Preparation method of sacubitril intermediate
Through the method of combining nickel catalyst with chiral bisphosphine ligand, asymmetric hydrogenation reaction is used to prepare sakubaquer intermediates in an autoclave, solving the problems of high cost and low catalytic efficiency in the prior art, and achieving economic, environmentally friendly and industrialized preparation methods.
Patent Information
- Application Number
- CN202411582673.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-07
- Publication Date
- 2025-03-14
AI Technical Summary
The prior art has problems such as high cost, limited industrial application and low catalytic efficiency when preparing shakubaqu intermediates.
The method of combining nickel catalyst with chiral bisphosphine ligand is used to prepare the sakubaquer intermediate in an autoclave through asymmetric hydrogenation reaction, and the reaction activity is improved using quaternary ammonium salt as an additive.
The preparation method of Shakubaqu intermediate with economic and environmental protection, good three-dimensional selectivity and high catalytic efficiency has been realized, reducing production costs and is suitable for industrial production.
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Figure CN119613294A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a method for synthesizing a sacubitril intermediate, and belongs to the technical field of pharmaceutical chemical synthesis. Background Art
[0002] Heart failure, referred to as "heart failure", is the final stage of the development of many heart diseases. It is also the most difficult and risky disease to treat in the cardiovascular field. Heart failure is a complex progressive clinical syndrome caused by a variety of cardiovascular diseases, manifested by a weakened ability of the heart to transport blood throughout the body. Its main pathogenesis includes myocardial cell loss, myocardial energy metabolism disorder, cardiac inflammation activation, etc.
[0003] Treatments for heart failure include medication, lifestyle changes (such as exercise), implantable devices, and surgery. The overall goal of heart failure treatment is to relieve symptoms and reduce hospitalization and mortality rates. Types of medications used to treat heart failure are usually diuretics, angiotensin-converting enzyme inhibitors, etc.
[0004] As a representative drug of angiotensin receptor neprilysin antagonist, sacubitril valsartan sodium tablets (trade name: Nuxintu @ Entresto @ ), which is composed of a compound of angiotensin II receptor antagonist valsartan and enkephalinase inhibitor sacubitril. Sacubitril-valsartan sodium is the first anti-heart failure drug developed by Novartis. It was approved for marketing by the FDA in July 2015 and by the National Medical Products Administration in 2017, and has entered the European and Asian markets successively. It has a dual-target regulatory effect, which can block AT1 receptors and inhibit enkephalinase (NEP), and is a new and effective drug for the treatment of heart failure. Compared with valsartan alone, sacubitril-valsartan sodium can lower blood pressure more effectively, and its therapeutic effect on heart failure and hypertension has an important impact on quality of life and resource utilization. As a breakthrough innovative drug for the treatment of chronic heart failure, the global sales of sacubitril-valsartan have grown rapidly year by year. In 2018, the global sales reached US$1 billion, and in 2022, the global sales have exceeded US$4.64 billion, and the market potential is rapidly exploding. The preparation methods of sacubitril intermediates are mainly asymmetric catalytic hydrogenation and asymmetric catalytic hydrogen transfer.
[0005] Novartis disclosed a method for preparing a sacubitril intermediate in patent CN101516831, and its synthetic route is as follows:
[0006]
[0007] The method uses (R,E)-5-([1,1`-biphenyl]-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methyl-2-pentenoic acid as a raw material, and undergoes asymmetric hydrogenation catalyzed by [Ru] or [Rh] / Mandyphos to efficiently prepare (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid, wherein S / C is 1000 and the dr value of the product is 98 / 2. The transition metal ruthenium / rhodium is expensive, the chiral ferrocene diphosphine series ligands have a complex structure and are relatively expensive, and the industrial production cost is relatively high.
[0008] Patent CN113321600 discloses a method for preparing sacubitril intermediates by Ru / (R,R)-Me-Duphos catalytic asymmetric hydrogenation. The synthetic route is as follows:
[0009]
[0010] The diastereoselectivity of this method is as high as 98.9 / 1.1dr. This route involves the use of transition metal ruthenium, which is relatively expensive, which inevitably limits its industrial application, and the S / C is only 1000.
