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[ CAS No. 36394-75-9 ] {[proInfo.proName]}

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Chemical Structure| 36394-75-9
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Product Details of [ 36394-75-9 ]

CAS No. :36394-75-9 MDL No. :MFCD00145252
Formula : C5H7ClO3 Boiling Point : -
Linear Structure Formula :ClCOCH(CH3)OCOCH3 InChI Key :ALHZEIINTQJLOT-VKHMYHEASA-N
M.W : 150.56 Pubchem ID :11094804
Synonyms :

Calculated chemistry of [ 36394-75-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.6
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.43
TPSA : 43.37 Ų

Pharmacokinetics

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) : -6.44 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.15
Log Po/w (XLOGP3) : 1.09
Log Po/w (WLOGP) : 0.7
Log Po/w (MLOGP) : 0.28
Log Po/w (SILICOS-IT) : 0.81
Consensus Log Po/w : 0.81

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.26
Solubility : 8.23 mg/ml ; 0.0547 mol/l
Class : Very soluble
Log S (Ali) : -1.59
Solubility : 3.84 mg/ml ; 0.0255 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.94
Solubility : 17.3 mg/ml ; 0.115 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.19

Safety of [ 36394-75-9 ]

Signal Word:Danger Class:8
Precautionary Statements:P261-P264-P270-P272-P280-P301+P312-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P321-P333+P313-P363-P405-P501 UN#:3265
Hazard Statements:H302-H314-H317 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 36394-75-9 ]

* 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.

  • Downstream synthetic route of [ 36394-75-9 ]

[ 36394-75-9 ] Synthesis Path-Downstream   1~101

  • 1
  • (S)-2-acetoxypropionic acid [ No CAS ]
  • [ 36394-75-9 ]
YieldReaction ConditionsOperation in experiment
93.7% With thionyl chloride at 50℃; for 2h; 1.1.2.2 1.2.2 Synthesis of intermediate (Va) 14.6 g (110.6 mmol) of intermediate (IVa)In a 250 ml reaction flask,Add thionyl chloride 48ml,50 reaction 2h,Concentrated under reduced pressure at 40 ° C to give a pale yellow oily liquid 15.6g, yield 93.7%.
31% With thionyl chloride at 20℃;
With thionyl chloride
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1.5h; Ambient temperature;
With thionyl chloride at 50℃; for 2h;
With thionyl chloride for 5h; Heating; Yield given;
With thionyl chloride; N,N-dimethyl-formamide for 2h; Yield given;
With thionyl chloride In diethyl ether at 0 - 10℃;
With thionyl chloride for 2h; Ambient temperature;
With thionyl chloride; N,N-dimethyl-formamide for 2h; Ambient temperature; Yield given;
With thionyl chloride at 95℃; for 2h; [0168] Compound 2 (19.94 gm) was heated with thionyl chloride (12 ml) gradually for two hours to a final temperature of 95° C., followed by distillation in vacuo (50° C./5 mm Hg) to give 18.17 gm of 3.
With thionyl chloride at 0 - 20℃; for 5h;
With thionyl chloride; N,N-dimethyl-formamide In toluene at 80℃; for 1h;
With thionyl chloride In 1,2-dichloro-ethane at 40℃; for 7h;
With thionyl chloride 3.3 3.3. Preparation with 6 reactors with distinct condensation unities. (S)-2-acetyloxypropionic acid was fed together with thionyl chloride into a series of 6 conti n uous reactors of a bout the sa me vol u me, each one endowed with its own reflux condensation unity. The condensate from each condensation unity was completely sent again to the starting stirred reactor. The total volume of the 6 reactors was of 4389 ml_. The titer of the (S)-2-acetyloxypropionic acid sol ution was 92% . The feeding flow rate of the solution into the first reactor was of 839 g/h . Into the first reactor was also fed thionyl chloride at a flow rate of 998 g/h . The feeding molar ratio between thionyl chloride and acetyloxypropionic acid was 1.26 moles/mole. With reference to the in let cond itions, ta king into accou nt the thionyl chloride density, the overall permanence time was 3.03 hours. Once reached the steady state, the temperature of the first reactor was 59°C, the one of the second 66°C and the one of the fourth 74°C. The compositions at the exit from each reactor were measured, obtaining the following results: Table 6 % (S)-2- % residual % acetyl % acetylated % acetyloxypropionic acetyloxypropionic chloride dimer SOCI2 acid chloride acid Reactor 1 4.05 74.08 0.72 11.10 10.05 Reactor 2 3.60 83.30 0.97 7.60 4.53 Reactor 3 3.20 85.14 1.01 6.30 4.35 Reactor 4 3.20 88.92 1.03 5.40 1.45 Reactor 5 3.10 89.14 0.98 4.60 2.18 Reactor 6 3.08 90.45 1.06 3.60 1.81 These results demonstrate that, with a number of reactors in series equal to 6 the a l most com plete conversion of (S)-2-acetyloxypropionic acid is obtained with a permanence time of 3 hours only.
With thionyl chloride; N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere; Schlenk technique; General procedure 1 for the preparation of (S)-3-amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1a31 General procedure 1 for the preparation of (S)-3-amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1a31 At first, SOCl2 (272.9mmol) was added dropwise to (S)-2-acetoxypropanoic acid 4a (68.23mmol) at 0°C. After the addition, the reaction mixture was stirred for an additional 4h at room temperature. Excess SOCl2 was removed in vacuo after which acyl chloride was added to a suspension of methyl 2-aminobenzoate (150mmol) in diethyl ether (150mL). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was washed with 2M HCl (2×100mL) and brine (100mL), the organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. Crystallisation of the crude mixture gave the corresponding amide (S)-methyl 2-(2-acetoxypropanamido)benzoate 5a in 85% yield and was used in the next step without further purification. To a solution of amide 5a (15.4g, 58.0mmol) in ethanol (20mL) was added hydrazine monohydrate (290mmol) in a Schlenk flask. The mixture was stirred for 4h at 150°C. After concentration under reduced pressure, water (50mL) was added and the mixture was extracted with diethyl ether (3×50mL). The organic layers were dried over Na2SO4 and the solvent was removed under vacuum. The residue was crystallised from ethanol and gave (S)-3-amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1a as a colourless solid in 86% yield.
With thionyl chloride at 50℃;

Reference: [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN106831475, 2017, A Location in patent: Paragraph 0039; 0040
[2]Buisson, Didier; Azerad, Robert [Tetrahedron Asymmetry, 1999, vol. 10, # 15, p. 2997 - 3002]
[3]Ohzeki; Mizoguchi; Koga; Yamada [Chemical and Pharmaceutical Bulletin, 1977, vol. 25, # 10, p. 2676 - 2680] Koga,K. et al. [Carbohydrate Research, 1974, vol. 36, p. C9 - C11] Bean; Kenyon; Phillips [Journal of the Chemical Society, 1936, p. 303,308] Lemoine, Rémy C.; Glinka, Tomasz W.; Watkins, William J.; Cho, Aesop; Yang, Jessie; Iqbal, Nadeem; Singh, Rajeshwar; Madsen, Deidre; Lolans, Karen; Lomovskaya, Olga; Oza, Uma; Dudley, Michael N. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5127 - 5131]
[4]Barton; Gateau-Olesker; Gero; Lacher; Tachdjian; Zard [Tetrahedron, 1993, vol. 49, # 21, p. 4589 - 4602]
[5]Konosu; Miyaoka; Tajima; Oida [Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2241 - 2246]
[6]Atkinson; Kelly; Williams [Tetrahedron, 1992, vol. 48, # 36, p. 7713 - 7730]
[7]Hulst, Ron; Vries, N. Koen de; Feringa, Ben L. [Tetrahedron, 1994, vol. 50, # 40, p. 11721 - 11728]
[8]Cahiez, Gerard; Metais, Eric [Tetrahedron Letters, 1995, vol. 36, # 36, p. 6449 - 6452]
[9]Maiti, Dilip K.; Ghoshdastidar, Partha Pratim; Bhattacharya, Pranab K. [Journal of Chemical Research - Part S, 1996, # 6, p. 306 - 307]
[10]Atkinson, Robert S.; Coogan, Michael P.; Lochrie, Ian S. T. [Journal of the Chemical Society. Perkin transactions I, 1997, # 6, p. 897 - 900]
[11]Babudri, Francesco; Fiandanese, Vito; Marchese, Giuseppe; Punzi, Angela [Tetrahedron, 1999, vol. 55, # 8, p. 2431 - 2440]
[12]Current Patent Assignee: ESSENTIAL THERAPEUTICALS - US2003/229097, 2003, A1 Location in patent: Page 46; 48
[13]Location in patent: experimental part Catir, Mustafa; Cakici, Murat; Karabuga, Semistan; Ulukanli, Sabri; Sahin, Ertan; Kilic, Hamdullah [Tetrahedron Asymmetry, 2009, vol. 20, # 24, p. 2845 - 2853]
[14]Location in patent: experimental part Suganuma, Koto; Horiuchi, Ken; Matsuda, Hironori; Cheng; Aoki, Akihiro; Asakura, Tetsuo [Macromolecules, 2011, vol. 44, # 23, p. 9247 - 9253]
[15]Shi, Xiu Xiao; He, Dian; Li, Shao Bai; Lei, Xin; Yang, Huan [Asian Journal of Chemistry, 2013, vol. 25, # 11, p. 6387 - 6390]
[16]Current Patent Assignee: BRACCO SPA - WO2014/90650, 2014, A1 Location in patent: Page/Page column 18
[17]Karabuga, Semistan; Karakaya, Idris; Ulukanli, Sabri [Tetrahedron Asymmetry, 2014, vol. 25, # 10-11, p. 851 - 855]
[18]Rong, Rong; Zhang, Rui-zhen; Wang, Xin; Dan, Yu-han; Zhao, Yun-li; Yu, Zhi-guo [Naunyn-Schmiedeberg's Archives of Pharmacology, 2020, vol. 393, # 6, p. 967 - 978]
  • 2
  • [ 36394-75-9 ]
  • [ 50911-24-5 ]
YieldReaction ConditionsOperation in experiment
88% With ammonia In dichloromethane at 20℃; for 1h;
With dichloromethane; ammonia
Yield given;
  • 3
  • [ 36394-75-9 ]
  • <1S,5R,5E,8E,10S,12E,14E,16S,18R,21S,22R>-7,12,21,22-tetramethyl-10,16-bis<<(1,1-dimethylethyl)dimethylsilyl>oxy>-3,20-dioxo-2,19,4-dioxaazatricyclo<16.3.1.05,21>docosa-6,8,12,14-tetraene [ No CAS ]
  • <1S,4(2S),5R,6E,8E,10S,12E,14E,16S,18R,21S,22R>-N-<2-acetoxy-1-oxopropyl>-7,12,21,22-tetramethyl-10,16-bis<<(1,1-dimethylethyl)dimethylsilyl>oxy>-3,20-dioxo-2,19,4-dioxaazatricyclo<16.3.1.05,21>docosa-6,8,12,14-tetraene [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With lithium hexamethyldisilazane In tetrahydrofuran at -78℃;
With lithium hexamethyldisilazane 1.) THF, -78 deg C, 5 min, 2.) THF, -78 deg C, 15 min; Yield given. Multistep reaction;
  • 5
  • [ 36394-75-9 ]
  • [ 160247-85-8 ]
  • (S)-2-((S)-2-Acetoxy-propionylamino)-3-(3-fluoro-4-nitro-phenyl)-propionic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With dmap; triethylamine In dichloromethane for 1h; Ambient temperature;
With dmap; triethylamine In dichloromethane Ambient temperature; Yield given;
  • 6
  • [ 36394-75-9 ]
  • [ 134-20-3 ]
  • [ 145041-21-0 ]
YieldReaction ConditionsOperation in experiment
89.9% In diethyl ether at -10 - 20℃; for 3h; 1.1.2.3 1.2.3 Synthesis of intermediate (VIIa) 60.0 g (395.8 mmol) of anthranilic acid methyl ester (VI)In 500ml reaction flask,Add anhydrous ether 150ml,Under stirring at -10 to 0 ° C, 15.6 g (103.7 mmol) of the intermediate (Va)After stirring at room temperature for 3h,Suction filtration, the filtrate was washed with hydrochloric acid, water, saturated sodium chloride, concentrated under reduced pressure to give light yellow crystals 24.7g, yield 89.9%.
