Hydrates of substituted 5-fluoro-1H-pyrazolopyridines

Abstract

The present application relates to a novel and efficient process for preparing novel substituted 5-fluoro-1H-pyrazolopyridines of the formula (VI) ##STR00001##
which are suitable as an intermediate for production of medicaments and for production of medicaments for treatment and/or prophylaxis of cardiovascular disorders. More particularly, the 5-fluoro-1H-pyrazolopyridines of the formula (VI) are suitable for preparation of the compound of the formula (I) ##STR00002##
which serves for production of medicaments, for production of medicaments for treatment and/or prophylaxis of cardiovascular disorders.

Claims

1. A hydrate of the compound of the formula (I) ##STR00086## wherein the hydrate is a monohydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 9.6, 18.2, and 25.7 or a dihydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 7.9, 24.9, and 25.5.

2. The hydrate according to claim 1, wherein the hydrate is a monohydrate containing about 4.1% water or a dihydrate containing about 7.8% water.

3. The hydrate according to claim 1, wherein the hydrate is a monohydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 8.5, 9.6, 18.2, 20.2, and 25.7 or a dihydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 7.9, 19.8, 24.9, 25.5, and 27.8.

4. The hydrate according to claim 1, wherein the hydrate is a monohydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 8.5, 9.6, 18.2, 20.2, 23.5, 25.7, and 29.4 or a dihydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 5.9, 7.9, 9.0, 19.8, 24.9, 25.5, and 27.8.

5. The hydrate according to claim 1, wherein the hydrate is a monohydrate containing about 4.1% water.

6. The hydrate according to claim 1, wherein the hydrate is a monohydrate with the x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 9.6, 18.2, and 25.7.

7. The hydrate according to claim 1, wherein the hydrate is a monohydrate with the x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 8.5, 9.6, 18.2, 20.2, and 25.7.

8. The hydrate according to claim 1, wherein the hydrate is a monohydrate with the x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 8.5, 9.6, 18.2, 20.2, 23.5, 25.7, and 29.4.

9. The hydrate according to claim 1, wherein the hydrate is a dihydrate containing about 7.8% water.

10. The hydrate according to claim 1, wherein the hydrate is a dihydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 7.9, 24.9, and 25.5.

11. The hydrate according to claim 1, wherein the hydrate is a dihydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 7.9, 19.8, 24.9, 25.5, and 27.8.

12. The hydrate according to claim 1, wherein the hydrate is a dihydrate with an x-ray diffractogram exhibiting peak maxima of the 2 theta angle at 5.9, 7.9, 9.0, 19.8, 24.9, 25.5, and 27.8.

Description

A. EXAMPLES

(1) Abbreviations:

(2) Ac acetyl

(3) CI chemical ionization (in MS)

(4) DCI direct chemical ionization (in MS)

(5) DMF dimethylformamide

(6) DMSO dimethyl sulphoxide

(7) eq. equivalent(s)

(8) ESI electrospray ionization (in MS)

(9) Et ethyl

(10) GC/MS gas chromatography-coupled mass spectrometry

(11) sat. saturated

(12) h hour(s)

(13) HPLC high-pressure high-performance liquid chromatography

(14) HV high vacuum

(15) conc. concentrated

(16) LC/MS liquid chromatography-coupled mass spectrometry

(17) Me methyl

(18) min minute(s)

(19) MS mass spectrometry

(20) NMR nuclear magnetic resonance spectroscopy

(21) rac racemic/racemate

(22) R.sub.f retention factor (in thin layer chromatography on silica gel)

(23) RT room temperature

(24) R.sub.t retention time (in HPLC)

(25) SFC supercritical fluid chromatography

(26) THF tetrahydrofuran

(27) UV ultraviolet spectrometry

(28) v/v volume to volume ratio (of a solution)

(29) All X-Ray Diffractometry Data were Obtained with the Following Acquisition Parameters:

(30) Diffractometer system PANalytical XPERT-PRO

(31) Scan axis Gonio

(32) Anode material Cu

(33) K-Alpha1 [] 1.54060

(34) K-Alpha2 [] 1.54443

(35) K-A2/K-A1 ratio 0.50000

(36) Scan Mode: Transmission

(37) Scan type: 2theta:omega

(38) 2theta figure: 0.2

(39) All Infrared Spectroscopy Data were Obtained with the Following Acquisition Parameters:

(40) Spectrometer: Perkin Elmer Spectrum One with diamond ATR unit

(41) Parameter: 32 scans

(42) Resolution: 2 cm.sup.1

Example 1

2,2,3,3-Tetrafluoropropyl trifluoromethanesulphonate

(43) ##STR00073##
Method A:

(44) 252.5 g (0.895 mol) of trifluoromethanesulphonic anhydride were heated to 40 C. and, at this temperature, 130.0 g (0.984 mol) of 2,2,3,3-tetrafluoro-1-propanol were metered in while cooling. After the metered addition had ended, the reaction mixture was heated to 7075 C. and stirred for 2 h. The mixture was cooled to 20 C. and the reaction solution was used without further purification in the reaction for Example 2.

