CN117964521A - Preparation method of sabatier starter intermediate - Google Patents
Preparation method of sabatier starter intermediate Download PDFInfo
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- CN117964521A CN117964521A CN202410129455.7A CN202410129455A CN117964521A CN 117964521 A CN117964521 A CN 117964521A CN 202410129455 A CN202410129455 A CN 202410129455A CN 117964521 A CN117964521 A CN 117964521A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000007858 starting material Substances 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 20
- 238000006722 reduction reaction Methods 0.000 claims abstract description 18
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims abstract description 17
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 230000020477 pH reduction Effects 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- HZQLUIZFUXNFHK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylbenzene Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1 HZQLUIZFUXNFHK-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- CBBDKPSPRBIIDO-ZCFIWIBFSA-N ethyl (2R)-2-methyl-4-nitrobutanoate Chemical compound C[C@@H](C(=O)OCC)CC[N+](=O)[O-] CBBDKPSPRBIIDO-ZCFIWIBFSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 101
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000000926 separation method Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 17
- -1 (2R, 4S) -5- [ (1, 1' -biphenyl) -4-yl ] -4-tert-butoxycarbonyl-2-methyl pentanoic acid Chemical compound 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010009 beating Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010925 quality by design Methods 0.000 description 2
- YNELJETWNMPEEH-QRIPLOBPSA-N (2r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(CC(C[C@@H](C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 YNELJETWNMPEEH-QRIPLOBPSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- NQRAWXHLZGWKRS-FTBISJDPSA-N [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 Chemical compound [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 NQRAWXHLZGWKRS-FTBISJDPSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 230000002194 synthesizing effect Effects 0.000 description 1
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- 238000007039 two-step reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a sabatier starter intermediate, and relates to the technical field of medicine synthesis. According to the invention, (2R) -4-nitro-2-methyl-ethyl butyrate and 4-bromomethyl biphenyl are used as initial raw materials, and a Sha Kuba-yeast intermediate can be prepared through condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salifying resolution reaction with R (+) -alpha-methylbenzylamine and acidification free treatment. The preparation method provided by the invention has the advantages of simple process, simple operation, high target product yield (36.5% of total yield of the embodiment 1), high purity, low raw material cost, low production cost and less three wastes, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a sabatier intermediate.
Background
Sha Kuba Tribute sodium (LCZ 696) is a new angiotensin receptor enkephalinase inhibitor, developed by Nohua corporation, which is the first available in the world, and has definite efficacy and good safety in treating heart failure and hypertension. The data show that, in 2022, the Sha Kuba trovaptan sodium tablet of North China is sold worldwide for 46.44 billion dollars and the market is huge. Sha Kuba the molecular structure of sartan sodium consists of one molecule of Sha Kuba koji (structural formula is shown below), one molecule of disodium salt of valsartan sodium and two molecules of semi-water.
The conventional synthesis method of Sha Kuba koji is to take the compound (2R, 4S) -5- [ (1, 1' -biphenyl) -4-yl ] -4-tert-butoxycarbonyl-2-methyl pentanoic acid (2) as a raw material, and obtain (Chen,Zhijun;et al,Optimization and process improvement for LCZ696 by employing quality by design(QbD)principles,Tetrahedron(2020),76(46),131558; patent WO2017009784A 1) through a two-step reaction, wherein the reaction process is as follows:
wherein, the compound 2 is a key intermediate for synthesizing Sha Kuba koji at present. Currently, patent WO2014032627A1 and WO2008031567A1 disclose the synthesis of Sha Kuba curve intermediate compound 2, by the following steps:
However, the synthetic method has a longer process route, uses expensive wittig reagent and chiral auxiliary catalyst, and has high raw material cost and large three-waste emission.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing a sabatier intermediate. The preparation method provided by the invention has the advantages of simple process steps, low preparation cost and less three wastes.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a sabatier starter intermediate, which comprises the following steps:
carrying out condensation reaction on (2R) -4-nitro-2-methyl-ethyl butyrate and 4-bromomethyl biphenyl to obtain an intermediate 1;
acidifying the intermediate 1 after hydrogenation reduction reaction to obtain an intermediate 2;
Performing amino protection reaction on the intermediate 2 and BOC anhydride, and then hydrolyzing to obtain an intermediate 3;
Carrying out salt-forming resolution reaction on the intermediate 3 and R (+) -alpha-methylbenzylamine to obtain an intermediate 4;
acidifying and dissociating the intermediate 4 to obtain Sha Kuba curved intermediate;
preferably, the molar ratio of the (2R) -4-nitro-2-methyl-ethyl butyrate to the 4-bromomethyl biphenyl is 0.95-1.05: 1.
