CN111303170A - Salt forming method of fubitasvir - Google Patents
Salt forming method of fubitasvir Download PDFInfo
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- CN111303170A CN111303170A CN202010172958.4A CN202010172958A CN111303170A CN 111303170 A CN111303170 A CN 111303170A CN 202010172958 A CN202010172958 A CN 202010172958A CN 111303170 A CN111303170 A CN 111303170A
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- forbivir
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for salifying forbitasvir, which comprises the steps of dissolving forbitasvir free alkali in a heated organic solvent, adding organic acid, stirring to generate forbitasvir organic acid salt, wherein the water solubility and stability of the salified product are better than those of the forbitasvir free alkali; the process flow is simple, the operation is easy, and the cost is low.
Description
Technical Field
The invention relates to preparation of a pharmaceutical compound, in particular to a salifying method of fubitavir.
Background
The fubitasvir is a novel HCV NS5A inhibitor, and the main action mechanism of the fubitasvir is to prevent HCV replication by inhibiting NS5A protein so as to achieve the effect of treating chronic hepatitis C. The structural formula of fubitasvir is as follows:
the structural formula of the fubitasvir compound is known, and the fubitasvir compound contains basic groups, so that researches show that the fubitasvir compound is poor in water solubility and not beneficial to absorption by a human body; however, the water solubility of the salified substance of fubitivir is greatly improved, and the technical problem which needs to be solved urgently by technical personnel in the field is to design a salifying method of fubitivir with simple process flow and low cost.
Disclosure of Invention
The invention aims to solve the technical problem of providing a salifying method of fubizivir, which has the advantages of simple process flow and low cost.
In order to solve the technical problems, the salifying method of fubitasvir provided by the invention comprises the following steps:
step a, adding an organic solvent into a reaction container, adding the fubivir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubivir free alkali is completely dissolved to obtain the fubivir free alkali solution;
b, adding the organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubivir free alkali solution, cooling to 0-10 ℃, and crystallizing and separating out a product;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir organic acid salt.
Further, in the step a, the organic solvent is at least one of isopropanol, methanol, ethanol, ethyl acetate, acetone and methyl tert-butyl ether.
Further, the organic acid in the step b is tartaric acid, and the forbizivir salt obtained in the step c is forbizivir tartrate.
Further, the organic acid in the step b is maleic acid, and the forbizivir salt obtained in the step c is forbizivir maleate.
Further, the organic acid in the step b is malic acid, and the forbizivir salt obtained in the step c is forbizivir malate.
Further, the organic acid in the step b is benzene sulfonic acid, and the forbizivir salt obtained in the step c is forbizivir benzene sulfonate.
Further, the organic acid in the step b is salicylic acid, and the forbizivir salt obtained in the step c is forbizivir salicylate.
Further, the organic acid in the step b is benzoic acid, and the forbizivir salt obtained in the step c is forbizivir benzoate.
Further, the organic acid in the step b is succinic acid, and the forbtavir salt obtained in the step c is forbtavir succinate.
Further, the organic acid in the step b is fumaric acid, and the forbizivir salt obtained in the step c is forbizivir fumarate.
The invention has the technical effects that: compared with the prior art, the method for salifying the fubitasvir comprises the steps of dissolving fubitasvir free alkali in a heated organic solvent, adding an organic acid, and stirring to generate the fubitasvir organic acid salt, wherein the water solubility and the stability of the salified product are better than those of the fubitasvir free alkali; the process flow is simple, the operation is easy, and the cost is low.
Detailed Description
To further illustrate the present invention, some specific embodiments are described below, and some implementation methods of the present invention are described in conjunction with specific operation procedures.
Example 1
A salifying method of forbitasvir comprises the following steps:
step a, adding an organic solvent into a reaction container, adding the fubivir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubivir free alkali is completely dissolved to obtain the fubivir free alkali solution;
b, adding the organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubivir free alkali solution, cooling to 0-10 ℃, and crystallizing and separating out a product;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir organic acid salt.
First we tried the salt formation experimental study of various organic acids with forbitasvir free base in isopropanol and the experimental data are shown in table 1.
