* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3584 - 3593
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
[3] Farmaco, 2001, vol. 56, # 1-2, p. 41 - 44
2
[ 266353-18-8 ]
[ 175463-32-8 ]
Yield
Reaction Conditions
Operation in experiment
68%
With sodium In ethanol for 1 h; Reflux
The oil 2 was dissolved in 50 mL of absolute ethanol,The solution was added dropwise to a solution of 4 g (0.17 mol) of metallic sodium in 100 mL of absolute ethanol under reflux with heating,Refluxed for 1 h.The solvent was distilled off under reduced pressure, and the residue was treated with 100 mLWater was dissolved and washed with ethyl acetate (30 mL * 2). The aqueous layer was adjusted to pH 4 with 1 mol / L hydrochloric acid, extracted with ethyl acetate,Dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to a residual solvent of about 20 mL, filtered and the cake washed with a small amount of ethyl acetateDry cake to give 16.5 g of a white solid. Yield: 68percent.
33.1 g
With sodium In ethanol at 25℃; Reflux
(4) 4.4 g Na tablets (0.19 mol) were added to 200 mL of anhydrous ethanol,Reaction at room temperature 25 4-5h, until the Na all dissolved.49.2 g (0.19 mol) of the general formula (13) was slowly added dropwise to the prepared ethanolic sodium alcohol solution,After the end of the dropwise addition, the mixture was stirred for 30 min and heated to reflux for 2-3 h. The reaction was monitored by TLC. Post-treatment, concentration under reduced pressure,Dissolve the residue in water and wash the aqueous layer twice with dichloromethane. The aqueous layer was adjusted to pH 4 with dilute hydrochloric acid. A white solid precipitated and was allowed to stand and suction filtered to give 33.1 g of the compound of formula (14) as a white solid.
649.7 g
at 78℃; for 0.5 h;
500 g of glycine ethyl ester hydrochloride, 187.2 g of NaOH and 1200 g of methanol were added to the reaction flask at room temperature for 1 h.The reaction solution was cooled to 0 ° C, and a solution of 267.1 g of acrylonitrile in 600 g of methanol was added dropwise to the reaction system at a temperature of 0 ° C, and the mixture was dropped over 2 h.The reaction solution was warmed to room temperature and stirred for 0.5 h. The reaction solution was warmed to 68 ° C, and stirred under reflux for 5 h.The reaction was monitored by TLC (hydrated ninhydrin baking method), the reaction solution was cooled to below 40 °C, and the temperature was controlled below 40 °C.Methanol to the net,575 g of a crude yellow oily crude intermediate I was obtained in a yield of 100percent, which was directly reacted without purification.The oil obtained in the above step was cooled to 2 ° C, and 1020.2 g of Boc anhydride was added, and the addition was completed.The reaction solution was slowly warmed to room temperature for 3 h, and the thin layer chromatography was confirmed to be completed (hydrated ninhydrin baking plate method).2500 g of dichloromethane was added, and the organic phase was respectively saturated with aqueous sodium hydrogencarbonate and water.Wash with saturated brine, dry over anhydrous sodium sulfate, filter and remove inorganic salts.The filtrate was concentrated to dryness under reduced pressure to give y.252.7 g of sodium methoxide was added to 2000 g of absolute ethanol.The obtained sodium methoxide solution in ethanol was heated to 78 ° C, and 912 g of the intermediate II obtained in the above step was dissolved in 500 g of absolute ethanol.The obtained ethanol solution of the intermediate II is slowly dropped into the above-mentioned ethanol solution of sodium methoxide in a reflux state,The reaction was monitored by TLC, and the reaction was completed in about 0.5 h. After confirming the completion of the reaction, the reaction solution was cooled to below 40 ° C.The ethanol was concentrated to a net under reduced pressure, and the residue was added to 2500 g of water, stirred and dissolved, and the activated carbon was decolorized for 30 min at room temperature, and the activated carbon was filtered off.The aqueous layer was extracted twice with 250 g of dichloromethane, the organic phase was discarded, the aqueous layer was cooled to 0 ° C, and the pH was adjusted to 7 with 30percent aqueous acetic acid, adjusted, and crystallized at 2 ° C for 1 h.After suction filtration, the filter cake was washed with water and dried to obtain 649.7 g of white crystals.That is, intermediate III, three-step total yield: 85.9percent, HPLC: 99.5percent.
