CN111978254A - Preparation process of altimezole hydrochloride - Google Patents
Preparation process of altimezole hydrochloride Download PDFInfo
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- CN111978254A CN111978254A CN201910429684.XA CN201910429684A CN111978254A CN 111978254 A CN111978254 A CN 111978254A CN 201910429684 A CN201910429684 A CN 201910429684A CN 111978254 A CN111978254 A CN 111978254A
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- altemezole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
Abstract
The invention relates to the technical field of compound preparation, in particular to a preparation process of altimezole hydrochloride, which comprises the following operation steps: 1) 4- (2-ethyl-2-indanone) imidazole and alkali react in an organic solvent; 2) adding hydrazine hydrate into the reaction liquid of the reaction 1) to obtain the altemezole; 3) adding the atipamezole obtained in the reaction 2) into concentrated hydrochloric acid to form salt, and obtaining the atipamezole hydrochloride. The problems of low yield, high cost, pollution and the like in the industrial synthesis of the altemezole hydrochloride in the prior art are solved, a brand-new preparation process for the altemezole is provided, the reaction efficiency is effectively improved, the altemezole is synthesized with high selectivity, the byproducts are reduced, the discharge of waste water and waste gas is effectively reduced, and the industrial production is facilitated.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation process of altimezole hydrochloride.
Background
Altemezole hydrochloride, CAS number: 104075-48-1, the molecular formula is C14H16N.HCl.
The altemezole hydrochloride is a main scientific research reagent and is widely applied to molecular biology, pharmacological research and the like. Altimezole is a selective α 2-adrenoceptor blocker (antagonist/blocker). The altemezole hydrochloride can selectively and competitively inhibit alpha 2-adrenergic receptors, and the altemezole can effectively eliminate the sedation and analgesia effect caused by alpha 2-adrenergic receptor agonist levomedetomidine injection or medetomidine injection and can reverse the change of cardiopulmonary function caused by dextromedetomidine or medetomidine in dogs and cats. At present, the domestic altimezole hydrochloride is produced less and is in a technological blank period.
At present, the main problems of the preparation process of the altemezole hydrochloride are as follows: 1. in the synthesis process in the prior art, 4- (2-ethyl-2-indanone) imidazole used as a raw material is reduced to obtain altemezole, and then hydrochloric acid is used for synthesizing altemezole hydrochloride, wherein the total yield is about 70 percent; 2. has poor salifying effect and is not beneficial to industrial production
Therefore, a preparation process of the altemezole hydrochloride is urgently needed to effectively solve the problems.
Disclosure of Invention
The invention aims to solve the technical problems that 1, 4- (2-ethyl-2-indanone) imidazole adopted in the synthesis process in the prior art is used as a raw material and is reduced to obtain altemazole, then hydrochloric acid is used for synthesizing altemazole hydrochloride, the total yield is about 75-80%, diethylene glycol is used as a reaction solvent in the prior art, and the reaction temperature is required to reach more than 180 ℃ when the diethylene glycol is used as the solvent, so that a good reaction effect can be achieved, the reaction temperature is high, the operation is unchanged, and the synthesis process is not suitable for industrial production; 2. has poor salifying effect and is not beneficial to industrial production.
In order to solve the above problems, the present invention discloses:
a preparation process of the altimezole hydrochloride comprises the following operation steps:
1) 4- (2-ethyl-2-indanone) imidazole and alkali react in an organic solvent;
2) adding hydrazine hydrate into the reaction liquid of the reaction 1) to obtain the altemezole;
3) adding the altemezole obtained in the reaction 2) into concentrated hydrochloric acid to form salt, so as to obtain the altemezole hydrochloride;
the specific process flow is as follows:
the further technical scheme of the invention is as follows: the organic solvent in the step 1 is: one of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMSO) and diethylene glycol.
The further technical scheme of the invention is as follows: the organic solvent in the step 1 is: diethylene glycol.
The further technical scheme of the invention is as follows: wherein the reaction in the step 1) is carried out under the heating condition, and the reaction temperature is selected from 175 ℃ and 190 ℃.
The further technical scheme of the invention is as follows: the reaction temperature of the step 1 is 180 ℃.
The further technical scheme of the invention is as follows: the alkali in the step 1 is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
The further technical scheme of the invention is as follows: the alkali in the step 1 is sodium hydroxide.