In diethyl ether Yield given;
In diethyl ether at 0℃; Inert atmosphere; Schlenk technique; General procedure 1 for the preparation of (S)-3-amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1a31 General procedure 1 for the preparation of (S)-3-amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1a31 At first, SOCl2 (272.9mmol) was added dropwise to (S)-2-acetoxypropanoic acid 4a (68.23mmol) at 0°C. After the addition, the reaction mixture was stirred for an additional 4h at room temperature. Excess SOCl2 was removed in vacuo after which acyl chloride was added to a suspension of methyl 2-aminobenzoate (150mmol) in diethyl ether (150mL). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was washed with 2M HCl (2×100mL) and brine (100mL), the organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. Crystallisation of the crude mixture gave the corresponding amide (S)-methyl 2-(2-acetoxypropanamido)benzoate 5a in 85% yield and was used in the next step without further purification. To a solution of amide 5a (15.4g, 58.0mmol) in ethanol (20mL) was added hydrazine monohydrate (290mmol) in a Schlenk flask. The mixture was stirred for 4h at 150°C. After concentration under reduced pressure, water (50mL) was added and the mixture was extracted with diethyl ether (3×50mL). The organic layers were dried over Na2SO4 and the solvent was removed under vacuum. The residue was crystallised from ethanol and gave (S)-3-amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1a as a colourless solid in 86% yield.
  • 9
  • [ 36394-75-9 ]
  • [ 185112-21-4 ]
  • (R)-((S)-2-Acetoxy-propionylamino)-(3-allyloxy-phenyl)-acetic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With dmap; triethylamine In dichloromethane at 0℃; for 1h;
  • 10
  • [ 867-56-1 ]
  • [ 36394-75-9 ]
  • 11
  • [ 867-56-1 ]
  • [ 75-36-5 ]
  • [ 36394-75-9 ]
  • 12
  • [ 61586-78-5 ]
  • [ 36394-75-9 ]
  • (1R,2S)-2-((S)-2-Acetoxy-propionyloxy)-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With pyridine In diethyl ether at 4℃; for 20h;
  • 13
  • [ 36394-75-9 ]
  • [ 262600-86-2 ]
  • [ 329729-36-4 ]
YieldReaction ConditionsOperation in experiment
88% With pyridine In dichloromethane at 20℃; for 24h;
  • 14
  • [ 58461-27-1 ]
  • [ 36394-75-9 ]
  • (S)-2-Acetoxy-propionic acid 2-isopropenyl-5-methyl-hex-4-enyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine In diethyl ether at 0 - 20℃;
  • 15
  • [ 617-27-6 ]
  • [ 36394-75-9 ]
  • N-[(S)-2-acetoxypropanoyl]alanine ethyl ester [ No CAS ]
  • 16
  • [ 36394-75-9 ]
  • [ 1722-95-8 ]
  • (2R,2'S)-1-(2'-Acetoxypropanoyl)-2-methylpiperidine [ No CAS ]
  • 17
  • [ 36394-75-9 ]
  • [ 178422-79-2 ]
  • [ 273404-63-0 ]
YieldReaction ConditionsOperation in experiment
87% With pyridine; N,N-dimethyl-formamide In dichloromethane at 20℃; for 24h;
  • 18
  • [ 36394-75-9 ]
  • [ 3197-42-0 ]
  • (2S,2'S)-1-(2'-Acetoxypropanoyl)-2-methylpiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With pyridine In dichloromethane for 1h;
  • 19
  • [ 36394-75-9 ]
  • [ 86953-79-9 ]
  • N-(tert-butoxycarbonyl)-2-(2-acetoxy-1-oxopropyl)pyrrolidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In tetrahydrofuran at -78℃; for 1h; Stage #2: With lithium chloride In tetrahydrofuran at -78℃; for 0.666667h; Stage #3: (S)-2-acetoxypropanoyl chloride In tetrahydrofuran at -78 - 20℃;
  • 20
  • [ 60857-16-1 ]
  • [ 36394-75-9 ]
  • [ 833489-47-7 ]
  • 21
  • [ 36394-75-9 ]
  • [ 833489-51-3 ]
  • [ 833489-52-4 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In dichloromethane at 0℃; for 1h;
  • 22
  • [ 36394-75-9 ]
  • [ 125424-58-0 ]
  • Acetic acid (S)-1-[(3-oxo-cyclohex-1-enyl)-(4-phenylselanyl-butyl)-carbamoyl]-ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: 3-(4-Phenylselanyl-butylamino)-cyclohex-2-enone With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h; Stage #2: (S)-2-acetoxypropanoyl chloride In tetrahydrofuran; hexane at -78 - 20℃;
  • 23
  • [ 96-47-9 ]
  • [ 36394-75-9 ]
  • 4-chloropentyl (S)-(-)-2-acetoxypropionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With bismuth(III) chloride In dichloromethane at 20℃;
  • 24
  • [ 854937-67-0 ]
  • [ 36394-75-9 ]
  • [ 854937-68-1 ]
YieldReaction ConditionsOperation in experiment
91% With TEA In dichloromethane at 20℃; for 1h;
  • 25
  • [ 885722-47-4 ]
  • [ 36394-75-9 ]
  • [ 854937-85-2 ]
YieldReaction ConditionsOperation in experiment
72% With TEA In dichloromethane at 20℃; for 1h;
  • 26
  • [ 885722-48-5 ]
  • [ 36394-75-9 ]
  • [ 854937-86-3 ]
YieldReaction ConditionsOperation in experiment
72% With TEA In dichloromethane at 20℃; for 1h;
  • 27
  • 4-bromo-3-(diphenyl-phosphinoyl)-naphthalen-2-ol [ No CAS ]
  • [ 36394-75-9 ]
  • 2-acetoxy-propionic acid 4-bromo-3-(diphenyl-phosphinoyl)-naphthalen-2-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With dmap; triethylamine In dichloromethane at 20℃; for 7h;
  • 28
  • polymer; monomer(s): n-hexyl isocyanate; sodium (4-vinylaniline)benzamide [ No CAS ]
  • [ 36394-75-9 ]
  • polymer; monomer(s): n-hexyl isocyanate; sodium 4-vinylbenzanilide; (S)-(-)-acetoxypropionyl chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine In tetrahydrofuran at -98℃; for 0.333333h;
  • 29
  • sodium N-(4-vinylphenyl)benzamide [ No CAS ]
  • [ 2525-62-4 ]
  • [ 36394-75-9 ]
  • polymer; monomer(s): n-hexyl isocyanate; sodium 4-vinylbenzanilide; (S)-(-)-acetoxypropionyl chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: sodium N-(4-vinylphenyl)benzamide; Hexyl isocyanate In tetrahydrofuran at -98℃; for 0.833333h; Stage #2: (S)-2-acetoxypropanoyl chloride With pyridine In tetrahydrofuran at -98℃;
  • 30
  • [ 2525-62-4 ]
  • [ 36394-75-9 ]
  • [ 74064-37-2 ]
  • polymer; monomer(s): n-hexyl isocyanate; sodium benzanilide; (S)-(-)-acetoxypropionyl chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: Hexyl isocyanate; sodium benzanilide In tetrahydrofuran at -98℃; for 0.833333h; Stage #2: (S)-2-acetoxypropanoyl chloride With pyridine In tetrahydrofuran at -98℃; for 0.333333h;
  • 31
  • [5,6-bis-(trimethyl-silanyloxy)-1,2,3,4,5,6-hexahydro-inden-3a-yl]-methanol [ No CAS ]
  • [ 36394-75-9 ]
  • 2-acetoxypropionic acid 5,6-bis(trimethyl-silanyloxy)-1,2,3,4,5,6-hexahydro-1H-inden-3a-yl methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With dmap; triethylamine In dichloromethane at 0℃; for 0.416667h;
  • 32
  • [ 36394-75-9 ]
  • [ 99-96-7 ]
  • 4-[(S)-2-acetoxypropionoyl]benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With triethylamine In tetrahydrofuran at 20℃;
  • 33
  • [ 885956-71-8 ]
  • [ 36394-75-9 ]
  • [ 1050239-66-1 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; for 2h; 17.A.1 Step 1 A solution of [5-fluoro-3-(trifluoromethyl)-phenyl](hydroxyimino)methylamine (28.04 g, 126.24 mmol), prepared as shown in Example 1, was dissolved in tetrahydrofuran (40 ml) and cooled to -78° C. A solution of(IS)-1-(chlorocarbonyl)ethyl acetate (20 g, 128.82 mmol) in tetrahydrofuran (20 ml) was added dropwise under an atmosphere of dry nitrogen, and stirred for 10 minutes after the addition was complete. A solution of diisopropylethylamine (27.0 ml, 155 mmol) was then added dropwise, and the reaction mixture allowed to warm to room temperature. The mixture was stirred for two hours, then the solvent removed under reduced pressure. The residue was poured into ethyl acetate (150 ml), washed with water (2*50 ml), brine (2*50 ml), and dried over sodium sulfate. Solvent was removed under reduced pressure, to provide 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]-1-azavinyl (2S)-2-acetyloxypropanoate as a pale yellow oil (39.04 g, MS mz 337.1 (M+H), which was used in the next reaction with no further purification.
Stage #1: 3-fluoro-N'-hydroxy-5-(trifluoromethyl)benzimidamide; (S)-2-acetoxypropanoyl chloride In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; Inert atmosphere; 18.A.1 Step 1[0235] A solution of [5-fluoro-3-(trifluoromethyl)-phenyl](hydroxyimino)methylamine (28.04g, 126.24 mmol), prepared as shown in Example 1, was dissolved in tetrahydrofuran (40 ml) and cooled to -78°C. A solution of (IS)-I- (chlorocarbonyl)ethyl acetate (20 g, 128.82 mmol) in tetrahydrofuran (20 ml) was added dropwise under an atmosphere of dry nitrogen, and stirred fo 10 minutes after the addition was complete. A solution of diisopropylethylamine (27.0 ml, 155 mmol) was then added dropwise, and the reaction mixture allowed to warm to room temperature. The mixture was stirred for two hours, then the solvent removed under reduced pressure. The residue was poured into ethyl acetate (150 ml), washed with water (2 x 50 ml), brine (2 x 50 ml), and dried over sodium sulfate. Solvent was removed under reduced pressure, to provide 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]-l- azavinyl (2S)-2-acetyloxypropanoate as a pale yellow oil (39.04 g, MS mz 337.1 (M+H), which was used in the next reaction with no further purification.
  • 34
  • [ 36394-75-9 ]
  • [ 95-84-1 ]
  • [ 941301-38-8 ]
YieldReaction ConditionsOperation in experiment
97% With 1H-imidazole In dichloromethane; acetone at 10 - 20℃;
  • 35
  • [ 36394-75-9 ]
  • [ 118-92-3 ]
  • [ 633305-68-7 ]
  • [ 633305-67-6 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In toluene at 0 - 20℃; for 1.5h; [0169] Anthranilic acid (11.0 gm, 0.080 mol) in dry toluene (400 ml) was cooled to 0° C. Triethylamine (33.64 ml, 0.24 mol) was added. A solution of 3 (18.17 gm, 0.121 mol) in toluene (10 ml) was added slowly to the reaction mixture over 30 min. After stirring at room temperature for 1 hour, the resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (300 ml), washed with water (50 ml), 1M HCl (50 ml), and brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a 19.98 gm of a mixture of 4 and 5.
  • 36
  • 5-amino-2,4,6-triiodoisophthaloyl dichloride [ No CAS ]
  • [ 36394-75-9 ]
  • L-5-(2-acetoxypropionylamino)-2,4,6-triiodoisophthaloyl dichloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In ISOPROPYLAMIDE at -2 - 20℃; for 21 - 23h; 1 Example 1; A 250 ml round-bottomed flask, fitted with mechanical stirring and kept under inert atmosphere, is loaded with N,N-dimethylacetamide (30 ml), then cooled at -2 - 0°C and L-2-acetoxypropionyl chloride (20 g; 0.133 moles; e. e. 97.4%) is added drop by drop in an hour. When the addition is completed, water (0.360 g; 20.1 mmoles) is added. Temperature is adjusted to 12°C and a solution of N,N-dimethylacetamide (30 ml) and 5-amino-2,4,6-triiodoisophthaloyl dichloride (40 g; 67 mmoles) is dropped therein in 6 hours. After that, the solution is warmed to 19-20°C, keeping this temperature for 14-16 hours. The mixture is cooled to 5-10°C and cellosolve (40 ml) is added, keeping temperature lower than 20°C. The solution is added drop by drop to water (280 ml) in about 1 hour, keeping temperature at 15-20°C. The suspension is stirred for 30 minutes and the precipitate is filtered, washed with water (2x30 ml) and dried under vacuum at 50°C until constant weight to obtain 42 g of the desired product. Titre ≥ 97%, 95% e. e., 89% yield.
