CN112824409B

CN112824409B - New impurity and preparation method thereof

Info

Publication number: CN112824409B
Application number: CN201911146675.6A
Authority: CN
Inventors: 王绍辉; 李红强
Original assignee: Chongqing Huabangshengkai Pharm Co ltd
Current assignee: Chongqing Huabangshengkai Pharm Co ltd
Priority date: 2019-11-21
Filing date: 2019-11-21
Publication date: 2023-12-26
Anticipated expiration: 2039-11-21
Also published as: CN112824409A

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a novel impurity related to atorvastatin and a preparation method thereof. The new impurity is 1- (6-bromo-2-pyridyl) -3- (1-pyrrolidinyl) -1-p-methylphenyl-1-propanol in the atorvastatin synthesis route and is generated in the process of preparing (E) -2-bromo-6- (3- (1-pyrrolidinyl) -1-p-tolyl-1-propenyl) pyridine by heating in sulfuric acid and generating elimination reaction, and the new impurity is 6-bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1, 2-alpha ] indole, is an important impurity in the atorvastatin synthesis, and is beneficial to quality control of atorvastatin bulk drugs. The preparation method adopts a mother liquor recovery crystallization method and an directional synthesis method, has short synthesis route and simple operation, and the obtained product has higher purity and can be applied to reference substance research and atorvastatin intermediate quality control.

Description

New impurity and preparation method thereof

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a novel impurity and a preparation method thereof.

Background

Atorvastatin is a strong competitive histamine H1 receptor antagonist with no significant anticholinergic effect. Is suitable for relieving allergic rhinitis including symptoms of hay fever, and is also suitable for treating chronic spontaneous urticaria, skin scarification, cholinergic urticaria and idiopathic acquired cold urticaria. 4 months 2003, SFDA approved its market in China.

Atorvastatin has the chemical name: (E) -3- [6- [ (E) -1- (4-methylphenyl) -3-pyrrolidin-1-yl-1-propenyl ] pyridin-2-yl ] -2-acrylic acid having the structural formula:

chinese patents CN200910086187.0, CN200910086870.4 and CN201510597158.6 disclose the preparation method of atorvastatin in sequence, the specific synthetic route is as follows:

in the atorvastatin synthesis process, a few impurities exist, and the content of the impurities in atorvastatin raw medicines and preparations has an important influence on the safety and effectiveness of medicines. The invention provides a new impurity, which is the main impurity of an atorvastatin synthesis intermediate in a formula III and is the main impurity affecting the quality of the intermediate. Meanwhile, because the existence of the aromatic bromine substituent is consistent with the structural characteristics of the intermediate formula III, the reaction takes part in the next heck reaction and the subsequent reaction steps, if effective control is not carried out, the quality level of the finished product is greatly influenced.

Disclosure of Invention

The invention aims to provide a novel impurity which is novel in structure and is generated in the process of synthesizing atorvastatin, and research on the impurity is helpful for quality control of atorvastatin bulk drug.

In order to achieve the above purpose, the present invention adopts the following scheme:

the new impurity is generated in the process of preparing (E) -2-bromo-6- (3- (1-pyrrolidinyl) -1-p-tolyl-1-propenyl) pyridine by heating 1- (6-bromo-2-pyridinyl) -3- (1-pyrrolidinyl) -1-p-methylphenyl-1-propanol in sulfuric acid for elimination reaction in the atorvastatin synthesis route, and the new impurity is 6-bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1, 2-alpha ] indole, and the structural formula is shown in formula I:

it is a second object of the present invention to provide a process for preparing the novel impurity.

the method adopts a mother liquor recovery crystallization method, and 1- (6-bromo-2-pyridyl) -3- (1-pyrrolidinyl) -1-p-methylphenyl-1-propanol (formula II) is heated in sulfuric acid to carry out elimination reaction to prepare a solution of (E) -2-bromo-6- (3- (1-pyrrolidinyl) -1-p-tolyl-1-propenyl) pyridine (formula III), and the reaction is shown as follows:

further, concentrating the mother liquor under reduced pressure, alkalizing, extracting, re-concentrating, and crystallizing to obtain the new impurity.

Further, the alkalizing agent used in the alkalization is an organic base or an inorganic base.

