阅读说明：本技术 一种卡利拉嗪的合成方法 (Synthesis method of cariprazine ) 是由 廖文静 葛建峰 张继承 黄鲁宁 陶安平 顾虹 于 2018-08-29 设计创作，主要内容包括：本发明提供一种卡利拉嗪的合成方法,该方法包括将化合物(I)在合适温度的反应溶剂中,与二甲氨基甲酰氯,在无机碱的水溶液中,进行酰化得到卡利拉嗪(化合物II),反应式如下：<Image he="153" wi="700" file="DDA0001781408760000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>该合成方法克服了现有技术反应时间长,杂质大难纯化等缺陷,提供了一种反应迅速,杂质小易纯化,产物纯度可高达99.0％以上,收率高,适用于商业化大生产的新方法。(The invention provides a synthesis method of cariprazine, which comprises the steps of acylating a compound (I) and dimethylcarbamoyl chloride in a reaction solvent with a proper temperature in an aqueous solution of inorganic base to obtain the cariprazine (compound II), wherein the reaction formula is as follows: the synthesis method overcomes the defects of long reaction time, large impurities, difficult purification and the like in the prior art, and provides a new method which has the advantages of rapid reaction, small impurities, easy purification, high product purity of over 99.0 percent, high yield and suitability for commercial mass production.)

1. A method for synthesizing Carilazine, which comprises acylating compound (I) with dimethylcarbamoyl chloride in aqueous solution of inorganic base in reaction solvent of suitable temperature to obtain Carilazine compound II, wherein the reaction formula is as follows:

2. the synthesis method according to claim 1, wherein the aqueous solution of inorganic base is NaOH, KOH, Na₂CO₃、K₂CO₃、KHCO₃Or NaHCO₃Aqueous solution or any combination thereof.

3. The synthesis method according to claim 2, wherein the aqueous solution of the inorganic base is Na₂CO₃Or K₂CO₃。

4. The synthesis process according to any one of claims 1 to 3, wherein the concentration of the aqueous solution of the inorganic base is 5 to 30%.

5. The synthesis process according to claim 1, characterized in that the solvent is chosen from solvents immiscible with water.

6. The synthesis method according to claim 5, wherein the solvent is selected from dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and the like, or any combination thereof.

7. The synthesis process according to claim 5 or 6, characterized in that the solvent is chosen from dichloromethane or 2-methyltetrahydrofuran.

8. The synthesis method according to claim 1, wherein the reaction temperature is 0-100 ℃.

9. The synthesis method according to claim 8, wherein the reaction temperature is 10-70 ℃.

10. The synthesis method according to claim 8 or 9, wherein the reaction temperature is 15-30 ℃.

Technical Field

The invention relates to the field of pharmaceutical chemicals, in particular to an industrial synthesis method of a drug cariprazine.

Background

Carragazine (Cariprazine), a partial antagonist of the dopamine D3 and D2 receptors developed by the original research company Gedeon Richter (large pharmaceutical factory, Hungary), for the treatment of schizophrenia, bipolar disorder, bipolar depression and major depressive illness.

9 month and 17 days 2015Us FDA approved Cariprazine (Cariprazine, trade name:

) The capsule is used for treating adult patients with schizophrenia and bipolar disorder. On 13.07/2017, the european union committee approved the new antipsychotic drug kalilazine (Cariprazine) for the treatment of adult patients with schizophrenia (schizophrenia).

Carilazine (Compound II) (CAS: 839712-12-8), structural formula as follows:

the existing synthesis route of the cariprazine mainly comprises the following steps:

1) patent WO 2005012266 reports a synthesis method for cariprazine,

in the patent, after the compound I of the method A and triphosgene are stirred at room temperature for 1 hour, dimethylamine hydrochloride is added, then triethylamine is added, and the stirring is continued for 20 hours. The mixture was filtered, the filtrate washed with water, dried and evaporated in vacuo. The product was recrystallized from methanol to afford cariprazine (compound II) in 52% yield. Method B preparation of Carilazine (Compound II) from Compound I by condensation with Dimethylcarbamoyl chloride requires stirring the reaction mixture at room temperature for 48 hours with a 65% yield.

