CN114369107A - Laramiditan intermediate compound - Google Patents
Laramiditan intermediate compound Download PDFInfo
- Publication number
- CN114369107A CN114369107A CN202011103899.1A CN202011103899A CN114369107A CN 114369107 A CN114369107 A CN 114369107A CN 202011103899 A CN202011103899 A CN 202011103899A CN 114369107 A CN114369107 A CN 114369107A
- Authority
- CN
- China
- Prior art keywords
- reaction
- potassium
- sodium
- intermediate compound
- catalyst
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a novel intermediate and a novel method for synthesizing rasemidetin by using the intermediate. The method takes 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine as a starting material, reacts with pinacol diboron to obtain a new intermediate 2- (1-methylpiperidine-4-yl acyl) -6-pyridine borate, and then reacts with 2,4, 6-trifluorobenzonitrile to obtain the lasiodiditant. Compared with the prior art, the preparation process for synthesizing the lamidittanol by using the intermediate can obviously shorten the process route, and the prepared lamidittanol has higher purity and 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 rasemiptan intermediate compound, a preparation method thereof and application thereof in synthesis 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 Eli Lilly, 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 processes of rasemiptan have been disclosed in several patents such as WO2011123654a1, US2019233393a1, CN03807363, US8697876B2, WO2011123654, CN110386918A, etc. 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 or reacting with thionyl chloride in THF to obtain N-methyl-4-piperidinoyl chloride hydrochloride, then 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 ℃ or reacting with a Grignard reagent (a THF solution of i-PrMgCl-LiCl) in THF to obtain a crude product of 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine, and purifying by column chromatography or salifying with an HBr solution; reacting the purified 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine with ammonia gas in a sealed autoclave under high temperature and pressure by using ethylene glycol as a solvent for 20 hours to obtain a crude product of 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine, salifying the crude product with concentrated hydrochloric acid, and purifying the salt to obtain 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine by using alkali; then reacting with 2,4, 6-trifluorobenzoyl chloride in anhydrous THF or chlorobenzene under the protection of nitrogen to obtain rasemidetan; finally, the mixture is salified with succinic acid in acetone to obtain the lasiodidittanol succinate.
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, inflammable and harsh in 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 pressurized to about 50psi (345kPa), which has high requirement on equipment; in addition, the 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine needs to be purified by repeatedly adjusting acid and alkali, the operation is complex, 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.
Furthermore, patent CN1642939A (CN100352817C) and document J.C.S.Perkin, T (24),3597-2(dba)3Reacting with benzophenone imine under the action of sodium tert-butoxide, removing benzophenone protection to obtain 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine, and performing amidation reaction with 2,4, 6-trifluorobenzoyl chloride to obtain rasemidetin. The route also relates to ultralow temperature operation at-70 ℃, has high requirements on process conditions, complicated process, lower yield and high price of used raw materials, and is not beneficial to industrial production.
Patent CN110386918B uses 2, 3-butanedione as starting material, and firstly makes 1, 4-addition reaction with 2-halogenated acrylonitrile, then makes pyridine cyclization reaction with ammonia to obtain 2-amino-6-acetylpyridine, then makes amino protected to obtain 2-disubstituted methylene amino-6-acetylpyridine, then makes hydroxyethylation reaction with ethylene oxide, does not need separation, directly makes sulfoesterification reaction, and makes cyclization reaction with methylamine to obtain 2-disubstituted methylene amino-6- (1-methylpiperidine-4-yl) formylpyridine; then removing a protecting group under the action of an acid catalyst, and finally carrying out amidation reaction with 2,4, 6-trifluorobenzoyl chloride to obtain the lamidotitan. However, the route uses flammable and explosive ethylene oxide with carcinogenicity, has long synthesis steps and complicated operation, and is not beneficial to industrial production.
From the above, the preparation difficulty of the existing lasimintan is related to the preparation of raw materials during the construction of an amido bond, and in the prior art, the use of 2,4, 6-trifluorobenzoyl chloride with strong corrosivity is involved during the construction of the amido bond, so that the requirement on equipment is high; meanwhile, the reaction conditions of the preparation process of the other intermediate 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine are harsh, and the operation is also complicated.
