Synthesis methods for upadacitinib and intermediate thereof

Abstract

The present disclosure relates to a JAK inhibitor upadacitinib intermediate and a preparation method therefor, and to a preparation method for a JAK inhibitor upadacitinib. The upadacitinib intermediate of the present application is as shown in Formula (II) or Formula (III), ##STR00001## wherein, R is a protective group of nitrogen atoms, and R.sub.1 is an open-chain or cyclic amine group. Compared with the prior art, the method for the synthesis of upadacitinib of the present application, significantly reduces cost, is environmentally-friendly. And the quality of the final product is well controlled.

Claims

1. A compound, having a structure shown Formula III: ##STR00038## wherein, R is a protective group of nitrogen atoms.

2. The compound according to claim 1, wherein, in Formula III, R is selected from the group consisting of benzyl, benzyloxycarbonyl, and allyloxycarbonyl.

Description

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

(1) The following embodiments describe the implementation of the present application, and those skilled m the art should realize that these specific embodiments only show the implementation technical solutions selected to achieve the purpose of this application, and are not limitations on the technical solutions. According to the teaching of this application, the improvement of the technical solution of this application in combination with the prior art is obvious, which all fall within the protection scope of this application.

(2) The implementation conditions employed by the embodiments may be further adjusted according to particular requirements, and undefined implementation conditions usually are conditions in conventional experiments.

(3) Among them, the brown chemical reagents used in the following embodiments are all commercially available chemical reagents or can be prepared by referring to the methods in WO2013043826A1 and WO2017066775A1.

(4) In the exemplary implementations of the present disclosure, those skilled in the art can also make changes to the synthetic route, for example, change specific reaction conditions or adjust a certain step or several steps of the synthetic route as needed. Any changes made without departing from the substance of this application are within the protection scope of this application.

(5) Abbreviations: TsCl: 4-toluenesulfonyl chloride; Cbz: benzyloxycarbonyl protective group; TBTU: O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate; X-Phos: 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl; Boc anhydride: di-tert-butyl dicarbonate; CDI: N,N-carbonyldiimidazole.

Embodiment 1

(6) ##STR00019##

(7) To a 100 mL three-necked flask were added 2.2 g of Compound 1, 22 mL of dichloromethane, 3.82 g of TBTU, and 1.38 g morpholine under N protection, the temperature was cooled to 0 to 10 C. 1.54 g of diisopropylethylamine was added dropwise. The reaction mixture was warmed to room temperature and was held for 1 h. Upon completion, 11 mL of water was added. The layers were separated. The aqueous phase was extracted with 22 ml dichloromethane. The organic phases were combined, washed with 6.6 mL of brine, concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 2.35 g of light yellow oil, namely Compound 2, with a yield of 87.0%.

(8) The NMR data of Compound 2 are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.36-7.34 (m, 5H), 5.15-5.11 (m, 2H), 3.83-3.27 (m, 13H), 2.26-2.19 (m, 1H), 1.39-1.35 (m, 2H), 0.95-0.89 (m, 3H).

(9) The mass spectrum data of Compound 2: [M+H].sup.+ 347.4.

Embodiment 2

(10) ##STR00020##

(11) To a 10 mL three-necked flask were added 120 rug of Compound 1, 84 mg of dimethylhydroxylamine hydrochloride, 209 mg of TBTU, and 1.8 mL of dichloromethane under N.sub.2 protection. The reaction was cooled to 0 to 10 C. 140 mg of diisopropylethylamine was added dropwise. The reaction mixture was warmed to room temperature and was held for 1 h. Upon reaction completion, 1 mL of water was added. The layers were separated. The aqueous phase was extracted with 10 mL of dichloromethane. The organic phases were combined, washed with 1 mL of brine, concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 105 mg of light yellow oil Compound 3, with a yield of 76.1%.

(12) The NMR data of Compound 3 are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.38-7.31 (m, 5H), 5.18-5.08 (m, 2H), 3.76-3.72 (m, 1H), 3.69 (s, 3H), 3.62-3.34 (m, 4H), 3.18 (s, 3H), 3.39-3.33 (m, 1H), 1.33-1.25 (m, 2H), 0.93-0.88 (m, 3H).

Embodiment 3

(13) ##STR00021##

(14) To a 100 mL three-necked flask were added 1.4 g of Compound 2 and 14 mL of tetrahydrofuran under N.sub.2 protection. The reaction mixture was cooled to below 60 C. 3.8 mL of methyl lithium solution in tetrahydrofuran (1.6 M) was added dropwise. Upon reaction completion, 10 mL of saturated ammonium chloride was added. The mixture was warmed to room temperature. 15 MT of ethyl acetate was added. The layers were separated. The aqueous phase was extracted with 15 mL of ethyl acetate. The organic phases were combined, washed with 5 mL of brine, concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 710 mg of light yellow oil Compound 4, with a yield of 645%.

