(R)-(1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl) tert-butyl carbamate intermediate as well as preparation method and application thereof

Abstract

The invention provides an (R)-(1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl) tert-butyl carbamate intermediate as well as a preparation method and application thereof, and relates to the technical field of organic synthesis. The (R)-(1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl) tert-butyl carbamate intermediate provided by the invention has a structure as shown in a formula I which is described in the specification. The intermediate is used for synthesizing (R)-(1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl) tert-butyl carbamate, a byproduct 4-hydroxyphthalic acid or 4-esterphthalic acid is obtained after the reaction, and the byproduct 4-hydroxyphthalic acid or 4-esterphthalic acid is insoluble in water, can be well separated and is easy to recycle, so that the treatment cost of three wastes (waste gas, waste water and industrial residues) can be reduced, and meanwhile, the production cost is reduced; and the reaction yield is high. The preparation method of the intermediate provided by the invention has the advantages of cheap and easily available raw materials, high reaction yield and mild reaction conditions.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate and a preparation method and application thereof. Background Art

[0002] Sacubitril is a neprilysin inhibitor developed by Novartis of Switzerland. Its trisodium hemipentahydrate compound Entresto formed with the angiotensin II receptor inhibitor valsartan was first approved by the FDA for marketing in July 2015 for the clinical treatment of chronic heart failure with reduced ejection fraction of grades II-IV.

[0003] (R)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate is a key intermediate of sacubitril, and its structure is shown in Formula IV:

[0004]

[0005] At present, the structure shown in Formula IV is mainly prepared by the succinimide method, in which (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane reacts with succinimide to obtain the compound shown in Formula V, and (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxyprop-2-yl)carbamic acid tert-butyl ester is synthesized from the compound shown in Formula V. The byproduct of this synthesis method is succinic acid, which is easily soluble in water and difficult to separate. The cost of treating the three wastes is high, and it is difficult to reuse, and the yield of this synthesis method is low.

[0006] Summary of the invention

[0007] In view of this, the object of the present invention is to provide a (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate and its preparation method and application. The intermediate provided by the present invention is used to synthesize (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester, and the product is easy to separate and recover, which can reduce the cost of three waste treatment and has a high yield.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate having a structure shown in Formula I:

[0010]

[0011] In formula I, R is -OH or R1 is an alkyl group.

[0012] Preferably, R1 is methyl or ethyl.

[0013] The present invention provides a method for preparing the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate described in the above technical scheme, comprising the following steps:

[0014] (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, a diketone compound, an organic solvent, triphenylphosphine and diisopropyl azodicarboxylate are mixed for dehydration reaction to obtain the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate; the diketone compound is 5-hydroxyisoindoline-1,3-dione or 5-hydroxyisoindoline-1,3-dione ester.

[0015] Preferably, the 5-hydroxyisoindoline-1,3-dione ester includes 5-hydroxyisoindoline-1,3-dione ethyl ester or 5-hydroxyisoindoline-1,3-dione propyl ester, wherein the 5-hydroxyisoindoline-1,3-dione ethyl ester is obtained by esterification reaction of 5-hydroxyisoindoline-1,3-dione with acetic anhydride, and the 5-hydroxyisoindoline-1,3-dione propyl ester is obtained by esterification reaction of 5-hydroxyisoindoline-1,3-dione with propionic anhydride.

[0016] Preferably, the molar ratio of the (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane to the diketone compound is 1:(1-5); the molar ratio of the (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, triphenylphosphine and diisopropyl azodicarboxylate is 1:1:1.1.

[0017] Preferably, the dehydration reaction is carried out at a temperature of 15 to 25° C. and for a time of 5 to 10 hours.

[0018] The present invention provides the use of the intermediate described in the above technical solution in the preparation of tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate.