(45) Method B:

(46) 50.0 g (0.379 mol) of 2,2,3,3-tetrafluoro-1-propanol were cooled to 0 C. and 106.8 g (0.379 mol) of trifluoromethanesulphonic anhydride were added dropwise at 0-4 C. Subsequently, the reaction mixture was stirred at 25 C. for 2 h, heated to 70-75 C. and stirred for 2 h. The mixture was cooled to 20 C. and the reaction solution was distilled at 116-118 C. This gave 85.1 g (85.1% of theory) of the title compound.

(47) .sup.1H NMR (400 MHz, CDCl.sub.3): =4.69 (t, J=11.86 Hz, 2H) 5.54-6.23 (m, 1H) ppm.

Example 2

4-(2,2,3,3-Tetrafluoropropyl)morpholine

(48) ##STR00074##
Method A:

(49) 311.9 g (3.58 mol) of morpholine were dissolved in 290 ml of dichloromethane and cooled to 15 C. At 15-0 C., 371.4 g (max. 0.895 mol) of the reaction solution from Example 1 were added dropwise while cooling and then the mixture was stirred at 0-5 C. for 30 min. The reaction mixture was heated to 40 C. and stirred for 4.5 h. After cooling to 20 C., 320 ml of water were added and the phases were separated. The organic phase was washed three times with 190 ml each time of water and concentrated on a rotary evaporator at 30 C./30 mbar. The residue (160.7 g) was distilled at 670-68 C./18 mbar. This gave 151.7 g (84.3% of theory) of the title compound.

(50) .sup.1H NMR (400 MHz, CDCl.sub.3): =2.53-2.70 (m, 4H) 2.89 (tt, J=14.03, 1.74 Hz, 2H) 3.61-3.78 (m, 4H) 5.83-6.22 (m, 1H) ppm.

(51) Method B:

(52) 158.5 g (1.82 mol) of morpholine were cooled to 5 C. At 50-10 C., 189.5 g (max. 0.455 mol) of the reaction solution from Example 1 were added dropwise while cooling and then the mixture was stirred at 50-10 C. for 30 min. The reaction mixture was heated to 40 C. and stirred for 1 h. After cooling to 20 C., 160 ml of water and 160 ml of toluene were added and the phases were separated. The organic phase was washed with 160 ml of water and concentrated on a rotary evaporator at 50 C./50 mbar. The residue (81.0 g) was distilled at 670-68 C./18 mbar. This gave 77.0 g (84.1% of theory) of the title compound.

Example 3

4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium methanesulphonate

(53) ##STR00075##
Method A:

(54) 143.7 g (1.31 mol) of methyl methanesulphonate were heated to 135 C. and, at this temperature, 250.0 g (1.243 mol) of the compound from Example 2 were added dropwise. Subsequently, the mixture was stirred at 100 C. for 22 h. The reaction mixture was cooled to 85 C. and 375 ml of isopropanol were added. After cooling to 0-5 C., the mixture was stirred for a further 30 min and the product was filtered off with suction. The product was washed three times with 125 ml each time of isopropanol and dried in a vacuum drying cabinet at 45 C. under a gentle nitrogen stream. This gave 336.8 g (87.1% of theory) of the title compound.

(55) .sup.1H NMR (400 MHz, D.sub.2O): =2.81 (s, 3H) 3.55 (s, 3H) 3.68-3.93 (m, 4H) 4.01-4.24 (m, 4H) 4.33-4.51 (m, 2H) 6.13-6.48 (m, 1H) ppm.

(56) Method B:

(57) 20.0 g (181.3 mmol) of methyl methanesulphonate were heated to 135 C. and, at this temperature, 35.1 g (172.7 mmol) of the compound from Example 2 were added dropwise. The mixture was stirred at 135 C. for 3 h and then 40 ml of water were added. After cooling to 50 C., the aqueous solution of the title compound was used in the subsequent stage (see Example 4).

Example 4

4-Methyl-4-[2,3,3-trifluoroprop-1-en-1-yl]morpholin-4-ium methanesulphonate

(58) ##STR00076##

(59) 16.9 g (189.9 mmol) of 45% sodium hydroxide solution were metered into the aqueous solution of the compound from Example 3, Method B (max. 172.7 mmol) at 50-55 C., and the mixture was stirred at 50 C. for 1 h. The reaction mixture was cooled to 20 C. and the precipitated salts were filtered off with suction and washed with 5 ml of water. The aqueous product solution (102.1 g; max. 172.7 mmol) was used in the subsequent stage (see Example 5).

