CN110183357B - Preparation method for preparing Sacubitril intermediate - Google Patents
Preparation method for preparing Sacubitril intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of an intermediate compound (R) -tert-butyl (1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl) carbamate, which is shown in a formula. The preparation method provided by the invention is short in steps, improves the reaction yield, is mild in reaction conditions, can directly carry out the next reaction without purifying most of intermediates obtained in the reaction process, is beneficial to large-batch synthesis, utilizes aminotransferase to efficiently synthesize stereospecific chiral amine, and is more suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method for preparing a Sacubitril intermediate (R) -tert-butyl (1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl) carbamate.
Background
LCZ696, a dual action angiotensin receptor enkephalinase inhibitor developed by noval, was approved by the FDA on 7/2015 for the development of treatments for heart failure patients with reduced ejection fraction. LCZ696 is a complex composed of sabotary (AHU-377) and valsartan (Diovan), which has a unique mode of action believed to reduce the strain of a failing heart. Wherein the Sacubitril can block the action mechanism of two polypeptides responsible for lowering blood pressure, and the valsartan can improve vasodilatation and stimulate the body to excrete sodium and water. The safety threshold for cardiovascular drugs is extremely high, and LCZ696 shows even higher safety than conventional drugs, and the outstanding performance of LCZ696 is considered to make this drug one of the most important advances in the field of cardiology in the past decade. Meanwhile, in the future years, no medicine can compete with LCZ696 in the cardiovascular field, so that the medicine prospect is wide.
The chemical name of the shakubiqu is as follows: 4- ((2S,3R) -1- (1, 1' -biphenyl-4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutyric acid (1), and the structural formula is shown as formula 1. (R) -tert-butyl (1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl) carbamate (2) as synthetic sand
The structure of a key intermediate of the library pymetrozine is shown as a compound 2 in a formula 2.
The document (J.Med.chem.,1995,38,1689-1700) discloses a preparation method of a Sacubitril intermediate (2), and the synthetic route is as follows (formula 3).
The raw material D-tyrosine in the route of the formula 3 is unnatural amino acid and is expensive; the trifluoromethanesulfonic anhydride used in the reaction process is expensive, has strong corrosivity and has high requirements on production operation; the Suzuki coupling step requires the use of expensive palladium catalysts.
Patent WO2014032627 discloses a preparation method of a shakubiqu intermediate (2), and a synthetic route of the preparation method is as follows (formula 4).
The route of the formula 4 introduces chiral centers through a chiral source, and although the route is short, the initiation of the Grignard reaction is difficult to control, and the post-treatment operation is complex. Triphenylphosphine was used in the Mitsunobu reaction, and triphenylphosphine oxide, a by-product, was not easily removed completely. Dialkyl azodicarboxylate is sensitive to light, heat, and shock, presenting a certain safety risk.
Patent WO2010081410 discloses a preparation method of shakubiqu intermediate (2), and a synthetic route of the shakubiqu intermediate is as follows (formula 5)
The route shown in the formula 5 is resolved by using a traditional resolution method, and has the disadvantages of long route, low yield and weak competitiveness.
Patent WO2013026773 discloses a preparation method of a shakubiqu intermediate (2), and the synthetic route thereof is as follows (formula 6).
The route of the formula 6 adopts a rhodium catalyst and a chiral ligand to catalyze and reduce to construct a chiral center, and the catalyst and the ligand are expensive and difficult to obtain, so that the compound 2 has high synthesis cost and harsh reaction conditions (3.0MPa), and industrialization is difficult to realize.
By analyzing the synthetic route reported in the above literature for preparing the Sacubitril intermediate (2), there are three main approaches in view of the difference in the way in which the chiral center is constructed. The first is introduced using a chiral source. The second method utilizes a conventional resolution method. The third method is obtained by chiral catalyst reduction. Intermediates directly used in the preparation process are not easy to obtain, the dosage of auxiliary reagents is large or the route is complicated, and the preparation 2 is not favorable in an economic mode.
Disclosure of Invention
The invention provides a method for preparing a Sacubitril intermediate (R) -tert-butyl (1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl) carbamate shown in a formula 2, which can overcome the defects of the prior art.
