CN114605410A - Preparation method of non-neferitone bulk drug - Google Patents
Preparation method of non-neferitone bulk drug Download PDFInfo
- Publication number
- CN114605410A CN114605410A CN202210359260.2A CN202210359260A CN114605410A CN 114605410 A CN114605410 A CN 114605410A CN 202210359260 A CN202210359260 A CN 202210359260A CN 114605410 A CN114605410 A CN 114605410A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- stirring
- drying
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title claims description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 90
- 238000010992 reflux Methods 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 229940125904 compound 1 Drugs 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 229940125782 compound 2 Drugs 0.000 claims abstract description 13
- 229940126214 compound 3 Drugs 0.000 claims abstract description 13
- 229940125898 compound 5 Drugs 0.000 claims abstract description 13
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZXENVSJZOHXCKL-UHFFFAOYSA-N 4-formyl-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1C=O ZXENVSJZOHXCKL-UHFFFAOYSA-N 0.000 claims abstract description 10
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000002576 ketones Chemical class 0.000 claims abstract description 7
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 3
- -1 acetoacetate compound Chemical class 0.000 claims abstract description 3
- 230000004913 activation Effects 0.000 claims abstract description 3
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 239000011975 tartaric acid Substances 0.000 claims abstract description 3
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 238000003756 stirring Methods 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 29
- 239000007787 solid Substances 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 25
- 238000001816 cooling Methods 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 13
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229910003158 γ-Al2O3 Inorganic materials 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 230000001376 precipitating effect Effects 0.000 claims description 10
- 239000008096 xylene Substances 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- LBKJNHPKYFYCLL-UHFFFAOYSA-N potassium;trimethyl(oxido)silane Chemical compound [K+].C[Si](C)(C)[O-] LBKJNHPKYFYCLL-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims description 5
- SSQZBQXJYGNUSC-UHFFFAOYSA-N 4-amino-5-methyl-1h-pyridin-2-one Chemical compound CC1=CNC(=O)C=C1N SSQZBQXJYGNUSC-UHFFFAOYSA-N 0.000 claims description 5
- WOFAGNLBCJWEOE-UHFFFAOYSA-N Benzyl acetoacetate Chemical compound CC(=O)CC(=O)OCC1=CC=CC=C1 WOFAGNLBCJWEOE-UHFFFAOYSA-N 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000000227 grinding Methods 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000001488 sodium phosphate Substances 0.000 claims description 5
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 5
- 239000012265 solid product Substances 0.000 claims description 5
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 5
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 claims description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000032683 aging Effects 0.000 claims description 3
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 3
- 238000001354 calcination Methods 0.000 claims description 3
- 238000007603 infrared drying Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- 239000011973 solid acid Substances 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 238000007033 dehydrochlorination reaction Methods 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 9
- 229940088679 drug related substance Drugs 0.000 claims 9
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 4
- ZICYSHJXIHXTOG-UHFFFAOYSA-N chloro hypochlorite zirconium hydrate Chemical compound O.[Zr].ClOCl ZICYSHJXIHXTOG-UHFFFAOYSA-N 0.000 claims 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims 1
- 229960003086 naltrexone Drugs 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- SWJVFAOGXDGTCX-UHFFFAOYSA-N 2-cyanoethyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OCCC#N SWJVFAOGXDGTCX-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 7
- 208000020832 chronic kidney disease Diseases 0.000 description 4
- BTBHLEZXCOBLCY-QGZVFWFLSA-N (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Chemical compound C1([C@@H]2C(=C(C)NC=3C(C)=CN=C(C2=3)OCC)C(N)=O)=CC=C(C#N)C=C1OC BTBHLEZXCOBLCY-QGZVFWFLSA-N 0.000 description 3
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 3
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 3
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 2
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 2
- VZJJZMXEQNFTLL-UHFFFAOYSA-N chloro hypochlorite;zirconium;octahydrate Chemical compound O.O.O.O.O.O.O.O.[Zr].ClOCl VZJJZMXEQNFTLL-UHFFFAOYSA-N 0.000 description 2
- 229940127108 compound 5g Drugs 0.000 description 2
- 229950004408 finerenone Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- GNENVASJJIUNER-UHFFFAOYSA-N 2,4,6-tricyclohexyloxy-1,3,5,2,4,6-trioxatriborinane Chemical compound C1CCCCC1OB1OB(OC2CCCCC2)OB(OC2CCCCC2)O1 GNENVASJJIUNER-UHFFFAOYSA-N 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical class CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a non-neferide ketone raw material medicine, which comprises the following steps: 4-formyl-3-methoxybenzonitrile and an acetoacetate compound are coupled to obtain a compound 1; dehydrating and cyclizing the compound 1 and 4-amino-5-methylpyridine-2-alcohol to obtain a compound 2; ethylating the compound 2 with ethyl orthoformate to obtain a compound 3; hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4; performing CDI activation and ammonolysis on the compound 4 to obtain a compound 5; and carrying out reflux reaction on the compound 5 under the action of a catalyst, and finally carrying out tartaric acid resolution to obtain the non-neferide ketone raw material medicine. According to the invention, the acetoacetic ester is used for replacing 3-oxobutyric acid 2-cyanoethyl ester, so that the raw materials are cheap and easily available, and the synthesis cost and difficulty are greatly reduced; the invention can also avoid high-pressure reaction, greatly improve the safety of the reaction and the production efficiency; after the final step of splitting, the configuration proportion is improved by using a catalyst, and the raw material medicine is obtained with high yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of raw material medicines, and particularly relates to a preparation method of a non-neferitone raw material medicine.
