CN106432044A - Synthesis method of intermediate 1-methylindole-3-carboxylic acid of granisetron drug - Google Patents
Synthesis method of intermediate 1-methylindole-3-carboxylic acid of granisetron drug Download PDFInfo
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- CN106432044A CN106432044A CN201610824135.9A CN201610824135A CN106432044A CN 106432044 A CN106432044 A CN 106432044A CN 201610824135 A CN201610824135 A CN 201610824135A CN 106432044 A CN106432044 A CN 106432044A
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- methylindole
- carboxylic acid
- granisetron
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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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
A synthesis method of intermediate 1-methylindole-3-carboxylic acid of a granisetron drug comprises the steps as follows: adding 130 ml of acrylonitrile and 0.32 mol of stannous chloride to a reaction vessel, controlling the stirring speed at 130 to 170 rpm, adding 0.053 mol of 1H-indazole-3-formic acid, increasing the temperature of the solution to 50-55 DEG C, preforming reflux for 5-6 h, slowly adding 0.061-0.063 mol of amine methane, performing reflux for 8-9 h, reducing the temperature of the solution to 5-9 DEG C, leaving the solution to stand for 30-32 h, separating a solid out, performing filtration, dissolving the solid in 150 ml of a potassium bromide solution, performing filtration, adding an oxalic acid solution to adjust the pH of the solution to 3-4, separating a solid out, performing suction filtration, performing washing with a saline solution and washing with nitromethane, performing dehydration with a dehydrating agent, and performing recrystallization in ethyl acetate to obtain 1-methylindole-3-carboxylic acid crystals; the saline solution in the step is any one of sodium sulfate and potassium nitrate.
Description
Technical field
The present invention relates to a kind of synthetic method of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid.
Background technology
The nausea and vomiting that granisetron medicine is used for radiotherapy, cytotoxin agents chemotherapy causes.This product will not
Impact or suppression cytochrome P-450 drug metabolizing system.At present, also there is no one clearly with regard to this product and other drugs
Between pharmacology or medicine generation interact research.Because granisetron be cytochrome P-450 drug metabolism enzyme through liver and
Metabolism, the material of any impact or this enzyme of suppression all will affect the metabolism of granisetron and eliminate the half-life.This product is a kind of
The 5-HT3 receptor antagonist of high selectivity, to because radiotherapy, chemotherapy and the nausea and vomiting that causes of operation have good prevention and
Therapeutical effect.The factors such as radiotherapy, chemotherapy and surgical operation can cause enterochromaffin cell release 5-HT, 5-HT can activate maincenter or fan
Walk nerve 5-HT3 receptor and the reflection that causes vomiting.This product controls the mechanism of nausea and vomiting, is by the chemistry sense of antagonism maincenter
By the 5-HT3 receptor of area and periphery vagus nerve ending, suppress the generation of Nausea and vomiting.This product selectivity is high, no extrapyramidal system
The side effect such as reaction, excess sedation.After this product 20 or 40 μ g/kg, mean plasma concentration peak is 13.7 and 42.8 μ g/L, and blood plasma disappears
Except about 3.1～5.9 hours half-life.This product is widely distributed in vivo, and Binding rate of serum protein is about 65%, most of rapid generation
Thank, main metabolic pathway is again by conjugation after N- alkylation removal and aromatic oxygenation.1- methylindole -3- carboxylic acid draws as lattice
Department's fine jade pharmaceutical intermediate, its synthetic method quality has important for improving pharmaceutical synthesis product quality, minimizing by-products content
Economic implications.
Content of the invention
It is an object of the invention to provide a kind of synthesis side of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid
Method, comprises the steps：
I () adds propionitrile 130ml, stannous chloride 0.32mol in reaction vessel, control mixing speed 130 170rpm,
Add 1H- indazole -3- formic acid (2) 0.053mol, raise solution temperature to 50--55 DEG C, flow back 5 6h, is slowly added to amine methane
(3) 0.061 0.063mol, flow back 8 9h, reduces solution temperature to 5--9 DEG C, stands 30 32h, separate out solid, filters,
Solid is dissolved in 150ml potassium bromide solution, adding oxalic acid solution to adjust pH value of solution after filtration is 34, separates out solid, sucking filtration, salt
Solution washs, and nitromethane washs, and dehydrant is dehydrated, and recrystallization in ethyl acetate obtains crystal 1- methylindole -3- carboxylic acid
(1)；Wherein, the potassium bromide solution mass fraction described in step (i) is 15 20%, the oxalic acid solution quality described in step (i)
Fraction is 30 35%, and the saline solution described in step (i) is sodium sulfate, any one in potassium nitrate, the nitre described in step (i)
Methylmethane mass fraction is 80 85%, and the dehydrant described in step (i) is anhydrous magnesium sulfate, any one in phosphorus pentoxide
Kind, the ethyl acetate mass fraction described in step (i) is 90 95%.
Whole course of reaction can use following reaction equation to represent：
The invention has the advantages that：Decrease the intermediate link of reaction, reduce reaction temperature and response time, improve anti-
Answer yield.
Specific embodiment
With reference to being embodied as example, the invention will be further described：
A kind of synthetic method of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid
Example 1：
Add propionitrile 130ml, stannous chloride 0.32mol in reaction vessel, control mixing speed 130rpm, add 1H-
Indazole -3- formic acid (2) 0.053mol, raises solution temperature to 50 DEG C, and flow back 5h, is slowly added to amine methane (3) 0.061mol, returns
Stream 8h, reduces solution temperature to 5 DEG C, stands 30h, separate out solid, filter, and it is 15% bromine that solid is dissolved in 150ml mass fraction
Change potassium solution, add mass fraction to be that 30% oxalic acid solution adjusts pH value of solution for 3 after filtration, separate out solid, sucking filtration, sodium sulfate is molten
Liquid washs, and nitromethane washs, and anhydrous magnesium sulfate is dehydrated, and is recrystallization in 90% ethyl acetate in mass fraction, obtains crystal 1-
Methylindole -3- carboxylic acid 8.02g, yield 86%.
