CN104529871A - Preparation method for frovatripan succinate - Google Patents
Preparation method for frovatripan succinate Download PDFInfo
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- CN104529871A CN104529871A CN201410799863.XA CN201410799863A CN104529871A CN 104529871 A CN104529871 A CN 104529871A CN 201410799863 A CN201410799863 A CN 201410799863A CN 104529871 A CN104529871 A CN 104529871A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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Abstract
The invention discloses a preparation method for frovatripan succinate, belonging to technical field of medicine synthesis and organic compound synthesis and preparation. The preparation method comprises the following steps: by taking 4-cyanophenylhydrazine hydrochloride as a starting raw material, performing cyclization with N-methyl-1,4-dioxaspiro[4.5] decane-8-amine hydrochloride in hydrochloric acid, splitting with L-pyroglutamic acid and then catalytically hydrolyzing by using a boron trifluoride-acetic acid complex, and then salifying by using succinic acid to form frovatripan succinate. The preparation method can be used for making up for the defects in the prior art, is simple in synthesis process, stable in yield, high in product purity and suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of succsinic acid furan sieve Qu Tan, belong to pharmaceutical synthesis and organic compound synthesis preparing technical field.
Background technology
Succsinic acid furan sieve Qu Tan, chinesization formal name used at school: R-(+) 3-methylamino-6-carboxamide-1,2,3,4-tetrahydro carbazole monosuccinic acid salt monohydrate, structural formula is as follows:
Molecular formula: C
14h
17n
3oC
4h
6o
4h
2o
Molecular weight: 379.4
Furan sieve Qu Tan is developed by Irish Elan Pharm acutieallne company, and ratified to go on the market with its succinate (1:1) form November calendar year 2001 by U.S. FDA, for having or the acute treatment of Migraine without aura, commodity are called Frova.This product is not in China's registration list marketing at present.
Furan sieve Qu Tan is a kind of novel antimigraine, belongs to selectivity 5-HT1B/1D receptor agonism medicine.Which overcome the shortcoming that first-generation 5-HT1B/1D receptor agonism medicine oral administration biaavailability is low, the transformation period is short, recurrence rate is high, it is effective medicine of adult's moderate or severe migraine, and to prevention menstrual migraine with regard to significant curative effect, and it is more less than other drug side effect, can predict this medicine and have good market outlook at home, therefore the commercial exploitation of furan sieve Qu Tan has very meaning.
Migraine is clinical modal primary headache type; clinical with ictal middle severe, sample of beating headache for main manifestations; headache mostly is inclined side; general lasting 4-72 hour; can with Nausea and vomiting; light, Sound stimulat or daily routines all can increase the weight of headache, and quiet environment, rest can alleviate headache.Migraine is a kind of common chronic forms vascular illness, and a lot of disease is children and pubescence, and the young and middle-aged phase reaches onset peak, and women is common, and men and women's Proportion of patients is about 1:2-3, and in crowd, morbidity is 5% ~ 10%, often has genetic background.Migrainous pathogenesis still imperfectly understands at present.This product alleviates headache mainly through suppressing the excessive diastole of the outer and entocranial artery of brain.
Patent CN103421855 mentions the synthetic method of the smooth intermediate of a kind of succsinic acid furan Luo Qu, but reactions steps is complicated, and the cycle is longer; CN1034072 utilizes high performance liquid phase chiral chromatographic column to be separated, and obtains furan sieve Qu Tan of single configuration, but this chiral separation method can only prepare a small amount of scientific research articles for use in laboratory, cannot realize in suitability for industrialized production; Final product obtained in CN1039491 is the raceme of furan sieve Qu Tan, and medicinal raw material is furan sieve Qu Tan of single configuration; Utilize the method for chiral separation to obtain the compound of single configuration in CN1200931, chiral separation is industrially widely used, simple to operate, and cost is lower, but needs catalysis pressure hydration in this route, higher to equipment requirements; The synthesis of the smooth and benzimidizole derivatives of Zhang Lijun, furan Luo Qu, Jilin University's Master's thesis, the method wherein mentioned is verified through inventor, and result proves that the method can not obtain furan sieve Qu Tan of single configuration, and its method is infeasible.
In sum, existing method all has some limitations, and make to yield poorly, purity is low, and the cycle is long.A kind of technique of current urgent need is simple, purity is high, be applicable to the synthetic method of industrial amplification production.