TABLE 1 selection of different salt forms of forbitasvir in the solvent isopropanol
| Serial number | Acid type | Concentration (mg/ml) | Whether or not to form salt | Water solubility |
| 1 | Maleic acid | 50 | Can form salt | Dissolution |
| 2 | Malic acid | 50 | Can form salt | Dissolution |
| 3 | Tartaric acid | 50 | Can form salt | Dissolution |
| 4 | Benzene sulfonic acid | 50 | Can form salt | Dissolution |
| 5 | Salicylic acid | 50 | Can form salt | Dissolution |
| 6 | Benzoic acid | 50 | Can form salt | Dissolution |
| 7 | Succinic acid | 50 | Can form salt | Dissolution |
| 8 | Fumaric acid | 50 | Can form salt | Dissolution |
The data show that the fubitasvir can be salified with different organic acids, and the water solubility and the stability of the salified product are better than those of free alkali.
Now, we also aim at the research of salifying the fubitasvir free base in different solvents, and we try to salify fubitas in various solvents such as methanol, ethanol, ethyl acetate, acetone, methyl tert-butyl ether and the like, and the salifying result is shown in table 2.
TABLE 2 salt formation results of forbitasvir in different solvents
The data show that the fubitasvir free alkali can form salt with different organic acids, can have good salt forming effect in various solvents, and the water solubility and the stability of the salified product are better than those of the free alkali.
Example 2
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of isopropanol serving as an organic solvent into a reaction container, adding 5.0g of fubis-tasvir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubis-tasvir free alkali is completely dissolved to obtain a fubis-tasvir free alkali solution;
step b, adding 0.93g of maleic acid serving as organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir maleate.
The water solubility and stability of the salt-formed fubivir maleate are better than that of fubivir free alkali.
Example 3
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of methanol into a reaction container as an organic solvent, adding 5.0g of fubis-tasvir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubis-tasvir free alkali is completely dissolved to obtain fubis-tasvir free alkali solution;
step b, adding 1.07g of malic acid serving as organic acid into a reaction vessel, stirring for 1-2 hours to enable the organic acid to fully react with the fubizivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir malate.
The water solubility and stability of the salt-formed fubitivir malate are better than that of fubitivir free alkali.
Example 4
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of ethanol as an organic solvent into a reaction vessel, adding 5.0g of fubis-tasvir free alkali into the reaction vessel, heating to 35-45 ℃, and stirring until the fubis-tasvir free alkali is completely dissolved to obtain fubis-tasvir free alkali solution;
b, adding 1.2g of tartaric acid serving as organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubizivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir tartrate.
The water solubility and stability of the salt-formed fubitivir tartrate are better than that of fubitivir free alkali.
Example 5
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of ethyl acetate into a reaction vessel as an organic solvent, adding 5.0g of fubivir free alkali into the reaction vessel, heating to 35-45 ℃, and stirring until the fubivir free alkali is completely dissolved to obtain the fubivir free alkali solution;
step b, adding 2.52g of benzenesulfonic acid serving as organic acid into a reaction container, stirring for 1-2 hours to ensure that the organic acid and the fubizivir free alkali solution fully react, and cooling to 0-10 ℃ to ensure that a product is crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir benzene sulfonate.
The water solubility and stability of the salt-formed fubivir benzene sulfonate are better than that of fubivir free alkali.
Example 6
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of acetone as an organic solvent into a reaction container, adding 5.0g of fubis-tasvir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubis-tasvir free alkali is completely dissolved to obtain fubis-tasvir free alkali solution;
step b, adding 2.20g of salicylic acid serving as organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubizivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir salicylate.
The water solubility and stability of the salified fubivir salicylate are better than that of fubivir free alkali.
Example 7
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of methyl tert-butyl ether into a reaction container as an organic solvent, adding 5.0g of fubivir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubivir free alkali is completely dissolved to obtain a fubivir free alkali solution;
b, adding 1.95g of benzoic acid serving as organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubizivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir benzoate.
The water solubility and stability of the salified fubivir benzoate are better than that of fubivir free alkali.
Example 8
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of isopropanol serving as an organic solvent into a reaction container, adding 5.0g of fubis-tasvir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubis-tasvir free alkali is completely dissolved to obtain a fubis-tasvir free alkali solution;
b, adding 0.94g of succinic acid serving as organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubizivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbitasvir succinate.
The solubility and stability of the salt-formed fubivir succinate are better than that of fubivir free alkali.