The invention relates to a preparation method of a compound 2- (R) -tert-butyl (1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl) carbamate shown in a formula 2, and the reaction process is shown in a formula 7, namely:
(1) reacting a compound 4-phenylbenzoic acid 25 serving as an initial raw material with an acid halogenating reagent or with chloroformate in an aprotic solvent under an alkaline condition to obtain a compound 26, wherein: the acyl halide reagent is any one of halogenated sulfoxide, oxalyl halide, phosphorus oxychloride, phosphorus pentachloride, methanesulfonyl chloride, arylsulfonyl chloride or trifluoromethanesulfonyl chloride; r is halogen or sulfonate or methyl carbonate or alkyl carbonate or aryl carbonate of less than six carbons; the alkali is any one of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, triethylene Diamine (DABCO), 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1, 5-diazabicyclo [4,3,0] non-5-ene (DBN), 4-dimethylaminopyridine or tetramethylethylenediamine: the aprotic solvent is any one of dichloromethane, methyl tert-butyl ether or toluene or any combination of the solvents;
(2) carrying out Wollf rearrangement reaction on the compound 26 and methyl tert-butyl ether of diazomethane by a microchannel reactor to obtain a compound 27;
(3) reacting the compound 27 with an acid halogenating agent or with chloroformate in an aprotic solvent under basic conditions to obtain a compound 28, wherein the basic conditions are composed of any one of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or triethylenediamine (DABCO), 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1, 5-diazabicyclo [4,3,0] non-5-ene (DBN), 4-dimethylaminopyridine or tetramethylethylenediamine;
(4) carrying out Wollf rearrangement reaction on the compound 28 and diazomethane through a microchannel reactor to obtain a chloroketone compound 29;
(5) converting compound 29 under basic conditions to give compound 30, wherein: the alkali is any one of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal formate, alkaline earth metal formate, alkali metal acetate or alkaline earth metal acetate;
(6) carrying out the aminotransferase enzyme catalytic reaction on the compound 30 to obtain a compound 12 with high stereoselectivity;
(7) reacting the compound 12 with di-tert-butyl dicarbonate under an alkaline condition to obtain a compound 2, wherein the base is any one of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide, pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethylethylenediamine.
Preferably, the preparation method for preparing the intermediate compound 2 of the Sacubitril of the invention is as follows:
in steps (1) to (5): the acid halogenating agent is thionyl chloride, and the alkyl group of less than six carbons includes: any one of methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl and tert-butyl, R is halogen or a sulfonate group or a methyl carbonate group or an alkyl carbonate group or an aryl carbonate group with less than six carbons is any one of chlorine, ethyl carbonate group or isobutyl carbonate group, and the base is any one of triethylamine, diisopropylethylamine or N-methylmorpholine;
in the step (5), the polar solvent of the compound 29 converted in the polar solvent under the alkaline condition to obtain the compound 30 is N, N-dimethylformamide, N-methylpyrrolidone, lower alkyl alcohol solvent or water, and the alkali is any one of sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, sodium formate or sodium acetate.
Preferably, the preferred base in step (7) of the preparation method for preparing the sabotabiqu intermediate compound 2 according to the present invention is potassium carbonate or sodium hydroxide.
Further, in the preparation method for preparing the intermediate compound 2 of the shakubitrex of the present invention: the methyl tert-butyl ether solution of diazomethane in steps (3) and (4) is prepared as follows: cooling methyl tert-butyl ether and diethylene glycol dimethyl ether in an ice water bath, adding methyl nitrosourea, uniformly stirring, preparing a methyl tert-butyl ether solution of diazomethane by using a micro-channel reactor by using a methyl nitrosourea solution and a 30% potassium hydroxide solution in a weight ratio of 3:1, preparing diazo nitride by using a micro-channel reactor by using a compound 26 solution and a methyl tert-butyl ether solution of diazomethane in a weight ratio of 1:1, flowing into water, slowly heating to 60 ℃, stirring for reaction for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding dichloromethane into residues, dropwise adding thionyl chloride under cooling of the ice water bath, removing a cooling bath after dropwise adding, heating to reflux for reaction for 2 hours, cooling to room temperature to obtain a compound 28 solution, preparing the diazo nitride by using the micro-channel reactor by using the compound 28 solution and the methyl tert-butyl ether solution of diazomethane in a weight ratio of 1:1, the mixture was poured into hydrochloric acid, cooled in an ice-water bath, and reacted for 1 hour with stirring. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
In the aforementioned production method for preparing the shakubitril intermediate compound 2, the base used in the step (5) is sodium hydroxide; in the preparation method for preparing the intermediate compound 2 of the Sacubitril, the base used in the step (7) is potassium carbonate.
