阅读说明：本技术 一种布南色林中间体的制备方法 (Preparation method of blonanserin intermediate ) 是由 段世辉 杨贞皓 曾乐乐 于 2021-08-20 设计创作，主要内容包括：本发明涉及一种布南色林中间体的制备方法,包括如下步骤,对氟苯甲酰乙腈在水溶液中,在酸式硫酸盐的存在下水解,然后用氨水中和至pH为8-9,过滤,干燥得到3-(4-氟苯基)-3氧代丙酰胺；3-(4-氟苯基)-3氧代丙酰胺和环辛酮在多聚磷酸和催化剂存在下反应,所述催化剂为吡啶或吡啶衍生物,然后于碱水中析晶,甲叔醚打浆,得到布南色林中间体；本发明的产物收率高,杂质少,放大生产时同样具有收率高的优点,适于工业化生产。(The invention relates to a preparation method of blonanserin intermediate, which comprises the following steps of hydrolyzing p-fluorobenzoylacetonitrile in a water solution in the presence of acid sulfate, then neutralizing with ammonia water until the pH value is 8-9, filtering, and drying to obtain 3- (4-fluorophenyl) -3 oxopropanamide; reacting 3- (4-fluorophenyl) -3 oxopropanamide with cyclooctanone in the presence of polyphosphoric acid and a catalyst, wherein the catalyst is pyridine or a pyridine derivative, then crystallizing in alkaline water, and pulping with methyl tert-ether to obtain a blonanserin intermediate; the method has the advantages of high product yield, less impurities, high yield during large-scale production and suitability for industrial production.)

1. A preparation method of blonanserin intermediate is characterized by comprising the following steps of hydrolyzing p-fluorobenzoylacetonitrile in an aqueous solution in the presence of acid sulfate, then neutralizing with ammonia water until the pH value is 8-9, filtering, and drying to obtain 3- (4-fluorophenyl) -3 oxopropanamide; reacting 3- (4-fluorophenyl) -3 oxopropanamide with cyclooctanone in the presence of polyphosphoric acid and a catalyst, wherein the catalyst is pyridine or a pyridine derivative, then crystallizing in alkaline water, and pulping with methyl tert-ether to obtain the blonanserin intermediate.

2. The process for preparing blonanserin intermediate as recited in claim 1, wherein said acid sulfate is sodium hydrogen sulfate or zirconium sulfate.

3. The method for preparing blonanserin intermediate as recited in claim 1, wherein the mass concentration of the acid sulfate in the reaction system is 30-90%.

4. The method for preparing blonanserin intermediate as recited in claim 3, wherein the mass concentration of the acid sulfate in the reaction system is 50-60%.

5. The method for preparing blonanserin intermediate as claimed in claim 1, wherein the reaction temperature in the hydrolysis reaction of p-fluorobenzoylacetonitrile is 40-70 ℃.

6. The process for preparing blonanserin intermediate as recited in claim 1, wherein the molar ratio of said acid sulfate to p-fluorobenzoylacetonitrile is 1-4: 1.

7. The process for the preparation of blonanserin intermediate as claimed in any one of claims 1 to 5, wherein the catalyst is N, N-dimethylaminopyridine.

8. The process for the preparation of blonanserin intermediate as claimed in any one of claims 1 to 5, wherein the molar ratio of catalyst to 3- (4-fluorophenyl) -3 oxopropanamide is between 0.005 and 0.5: 1.

9. the process of preparing blonanserin intermediate as claimed in claim 8, wherein the molar ratio of catalyst to 3- (4-fluorophenyl) -3 oxopropanamide is 0.05-0.2: 1.

10. the process for preparing blonanserin intermediate as claimed in any one of claims 1 to 5, wherein the reaction temperature of 3- (4-fluorophenyl) -3 oxopropanamide and cyclooctanone is 110-120 ℃.

Technical Field

The invention belongs to the field of medical chemistry, and particularly relates to a preparation method of a blonanserin intermediate.

Background

The blonanserin intermediate is 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine-2 (1H) -ketone, is an important intermediate in the synthesis process of a new atypical antipsychotic blonanserin (blonanserin), and has the structure shown as the following formula:

JP4099758A and EP0385237 report the synthesis of BN-03 by reaction of p-fluorobenzoylacetonitrile and cyclooctanone as starting materials in polyphosphoric acid to give 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocyclooctapentadin-2 (1H) -one, the reaction being carried out at 120 ℃ and being represented by the following reaction scheme:

the literature reports that the yield of the compound of formula BN-03 in the preparation process provided by this synthetic route is 60%, but the present inventors prepared 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocyclooctane pyrido-2 (1H) -one according to the above-mentioned literature process in a yield of only about 20%, similar to the yield of about 18% obtained when the inventors repeat the patent of the invention, such as Wanjun Fang (CN 101747273A).

