RU2557241C1 - Method for synthesis of fluoroclozapine and derivatives thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method includes reacting 2,4-difluoro-5-nitro-1-chlorobenzene (2) with a compound of formula (3)

to obtain a compound of formula (4)

, reducing the compound of formula (4) with sodium dithionite in a suitable solvent to obtain a compound of formula (5)

, ring closure of the compound of formula (5) to form a compound of formula (6)

, crystallising a compound of formula (7)

from the compound of formula (6), reacting said compound of formula (7) with an amino derivative of a compound of formula (9)

EFFECT: high degree of purity.

10 cl, 4 dwg, 4 ex

Description

FIELD OF TECHNOLOGY

The invention relates to the field of pharmacology and medicine and relates to a method for the synthesis of fluoroclozapine and its derivatives, which can be used for the manufacture of medicines for the treatment of mental illnesses or mental disorders.

BACKGROUND

Currently, mental health is one of the most serious problems facing all countries, since at least one in four people have such problems at one time or another. The development of new antipsychotic drugs is an extremely important task facing modern medicine, since the only drug that effectively eliminates the positive and negative symptoms of schizophrenia - clozapine - also has dangerous side effects that limit its use in medical practice.

The fluorinated analogs of clozapine are effective antipsychotic drugs in which comparable with clozapine high efficiency is combined with relative safety of use. The preparation of high-purity clozapine fluoro derivatives is important, since even small amounts of impurities can significantly change the pharmacological effect and the safety profile of the substance.

The prior art method for the synthesis of one of the derivatives of fluoroclozapine (RF patent No. 2441867, IPC C07B 403/04, LLC Valentec, publ. 02/10/2012), the general scheme of which is as follows:

One of the stages of this method is the stage of obtaining the compounds of formula (b). To do this, 89 g of the compound of formula (a) are dissolved in 1335 ml of absolute ethanol. 112.2 ml of concentrated hydrochloric acid solution are added to the mixture, 206.5 g of tin chloride are sprinkled on and the reaction mixture is heated to boiling. The mixture is boiled for 12 hours. Then the mixture is cooled to room temperature, the solvent is evaporated on a rotary film evaporator (EPI). 1 L of water was added to the still residue and made basic with an aqueous NaOH solution to pH 9. The resulting suspension was extracted with ethyl acetate three times in 250 ml. The product is obtained in the form of a light yellow or light green powder. Yield 64.9 g, 81% of theory.

However, the final product obtained by a known method is contaminated, and contains at least 0.15% of a single impurity, presumably a dichloro derivative of the following formula:

The appearance of an impurity can be monitored at the stage of reduction with tin chloride.

Although the dichloro derivative is close in its structure to the target fluorochloro derivative, it is known that the chlorine atom is in nature a more voluminous substituent, therefore, the receptor profile of the compounds can differ significantly. In addition, the C-Cl bond is more susceptible to hydrolysis compared to the C-F bond, and the formation of a reactive metabolite of the dichloro derivative is more likely. Therefore, the presence of an impurity of a dichloro derivative in the final product is extremely undesirable.

SUMMARY OF THE INVENTION

The objective of the invention is the creation of a new method for the synthesis of fluoroclozapine and its derivatives of high purity, where these compounds are collectively represented by the general formula (1):

where cycle A represents phenyl, a 5- or 6-membered heteroaryl containing 1 O atom, or 1 O atom and 1-2 Ν atoms, or 1 S atom, or 1 S atom and 1-2 Ν atoms, or 1- 3 atoms Ν, while cycle A is optionally substituted with 1-3 substituents R ₁ ;

cycle B is a 5-7 membered saturated or partially unsaturated heterocycle containing 1 O atom, or 1 O atom and 1-2 N atoms, or 1 S atom, or 1 S atom and 1-2 N atoms, or 1-3 an N atom, wherein cycle B is optionally substituted with 1-3 substituents R ₂ ; Where

R ₁ is hydrogen, C _1-3 alkyl, optionally substituted with 1-3 R ₃ , OC _1-3 alkyl, optionally substituted with 1-3 R ₃ , C _1-3 alkyl-O-C _1-3 alkyl optionally substituted with 1-3 R ₃ or halogen,

R ₂ represents hydrogen, halogen or C _1-3 alkyl optionally substituted with 1-3 R ₃ ,

R ₃ represents halogen or OH.