(15) The NMR data of Compound 4 are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37-7.30 (m, 5H), 5.15-5.12 (m, 2H), 3.72-3.65 (m, 1H), 3.58-3.19 (m, 4H), 2.38-2.34 (m, 1H), 2.18 (s, 3H), 1.40-1.26 (m, 2H), 0.96-0.91 (m, 3H).

Embodiment 4

(16) ##STR00022##

(17) To a 10 mL three-necked flask were added 90 mg of Compound 3 and 1.8 mi of tetrahydrofuran under N.sub.2 protection. 0.3 ml of methyl lithium solution in tetrahydrofuran (1.6 M) was added dropwise at below 60 C. Upon reaction completion, 2 mL of saturated ammonium Chloride was added. The mixture was warmed to room temperature. 5 mL of ethyl acetate was added. The layers were separated. The aqueous phase was extracted with 10 mL of ethyl acetate. The organic phases were combined, washed with 5 mL of brine, concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 70 mg of light yellow oil Compound 4, with a yield of 90.9%.

(18) The NMR data of Compound 4 are as follows: .sup.1H NMR (400 CDCl.sub.3) 7.37-7.30 (m, 5H), 5.15-5.12 (m, 2H), 3.72-3.65 (m, 1H), 3.58-3.19 (m, 4H), 2.38-2.34 (m, 1H), 2.18 (s, 3H), 1.40-1.26 (m, 2H), 0.96-0.91 (m, 3H).

Embodiment 5

(19) ##STR00023##

(20) To a 10 mL three-necked flask were added 200 mg of Compound 4, 2.0 mL of methanol, 440 mg of 40% HBr aqueous solution, and 697 rug of bromine under N.sub.2 protection. The reaction mixture was stirred at room temperature. Upon reaction completion, 2 mL of saturated sodium thiosulfate aqueous solution was added, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7, then 10 mL ethyl acetate was added. The lavers were separated. The aqueous phase was extracted twice with 10 mL of ethyl acetate (10 mL each time). The organic phases were combined, concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 182 mg of light yellow oil. Compound 5, with a yield of 70.7%;

(21) The mass spectrum data of Compound 5: [M+H].sup.+ 354.1.

Embodiment 6

(22) ##STR00024##

(23) To a 25 mL round-bottom flask were added 5 (0.2 of Compound 6, 7.5 mL of acetonitrile, and 2.7 g of acetic acid. To another 100 mL three-necked flask were added 6.8 mL of acetonitrile, 1.8 g of acetic acid, and 3.1 g of iodine, 6.1 g of 20% sulfuric acid and 3.2 g of sodium iodate was added at 65-75 C. To the 100 mL three-necked flask were added the mixed solution in the 25 mL single-necked flask dropwise. The reaction mixture was warmed to 75 to 85 C. Upon reaction completion, the system was cooled to 60 to 70 C. To the solution reaction mixture were added 15 g of 40% NaHSO.sub.3 aqueous solution, 30 of water, and 17 g of 30% NaOH aqueous solution. After being cooled to 0 to 10 C., the mixture was filtered. The cake was recrystallized in toluene to give 4.6 g of Compound 7, with a yield of 54.0%.

(24) The mass spectrum data of Compound 7: [M+H].sup.+ 299.9.

Embodiment 7

(25) ##STR00025##

(26) To a 250 mL three-necked flask were added 10 g of Compound 6, 15.3 g of N-bromosuccinimide, and 100 mg of 1,4-dioxane under N.sub.2 protection at room temperature. Upon reaction completion, 20 mL of saturated sodium thiosulfate aqueous solution was added. The layers were separated. The aqueous phase was extracted with 50 ml of dichloromethane. The organic phases were combined, washed with 10 of brine, concentrated under vacuum to give crude Compound 8, which was recrystallized from n-heptane and ethyl acetate to give 7.1 g of Compound 8, with a yield of 72%;

(27) The mass spectrum data of Compound 8: [M+H].sup.+ 251.9.

Embodiment 8

(28) ##STR00026##

(29) To a 25 mL three-necked flask were added 0.82 g of Compound 7, 0.43 g of triethylamine, 4 mL of dichloromethane, and 250 mg of methyl butanol under N.sub.2 protection. 7.7 rug of CuCl and 22.7 mg of PdCl.sub.2(PPh.sub.3).sub.2 were added. The reaction system was refilled with N.sub.2 for three times. The reaction was stirred at 20 to 30 C., for 12 h. Upon completion, 5 mi, of water and 20 mL of dichloromethane were added. The layers were separated, the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 0.54 g of Compound 9, with a yield of 77%.