[0019] The present invention provides a method for preparing tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, comprising the following steps:

[0020] The intermediate described in the above technical solution is mixed with potassium acetate and water to carry out a first hydrolysis reaction to obtain a compound represented by formula II;

[0021] The compound represented by formula II is mixed with ethanol, water and di-tert-butyl dicarbonate to carry out acylation reaction to obtain the compound represented by formula III;

[0022] The compound represented by formula III is subjected to a second hydrolysis reaction to obtain tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate;

[0023]

[0024] Preferably, the molar ratio of the intermediate, potassium acetate and water is 1:2:100; the first hydrolysis reaction is carried out under reflux conditions for 15 to 24 hours.

[0025] Preferably, the molar ratio of the compound represented by formula II to di-tert-butyl dicarbonate is 1:1-3; the temperature of the acylation reaction is 50-60° C., and the time is 4 hours.

[0026] Preferably, the second hydrolysis reaction is carried out under alkaline conditions, and the temperature of the second hydrolysis reaction is 30-35°C.

[0027] The present invention provides a (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate having a structure shown in Formula I. The intermediate provided by the present invention is used to synthesize (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester, and the intermediate is reacted to obtain by-product 4-hydroxyphthalic acid or 4-ester phthalic acid, which is difficult to dissolve in water, can be well separated and can be used as a raw material for preparing 5-hydroxyisoindoline-1,3-dione or 5-hydroxyisoindoline-1,3-dione ester, which can reduce the cost of three waste treatment, while reducing the production cost and production by-products; and the reaction yield is high.

[0028] The present invention provides a method for preparing the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate described in the above technical scheme, which has cheap and readily available raw materials, high reaction yield and mild reaction conditions. DETAILED DESCRIPTION

[0029] The present invention provides a (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate having a structure shown in Formula I (chemical name is (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloropropan-2-yl)-5-hydroxyisoindole-1,3-dione or (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloropropan-2-yl)-5-acylhydroxyisoindole-1,3-dione):

[0030]

[0031] In formula I, R is -OH or R1 is an alkyl group.

[0032] In the present invention, the R1 is preferably a methyl group or an ethyl group.

[0033] The present invention provides a method for preparing the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate described in the above technical scheme, comprising the following steps:

[0034] (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, a diketone compound, an organic solvent, triphenylphosphine and diisopropyl azodicarboxylate (DIAD) are mixed for dehydration reaction to obtain the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate; the diketone compound is 5-hydroxyisoindoline-1,3-dione or 5-hydroxyisoindoline-1,3-dione ester.

[0035] In the present invention, unless otherwise specified, the raw materials involved are commercially available products in the art or are prepared according to methods well known to those skilled in the art.

[0036] In the present invention, the structural formula of the diketone compound is as follows:

[0037]

[0038] In the present invention, the structure of the 5-hydroxyisoindoline-1,3-dione is shown in formula a. In the present invention, the 5-hydroxyisoindoline-1,3-dione ester preferably includes 5-hydroxyisoindoline-1,3-dione ethyl ester (structure shown in formula b) or 5-hydroxyisoindoline-1,3-dione propyl ester (structure shown in formula c).

[0039]

[0040] In the present invention, the 5-hydroxyisoindoline-1,3-dione ethyl ester is preferably obtained by esterification reaction of 5-hydroxyisoindoline-1,3-dione with acetic anhydride, and the 5-hydroxyisoindoline-1,3-dionone propyl ester is obtained by esterification reaction of 5-hydroxyisoindoline-1,3-dione with propionic anhydride.

[0041] In the present invention, the preparation method of 5-hydroxyisoindoline-1,3-dione ethyl ester preferably comprises the following steps:

[0042] Mixing 5-hydroxyisoindoline-1,3-dione, acetic anhydride and acetic acid under reflux conditions to carry out an esterification reaction to obtain an esterification reaction liquid;

[0043] The esterification reaction liquid is concentrated and then mixed with anhydrous ethanol, stirred and cooled to below room temperature, filtered, rinsed with anhydrous ethanol and dried in sequence to obtain 5-hydroxyisoindoline-1,3-dione ethyl ester.

