阅读说明：本技术 一种棕榈酸帕里哌酮中间体的制备方法 (Preparation method of paliperidone palmitate intermediate ) 是由 闫雪峰 张海明 张小兵 于 2019-02-01 设计创作，主要内容包括：本发明涉及一种棕榈酸帕里哌酮中间体的制备方法。本发明涉及一种如式二所示结构的棕榈酸帕利哌酮中间体合成方法,该方法能够极大提高此类中间体纯度及收率,从而减少棕榈酸帕利哌酮的纯化操作,在棕榈酸帕利哌酮的合成过程中,首次利用有机路易斯酸做催化剂完成傅克反应,将制备棕榈酸帕利哌酮中间体的收率提高2.5倍以上。<Image he="321" wi="582" file="DDA0001966245660000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a preparation method of a paliperidone palmitate intermediate. The invention relates to a synthesis method of a paliperidone palmitate intermediate with a structure shown as formula II, which can greatly improve the purity and yield of the intermediate, thereby reducing the purification operation of paliperidone palmitate, and in the synthesis process of paliperidone palmitate, organic Lewis acid is used as a catalyst for the first time to complete Friedel-crafts reaction, so that the yield of the paliperidone palmitate intermediate is improved by more than 2.5 times.)

1. Synthetic method of paliperidone palmitate intermediate shown as formula II

2. The method of claim 1, wherein R in the structure₁Selected from acetyl, formyl, Bn, Cbz, Fmoc, Tfa, Trt, Pht, Alloc, Teoc, Tos, PMB, Dmb.

3. The process of claim 1 wherein the m-difluorobenzene is added to the reaction solvent at a temperature of-20 ℃ to 20 ℃.

4. The process of claim 3, wherein the reaction solvent is selected from one or more of dichloromethane, 1.2-dichloroethane, chloroform, 2-methyltetrahydrofuran, anisole.

5. The method of claim 4, wherein the Lewis acid is added to the system at a mixing temperature of-20 ℃ to 20 ℃.

6. The method of claim 5, wherein N-acetylpiperidine-4-carbonyl chloride is added to the system at a reaction temperature of 25 ℃ to 50 ℃.

7. The process of claim 5 wherein the Lewis acid is selected from the group consisting of boron trifluoride, trimethylsilyl trifluoromethanesulfonate, aluminum trichloride, SbF5, and niobium pentachloride.

8. The method of claim 1, wherein the reaction time is 5 to 20 hours.

Technical Field

The invention relates to a preparation method of a paliperidone palmitate intermediate.

Background

Paliperidone palmitate is developed by Qiangsheng company and is marketed, and the injection is a long-acting novel anti-schizophrenia drug. Paliperidone is the major metabolite of risperidone. The mechanism of action is not clear, but is currently thought to be mediated by a combination of central dopamine 2(D2) and 5-hydroxytryptamine 2(5HT2A) receptor antagonism. Paliperidone is also an antagonist of the α 1 and α 2 adrenergic receptors as well as the H1 histamine receptor, which may be responsible for some other effects of the drug. Paliperidone has no affinity with cholinergic muscarinic receptors or β 1-and β 2-adrenergic receptors. In vitro, the pharmacological effects of the (+) -and (-) -paliperidone enantiomers were similar.

Paliperidone palmitate has a structure shown as formula one:

the method comprises the following steps: paliperidone palmitate

Documents US8481729B2, US7629469B2, US8940749B2, CN101014601B provide several methods for synthesizing paliperidone palmitate, but the total yield of these methods is less than 9%, and the cost of the raw material drug is very high.

Disclosure of Invention

The inventor finds that the paliperidone palmitate is generated by condensing an oximate and a hydroxyl tetrahydropyridine compound, the quality and the yield of the oximate and the hydroxyl tetrahydropyridine compound directly influence the quality and the yield of the finished paliperidone palmitate, the key step of preparing the oximate is a Friedel-crafts process, and the key of the Friedel-crafts process is how to improve the quality and the yield of a midbody of a formula II:

the second formula: paliperidone palmitate intermediate

Wherein R1 represents acetyl, formyl, Bn, Cbz, Fmoc, Tfa, Trt, Pht, Alloc, Teoc, Tos, PMB, Dmb, etc.

