Process for the preparation of carbamoylamino pyrazole derivatives

Abstract

The present invention relates to a process for the preparation of carbamoylamino pyrazole derivatives using diacetoxyiodobenzene (PhI(OAc).sub.2) in combination with a non-nucleophilic base.

Claims

1. Process for production of a compound of formula ##STR00037## wherein R.sub.1 is H, straight or branched C.sub.1-C.sub.6 alkyl, optionally substituted by 1 to 5 hydroxy groups which may be protected or halogen atoms, R.sub.2 is H, straight or branched C.sub.1-C.sub.6 alkyl or an amino protecting group, or R.sub.1 and R.sub.2 are bonded together to form C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene, R.sub.3 is H, straight or branched C.sub.1-C.sub.6 alkyl or an amino protecting group, wherein R.sub.3 is not H if R.sub.2 is H, R.sub.4 is ##STR00038## wherein a is 0, 1, 2, 3, 4, 5 or 6, R.sub.5 is H or hydroxy which may be protected, and R.sub.6 is H, C.sub.1-C.sub.6 straight or branched alkyl, mono or di straight or branched C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkyl amino, C.sub.6-C.sub.12 aryl, C.sub.6-C.sub.12 aryl amino, protected amino, protected guanidino or a saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms, wherein the cycloalkyl or aryl is optionally substituted by one or more C.sub.1-C.sub.3 straight or branched alkyl and the heterocyclic group is optionally substituted by one or more protected amino groups comprising reacting a compound of formula ##STR00039## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above with a compound of formula ##STR00040## wherein a, R.sub.5 and R.sub.6 are as defined above and PhI(OAc).sub.2 in the presence of a non-nucleophilic base to produce the compound of formula I.

2. The process according to claim 1, wherein R.sub.1 is straight or branched C.sub.1-C.sub.6 alkyl.

3. The process according to claim 1, wherein R.sub.2 is an amino protecting group.

4. The process according to claim 1, wherein R.sub.3 is H.

5. The process according to claim 1, wherein R.sub.4 is ##STR00041## wherein a is 0, 1, 2, 3, 4, 5 or 6, R.sub.5 is H or hydroxy which may be protected, and R.sub.6 is H, mono or di straight or branched C.sub.1-C.sub.6 alkylamino or straight or branched C.sub.1-C.sub.6 alkoxycarbonylamino.

6. The process according to claim 1, wherein R.sub.4 is ##STR00042## wherein a is 1, 2, or 3, R.sub.5 is H, and R.sub.6 is straight or branched C.sub.1-C.sub.6 alkoxycarbonylamino.

7. The process according to claim 1, wherein R.sub.1 is methyl, R.sub.2 is an amino protecting group, R.sub.3 is H, and R.sub.4 is ##STR00043## wherein a is 2, R.sub.5 is H, and R.sub.6 is protected amino.

8. The process according to claim 1, wherein R.sub.1 is methyl, R.sub.2 is Boc or trityl, R.sub.3 is H, and R.sub.4 is ##STR00044## wherein a is 2, R.sub.5 is H, and R.sub.6 is NH-Boc.

9. The process according to claim 1, wherein the non-nucleophilic base is 1,8-diazabicycloundec-7-ene.

10. The process according to claim 1, wherein production of the compound of formula I is conducted in a non-nucleophilic solvent.

11. The process according to claim 1, wherein production of the compound of formula I is conducted under anhydrous conditions.

12. The process according to claim 1, wherein the compounds of formula II and formula III are used in a molar ratio of 1/1.2 to 1/3.

13. The process according to claim 1, wherein the compound of formula II and PhI(OAc).sub.2 are used in a molar ratio of 1/1.1 to 1/1.9.

14. The process according to claim 1, wherein the compound of formula II is prepared by a process of converting a compound of formula ##STR00045## wherein R.sub.1 and R.sub.2 are as defined in claim 1, and R.sub.3 is straight or branched C.sub.1-C.sub.6 alkyl or an amino protecting group into the compound of formula II.