Background
Non-neferitone (BAY 94-8862) is a non-steroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the deleterious effects of mineralocorticoid receptor over-activation. In diabetic patients, mineralocorticoid receptor overactivation is thought to lead to chronic kidney disease progression and cardiovascular impairment, which may be driven by metabolic, hemodynamic or inflammatory and fibrotic factors.
Month 7 2021, based on positive results of the FIDELIO-DKD phase III clinical study in adult patients with chronic kidney disease with type 2 diabetes, FDA approved non-nellione (finerenone,) On the market, the non-neferide ketone is submitted to market application in China and other countries around the world and is under examination.
In 12 months 2021, European Medicines Administration (EMA) recommended a marketed application for approval of the nsaid, non-neyrone, by the human medical products Committee (CHMP), and for the treatment of adult patients with chronic kidney disease (stages 3 and 4 with albuminuria) with type 2 diabetes, non-neyrone (10mg or 20mg) which, once approved, would be the first nsaid antagonist to improve the renal prognosis in adult patients with chronic kidney disease with type 2 diabetes.
The chemical structure of the non-nekinone is shown as follows:
at present, the patent US2018244668a1 discloses a preparation method of non-nerolidone (Finerenone), which uses 3-oxobutanoic acid 2-cyanoethyl ester as a raw material, and the synthetic route is as follows:
the prior art mainly has the following problems: 1) the 3-oxobutyric acid 2-cyanoethyl ester is not common, and the source of raw materials is few, so that the preparation has certain limitation; 2) the second step adopts high-pressure reaction, so that the danger coefficient is high, and the amplification production is not facilitated; 3) the loss of the final splitting step is large, and the like.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of a non-neferitone bulk drug.
The technical scheme adopted by the invention is as follows:
a preparation method of a non-neferitone bulk drug comprises the following steps:
(1) 4-formyl-3-methoxybenzonitrile and acetoacetate ester compounds are coupled to obtain a compound 1 with a structural formula shown in (I);
(2) dehydrating and cyclizing the compound 1 and 4-amino-5-methylpyridine-2-alcohol to obtain a compound 2 with a structural formula shown in (II);
(3) the compound 2 is ethylated by ethyl orthoformate to obtain a compound 3 with a structural formula shown as (III);
(4) hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4 with a structural formula shown as (IV);
(5) performing CDI activation and ammonolysis on the compound 4 to obtain a compound 5 with a structural formula shown as (V);
(6) and carrying out reflux reaction on the compound 5 under the action of a catalyst, and finally carrying out tartaric acid resolution to obtain the non-neferide ketone raw material medicine.
The synthetic route is as follows:
preferably, the catalyst in step (6) is S2O8 2-/ZrO2/γ-Al2O3. Experiments prove that the catalyst adopted by the invention can improve the configuration proportion of the bulk drugs.
Preferably, the catalyst is prepared by the following method: weighing 50g of zirconium oxychloride octahydrate, adding 450g of deionized water to prepare a solution with the mass fraction of 10%, slowly dropwise adding ammonia water under the condition of uniform stirring until the pH value reaches 10, and stopping adding the ammonia water to generate a white precipitate Zr (OH)4(ii) a Standing and aging the precipitate for 24 hours; vacuum filtering, and washing with deionized water until no Cl is formed-Drying in infrared ray fast drier; grinding, adding 20g of gamma-Al2O3Uniformly mixing, grinding and sieving with a 100-mesh sieve to obtain mixture powder; after the mixture powder was immersed in 300g of a 10% ammonium persulfate solution; vacuum filtering, infrared drying, and calcining at 650 deg.C for 3 hr in muffle furnace to obtain solid acid catalyst S2O8 2-/ZrO2/γ-Al2O3。
Preferably, the reaction solvent adopted in the step (1) is one or any combination of more than two of xylene, toluene, butanol and isopropanol; the reaction solvent adopted in the step (2) is one or any combination of more than two of dimethylbenzene, methylbenzene, ethanol and isopropanol; the reaction solvent adopted in the step (3) is one or any combination of more than two of DMAC, NMP, DMF and DME; the reaction solvent adopted in the step (4) is one or any combination of more than two of methanol, ethanol, DMF and THF; the reaction solvent adopted in the step (5) is one or any combination of more than two of toluene, acetonitrile, DMF and THF; the reaction solvent adopted in the step (6) is one or any combination of more than two of toluene, xylene, chlorobenzene and NMP.
