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CAS No. : | 198904-85-7 | MDL No. : | MFCD04035550 |
Formula : | C17H21N3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GIMJTKJSKPENNG-UHFFFAOYSA-N |
M.W : | 299.37 | Pubchem ID : | 9796325 |
Synonyms : |
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 85.99 |
TPSA : | 63.25 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.15 cm/s |
Log Po/w (iLOGP) : | 3.04 |
Log Po/w (XLOGP3) : | 2.78 |
Log Po/w (WLOGP) : | 3.13 |
Log Po/w (MLOGP) : | 2.16 |
Log Po/w (SILICOS-IT) : | 2.47 |
Consensus Log Po/w : | 2.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.39 |
Solubility : | 0.122 mg/ml ; 0.000408 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.76 |
Solubility : | 0.0515 mg/ml ; 0.000172 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.94 |
Solubility : | 0.000345 mg/ml ; 0.00000115 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.72 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In isopropyl alcohol;Heating / reflux; | Synthesis of tert-butyl 2-((2S,3S)-3-(tert-butoxyearbonylammo)-2-hydroxy-4-phenylbutyl)-2-(4-(pyndin-2-yl)b enzyl)hydrazinccarboxylate (XV, YIa = YIb = H).; A mixture of tert-butyl (S)-1-((R)-oxian-2-yl)-2-phenylthylcarbamate XIV (1.18 g. 4.48 mmol), XIII, Y1a = Y1b = H (1.23 g, 4.11 mmol) and isopropanol (15 mL) was kept at reflux under nitrogen overnight. The solvent was removed in a rotary evaporator and the residue was purified by chromatography on silica (100 g) with 8:2 dichloromethane/ethyl acetate to give product XV, wherein Y1a = Y1b = II (1.74 g, 75%). |
62.5% | In isopropyl alcohol; for 24h;Reflux; | Step 1: Synthesis of tert -butyl 2-((2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4- phenylbutyl)-2-(4-(pyridin-2-yl)benzyl)hydrazinecarboxylate:A stirred solution of tert-butyl 2-(4-(pyridin-2- yl)benzyl)hydrazinecarboxylate (about 1.3 g, 4.347 mmol) and tert-butyl (S)-1-((R)- oxiran-2-yl)-2-phenylethylcarbamate (about 1.7 g, 6.521 mmol) in Isopropanol was refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture brought to room temperature and water (23 ml) was added and stirred at same temperature for about 16 hours. Resulting solid precipitation was filtered and washed with water (23 ml), cold methyltertiarybutyl ether (3 ml) then dissolved in acetonitrile, water (35 ml) was added and filtered, the resulting solid purified by silica gel column (100-200 mesh, elution: 20% EtOAc in Hexane) to afford the title compound as an off white solid. Wt:1.5 g; Yield: 62.5 %; NMR (300 MHz, CDCI3): delta 8.69 (d, 1H, J = 4.5 Hz,), 7.95 (d, 2H, J = 8.1 Hz), 7.76-7.69 (m, 2H), 7.41 (d, 2H, J = 8.1 Hz), 7.25-7.23 (m, 6H), 5.25 (s, 1H), 5.12 (d, 1H, J =9.3 Hz), 4.54 (s.1H).4.07-3.94 (m, 2H), 3.68-3.55 (m, 2H).2.95-2.80 (m, 3H), 2.46 (d, 1H, J= 10.2 Hz), 1.38 (s, 9H), 1.32 (s, 9H); Mass: [M+H}+ 563 (3%), [M+Na) + 585 (100%). |
N-1 -(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)-benzyl]-hydrazine (II) (100 g, 0.33 mole) and (2R)-[(rS)-Boc-amino-2'-phenylethyl]oxirane (I) (102.8 g, 0.39 mole) were added in IPA (400mL), and heated to reflux for 30 hours. Water (50 mL) was added slowly and stirred at 60 - 70C for 2 hours. Cooled to 15 - 20C and solid was filtered, washed with a mixture of IPA and water. Wet solid was crystallized from methanol-water, to give 160 g of hydroxy compound (III). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogen;palladium 10% on activated carbon; In methanol; for 4h; | Example 4B; tert-butyl 2- [4- (2-pyridinyl) benzyl] hydrazinecarboxylate; Example 4A (15 g, 0.05 mol) was dissolved in methanol (100 mL) and treated with 10% Pd/C (1.5 g) and a hydrogen balloon for 4 h. The catalyst was filtered, and the solvents were evaporated to give 15 g (98%) of the title compound. |
