CN114685439A - Preparation method of rasemiptan - Google Patents
Preparation method of rasemiptan Download PDFInfo
- Publication number
- CN114685439A CN114685439A CN202011610377.0A CN202011610377A CN114685439A CN 114685439 A CN114685439 A CN 114685439A CN 202011610377 A CN202011610377 A CN 202011610377A CN 114685439 A CN114685439 A CN 114685439A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- preparation
- temperature
- filtering
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 238000001914 filtration Methods 0.000 claims description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 30
- 238000005406 washing Methods 0.000 claims description 27
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- FEQPHYCEZKWPNE-UHFFFAOYSA-K trichlororhodium;triphenylphosphane Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FEQPHYCEZKWPNE-UHFFFAOYSA-K 0.000 claims description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- -1 2' -bipyridine Chemical compound 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- KZXODWQOXSIVDW-UHFFFAOYSA-N 3,8-dithiophen-2-yl-1,10-phenanthroline Chemical compound C1=CSC(C=2C=C3C(C4=NC=C(C=C4C=C3)C=3SC=CC=3)=NC=2)=C1 KZXODWQOXSIVDW-UHFFFAOYSA-N 0.000 claims description 3
- OADZHFGJIVKDJN-UHFFFAOYSA-N 3-bromo-1,10-phenanthroline Chemical compound C1=CN=C2C3=NC=C(Br)C=C3C=CC2=C1 OADZHFGJIVKDJN-UHFFFAOYSA-N 0.000 claims description 3
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- XSRWPJFTHDOKTA-UHFFFAOYSA-M [Rh]Cl.C1CC=CCCC=C1 Chemical class [Rh]Cl.C1CC=CCCC=C1 XSRWPJFTHDOKTA-UHFFFAOYSA-M 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims description 2
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 9
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 230000001276 controlling effect Effects 0.000 description 22
- 229910052786 argon Inorganic materials 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- XEDHVZKDSYZQBF-UHFFFAOYSA-N lasmiditan Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(NC(=O)C=2C(=CC(F)=CC=2F)F)=N1 XEDHVZKDSYZQBF-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- NLUDEWJJEMHIIL-UHFFFAOYSA-N 1-methylpiperidin-1-ium-4-carboxylic acid;chloride Chemical compound [Cl-].C[NH+]1CCC(C(O)=O)CC1 NLUDEWJJEMHIIL-UHFFFAOYSA-N 0.000 description 1
- MIVZCINZDWIBJS-UHFFFAOYSA-N 1-methylpiperidine-4-carbonyl chloride Chemical compound CN1CCC(C(Cl)=O)CC1 MIVZCINZDWIBJS-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SIFIJQFBERMWMU-UHFFFAOYSA-N 2,4,6-trifluorobenzoyl chloride Chemical compound FC1=CC(F)=C(C(Cl)=O)C(F)=C1 SIFIJQFBERMWMU-UHFFFAOYSA-N 0.000 description 1
- FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 description 1
- NKQIZBOGYBMJDU-UHFFFAOYSA-N 6-(1-methylpiperidin-4-yl)pyridin-2-amine Chemical compound C1CN(C)CCC1C1=CC=CC(N)=N1 NKQIZBOGYBMJDU-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229950009142 lasmiditan Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of lamidotitan, which comprises the following steps: under the protection of inert gas, adding a catalyst, a ligand, alkali and a solvent A into a closed device, controlling the temperature to react, cooling the reaction liquid to room temperature after the reaction is finished, adding a compound SM-1 and a compound SM-2, heating to react, and after the reaction is finished, carrying out post-treatment to obtain a compound I; the preparation process has simple route, and the obtained compound has high purity and high yield and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of rasemiptan.