Preferably, in the preparation method for preparing the intermediate compound 2 of the shakubitrex of the present invention: the methyl tert-butyl ether solution of diazomethane in steps (3) and (4) is prepared as follows: adding methyl nitrosourea into methyl tert-butyl ether and diethylene glycol dimethyl ether under the cooling of an ice water bath, uniformly stirring, preparing a methyl nitrosourea solution and a 30% potassium hydroxide solution by weight ratio of 3:1 through a microchannel reactor to obtain a diazomethane methyl tert-butyl ether solution, preparing diazo-containing compound 26 solution and the diazomethane methyl tert-butyl ether solution by weight ratio of 1:1 through the microchannel reactor to prepare diazo, flowing into water, slowly heating to 60 ℃, stirring for reaction for 1 hour, standing for layering, concentrating under reduced pressure by organic phase, adding dichloromethane into residues, dropwise adding triethylamine under the cooling of the ice water bath, controlling the temperature to be-5-0 ℃, dropwise adding ethyl chloroformate, preserving heat and stirring for reaction for 1 hour after dropwise adding, filtering to obtain a compound 28 solution, preparing the diazo by using the microchannel reactor through the solution of the compound 28 solution and the diazomethane methyl tert-butyl ether solution by weight ratio of 1:1, flowing into hydrochloric acid, cooling in an ice-water bath, stirring for reacting for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding N, N-dimethylformamide and sodium formate into the concentrated residue, heating to 90 ℃, stirring for reacting for 5 hours, cooling to room temperature, adding 100mL hydrochloric acid, continuously heating to 100 ℃, stirring for 1 hour, cooling to room temperature, precipitating a solid product, filtering to obtain a compound 30, adding polyethylene glycol into the compound 30, stirring for 10 minutes, adding a phosphate buffer solution with the pH of 8.0, isopropylamine, pyridoxal phosphate and transaminase, and stirring at 45 ℃ for 20 hours under heat preservation. Adjusting the pH value to be more than 10 by using a sodium hydroxide solution, filtering to obtain a crude product, adding ethanol and water into the crude product, heating the system to 45-50 ℃, stirring for 30min, dropwise adding di-tert-butyl dicarbonate and the sodium hydroxide solution at a controlled temperature, controlling the pH value of the system to be 9-10, and carrying out heat preservation reaction for 3 hours after dropwise adding. Recovering ethanol under reduced pressure, cooling to room temperature, and filtering to obtain a product 2.
Alternatively, the preparation method for preparing the intermediate compound 2 of the Sacubitril adopts the following measures: the methyl tert-butyl ether solution of diazomethane in steps (3) and (4) is prepared as follows: adding methyl nitrosourea into methyl tert-butyl ether and diethylene glycol dimethyl ether under the cooling of an ice water bath, uniformly stirring, preparing a methyl tert-butyl ether solution of diazomethane by using a microchannel reactor through a methyl nitrosourea solution and a 30% potassium hydroxide solution according to the weight ratio of 3:1, preparing diazo nitride by using a microchannel reactor through a compound 26 solution and a methyl tert-butyl ether solution of diazomethane according to the weight ratio of 1:1, flowing into water, slowly heating to 60 ℃, stirring for reaction for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding dichloromethane into residues, dropwise adding N-methylmorpholine under the cooling of an ice water bath, controlling the temperature to be-10 to-5 ℃, dropwise adding isobutyl chloroformate, preserving the temperature for reaction for 30 minutes after dropwise adding, filtering to obtain a compound 28 solution, preparing the diazo nitride by using a microchannel reactor through a compound 28 solution and a methyl tert-butyl ether solution of diazomethane according to the weight ratio of 1:1, flowing into hydrochloric acid, cooling in an ice-water bath, stirring for reaction for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding water and potassium hydroxide into the concentrated residue, heating to slightly boil, stirring for reaction for 8 hours, cooling to room temperature, extracting with dichloromethane, separating out an organic phase, recrystallizing with methyl tert-butyl ether after concentration to obtain compound 30, compound 30 and polyethylene glycol, stirring for 10 minutes, adding phosphate buffer solution with pH of 8, isopropylamine, pyridoxal phosphate and transaminase, stirring at 45 ℃ for 20 hours, adjusting pH to more than 10 with sodium hydroxide solution, filtering to obtain a crude product, adding water and ethanol into the crude product obtained in the previous step, heating to 40-50 ℃, stirring for 30 minutes to dissolve, dropwise adding triethylamine, slowly cooling to room temperature, dropwise adding di-tert-butyl dicarbonate, reacting at 45 hours after dropwise addition, recovering ethanol under reduced pressure, cooling to room temperature, filtering to obtain a product 2.
Compared with the reported synthetic method of the Sacubitril intermediate (2), the method provided by the invention has the advantages of short steps, high reaction yield, mild reaction conditions, direct next-step reaction without purification of most of the intermediates obtained in the reaction process, contribution to large-batch synthesis, efficient synthesis of stereospecific chiral amine by using aminotransferase and more suitability for industrial production.
Detailed Description
The invention is illustrated below with reference to examples.
The first embodiment is as follows: in the synthetic route shown in formula 7, the acyl halide reagent is thionyl chloride, and R is chlorine atom; the base used to convert compound 29 to compound 30 is sodium hydroxide.