98% | With hydrogen;palladium 10% on activated carbon; In methanol; | EXAMPLE 4B Tert-butyl 2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate Example 4A (15 g, 0.05 mol) was dissolved in methanol (100 mL) and treated with 10% Pd/C (1.5 g) and a hydrogen balloon for 4 h. The catalyst was filtered, and the solvents were evaporated to give 15 g (98%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5. Synthesis of 1,14-Di(methyl-d3) (3S,8S,9S, 12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d9]-8-hydroxy-4,11-dioxo-9-(p henylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioate (Compound 120).; [Show Image] Compound 120 was prepared according to Scheme 1b, above. 1H-NMR (300 MHz, CDCl3): delta 0.78 (s, 9H), 2.72 (dd, 2H), 2.94 (d, 2H), 3.58-3.63 (m, 2H). 3.78 (d, 1H), 3.92-4.09 (m, 3H), 4.88 (s, 1H), 5.28 (dd, 2H), 6.46 (d, 1H), 6.73 (s, 1H), 7.14-7.25 (m, 6H, partially obscured by CDCl3), 7.42 (d, 2H), 7.68-7.78 (m, 2H), 7.94 (d, 2H), 8.68 (d, 1H). HPLC (method: 20 mm C18-RP column - gradient method 2-95% ACN + 0.1% formic acid in 3.3 min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention time: 3.23 min; purity: 99.6%. MS (M+H+): 720.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In isopropyl alcohol; at 80℃; for 15h; | Compound 39; In a 50 mL round bottom flask, isopropanol (6 mL) was added to a mixture of Compound 37 (690 mg, 1.61 mmol, 1.0 eq.) and Compound 38 (481 mg, 1.1 eq.). The reaction mixture was refluxed at 800C for 15 hours. The reaction mixture was concentrated and purified by silica gel chromatography (40-100% EtOAc/hexane) to give Compound 39 as a white solid (916 mg, 78%). LC-MS shows 729.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | In isopropyl alcohol; for 18h;Heating / reflux; | [00446] Example 94. Preparation of tert-butyl 2-((2S,3S)-2-hydroxy-4-phenyl-3-[(benzyloxy) carbonyl]amino}butyl)-2-(4-pyridin-2-ylbenzyl)hydrazinecarboxylate; [00447] To a solution of (l-oxiranyl-2-phenyl-ethyQ-carbamic acid benzyl ester (0.75 g, 2.5 mmol, WO 2005061487) in 2-propanol (10 mL) was added N-(4-pyridin-2-ylbenzyl)hydrazine carboxylic acid tert-butyl ester (0.75 g, 2.5 mmol, WO 2005061487) and the solution was refluxed for 18 hours, after which time it was cooled, solvent was removed in vacuo and the crude residue was purified by column chromatography on silica gel (10% EtOAc/hexane) to give 100 mg, 7% of the compound of this Example. NMR (CDC13) delta ppm 8.62 - 8.76 (m, I H) 7.86 - 8.06 (m, 2 H) 7.65 - 7.82 (m, 2 H) 7.09 - 7.51 (m, 14 H) 5.18 - 5.46 (m, 2 H) 5.00 - 5.10 (m, 2 H) 3.52 - 4.11 (m, 4 H) 2.87 - 3.02 (m, 2 H) 2.72 - 2.87 (m, 1 H) 1.33 (s, 9 H); MS (M + H+) = 597. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With hydrogen;palladium on carbon; In methanol; under 517.1619999999999 Torr; for 4h; | Synthesis of tert-butyl 2-(4-(pyridin-2-yl)benzyl)hydrazinecarboxylate (XIII), Y1a = Y1b = H). ; A solution of XII, Y1a = H (23.15 g, 77.85 mmol) in method (350 mL) was treated with 20% palladium on activated carbon (2.3 g, 50% wet) and hydrogenated at 10 psi for 4 hrs. The reaction mixture was filtered through Celite, the filter cake was washed with methanol and the solvent was removed in a rotary cvaporator. The residue was recrystallized from heptane and dried in a vacuum oven (40 C) to give XIII, wherein Y1a = Y1b = H (22.48 g, 96.5%). |
