Eutectic compound as well as preparation method and application thereof

Abstract

The invention provides a 4-bromo-2-isopropyl phenol 4-dimethylaminopyridine eutectic compound, a preparation method of the 4-bromo-2-isopropyl phenol 4-dimethylaminopyridine eutectic compound, and a method for preparing gefarpinene or a salt of gefarpinene by using the 4-bromo-2-isopropyl phenol 4-dimethylaminopyridine eutectic compound. The method provided by the invention is high in yield, low in raw material price, easy in intermediate separation, simple to operate and very suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a 4-bromo-2-isopropylphenol 4-dimethylaminopyridine eutectic compound and a preparation method and application thereof. Background Art

[0002] Gefapixel is an investigational oral, selective P2X3 receptor antagonist developed by Merck for the treatment of intractable or unexplained chronic cough. Its chemical structure is as follows:

[0003]

[0004] 4-Bromo-2-isopropylphenol is an important intermediate in the preparation of gefapizoline, but it is difficult to crystallize, which has an adverse effect on purification and operation during the industrial preparation process. Summary of the invention

[0005] The object of the present invention is to provide a 4-bromo-2-isopropylphenol-4-dimethylaminopyridine eutectic compound, the structural formula of which is shown below:

[0006]

[0007] In one embodiment, the 4-bromo-2-isopropylphenol-4-dimethylaminopyridine cocrystal compound powder X-ray diffraction spectrum 2θ values ​​have diffraction peaks at 7.7±0.2°, 15.6±0.2°, 18.5±0.2°, 21.9±0.2°, 22.4±0.2°, and 25.4±0.2°.

[0008] In one embodiment, the 4-bromo-2-isopropylphenol-4-dimethylaminopyridine eutectic compound powder X-ray diffraction spectrum 2θ values ​​have diffraction peaks at 7.7±0.2°, 10.5±0.2°, 13.0±0.2°, 15.6±0.2°, 16.8±0.2°, 18.5±0.2°, 21.9±0.2°, 22.4±0.2°, and 25.4±0.2°.

[0009] In one embodiment, the co-crystal compound has Figure 1 Powder X-ray diffraction pattern shown.

[0010] In one embodiment, a method for preparing a 4-bromo-2-isopropylphenol-4-dimethylaminopyridine cocrystal compound is provided, comprising the steps of converting 2-isopropylphenol into a 4-bromo-2-isopropylphenol-4-dimethylaminopyridine cocrystal:

[0011]

[0012] In one embodiment, 2-isopropylphenol is subjected to a bromination reaction to form 4-bromo-2-isopropylphenol, and 4-bromo-2-isopropylphenol is then treated with dimethylaminopyridine, and the solid co-crystal shown in Compound 3 is obtained by separation.

[0013] In one embodiment, 2-isopropylphenol is treated with N-bromosuccinimide, methanesulfonic acid and a solvent such as acetonitrile to form 4-bromo-2-isopropylphenol, and the above conversion is carried out at a temperature of about -5°C to 10°C, or more specifically at a temperature of about -5°C to 0°C. 4-bromo-2-isopropylphenol is then treated with dimethylaminopyridine to produce a solid co-crystal of 4-bromo-2-isopropylphenol and dimethylaminopyridine. Preferably, the precipitated 4-bromo-2-isopropylphenol 4-dimethylaminopyridine co-crystal is formed in a mixed solvent of toluene and n-heptane, and then the 4-bromo-2-isopropylphenol 4-dimethylaminopyridine co-crystal is isolated as a solid.

[0014] Another aspect of the present invention provides the use of a 4-bromo-2-isopropylphenol-4-dimethylaminopyridine cocrystal compound in the preparation of compound 1 or a pharmaceutically acceptable salt thereof. The structure of compound 1 is shown below:

[0015]

[0016] Another aspect of the present invention provides a method for preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising the step of converting 2-isopropylphenol shown in Compound 2 into 4-bromo-2-isopropylphenol 4-dimethylaminopyridine cocrystal shown in Compound 3:

[0017]

[0018] The method for converting compound 2 to compound 3 is the same as described above.