The term “halogen” as mentioned above is understood to mean fluorine, chlorine, bromine, iodine.

The technical result achieved by using the invention is to increase the purity of fluoroclozapine and its derivatives, together represented by the above general formula (1), by reducing the content of impurities.

The task and the required technical result are achieved due to a new method for the synthesis of compounds of the above formula, which includes:

the interaction of 2,4-difluoro-5-nitro-1-chlorobenzene (2) with a compound of the general formula (3)

in which cycle A and R _{1 are as} defined above, to give a compound of general formula (4)

reducing said compound of general formula (4) with sodium dithionite in a suitable solvent to give a compound of general formula (5)

cyclization of said compound of general formula (5) to form a compound of general formula (6)

crystallization from said compound of general formula (6) of compound of general formula (7)

in a suitable solvent;

the interaction of the specified compounds of General formula (7) with an amino derivative of the General formula (9)

in which cycle B and R _{2 are} defined above, to obtain a compound of general formula (8)

the interaction of the compounds of formula (2) with the compound of formula (3) is carried out in the presence of KF, heating the reaction mixture for 5-6 days at 140-180 ° C, under basic conditions in a polar aprotic solvent, where NaH, KH are used as the base, t-BuOK, LiOH or CsCO ₃ , and dimethylformamide, N-methylpyrrolidone, DMSO or THF is used as a solvent, in addition, the compound of formula (7) is reacted with a compound of formula (9) in an aprotic solvent, for example, DMSO or toluene, stage cyclization is carried out under acidic conditions, and on tadii crystallization is used as solvent, diethyl ether, methyl tert-butyl ether, dioxane, and in the reduction step using the THF, 2-methyltetrahydrofuran, cyclopentyl methyl ether.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 - shows the LC MS of the recovery-cyclization product (compound of formula (6 ′) obtained by the proposed method.

In FIG. 2 - shows the LC MS of compound A-1.

In FIG. 3 - shows the LC MS of a mixture of intermediate 6 ′ and impurities A-1.

In FIG. 4 - shows a chromatogram of a fluoroclozapine sample.

DETAILED DESCRIPTION OF THE INVENTION

Below, in order to clarify the significant differences of the proposed invention, a general scheme for the synthesis of compounds of the above formula (1) is presented.

The compound of the above formula (4) can be obtained from 2,4-difluoro-5-nitro-1-chlorobenzene 2 and the corresponding nitrile (3) in the presence of KF by heating the reaction mixture for 5-6 days at 140-180 ° C.

Alternatively, a combination of compounds of formula (2) and (3) can be carried out under basic conditions in a polar aprotic solvent. Suitable bases include NaH, KH, t-BuOK, LiOH, CsCO ₃ . As solvents, dimethylformamide, Ν-methylpyrrolidone, DMSO, THF can be used. 2,4-difluoro-5-nitro-1-chlorobenzene (2) can be obtained from 2,4-difluoro-5-nitro-1-chlorobenzene by a standard procedure.

The compound of formula (5) can be obtained from the compound of formula (4) by reduction with sodium dithionite, for example, in THF. Known from the prior art, a method of producing analogues of the compounds of formula (5) involves the reduction of the nitro group with tin chloride. However, chlorine ions are able to replace the fluorine atom of the compounds of formula (4) and (5), which leads to the formation of an undesirable by-product, the compound of formula (5b), which is very difficult to separate from the target compound of formula (5). When using Na ₂ S ₂ O ₄ as a reducing agent, the formation of a by-product of formula (5b) is eliminated, and the reaction proceeds with the formation of only the compounds of formula (5).

The cyclization of the compounds of formula (5) with the formation of the compounds of formula (6) is carried out under acidic conditions. The chloride of formula (7) is crystallized from the free base of formula (6) in a suitable solvent, for example, diesel ether.