Preferably, the step (1) is specifically: sequentially adding isopropanol, 4-formyl-3-methoxybenzonitrile, piperidine and acetic acid into a reactor, starting to add acetoacetic ester in batches when the temperature of a reaction liquid is 30 ℃, maintaining the temperature of 30 ℃ to a reflux temperature, and stirring for 1h at the same temperature after dropwise addition is finished; after the reaction is finished, cooling to 0-30 ℃, stirring for 0.5 hour, fully separating the materials, filtering, drying by pressure, washing twice by using ice isopropanol to obtain a product, and drying the product at 55 ℃ to obtain the product; the acetoacetic ester is selected from one of benzyl acetoacetate, methyl acetoacetate, ethyl acetoacetate and tert-butyl acetoacetate; the mol ratio of 4-formyl-3-methoxybenzonitrile, acetoacetic ester, piperidine and acetic acid is 1: 1.1: 0.1: 0.1.
preferably, the step (2) is specifically: adding toluene into a reaction bottle, adding a compound 1 and 4-amino-5-methylpyridine-2-ol, adding p-toluenesulfonic acid, reacting at 60 ℃ to a reflux temperature for 10-24 hours, cooling to 5 ℃ after the reaction is finished, stirring for 0.5 hour, performing suction filtration, rinsing a filter cake with glacial isopropanol to obtain a yellow solid, and drying to obtain a product; wherein the mol ratio of the 4-amino-5-methylpyridine-2-alcohol to the compound 1 to the p-toluenesulfonic acid is 1: 1.05: 0.21.
preferably, the step (3) is specifically: adding a compound 2 into a reaction bottle, adding a solvent DMF (dimethyl formamide), adding triethyl orthoformate, adding sulfuric acid, heating to 60-150 ℃, reacting for 2-6 hours, cooling to room temperature after the reaction is finished, dripping water for precipitation, adding methanol, stirring for 0.5 hour, precipitating a yellow solid product, and drying to obtain a product; wherein the molar ratio of the compound 2 to the triethyl orthoformate to the sulfuric acid is 1: 1.5: 0.1.
preferably, the step (4) is specifically: adding a compound 3 into a reaction bottle, adding a solvent anhydrous THF (tetrahydrofuran), adding potassium trimethylsilanolate, reacting at room temperature-60 ℃ for 1-12 h, after the reaction is finished, adding ethyl acetate for separating liquid, adjusting the pH of a water phase to 5-6 by using concentrated hydrochloric acid, separating out a solid, recrystallizing by using methanol to obtain an off-white solid, and drying to obtain an off-white product; wherein the molar ratio of the compound 3 to the potassium trimethylsilanolate is 1: 2.
preferably, the step (5) is specifically: adding THF (tetrahydrofuran) into a reaction bottle, adding a compound 4, adding CDI (dehydrochlorination) into the reaction bottle, carrying out reflux reaction for 1-12 h at room temperature, adding ammonia water after TLC is finished, carrying out reflux reaction for 1-20 h, adding water to dilute reaction liquid after the reaction is finished, adding ethyl acetate to extract the reaction liquid, washing the reaction liquid with saline water, drying, and carrying out rotary evaporation to dryness to obtain a white solid; wherein the mol ratio of the compound 4 to the CDI to the ammonia water is 1: 1.1: 2 to 10.
Preferably, the step (6) is specifically: adding a solvent xylene into a reaction bottle, adding a compound 5, adding a catalyst, stirring at room temperature to reflux for 1-12 h, and measuring the target configuration by HPLC: non-target configuration 84:16, finishing the rotation structure; filtering, carrying out spin drying on the mother liquor to obtain a crude product, adding ethanol (methanol, isopropanol or propanol can also be selected), adding water, stirring for dissolving, adding D-dibenzoyltartaric acid, heating for refluxing for 1-5 h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH value to 7.5, stirring for 0.5h, precipitating, filtering to obtain a crude product, and recrystallizing with ethanol to obtain a non-neferide bulk drug; wherein the mol ratio of the compound 5 to the catalyst is 1: 0.2.
in the first step of the invention, common lipids such as methyl acetoacetate, ethyl acetoacetate, tert-butyl acetoacetate and the like are adopted to replace 3-oxobutanoic acid 2-cyanoethyl ester, so that the raw materials are cheap and easy to obtain, and the synthesis cost and difficulty are greatly reduced; in the second step, toluene is used as a solvent, p-toluenesulfonic acid is used for catalysis, and a product can be obtained through a reflux reaction, so that a high-pressure reaction is avoided, and the safety and the production efficiency of the reaction are greatly improved; after the last step of resolution, the other configuration adopts xylene as solvent and adds catalyst S2O8 2-/ZrO2/γ-Al2O3High-temperature reflux can convert the configuration into a required configuration, thereby greatly improving the yieldAnd (4) the ratio.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention avoids high-pressure reaction, and improves the reaction efficiency and safety;
2. the catalyst has the advantages of high activity, good stability, high dispersion degree of active components, long service life, repeated use and the like, and has short preparation flow, simple operation, easy control of reaction and simple equipment requirement;
3. the configuration proportion is improved by using a catalyst, and the raw material medicine is obtained with high yield;
4. by adopting the common C1-C7 lipids such as benzyl acetoacetate, methyl acetoacetate, ethyl acetoacetate, tert-butyl acetoacetate and the like to replace 3-oxobutanoic acid 2-cyanoethyl ester, the raw materials are easy to obtain, the cost is reduced, and the non-neyrone is synthesized efficiently.
Drawings
FIG. 1 is a nuclear magnetic spectrum of prepared non-neferone.