Preferably, the condensation reaction is carried out in the presence of an alkaline agent and an organic solvent;
The alkaline reagent comprises one or more of potassium carbonate, sodium carbonate and triethylamine;
the molar ratio of the (2R) -4-nitro-2-methyl-ethyl butyrate to the alkaline reagent is 1:1 to 1.1;
the organic solvent comprises N, N-dimethylformamide and/or acetonitrile;
the temperature of the condensation reaction is 50-60 ℃ and the time is 5-7 h.
Preferably, the hydrogenation reduction reaction is carried out in the presence of a catalyst and hydrogen; the catalyst comprises Raney nickel and/or palladium carbon;
the hydrogenation reduction reaction is carried out in the presence of an organic solvent, which comprises ethanol and/or methanol.
Preferably, the hydrogenation reduction reaction is carried out at a temperature of 35-45 ℃ for 13-17 hours and under a hydrogen pressure of 0.85-1.15 MPa.
Preferably, the pH value of the acidizing system is 3-4.
Preferably, the molar ratio of the intermediate 2 to the BOC anhydride is 1:1.05 to 1.15;
the temperature of the amino protection reaction is 45-55 ℃ and the time is 2-4 h.
Preferably, the hydrolysis is carried out under acidic conditions, the pH of which is between 5 and 6.
Preferably, the molar ratio of intermediate 3 to R (+) - α -methylbenzylamine is 1:0.8 to 1.3;
the temperature of the salification resolution reaction is 45-55 ℃ and the time is 0.5-2 h.
Preferably, the acid adopted by the acidification free treatment comprises one or more of acetic acid, hydrochloric acid and sulfuric acid;
the molar ratio of the intermediate 4 to the acid is 1:1.1 to 1.3.
According to the invention, (2R) -4-nitro-2-methyl-ethyl butyrate and 4-bromomethyl biphenyl are used as initial raw materials, and a Sha Kuba-yeast intermediate can be prepared through condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salifying resolution reaction with R (+) -alpha-methylbenzylamine and acidification free treatment. The preparation method provided by the invention has the advantages of simple process, simple operation, high target product yield (36.5% of total yield of the embodiment 1), high purity, low raw material cost, low production cost and less three wastes, and is suitable for industrial production.
Drawings
FIG. 1 is a nuclear resonance hydrogen spectrum of intermediate 4;
FIG. 2 is an infrared spectrum of intermediate 4;
FIG. 3 is a nuclear collision resonance hydrogen spectrum of the sabatier intermediate;
FIG. 4 is an infrared spectrum of a sabatier intermediate;
Fig. 5 is a mass spectrum of the sabatier intermediate.
Detailed Description
The invention provides a preparation method of a sabatier starter intermediate, which comprises the following steps:
carrying out condensation reaction on (2R) -4-nitro-2-methyl-ethyl butyrate and 4-bromomethyl biphenyl to obtain an intermediate 1;
acidifying the intermediate 1 after hydrogenation reduction reaction to obtain an intermediate 2;
Performing amino protection reaction on the intermediate 2 and BOC anhydride, and then hydrolyzing to obtain an intermediate 3;
Carrying out salt-forming resolution reaction on the intermediate 3 and R (+) -alpha-methylbenzylamine to obtain an intermediate 4;
acidifying and dissociating the intermediate 4 to obtain Sha Kuba curved intermediate;
unless otherwise specified, materials and equipment used in the present invention are commercially available in the art.
The invention carries out condensation reaction on (2R) -4-nitro-2-methyl-ethyl butyrate and 4-bromomethyl biphenyl to obtain an intermediate 1.
In the present invention, the molar ratio of the (2R) -4-nitro-2-methyl-butanoic acid ethyl ester to the 4-bromomethyl biphenyl is preferably 0.95 to 1.05:1, more preferably 1 to 1.02:1.