[0044] In the present invention, the molar ratio of the 5-hydroxyisoindoline-1,3-dione, acetic anhydride and acetic acid is preferably 1:2:2; the time of the esterification reaction is preferably 3 to 4 hours; and the concentration is based on concentration until there is no flow.

[0045] In the present invention, the preparation method of 5-hydroxyisoindoline-1,3-diketopropyl ester is the same as the preparation method and conditions of 5-hydroxyisoindoline-1,3-diketoethyl ester, and only acetic anhydride needs to be replaced by propionic anhydride, and acetic acid needs to be replaced by propionic acid. In the present invention, the reaction formulas involved in preparing 5-hydroxyisoindoline-1,3-diketoethyl ester and preparing 5-hydroxyisoindoline-1,3-diketopropyl ester are as follows:

[0046]

[0047] In the present invention, the molar ratio of the (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane to the diketone compound is preferably 1:(1-5), more preferably 1:(1-2), and further preferably 1:(1-1.5).

[0048] In the present invention, the organic solvent preferably includes one or more of xylene, cyclohexane, benzene and toluene, more preferably benzene or toluene, and the organic solvent increases the contact between (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane and the diketone compound. In the present invention, the mass ratio of the (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane to the organic solvent is preferably 1:(10-15), more preferably 1:(10-12), and the amount of the organic solvent added determines the reaction rate within a certain ratio range.

[0049] In the present invention, the molar ratio of (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, triphenylphosphine and diisopropyl azodicarboxylate is preferably 1:1:1.1. In the present invention, the triphenylphosphine is used as a Lewis base catalyst, and the isopropyl azodicarboxylate is used as a catalyst for the dehydration reaction of imine and hydroxyl.

[0050] In the present invention, the method of mixing the (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, the diketone compound, the organic solvent, triphenylphosphine and diisopropyl azodicarboxylate is preferably:

[0051] After the organic solvent and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane are mixed and stirred for 20 minutes, water is added at normal pressure; after the water addition is completed, the resulting solution is cooled to below 30°C under nitrogen protection, triphenylphosphine and diketone compounds are added thereto, the resulting mixed solution is cooled to 15-20°C, and diisopropyl azodicarboxylate is added dropwise thereto. The present invention has no special requirements for the specific operation of adding water, and the water addition operation familiar to those skilled in the art can be used.

[0052] In the present invention, the temperature of the dehydration reaction (hydroxyl and imine undergo dehydration reaction) is preferably 15-25°C, more preferably 18-22°C, and the time is preferably 5-10h. The time of the dehydration reaction is calculated from the completion of the dropwise addition of isopropyl azodicarboxylate. The time of the dehydration reaction is specifically based on the mass content of (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane in the reaction solution ≤0.5% (detected by HPLC tracking). In the present invention, the dehydration reaction is preferably carried out under a nitrogen atmosphere.

[0053] In the present invention, the reaction formula involved in the dehydration reaction is as follows (R in the reaction formula is consistent with R in the structure shown in Formula I):

[0054]

[0055] After the dehydration reaction, the present invention also preferably performs post-treatment on the obtained dehydration reaction liquid, and the post-treatment preferably comprises the following steps:

[0056] The dehydrated reaction liquid is subjected to reduced pressure distillation to obtain a concentrate;

[0057] mixing the concentrate with ethanol under heating conditions to obtain a solution;

[0058] The solution is mixed with water and cooled, filtered, washed and dried in sequence to obtain pure (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloropropane-2-yl)-5-hydroxyisoindole-1,3-dione or (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloropropane-2-yl)-5-acylhydroxyisoindole-1,3-dione.

[0059] In the present invention, the temperature of the vacuum distillation is preferably ≤80°C, more preferably 60-75°C, and the time of the vacuum distillation is based on the concentration until there is no flow (ie, no liquid flows out). The solvent is evaporated by the vacuum distillation.

