CN111205247B - Preparation method of levocetirizine - Google Patents
Preparation method of levocetirizine Download PDFInfo
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- CN111205247B CN111205247B CN202010320680.0A CN202010320680A CN111205247B CN 111205247 B CN111205247 B CN 111205247B CN 202010320680 A CN202010320680 A CN 202010320680A CN 111205247 B CN111205247 B CN 111205247B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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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
Abstract
The invention provides a preparation method of levocetirizine, which comprises the following steps: reacting the compound shown in the formula (I) under the action of a reduction system and L-tartaric acid to obtain a compound shown in a formula (II); the compound shown in the formula (II) reacts with the compound shown in the formula (III) under the action of NaH, N-dimethylformamide and tetrabutylammonium bromide to obtain levocetirizine. The invention takes a compound of a formula (I) and a compound of a formula (III) as raw materials to prepare levocetirizine, firstly, the compound of the formula (I) is descaled and racemized to obtain a compound of a formula (II); the compound of the formula (II) reacts with the compound of the formula (III) to obtain the levocetirizine. The method provided by the invention has a short reaction route, the yield can reach more than 54%, and the purity can reach 99.65% to the maximum.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of levocetirizine.
Background
Levocetirizine hydrochloride, also known as levocetirizine hydrochloride, has the chemical name: (-) - [2- [4- (R) -4-chlorophenyl-benzyl-1-piperazinyl ] ethoxy ] acetic acid dihydrochloride; CAS registry number 130018-87-0; the common English name is levocetirizine dihydrochloride. The structural formula is as follows:
levocetirizine hydrochloride is the third generation H developed by the company UCB Belgium1The receptor antagonist is firstly marketed in Germany in 2 months in 2001, has a trade name of XYzal, and levocetirizine hydrochloride is an R-type optical isomer of cetirizine hydrochloride, overcomes central nervous system side effects of somnolence, sedation and the like caused by an S-type optical isomer in the racemic cetirizine hydrochloride clinically, is used for treating allergic diseases of respiratory systems, eyes and skins, is wide in applicable population, can be used for pregnant women and children, and is popular in clinical application.
The prior art discloses a plurality of synthesis methods of levocetirizine, for example, a method for resolving racemic 4-chloro-benzhydrylpiperazine by a chemical resolution method is reported by Cossement et al (Process for preparation of a1-Piperazine-Ethoxyacetic acid. GB2225321,1990-05-30). The mixed 4-chloro-diphenylmethyl piperazine is resolved by L- (+) tartaric acid to obtain the levo-4-chloro-diphenylmethyl piperazine, the resolution yield is only 12.7%, then the levo-4-chloro-diphenylmethyl piperazine and 2-chloroethoxy acetonitrile are subjected to alkylation reaction, and then the levo-cetirizine dihydrochloride serving as a target compound is obtained through hydrolysis, salt formation and the like. Based on levo-4-chloro-benzhydryl piperazine as a starting material, the total yield is 57.3%, and the optical purity is 95%. But the synthetic route is long. The synthetic route is as follows:
disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing levocetirizine, which has a short preparation route and high yield and purity.
The invention provides a preparation method of levocetirizine, which comprises the following steps:
step 1, reacting a compound shown in a formula (I) under the action of a reduction system and L-tartaric acid to obtain a compound shown in a formula (II);
and 2, reacting the compound shown in the formula (II) with the compound shown in the formula (III) under the action of NaH, N' N-Dimethylformamide (DMF) and tetrabutylammonium bromide to obtain the levocetirizine.
The invention takes a compound of a formula (I) and a compound of a formula (III) as raw materials to prepare levocetirizine, firstly, the compound of the formula (I) is descaled and racemized to obtain a compound of a formula (II); the compound of the formula (II) reacts with the compound of the formula (III) to obtain the levocetirizine. The method provided by the invention has a short reaction route, the yield can reach more than 54%, and the purity can reach 99.65% to the maximum.