  • 37
  • N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide [ No CAS ]
  • [ 36394-75-9 ]
  • C22H26FN3O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 23℃; for 0.5h; 29 To a solution of N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo [3.1. 0] hex-6-yl]-3- FLUOROPHENYL}-2-OXO-1, 3-OXAZOLIDIN-5-YL) methyl] acetamide (0.13 g, 0.39 mmol, 1 equivalent) in CH2C12 (20 mL) at 23°C was added triethyl amine (0.22 mL, 1.58 mmol, 4.0 equiv. ), followed by (S)- (-)-2-ACETOXYPROPIONYL chloride (0.07 mL, 0.55 mmol, 1.4 equiv. ). The reaction mixture was stirred at the same temperature for 30 min, diluted with saturated NaHC03 aqueous and extracted with CH2C12 (3X100 mL). The combined organic layers were washed (H20, brine), dried (NA2S04), filtered and evaporated to dryness. The crude acetoxy-protected intermediate was used directly in the next step without further purification.
  • 38
  • [ 848415-72-5 ]
  • [ 36394-75-9 ]
  • (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl} oxy)piperidin-1-yl]-1-oxopropan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 0.5h; 35 N- (3-CHLORO-2-FLUOROPHENYL)-6-METHOXY-7- (PIPERIDIN-4-YLOXY) QUINAZOLIN-4-AMINE (500 mg, 1.05 mmol) and 4-DIMETHYLAMINOPYRIDINE (128 mg, 1.05 mmol) were stirred in acetonitrile (2.5 ml) and diisopropylethylamine (0.366 ml, 2.10 mmol) was added. The mixture was cooled to 0°C and a solution of (S)- (-)-2-ACETOXYPROPIONYL chloride (0.166 ML, 1.31 mmol) in acetonitrile (0.5 ml) was added drop-wise. The reaction mixture was then stirred at this temperature for 0.5 hours. Water (1.0 ml) and potassium hydroxide (0.641 ml of a 49% w/w solution in water) were added and the mixture stirred at room temperature over night. The layers were separated and the organic layer diluted with ethyl acetate (2.5 ml). Water was added followed by glacial acetic acid (0.210 ml). The mixture was stirred and partitioned. The organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title product (215mg, 43%) as a white solid
  • 39
  • N-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-amine trihydrochloride [ No CAS ]
  • [ 36394-75-9 ]
  • (2S)-1-(4-[4-[3-chloro-2-fluoroanilino]-6-(2-pyrrolidin-1-ylethoxy)quinazolin-7-yl]oxy} piperidin-1-yl)-1-oxopropan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.6% With triethylamine In dichloromethane at -10 - 20℃; for 0.5h; 18 (S)- (-)-2-ACETOXYPROPRIONYL chloride (0.131 g, 0.87 mmol) was added to a stirred solution of N- (3-CHLORO-2-FLUOROPHENYL)-7- (PIPERIDIN-4-YLOXY)-6- (2-PYRROLIDIN-1- ylethoxy) quinazolin-4-amine tri hydrochloride (220 mg, 0.395 mmol) and triethylamine (0. 110 ml, 0.79 mmol) in methylene chloride (10 ML) AT-10°C. The resulting solution was allowed to warm to room temperature and stirred for 30 minutes. The resulting yellow solution was diluted with methylene chloride (10 ml) and washed with water (3 X 5 ML), dried (MGS04) and evaporated. The resulting foam was dissolved in THF (1 ml) and pyrrolidine (1 ml) was added. The mixture was heated at 70°C for 3 hours, evaporated and the residues purified by flash chromatography on silica gel eluting with DICHLOROMETHANE/7N ammonia in methanol (95/5). Fractions containing the desired product were combined and evaporated to give the title product as a white solid. (0.099 g, 45.6%)
  • 40
  • 3-(2-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine [ No CAS ]
  • [ 36394-75-9 ]
  • (S)-acetic acid 1-[3-(2-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylcarbamoyl]-ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% Stage #1: 3-(2-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine; (S)-2-acetoxypropanoyl chloride In tetrahydrofuran at 20 - 70℃; Stage #2: With PS-Trisamine In tetrahydrofuran at 50℃; for 4h; 1 To a solution of 3- (chlorophenyl)-3-oxo-propionitrile (4.0 g, 22.2 mmol) in absolute ethanol (21 mL) was added hydrazine hydrate (6.5 mL, 134 mmol). The reaction mixture was stirred at 80°C for 15 hours, then it was concentrated in vacuo and purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to give 3.8 g (87% yield) of 5-amino-3- (2- chlorophenyl) pyrazole as a yellow solid. lH NE (d6-DMSO) õ : 11.7 (broad s, 1H), 7.66 (d, 1H), 7.48 (d, 1H), 7.35 (t, 1H), 7.30 (t, 1H), 5.83 (s, 1H), 4. 84 (broad s, 2H); HPLC/MS m/z: 194.1 [MH] +. [0203] To a solution of 5-amino-3- (2-chlorophenyl) pyrazole (3. 8 g, 19.6 mmol) in THF (150 mL) was added dropwise benzoyl isothiocyanate (2.9 mL, 21. 56 mmol). The reaction mixture was stirred at room temperature for 4 hours, then 4 N aqueous solution of NaOH (8 mL) was added, and the reaction mixture was further stirred at room temperature for 17 hours. The reaction mixture was neutralized to pH 7 with 1 N aqueous HC1, and extracted with EtOAc (3x). The combined organic layers were directly purified on silica gel with 0- 10% MeOH in CH2C12 as eluent to provide 3.47 g (72 % yield) of [5- (2-chloro-phenyl)-2H- pyrazol-3-yl]-thiourea as a tan solid. [0204] To a solution of [5- (2-chloro-phenyl)-2H-pyrazol-3-yl]-thiourea (2.25 g, 8.9 mmol) in glacial AcOH (900 mL) was added a 1.5 M solution of bromine in AcOH (20 mL) dropwise under vigorous stirring. The resulting heterogeneous mixture was stirred at room temperature for 2 hours then it was concentrated to dryness. Water was added followed by a saturated solution of aqueous sodium bicarbonate to neutralize to pH 7. The resulting precipitate was filtered, washed with water and dried in vacuo. Recrystallization from isopropyl alcohol afforded 1.48 g (66% yield) of 3-(2-chloro-phenyl)-lH-pyrazolo [3, 4- d] thiazol-5-ylamine as a tan solid. lH-NMR (d4-MeOH) d : 7.64 (broad s, 1H), 7.53 (d, 1H), 7.42 (m, 2H); HPLC/MS m/z: 251 [MH] +. [0205] To a vial charged with 3- (2-chloro-phenyl)-lH-pyrazolo [3,4-d] thiazol-5-ylamine (30 mg, 0.12 mmol) and PS-DMAP (Argonaut resin, 450 mg, 5 equiv. ) were added THF (0.8 mL) and (S)-(-)-2-acetoxypropionyl chloride (126 mg, 0.84 mmol). The reaction mixture was shaken at 70°C overnight, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 1.03 g, 30 equiv. ) at 50°C for 4 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification by reverse-phase preparative HPLC provided 21 mg (48% yield) of the title compound. IH-NMR (d6-DMSO) , 5. 7.78 (broad m, 1H), 7.61 (broad m, 1H), 7.47 (broad m, 2H), 5.13 (q, 1H), 2.09 (s, 3H), 1.44 (d, 3H); HPLC/MS m/z: 365.0 [MH] +.
  • 41
  • [ 100-02-7 ]
  • [ 36394-75-9 ]
  • [ 871822-63-8 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at -20℃; for 3.25h; 4.1 Diisopropylethylamine (3.5 mL, 20 mmol) was added to suspension of 4-nitrophenol (2.78 g, 20 mmol) in dichloromethane (60 mL). The solution was cooled to -20 °C and a solution of (S)-2-acetoxypropionyl chloride (3.01 g, 20 mmol) dichloromethane (12 mL) was added dropwise over 15 min. The reaction mixture was stirred at this temperature for 3 hours and then poured into 0.5 N aqueous HCl (300 mL). Organic layer was diluted by dichloromethane (100 mL), washed with water, brine and dried over magnesium sulfate. After evaporation of solvents (S) - 2-acetoxypropionic acid 4-nitro-phenyl ester (5.08 g,00%) was obtained.
  • 42
  • 5(R)((N-isoxazol-3-yl-N-tertbutoxycarbonyl)aminomethyl)-3-(3,5-difluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one hydrochloride [ No CAS ]
  • [ 36394-75-9 ]
  • 5(R)-(N-isoxazol-3-yl-N-tertbutoxycarbonyl)-aminomethyl-3-(3,5-difluoro-4-(1-(2(S)-acetoxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-oxazolidin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; 57.24 (S)-2-Acetoxypropanoyl chloride (65 mg, 0.43 mmol) was added dropwise at room temperature to a stirred suspension of Reference Example 10 (200 mg, 0.39 mmol) and N,N diisopropyl ethylamine (106 mg, 0.82 mmol) in dichloromethane (10 ml). The reaction was stirred at room temperature for 2 hr then purified by flash chromatography (Merck 9385 silica, ethyl acetate/iso-hexane (7/3)) to give the title compound (177 mg, 77%) as a colourless solid. 1H-NMR (300 MHz, CDCl3): δ=1.45-1.52 (m, 3H), 1.57 (s, 9H), 2.14 (s, 3H), 2.42-2.62 (m, 2H), 3.69 (t, 2H), 3.80 (dd, 1H), 3.93-4.20 (m, 2H), 4.20-4.26 (m, 2H), 4.37 (dd, 1H), 5.04-5.16 (m, 1H), 5.37-5.55 (m, 1H), 5.81(m) & 5.89 (m) (1H), 6.90 (s(br), 1H), 7.16 (d, 2H), 8.27 (s, 1H). MS: ESP+ (M+H)+=591.
  • 43
  • [ 252328-98-6 ]
  • [ 36394-75-9 ]
  • [ 7087-68-5 ]
  • 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-acetoxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% In methanol; dichloromethane 47 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-acetoxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one EXAMPLE 47 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-acetoxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one (S)-2-Acetoxypropionyl chloride (126 mg, 0.84 mmol) was added dropwise at room temperature to a stirred suspension of Reference Example 11 (300 mg, 0.76 mmol) and N,N diisopropyl ethylamine (210 mg, 1.63 mmol) in dichloromethane (10 ml). The reaction was stirred at room temperature for 2 hr then purified by flash chromatography (Merck 9385 silica, 2.5% MeOH/dichloromethane) to give the title compound (322 mg, 90%) as a colourless solid. MS: ESP+(M+H)+=474. 1H-NMR (300 MHz, CDCl3): δ=1.48 (s) and 1.51 (s) (3H), 2.14 (s, 3H), 2.50-2.74 (m, 2H), 3.68 (m) and 3.96 (m) (3H), 4.05-4.36 (m, 3H), 4.47-4.62 (m, 2H), 5.04 (m, 1H), 5.35-5.55 (m, 1H), 5.97 (m, 1H), 6.00 (d, 1H), 7.20-7.30 (m, 2H), 7.45 (d, 1H), 8.15 (d, 1H).