[0060] In the present invention, the mass ratio of the concentrate to ethanol is preferably 1:7 to 8. In the present invention, the heating temperature is preferably 75°C; in the present invention, ethanol is preferably added to the concentrate, the temperature is raised to 75°C, and the solution is obtained by stirring and dissolving.

[0061] In the present invention, water is preferably added dropwise to the solution and stirred for 0.5 h.

[0062] In the present invention, the final temperature of the cooling is preferably 0-5°C, the final temperature holding time is preferably 1h, and the holding process is preferably stirred. In the present invention, the system after the solution and water are mixed is preferably naturally cooled to room temperature, and then cooled to 0-5°C. In the present invention, the reagent used for the washing is preferably an ethanol aqueous solution, the mass percentage of ethanol in the ethanol aqueous solution is preferably 50%, and the washing is preferably elution. In the present invention, the drying is preferably oven drying.

[0063] The method for preparing the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate of the present invention has the advantages of cheap and readily available raw materials, high reaction yield, easy separation and recovery of products, and reduced three waste treatment costs.

[0064] The present invention provides the use of the intermediate described in the above technical solution in the preparation of tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate.

[0065] The present invention provides a method for preparing tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, comprising the following steps:

[0066] The intermediate described in the above technical solution is mixed with potassium acetate and water to carry out a first hydrolysis reaction to obtain a compound represented by formula II;

[0067] The compound represented by formula II is mixed with ethanol, water and di-tert-butyl dicarbonate to carry out acylation reaction to obtain the compound represented by formula III;

[0068] The compound represented by formula III is subjected to a second hydrolysis reaction under alkaline conditions to obtain tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate;

[0069]

[0070] The present invention mixes the intermediate (structure shown in formula I) described in the above technical solution with potassium acetate and water to carry out a first hydrolysis reaction to obtain a compound shown in formula II.

[0071] In the present invention, the molar ratio of the intermediate, potassium acetate and water is preferably 1:2:100. In the present invention, the first hydrolysis reaction is preferably carried out under reflux conditions, and the time is preferably 15 to 24 hours. In the present invention, the reaction formula involved in the first hydrolysis reaction is as follows:

[0072]

[0073] After the first hydrolysis reaction, the present invention preferably reduces the pressure to concentrate the obtained reaction solution to remove part of the water, cools it to 30-35°C, adds dichloromethane, keeps it at 30±5°C and stirs to dissolve for 2h, separates the layers to obtain a dichloromethane layer and a water layer, and collects the dichloromethane layer. According to the present invention, the pH value of the water layer is adjusted to below 1 by using hydrochloric acid. The water layer contains 4-hydroxyphthalic acid or 4-ester phthalic acid as a byproduct of hydrolysis. The 4-hydroxyphthalic acid or 4-ester phthalic acid is difficult to dissolve in water (that is, the water layer is a suspension). The 4-hydroxyphthalic acid or 4-ester phthalic acid can be conveniently separated from the water layer. If a direct filtration method is adopted, the separated 4-hydroxyphthalic acid or 4-ester phthalic acid can be used as a raw material for preparing 5-hydroxyisoindoline-1,3-dione or 5-hydroxyisoindoline-1,3-dione ester, which can reduce the cost of three wastes treatment and the production cost at the same time. The dichloromethane layer contains the compound shown in formula II, and the next step of reaction is carried out.

[0074] After obtaining the compound shown in formula II, the present invention mixes the compound shown in formula II with ethanol, water and di-tert-butyl dicarbonate to carry out acylation reaction to obtain the compound shown in formula III.

[0075] In the present invention, the molar ratio of the compound represented by formula II, ethanol and water is preferably 1:20-40:20-40, and the molar ratio of the compound represented by formula II and di-tert-butyl dicarbonate is preferably 1:1-3. In the present invention, the temperature of the acylation reaction is preferably 50-60°C, and the time is preferably 4h. The present invention preferably concentrates the above-mentioned dichloromethane layer to no flow, adds ethanol and water thereto, heats the system to 50-60°C, then controls the temperature at 50-60°C, and slowly drips di-tert-butyl dicarbonate. In the present invention, the time of the acylation reaction is calculated from the completion of the dripping of di-tert-butyl dicarbonate. In the present invention, the reaction formula involved in the acylation reaction is as follows:

[0076]

[0077] After the acylation reaction, the next step reaction can be directly carried out without post-treatment.