Detailed Description
The invention is further illustrated with reference to specific examples, without however being limited thereto. Those skilled in the art can and should understand that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope of the present invention.
The raw materials mentioned herein are all available on the market unless otherwise specified, and the percentages mentioned herein are percentages by mass unless otherwise specified.
Catalyst S2O8 2-/ZrO2/γ-Al2O3The preparation of (1):
weighing 50g of zirconium oxychloride octahydrate, adding 450g of deionized water to prepare a solution with the mass fraction of 10%, slowly dropwise adding ammonia water under the condition of uniform stirring until the pH value reaches 10, and stopping adding the ammonia water to generate a white precipitate Zr (OH)4(ii) a Standing and aging the precipitate for 24 hours; vacuum filtering, and washing with deionized water until no Cl is formed-Drying in infrared ray fast drier; grinding, adding 20g of gamma-Al2O3Mixing, grindingSieving with 100 mesh sieve to obtain mixture powder; after the mixture powder was immersed in 300g of a 10% ammonium persulfate solution; vacuum filtering, infrared drying, and calcining at 650 deg.C for 3 hr in muffle furnace to obtain solid acid catalyst S2O8 2-/ZrO2/γ-Al2O3。
Example 1
(1) Synthesis of Compound 1:
150g of isopropanol, 33.8g (0.21mol) of 4-formyl-3-methoxybenzonitrile, 1.86g (0.021mol) of piperidine and 1.26g (0.021mol) of acetic acid are sequentially added into a reactor, the temperature of the reaction solution is kept at 30 ℃, the acetoacetic ester is added in batches, the temperature is kept at 35-40 ℃, and after the dropwise addition is finished, the mixture is stirred for 1h at the same temperature. HPLC detection, starting cooling, cooling to T ═ 0-3 ℃, stirring for 0.5 hour, fully separating out materials, filtering, drying under pressure, washing twice with ice isopropanol to obtain a product, drying the product T ═ 55 ℃ to obtain the product, wherein the yield of various acetoacetic acid esters is shown in Table 1:
TABLE 1
(2) Synthesis of Compound 2:
80g of toluene was charged into a reaction flask, and 14.07g (0.042mol) of Compound 1 and 5g (0.04mol) of 4-amino-5-methylpyridin-2-ol were added to the flask, and 1.44g (0.0084mol) of p-toluenesulfonic acid was added to the flask, and the mixture was heated to reflux reaction for 16 hours. The reaction was complete by TLC and a large amount of yellow solid appeared, stopping the reaction. Cooling to 5 deg.c, stirring for 0.5 hr, suction filtering, rinsing the filter cake with small amount of glacial isopropanol to obtain yellow solid, and stoving to obtain yellow solid 16.3g in 92% yield.
(3) Synthesis of Compound 3:
15.4g (0.035mol) of Compound 2 was charged into a reaction flask, 80g of DMF as a solvent was added, 7.8g (0.053mol) of triethyl orthoformate was added, 0.35g (0.0035mol) of sulfuric acid was added, and the mixture was heated to 120 ℃ to react for 4 hours. After the reaction is finished, cooling to room temperature, slowly dropping water for precipitation, adding 10g of methanol, stirring for 0.5h, precipitating a yellow solid product, and drying to obtain a 14.7 product with the yield of 90%.
(4) Synthesis of Compound 4:
14.4g (0.0308mol) of compound 3 was charged into a reaction flask, solvent anhydrous THF 80g was added, 7.88g (0.0616mol) potassium trimethylsilanolate was added, reaction was carried out at 30 ℃ for 8 hours, after passing HPLC detection, 80g ethyl acetate was added after completion of the reaction for liquid separation, the aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid to precipitate a solid, recrystallization was carried out with 20g methanol to obtain an off-white solid, and drying was carried out to obtain 10.5g of an off-white product with a yield of 90%.
(5) Synthesis of Compound 5:
adding 60g of THF (tetrahydrofuran) into a reaction flask, adding 9g (0.0237mol) of compound 4, adding 4.23g (0.0261mol) of CDI, heating to 60 ℃ for reacting for 8h, adding 6.45g of 25% ammonia water after TLC (thin layer chromatography) is finished, carrying out reflux reaction for 12h, adding water to dilute the reaction solution after TLC detection reaction is finished, adding ethyl acetate to extract the reaction solution, washing the reaction solution with saline, drying, and carrying out rotary evaporation to dryness to obtain 7.88g of white solid with the yield of 88%.
(6) Synthesis of Compound 6:
the solvent xylene was added to a reaction flask, 7g (0.0185mol) of Compound 5 was added, and 1.4g of catalyst S was added2O8 2-/ZrO2/γ-Al2O3And stirring under reflux for 8 h. HPLC determination of target configuration: the off-target configuration 84:16, end-turn configuration. Filtering, carrying out spin drying on the mother liquor to obtain a crude product, adding 15g of ethanol, adding 5g of water, stirring for dissolving, adding 5.84g (0.0155mol) of D-dibenzoyltartaric acid, heating and refluxing for 3h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH to 7.5, stirring for 0.5h, precipitating, filtering to obtain a crude product, and recrystallizing with 20g of ethanol to obtain 5.6g of the non-neyrone raw material medicine with the yield of 80%. The nuclear magnetic spectrum of the prepared non-neferide ketone is shown in figure 1.
