CN111039784A - Preparation method of bilastine intermediate - Google Patents
Preparation method of bilastine intermediate Download PDFInfo
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- CN111039784A CN111039784A CN201911305573.4A CN201911305573A CN111039784A CN 111039784 A CN111039784 A CN 111039784A CN 201911305573 A CN201911305573 A CN 201911305573A CN 111039784 A CN111039784 A CN 111039784A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
Abstract
A preparation method of a bilastine intermediate relates to the technical field of organic matter synthesis, and the bilastine intermediate is a compound 2
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, and particularly relates to a preparation method of a bilastine intermediate.
Background
Bilastine is chemically known as 2- [4- [2- [4- [ l- (2-ethoxyethyl) -lH-benzimidazol-2-yl ] piperidin-1-yl ] ethyl ] phenyl ] -2-methylpropionic acid and has the structural formula:
is an antihistamine of new chemical structure developed by spanish FAES pharmaceutical companies. The composition has no sedative effect, no cardiotoxicity, no interaction with cytochrome P450 enzyme substrate, and strong antihistamine, and meets the standard requirements of current therapeutic medicine for treating allergic diseases formulated by European anaphylaxis and clinical immunology society and the influence standard of allergic rhinitis on asthma. Bilastine has now been approved in the european union for the treatment of antiallergic, urticaria and allergic rhinitis in adults and adolescents >12 years of age.
Bilastine is a new second generation antihistamine with a chemical structure different from existing antihistamines, with better pharmacological profile than other second generation H1 antihistamines. The efficacy of 20mg/d bilastine in improving allergic symptoms and quality of life of patients is at least equivalent to 5mg/d levocetirizine, while the effect on the central nervous system appears to be less than that of cetirizine . Compared with certain second-generation antihistamines, the bilastine hardly penetrates through a blood brain barrier, has no obvious influence on the QT/QTc interval of the heart even if the bilastine is 10 times of clinical treatment dosage, has quick response and 24h sustainable action, avoids adverse reactions of the central nervous system and the cardiovascular system, and has good pharmacokinetic properties (namely quick absorption, high bioavailability, long half-life in vivo, no metabolism by the liver and main excretion with feces).
The literature indicates that bilastine is composed of two segments of 2- (4-piperidyl) benzimidazole and 2-methyl-2-phenylpropionic acid derivative. As shown for compounds 1 and 2:
As reported in PCT patent application WO2014188453, the preparation of compound 2 is divided into two steps: firstly, carrying out substitution reaction of a compound 3 and chloroacetyl chloride in aluminum trichloride and dichloromethane, and quenching the reaction with water after the reaction is finished to remove excessive aluminum trichloride; in the second step, the compound 4 is subjected to carbonyl reduction reaction under the conditions of titanium tetrachloride and triethylsilane to prepare a compound 2.
These two reactions have the following drawbacks: 1. in the first step, water is used for quenching reaction, a large amount of heat is released, so that the risk of an experiment is increased, and aluminum trichloride is quenched by water to generate a large amount of aluminum hydroxide, so that great inconvenience is brought to aftertreatment. The second step uses titanium tetrachloride and triethylsilane, because titanium tetrachloride has strong hygroscopicity, the reaction system needs to be kept dry, and if the product compound 4 in the first step needs to be dried, the reaction vessel needs to be dried, otherwise the activity of titanium tetrachloride is affected, the dosage of the catalyst is increased, and the reaction efficiency is affected.
So to say, the method reported in the prior art has severe reaction heat release and has great potential safety hazard; and the method requires harsh anhydrous operation, and is not suitable for industrial production.
Disclosure of Invention
In view of the drawbacks of the prior art, the object of the present invention is to develop a novel process for the preparation of compound 2 which overcomes at least the drawbacks of one aspect of the prior art.
The inventors found in the course of experiments a two-step reaction for the preparation of compound 2: the substitution reaction of the compound 3 and chloroacetyl chloride and the carbonyl reduction reaction of the compound 4 can be carried out by a one-pot method, after the reaction of the first step is finished, 1,3, 3-Tetramethyldisiloxane (TMDS) is directly added, and after the reaction of the second step is finished, the reaction is quenched, so that the exothermic quenching reaction is not obvious, and the experimental safety is improved; the reaction in the second step adopts 1,1,3, 3-tetramethyldisiloxane, does not need strict anhydrous condition, and has simple and convenient operation and mild reaction condition.
In order to realize the purpose of the invention, the invention is realized by the following technical scheme:
a novel process for the preparation of compound 2,
it includes: the compound 3, halogenated acetyl halide and aluminum trihalide are subjected to substitution reaction in an organic solvent, TMDS is directly added into reaction liquid after the reaction is finished to carry out reduction reaction, and the reaction liquid is dropped into water after the reaction is finished to quench the reaction.
In some embodiments, the temperature control procedure for the substitution reaction of compound 3 with chloroacetyl chloride is: at the temperature of between 10 ℃ below zero and 0 ℃ below zero, the chloracetyl chloride is dripped into the compound 3, and after the chloracetyl chloride is added, the reaction system is heated to between 15 and 25 ℃ for substitution reaction.
In some embodiments, the reduction reaction is carried out at-10 ℃ to-0 ℃, preferably-5 ℃.
In some embodiments, the organic solvent is a halogenated hydrocarbon such as dichloromethane, trichloromethane, or carbon tetrachloride, among others
The amount of haloacetyl halide used in the process may be in an equivalent or excess amount, in some embodiments 1 to 3 equivalents, relative to the compound of formula (3). And in some embodiments from 1 to 2 equivalents. The amount of aluminum trihalide used in the process may be in an equivalent or excess, in some embodiments 1 to 5 equivalents, relative to the compound of formula (3). And in some embodiments from 1 to 3 equivalents. The amount of TMDS used in the process may be equivalent to or in excess of the compound represented by formula (3).
In some embodiments, the haloacetyl halide can be chloroacetyl chloride, bromoacetyl chloride, or bromoacetyl bromide, and the like. The aluminum trihalide may be aluminum trichloride or aluminum tribromide.
The invention has the beneficial effects that:
two-step reaction to prepare compound 2: the substitution reaction of a compound 3 and chloroacetyl chloride, the carbonyl reduction reaction of a compound 4, the two-step reaction is processed by adopting a one-pot method, 1,3, 3-Tetramethyldisiloxane (TMDS) is directly added after the reaction of the first step is finished, and the reaction is quenched after the reaction of the second step is finished, so that the exothermic quenching reaction is not obvious, and the experimental safety is improved; the compound 4 does not need to be separated in the reaction process, so that the treatment process is simplified; the reaction in the second step adopts 1,1,3, 3-tetramethyldisiloxane, does not need strict anhydrous condition, and has simple and convenient operation and mild reaction condition; in addition, the post-treatment of the preparation method adopts the way that the reaction liquid is dripped into water to quench the reaction, so that the extraction times are reduced, the operation is simplified, and the purity of the product after one post-treatment can reach more than 95%, preferably more than 97%.
In the context of the present invention, the completion of the reaction can be carried out by the usual methods for monitoring chemical reactions, for example by thin layer chromatography TLC or high performance liquid chromatography, gas chromatography, etc. As will be appreciated by those skilled in the art, if the reaction is monitored by thin layer chromatography TLC, the reaction is considered complete when little or no color is developed in the reaction; when the HPLC purity of the reactant is less than 2%, 1.5%, or 1.0%, or 0.5%, as determined by HPLC, the reaction is considered complete.
The reagents used in the context of the present invention may all be purchased from commercial sources such as from the Kodak chemical industry.
In the context of the present invention, TMDS stands for 1,1,3, 3-tetramethyldisiloxane.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
EXAMPLE 1A novel Process for the preparation of Compound 2
1. 1000mL of dichloromethane, 230.00g of anhydrous aluminum trichloride and 1.73mol of anhydrous aluminum trichloride are added into the flask in sequence;
2. 100.00g, 0.56mol of Compound 3 (dissolved with a small amount of methylene chloride) was slowly added dropwise to the flask at-5 ℃; then slowly dripping 76.00g and 0.67mol of chloroacetyl chloride, heating to 20 ℃ after the dripping is finished, reacting, monitoring the reaction by TCL, and finishing the reaction for 3 hours;
3. cooling the reaction liquid to-5 ℃, slowly adding 75.50g, 0.56mol of 1,1,3, 3-tetramethyldisiloxane dropwise, monitoring the reaction by TCL, and finishing the reaction for 1 h;
4. cooling to-5 deg.c, and slowly dropping the reaction liquid into water for quenching; separating, washing the organic phase once by using a saturated NaCl solution, drying, and distilling under reduced pressure to remove the solvent to obtain a crude product; the crude product is distilled under reduced pressure again to obtain 108.50g of a refined product of the compound 2, the purity is 97 percent by GC detection, and the total yield of the two steps is 85.2 percent.
Nuclear magnetic hydrogen spectrum of compound 4:1H NMR(400MHz,CDCl3δppm):δ7.92-7.97(m,2H,Ph-H),7.45-7.47(m,2H,Ph-H),4.71(s,2H,CH2Cl),3.67(s,3H,OCH3),1.61(s,6H,CH3).
compound 2 nuclear magnetic hydrogen spectrum:1H NMR(400MHz,CDCl3δppm):δ7.12-7.29(m,4H,Ph-H),3.73(m,2H,CH2Cl),3.68(s,3H,OCH3),3.08(m,2H，Ph-CH2)，1.61(s,6H,CH3).
EXAMPLE 2A novel Process for the preparation of Compound 2
1. 1000mL of dichloromethane, 230.00g and 1.73mol of anhydrous aluminum tribromide are sequentially added into the flask;
2. 100.00g, 0.56mol of Compound 3 (dissolved with a small amount of methylene chloride) was slowly added dropwise to the flask at-5 ℃; then slowly adding 76.00g and 0.67mol of bromoacetyl chloride dropwise, heating to 25 ℃ after the addition is finished, reacting, monitoring the reaction by TCL, and finishing the reaction for 3 hours;
3. cooling the reaction liquid to-5 ℃, slowly adding 75.50g, 0.56mol of 1,1,3, 3-tetramethyl disiloxane dropwise, monitoring the reaction by TCL, and finishing the reaction for 1 h;
4. cooling to-5 deg.c, and slowly dropping the reaction liquid into water for quenching; separating, washing the organic phase once by using a saturated NaCl solution, drying, and distilling under reduced pressure to remove the solvent to obtain a crude product; the crude product was again distilled under reduced pressure to obtain 106.50g of a fine product of Compound 2, which was 96.2% pure by GC.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A novel process for the preparation of compound 2,
it includes: the compound 3, halogenated acetyl halide and aluminum trihalide are subjected to substitution reaction in an organic solvent, TMDS is directly added into reaction liquid after the reaction is finished to carry out reduction reaction, and the reaction liquid is dropped into water after the reaction is finished to quench the reaction.
2. The novel process of claim 1, wherein the temperature control procedure for the substitution reaction of compound 3 with chloroacetyl chloride is: at the temperature of between 10 ℃ below zero and 0 ℃ below zero, the chloracetyl chloride is dripped into the compound 3, and after the chloracetyl chloride is added, the reaction system is heated to between 15 and 25 ℃ for substitution reaction.
3. A novel process according to claim 1, wherein the reduction is carried out at a temperature of from-10 ℃ to-0 ℃.
4. A novel process according to claim 3, wherein the reduction is carried out at-5 ℃.
5. The novel process of claim 1, wherein the organic solvent is methylene chloride, chloroform, or carbon tetrachloride.
6. The novel process according to claim 1, characterized in that the amount of haloacetyl halide is equivalent or in excess with respect to the compound of formula (3).
7. A novel process according to claim 1, characterized in that the amount of aluminum trihalide is from 1 to 3 equivalents with respect to the compound of formula (3).
8. The novel process according to claim 1, wherein the amount of TMDS is equivalent or in excess with respect to the compound of formula (3).
9. A novel process according to any one of claims 1 to 10, characterised in that the haloacetyl halide is chloroacetyl chloride,
Bromoacetyl chloride or bromoacetyl bromide, and the aluminum trihalide is aluminum trichloride or aluminum tribromide.
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| CN201911305573.4A CN111039784A (en) | 2019-12-18 | 2019-12-18 | Preparation method of bilastine intermediate |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675101A (en) * | 2012-05-16 | 2012-09-19 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
| WO2014188453A2 (en) * | 2013-05-24 | 2014-11-27 | Msn Laboratories Private Limited | Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid |
| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN104961715A (en) * | 2015-07-10 | 2015-10-07 | 浙江美诺华药物化学有限公司 | Preparation method for Dapagliflozin |
| CN105611920A (en) * | 2013-10-12 | 2016-05-25 | 泰拉科斯萨普有限责任公司 | Preparation of hydroxy-benzylbenzene derivatives |
| CN106188190A (en) * | 2016-07-28 | 2016-12-07 | 威海迪素制药有限公司 | A kind of preparation method of the clean monohydrate of Tuo Gelie |
-
2019
- 2019-12-18 CN CN201911305573.4A patent/CN111039784A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675101A (en) * | 2012-05-16 | 2012-09-19 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
| WO2014188453A2 (en) * | 2013-05-24 | 2014-11-27 | Msn Laboratories Private Limited | Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid |
| CN105611920A (en) * | 2013-10-12 | 2016-05-25 | 泰拉科斯萨普有限责任公司 | Preparation of hydroxy-benzylbenzene derivatives |
| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN104961715A (en) * | 2015-07-10 | 2015-10-07 | 浙江美诺华药物化学有限公司 | Preparation method for Dapagliflozin |
| CN106188190A (en) * | 2016-07-28 | 2016-12-07 | 威海迪素制药有限公司 | A kind of preparation method of the clean monohydrate of Tuo Gelie |
Non-Patent Citations (1)
| Title |
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| 赵临襄主编: "《化学制药工艺学》", 31 August 2015, 中国医药科技出版社 * |
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