86.6% | With 0.5% Pd/C; hydrogen; In methanol; at 35℃; for 12h;Industrial scale; | 1) Add 100kg of methanol to the 500L reactor,N1-(tert-butoxycarbonyl)-N2-[4-(2-pyridyl)benzylidene]hydrazine20 kg (molar amount 297.15,a molar amount of 67 mol), palladium with a palladium content of 0.5% is added to 2 kg, and the temperature is controlled at 35 C.After nitrogen replacement, hydrogenation was carried out, and the reaction was monitored by HPLC, and the reaction was completed in 12 hours;2) Reaction hydraulic filtration, the filtrate was concentrated to dryness under reduced pressure, and the weight of the liquid oil was 20 kg, and the mixture was beaten with n-hexane overnight, and dried to obtain 17.3 kg of solid, the yield was 86.6%, and the purity was 99.3%. |
65% | With palladium 10% on activated carbon; sodium formate; In ethanol; water; | General procedure: The hydrazones 1b, 8b-14b were subjected to catalytic reduction with Pd/C 10% (0.2 equiv.) andHCOONa (1.8 equiv.) dissolved in a 5:1 mixture of ethanol/water (1 mL/mmol). The mixture was stirredfor 1.5 h at 60 C and then cooled down to a temperature below 40 C and stirred for 12 h [22]. At theend of the reaction, the solution was extracted with EtOAc, dried over MgSO4, and concentratedin vacuo. The residue was purified by column chromatography (cyclohexane/EtOAc, 8:2) in yields of 70% (1c); 70% (8c, 9c, 12c) and 65% (11c, 13c). |
With hydrogen;5%-palladium/activated carbon; In methanol; at 20℃; for 8h;Conversion of starting material; | 2 g (6.7 mmol) of N-1-(tert-butoxycarbonyl)-N-2-{4-[(2-pyridyl)-phenyl]-methylidene}-hydrazone and 0.2 g of palladium/C 5% in 30 ml of methanol, are hydrogenated at ambient pressure and at ambient temperature for 8 hours. The catalyst is filtered and washed with methanol. The solvent is removed by distillation at reduced pressure. An oily residue is obtained which, by crystallisation from cyclohexane, provides a colourless solid having a m.p. of 77-79 C. [00135] TLC: Rf=0.46 (methylene chloride:methanol=15:1) 1H-NMR (200 MHz, CDCl3): ppm 8.69 (1H, m); 7.69 (2H, d, J=2 Hz); 7.45 (2H, d, J=2 Hz); 7.8-7.65 (2H, m); 7.22 (1H, m); 4.06 (2H,s); 1.47 (9H, s). | |
With ammonium formate;1% Pd/C; In methanol; water; at 50℃;Industry scale; Inert atmosphere;Product distribution / selectivity; | In a stainless steel reactor, under inert atmosphere, charge the hydazone (540 kg, 1.82 kmol), methanol (It 3200), ammonium formate (238 kg, 3.78 kmol), water (165 It) and then Pd/C 50% wet (38 kg).Warm the mixture at 500C under a good agitation. When the reaction is complete (residual hydrazone under 0.2% by HPLC test) cool the mixture at25C and filter the catalyst. Concentrate the filtrate solution under reduced pressure to obtain a residual viscous mass. Charge cyclohexane (1720 It) and water (167 It) and warm to 65C. At this temperature separate the phase. Cool the organic phase at 250C under stirring in order to have a complete crystallisation of the product.Filter the product and wash the cake with cold cyclohexane. Dry at reduced pressure at a temperature of 45C obtaining about kg 480 of Nl-(t- butoxycarbonyl)-N2-(4-(2'pyridyl)benzyl)hydrazine. | |
The weight ratio of 2-2- [4- (2'-pyridyl) benzylidene] -hydrazinecarboxylic acid tert-butyl ester and ethanol was C, 2-2- [4- (2-pyridyl ) Benzylidene] -hydrazinecarboxylic acid tert-butyl ester and palladium on carbon in a weight ratio of D were charged into a reaction kettle and stirred. 1 hour drop 50% sodium formate aqueous solution 250KG, drop Bi, insulation 65 ~ 70 C reaction 4 ~ 5 hours; filter palladium carbon, washed with ethanol, dry. (2-pyridyl) benzyl] -hydrazinecarboxylic acid tert-butyl ester was obtained by dissolving, crystallizing and filtering and drying in a temperature of 3 to 5 times the amount of 120 Sampling detection, the content of X2, the yield of Y2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In isopropyl alcohol; at 65℃; for 16h; | EXAMPLE 7A Tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate A solution of Example 4B (0.84 g, 2.8 mmol) in isopropanol (9 mL) was treated with (2S,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (0.74 g, 1 equivalent), stirred at 65 C. for 16 hrs and cooled to room temperature. The mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were concentrated. Ether was added to precipitate the solid which was filtered to give 0.8 g (57%) of the title compound. |