Summary of the invention
The object of the invention is to make up prior art deficiency, provide a kind of synthesis technique simple, stable yield and product purity is high, be suitable for the smooth synthetic method of furan Luo Qu of suitability for industrialized production.
For achieving the above object, the present invention with 4-cyanophenylhydrazine hydrochloride (compound 1) for starting raw material, with N-methyl isophthalic acid, hydrochloride (compound 2) cyclization in hydrochloric acid of 4-dioxo spiro [4.5] decane-8-amido, with the hydrolysis of boron trifluoride acetic acid complex catalysis after splitting with L-Glutimic acid, then obtain finished product succsinic acid furan sieve Qu Tan with succsinic acid salify.
The compound 1 that the present invention relates to is 4-cyanophenylhydrazine hydrochloride; Compound 2 is N-methyl isophthalic acid, 4-dioxo spiro [4.5] decane-8-amido hydrochloride; Compound 3 is (±)-6-cyano group-3-methylamino-1,2,3,4-tetrahydro carbazole; Compound 4 is (+)-6-cyano group-3-methylamino-1,2,3,4-tetrahydro carbazole-L pyroglutamate; Compound 5 is R-(+)-6-carbamyl-3-methylamino-1,2,3,4-tetrahydro carbazole.
Concrete preparation process of the present invention is:
1, by soluble in water for compound 1, add in reactor, add compound 2 and concentrated hydrochloric acid again, stir, be warming up to 70-90 DEG C of reaction 10h, after reaction terminates, reaction solution is chilled to 5-10 DEG C, stir 2h, suction filtration, be washed with water to filtrate pH5-7, suction filtration, gained filter cake is added in the mixed solvent of water and tetrahydrofuran (THF), stir, with NaOH aqueous solution regulator solution pH >=12, 30-50 DEG C of concentrating under reduced pressure, residuum keeps 5 DEG C to stir 2h, suction filtration, be washed with water to filtrate pH < 9, suction filtration, solid 30-50 DEG C of vacuum-drying 15-20h, wash by ethyl acetate again, suction filtration, solid 30-50 DEG C of vacuum-drying 10h, obtain faint yellow solid, for midbody compound 3,
2, L-Glutimic acid and MeOH are dropped in reactor, stir and be warming up to 30-40 DEG C, for subsequent use; Midbody compound 3 and MeOH are dropped in another reactor, stir and be warming up to 30-40 DEG C, insulation 1h, elimination insolubles, pours in above-mentioned insulation L-Glutimic acid methanol solution for subsequent use by filtrate, temperature rising reflux reaction 1h.Be cooled to 10-20 DEG C, drip acetic acid, be cooled to 5-10 DEG C after terminating, stirring and crystallizing 3h, suction filtration, filter cake methanol wash, solid 30-40 DEG C of vacuum-drying 10h, obtains off-white color solid.By gained solids with methanol and water mixed solvent reflux, keep 0.5h after solution clarification, be cooled to 5-10 DEG C, stirring and crystallizing 3h, suction filtration, solid 30-40 DEG C vacuum-drying, obtains white solid, is midbody compound 4;
3, midbody compound 4 is dissolved in acetic acid, drops in reactor, add water and boron trifluoride acetic acid complex compound, stir and be warming up to 80-90 DEG C, after 7h, in reactor, instill frozen water and propyl carbinol, stir, with NaOH aqueous solution regulator solution pH >=12.Leave standstill separatory, aqueous phase propyl carbinol extracts at twice, merges organic layer, with concentrating under reduced pressure after sodium carbonate solution washing, add the gac of saturated sodium bicarbonate alkalization, reflux 15min, be chilled to room temperature, suction filtration, filtrate reduced in volume is done, add ethyl acetate in resistates, be chilled to 5-10 DEG C, making beating washing 1h, suction filtration, solid with ethyl acetate making beating washing, suction filtration, solid 30-40 DEG C of vacuum-drying 10h, obtains off-white color solid, is midbody compound 5;
4, midbody compound 5, propyl carbinol and ethanol are dropped in reaction flask, be warming up to 70-90 DEG C of stirring and dissolving, while hot elimination insolubles, filtrate keeps temperature 50-70 DEG C, for subsequent use; Succsinic acid, second alcohol and water are dropped in reactor, is warming up to 30-40 DEG C, stirs clearly molten.By above-mentioned stock solution, in instillation succinic acid solution, drip and terminate, reacting liquid temperature is warming up to 50-70 DEG C, reaction 2h, is cooled to 10-20 DEG C, adds propyl carbinol, continue to be cooled to 5-10 DEG C, stir 4h, suction filtration, after filter cake absolute ethanol washing, 30-40 DEG C of vacuum-drying 10h, obtains the smooth crude product of succsinic acid furan Luo Qu;
5, by the ethanol of smooth for succsinic acid furan Luo Qu input 80%, reflux, dissolve clarification, elimination insolubles while hot, after filtrate naturally cools to room temperature, continue to be cooled to 5-10 DEG C, stirring and crystallizing 4h, suction filtration, solid 70-90% washing with alcohol, 30-40 DEG C of vacuum-drying 10h, obtains the smooth finished product of succsinic acid furan Luo Qu;
The chemical equation that the present invention relates to is:
Compared with prior art, method choice is reasonable, and operational path is simple, and the smooth high purity 99.9% of separating obtained succsinic acid furan Luo Qu, overcomes prior art problem, be applicable to industrialized production in the present invention.