  • 44
  • [ 41526-55-0 ]
  • [ 36394-75-9 ]
  • C24H26N2O5 [ No CAS ]
  • C24H26N2O5 [ No CAS ]
  • C24H26N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 28% 2: 32% 3: 8% Stage #1: ethanol; 2-phenylmethylene-7-methoxy-1-tetralone With hydrazine; Trimethylacetic acid In water for 6h; Heating / reflux; Stage #2: (S)-2-acetoxypropanoyl chloride at 20℃; for 0.5h; A solution of 2-(4-methoxy-benzylidene)- 1 -tetralone (Ll g, 0.0037 mol), trimethylacetic acid (6.0 g), hydrazine hydrate (1.1 mL) in ethanol (5 mL) was refluxed for 6 h, and concentrated under vacuum. The residue obtained was dissolved in ethyl acetate (200 mL) and it was slowly poured on saturated NaHCOs solution (200 mL), and the resulting solution was slowly treated with (5)-acetoxy-propionyl chloride (2.350 mL, 0.018 mol). and stirred at room temperature for 30 minutes. The ethyl acetate layer was separated, washed with water, brine, dried on Na2SO4 and concentrated. The residue purified on the silica gel column using ethyl acetate - hexane (35%). Earlier fractions furnished (139) (0.440 g, 28%), and the later fractions furnished (100) (0.508 g, 32%), and (101) (0.130 mg, 8%).(139): mp 146-50 0C, 1H NMR (500 MHz, CDCl3): 1.50 (d, J = 7.0 Hz5 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.88 - 1.99 (m, 2H), 2.08 (s, 3H), 2.09 (s, 3H), 2.24 - 2.32 (m, 2H), 2.82 - 2.92 (m, 4H), 3.14 - 3.20 (m, 2H), 3.79 (s, 6H), 3.87 (s, 6H), 4.91 - 4.98 (m, 2H), 5.86 - 5.93 (m, 2H), 6.86 - 6.94 (m, 5H), 7.10 (d, J = 8.5 Hz, 2H), 7.19 - 7.26 (m, 5H), 7.41 - 7.43 (m, 2H). Anal. Calcd for C24H26N2O5: C, 68.23; H5 6.20; N, 6.63. Found: C, 67.96; H, 6.20; N5 6.36. (100): mp 70-76 0C (dec.),.1H NMR (500 MHz, CDCl3): 0.97 - 1.06 (m, IH), 1.56 (d, J = 7.0 Hz, 3H), 1.75 - 1.79 (m, IH), 2.10 (s, 3H), 2.73 - 2.86 (m, 2H), 3.48 - 3.53 (m, IH), 3.74 (s, 3H), 3.86 (s, 3H), 5.64 (d, J = 11.0 Hz, IH), 6.03 (dd, J = 7.0 and 14.0 Hz, IH), 6.81 (d, J = 9.0 Hz, 2H), 6.90 - 6.92 (dd, J = 3.0 and 9.0 Hz, IH), 7.02 - 7.06 (m, 3H), 7.51 (d, J= 3.0 Hz, IH). HFABMS m/z 423.1927 (CaIC fOr C24H26N2O59 MH+, 423.1920). • • -(101): mp 139-42 0C (dec), 1H NMR (400 MHz, CDCl3): 1.12 - 1.18 (m, IH), 1.60 (d, J = 6.8 Hz, 3H), 1.70 - 1.74 (m, IH), 2.12 (s, 3H), 2.78 - 2.85 (m, 2H), 3.50 - 3.57 (m, IH), 3.75 (s, 3H), 3.85 (s, 3H), 5.65 (d, J = 11.2 Hz, IH), 5.80 - 5.90 (dd, J = 5.6 and 11.6 Hz5 IH), 6.79 (d, J = 8.4 Hz, 2H), 6.91 - 6.97 (m, 3H), 7.07 (d, J = 8.0 Hz, IH), 7.52 (d, J = 3.2 Hz, IH). Anal. Calcd for C24H26N2O5: C, 68.23; H, 6.20; N, 6.63. Found: C, 67.99; H, 6.32; N, 6.50.
  • 45
  • [ 36394-75-9 ]
  • [ 150544-01-7 ]
  • [ 1082989-94-3 ]
YieldReaction ConditionsOperation in experiment
99% With piperidine In tetrahydrofuran at -40 - 20℃; 98 The stirred solution of 5-fluoro-6-amino-l,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to -40 °C in an acetone-dry ice bath and added with (S)- acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid l-(5-fluoro- 2-oxo-2,3-dihydro-lH-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid. MS m/z (ESI): 279[M-I]
  • 46
  • (S)-N,N'-bis[2-acetyloxy-1-[(acetyloxymethyl]ethyl]-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide [ No CAS ]
  • [ 81836-37-5 ]
  • [ 36394-75-9 ]
  • [ 75294-52-9 ]
YieldReaction ConditionsOperation in experiment
82% With hydrogenchloride In N,N-dimethyl acetamide 5 EXAMPLE 5 EXAMPLE 5 Preparation of (S)-N,N'-bis(2,2-dimethyl-1,3-dioxan-5-yl)-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide ((IV): -R=a Group A wherein R1 and R2 are Methyl) The compound prepared in Example 1 (15 g, 19 mmol) is dissolved in N,N-dimethylacetamide (80 mL) containing HCl gas (0.073 g, 2 mmol). (S)-2-(Acetyloxy)propanoyl chloride (8 g, 53 mmol) is dripped over 30 min into the obtained solution cooled to 15° C. After two hours at the same temperature, the reaction mixture is allowed to warm up to room temperature and stirred for additional 12 hours. The solvent is then evaporated under vacuum and the residue is taken up with 4% NaHCO3 (130 mL). The solid obtained is filtered, washed and dried to give the compound of the title (14 g, 15.6 mmol). Yield: 82% The 1H-NMR, 13C-NMR, IR and MS are consistent with the indicated structure.
  • 47
  • [ 910215-56-4 ]
  • [ 36394-75-9 ]
  • (S)-(+)-2,2'-bis((S)-2-acetoxypropionato)-3,3',4,4',5,5',6,6',7,7',8,8'-dodecafluoro-1,1'-binaphthyl [ No CAS ]
  • (R)-(-)-2,2'-bis((S)-2-acetoxypropionato)-3,3',4,4',5,5',6,6',7,7',8,8'-dodecafluoro-1,1'-binaphthyl [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With triethylamine In diethyl ether at 20℃; for 8h;
  • 48
  • [ 1029623-78-6 ]
  • [ 36394-75-9 ]
  • [ 1029623-79-7 ]
  • [ 1029623-80-0 ]
YieldReaction ConditionsOperation in experiment
1: 21.4% 2: 20.7% With triethylamine In dichloromethane at 40℃; 11.F Step F: Acylation Compound 11-6 (58.0 mg, 0.11 mmol) was dissolved in DCM in a screw cap vial. (iS)-2-Acetoxypropanoyl chloride (0.042 rnL, 0.33 mmol) and triethylamine (0.046 mL, 0.33 mmol) were then added. The vial was sealed and heated to 40 degrees celcius. The reaction was stirred at 40 degrees celcius overnight. After reaction completion, the solvent was removed under vacuum. The reaction mixture was taken up in acetonitrile and water, and the isomers were separated using reverse phase chromatography. The iS-isomer showed a retention time of 1.29 minute on LCMS; the i?-isomer showed a retention time of 1.33 minute, Yield of the ^-isomer: 15.4 mg (20.7%). Yield of the i?-isomer: 15.9 mg (21.4%).
  • 49
  • [ 36394-75-9 ]
  • [ 37441-29-5 ]
  • [ 60166-91-8 ]
YieldReaction ConditionsOperation in experiment
92.3% In N,N-dimethyl acetamide at 0 - 20℃; Inert atmosphere; 1.1; 6.1 (1) Synthesis of 5-[(2(S)-2-acetoxypropionyl)amino]-2,4,6-triiodo-1,3-phthaloyl chloride (compound of formula 3) According to the molar ratio of 5-amino-2,4,6-triiodo-1,3-phthaloyl chloride to 2(S)-2-acetoxypropionyl chloride of 1:2.2, 30 g of 5-amino-2, 4,6-triiodo-1,3-phthaloyl chloride was placed in a 250 ml reaction flask, 60 mL of N,N-dimethylacetamide was added under nitrogen, stirred at room temperature until completely dissolved, and cooled to 0-5 ° C. And heat preservation, slowly add 16.5g of 2(S)-2-acetoxypropionyl chloride slowly, after the addition is completed, naturally heat up to 15-20 ° C for 30-40 hours, add 150mL of dichloromethane, stir for 3-5 minutes Wash three times with 300 mL of water each time, then wash twice with 200 mL of saturated brine each time, separate the organic phase, concentrate to dryness under reduced pressure, add 90 mL of isopropanol, stir and crystallize, filter, and dry to obtain 32 g of white 5-[(2(S)-2-acetoxypropionyl)amino]-2,4,6-triiodo-1,3-phthaloyl chloride,The yield is 92.3%.The purity was determined by HPLC to be 95%.
91.4% In N,N-dimethyl acetamide at 0 - 20℃; for 38h; Inert atmosphere; 1.1 (1) Synthesis of 5-[(2(S)-acetoxypropionyl)amino]-2,4,6-triiodo-1,3-di(chloroformyl)benzene (formula (II) compound) According to 5-amino-2,4,6-triiodo-1,3-di(chloroformyl)benzene and 2(S)-acetoxypropionylchloride molar ratio of 1: 2, 59.6g 5-amino-2,4,6-triiodo-1,3-di(chloroformyl)benzeneplaced in 250mL reaction flask under nitrogen atmosphere was added 120mL N,N-dimethylacetamide, stirred until completely dissolved at room temperature, cooled to 0 ~ 5 deg. C,was slowly added dropwise 30g 2(S)-acetoxypropionyl chloride, maintaining the temperature of the solution during the addition at less than 5 deg. C, then naturally warmed to 15 ~ 20 deg. C, the reaction insulated for 38 hours, then according to dichloromethane and N, N- dimethylacetamide volume ratio of 1: 2.5, 250mL of methylene chloride was added to the solution, after stirring for 3 to 5 minutes, the solution was washed with water 3 times, 300mL each, washed with brine twice, 200 mL each time, the organic phase was separated, concentrated under reduced pressure, a mixed solution of 180mL precooled water and an equal volume of isopropanol was added to the residue, stirred for 30 minutes, filtered under reduced pressure, and dried to give 64.8g white 5-[(2(S)-acetoxypropionyl)amino]-2,4,6-triiodo-1,3-di(chloroformyl)benzene, yield 91.4%, purity determined by HPLC to be 95.2%.
90% Stage #1: (S)-2-acetoxypropanoyl chloride In N,N-dimethyl acetamide at -2 - 0℃; for 1h; Stage #2: 5-amino-2,4,6-triiodoisophthalic acid dichloride at 12℃; for 6h; Stage #3: With 2-ethoxy-ethanol more than 3 stages; A 250 ml round-bottomed flask, fitted with mechanical stirring and kept under inert atmosphere, is loaded with N,N-dimethylacetamide (60 ml), then cooled at -2 - 0C and L-2-acetoxypropionyl chloride (20 g; 0.133 moles; e. e. 97.4%) is added drop by drop in an hour. When the addition is completed, methanol (0.645 g; 20.1 mmoles) is added. Temperature is adjusted to 12C and 5-amino-2,4,6-triiodoisophthaloyl dichloride (40 g; 67 mmoles) is added in 6 equal portions, one per hour. After that, the solution is warmed to 19-20C, keeping this temperature for 14-16 hours. The mixture is cooled to 5-10C and cellosolve (40 ml) is added, keeping temperature lower than 20C. The solution is added drop by drop to water (280 ml) in about 1 hour, keeping temperature at 15-20C. The suspension is stirred for 30 minutes and the precipitate is filtered, washed with water (2x30 ml) and dried under vacuum at 50C until constant weight to obtain 43 g of the desired product. Titre >= 97%, 94.8% e. e., 90% yield.
89% Stage #1: (S)-2-acetoxypropanoyl chloride In N,N-dimethyl acetamide at -2 - 0℃; for 1h; Stage #2: 5-amino-2,4,6-triiodoisophthalic acid dichloride In N,N-dimethyl acetamide at 12℃; for 6h; Stage #3: With 2-ethoxy-ethanol more than 3 stages; A 250 ml round-bottomed flask, fitted with mechanical stirring and kept under inert atmosphere, is loaded with N,N-dimethylacetamide (30 ml), then cooled at -2 - 0C and L-2-acetoxypropionyl chloride (20 g; 0.133 moles; e. e. 97.4%) is added drop by drop in one hour. When the addition is completed, methanol (0.215 g; 6.7 mmoles) is added. Temperature is adjusted to 12C and a solution of N,N-dimethylacetamide (30 ml) and 5-amino-2,4,6-triiodoisophthaloyl dichloride (40 g; 67 mmoles) is dropped therein in 6 hours. After that, the solution is warmed to 19-20C, keeping this temperature for 14-16 hours. The mixture is cooled to 5-10C and cellosolve (40 ml) is added, keeping temperature lower than 20C. The solution is added drop by drop to water (280 ml) in about 1 hour, keeping temperature at 15-20C. The suspension is stirred for 30 minutes and the precipitate is filtered, washed with water (2x30 ml) and dried under vacuum at 50C until constant weight to obtain 42.5 g of the desired product. Titre >= 97%, 93.6% e. e., 89% yield.
With N,N-dimethylacetamide hydrochloride In ISOPROPYLAMIDE at 10 - 25℃; 4 5-amino-2,4,6-triiodoisophtalic acid dichloride (I) (506 g, 0.85 mol) and dimethylacetamide hydrochloride (37 g) were dissolved in DMA (690 g) at 25°C. To the thus obtained solution, (S)-[2-(acetyloxy)]propionic acid chloride was then added over 4 hours, keeping the temperature between about 10° and 150C. The temperature of the solution was then set to about 200C and stirring was continued for 30 hours. The crude material was used as such, as indicated in the following Examples 5-9. HPLC profile: compound (II): 94%; 5-amino-2,4,6-triiodoisophtalic acid dichloride (I): <0.1%.