Example 2
(1) Synthesis of Compound 1:
150g of isopropanol, 33.8g (0.21mol) of 4-formyl-3-methoxybenzonitrile, 1.86g (0.021mol) of piperidine and 1.26g (0.021mol) of acetic acid are sequentially added into a reactor, the temperature T of the reaction solution is 30 ℃, 44.3g (0.231mol) of benzyl acetoacetate are added in portions, the temperature is maintained at 35-40 ℃, and after the dropwise addition, the mixture is stirred at the same temperature for 1 h. And (5) carrying out HPLC detection, and starting cooling. Cooling to 0-3 deg.c, stirring for 0.5 hr, filtering, press drying and washing twice with ice isopropanol to obtain product, and drying at 55 deg.c to obtain 64g of product in 91% yield.
(2) Synthesis of Compound 2:
80g of toluene was charged into a reaction flask, and 14.07g (0.042mol) of Compound 1 and 5g (0.04mol) of 4-amino-5-methylpyridin-2-ol were added thereto, and 1.44g (0.0084mol) of p-toluenesulfonic acid was added thereto, and the mixture was heated to 80 ℃ to react for 26 hours. The reaction was complete by TLC and a large amount of yellow solid appeared, stopping the reaction. Cooling to 5 deg.c, stirring for 0.5 hr, suction filtering, rinsing the filter cake with small amount of ice isopropanol to obtain yellow solid, and stoving to obtain yellow solid 13.6g in yield of 77%.
(3) Synthesis of Compound 3:
15.4g (0.035mol) of Compound 2 was charged into a reaction flask, solvent 80g DMF was added, 6.1g (0.042mol) triethyl orthoformate was added, 0.35g (0.0035mol) sulfuric acid was added, and the temperature was raised to 110 ℃ for reaction for 4 hours. After the reaction is finished, cooling to room temperature, slowly dropping water for precipitation, adding 10g of methanol, stirring for 0.5h, precipitating a yellow solid product, and drying to obtain a 12.6 product with a yield of 76.8%.
(4) Synthesis of Compound 4:
14.4g (0.0308mol) of compound 3 was charged into a reaction flask, solvent anhydrous THF 80g was added, 5.91g (0.0462mol) potassium trimethylsilanolate was added, reaction was carried out at 40 ℃ for 8 hours, after passing HPLC detection, 80g ethyl acetate was added after completion of the reaction for separation, the aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid to precipitate a solid, the solid was recrystallized from 20g methanol to give an off-white solid, which was dried to give 8.6g of an off-white product with a yield of 73.7%. EI-MS M/z 380.4[ M + H ]]+。
(5) Synthesis of Compound 5:
adding 60g of THF (tetrahydrofuran) into a reaction flask, adding 9g (0.0237mol) of compound 4, adding 4.23g (0.0261mol) of CDI, heating to 60 ℃ for reacting for 8h, adding 12.8g of 25% ammonia water after TLC (thin layer chromatography) is finished, carrying out reflux reaction for 12h, adding water to dilute the reaction solution after TLC detection reaction is finished, adding ethyl acetate to extract the reaction solution, washing the reaction solution with saline, drying, and carrying out rotary evaporation to dryness to obtain 6.9g of white solid with the yield of 77%.
(6) Synthesis of Compound 6:
the solvent xylene was added to the reaction flask, 7g (0.0185mol) of compound 5 was added, 2.8g of catalyst was added, and the mixture was stirred under reflux for 8 hours. HPLC determination of target configuration: the off-target configuration is 84:16, and the end-turn configuration. Filtering, adding 15g of ethanol, adding 5g of water, stirring to dissolve, adding 5.84g (0.0155mol) of D-dibenzoyltartaric acid, heating and refluxing for 3h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH to 7.5, stirring for 0.5h, precipitating, filtering to obtain the crude product, and recrystallizing with 20g of ethanol to obtain 5.6g of the non-neferide bulk drug, wherein the yield is 80%.