In the present invention, the condensation reaction is preferably carried out in the presence of an alkaline agent and an organic solvent. In the present invention, the alkaline agent preferably includes one or more of potassium carbonate, sodium carbonate and triethylamine; the molar ratio of the (2R) -4-nitro-2-methyl-ethyl butyrate to the alkaline reagent is preferably 1:1 to 1.1, more preferably 1:1.02 to 1.05. In the present invention, the organic solvent preferably includes N, N-dimethylformamide and/or acetonitrile, more preferably N, N-dimethylformamide; the dosage ratio of the (2R) -4-nitro-2-methyl-ethyl butyrate to the organic solvent is preferably 1mol:1800 to 2200g, more preferably 1mol:1900 to 2100g, more preferably 1mol:2000g.
In the present invention, the temperature of the condensation reaction is preferably 50 to 60 ℃, more preferably 55 ℃; the time of the condensation reaction is preferably 5 to 7 hours, more preferably 6 hours.
After the condensation reaction is completed, the condensation reaction liquid obtained by the condensation reaction is concentrated until no solvent flows out, the temperature is reduced to 27-33 ℃ (more preferably 30 ℃), dichloromethane and water are added for dichloromethane extraction, and the obtained organic phase is concentrated to constant weight, so that the intermediate 1 is obtained. In the present invention, the number of times of the water washing is preferably 1 to 3 times, more preferably 2 times.
After the intermediate 1 is obtained, the intermediate 1 is subjected to hydrogenation reduction reaction and then is acidified to obtain an intermediate 2.
In the present invention, the hydrogenation reduction reaction is preferably carried out in the presence of a catalyst and hydrogen; the catalyst preferably comprises Raney nickel and/or palladium on carbon, more preferably Raney nickel. In the present invention, the ratio of the intermediate 1 to the catalyst is preferably 1mol:45 to 55g, more preferably 1mol:48 to 52g, more preferably 1mol:50g.
In the present invention, the hydrogenation reduction reaction is preferably carried out in the presence of an organic solvent, which preferably includes ethanol and/or methanol, more preferably ethanol. In the present invention, the ratio of the intermediate 1 to the organic solvent is preferably 1mol:1800 to 2200g, more preferably 1mol:1900 to 2100g, more preferably 1mol:2000g.
In the present invention, the temperature of the hydrogenation reduction reaction is preferably 35 to 45 ℃, more preferably 40 ℃; the hydrogenation reduction reaction time is preferably 13 to 17 hours, more preferably 14 to 15 hours; the hydrogen pressure of the hydrogenation reduction reaction is preferably 0.85 to 1.15MPa, more preferably 1MPa.
After the completion of the hydrogenation reduction reaction, the present invention preferably further comprises: and carrying out solid-liquid separation on the hydrogenation reaction liquid obtained by the hydrogenation reaction, and concentrating the obtained liquid component to constant weight. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method known to those skilled in the art, such as filtration, suction filtration, or centrifugal separation.
In the present invention, the pH of the acidified system is preferably 3 to 4, more preferably 3.5; and separating out a solid product in the acidification process. In the present invention, the acid for acidification preferably includes hydrochloric acid or sulfuric acid; the concentration of the acid is not particularly limited, and the pH of the system may be adjusted to 3 to 4 by using an acid known to those skilled in the art, specifically, concentrated hydrochloric acid or a 70wt% sulfuric acid aqueous solution.
After the acidification is completed, the invention preferably further comprises: and (3) carrying out solid-liquid separation on the acidizing system obtained by acidizing, and drying the obtained solid product to constant weight to obtain the intermediate 2. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method known to those skilled in the art, such as filtration, suction filtration, or centrifugal separation.
After the intermediate 2 is obtained, the intermediate 2 and BOC anhydride are subjected to amino protection reaction and then are hydrolyzed to obtain an intermediate 3.
In the present invention, the molar ratio of intermediate 2 to BOC anhydride is preferably 1:1.05 to 1.15, more preferably 1:1.1.
In the present invention, the amino-protecting reaction is preferably carried out in the presence of an alkaline agent. In the present invention, the alkaline agent preferably includes sodium hydroxide and/or potassium hydroxide, more preferably sodium hydroxide; the alkaline agent is preferably used in the form of an aqueous alkaline agent solution, and the concentration of the aqueous alkaline agent solution is preferably 35 to 40wt%, more preferably 40wt%. In the present invention, the molar ratio of the intermediate 2 to the alkaline agent is preferably 1:1.9 to 2.1, more preferably 1:2.