(60) For analytical purposes, a sample was concentrated and dried.

(61) .sup.1H NMR (400 MHz, D.sub.2O): =2.81 (s, 3H) 3.59 (s, 3H) 3.76-3.85 (m, 2H) 3.97-4.09 (m, 4H) 4.12-4.20 (m, 2H) 6.39-6.69 (m, 1H) 6.74-6.83 (m, 1H) ppm.

Example 5

2-Fluoro-3-(morpholin-4-yl)acrylaldehyde

(62) ##STR00077##
Method A:

(63) An aqueous solution of the compound from Example 4 (max. 251.5 mmol) was heated to 75 C. Subsequently, 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine were added dropwise. The mixture was stirred at 75 C. for 2 h and cooled to 23 C., and 290 ml of dichloromethane and 100 ml of triethylamine were added. The phases were separated, the aqueous phase was washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, and the combined organic phases were filtered, washed with 250 ml of sat. aqueous potassium carbonate solution and concentrated on a rotary evaporator at 40 C. 50 ml of toluene were added and the mixture was concentrated further. This gave 34.2 g (81.9% of theory) of the title compound.

(64) Method B:

(65) A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine was heated to 75 C. and an aqueous solution of the compound from Example 4 (max. 251.5 mmol) was added dropwise within 25 min. Subsequently, the mixture was stirred at 75 C. for 2 h and cooled to 23 C., and 290 ml of dichloromethane and 100 ml of triethylamine were added. The mixture was filtered, the phases were separated, the aqueous phase was washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, and the combined organic phases were washed with 250 ml of sat. aqueous potassium carbonate solution and concentrated on a rotary evaporator at 40 C. 50 ml of toluene were added and the mixture was concentrated further. This gave 35.3 g (83.4% of theory) of the title compound.

(66) .sup.1H NMR (500 MHz, CDCl.sub.3): =3.51-3.60 (m, 4H) 3.72-3.83 (m, 4H) 6.16 (d, J=27.1 Hz, 1H) 8.59 (d, J=18.9 Hz, 1H) ppm.

(67) Method C:

(68) A mixture of 30.2 g (345.3 mmol) of morpholine and 52.5 g (518.0 mmol) of triethylamine was heated to 75 C. and the aqueous solution of the compound from Example 4, Method B (max. 172.7 mmol) was added dropwise at 750-80 C. The mixture was stirred under reflux for 2 h, cooled to 23 C. and washed with 100 ml of dichloromethane. The aqueous phase was washed twice with a mixture of 100 ml of dichloromethane and 15 ml of triethylamine, and the combined organic phases were washed with 85 ml of sat. aqueous potassium carbonate solution and concentrated under reduced pressure at 450-50 C. 120 ml of toluene and 60 ml of toluene were distilled off. The suspension was stirred at room temperature overnight, and the product was filtered off with suction and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 19.2 g (68.3% of theory) of the title compound.

Example 6

Ethyl 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

(69) ##STR00078##
Method A:

(70) 22.3 g (84.8 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for Example 20A in WO 00/06569) were initially charged in 59.5 ml of ethanol, and 11.0 ml (169.6 mmol) of methanesulphonic acid, 9.0 g (212.1 mmol) of lithium chloride and 15.0 g (84.8 mmol) of the compound from Example 5 were added at RT. The mixture was stirred at reflux temperature for 4.5 h. After cooling to room temperature, the product was filtered off with suction, washed twice with 4.5 ml of ethanol and stirred with 325 ml of water for 1 h. The solids were filtered off with suction, washed twice with 11.5 ml of water and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 21.8 g (81.0% of theory) of the title compound.

(71) MS (ESIpos): m/z=318 (M+H).sup.+

(72) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H), 7.15-7.27 (m, 3H), 7.36-7.41 (m, 1H), 8.25 (d, 1H), 8.78 (s br., 1H) ppm.

(73) Method B:

(74) 27.0 g (635.2 mmol) of lithium chloride and 42.2 g (254.1 mmol) of the compound from Example 5 were initially charged in 75 ml of ethanol and heated to reflux temperature. At this temperature, a solution of 66.9 g (254.1 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for Example 20A in WO 00/06569) and 33.0 ml (508.2 mmol) of methanesulphonic acid in 180 ml of ethanol were added within 10 min. The mixture was stirred at reflux temperature for 2 h, then 120 ml of isopropanol were added, the mixture was cooled to 62 C., 0.6 g of the title compound were used for seeding and the mixture was cooled to 5 C. within 4 h. The product was filtered off with suction, stirred with 120 ml of isopropanol, filtered off with suction, washed with 180 ml of water, stirred with 300 ml of water for 0.5 h, filtered off with suction, washed with 300 ml of water and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 65.1 g (80.7% of theory) of the title compound.