(30) The NMR data of Compound 9 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 8.08 (s, 1H), 6.75 (s, 2H), 5.66 (s, 1H), 1.49 (s, 6H).

(31) The mass spectrum data of Compound 9: [M+H].sup.+ 756.1.

Embodiment 9

(32) ##STR00027##

(33) To a 150 mL three-necked flask were added 5 g of Compound 8, 2.4 g of triethylamine and 25 mL of 1,4-dioxane under N.sub.2 protection. 0.182 g of CuCl, 120 mg of PdCl.sub.2(PPh.sub.3).sub.2 and 2.0 g of methyl butanol was added. The reaction was refilled with N.sub.2 for three times. The reaction was stirred at 75 C. for 12 h. Upon completion, the solution reaction mixture was cooled to room temperature. 74 ml of 1 N hydrochloric acid and 25 oil, of dichloromethane were added. The layers were separated. The aqueous phase was washed with 25 mL of dichloromethane. 12 g of 30 wt % NaOH aqueous solution was added to the aqueous phase. The resulting suspension was filtered to give 4.9 g of Compound 9, with a yield of 96%.

(34) The NMR data of Compound 9 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 8.08 (s, 1H), 6.75 (s, 2H), 5.66 (s, 1H), 1.49 (s, 6H).

(35) The mass spectrum data of Compound 9: [M+H].sup.+ 256.1.

Embodiment 10

(36) ##STR00028##

(37) To a 10 mL three-necked flask were added 200 rug of Compound 9, 1.0 mL of N-methylpyrrolidone, and 0.9 g of 10 wt % NaOH aqueous solution under N.sub.2 protection. The reaction was stirred at 70 C. Upon completion, the reaction mixture was cooled to room temperature, stirred for 2 h. The resulting suspension was filtered. The solid was dried to give 100 mg of Compound 10, with a yield of 65%.

(38) The NMR data of Compound 10 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 12.38 (br, 1H), 8.39 (s, 1H), 8.00 (m, 1H), 6.67 (m 1H).

Embodiment 11

(39) ##STR00029##

(40) To a 1000 mL three-necked flask were added 65 g of Compound 10 and 260 mL, of N,N-dimethylformamide under N.sub.2 protection. 15.7 g of NaH was added portion wise at 0 to 10 After 1 h, a solution of 75.1 g of TsCl in 260 mL N,N-dimethylfomamide was added at 0-10 C. Upon completion, 520 ml of water was added. The resulting suspension was stirred for 2 h. Filtration and recrystallized from ethyl acetate and n-heptane to give 99.0 g of Compound 11, with a yield of 86.1%.

(41) The NNW, data of Compound 11 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 8.58 (s, 1H), 8.37-8.36 (m, 1H), 8.00-7.98 (dd, 2H), 7.45-7.42 (m, 2H), 7.02-7.01 (m, 1H), 2.34 (s, 3H).

(42) The mass spectrum data of Compound 11: [M+H].sup.+ 353.2.

Embodiment 12

(43) ##STR00030##

(44) To a 1000 ml three-necked flask were added 50 g of Compound 11, 500 rant of toluene, 58.9 g of potassium carbonate, 50 g of tart-butyl carbamate. 637 mg of palladium acetate. 2.7 g of X-Phos, and 31 g of Boc anhydride. The system was refilled with N.sub.2 for six times. The reaction was stirred at 90-100 C. Upon completion, the reaction mixture was cooled to 50-60 C. and was filtered. The filtrate was concentrated and purified by silica gel column chromatography to give 46.1 g of Compound 12, with a yield of 83.6%.

(45) The NMR data of Compound 12 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 9.08 (s, 1H), 8.05-8.03 (m, 2H), 7.93-7.92 (m, 1H), 7.49 (s, 1H), 7.30-7.28 (m, 1H), 6.63-6.62 (m, 1H), 4.51 (s, 1H), 2.39 (s, 3H), 1.54 (s, 9H).