  • 50
  • [ 36394-75-9 ]
  • [ 150544-01-7 ]
  • [ 945381-83-9 ]
YieldReaction ConditionsOperation in experiment
99% With piperidine In tetrahydrofuran at -40 - 20℃; 98 The stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to -40° C. in an acetone-dry ice bath and added with (S)-acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid.MS m/z (ESI): 279 [M-1]
  • 51
  • [ 1220701-01-8 ]
  • [ 36394-75-9 ]
  • [ 1220700-92-4 ]
YieldReaction ConditionsOperation in experiment
83% With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; 15.3 Step 3; A mixture of compound 82 (600 mg, 1.6 mmol), (S)-(-)-2-acetoxypropionyl chloride (362 mg, 0.304 mmol) in anhydrous CH2CI2 (10 ml_) was treated with Et3N (486 mg, 4.81 mmol) at room temperature. The resulting reaction mixture was stirred under nitrogen at room temperature for 30 min under nitrogen. After 30 mins, LC-MS showed the reaction was completed. The reaction mixture was concentrated to give the crude product as a yellow solid which was purified by Biotage (Si, 40M) using gradient 1 -5% MeOH in CH2CI2 to afford compound 83 as light yellow solid (650 mg, 83%). 1H NMR (300 MHz, CDCI3) δ 1.47 (d, J=6.40 Hz, 3 H) 1.95 - 2.11 (m, 4 H) 2.14 (s, 3 H) 2.68 (s, 3 H) 2.76 - 2.91 (m, 2 H) 2.91 - 3.04 (m, 1 H) 3.23 - 3.37 (m, 1 H) 3.62 (s, 3 H) 3.94 - 4.20 (m, 1 H) 5.50 (br s, 1 H) 7.39 (d, J=8.10 Hz, 1 H) 8.03 (d, J=9.04 Hz, 1 H) 8.28 (dd, J=8.10, 2.07 Hz, 1 H) 8.51 (d, J=8.85 Hz, 1 H) 8.75 (s, 1 H) 9.23 (br s, 1 H).
  • 52
  • [ 1220700-96-8 ]
  • [ 36394-75-9 ]
  • [ 1220700-97-9 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; 17.3 Step 3; A mixture of 8-(1 H-indazol-4-yl)-3-methyl-1 -(piperidin-4-yl)-1 /-/-imidazo[4,5- c][1 ,5]naphthyridin-2(3H)-one trihydrochloride (90) (1.20 g, 2.36 mmol), and (S)-(-)-2- acetoxypropionyl chloride (1.06 g. 7.07 mmol) in anhydrous CH2CI2 (10 ml_) was treated with Et3N (1.19 g, 11.8 mmol) at rt. The resulting reaction solution was stirred at rt under nitrogen for 1 h. Water (30 ml_) and CH2CI2 (40 ml_) were added, and layers were separated. The aqueous layer was extracted with CH2CI2 (20 ml_). The organic extracts were washed with brine, dried over sodium sulfate, and concentrated to give a waxy, yellow solid (1.21 g, 100%). The solid was suspended in MeOH/THF (10 mL/10 ml_), and followed by the addition of 2 M LiOH (5.9 ml_, 11.8 mmol). The resulting reaction mixture was stirred at rt for 3 h. After removal of the organic solvent, the aqueous residue was diluted with water (10 ml_) and adjusted to pH 7 with 2 M HCI. The resulting mixture was concentrated to a low volume and vigorously stirred to form more solid, which was collected by vacuum-filtration and further dried to give the crude product as a yellow solid. The crude product was dissolved in 10% MeOH/CH2CI2 (150 ml_) and filtered. The filtrate was concentrated to a low volume until solid formed. The mixture was stirred for 2 h while the solid was precipitating. The precipitated solid was collected by vacuum-filtration, rinsed with MeOH, and further dried to yield 362 mg (33%) of the title compound 255 as a pale yellow solid. 1H NMR (400 MHz, DMSO- Cf6) δ 1.18 (d, J=6.32 Hz, 3 H), 1.99 (br s, 2 H), 2.55 (br s, 3 H), 2.96 (t, J=12.63 Hz, 1 H), 3.53 (s, 3 H), 4.15 (d, J=12.38 Hz, 1 H), 4.35 - 4.71 (m, 2 H), 4.91 (br s, 1 H), 6.35 (br s, 1 H), 7.49 - 7.63 (m, 1 H), 7.66 - 7.87 (m, 2 H), 8.26 (d, J=9.09 Hz, 1 H), 8.53 (d, J=8.84 Hz, 1 H), 8.60 (s, 1 H), 8.98 (s, 1 H), 13.35 (s, 1 H).
  • 53
  • [ 1156466-52-2 ]
  • [ 36394-75-9 ]
  • [ 1156468-43-7 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In tetrahydrofuran at 20℃; for 3h; 126.1 Example Compound 126:; (25)-iV-{(lR)-2-[4-({6-Amino-8-[(7-bromo-2,3-dihydro-l ,4-benzodioxin-6-yl)thio]-9iy- purin-9-yl}methyl)piperidin-l-yl]-l-methyl-2-oxoethyl}-2-hydroxypropanamide; Step 1 :; 9-({ l-[(2i?)-2-Aminopropanoyl]piperidin-4-yl}methyl)-8-[(7-bromo- 2,3-dihydro-l ,4-benzodioxin-6-yl)thio]-9H-purin-6-amine (0.01Og, 0.018 mmol) was dissolved in THF (5 mL), followed by the addition of TEA (0.005 mL, 0.018 mmol) and acetic acid (S)-l-chlorocarbonyl-ethyl ester (0.002 mL, 0.036 mmol). After stirring for 3 h at rt, the reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to afford (llS)-2-({(li?)-2-[4-({6-amino-8-[(7-bromo-2,3-dihydro-l ,4-benzodioxin-6-yl)thio]-9/f- purin-9-yl}methyl)piperidin- 1 -yl]- 1 -methyl-2-oxoethyl} amino)- 1 -methyl-2-oxoethyl acetate (0.010 g) as a light yellow oil; LC-MS [M+H]+ 662.1
  • 54
  • [ 1156467-71-8 ]
  • [ 36394-75-9 ]
  • [ 1156468-97-1 ]
YieldReaction ConditionsOperation in experiment
31% With triethylamine In tetrahydrofuran; methanol for 4h; 212.1 Example Compound 212:; (25')-l-(4- {6-amino-8-[(6-bromo-l ,3-benzodioxol-5-yl)thio]-9/f-purin-9-yl}piperidin-l- yl)- 1 -oxopropan-2-ol; Step 1. (lS)-2-(4-{6-amino-8-[(6-bromo-l ,3-benzodioxol-5-yl)thio]-9/f- purin-9-yl } piperidin- 1 -yl)- 1 -methyl-2-oxoethyl acetate :; 8-[(6-bromo-l ,3-benzodioxol-5-yl)thio]-9-piperidin-4-yl-9H-purin-6-amine (0.010 g, 0.022 mmol) was dissolved in THF: MeOH (2 niL), followed by the addition of TEA (0.006 mL, 0.044 mmol) and acetic acid (S)-l-chlorocarbonyl-ehtyl ester (0.003 mL, 0.022 mmol). After stirring for 4 h, the reaction was concentrated in vacuum and the residue was purified by HPLC to afford (15')-2-(4- {6-amino-8-[(6-bromo-l ,3- benzodioxol-5-yl)thio]-9H-purin-9-yl}piperidin-l-yl)-l -methyl-2-oxoethyl acetate (4 mg, 31 %) as a white solid; LC-MS [M+H]+ 563.08
  • 55
  • [ 1092113-64-8 ]
  • [ 36394-75-9 ]
  • [ 1092113-72-8 ]
YieldReaction ConditionsOperation in experiment
92% With pyridine In dichloromethane at 0℃; for 1h; 62.1 3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-totraazabenzo[e]azulen-5-yl)benzoic hydrazide (720 mg, 1.87 mmol) obtained in Step 1 of Example 59 was dissolved in dichloromethane (9.4 mL), and the mixture was stirred at 0°C for 1 hour after adding pyridine (0.23 mL, 2.81 mmol) and (S)-2-acctoxypropionyl chloride (0.26mL, 2.06 mmol) at 0°C Thereafter, water and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid-N'-(2S)-acetoxypropionyl hydrazide (1.04 g, 92%). ESI-MS: m/z 499 [M + H]+.
  • 56
  • 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine [ No CAS ]
  • [ 36394-75-9 ]
  • C26H33F3N10O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 51h; Cooling with ice; 124 Triethylamine (70.2 μl, 0.50 mmol) and (S)-(-)-2-acetoxypropionyl chloride (32.9 μl, 0.25 mmol) were added to a methylene chloride suspension (7.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (112.7 mg, 0.23 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 hours followed by the addition of (S)-(-)-2-acetoxypropionyl chloride (9.0 μl, 0.07 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in methylene chloride (7.0 ml) followed by the addition of triethylamine (140.3 μl, 1.01 mmol) and (S)-(-)-2-acetoxypropionyl chloride (65.7 μl, 0.50 mmol) with ice cooling, and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (157.0 μl, 0.69 mmol) was added to a methanol (6.0 ml) solution of the resulting residue, and the resulting mixture was stirred at 50° C. for 22 hours. The resulting mixture was left standing to cool and then the reaction mixture was poured into methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (132.6 mg, 96%) as a pale yellow solid.1H-NMR (CDCl3) δ: 1.38-1.44 (3H, m), 1.52 (3H, d, J=6.88 Hz), 1.55-1.61 (3H, m), 3.10-3.31 (4H, m), 3.79 (1H, d, J=8.25 Hz), 3.82-3.89 (4H, m), 3.95-4.05 (1H, m), 4.09-4.37 (4H, brm), 4.38-4.49 (1H, m), 4.66-4.90 (3H, m), 5.26 (2H, s), 9.24 (2H, s).
  • 57
  • [ 666235-33-2 ]
  • [ 36394-75-9 ]
  • [ 1236862-53-5 ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane at 0℃; Reflux; 6.1.C (1S)-2-Chloro-1-methyl-2-oxoethyl acetate (12 mL, 95 mmol) was slowly added drop-wise to an ice-cooled suspension of C29 (16.4 g, 84.4 mmol) in anhydrous 1,4-dioxane (200 mL). After being stirred at 0° C. for 40 mins, the reaction mixture was heated at reflux for 2 h. It was then cooled to room temperature and concentrated in vacuo, to afford C30, which was used directly in the next step.
In 1,4-dioxane at 0℃; for 2.66667h; Reflux;
  • 58
  • [ 1082745-50-3 ]
  • [ 36394-75-9 ]
  • [ 1236862-47-7 ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; for 2h;Reflux; (1S)-2-Chloro-1-methyl-2-oxoethyl acetate (30 g, 199 mmol) was added to a suspension of C2 (38.1 g, 181 mmol) in dry dioxane (1000 mL). The mixture was heated at reflux for 2 h, then concentrated in vacuo to provide C3, which was used in the next step without purification.
  • 59
  • [ 1256290-53-5 ]
  • [ 36394-75-9 ]
  • 4-[(3-chloro-2-methylphenyl)methyl]-5-[(1S)-1-hydroxyethyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide; (S)-2-acetoxypropanoyl chloride In tetrahydrofuran at 60℃; for 3h; Stage #2: With sodium hydroxide In tetrahydrofuran; methanol for 0.5h; Stage #3: With hydrogenchloride In tetrahydrofuran; methanol; water 80 To a solution of 4-[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-l,3- thiazole-5-carboxamide (200 mg, 0.545 mmol) in Tetrahydrofuran (TΗF) (2000 μl) was added (lS)-2-chloro-l-methyl-2-oxoethyl acetate (164 mg, 1.090 mmol). The mixture was stirred at room temperature overnight, and then stirred at 60 0C for 3 h. To the mixture was added sodium hydroxide (454 μl, 2.73 mmol) and methanol (0.5 mL). After 30 min, the mixture was acidified (pΗ ~5) with 6N HCl, and then concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude was purified by reversed-phase ΗPLC and subsequently converted to the HCl salt to provide 4-[(3-chloro-2- methylphenyl)methy 1] -5 - [( 1 S)- 1 -hydroxy ethyl]-2-(4-morpholinyl) [ 1 ,3 ]thiazolo [4,5 - J]pyrimidin-7(4H)-one. (14 mg, 6%); LC/MS: MS(ES+) m/e 421 (MH+); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.34 (d, J=6.3 Hz, 3 H), 2.44 (s, 3 H), 3.53 - 3.62 (m, 4 H), 3.67 (m, 4 H), 4.57 (q, J=6.3 Hz, 1 H), 5.67 (s, 2 H), 6.51 (d, J=7.8 Hz, 1 H), 7.14 (m, 1 H), 7.37 (d, J=7.8 Hz, I H).