In the present invention, the compound represented by the formula (I) is prepared according to the following method:
reacting a compound shown in a formula (IV), p-chlorobenzaldehyde and bromobenzene under the action of a catalyst to obtain a compound shown in a formula (I);
Wherein the compound of formula (IV) is prepared according to the following method:
piperazine and p-toluenesulfonyl chloride were reacted in triethylamine and Dichloromethane (DCM) to give the compound of formula (IV).
Specifically, piperazine, p-toluenesulfonyl chloride, triethylamine and dichloromethane are mixed and reacted to obtain the compound of formula (IV). Wherein the reaction temperature is 20-25 ℃ and the reaction time is 2-4 h. The mass ratio of the piperazine to the p-toluenesulfonyl chloride to the triethylamine to the dichloromethane is (40-60: 120-160): 60-100: 350-450.
After the compound of the formula (IV) is obtained, the compound is mixed with p-chlorobenzaldehyde, bromobenzene and a catalyst for reaction to obtain the compound of the formula (I). Specifically, the reaction temperature is 70-75 ℃, and the reaction time is 4-6 h. The reaction is carried out in acetonitrile. The catalyst is selected from cobalt bromide, zinc bromide or zinc powder. The mass ratio of the compound of the formula (IV), p-chlorobenzaldehyde, bromobenzene and catalyst is 45-55: 25-35: 30-40: 1-3.
The compound of the formula (I) reacts under the action of a reduction system and L-tartaric acid to obtain the compound of the formula (II).
Specifically, the compound of formula (I) is deprotected in a reducing system, and then racemized by the action of L-tartaric acid.
In one embodiment, the reducing system is selected from hydrogen bromide and acetic acid. And (2) mixing the compound shown in the formula (I), hydrogen bromide and acetic acid for deprotection, wherein the reaction temperature is 10-15 ℃, and the reaction time is 2-4 h.
Adding methanol and L-tartaric acid into the obtained product after deprotection, and racemizing to obtain the compound shown in the formula (II). The reaction temperature is 60-65 ℃, and the reaction time is 1-2 h.
In the present invention, the compound of formula (III) is prepared according to the following method:
the 1, 4-dioxane reacts under the action of potassium monopersulfate complex salt to obtain the compound shown in the formula (III).
Reacting 1, 4-dioxane and potassium monopersulfate composite salt in thionyl chloride to obtain the compound shown in the formula (III). Wherein the reaction temperature is 20-25 ℃ and the reaction time is 3-5 h.
After the compound (III) is obtained, the compound (III) reacts with the compound of the formula (III) under the action of NaH, DMF and tetrabutylammonium bromide to obtain the levocetirizine.
Specifically, the compound of formula (II), the compound of formula (III), tetrabutylammonium bromide and DMF are added into a reaction bottle, and sodium hydride is added under the protection of nitrogen for reaction. Wherein the reaction temperature is 90-95 ℃ and the reaction time is 4-6 h.
The invention takes a compound of a formula (I) and a compound of a formula (III) as raw materials to prepare levocetirizine, firstly, the compound of the formula (I) is descaled and racemized to obtain a compound of a formula (II); the compound of the formula (II) reacts with the compound of the formula (III) to obtain the levocetirizine. The method provided by the invention has a short reaction route, the yield can reach more than 54 percent, the highest yield can reach 86.5 percent, the purity can reach more than 95.5 percent, and the highest purity can reach 99.65 percent.
Drawings
FIG. 1 is a high performance liquid chromatogram of levocetirizine provided by the embodiment of the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reagents used in the following examples are all commercially available.
Example 1
Step 1, adding 60g of 1, 4-dioxane, 89.1g of thionyl chloride and 30g of potassium monopersulfate composite salt into a reaction bottle, wherein the reaction temperature is 25 ℃, the reaction time is 4 hours, the dioxane reaction is completely detected by GC, and the product of the compound shown in the formula (III) is obtained after distillation, the purity is 98.6% by GC detection, and the yield is 96.1%.