In the present invention, the solvent used in the amino-protecting reaction is preferably water, and the ratio of the amount of the intermediate 2 to the amount of water is preferably 1mol:80 to 120g, more preferably 1mol:90 to 110g, more preferably 1 mol/100 g.
In the present invention, the subjecting the intermediate 2 and BOC anhydride to an amino protection reaction preferably comprises: the intermediate is stirred and mixed with water, and then an aqueous alkaline reagent solution is added dropwise. In the present invention, the temperature of the stirring and mixing is preferably 15 to 25 ℃, more preferably 20 ℃; the stirring and mixing time is preferably 25 to 40 minutes, more preferably 30 to 35 minutes.
In the present invention, the temperature of the amino group protection reaction is preferably 45 to 55 ℃, more preferably 48 to 52 ℃, still more preferably 50 ℃; the time for the amino group protection reaction is preferably 2 to 4 hours, more preferably 2.5 to 3.5 hours, and still more preferably 3 hours.
In the present invention, the hydrolysis is preferably carried out under acidic conditions, the pH of which is preferably 5 to 6, more preferably 5.5. In the present invention, the acid used in the acidic condition preferably includes one or more of acetic acid, hydrochloric acid and sulfuric acid; the acid is preferably used in the form of an aqueous acid solution, and the concentration of the aqueous acid solution is not particularly limited in the present invention, and the pH of the system may be adjusted to 5 to 6.
After the hydrolysis, the present invention preferably further comprises: concentrating the hydrolysate obtained by hydrolysis to constant weight, adding water, stirring and pulping, performing solid-liquid separation, and drying the obtained solid product to constant weight to obtain the intermediate 3. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method known to those skilled in the art, such as filtration, suction filtration, or centrifugal separation. In the present invention, the ratio of the intermediate 2 to the water for beating with stirring is preferably 1mol:900 to 1100g, more preferably 1mol:950 to 1050g, more preferably 1 mol/1000 g.
After the intermediate 3 is obtained, the intermediate 3 and R (+) -alpha-methylbenzylamine are subjected to salt-forming resolution reaction to obtain an intermediate 4.
In the present invention, the molar ratio of the intermediate 3 to R (+) - α -methylbenzylamine is preferably 1:0.8 to 1.3, more preferably 1:1.1 to 1.3, more preferably 1:1.2.
In the present invention, the salt-forming resolution reaction of the intermediate 3 with R (+) - α -methylbenzylamine preferably comprises: dissolving the intermediate 3 in an organic solvent, and dropwise adding an R (+) -alpha-methylbenzylamine solution to carry out salt-forming resolution reaction. In the present invention, the organic solvent preferably includes Ethyl Acetate (EA) and/or isopropyl alcohol, more preferably ethyl acetate; the ratio of the intermediate 3 to the organic solvent is preferably 1mol:320 to 350g, more preferably 1mol:340 to 350g, more preferably 1mol:350g. In the present invention, the solvent in the R (+) - α -methylbenzylamine solution preferably comprises Ethyl Acetate (EA) and/or isopropyl alcohol, more preferably ethyl acetate; the dosage ratio of the R (+) -alpha-methylbenzylamine to the solvent in the R (+) -alpha-methylbenzylamine solution is preferably 1mol:350 to 400g, more preferably 1mol:360 to 390g, more preferably 1mol:375g.
In the invention, the temperature of the salification resolution reaction is preferably 45-55 ℃, more preferably 50 ℃; the salt-forming resolution reaction time is preferably 0.5 to 2 hours, more preferably 1 to 1.5 hours.
After the salt-forming resolution reaction is completed, the invention preferably further comprises: crystallizing the salified resolution reaction liquid obtained by the salified resolution reaction to obtain an intermediate 4. And (3) carrying out solid-liquid separation, washing the obtained solid product ethyl acetate, and drying to constant weight to obtain the intermediate 4. In the present invention, the crystallization is preferably a cooling crystallization, which is preferably naturally cooled from the temperature of the salt-forming resolution reaction to-5 to 5 ℃ (more preferably 0 ℃). The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method known to those skilled in the art, such as filtration, suction filtration, or centrifugal separation.
After obtaining the intermediate 4, the invention carries out acidification and ionization treatment on the intermediate 4 to obtain Sha Kuba curved intermediate.