Specific embodiment
Below in conjunction with embodiment, the present invention is elaborated further.
Embodiment:
Identical with summary of the invention of the technique main procedure that the present embodiment relates to, wherein the specific embodiment of compound 4, compound 5 is as follows:
1, the preparation of compound 4:
L-Glutimic acid and MeOH are dropped in 50L reactor, stirs and be warming up to 50 DEG C, for subsequent use; Midbody compound 3 and MeOH are dropped in another 50L reactor, stir and be warming up to 50-55 DEG C, insulation 1h, while hot elimination insolubles, pour in above-mentioned insulation L-Glutimic acid methanol solution for subsequent use by filtrate, temperature rising reflux reaction 1h.Temperature fall to 20 DEG C, drips acetic acid, drips and terminates rear slow cooling to 0 DEG C, stirring and crystallizing 3h, suction filtration, and the filter cake methanol wash of a small amount of 5 DEG C, solid 40 DEG C of vacuum-drying 10h, obtain off-white color solid.By gained solids with methanol and water (MeOH/H
2o=10:1) mixed solvent reflux, keep 0.5h after solution clarification, be cooled to 5 DEG C, stirring and crystallizing 3h, suction filtration, solid 40 DEG C of vacuum-drying 10h, obtain white solid, are midbody compound 4, yield: 45%;
2, the preparation of compound 5:
Compound 4 is dissolved in acetic acid, drop in reactor, add water and boron trifluoride acetic acid complex compound, stirring is warming up to 90 DEG C, and after 7h, reaction terminates, in reactor, instill frozen water, add propyl carbinol again, stir, with the NaOH aqueous solution regulator solution pH=12-13 of 6mol/L, control solution temperature not higher than 30 DEG C.Leave standstill separatory, aqueous phase propyl carbinol extracts at twice, merges organic layer, be evaporated to half volume with after 10% sodium carbonate solution washing, add the gac of saturated sodium bicarbonate alkalization, reflux 15min, be chilled to room temperature, suction filtration, filtrate reduced in volume is done, add ethyl acetate in resistates, be chilled to 5 DEG C of making beating washing 1h, suction filtration, solid with ethyl acetate making beating washing, suction filtration, solid 40 DEG C of vacuum-drying 10h, obtaining off-white color solid, is midbody compound 5, yield 98%.