In Chinese patent CN101747273A, the inventor of Wangjun et al disclosed a modification of the method, i.e., hydrolyzing p-fluorobenzoylacetonitrile to 3- (4-fluorophenyl) -3 oxopropanamide, and then dehydrating with cyclooctanone using p-toluenesulfonic acid to prepare 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocyclooctane pyrido-2 (1H) -one (BN-03). The method improves the yield to 80%. We have found that, when studied in this way, a yield of 84% can be achieved at small feed rates, but on scale the yield decreases, as reported by itself, to 71.7% and even 63.5%, as detailed in example 2 and example 3 of CN 101747273A.

In the process of implementing the invention, the inventor finds that the prior art has at least the following problems:

when the reaction is carried out according to the method of JP4099758A by HPLC tracing, the reaction process is found to pass through a 3- (4-fluorophenyl) -3 oxopropanamide intermediate and then be converted into a product 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocyclooctane pyridine-2 (1H) -ketone (BN-03), but the product is complex at the end of the reaction, difficult to separate, extremely low in yield and difficult to control the quality of the product. Then, according to the research of the synthesis of the document blonanserin [ handsome et al, journal of the chinese medical industry, 2009,40(4),247 ] and CN101747273A, it is found that in the process of hydrolyzing p-fluorobenzoylacetonitrile into 3- (4-fluorophenyl) -3 oxopropanamide by polyphosphoric acid, polyphosphoric acid is very viscous, the dosage is large, stirring is difficult, the yield is reduced during amplification, and the environmental protection treatment difficulty is large. In addition, in the condensation process of the 3- (4-fluorophenyl) -3 oxopropanamide and the cyclooctanone, a small amount of the raw materials has good feeding effect, explosive boiling and material rushing are easy to occur during amplification, and the yield is reduced.

CN102030707A discloses a method for synthesizing 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocyclooctane pyridine-2 (1H) -ketone (BN-03), wherein para-fluorobenzoylacetonitrile is hydrolyzed by Wang parahong fungus by using 80-85% sulfuric acid instead of polyphosphoric acid to generate 3- (4-fluorophenyl) -3 oxopropanamide, and then the 3- (4-fluorophenyl) -3 oxopropanamide and cyclooctanone are catalyzed by p-toluenesulfonic acid in toluene to generate 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine-2 (1H) -ketone (BN-03). See the following equation:

according to the study of CN102030707A, it is found that in the process of hydrolyzing p-fluorobenzoylacetonitrile into 3- (4-fluorophenyl) -3 oxopropanamide by sulfuric acid, the hydrolysis is easy to pass through, and 3- (4-fluorophenyl) -3 oxopropanoic acid is generated as an impurity. Because of heterogeneous solid-liquid reaction, the raw materials are easily wrapped by the products, and particularly the raw materials are obviously enlarged to a kilogram level. Moreover, the use of a large amount of sulfuric acid brings certain dangers in terms of actual operation (strong oxidizing property and strong acidity of concentrated sulfuric acid, explosive boiling caused by intense heat release during dilution and the like), and the biggest problem is that a large amount of waste acid water is generated, thus bringing certain pressure on environmental protection.

CN102093289B discloses a synthesis method of 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine-2 (1H) -ketone (BN-03), wherein Schopper et al use a composition of concentrated sulfuric acid and p-toluenesulfonic acid to catalyze a ring-closing reaction of p-fluorobenzoyl acetonitrile and cyclooctanone to generate 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine-2 (1H) -ketone (BN-03). See the following equation:

according to the method provided by the patent, the inventor carries out relevant experimental research, and according to the intermediate monitoring result of HPLC, the time of the reaction reaching the end point is longer, and the product is more complex at the end point, so that not only the impurity 3- (4-fluorophenyl) -3 oxopropanoic acid is generated, but also more BN-02 bis-ketal is generated, particularly after amplification, the method is more obvious, and obviously, the effect provided by the patent is not achieved.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of a blonanserin intermediate, which has the advantages of high yield, less impurities, high yield during large-scale production and suitability for industrial production.