In the present invention, the acid used in the acidification ionization treatment preferably includes one or more of acetic acid, hydrochloric acid and sulfuric acid, and more preferably acetic acid. In the present invention, the molar ratio of the intermediate 4 to the acid is preferably 1:1.1 to 1.3, more preferably 1:1.2.
In the present invention, the acidification and dissociation treatment of the intermediate 4 preferably comprises: dissolving the intermediate 4 in an organic solvent, and dropwise adding acid for acidification and ionization treatment. In the present invention, the organic solvent preferably includes methylene chloride and/or toluene, more preferably methylene chloride; the ratio of the intermediate 4 to the organic solvent is preferably 1mol:3500 to 4500g, more preferably 1mol:3800 to 4200g, more preferably 1mol:4000g.
In the present invention, the temperature of the acidification ionization treatment is preferably 15 to 25 ℃, more preferably 20 to 25 ℃; the time for the acidification ionization treatment is preferably 0.2 to 1h, more preferably 0.5h, when the acid addition is started after completion of the acid addition.
After the acidification and dissociation treatment is completed, the invention preferably further comprises: mixing the acidified free treatment liquid obtained by the acidified free treatment with water for layering to obtain a layered water phase and an organic phase respectively, washing the organic phase with water to obtain a water-washed water phase and a water-washed organic phase respectively, combining the layered water phase and the water-washed water phase, back-extracting dichloromethane, combining the obtained dichloromethane back-extracting phase with the water-washed organic phase, concentrating to constant weight, adding a beating reagent for beating, carrying out solid-liquid separation, washing the obtained solid product with normal hexane, and drying to constant weight to obtain Sha Kuba yeast intermediate. In the present invention, the number of times of the water washing is preferably 2 to 4 times, more preferably 3 times. In the present invention, the ratio of the intermediate 4 to the dichloromethane for stripping is preferably 1mol:900 to 1100g, more preferably 1mol:1000g. In the present invention, the beating agent preferably comprises n-hexane and methylene chloride, and the ratio of the amount of the intermediate 4, n-hexane and methylene chloride is preferably 1mol: 1400-1600 g:140 to 160g, more preferably 1mol:1500g:150g. In the present invention, the beating temperature is preferably-5 to 5 ℃, more preferably 0 ℃; the beating time is preferably 0.4 to 1 hour, more preferably 0.5 hour. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method known to those skilled in the art, such as filtration, suction filtration, or centrifugal separation.
The following examples are provided to illustrate the invention in more detail, but are not to be construed as limiting the scope of the invention.
Example 1
Step 1: synthesis of ethyl (2R) -5- ([ 1,1' -biphenyl ] -4-yl) -4-nitro-2-methylpentanoate (intermediate 1).
(2R) -4-nitro-2-methyl-ethyl butyrate (175 g,1 mol), 4-bromomethyl biphenyl (247 g,1 mol), DMF 2000g and potassium carbonate (145 g,1.05 mol) were mixed, reacted for 6h after heating to 55 ℃, the HPLC content of 4-bromomethyl biphenyl was less than 0.3wt%, the reaction was stopped, concentrated under reduced pressure until no outflow was produced, cooled to 30 ℃, dichloromethane 2500g was added, water 1000g was stirred and layered, the obtained organic phases were washed 2 times (500 g of water consumption per unit time), the organic phases were combined, and concentrated to constant weight to obtain (2R) -5- ([ 1,1' -biphenyl ] -4-yl) -4-nitro-2-methyl ethyl valerate (intermediate 1).
Step 2: synthesis of ethyl (2R) -5- ([ 1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate hydrochloride (intermediate 2).
Dissolving the intermediate 1 in 2000g of ethanol, adding 50g of Raney nickel, replacing air with nitrogen, replacing nitrogen with hydrogen, then charging hydrogen to the pressure of 1MPa, heating to 40 ℃ and reacting for 15h, wherein the HPLC content of the intermediate 1 is less than 0.3wt%. Stopping the reaction, filtering to remove Raney nickel, concentrating the filtrate, distilling off ethanol, adding 1500g of methylene chloride for dissolution, adjusting the pH of the system with concentrated hydrochloric acid to be 3-4, separating out a pale yellow solid compound, filtering, and drying the obtained solid compound to constant weight to obtain an intermediate 2 (308 g, calculated as 4-bromomethylbiphenyl, yield is 88.5%, and HPLC purity is 99.52%).