In various reaction routes for preparing paliperidone palmitate, a special intermediate with a structure shown as a formula II is used, the intermediate is prepared by adopting a Lewis acid-catalyzed Friedel-crafts reaction, and the purity and the yield of the intermediate with the structure shown as the formula II determine the total yield of the synthesis route.

Generally, the reaction conditions of the compound in the key step of preparing paliperidone palmitate are strictly controlled, and the research surprisingly discovers that the compound of the formula II intermediate with high quality and high yield can be prepared in a simple and mild mode, and the yield of the compound of the formula II intermediate can be improved by more than 2.5 times compared with the prior art.

With R₁As an example, acetyl is represented by the following formula:

when dichloromethane is used as a solvent and trimethylsilyl trifluoromethanesulfonate is used as a Lewis acid catalyst in the reaction, the reaction is carried out at the temperature of 5 +/-8 ℃, the change of impurities is shown in figure 1 along with the prolonging of the reaction time, and the experimental result shows that: with the increase of the reaction time, impurities in the system are gradually reduced, and the purity and the yield are gradually increased. After the reaction is carried out for 8 hours, partial raw materials of the system still do not completely react, the reaction is carried out for 11 hours, the reaction is completed, the reaction time is prolonged to 15 hours, and the yield and the purity are not obviously changed. The proper system temperature and time are selected, so that the impurity content of the paliperidone palmitate intermediate can be effectively reduced, and the total yield of the paliperidone palmitate intermediate is improved by more than 2.5 times.

According to the invention, organic Lewis acid (trimethylsilyl trifluoromethanesulfonate and boron trifluoride ether) is successfully used as a catalyst for the first time to complete Friedel-crafts reaction, and the intermediate is used as a starting material to be converted into a target product through subsequent reaction, so that a high-quality raw material medicine can be prepared, the overall yield is improved, the purification operation is reduced, and the cost is saved.

The invention relates to R in intermediate structure of paliperidone palmitate₁Represents acetyl, formyl, Bn, Cbz, Fmoc, Tfa, Trt, Pht, Alloc, Teoc, Tos, PMB, Dmb, etc.; most preferred is acetyl.

The reaction solvent used in the intermediate production method provided by the present invention is generally selected from dichloromethane, 1.2-dichloroethane, chloroform, tetrahydrofuran, 1.4-dioxane, 2-methyltetrahydrofuran, anisole, etc., preferably dichloromethane, chloroform, tetrahydrofuran, most preferably dichloromethane.

In the preparation method of the paliperidone palmitate intermediate, the reaction temperature adopted for adding the m-difluorobenzene into the organic solvent is generally selected to be-20 ℃; preferably 0 ℃ to 15 ℃, most preferably 10 ℃ to 15 ℃; the reaction temperature adopted for adding the Lewis acid into the system is generally selected to be-20 ℃; preferably 0 ℃ to 15 ℃, most preferably 5 ℃ to 11 ℃; the reaction temperature adopted for adding the N-acetylpiperidine-4-formyl chloride into the system is generally 25-50 ℃; preferably 30 ℃ to 45 ℃, most preferably 30 ℃ to 40 ℃.

The Lewis acid catalyst used in the preparation method of the paliperidone palmitate intermediate can be selected from boron trifluoride, trimethylsilyl trifluoromethanesulfonate, stannic chloride, aluminum trichloride, SbF5, ferric trichloride, niobium pentachloride and the like, preferably boron trifluoride, trimethylsilyl trifluoromethanesulfonate, aluminum trichloride and the like, and most preferably boron trifluoride and trimethylsilyl trifluoromethanesulfonate.

The reaction time adopted in the preparation method of the paliperidone palmitate intermediate is generally 5-20 hours, preferably 10-20 hours, and most preferably 11-12 hours.

The method prepares the high-quality and high-yield compound of the formula II by a simple and mild mode, effectively reduces the impurity content of the paliperidone palmitate intermediate under the conditions of a proper system, temperature and time, improves the total yield of the paliperidone palmitate intermediate by more than 2.5 times, can prepare high-quality raw material medicines by using the intermediate as a starting material, improves the total yield, reduces the purification operation and saves the production cost.

Drawings

FIG. 1 Process of the invention produces a time-dependent change in the impurities of the intermediates.

Detailed Description

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the inventors have verified that the following schemes have similar results when the amount of the raw materials is scaled up or down.