[0011] In 2020, Zhang Xumu's research group developed a class of oxyhelix bisphosphine ligands (O-SDP). These ligands form catalysts with metal Ru and have achieved breakthrough research results in the asymmetric catalytic hydrogenation of α, β-unsaturated carboxylic acids and sacubitril intermediates with S / C as high as 30000, >99 / 1dr, but the ligand is not easy to prepare.
[0012]
[0013] Patent CN111269148 discloses a method for preparing sacubitril intermediates by nickel-catalyzed hydrogen transfer reaction. The synthesis route is as follows:
[0014]
[0015] This method is a combination of nickel salt and (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexanediamine, with a catalytic activity S / C=100, which needs to be further optimized.
[0016] Therefore, since sacubitril has good medicinal prospects, it is very necessary to develop an economical, environmentally friendly, stereoselective and catalytically efficient method for preparing sacubitril intermediates. Summary of the invention
[0017] In view of the problems existing in the current preparation technology, the present invention proposes a method for preparing a sacubitril intermediate which is economical, environmentally friendly, has good stereoselectivity and high catalytic efficiency. The method is simple to operate, has low production cost, is safe to operate, and is suitable for industrial production.
[0018] The technical solution adopted by the present invention is as follows:
[0019] The present invention provides a method for preparing a sacubitril intermediate, the structural formula of which is shown in formula (I), and the preparation method comprises the following steps:
[0020] A method for preparing a sacubitril intermediate as shown in formula (I), characterized in that the preparation method comprises the following steps:
[0021] (1) under nitrogen atmosphere and room temperature, adding metal nickel salt and chiral diphosphine ligand to a solvent in sequence, stirring and reacting at room temperature for 0.5 to 6.0 hours to prepare a nickel catalyst solution;
[0022] (2) under nitrogen protection, compound (II), the nickel catalyst solution prepared in step (1), solvent and additives are sequentially added to an autoclave, and the mixture is reacted at 20 to 100° C. and a hydrogen pressure of 1.0 to 6.0 MPa for 6 to 30 hours. After the reaction is completed, the solvent is removed by concentration under reduced pressure, and the residue is recrystallized with a mixed solvent of isopropyl acetate and n-heptane to obtain sacubitril intermediate (I);
[0023] The specific reaction route is as follows:
[0024]
[0025] The metal nickel salt is selected from one of NiCl2, NiBr2, NiI2, Ni(OTf)2, Ni(CF3CO2)2, Ni(OAc)2·4H2O, and Ni(BF4)2·6H2O.
[0026] The chiral bisphosphine ligand is any one of (R,R)-Skewphos, (R,R)-3,5-Xyl-Skewphos, (2R,4R)-PTBP-Skewphos, and (R,R)-Ph-BPE:
[0027]
[0028] Furthermore, the molar ratio of the metal nickel salt to the chiral diphosphine ligand is 0.8-1.0:1; the molar ratio of the compound (II) to the metal nickel salt is 1:0.005-0.02, preferably 1:0.008-0.01.
[0029] Furthermore, the solvent in step (1) or step (2) is one or a mixture of any proportion of methanol, ethanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol and hexafluoroisopropanol.
[0030] Furthermore, in the reaction solution formed by mixing the compound (II), the nickel catalyst solution, the solvent and the additive in step (2), the dispersion concentration of the compound (II) is 0.5-1.0 mol / L.
[0031] Furthermore, in step (2), the additive is one of sodium bromide, sodium iodide, potassium bromide, potassium iodide, sodium acetate, potassium acetate, sodium trifluoroacetate, sodium trifluoromethanesulfonate, ammonium bromide, ammonium iodide, tetrabutylammonium bromide, tetrabutylammonium iodide, and sodium benzoate.
[0032] Furthermore, the molar ratio of the compound (II) to the additive is 1:0.01-0.1, preferably 1:0.04-0.06.
[0033] Furthermore, in step (2), the reaction temperature is 30-50° C., the hydrogen pressure is 3.0-4.5 MPa, and the reaction time is 15-30 hours.
[0034] Furthermore, the volume ratio of isopropyl acetate to n-heptane in the solvent used for recrystallization in step (2) is 1:0.8-1.2.