35 - 57% | In isopropyl alcohol; at 65 - 85℃; for 16h;Product distribution / selectivity; | Example 7A; tert-butyl 2-f (2S, 3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2- pyridinyl) benzyl] hydrazinecarboxylate; A solution of Example 4B (0.84 g, 2.8 mmol) in isopropanol (9 mL) was treated with (2S, 3)-3-N-tert-butoxycarbonylamino-1, 2-epoxy-4-phenylbutane (0. 74 g, 1 equivalent), stirred at 65C for 16 hrs and cooled to room temperature. The mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were concentrated. Ether was added to precipitate the solid which was filtered to give 0. 8 g (57%) of the title compound.; Example 191A; ter-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2- pyridinyl) benzyl] hydrazinecarboxylate; (2S, 3S)-3-N-tert-butoxycarbonylamino-1, 2-epoxy-4-phenylbutane (3 g, 0.011 mol) in isopropanol (50 mL) was combined with Example 4B (3.41 g, 1 equivalent), stirred at 85C for 16 hrs. The mixture was cooled to room temperature, evaporated and partitioned between CHC13 and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil which was crystallized by trituration with diethyl ether, filtered, and dried in vacuo to give 2.27 g (35%) of the title compound. |
35% | In isopropyl alcohol; at 85℃; for 16h; | EXAMPLE 191A Tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate (2S,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (3 g, 0.011 mol) in isopropanol (50 mL) was combined with Example 4B (3.41 g, 1 equivalent), stirred at 85 C. for 16 hrs. The mixture was cooled to room temperature, evaporated and partitioned between CHCl3 and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil which was crystallized by trituration with diethyl ether, filtered, and dried in vacuo to give 2.27 g (35%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 25℃; for 16h; | Example 198A; tert-butyl 2- (2S, 3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-1, 3-thiazol-4-yl) methyl]- 2-oxo-1-imidazolidinyl} butanoyl) amino]-4-phenylbutyl}-2- [4- (2- pyridinyl) benzyl] hydrazinecarboxylate; Example 61 (64 mg, 0.22 mmol) was dissolved in THF (3 mL) and DMF (0.5 mL) and treated with HOBT (44 mg, 1.5 equivalents), EDAC (75 mg, 1.8 equivalent), and N, N-di- isopropylethylamine (DIPEA) (38 muL, 1 equivalent) followed by Example 4G (100 mg, 1 equivalent). The mixture was stirred at 25C for 16 hrs. The solvents were evaporated and partitioned between ethyl acetate and saturated NaHCO3. The organic layer was separated and washed with brine, dried over sodium sulfate and evaporated. The residue was purified using 2% methanol/CHC13 to give 120 mg (75%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | In isopropyl alcohol; at 65℃; for 16h; | Example 4F; tert-butyl 2-f (2S, 3)-2-hydroxy-4-phenyl-3- [ (trifluoromethyl) amino] butyl}-2- [4- (2- pyridinyl) benzyl] hydrazinecarboxylate; Example 4E (1.5 g, 5.8 mmol) was dissolved in isopropanol (22 mL) and treated with Example 4B (1.7 g, 1 equivalent) at 65C for 16 hrs. The solvents were evaporated and the crude residue was purified using 0-50% chloroform in ethyl acetate to give 0.86 g (28%) of the title compound. |