15. A process for preparation of Ceftolozane or a salt thereof which comprises a) preparing a compound of formula I by the process according to claim 1 wherein R.sub.1 is methyl, R.sub.2 is H or an amino protecting group, R.sub.3 is an amino protecting group, and R.sub.4 is ##STR00046## wherein a is 2, R.sub.5 is H, and R.sub.6 is protected amino, b) reacting the compound of formula I, optionally after deprotection, with at least one other intermediate product and removing any remaining protection group to obtain Ceftolozane or salt thereof.

Description

EXAMPLE 1

Synthesis of di-tert-butyl (4-cyano-1-methyl-1H-pyrazol-5-yl)imidodicarbonate

(1) ##STR00027##

(2) In a 10 L reactor, 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (501.95 g, 4.11 mol, 1 equiv) was suspended in 2-methyltetrahydrofuran (Me-THF, 7.5 L). To this suspension, triethylamine (828.6 g, mL, 8.19 mol, 2 equiv) and DMAP (85.0 g, 0.69 mol, 0.17 equiv) were added in one portion, keeping the inner temperature at 25 C. in a separate 6 L reactor, di-tert-butyl dicarbonate (1966 g, 9.0 mol, 2.2 equiv) was dissolved in Me-THF (2.5 L). This solution was added to the main reactor over 23 min keeping the reaction temperature 30 C. (caution: gas evolution). The reaction was heated to +47 C. and stirred for 4.8 h, after which HPLC control indicated complete disappearance of the starting material. The reaction was cooled to +25 C. and charged with water (2.0 L). The pH was adjusted to 3.1 with 10% aq. HCl (3257 g), and the phases separated. The aqueous phase was discarded and the organic phase charged with water (1.75 L) and sat. aq. NaCl (1.75 L). The pH was adjusted to 10.2 with 1M NaOH (813 g) and the solution stirred for 5 min. The stirring was stopped and phases separated. The aqueous phase was discarded and the organic phase charged with sat. aq. NaCl (2.5 L), stirred for 10 min and the phases separated. The aqueous phase was discarded and the organic phase was transferred to a rotary evaporator. Volatiles were removed under reduced pressure to afford the title product as a clear gum (1402 g) which slowly solidified, and was used without further purification.

(3) Characterization Data for the Product:

(4) .sup.1H NMR (300 MHz, DMSO): 8.12 (s, 1H), 3.71 (s, 3H), 1.41 (s, 18H).

EXAMPLE 2

Synthesis of 1-methyl-5-(tritylamino)-1H-pyrazole-4-carbonitrile

(5) ##STR00028##

(6) In a two-neck round bottom flask, 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (970.9 g, 7.95 mmol, 1 equiv) was suspended in pyridine (10 mL). To this suspension trityl chloride (1.99 g, 7.15 mmol, 0.9 equiv) was added, and the reaction was heated to 60 C., whereby a clear solution was initially formed, followed by the gradual appearance of a precipitate. The reaction was stirred for 15 h, after which further trityl chloride (1.11 g, 3.97 mmol, 0.5 equiv) was added, followed by ethanol (2.32 mL). The reaction was stirred for 23 h, after which HPLC control indicated 94% conversion of the starting material. The reaction was charged with water (50 mL) and dichloromethane (50 mL) and pH was adjusted to 2.25 with 50% aq. H.sub.2SO.sub.4. The phases were separated, the organic phase charged was charged with water (50 mL) and pH was adjusted to 10 with 2M NaOH. The phases were separated, the organic phase was washed with sat. aq. NaCl (50 mL), dried over Na.sub.2SO.sub.4 and filtered. To the filtrate was added 100 mL diisopropylether (DIPET) and the solution was concentrated under reduced pressure to 25 g, initiating crystallization. The crystal suspension was cooled at 4 C. for 1 h and filtered, washing the filter cake with cold DIPET. Drying at 30 C. under reduced pressure for 17 h gave the title product as white crystalline solid (1.47 g, 4.0 mmol, 50%).