The invention relates to a preparation method of blonanserin intermediate, which comprises the following steps,

p-fluorobenzoylacetonitrile is hydrolyzed in aqueous solution in the presence of acid sulfate, then ammonia water is used for neutralizing until the pH value is 8-9, and the 3- (4-fluorophenyl) -3 oxopropanamide is obtained after filtration and drying;

reacting 3- (4-fluorophenyl) -3 oxopropanamide with cyclooctanone in the presence of polyphosphoric acid and a catalyst, wherein the catalyst is pyridine or a pyridine derivative, crystallizing in alkaline water (alkaline water is potassium hydroxide or sodium hydroxide, preferably alkene alkaline water, the mass concentration is preferably 10%), and pulping with methyl tert-ether to obtain blonanserin intermediate.

In the process for producing 3- (4-fluorophenyl) -3 oxopropanamide (step 1), the following reaction conditions are preferred:

the acid sulfate is preferably sodium hydrogen sulfate or zirconium sulfate, more preferably zirconium sulfate;

in the reaction system of the 3- (4-fluorophenyl) -3 oxopropanamide, the mass concentration of the acid sulfate is 30-90%, preferably 50-60%;

the reaction temperature is 40-70 ℃, the reaction time is 0.5-2h, preferably, the reaction temperature is 50-60 ℃, and the reaction time is 1-2 h;

the molar ratio of the acid sulfate to the p-fluorobenzoylacetonitrile is 1-4:1, preferably 1.5-2.5: 1.

The blonanserin intermediate is 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine-2 (1H) -ketone (BN-03), and in the preparation method (step 2), the following reaction conditions are preferably selected:

the catalyst is preferably N, N-Dimethylaminopyridine (DMAP);

the molar ratio of the catalyst to the 3- (4-fluorophenyl) -3 oxopropanamide is 0.005-0.5: 1, preferably 0.05 to 0.2: 1;

the reaction temperature of the 3- (4-fluorophenyl) -3-oxopropanamide and the cyclooctanone is 110-120 ℃, and the reaction time is 3-5 h.

The beneficial effect of the invention is that,

1) the invention utilizes the characteristic that the acid sulfate is inorganic medium-strong acid which is stable under the heating condition, and the nitrile group in the p-fluorobenzoylacetonitrile is hydrolyzed into the amide under the heating condition (preferably 50-60 ℃), thereby quickening the reaction speed, shortening the reaction time, controlling the side reaction of further hydrolyzing the amide into the carboxylic acid, improving the effective conversion rate of the step to more than 95 percent, and keeping the effective conversion rate stable after amplification.

2) In the invention, the acid sulfate is added in the step 1, water is used as a solvent, the stirring effect is ensured, particularly when zirconium sulfate is used as a hydrolysis catalyst, zirconium sulfate and generated amide can form a complex, the uniformity of the feed liquid is increased, and the reaction speed is accelerated.

3) In the step 2 of the invention, pyridine or pyridine derivatives such as N, N-dimethylaminopyridine are used for catalyzing condensation and cyclization of 3- (4-fluorophenyl) -3 oxopropanamide and cyclooctanone to generate pyridone, the reaction is fast, the conversion rate is high, after the reaction is finished, a proper amount of solvent is added for dilution, and the mixture is dripped into dilute alkali water for crystallization, and the product purity reaches over 99 percent.

4) The method has simple reaction steps and convenient post-treatment, avoids the influence of a large amount of acidic waste liquid on the environment, accords with the characteristics of environmental protection, and meets the requirement of industrial production.

Drawings

FIG. 1 is a schematic diagram of the reaction scheme of the present invention.

Detailed Description

The following examples are intended to illustrate the invention in detail, but are not intended to limit the invention.

Example 1

1. Preparation of 3- (4-fluorophenyl) -3 oxopropanamide with sodium bisulfate as catalyst

In a 250ml clean reaction flask, 25.0g (0.15mol) of p-fluorobenzoylacetonitrile, 36ml of water, 36g of sodium hydrogen sulfate (0.3mol) (analytical purity) were added. After the addition, the reaction mixture was heated to 60 ℃ with rapid stirring, and the temperature was controlled for reaction for 3 hours. And (3) monitoring the reaction process by HPLC (high performance liquid chromatography), when the residual amount of the p-fluorobenzoylacetonitrile in the system is less than 1%, determining that the reaction is complete, after the reaction is finished, cooling to below 30 ℃, dropwise adding ammonia water with the mass concentration of 12%, and adjusting the pH to 9. The temperature is controlled to 15 ℃, the mixture is stirred and crystallized for 1 hour, and the mixture is filtered, washed, filtered and dried at 80 ℃ to obtain 25.5g of 3- (4-fluorophenyl) -3 oxopropanamide, the yield is 92 percent and the HPLC is 98.5 percent.