28% | In isopropyl alcohol; at 65℃; for 16h; | EXAMPLE 4F Tert-butyl 2-{(2S,3S)-2-hydroxy-4-phenyl-3-[(trifluoromethyl)amino]butyl}-2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate Example 4E (1.5 g, 5.8 mmol) was dissolved in isopropanol (22 mL) and treated with Example 4B (1.7 g, 1 equivalent) at 65 C. for 16 hrs. The solvents were evaporated and the crude residue was purified using 0-50% chloroform in ethyl acetate to give 0.86 g (28%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 8 The reaction mixture of Example 3 was filtrated in a hydrogen/nitrogen (ca. 1/2) mixed gas and sodium hydrosulfite (100 mg) was added to the obtained filtrate at the same temperature, which was followed by evaporation of methanol under reduced pressure. To the obtained residue was added heptane/isopropanol (volume ratio=9/1). The mixture was heated to 65 C. and filtrated in a nitrogen gas, after which the filtrate was cooled to allow crystallization to give N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)benzyl]hydrazine (4.2 g, yield: 83%). As a result of the HPLC analysis of the crystals, a peak corresponding to the starting material, N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenyl]methylidene}-hydrazine, was not detected. This application is based on patent application No. 215031/2000 filed in Japan, the contents of which are hereby incorporated by reference. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.6% | EXAMPLE 1 N-(tert-Butoxycarbonyl-N'-4- (pyridin-2yl) phenylmzethylidene]hydrazine (26 g, 67.3 mmol)) isopropyl alcohol (80 ml) and palladium-carbon (1 g) were charged in a 300 ml four-necked flask, and hydrogen was added at 50 C. under atmospheric pressure. Hydrogen was continuously added for 8 hr under the same conditions. The reaction mixture was filtered to remove the catalyst. Sodium hydrosulfite (1 g) and active charcoal (1 g) were added to the filtrate and the mixture was stirred at 20-30 C. for 30 min. The reaction mixture was filtered to reeve sodium hydrosulfite and active charcoal. After 90% of isopropyl alcohol in the obtained filtrate was evaporated by concentration, the same volume of heptane was added. The mixture was cooled with stirring and crystals were precipitated at around 40 C. The mixture was further cooled to 5 C. with stirring and the precipitated crystals were collected by filtration and dried to give 16.84 g of tert-butyl3-(4-(pyridin-2-yl)benzyl]carbazate as white crystals. The yield was 83.6% of N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.0% | palladium-carbon; In n-heptane; hydrogen; | REFERENCE EXAMPLE 1 N-(tert-Butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine (20 g, 67.3 mmol), isopropyl alcohol (80 ml) and palladium-carbon (1 g) were charged in a 300 ml four-necked flask and hydrogen was added at 50 C. under atmospheric pressure. Hydrogen was continuously added for 8 hr under the same conditions. The reaction mixture was filtered to remove the catalyst. After 90% of isopropyl alcohol in the obtained filtrate was evaporated by concentration, the same volume of heptane was added. The mixture was cooled with stirring and crystals were precipitated at around 40 C. The mixture was further cooled to 5 C. with stirring and the precipitated crystals were collected by filtration and dried to give 16.91 g of tert-butyl3-[4-(pyridin-2-yl)benzyl]carbazate as white crystals. The yield was 84.0% of N-(tert-butoxycarbonyl)-N'-[4-5 (pyridin-2-yl)phenylmethylidene]hydrazine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Example 18B; methyl (1S)-2-methyl-1-( (f2- [4- (2-pyridinyl) benzyl] hydrazino} carbonyl) propylcarbamate; A solution of Example 4B (0. 18 g, 0.6 mmol) in dichloromethane: trifluoroacetic acid (4 mL, 1 : 1) was stirred at 25C for 1 h, and the solvents were evaporated. This material was dissolved in THF (1 mL) and treated with diisopropylethyl amine (0.31 mL, 3 equivalents), DEPBT (0.36 g, 2 equivalents), and Example 18A (0.105 g, 1 equivalent), stirred at 25C for 3 h. The mixture was partitioned between dichloromethane and 10% sodium carbonate, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified using 2% methanol/chloroform to give 0.1 g (47%) of the title compound. | |