The compound of formula (8) can be obtained from the compound of formula (7) and the corresponding amino derivative of formula (9). The reaction is carried out in an aprotic solvent, for example, DMSO or toluene.

Below, to illustrate certain aspects of the invention, examples of the implementation of the proposed method, namely, the production of fluoroclozapine (8 ′) and its derivatives (9 ′), (10) and (16), are given. The following examples are not intended to limit the scope of the present invention in any way.

Example. 1. The method of synthesis of fluoroclozapine

1.1. 2,4-difluoro-5-nitro-1-chlorobenzene, a compound of the formula (2)

To a nitric acid cooled to 0 ° C (1.5 L), 0.5 L of a compound of formula (2a) is added dropwise. The mixture is stirred for 15 minutes and poured into 25 l of water, cooled to + 5 ° C. The reaction mass is stirred for 2 minutes and allowed to stand for 1 hour. The product forms at the bottom as a heavy oil. The aqueous phase is decanted, extracted with 1 l of CH ₂ Cl ₂ . The extract is combined with the product, washed 4 times with water to pH 7. The organic layer is dried with sodium sulfate, the solvent is removed on EPI. The yield of the compounds of formula (2) is 90-95%.

1.2. 2- (2-nitro-5-fluoro-4-chlorophenylamino)

benzonitrile, a compound of the general formula (4)

Into a 500 ml flask equipped with a sand bath, a thermocouple and a magnetic stirrer, 115 g of a compound of formula (2), 34.5 g of KF and 84.2 g of a compound of formula (3 ′) are placed. The reaction mass is heated with stirring at 150-160 ° C for 5-6 days, controlling the progress of the reaction by NMR. The reaction is considered complete when the content of the starting compound of formula (2) is not more than 15% with respect to the product.

The reaction mixture is cooled to 60 ° C and 500 ml of rectified ethyl alcohol are added with stirring. The mixture is cooled with stirring to 20 ° C, filtered, wring out. The substance is washed on the filter with three 150 ml portions of ethanol and two 200 ml portions of water. Yield 87 g, 50% of theoretical.

1.3. 2- (2-amino-5-fluoro-4-chlorophenylamino)

benzonitrile, a compound of the general formula (5)

48.5 g of the compound of formula (4 ′) are dissolved in 670 ml of tetrahydrofuran. Then a solution of 144.7 g of sodium dithionite in 560 ml of water and 45 ml of methanol is added. The reaction mass is kept with stirring for 1 hour. After completion of the reaction, a solution of 70.5 g of sodium bicarbonate in 750 ml of water is added to the reaction mixture. Stirred for 15 minutes. The product is obtained in the form of a light gray powder. Yield 60 g, 65% of theory.

1.4. 11-amino-7-fluoro-8-chloro-5H-dibenzo [b, e] [1,4] diazepine, a compound of the general formula (6)

105 g of the compound of formula (5 ′) are dissolved in 1 l of rectified ethyl alcohol. 68 ml of a concentrated aqueous HCl solution are added to the mixture. The reaction mass is heated to boiling with stirring and boiling is continued for 4-5 hours. Then the mixture was cooled to room temperature and the solvent was removed on EPI. 800 ml of acetonitrile are added to the bottom residue. The mixture is stirred for 15 minutes. The crystals formed are filtered off, squeezed and washed on a filter with 200 ml of acetonitrile. Yield 85 g, 81% of theory.

1.5. 11-amino-7-fluoro-8-chloro-5H-dibenzo [b, e] [1,4] diazepine hydrochloride, a compound of the general formula (7)

124 ml of 3M HCl in dioxane are added to a suspension of 64.9 g of the compound of formula (6 ′) in 45C ml of diethyl ether. The reaction mass is stirred for 30 minutes. The resulting crystals are filtered off, squeezed and washed on the filter with two portions of 150 ml of diethyl ether. Yield 73 g, 98% of theory.