Reference：
[1] Archiv der Pharmazie, 2011, vol. 344, # 8, p. 523 - 529
[2] European Journal of Medicinal Chemistry, 2010, vol. 45, # 11, p. 5498 - 5506
[3] Patent: CN105585518, 2016, A, . Location in patent: Paragraph 0024; 0026
[4] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3584 - 3593
[5] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
[6] Patent: CN104072498, 2016, B, . Location in patent: Paragraph 0086; 0098; 0149
[7] Patent: CN104693088, 2018, B, . Location in patent: Paragraph 0027; 0038
[8] Patent: CN108623608, 2018, A, . Location in patent: Paragraph 0045-0068; 0164-0169
3
[ 266353-19-9 ]
[ 175463-32-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 3080 - 3084
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 14, p. 4273 - 4278
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5767 - 5771
4
[ 44981-94-4 ]
[ 175463-32-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3584 - 3593
[3] Archiv der Pharmazie, 2011, vol. 344, # 8, p. 523 - 529
[4] Patent: CN104072498, 2016, B,
[5] Patent: CN104693088, 2018, B,
[6] Patent: CN108623608, 2018, A,
5
[ 3088-42-4 ]
[ 175463-32-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 3080 - 3084
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5767 - 5771
[3] Patent: CN104072498, 2016, B,
6
[ 24424-99-5 ]
[ 175463-32-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
[2] Archiv der Pharmazie, 2011, vol. 344, # 8, p. 523 - 529
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5767 - 5771
[4] Patent: CN105585518, 2016, A,
[5] Patent: CN104693088, 2018, B,
7
[ 44915-39-1 ]
[ 175463-32-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 3080 - 3084
(4.5 g, 43 mmol) was dissolved in absolute ethanol (250 ml) and stirred at 60 ° C for 3 h. The solvent was distilled off under reduced pressure and saturated sodium bicarbonate solution (50 ml) was added to a solid completely dissolved,The extracted organic phase was removed by evaporation under reduced pressure to give the white solid Ib (6.3 g, yield 66percent) which was used in the next step without further purification.
31.4 g
With hydrazine hydrochloride In ethanol at 60℃;
(5) 33.6 g (0.16 mol) of the general formula (14) was added to 200 mL of anhydrous ethanol,16.6 g (0.16 mol) of hydrazine hydrochloride was added in batches and reacted at 60 ° C for 4-5 h. The reaction was monitored by TLC.The reaction mixture was concentrated and the filtrate was concentrated under reduced pressure to obtain 31.4 g of a white solid of the general formula (16).
18 g
With hydrazine hydrate; acetic acid In ethanol at 20 - 85℃; for 14 h;
A solution of tert-Butyl 3-cyano-4-oxopyrrolidine-l-carboxylate (CAS Number 175463-32-8; 30.00 g, 142.7 mmol) in EtOH (600 ml) was added AcOH (57 ml, 1000 mmol) and hydrazine hydrate 99percent (35 ml, 714 mmol) at rt. The reaction mixture was heated at 85°C for 14 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with EtOAc (400 ml) and water (400 ml), pH was adjusted up to ~8 with by portion wise addition of solid Na2CO3. The resulting mixture extracted with EtOAc (2 x 400 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (5percent MeOH in DCM) yielding tert-butyl 3-amino-4,6-dihydropyrrolo[3,4- c]pyrazole-5(lH)-carboxylate (18.0 g, 80.357 mmol). LCMS: Method 1, 1.707 min, MS: ES+ 225.33.