Step 2, adding 60g of piperazine, 146.1g of paratoluensulfonyl chloride, 84.6g of triethylamine and 397.5g of dichloromethane into a reaction bottle, wherein the reaction temperature is 25 ℃, the reaction time is 3 hours, detecting the piperazine reaction by TLC, adding water for quenching, washing an organic phase twice by using 60g of water, and concentrating at 45 ℃ until no liquid drops drop exists, so as to obtain the compound of the formula (IV), wherein the purity is 95.4%, and the yield is 91.2%.
And 3, adding 50g of the compound shown in the formula (IV), 30.7g of p-chlorobenzaldehyde, 34.3g of bromobenzene and 300ml of acetonitrile into a reaction bottle, heating to 75 ℃ under the protection of nitrogen, and reacting for 5 hours under the action of 2.5g of cobalt bromide catalyst. TLC detection raw material reaction is complete, filtration is carried out, filtrate is concentrated to small volume, 100ml of methanol is added, concentration is carried out to small volume viscous state, 50ml of methanol is added, stirring is carried out for 0.5h at room temperature, and filtration is carried out, thus obtaining the compound shown in formula (I), the yield is 86.5%, and the purity is 91.5%.
And 4, adding 50g of the compound shown in the formula (I) into 250g of dichloromethane, carrying out nitrogen protection, cooling to 10 ℃, adding 11g of hydrogen bromide and 8.2g of acetic acid, reacting for 3 hours, detecting that the raw materials are completely reacted by TLC, adding 200g of 8% sodium bicarbonate solution, extracting and separating, concentrating an organic phase to a small volume, adding 500ml of methanol and 16.5g of L-tartaric acid, heating to 65 ℃, reacting for 2 hours, cooling and crystallizing, filtering, dissolving a solid by adding water, adjusting the pH to 11 by using alkali, extracting twice by adding 200ml of dichloromethane, combining organic phases, adding 100ml of water for washing, concentrating the organic phase to be dry, adding 150 ml of n-hexane, stirring and crystallizing, filtering and drying to obtain the compound shown in the formula (II), wherein the yield is 82.3% and the purity is 93.6%.
And step 5, adding 20g of the compound formula (II), 10.6g of the compound formula (III), 1.1g of tetrabutylammonium bromide and 80ml of DMF into a reaction bottle, adding 4.1g of sodium hydride under the protection of nitrogen, heating to 95 ℃, reacting for 5h, detecting that the raw materials are completely reacted by TLC, pouring the reaction solution into 600ml of water, stirring for 1h at room temperature, and filtering to obtain levocetirizine, wherein the yield is 86.5% and the purity is 95.5%.
Referring to fig. 1 and table 1, fig. 1 is a high performance liquid chromatogram of levocetirizine provided by the embodiment of the invention, and table 1 is high performance liquid chromatogram data of levocetirizine provided by the embodiment of the invention.
Table 1 high performance liquid chromatography data for levocetirizine provided in the examples of the present invention
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A preparation method of levocetirizine comprises the following steps:
step 1, adding a compound shown in a formula (I) into dichloromethane, cooling to 10 ℃ under the protection of nitrogen, and then adding hydrogen bromide and acetic acid to react for 3 hours; then adding 8% sodium bicarbonate solution, extracting, separating liquid, concentrating an organic phase, adding methanol and L-tartaric acid, heating to 65 ℃ for reacting for 2 hours, cooling, crystallizing, filtering, dissolving a solid in water, adjusting the pH value, extracting twice by using dichloromethane, combining the organic phases, washing, concentrating, adding n-hexane for crystallizing, filtering and drying to obtain a compound shown in a formula (II);
step 2, reacting the compound shown in the formula (II) with a compound shown in a formula (III) under the action of NaH, N-dimethylformamide and tetrabutylammonium bromide to obtain levocetirizine;
2. The process according to claim 1, wherein, in step 1, the compound represented by the formula (I) is prepared by the following method:
reacting a compound shown in a formula (IV), p-chlorobenzaldehyde and bromobenzene under the action of a catalyst to obtain a compound shown in a formula (I);
3. The method according to claim 2, wherein in the preparation of the compound of formula (I), the catalyst is selected from cobalt bromide, zinc bromide or zinc powder; the reaction is carried out in acetonitrile; the reaction temperature is 70-75 ℃, and the reaction time is 4-6 h.