Further, the pH of the alkalization is 7 to 14, preferably 8 to 10.

Further, the alkalizing agent is ammonia water.

Further, the extraction solvent used for extraction is one or more of ethyl acetate, toluene, methylene dichloride, methyl isobutyl ketone and isopropyl ether.

Preferably, ethyl acetate is used.

Further, the solvent used for crystallization was n-hexane.

Further, after crystallization, continuously collecting residual mother liquor, concentrating under reduced pressure, dissolving the benign solvent, crystallizing the poor solvent, concentrating again, refining and drying to obtain the new impurity, and repeatedly operating until the purity of the new impurity is not lower than 75%.

Further, the benign solvent is one or more of ethyl acetate, toluene, methylene dichloride, methyl isobutyl ketone and isopropanol, and the poor solvent is one or more of n-hexane, petroleum ether, cyclohexane and n-heptane.

Further, the volume ratio of the poor solvent to the benign solvent is 50:1 to 2:1, preferably 20:1 to 4:1.

20. the other preparation method of the new impurity is that an oriented synthesis method is adopted, the formula III is added into sulfuric acid solution, so that an olefinic bond in the formula III is attacked by protons to generate an intermediate state of the formula X, charges of two adjacent aromatic rings are induced to transfer, intramolecular rearrangement ring closing reaction is carried out, and the new impurity shown in the formula I is obtained, wherein the reaction route is as follows:

and further, adding the compound shown in the formula III into sulfuric acid solution, heating for reaction, and then alkalizing, extracting, concentrating, dissolving, crystallizing to obtain the new impurity.

Further, the concentration of sulfuric acid is 60% to 98%, preferably 85% to 95%.

Further, the mass ratio of sulfuric acid to the compound of formula iii is 2: 1-10:1, preferably 3: 1-5:1.

Further, the extraction solvent used for the extraction is one or more of ethyl acetate, toluene, methylene chloride, methyl isobutyl ketone and isopropyl ether, preferably ethyl acetate.

Further, the alkalizing agent is ammonia water, and the pH value of alkalization is 7-14.

Further, after concentration, adding a good solvent and a poor solvent, heating, refluxing and dissolving clear, dripping the poor solvent, cooling and crystallizing, wherein the good solvent is one or more of ethyl acetate, toluene, methylene dichloride, methyl isobutyl ketone and isopropanol, and is preferably ethyl acetate; the poor solvent is one or more of n-hexane, petroleum ether, cyclohexane and n-heptane, preferably n-hexane.

Further, the temperature of the temperature-rising reaction is 80-120 ℃ and the time is 3-6 hours.

The invention has the beneficial effects that:

1) The novel impurity 6-bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1, 2-alpha ] indole related to atorvastatin provided by the invention has a novel structure, is an important impurity in the synthesis of atorvastatin, and is beneficial to the quality control of atorvastatin bulk drugs;

2) The preparation method of the novel impurity provided by the invention comprises a mother liquor recovery crystallization method and an orientation synthesis method, the synthesis route is short, the operation is simple, the purity of the obtained product is higher, and the method can be applied to reference substance research and atorvastatin intermediate quality control.

Drawings

Fig. 1 is an HPLC chromatogram of a new impurity.

FIG. 2 is an infrared spectrum detection spectrum of a new impurity.

Fig. 3 is a mass spectrum of a new impurity.

FIG. 4 is a hydrogen spectrum of a new impurity.

Fig. 5 is a carbon spectrum of a new impurity.

FIG. 6 is a new directional synthesis HPLC chromatogram of directional synthesis.

Detailed Description

The examples are presented for better illustration of the invention, but the invention is not limited to the examples. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible in light of the above teachings and are intended to be within the scope of the invention.