Preparation of Compound 26
Compound 25(19.8g, 0.1mol) was charged into a 500mL three-necked flask, 100mL of toluene was added, and thionyl chloride (14.3g, 0.12mol) was added dropwise with cooling in an ice-water bath. And after the dripping is finished, removing the cooling bath, heating to reflux reaction for 5 hours, cooling to room temperature, and storing for later use.
Preparation of Compound 27
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 26 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into water, the water is slowly heated to 60 ℃, and the reaction is stirred for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 28
Compound 27(21.2g, 0.1mol) was charged into a 500mL three-necked flask, 100mL of methylene chloride was added, and thionyl chloride (14.3g, 0.12mol) was added dropwise with cooling in an ice-water bath. And after the dripping is finished, removing the cooling bath, heating to reflux for reaction for 2 hours, cooling to room temperature, and storing for later use.
Preparation of Compound 29
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 28 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into hydrochloric acid, and the diazo compound is cooled in ice water bath and stirred for reaction for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 30
To the above-concentrated residue was added 100mL of water, sodium hydroxide (8g, 0.2mol) was added, the mixture was heated to a slight boiling state, stirred and reacted for 8 hours, cooled to room temperature, extracted with 200mL of dichloromethane, the organic phase was separated, concentrated and recrystallized from methyl t-butyl ether to obtain compound 30(17g, yield 75%).
Preparation of Compound 12
Compound 30(10g, 0.044mol) and 15mL of polyethylene glycol 400 were added to a reaction flask, stirred for 10 minutes, 200mL of phosphate buffer (pH 8.0), isopropylamine (3.1g), pyridoxal phosphate (0.75g), transaminase (2.0g) were added, and stirred at 45 ℃ for 20 hours. Adjusting pH to above 10 with 2.0M sodium hydroxide solution, filtering to obtain crude product, and directly using in the next step.
Preparation of Compound 2
The crude product from the above filtration was added to a 250mL three-necked flask, and 100mL of methylene chloride and 30mL of water were added. And (3) heating the system to 45-50 ℃, stirring for 30min to dissolve, adding potassium carbonate (17g, 0.13mol), slowly cooling to room temperature, dropwise adding di-tert-butyl dicarbonate (11g, 0.048mol), and reacting for 3 hours in a heat preservation manner after dropwise adding. The dichloromethane was recovered at normal pressure, cooled to room temperature and filtered to obtain 12.6g of product with 84% yield.
Example two: in the synthetic route shown in formula 7, the acyl halide reagent is oxalyl chloride, and R is chlorine atom; the base used to convert compound 29 to compound 30 is sodium formate.
Preparation of Compound 26
Compound 25(19.8g, 0.1mol) was charged into a 500mL three-necked flask, 100mL of methylene chloride was added, and oxalyl chloride (13.7g, 0.12mol) was added dropwise with cooling in an ice-water bath. And after the dripping is finished, removing the cooling bath, raising the temperature to room temperature for reaction for 4 hours, cooling to room temperature, and storing for later use.
Preparation of Compound 27
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 26 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into water, the water is slowly heated to 60 ℃, and the reaction is stirred for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 28
Compound 27(21.2g, 0.1mol) was charged into a 500mL three-necked flask, 200mL of methyl t-butyl ether was added, and oxalyl chloride (13.7g, 0.12mol) was added dropwise under cooling in an ice-water bath. And after the dripping is finished, removing the cooling bath, raising the temperature to room temperature for reaction for 4 hours, cooling to room temperature, and storing for later use.
Preparation of Compound 29
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 28 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into hydrochloric acid, and the diazo compound is cooled in ice water bath and stirred for reaction for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 30
To the above-concentrated residue was added 100mL of N-dimethylformamide, and sodium formate (13.6g, 0.2mol) was added, and the mixture was heated to 90 ℃, stirred and reacted for 5 hours, cooled to room temperature, added 100mL of hydrochloric acid, further heated to 100 ℃, stirred for 1 hour, cooled to room temperature, and the solid product was precipitated, and filtered to obtain compound 30(18g, yield 80%).
Preparation of Compound 12
Compound 30(10g, 0.044mol) and 15mL of polyethylene glycol 400 were added to a reaction flask, stirred for 10 minutes, 200mL of phosphate buffer (pH 8.0), isopropylamine (3.1g), pyridoxal phosphate (0.75g), transaminase (2.0g) were added, and stirred at 45 ℃ for 20 hours. Adjusting pH to above 10 with 2.0M sodium hydroxide solution, filtering to obtain crude product, and directly using in the next step.