[0078] After obtaining the compound represented by formula III, the present invention performs a second hydrolysis reaction on the compound represented by formula III to obtain tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate.

[0079] In the present invention, the second hydrolysis reaction is preferably carried out under alkaline conditions, the alkaline conditions are preferably provided by sodium hydroxide, and the temperature of the second hydrolysis reaction is preferably 30-35°C. In the present invention, the specific operation of the second hydrolysis reaction is preferably: the temperature of the reaction solution obtained by the acylation reaction is controlled at 30-35°C, and the liquid alkali is slowly added dropwise to adjust the pH value of the system to 10±1, and after the addition is completed, the pH is stirred for 0.5h and the pH is re-measured to make pH=10±1, and the stirring reaction is continued for 2h. In the present invention, the reaction formula involved in the second hydrolysis reaction is as follows:

[0080]

[0081] After the second hydrolysis reaction, the obtained reaction solution is preferably acidified, distilled under reduced pressure, cooled and filtered in sequence to obtain tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate. In the present invention, the acid reagent used in the acidification is preferably hydrochloric acid, and the end point pH of the acidification is 6.5 to 7; the temperature of the distillation under reduced pressure does not exceed 70° C., and the distillation under reduced pressure is performed until there is no droplet.

[0082] The method for preparing tert-butyl (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate provided by the present invention has the advantages that the product can be easily separated and recovered, the cost of three waste treatment can be reduced, and the yield is high.

[0083] In order to further illustrate the present invention, the (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate provided by the present invention and its preparation method and application are described in detail below in combination with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0084] Example 1

[0085] 250 g of toluene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 30°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione (15.9 g, 0.10 mol) were added, and the temperature was further lowered to 20°C. Diisopropyl azodicarboxylate (23 g, The reaction was stopped after the addition was completed. The reaction was controlled at 22°C for 5 h with nitrogen protection throughout the process. The reaction was stopped when the concentration of (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5% by HPLC tracking. The toluene was concentrated under reduced pressure to 70°C until no flow was observed. 187.5 g of ethanol was added and the temperature was raised to 75°C with stirring to dissolve. 93.8 g of water was added dropwise and stirred for 0.5 h. The mixture was cooled to room temperature naturally and then cooled to 0°C with stirring for 1 h. The mixture was filtered, washed with 10 g of 50 wt% ethanol aqueous solution, and dried to obtain 34.9 g of the intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-hydroxyisoindole-1,3-dione, with a molar yield of 88.45% and a HPLC purity of 99.1%.

[0086] Example 2

[0087] 250 g of xylene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 28°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione (15.9 g, 0.10 mol) were added, and the temperature was further lowered to 15°C. Diisopropyl azodicarboxylate (23 g, The reaction was stopped after the addition was completed. The reaction was controlled at 18°C ​​and kept warm for 5 hours. The whole process was nitrogen-protected. The reaction was stopped when the concentration of (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5% by HPLC tracking. The temperature was raised to 60°C and the xylene was concentrated under reduced pressure until there was no flow. 187.5 g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve. 93.8 g of water was added dropwise and stirred for 0.5 h. The mixture was cooled to room temperature naturally and then cooled to 5°C and kept warm for 1 h. The mixture was filtered, washed with 10 g of a 50 wt% ethanol aqueous solution, and dried to obtain 34.1 g of an intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-hydroxyisoindole-1,3-dione. The molar yield was 86.34% and the HPLC purity was 99.0%.