Reference：
[1] Patent: CN106279177, 2017, A, . Location in patent: Paragraph 0103; 0104; 0105
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 3080 - 3084
[3] Patent: WO2007/87231, 2007, A2, . Location in patent: Page/Page column 37
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 14, p. 4273 - 4278
[5] Patent: CN104072498, 2016, B, . Location in patent: Paragraph 0150
[6] Patent: WO2017/158381, 2017, A1, . Location in patent: Page/Page column 57; 65; 75
10
[ 175463-32-8 ]
[ 398491-59-3 ]
Yield
Reaction Conditions
Operation in experiment
31%
With sodium hydrogencarbonate In ethanol
EXAMPLE 4 Preparation of 3-Amino-5-(Carbo-tbutoxy)-4,6-Dihydro-Pyrrolo[3,4-c]Pyrazole A mixture of tert-butyl 3-cyano-4-oxo-1-pyrrolidine carboxylate (0.0856 mol, 18.0 g) and hydrazine dihydrochloride (0.1027 mol, 10.8 g) in 450 ml of ethanol was stirred at 60° C., for 4 hours. After cooling the obtained mixture to 0° C., a solution of saturated sodium bicarbonate (100 ml) was slowly added dropwise. The solvent was evaporated under vacuum, the residual water extracted with EtOAc and the organic phase dried over anhydrous Na2SO4. The solvent was evaporated to dryness to give a solid product which was purified by flash chromatography over silica gel using dichloromethane:methanol (46:4) as eluent, to afford the title compound as a white solid (5.91 g, 31percent). m.p. 195-197° C. (M+H)+=224
Reference：
[1] Patent: US2003/171357, 2003, A1,
11
[ 25544-75-6 ]
[ 175463-32-8 ]
[ 398495-65-3 ]
Yield
Reaction Conditions
Operation in experiment
40.3 g
at 60℃;
5) 33.1 g (0.16 mol) of the general formula (14) was added to 200 mL of anhydrous ethanol,22.4 g (0.16 mol) of ethyl hydrazinecarboxylate hydrochloride was added in portions, and the reaction was carried out at 60 ° C for 4 to 5 hours. The reaction was monitored by TLC.The filtrate was concentrated under reduced pressure to give 40.3 g of a white solid of general formula (17).
(2S,4S)-2-{3-(Allyloxycarbonylamino-methyl)-4-[(Z)-methoxyimino]-pyrrolidine-1-carbonyl}-4-mercapto-pyrrolidine-1-carboxylic acid allyl ester[ No CAS ]
(2S,4S)-2-{3-(Allyloxycarbonylamino-methyl)-4-[(Z)-hydroxyimino]-pyrrolidine-1-carbonyl}-4-mercapto-pyrrolidine-1-carboxylic acid allyl ester[ No CAS ]
(2S,4S)-4-Acetylsulfanyl-2-{3-(allyloxycarbonylamino-methyl)-4-[(Z)-methoxyimino]-pyrrolidine-1-carbonyl}-pyrrolidine-1-carboxylic acid allyl ester[ No CAS ]
(2S,4S)-4-Acetylsulfanyl-2-{3-(allyloxycarbonylamino-methyl)-4-[(Z)-hydroxyimino]-pyrrolidine-1-carbonyl}-pyrrolidine-1-carboxylic acid allyl ester[ No CAS ]
(4R,5S,6S)-3-((3S,5S)-5-{3-Aminomethyl-4-[(Z)-methoxyimino]-pyrrolidine-1-carbonyl}-pyrrolidin-3-ylsulfanyl)-6-((R)-1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid[ No CAS ]
(4R,5S,6S)-3-((3S,5S)-5-{3-Aminomethyl-4-[(Z)-hydroxyimino]-pyrrolidine-1-carbonyl}-pyrrolidin-3-ylsulfanyl)-6-((R)-1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid[ No CAS ]
(4R,5S,6S)-3-((3S,5S)-1-Allyloxycarbonyl-5-{3-(allyloxycarbonylamino-methyl)-4-[(Z)-methoxyimino]-pyrrolidine-1-carbonyl}-pyrrolidin-3-ylsulfanyl)-6-((R)-1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester[ No CAS ]
(4R,5S,6S)-3-((3S,5S)-1-Allyloxycarbonyl-5-{3-(allyloxycarbonylamino-methyl)-4-[(Z)-hydroxyimino]-pyrrolidine-1-carbonyl}-pyrrolidin-3-ylsulfanyl)-6-((R)-1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester[ No CAS ]
With triethylamine; In methanol; for 22h;Heating / reflux;
To a stirred suspension of Compound (II) (10.5 g, 0.05 mol) in 100 IIIE. of methanol were added methoxylamine hydrochloride (5.0 g, 1.2 equiv) and triethylamine (8.4 MC, 1.2 equiv) and the mixture was heated at reflux for 22 hours. The reaction mixture was cooled to room temperature. The mixture was concentrated under vacuum, and ethyl acetate (50 M. C) was added to the residue. The organic layer was washed twice with saturated aqueous NAHC03 solution (100 IU) and twice with brine (100 MNo.). Anhydrous magnesium sulfate was added, filtered, and the filtrate was concentrated under vacuum to give Compound (III) (11.35 G, Yield 95.0%).