The 6-bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1,2- α ] indole prepared in the following example was measured by High Performance Liquid Chromatography (HPLC), under the following chromatographic conditions:

chromatographic column: shimpack VP ODS, 4.6mm.times.250 mm,5 μm

Mobile phase a:0.05mol/L ammonium acetate solution (containing 0.2% triethylamine, pH 6.7 with phosphoric acid)

Mobile phase B: acetonitrile

Mobile phase C: methanol

Detection wavelength: 245nm

Flow rate: 1.0ml/min

Column temperature: 30 DEG C

Sample injection amount: 10 μl of

The gradient elution procedure is shown in the following table:

time (min)	Mobile phase a (%)	Mobile phase B (%)	Mobile phase C (%)
				0	75	15	10
2	75	15	10
				25	20	70	10
35	20	70	10
				36	75	15	10
45	75	15	10

Test solution: weighing a proper amount of the test sample, dissolving with 0.1% acetonitrile formate solution, and diluting to obtain a solution containing about 0.4mg per 1 ml.

And (3) 10 μl of the sample solution is taken, injected into a liquid chromatograph, the chromatogram is recorded, and the total impurity content in the sample is calculated according to a peak area normalization method. The main component content is 100% minus the total impurity content and dry weight loss content of the related substances (TGA method).

And (3) judging results: if the content of the main component of the product is not less than 95.0%, the product is judged to be in accordance with the regulations.

Example 16 preparation of bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1,2- α ] indole (mother liquor recovery crystallization)

Concentrating about 4.5L of (E) -2-bromo-6- (3- (1-pyrrolidinyl) -1-p-tolyl-1-propenyl) pyridine (formula III) mother liquor at 50-60 ℃ under reduced pressure to about 200-300 ml, then adding about 5L of drinking water and 1L of ethyl acetate into the concentrated residue, adding ammonia water to adjust the pH to 8-10 under stirring, standing for layering, separating an organic layer, and extracting an aqueous layer once again with 500ml of ethyl acetate; the organic layers were combined and washed three times with saturated aqueous sodium chloride. Adding 20g of active carbon and 180g of anhydrous sodium sulfate into the organic layer, drying for 30 minutes, carrying out suction filtration, concentrating the mother liquor under reduced pressure until the mother liquor is dried, adding 600g of normal hexane, stirring and dissolving the solution at 60-70 ℃, cooling to-5-0 ℃ for crystallization for 1 hour, and carrying out suction filtration; collecting mother liquor, concentrating under reduced pressure at 40-50 ℃, adding a proper amount of ethyl acetate for dissolving, adding 5g of active carbon and 100g of anhydrous sodium sulfate, stirring for 45 minutes, carrying out suction filtration, concentrating the mother liquor under reduced pressure until the mother liquor is dry, adding 300ml of n-hexane for dissolving, placing in a freezer, freezing and crystallizing overnight, discarding precipitated oily matters, collecting supernatant, concentrating under reduced pressure, adding 200ml of n-hexane for dispersion, carrying out suction filtration, and collecting solids; the solid was once purified with 100ml of n-hexane, and then with a mixture of 70ml of n-hexane and 7ml of ethyl acetate, and dried to obtain 6.0g of a product with a purity of 99.0%.

Example 2

The prepared 6-bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1,2- α ] indole was subjected to HPLC, IR, m/z, hydrogen and carbon spectrum identification, with the following results:

HPLC:99.0% (FIG. 1).

The results of the HPLC integration are shown in the following table:

IR:1699cm-1, 1674cm-1, 1625cm-1, 1606cm-1, 1484cm-1, 2964cm-1, 2873cm-1, 1375cm-1 (FIG. 2).

m/z:357.3, 359.3[ M+H ] + (FIG. 3).

1HNMR (600 MHz, CD3 OD): 8.816 (s, 1H); 7.684-7.698 (d, 1H); 7.478-7.494 (dd, 1H); 7.245-7.259;6.707-6.720;6.648-6.675;3.196-3.224 (m, 2H); 2.729-2.756 (m, 2H); 2.674-2.683 (m, 4H); 2.541 (s, 3H); 1.846-1.868 (m, 4H) (FIG. 4).

13CNMR (600 MHz, CD3 OD): 136.514;132.314;130.145;128.221;125.347;120.657;118.396;116.932;116.832;115.790;114.510;104.363;57.245;54.516;23.753;23.600;21.883 (FIG. 5).