[0035] Compared with the prior art, the present invention has the following beneficial effects: (1) the use of cheap metal nickel salts and relatively cheap chiral ligands (R,R)-Skewphos makes the preparation cost of the catalyst low; (2) the addition of quaternary ammonium salts as additives in the catalytic system increases the reaction activity, significantly improves the reaction conversion rate and diastereoselectivity, and provides a new strategy for the high-yield metal asymmetric catalysis of α,β-unsaturated olefins and other bioactive molecules.
[0036] The preparation method of the invention has simple operation, mild conditions and potential industrial application value. DETAILED DESCRIPTION
[0037] The present invention is further described below in conjunction with specific examples, but is not limited to the implementation schemes described in the specific examples listed in the present invention.
[0038] The chiral bisphosphine ligands (R,R)-Skewphos, (R,R)-3,5-Xyl-Skewphos, (2R,4R)-PTBP-Skewphos, and (R,R)-Ph-BPE in the embodiments of the present invention are all commercially available ligands and can be purchased on the website of J&K Reagents.
[0039] Example 1: Preparation of (2R, 4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (I)
[0040] (1) Under nitrogen atmosphere, Ni(OAc)2·4H2O (74 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and trifluoroethanol (5 mL) were added sequentially into a single-necked bottle and stirred at room temperature for 2 hours to obtain an orange nickel catalyst solution.
[0041] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), trifluoroethanol (35 mL) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After stirring and reacting at 50°C for 20 hours, the mixture was cooled to room temperature and the reaction solution was tested by HPLC. The reaction conversion rate was 99% and the dr value of the crude product was 83 / 17. The solvent was recovered by vacuum concentration and the residue was recrystallized with isopropyl acetate and n-heptane (1:1) to obtain a white solid (I), 6.40 g, with a yield of 55%. The pure product had a dr value of 99 / 1 and an ee value of 99%.
[0042] In Example 1, no additives were added, the dr value of the crude product obtained by the reaction was not high, and the reaction yield was low.
[0043] Embodiment 2:
[0044] (1) Under nitrogen atmosphere, NiCl2 (39 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and methanol (5 mL) were added sequentially into a single-necked bottle and stirred at room temperature for 2 hours to obtain a yellow nickel catalyst solution.
[0045] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), methanol (35 mL), sodium iodide (1.5 mmol), and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing the nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After stirring and reacting at 50°C for 30 hours, the reaction solution was tested by HPLC. The reaction conversion rate was 96%, and the dr value of the crude product was 88 / 12. The solvent was recovered by vacuum concentration, and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain a white solid (I), 7.23 g, with a yield of 62%. The pure product has a dr value of 99 / 1 and an ee value of 99%.
[0046] Embodiment 3:
[0047] (1) Under nitrogen atmosphere, Ni(OTf)2 (107 mg, 0.3 mmol), ligand (R,R)-3,5-Xyl-Skewphos (207 mg, 0.375 mmol) and tert-butyl alcohol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 hours to obtain a yellow nickel catalyst solution.
[0048] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), tert-butyl alcohol (35 mL), ammonium iodide (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing the nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added, and the mixture was stirred at 30°C for 20 hours. The reaction solution was tested by HPLC, and the reaction conversion rate was 99%, and the dr value of the crude product was 83 / 17. The solvent was recovered by vacuum concentration, and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 6.38 g of white solid (I), with a yield of 55%. The pure product had a dr value of 99 / 1 and an ee value of 99%.
[0049] Embodiment 4:
[0050] (1) Under nitrogen atmosphere, Ni(OAc)2·4H2O (74 mg, 0.3 mmol), ligand (R,R)-Ph-BPE (152 mg, 0.3 mmol) and trifluoroethanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 h to obtain an orange nickel catalyst solution.
[0051] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), trifluoroethanol (35 mL), tetrabutylammonium iodide (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing the nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After stirring and reacting at 60°C for 15 hours, the mixture was cooled to room temperature and the reaction solution was tested by HPLC. The reaction conversion rate was 99% and the dr value of the crude product was 97 / 3. The solvent was recovered by vacuum concentration and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 10.49 g of a white solid (I) with a yield of 90%. The product had a dr value of 99 / 1 and an ee value of 99%.
