Preparation method of (R)-5-([1, 1 '-biphenyl]-4-yl)-2-methyl-4-oxovaleric acid calcium salt

Abstract

The invention provides a preparation method of a key chiral intermediate (R)-5-([1, 1 '-biphenyl]-4-yl)-2-methyl-4-oxo valeric acid calcium salt for sacubitril valsartan sodium. According to the method, the reaction catalyst is low in equivalent weight and good in selectivity, both the intermediate and the target product can form calcium salt, refining crystallization is convenient, purification is facilitated, the optical purity is improved, and when the method is applied to the subsequent sacubitril valsartan sodium synthesis process, cost reduction and product quality improvement are facilitated.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a method for preparing a key chiral intermediate (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt for sacubitril-valsartan sodium. Background Art

[0002] Patent WO2017098430A reports a method for synthesizing (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid, which uses 4-methoxy-2-methylene-4-oxobutanoic acid to reduce under the action of a chiral catalyst to obtain (R)-4-methoxy-2-methyl-4-oxobutanoic acid, and then uses biphenylacetic acid to extract hydrogen under the action of isopropyl magnesium chloride and react with it, and then decarboxylates in one pot to obtain (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid.

[0003]

[0004] The amount of catalyst used in the hydrogenation reaction of this route is large, but the chiral selectivity is general. The intermediate (R)-4-methoxy-2-methyl-4-oxobutanoic acid obtained is an oily substance, which is difficult to purify and has poor optical purity. In addition, the Grignard reaction requires the use of a large amount of isopropylmagnesium chloride and lithium chloride reagents, which consumes a lot of materials. The purification methods for the purity of the final product are limited, the overall cost is high, and the competitiveness for scale-up production is weak. Therefore, it is still necessary to explore and find a method with a simple process route, high yield, low cost, and suitable for industrial production. Summary of the invention

[0005] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing a compound (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid that can be used to synthesize sacubitril-valsartan sodium. The method has a simple process route, high yield, low cost, and is suitable for industrial production.

[0006] To achieve the purpose of the invention, the present invention provides two new intermediate compounds.

[0007] A (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2, whose structural formula is:

[0008]

[0009] A (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3, whose structural formula is:

[0010]

[0011] The present invention also provides a method for preparing a (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2, which adopts the following technical scheme:

[0012] A preparation method of a (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2, comprising hydrogenating and reducing 4-(benzyloxy)-2-methylene-4-oxobutyric acid under the action of a catalyst or using an enzyme to reduce the acid to obtain (R)-4-benzyloxy-2-methyl-4-oxobutyric acid, and then salifying the acid under the action of a calcium salt to obtain a calcium salt intermediate 2;

[0013]

[0014] Furthermore, the reduction reaction is carried out by hydrogenation under the action of a catalyst, and the catalyst is selected from (1,2-bis((2R,5R)-2,5-diethylphospholane-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-dimethylphosphino]benzene(cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-diethylphosphino]benzene(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), Rhodium fluoroborate (I), 1,2-bis[(2R,5R)-2,5-(dimethylphosphino)ethane (cyclooctadiene) rhodium tetrafluoroborate (I), (R,R)-Ph-BPE-Rh(acac) or Rh(COD)(R,R-DIPAMP)BF4; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate; the reaction temperature is 0-60°C; the salt-forming solvent is selected from water or a mixed solvent system consisting of water and one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, acetone or acetonitrile.

[0015] Furthermore, the reduction reaction is carried out under the action of an enzyme catalyst, the enzyme catalyst includes olefin reductase and a coenzyme, the olefin reductase is selected from ERED, OYEs, OPR1 or OPR3; the coenzyme is selected from NADH or NADPH; the reducing agent is selected from glucose or isopropanol; the selected reaction system is DMSO, acetone, ethanol, isopropanol or water and a mixed solution of any two of them; the selected buffer is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate or Tris·HCl.

[0016] The present invention also provides a method for preparing (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3, which adopts the following technical scheme:

[0017] A method for preparing a (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3, comprising subjecting a compound 2 and 2-([1,1'-biphenyl]-4-yl)acetic acid to a condensation reaction under the action of a magnesium or lithium reagent, followed by one-pot decarboxylation, and finally salting under the action of a calcium salt to obtain the target product compound 3;

[0018]

[0019] Furthermore, the condensation reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the magnesium-lithium reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride complex, phenyl magnesium chloride, cyclohexyl magnesium chloride, tert-butyl magnesium chloride or n-butyl lithium; the reaction temperature is selected between -80 and 50°C; the acidified acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid; the salt-forming solvent is selected from water or a mixed solvent system consisting of water and one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, acetone or acetonitrile.