[0019] Another aspect of the present invention provides a method for preparing Compound 1 or a pharmaceutically acceptable salt thereof, comprising the step of reacting the 4-bromo-2-isopropylphenol-4-dimethylaminopyridine cocrystal shown in Compound 3 with sodium methoxide to form 2-isopropyl-4-methoxyphenol shown in Compound 4:

[0020]

[0021] In one embodiment, the above reaction is carried out in the presence of a copper salt as a catalyst, preferably copper bromide.

[0022] In one embodiment, the above reaction is carried out in the presence of methanol and DMF.

[0023] In one embodiment, 2-isopropyl-4-methoxyphenol is extracted with an organic solvent and water and separated into layers, wherein the organic solvent is preferably toluene, and the organic phase is separated and the solvent is evaporated to obtain 2-isopropyl-4-methoxyphenol in the form of an oil.

[0024] In one embodiment, the method of the present invention further comprises the step of reacting 2-isopropyl-4-methoxyphenol shown in compound 4 with halogenated acetonitrile shown in compound 5 to form 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile:

[0025]

[0026] In one embodiment, the above reaction is carried out in the presence of NMP and toluene. Other polar aprotic solvents may also be used instead.

[0027] In one embodiment, the above reaction is carried out in the presence of a base. In one embodiment, the base is NaOH. Other hydroxide or carbonate bases may also be used.

[0028] In one embodiment, the halogenated acetonitrile is, for example, chloroacetonitrile, bromoacetonitrile, iodoacetonitrile. In one embodiment, the halogenated acetonitrile is chloroacetonitrile.

[0029] In one embodiment, the above reaction is carried out at a temperature of about 0°C to about 10°C.

[0030] In one embodiment, the method of the present invention further comprises the step of converting the 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile compound shown in the following formula 5 into 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine shown in compound 6:

[0031]

[0032] In one embodiment, the above conversion is carried out by first reacting 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile with ethyl formate in the presence of a strong base such as potassium tert-butoxide in a mixed solvent such as toluene and NMP, and then directly mixing with a guanidine source for further reaction to obtain 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine.

[0033] In one embodiment, the source of guanidine is guanidine hydrochloride. In another embodiment, other salt forms of guanidine may be used, including guanidine carbonate and guanidine bisulfate.

[0034] In one embodiment, the above reaction between the mixture and guanidine is carried out at between about 95°C and 110°C.

[0035] In one embodiment, toluene is distilled off from the reaction mixture prior to crystallization and water is then added to precipitate a solid.

[0036] In one embodiment, the method of the present invention further comprises reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine shown in compound 6 with chlorosulfonic acid, followed by reacting with ammonia to form compound 1:

[0037]

[0038] In one embodiment, ammonia is introduced as aqueous ammonia. In another embodiment, other ammonium salts may be used. In another embodiment, ammonia in an organic solvent is used.

[0039] In one embodiment, the above reaction between 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and chlorosulfonic acid is carried out in the presence of acetonitrile.

[0040] In one embodiment, the above reaction between 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and chlorosulfonic acid is carried out at a temperature of about 25°C to about 45°C.

[0041] In one embodiment, the free base of compound 1 can be prepared in a mixed solvent containing DMSO and an anti-solvent, wherein the anti-solvent is an alcohol solvent or acetonitrile, and the alcohol solvent can be a C1-C3 lower alcohol, such as methanol, ethanol, isopropanol for crystallization. According to a preferred embodiment of the present invention, the amount of DMSO required per gram of the free base of compound 1 is 5-7 ml. According to a preferred embodiment of the present invention, the amount of anti-solvent required per gram of the free base of compound 1 is 9-10 ml. The crystallization system described in the present invention is very beneficial to impurity control and improvement of product purity.

[0042] In one embodiment, the free base of compound 1 is dissolved in DMSO, and then an anti-solvent is added to precipitate the product. The dissolution can be carried out under heating conditions, for example, heating to 45-55°C; after the product is precipitated, it can be further cooled to a constant temperature or below for precipitation.

