CN113336753A - Riociguat synthesis method - Google Patents
Riociguat synthesis method Download PDFInfo
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- CN113336753A CN113336753A CN202110611050.3A CN202110611050A CN113336753A CN 113336753 A CN113336753 A CN 113336753A CN 202110611050 A CN202110611050 A CN 202110611050A CN 113336753 A CN113336753 A CN 113336753A
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- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960000529 riociguat Drugs 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 63
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 12
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- -1 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-pyrimidinecarbamic acid methyl ester hydrochloride Chemical compound 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RCKYXYXLIJBCOE-UHFFFAOYSA-N 2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine Chemical compound NC1=C(N)C(N)=NC(C=2C3=CC=CN=C3N(CC=3C(=CC=CC=3)F)N=2)=N1 RCKYXYXLIJBCOE-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 5
- 229940125782 compound 2 Drugs 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 229940126214 compound 3 Drugs 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 abstract description 3
- 230000011987 methylation Effects 0.000 abstract description 3
- 238000007069 methylation reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000002585 base Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012535 impurity Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000007605 air drying Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MXJGZAMERDEUKM-UHFFFAOYSA-N N[Li].C[Si](N[Si](C)(C)C)(C)C Chemical compound N[Li].C[Si](N[Si](C)(C)C)(C)C MXJGZAMERDEUKM-UHFFFAOYSA-N 0.000 description 1
- HBRKARKAZQJZEO-UHFFFAOYSA-N [4,6-diamino-2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-methylcarbamic acid Chemical compound N1=C(N)C(N(C(O)=O)C)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F HBRKARKAZQJZEO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229940127296 soluble guanylate cyclase stimulator Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicine synthesis, in particular to a preparation method of Riociguat (Riociguat), which takes a compound 3 as a raw material to react with methyl chloroformate to obtain hydrochloride of a compound 2, and the hydrochloride of the intermediate 2 reacts with a methylation reagent under the catalysis of alkali to obtain the Riociguat. The synthesis of the compound 2 in the invention avoids pyridine used as a solvent and a base; the use of unsafe and expensive reagents such as NaH and LiHMDS is avoided in the synthesis of the compound 1. The method for synthesizing riociguat has the advantages of simple and convenient operation, mild conditions, environmental friendliness, high total yield and purity, low cost and the like, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, relates to a preparation method of an sGC (partial gas chromatography) stimulant, and particularly relates to a preparation method of a compound 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridine-3-yl ] -5-pyrimidinyl-N-methyl carbamate (riociguat).
Background
4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b]Pyridin-3-yl]-5-pyrimidinyl-N-methylcarbamate is a novel soluble guanylate cyclase stimulator for cardiovascular diseases and pulmonary hypertension, and has the formula C20H19FN8O2Has a structure shown in formula I:
CN1665811A, US7173037B2 discloses a method for synthesizing riociguat, which comprises the following steps: the material 3 directly reacts with methyl chloroformate in an alkaline environment to obtain an intermediate 2, and the intermediate is subjected to hydrogen extraction by using sodium hydride or lithium hexamethyldisilazide and then reacts with methyl iodide to obtain riociguat. The synthetic route is as follows:
however, the following problems are found in the actual synthesis process: 1) pyridine is used as a solvent in the first step of reaction, and has high toxicity, and the odor of the pyridine is unbearable to operators; 2) the post-treatment is difficult, and the method is not suitable for industrial production; 3) sodium hydride or hexamethyldisilazane lithium amide is used as a dehydrogenating agent in the second step reaction, so that the price is high, the operation is unsafe, the generated impurities are many, and the product is required to be recrystallized for many times when the single impurity content is controlled to be below 0.1 percent, so that the loss is large. The literature uses column chromatography to improve the purity of the target product, and is not suitable for mass preparation.
The patent CN106831760A discloses a method for preparing riociguat, which takes a compound 2 as a raw material to react with a methylation reagent Me-X in the presence of alkali to prepare the riociguat.