  • 60
  • [ 1256290-53-5 ]
  • [ 36394-75-9 ]
  • [ 1256290-07-9 ]
YieldReaction ConditionsOperation in experiment
9% In tetrahydrofuran at 20 - 60℃; 99 To a solution of 4-[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-l,3- thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) was added (lS)-2-chloro-l-methyl-2-oxoethyl acetate (82 mg, 0.545 mmol). The mixture was stirred at room temperature overnight, then additional (lS)-2-chloro-l-methyl-2-oxoethyl acetate (1 equiv.) was added and stirring was continued at 60 0C for 2 h. The mixture was quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide (15)-l-[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo- 4,7-dihydro[l,3]thiazolo[4,5-J]pyrimidin-5-yl]ethyl acetate. (11 mg, 9%); LC/MS: MS(ES+) m/e 463 (MH+); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.37 (d, J=6.3 Hz, 3H), 1.71 (s, 3H), 2.40 (s, 3H), 3.51 - 3.54 (m, 4H), 3.67 (m, 4H), 5.48 - 5.61 (m, 2H), 5.69 (q, J=6.3 Hz, IH), 6.56 (d, J=7.6 Hz, IH), 7.16 (m, 1H),7.38 (d, J=7.8 Hz, IH).
  • 61
  • [ 955381-19-8 ]
  • [ 36394-75-9 ]
  • [ 955971-05-8 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In tetrahydrofuran; acetonitrile at 0 - 20℃; for 18.0167h; 255 (S)-N-((1S,2R,3S,4R)-4-{6-(2,2-Diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-hydroxy-propionamide Example 255 (S)-N-((1S,2R,3S,4R)-4-{6-(2,2-Diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-hydroxy-propionamide A mixture comprising 1-{(R)-1-[9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea (Example 26 step 2) (0.1 g, 0.16 mmol) and TEA (24 μl, 0.18 mmol) in THF (7 ml) at room temperature is treated with (S)-(-)-2-acetoxy-propionyl chloride (24 mg, 0.16 mmol) in MeCN (1 ml) at (0° C.) over 1 minute. The mixture is allowed to stir at room temperature for 18 h and then treated with sat. Na2CO3 (1 ml) and MeOH (1 ml) and then stirred for a further 2 days. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute C18, 0-100% acetonitrile in water-0.3% NH3) affords the title compound as a white solid. (MH+ 707.7)
  • 62
  • [ 1338780-04-3 ]
  • [ 36394-75-9 ]
  • [ 1338780-15-6 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 0.25h; 4 Example 4; (S)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide ProcedureAmide Bond Formation To a solution of (3R,4R)-benzyl 3-(((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (1.5 g, 2.53 mmol) in dichloromethane (25 mL, 0.1 M solution) at room temperature was added triethylamine (458 μL, 3.29 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (416 μL, 3.29 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for overnight. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the desired (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate was purified on flash column chromatography (0%-400%, EtOAc in hexanes). LC/MS (uplc): MH+ 706.5, 1.34 min.
  • 63
  • [ 1338780-11-2 ]
  • [ 36394-75-9 ]
  • [ 1338780-17-8 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 0.25h; 6 Example 6; (S)-N-((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide Amide Bond Formation To a solution of (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (1.48 g, 2.43 mmol) in dichloromethane (25 mL, 0.1 M solution) at room temperature was added triethylamine (440 μL, 3.16 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (400 μL, 3.16 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for overnight. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the desired (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate was purified by flash column chromatography (0%-100%, EtOAc in hexanes). LC/MS (uplc) MH+ 724.4, 1.34 min.
  • 64
  • [ 1342804-03-8 ]
  • [ 36394-75-9 ]
  • [ 1342804-05-0 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difiuorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: With sodium hydrogencarbonate In dichloromethane 1.O Step O: Amide Bond Formation[00152] To a solution of (3J?,4^)-benzyl 3-(((«)-l-(5-benzyl-2-(2,5- difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-l- carboxylate (130 mg, 0.214 mmol) in dichloromethane (2.1 mL, 0.1 M solution) at room temperature was added Ν,Ν-diisopropylethylamine (1 12 , 0.64 mmol). (S)-l-Chloro-l- oxopropan-2-yl acetate (54.2 , 0.428 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHC03 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude product was purified on flash column chromatography to yield (3R,4J?)-benzyl 3-(((S)-2-acetoxy-N-((R)- l-(5-benzyl-2- (2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4- fluoropyrrolidine-l-carboxylate (115 mg, 75%). 1H NMR (CDC13, 400 MHz): 6 7.85 (IH, m), 7.37-7.24 (7H, m), 7.21 (IH, m), 7.09 (2H, m), 7.05 (IH, m), 6.96 (IH, m), 6.1 (I H, m), 5.4 (2H, m), 5.28 (IH, m), 4.82 (2H, m), 4.19-3.97 (3H, m), 3.70-3.49 (2H, m), 3.13 (IH, m), 2.76 ( IH, m), 2.52 (IH, m), 2.18 (3H, s), 1.61 (3H, m), 0.99 (9H, s). LC/MS (uplc): MH+ 722.3, 1.40 min.
  • 65
  • 2-((2S)-4-(1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)-1-fluorobutan-2-yl)isoindoline-1,3-dione [ No CAS ]
  • [ 36394-75-9 ]
  • [ 1342804-15-2 ]
  • [ 1342804-13-0 ]
YieldReaction ConditionsOperation in experiment
1: 23% 2: 12% Stage #1: 2-((2S)-4-(1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)-1-fluorobutan-2-yl)isoindoline-1,3-dione; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; Stage #2: With sodium hydrogencarbonate In dichloromethane 3.B Step B: Amide Bond Formationnonpolar polar [00158] To a solution of 2-((2S)-4-(l-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)- 2,2-dimethylpropylamino)-l-fluorobutan-2-yl)isoindoline-l ,3-dione (65 mg, 0.125 mmol) in dichloromethane (1 mL, 0.1 M solution) at room temperature was added DIEA (65.3 iL, 0.375 mmol). (S)-l-Chloro-l-oxopropan-2-yl acetate (35 μ,, 0.276 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NaHC03 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude diastereomers were purified by preparative reverse phase HPLC. The combined fractions of each diastereomer were neutralized with saturated NaHC(½ solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The nonpolar diastereomer, (ii)-l-(((/?)-l -(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2- dimethylpropyl)((S)-3-(l ,3-dioxoisoindolin-2-yl)-4-fluorobuty])amino)- 1 -oxopropan-2-yl acetate, was obtained in 23% (10 mg). LC MS (uplc) MH+ 706.2, 1.37 min. The polar isomer, (tf)-l-(((S)- l-(5-benzyl-2-(2,5-difluoroph^dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-l-oxopropan-2-yl acetate, was obtained in 12% (5 mg). LC MS (uplc) MtT 706.2, 1.36 min.
  • 66
  • [ 1342804-29-8 ]
  • [ 36394-75-9 ]
  • [ 1342804-32-3 ]
  • [ 1342804-31-2 ]
YieldReaction ConditionsOperation in experiment
1: 17% 2: 16% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; 4.H Step Hi Amide Bond Formation(00167] To a solution of (+/-)-(3R,4R)-h nzyl 3-((l-(5-benzyl-2-(2,5- difluorophenyl)oxazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-l- carboxylate (37 mg, 0.063 mmol) in dichloro methane (0.63 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (55 μ, 0.313 mmol). (5 -l-Chloro-l - oxopropan-2-yl acetate ( 15.8 μΙ_-, 0.125 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHC03 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Two diastereomers were separated on preparative TLC (2% MeOH indichloromethane). The polar diastereomer, (3-?,4i¥)-benzyl 3-(((5)-2-acetoxy-N-((j?)-l -(5- benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4- fluoropyrrolidine-l-carboxylate, was obtained in 17% yield (7.5 mg). LC/MS (uplc): MtT 706.4, 1.34 min. The nonpolar diastereomer, (3i,4i?)-benzy] 3-(((S -2-acetoxy-N-((5)- l-(5- benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4- fluoropyrrolidine-l-carboxylate, was obtained in 16% yield (7.0 mg). LC/MS (uplc): MrT 706.4, 1.35 min.
  • 67
  • [ 1342804-36-7 ]
  • [ 36394-75-9 ]
  • [ 1342804-40-3 ]
  • [ 1342804-38-9 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; 5.B Step B: Amide Bond Formation[001711 To a solution of crude (+/-)-2-((2S)-4-(l-(5-benzyl-2-(2,5- difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)- 1 -fluorobutan-2-yl)isoindoline- 1 ,3- dione (39 mg, 0.068 mmol) in dichloromethane (0.5 mL) at room temperature was added DIEA (52 μ, 0.29 mmol). (5)-l-Chloro-l-oxopropan-2-yl acetate (28 μ, 0.22 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCCb solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude diastereomers were purified by preparative TLC. The polar compound on TLC, (5)-l-(((j?)-l-(5-benzyl-2-(2,5- difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)((iS)-3-(l,3-dioxoisoindolin-2-yl)-4- fluorobutyl)amino)-l-oxopropan-2-yl acetate, was obtained in 17% (8 mg). LC MS (uplc) MH+ 690.3, 1.27 min. The nonpolar one, (S -l-(((iS)- l -(5-benzyl-2-(2,5- difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)((S)-3-(l,3-dioxoisoindolin-2-yl)-4- fluorobutyl)amino)- 1 -oxopropan-2-yl acetate, was obtained in 17% (8 mg). LC MS (uplc) MH* 690.3, 1.28 min.
  • 68
  • [ 1366050-52-3 ]
  • [ 36394-75-9 ]
  • [ 1366050-53-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 2h; 1 To a solution of 8-chloro-1 -(pipehdin-4-yl)-1 H-[1 ,2,3]thazolo[4,5-c][1 ,5] naphthyhdine hydrochloride (1 g, 3.08 mmol) in 10ml_ of CH2CI2 was added (S)-1 - chloro-1 -oxopropan-2-yl acetate(1 .4 g, 9.23 mmol) and Et3N (2.2 mL ). After the mixture was stirred at room temperature for 2h, it was quenched with water (10 mL). The resulting mixture was extracted with CH2CI2 (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, and then was concentrated in vacuo to afford the (S)-1 -(4-(8-chloro-1 H-[1 ,2,3]triazolo[4,5-c][1 ,5]naphthyridin-1 -yl) piperidin-1 -yl) -1 - oxopropan-2-yl acetate (1 .2 g). MS (m/z): 403 (M+H)+.
1.2 g With triethylamine In dichloromethane at 20℃; for 2h; 1 EXAMPLE 1 Synthesis of Compounds 1-20 Compound 1 (S)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (1 g, 3.08 mmol) in 10 mL of CH2Cl2 was added (S)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et3N (2.2 mL). After the mixture was stirred at room temperature for 2 h, it was quenched with water (10 mL). The resulting mixture was extracted with CH2Cl2 (2*20 mL). The combined organic layer was dried over anhydrous Na2SO4, and then was concentrated in vacuo to afford the (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g). MS (m/z): 403 (M+H)+.