(7) Characterization Data for the Product:

(8) .sup.1H NMR (300 MHz, DMSO): 7.46 (s, 1H), 7.37-7.16 (m, 15H), 6.77 (s, 1H), 3.53 (s, 3H).

(9) .sup.13C NMR (75 MHz, DMSO): 147.8, 144.7, 141.1, 128.9, 127.7, 127.5, 114.8, 81.3, 71.8, 35.6.

EXAMPLE 3

Synthesis of tert-butyl (4-carbamoyl-1-methyl-1H-pyrazol-5-yl)carbamate

(10) ##STR00029##

(11) In a 30 L reactor equipped with a gas exhaust (20 L/h flow rate) and a reflux condenser, di-tert-butyl (4-cyano-1-methyl-1H-pyrazol-5-yl) imidodicarbonate prepared according to Example 1 (1349 g, 1 equiv) was dissolved in ethanol (6.8 L). To this solution, 1M NaOH (11.9 L) was added in one portion, keeping the reaction temperature at 30 C. A 35% aqueous H.sub.2O.sub.2 solution (2788 g) was then added over 120 min (caution: gas evolution) keeping the inner temperature below 40 C. The reaction was stirred for an additional 1 h, after which HPLC control indicated complete disappearance of the starting material and <1% of the mono Boc-protected intermediate tert-butyl (4-cyano-1-methyl-1H-pyrazol-5-yl)carbamate. A solution of Na.sub.2SO.sub.3 (720 g) in water (6 L) was added to the reaction mixture over 5 min, and the mixture was stirred for 17 min. The pH was adjusted to 10.7 with 10% aq. HCl (1265 g), and the crude reaction mixture extracted with EtOAc (415 L). The combined organic layers (70 L) were divided into 2 portions and each portion concentrated under reduced pressure to ca. 10 L, stripped with EtOAc by continuous addition of solvent and evaporation while keeping the volume at ca. 10 L and seeded, initiating crystallization. Each portion of the crystal suspension was further evaporated to an end mass of ca. 3400 g and both portions were combined and kept at 20 C. for 20 h. The crystal suspension was filtered washing the filter cake with a cold cyclohexane/EtOAc (2:1) solution. Drying at 40 C. under reduced pressure for 16 h gave the title product as white crystalline solid (882 g, 3.67 mol, 89% over 2 steps).

(12) Characterization Data for the Product:

(13) .sup.1H NMR (300 MHz, (CD.sub.3).sub.2O): 8.56 (br s, 1H), 7.81 (s, 1H), 7.10 (br s, 1H), 6.50 (br s, 1H), 3.77 (s, 3H), 1.50 (s, 9H).

(14) .sup.13C NMR (75 MHz, DMSO): 163.5, 153.0, 137.7, 137.4, 109.7, 79.9, 35.6, 27.9.

EXAMPLE 4

Synthesis of 1-methyl-5-(tritylamino)-1-pyrazole-4-carboxamide

(15) ##STR00030##

(16) In a two-neck round bottom flask, 1-methyl-5-(tritylamino)-1H-pyrazole-4-carbonitrile prepared according to Example 2 (634.0 mg, 1.74 mmol, 1 equiv) was dissolved in DMSO (7 mL). To this solution 5 M NaOH (1.19 mL, 5.95 mmol, 3.4 equiv) was added, followed by 35% aq. H.sub.2O.sub.2 (1.4 mL, 9 equiv) dropwise (caution: reaction highly exothermic). The foaming reaction was cooled by the addition of 10 mL DMSO and stirred for 30 min, after which HPLC analysis indicated 98% conversion. The reaction was charged with water (30 mL), stirred for 30 min and filtered, washing the filter cake with water (10 mL). Drying at under reduced pressure gave the title product as white crystalline solid (560 mg, 1.46 mmol, 84%).