(75) Method C:

(76) 5.42 g (20.6 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for Example 20A in WO 00/06569) were initially charged in 20 ml of ethanol, and 1.5 g (41.1 mmol) of hydrogen chloride were introduced. This solution was metered into 3.42 g (20.6 mmol) of the compound from Example 5 in 50 ml of ethanol at reflux temperature within 10 min. The mixture was stirred at reflux temperature for 2 h, then 10 ml of isopropanol were added and the mixture was cooled to 5 C. The product was filtered off with suction, washed with 10 ml of isopropanol and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 4.84 g (74.2% of theory) of the title compound.

Example 7

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

(77) ##STR00079##

(78) 10 ml of ethanol, 14.9 ml (441.2 mmol) of formamide and 3.6 g (66.2 mmol) of sodium methoxide solution in methanol (30%) were added to 7.0 g (22.1 mmol) of the compound obtained in Example 6. The reaction mixture was heated to 95-100 C. and the low boilers were distilled off. The mixture was stirred at 125 C. for 1.5 h, 30 ml of water were added, and the mixture was cooled to room temperature and stirred for 1 h. The precipitated solids were filtered off with suction, washed three times with 8.5 ml each time of water and dried in a vacuum drying cabinet at 45 C. under a gentle nitrogen stream. This gave 6.2 g (97.5% of theory) of the title compound.

(79) MS (ESIpos): m/z=289 (M+H).sup.+

(80) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =5.87 (s, 2H), 7.12-7.26 (m, 3H), 7.34-7.40 (m, 1H), 7.60 (s br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd, 1H) ppm.

Example 8

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

(81) ##STR00080##

(82) 17.3 g (60.0 mmol) of the compound obtained in Example 7 were heated to 103-107 C. in 40.5 ml of sulpholane and 5.4 ml of acetonitrile. Thereafter, 6.9 g (45.0 mmol) of phosphorus oxychloride were slowly added dropwise while stirring, the dropping funnel was rinsed with 2.8 ml of acetonitrile, then the mixture was stirred at 107 C. for 1.5 h until conversion was complete (HPLC). Thereafter, the mixture was cooled to room temperature, and 2.8 ml of sulpholane/acetonitrile (5:1 vol/vol) and then 17.8 ml of water were added dropwise. The mixture was stirred for 0.5 h, a solution of 9.4 g of aqueous ammonia (28%) in 22.7 ml of water was added dropwise and the mixture was stirred for a further 2 h. The precipitated solids were filtered off with suction, washed three times with 20.5 ml each time of water and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 14.7 g (91.9% of theory) of the title compound.

(83) MS (ESIpos): m/z=271 (M+H).sup.+

(84) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =5.87 (s, 2H), 7.17-7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H) ppm.

Example 9

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride

(85) ##STR00081##

(86) 406.0 g (1.50 mol) of the compound from Example 8 were suspended in 2.08 l of ethanol. Subsequently, 54.1 g (0.30 mol) of sodium methoxide in methanol (30%) were added and the mixture was stirred at room temperature overnight. 88.4 g (1.65 mol) of ammonium chloride were added, and the mixture was heated to 65 C. and stirred at 65 C. for 3.5 h. The solvents were distilled off and the residue was stirred with 1.6 l of ethyl acetate overnight. The precipitated solids were filtered off with suction, washed twice with 140 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 441.4 g (90.7% of theory) of the title compound.

(87) MS (ESIpos): m/z=288 (M+H).sup.+

(88) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =5.90 (s, 2H), 7.15-7.20 (m, 1H), 7.22-7.28 (m, 1H), 7.29-7.35 (m, 1H), 7.36-7.43 (m, 1H), 8.48 (dd, 1H), 8.86 (dd, 1H), 9.35 (br. s, 3H) ppm.

Example 10

[(E)-phenyldiazenyl]malononitrile

(89) ##STR00082##
Method A:

(90) 262 g of conc. hydrochloric acid (2.59 mol) and 117.5 ml of water were added dropwise at 0-5 C. to 1525 ml of water and 117.5 g (1.26 mol) of aniline. Subsequently, a solution of 87.1 g (1.26 mol) of sodium nitrite in 222.5 ml of water was added dropwise within 1 h and rinsed in with 60 ml of water, and the mixture was stirred at 0-5 C. for 15 min. Thereafter, at this temperature, a solution of 131.4 g (1.60 mol) of sodium acetate in 665 ml of water (19 ml) was added dropwise within 45 min and rinsed in with 60 ml of water, and a solution of 83.4 g (1.26 mol) of malononitrile in 233 ml of ethanol was added dropwise within 1 h. 68.5 ml of ethanol were used to rinse it in, and the mixture was stirred at 0-5 C. for 2 h. The yellow solids were filtered off with suction and washed three times with 625 ml each time of water and with 488 ml of cold toluene. The still-moist residue was dissolved in 872 g of DMF. This gave 1117.0 g of DMF solution of the title compound.