Step 3: synthesis of (2R) -N-t-Butoxycarbonyl 5- ([ 1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoic acid (intermediate 3).
Intermediate 2 (174 g,0.5 mol), ethanol 500g, stirring at 20 ℃ for 0.5h, dropwise adding 100g of 40wt% sodium hydroxide aqueous solution, heating to 50 ℃, and dropwise adding (120 g,0.55 mol) BOC anhydride, wherein the reaction time is 3h until the residual amount of intermediate 2 is less than 0.2wt%. Adjusting pH with hydrochloric acid to be between 5 and 6, steaming to remove ethanol, adding 500g of water, stirring, pulping, dispersing, filtering, and drying the obtained solid product to constant weight to obtain an intermediate 3, wherein the intermediate 3 is directly used for the next reaction without purification.
Step 4: synthesis of R-alpha-methylbenzylamine salt of (2R, 4S) -5- [ (1, 1' -biphenyl) -4-yl ] -4-t-butoxycarbonyl-2-methylpentanoic acid (intermediate 4).
The intermediate 3 and ethyl acetate 1750g are heated to 50 ℃ and stirred for dissolution, then a mixed solution of R (+) -alpha-methylbenzylamine (48.5 g,0.4 mol) and ethyl acetate (150 g) is added dropwise, the mixture is stirred for 1h after the dripping is finished, then the temperature is naturally reduced to 0 ℃, the filtration is carried out, the obtained solid product is leached by 50g of ethyl acetate and then dried, and intermediate 4 (white solid, 106.5g, calculated by the intermediate 2, yield is 42.3%, HPLC purity is 99.68%, and melting point is 141.5-142.1 ℃).
FIG. 1 is a nuclear collision resonance hydrogen spectrum of intermediate 4 ,1H-NMR(CDCl3,600MHz)：δ1.04(d,3H,CH3),1.29(d,3H,CH3),1.32(s,3,CH3),1.34(s,6H,2CH3),1.37(m,1,1/2CH2),1.74(m,1H,1/2CH2),2.38(m,1H,CH),2.68(d,2H,CH2),3.65(m,1H,CH),4.01(q,1H,CH),7.18～7.64(m,14H,Ph-Ph-H,Ph-H).
FIG. 2 is an infrared spectrum of intermediate 4 (IR,KBr,cm-1)：3372(νNH2),2971(δCH3),2933(νOH),1682(νC＝O),1517(νCONH),1458(δCH2),1399(δCH),1247(νCOC),1175(δPh-H),1077(δPh-H),731(гPh-H),698(νCH).
Elemental analysis (C 23H29NO4.C8H11 N,%) of intermediate 4 (measured/calculated): C73.69/73.78H8.05/7.99N 5.57/5.55.
Step 5: sha Kuba synthesis of intermediates.
Uniformly mixing intermediate 4 (50.4 g,0.1 mol) and 400g of dichloromethane, dropwise adding glacial acetic acid (7.2 g,0.12 mol) at 20 ℃, continuously stirring for 0.5h after the completion of dropwise adding, adding 100g of water, layering to respectively obtain a layered water phase and an organic phase, and washing the organic phase with water for 3 times (single use of 100 g) to respectively obtain a water-washed organic phase and a water-washed water phase; all aqueous phases are combined, 100g of dichloromethane are added for back extraction, a dichloromethane back extraction phase is obtained, and the water-washed organic phase and the dichloromethane back extraction phase are combined and then concentrated to constant weight. 150g of n-hexane, 15g of dichloromethane and pulping for 0.5h are added, filtration is carried out, and the obtained solid product is dried after leaching by 5g of n-hexane, thus obtaining Sha Kuba-bent intermediate (white solid, 37.3g, yield is 97.5%, HPLC purity is 99.76%, melting point is 148.5-148.6 ℃, specific rotation (2% methanol, namely the dosage ratio of compound to methanol is 2g:100 mL): 7.2 °).
FIG. 3 is a nuclear collision resonance hydrogen spectrum of a sabatier intermediate ,1H-NMR(CDCl3,600MHz)：δ1.20(d,3H,CH3),1.29(s,3H,CH3),1.41(s,6H,CH3),1.49(q,1H,CH),1.9(m,1H,CH),2.58～2.67(dd,1H,1/2CH2),2.8(m,2H,CH2),3.92～4.01(dd,1H,1/2CH2),4.56(d,1H,NH),6.37(s,1H,COOH),7.23～7.58(m,9H,Ph-Ph-H).