Example 3
(1) Synthesis of Compound 1:
1500g of isopropanol were added to the reactor successively, 338g (2.1mol) of 4-formyl-3-methoxybenzonitrile, 37.2g (0.42mol) of piperidine and 25.2g (0.42mol) of acetic acid were added, 443g (2.31mol) of benzyl acetoacetate were initially added in portions at a temperature T of 30 ℃ and the temperature was maintained at 35-40 ℃ and after the addition was complete, the mixture was stirred at the same temperature for 1 hour. And (5) carrying out HPLC detection, and starting cooling. The mixture was cooled to 0-3 ℃ and stirred for 0.5h to precipitate thoroughly, filtered, press dried and washed twice with ice isopropanol to give the product, which was dried at 55 ℃ to give 647.22g with 92% yield. EI-MS M/z 336.3[ M + H ]]+。
(2) Synthesis of Compound 2:
500g of toluene was charged in a reaction flask, 201g (0.6mol) of Compound 1 and 50g (0.4mol) of 4-amino-5-methylpyridin-2-ol were added, 14.4g (0.084mol) of p-toluenesulfonic acid was added, and the mixture was heated to reflux reaction for 16 hours. The reaction was complete by TLC and a large amount of yellow solid appeared, stopping the reaction. Cooling to 5 deg.c and stirring for 0.5 hr, suction filtering, rinsing the filter cake with small amount of glacial isopropanol to obtain yellow solid, and stoving to obtain yellow solid 161.46g in 90.8% yield. EI-MS M/z 442.2[ M + H ]]+。
(3) Synthesis of Compound 3:
to a reaction flask was added 154.3g (0.35mol) of compound 2, solvent 1000g of DMF, 78g (0.53mol) of triethyl orthoformate, 3.5g (0.035mol) of sulfuric acid, and the mixture was heated to 130 ℃ for 4 hours. After the reaction is finished, cooling to room temperature, slowly dripping water for precipitation, adding 50g of methanol, stirring for 0.5h, precipitating a yellow solid product, and drying to obtain 147.7 product with the yield of 90%. EI-MS M/z 470.4[ M + H ]]+。
(4) Synthesis of Compound 4:
144.4g (0.308mol) of compound 3 was charged into a reaction flask, 800g of anhydrous THF was added as a solvent, 51.2g (0.4mol) of potassium trimethylsilanolate was added, the reaction was carried out at 30 ℃ for 8 hours, after passing HPLC detection, 800g of ethyl acetate was added after completion of the reaction to separate the solution, the pH of the aqueous phase was adjusted to 5 to 6 with concentrated hydrochloric acid to precipitate a solid, the solid was recrystallized from 300g of methanol to obtain an off-white solid, and the off-white solid was dried to obtain 95g of an off-white product with a yield of 81.4%. EI-MS M/z 380.3[ M + H ]]+。
(5) Synthesis of Compound 5:
adding 600g of THF (tetrahydrofuran) into a reaction bottle, adding 90g (0.237mol) of compound 4, adding 57.5g (0.355mol) of CDI, heating to 60 ℃ for reaction for 8h, adding 160g of 25% ammonia water after TLC is finished, carrying out reflux reaction for 12h, adding water to dilute the reaction solution after TLC detection reaction is finished, adding ethyl acetate to extract the reaction solution, washing the reaction solution with saline, drying, and carrying out rotary evaporation to dryness to obtain 78g of white solid with the yield of 87%. EI-MS M/z 379.4[ M + H ]]+。
(6) Synthesis of Compound 6:
the solvent xylene was added to the reaction flask, 70g (0.185mol) of Compound 5 was added, 30g of catalyst was added, and the mixture was stirred under reflux for 8 hours. HPLC determination of target configuration: the off-target configuration 84:16, end-turn configuration. Filtering, adding 150g of ethanol, adding 50g of water, stirring to dissolve, adding 58.4g (0.155mol) of D-dibenzoyltartaric acid, heating and refluxing for 3h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH to 7.5, stirring for 0.5h, precipitating, filtering to obtain the crude product, and recrystallizing with 200g of ethanol to obtain 56g of the non-neferide ketone bulk drug with the yield of 80%. EI-MS M/z 379.4[ M + H ]]+。
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A preparation method of a non-naltrexone raw material medicine is characterized by comprising the following steps:
(1) 4-formyl-3-methoxybenzonitrile and acetoacetate ester compounds are coupled to obtain a compound 1 with a structural formula shown in (I);
(2) dehydrating and cyclizing the compound 1 and 4-amino-5-methylpyridine-2-alcohol to obtain a compound 2 with a structural formula shown in (II);
(3) the compound 2 is ethylated by ethyl orthoformate to obtain a compound 3 with a structural formula shown as (III);
(4) hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4 with a structural formula shown as (IV);
(5) performing CDI activation and ammonolysis on the compound 4 to obtain a compound 5 with a structural formula shown as (V);
(6) and carrying out reflux reaction on the compound 5 under the action of a catalyst, and finally carrying out tartaric acid resolution to obtain the non-neferide ketone raw material medicine.
2. The method of claim 1 for preparing a non-neferitone drug substance, wherein: in the step (6), the catalyst is S2O8 2-/ZrO2/γ-Al2O3。
3. The method of claim 2 for preparing a non-neupon drug substance, wherein: the catalyst is prepared by the following method: 50g of eight are weighedAdding 450g of deionized water into zirconium oxychloride hydrate to prepare a solution with the mass fraction of 10%, slowly dripping ammonia water under the condition of uniform stirring until the pH value reaches 10, and stopping adding the ammonia water to generate a white precipitate Zr (OH)4(ii) a Standing and aging the precipitate for 24 hours; vacuum filtering, and washing with deionized water until no Cl is formed-Drying in infrared ray fast drier; grinding, adding 20g of gamma-Al2O3Uniformly mixing, grinding and sieving with a 100-mesh sieve to obtain mixture powder; after the mixture powder was immersed in 300g of a 10% ammonium persulfate solution; vacuum filtering, infrared drying, and calcining at 650 deg.C for 3 hr in muffle furnace to obtain solid acid catalyst S2O8 2-/ZrO2/γ-Al2O3。
4. The method of claim 2 for preparing a non-neupon drug substance, wherein: the reaction solvent adopted in the step (1) is one or any combination of more than two of dimethylbenzene, methylbenzene, butanol and isopropanol; the reaction solvent adopted in the step (2) is one or any combination of more than two of dimethylbenzene, methylbenzene, ethanol and isopropanol; the reaction solvent adopted in the step (3) is one or any combination of more than two of DMAC, NMP, DMF and DME; the reaction solvent adopted in the step (4) is one or any combination of more than two of methanol, ethanol, DMF and THF; the reaction solvent adopted in the step (5) is one or any combination of more than two of toluene, acetonitrile, DMF and THF; the reaction solvent adopted in the step (6) is one or any combination of more than two of toluene, xylene, chlorobenzene and NMP.
