WO2018003867A1 - Method for producing n-(3,5-dichloropyrid-4-yl)-n-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide - Google Patents

Abstract

The present invention provides a method for producing a compound represented by formula (I), which comprises a step for obtaining a compound represented by formula (I) by reacting a compound represented by formula (II) and an alkali metal salt represented by formula (III) with each other. (In the formulae, X represents a halogen atom or a C_1-4 alkyl carbonyloxy group; and M represents an alkali metal ion.)

Description

Process for producing N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

The present invention relates to a process for producing N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide.

Phosphodiesterase (PDE) inhibitors are known to be effective for treating inflammatory diseases. In particular, PDE4 inhibitors are effective in the treatment of inflammatory diseases of the respiratory tract such as asthma or airway obstruction (eg, COPD = chronic obstructive pulmonary disease). PDE4 inhibitors include N- (3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (also called roflumilast). Patent Documents 1 to 3 are known as methods for producing roflumilast.

International Publication No. 95/01338 International Publication No. 1994/002465 International Publication No. 2004/080967 International Publication No. 2016/063906

The present inventors have found that compounds such as N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide are useful as prodrugs for roflumilast, It was found to have skin permeability (see Patent Document 4).

However, in order to produce N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide using roflumilast as a raw material, it is necessary to purchase expensive roflumilast. is there. There is also a problem that it is difficult to remove unreacted roflumilast.

On the other hand, Non-Patent Document 1 discloses that N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide was produced, but Roflumilast Only Patent Document 3 and Non-Patent Document 2 that disclose the production method are cited, and specific methods, yields, and the like are not described (see Patent Document 3, Non-Patent Documents 1 and 2).

Accordingly, an object of the present invention is to provide a compound represented by formula (I) (N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, “compound (I) is also provided in a high yield and high purity.

The present inventors have found a method for producing compound (I), which includes a step of obtaining compound (I) by reacting compound (II) with alkali metal salt (III).

[Wherein, X represents a halogen atom or a C _1-4 alkylcarbonyloxy group, and M represents an alkali metal ion. ]

The method preferably includes reacting compound (IV) with an alkali metal hydride or alkali metal alkoxide to obtain an alkali metal salt (III). A preferred alkali metal is sodium.

According to the present invention, a new method for producing compound (I) can be provided. Moreover, according to the method of the present invention, compound (I) can be obtained in high yield and high purity.

One embodiment of the present invention is a method for producing compound (I), comprising the step of obtaining compound (I) by reacting compound (II) with alkali metal salt (III). In the formula, X represents a halogen atom or a C _1-4 alkylcarbonyloxy group, and M represents an alkali metal ion.

This embodiment includes a step (step A) of reacting compound (II) with alkali metal salt (III) to obtain compound (I). In the formula, X represents a halogen atom or a C _1-4 alkylcarbonyloxy group, and M represents an alkali metal ion.

Compound (II) is a compound in which the carboxyl group of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is more activated, and X in formula (II) represents a halogen atom or a C _1-6 alkylcarbonyloxy group. Show.

Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom, and a preferred halogen atom is a chlorine atom.

The C _1-6 alkylcarbonyloxy group is a group in which a carbonyloxy group is bonded to an alkyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkylcarbonyloxy group include acetyl group, propionyl group, butyryl group, 2-methylpropionyl group, pentanoyl group, 2-methylbutyryl group, 3-methylbutyryl group, pivaloyl group, hexanoyl group, 2-methyl Examples include a pentanoyl group, a 3-methylpentanoyl group, and a 4-methylpentanoyl group.

The alkali metal salt (III) is a salt composed of an anion obtained by deprotonation of the amine nitrogen of the compound (IV) and an alkali metal ion.

Examples of the alkali metal include lithium, sodium and potassium. The preferred alkali metal is sodium.

The number of moles of the alkali metal salt (III) used is preferably 1 to 10 times, and more preferably 1 to 3 times, based on the number of moles of the compound (II).

Process A is usually performed in a solvent. The solvent should just be what does not inhibit reaction of the process A. Examples of the solvent include dichloromethane, toluene, xylene, tetrahydrofuran, dimethylformamide, and N-methylpyrrolidone. A preferred solvent is toluene or tetrahydrofuran.

In step A, alkali metal salt (III) or a solution thereof may be added to compound (II) or a solution thereof, and compound (II) or a solution thereof is added to alkali metal salt (III) or a solution thereof. May be. Compound (II) or a solution thereof is preferably added to alkali metal salt (III) or a solution thereof.

The reaction temperature in step A is usually between 0 ° C. and the boiling point of the solvent used. A preferable reaction temperature is 0 to 100 ° C., and a more preferable reaction temperature is 5 to 35 ° C.