47% | EXAMPLE 18B Methyl (1S)-2-methyl-1-({2-[4-(2-pyridinyl)benzyl]hydrazino}carbonyl)propylcarbamate A solution of Example 4B (0.18 g, 0.6 mmol) in dichloromethane:trifluoroacetic acid (4 mL, 1:1) was stirred at 25 C. for 1 h, and the solvents were evaporated. This material was dissolved in THF (1 mL) and treated with diisopropylethyl amine (0.31 mL, 3 equivalents), DEPBT (0.36 g, 2 equivalents), and Example 18A (0.105 g, 1 equivalent), stirred at 25 C. for 3 h. The mixture was partitioned between dichloromethane and 10% sodium carbonate, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified using 2% methanol/chloroform to give 0.1 g (47%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 60 - 65℃; | Example 4: Preparation of l-r4-(Pyridine-2-yl)-phenyl1-4(s)-hvdroxy-2-N-teit- butoxycarbonylamino-5(S)-N-(N-methoxycarbonyl-(L)-teit-leucyl)amino-6-phenyl-2- azahexane Formula VII To the organic layer of methyl [(2S)-3,3-dimethyl-l-({(lS)-l-[(2R)-oxiran-2-yl]-2- phenylethyl} amino)- 1 -oxobutan-2-yl]carbamate and N- 1 -(tert-butoxycarbonyl)-N-2-[4- (pyridine-2-yl)benzyl]hydrazine (obtained in Example 3; entire quantity), de-ionized water (2600 mL) was added and the reaction mixture was heated to 40C to 45C to recover dichloromethane atmospherically. The reaction mixture was stirred for 14 hours to 16 hours at 60C to 65C. The completion of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was filtered and the wet cake obtained was washed with de-ionized water (400 mL) at 60C to 65C. The wet cake was added to dichloromethane (1600 mL) at 20C to 25C and stirred at 35C to 40C to get a clear solution. The reaction mixture was cooled to 25C to 30C and the organic layer was separated. Toluene (1600 mL) was added to the organic layer and dichloromethane was recovered under vacuum at 40C to 50C. The reaction mixture was stirred for 20 minutes to 30 minutes at 60C to 65C, then cooled to 20C to 25C and stirred at the same temperature for 2 hours to 3 hours. The reaction mixture was filtered; the wet cake obtained was washed with toluene (200 mL) and dried to afford the title compound. Yield (w/w) = 1.4 | |
In dichloromethane; water; at 40 - 65℃; | Example 4 Preparation of 1-[4-(Pyridine-2-yl)-phenyl]-4(s)-hydroxy-2-N-tert-butoxycarbonylamino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane To the organic layer of methyl[(2S)-3,3-dimethyl-1-({(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethyl}amino)-1-oxobutan-2-yl]carbamate and <strong>[198904-85-7]N-1-(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)benzyl]hydrazine</strong> (obtained in Example 3; entire quantity), de-ionized water (2600 mL) was added and the reaction mixture was heated to 40 C. to 45 C. to recover dichloromethane atmospherically. The reaction mixture was stirred for 14 hours to 16 hours at 60 C. to 65 C. The completion of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was filtered and the wet cake obtained was washed with de-ionized water (400 mL) at 60 C. to 65 C. The wet cake was added to dichloromethane (1600 mL) at 20 C. to 25 C. and stirred at 35 C. to 40 C. to get a clear solution. The reaction mixture was