Preparation of Compound 2
The crude product from the above filtration was added to a 250mL three-necked flask, and 70mL ethanol and 30mL water were added. And heating the system to 45-50 ℃, stirring for 30min, dropwise adding di-tert-butyl dicarbonate (11g, 0.048mol) and 30% sodium hydroxide solution at controlled temperature, controlling the pH of the system to be 9-10, and carrying out heat preservation reaction for 3 hours after the dropwise addition. The ethanol was recovered under reduced pressure, cooled to room temperature, and filtered to give 11.8g of product in 82% yield.
Example three: in the synthetic route shown in formula 7, the acyl halide reagent is phosphorus oxychloride, and R is a chlorine atom; the base used to convert compound 29 to compound 30 is potassium hydroxide.
Preparation of Compound 26
Compound 25(19.8g, 0.1mol) was charged into a 500mL three-necked flask, 100mL of methylene chloride was added, and phosphorus oxychloride (18.4g, 0.12mol) was added dropwise with cooling in an ice-water bath. After the dripping is finished, the cooling bath is removed, the temperature is raised to room temperature for reaction for 2 hours, and the mixture is stored for standby.
Preparation of Compound 27
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 26 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into water, the water is slowly heated to 60 ℃, and the reaction is stirred for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 28
Compound 27(21.2g, 0.1mol) was charged into a 500mL three-necked flask, 200mL of methyl t-butyl ether was added, and phosphorus oxychloride (18.4g, 0.12mol) was added dropwise with cooling in an ice-water bath. After the dripping is finished, the cooling bath is removed, the temperature is raised to room temperature for reaction for 2 hours, and the mixture is stored for standby.
Preparation of Compound 29
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 28 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into hydrochloric acid, and the diazo compound is cooled in ice water bath and stirred for reaction for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 30
To the above-concentrated residue was added 100mL of water, potassium hydroxide (11.2g, 0.2mol) was added, the mixture was heated to slight boiling, stirred and reacted for 8 hours, the temperature was reduced to room temperature, 200mL of dichloromethane was added for extraction, the organic phase was separated, and after concentration, the mixture was recrystallized from methyl t-butyl ether to obtain compound 30(15.8g, yield 70%).
Preparation of Compound 12
Compound 30(10g, 0.044mol) and 15mL of polyethylene glycol 400 were added to a reaction flask, stirred for 10 minutes, 200mL of phosphate buffer (pH 8.0), isopropylamine (3.1g), pyridoxal phosphate (0.75g), transaminase (2.0g) were added, and stirred at 45 ℃ for 20 hours. Adjusting pH to above 10 with 2.0M sodium hydroxide solution, filtering to obtain crude product, and directly using in the next step.
Preparation of Compound 2
The crude product from the above filtration was added to a 250mL three-necked flask, and 70mL of water and 30mL of ethanol were added. Heating to 40-50 ℃, stirring for 30min to dissolve, dropwise adding triethylamine (18g, 0.18mol), slowly cooling to room temperature, dropwise adding di-tert-butyl dicarbonate (11g, 0.048mol), and reacting for 5 hours under heat preservation after dropwise adding. The ethanol was recovered under reduced pressure, cooled to room temperature, and filtered to give 12.8g of product in 87% yield.
Example four: in the synthetic route shown in the formula 7, carboxylic acid is reacted with ethyl chloroformate in triethylamine as base to obtain active ester, wherein R is ethyl carbonate; the base used to convert compound 29 to compound 30 is sodium formate.
Preparation of Compound 26
Adding the compound 25(19.8g, 0.1mol) into a 500mL three-necked flask, adding 200mL methyl tert-butyl ether, cooling in an ice-water bath, dropwise adding triethylamine (20.2g, 0.2mol), controlling the temperature to be-5-0 ℃, and dropwise adding ethyl chloroformate (16.3g, 0.15 mol). After dripping, stirring and reacting for 1 hour, filtering, and storing the filtrate at low temperature for later use.
Preparation of Compound 27
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 26 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into water, the water is slowly heated to 60 ℃, and the reaction is stirred for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 28
Adding the compound 27(21.2g, 0.1mol) into a 500mL three-necked flask, adding 200mL methyl tert-butyl ether, cooling in an ice-water bath, dropwise adding triethylamine (20.2g, 0.2mol), controlling the temperature to be-5-0 ℃, and dropwise adding ethyl chloroformate (16.3g, 0.15 mol). After dripping, stirring and reacting for 1 hour, filtering, and storing the filtrate at low temperature for later use.
Preparation of Compound 29
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 28 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into hydrochloric acid, and the diazo compound is cooled in ice water bath and stirred for reaction for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 30
To the above-concentrated residue was added 100mL of N-dimethylformamide, and sodium formate (13.6g, 0.2mol) was added, and the mixture was heated to 90 ℃, stirred and reacted for 5 hours, cooled to room temperature, added 100mL of hydrochloric acid, further heated to 100 ℃, stirred for 1 hour, cooled to room temperature, and the solid product was precipitated, and filtered to obtain compound 30(18g, yield 80%).