1.6. 11- (4-methylpiperazin-1-yl) -7-fluoro-8-chloro-5H-dibenzo [b, e] [1,4] diazepine, a compound of the general formula (8)

In a 2 L flat-bottomed flask equipped with a magnetic stirrer and reflux condenser, 98 g of the compound of formula (7 ′) were dissolved in toluene: DMSO = 490: 490 ml, 291.7 ml of methylpiperazine were added. The device is purged with argon, the inert gas supply is removed from the balloon (leaving the ball filled with argon) and boiled for 36 hours. The reaction mixture is poured into water and extracted with 150 ml portions of ethyl acetate three times. The combined organic layer was washed with three 150 ml portions of water. It is dried over sodium sulfate and the solvent is distilled off on EPI.

500 ml of chloroform are added to the still residue, and stirred on MPU for 10 minutes. The precipitated crystals are filtered off, squeezed on the filter and washed with 100 ml of methanol on the filter. The product of formula (8 ′) is purified by recrystallization from activated carbon methanol, calculating the solvent volume per 1 g of product — 15 ml of methanol and 10% by weight of the compound of formula (8 ′) activated carbon. Yield 59 g, 61%.

Example 2. Synthesis of 11- (piperazin-1-yl) -7-fluoro-8-chloro-5H-dibenzo [b, e] [1,4] diazepine

In a 2 L flat-bottomed flask equipped with a magnetic stirrer and reflux condenser, dissolve 63 g of the compound of formula (7 ′) in toluene: DMSO = 315: 315 ml, 145.6 g of piperazine are added. The device is purged with argon, the inert gas supply is removed from the balloon (leaving the ball filled with argon) and the reaction mass is boiled for 36 hours. TLC control (dichloromethane: methanol = 20: 1).

The mixture was cooled to room temperature and poured into 2 L of water. Extracted with three portions of 200 ml of ethyl acetate. The combined organic layers are washed with three 100 ml portions of water. Then the organic layer is dried over sodium sulfate.

The organic phase is filtered through a 10 mm silica gel layer and washed on the filter with 2 liters of ethyl acetate. The mother liquor is extracted with 4 Μ hydrochloric acid in water. After this, the aqueous phase is washed with three 150 ml portions of ethyl acetate. Then, with cooling, the aqueous phase is made alkaline with a pre-cooled 4 Na NaOH solution to pH 10. The precipitated crystals are filtered off, squeezed and washed on the filter with three portions of 150 ml of water.

The resulting product of formula (8 ") is recrystallized from toluene (ethanol, methyl ethyl ketone), calculating the volume of solvent per 1 g of product 3 ml of solvent. Yield 45 g, 50% of theory.

Example 3. Synthesis of 11- (4- (2- (2-hydroxyethoxy) ethyl) piperazin-1-yl) -7-fluoro-8-chloro-5H-dibenzo [b, e] [1,4] diazepine

In a 2 L flat-bottomed flask equipped with a magnetic stirrer and reflux condenser, 75 g of the compound of formula (7 ′) are dissolved in toluene: DMSO = 375: 375 ml, 413 ml of 1- [2- (2-hydroxytoxy) ethyl] piperazine are added. The device is purged with argon, the inert gas supply is removed from the cylinder (leaving the ball filled with argon) and boiled for 36 hours. Yield 48 g 61%.

Example 4. 2-methyl-4- (4-methylpiperazin-1-yl) -8-fluoro-7-chloro-10H-benzo [b] thieno [2,3-e] [1,4] diazepine, a compound of the formula (16)

4.1. 2-amino-5-methylthiophene-3-carbonitrile, a compound of the formula (11)

Sulfur (S ₈ , 0.9 g), propionic aldehyde (2 ml) and dimethylformamide (6 ml) are transferred to a three-necked round-bottom flask equipped with a dropping funnel and a refrigerator. The mixture was cooled to 0 ° C. and triethylamine (2.3 ml) was added dropwise. The resulting dark solution is warmed to room temperature for 1 hour. A solution of malononitrile (1.71 ml) in DMF (3.2 ml) is transferred to a funnel and added dropwise. The resulting brown liquid is stirred overnight at room temperature.