Example 9
A salifying method of forbitasvir comprises the following steps:
step a, adding 50ml of isopropanol serving as an organic solvent into a reaction container, adding 5.0g of fubis-tasvir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubis-tasvir free alkali is completely dissolved to obtain a fubis-tasvir free alkali solution;
step b, adding 0.93g of fumaric acid as an organic acid into a reaction vessel, stirring for 1-2 hours to enable the organic acid to fully react with the fubizivir free alkali solution, and cooling to 0-10 ℃ to enable a product to be crystallized and separated out;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir fumarate.
The water solubility and stability of the salt-formed fubitivir fumarate are better than that of fubitivir free alkali.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (10)
1. A salifying method of fubitasvir is characterized by comprising the following steps:
step a, adding an organic solvent into a reaction container, adding the fubivir free alkali into the reaction container, heating to 35-45 ℃, and stirring until the fubivir free alkali is completely dissolved to obtain the fubivir free alkali solution;
b, adding the organic acid into a reaction container, stirring for 1-2 hours to enable the organic acid to fully react with the fubivir free alkali solution, cooling to 0-10 ℃, and crystallizing and separating out a product;
and c, filtering the product obtained in the step b, and drying to obtain the forbizivir organic acid salt.
2. A process for salifying forbitasvir as claimed in claim 1, wherein in step a, the organic solvent is at least one of isopropanol, methanol, ethanol, ethyl acetate, acetone and methyl tert-butyl ether.
3. The process for salifying forbivir according to claim 2, wherein the organic acid in the step b is tartaric acid, and the forbivir salt obtained in the step c is forbivir tartrate.
4. The process for salifying forbivir according to claim 2, wherein the organic acid in step b is maleic acid, and the salt of forbivir obtained in step c is forbivir maleate.
5. The process for salifying forbivir according to claim 2, wherein the organic acid in the step b is malic acid, and the forbivir salt obtained in the step c is forbivir malate.
6. The process for salifying forbivir according to claim 2, wherein the organic acid in the step b is benzenesulfonic acid, and the forbivir salt obtained in the step c is forbivir benzene sulfonate.
7. The process for salifying forbivir according to claim 2, wherein the organic acid in step b is salicylic acid and the salt of forbivir obtained in step c is forbivir salicylate.
8. The process for salifying forbivir according to claim 2, wherein the organic acid in step b is benzoic acid, and the salt of forbivir obtained in step c is forbivir benzoate.
9. The process for salifying forbivir according to claim 2, wherein the organic acid in the step b is succinic acid, and the forbivir salt obtained in the step c is forbivir succinate.
10. The process for salifying forbivir according to claim 2, wherein the organic acid in step b is fumaric acid, and the salt of forbivir obtained in step c is forbivir fumarate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019113493391 | 2019-12-24 | ||
| CN201911349339 | 2019-12-24 |
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| CN111303170A true CN111303170A (en) | 2020-06-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112461971A (en) * | 2020-11-20 | 2021-03-09 | 常州寅盛药业有限公司 | Fubitasvir and detection method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045667A (en) * | 2013-03-14 | 2014-09-17 | 上海卫思化学科技有限公司 | Preparation method of tenofovir disoproxil fumarate hemifumarate |
| CN104860931A (en) * | 2014-02-21 | 2015-08-26 | 常州寅盛药业有限公司 | Hepatitis C virus inhibitors and pharmaceutical uses thereof |
| CN109846878A (en) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | HCV-Ab IgG combination medicine |
-
2020
- 2020-03-13 CN CN202010172958.4A patent/CN111303170A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045667A (en) * | 2013-03-14 | 2014-09-17 | 上海卫思化学科技有限公司 | Preparation method of tenofovir disoproxil fumarate hemifumarate |
| CN104860931A (en) * | 2014-02-21 | 2015-08-26 | 常州寅盛药业有限公司 | Hepatitis C virus inhibitors and pharmaceutical uses thereof |
| CN109846878A (en) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | HCV-Ab IgG combination medicine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112461971A (en) * | 2020-11-20 | 2021-03-09 | 常州寅盛药业有限公司 | Fubitasvir and detection method thereof |
| CN112461971B (en) * | 2020-11-20 | 2022-10-04 | 常州寅盛药业有限公司 | Forbitasvir and detection method thereof |
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