[0088] Example 3

[0089] 250 g of benzene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 26°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione (15.9 g, 0.10 mol) were added, and the temperature was further lowered to 17°C. Diisopropyl azodicarboxylate (23 g, The reaction was stopped after the addition was completed. The reaction was controlled at 19°C for 5 h with nitrogen protection throughout the process. The reaction was stopped when the concentration of (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5% by HPLC tracking. The temperature was raised to 68°C and the benzene was concentrated under reduced pressure until there was no flow. 187.5 g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve. 93.8 g of water was added dropwise and stirred for 0.5 h. The mixture was cooled to room temperature naturally and then cooled to 4°C and stirred for 1 h. The mixture was filtered, washed with 10 g of a 50 wt% ethanol aqueous solution, and dried to obtain 34.9 g of an intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-hydroxyisoindole-1,3-dione, with a molar yield of 88.54% and a HPLC purity of 99.2%.

[0090] Example 4

[0091] 250 g of cyclohexane and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 22°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione (15.9 g, 0.10 mol) were added, and the temperature was further lowered to 15-20°C. Diisopropyl azodicarboxylate (23 g, 0.10 mol) was added dropwise. , 0.11mol), after the addition was completed, the temperature was controlled at 20°C and the reaction was kept warm for 5h, with nitrogen protection throughout the process. The reaction was stopped when the concentration of (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5% by HPLC tracking; the temperature was raised to 71°C and the cyclohexane was concentrated under reduced pressure until there was no flow, 187.5g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve, 93.8g of water was added dropwise and stirred for 0.5h, and the temperature was naturally reduced to room temperature and then cooled to 3°C and kept warm and stirred for 1h, filtered, washed with 10g of 50wt% ethanol aqueous solution, and dried to obtain 34.8g of the intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-hydroxyisoindole-1,3-dione, with a molar yield of 88.02% and a HPLC purity of 98.9%.

[0092] Example 5

[0093] 250 g of toluene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 20°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione (19.1 g, 0.12 mol) were added, and the temperature was further lowered to 16°C. Diisopropyl azodicarboxylate (23 g, The reaction was stopped after the addition was completed. The temperature was controlled at 21°C and the reaction was kept warm for 5 hours. The whole process was nitrogen-protected. HPLC tracking was performed until (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5%. The reaction was stopped, the temperature was raised to 73°C and the toluene was concentrated under reduced pressure until there was no flow. 187.5 g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve. 93.8 g of water was added dropwise and stirred for 0.5 h. The mixture was cooled to room temperature naturally and then cooled to 5°C and kept warm and stirred for 1 h. The mixture was filtered, washed with 10 g of 50 wt% ethanol aqueous solution, and dried to obtain 35.7 g of the intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-hydroxyisoindole-1,3-dione. The molar yield was 90.57% and the HPLC purity was 99.2%.

[0094] Example 6

[0095] 250 g of toluene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 20°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione (19.1 g, 0.12 mol) were added, and the temperature was further lowered to 20°C. Diisopropyl azodicarboxylate (23 g, The reaction was stopped after the addition was completed. The reaction was controlled at 19°C for 5 h with nitrogen protection throughout the process. The reaction was stopped after HPLC tracking until (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane ≤0.5%. The temperature was raised to 63°C and the toluene was concentrated under reduced pressure until there was no flow. 187.5 g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve. 93.8 g of water was added dropwise and stirred for 0.5 h. The mixture was cooled to room temperature naturally and then cooled to 1°C and stirred for 1 h. The mixture was filtered, washed with 10 g of 50 wt% ethanol aqueous solution, and dried to obtain 35.8 g of the intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl]-4-yl)-3-chloroprop-2-yl)-5-hydroxyisoindole-1,3-dione, with a molar yield of 90.74% and a HPLC purity of 99.1%.