The obtained compound (I) can be purified by a method that can be used by those skilled in the art in the field of organic chemistry.

This embodiment may further comprise preparing compound (II) from 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (step B). In the formula, X represents a halogen atom or a C _1-4 alkylcarbonyloxy group.

Step B is a step for preparing compound (II) by adding an activator to a solution containing, for example, 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and an organic solvent.

The activator is a reagent that activates the carboxyl group of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. Examples of the activator include thionyl chloride, oxalyl chloride, and pivaloyl chloride. When the activator is thionyl chloride or oxalyl chloride, X in formula (II) is a chlorine atom, and when the activator is pivaloyl chloride, X in formula (II) is a pivaloyloxy group.

The amount of the activator is preferably 1 to 10 times, and more preferably 1 to 3 times, based on the number of moles of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid.

When the activator is thionyl chloride or oxalyl chloride, N, N-dimethylformamide (DMF) is used to promote the reaction between 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and the activator. It may be added. The amount of DMF used may be 1 to 5% by weight or 1 to 3% by weight based on the weight of thionyl chloride. By adding DMF, the production of by-products such as compounds from which chlorine atoms or cyclopropylmethyl groups are eliminated tends to be suppressed.

The organic solvent may be any one that does not inhibit the reaction in the step B. Examples of the organic solvent include tetrahydrofuran, toluene, and xylene. A preferred organic solvent is toluene.

The reaction temperature in Step B is usually 0 to 100 ° C., preferably 30 to 60 ° C.

As a specific example of the process B, the following method is used. To a toluene solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, a catalytic amount of DMF is added, heated to 40-50 ° C., and then thionyl chloride is slowly added. After the thionyl chloride was added, the resulting reaction mixture was stirred at 40-50 ° C., and after a specified time, the reaction mixture was concentrated under reduced pressure to give 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl. Get the chloride. The resulting 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride can be subjected to the next reaction without further purification.

The present embodiment may further include a step (step C) of preparing the alkali metal salt (III) by reacting the compound (IV) with an alkali metal hydride or an alkali metal alkoxide. In the formula, M represents an alkali metal ion.

Examples of the alkali metal hydride include sodium hydride and potassium hydride. The number of moles of alkali metal hydride is preferably 1 to 10 times greater, more preferably 1 to 3 times greater, based on the number of moles of compound (IV).

Examples of the alkali metal alkoxide include sodium methoxide, sodium ethoxide, sodium propoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium n-butoxide and potassium t- Butoxide is mentioned. A preferred alkali metal alkoxide is sodium t-butoxide. The number of moles of alkali metal alkoxide is preferably 1 to 10 times greater, more preferably 1 to 3 times greater, based on the number of moles of compound (IV).

Step C is preferably performed in a solvent. Any solvent may be used as long as it does not inhibit the reaction in Step C, and examples thereof include tetrahydrofuran.

The reaction temperature in step C is preferably 0 to 45 ° C.

As a specific example of Step C, for example, sodium hydride is added little by little at a temperature of 10 to 25 ° C. with stirring to a tetrahydrofuran solution of Compound (IV). According to this method, deprotonation of compound (IV) can proceed under mild conditions, and a salt of compound (IV) and sodium ion can be prepared.

Compound (IV) can be prepared from 4-cyano-3,5-dichloropyridine by the method described in Non-Patent Document 3, for example.

This embodiment may further comprise preparing compound (IV) by reacting readily available 4-amino-3,5-dichloropyridine with a methylating agent in the presence of a base (step D). Good.

Examples of the base include alkali metal hydrides and alkali metal alkoxides. Specific examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium propoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium n-butoxide, potassium t-butoxide and the like. A preferred base is sodium hydride or potassium t-butoxide. The number of moles of the base is preferably 1 to 10 times greater, more preferably 1 to 3 times greater, based on the number of moles of 4-amino-3,5-dichloropyridine.

Examples of the methylating agent include halogenated methane such as iodomethane and bromomethane, and dimethyl sulfate. Preferred methylating agents are iodomethane or dimethyl sulfate. The number of moles of the methylating agent is preferably 1 to 10 times, and more preferably 1 to 3 times, based on the number of moles of 4-amino-3,5-dichloropyridine.

Step D is preferably performed in an organic solvent. The organic solvent should just be what does not inhibit a monomethylation reaction. Examples of the organic solvent include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. A preferred organic solvent is tetrahydrofuran.