(91) Method B:

(92) 87.4 g of conc. hydrochloric acid (0.86 mol) and 39.5 ml of water were added dropwise at 0-5 C. to 508.5 ml of water and 39.2 g (0.42 mol) of aniline. Subsequently, a solution of 29.0 g (0.42 mol) of sodium nitrite in 74.5 ml of water was added dropwise within 1 h and rinsed in with 20 ml of water, and the mixture was stirred at 0-5 C. for 15 min. Thereafter, at this temperature, a solution of 43.8 g (0.54 mol) of sodium acetate in 221.5 ml of water was added dropwise within 45 min and rinsed in with 20 ml of water, and a solution of 27.8 g (0.42 mol) of malononitrile in 77.5 ml of ethanol was added dropwise within 1 h. 23 ml of ethanol were used to rinse it in, and the mixture was stirred at 0-5 C. for 2 h. The yellow solids were filtered off with suction and washed three times with 208.5 ml each time of water and with 162.5 ml of cold toluene. 103.1 g of moist product were obtained. 13.8 g of the moist product were dissolved in 13.9 g of sulpholane. This gave 27.7 g of sulpholane solution of the title compound.

Example 11

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine

(93) ##STR00083##
Method A:

(94) 448.2 g (1.38 mol) of the compound from Example 9 were suspended in 1059 ml of DMF. The mixture was heated to 85 C. and 212 ml (1.52 mol) of triethylamine were added dropwise at this temperature. Subsequently, 1751 g of the DMF solution from Example 10 were added dropwise within 20 min and rinsed in with 490 ml of DMF, and the mixture was stirred at 100 C. overnight. The reaction mixture was cooled to RT, 656 ml of water were added dropwise and the mixture was stirred at RT for 0.5 h, then cooled to 0-5 C. and stirred for a further 1 h. The solids were filtered off with suction, washed twice, each time with a solution of 1443 g of water and 236 g of methanol, and then washed with 586 ml of methanol, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 522.2 g (82.5% of theory) of the title compound.

(95) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =5.84 (s, 2H) 7.14-7.28 (m, 3H) 7.34-7.41 (m, 2H) 7.46-7.52 (m, 2H) 7.95 (br. s, 2H) 8.02 (dd, 2H) 8.50 (br. s, 2H) 8.70-8.73 (m, 1H) 9.02-9.06 (m, 1H) ppm.

(96) Method B:

(97) 30.0 g (92.7 mmol) of the compound from Example 9 were suspended in 72 ml of DMF. The mixture was heated to 100 C. and a mixture of 14.2 ml (101.9 mmol) of triethylamine and 150 g of the DMF solution from Example 10 was added dropwise at this temperature within 30 min. 30 ml of DMF were used to rinse it in and the mixture was stirred at 100 C. for 20 h. The reaction mixture was cooled to 95-90 C., 24 ml of water were added dropwise within 10 min, then the mixture was cooled to 0-5 C. within 1.5 h and stirred for 1 h. The solids were filtered off with suction, washed with a solution of 60 g of water and 60 g of dimethylformamide, washed twice, each time with a solution of 50 g of water and 50 g of methanol, and then with 40 ml of methanol, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 35.5 g (83.7% of theory) of the title compound.

(98) Method C:

(99) 11.7 g (36.0 mmol) of the compound from Example 9 were suspended in 15.6 ml of sulpholane. The mixture was heated to 100 C. and a mixture of 5.5 ml (39.6 mmol) of triethylamine and 27.7 g of the sulpholane solution from Example 10 Method B was added dropwise at this temperature within 35 min. 2 ml of sulpholane were used to rinse it in and the mixture was stirred at 100 C. for 2.5 h. The reaction mixture was cooled to 60 C., 90 ml of isopropanol were added dropwise, then the mixture was cooled to 0-5 C. within 15 min and stirred for 2.5 h. The solids were filtered off with suction, washed three times, each time with 50 g of water and 24 ml of isopropanol, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 14.2 g (85.9% of theory) of the title compound.