The reaction mixture is poured into 80 ml of water and ice, the resulting orange precipitate is filtered off, washed with cold water and dried in vacuum. Yield 78%.

4.2. 5-methyl-2- (2-nitro-5-fluoro-4-chlorophenyl-amino) thiophene-3-carbonitrile, compound of the formula (12)

To 0.26 g of NaH (obtained from a 55% suspension in oil by washing in hexane), 1 ml of anhydrous THF was added. 0.5 g of the compound of formula (11) and 0.7 g of the compound of formula (2) are dissolved in 1.5 ml of anhydrous THF and added dropwise to the NaH suspension, keeping the temperature below 30 ° C. The reaction mixture was stirred overnight under nitrogen.

The mixture was poured into 11 ml of ice-water, neutralized with concentrated HCl, and extracted with 36 ml of dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent ethyl acetate: hexane 1: 9). Yield 0.68 g, 60%.

4.3. 2- (2-amino-5-fluoro-4-chlorophenylamino) -5-methylthiophene-3-carbonitrile, a compound of the formula (13)

0.52 g of the compound of formula (12) is dissolved in 6.7 ml of tetrahydrofuran. Then a solution of 1.45 g of sodium dithionite in 5.6 ml of water and 0.4 to 5 ml of methanol is added. The reaction mass is kept with stirring for 1 hour. After complete reaction, a solution of 0.70 g of sodium bicarbonate in 7.5 ml of water is added to the reaction mixture. Stirred for 15 minutes. The product is obtained in the form of a light gray powder. Yield 0.25 g, 53% of theory.

4.4. 4-amino-2-methyl-8-fluoro-7-chloro-10H-benzo [b] thieno [2,3-e] [1,4] diazepine, compound of the formula (14)

1.13 g of the compound of formula (13) are dissolved in 10 ml of 96% ethanol. 0.68 ml of a concentrated aqueous HCl solution was added to the mixture. The reaction mass is heated to boiling with stirring and boiling is continued for 4-5 hours. Then the mixture was cooled to room temperature and the solvent was removed on EPI. 8 ml of acetonitrile are added to the bottom residue. The mixture is stirred for 15 minutes. The crystals formed are filtered off, squeezed and washed on the filter with 2 ml of acetonitrile. Yield 1 g, 89% of theoretical.

4.5. 4-amino-2-methyl-8-fluoro-7-chloro-10H-benzo [b] thieno [2,3-e] [1,4] diazepine hydrochloride, a compound of the formula (15)

To a suspension of 0.7 g of compound 14 in 4.5 ml of diesel ether was added 1.24 ml of 3M HCl in dioxane. The reaction mass is stirred for 30 minutes. The resulting crystals are filtered off, squeezed and washed on the filter with two portions of 1.5 ml of diethyl ether. Yield 0.78 g, 98% of theory.

4.6. 2-methyl-4- (4-methylpiperazin-1-yl) -8-fluoro-7-chloro-10H-benzo [b] thieno [2,3-e] [1,4] diazepine, compound of the formula (16)

1.2 compounds of 15 are dissolved in toluene: DMSO = 4.9: 4.9 ml, 2.9 ml of methylpiperazine are added. The mixture is boiled under an inert gas atmosphere for 36 hours. The reaction mixture is poured into water and extracted with 1.5 ml portions of ethyl acetate three times. The combined organic layer was washed with three 1.5 ml portions of water. It is dried over sodium sulfate and the solvent is distilled off on EPI. Yield 1.1 g, 77% of theoretical.

Below are the data confirming the increase in purity of the product obtained by the proposed method.

Sample FC No. 1 was synthesized according to standard methods using SnCl ₂ . Analysis of sample No. 1 showed that the content of a single impurity does not exceed 0.332%, and the total content of impurities -1.248%. The study of intermediates showed that the formation of impurities occurs at the stage of reduction of SnCl ₂ .

In FIG. 1 shows the LC MS of the recovery-cyclization product (compound of formula (6 ′)) obtained by the proposed method. It has been suggested that the main impurity formed in the reduction step is a dichlorodibenzodiazepine A-1 derivative.