[0043] In one embodiment, the method of the present invention further comprises the step of converting the free base of Compound 1 into Compound 1 or a pharmaceutically acceptable salt thereof. The Compound 1 or a pharmaceutically acceptable salt thereof is preferably a citrate salt of Compound 1.

[0044] In one embodiment, the method for preparing Compound 1 or a pharmaceutically acceptable salt thereof comprises the following steps:

[0045] (a) Converting 2-isopropylphenol into 4-bromo-2-isopropylphenol / 4-bromo-2-isopropylphenol / 4-dimethylaminopyridine cocrystal:

[0046]

[0047] (b) Converting 4-bromo-2-isopropylphenol 4-bromo-2-isopropylphenol 4-dimethylaminopyridine cocrystal into 2-isopropyl-4-methoxyphenol in the presence of sodium methoxide:

[0048]

[0049] (c) reacting 2-isopropyl-4-methoxyphenol with chloroacetonitrile to form 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile:

[0050]

[0051] (d) Converting 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile into 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine:

[0052]

[0053] and

[0054] (e) reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with chlorosulfonic acid, followed by reaction with aqueous ammonia to form compound 1, and optionally, converting compound 1 into a pharmaceutically acceptable salt thereof:

[0055]

[0056]

[0057] The preparation method provided by the invention has high yield, cheap raw materials, easy separation of intermediates, simple operation and is very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 is the powder X-ray diffraction pattern of compound 3 prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0059] The following examples are intended to illustrate only and are not intended to be limiting in any way. The abbreviations used herein and in the specification are conventional abbreviations in the art or are as follows:

[0060] DABCO 1,4-diazabicyclo[2.2.2]octane

[0061] NMP N-Methyl-2-pyrrolidone

[0062] DSMO Dimethyl sulfoxide

[0063] DMF N,N-Dimethylformamide

[0064] Detection conditions of powder X-ray diffractometer:

[0065] Powder X-ray diffractometer: BRUKER D8 Advance

[0066] Tube type: Ceramic X-ray tube (copper target)

[0067] Voltage and current: 40kV, 40mA

[0068] Goniometer: Vertical goniometer, radius 280mm

[0069] Slit: Divergence slit: 0.6mm, Sola slit: 2.5°

[0070] Detector: LYNXEYE detector

[0071] Scan mode: Continuous scan

[0072] Scanning range (2θ): 3.0°-40.0°

[0073] Step size (2θ): 0.02°

[0074] Each step counting time: 0.2s

[0075] Total scanning time: 370s

[0076] Example 1: Preparation of 4-bromo-2-isopropylphenol 4-dimethylaminopyridine cocrystal (Compound 3)

[0077] Compound 2 (50.0 g, 3671 mmol) was mixed with 150 mL of acetonitrile and methanesulfonic acid (0.35 g, 3.671 mmol), N-bromosuccinimide (65.3 g, 3671 mmol) was added, and the mixture was reacted at -5°C to 0°C. After the reaction of compound 2 was completed, the mixture was heated to 20°C, 300 mL of water and 150 mL of toluene were added for extraction, 100 mL of 9% phosphoric acid aqueous solution was added to the organic phase for washing, 50 mL of toluene was added to the aqueous phase for back extraction once, the organic phases were combined and washed once with 100 mL of 5% sodium chloride aqueous solution, the organic phase was concentrated to dryness at 50°C, toluene was added to a volume of 200 mL, 4-dimethylaminopyridine (44.85 g, 3671 mmol) was added, 600 mL of n-heptane was added to precipitate a solid, the mixture was stirred at low temperature for 2 hours, filtered, and washed with n-heptane to obtain an off-white solid, which was dried in vacuo at 25°C to obtain compound 3 with a purity of 99.5% and a yield of 89.0%. Its powder X-ray diffraction pattern is as follows Figure 1 shown.1 H NMR(600MHz,DMSO)δ9.66(s,1H),8.10(d,J=6.3Hz,2H),7.20(d,J=2.3Hz,1H),7.14(dd,J=8.5,2.4Hz,1H),6 .74(d,J=8.5Hz,1H),6.58(d,J=6.3Hz,2H),3.17(dt,J=13.8,6.9Hz,1H),2.94(s,6H),1.14(d,J=6.9Hz,6H).