95.0%
With sodium acetate; In ethanol; for 18h;Heating / reflux;
To a stirred suspension of Compound (II) (10.5 g, 0.05 mol) in 100 MNo. of methanol were added methoxylamine hydrochloride (5.0 g, 1.2 equiv) and sodium acetate (4.92 g, 1.2 equiv) and the mixture was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature. The mixture was concentrated under vacuum and ethyl acetate (50 inC) was added to the residue. The organic layer was washed twice with saturated aqueous NAHCO3 solution (100 INE) and twice with brine (100 MNo.). Anhydrous magnesium sulfate was added, filtered, and the filtrate was concentrated under vacuum to give Compound (III) (11.35 g, Yield 95.0%).
92.8%
With pyridine; In methanol; at 20℃; for 5h;
To a stirred solution of Compound (II) (10. 5 g, 0.05 mol) in 100 LILT of methanol in the presence of pyridine (4.84 ine, 1.2 equiv) was added methoxylamine hydrochloride (5.0 g, 1.2 equiv) at room temperature. After 5 hours, the completion of reaction was confirmed by HPLC under the following conditions: Column : CAPCELLPAK C18 Solvent: AN/H20/TFA=60/40/0. 1 Wavelength: 210 nm Flow rate: 1 MNo./MIN Temperature: room temp. The volatiles were thoroughly removed under vacuum, and ethyl acetate (50 MNo.) was added to the residue. The organic layer was washed twice with saturated aqueous NaHCO3 solution (100 MI) and twice with brine (100 LUT). Anhydrous magnesium sulfate was added to the organic layer to remove the moisture, and the mixture was concentrated under vacuum to give Compound (III) (11.09 g, Yield 92.8%). 'H NMR (400MHZ, CDCl3) 6 (PPM) : 1.47 (s, 9H), 3.69 (dd, 1H), 3.95 (s, 3H), 3. 98~4. 06 (m, 2H), 4. 10-4. 22 (m, 2H)
EXAMPLE 4 Preparation of 3-Amino-5-(Carbo-tbutoxy)-4,6-Dihydro-Pyrrolo[3,4-c]Pyrazole A mixture of tert-butyl 3-cyano-4-oxo-1-pyrrolidine carboxylate (0.0856 mol, 18.0 g) and hydrazine dihydrochloride (0.1027 mol, 10.8 g) in 450 ml of ethanol was stirred at 60 C., for 4 hours. After cooling the obtained mixture to 0 C., a solution of saturated sodium bicarbonate (100 ml) was slowly added dropwise. The solvent was evaporated under vacuum, the residual water extracted with EtOAc and the organic phase dried over anhydrous Na2SO4. The solvent was evaporated to dryness to give a solid product which was purified by flash chromatography over silica gel using dichloromethane:methanol (46:4) as eluent, to afford the title compound as a white solid (5.91 g, 31%). m.p. 195-197 C. (M+H)+=224
INTERMEDIATE 7; 2-Methyl-6J-dihvdro-5H-pyrazolo[l,5-alphalpyrrolor3,4-cr]pyrimidine-8-amine; Step A: tert-Butyl 8-amino-2-methyl-5H-pyrazolo[ 1 ,5-fl]pyrrolor3,4-cf1pyrimidine-6(7H)- carboxylate; To a stirred solution of 250 mg (1.19 mmol) of tert-buty 3-cyano-4- oxopyrrolidine-1 carboxylate in ethanol (5 mL) was added 115 mg (1.19 mmol) of 3 -methyl- IH- pyrazol-5-amine. The reaction mixture was refluxed for 1 h, cooled to ambient temperature and the solvent evaporated in vacuo. The resulting residue was chromatographed on a Biotage Horizon system (silica gel, 0 to 100% ethyl acetate/hexanes gradient) to yield the title compound as a white solid. LC/MS 290.1 (M+l).