Embodiment 13

(46) ##STR00031##

(47) To a 500 mL three-necked flask were added 39.5 g of Compound 12 and 180 mL of N,N-dimethylacetamide under nitrogen protect. 8.96 g of lithium tert-butoxide was added at 5 C. After 1 h, the system was cooled to 15 C. A solution of 39.1 g of Compound 5 in N,N-dimethylacetamide (180 mL) was added dropwise at 20 to 10 C. After 1 h, 17.03 g of acetic acid was added. The reaction mixture was stirred at room temperature for 0.5 h. 360 of water and 360 ml of isopropyl acetate were added. The layers were separated. The aqueous phase was extracted once with 180 mL of isopropyl acetate. The organic phases were combined, and washed twice with 180 mL of 4% sodium bicarbonate solution, once with 180 mL of water. The organic phase was concentrated under reduced pressure, added 468 mL of methanol, then the mixture was warmed to 35C, stirred for 0.5 h, then added 70 mg seed, stirred for another 0.5 h. added 54 mL of water, and stirred overnight. The resulting suspension was filtered. The solid was dried to give 42.08 g of Compound 13, with a yield of 62.57%.

(48) The NMR data of Compound 13 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 8.74 (s, 1H), 8.21-8.17 (m, 1H), 8.00-7.97 (m, 2H), 7.44-7.42 (m, 2H), 7.34-7.27 (m, 5H), 6.79-6.66 (m, 1H), 5.06-5.05 (m, 2H), 4.74 (s, 2H), 3.65-3.58 (m, 1H), 3.52-3.43 (m, 3H), 3.21-3.16 (m, 1H), 2.40-2.38 (m, 1H), 2.34 (s, 3H), 1.29-1.46 (m, 10H), 1.29-1.23 (m, 1H), 0.91-0.86 (m, 3H).

Embodiment 14

(49) ##STR00032##

(50) To a 500 mL three-necked flask were added 30 g of Compound 13-180 mL of acetonitrile, 38.1 g of trifluoroacetic anhydride, and 9.7 g. of pyridine. The reaction mixture was stirred at 70-80 C. for 2 h. The reaction solution was concentrated under reduced pressure. 210 mL of 2-methyltetrahydrofuran and 210 g of 20 wt % NaOH aqueous solution were added. The mixture was heated to 45-55 C. for 2 hours. After being cooled to room temperature, the layers were separated. The organic phase was washed with 105 g of saturated brine. After being concentrated under reduced pressure, the crude product was purified by silica gel column chromatography to give 15.8 g of Compound 14, with a yield of 90.0%.

(51) The NMR data of Compound 14 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 12.30 (s, 1H), 8.59 (s, 1H), 7.58-7.57 (m, 1H), 7.45-7.31 (m, 6H), 7.00-6.97 (m, 1H), 5.15-5.13 (m, 2H), 4.39-4.34 (m, 1H), 3.93-3.71 (m, 3H), 3.34-3.28 (m, 1H), 2.57-2.50 (m, 1H), 1.09-1.02 (m, 1H), 0.91-0.83 (m, 1H), 0.63-0.58 (m, 3H).

(52) The mass spectrum data of Compound 14: [M+H].sup.+ 390.2.

Embodiment 15

(53) ##STR00033##

(54) To a 100 mL three-necked flask were added 6 g of Compound 14 and 60 mL of tetrahydrofuran under N.sub.2 protection, 3.46 mL of potassium tert-butoxide was added portion wise at 0-10 C. After 1 h, 4.4 g p-toluenesulfonyl chloride was added. Upon completion, 1.85 g of acetic acid was added, followed by the addition of 30 mL of water and 60 mL of ethyl acetate. The layers were separated. The organic phase was washed with 30 ml of saturated brine and concentrated. The crude product was purified by silica gel column chromatography to give 7.0 g of Compound 15, with a yield of 83.0%.

(55) The NMR data of Compound 15 are as follows: NMR (400 MHz, d-DMSO) 8.77 (s, 1H), 8.04-8.02 (m, 2H), 7.98-7.97 (m, 1H), 7.70-7.69 (m, 1H), 7.44-7.29 (m, 1H), 5.16-5.08 (m, 2H), 4.35-4.30 (m, 1H), 3.87-3.70 (m, 3H), 3.34-3.27 (m, 1H), 2.47-2.46 (m, 1H), 2.33 (s, 3H), 0.99-0.94 (m, 1H), 0.88-0.82 (m, 1H), 0.60-0.55 (m, 3H).

(56) The mass spectrum data of Compound 15: [M+H].sup.+ 544.1.

Embodiment 16

(57) ##STR00034##

(58) To a 25 mL three-necked flask were added 1 g of Compound 13, 10 mL of acetonitrile and 1.3 g of trifluoroacetic anhydride. The reaction mixture was stirred at 70-80 C. Upon completion, 5 mL of water and 30 mL of ethyl acetate was added. The layers were separated. The organic phase was washed with 10 mL of saturated brine and was concentrated. The crude product was purified by silica gel column chromatography to give 0.5 g of Compound 15, with a yield of 61.0%.