In conclusion, the existing preparation method of rasemistane has the problems of low process safety, 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 defects of the existing preparation technology of the rasemistane, the invention provides a new intermediate compound II and a new method for synthesizing the rasemistane by using the intermediate. The method is simple and efficient, and the target product prepared by the method has higher purity and yield.
The invention is realized by the following technical scheme:
a rasemiptan intermediate compound is shown as a formula II, and the structural formula is as follows:
a preparation method of an intermediate compound II comprises the following steps of taking 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine, namely SM-1 as a raw material, and carrying out catalytic reaction with pinacol ester diboron under an alkaline environment to obtain the intermediate compound II, wherein the reaction formula is as follows:
the method specifically comprises the following steps:
under the protection of inert gas, adding 2-bromo-6- (1-methylpiperidine-4-yl acyl) -pyridine, namely SM-1, diboronic acid pinacol ester, alkali and a catalyst into a reaction solvent A, carrying out temperature-controlled reaction, and carrying out post-treatment after TLC detection reaction to obtain an intermediate compound II.
Preferably, the catalyst is Pd (PPh)3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2、Pd2(dba)3Preferably Pd (dppf) Cl2。
Preferably, the alkali is one or a combination of sodium acetate, potassium acetate, sodium bicarbonate and potassium bicarbonate, and potassium acetate is preferred.
Preferably, the feeding molar ratio of the SM-1 to the pinacol diboron, the alkali and the catalyst is 1: 1.05-1.3: 1.1-1.7: 0.03-0.08.
Preferably, the feeding molar ratio of the SM-1 to the pinacol diboron is 1: 1.05-1.3, preferably 1: 1.2.
Preferably, the feeding molar ratio of the SM-1 to the alkali is 1: 1.1-1.7, preferably 1: 1.4.
Preferably, the feeding molar ratio of the SM-1 to the catalyst is 1: 0.03-0.08, and preferably 1: 0.05.
Preferably, the reaction solvent A is selected from one or a combination of dimethyl sulfoxide, N-dimethylformamide, 1, 4-dioxane and acetonitrile, and is preferably 1, 4-dioxane.
Preferably, the temperature-controlled reaction temperature is 80-110 ℃, and preferably 90-95 ℃.
In the present invention, the inert gas is generally selected from nitrogen or argon, preferably argon.
In a preferred embodiment, the post-treatment step is: after the reaction is finished, filtering the reaction solution, washing a filter cake by using ethyl acetate, combining organic phases, and concentrating the organic phases to be dry by a rotary evaporator under reduced pressure; with n-hexane/diethyl ether (V)N-hexane:VEther (A)Recrystallizing with mixed solvent of (5: 1), filtering, and adding n-hexane/diethyl ether (V) into filter cakeN-hexane:VEther (A)And (2) washing with a mixed solvent of 20:1), and drying to obtain an intermediate compound II.
In another aspect, the invention provides a method for preparing rasemiptan from an intermediate compound shown as a formula II, which comprises the following steps: and (3) carrying out catalytic reaction on the intermediate compound II and 2,4, 6-trifluorobenzonitrile under an alkaline condition by using a catalyst to obtain the lamidetan, wherein the reaction formula is as follows:
the method specifically comprises the following steps:
and adding the intermediate II, 2,4, 6-trifluorobenzonitrile, a catalyst and a base into a reaction solvent B, controlling the temperature until the reaction is finished, and performing post-treatment to obtain the lamivudine.
Preferably, the catalyst is CuSO4、Cu(OAc)2、CuCl2、CuBr2、CuI2、Cu(OTf)2、Cu(NO3)2One or the combination of CuCl, CuBr and CuI, and CuCl is preferred2。
Preferably, the base is one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium n-butoxide, potassium n-butoxide, sodium t-butoxide and potassium t-butoxide, and preferably potassium t-butoxide.
Preferably, the reaction solvent B is one or a combination of methanol, ethanol, isopropanol, n-butanol and tert-butanol, preferably tert-butanol.
Preferably, the feeding molar ratio of the intermediate II to the 2,4, 6-trifluorobenzonitrile, the catalyst and the base is 1: 1.05-1.4: 0.03-0.08: 1.5-4
Preferably, the feeding molar ratio of the intermediate II to the 2,4, 6-trifluorobenzonitrile is 1: 1.05-1.4, preferably 1: 1.15.