Background
Rasemitan (lasmiditan), chemical name 2,4, 6-trifluoro-N- [6- [ (1-methyl-4-piperidinyl) carbonyl]-2-pyridyl]Benzamide, an oral prescription developed by EliLilly, the succinate salt of which is used clinically for acute treatment of migraine with or without aura in adults, was approved by the FDA in us 10 months of 2019 (trade name)
) It is the first new class of acute migraine treatment drugs approved by FDA for more than 20 years. Laramiditan is an oral, central nervous system permeable, selective, 5-hydroxytryptamine 1F (5-HT)1F) Agonists, structurally and mechanistically different from currently approved migraine drugs, and lack vasoconstrictor activity. The chemical structural formula is as follows:
the synthesis process of lasiditan has been disclosed in several patents, such as WO2011123654a1, US2019233393a1, CN03807363, US8697876B2, WO2011123654, CN 110386918A. However, the idea of the method is substantially consistent with that of the original patent WO03084949, and the synthesis method disclosed by the method comprises the following steps: reacting N-methyl-4-piperidinecarboxylic acid hydrochloride with DMF/oxalyl chloride to obtain hydrochloride of N-methyl-4-piperidinoyl chloride, dropwise adding a THF solution of dimethylamine and triethylamine, and performing post-treatment to obtain N, N' -dimethyl-N-methylpiperidine-4-formamide; then reacting with 2, 6-dibromopyridine and n-butyllithium at about-70 ℃ to obtain 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine; then in a sealed autoclave, taking ethylene glycol as a solvent, pressurizing at high temperature, reacting with ammonia gas for 20h to obtain 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine hydrochloride, adjusting alkali, and dissociating to obtain 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine; then under the protection of nitrogen, 2-amino-6- (1-methylpiperidin-4-yl) -pyridine reacts with 2,4, 6-trifluorobenzoyl chloride in anhydrous THF to obtain 2,4, 6-trifluoro-N- [6- (l-methyl-piperidin-4-yl-acyl) -pyridin-2-yl ] -benzamide; and finally, salifying the product with succinic acid in acetone to obtain a target product.
However, the method has the following disadvantages: firstly, when the 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine is prepared, n-butyllithium which is sensitive to water and has harsh reaction conditions is needed, so that the industrial scale-up production is not facilitated; ② when ammoniation is used for preparing 2-amino-6- (1-methylpiperidine-4-acyl) -pyridine, ammonia gas is needed to be used for pressurization about 50psi (345kPa) for reaction, and the requirement on equipment is high; in addition, the 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine needs to be purified by repeatedly adjusting acid and alkali, so that the operation is complicated and the yield (63%) is low; ③ when preparing the lamidottan, nitrogen protection is needed, and the used solvent THF needs strict anhydrous treatment, and meanwhile, the post-treatment also needs repeated acid and alkali adjustment for purification, thus the operation is complicated.
In conclusion, the existing preparation method of rasemistane has many defects in the aspects of safe process, complex operation, low yield, high production cost and the like, so that the research and search of a reaction route which has mild reaction conditions, simple and convenient operation process, high product yield and high purity and is suitable for industrial production of rasemistane still needs to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing preparation technology of rasemiptan, the invention provides a novel preparation method of rasemiptan.
The specific technical scheme of the invention is as follows:
the compound I is obtained by the reaction of a compound SM-1 and a compound SM-2, and the specific route is as follows:
a preparation method of rasemiptan specifically comprises the following steps:
under the protection of inert gas, adding a catalyst, a ligand, alkali and a solvent A into a closed device, controlling the temperature to react, cooling the reaction liquid to room temperature after the reaction is finished, adding a compound SM-1 and a compound SM-2, heating to react, and after the reaction is finished, carrying out post-treatment to obtain a compound I.
Preferably, the catalyst is one or the combination of triphenylphosphine rhodium chloride, dimeric rhodium acetate, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, dicarbonyl acetylacetone rhodium (I) and (1, 5-cyclooctadiene) chlororhodium (I) dimer, and the triphenylphosphine rhodium chloride is further preferred.