The further technical scheme of the invention is as follows: the step 2 also comprises purification treatment after reaction, and the purification treatment comprises the following steps: and (3) adjusting the pH of the reaction solution to 4-4.5 by using dilute hydrochloric acid under the stirring condition, continuously stirring for 1 hour, filtering, washing a filter cake by using water, and then washing the filter cake by using an organic solvent.
Further, in the step 3, the salt formation process is as follows: and (3) adding the altemezole obtained in the step (2) into concentrated hydrochloric acid, then carrying out reduced pressure concentration, then heating and stirring, transferring the mixture into a rear crystallization tank after stirring, controlling the temperature at 0-5 ℃, and then crystallizing to obtain the altemezole.
Further, the step 3 also comprises a purification treatment after the reaction, and the purification treatment comprises the following steps: dissolving the altemezole hydrochloride in an organic solvent, washing, and spin-drying the organic solvent after washing to obtain the purified altemezole hydrochloride.
Compared with the prior art, the invention has the beneficial effects that:
1. the problems of low yield, high cost, pollution and the like in the industrial synthesis of the altemezole hydrochloride in the prior art are solved, a brand-new preparation process for the altemezole is provided, the reaction efficiency is effectively improved, the altemezole is synthesized with high selectivity, the byproducts are reduced, and the waste water and waste gas emission is effectively reduced.
2. The invention realizes high-efficiency, low-toxicity, green and environment-friendly production.
3. The hydrochloride of the invention has high production speed and high purity, and the stability effect is good in the hydrochloride salt forming process, thereby realizing industrial production.
Detailed Description
The present invention will be further illustrated below with reference to specific embodiments, which are to be understood as merely illustrative and not limitative of the scope of the present invention.
Example 1
A preparation process of the altimezole hydrochloride comprises the following operation steps:
1) 4- (2-ethyl-2-indanone) imidazole and alkali react in an organic solvent;
2) adding hydrazine hydrate into the reaction liquid of the reaction 1) to obtain the altemezole;
3) adding the altemezole obtained in the reaction 2) into concentrated hydrochloric acid to form salt, so as to obtain the altemezole hydrochloride;
the specific process flow is as follows:
in this example, the organic solvents in step 1 are: one of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMSO) and diethylene glycol.
In this example, the organic solvents in step 1 are: diethylene glycol.
In the present embodiment, the reaction in step 1) is carried out under heating conditions, and the reaction temperature is selected from 175 ℃ and 190 ℃.
In this example, the reaction temperature of step 1 was 180 ℃.
In this embodiment, the base in step 1 is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
In this embodiment, the alkali in step 1 is sodium hydroxide.
In this embodiment, after the step 2 reaction, the method further includes a purification process, where the purification process includes: and (3) adjusting the pH of the reaction solution to 4-4.5 by using dilute hydrochloric acid under the stirring condition, continuously stirring for 1 hour, filtering, washing a filter cake by using water, and then washing the filter cake by using an organic solvent.
In this embodiment, in step 3, the salt formation process is as follows: and (3) adding the altemezole obtained in the step (2) into concentrated hydrochloric acid, then carrying out reduced pressure concentration, then heating and stirring, transferring the mixture into a rear crystallization tank after stirring, controlling the temperature at 0-5 ℃, and then crystallizing to obtain the altemezole.
In this embodiment, the step 3 further includes a purification process after the reaction, and the purification process includes the steps of: dissolving the altimezole in an organic solvent, washing, and spin-drying the organic solvent after washing to obtain the purified altimezole.
Example 2
Adding sodium hydroxide (80 g), water (1L) and a diethylene glycol solvent (750mL) into a reaction bottle at room temperature, adding 4- (2-ethyl-2-indanone) imidazole (339 g) under stirring, adding hydrazine hydrate (316 g) under the protection of nitrogen, heating to 175 ℃ for reaction, slowly adding the diethylene glycol solvent (250 mL) into the reaction system after the reaction is carried out for 3 hours, and continuing the reaction for 4 hours after the addition is finished. After the reaction is finished, cooling the reaction liquid to below 25 ℃, adjusting the pH of the reaction liquid to 4 by using dilute hydrochloric acid under the stirring condition, continuing stirring for 1 hour, filtering, washing a filter cake by using water, then washing the filter cake by using ethanol, and drying to obtain the petimezole (212g) with the HPLC purity of 99.8%.