The smooth sample survey result of succsinic acid furan Luo Qu
Claims (2)
1. a preparation method of succsinic acid furan sieve Qu Tan, is characterized in that technological process is:
A. by soluble in water for compound 1, add in reactor, add compound 2 and concentrated hydrochloric acid again, stir, be warming up to 70-90 DEG C of reaction 10h, after reaction terminates, reaction solution is chilled to 5-10 DEG C, stir 2h, suction filtration, be washed with water to filtrate pH5-7, suction filtration, gained filter cake is added in the mixed solvent of water and tetrahydrofuran (THF), stir, with NaOH aqueous solution regulator solution pH >=12, 30-50 DEG C of concentrating under reduced pressure, residuum keeps 5 DEG C to stir 2h, suction filtration, be washed with water to filtrate pH < 9, suction filtration, solid 30-50 DEG C of vacuum-drying 15-20h, wash by ethyl acetate again, suction filtration, solid 30-50 DEG C of vacuum-drying 10h, obtain faint yellow solid, for midbody compound 3,
B. L-Glutimic acid and MeOH are dropped in reactor, stir and be warming up to 30-40 DEG C, for subsequent use; Midbody compound 3 and MeOH are dropped in another reactor, stir and be warming up to 30-40 DEG C, insulation 1h, elimination insolubles, pours in above-mentioned insulation L-Glutimic acid methanol solution for subsequent use by filtrate, temperature rising reflux reaction 1h; Be cooled to 10-20 DEG C, drip acetic acid, be cooled to 5-10 DEG C after terminating, stirring and crystallizing 3h, suction filtration, filter cake methanol wash, solid 30-40 DEG C of vacuum-drying 10h, obtains off-white color solid; By gained solids with methanol and water mixed solvent reflux, keep 0.5h after solution clarification, be cooled to 5-10 DEG C, stirring and crystallizing 3h, suction filtration, solid 30-40 DEG C vacuum-drying, obtains white solid, is midbody compound 4;
C. midbody compound 4 is dissolved in acetic acid, drops in reactor, add water and boron trifluoride acetic acid complex compound, stir and be warming up to 80-90 DEG C, after 7h, in reactor, instill frozen water and propyl carbinol, stir, with NaOH aqueous solution regulator solution pH >=12; Leave standstill separatory, aqueous phase propyl carbinol extracts at twice, merges organic layer, with concentrating under reduced pressure after sodium carbonate solution washing, add the gac of saturated sodium bicarbonate alkalization, reflux 15min, be chilled to room temperature, suction filtration, filtrate reduced in volume is done, add ethyl acetate in resistates, be chilled to 5-10 DEG C, making beating washing 1h, suction filtration, solid with ethyl acetate making beating washing, suction filtration, solid 30-40 DEG C of vacuum-drying 10h, obtains off-white color solid, is midbody compound 5;
D. midbody compound 5, propyl carbinol and ethanol are dropped in reaction flask, be warming up to 70-90 DEG C of stirring and dissolving, while hot elimination insolubles, filtrate keeps temperature 50-70 DEG C, for subsequent use; Succsinic acid, second alcohol and water are dropped in reactor, is warming up to 30-40 DEG C, stirs clearly molten; By above-mentioned stock solution, in instillation succinic acid solution, drip and terminate, reacting liquid temperature is warming up to 50-70 DEG C, reaction 2h, is cooled to 10-20 DEG C, adds propyl carbinol, continue to be cooled to 5-10 DEG C, stir 4h, suction filtration, after filter cake absolute ethanol washing, 30-40 DEG C of vacuum-drying 10h, obtains the smooth crude product of succsinic acid furan Luo Qu;
E. by the ethanol of smooth for succsinic acid furan Luo Qu input 80%, reflux, dissolve clarification, elimination insolubles while hot, after filtrate naturally cools to room temperature, continue to be cooled to 5-10 DEG C, stirring and crystallizing 4h, suction filtration, solid 70-90% washing with alcohol, 30-40 DEG C of vacuum-drying 10h, obtains the smooth finished product of succsinic acid furan Luo Qu.
2. the preparation method of succsinic acid furan sieve Qu Tan according to claim 1, is characterized in that the chemical equation related to is:
。
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| CN201410799863.XA CN104529871A (en) | 2014-12-22 | 2014-12-22 | Preparation method for frovatripan succinate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117402103A (en) * | 2023-10-17 | 2024-01-16 | 正大制药（青岛）有限公司 | Preparation method of furotriptan succinate degradation impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095712A (en) * | 1992-12-21 | 1994-11-30 | 史密丝克莱恩比彻姆有限公司 | Compounds |
| CN1305460A (en) * | 1998-04-16 | 2001-07-25 | 弗纳里斯有限公司 | Process for preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole |
-
2014
- 2014-12-22 CN CN201410799863.XA patent/CN104529871A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095712A (en) * | 1992-12-21 | 1994-11-30 | 史密丝克莱恩比彻姆有限公司 | Compounds |
| CN1305460A (en) * | 1998-04-16 | 2001-07-25 | 弗纳里斯有限公司 | Process for preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole |
Non-Patent Citations (1)
| Title |
|---|
| EDUARDO BUSTO,ET AL.: ""Chemoenzymatic Asymmetric Synthesis of Serotonin Receptor Agonist (R)-Frovatriptan"", 《EUR. J. ORG. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117402103A (en) * | 2023-10-17 | 2024-01-16 | 正大制药（青岛）有限公司 | Preparation method of furotriptan succinate degradation impurity |
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Application publication date: 20150422 |