2. Preparation of BN-03(4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta pyridine-2 (1H) -one) by pyridine catalysis

In a 250ml clean reaction flask, 125g of polyphosphoric acid, 25g of 3- (4-fluorophenyl) -3 oxopropanamide, 20.0g of cyclooctanone and 2ml of pyridine were added in this order. After the addition, the temperature was raised to 115 ℃ and the reaction was carried out for 4 hours under controlled temperature. The reaction progress was monitored by HPLC, and the reaction was considered complete when the residual amount of 3- (4-fluorophenyl) -3 oxopropanamide in the system was less than 3%. Cooling to 80 deg.C, adding 120ml ethanol, stirring thoroughly, dropping the material into 1200ml diluted alkaline water (10% sodium hydroxide solution), stirring for crystallization for 1h, filtering to obtain white solid, and soaking and washing with 200ml tert-butyl methyl ether to obtain white crystalline solid 33.6 g. The yield is 90.0%, the purity (HPLC) is 99.36%, the melting point is 235.2-236.0 ℃.

Example 2

1. Preparation of 3- (4-fluorophenyl) -3 oxopropanamide using zirconium sulfate as catalyst

In a 250ml clean reaction flask, 25.0g (0.15mol) of p-fluorobenzoylacetonitrile, 36ml of water, 85g of zirconium sulfate (0.3mol) (analytical purity) were added. Otherwise, as in step 1 of example 1, after drying at 80 ℃ C, 26.3g of 3- (4-fluorophenyl) -3 oxopropanamide was obtained in 95% yield by HPLC 99.2%.

2. Preparation of BN-03(4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta pyridine-2 (1H) -one) by pyridine catalysis

In a 250ml clean reaction flask, 125g of polyphosphoric acid, 25g of 3- (4-fluorophenyl) -3 oxopropanamide obtained in step 1, 20.0g of cyclooctanone, and 2ml of pyridine were sequentially added. Otherwise, 34g of a white crystalline solid was obtained in the same manner as in step 2 of example 1. The yield is 91.07%, the purity (HPLC) is 99.3%, the melting point is 235.0-236.0 ℃.

Example 3

1. 3- (4-fluorophenyl) -3 oxopropanamide was prepared using zirconium sulfate as catalyst, the procedure was as in 1 of example 2.

2. Preparation of BN-03(4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta-pyrido-2 (1H) -one) using DMAP (N, N-dimethylaminopyridine) as catalyst

In a 250ml clean reaction flask, 125g of polyphosphoric acid, 25g of 3- (4-fluorophenyl) -3 oxopropanamide, 20.0g of cyclooctanone, and 1.85g (0.02mol) of DMAP were added in this order. After the addition, the temperature was raised to 115 ℃ and the reaction was carried out for 4 hours under controlled temperature. The reaction progress was monitored by HPLC, and the reaction was considered complete when the residual amount of 3- (4-fluorophenyl) -3 oxopropanamide in the system was less than 3%. Cooling to 80 ℃, adding 120ml of ethanol, fully stirring, then dripping the material into 1200ml of dilute alkaline water, stirring and crystallizing for 1h, filtering to obtain a white-like solid, and fully soaking and washing with 200ml of tert-butyl methyl ether to obtain 35.5g of a white crystalline solid. 95% yield and purity (HPLC) 99.42%, melting point 235.4-236.2 ℃.

Example 4

1. Preparation of 3- (4-fluorophenyl) -3 oxopropanamide using zirconium sulfate as catalyst

In a 30L clean reaction vessel, 2.5kg (15mol) of p-fluorobenzoylacetonitrile, 8.5kg of water, 8.5kg of zirconium sulfate (analytical grade) were added. After the addition, heating the reaction mixture to 60 ℃ under rapid stirring, controlling the temperature to react for 3 hours, monitoring the reaction process by HPLC, judging that the reaction is complete when the residue of the p-fluorobenzoylacetonitrile in the system is less than 1%, cooling to below 30 ℃ after the reaction is finished, dropwise adding ammonia water with the mass concentration of 12%, and adjusting the pH to 8-9. And controlling the temperature to be 15-20 ℃, stirring and crystallizing for 1 hour, filtering, washing, draining, and drying at 80 ℃ to obtain 2.68kg of 3- (4-fluorophenyl) -3 oxopropanamide, wherein the yield is 96.8 percent and HPLC 99.18 percent.