Example 12

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

(100) ##STR00084##
Method A:

(101) 182.0 g (0.39 mol) of the compound from Example 11 were initially charged in 1.82 l of DMF and then 4.2 g of palladium (5% on carbon, 50% water-moist) were added. Hydrogenation was effected at 60 C. and hydrogen pressure 60 bar while stirring overnight. The mixture was filtered through kieselguhr and washed through with 150 ml of DMF and then with 150 ml of methanol, and concentrated at 60-70 C. down to a weight of 425 g of distillation residue. The residue was heated to 750-80 C., 300 ml of methanol were added dropwise at this temperature and the mixture was stirred for 15 min. The mixture was cooled to RT within 1 h, then 1290 ml of water were added dropwise and the mixture was stirred overnight. The solids were filtered off with suction, washed twice with 500 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 159.7 g of the title compound. The product has a content of 73.7% by weight and 12.4% by weight of DMF (80.3% of theory) and was used thus in the subsequent stage. According to the intensity of the water wash, the DMF content was in the range of 10-17% by weight.

(102) Method B:

(103) 25.0 g of the DMF-containing solids from Method A were suspended in 220 ml of water and filtered with suction through a suction filter. The solids were washed four times on the suction filter with 100 ml each time of water at 95 C., suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 21.2 g of the DMF-free title compound.

(104) MS (ESIpos): m/z=369 (M+H).sup.+

(105) For analytical purposes, a sample was purified by means of silica gel filtration:

(106) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =4.04 (br. s, 2H) 5.75 (s, 2H) 5.86 (br. s, 4H) 7.10-7.26 (m, 3H) 7.32-7.39 (m, 1H) 8.61-8.64 (m, 1H) 8.85 (dd, 1H) ppm.

Example 13

Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

(107) ##STR00085##
Method A:

(108) 4.0 g (77.0% by weight, 8.36 mmol) of the compound from Example 12 in 37.9 ml of isopropanol were heated to 35 C. and then 0.84 ml (10.87 mmol) of methyl chloroformate was added dropwise. The mixture was stirred at 350-40 C. for 20 h and heated to 50 C., and 9.5 ml of methanol were added. Subsequently, 1.9 ml of triethylamine were added dropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50 C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of ethanol, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of the crude product were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethyl acetate and 50 mg of activated carbon were added, and the mixture was heated at reflux (84 C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 1.9 ml of ethyl acetate.sup.1). 60 ml of ethyl acetate and 16 ml of ethanol were heated to 60 C., and the combined filtrates were added dropwise and stirred at 60 C. for 1.5 h. The suspension was cooled to RT within 25 min, stirred for a further 1.5 h, cooled further to 0-5 C. and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 6.4 ml each time of ethyl acetate, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) of the title compound.

(109) MS (ESIpos): m/z=427 (M+H).sup.+

(110) .sup.1H NMR (400 MHz, DMSO-d.sub.6): =3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H) ppm. 1) According to the preparation process described, the di-dimethyl sulphoxide solvate is obtained at this point, and this is characterized in Tables 2 and 4 by the reflections in the x-ray diffractogram and bands in the IR spectrum.

(111) The di-dimethyl sulphoxide solvate of the compound of the formula (I) has the advantage of much better filterability than the substance in the prior art. Furthermore, the preparation process via the di-dimethyl sulphoxide solvate of the compound of the formula (I) leads to a very high purity of the compound of the formula (I).

(112) Method B:

(113) 4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35 C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 350-40 C. for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia (28%) were added. Subsequently, 4.2 ml of water were added and the mixture was stirred for 2.5 h. The solids were filtered off with suction, washed twice with 5 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 4.4 g of crude product.

(114) Method C:

(115) 4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35 C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 350-40 C. for 16.5 h, and 9.5 ml of methanol were added at 50 C. Subsequently, 2.42 ml of triethylamine were added dropwise within 20 min and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50 C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of methanol, suction-dried and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 4.3 g of crude product.

(116) Method D:

(117) 6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min, 30.0 ml of ethyl acetate and 115 mg of activated carbon were added, and the mixture was heated at reflux (84 C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 4.4 ml of ethyl acetate. 138 ml of ethyl acetate were heated to 50 C., and the combined filtrates were added dropwise and stirred at 45-50 C. for 1 h. The suspension was cooled to 0-5 C. within 1.5 h and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 14.8 ml each time of ethyl acetate and suction-dried for 1 h. 6.4 g of the di-dimethyl sulphoxide solvate were obtained as a moist product).

(118) Method E:

(119) 2.0 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed four times with 1.4 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50 C. under a gentle nitrogen stream. This gave 1.4 g of the title compound present in polymorph I.

(120) Method F:

(121) 0.5 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 12.5 ml of solvent for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed with 2 ml of solvent and suction-dried for 30 min. This gave 0.3 g of the title compound present in polymorph I.