Preferably, the ligand is one or a combination of 1, 10-phenanthroline, 2' -bipyridine, 3, 8-di (thiophen-2-yl) -1, 10-phenanthroline, 2' -bipyridine-4, 4' -dicarboxaldehyde and 3-bromo-1, 10-phenanthroline, and more preferably 1, 10-phenanthroline.
Preferably, the base is one or a combination of potassium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium tert-butoxide and sodium hydride, and is further preferably sodium tert-butoxide.
Preferably, the solvent A is one or a combination of toluene, xylene, N-dimethylformamide and N-methylpyrrolidone, and is further preferably toluene.
Preferably, the temperature control reaction and the temperature rise reaction can be carried out, the sealing device can be placed in heating equipment with the temperature of 100-120 ℃, and the heating equipment can be oil bath heating, electric heating sleeves, steam heating, electric furnaces and other heating equipment; the sealing equipment can be selected from a sealed glass tube, a stainless steel reaction kettle with good sealing performance, a sealed Schlenk device and the like, and the Schlenk device is preferably selected for verification in the invention.
Preferably, the feeding molar ratio of SM-1 to SM-2, catalyst, ligand and alkali is 1: 1.05-1.3: 0.06-0.10: 0.06-0.10: 0.1 to 0.5, and more preferably 1: 1.1: 0.08: 0.08: 0.3.
preferably, the temperature-controlled reaction temperature is 100-120 ℃.
Preferably, the temperature rise reaction temperature is 100-120 ℃.
Preferably, the post-treatment step is: filtering the reaction solution, concentrating the filtrate under reduced pressure to dryness, dissolving with hydrochloric acid, filtering, washing the filtrate with solvent B, adjusting pH with sodium hydroxide solution, extracting with solvent C, combining organic phases, washing with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain compound I.
Preferably, the concentration of the hydrochloric acid solution is 1-5 mol/L.
Preferably, the solvent B is one or a combination of ethyl acetate, dichloromethane, chloroform and methyl tert-butyl ether, and dichloromethane is further preferred.
Preferably, the concentration of the sodium hydroxide solution is 4-7.5 mol/L.
Preferably, the pH adjusting range is 12-14, and the pH is preferably 13.
Preferably, the solvent C is one or a combination of ethyl acetate, dichloromethane, chloroform and methyl tert-butyl ether, and is further preferably methyl tert-butyl ether.
In the present invention, the inert gas is generally selected from nitrogen and argon, and more preferably argon.
The invention has the following beneficial effects:
1. the invention provides a novel preparation method of rasemiptan.
2. The preparation process has simple route, and the obtained compound has high purity and high yield and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The structure of the obtained rasemiptan compound is confirmed as follows:
ESI-HRMS(m/z):378.1441[M+H]+；
1HNMR(400MHz,DMSO-d6)δ：8.16(s,1H),7.91～7.78(m,1H),7.66～7.52(m,1H),7.50～7.39(m,1H),6.84～6.66(m,2H),2.98～2.83(m,1H),2.79～2.61(m,2H),2.28(s,3H),2.25～2.11(m,2H),1.99～1.87(m,2H),1.75～1.58(m,2H)；
13CNMR(100MHz,DMSO-d6)δ199.62,165.31,162.59,162.00,160.34,155.53,151.19,144.25,125.64,119.18,109.24,101.16,101.16,53.77,46.05,43.90,28.03；
the invention adopts HPLC to measure the purity of the rasemiptan, and the chromatographic conditions are as follows:
a chromatographic column: WelchultimateXB-C18(4.6mm x 250mm,5 μm) or equivalent performance columns;
mobile phase: mobile phase A: 0.02mol/L ammonium dihydrogen phosphate +2.1ml triethylamine, pH adjusted to 7.0 with phosphoric acid, mobile phase B: acetonitrile, gradient elution (0min: A85%, 25min: A65%, 35min: 50%, 60min: 85%);
column temperature: 35 ℃;
detection wavelength: 223 nm;
flow rate: 1.0 ml/min;
sample introduction amount: 10 mu l of the mixture;
wherein the retention time of rasemiptan is about 26.3 min.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Under the protection of argon, adding triphenylphosphine rhodium chloride (7.61g, 8.0mmol), 1, 10-phenanthroline (1.44g, 8.0mmol), sodium tert-butoxide (2.88g, 0.03mol) and toluene (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃ for reaction, reducing the temperature of the reaction liquid to room temperature after the reaction is finished, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), continuously controlling the temperature to be 105-110 ℃ for reaction, filtering the reaction liquid after the reaction is finished, dissolving the filtrate under reduced pressure to dryness, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with dichloromethane (50ml multiplied by 2), adjusting the pH of the solution with sodium hydroxide (5mol/L) to about 13, extracting methyl tert-butyl ether (50ml multiplied by 3), combining organic phases, washing with purified water (50ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to dryness, compound I (36.49g) in 96.5% yield and 99.92% purity.