[0078] Example 2: Preparation of Compound 4

[0079] The above-mentioned compound 3 (80.0 g, 2372 mmol) was added to a mixed solution of 30% sodium methoxide methanol solution (192.2 g, 10670 mmol) and 40 mL DMF, and CuBr (1.7 g, 12.1 mmol) was added. The temperature was raised to 70° C., and the reaction of compound 3 was detected to be complete. 240 mL of 6 mol HCl was added, and the pH was <5. 320 mL of toluene and 480 mL of water were added for extraction. The organic phase was washed twice with 160 mL of water, and the organic phase was concentrated to dryness at 50° C. to obtain compound 4 as a red oil with a purity of 96.3% and a yield of about 98.0%. 1 HNMR (600MHz, DMSO) δ8.77(s,1H),6.67(dd,J=11.3,5.8Hz,2H),6.56(dd,J=8.6,2.9Hz,1H),3.65(s,3H),3.22–3.08(m,1H),1.14(d,J=6.9Hz,6H).

[0080] Example 3: Preparation of Compound 5

[0081] Compound 4 (38.0 g, 228.6 mmol) was added to 19.0 g of toluene, and then 190 mL of NMP was added, and 50% sodium hydroxide aqueous solution (27.4 g, 342.9 mmol) was added dropwise at low temperature. After the addition was complete, chloroacetonitrile (25.9 g, 342.9 mmol) was added dropwise. The reaction of compound 4 was detected to be complete. 152 mL of toluene and 228 mL of water were added dropwise at low temperature for extraction. The organic phase was washed once with 76 mL of water, and once with 76 mL of 20% sodium chloride aqueous solution. The organic phase was concentrated to dryness at 50° C. to obtain compound 5 as a yellow-brown oil with a purity of 96.5% and a yield of about 95.0%. 1H NMR (600MHz, DMSO) δ7.05 (d, J = 8.8 Hz, 1H), 6.84–6.75 (m, 2H), 5.11 (s, 2H), 3.72 (s, 3H), 3.20 (s, 1H), 1.16 (d, J = 6.9 Hz, 6H).

[0082] Example 4: Preparation of Compound 6

[0083] Potassium tert-butoxide (49.2 g, 438.5 mmol) was added to 200 mL of NMP, and a mixed solution of compound 5 (40.0 g, 194.9 mmol), ethyl formate (28.8 g, 389.8 mmol) and 80 mL of toluene was slowly added dropwise at -5°C to 0°C. The reaction of compound 5 was detected to be complete, and 148.9 g of guanidine hydrochloride (148.9 g, 15590 mmol) was added. The temperature was raised to 108°C and stirred for 6-8 hours, then cooled to 50°C, 220 mL of water was added, and toluene was distilled off. The temperature was raised to 85°C and stirred for 2 hours, 220 mL of water was added, and the temperature was slowly lowered to 20°C and stirred for 10 hours. The mixture was filtered, washed with NMP: water = 1:2, and washed with water to obtain a gray solid, which was dried under vacuum at 50°C for 12 to 16 hours to obtain compound 6 with a purity of 98.7% and a yield of 91.0%. 1 H NMR (600MHz, DMSO) δ7.24(s,1H),6.83(d,J=2.6Hz,1H),6.70(dd,J=8.8,2.7Hz,1H),6.63(d,J =8.8Hz,1H),6.34(s,2H),5.77(s,2H),3.71(s,3H),3.33–3.27(m,1H),1.21(d,J=6.9Hz,6H).