(122) The following solvents were used:

(123) 1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water

(124) 2.) 12.5 ml of isopropanol

(125) 3.) 12.5 ml of isopropanol/0.3 ml of water

(126) 4.) 12.5 ml of methanol

(127) 5.) 12.5 ml of methanol/0.3 ml of water

(128) 6.) 12.5 ml of acetonitrile

(129) 7.) 12.5 ml of acetone

(130) 8.) 12.5 ml of tetrahydrofuran,

(131) 9.) 12.5 ml of methyl tert-butyl ether

(132) Table 1 indicates the reflections of the x-ray diffractogram. Table 3 shows the bands of the IR spectrum.

(133) The compound (I) in crystalline polymorph I is notable for higher stability and more particularly for the fact that it is stable in the micronization process and hence no conversion and recrystallization takes place.

(134) The compound of the formula (I) can be prepared by processes described above. This affords the compound of the formula (I) in a crystal polymorph referred to hereinafter as polymorph I. Polymorph I has a melting point of 257 C. and a characteristic x-ray diffractogram featuring the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum featuring the band maxima (in cm.sup.1) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, FIGS. 1 and 5).

(135) Surprisingly, four further polymorphs, a monohydrate, a dihydrate, a DMF/water solvate and a di-dimethyl sulphoxide solvate, and also a triacetic acid solvate of the compound of the formula (I) were found. The compound of the formula (I) in polymorph II melts at approx. 253 C.; the compound of the formula (I) in polymorph III has a melting point of approx. 127 C. Polymorph IV of the compound of the formula I melts at a temperature of 246 C., while polymorph V has a melting point of 234 C. The monohydrate contains approx. 4.1% water, the dihydrate contains 7.8% water, the DMF/water solvate contains 13.6% dimethylformamide and 0.9% water, the di-DMSO solvate contains 26.8% dimethyl sulphoxide and the triacetic acid solvate contains 29.7% acetate. Each of the crystalline forms mentioned has a characteristic x-ray diffractogram and IR spectrum (Tables 2 and 3, FIGS. 1-4, 6-14).

(136) TABLE-US-00001 TABLE 1 X-ray diffractometry for polymorphs I to V Reflections Poly- Poly- Poly- Poly- Poly- morph I morph II morph III morph IV morph V [2 theta] [2 theta] [2 theta] [2 theta] [2 theta] 5.9 4.9 6.2 6.2 3.2 6.9 7.3 6.8 8.7 5.1 8.3 9.7 8.7 12.4 5.4 10.4 9.9 9.8 15.8 6.4 10.5 10.8 12.4 18.1 6.6 11.3 14.3 15.8 18.6 10.2 11.6 14.9 17.5 19.2 10.7 11.9 15.6 18.1 19.6 11.8 12.2 16.5 18.6 20.2 12.8 14.5 18.1 19.1 20.9 13.2 14.7 18.3 19.6 21.8 15.2 15.1 19.6 20.1 22.3 15.5 16.2 21.0 21.0 23.1 15.7 16.5 21.8 21.9 23.7 16.3 20.0 22.4 22.8 24.2 17.0 21.9 23.1 23.7 26.0 17.7 22.7 23.7 24.5 26.5 17.9 23.5 27.1 25.3 29.2 19.6 24.1 28.1 25.7 31.3 22.1 24.7 26.8 33.8 22.8 25.4 27.5 23.5 25.7 28.2 24.4 26.6 29.6 26.3 28.0 30.9 27.9 30.2 31.3 28.3 31.6 29.3 32.8 30.3 33.8 34.6

(137) TABLE-US-00002 TABLE 2 X-ray diffractometry for polymorph hydrates and solvates Reflections DMF/ di- Acetic Mono- Di- water DMSO acid hydrate hydrate solvate solvate solvate [2 theta] [2 theta] [2 theta] [2 theta] [2 theta] 6.0 5.9 8.2 6.9 5.3 8.5 7.9 9.2 11.0 7.2 9.6 8.7 9.7 12.0 9.3 12.1 9.0 11.9 13.8 10.0 13.6 11.8 12.5 14.1 10.7 15.5 13.7 12.7 15.7 11.0 17.3 14.7 13.3 16.1 11.6 18.2 15.8 14.1 16.2 11.9 19.3 16.4 15.6 16.6 12.5 19.7 18.1 16.0 17.1 14.1 20.2 19.3 16.5 17.7 14.4 20.9 19.8 16.8 17.8 14.8 21.5 20.6 17.6 18.8 16.6 22.2 21.7 18.3 19.9 18.0 23.5 21.7 19.3 20.3 18.8 24.1 22.5 19.4 20.7 19.2 25.7 22.7 19.6 21.3 19.4 26.8 22.9 19.8 21.7 19.6 27.5 23.4 20.0 21.9 19.7 29.4 23.7 20.5 22.4 20.1 30.8 24.9 20.6 22.8 20.4 32.2 25.5 20.7 23.6 21.0 26.0 21.0 24.1 21.6 26.8 21.8 24.4 22.9 27.1 22.2 25.2 23.5 27.8 22.4 25.5 24.1 28.9 22.8 25.9 24.4 30.7 23.1 26.6 24.8 31.3 23.6 26.9 25.5 32.0 23.9 28.9 26.5 24.8 29.9 26.8 25.2 30.9 27.7 25.6 33.2 31.5 25.8 33.4 26.1 33.9 26.7 26.8 27.2 27.6 28.1 28.4 28.6 29.4 29.7 30.3 30.6 31.4 31.5 31.7 32.1 32.4 32.6 32.7 34.1 34.3 34.7 35.6 35.9 36.6