cooled to 25 C. to 30 C. and the organic layer was separated. Toluene (1600 mL) was added to the organic layer and dichloromethane was recovered under vacuum at 40 C. to 50 C. The reaction mixture was stirred for 20 minutes to 30 minutes at 60 C. to 65 C., then cooled to 20 C. to 25 C. and stirred at the same temperature for 2 hours to 3 hours. The reaction mixture was filtered; the wet cake obtained was washed with toluene (200 mL) and dried to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With borane pyridine; acetic acid; In methanol; at 0 - 20℃; for 2h; | To a mixture of N-tert-butoxycarbonylhydrazine (18; 249 mg, 1.88 mmol) and 4-(pyridin-2-yl)benzaldehyde (16; 344 mg, 1.88 mmol) in MeOH (5 mL) was added AcOH (0.5 mL) and alpha-PicBH3 (201mg, 1.88 mmol) at 0 C. The reaction mixture was allowed to warm to r.t. and stirred for 2 h at the same temperature. The mixture was mL) at 0 C. The mixture was warmed to r.t. and stirred for 30 min at the same temperature. After cooling to 0 C, 25% aq Na2CO3 (20mL) was added to the mixture and extracted with EtOAc (3 × 20mL). The combined extracts were washed with brine (10 mL), dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 5:1-1:1) to give 17; yield: 437 mg (78%); colorless oil. IR (neat): 3410, 1683 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium iodide (12.4 g, 83 mmol) was added to 2-methyltetrahydrogen containing compound II (22.6 g, 76 mmol) at room temperatureIn furan (250 ml), after stirring for 30 minutes, a solution of compound I (24.8 g, 83 mmol mmol) in 2-methyltetrahydrofuran (350 ml) was added and stirring was continued for 30 min. Sodium hydroxide (6.1 g, 152 mmol) was added at room temperature. After stirring for 12 h, 2-methyltetrahydrofuran was removed under reduced pressure. The system was diluted with ethyl acetate (800 ml), washed twice with saturated potassium hydrogen sulfate (300 ml), washed with brine (600 ml), dried, and concentrated to give a crude product. After refluxing with ethanol/water = 1:2, the system gradually became transparent and was allowed to come to room temperature. The ethanol was evaporated under reduced pressure and the aqueous phase was extracted three times with ethyl acetate (200 ml). The organic phases were combined, dried and concentrated to give compound III. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.2 g | With zinc dibromide In dichloromethane at 20 - 40℃; | 1-6 Example 1 At room temperature, add 150ml of dichloromethane to the clean reactor, add 50g (0.167mol) of tert-butyl hydrazinocarboxylate of formula I and compound of formula II (2R, 3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane40g (0.152mol), then, then add 1.2g (0.0053mol) of zinc bromide in catalytic amount as a catalyst, slowly raise the temperature to 25-30 to carry out the addition reaction for 16-20 hours, After the reaction is complete, began to slowly cool down to 20°C, then add 36g (0.16mol) of zinc bromide, then, the temperature is raised to 30-40 °C to react, keep warm for 12 hours, after the end, then directly add 100ml to the reaction solution, wash with water twice, stand still and separate into layers, collect the organic phase and distill to remove the dichloromethane solvent, add 200ml n-hexane to slowly cool down to 05 and keep it at this temperature and stir to fill the analytical crystals for 1-2 hours, filter the wet product, control the temperature to dry at 40-50 °C, obtain the solid product of atazanavir main chain intermediate compound of formula V (1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane) 52.2g (0.144mol), HPLC purity is 99.85%. |
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