Example 2：
Add propionitrile 130ml, stannous chloride 0.32mol in reaction vessel, control mixing speed 150rpm, add 1H-
Indazole -3- formic acid (2) 0.053mol, raises solution temperature to 53 DEG C, and flow back 5h, is slowly added to amine methane (3) 0.062mol, returns
Stream 8h, reduces solution temperature to 5 DEG C, stands 31h, separate out solid, filter, and it is 17% bromine that solid is dissolved in 150ml mass fraction
Change potassium solution, add mass fraction to be that 32% oxalic acid solution adjusts pH value of solution for 3 after filtration, separate out solid, sucking filtration, potassium nitrate is molten
Liquid washs, and mass fraction is 82% nitromethane washing, and phosphorus pentoxide is dehydrated, and is weight in 92% ethyl acetate in mass fraction
Crystallization, obtains crystal 1- methylindole -3- carboxylic acid 8.30g, yield 89%.
Example 3：
Add propionitrile 130ml, stannous chloride 0.32mol in reaction vessel, control mixing speed 170rpm, add 1H-
Indazole -3- formic acid (2) 0.053mol, raises solution temperature to 55 DEG C, and flow back 6h, is slowly added to amine methane (3) 0.063mol, returns
Stream 9h, reduces solution temperature to 9 DEG C, stands 32h, separate out solid, filter, and it is 20% bromine that solid is dissolved in 150ml mass fraction
Change potassium solution, add mass fraction to be that 35% oxalic acid solution adjusts pH value of solution for 4 after filtration, separate out solid, sucking filtration, sodium sulfate is molten
Liquid washs, and mass fraction is 85% nitromethane washing, and anhydrous magnesium sulfate is dehydrated, and is weight in 95% ethyl acetate in mass fraction
Crystallization, obtains crystal 1- methylindole -3- carboxylic acid 8.68g, yield 93%.
Claims (4)
1. a kind of synthetic method of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid is it is characterised in that include following walking
Suddenly：
I () adds propionitrile 130ml, stannous chloride 0.32mol in reaction vessel, control mixing speed 130 170rpm, adds
1H- indazole -3- formic acid (2) 0.053mol, raises solution temperature to 50--55 DEG C, and flow back 5 6h, is slowly added to amine methane (3)
0.061 0.063mol, flow back 8 9h, reduces solution temperature to 5--9 DEG C, stands 30 32h, separate out solid, filters, will consolidate
Body is dissolved in 150ml potassium bromide solution, and adding oxalic acid solution to adjust pH value of solution after filtration is 34, separates out solid, sucking filtration, saline solution
Washing, nitromethane washs, and dehydrant is dehydrated, and recrystallization in ethyl acetate obtains crystal 1- methylindole -3- carboxylic acid (1)；Its
In, the potassium bromide solution mass fraction described in step (i) is 15 20%, and the oxalic acid solution mass fraction described in step (i) is
30 35%, the saline solution described in step (i) is sodium sulfate, any one in potassium nitrate.
2. a kind of synthetic method of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid according to claim 1, it is special
Levy and be, the nitromethane mass fraction described in step (i) is 80 85%.
3. a kind of synthetic method of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid according to claim 1, it is special
Levy and be, the dehydrant described in step (i) is anhydrous magnesium sulfate, any one in phosphorus pentoxide.
4. a kind of synthetic method of granisetron pharmaceutical intermediate 1- methylindole -3- carboxylic acid according to claim 1, it is special
Levy and be, the ethyl acetate mass fraction described in step (i) is 90 95%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2016102275A AU2016102275A4 (en) | 2015-12-24 | 2016-12-24 | Granisetron drug intermediates 1-methyl-indole-3-carboxylic acid synthesis method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015109990459 | 2015-12-24 | ||
| CN201510999045.9A CN105503694A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of granisetron drug intermediate 1-methylindole-3-carboxylic acid |
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| CN106432044A true CN106432044A (en) | 2017-02-22 |
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| CN201510999045.9A Pending CN105503694A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of granisetron drug intermediate 1-methylindole-3-carboxylic acid |
| CN201610824135.9A Pending CN106432044A (en) | 2015-12-24 | 2016-09-14 | Synthesis method of intermediate 1-methylindole-3-carboxylic acid of granisetron drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098882A (en) * | 2017-04-17 | 2017-08-29 | 长园华盛(泰兴)锂电材料有限公司 | A kind of synthetic method of methane-disulfonic acid methylene ester |
-
2015
- 2015-12-24 CN CN201510999045.9A patent/CN105503694A/en active Pending
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2016
- 2016-09-14 CN CN201610824135.9A patent/CN106432044A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098882A (en) * | 2017-04-17 | 2017-08-29 | 长园华盛(泰兴)锂电材料有限公司 | A kind of synthetic method of methane-disulfonic acid methylene ester |
| CN107098882B (en) * | 2017-04-17 | 2019-11-12 | 泰兴华盛精细化工有限公司 | A kind of synthetic method of methane-disulfonic acid methylene ester |
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| CN105503694A (en) | 2016-04-20 |
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Application publication date: 20170222 |