Preferably, the feeding molar ratio of the intermediate II to the catalyst is 1: 0.03-0.08, preferably 1: 0.06.
Preferably, the feeding molar ratio of the intermediate II to the alkali is 1: 1.5-4, preferably 1: 2.5.
Preferably, the temperature-controlled reaction temperature is 15-40 ℃.
In a preferred embodiment, the post-treatment step is: after the reaction is finished, pouring the reaction solution into purified water, extracting by using an organic solvent, combining organic phases, washing by using purified water, drying, filtering, concentrating the obtained filtrate under reduced pressure to dryness, and recrystallizing by using methyl tert-butyl ether to obtain the lamidotitan; the extraction solvent may be one or a combination of ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether, preferably dichloromethane.
The invention has the beneficial effects that:
the invention provides a new rasemiptan intermediate compound II and a new method for preparing rasemiptan by using the compound II; SM-1 is taken as an initial material, and the construction of N-in amido bond is from 2,4, 6-trifluorobenzonitrile, so that the problems of complex operation and low overall yield when 2-amino-6- (1-methylpiperidine-4-yl acyl) -pyridine is taken as a raw material for preparation can be effectively avoided; compared with the prior art, the preparation process for synthesizing the lamiditan by using the intermediate compound can obviously shorten the process route, and the prepared lamiditan has higher purity and 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.
In the following examples, the procedures and methods not described in detail are conventional methods well known in the art, and reagents used are commercially available, analytically pure or chemically pure, without source or specification.
The structure of the intermediate compound II obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):331.2188[M+H]+；1H-NMR(400MHz,DMSO-d6)δ：8.02(t,J＝12.2Hz1H),7.91～7.75(m,2H),2.87～2.74(m,1H),2.70～2.64(m,2H),2.44～2.28(m,2H),2.24(s,3H),2.15～2.03(m,2H),1.90～1.75(m,2H),1.24(s,12H)；13C-NMR(101MHz,DMSO-d6)δ：199.60,156.43,148.13,136.36,131.76,125.00,86.49,52.77,46.43,43.85,28.06,22.70。
the structure of the obtained rasemiptan compound is confirmed as follows:
ESI-HRMS(m/z):378.1442[M+H]+；1H-NMR(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)；13C-NMR(101MHz,DMSO-d6)δ：199.62,165.31,162.59,162.00,160.34,155.53,151.19,144.25,125.64,119.18,109.24,101.16,101.16,53.77,46.05,43.90,28.03。
the invention adopts HPLC to measure the purity of the rasemiptan, and the chromatographic conditions are as follows:
a chromatographic column: welch Ultimate XB-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.
Example 1
2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.32g, 0.1mol), pinacol diboron (30.47g, 0.12mol), potassium acetate (13.74g, 0.14mol), Pd (dppf) Cl under argon2(3.66g, 5.0mmol) in a dry round bottom flask, adding dry 1, 4-dioxane (250ml), reacting at 90-95 deg.C, TLC detecting reaction, filtering with celite, washing filter cake with ethyl acetate (20ml × 3), combining organic phases, concentrating to dryness under reduced pressure by rotary evaporator, adding n-hexane/diethyl ether (V)N-hexane:VEther (A)Recrystallizing with mixed solvent of (5: 1), filtering, and adding n-hexane/diethyl ether (V) into filter cakeN-hexane:VEther (A)Yield 95.3% and purity 99.1% intermediate compound II was obtained by washing with 20: 1).
Example 2
Under the protection of argon, 2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.34g, 0.1mol), pinacol diboron (26.66g, 0.105mol), potassium acetate (13.72g, 0.14mol), Pd (PPh)3)4(5.78g, 5.0mmol) was added to a dry round-bottom flask, dried dimethyl sulfoxide (250ml) was added, the temperature was controlled at 95-100 ℃ for reaction, after completion of TLC detection reaction, celite was packed, the filter cake was washed with ethyl acetate (20ml × 3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, recrystallized with a mixed solvent of n-hexane/ether 5/1, filtered, and the filter cake was washed with n-hexane/ether 20/1 to give intermediate compound II in 92.7% yield and 99.0% purity.