5. The method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (1) is specifically as follows: sequentially adding isopropanol, 4-formyl-3-methoxybenzonitrile, piperidine and acetic acid into a reactor, keeping the temperature of the reaction liquid at 30 ℃, adding acetoacetic ester in batches, keeping the temperature at 30 ℃ to the reflux temperature, and stirring for 1h at the same temperature after dropwise addition; after the reaction is finished, cooling to 0-30 ℃, stirring for 0.5 hour, fully separating the materials, filtering, drying by pressure, washing twice by using ice isopropanol to obtain a product, and drying the product at 55 ℃ to obtain the product; the acetoacetic ester is selected from one of benzyl acetoacetate, methyl acetoacetate, ethyl acetoacetate and tert-butyl acetoacetate; the mol ratio of 4-formyl-3-methoxybenzonitrile, acetoacetic ester, piperidine and acetic acid is 1: 1.1: 0.1: 0.1.
6. the method for preparing a non-neferone drug substance according to claim 3, wherein the step (2) is specifically: adding toluene into a reaction bottle, adding a compound 1 and 4-amino-5-methylpyridine-2-ol, adding p-toluenesulfonic acid, reacting at 60 ℃ to a reflux temperature for 10-24 hours, cooling to 5 ℃ after the reaction is finished, stirring for 0.5 hour, performing suction filtration, rinsing a filter cake with glacial isopropanol to obtain a yellow solid, and drying to obtain a product; wherein the mol ratio of the 4-amino-5-methylpyridine-2-alcohol to the compound 1 to the p-toluenesulfonic acid is 1: 1.05: 0.21.
7. the method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (3) is specifically as follows: adding a compound 2 into a reaction bottle, adding a solvent DMF, adding triethyl orthoformate, adding sulfuric acid, heating to 60-150 ℃ for reaction for 2-6 hours, cooling to room temperature after the reaction is finished, dropwise adding water for precipitation, adding methanol, stirring for 0.5 hour, precipitating a yellow solid product, and drying to obtain a product; wherein the mol ratio of the compound 2 to the triethyl orthoformate to the sulfuric acid is 1: 1.5: 0.1.
8. the method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (4) is specifically as follows: adding a compound 3 into a reaction bottle, adding a solvent anhydrous THF (tetrahydrofuran), adding potassium trimethylsilanolate, reacting at room temperature-60 ℃ for 1-12 h, after the reaction is finished, adding ethyl acetate for separating liquid, adjusting the pH of a water phase to 5-6 by using concentrated hydrochloric acid, separating out a solid, recrystallizing by using methanol to obtain an off-white solid, and drying to obtain an off-white product; wherein the molar ratio of the compound 3 to the potassium trimethylsilanolate is 1: 2.
9. the method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (5) is specifically: adding THF (tetrahydrofuran) into a reaction bottle, adding a compound 4, adding CDI (dehydrochlorination) into the reaction bottle, carrying out reflux reaction for 1-12 h at room temperature, adding ammonia water after TLC is finished, carrying out reflux reaction for 1-20 h, adding water to dilute reaction liquid after the reaction is finished, adding ethyl acetate to extract the reaction liquid, washing the reaction liquid with saline water, drying, and carrying out rotary evaporation to dryness to obtain a white solid; wherein the mol ratio of the compound 4 to the CDI to the ammonia water is 1: 1.1: 2 to 10.
