Hydrate of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride, preparation method and use of the same

Abstract

The present invention relates to 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate and a preparation method of the same. The 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate has a very good crystal form and is well suitable for recrystallization purification; further, the effect of impurity removal effect is very good, and any single impurity can be controlled less than 0.1%.

Claims

1. A crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride monohydrate, wherein the X-ray powder diffraction pattern thereof exhibits characteristic peaks at the following 20.2 degrees: 10.4, 13.4, 15.9, 17.3, 19.3, 20.3, 20.9, 21.4, 21.9, 23.6, 24.5, 25.3, 25.8, 26.2, 27.0, 27.8, 28.2, 29.5, 30.9, 31.5, 32.2, 33.6, 34.2, 35.0.

2. A method of preparing the crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate according to claim 1, the method comprising: dissolving 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)pyridine in an alcoholic solvent, and reducing by hydrogenating reduction via a noble metal catalyst to obtain 2-isopropoxy- 5-methyl-4-(piperidin-4-yl) aniline free base; and reacting the 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline free base with an alcoholic solution of hydrochloric acid or hydrogen chloride.

3. The crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride monohydrate according to claim 1, wherein the crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride monohydrate exhibits a decomposition point at about 230 C. as determined by differential scanning calorimetry.

Description

BRIEF DESCRIPTIONS OF THE DRAWINGS

(1) FIG. 1 is an X-ray powder diffraction pattern of crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate.

(2) FIG. 2 is a differential scanning calorimetry curve of crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate.

(3) FIG. 3 is differential scanning calorimetry curve and thermogravimetric curve of crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate.

(4) FIG. 4 is an infrared spectrum of crystal form A of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate.

DESCRIPTION OF THE EMBODIMENTS

(5) The present invention may be fully understood by the following examples, but they are not intended to limit the invention in any way.

Example 1

Preparation of 2-chloro-4-fluoro-5-nitrotoluene

(6) ##STR00006##

(7) 135 ml of concentrated sulfuric acid was added into the reaction flask, and cooled in an ice bath under stirring, 43.4g fuming nitric acid was then added therein dropwise. After the completion of addition, the mixture was stirred continuously for 30 min to form a mixed acid. Meanwhile, 315 ml of concentrated sulfuric acid and 90.0 g of 2-chloro-4-fluorotoluene were added in another three-necked flask. The abovementioned mixed acid of nitric acid and sulfuric acid was added to the sulfuric acid solution of 2-chloro-4-fluorotoluene under cooling in an ice-salt bath, and the reaction was continued for 1 to 2 hours. The reaction solution was slowly added to the crushed ice under stirring to quench, and then extracted with ethyl acetate twice. The ethyl acetate layers was combined, and washed twice with water and once with saturated brine. The organic phase was concentrated to dryness to give oily 2-chloro-4-fluoro-5-nitrotoluene.

(8) H NMR Data

(9) .sup.1H NMR(CDCl.sub.3, 400 MHz): 7.95(d, 3.8, 1H), 7.51(d, 4.2, 1H), 2.45(s, 3H).

Example 2

Preparation of 2-chloro-4-isopropyoxy-5-nitrotoluene

(10) ##STR00007##

(11) 2-chloro-4-fluoro-5-nitrotoluene was dissolved in 1200 ml of isopropanol and the solution was added in a 2 L of a three-necked flask. 429 g of anhydrous potassium carbonate powder was added therein. The mixture was heated to reflux under stirring. The reaction was conducted for about 40 hours under reflux. Most of the isopropanol was removed via concentration. 2 L of water was added and the mixture was extracted with ethyl acetate twice. The ethyl acetate layer was combined and washed with water. Ethyl acetate layer was concentrated to give 2-chloro-4-isopropoxy-5-nitrotoluene as a brown substance.