[0052] In Example 4, the additive added was tetrabutylammonium iodide (1.5 mmol), the dr value of the reaction was very high (97:3), and the recrystallization yield reached 90%.
[0053] Embodiment 5:
[0054] (1) Under nitrogen atmosphere, Ni(BF4)2·6H2O (102 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and ethanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 hours to obtain a yellow nickel catalyst solution.
[0055] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), toluene (35 mL), sodium acetate (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing nitrogen with hydrogen several times, hydrogen (3.0 MPa) was added, and the mixture was stirred at 100°C for 20 hours. After cooling to room temperature, the reaction solution was tested by HPLC. The conversion rate of the reaction was 45%, and the dr value of the crude product was 68 / 32. The solvent was recovered by vacuum concentration, and 3.84 g of white solid (I) was obtained by column chromatography separation (elution solvent was dichloromethane: methanol = 5:1, v / v), with a yield of 30%. The pure product had a dr value of 99 / 1 and 99% ee.
[0056] In Example 5, toluene was used as the reaction solvent, and the reaction yield was low, which shows that the selection of solvent has a great influence on the reaction result. In addition, the reaction was almost non-reactive in THF.
[0057] Embodiment 6:
[0058] (1) Under nitrogen atmosphere, Ni(CF3COO)2 (85.4 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and isopropanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 hours to obtain a yellow nickel catalyst solution.
[0059] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), isopropanol (35 mL), sodium benzoate (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After stirring at 30°C for 30 hours, the reaction solution was tested by HPLC. The conversion rate of the reaction reached >99%, and the dr value of the crude product was 84 / 16. The solvent was recovered by vacuum concentration, and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 6.76 g of white solid (I), with a yield of 67%. The product had a dr value of 99 / 1 and an ee value of 99%.
[0060] Embodiment 7:
[0061] (1) Under nitrogen atmosphere, Ni(OAc)2·4H2O (74 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and trifluoroethanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 hours to obtain an orange nickel catalyst solution.
[0062] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), trifluoroethanol (35 mL), tetrabutylammonium iodide (3 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After stirring and reacting at 30°C for 20 hours, the reaction solution was tested by HPLC. The conversion rate of the reaction was 98%, and the dr value of the crude product was 96 / 4. The solvent was recovered by concentration under reduced pressure, and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 10.2 g of white solid (I) with a yield of 88%. The pure product had a dr value of 99 / 1 and 99% ee.
[0063] Embodiment 8:
[0064] (1) Under nitrogen atmosphere, Ni(OAc)2·4H2O (74 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and trifluoroethanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 hours to obtain an orange nickel catalyst solution.
[0065] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), trifluoroethanol (35 mL), tetrabutylammonium iodide (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing the nitrogen with hydrogen several times, hydrogen (6.0 MPa) was added and stirred at 30°C for 30 hours. The reaction solution was tested by HPLC. The conversion rate of the reaction was 99% and the dr value of the crude product was 95 / 5. The solvent was recovered by vacuum concentration and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 10.0 g of white solid (I) with a yield of 86%. The pure product had a dr value of 99 / 1 and 99% ee.
[0066] Embodiment 9:
[0067] (1) Under nitrogen atmosphere, Ni(OAc)2·4H2O (74 mg, 0.3 mmol), ligand (2R,4R)-PTBP-Skewphos (199.5 mg, 0.3 mmol) and trifluoroethanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 hours to obtain an orange nickel catalyst solution.
[0068] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), trifluoroethanol (35 mL), tetrabutylammonium iodide (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing the nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After stirring and reacting at 50°C for 20 hours, the reaction solution was tested by HPLC. The conversion rate of the reaction was 99%, and the dr value of the crude product was 94 / 6. The solvent was recovered by vacuum concentration, and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 10.5 g of white solid (I) with a yield of 90%. The product had a dr value of 99 / 1 and 99% ee.