Preparation of Compound 12
Compound 30(10g, 0.044mol) and 15mL of polyethylene glycol 400 were added to a reaction flask, stirred for 10 minutes, 200mL of phosphate buffer (pH 8.0), isopropylamine (3.1g), pyridoxal phosphate (0.75g), transaminase (2.0g) were added, and stirred at 45 ℃ for 20 hours. Adjusting pH to above 10 with 2.0M sodium hydroxide solution, filtering to obtain crude product, and directly using in the next step.
Preparation of Compound 2
The crude product from the above filtration was added to a 250mL three-necked flask, and 70mL ethanol and 30mL water were added. And heating the system to 45-50 ℃, stirring for 30min, dropwise adding di-tert-butyl dicarbonate (11g, 0.048mol) and 30% sodium hydroxide solution at controlled temperature, controlling the pH of the system to be 9-10, and carrying out heat preservation reaction for 3 hours after the dropwise addition. The ethanol was recovered under reduced pressure, cooled to room temperature, and filtered to give 11.8g of product in 82% yield.
Example five: in the synthetic route shown in formula 7, carboxylic acid reacts with isobutyl chloroformate to obtain active ester in N-methylmorpholine serving as base, and R is isobutyl carbonate group; the base used to convert compound 29 to compound 30 is potassium hydroxide.
Preparation of Compound 26
Compound 25(19.8g, 0.1mol) was charged into a 500mL three-necked flask, 200mL of methylene chloride was added, and N-methylmorpholine (21.2g, 0.21mol) was added dropwise with cooling in an ice-water bath. Controlling the temperature to be minus 10 to minus 5 ℃, dropwise adding isobutyl chloroformate (20.5g, 0.15mol), preserving the temperature for reaction for 30 minutes after dropwise adding, filtering, and preserving the filtrate at low temperature for later use.
Preparation of Compound 27
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 26 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into water, the water is slowly heated to 60 ℃, and the reaction is stirred for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 28
Compound 25(19.8g, 0.1mol) was charged into a 500mL three-necked flask, 200mL of methylene chloride was added, and N-methylmorpholine (21.2g, 0.21mol) was added dropwise with cooling in an ice-water bath. Controlling the temperature to be minus 10 to minus 5 ℃, dropwise adding isobutyl chloroformate (20.5g, 0.15mol), preserving the temperature for reaction for 30 minutes after dropwise adding, filtering, and preserving the filtrate at low temperature for later use.
Preparation of Compound 29
250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether are added into a 500mL three-necked bottle, methyl nitrosourea (30g, 0.29mol) is added under the cooling of an ice water bath, and the mixture is stirred for 10 minutes and stored at low temperature for standby. A solution of methylnitrosourea and a 30% potassium hydroxide solution (50g, 0.89mol) were passed through a microchannel reactor in a weight ratio of 3:1 to prepare a methyl tert-butyl ether solution of diazomethane.
The solution of the compound 28 and the methyl tert-butyl ether solution of diazomethane are prepared into the diazo compound by a microchannel reactor according to the weight ratio of 1:1, the diazo compound flows into hydrochloric acid, and the diazo compound is cooled in ice water bath and stirred for reaction for 1 hour. Standing for layering, concentrating the organic phase under reduced pressure, and directly reacting the residue in the next step.
Preparation of Compound 30
To the above-concentrated residue was added 100mL of water, potassium hydroxide (11.2g, 0.2mol) was added, the mixture was heated to slight boiling, stirred and reacted for 8 hours, the temperature was reduced to room temperature, 200mL of dichloromethane was added for extraction, the organic phase was separated, and after concentration, the mixture was recrystallized from methyl t-butyl ether to obtain compound 30(15.8g, yield 70%).
Preparation of Compound 12
Compound 30(10g, 0.044mol) and 15mL of polyethylene glycol 400 were added to a reaction flask, stirred for 10 minutes, 200mL of phosphate buffer (pH 8.0), isopropylamine (3.1g), pyridoxal phosphate (0.75g), transaminase (2.0g) were added, and stirred at 45 ℃ for 20 hours. Adjusting pH to above 10 with 2.0M sodium hydroxide solution, filtering to obtain crude product, and directly using in the next step.
Preparation of Compound 2
The crude product from the above filtration was added to a 250mL three-necked flask, and 70mL of water and 30mL of ethanol were added. Heating to 40-50 ℃, stirring for 30min to dissolve, dropwise adding triethylamine (18g, 0.18mol), slowly cooling to room temperature, dropwise adding di-tert-butyl dicarbonate (11g, 0.048mol), and reacting for 5 hours under heat preservation after dropwise adding. The ethanol was recovered under reduced pressure, cooled to room temperature, and filtered to give 12.8g of product in 87% yield.