[0020] More specifically, the preparation method of a (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3 of the present invention adopts the following technical scheme:

[0021] A method for preparing a (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3,

[0022] 1) Using 4-(benzyloxy)-2-methylene-4-oxobutanoic acid compound 1 as a starting material, hydrogenating and reducing it under the action of a catalyst or using an enzyme to reduce it, and then forming a salt with calcium chloride to obtain an intermediate compound 2;

[0023] 2) Compound 2 is subjected to condensation reaction with 2-([1,1'-biphenyl]-4-yl)acetic acid in the presence of magnesium or lithium reagent, and then decarboxylated in one pot, and finally salted in the presence of calcium chloride to obtain the target product compound 3. The reaction route is:

[0024]

[0025] Further, the catalyst is selected from (1,2-bis((2R,5R)-2,5-diethylphospholane-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-dimethylphosphino]benzene(cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-diethylphosphino]benzene(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), Rhodium (I), 1,2-bis[(2R,5R)-2,5-(dimethylphosphino)ethane (cyclooctadiene) rhodium tetrafluoroborate (I), (R,R)-Ph-BPE-Rh(acac) or Rh(COD)(R,R-DIPAMP)BF4; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate; the salt-forming solvent is selected from water or a mixed solvent system consisting of water and one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, acetone or acetonitrile.

[0026] Furthermore, the enzyme catalyst comprises olefin reductase and a coenzyme, the olefin reductase is selected from ERED, OYEs, OPR1 or OPR3, and the coenzyme is selected from NADH or NADPH; the reducing agent is selected from glucose or isopropanol; the reaction system is DMSO, acetone, ethanol, isopropanol or water and a mixed solution of any two of them; the buffer is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate or Tris·HCl.

[0027] Furthermore, the condensation reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the magnesium-lithium reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride complex, phenyl magnesium chloride, cyclohexyl magnesium chloride, tert-butyl magnesium chloride or n-butyl lithium; the acidified acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid; the salt-forming solvent is selected from water or a mixed solvent system consisting of water and one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, acetone or acetonitrile.

[0028] The present invention relates to a method for preparing a calcium salt compound 3 of (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid. The method has a low reaction catalyst equivalent and good selectivity, and both the intermediate and the target product can form calcium salts. The refined crystallization is convenient for purification and improves the optical purity. Compound 3 is used in the subsequent process of synthesizing sacubitril valsartan sodium, which helps to reduce costs and improve product quality. Specific implementation method:

[0029] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.

[0030] Example 1

[0031]

[0032] Add 4-(benzyloxy)-2-methylene-4-oxobutanoic acid compound 1 (22.02 g, 100 mmol) to the hydrogenation bottle, add methanol (110 mL) and stir to dissolve, add (1,2-bis((2R,5R)-2,5-diethylphosphacyclopentane-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (0.01 mmol 7.2 mg), switch the vacuum to nitrogen 3 times, then switch the vacuum to hydrogen 3 times, pressurize to 0.9-1.1 MPa and keep the internal temperature at 38-42°C for 28-32 hours. After the reaction is completed, filter with diatomaceous earth, concentrate the filtrate to remove part of the methanol, add water (66 mL), add sodium hydroxide to adjust the pH to 11-12, add 10% calcium chloride solution (10%, 66.6 mL), and a large amount of solid precipitates. The solid was collected by filtration and dried to obtain intermediate 2 (20.92 g, ee.=98.6%, yield 86.7%).

[0033] MS (ESI-) m / z = 221.1

[0034] 1 H NMR(500MHz,DMSO)δ7.28-7.38(m,5H),5.05(s,2H),2.75(dd,J=6.0,15.5Hz ,1H),2.50-2.54(m,1H),2.21(dd,J=8.5,16.0Hz,1H),1.01(d,J=7.5Hz,3H).

[0035] In Example 1, (1,2-bis((2R,5R)-2,5-diethylphospholane-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate can be prepared by using R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-dimethylphosphino]benzene(cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-dimethylphosphino]benzene(cyclooctadiene)rhodium tetrafluoroborate(I), 5-diethylphosphinoalkyl]benzene(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-(dimethylphosphino)ethane(cyclooctadiene)rhodium tetrafluoroborate(I), (R,R)-Ph-BPE-Rh(acac) or Rh(COD)(R,R-DIPAMP)BF4; methanol can be replaced by ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate.