The hypothesis was confirmed by comparing the LC MS spectrum of the reduction product and dichlorodibenzodiazepine. In FIG. 2 shows LC MS of compound A-1. In FIG. Figure 3 shows the LC MS of a mixture of intermediate 6 ′ and impurity A-1.

Sample fluoroclozapine FC No. 2 was synthesized according to the proposed method, in which the reduction was carried out using sodium dithionite. In FIG. 4 shows a chromatogram of the indicated compound. The peak area in FIG. 4 corresponds to the amount of impurity. It can be seen that the content of the main substance (peak No. 8)> 99.85%, the total content of impurities in the new sample is 0.15%, and the maximum content of a single impurity is 0.047% (peak No. 6). Thus, comparing the data for sample FC No. 1, obtained from the prototype, and data for sample FC No. 2, obtained according to the invention, it is seen that the purity of fluoroclozapine FC No. 2 obtained by the method according to the invention is higher, which confirms the achievement of the technical result. .

The proposed invention is not limited to the embodiments described above, but rather it encompasses various modifications and variations within the spirit and scope of the proposed claims.

Claims (10)

1. The method of obtaining the compounds of formula (1):

where cycle A is phenyl, a 5- or 6-membered heteroaryl containing 1 O atom, or 1 O atom and 1-2 N atoms, or 1 S atom, or 1 S atom and 1-2 N atoms, or 1- 3 N atoms, wherein cycle A is optionally substituted with 1-3 substituents R ₁ ;
cycle B is a 5-7-membered saturated or partially unsaturated heterocycle containing 1 O atom, or 1 O atom and 1-2 N atoms, or 1 S atom, or 1 S atom and 1-2 N atoms, or 1- 3 N atoms, while cycle B is optionally substituted with 1-3 substituents R ₂ ; Where
R ₁ represents hydrogen, C _1-3 alkyl, optionally substituted 1-3 R ₃ , O-C _1-3 -alkyl, optionally substituted 1-3 R ₃ , C _1-3 -alkyl-O-C _1-3 -alkyl optionally substituted with 1-3 R ₃ , or halogen,
R ₂ represents hydrogen, halogen or C _1-3 alkyl optionally substituted with 1-3 R ₃ ,
R ₃ represents halogen or OH,
which includes:
the interaction of 2,4-difluoro-5-nitro-1-chlorobenzene (2) with a compound of the formula (3)

in which cycle A and R _{1 are} defined above, to obtain a compound of formula (4)

reducing said compound of formula (4) with sodium dithionite in a suitable solvent to give a compound of formula (5)

cyclization of said compound of formula (5) to form a compound of formula (6)

crystallization from said compound of formula (6) a compound of formula (7)

in a suitable solvent;
the interaction of the specified compounds of formula (7) with an amino derivative of the formula (9)

in which cycle B and R _{2 are} defined above, to obtain a compound of formula (8)

2. The method according to p. 1, in which the interaction of the compounds of formula (2) with the compound of the formula (3) is carried out in the presence of KF, heating the reaction mixture for 5-6 days at 140-180 ° C. 3. The method according to p. 1, in which the interaction of the compounds of formula (2) with the compound of the formula (3) is carried out under basic conditions in a polar aprotic solvent. 4. The method according to p. 3, in which NaH, KH, t-BuOK, LiOH or CsCO ₃ are used as the base. 5. The method according to p. 3, in which dimethylformamide, Ν-methylpyrrolidone, DMSO or THF is used as a solvent. 6. The method according to p. 1, in which the interaction of the compounds of formula (7) with the compound of the formula (9) is carried out in an aprotic solvent. 7. The method according to claim 6, in which DMSO or toluene is used as a solvent. 8. The method according to p. 1, in which the cyclization is carried out under acidic conditions. 9. The method according to p. 1, in which at the stage of crystallization, diethyl ether, methyl tert-butyl ether, and dioxane are used as a solvent. 10. The method of claim 1, wherein THF, 2-methyltetrahydrofuran, cyclopentyl methyl ether are used as a solvent in the reduction step.

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