In the preparation method, potassium carbonate is used as an alkaline catalyst, methyl iodide is used as a methylation reagent, and organic solvents such as N-methyl pyrrolidone and the like are used as reaction solvents. Although the synthesis process is greatly improved, the following problems still exist: the synthesized intermediate compound 2 is free alkali, the stability is not as good as that of hydrochloride thereof, especially, methyl ester of the intermediate compound is easy to perform cyclization reaction with ortho-amino in the reaction process to generate two impurities with the content of more than 5 percent, so that the generation amount of the product is reduced, and the two impurities are difficult to remove in the post-treatment and purification processes, and finally, the medical grade riociguat is difficult to obtain.
Thus, if the prior patented method is adopted to prepare the pharmaceutical grade riociguat product with the purity of more than 99 percent and the single impurity of less than 0.05 percent, the production cost is very high, and the problems of production safety, environmental damage and the like exist. After a large amount of process design and experimental optimization research, the inventor creatively overcomes the original technical problem, obtains a new Riociguat synthesis process, has the remarkable advantages of simple and convenient operation, easy purification, environmental protection, safe and efficient synthesis, high total yield, low production cost and the like, and is very suitable for industrialized production of Riociguat.
Disclosure of Invention
The invention provides a method for preparing riociguat, which comprises the following technical scheme of realizing the high-efficiency, safe and low-cost synthesis of riociguat, and is characterized by comprising the following steps:
step one, preparation of a compound of formula 2: 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -4, 5, 6-pyrimidinetriamine (a compound of formula 3) is reacted with methyl chloroformate in a suitable organic solvent under reaction conditions to directly obtain chemically stable 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-pyrimidinecarbamic acid methyl ester hydrochloride (a compound of formula 2).
Step 2, preparation of riociguat: 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-pyrimidinylcarbamic acid methyl ester hydrochloride (compound of formula 2) is directly reacted with a methylating agent in an organic solvent under the catalysis of a proper basic catalyst and reaction conditions without being processed into a free base to obtain riociguat (compound of formula 1).
In the first step:
the suitable organic solvent is methanol, ethanol, propanol, isopropanol, N-butanol, tert-butanol, tetrahydrofuran, dimethyltetrahydrofuran, dimethylsulfoxide, N-dimethylformamide, acetone, acetonitrile, toluene, dichloromethane, dichloroethane, N-methylpyrrolidone, or the like, or a mixed solvent of any two or more of the above solvents. More suitable organic solvents are tetrahydrofuran, dimethyltetrahydrofuran, acetonitrile, toluene, dichloromethane, or the like, or a mixed solvent of any two or more of the above solvents, with acetonitrile being preferred.
One of the appropriate reaction conditions is a reaction molar ratio, i.e. the molar ratio of the compound of formula 3 to the methyl chloroformate is 1: 1-5. More preferably, the molar ratio is 1: 1 to 3, preferably 1: 1.5;
the second suitable reaction condition is reaction temperature, namely reaction temperature is 20-80 ℃, more suitable reaction temperature is 40-80 ℃, and preferably 60 ℃;
the third suitable reaction condition is reaction time, the reaction time is 1-5 hours, more suitable reaction time is 1-3 hours, and 2 hours is preferred.
In the second step:
the organic solvent is selected from methanol, ethanol, propanol, isopropanol, N-butanol, tert-butanol, tetrahydrofuran, dimethyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, acetone, acetonitrile, toluene, N-methylpyrrolidone, and the like, or a mixed solvent of any two or more of the above solvents. More suitable organic solvents are dimethylsulfoxide, N-dimethylformamide, acetonitrile, N-methylpyrrolidone, etc., or a mixed solvent of any two or more of the above solvents, and N, N-dimethylformamide is preferred.