(17) Characterization Data for the Product:

(18) .sup.1H NMR (300 MHz, DMSO): 8.93 (s, 1H), 7.63 (s, 1H), 7.47-7.15 (m, 16H), 6.76 (br s, 1H), 2.88 (s, 3H).

(19) .sup.13C NMR (75 MHz, DMSO): 166.45, 149.1, 156.6, 137.2, 128.3, 128.0, 127.0, 101.3, 71.7, 38.3.

EXAMPLE 5

Synthesis of tert-butyl (2-(3-(5-tert-butoxycarbonyl)amino-1-methyl-1H-pyrazol-4-yl)ureido)ethyl)carbamate

(20) ##STR00031##

(21) In a 20 L reactor, tert-butyl (4-carbamoyl-1-methyl-1H-pyrazol-5-yl)carbamate prepared according to Example 3 (783.4 q, 3.26 mol, 1 equiv) was suspended in Me-THF (8.3 L) and the reaction was cooled to 0 C. To this suspension, tert-butyl (2-aminoethyl)carbamate (BocEDA, 1033.5 g, 6.45 mol, 1.86 equiv) was added in one portion, followed by DBU (1768.8 g, 11.6 mol, 3.3 equiv) keeping the inner temperature at 0 C. Diacetoxyiodobenzene (665.4 g, 2.07 mol, 0.6 equiv) was added in one portion and the reaction was stirred for 68 min at 0 C. A second portion of diacetoxyiodobenzene (663.6 g, 2.06 mol, 0.6 equiv) was added and the reaction was stirred for 4 h at 0 C. The reaction was warmed up to 20 C. and charged with 17% aq. NaCl solution (7 L), stirred and the phases were separated. The organic phase was charged with 10% aq. Na.sub.2SO.sub.3 solution (4.2 L) and stirred. The pH was adjusted to 3.5 with 10% aq. HCl (2969 g) and the phases separated. The organic phase was charged with 8% aq. NaHCO.sub.3 solution, stirred and the phases were separated. The organic phase was evaporated under reduced pressure to dryness, the residue was redissolved in MeOH (6.7 L) and extracted with heptane (36.7 L). The combined heptane phases were discarded and the methanol phase was evaporated under reduced pressure to dryness, redissolved in acetone (3.3 L) and evaporated to dryness again. The residue was taken up in acetone (5 L) and stirred for 1 h at 20 C., whereby crystallization was initiated. Cyclohexane (7.5 L) was added dropwise over 42 min and the crystal suspension was stirred for 52 min, cooled to 10 C. and stirred for further 13 h. The suspension was filtered, washing the filter cake with cold (10 C.) solution of acetone/cyclohexane (1:3) (4 L). Drying at 40 C. under reduced pressure for 16 h gave the title product as white crystalline solid (803 g, 2.01 mol, 62%).

(22) Characterization Data for the Product:

(23) .sup.1H NMR (300 MHz, DMSO): 8.72 (br s, 1H), 7.49 (s, 1H), 6.81 (br s, 1H), 6.34 (br s, 1H), 3.55 (s, 3H), 3.15-3.02 (m, 2H), 3.02-2.90 (m, 2H), 1.51-1.30 (m, 18H).

(24) .sup.13C NMR (75 MHz, DMSO): 155.6, 155.4, 153.3, 130.4, 125.0, 116.6, 79.8, 77.6, 40.5, 39.1, 35.3, 28.2, 27.9.