[0096] Example 7

[0097] 5-Hydroxyisoindoline-1,3-dione (163 g, 1 mol), acetic anhydride (204 g, 2 mol), and acetic acid (120 g, 2 mol) were mixed and stirred for 20 min, and then the mixture was heated and refluxed for 3 h, and concentrated to no flow. 200 g of anhydrous ethanol was added, and the temperature was cooled to 21° C. by stirring, and the mixture was filtered, rinsed with 20 g of anhydrous ethanol, and dried to obtain 194.5 g of 5-hydroxyisoindoline-1,3-dione ethyl ester (structure shown in formula b), with a molar yield of 94.9% and a HPLC purity of 99.1%.

[0098] 250 g of toluene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 28°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-dione ethyl ester (24.1 g, 0.12 mol) were added, and the temperature was further lowered to 20°C. Diisopropyl azodicarboxylate (23 g, 0.10 mol) was added dropwise. , 0.11 mol), after the addition was completed, the temperature was controlled at 20°C and the reaction was kept warm for 5 hours, with nitrogen protection throughout the process. The reaction was stopped when the concentration of (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5% by HPLC tracking; the temperature was raised to 65°C and the toluene was concentrated under reduced pressure until there was no flow, 187.5 g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve, 93.8 g of water was added dropwise and stirred for 0.5 h, the temperature naturally dropped to room temperature and then cooled to 5°C and kept warm and stirred for 1 h, filtered, washed with 10 g of 50 wt% ethanol aqueous solution, and dried to obtain 39.3 g of the intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-acetylhydroxyisoindole-1,3-dione, with a molar yield of 89.58% and a HPLC purity of 98.7%.

[0099] Example 8

[0100] 5-Hydroxyisoindoline-1,3-dione (163 g, 1 mol), propionic anhydride (260 g, 2 mol) and propionic acid (148 g, 2 mol) were mixed and stirred for 20 min, then the mixture was heated and refluxed for 4 h, concentrated to no flow, 200 g of anhydrous ethanol was added, the temperature was dropped to 20° C. with stirring, filtered, rinsed with 20 g of anhydrous ethanol, and dried to obtain 198.3 g of 5-hydroxyisoindoline-1,3-dione propyl ester with a molar yield of 90.5% and a HPLC purity of 98.8%.

[0101] 250 g of toluene and (s)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane (25 g, 0.10 mol) were mixed and stirred for 20 min, and then water was added under normal pressure. After the water addition was completed, nitrogen was protected and the temperature was lowered to 28°C. Triphenylphosphine (29 g, 0.10 mol) and 5-hydroxyisoindoline-1,3-diketopropyl ester (25.8 g, 0.12 mol) were added, and the temperature was further lowered to 20°C. Diisopropyl azodicarboxylate (23 g, 0.10 mol) was added dropwise. , 0.11 mol), after the addition was completed, the temperature was controlled at 22°C and the reaction was kept warm for 5 hours, with nitrogen protection throughout the process. The reaction was stopped when the concentration of (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane was ≤0.5% by HPLC tracking; the temperature was raised to 75°C and the toluene was concentrated under reduced pressure until there was no flow, 187.5 g of ethanol was added and the temperature was raised to 75°C and stirred to dissolve, 93.8 g of water was added dropwise and stirred for 0.5 h, the temperature naturally dropped to room temperature and then cooled to 5°C and kept warm and stirred for 1 h, filtered, washed with 10 g of 50 wt% ethanol aqueous solution, and dried to obtain 40.2 g of the intermediate (white solid), i.e., (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloroprop-2-yl)-5-propionylhydroxyisoindole-1,3-dione, with a molar yield of 88.49% and a HPLC purity of 98.4%.