Example 2
Under the protection of argon, adding rhodium diacetate (2.65g, 6.0mmol), 2' -bipyridine (0.94g, 6.0mmol), potassium tert-butoxide (3.36g, 0.03mol) and N-methylpyrrolidone (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, reducing the temperature of reaction liquid to room temperature after the reaction is finished, adding SM-1(21.93g, 0.1mol) and SM-2(17.02g, 0.105mol), continuously controlling the temperature to be 105-110 ℃, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to be dry, dissolving with hydrochloric acid (1mol/L, 300ml), filtering, washing the filtrate with dichloromethane (70ml multiplied by 2), adjusting the pH of sodium hydroxide (7.5mol/L) solution to be about 13, extracting methyl tert-butyl ether (40ml multiplied by 3), combining organic phases, washing with purified water (40ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to be dry, compound I (35.66g) was obtained in 94.3% yield and 99.85% purity.
Example 3
Under the protection of argon, adding dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (4.95g, 8.0mmol), 3, 8-bis (thiophen-2-yl) -1, 10-phenanthroline (2.76g, 8.0mmol), potassium carbonate (4.14g, 0.03mol) and N, N-dimethylformamide (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, reducing the temperature of a reaction solution to room temperature after the reaction is finished, adding SM-1(21.93g, 0.1mol) and SM-2(16.21g, 0.1mol), continuously controlling the temperature to be 105-110 ℃ for reaction, filtering after the reaction is finished, concentrating a filtrate under reduced pressure to dryness, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with ethyl acetate (50ml multiplied by 2), regulating the pH of a sodium hydroxide (5mol/L) solution to be about 12, extracting methyl tert-butyl ether (50ml by 3), combining organic phases, purified water (50 ml. times.2) was washed, dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated to dryness under reduced pressure to obtain Compound I (34.83g) in 92.1% yield and 99.83% purity.
Example 4
Under the protection of argon, adding dicarbonyl acetylacetone rhodium (I) (2.07g, 8.0mmol), 2 '-bipyridine-4, 4' -diformaldehyde 1.69g, 8.0mmol), sodium hydride (2.24g, 0.03mol) and toluene (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, after the reaction is finished, cooling the reaction liquid to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(21.07g, 0.13mol), controlling the temperature to be 105-110 ℃ continuously for reaction, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to be dry, dissolving the filtrate by hydrochloric acid (5mol/L, 100ml), filtering, washing the filtrate by dichloromethane (30ml multiplied by 2), adjusting the pH to be about 13 by sodium hydroxide (4mol/L) solution, extracting by methyl tert-butyl ether (30ml multiplied by 3), combining organic phases, washing by purified water (30ml multiplied by 2), drying anhydrous sodium sulfate, filtering, the obtained filtrate was concentrated to dryness under reduced pressure to obtain Compound I (35.74g), yield 94.5%, purity 99.79%.