With hydrazine; In ethanol; for 3h;Heating / reflux;
INTERMEDIATE 8; <n="48"/>2-Methyl-8,9-dihydro-7-H-pyrrolo[3 ',4' :3,4]pyrazoloF 1 ,5-alpha]pyrimidine; Step A: tgrt-Butyl 3-amino-2,6-dihvdropyrrolo|'3,4-c]pyrazole-5(4H)-carboxylate; To a stirred solution of 1 g (4.76 mmol) of tert-butyl 3-cyano-4-oxopyitauolidine-l carboxylate in ethanol (28 mL) was added 0.326 g (4.76 mmol) of hydrazine hydrochloride and the reaction mixture heated at 0C for 3 h. The mixture was cooled to 00C and saturated aqueous sodium hydrogen carbonate (60 mL) added. The solvent was evaporated in vacuo and the aqueous phase extracted with ethyl acetate (10 x 10 mL). The combined organic fractions were dried (anhydrous sodium sulfate), filtered and the solvent evaporated in vacuo. The resulting residue was chromatographed on a Biotage Horizon system (silica gel, 0 to 10% methanol/ethyl acetate gradient) to yield the title compound as a orange solid. LC/MS 225.2 (M+ 1).
Synthesis of Intermediates; Tert-butyl 3-amino-4-cyano-2,5-dihydro-lH-pyrrole-l-carboxylate; [00391] A mixture of tert-butyl 3-cyano-4-oxopyrrolidine-l-carboxylate (5.15 g, 24.5 mmol) and ammonium formate (2.32 g, 36.7 mmol) in ethanol (70 mL) was heated to reflux and stirred overnight. After allowing to cool to room temperature, the ethanol was removed under vacuum and the residue was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organics were washed with brine (3 x 50 mL), dried (MgSO4), filtered and concentrated under vacuum to leave a crue residue. The residue was purified by column chromatography on silica gel using EtOAc / hexanes (0 to 50% over 30 minutes) as eluent to give the product (3.09 g, 58%) as solid. 1H NMR (400 MHz;
9.0 g
With ammonium formate; In ethanol; at 70℃; for 16h;
Step a. To a solution of tert-butyl 3 -cyano-4-oxopyrrolidine-l -carboxylate (CAS Number 175463- 32-8; 10.0 g, 47.59 mmol) in EtOH (150 ml) was added ammonium formate (4.42g, 71.29 mmol) at rt. The reaction mixture was heated at 70C for 16 h. The resulting reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was extracted with EtOAc (3 x 150 ml). The combined organic phase was washed with brine (100 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by trituration using solvent n-hexane to yield tert-butyl 3-amino-4-cyano-2,5-dihydro-lH-pyrrole-l-carboxylate (9.0 g, 43.06 mmol). LCMS: Method E, 3.464min, MS: ES- 208.3.
General procedure: To a solution of methoxylamine/ethoxylamine hydrochloride (1.2 mol) and pyridine (80 mL, 1.0 mol) dissolved in MeOH (1000 mL) was added N-tert-butoxycarbonyl-3-cyano-4-oxopyrrolidine (5, 210 g, 1.0 mol) at room temperature. The reaction mixture was stirred at the same temperature overnight and concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compounds 6a,b as light yellow oils. The crude products were used directly without further purification.
General procedure: To a solution of methoxylamine/ethoxylamine hydrochloride (1.2 mol) and pyridine (80 mL, 1.0 mol) dissolved in MeOH (1000 mL) was added N-tert-butoxycarbonyl-3-cyano-4-oxopyrrolidine (5, 210 g, 1.0 mol) at room temperature. The reaction mixture was stirred at the same temperature overnight and concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compounds 6a,b as light yellow oils. The crude products were used directly without further purification.
To a solution of tert-butyl 3 -cyano-4-oxopyrrolidine-l -carboxylate (CAS Number 175463-32- 8 available from Combi Blocks) (2.00 g, 9.52 mmol) in EtOH (20 ml) was added methyl hydrazine (0.44 g, 9.52 mmol) at rt. The reaction mixture was heated at 80C for 10 h. The resulting reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography (42% EtOAc in hexane) yielding tert-butyl 3-amino-2-methyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (0.600 g, 2.521 mmol). LCMS: Method 1, 2.00 min, MS: ES+ 239.23; 1H NMR (400 MHz, DMSO-d6) delta ppm 4.97 (s, 2 H), 4.20 (d, J=7.6 Hz, 2 H), 4.09 (d, J=10.8 Hz, 2 H), 3.18 (d, J=6.8 Hz, 3 H), 1.41 (s, 9 H). LCMS analysis showed an approximately 8: 1 regioisomer ratio in favour of the desired isomer, confirmed by NOE analysis.
7-(2-methyl-3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-1-cyclopropyl-6-fluoro-8-difluoromethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid[ No CAS ]
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