[0036] Example 2

[0037]

[0038] Add 4-(benzyloxy)-2-methylene-4-oxobutanoic acid compound 1 (22.02 g, 100 mmol) to the hydrogenation bottle, add methanol (110 mL) and stir to dissolve, add 1,2-bis[(2R,5R)-2,5-diethylphosphinoalkyl]benzene(1,5-cyclooctadiene)tetrafluoroborate rhodium (I) (0.01 mmol 6.6 mg), switch the vacuum to nitrogen 3 times, then switch the vacuum to hydrogen 3 times, pressurize to 0.9-1.1 MPa and keep the internal temperature at 38-42°C for 28-32 hours. After the reaction is completed, filter with diatomaceous earth, concentrate the filtrate to remove part of the methanol, add water (66 mL), add sodium hydroxide and sodium hydrogen to adjust the pH to 11-12, add 10% calcium chloride solution (10%, 66.6 mL), and a large amount of solid precipitates. The solid was collected by filtration and dried to obtain intermediate 2 (21.76 g, ee.=99.5%, yield 90.2%).

[0039] Example 3

[0040]

[0041] Add 4-(benzyloxy)-2-methylene-4-oxobutanoic acid (22.02 g, 100 mmol) to the hydrogenation bottle, add methanol (110 mL) and stir to dissolve, add 1,2-bis[(2R,5R)-2,5-diethylphosphinoalkyl]benzene(1,5-cyclooctadiene)tetrafluoroborate rhodium (I) (0.005 mmol 3.3 mg), switch the vacuum to nitrogen 3 times, then switch the vacuum to hydrogen 3 times, pressurize to 0.9-1.1 MPa and keep the internal temperature at 38-42°C for 28-32 hours. After the reaction is completed, filter with diatomaceous earth, concentrate the filtrate to remove part of the methanol, add water (66 mL), add sodium hydroxide to adjust the pH to 11-12, add 10% calcium chloride solution (10%, 66.6 mL), and a large amount of solid precipitates. The solid was collected by filtration and dried to obtain intermediate 2 (21.35 g, ee.=98.8%, yield 88.5%).

[0042] Example 4

[0043]

[0044] Add 4-(benzyloxy)-2-methylene-4-oxobutanoic acid (22.02g, 100mmol) to a three-necked flask, add DMSO (110mL) and water (220mL) and stir to fully dissolve, add Tris·HCl to adjust the pH to 6.8-7.2, add olefin reductase (25mg, OPR3) and NADH (0.2g) after the addition, keep warm to 35℃±0.5℃ and react for 16-24 hours. After the reaction, add sodium hydroxide to adjust the pH to 11-12, add ethyl acetate (110mL) for extraction, discard the organic phase, add 10% calcium chloride solution (10%, 66.6mL) to the aqueous phase, and a large amount of solid precipitates. Filter, collect the solid, and dry to obtain intermediate 2 (20.63g, ee.=99.4%, yield 85.5%)

[0045] In Example 4, OPR3 can be replaced by ERED, OYEs or OPR1; NADH can be replaced by NADPH; DMSO can be replaced by acetone, ethanol or isopropanol; Tris·HCl can be replaced by potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0046] Example 5

[0047]

[0048] Compound 2 (48.25 g, 100 mmol) and toluene (482 mL) were added to a three-necked flask under nitrogen protection. After stirring and dissolving, the mixture was cooled to -10 to 0 °C. 2-([1,1'-biphenyl]-4-yl)acetic acid (44.57 g, 210 mmol) was added and isopropylmagnesium chloride and lithium chloride tetrahydrofuran solution (1.0 M, 420 mL) was slowly added dropwise. After the addition was completed, the mixture was kept at -10 to 0 °C for 1 hour and then heated to room temperature for 4 to 6 hours. After the reaction was completed, dilute hydrochloric acid (6.0N, 241 mL) was added to quench the reaction and stirred for 2 hours. The liquids were separated, and the aqueous phase was extracted once with ethyl acetate (241 mL). The organic phases were combined and sodium hydroxide solution (0.5N, 400 mL) was added. The mixture was stirred and separated. The aqueous phase was collected, ethanol (96 mL) was added, and calcium chloride solution (10%, 111.0 mL) was slowly added dropwise. The mixture was slowly cooled to 0-5°C for crystallization, filtered, and the solid was collected and dried to obtain compound 3 (22.12 g, 73.4%).

[0049] MS (ESI-) m / z = 281.0

[0050] 1 H NMR (500MHz, DMSO) δ7.62(d,J=7.5Hz,2H),7.56(d,J=8.0Hz,2H),7.44(t,J=8.0Hz,2H),7.34(t,J=7.5Hz,1H)7.25(d,J=8. 0Hz,2H),3.80(s,2H),2.90(dd,J=6.5,16.5Hz,1H),2.55-2.65(m,1H),2.33(dd,J=7.0,16.5Hz,1H),1.00(d,J=7.0Hz,3H).