FIG. 4 is an infrared spectrum of a sabatier intermediate (IR,KBr,cm-1)：3221(νOH),2974(δCH3),1705(νC＝O),1647(νCONH),1487(δCH2),1431(δCH),1241(νCOC),1171(δPh-H),1049(δPh-H),764(гPh-H),696(νCH).
Fig. 5 is a mass spectrum of the sababamectin intermediate, M-1=382 (m=383).
Elemental analysis (C 23H29NO4,%) of Sha Kuba curved intermediates (measured/calculated): C72.10/72.04H 7.68/7.62N 3.57/3.65.
Example 2
Sha Kuba a curved intermediate was prepared following the procedure of example 1, differing from example 1 only in:
In the step 1, DMF is replaced by acetonitrile;
in the step 2, ethanol is replaced by methanol, and Raney nickel is replaced by 5% palladium carbon; the yield of intermediate 2 was 86.7% and the HPLC purity was 99.48% based on 4-bromomethylbiphenyl;
the amount of R (+) -alpha-methylbenzylamine used in step 4 was 0.55mol (1.1 eq); the yield of intermediate 4 was 42.8% and HPLC purity 99.32% based on intermediate 2;
400g of methylene chloride was replaced with 800g of toluene in step 5; the yield of Sha Kuba% of the curved intermediate was 96.6% and the HPLC purity was 99.73%.
While the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments of the invention can be made and still fall within the scope of the invention without undue effort.
Claims (10)
1. The preparation method of the sabatier starter intermediate is characterized by comprising the following steps of:
carrying out condensation reaction on (2R) -4-nitro-2-methyl-ethyl butyrate and 4-bromomethyl biphenyl to obtain an intermediate 1;
acidifying the intermediate 1 after hydrogenation reduction reaction to obtain an intermediate 2;
Performing amino protection reaction on the intermediate 2 and BOC anhydride, and then hydrolyzing to obtain an intermediate 3;
Carrying out salt-forming resolution reaction on the intermediate 3 and R (+) -alpha-methylbenzylamine to obtain an intermediate 4;
acidifying and dissociating the intermediate 4 to obtain Sha Kuba curved intermediate;
2. the preparation method according to claim 1, wherein the molar ratio of (2R) -4-nitro-2-methyl-butanoic acid ethyl ester to 4-bromomethyl biphenyl is 0.95-1.05: 1.
3. The production method according to claim 1 or 2, wherein the condensation reaction is performed in the presence of an alkaline agent and an organic solvent;
The alkaline reagent comprises one or more of potassium carbonate, sodium carbonate and triethylamine;
the molar ratio of the (2R) -4-nitro-2-methyl-ethyl butyrate to the alkaline reagent is 1:1 to 1.1;
the organic solvent comprises N, N-dimethylformamide and/or acetonitrile;
the temperature of the condensation reaction is 50-60 ℃ and the time is 5-7 h.
4. The process according to claim 1, wherein the hydrogenation reduction is carried out in the presence of a catalyst and hydrogen; the catalyst comprises Raney nickel and/or palladium carbon;
the hydrogenation reduction reaction is carried out in the presence of an organic solvent, which comprises ethanol and/or methanol.
5. The method according to claim 1, wherein the hydrogenation reduction reaction is carried out at a temperature of 35 to 45 ℃ for 13 to 17 hours and at a hydrogen pressure of 0.85 to 1.15MPa.
6. The process according to claim 1, wherein the pH of the acidified system is 3 to 4.
7. The process of claim 1, wherein the molar ratio of intermediate 2 to BOC anhydride is 1:1.05 to 1.15;
the temperature of the amino protection reaction is 45-55 ℃ and the time is 2-4 h.
8. The process according to claim 1, wherein the hydrolysis is carried out under acidic conditions having a pH of 5 to 6.
9. The preparation method according to claim 1, wherein the molar ratio of the intermediate 3 to the R (+) - α -methylbenzylamine is 1:0.8 to 1.3;
the temperature of the salification resolution reaction is 45-55 ℃ and the time is 0.5-2 h.
10. The method according to claim 1, wherein the acid used in the acidification ionization treatment comprises one or more of acetic acid, hydrochloric acid and sulfuric acid;
the molar ratio of the intermediate 4 to the acid is 1:1.1 to 1.3.
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