(12) H NMR Data

(13) .sup.1H NMR (CDCl.sub.3): 7.71(s, 1H), 7.07(s, 1H), 4.61(m, 1H), 2.34(s, 3H), 1.40(d, 3.2, 6H).

Example 3

Preparation of 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)pyridine

(14) ##STR00008##

(15) 78 g of 2-chloro-4-isopropoxy-5-nitrotoluene, 42 g of 4-pyridineboric acid, 97 g of potassium carbonate, 780 mL of dioxane, 390 mL of purified water, 7.67 g of palladium acetate, and 35.85 g of triphenylphosphine were added into a 2 L three-necked flask. Under the protection of nitrogen, the reaction was conducted for 24 hours under stirring and refluxing. Most of the dioxane was removed via concentration. 1.5 L of water was added and the mixture was extracted with ethyl acetate twice. The ethyl acetate layers were combined and washed with saturated brine twice, and the organic phase was concentrated to dryness to give a 4-(5-isopropoxy-2-methyl-4-nitro-phenyl) pyridine as a brown solid, i.e. the compound 3.

(16) H NMR Data

(17) .sup.1H NMR(CDCl.sub.3): 8.72(m, 2H), 7.71(s, 1H), 7.31(m, 2H), 6.89(s, 1H), 4.63(m, 1H), 2.21(s, 3H), 1.38(d, 3.0, 6H).

Example 4

Preparation of 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)-1-benzyl-pyridinium bromide

(18) ##STR00009##

(19) 4-(5-isopropoxy-2-methyl-4-nitro-phenyl) pyridine (33 g), bromobenzyl (31.08 g) and tetrahydrofuran (330 mL) were added to a 1000 mL reaction flask. The mixture was stirred and reacted by heating to reflux overnight. After the resultant was cooled to room temperature, 330 mL of heptane was slowly added therein. The resultant was stirred continuously for 1 hour and then filtered. The filter cake was dried to give 4-(5-isopropyl-2-methyl-4-nitro-phenyl)-1-benzyl-pyridinium bromide. Purity is 99%.

(20) MS(ESI+): 363.2(M).sup.+. .sup.1H NMR(DMSO-d.sub.6): 9.40(d, 3.4, 2H), 8.33(d, 3.4, 2H), 7.89(s, 1H), 7.65-7.68(m, 2H), 7.45-7.51(m, 3H), 7.43(s, 1H), 5.96(s, 2H), 4.84-4.88(m, 1H), 2.25(s, 3H), 1.27(d, 3.0, 6H).

Example 5

Preparation of 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine

(21) ##STR00010##

(22) 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)-1-benzyl-pyridinium bromide (17.8 g) and methanol (535 mL) were added to a 1000 mL reaction flask. The mixture was stirred and cooled. NaBH.sub.4 (15.13 g) was added in portions. 9 mL of 3N hydrochloric acid was slowly added therein. It is confirmed that no NaBH.sub.4 remained. Then the solvent is removed by evaporating, and then 190 mL of water was added and the mixture was stirred. After that, ethyl acetate (190 mL) was added therein, the liquid was separated, the organic phase was collected, and the aqueous phase was further extracted with ethyl acetate (190 mL2). The organic phases were then combined, washed once with water and saturated brine (190 mL) respectively. The organic phase was evaporated to dryness to give 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine.

(23) MS(ESI+):337.3(M+1).sup.+. .sup.1H NMR(CDCl.sub.3): 7.26-7.44(m, 5H), 6.59(s, 1H), 6.53(s, 1H), 5.50(m, 1H), 4.44(m, 1H), 3.72(s, 2H), 3.19-3.24(m, 2H), 2.72-2.80(m, 2H), 2.41-2.44(m, 2H), 2.16(m, 3H), 1.33(d, 3.0, 6H).

Example 6

Preparation of 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine hydrochloride

(24) ##STR00011##

(25) 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine (12.5 g) was dissolved in 125 mL of isopropanol, the mixture was cooled, and the solution of hydrogen chloride in isopropanol was added therein dropwisely until pH=1. The resultant was filtered and the filter cake was collected and dried in vacuum to give 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine hydrochloride. Purity is 99%.

