stratification, and organic phase is concentrated under reduced pressure, remaining Methylene chloride is added in object, under ice-water bath is cooling, triethylamine is added dropwise, temperature control -5~0 DEG C is added dropwise ethyl chloroformate, keeps the temperature after dripping off It is stirred to react 1 hour, filters, obtain the solution of compound 28, the solution of compound 28 and the methyl tertiary butyl ether(MTBE) of diazomethane Solution prepares diazonium compound through micro passage reaction by weight 1:1, flows into hydrochloric acid, and ice-water bath is cooling, and it is small to be stirred to react 1 When, stratification, organic phase is concentrated under reduced pressure, and n,N-Dimethylformamide, sodium formate are added in the residue after concentration, is heated to It 90 DEG C, is stirred to react 5 hours, is cooled to room temperature, 100mL hydrochloric acid is added, continue to be heated to 100 DEG C of stirrings 1 hour, be cooled to room Solid product is precipitated in temperature, and filtering obtains compound 30, and polyethylene glycol is added in compound 30, stirs 10 minutes, and pH=8.0 is added Phosphate buffer, isopropylamine, phosphopyridoxal pyridoxal phosphate and transaminase, 45 DEG C insulated and stirred 20 hours.With sodium hydroxide solution tune PH to 10 or more filters to obtain crude product, and second alcohol and water is added in crude product, and system is warming up to 45~50 DEG C, stirs 30min, and temperature control is added dropwise Di-tert-butyl dicarbonate and sodium hydroxide solution, control system pH=9~10 drip off rear insulation reaction 3 hours.Second is recovered under reduced pressure Alcohol is cooled to room temperature, and filtering obtains product 2.
- 8. according to claim 3 be used to prepare preparation method of the Sha Ku than bent midbody compound 2, it is characterised in that: The preparation of the t-butyl methyl ether solution of diazomethane in step (3) and (4) are as follows: by methyl tertiary butyl ether(MTBE) and diethylene glycol two Methyl ether stirs evenly after methyl-nitroso-urea is added in the case where ice-water bath is cooling, then by the solution and weight ratio of methyl-nitroso-urea It is prepared by weight 3:1 through micro passage reaction for 30% potassium hydroxide solution, obtains the methyl tertiary butyl ether(MTBE) of diazomethane Solution, by the t-butyl methyl ether solution of the solution of compound 26 and diazomethane by weight 1:1 through micro passage reaction system Standby diazonium compound, flows into water, is slowly heated to 60 DEG C, is stirred to react 1 hour, stratification, and organic phase is concentrated under reduced pressure, remaining Methylene chloride is added in object, under ice-water bath is cooling, N-methylmorpholine is added dropwise, temperature control -10~-5 DEG C are added dropwise isobutyl chlorocarbonate, drip off The solution of compound 28 is obtained by filtration in insulation reaction 30 minutes afterwards, by the methyl- tert fourth of the solution of compound 28 and diazomethane Base ethereal solution prepares diazonium compound through micro passage reaction by weight 1:1, flows into hydrochloric acid, and ice-water bath is cooling, is stirred to react 1 Hour, stratification, organic phase is concentrated under reduced pressure, and water and potassium hydroxide are added into the residue after concentration, is heated to slightly boiled, stirs Reaction 8 hours is mixed, room temperature is cooled to, is extracted with dichloromethane, separate organic phase, recrystallized after concentration with methyl tertiary butyl ether(MTBE), Compound 30, compound 30 and polyethylene glycol are obtained, stirs 10 minutes, the phosphate buffer, isopropylamine, phosphorus of pH=8 is added Sour pyridoxal and transaminase, 45 DEG C insulated and stirred 20 hours, then with sodium hydroxide solution tune pH to 10 or more, filter to obtain crude product, It is obtained by filtration in crude product in upper step and water and ethyl alcohol is added, be warming up to 40~50 DEG C, stir 30min dissolved clarification, triethylamine is added dropwise, slowly It is down to room temperature, di-tert-butyl dicarbonate is added dropwise, drips off rear insulation reaction 5 hours, ethyl alcohol is recovered under reduced pressure, is cooled to room temperature, is filtered, Obtain product 2.
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