Example 3
2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.31g, 0.1mol), pinacol diboron (25.39g, 0.10mol), sodium acetate (11.48g, 0.14mol), Pd (dppf) Cl under argon2(3.66g, 5.0mmol) was added to a dry round-bottom flask, dried N, N-dimethylformamide (250ml) was added, the temperature was controlled at 105 to 110 ℃ for reaction, after the completion of TLC detection reaction, celite filtration was performed, the filter cake was washed with ethyl acetate (20ml × 3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, recrystallized with a mixed solvent of N-hexane/ether-5/1, filtered, and the filter cake was washed with N-hexane/ether-20/1 to obtain intermediate compound II, yield 88.7%, purity 98.0%.
Example 4
2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.34g, 0.1mol), pinacol diboron (33.01g, 0.13mol), sodium bicarbonate (11.76g, 0.14mol), Pd (PPh) under argon3)2Cl2(3.51g, 5.0mmol) was added to a dry round bottom flask, acetonitrile (250ml) was added, the reaction was refluxed at controlled temperature, after completion of the TLC check, the pad was filtered through celite, the filter cake was washed with ethyl acetate (20 ml. times.3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, and the mixture was concentrated to dryness in n-hexane/ethyl acetateThe intermediate compound II was obtained in 94.2% yield and 98.6% purity by recrystallizing the mixed solvent of ether 5/1, filtering, and washing the filter cake with n-hexane/ether 20/1.
Example 5
2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.33g, 0.1mol), pinacol diboron (35.55g, 0.14mol), potassium bicarbonate (14.02g, 0.14mol), Pd under protection of argon2(dba)3(4.58g, 5.0mmol) was added to a dry round-bottomed flask, N-dimethylformamide (250ml) was added, the reaction was controlled at 80 to 85 ℃, after completion of the TLC detection reaction, the cake was filtered through celite, washed with ethyl acetate (20ml × 3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, recrystallized from a mixed solvent of N-hexane/ether-5/1, filtered, and washed with N-hexane/ether-20/1 to give intermediate compound II in 90.2% yield and 97.9% purity.
Example 6
Under the protection of argon, 2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.33g, 0.1mol), pinacol diboron (30.47g, 0.12mol), potassium acetate (10.80g, 0.11mol), Pd (PPh)3)2Cl2(3.51g, 5.0mmol) was added to a dry round-bottomed flask, 1, 4-dioxane (250ml) was added, the temperature was controlled at 85 to 90 ℃ for reaction, after completion of the TLC detection reaction, celite was packed, the filter cake was washed with ethyl acetate (20ml × 3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, recrystallized from a mixed solvent of n-hexane/ether (5/1), filtered, and the filter cake was washed with n-hexane/ether (20/1) to give intermediate compound II in 93.5% yield and 98.5% purity.
Example 7
Under the protection of argon, 2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.32g, 0.1mol), pinacol diboron (30.48g, 0.12mol), potassium acetate (16.68g, 0.17mol), Pd (PPh)3)4(5.78g, 5.0mmol) was added to a dry round bottom flask, acetonitrile (250ml) was added, the reaction was refluxed at controlled temperature, after completion of the TLC check, the pad was filtered through celite, the filter cake was washed with ethyl acetate (20 ml. times.3), the organic phases were combined and evaporated by rotary evaporationThe reaction mixture was concentrated to dryness under reduced pressure, recrystallized from a mixed solvent of n-hexane/diethyl ether (5/1), filtered, and the filter cake was washed with n-hexane/diethyl ether (20/1) to give intermediate compound II in 94.0% yield and 98.1% purity.
Example 8
2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.35g, 0.1mol), pinacol diboron (30.47g, 0.12mol), potassium bicarbonate (14.02g, 0.14mol), Pd (dppf) Cl under argon2(2.20g, 3.0mmol) was added to a dry round-bottomed flask, 1, 4-dioxane (250ml) was added, the temperature was controlled at 95 to 100 ℃ for reaction, after the completion of TLC detection reaction, celite was packed, the filter cake was washed with ethyl acetate (20ml × 3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, recrystallized with a mixed solvent of n-hexane/ether-5/1, filtered, and the filter cake was washed with n-hexane/ether-20/1 to obtain intermediate compound II, with a yield of 92.0% and a purity of 99.0%.