[0069] Embodiment 10:
[0070] (1) Under nitrogen atmosphere, Ni(OAc)2·4H2O (74 mg, 0.3 mmol), ligand (R,R)-Skewphos (131 mg, 0.30 mmol) and hexafluoroisopropanol (5 mL) were added to a single-necked bottle in sequence and stirred at room temperature for 2 h to obtain an orange nickel catalyst solution.
[0071] (2) Under nitrogen atmosphere, compound II (11.6 g, 30 mmol), hexafluoroisopropanol (35 mL), tetrabutylammonium iodide (1.5 mmol) and the nickel catalyst solution prepared in step (1) were added to the autoclave in sequence. After replacing nitrogen with hydrogen several times, hydrogen (4.5 MPa) was added. After reacting at 30°C for 20 hours, the reaction solution was tested by HPLC. The conversion rate of the reaction was 99%, and the dr value of the crude product was 98 / 2. The solvent was recovered by vacuum concentration, and the residue was recrystallized with isopropyl acetate and n-heptane (1:1, v / v) to obtain 11.1 g of white solid (I) with a yield of 94%. The pure product had a dr value of >99 / 1 and >99% ee.
[0072] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.
Claims
1. A method for preparing a sacubitril intermediate as shown in formula (I), characterized in that The preparation method comprises the following steps: (1) under nitrogen atmosphere and room temperature, adding metal nickel salt and chiral diphosphine ligand to a solvent in sequence, stirring and reacting at room temperature for 0.5 to 6.0 hours to prepare a nickel catalyst solution; (2) In a nitrogen atmosphere, compound (II), the nickel catalyst solution prepared in step 1), a solvent and an additive are sequentially added to an autoclave, and the mixture is reacted at 20 to 100° C. and a hydrogen pressure of 1.0 to 6.0 MPa for 6 to 30 hours. After the reaction is completed, the solvent is removed by concentration under reduced pressure, and the mixture is recrystallized to obtain sacubitril intermediate (I). The specific reaction route is as follows: The molar ratio of the metal nickel salt to the chiral diphosphine ligand is 0.8 to 1.0:1; the molar ratio of the compound (II) to the metal nickel salt is 1:0.005-0.02, preferably 1:0.008-0.
01.
2. The method for preparing the sacubitril intermediate according to claim 1, characterized in that The metal nickel salt is selected from one of NiCl2, NiBr2, NiI2, Ni(OTf)2, Ni(CF3CO2)2, Ni(OAc)2·4H2O, and Ni(BF4)2·6H2O.
3. The method for preparing the sacubitril intermediate according to claim 1, characterized in that The chiral diphosphine ligand is any one of (R,R)-Skewphos, (R,R)-3,5-Xyl-Skewphos, (2R,4R)-PTBP-Skewphos and (R,R)-Ph-BPE.
4. The method for preparing the sacubitril intermediate according to claim 1, characterized in that The solvent in step (1) or step (2) is one or a mixture of any proportion of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol and hexafluoroisopropanol.
5. The method for preparing the sacubitril intermediate according to claim 4, characterized in that In the reaction solution formed by mixing the compound (II), the nickel catalyst solution, the solvent and the additive in step (2), the dispersion concentration of the compound (II) is 0.5-1.0 mol / L.
6. The method for preparing the sacubitril intermediate according to claim 1, characterized in that In step (2), the additive is one of potassium bromide, potassium iodide, sodium bromide, sodium iodide, sodium acetate, potassium acetate, sodium trifluoroacetate, sodium trifluoromethanesulfonate, ammonium bromide, ammonium iodide, tetrabutylammonium bromide, tetrabutylammonium iodide, and sodium benzoate.
7. The method for preparing a sacubitril intermediate according to claim 1, characterized in that The molar ratio of the compound (II) to the additive is 1:0.01-0.1, preferably 1:0.04-0.
06.
8. The method for preparing a sacubitril intermediate according to claim 1, characterized in that In step (2), the reaction temperature is 30-50° C., the hydrogen pressure is 3.0-4.5 MPa, and the reaction time is 15-30 hours.
9. The method for preparing a sacubitril intermediate according to claim 1, characterized in that The solvent used for recrystallization in step (2) is a mixed solvent of isopropyl acetate and n-heptane, and the volume ratio of isopropyl acetate to n-heptane is 1:0.8-1.2.