2. Preparation of BN-03(4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta-pyrido-2 (1H) -one) using DMAP (N, N-dimethylaminopyridine) as catalyst

In a 30L clean reaction vessel, 12.5kg of polyphosphoric acid, 2.5kg of 3- (4-fluorophenyl) -3 oxopropanamide, 2.0kg of cyclooctanone, and 185g of DMAP were sequentially added. After the addition, the temperature was raised to 115 ℃ and the reaction was carried out for 4 hours under controlled temperature. The reaction progress was monitored by HPLC, and the reaction was considered complete when the residual amount of 3- (4-fluorophenyl) -3 oxopropanamide in the system was less than 3%. Cooling to 80 deg.C, adding 10kg ethanol, stirring, dripping the material liquid into 120kg diluted alkaline water, stirring for crystallizing for 1 hr, filtering to obtain white solid, and soaking and washing with 4kg tert-butyl methyl ether to obtain white crystalline solid 3.6 kg. The yield is 96.3%, the purity (HPLC) is 99.46%, the melting point is 235.6-236.2 ℃.

The total yield of BN-03(4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine-2 (1H) -ketone) prepared by two steps under different conditions can reach over 90 percent, and is obviously improved compared with the numerical values provided by the prior literature.

Comparative example 1

1. Preparation of 3- (4-fluorophenyl) -3 oxopropanamide using phosphoric acid as catalyst

In a 250ml clean reaction flask, 25.0g (0.15mol) of p-fluorobenzoylacetonitrile, 36ml of water, 25g of phosphoric acid (analytical purity) were added. After the addition, the reaction mixture was heated to 60 ℃ with rapid stirring, and the temperature was controlled for reaction for 3 hours. And (3) monitoring the reaction process by HPLC (high performance liquid chromatography), when the residual amount of the p-fluorobenzoylacetonitrile in the system is less than 1%, determining that the reaction is complete, after the reaction is finished, cooling to below 30 ℃, dropwise adding ammonia water with the mass concentration of 12%, and adjusting the pH to 9. And controlling the temperature to be 15-20 ℃, stirring and crystallizing for 1 hour, filtering, washing, draining, and drying at 80 ℃ to obtain 23.5g of 3- (4-fluorophenyl) -3 oxopropanamide, wherein the yield is 85 percent, and the HPLC is 97.8 percent.

2. Preparation of BN-03(4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta pyridine-2 (1H) -one) by pyridine catalysis

In a 250ml clean reaction flask, 125g of polyphosphoric acid, 23g of 3- (4-fluorophenyl) -3 oxopropanamide, 23.0g of cyclooctanone, and 2ml of pyridine (0.024mol) were added in this order. After the addition, the temperature was raised to 115 ℃ and the reaction was carried out for 4 hours under controlled temperature. The reaction progress was monitored by HPLC, and the reaction was considered complete when the residual amount of 3- (4-fluorophenyl) -3 oxopropanamide in the system was less than 3%. Cooling to 80 ℃, adding 120ml of ethanol, fully stirring, then dripping the material into 1200ml of dilute alkaline water, stirring and crystallizing for 1h, filtering to obtain a white-like solid, and fully soaking and washing with 200ml of tert-butyl methyl ether to obtain 30.9g of a white crystalline solid. The yield is 82.77%, the purity (HPLC) is 99.4%, the melting point is 235.4-236.2 ℃.

The yield in step 1 is significantly reduced because the catalytic effect of phosphoric acid is less favorable under the same experimental conditions, resulting in a slightly lower quality and yield of the obtained 3- (4-fluorophenyl) -3 oxopropanamide.

The actual amount of 3- (4-fluorophenyl) -3 oxopropanamide available in step 2 is not so large due to the slightly inferior quality of 3- (4-fluorophenyl) -3 oxopropanamide, coupled with the possible influence of the phosphate salt of 3- (4-fluorophenyl) -3 oxopropanamide formed, thus resulting in a lower yield.

Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the spirit of the present disclosure, features from the above embodiments or from different embodiments may also be combined, steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments in this application as described above, which are not provided in detail for the sake of brevity.

It is intended that the one or more embodiments of the present application embrace all such alternatives, modifications and variations as fall within the broad scope of the appended claims. Therefore, any omissions, modifications, substitutions, improvements, and the like that may be made without departing from the spirit and principles of one or more embodiments of the present disclosure are intended to be included within the scope of the present disclosure.