And then adding the altemezole into concentrated hydrochloric acid, concentrating under reduced pressure, heating and stirring, transferring into a rear crystallization tank after stirring, controlling the temperature at 0 ℃, and crystallizing to obtain the altemezole hydrochloride.
Example 3
Adding potassium hydroxide (112 g), water (1L) and N, N-dimethylformamide (750mL) into a reaction bottle at room temperature, adding 4- (2-ethyl-2-indanone) imidazole (339 g) under stirring, adding hydrazine hydrate (316 g) under the protection of nitrogen, heating to 185 ℃ for reaction, slowly adding N, N-dimethylformamide solvent (250 mL) into the reaction system after the reaction is carried out for 3 hours, and continuing the reaction for 4 hours after the addition is finished. After the reaction is finished, cooling the reaction liquid to below 25 ℃, adjusting the pH of the reaction liquid to 4.5 by using dilute hydrochloric acid under the stirring condition, continuing stirring for 1 hour, filtering, washing a filter cake by using water, then washing the filter cake by using ethyl acetate, and drying to obtain the petimezole (212g) with the HPLC purity of 99.8%.
Then adding the altemezole into concentrated hydrochloric acid, decompressing and concentrating, then heating and stirring, transferring into a rear crystallization tank after stirring, controlling the temperature at 5 ℃, and crystallizing to obtain the altemezole hydrochloride.
Example 4
Adding potassium hydroxide (80 g), water (1L) and N, N-dimethylacetamide (750mL) into a reaction bottle at room temperature, adding 4- (2-ethyl-2-indanone) imidazole (339 g) under stirring, adding hydrazine hydrate (316 g) under the protection of nitrogen, heating to 185 ℃ for reaction, slowly adding N, N-dimethylacetamide (250 mL) into the reaction system after 3 hours of reaction, and continuing the reaction for 4 hours after the addition. After the reaction is finished, cooling the reaction liquid to below 25 ℃, adjusting the pH of the reaction liquid to 4.2 by using dilute hydrochloric acid under the stirring condition, continuing stirring for 1 hour, filtering, washing a filter cake by using water, then washing the filter cake by using acetone, and drying to obtain the petimezole (212g) with the HPLC purity of 99.8%.
Then adding the altemezole into concentrated hydrochloric acid, concentrating under reduced pressure, heating and stirring, transferring into a rear crystallizing tank after stirring, controlling the temperature at 2 ℃, crystallizing to obtain the altemezole hydrochloride, dissolving the altemezole hydrochloride in acetone, washing, and spin-drying the acetone to obtain the purified altemezole hydrochloride.
Example 5
Adding potassium hydroxide (80 g), water (1L) and a DMSO solvent (750mL) into a reaction bottle at room temperature, adding 4- (2-ethyl-2-indanone) imidazole (339 g) under stirring, adding hydrazine hydrate (316 g) under the protection of nitrogen, heating to 190 ℃ for reaction, after 3 hours of reaction, slowly adding the DMSO solvent (250 mL) into the reaction system, and after the addition is finished, continuing the reaction for 4 hours. After the reaction is finished, cooling the reaction liquid to below 25 ℃, adjusting the pH of the reaction liquid to 4-4.5 by using dilute hydrochloric acid under the stirring condition, continuing stirring for 1 hour, filtering, washing a filter cake by using water, then washing the filter cake by using ethyl acetate, and drying to obtain the petimezole (212g) with the HPLC purity of 99.8%.
And then adding the altemezole into concentrated hydrochloric acid, concentrating under reduced pressure, heating and stirring, transferring into a rear crystallization tank after stirring, controlling the temperature at 3 ℃, crystallizing to obtain the altemezole hydrochloride, dissolving the altemezole hydrochloride in ethyl acetate, washing, and spin-drying the ethyl acetate to obtain the purified altemezole hydrochloride.
Example 6
Adding potassium hydroxide (80 g), water (1L) and a diethylene glycol solvent (750mL) into a reaction bottle at room temperature, adding 4- (2-ethyl-2-indanone) imidazole (339 g) under stirring, adding hydrazine hydrate (316 g) under the protection of nitrogen, heating to 180 ℃ for reaction, slowly adding the diethylene glycol solvent (250 mL) into the reaction system after the reaction is carried out for 3 hours, and continuing the reaction for 4 hours after the addition is finished. After the reaction is finished, cooling the reaction liquid to below 25 ℃, adjusting the pH of the reaction liquid to 4.5 by using dilute hydrochloric acid under the stirring condition, continuing stirring for 1 hour, filtering, washing a filter cake by using water, then washing the filter cake by using ethanol, and drying to obtain the petimezole (212g) with the HPLC purity of 99.8%.