Example 5
Under the protection of argon, adding (1, 5-cyclooctadiene) chlororhodium (I) dimer (3.95g, 8.0mmol), 3-bromo-1, 10-phenanthroline (2.07g, 8.0mmol), sodium bicarbonate (2.52g, 0.03mol) and xylene (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, after the reaction is finished, cooling the reaction liquid to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(22.70g, 0.14mol), continuously controlling the temperature to be 105-110 ℃, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to be dry, dissolving with hydrochloric acid (1mol/L, 200ml), filtering, washing the filtrate with chloroform (50ml × 2), adjusting the pH to be about 13 with sodium hydroxide (5mol/L) solution, extracting with ethyl acetate (50ml × 3), combining organic phases, washing with purified water (50ml × 2), drying without water, filtering, the resulting filtrate was concentrated to dryness under reduced pressure to give Compound I (34.64g) in 91.6% yield and 99.78% purity.
Example 6
Under the protection of argon, adding triphenylphosphine rhodium chloride (5.56g, 6.0mmol), 1, 10-phenanthroline (1.08g, 6.0mmol), sodium tert-butoxide (2.88g, 0.03mol) and N-methylpyrrolidone (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, reducing the temperature of a reaction solution to room temperature after the reaction is finished, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), continuously controlling the temperature to be 105-110 ℃, filtering after the reaction is finished, concentrating the filtrate under reduced pressure to be dry, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with methyl tert-butyl ether (50ml multiplied by 2), adjusting the pH of a sodium hydroxide solution (5mol/L) to be about 13, extracting dichloromethane (50ml multiplied by 3), combining organic phases, washing with purified water (50ml by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to be dry, compound I (34.98g) was obtained in 92.5% yield and 99.79% purity.
Example 7
Under the protection of argon, adding triphenylphosphine rhodium chloride (4.63g, 5.0mmol), 1, 10-phenanthroline (0.9g, 5.0mmol), sodium tert-butoxide (2.88g, 0.03mol) and N, N-dimethylformamide (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, after the reaction is finished, cooling the reaction solution to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), controlling the temperature to be 105-110 ℃ continuously for reaction, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to be dry, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with ethyl acetate (50ml multiplied by 2), adjusting the pH of sodium hydroxide (5mol/L) solution to be about 13, extracting with chloroform (50ml multiplied by 3), combining organic phases, washing with purified water (50ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to be dry, compound I (34.34g) was obtained in 90.8% yield and 99.77% purity.
Example 8
Under the protection of argon, adding triphenylphosphine rhodium chloride (9.25g, 10.0mmol), 1, 10-phenanthroline (1.8g, 10.0mmol), sodium tert-butoxide (2.88g, 0.03mol) and xylene (250ml) into a Schlenk device, controlling the temperature to be 105-110 ℃, after the reaction is finished, cooling the reaction solution to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), continuing to control the temperature to be 105-110 ℃, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to be dry, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with dichloromethane (50ml multiplied by 2), adjusting the pH to be about 14 with sodium hydroxide (5mol/L) solution, extracting methyl tert-butyl ether (50ml multiplied by 3), combining organic phases, washing with purified water (50ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to be dry to obtain a compound I (35.09g), the yield is 92.8 percent, and the purity is 99.73 percent.
Example 9
Under the protection of argon, adding triphenylphosphine rhodium chloride (9.16g, 11.0mmol), 1, 10-phenanthroline (1.78g, 11.0mmol), sodium tert-butoxide (2.88g, 0.03mol) and xylene (250ml) into a Schlenk device, controlling the temperature to 95-100 ℃, after the reaction is finished, cooling the reaction solution to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), continuing to control the temperature to 105-110 ℃, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to dryness, dissolving with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with dichloromethane (50ml × 2), adjusting the pH of sodium hydroxide (5mol/L) solution to about 14, extracting with dichloromethane (50ml × 3), combining organic phases, washing with purified water (50ml × 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to dryness to obtain a compound I (34.30g), the yield is 90.7%, and the purity is 98.73%.