10. The method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (6) is specifically as follows: adding a solvent xylene into a reaction bottle, adding a compound 5, adding a catalyst, stirring at room temperature to reflux for 1-12 h, and measuring the target configuration by HPLC: non-target configuration 84:16, finishing the rotation structure; filtering, carrying out spin drying on the mother liquor to obtain a crude product, adding ethanol, adding water, stirring for dissolving, adding D-dibenzoyltartaric acid, heating and refluxing for 1-5 h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution, adjusting the pH value to 7.5, stirring for 0.5h, precipitating, filtering to obtain a crude product, and recrystallizing with ethanol to obtain a non-neferitone bulk drug; wherein the mol ratio of the compound 5 to the catalyst is 1: 0.2.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210359260.2A CN114605410B (en) | 2022-04-06 | 2022-04-06 | Preparation method of non-neridrone bulk drug |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210359260.2A CN114605410B (en) | 2022-04-06 | 2022-04-06 | Preparation method of non-neridrone bulk drug |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114605410A true CN114605410A (en) | 2022-06-10 |
CN114605410B CN114605410B (en) | 2023-12-29 |
Family
ID=81869043
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210359260.2A Active CN114605410B (en) | 2022-04-06 | 2022-04-06 | Preparation method of non-neridrone bulk drug |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114605410B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023138336A1 (en) * | 2022-01-19 | 2023-07-27 | 奥锐特药业股份有限公司 | Method for preparing finerenone and intermediate thereof |
WO2024094181A1 (en) * | 2022-11-04 | 2024-05-10 | 南京威凯尔生物医药科技有限公司 | Method for preparing finerenone by means of resolving racemate with diastereomeric tartaric ester |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108137587A (en) * | 2015-08-21 | 2018-06-08 | 拜耳制药股份公司 | (4S) -4- (4- cyano -2- methoxyphenyls) -5- ethyoxyls -2 are prepared by electrochemical process, 8- dimethyl -1,4- dihydros -1,6- naphthyridines -3- formamides and recycling (4S) -4- (4- cyano -2- methoxyphenyls) -5- ethyoxyls -2,8- dimethyl -1, the method of 4- dihydro -1,6- naphthyridines -3- formamides |
WO2019206909A1 (en) * | 2018-04-24 | 2019-10-31 | Bayer Aktiengesellschaft | Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide by racemate separation by means of diastereomeric tartaric acid esters |
CN110511219A (en) * | 2018-05-22 | 2019-11-29 | 广东东阳光药业有限公司 | The dihydronaphthridine class compound and application thereof that phenyl replaces |
-
2022
- 2022-04-06 CN CN202210359260.2A patent/CN114605410B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108137587A (en) * | 2015-08-21 | 2018-06-08 | 拜耳制药股份公司 | (4S) -4- (4- cyano -2- methoxyphenyls) -5- ethyoxyls -2 are prepared by electrochemical process, 8- dimethyl -1,4- dihydros -1,6- naphthyridines -3- formamides and recycling (4S) -4- (4- cyano -2- methoxyphenyls) -5- ethyoxyls -2,8- dimethyl -1, the method of 4- dihydro -1,6- naphthyridines -3- formamides |
WO2019206909A1 (en) * | 2018-04-24 | 2019-10-31 | Bayer Aktiengesellschaft | Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide by racemate separation by means of diastereomeric tartaric acid esters |
CN112041318A (en) * | 2018-04-24 | 2020-12-04 | 拜耳公司 | Method for producing (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide by racemate resolution using the diastereomer tartrate |
CN110511219A (en) * | 2018-05-22 | 2019-11-29 | 广东东阳光药业有限公司 | The dihydronaphthridine class compound and application thereof that phenyl replaces |
Non-Patent Citations (2)
Title |
---|
LARS BRFACKER: "Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases", 《CHEMMEDCHEM》 * |
米未等: "非甾体类盐皮质激素受体拮抗剂finerenone", 《现代药物与临床》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023138336A1 (en) * | 2022-01-19 | 2023-07-27 | 奥锐特药业股份有限公司 | Method for preparing finerenone and intermediate thereof |
WO2024094181A1 (en) * | 2022-11-04 | 2024-05-10 | 南京威凯尔生物医药科技有限公司 | Method for preparing finerenone by means of resolving racemate with diastereomeric tartaric ester |
Also Published As
Publication number | Publication date |
---|---|
CN114605410B (en) | 2023-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN114605410A (en) | Preparation method of non-neferitone bulk drug | |
WO2010083752A1 (en) | High-purity febuxostat and the method for preparation | |
SK285429B6 (en) | Polymorphic crystal modification B of telmisartan, process for its preparing and its use | |
CN104854099B (en) | The monohydrate crystal of Fimasartan potassium salt, its preparation method and comprise its pharmaceutical composition | |
CN103664922A (en) | Novel crystal-form azilsartan and preparation method for same | |
CN108727232B (en) | Preparation method of Iguratimod formylation intermediate | |
CN109734656B (en) | Preparation method of nitrendipine | |
CN106749226A (en) | A kind of preparation method of avatrombopag maleates crystal formation C | |
CN102898480B (en) | Microwave-assisted synthesis method for ruthenium (II) arene compound | |
CN103058936B (en) | The preparation method of 4-[(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl | |
CN106831759A (en) | The preparation method of Pabuk former times profit cloth and its intermediate | |
CN114656400A (en) | Preparation method of key intermediate of non-neferitone | |
CN109851563B (en) | Preparation method of bisphenol monomer containing phthalazinone structure | |
CN104447930A (en) | Preparation method of 16a,17a-dyhydroxyl-21-acetoxyl-1,4-pregnene diene-3,11,20-triketone | |
CN106279205A (en) | The method preparing rifamycin-S derivant | |
CN116023425B (en) | Triamcinolone derivatives and medical application thereof | |
CN102382041A (en) | Preparation method of amlodipine maleate | |
CN104140429B (en) | Lixivaptan crystalline form V and its production and use | |
CN114149426B (en) | Parbosini pharmaceutical co-crystal and preparation method thereof | |
CN104059070B (en) | Lixivaptan crystalline form I and its production and use | |
CN106083614B (en) | A kind of preparation method of metoprolol salt | |
CN103755707B (en) | Lixivaptan crystal form II and its production and use | |
CN111574435B (en) | 4,4' -dipyridyl methylpyrazine derivative eutectic crystal | |
CN117924274A (en) | Synthesis method of non-neridrones | |
CN107722003B (en) | A kind of synthetic method of Pabuk former times profit cloth |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |