CN116903544A - Preparation method of olanzapine and intermediate thereof - Google Patents
Preparation method of olanzapine and intermediate thereof Download PDFInfo
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- CN116903544A CN116903544A CN202310739063.8A CN202310739063A CN116903544A CN 116903544 A CN116903544 A CN 116903544A CN 202310739063 A CN202310739063 A CN 202310739063A CN 116903544 A CN116903544 A CN 116903544A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
本发明公开了一种奥比塞曲匹及其中间体的制备方法，奥比塞曲匹中间体(即4‑(2‑((3,5‑双三氟甲基苄基)氨基)嘧啶‑5‑氧基)丁酸乙酯)的制备方法包括：采用水相胶束介质作为溶剂，使2‑氯‑5‑羟基嘧啶、4‑溴丁酸乙酯在水相胶束介质中、在碱性物质存在下经烷基化反应，生成4‑(2‑氯嘧啶‑5‑氧基)丁酸乙酯；使4‑(2‑氯嘧啶‑5‑氧基)丁酸乙酯、3,5‑双三氟甲基苄胺在水相胶束介质中、在碱性物质存在下经芳香亲核取代反应，即可生成；其中，水相胶束介质通过将表面活性剂分散在水中形成，本发明方法兼具合成步骤较少、后处理简单、产率高等优点，可以用于奥比塞曲匹的制备。The invention discloses a preparation method of obisetrapib and its intermediate. The obisetrapib intermediate (i.e. 4-(2-((3,5-bistrifluoromethylbenzyl)amino)pyrimidine The preparation method of -5-oxy)ethyl butyrate) includes: using an aqueous micellar medium as a solvent, making 2-chloro-5-hydroxypyrimidine, 4-bromobutyric acid ethyl ester in the aqueous micellar medium, Alkylation reaction in the presence of alkaline substances produces ethyl 4-(2-chloropyrimidine-5-oxy)butyrate; ethyl 4-(2-chloropyrimidine-5-oxy)butyrate, 3,5-Bistrifluoromethylbenzylamine can be generated through an aromatic nucleophilic substitution reaction in an aqueous micellar medium in the presence of an alkaline substance; wherein the aqueous micellar medium disperses surfactants in Formed in water, the method of the present invention has the advantages of fewer synthesis steps, simple post-processing, and high yield, and can be used for the preparation of obisetrapib.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of olanzapine and an intermediate thereof.
Background
Olanexidine (or oxetrapib), INN designation (International Nonpropietary Names for Pharmaceutical Substances, INN) is obicerapib, an oral selective Cholesterol Ester Transfer Protein (CETP) inhibitor under investigation by NewAmsterdam company. The company just announced that the first patient administration of the phase 3 clinical study of Obicetrapib was completed in month 1 of 2022, and the targeted patient population was the same as the indication of the current batch clinical in china. Obicetrapib is being developed as a CETP inhibitor for lowering LDL-C (low density lipoprotein cholesterol) and preventing major adverse cardiovascular events. Wherein ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidine-5-oxy) butyrate is an important intermediate for synthesizing Obicetrapib, and has the structural formula:
the current route for the synthesis of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-oxy) butyrate is:
in the route, 3, 5-bis (trifluoromethyl) benzylamine and 2-chloro-5-bromopyrimidine are used as raw materials, and the three steps of aromatic nucleophilic substitution, amino protection, phenolic hydroxylation, etherification and deprotection are carried out; however, the process has the advantages of longer steps, complex post-treatment, high cost, low yield (about 33% of total yield) and more three wastes.
Disclosure of Invention
The invention aims to overcome one or more defects in the prior art and provides a novel method for preparing an olanzapine intermediate (ethyl 4- (2- ((3, 5-bistrifluoromethyl benzyl) amino) pyrimidine-5-oxo) butyrate), which has the advantages of fewer synthesis steps, simple post-treatment, high yield and the like.
The invention also provides a novel intermediate for synthesizing the ethyl 4- (2- ((3, 5-bistrifluoromethyl benzyl) amino) pyrimidine-5-oxyl) butyrate.
The invention also provides a synthesis method of the obipratropium containing the preparation process of the ethyl 4- (2- ((3, 5-bistrifluoromethyl benzyl) amino) pyrimidine-5-oxyl) butyrate.
In order to achieve the above purpose, the invention adopts a technical scheme that:
a process for preparing ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate, the process comprising:
using aqueous phase micelle medium as solvent to make 2-chloro-5-hydroxy pyrimidine (structural formula:) Ethyl 4-bromobutyrate (structural formula:) Alkylation reaction is carried out in aqueous phase micelle medium in the presence of alkaline substances to generate 4- (2-chloropyrimidine-5-oxy) ethyl butyrate +.>The synthetic route is as follows:
ethyl 4- (2-chloropyrimidine-5-oxy) butyrate, 3, 5-bistrifluoromethylbenzylamine (structural formula:) In an aqueous phase micelle medium, carrying out aromatic nucleophilic substitution reaction in the presence of alkaline substances to generate 4- (2- ((3, 5-bistrifluoromethyl benzyl) amino) pyrimidine-5-oxy) ethyl butyrate, wherein the synthetic route is as follows:
wherein the aqueous phase micellar medium is formed by dispersing a surfactant in water.
According to some preferred aspects of the present invention, the aqueous phase micellar medium comprises 0.5 to 5.0 mass% of the surfactant.
Further, in terms of mass percent, the mass percent of the surfactant in the aqueous phase micelle medium is 1.0% -2.5%.
According to a specific aspect of the invention, the mass percentage of the surfactant in the aqueous phase micelle medium is 1.8% -2.2%.
According to some preferred aspects of the present invention, the surfactant is a combination of one or more selected from laureth (also known as Brij-30), polyethylene glycol octylphenyl ether (also known as Triton X-100), cetyltrimethylammonium bromide (also known as CTAB) and sodium dodecyl sulfate (also known as SDS).
In the invention, the molecular structure of the surfactant is composed of two parts, and one end of the molecule is a lipophilic nonpolar group, which is also called a hydrophobic group; the other end of the molecule is a hydrophilic polar or ionic group, also known as a hydrophilic group. As the concentration of the aqueous solution of the surfactant increases, hydrophobic groups of the surfactant molecules aggregate to form nuclei, and hydrophilic groups are splayed outwards to form micelles. The minimum concentration of surfactant to produce micelles is known as the Critical Micelle Concentration (CMC). The surfactant type and solution conditions are different, and the formed micelle forms are different, and may be round, ellipsoidal or rod-shaped micelle.
Further, the surfactant is one or a combination of more selected from laureth (also called Brij-30), polyethylene glycol octyl phenyl ether (also called Triton X-100) and cetyltrimethylammonium bromide (also called CTAB), and has better effect compared with sodium dodecyl sulfate (also called SDS).
According to some preferred aspects of the present invention, the basic substance employed in the alkylation reaction, the aromatic nucleophilic substitution reaction is independently selected from one or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, sodium hydroxide, and potassium hydroxide.
Further, in some preferred embodiments of the present invention, the surfactant is polyethylene glycol octyl phenyl ether, and the alkaline substance is one or a combination of more selected from potassium carbonate, sodium hydroxide, potassium hydroxide; or the surfactant is laurinol polyoxyethylene ether, and the alkaline substance is potassium carbonate and/or sodium carbonate; or, the surfactant is cetyl trimethyl ammonium bromide, and the alkaline substance is triethylamine and/or diisopropylethylamine.
According to some preferred aspects of the invention, the reaction temperature of the alkylation reaction, the reaction temperature of the aromatic nucleophilic substitution reaction are independently 40-80 ℃.
Further, the reaction temperature of the alkylation reaction and the reaction temperature of the aromatic nucleophilic substitution reaction are independently 40-70 ℃.
Further, the reaction temperature of the alkylation reaction and the reaction temperature of the aromatic nucleophilic substitution reaction are independently 45-60 ℃.
According to some preferred and specific aspects of the invention, the reaction temperature of the alkylation reaction, the reaction temperature of the aromatic nucleophilic substitution reaction are independently 45-55 ℃.
According to some preferred aspects of the invention, the alkylation reaction has a reaction time of from 4 to 16 hours.
According to some preferred aspects of the invention, the aromatic nucleophilic substitution reaction has a reaction time of from 8 to 24 hours.
According to some preferred aspects of the present invention, in the alkylation reaction, the feeding molar ratio of the ethyl 4-bromobutyrate, the alkaline substance and the 2-chloro-5-hydroxypyrimidine is 1:1-2:1-1.5, wherein the concentration of the ethyl 4-bromobutyrate in the aqueous phase micellar medium is controlled to be 0.1-0.5mol/L.
According to some preferred aspects of the present invention, in the aromatic nucleophilic substitution reaction, the molar ratio of the basic substance to the 3, 5-bis (trifluoromethyl) benzylamine to the ethyl 4-bromobutyrate is controlled to be 1-2:1-1.5:1 based on the amount of the ethyl 4-bromobutyrate used in the alkylation reaction.
According to some preferred and specific aspects of the invention, the preparation method is a one-pot method, embodiments of which include:
adding ethyl 4-bromobutyrate and an alkaline substance into a water phase micelle medium, heating to a preset reaction temperature, dropwise adding 2-chloro-5-hydroxypyrimidine, reacting, adding 3, 5-bis (trifluoromethyl) benzylamine and a new alkaline substance into a reaction system (without a cooling and post-treatment operation) after the reaction is finished, and reacting to generate ethyl 4- (2- ((3, 5-bis (trifluoromethyl) benzyl) amino) pyrimidine-5-oxy) butyrate.
According to the invention, the post-treatment is simple, and after the reaction is finished, the target product can be obtained by directly adopting organic solvent (such as ethyl acetate) for extraction, drying, concentration and silica gel column chromatography, so that the three wastes are less.
The invention provides another technical scheme that: an intermediate for synthesizing ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidine-5-oxy) butyrate, wherein the intermediate is ethyl 4- (2-chloropyrimidine-5-oxy) butyrate, and the structural formula is as follows:
the invention provides another technical scheme that: a synthesis method of the obipratropium, which comprises the preparation method of the ethyl 4- (2- ((3, 5-bistrifluoromethyl benzyl) amino) pyrimidine-5-oxy) butyrate.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
based on the defect that the prior art has the preparation of 4- (2- ((3, 5-bis (trifluoromethyl) benzyl) amino) pyrimidine-5-oxy) ethyl butyrate, the inventor of the invention conducts intensive research and unexpectedly discovers that an intermediate is generated by alkylation reaction by taking aqueous phase micelle medium as a solvent and taking 2-chloro-5-hydroxy pyrimidine and 4-bromoethyl butyrate as raw materials: the ethyl 4- (2-chloropyrimidine-5-oxy) butyrate and 3, 5-bis (trifluoromethyl) benzylamine can be directly subjected to aromatic nucleophilic substitution reaction to generate corresponding target products, and compared with the existing method, the method has the advantages of short reaction route, simple post-treatment, high yield, mild conditions and the like.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of ethyl 4- (2-chloropyrimidine-5-oxy) butyrate, an intermediate prepared in example 1.
Detailed Description
The above-described aspects are further described below in conjunction with specific embodiments; it should be understood that these embodiments are provided to illustrate the basic principles, main features and advantages of the present invention, and that the present invention is not limited by the scope of the following embodiments; the implementation conditions employed in the examples may be further adjusted according to specific requirements, and the implementation conditions not specified are generally those in routine experiments.
All starting materials are commercially available or prepared by methods conventional in the art, not specifically described in the examples below.
In the following, "wt.%" refers to weight percent concentration.
Polyethylene glycol octyl phenyl ether (also known as Triton X-100), available from Allatin, CAS number: 9002-93-1; laurinol polyoxyethylene ether (also known as Brij-30), available from aladine, CAS No.: 9002-92-0; cetyl trimethylammonium bromide (also known as CTAB), available from Allatin, CAS number: 57-09-0; sodium dodecyl sulfate (also known as SDS), purchased from aladine, CAS number: 151-21-3.
The 2wt.% Triton X-100 aqueous micelle solution in the following examples was prepared by the following method: 2g of Triton X-100 was added to 98mL of distilled water and stirred at room temperature until completely dissolved, thereby obtaining 2wt.% Triton X-100 aqueous micelle solution (2 wt.% means the weight percentage concentration of Triton X-100 in aqueous micelle medium (Triton X-100 and water)). The other aqueous micelle solution preparation methods are the same.
In the following examples, ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate was synthesized as follows:
example 1
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of potassium carbonate (2.07 g) were added to 10mL of 2wt.% Triton X-100 aqueous micelle medium, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethyl benzylamine (2.67 g) and 15mmol of potassium carbonate (2.07 g) were directly added without cooling and post-treatment, and reacted at the same temperature for 16 hours. After the reaction, cooling to room temperature, extracting (ethyl acetate 15mL multiplied by 3), drying, concentrating, and performing silica gel column chromatography to obtain 3.38g of target product ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidine-5-oxyl) butyrate, wherein the purity is 97%, and the yield is 75%.
In this example, the following intermediate procedure is repeated:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of potassium carbonate (2.07 g) are added into 10mL of 2wt.% Triton X-100 aqueous phase micelle medium, stirred at room temperature for 5min, heated to 50 ℃, 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) is added dropwise for continuous reaction for 16h, after the reaction is finished, the obtained intermediate ethyl 4- (2-chloropyrimidine-5-oxy) butyrate reaction solution is concentrated, column chromatography and ethyl acetate-petroleum ether elution are carried out, the yield is 95%, the purity is 97%, and the nuclear magnetic spectrum diagram of the obtained intermediate ethyl 4- (2-chloropyrimidine-5-oxy) butyrate is shown in figure 1.