The alkali is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, cesium hydroxide, potassium hydroxide, sodium hydroxide, cesium carbonate, potassium carbonate, sodium ethoxide and sodium methoxide. More preferably, the base is selected from one of sodium hydroxide, cesium carbonate, lithium carbonate, potassium carbonate and sodium methoxide, and lithium carbonate is preferred.
The methylating agent is selected from methyl iodide, dimethyl carbonate, dimethyl sulfate or methyl tosylate. More suitably the methylating agent is selected from methyl iodide, dimethyl sulphate, preferably methyl iodide.
One of the appropriate reaction conditions is a reaction molar ratio, and the molar ratio of the compound in the formula 2 to the lithium carbonate to the methyl iodide is 1 to (1-5). More suitably, the molar ratio of the compound of formula 2 to the lithium carbonate to the methyl iodide is 1: 2-4: 1-3.5, preferably 1: 2.0: 1.3;
the second suitable reaction condition is reaction temperature, namely reaction temperature is 20-80 ℃, more suitable reaction temperature is 20-45 ℃, and preferably 30 ℃; (ii) a
The third suitable reaction condition is a reaction time of 1 to 5 hours, more suitably 2 to 4 hours, preferably 3 hours.
By combining the description of the process, compared with the prior art, the invention has the following advantages:
in the first step, the hydrogen chloride generated by the reaction of the compound of the formula 3 and methyl chloroformate is directly neutralized by utilizing the alkalinity of the compound, and no acid removing agent such as any organic base or inorganic base is required to be added; acetonitrile is used as a reaction solvent, so that a pyridine solvent with high toxicity and foul smell is avoided, the generated hydrochloride of the compound in the formula 2 is directly and quantitatively separated out from the solvent, the hydrochloride can be obtained by suction filtration, the pyridine solvent is removed by high-temperature distillation and then crystallized from water in the patent document, the hydrochloride of the compound in the formula 2 with high and stable purity can be obtained by simple suction filtration operation, the post-treatment operation is very convenient, and the obtained product has the effects of being far better than those of patents (CN1665811A, US7173037B2) in yield and purity (more than 99 percent and less than 1 percent of single impurity) and color; meanwhile, the obtained hydrochloride of the compound shown in the formula 2 has better chemical stability than free alkali, and is favorable for storage and subsequent reaction. In the second step, the operation of patent CN106831760A requires reaction at 0-10 ℃ for 24 hours under the protection of nitrogen, however, intramolecular cyclic impurities are generated even under such strict operation conditions. The invention uses lithium carbonate as an alkali catalyst and N, N-dimethylformamide as a solvent, which are not mentioned and used in the prior documents and patents, and the reaction can be carried out for 2 to 4 hours at room temperature without the protection of inert gas. Compared with the patent literature, the use of expensive, unstable and dangerous lithium hexamethyldisilazide is avoided, the anhydrous low-temperature environment is not required to be kept in the reaction process, the reaction can be well carried out under the room temperature condition, and the reaction time is obviously shortened; more importantly, the reaction system effectively avoids two impurities which are difficult to remove and are generated by intramolecular cyclization reaction of the compound of the formula 2, so that the post-treatment is simple, a medicinal pure product can be obtained only by once crystallization and purification, the single impurity is about 0.1 percent, the yield is about 87 percent, the patent literature method needs three times of crystallization, and the yield is only 28-35 percent.
Therefore, the novel process for synthesizing riociguat disclosed by the invention has the remarkable advantages of simplicity and convenience in operation, easiness in purification, environmental friendliness, safety and high efficiency in synthesis, high total product yield, good quality, low production cost and the like, and is very suitable for industrial production of riociguat.
Detailed Description
The following examples are illustrative of the preferred embodiments of the present invention and are not intended to limit the invention in any way.