(59) The NMR data of Compound 15 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 8.77 (s, 1H), 8.04-8.02 (m, 2H), 7.98-7.97 (m, 1H), 7.70-7.69 (m, 1H), 7.44-7.29 (m, 1H), 5.16-5.08 (m, 2H), 4.35-4.30 (m, 1H), 3.87-3.70 (m, 3H), 3.34-3.27 (m, 1H), 2.47-2.46 (m, 1H), 2.33 (s, 3H), 0.99-0.94 (m, 1H), 0.88-0.82 (m, 1H), 0.60-0.55 (m, 3H).

(60) The mass spectrum data of Compound 15: [M+H].sup.+ 544.1.

Embodiment 17

(61) ##STR00035##

(62) To a 25 mL three-necked flask were added 1 g of Compound 15, 15 mL of ethyl alcohol and 0.2 g of Pd/C. the reaction mixture was stirred under hydrogen atmosphere at 50-60 C. Upon completion, this solution was filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography to give 315 mg of Compound 16, with a yield of 70.0%.

(63) The NMR data of Compound 16 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 9.89 (br, 1H), 8.79 (s, 1H), 8.04-8.00 (m, 3H), 7.90 (s, 1H), 7.45-7.43 (m, 3H), 4.45-4.43 (m, 1H), 3.72-3.61 (m, 3H), 3.18-3.13 (m, 1H), 2.61-2.57 (m, 1H), 2.33 (s, 3H), 0.90-0.86 (m, 2H), 0.59-0.56 (m, 3H).

(64) The mass spectrum data of Compound 16: [M+H].sup.+ 410.2.

Embodiment 18

(65) ##STR00036##

(66) To a 25 mL three-necked flask were added 278 mg of CDI and 2.5 of tetrahydrofuran under N.sub.2 protection. 182 mg of 2,2,2-trifluoroethylamine was added dropwise at 20-30 C. The mixture was stirred for 1 h. To another 25 mL three-necked flask were added 500 rag of Compound 16, 4 ml of tetrahydrofuran, 1 of water, 234 ma of dipotassium hydrogen phosphate. The pH was adjusted to 8 to 9.5 with 10 wt % KOH aqueous solution. To this solution was added the mixture in the first three-necked flask. The reaction was stirred for 2 h. Upon completion, 3 mi, of 20% citric acid and 10 of ethyl acetate were added. After being stirred at 20 to 30 C. for 1 h, the layers were separated. The organic phase was washed once with 5 mL of saturated brine and was concentrated. The crude product was purified by silica gel column chromatography to give 466 mg of Compound 17, with a yield of 71.5%.

(67) The NMR data of Compound 17 are as follows: .sup.1H NMR (400 MHz, d-DMSO) 8.77 (s, 1H), 8.05-8.03 (d, 2H), 7.99-7.97 (d, 1H), 7.59 (s, 1H), 7.46-7.43 (m, 3H), 6.94 (1, 1H), 4.34-4.29 (m, 1H), 3.88-3.65 (m, 5H), 3.27-3.23 (m, 1H), 2.46-2.54 (m, 1H), 2.35 (s, 3H), 1.04-0.99 (m, 1H), 0.82-0.77 (m, 1H), 0.63-0.60 (m, 3H).

Embodiment 19

(68) ##STR00037##

(69) To a 25 mL three-necked flask were added 300 mg of Compound 17, 4.5 mL of 1,4-dioxane and 1.7 ml of 1N NaOH aqueous solution. The reaction mixture was stirred at 50-60 C. Upon completion, the reaction mixture was cooled to room temperature. 5 mL of water and 10 mL of ethyl acetate were added. The layers were separated. The aqueous phase was extracted once with 10 mL of ethyl acetate. The organic phases were combined, washed once with 10 mL of saturated brine, and was concentrated. The crude product was purified by silica gel column chromatography to give 186 mg of Compound 18, with a yield of 87.3%.

(70) The NMR data of Compound 18 are as follows: Ili NMR (400 MHz, d-DMSO) 12.27 (s, 1H), 8.58 (s, 1H), 7.47-7.43 (m, 2H), 7.00-6.94 (m, 2H), 4.38-4.3.3 (m, 1H), 3.92-3.67 (m, 5H), 3.33-3.25 (m, 1H), 2.59-2.54 (m, 1H), 1.14-1.08 (m, 1H), 0.86-0.78 (m, 1H), 0.65-0.62 (m, 3H).

(71) The mass spectrum data of Compound 18: [M+H].sup.+ 381.2.

(72) This application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement made under the principle of the spirit of this application will be deemed to be within the protection scope of this application.