[0084] Example 5: Preparation of Compound 1

[0085] Compound 6 (10.0 g, 36.5 mmol) was added to 30 mL of acetonitrile, and chlorosulfonic acid (23.4 g, 200.8 mmol) was slowly added dropwise at -5°C-0°C, and the temperature was raised to 25°C and stirred for 1 hour, and then raised to 45°C and stirred for 6-10 hours. The reaction of compound 5 was detected to be complete, and 50 mL of ammonia water and 15 mL of acetonitrile were added dropwise at -5°C-0°C, and the temperature was raised to 10°C and stirred for 1 hour, and then raised to 25 ℃ and stirred for 1 hour, 40mL of 50% sodium hydroxide aqueous solution and 120mL of water were added, the temperature was raised to 35℃ and stirred for 1 hour, the temperature was lowered to 20℃, 30% citric acid aqueous solution was added dropwise to adjust the pH to 10.5-11.3, a solid was precipitated, the mixture was stirred for 2 hours, filtered with suction, and washed with water to obtain an off-white solid, which was dried in vacuo at 55℃ for 12-16 hours to obtain a crude compound 1 with a purity of 96.2% and a yield of 89.0%. The crude compound 1 was added to 60mL of DMSO, the temperature was raised to 45-55℃ and dissolved, 100mL of methanol was added dropwise, a solid was precipitated after the dropwise addition, the temperature was slowly lowered to 0℃ and stirred for 4 hours, filtered with suction, and washed with methanol to obtain a white solid, which was dried in vacuo at 45℃ for 12-16 hours to obtain compound 1 with a purity of 99.4% and a yield of 85.0%. 1 H NMR (600MHz, DMSO) δ7.36 (s, 1H), 7.08 (s, 1H), 7.00 (d, J = 10.8Hz, 3H), 6.39 (s,2H),5.86(s,2H),3.90(s,3H),3.45–3.38(m,1H),1.27(d,J=6.9Hz,6H).

[0086] Embodiment 6:

[0087] The crude compound 1 of Example 5 was replaced with the following solvents, and the experimental data obtained were as follows:

[0088] Example Recrystallization solvent dosage Recrystallization solvent Purity after purification Yield Example 6 160ml DMSO:acetonitrile=7:9 99.5％ 85.0％

Claims

1. The co-crystal compound shown in compound 3 has the following structural formula:

2. The cocrystal compound of Compound 3 according to claim 1 has a powder X-ray diffraction spectrum with 2θ values ​​having diffraction peaks at 7.7±0.2°, 15.6±0.2°, 18.5±0.2°, 21.9±0.2°, 22.4±0.2°, and 25.4±0.2°, and further preferably has a powder X-ray diffraction pattern as shown in Figure 1.

3. A method for preparing the cocrystal compound shown in Compound 3, comprising the step of converting Compound 2 into the cocrystal compound of Compound 3:

4. The preparation method according to claim 3 comprises subjecting compound 2 to a bromination reaction to form 4-bromo-2-isopropylphenol, treating 4-bromo-2-isopropylphenol with dimethylaminopyridine, and separating to obtain a solid eutectic shown in compound 3.

5. Use of the cocrystal compound of claim 1 in the preparation of compound 1 or a pharmaceutically acceptable salt thereof, wherein the structure of compound 1 is as follows:

6. A method for preparing compound 1 or a pharmaceutically acceptable salt thereof, The method comprises the steps of converting compound 2 into the co-crystal compound shown in compound 3 as shown below:

7. The method of claim 6, further comprising the step of converting compound 3 into compound 4 as shown below:

8. The method of claim 7, further comprising the step of reacting compound 4 with a halogenated acetonitrile to form compound 5 as shown below: And the steps of converting compound 5 into compound 6: and the step of reacting compound 6 with chlorosulfonic acid and then with ammonia to form compound 1: And optionally, converting Compound 1 into a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein: The step of reacting 2-isopropyl-4-methoxyphenol with a halogenated acetonitrile to form 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile is carried out using sodium hydroxide in a mixture of toluene and NMP; preferably the halogenated acetonitrile is chloroacetonitrile; The conversion of 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is carried out in NMP in the presence of potassium tert-butoxide, preferably in a solution of ethyl formate and toluene; The conversion of 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is carried out in the presence of guanidine hydrochloride; The step of reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and chlorosulfonic acid is carried out in acetonitrile.

10. The method according to claim 6, wherein compound 1 is purified using a mixed solvent of DMSO and an anti-solvent, wherein the anti-solvent is preferably acetonitrile or a C1-C3 lower alcohol, and the lower alcohol is further selected from methanol, ethanol, and isopropanol.