Example 10
Under the protection of argon, adding triphenylphosphine rhodium chloride (5.71g, 6.0mmol), 1, 10-phenanthroline (1.08g, 6.0mmol), sodium tert-butoxide (0.96g, 0.01mol) and N, N-dimethylformamide (250ml) into a Schlenk device, controlling the temperature to be 100-105 ℃, reducing the temperature of a reaction solution to room temperature after the reaction is finished, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), controlling the temperature to be 105-110 ℃ continuously for reaction, filtering after the reaction is finished, concentrating the filtrate under reduced pressure to be dry, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with methyl tert-butyl ether (50ml multiplied by 2), adjusting the pH of the solution of sodium hydroxide (5mol/L) to be about 13, extracting the methyl tert-butyl ether (50ml multiplied by 3), combining organic phases, washing with purified water (50ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to be dry, compound I (35.47g) was obtained in 93.8% yield and 99.74% purity.
Example 11
Under the protection of nitrogen, adding triphenylphosphine rhodium chloride (5.71g, 6.0mmol), 1, 10-phenanthroline (1.08g, 6.0mmol), sodium tert-butoxide (4.8g, 0.05mol) and N, N-dimethylformamide (250ml) into a Schlenk device, controlling the temperature to 110-120 ℃, after the reaction is finished, cooling the reaction solution to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), continuously controlling the temperature to 105-110 ℃, filtering after the reaction is finished, concentrating the filtrate under reduced pressure to dryness, dissolving the filtrate with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with dichloromethane (50ml multiplied by 2), adjusting the pH of the solution of sodium hydroxide (5mol/L) to about 13, extracting methyl tert-butyl ether (50ml multiplied by 3), combining organic phases, washing with purified water (50ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to dryness, compound I (35.43g) was obtained in 93.7% yield and 99.72% purity.
Example 12
Under the protection of nitrogen, adding triphenylphosphine rhodium chloride (5.71g, 6.0mmol), 1, 10-phenanthroline (1.08g, 6.0mmol), sodium tert-butoxide (0.48g, 0.005mol) and xylene (250ml) into a Schlenk device, controlling the temperature to 120-125 ℃, after the reaction is finished, cooling the reaction solution to room temperature, adding SM-1(21.93g, 0.1mol) and SM-2(19.61g, 0.11mol), continuing to control the temperature to 105-110 ℃, after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to dryness, dissolving with hydrochloric acid (2mol/L, 200ml), filtering, washing the filtrate with dichloromethane (50ml multiplied by 2), adjusting the pH of sodium hydroxide (5mol/L) solution to about 13, extracting with methyl tert-butyl ether (50ml multiplied by 3), combining organic phases, washing with purified water (50ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to dryness to obtain a compound I (34.30g), the yield is 90.7 percent, and the purity is 99.70 percent.
Claims (10)
1. The preparation method of rasemiptan is characterized in that a compound SM-1 and a compound SM-2 react to obtain a compound I, and the synthetic route is as follows:
2. the preparation method according to claim 1, which comprises the following steps:
under the protection of inert gas, adding a catalyst, a ligand, alkali and a solvent A into a closed device, controlling the temperature to react, adding a compound SM-1 and a compound SM-2 after the reaction is finished, heating to react, and carrying out post-treatment to obtain a compound I.
3. The method of claim 2, wherein the catalyst is one or a combination of triphenylphosphine rhodium chloride, dimeric rhodium acetate, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, dicarbonyl acetylacetonato rhodium (I), and (1, 5-cyclooctadiene) chlororhodium (I) dimer.
4. The method according to claim 2, wherein the ligand is one of 1, 10-phenanthroline, 2' -bipyridine, 3, 8-di (thien-2-yl) -1, 10-phenanthroline, 2' -bipyridine-4, 4' -dicarbaldehyde, and 3-bromo-1, 10-phenanthroline.
5. The preparation method of claim 2, wherein the base is one or a combination of potassium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium tert-butoxide and sodium hydride.