Claims (8)
1. A preparation method of (R) -tert-butyl (1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl) carbamate of a compound 2 shown as a formula I is disclosed, wherein the reaction process is shown as a formula II:
(1) reacting a compound 4-phenylbenzoic acid 25 serving as an initial raw material with an acid halogenating reagent or with chloroformate in an aprotic solvent under an alkaline condition to obtain a compound 26, wherein: the acyl halide reagent is any one of halogenated sulfoxide, oxalyl halide, phosphorus oxychloride, phosphorus pentachloride, methanesulfonyl chloride, arylsulfonyl chloride or trifluoromethanesulfonyl chloride; r is halogen or sulfonate or methyl carbonate or alkyl carbonate or aryl carbonate of less than six carbons; the base is any one of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or triethylene Diamine (DABCO), 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1, 5-diazabicyclo [4,3,0] non-5-ene (DBN), 4-dimethylaminopyridine or tetramethylethylenediamine: the aprotic solvent is any one of dichloromethane, methyl tert-butyl ether or toluene or any combination of the solvents;
(2) carrying out Wollf rearrangement reaction on the compound 26 and methyl tert-butyl ether of diazomethane by a microchannel reactor to obtain a compound 27;
(3) reacting the compound 27 with an acid halogenating agent or with chloroformate in an aprotic solvent under basic conditions to obtain a compound 28, wherein the basic conditions are composed of any one of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or triethylenediamine (DABCO), 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1, 5-diazabicyclo [4,3,0] non-5-ene (DBN), 4-dimethylaminopyridine or tetramethylethylenediamine;
(4) carrying out Wollf rearrangement reaction on the compound 28 and diazomethane through a microchannel reactor to obtain a chloroketone compound 29;
(5) converting compound 29 under basic conditions to give compound 30, wherein: the alkali is any one of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal formate, alkaline earth metal formate, alkali metal acetate or alkaline earth metal acetate;
(6) carrying out the aminotransferase enzyme catalytic reaction on the compound 30 to obtain a compound 12 with high stereoselectivity;
(7) reacting the compound 12 with di-tert-butyl dicarbonate under an alkaline condition to obtain a compound 2, wherein the base is any one of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide, pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine or tetramethylethylenediamine.
2. A process for the preparation of compound 2 according to claim 1, characterized in that:
in steps (1) to (5): the acid halogenating agent is thionyl chloride, and the alkyl group of less than six carbons includes: any one of methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl and tert-butyl, R is halogen or a sulfonate group or a methyl carbonate group or an alkyl carbonate group or an aryl carbonate group with less than six carbons is any one of chlorine, ethyl carbonate group or isobutyl carbonate group, and the base is any one of triethylamine, diisopropylethylamine or N-methylmorpholine;
in the step (5), the polar solvent of the compound 29 converted in the polar solvent under the alkaline condition to obtain the compound 30 is N, N-dimethylformamide, N-methylpyrrolidone and water, and the alkali is any one of sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, sodium formate or sodium acetate.
3. The production method for producing the compound 2 according to claim 1 or 2, characterized in that the preferred base in the step (7) is potassium carbonate or sodium hydroxide.
4. The production method for producing the compound 2 according to claim 3, characterized in that: the rearrangement reaction in steps (2) and (4) is: cooling methyl tert-butyl ether and diethylene glycol dimethyl ether in an ice water bath, adding methyl nitrosourea, uniformly stirring, preparing a methyl tert-butyl ether solution of diazomethane by using a micro-channel reactor by using a methyl nitrosourea solution and a 30% potassium hydroxide solution in a weight ratio of 3:1, preparing diazo nitride by using a micro-channel reactor by using a compound 26 solution and a methyl tert-butyl ether solution of diazomethane in a weight ratio of 1:1, flowing into water, slowly heating to 60 ℃, stirring for reaction for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding dichloromethane into residues, dropwise adding thionyl chloride under cooling of the ice water bath, removing a cooling bath after dropwise adding, heating to reflux for reaction for 2 hours, cooling to room temperature to obtain a compound 28 solution, preparing the diazo nitride by using the micro-channel reactor by using the compound 28 solution and the methyl tert-butyl ether solution of diazomethane in a weight ratio of 1:1, flowing into hydrochloric acid, cooling in ice water bath, stirring for reaction for 1 hr, standing for layering, concentrating the organic phase under reduced pressure, and reacting the residue.
5. The process for preparing a body compound 2 according to claim 4, characterized in that the base used in step (5) is sodium hydroxide.