  • 69
  • 8-((6-bromobenzo[d][1,3]dioxol-5-yl)thio)-9-(2-(piperidin-4-yl)ethyl)-9H-purin-6-amine [ No CAS ]
  • [ 36394-75-9 ]
  • [ 958025-66-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 8-((6-bromobenzo[d][1,3]dioxol-5-yl)thio)-9-(2-(piperidin-4-yl)ethyl)-9H-purin-6-amine; (S)-2-acetoxypropanoyl chloride With triethylamine In tetrahydrofuran; dichloromethane at 20℃; Stage #2: With silver carbonate In methanol; dichloromethane for 6h; [0139] Step 5: (25)-l-[4-(2-{6-amino-8-[(6-bromo-l,3-benzodioxol-5-yl)sulfanyl]-9H-purin- 9-yl} ethyl)piperidin- 1 -yl] -2-hydroxypropan- 1 -one :[0140] To a suspension of 8-[(6-bromo-l ,3-benzodioxol-5-yl)sulfanyl]-9-[2-(piperidin-4- yl)ethyl]-9H-purin-6-amine (6.3 mmol, 3.0 g) in DCM-THF (15 mL, 1 : 1) was added triethyl amine (18.9 mmol, 2.63 mL) followed by [(15)-2-chloro-l-methyl-2-oxo-ethyl] acetate (7.56 mmol, 957 μ) at room temperature drop wise. After complete addition of [(15)-2-chloro-l- methyl-2-oxo-ethyl] acetate, the mixture was kept at room temperature stirring overnight. At the end of this period the reaction mixture was diluted with CHCI3 (60 mL) washed with sat. aq. NaHC03 solution (50 mL), followed by brine (50 mL). The organic layer was dried over Na2S04, filtered and the solvent was evaporated under reduced pressure. The product was purified by trituration with MeOH. The above product (3.89 mmol, 2.3 g) was taken in MeOH- DCM (25 mL, 1 : 1) and added K2C03 (7.79 mmol, 1.07 g) and stirred for 6 h. The product was crashed out as solid. The reaction mixture was filtered to collect product as solid along with K2C03. The solid was then washed with water and dried to afford (25)-l-[4-(2-{6-amino-8-[(6- bromo- 1 ,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl} ethyl)piperidin-l -yl]-2-hydroxypropan- 1 - one. 1H NMR (CD3OD) δ 8.31 (s, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 6.09 (s, 2H), 4.60-4.45 (m, 2H), 4.37 (t, J = 7.8 Hz, 2H), 4.00 (d, J= 12.0 Hz, 1H), 3.10-2.98 (m, 1H), 2.70-2.56 (m, 1H), 1.96-1.79 (m, 4H), 1.70-1.55 (m, 1H), 1.30 (dd, J = 7.0, 10.1 Hz, 3H), 1.26-1.10 (m, 2H); LC- MS [M+H]+ 549.1
  • 70
  • [ 35453-19-1 ]
  • [ 36394-75-9 ]
  • (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% In ISOPROPYLAMIDE; at 20 - 50℃; for 22h; Example 2:Preparation of (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophtha)ic acid; (S)-1-chloro-1-oxopropan-2-yl acetate (37.4 ml^ 295.4 mmol) was added slowly to a suspension of <strong>[35453-19-1]5-amino-2,4,6-triiodoisophthalic acid</strong> (50.0 g, 89.5 mmol) in DMA (100 ml) at a temperature of between 25 C and 29 C. The resulting mixture was heated to about 50 C and stirred at this temperature for about 8 hours after which heating was removed and the mixture was stirred for about 14 hours at room temperature. The reaction mixture was added slowly over water (500 ml) with strong stirring at a temperature between 22 C and 30 C. After addition 300 ml of water were added to the suspension. The suspension was stirred for 5 further hours at about 22 C after which the white solid was filtered and washed with water previously cooled at about 5 C twice (30 ml each time). The product was dried in a vacuum oven at about 50 C to yield (S)-5-(2-acetoxypropanamido)~2,4,6~triiodoisophthaiic acid (48.8 g, 72.5 mmol). Yield: 81 %[alpha]43620 = -21.69 (99.25 mg/ml, Ethanol)Purity by HPLC: 99.4 % (HPLC conditions as used for example 1)Melting point: 214.7 C (with decomposition)
81% In N,N-dimethyl acetamide; at 20 - 50℃; for 22h; (S)-1-chloro-1-oxopropan-2-yl acetate (37.4 ml, 295.4 mmol) was added slowly to a suspension of <strong>[35453-19-1]5-amino-2,4,6-triiodoisophthalic acid</strong> (50.0 g, 89.5 mmol) in DMA (100 ml) at a temperature of between 25 C. and 29 C. The resulting mixture was heated to about 50 C. and stirred at this temperature for about 8 hours after which heating was removed and the mixture was stirred for about 14 hours at room temperature. The reaction mixture was added slowly over water (500 ml) with strong stirring at a temperature between 22 C. and 30 C. After addition 300 ml of water were added to the suspension. The suspension was stirred for 5 further hours at about 22 C. after which the white solid was filtered and washed with water previously cooled at about 5 C. twice (30 ml each time). The product was dried in a vacuum oven at about 5.0 C. to yield (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid (48.8 g, 72.5 mmol). [0018] Yield: 81% [0019] [alpha]43620=-21.69 (99.25 mg/ml, Ethanol) [0020] Purity by HPLC: 99.4% (HPLC conditions as used for example 1) [0021] Melting point: 214.7 C. (with decomposition)
  • 71
  • C19H19(2)H2BrN6O2S*C2HF3O2 [ No CAS ]
  • [ 36394-75-9 ]
  • [ 1425565-38-3 ]
YieldReaction ConditionsOperation in experiment
147 mg With triethylamine In tetrahydrofuran; dichloromethane at 0℃; for 12h; Inert atmosphere; Step 4: (2S)-1-[4-(2-{6-amino-8-[(6-bromo-2,2-d2-benzo[d][1,3]dioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate A solution of tent-Butyl 4-(2-{6-amino-8-[(6-bromo-2,2-d2-benzo[d][1,3]dioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidine-1-carboxylate (190 mg, 0.328 mmol) in CH2Cl2 (3 mL) was treated with TFA (487 μL, 6.56 mmol) at 0° C. After stirring for 8 h at rt, the mixture was concentrated under vacuum and the residual TFA was removed by an azeotrope with toluene to afford the Boc deprotected product as a TFA salt which was directly used for the next step without further purification. A suspension of the crude compound (290 mg) in a mixture of THF (3.3 mL) and CH2Cl2 (1.3 mL) was treated with NEt3 (182 μL, 1.31 mmol) at 0° C., followed by (S)-(-)-2-acetoxypropionyl chloride (46 μL, 0.36 mmol). After stirring for 12 h at rt, the mixture was diluted with CH2Cl2, washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by trituration using EtOAc to yield the title compound (147 mg, 75%, two steps); TOF LC/MS [M+H]+ 593.11.
  • 72
  • N-(3-(1H-imidazol-1-yl)propyl)-2-(isopentylamino)thiazole-5-carboxamide [ No CAS ]
  • [ 36394-75-9 ]
  • (2S)-1-[(5-[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)(3-methylbutyl)amino]-1-oxopropan-2-yl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine In dichloromethane at 25℃; for 2h; 153 General procedure: Example 6B (0.2 g, 0.556 mmol) was dissolved in dichloromethane (2.7 ml) and pyridine (0.3 ml) and was treated dropwise with a solution of 3-methylbutanoyl chloride (0.102 ml, 0.835 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred at 25 °C for 2 hours, concentrated, and purified using reverse phase HPLC (Phenomenex Luna C8(2) 5 um ΙΟθΑ AXIA column (30mm x 75mm) run with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0- 10.0 min 95% A, 10.0-12.0 min linear gradient 95- 10% A) to afford the title compound.
  • 73
  • (3R,4R)-tert-butyl 3-((((R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2.08333h; Inert atmosphere; 13 (3R,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-1 -(1 -benzyl-4-(2,5-dif luorophenyl)-1 H- imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)propanamido)methyl)-4-fluoropyrrolidine-1- carboxylate (3R,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-1 -(1 -benzyl-4-(2,5-dif luorophenyl)-1 H- imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)propanamido)methyl)-4-fluoropyrrolidine-1- carboxylate Under N2: (3R,4R)-tert-butyl 3-((((R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2-yl)- 2,2-dimethylbut-3-en-1-yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate (3.03 g, 5.33 mmol) in CH2CI2 (50 mL) at 0 C was added DIPEA (4.65 ml, 26.6 mmol) followed by (S)- 2-acetoxy propionyl chloride (1.349 ml, 10.66 mmol). The resulting solution was stirred at 0°C for 5min then warmed up to RT and stirred for 2h. Reaction mixture was diluted with DCM and washed with sat. NaHC03 then sat. NaCI. The organic layer was dried, concentrated and absorbed onto isolute. The desired product was obtained after purification by column chromatography (120 g silica gel, 0 to 50 % EtOAc in Heptane, 3.143 g, 4.6 mmol, 86%) as a colorless solid. LC/MS (Method A): MH+ 683.3, 1.51 min.
  • 74
  • (3R,4S)-tert-butyl 3-((((S)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2-methoxy-2-methylpropyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((S)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2-methoxy-2-methylpropyl)propanamido)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; 23 (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((S)-1-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol- 2-yl)-2-methoxy-2-methylpropyl)propanamido)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate. (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((S)-1-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol- 2-yl)-2-methoxy-2-methylpropyl)propanamido)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate. For the preparation of this compound, follow procedure described for analogous compound of the THP series. Crude purified by normal phase column chromatography (PrepLC Method A). LC/MS (uplc): M+ 799.5, 1.69 min (Method A).
  • 75
  • (3R,4S)-tert-butyl 3-((((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1.58333h; 25 (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1 -carboxylate (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1 -carboxylate To a solution of (3R,4S)-tert-butyl 3-((((R)-(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (1.79 g, 2.57 mmol) in dry DCM (26 ml) was slowly added at 0°C N-ethyl-N-isopropylpropan-2-amine (0.63 ml, 3.60 mmol) followed by (S)-1-chloro-1-oxopropan-2-yl acetate (0.36 ml, 2.83 mmol). The reaction mixture was stirred at 0 °C for 5 mins then allowed to warm to RT and was stired for an additional 1.5h. The reaction was quenched with a saturated aqueous solution of NaHC03 and extracted with DCM. The organic extractes were combined, dried over Na2S04, filtered and concentrated to dryness. Purification of the crude product by chromatography on silica elutuing with 0 - 100% ethylacetate in heptane afforded the title compound as an pale yellow oil in 88% yield; UPLC-MS: Rt = 1.63 mins; MS m/z [M+H]+ 81 1.2; Method A.
  • 76
  • (3S,4R)-tert-butyl 3-((((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3S,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane at 20℃; for 1.5h; 25 (3S,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-( 1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1 -carboxylate (3S,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-( 1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1 -carboxylate quantitative yield; UPLC-MS: Rt = 1.63 mins; MS m/z [M+H]+ 81 1.0; Method A.
  • 77
  • (3R,4S)-tert-butyl 3-((((R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With triethylamine In dichloromethane at 20℃; for 1.5h; 26 (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-1 -(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol- 2-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1 - carboxylate (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-1 -(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol- 2-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1 - carboxylate 39% yield; UPLC-MS: Rt = 3.86 mins; MS m/z [M+H]+ 783.6; Method E.
  • 78
  • (3R,4R)-tert-butyl 3-((((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; 29 (3R,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)propanamido)methyl)-4-fluoropyrrolidine- 1-carboxylate (3R,4R)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)propanamido)methyl)-4-fluoropyrrolidine- 1-carboxylate 87% yield; UPLC-MS: Rt = 3.05 mins; MS m/z [M+H]+ 804.5; Method E.
  • 79
  • benzyl 4-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)((((3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)methyl)amino)methyl)piperidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • benzyl 4-((R)-((S)-2-acetoxy-N-(((3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)methyl)propanamido)(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; 30 benzyl 4-((R)-((S)-2-acetoxy-N-(((3R,4R)-1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl)methyl)propanamido)(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)methyl)piperidine-1 -carboxylate benzyl 4-((R)-((S)-2-acetoxy-N-(((3R,4R)-1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl)methyl)propanamido)(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)methyl)piperidine-1 -carboxylate 76% yield; UPLC-MS: Rt = 3.15 mins; MS m/z [M+H]+ 832.5; Method E.
  • 80
  • (3R,4S)-tert-butyl 3-((((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; 31 (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-(((tert- butyldimethylsilyl)oxy)methyl) pyrrolidine-1 -carboxylate (3R,4S)-tert-butyl 3-(((S)-2-acetoxy-N-((R)-(1-benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)propanamido)methyl)-4-(((tert- butyldimethylsilyl)oxy)methyl) pyrrolidine-1 -carboxylate To a solution of (3R,4S)-tert-butyl 3-((((R)-(1 -benzyl-4-(2,5-difluorophenyl)-1 H-imidazol-2- yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-4-(((tert-butyldimethylsilyl)oxy)m pyrrolidine-1 -carboxylate (3.9 g, 5.49 mmol) in DCM (55 ml) at 0°C was added diisopropylethylamine (1 .34 ml, 7.68 mmol) followed by (S)-1 -chloro-1 -oxopropan-2-yl acetate (0.83 ml, 6.58 mmol) and the reaction mixture was allowed to warm to RT and was stirred for 16h. The reaction was extracted with DCM and was washed with saturated aqueous NaHC03 solution. The organic extracts were combined, dried over Na2S04, filtered and concentrated to dryness. Purification of the crude product by chromatography on silica elutuing with 0 - 100% ethylacetate in heptane afforded the title compound as an pale yellow oil in 78% yield; UPLC-MS: Rt = 3.54 mins; MS m/z [M+H]+ 825.6; Method E.