Example 9
2-bromo-6- (1-methylpiperidin-4-ylacyl) -pyridine (SM-1, 28.30g, 0.1mol), pinacol diboron (30.45g, 0.12mol), sodium acetate (11.48g, 0.14mol), Pd (dppf) Cl under argon2(5.85g, 8.0mmol) was added to a dry round-bottom flask, dimethylsulfoxide (250ml) was added, the temperature was controlled at 90-95 ℃ for reaction, after completion of TLC detection reaction, celite was packed and filtered, the filter cake was washed with ethyl acetate (20ml × 3), the organic phases were combined, concentrated to dryness under reduced pressure by a rotary evaporator, recrystallized with a mixed solvent of n-hexane/ether (5/1), filtered, and the filter cake was washed with n-hexane/ether (20/1) to obtain intermediate compound II, yield 93.9%, and purity 98.3%.
Example 10
Intermediate II (16.51g, 0.05mol), 2,4, 6-trifluorobenzonitrile (9.03g, 0.0575mol), CuCl2(0.40g, 3.0mmol) and potassium tert-butoxide (14.03g, 0.125mol) are added into tert-butyl alcohol (150ml) to react at room temperature, after the TLC detection reaction is finished, the reaction solution is poured into purified water (600ml), dichloromethane (200ml multiplied by 3) is extracted, an organic phase is collected, the purified water (150ml multiplied by 2) is washed, dried and filtered, the obtained filtrate is concentrated to dryness under reduced pressure and is treated by methyl tert-butyl etherRecrystallizing to obtain the rasemidetin with the yield of 94.7 percent and the purity of 99.3 percent.
Example 11
Intermediate II (16.50g, 0.05mol), 2,4, 6-trifluorobenzonitrile (8.25g, 0.0525mol), CuSO4(0.48g, 3.0mmol) and sodium methoxide (6.75g, 0.125mol) are added into methanol (150ml) to react at the temperature of 30-35 ℃, after the TLC detection reaction is finished, the reaction solution is poured into purified water (600ml), ethyl acetate (200ml multiplied by 3) is extracted, an organic phase is collected, the purified water (150ml multiplied by 2) is washed, dried and filtered, the obtained filtrate is concentrated under reduced pressure to be dry, and is recrystallized by methyl tert-butyl ether to obtain the rasemiptan, the yield is 91.9 percent, and the purity is 98.6 percent.
Example 12
Intermediate II (16.54g, 0.05mol), 2,4, 6-trifluorobenzonitrile (7.85g, 0.05mol), Cu (OAc)2(0.55g, 3.0mmol) and sodium ethoxide (8.51g, 0.125mol) are added into ethanol (150ml), the temperature is controlled to 35-40 ℃ for reaction, after the detection reaction is finished, the reaction solution is poured into purified water (600ml), dichloromethane (200ml multiplied by 3) is extracted, an organic phase is collected, the purified water (150ml multiplied by 2) is washed, dried and filtered, the obtained filtrate is decompressed and concentrated to be dry, and is recrystallized by methyl tert-butyl ether, thus obtaining the rasagilitant I, the yield is 89.1%, and the purity is 98.1%.
Example 13
Intermediate II (16.51g, 0.05mol), 2,4, 6-trifluorobenzonitrile (11.00g, 0.07mol), CuBr2(0.67g, 3.0mmol) and potassium isopropoxide (12.27g, 0.125mol) are added into isopropanol (150ml), the temperature is controlled at 15-20 ℃ for reaction, after the reaction is detected, the reaction solution is poured into purified water (600ml), ethyl acetate (200ml multiplied by 3) is used for extraction, an organic phase is collected, the purified water (150ml multiplied by 2) is used for washing, drying and filtering, the obtained filtrate is decompressed and concentrated to be dry, and is recrystallized by methyl tert-butyl ether, thus obtaining the rasemiptan I, the yield is 93.8%, and the purity is 99.0%.