6. The process for preparing compound 2 according to claim 5, wherein the base used in step (7) is potassium carbonate.
7. The preparation process according to claim 3 for preparing compound 2, characterized in that: the rearrangement reaction in steps (2) and (4) is: adding methyl nitrosourea into methyl tert-butyl ether and diethylene glycol dimethyl ether under the cooling of an ice water bath, uniformly stirring, preparing a methyl nitrosourea solution and a 30% potassium hydroxide solution by weight ratio of 3:1 through a microchannel reactor to obtain a diazomethane methyl tert-butyl ether solution, preparing diazo-containing compound 26 solution and the diazomethane methyl tert-butyl ether solution by weight ratio of 1:1 through the microchannel reactor to prepare diazo, flowing into water, slowly heating to 60 ℃, stirring for reaction for 1 hour, standing for layering, concentrating under reduced pressure by organic phase, adding dichloromethane into residues, dropwise adding triethylamine under the cooling of the ice water bath, controlling the temperature to be-5-0 ℃, dropwise adding ethyl chloroformate, preserving heat and stirring for reaction for 1 hour after dropwise adding, filtering to obtain a compound 28 solution, preparing the diazo by using the microchannel reactor through the solution of the compound 28 solution and the diazomethane methyl tert-butyl ether solution by weight ratio of 1:1, flowing into hydrochloric acid, cooling in an ice-water bath, stirring for reacting for 1 hour, standing for layering, concentrating under reduced pressure by using an organic phase, adding N, N-dimethylformamide and sodium formate into the concentrated residue, heating to 90 ℃, stirring for reacting for 5 hours, cooling to room temperature, adding 100mL of hydrochloric acid, continuously heating to 100 ℃, stirring for 1 hour, cooling to room temperature, precipitating a solid product, filtering to obtain a compound 30, adding polyethylene glycol into the compound 30, stirring for 10 minutes, adding a phosphate buffer solution with the pH of 8.0, isopropylamine, pyridoxal phosphate and transaminase, stirring at 45 ℃ for 20 hours, adjusting the pH to more than 10 by using a sodium hydroxide solution, filtering to obtain a crude product, adding ethanol and water into the crude product, heating the system to 45-50 ℃, stirring for 30 minutes, dropwise adding di-tert-butyl dicarbonate and the sodium hydroxide solution at a controlled temperature, controlling the system pH to be 9-10, reacting at a maintained temperature for 3 hours after dropwise adding, recovering ethanol under reduced pressure, cooling to room temperature, and filtering to obtain a product 2.
8. A process for the preparation of compound 2 according to claim 3, characterized in that: the rearrangement reaction in steps (2) and (4) is: adding methyl nitrosourea into methyl tert-butyl ether and diethylene glycol dimethyl ether under the cooling of an ice water bath, uniformly stirring, preparing a methyl tert-butyl ether solution of diazomethane by using a microchannel reactor through a methyl nitrosourea solution and a 30% potassium hydroxide solution according to the weight ratio of 3:1, preparing diazo nitride by using a microchannel reactor through a compound 26 solution and a methyl tert-butyl ether solution of diazomethane according to the weight ratio of 1:1, flowing into water, slowly heating to 60 ℃, stirring for reaction for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding dichloromethane into residues, dropwise adding N-methylmorpholine under the cooling of an ice water bath, controlling the temperature to be-10 to-5 ℃, dropwise adding isobutyl chloroformate, preserving the temperature for reaction for 30 minutes after dropwise adding, filtering to obtain a compound 28 solution, preparing the diazo nitride by using a microchannel reactor through a compound 28 solution and a methyl tert-butyl ether solution of diazomethane according to the weight ratio of 1:1, flowing into hydrochloric acid, cooling in an ice-water bath, stirring for reaction for 1 hour, standing for layering, concentrating organic phase under reduced pressure, adding water and potassium hydroxide into the concentrated residue, heating to slightly boil, stirring for reaction for 8 hours, cooling to room temperature, extracting with dichloromethane, separating out an organic phase, recrystallizing with methyl tert-butyl ether after concentration to obtain compound 30, compound 30 and polyethylene glycol, stirring for 10 minutes, adding phosphate buffer solution with pH of 8, isopropylamine, pyridoxal phosphate and transaminase, stirring at 45 ℃ for 20 hours, adjusting pH to more than 10 with sodium hydroxide solution, filtering to obtain a crude product, adding water and ethanol into the crude product obtained in the previous step, heating to 40-50 ℃, stirring for 30 minutes to dissolve, dropwise adding triethylamine, slowly cooling to room temperature, dropwise adding di-tert-butyl dicarbonate, reacting at 45 hours after dropwise addition, recovering ethanol under reduced pressure, cooling to room temperature, filtering to obtain a product 2.
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