EXAMPLE 3 preparation of bromo-3-methyl-10- (2- (1-pyrrolidinyl) ethyl) pyrido [1,2- α ] indole (Directional Synthesis method)

Adding 20g of water into 500ml of a three-necked flask, slowly adding 184g of sulfuric acid, and controlling the temperature to be lower than 90 ℃; 50g of (E) -2-bromo-6- (3- (1-pyrrolidinyl) -1-p-tolyl-1-propenyl) pyridine (formula III) is added, the temperature is raised to 108-120 ℃ for reaction for 4 hours, and sampling and central control are carried out until the reaction meets the requirements. Cooling to 15-20 deg.c, dropping ammonia water to regulate pH value to 8-10, extracting with ethyl acetate 200ml×3, merging organic layers, washing with water 200ml×3, and concentrating to dry. Adding 10ml of ethyl acetate and 50ml of n-hexane into the mixture, heating, refluxing and dissolving the mixture, dripping 150ml of n-hexane into the mixture, slowly cooling and crystallizing the mixture, crystallizing the mixture for 1 to 2 hours at the temperature of between 0 and 10 ℃, filtering the mixture, washing the mixture with 20ml of frozen n-hexane, and pumping the mixture; and (3) carrying out HPLC detection on the solid sample, and purifying by using the same crystallization method if the solid sample is unqualified until the purity is more than 95%. 11.5g of solid was finally obtained in a yield of 57.5% and a purity of 96.7% (FIG. 6), the results of the integration by HPLC being shown in the following table.

Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.

Claims

1. A preparation method of a new impurity is characterized in that a mother liquor recovery crystallization method is adopted, and 1- (6-bromo-2-pyridyl) -3- (1-pyrrolidinyl) -1-p-methylphenyl-1-propanol is heated in sulfuric acid to carry out elimination reaction to prepare a solution of (E) -2-bromo-6- (3- (1-pyrrolidinyl) -1-p-tolyl-1-propenyl) pyridine for recovery crystallization; concentrating the mother liquor under reduced pressure, alkalizing, extracting, re-concentrating, and crystallizing to obtain the new impurities; the extraction solvent used for extraction is ethyl acetate; the solvent used for crystallization is n-hexane; continuously collecting residual mother liquor after crystallization, concentrating under reduced pressure, dissolving and clearing benign solvent, crystallizing poor solvent, concentrating again, refining and drying to obtain the new impurity, and repeatedly operating until the purity of the new impurity is not lower than 75%; the benign solvent is ethyl acetate, and the poor solvent is n-hexane;

the structural formula of the new impurity is shown as formula I:

2. the preparation method according to claim 1, wherein the alkalizing agent used in the alkalizing is an organic base or an inorganic base.

3. The preparation method according to claim 1, wherein the alkalized pH is 7 to 14.

4. The method according to claim 2, wherein the alkalizing agent is aqueous ammonia.

5. The method of claim 1, wherein the volume ratio of poor solvent to benign solvent is 50:1 to 2:1.

6. A preparation method of a novel impurity is characterized in that an oriented synthesis method is adopted, a formula III is added into sulfuric acid solution, an olefinic bond in the formula III is attacked by protons to generate an intermediate state of a formula X, charges of two adjacent aromatic rings are induced to transfer, intramolecular rearrangement ring closing reaction is carried out, and the novel impurity shown in the formula I is obtained, wherein the reaction route is as follows:

the new impurity has a structural formula shown in formula I, and specifically comprises the following components: adding the compound shown in the formula III into sulfuric acid solution, heating for reaction, alkalizing, extracting, concentrating, dissolving, crystallizing to obtain the new impurity.

7. The method of claim 6, wherein the concentration of sulfuric acid is 60% to 98%.

8. The process according to claim 6, wherein the mass ratio of sulfuric acid to the compound of formula III is 2: 1-10:1.

9. The process according to claim 6, wherein the extraction solvent used for the extraction is ethyl acetate.

10. The method according to claim 6, wherein the alkalizing agent is aqueous ammonia and the pH of the alkalization is 7 to 14.

11. The method according to claim 6, wherein the good solvent and the poor solvent are added after concentration, the solution is heated to reflux, the poor solvent is added dropwise, the temperature is lowered and crystallization is performed, the good solvent is ethyl acetate, and the poor solvent is n-hexane.

12. The process according to claim 6, wherein the temperature of the elevated temperature reaction is 80 to 120℃for 3 to 6 hours.