(26) MS(ES+): 337.3(M+1).sup.+. .sup.1H NMR(DMSO-d.sub.6): 7.71-7.74(m, 2H), 7.45-7.47(m, 3H), 7.22(s, 1H), 6.90(s, 1H), 5.56(s, 2H), 4.65-4.68(m, 1H), 4.36-4.46(m, 2H), 3.60-3.72(m, 2H), 3.51-3.54(m, 1H), 3.20-3.22(m, 1H), 2.85-2.89(m, 1H), 2.20(s, 1H), 1.28(d, 2.8 6H).

Example 7

2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate

(27) ##STR00012##

(28) 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine hydrochloride (10.05 g), methanol (100 mL) and 0.5 g of palladium on carbon were added to the hydrogenation vessel. The vessel was purged with nitrogen. It was heated to 90 C. and pressurized to 1.0 MPa, and the reaction was conducted for 8 hours. The resultant was cooled to room temperature, and then filtered to remove the catalyst. The filtrate was evaporated to remove the solvent and 100 mL of IPA was added thereto. HCl/IPA was added dropwise under cooling in an ice bath to adjust the pH to acidity. After filtration, the filter cake was washed with IPA (10 mL). Then it was dried to obtain 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate. Purity is 99%.

(29) MS(ES+): 249.3(M+1).sup.+. .sup.1H NMR(DMSO-d): 7.18(s,1H), 6.92(s, 1H), 4.62-4.65(m, 1H), 3.29(d, 4.8, 2H), 2.97-3.03(m, 3H), 2.22(s, 1H), 1.97-2.00(m, 2H), 1.76(d, 5.2, 2H), 1.29(d, 2.4, 6H).

Example 8

2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate

(30) ##STR00013##

(31) 4-(5-isopropoxy-2-methyl-4-nitro-phenyl) pyridine (1 Kg) obtained in Example 3, methanol (10 L) and 100 g of 10% palladium on carbon were added into a hydrogenation vessel. The vessel was purged with nitrogen. It was heated to 100 C. and pressurized to 1 to 1.5 MPa, and the reaction was conducted for 8 hours and then completed. The resultant was cooled to room temperature, and then filtered to remove the catalyst. The solvent was distilled off from the filtrate, and 5 L of isopropanol was added to give 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline free base. The isopropanol solution of hydrogen chloride was added dropwise under cooling in an ice bath to adjust the pH to acidity. After filtration, the filter cake was washed with isopropanol (1 L). Then it was dried to obtain 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate. Purity is 99%. MS(ES+): 249.3(M+1).sup.+. .sup.1H NMR(DMSO-d.sub.6): 7.18(s, 1H), 6.92(s, 1H), 4.62-4.65(m, 1H), 3.29(d, 4.8, 2H), 2.97-3.03(m, 3H), 2.22(s, 1H), 1.97-2.00(m, 2H), 1.76(d, 5.2, 2H), 1.29(d, 2.4, 6H).

Example 9

2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate

(32) ##STR00014##

(33) 4-(5-isopropoxy-2-methyl-4-nitro-phenyl) pyridine (1 Kg) obtained in Example 3, isopropanol (10 L) and 100 g of 5% palladium on carbon were added into a hydrogenation vessel. The vessel was purged with nitrogen. It was heated to 110 C. and pressurized to 1 to 1.5 MPa, and the reaction was conducted for 8 hours and then completed. The resultant was cooled to room temperature, and then filtered to remove the catalyst. The solvent was distilled off from the filtrate, and then 5 L of isopropanol was added to give 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline free base. The isopropanol solution of hydrogen chloride was added dropwise under cooling in an ice bath to adjust the pH to acidity. After filtration, the filter cake was washed with isopropanol (1 L). Then it was dried to obtain 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate. Purity is 99%. MS(ES+): 249.3(M+1).sup.+. .sup.1H NMR(DMSO-d.sub.6): 7.18(s, 1H), 6.92(s, 1H), 4.62-4.65(m, 1H), 3.29(d, 4.8, 2H), 2.97-3.03(m, 3H), 2.22(s, 1H), 1.97-2.00(m, 2H), 1.76(d, 5.2, 2H), 1.29(d, 2.4, 6H).

Example 10

Purification of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate

(34) ##STR00015##

(35) 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate (10.0 g), isopropanol (100 mL) and water (6.0 g) were added in the reaction flask. The vessel was purged with nitrogen. The mixture was stirred and heated to reflux and dissolved clarification. The resultant was cooled to 0 C. and crystallized. After filtration, the filter cake was collected. Then it was dried to obtain 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate. Purity is 99.5%. MS(ES+): 249.3(M+1).sup.+. 1H NMR(DMSO-d.sub.6): 7.18(s, 1H), 6.92(s, 1H), 4.62-4.65(m, 1H), 3.29(d, 4.8, 2H), 2.97-3.03(m, 3H), 2.22(s, 1H), 1.97-2.00(m, 2H), 1.76(d, 5.2, 2H), 1.29(d, 2.4, 6H).

Example 11

Preparation of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine dihydrochloride

(36) ##STR00016##

(37) 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate (17.00 g) and 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl) pyrimidin-4-amine (commercially available) (18.32 g) were added to a 500 mL three-necked flask, and 170 mL of isopropanol was added thereto. The mixture was stirred, heated to reflux and reacted overnight. After cooling to room temperature, the mixture was filtered and washed, the filter cake was collected. The filter cake was dried to obtain 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine dihydrochloride. Purity is 99%.

(38) MS(ESI+): 558.1(M+1).sup.+. .sup.1H NMR(DMSO-d.sub.6): 10.15(s, 1H), 9.18-9.38(m, 3H), 8.54(s, 1H), 8.06-8.08(m, 1H), 7.92-7.94(d, 3.2, 1H)7.73-7.77(t, 3.8, 1H), 7.54-7.58(t, 4.0, 1H), 7.31(s, 1H), 6.82(s, 1H), 4.51-4.57(m, 1H), 3.45-3.52(m, 1H), 3.30-3.32(d, 5.8, 2H), 2.93-3.03(m, 3H), 1.89-1.99(m, 5H), 1.73-1.77(d, 6.4, 2H), 1.24-1.26(d, 3.2, 6H), 1.10-1.111(d, 3.2, 6H).

Example 12

Preparation of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine (LDK-378)

(39) ##STR00017##

(40) 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl) phenyl)-2,4-diamine dihydrochloride (6.31 g) was added to a 50 mL three-necked flask. 19 g of acetone aqueous solution (3: 1, v/v) was added. The mixture was stirred and heated to 55 C., and 10 g of about 10% aqueous NaOH was added dropwise. After the dripping was complete, the mixture was cooled to room temperature, diluted with 42 g of purified water, and continuously stirred for 1 hour. After filtration, the filter cake was collected and dried in vacuum to give 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine. Purity is not less than 99%, and a single impurity is not higher than 0.1%.

(41) MS(ESI+):558.1(M+1).sup.+. .sup.1H NMR(DMSO-d.sub.6): 8.44(d, 3.4, 1H), 8.20(s, 1H), 8.02(s, 1H), 7.80-7.82(m, 1H), 7.56-7.60(m, 1H), 7.49(s, 1H), 7.30-7.33(m, 1H), 6.80(s, 1H), 4.49-4.54(m, 1H), 3.42-3.47(m, 1H), 3.02(d, 4.8, 2H), 2.57-2.72(m, 3H), 2.10(m, 3H), 1.47-1.60(m, 4H), 1.21(d, 2.4, 6H), 1.14(d, 2.6, 6H).