[0051] In Example 5, toluene can be replaced by tetrahydrofuran or 2-methyltetrahydrofuran; isopropylmagnesium chloride and lithium chloride can be replaced by isopropylmagnesium chloride, isopropylmagnesium bromide, phenylmagnesium chloride, cyclohexylmagnesium chloride, tert-butylmagnesium chloride or n-butyllithium; hydrochloric acid can be replaced by sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid; ethanol can be replaced by methanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, acetone or acetonitrile.

[0052] Example 6

[0053]

[0054] Under nitrogen protection, compound 2 (48.25 g, 100 mmol) and tetrahydrofuran (482 mL) were added to a three-necked flask. After stirring and dissolving, the mixture was cooled to -10 to 0°C. 2-([1,1'-biphenyl]-4-yl)acetic acid (44.57 g, 210 mmol) was added, and isopropylmagnesium chloride and lithium chloride solution (1.0 M, 420 mL) was slowly added dropwise. After the addition was completed, the mixture was kept at -10 to 0°C for 1 hour, and then the mixture was heated to room temperature for 4 to 6 hours. After the reaction, dilute hydrochloric acid (6.0N, 241mL) was added to quench the reaction and stirred for 2 hours. Most of the tetrahydrofuran was evaporated by concentration, and ethyl acetate (482mL) was added for extraction. The aqueous phase was extracted once with ethyl acetate (241mL) again, and the organic phases were combined and sodium hydroxide solution (0.5N, 400mL) was added. The mixture was stirred and separated. The aqueous phase was collected and calcium chloride solution (10%, 111.0mL) was slowly added dropwise. The mixture was slowly cooled to 0-5°C for crystallization, filtered, and the solid was collected and dried to obtain compound 3 (24.86g, 82.5%).

Claims

1. A (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2, whose structural formula is:

2. A (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3, whose structural formula is:

3. A method for preparing a (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2, characterized in that: The method comprises the steps of hydrogenating and reducing 4-(benzyloxy)-2-methylene-4-oxobutanoic acid under the action of a catalyst or using an enzyme to obtain (R)-4-benzyloxy-2-methyl-4-oxobutanoic acid and then salifying the 4-(benzyloxy)-2-methylene-4-oxobutanoic acid under the action of a calcium salt to obtain a calcium salt intermediate 2; 4. The method for preparing a (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2 according to claim 3, characterized in that: The reduction reaction is carried out by hydrogenation reduction under the action of a catalyst, and the catalyst is selected from (1,2-bis((2R,5R)-2,5-diethylphospholane-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-dimethylphosphino]benzene(cyclooctadiene)rhodium tetrafluoroborate(I), 1,2-bis[(2R,5R)-2,5-diethylphosphino]benzene(1,5-cyclooctadiene)rhodium tetrafluoroborate(I), The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention. The invention relates to a method for preparing the invention.

5. The method for preparing a (R)-4-benzyloxy-2-methyl-4-oxobutyric acid calcium salt compound 2 according to claim 3, characterized in that: The reduction reaction is carried out under the action of an enzyme catalyst, the enzyme catalyst comprises olefin reductase and a coenzyme, the olefin reductase is selected from ERED, OYEs, OPR1 or OPR3, the coenzyme is selected from NADH or NADPH; the reducing agent is selected from glucose or isopropanol; the reaction system is DMSO, acetone, ethanol, isopropanol or water and a mixed solution of any two of them; the buffer is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate or Tris·HCl.

6. A method for preparing (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3, characterized in that: The method comprises subjecting compound 2 and 2-([1,1'-biphenyl]-4-yl)acetic acid to a condensation reaction under the action of a magnesium or lithium reagent, and performing a one-pot decarboxylation reaction, and finally forming a salt under the action of a calcium salt to obtain a target product compound 3; 7. The method for preparing the (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3 according to claim 6, characterized in that: The condensation reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the magnesium-lithium reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride complex, phenyl magnesium chloride, cyclohexyl magnesium chloride, tert-butyl magnesium chloride or n-butyl lithium; the acidified acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid; the salt-forming solvent is selected from water or a mixed solvent system consisting of water and one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, acetone or acetonitrile.

8. A method for preparing (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid calcium salt compound 3, characterized in that: 1) Using 4-(benzyloxy)-2-methylene-4-oxobutanoic acid compound 1 as a starting material, hydrogenating and reducing it under the action of a catalyst or using an enzyme to reduce it, and then forming a salt with calcium chloride to obtain an intermediate compound 2; 2) Compound 2 is subjected to condensation reaction with 2-([1,1'-biphenyl]-4-yl)acetic acid in the presence of magnesium or lithium reagent, and then decarboxylated in one pot, and finally salted in the presence of calcium chloride to obtain the target product compound 3. The reaction route is:

Images