6. The preparation method according to claim 2, wherein the solvent A is one of toluene, xylene, N-dimethylformamide, N-methylpyrrolidone or a combination thereof.
7. The preparation method according to claim 2, wherein the feeding molar ratio of SM-1 to SM-2, the catalyst, the ligand and the base is 1: 1.05-1.3: 0.06-0.10: 0.06-0.10: 0.1 to 0.5.
8. The preparation method according to claim 2, wherein the temperature-controlled reaction temperature is 100-120 ℃; the temperature rise reaction temperature is 100-120 ℃.
9. The method of claim 2, wherein the post-treating step comprises:
filtering the reaction solution, concentrating the filtrate under reduced pressure to dryness, dissolving with hydrochloric acid, filtering, washing the filtrate with solvent B, adjusting pH with sodium hydroxide solution, extracting with solvent C, mixing organic phases, washing the organic phase with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain compound I.
10. The preparation method according to claim 9, wherein the solvent B is one or a combination of ethyl acetate, dichloromethane, chloroform and methyl tert-butyl ether; the solvent C is one or the combination of ethyl acetate, dichloromethane, chloroform and methyl tert-butyl ether; the pH adjusting range is 12-14.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011610377.0A CN114685439A (en) | 2020-12-30 | 2020-12-30 | Preparation method of rasemiptan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011610377.0A CN114685439A (en) | 2020-12-30 | 2020-12-30 | Preparation method of rasemiptan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114685439A true CN114685439A (en) | 2022-07-01 |
Family
ID=82133230
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011610377.0A Pending CN114685439A (en) | 2020-12-30 | 2020-12-30 | Preparation method of rasemiptan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114685439A (en) |
-
2020
- 2020-12-30 CN CN202011610377.0A patent/CN114685439A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106366022B (en) | It is a kind of to be used to prepare AZD9291 intermediate and its preparation method and application | |
| CN112898298A (en) | Preparation method of tocaintinib intermediate | |
| CN110078695B (en) | Quercetin derivative and preparation method thereof | |
| CN104910158B (en) | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN104311485B (en) | A kind of preparation method treating leukemic medicine bosutinib | |
| CN114685439A (en) | Preparation method of rasemiptan | |
| CN112094220B (en) | Green synthesis method of 3-sulfone methyl-1H-indole compound | |
| CN114671867A (en) | Preparation method of 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine serving as intermediate of tocainib | |
| CN103896889B (en) | Lapatinib intermediate and its preparation method and application | |
| CN111171002B (en) | Preparation method of PARP inhibitor intermediate | |
| CN107163036A (en) | One kind is containing assimilation compound of 5,6 disubstituted pyridines of thiazole ring 2 and preparation method thereof | |
| CN113620866A (en) | Preparation method of deuterated nitrogen-containing heterocyclic compound | |
| CN106478624A (en) | A kind of purification process of moxifloxacin hydrochloride | |
| CN113045496A (en) | Method for selectively synthesizing dihydrophenanthridine or phenanthridine compounds | |
| CN111116552B (en) | Quinazolinone compound and preparation method thereof | |
| CN105198806A (en) | Method for synthesizing quinoline by aromatic amine and diketone | |
| CN106117200B (en) | Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis | |
| CN106632330B (en) | A kind of pyrido [2 ', 1 ':2,3] piperidines [1,6-a] indoles salt and its synthetic method | |
| CN105001163A (en) | Tetra-substituted imidazole synthesis method | |
| CN112898277B (en) | Preparation method of afatinib intermediate | |
| CN114773252B (en) | Chiral amino indoline derivative and preparation method and application thereof | |
| CN110423234A (en) | Thiosemicarbazone derivative of the segment containing indoles and its preparation method and application | |
| CN114621217A (en) | Preparation method of zolpidem | |
| CN114524805B (en) | Application of solid acid catalysis multi-component reaction in preparation of fluorine-containing medicine |
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 |