Example 1
Step 1
20.0g (57.0mmol) of compound 3 was added to 300mL of acetonitrile under nitrogen, stirred, 8.1g (86.0mmol) of methyl chloroformate was added at room temperature, the temperature was raised to 60 ℃ and the reaction was stirred for 2 hours, and then the reaction end point was monitored by HLPC. After the reaction is finished, the reaction solution is cooled to room temperature, unreacted methyl chloroformate is destroyed, the filtration is carried out, the mixture is stirred and washed by 200mL of acetonitrile, the suction is carried out, and the forced air drying is carried out, so as to obtain 25.7g of yellow solid.
Step 2
20.0g (43.3mmol) of the intermediate product synthesized in the previous step were dissolved in 100mL of N, N-dimethylformamide, stirred, 64.0g (86.6mmol) of lithium carbonate were added in portions, temperature was controlled at 30. + -. 5 ℃ and 8.0g (56.3mmol) of methyl iodide was added with stirring. The reaction endpoint was monitored by HPCL after stirring for 2 hours with temperature controlled at 30. + -. 5 ℃. After the reaction is finished, 1200mL of water is added, the mixture is stirred for 30min, filtered, stirred and washed for 1 time by 500mL of water, filtered, rinsed once by 500mL of water and drained. Vacuum drying to obtain light yellow crude Riociguat 17.2 g.
Purification of
Taking 17.0g crude riociguat, adding 30mL of dimethyl sulfoxide and 214mL of tetrahydrofuran, heating and refluxing to be clear, adding activated carbon for decoloring, performing heat filtration, crystallizing at room temperature overnight, performing suction filtration, washing a filter cake with 50mL of ethyl acetate, performing suction drying, adding a solid into 85mL of ethyl acetate, and heating and refluxing for half an hour. Cooling, cooling to room temperature, suction filtering, washing the solid with 20mL ethyl acetate, suction drying, air drying to obtain 13.2g product (purity is more than 99%, single impurity is less than 0.1%).
Example 2
Step 1
1200g (3.42mol) of Compound 3 are introduced under nitrogen into 1800mL of acetonitrile, stirred, 486.0g (6.88mol) of methyl chloroformate are added at room temperature, the temperature is raised to 60 ℃ and after stirring for 2 hours, the end of the reaction is monitored by HLPC. After the reaction is finished, cooling to room temperature, adding methyl chloroformate destroying reagent, stirring, carrying out suction filtration, washing with 1200mL of acetonitrile, carrying out suction drying, and carrying out forced air drying to obtain 1536g of yellow solid.
Step 2
Dissolving 1500.0g (3.25mol) of the intermediate product synthesized in the last step in 750mL of N, N-dimethylformamide, adding 4808g (6.5mol) of lithium carbonate in batches, controlling the temperature to be 30 +/-5 ℃, adding 600.0g (4.22mol) of methyl iodide, controlling the temperature to be 30 +/-5 ℃, stirring for 2 hours, monitoring the reaction end point by HPLC, adding 8.25L of water after the reaction is finished, stirring for 30min, performing suction filtration, adding 1500mL of water, stirring for 1 time, draining, and drying in vacuum to obtain 1377.0g of light yellow crude Riocigua.
Purification of
1377g of crude Riociguat product is taken, 2.4L of dimethyl sulfoxide and 19.2L of tetrahydrofuran are added, the mixture is heated and refluxed to dissolve the solid, activated carbon is added for decoloration, hot filtration is carried out, crystallization is carried out at room temperature overnight, suction filtration is carried out, 2.1L of ethyl acetate is used for washing, after suction drying, the solid is added into 6.8L of ethyl acetate, heating and refluxing are carried out for half an hour, cooling is carried out, the room temperature is reduced, suction filtration is carried out, 1.5L of ethyl acetate is used for washing the solid, suction drying is carried out, and air drying is carried out, thus 1074.2g of finished Riociguat product (the purity is more than 99 percent, and.
Claims (3)
1. The invention relates to a preparation method of an anti-pulmonary hypertension drug riociguat, which is characterized by comprising the following steps:
step one, preparation of a compound of formula 2: 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -4, 5, 6-pyrimidinetriamine (a compound of formula 3) is reacted with methyl chloroformate in a suitable organic solvent under reaction conditions to directly obtain chemically stable 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-pyrimidinecarbamic acid methyl ester hydrochloride (a compound of formula 2).