Example 14
Intermediate II (16.52g, 0.05mol), 2,4, 6-trifluorobenzonitrile (11.78g, 0.075mol), and CuI2(0.95g, 3.0mmol) and sodium isopropoxide (10.26g, 0.125mol) are added into isopropanol (150ml), the temperature is controlled to be 15-20 ℃ for reaction, and after the reaction is detected, the reaction is carried outThe reaction solution was filtered, the filtrate was poured into purified water (600ml), extracted with dichloromethane (200ml × 3), the organic phase was collected, washed with purified water (150ml × 2), dried, filtered, the obtained filtrate was concentrated to dryness under reduced pressure, and recrystallized from methyl tert-butyl ether to give rasagilitant I with a yield of 90.6% and a purity of 97.4%.
Example 15
Intermediate II (16.55g, 0.05mol), 2,4, 6-trifluorobenzonitrile (9.03g, 0.0575mol), CuCl2(0.20g, 1.5mmol) and sodium n-butoxide (12.01g, 0.125mol) are added into n-butanol (150ml), the temperature is controlled to be 25-30 ℃ for reaction, after the detection reaction is finished, the reaction solution is poured into purified water (600ml), chloroform (200ml multiplied by 3) is used for extraction, an organic phase is collected, the purified water (150ml multiplied by 2) is used for washing, drying and filtering, the obtained filtrate is decompressed and concentrated to be dry, and is recrystallized by methyl tert-butyl ether, thus obtaining the rasagilitant I, the yield is 92.0 percent, and the purity is 98.5 percent.
Example 16
Intermediate II (16.49g, 0.05mol), 2,4, 6-trifluorobenzonitrile (9.03g, 0.0575mol), Cu (NO)3)2(0.75g, 4.0mmol) and potassium n-butoxide (14.03g, 0.125mol) are added into n-butanol (150ml), the temperature is controlled to 15-20 ℃ for reaction, after the detection reaction is finished, the reaction solution is poured into purified water (600ml), chloroform (200ml multiplied by 3) is extracted, an organic phase is collected, the purified water (150ml multiplied by 2) is washed, dried and filtered, the obtained filtrate is decompressed and concentrated to be dry, and is recrystallized by methyl tert-butyl ether, thus obtaining rasemidetin I, the yield is 94.0%, and the purity is 98.2%.
Example 17
Intermediate II (16.51g, 0.05mol), 2,4, 6-trifluorobenzonitrile (9.03g, 0.0575mol), Cu (OTf)2(1.09g, 3.0mmol) and potassium tert-butoxide (8.42g, 0.075mol) are added into tert-butyl alcohol (150ml), the temperature is controlled to be 25-30 ℃ for reaction, after the detection reaction is finished, the reaction solution is poured into purified water (600ml), methyl tert-butyl ether (200ml multiplied by 3) is extracted, an organic phase is collected, the purified water (150ml multiplied by 2) is washed, dried and filtered, the obtained filtrate is decompressed and concentrated to be dry, and is recrystallized by the methyl tert-butyl ether, thus obtaining the rasemiptan I, the yield is 92.3 percent, and the purity is 98.8 percent.
Example 18
Adding the intermediate II (16.50g, 0.05mol), 2,4, 6-trifluorobenzonitrile (9.03g, 0.0575mol), CuBr (0.43g, 3.0mmol) and sodium tert-butoxide (19.22g, 0.20mol) into tert-butyl alcohol (150ml), controlling the temperature to be 15-20 ℃ for reaction, pouring the reaction solution into purified water (600ml) after the reaction is detected to be finished, extracting methyl tert-butyl ether (200ml multiplied by 3), collecting an organic phase, washing the purified water (150ml multiplied by 2), drying and filtering, concentrating the obtained filtrate under reduced pressure to be dry, and recrystallizing through the methyl tert-butyl ether to obtain the lasiodidittanan I with the yield of 93.4% and the purity of 99.1%.