Favorable conditions for step D are, for example, the following methods. 4-Amino-3,5-dichloropyridine is dissolved in tetrahydrofuran, potassium t-butoxide is slowly added with stirring, further iodomethane is added, and the resulting reaction mixture is stirred at 5-15 ° C. for 2 hours. Water and isopropyl acetate are added to the reaction mixture and stirred, and then the organic layer is separated. The organic layer is washed successively with water and saturated brine, and the organic layer is concentrated. According to this condition, the generation of by-products such as 3,5-dichloro-4- (dimethylamino) pyridine and 3,5-dichloro-1-methyl-4- (methylamino) pyridinium can be further suppressed. The compound (IV) with high purity can be obtained by a simpler operation. By suppressing the production of the by-product having physical properties similar to those of compound (IV), high-purity compound (I) can be obtained by a simpler operation in the subsequent steps.

Compound (I) is excellent in water solubility and transdermal absorbability, and is rapidly converted into roflumilast in vivo.

Compound (I) can exert effects that can be expected by administration of roflumilast. That is, by administering the compound or a pharmaceutical composition containing the compound, acute and chronic (especially performance and allergen-induced) airway diseases (eg, bronchitis, allergic bronchitis, bronchial asthma, Emphysema, chronic obstructive pulmonary disease (COPD), proliferative, inflammatory or allergic skin diseases (eg psoriasis (eg psoriasis vulgaris), toxic and allergic contact dermatitis, atopic dermatitis, Seborrheic dermatitis, lichen planus, sunburn, pruritus in the genital area, alopecia, hypertrophic scar, discoid lupus erythematosus, follicular and pervasive pyoderma, intrinsic and extrinsic acne, Tadpole So and other proliferative, inflammatory and allergic skin diseases), diseases based on excessive release of TNF by leukotrienes (eg rheumatoid arthritis, rheumatoid arthritis) Spondylitis, osteoarthritis and other arthritic conditions), immune system diseases (eg AIDS, multiple sclerosis), shocks (eg septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome) And ARDS (Adult Respiratory Disorder Syndrome)), diffuse inflammation in the gastrointestinal region (eg, Crohn's disease, ulcerative colitis), allergic properties in the upper respiratory tract region (pharyngeal cavity, nose) and its adjacent regions (sinus sinus, eye) And / or diseases based on chronic abnormal immune responses (eg allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps) and diseases that can be treated with PDE inhibitors (eg Treatment of heart diseases such as heart failure, erectile dysfunction, kidney and ureteral colic associated with kidney stones, depression, arteriosclerotic dementia, etc. It can be preventing.

Synthesis Example 1: Preparation of 3,5-dichloro-4- (methylamino) pyridine A solution of 862 g (10.0 v / w) of tetrahydrofuran in 100 g (613.5 mmol) of 4-amino-3,5-dichloropyridine under an argon stream After cooling to 8 ° C., 103.54 g (922.7 mmol) of potassium t-butoxide was added and stirred for 30 minutes. After the reaction mixture was cooled to 4 ° C., 113.24 g (797.8 mmol) of iodomethane was added dropwise and stirred for 2 hours. 8.79 g (61.9 mmol) of iodomethane was added dropwise, and the mixture was further stirred for 2 hours. To the obtained reaction mixture, 501 g (5.00 v / w) of water and 430 g (5.00 v / w) of isopropyl acetate were added and stirred for 6 minutes, and then the organic layer was separated. The aqueous layer was extracted with 255 g (3.00 v / w) of isopropyl acetate. The combined organic layers were washed successively with water and 20% by mass brine and concentrated under reduced pressure. After adding 50 mL of n-heptane to the obtained residue, the mixture was stirred for 1 hour under ice cooling. The precipitated solid was filtered and washed with 75 mL of cold n-heptane. The obtained solid was dried by ventilation at 40 ° C. to obtain 56.45 g (yield 52%) of a crude product of 3,5-dichloro-4- (methylamino) pyridine as tan needles.
A solution of 43.3 g of a crude product of 3,5-dichloro-4- (methylamino) pyridine in methanol and 172 g of methanol was heated to 54 ° C. under an argon stream, 217 g of water was added, and the mixture was heated to 72 ° C. over 40 minutes. Cooled with stirring to 25 ° C. over 2 hours. The solution was stirred at 25 ° C. for a further 2 hours. The precipitated solid was filtered, washed twice with water-containing methanol (methanol: water = 1: 2, volume ratio) and dried by ventilation to give 37.15 g (purity 99.6%) of the title compound as yellowish white needle-like crystals. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.32 (d, J = 7 Hz, 3H), 4.84 (brs, 1H), 8.15 (s, 2H).