Step 2, preparation of riociguat: 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-pyrimidinylcarbamic acid methyl ester hydrochloride (compound of formula 2) is directly reacted with a methylating agent in an organic solvent under the catalysis of a proper basic catalyst and reaction conditions without being processed into a free base to obtain riociguat (compound of formula 1).
2. The method of synthesis of claim 1, wherein in step one:
the suitable organic solvent is methanol, ethanol, propanol, isopropanol, N-butanol, tert-butanol, tetrahydrofuran, dimethyltetrahydrofuran, dimethylsulfoxide, N-dimethylformamide, acetone, acetonitrile, toluene, dichloromethane, dichloroethane, N-methylpyrrolidone, or the like, or a mixed solvent of any two or more of the above solvents.
One of the appropriate reaction conditions is a reaction molar ratio, namely the molar ratio of the compound shown in the formula 3 to the methyl chloroformate is 1: 1-5;
the second suitable reaction condition is the reaction temperature, namely the reaction temperature is 20-80 ℃;
the third suitable reaction condition is reaction time which is 1-5 hours.
In the second step:
the organic solvent is selected from methanol, ethanol, propanol, isopropanol, N-butanol, tert-butanol, tetrahydrofuran, dimethyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, acetone, acetonitrile, toluene, N-methylpyrrolidone, and the like, or a mixed solvent of any two or more of the above solvents.
The alkali is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, cesium hydroxide, potassium hydroxide, sodium hydroxide, cesium carbonate, lithium carbonate, potassium carbonate, sodium ethoxide and sodium methoxide.
The methylating agent is selected from methyl iodide, dimethyl carbonate, dimethyl sulfate or methyl tosylate.
One of the appropriate reaction conditions is a reaction molar ratio, and the molar ratio of the compound in the formula 2 to the lithium carbonate to the methyl iodide is 1 to (1-5);
the second suitable reaction condition is the reaction temperature, namely the reaction temperature is 20-80 ℃;
the third suitable reaction condition is reaction time, and the reaction time is 1-5 hours.
3. The method of synthesis according to claim 2, wherein in step one:
the suitable organic solvent is tetrahydrofuran, dimethyltetrahydrofuran, acetonitrile, toluene, dichloromethane, or the like, or a mixed solvent of any two or more of the above solvents, preferably acetonitrile.
One of the appropriate reaction conditions is a reaction molar ratio, namely the molar ratio of the compound shown in the formula 3 to the methyl chloroformate is 1: 1-3, preferably 1: 1.5;
the second suitable reaction condition is reaction temperature, i.e. the reaction temperature is 40-80 ℃, preferably 60 ℃;
the third suitable reaction condition is reaction time, and the reaction time is 1-3 hours, preferably 2 hours.
In the second step:
the solvent used in the reaction is selected from dimethyl sulfoxide, N-dimethylformamide, acetonitrile, N-methylpyrrolidone and the like or a mixed solvent of any two or more of the solvents, and is preferably N, N-dimethylformamide.
The alkali catalyst is selected from one of sodium hydroxide, cesium carbonate, lithium carbonate, potassium carbonate and sodium methoxide, and is preferably lithium carbonate.
The methylating agent is selected from methyl iodide and dimethyl sulfate, preferably methyl iodide.
One of the appropriate reaction conditions is a reaction molar ratio, wherein the molar ratio of the compound in the formula 2 to the lithium carbonate to the methyl iodide is 1: 2-4: 1-3.5, and is preferably 1: 2.0: 1.3;
the second suitable reaction condition is reaction temperature, i.e. the reaction temperature is 20-45 ℃, preferably 30 ℃;
the third suitable reaction condition is reaction time, and the reaction time is 2-4 hours, preferably 3 hours.
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