[0102] Example 9

[0103] (S)-2-(1-(1,1-biphenyl-4-yl)-3-chloropropane-2-yl)-5-hydroxyisoindole-1,3-dione (39.1 g, 0.1 mol, prepared by the method of Example 1), potassium acetate (19.6 g, 0.2 mol), and water (180 g, 10 mol) were put into a reaction bottle, and the mixture was heated and refluxed for 18 hours, and 90 g of water was concentrated under reduced pressure. The mixture was cooled to 30° C., 400 g of dichloromethane was added, and the mixture was stirred and dissolved at 30° C. for 2 hours, and the dichloromethane layer was separated and the dichloromethane layer was collected; the pH value of the water layer was adjusted to below 1 with hydrochloric acid, and the by-product 4-hydroxyphthalic acid was obtained by filtration;

[0104] The dichloromethane layer was concentrated until there was no flow, 200 g of ethanol and 150 kg of water were added, the system was heated to 50°C, and then the temperature was controlled at 50°C, di-tert-butyl dicarbonate (26.1 g, 0.12 mol) was slowly added, and after the addition was completed, the reaction was stirred at 50°C for 4 hours, and the reaction was completed;

[0105] Control the temperature of the reaction liquid to 30°C, slowly add liquid alkali to adjust the pH value of the system to 10±1, after the addition, measure the pH value of the system to 10±1, stir for 0.5h and measure the pH value again, the pH value is required to be 10±1, continue stirring and reacting for 2h;

[0106] After the reaction was completed, the pH was adjusted to 6.5-7 with hydrochloric acid, the temperature of the reaction system was controlled not to exceed 70°C, and the reaction was distilled under reduced pressure until no droplets appeared. The temperature was lowered to 20°C, and the product (R)-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester was obtained by filtration, with a molar yield of 89.9% and a HPLC purity of 98.6%.

[0107] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate, characterized in that: It has the structure shown in formula I: In formula I, R is -OH or R1 is an alkyl group.

2. The (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate according to claim 1, characterized in that: The R1 is methyl or ethyl.

3. The method for preparing the (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate according to claim 1, characterized in that: The following steps are involved: (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, a diketone compound, an organic solvent, triphenylphosphine and diisopropyl azodicarboxylate are mixed for dehydration reaction to obtain the (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester intermediate; the diketone compound is 5-hydroxyisoindoline-1,3-dione or 5-hydroxyisoindoline-1,3-dione ester.

4. The preparation method according to claim 3, characterized in that: The 5-hydroxyisoindoline-1,3-dione ester includes 5-hydroxyisoindoline-1,3-dione ethyl ester or 5-hydroxyisoindoline-1,3-dione propyl ester. The 5-hydroxyisoindoline-1,3-dione ethyl ester is obtained by esterification reaction of 5-hydroxyisoindoline-1,3-dione with acetic anhydride, and the 5-hydroxyisoindoline-1,3-dione propyl ester is obtained by esterification reaction of 5-hydroxyisoindoline-1,3-dione with propionic anhydride.

5. The preparation method according to claim 3 or 4, characterized in that: The molar ratio of the (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane to the diketone compound is 1:(1-5); the molar ratio of the (S)-1-(1,1-biphenyl-4-yl)-3-chloro-2-hydroxy-propane, triphenylphosphine and diisopropyl azodicarboxylate is 1:1:1.1; the temperature of the dehydration reaction is 15-25°C, and the time is 5-10 hours.

6. Use of the intermediate according to claim 1 or 2 in the preparation of tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate.

7. A method for preparing tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, characterized in that: The following steps are involved: The intermediate of claim 1 or 2 is mixed with potassium acetate and water to carry out a first hydrolysis reaction to obtain a compound of formula II; The compound represented by formula II is mixed with ethanol, water and di-tert-butyl dicarbonate to carry out acylation reaction to obtain the compound represented by formula III; The compound represented by formula III is subjected to a second hydrolysis reaction to obtain tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate; 8. The method according to claim 7, characterized in that The molar ratio of the intermediate, potassium acetate and water is 1:2:100; the first hydrolysis reaction is carried out under reflux conditions for 15 to 24 hours.

9. The method according to claim 7, characterized in that: The molar ratio of the compound represented by formula II to di-tert-butyl dicarbonate is 1:1-3; the temperature of the acylation reaction is 50-60°C and the time is 4 hours.

10. The method according to claim 7, characterized in that The second hydrolysis reaction is carried out under alkaline conditions, and the temperature of the second hydrolysis reaction is 30-35°C.

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