Example 2
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of NaOH (0.6 g) were added to 10mL of 2wt.% Triton X-100 aqueous micelle medium, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for a further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethyl benzylamine (2.67 g) and 15mmol of NaOH (0.6 g) were directly added without cooling and working up, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 3.43g of the target product with a purity of 95% and a yield of 76%.
Example 3
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of triethylamine (2.08 mL) were added to 10mL of 2wt.% Triton X-100 aqueous micelle medium, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethylbenzylamine (2.67 g) and 15mmol of triethylamine (2.08 mL) were directly added thereto without cooling and working up, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 2.80g of the target product with a purity of 97% and a yield of 62%.
Example 4
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of triethylamine (2.08 mL) were added to 10mL of 2wt.% SDS aqueous micelle medium, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethylbenzylamine (2.67 g) and 15mmol of triethylamine (2.08 mL) were directly added thereto without cooling and working up, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 2.16g of the target product with a purity of 97% and a yield of 48%.
Example 5
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of potassium carbonate (2.07 g) were added to 10mL of 2wt.% Brij-30 aqueous micelle medium, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethyl benzylamine (2.67 g) and 15mmol of potassium carbonate (2.07 g) were directly added without cooling and post-treatment, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 3.24g of the target product with a purity of 97% and a yield of 72%.
Example 6
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of potassium carbonate (2.07 g) were added to 10mL of 2wt.% Triton X-100 aqueous micelle medium, stirred at room temperature for 5min, warmed to 40℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethyl benzylamine (2.67 g) and 15mmol of potassium carbonate (2.07 g) were directly added without cooling and post-treatment, and reacted at the same temperature for 16 hours. After the reaction, cooling to room temperature, extracting (ethyl acetate 15mL multiplied by 3), drying, concentrating, and performing silica gel column chromatography to obtain 2.97g of target product ethyl 4- (2- ((3, 5-bistrifluoromethyl benzyl) amino) pyrimidine-5-oxyl) butyrate, wherein the purity is 95%, and the yield is 66%.
Example 7
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of potassium carbonate (2.07 g) were added to 10mL of 2wt.% Triton X-100 aqueous micelle medium, stirred at room temperature for 5min, warmed to 60℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethyl benzylamine (2.67 g) and 15mmol of potassium carbonate (2.07 g) were directly added without cooling and post-treatment, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture is cooled to room temperature, extracted (ethyl acetate 15mL multiplied by 3), dried, concentrated and subjected to silica gel column chromatography to obtain 3.33g of target product ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidine-5-oxyl) butyrate, wherein the purity is 96 percent and the yield is 74 percent.
Example 8
This example provides a process for the preparation of ethyl 4- (2- ((3, 5-bistrifluoromethylbenzyl) amino) pyrimidin-5-yloxy) butyrate comprising:
10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of triethylamine (2.08 mL) were added to 10mL of 2wt.% CTAB aqueous micelle medium, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethylbenzylamine (2.67 g) and 15mmol of triethylamine (2.08 mL) were directly added thereto without cooling and working up, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 3.52g of the target product with a purity of 97% and a yield of 78%.
Comparative example 1
Substantially the same as in example 8, the only difference is that: water was directly employed as solvent to replace 2wt.% CTAB aqueous micellar medium.
The method comprises the following specific steps: 10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of triethylamine (2.08 mL) were added to 10mL of water, and the mixture was stirred at room temperature for 5min, heated to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise thereto for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethylbenzylamine (2.67 g) and 15mmol of triethylamine (2.08 mL) were directly added thereto without cooling and working up, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 1.04g of the target product with a purity of 97% and a yield of 23%.
Comparative example 2
Substantially the same as in example 8, the only difference is that: water was directly used as solvent to replace 2wt.% of the CTAB aqueous micellar medium, and triethylamine was replaced with an equivalent molar amount of potassium carbonate.
The method comprises the following specific steps: 10mmol of ethyl 4-bromobutyrate (1.94 g) and 15mmol of potassium carbonate (2.07 g) were added to 10mL of water, stirred at room temperature for 5min, warmed to 50℃and 11mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) were added dropwise for further reaction for 16h. After the completion of the reaction, 11mmol of 3, 5-bistrifluoromethyl benzylamine (2.67 g) and 15mmol of potassium carbonate (2.07 g) were directly added without cooling and post-treatment, and reacted at the same temperature for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, extracted (ethyl acetate 15 mL. Times.3), dried, concentrated and subjected to silica gel column chromatography to obtain 1.71g of the target product with a purity of 93% and a yield of 38%.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
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| CN103172562A (en) * | 2006-01-31 | 2013-06-26 | 田边三菱制药株式会社 | Trisubstituted amine compounds as inhibitors of cholesteryl ester transfer protein CETP |
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