2) Patent CN105330616 discloses a process for preparing compound II from compound I:

the compound I, diisopropylethylamine and dichloromethane are added dropwise at low temperature to obtain a dichloromethane solution of dimethylaminocarbonyl chloride, and the reaction yield is 63.8% at room temperature.

In summary, the synthesis method disclosed in the prior patent literature for preparing the compound II from the compound I requires 36 to 48 hours of reaction, and the disubstituted condensation impurities gradually increase from 0.1% to 0.6% with the time from 18 hours, and the structure of the disubstituted condensation impurities is as follows:

the impurity has poor solubility, is difficult to purify, has low production efficiency and is not suitable for large-scale production. Therefore, there is still a need in the art to develop new synthetic methods that are simple to operate, easy to purify the product, and have high chemical yield.

Disclosure of Invention

The invention aims to provide a synthesis method of cariprazine, which is a new synthesis method with rapid reaction, small impurities and easy purification, and overcomes the defects of long reaction time, large impurities and difficult purification and the like in the prior art.

The invention provides a synthesis method of cariprazine, which comprises the steps of acylating compound (I) and dimethylcarbamoyl chloride in a reaction solvent with a proper temperature in an aqueous solution of inorganic base to obtain the cariprazine (compound II):

the compound I can adopt a compound with reagent grade or industrial grade purity; can also be synthesized using existing or known methods and techniques;

the aqueous solution of the inorganic base is NaOH, KOH or Na₂CO₃、K₂CO₃、KHCO₃Or NaHCO₃One or any combination of the above aqueous solutions, preferably Na₂CO₃Or K₂CO₃The concentration of the aqueous solution of the inorganic base is preferably 5-30%;

the reaction solvent is a solvent which is not mutually soluble with water, preferably one or any combination of solvents such as dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran and the like; further preferably dichloromethane or 2-methyltetrahydrofuran;

the appropriate temperature is 0-100 ℃, and different reaction temperatures are selected to carry out under different reaction conditions within the temperature range on the principle of not damaging other functional groups in reactants and facilitating the reaction, wherein the reaction temperature is preferably 10-70 ℃, and is further preferably 15-30 ℃.

The beneficial technical effects of the invention are as follows: the method provided by the invention has the advantages of short reaction time, simple post-treatment, mild reaction conditions, obvious reduction of double-condensation impurities, high total yield of the product, and suitability for small-scale preparation in a laboratory and large-scale industrial production, and the purity of the product can reach more than 99.0%.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The technical solutions and the technical effects thereof will be further described with reference to the following examples, but the present invention is not limited to the scope of the examples.

Comparative example 1: preparation of cariprazine

Adding 17.8g (50mmol, 1.0eq) of compound I, 300mL of dichloromethane and 10.0g (80mmol, 1.6eq) of diisopropylethylamine into a 1000mL three-necked bottle, dropwise adding 0.64g (60mmol, 1.2eq) of dimethylcarbamoyl chloride, stirring at 20-30 ℃ for 12 hours, detecting that 25% of raw materials remain and 0.23% of double-condensation impurities, continuing stirring for 36 hours, detecting that the raw materials completely react by HPLC (high performance liquid chromatography), sequentially washing the reaction liquid by 100mL of 1% ammonia water and 100mL of saturated saline, drying anhydrous sodium sulfate, concentrating under reduced pressure, crystallizing the residue to obtain 14.1g of white-like solid kalilazine (II), namely 14.1g of powdery solid (with the content of 98%, the purity of 98.9% and the yield of the double-condensation impurities of 0.56%), then crystallizing by using ethyl acetate/n-heptane and a methanol/dichloromethane system for multiple times, reducing the yield of the double-impurities to 0.15%, thus obtaining 4.57g of white-like solid kalilazine (II), the yield thereof was found to be 20.5%.