EXAMPLE 6

Synthesis of 4-(3-{2-[(tert-butoxycarbonyl) amino]ethyl}ureido)-1-methyl-5-triphenylmethylaminopyrazole

(25) ##STR00032##

(26) In a two-neck round bottom flask, 1-methyl-5-(tritylamino)-1H-pyrazole-4-carboxamide prepared according to Example 4 (92 mg, 0.24 mmol, 1 equiv) was suspended in dichloromethane (2.5 mL). To this suspension, tert-butyl (2-aminoethyl)carbamate (BocEDA, 97.3 mg, 0.58 mmol, 2.4 equiv) was added in one portion, followed by DBU (134 L, 0.9 mmol, 3.7 equiv), whereby a clear solution was obtained after several minutes of stirring. The reaction was cooled to 0 C. and diacetoxyiodobenzene (105.2 mg, 0.33 mmol, 1.4 equiv) was added in one portion and the reaction was stirred for 75 min at 0 C., after which HPLC indicated complete conversion. The crude reaction mixture was evaporated under reduced pressure to dryness, the residue was redissolved in MeOH (5 mL) and extracted with heptane (45 mL). The combined heptane phases were discarded and the methanol phase was evaporated under reduced pressure to dryness, redissolved in dichloromethane (10 mL) and washed with 17% aq. NaCl solution (15 mL). The phases were separated, and the organic phase allowed to stand at r.t., whereby crystallization initiated. The crystal suspension was allowed to stand at 20 C. for 2 days and filtered. Drying at r.t. under reduced pressure for 2 h gave the title product as white crystalline solid (80 mg, 0.15 mmol, 62%).

(27) Characterization Data for the Product:

(28) .sup.1H NMR (300 MHz, DMSO): 8.72 (br s, 1H), 7.49 (s, 1H), 6.81 (br s, 1H), 6.34 (br s, 1H), 3.55 (s, 3H), 3.15-3.02 (m, 2H), 3.02-2.90 (m, 2H), 1.51-1.30 (m, 18H). .sup.13C NMR (75 MHz, DMSO): 156.2, 155.6, 145.8, 136.5, 132.6, 129.1, 127.3, 126.7, 115.0, 77.6, 72.1, 40.6, 39.3, 34.6, 28.2.

EXAMPLE 7

Synthesis of tert-butyl (2-(3-(5-amino-1-methyl-1H-pyrazol-4-yl)ureido)ethyl)carbamate

(29) ##STR00033##

(30) In a 3-neck round bottom flask equipped with a reflux condenser, tert-butyl (2-(3-(5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-4-yl)ureido)ethyl)carbamate prepared according to Example 5 (43.6 g, 109.5 mmol, 1 equiv) was dissolved in absolute ethanol (90 mL). To this solution, water (450 mL) was added. The resulting suspension was heated to 110 C. with vigorous stirring, whereby the suspension slowly dissolved (solid encrusted on the reaction vessel walls was washed with additional 5 mL ethanol). After a total of 5 h, HPLC control indicated 94% conversion. The reaction was cooled to 85 C., stirred for an additional 1.5 h and cooled to r.t. The crude reaction mixture was diluted with THF (450 mL), charged with 25% aq. NaCl solution (450 mL) and the phases were separated. The aqueous phase was extracted with THF (1450 mL and 1250 mL). The combined organic phases were evaporated under reduced pressure, the residue was redissolved in methanol (250 mL) and evaporated to dryness again. Drying at 50 C. under reduced pressure for 17 h gave the title product as white crystalline solid (26.3 g, 88.1 mmol, 81%).

(31) Characterization Data for the Product:

(32) .sup.1H NMR (300 MHz, DMSO): 7.52 (br s, 1H), 6.98 (s, 1H), 6.81 (br s, 1H), 6.09 (br s, 1H), 4.84 (br s, 2H), 3.50 (s, 3H), 3.11-3.01 (m, 2H), 3.01-2.91 (m, 2H), 1.38 (s, 9H).

(33) .sup.13C NMR (75 MHz, DMSO): 156.8, 155.6, 140.2, 133.6, 103.4, 77.5, 40.6, 39.4, 34.7, 28.2.