Claims (10)
1. A rasemiptan intermediate compound has a structure shown in a formula II:
2. a method for preparing the compound of claim 1, which is characterized in that SM-1 is used as a raw material to perform a catalytic reaction with pinacol diboron in an alkaline environment to prepare an intermediate compound II, wherein the reaction formula is as follows:
3. the preparation method according to claim 2, characterized by comprising the following steps: under the protection of inert gas, adding SM-1, diboron pinacol ester, alkali and a catalyst into a reaction solvent A, controlling the temperature to react, and after TLC detection reaction is finished, carrying out post-treatment to obtain an intermediate compound II.
4. The method according to claim 3, wherein the catalyst is Pd (PPh)3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2、Pd2(dba)3One or a combination thereof.
5. The preparation method according to claim 3, wherein the alkali is one or a combination of sodium acetate, potassium acetate, sodium bicarbonate and potassium bicarbonate.
6. The preparation method according to claim 3, wherein the feeding molar ratio of SM-1 to pinacol diboron, the base and the catalyst is 1: 1.05-1.3: 1.1-1.7: 0.03-0.08.
7. The method according to claim 3, wherein the reaction temperature is 80 to 110 ℃.
8. A process for preparing lasiodiditant from compound II according to claim 1, comprising the steps of:
and (3) carrying out catalytic reaction on the intermediate compound II and 2,4, 6-trifluorobenzonitrile under an alkaline condition by using a catalyst to obtain the lamidetan, wherein the reaction formula is as follows:
9. the method of claim 8, wherein the catalyst is CuSO4、Cu(OAc)2、CuCl2、CuBr2、CuI2、Cu(OTf)2、Cu(NO3)2One or the combination of CuCl, CuBr and CuI.
10. The method according to claim 8, wherein the base is one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium n-butoxide, potassium n-butoxide, sodium t-butoxide and potassium t-butoxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011103899.1A CN114369107A (en) | 2020-10-15 | 2020-10-15 | Laramiditan intermediate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011103899.1A CN114369107A (en) | 2020-10-15 | 2020-10-15 | Laramiditan intermediate compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114369107A true CN114369107A (en) | 2022-04-19 |
Family
ID=81138877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011103899.1A Pending CN114369107A (en) | 2020-10-15 | 2020-10-15 | Laramiditan intermediate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114369107A (en) |
-
2020
- 2020-10-15 CN CN202011103899.1A patent/CN114369107A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3013848B1 (en) | Process for the preparation of abiraterone and intermediates thereof | |
| EP2914574B1 (en) | New process | |
| CN110028447B (en) | Preparation method of 2-fluoromethylquinoline derivative | |
| CN114369107A (en) | Laramiditan intermediate compound | |
| CN108084145B (en) | Ticagrelor intermediate and preparation method thereof | |
| CN110981934B (en) | Synthetic method of argatroban hydrate | |
| WO2016035609A1 (en) | Method for producing 2-amino-substituted benzaldehyde compound | |
| CN103168030B (en) | Method for preparing amlodipine | |
| CN105461688A (en) | Synthesis method of benzimidazole compound K | |
| CN114621218A (en) | Zolpidem intermediate compound | |
| CN113754605A (en) | Nitrogen-containing ligand and preparation method and application thereof | |
| AU776300B2 (en) | Synthesis of 3-amino-3-aryl propanoates | |
| CN114524805B (en) | Application of solid acid catalysis multi-component reaction in preparation of fluorine-containing medicine | |
| CN115947718A (en) | Preparation method of rasemiptan intermediate | |
| CN115477635A (en) | Preparation method of rasemiptan | |
| CN117105909A (en) | Preparation method of intermediate of lasmidbody | |
| CN103372461A (en) | Chiral emulsion catalyst as well as preparation method and application thereof | |
| CN114621217A (en) | Preparation method of zolpidem | |
| JP4173335B2 (en) | Method for producing optically active 2,3-epoxypropane derivative | |
| CN114249723A (en) | Preparation method of zolpidem and key intermediate thereof | |
| WO2024015861A1 (en) | Methods of preparation of heterocyclic compounds | |
| CN113929628A (en) | Preparation method of imidazoline derivative | |
| JP2011515328A (en) | Efficient method for producing atorvastatin | |
| CN112724077A (en) | Synthetic method of Laolatinib intermediate | |
| WO1996008489A1 (en) | Derivatives of benzopyran and of benzothiopyran, their preparation and their use as agonists of dopaminergic receptors |
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 |