(138) TABLE-US-00003 TABLE 3 IR spectra of polymorphs I to V Band maxima Poly- Poly- Poly- Poly- Poly- morph I morph II morph III morph IV morph V [cm.sup.1] [cm.sup.1] [cm.sup.1] [cm.sup.1] [cm.sup.1] 690 691 697 698 691 744 752 744 752 745 761 771 753 773 759 774 779 773 809 773 810 810 808 833 809 845 848 835 873 847 872 871 873 911 873 899 903 913 936 896 960 933 935 955 912 1059 958 954 1058 933 1072 1031 1034 1077 961 1112 1067 1059 1104 1033 1157 1082 1075 1161 1057 1208 1111 1103 1207 1083 1223 1202 1161 1225 1112 1255 1223 1206 1237 1152 1305 1249 1256 1207 1319 1264 1237 1277 1224 1353 1305 1253 1317 1255 1370 1349 1278 1356 1305 1435 1368 1319 1370 1318 1475 1436 1355 1425 1351 1566 1456 1370 1457 1371 1620 1480 1424 1472 1436 1633 1566 1437 1490 1478 1707 1620 1458 1496 1567 2956 1704 1476 1573 1628 3130 2953 1489 1585 1707 3277 3132 1570 1618 2956 3332 3278 1587 1691 3143 3385 3361 1619 3208 3277 3490 3488 1695 3290 3319 3503 3203 3376 3452 3315 3482 3492 3379 3479

(139) TABLE-US-00004 TABLE 4 IR spectra of the hydrates and solvates Band maxima DMF/ di- Acetic Mono- Di- water DMSO acid hydrate hydrate solvate solvate solvate [cm.sup.1] [cm.sup.1] [cm.sup.1] [cm.sup.1] [cm.sup.1] 696 745 662 713 709 743 752 724 762 739 761 760 745 778 762 774 774 771 811 777 810 809 812 873 801 834 835 846 902 835 873 874 867 953 872 912 913 896 1017 918 953 937 932 1041 941 1066 955 965 1078 955 1079 1032 1054 1111 1059 1104 1061 1072 1164 1099 1160 1080 1096 1210 1113 1176 1105 1117 1234 1167 1205 1160 1160 1281 1236 1222 1174 1209 1321 1252 1236 1206 1243 1364 1357 1249 1224 1304 1432 1423 1278 1236 1356 1457 1456 1356 1259 1389 1481 1492 1370 1309 1434 1521 1577 1423 1356 1481 1569 1601 1456 1371 1561 1628 1643 1474 1422 1624 1720 1702 1491 1473 1654 3144 3342 1575 1497 1729 3288 1620 1575 3159 3423 1669 1622 3404 3294 1688 3498 3331 3195 3479 3304 3472 3676

FIGURES

(140) FIG. 1: IR spectrum of the compound of the formula (I) in polymorphs I, II and III

(141) FIG. 2: IR spectrum of the compound of the formula (I) in polymorphs IV, V and as the triacetic acid solvate

(142) FIG. 3: IR spectrum of the compound of the formula (I) as the di-DMSO solvate, DMF/water solvate and monohydrate

(143) FIG. 4: IR spectrum of the compound of the formula (I) as the dihydrate

(144) FIG. 5: X-ray diffractogram of the compound of the formula (I) in polymorph I

(145) FIG. 6: X-ray diffractogram of the compound of the formula (I) in polymorph II

(146) FIG. 7: X-ray diffractogram of the compound of the formula (I) in polymorph III

(147) FIG. 8: X-ray diffractogram of the compound of the formula (I) in polymorph IV

(148) FIG. 9: X-ray diffractogram of the compound of the formula (I) in polymorph V

(149) FIG. 10: X-ray diffractogram of the compound of the formula (I) as the triacetic acid solvate

(150) FIG. 11: X-ray diffractogram of the compound of the formula (I) as the di-DMSO solvate

(151) FIG. 12: X-ray diffractogram of the compound of the formula (I) as the DMF-water solvate

(152) FIG. 13: X-ray diffractogram of the compound of the formula (I) as the monohydrate

(153) FIG. 14: X-ray diffractogram of the compound of the formula (I) as the dihydrate