Synthesis Example 2: Preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride Under an argon stream, 4-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 45.0 g (174.3 mmol) of toluene 238 g (6.00 v / w) 0.43 g of DMF was added to the solution, and 41.42 g (348.6 mmol) of thionyl chloride was added dropwise. The reaction mixture was heated to 40 ° C. and stirred for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue, 200 g (5.00 v / w) of tetrahydrofuran was added and subjected to the next reaction.

Synthesis Example 3: Preparation of N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide 3,5-dichloro-4- (methylamino) under an argon stream ) A solution of 35.3 g (199.4 mmol) of pyridine in 355 g (10.00 v / w) of tetrahydrofuran was cooled to 4 ° C., and sodium hydride (content 63%, 16.46 g, 433.7 mmol) was slowly added. The mixture was stirred for 1 hour while maintaining about 15 ° C. The obtained reaction mixture was cooled to 9 ° C. and a solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride in tetrahydrofuran prepared in Synthesis Example 2 (228 g, 40 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid ( 155 mmol)) was added dropwise over 80 minutes. After dropping, the mixture was stirred overnight while the temperature was raised from 9 ° C to room temperature.
To the obtained reaction mixture, 40.2 g of 35% hydrochloric acid, 401 g (10.00 v / w) of water and 180 g (5.00 v / w) of ethyl acetate were added and stirred at 10 ° C. for 50 minutes. 200 g of 10 w / w% potassium carbonate aqueous solution was added, and the mixture was further stirred at 18 ° C. for 5 minutes to separate the organic layer. The obtained organic layer was washed with 200 g of 10% brine, the insoluble matter was filtered, washed with 20 mL of ethyl acetate, and then concentrated under reduced pressure. The obtained residue was purified by a conventional method to obtain 52.65 g (yield 82%, purity 99.8%) of the title compound.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.32 (m, 2H), 0.63 (m, 2H), 1.20 (m, 1H), 3.31 (s, 3H), 3.76 (D, 2H), 6.57 (t, 1H), 6.90 (dd, 1H), 6.94 (d, 1H), 7.08 (d, 1H), 8.48 (s, 2H) .

Compound (I) was produced with reference to the synthesis method of roflumilast described in Patent Document 3. Specific methods are shown as Comparative Synthesis Examples 1 and 2.

Comparative Synthesis Example 1: Preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride Under a nitrogen stream, DMF36 was added to a 20 mL toluene solution of 3.5 g (13.6 mmol) 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. After adding .8 μL, 2.42 g (20.3 mmol) of thionyl chloride was added dropwise. After the addition, the reaction mixture was heated to 75 ° C. and stirred for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 8 mL of DMF was added and subjected to the next reaction.

Comparative Synthesis Example 2: Preparation of N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide Under a nitrogen stream, 4-methylamino-3,5-dichloro Pyridine 5.27 g (29.8 mmol) was dissolved in DMF (32.4 mL), and potassium tert-butoxide 3.33 g (29.8 mmol) was gradually added at 18-30 ° C. To the obtained reaction mixture, at 23 to 30 ° C., 12.1 g of a DMF solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride (3.5 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, 13. 6 equivalents) was added dropwise over 75 minutes. After the addition, the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, 17.5 mL of water was added dropwise, and concentrated hydrochloric acid was added to adjust to pH 2. After standing at room temperature for 2 days, the precipitated solid was collected by filtration and washed with water. The obtained solid was suspended in 22.4 g of an aqueous sodium hydroxide solution having a pH of 10 and stirred for 30 minutes. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure to give 3.54 g (yield 62%, purity 99.4%) of crude crystals of the title compound. The obtained crude crystals (3.00 g) were recrystallized from hydrous isopropyl alcohol to obtain 2.14 g (recovery: 71%, purity: 99.8%) of the title compound.

According to the method for producing compound (I) according to this embodiment, compared to the case of producing compound (I) according to the method for producing roflumilast described in Patent Document 3, a high yield (82% yield). ) And high purity (purity 99.8%), the compound (I) can be obtained, which is industrially useful.

Claims (4)

1. A compound represented by formula (I), comprising a step of obtaining a compound represented by formula (I) by reacting a compound represented by formula (II) with an alkali metal salt represented by formula (III) Manufacturing method.
   

   

   [Wherein, X represents a halogen atom or a C _1-4 alkylcarbonyloxy group, and M represents an alkali metal ion. ]
2. The method according to claim 1, comprising reacting a compound represented by the formula (IV) with an alkali metal hydride or an alkali metal alkoxide to obtain an alkali metal salt represented by the formula (III).
   

   
3. The method according to claim 1 or 2, wherein the alkali metal is sodium.
4. The method according to any one of claims 1 to 3, wherein X is a halogen atom.