4. The process according to claim 2, wherein the compound of formula (IV) is prepared by the following process:
piperazine and p-toluenesulfonyl chloride are reacted in triethylamine and dichloromethane to give the compound of formula (IV).
5. The preparation method of the compound of the formula (IV) according to claim 4, wherein the reaction temperature is 20-25 ℃ and the reaction time is 2-4 h.
6. The process according to claim 1, wherein the compound of formula (III) is prepared by the following process:
the 1, 4-dioxane reacts under the action of potassium monopersulfate complex salt and thionyl chloride to obtain the compound shown in the formula (III).
7. The preparation method according to claim 6, wherein in the preparation process of the compound shown in the formula (III), the reaction temperature is 20-25 ℃ and the reaction time is 3-5 h.
8. The preparation method according to claim 1, wherein in the step 2, the reaction temperature is 90-95 ℃ and the reaction time is 4-6 h.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2225321A (en) * | 1988-11-23 | 1990-05-30 | Ucb Sa | Process for preparation of a 1-piperazine-ethoxyacetic acid |
| CN101360727A (en) * | 2005-12-08 | 2009-02-04 | 埃吉斯药物股份公开有限公司 | Process for the preparation of a pharmaceutical intermediate |
| WO2009062036A2 (en) * | 2007-11-09 | 2009-05-14 | Dr. Reddy's Laboratories Ltd. | Processes for preparing levocetirizine and pharmaceutically acceptable salts thereof |
| CN101657437A (en) * | 2007-03-12 | 2010-02-24 | 克卡制药新梅斯托股份公司 | The novel method of preparation levocetirizine and intermediate thereof |
| CN102046612A (en) * | 2008-06-02 | 2011-05-04 | 希普拉有限公司 | Processes for the synthesis of levocetirizine and intermediates for use therein |
| CN103351361A (en) * | 2012-10-30 | 2013-10-16 | 华烁科技股份有限公司 | Levocetirizine preparation method and levocetirizine dihydrochloride preparation method |
| CN103373973A (en) * | 2011-10-15 | 2013-10-30 | 湖南九典制药有限公司 | Novel synthetic process for levocetirizine and key intermediates |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9305282D0 (en) * | 1993-03-15 | 1993-05-05 | Ucb Sa | Enantiomers of 1-(4-chlorophenyl)phenylmethyl)-4-(4-methylphenyl)sulphonyl)piperazine |
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- 2020-04-22 CN CN202010320680.0A patent/CN111205247B/en active Active
Patent Citations (7)
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|---|---|---|---|---|
| GB2225321A (en) * | 1988-11-23 | 1990-05-30 | Ucb Sa | Process for preparation of a 1-piperazine-ethoxyacetic acid |
| CN101360727A (en) * | 2005-12-08 | 2009-02-04 | 埃吉斯药物股份公开有限公司 | Process for the preparation of a pharmaceutical intermediate |
| CN101657437A (en) * | 2007-03-12 | 2010-02-24 | 克卡制药新梅斯托股份公司 | The novel method of preparation levocetirizine and intermediate thereof |
| WO2009062036A2 (en) * | 2007-11-09 | 2009-05-14 | Dr. Reddy's Laboratories Ltd. | Processes for preparing levocetirizine and pharmaceutically acceptable salts thereof |
| CN102046612A (en) * | 2008-06-02 | 2011-05-04 | 希普拉有限公司 | Processes for the synthesis of levocetirizine and intermediates for use therein |
| CN103373973A (en) * | 2011-10-15 | 2013-10-30 | 湖南九典制药有限公司 | Novel synthetic process for levocetirizine and key intermediates |
| CN103351361A (en) * | 2012-10-30 | 2013-10-16 | 华烁科技股份有限公司 | Levocetirizine preparation method and levocetirizine dihydrochloride preparation method |
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