Adding the altemezole into concentrated hydrochloric acid, concentrating under reduced pressure, heating and stirring, transferring into a rear crystallizing tank after stirring, controlling the temperature at 4 ℃, crystallizing to obtain the altemezole hydrochloride, dissolving the altemezole hydrochloride in ethanol, washing, and spin-drying the ethanol to obtain the purified altemezole hydrochloride.
The technical means disclosed in the invention scheme are not limited to the technical means disclosed in the above embodiments, but also include the technical scheme formed by any combination of the above technical features. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (8)
1. A preparation process of the altimezole hydrochloride is characterized in that:
the method comprises the following operation steps:
1) 4- (2-ethyl-2-indanone) imidazole and alkali react in an organic solvent;
2) adding hydrazine hydrate into the reaction liquid of the reaction 1) to obtain the altemezole;
3) adding the altemezole obtained in the reaction 2) into concentrated hydrochloric acid to form salt, so as to obtain the altemezole hydrochloride;
the specific process flow is as follows:
the process for preparing altemezole hydrochloride according to claim 1, wherein: the organic solvent in the step 1 is: one of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMSO) and diethylene glycol.
The process for preparing altemezole hydrochloride according to claim 2, wherein: the organic solvent in the step 1 is: diethylene glycol.
2. The process for preparing altemezole hydrochloride according to claim 1, wherein: wherein the reaction in the step 1) is carried out under the heating condition, and the reaction temperature is selected from 175 ℃ and 190 ℃.
3. The process for preparing altemezole hydrochloride according to claim 4, wherein: the reaction temperature of the step 1 is 180 ℃.
4. The process for preparing altemezole hydrochloride according to claim 1, wherein: the alkali in the step 1 is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
5. The process for preparing altemezole hydrochloride according to claim 6, wherein: the alkali in the step 1 is sodium hydroxide.
6. The process for preparing altemezole hydrochloride according to claim 2, wherein: the step 2 also comprises purification treatment after reaction, and the purification treatment comprises the following steps: and (3) adjusting the pH of the reaction solution to 4-4.5 by using dilute hydrochloric acid under the stirring condition, continuously stirring for 1 hour, filtering, washing a filter cake by using water, and then washing the filter cake by using an organic solvent.
7. The process for preparing altemezole hydrochloride according to claim 1, wherein: in the step 3, the salt forming process is as follows: and (3) adding the altemezole obtained in the step (2) into concentrated hydrochloric acid, then carrying out reduced pressure concentration, then heating and stirring, transferring the mixture into a rear crystallization tank after stirring, controlling the temperature at 0-5 ℃, and then crystallizing to obtain the altemezole hydrochloride.
8. The process for preparing altemezole hydrochloride according to claim 1, wherein: the step 3 also comprises purification treatment after reaction, and the purification treatment comprises the following steps: dissolving the altemezole hydrochloride in an organic solvent, washing, and spin-drying the organic solvent after washing to obtain the purified altemezole hydrochloride.
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| CN201910429684.XA CN111978254A (en) | 2019-05-22 | 2019-05-22 | Preparation process of altimezole hydrochloride |
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| CN201910429684.XA CN111978254A (en) | 2019-05-22 | 2019-05-22 | Preparation process of altimezole hydrochloride |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4689339A (en) * | 1984-11-23 | 1987-08-25 | Farmos Yhtyma Oy | 4-dihydroinden-2-yl-, 4-tetrahydronaphth-2-yl-, and 4-dihydrobenzofuran-2-ylimidazoles, useful to block α2 -adrenergic receptors |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4689339A (en) * | 1984-11-23 | 1987-08-25 | Farmos Yhtyma Oy | 4-dihydroinden-2-yl-, 4-tetrahydronaphth-2-yl-, and 4-dihydrobenzofuran-2-ylimidazoles, useful to block α2 -adrenergic receptors |
Non-Patent Citations (1)
| Title |
|---|
| 李斌等: "阿替美唑盐酸盐合成工艺的改进", 《精细化工》 * |
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Application publication date: 20201124 |