COMPARATIVE EXAMPLE 1

Overview of Attempted Hofmann Rearrangement Using Classical Reagents

(34) TABLE-US-00001 R Reagent equiv Base equiv Solvent Temp, C. Time, h Result H Br.sub.2 1 KOH 14 H.sub.2O 5 to 80 17 3% product + decomp. H NaOCl 1 NaOH 1.9 H.sub.2O 70 3.5 educt + decomposition H NBS 1.5 KOH 6 MeOH/H.sub.2O 0 to r.t. 5 no conversion Boc NBS 1.5 DBU 10 1,4-dioxane 10 to r.t. 1 decomposition Boc NBS 1.5 KOH 10 1,4-dioxane r.t. to 65 1.5 no conversion

COMPARATIVE EXAMPLE 2

Synthesis of tert-butyl (4-amino-1-methyl-1H-pyrazol-5-yl)carbamate

(35) ##STR00035##

(36) In a two-neck round bottom flask, tert-butyl (4-carbamoyl-1-methyl-1H-pyrazol-5-yl)carbamate prepared according to Example 3 (300 mg, 1.25 mmol, 1 equiv) was dissolved in 1,4-dioxane (3 mL). To this solution was added water (0.3 mL) and 50% aq. KOH solution (930 L, 12.5 mmol, 10 equiv). The resulting emulsion was heated to 40 C. and a solution of diacetoxyiodobenzene (603 mg, 1.87 mmol, 1.5 equiv) in 1,4-dioxane (3 mL) and water (0.3 mL) was added dropwise over 30 min. The reaction was stirred for 1 h at 40 C. and a second portion of diacetoxyiodobenzene (80 mg, 0.25 mmol, 0.2 equiv) was added in one portion. The reaction was stirred for 3 h at 40 C., cooled to r.t and diluted with dichloromethane (30 mL). The pH was adjusted to 8.5 with 50% aq. H.sub.2SO.sub.4 solution, resulting in phase separation. The phases were separated and the aqueous phase washed with dichloromethane (20 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. Drying at 40 C. under high vacuum for 17 h gave the title product as pale brown gum which solidified upon standing (127 mg, 0.60 mmol, 48%).

(37) Characterization Data for the Product:

(38) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.13 (s, 1H), 6.44 (br s, 1H), 3.66 (s, 3H), 3.19 (br s, 2H), 1.50 (s, 9H).

COMPARATIVE EXAMPLE 3

Synthesis of tert-butyl methyl (1-methyl-1H-pyrazole-4,5-diyl)dicarbamate

(39) ##STR00036##

(40) In a two-neck round bottom flask, tert-butyl (4-carbamoyl-1-methyl-1H-pyrazol-5-yl)carbamate prepared according to Example 3 (1 g, 4.16 mmol, 1 equiv) was suspended in methanol (10 mL) and charged with water (1 mL). The resulting clear solution was cooled to 0 C. and charged with 50% aq. KOH solution (3.1 mL, 41.6 mmol, 10 equiv) (caution: exothermic). Diacetoxyiodobenzene (2.01 g, 6.24 mmol, 1.5 equiv) was added in one portion (caution: exothermic). The resulting grey suspension was stirred at 0 C. for 10 min and the cooling was removed, whereby a red solution was formed. After 1 h, HPLC control indicated complete conversion of the starting material and the reaction was diluted with EtOAc (50 mL). The crude reaction mixture was extracted with sat. aq. NaHCO.sub.3 (50 mL), the aqueous phase was washed with EtOAc (25 mL) and the combined organic phases were tried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. Drying at 30 C. under reduced pressure for 48 h gave the title product as off-white crystalline solid (571 mg, 2.11 mmol, 51%).

(41) Characterization Data for the Product:

(42) .sup.1H NMR (300 MHz, DMSO): 7.44 (s, 1H), 6.65 (br s, 1H), 6.49 (br s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 1.5 (s, 9H).

(43) .sup.13C NMR (75 MHz, DMSO): 154.5, 153.0, 131.3, 127.1, 114.4, 79.6, 51.6, 35.6, 27.9.