  • 81
  • (3R,4R)-benzyl 3-((((R)-1-(4-(2,5-difluorophenyl)-1-(3-(methoxymethoxy)benzyl)-1H-imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(4-(2,5-difluorophenyl)-1-(3-(methoxymethoxy)benzyl)-1H-imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.545 g With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; 35 (3R.4R)-benzyl 3-(S)-2-acetoxy-N-((R)-1 -(4-(2.5-dif luorophenylH -(3- (methoxymethoxy)benzyl)-1 H-imidazol-2-yl)-2,2-dimethylbut-3-en-1- yl)propanamido)methyl)-4-fluoropyrrolidine-1 -carboxylate (3R.4R)-benzyl 3-(S)-2-acetoxy-N-((R)-1 -(4-(2.5-dif luorophenylH -(3- (methoxymethoxy)benzyl)-1 H-imidazol-2-yl)-2,2-dimethylbut-3-en-1- yl)propanamido)methyl)-4-fluoropyrrolidine-1 -carboxylate A solution of (3R,4R)-benzyl 3-((((R)-1-(4-(2,5-difluorophenyl)-1-(3- (methoxymethoxy)benzyl)-1 H-imidazol-2-yl)-2,2-dimethylbut-3-en-1- yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate_(3.85g) in anhydrous DCM (50ml_) was cooled to 0°C with an ice bath. To this solution was addded DIPEA (1.978ml_) and (S)-1-Chloro-1-oxopropan-2-yl acetate (0.956ml_, Fluka) - cloudy fumes observed. The dark-orange coloured reaction mixture was allowed to warm to room temperature and stirring continued for 1 hour - by which time LC-MS showed reaction to be complete with conversion to desired product. The volatiles were removed under high vacuum and the crude material purified directly as follows: System : Biotage SP4 Normal Phase Purification System Stationary Phase: 40+M Silica Cartridge Binary Solvent System: Polar Solvent : ethyl acetate, Non-Polar Solvent : n-heptane Stepwise Gradient : 1. 0% Polar solvent -> Maintained for 10 Minutes 2. 0% Polar Solvent -> Ramped to 46% Polar Solvent over 20 Minutes 3. 46% Polar solvent -> Maintained for 30 Minutes - By this stage, all desired product had already eluted from the column. The run was stopped at this point. Product containing fractions were combined and concentrated in vacuo to give a brown oil Yield : 2.545g - 95% Pure by LC-MS. UPLC-MS: Rt = 1.49 min; MS m/z [M+H]+ 777.5; Method A.
  • 82
  • (3R,4R)-benzyl 3-((((R)-1-(4-(2,5-difluorophenyl)-1-(3-fluoro-5-(methoxymethoxy)benzyl)-1H-imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
  • [ 36394-75-9 ]
  • (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(4-(2,5-difluorophenyl)-1-(3-fluoro-5-(methoxymethoxy)benzyl)-1H-imidazol-2-yl)-2,2-dimethylbut-3-en-1-yl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.4 g With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; 35 (3R.4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1 -(4-(2.5-difluorophenyl)-1 -(3-fluoro-5- (methoxymethoxy)benzyl)-1 H-imidazol-2-yl)-2,2-dimethylbut-3-en-1- yl)propanamido)methyl)-4-fluoropyrrolidine-1 -carboxylate (3R.4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1 -(4-(2.5-difluorophenyl)-1 -(3-fluoro-5- (methoxymethoxy)benzyl)-1 H-imidazol-2-yl)-2,2-dimethylbut-3-en-1- yl)propanamido)methyl)-4-fluoropyrrolidine-1 -carboxylate A solution of (3R,4R)-benzyl 3-((((R)-1-(4-(2,5-difluorophenyl)-1-(3-fluoro-5- (methoxymethoxy)benzyl)-1 H-imidazol-2-yl)-2,2-dimethylbut-3-en-1- yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate_(1.2g) in anhydrous DCM (20ml_) was cooled to 0°C with an ice bath. To this solution was addded DIPEA (0.822ml_) and (S)-1-Chloro-1-oxopropan-2-yl acetate (0.397ml_, Fluka) - cloudy fumes observed. The dark-orange coloured reaction mixture was allowed to warm to RT and stirring continued for 1 hour - by which time LC-MS showed reaction to be complete with conversion to desired product. The reaction mixture was then partitioned between de-ionised water ( 100ml_) and dichloromethane (70ml). After extraction, the aqueous phase was re- extracted with dichloromethane (70ml_). The combined organics were then washed with sat. brine ( 100ml_), dried over MgSC>4, filtered through No.1 filter paper and concentrated in vacuo to give a dark orange-coloured oil. Yield: 1 .4g UPLC-MS: Rt = 1 .46 min; MS m/z [M+H]+ 796.5; Method A. The material was of suitable purity to be used directly in the next step without need for further purification.
  • 83
  • [ 31166-44-6 ]
  • [ 36394-75-9 ]
  • C17H22N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In acetonitrile at 0 - 0.25℃; for 0.5h; Inert atmosphere; Intermediate AB: Preparation of (S)-2-Hydroxy-l-piperazin-l-yl-propan-l-one (AB) To a solution of AB-1 (1.0 g, 4.5 mmol) and TEA (1.3 mL, 9.1 mmol) in MeCN (25 mL) at 0 °C is added AB-2 (0.7 g, 4.5 mmol). The resultant mixture is warmed to ambient temperature, stirred for 30 min, poured into ice water, and extracted with EtOAc. The organic layer is extracted with saturated aqueous NaHCC>3 and brine, dried over Na2S04, filtered and concentrated to afford AB-3. To a solution of AB-3 (1.3 g, 3.8 mmol) in a mixture of dioxane (10 mL) and water (10 mL) is added LiOH (0.40 g, 9.7 mmol). The resultant mixture is stirred for 2 h, neutralized with concentrated HCl, and extracted with EtOAc .The organic layer is dried over Na2S04, filtered and concentrated to give AB-4. To a solution of AB-4 (1.3 g, 4.4 mmol) in EtOH (25 mL) is added 10% Pd/C (0.3 g). The mixture is stirred for 4 h under an atmosphere of H2, filtered through a pad of diatomaceous earth, and concentrated to give the title product (AB).
  • 84
  • 2-(3,8-diaza-bicyclo[3.2.1]oct-8-ylmethyl)-6-{5-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-pyridin-2-yloxy}-quinoline [ No CAS ]
  • [ 36394-75-9 ]
  • C35H44N6O5Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.25℃; for 13h; Inert atmosphere; 57 Example 57: Preparation of (S)-2-Hydroxy-l-(8-{6-[5-(2H-pyrazol-3-yl)-pyridin-2- yloxy]-quinolin-2-ylmethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-propan-l-one (57)To a solution of N (100 mg, 0.184 mmol) in DMF (1 mL) is added 57-1 (35.0 JL, 0.276 mmol) followed by DIPEA (98.4 μL·, 0.553 mmol) at ambient temperature. After 13 h, the crude reaction mixture is purified on RP-HPLC (CI 8 column, Solvents = MeCN+0.1 TFA : H2O+0.1 TFA; Gradient = 5:95 to 95:5 over 20 min; Flow rate = 30 mL/min). The desired fractions are pooled and lyophilized. The residue is dissolved in MeOH, passed through a PL-HC03 cartridge, and concentrated to give 57-2. To a solution of 57-2 (105.8 mg, 0.161 mmol) in Methanol (5 mL) is added a solution of NaOMe in MeOH (0.5 M, 322 μ,, 0.161 mmol). The reaction is stirred for 18 h, neutralized with AcOH, and concentrated to give 57-3, which is dissolved in DCM (1 mL) and treated with TFA (300 μ). The resultant mixture is stirred at ambient temperature for 3 h, concentrated, and purified on RP-HPLC (CI 8 column, Solvents = MeCN+0.1 TFA : H2O+0.1 TFA; Gradient = 5:95 to 95:5 over 20 min; Flow rate = 30 mL/min). The desired fractions are pooled and lyophilized. The residue is dissolved in MeOH, passed through a PL-HC03 cartridge, and concentrated to give the title product (57).
  • 85
  • 6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ No CAS ]
  • [ 36394-75-9 ]
  • (S)-1-oxo-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-2-yl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% With pyridine In dichloromethane for 1h; 173.A Step A 6-( 1 -(Azetidin-3-yl)- 1 H-pyrazol-4-yl)-4-( 1 -(pentan-3-yl)- 1 H-pyrazol-4-yl)pyrazolo{1,5-ajpyrazine (30 mg, 0.080 mmol) was dissolved in CH2C12 (1 mL) and pyridine (25.7 j.iL, 0.32 mmol) was added, followed by (S)-1-chloro-1-oxopropan-2-yl acetate (20.2 1iL, 0.16 mmol). After stirring for 1 hour, the reaction mixture was quenched with water (0.1 mL) and concentrated. The residue was purified by reverse phase chromatography (C18, 10-95% CH3CN in water) to afford (S)- 1 -oxo- 1 -(3 -(4-(4-( 1 -(pentan-3 -yl)- I H-pyrazol-4-yl)pyrazolo [1,5- ajpyrazin-6-yl)- 1 H-pyrazol- 1 -yl)azetidin- 1 -yl)propan-2-yl acetate (25 mg, 64% yield).
  • 86
  • [ 1267986-38-8 ]
  • [ 36394-75-9 ]
  • (S)-4-chloro-N-(2-acetoxypropionyl)deacetyl colchicine [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine In dichloromethane at 20℃; Cooling with ice; Inert atmosphere; 125 Synthesis of (S)-4-chloro-N-(2-acetoxypropionyl)deacetyl colchicine To the dichloromethane (5 mL) of 4-chloro deacetyl colchicine (100 mg, 0.255 mmol), (S)-2-acetoxypropionic acid chloride (35.5 muL, 0.255x1.1 mmol) and triethylamine (39.1 muL, 0.255x1.1 mmol) were added and stirred overnight and returning to a room temperature gradually under ice-cooling and argon gas atmosphere. The reaction mixture was purified by flash chromatography (equipment: Biotage Isolera One, and chloroform/methanol) to obtain title compound (an opalescence solid, 123 mg, 0.243mmol, 95%) .
  • 87
  • C18H21N5 [ No CAS ]
  • [ 36394-75-9 ]
  • C23H27N5O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
47% With pyridine In dichloromethane at -15℃; for 0.5h; Inert atmosphere; 34.1 Step 1: A solution of (S)-1-chloro-1-oxopropan-2-yl acetate (240 mg,1.6 mmol, 2.0 eq) in DCM (3 mL) was added dropwise to a mixture of compound 28-14 (250 mg, 0.81 mmol, 1.0 eq) and pyridine (165 uL, 2.0 mmol, 2.5 eq) in DCM (10 mL) at -15 °C under a nitrogen atmosphere. The reaction was stirred at this temperature for 0.5 hr. The reaction mixture was diluted with a saturated solution of NaHCO3 (15 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prepTLC (10% MeOH in DCM) to afford compound 34-10 (250 mg, 0.39 mmol, 47% yield) as a yellow solid. ESI m/z 422.2 [M÷1].
  • 88
  • [ 36394-75-9 ]
  • N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine -2,3-diamine [ No CAS ]
  • (S)-1-[3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
59.8 g Stage #1: (S)-2-acetoxypropanoyl chloride; N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine -2,3-diamine With pyridine at 20℃; for 0.5h; Stage #2: With sodium hydroxide In ethanol; water at 20℃; for 4.5h; 5.1 Step 1: Synthesis of (S) -1- [3-methyl-6- (trifluoromethyl) -3H-imidazo [4,5- b] pyridin-2-yl]ethanol To a mixed solution of 37.7 g of N 2 -methyl-5- (trifluoromethyl) pyridine-2,3-diamine and 150 ml of pyridine,At -20 ° C., 32.8 g of (S) - (-) - 2-acetoxypropionyl chloride was added.After completion of the addition,The mixture was stirred at room temperature for 30 minutes.After completion of stirring, the solvent was distilled off under reduced pressure.The obtained residue was dissolved in 150 ml of ethanol, and 39.4 ml of 10 mol / L sodium hydroxide aqueous solution was added at room temperature. After completion of the addition, the reaction mixture was stirred under heating reflux for 2 hours. After completion of the stirring, 20 ml of a 10 mol / L sodium hydroxide aqueous solution was added to the reaction mixture at room temperature. After completion of the addition, the mixture was stirred under heating reflux for 4.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. 12 mol / L hydrochloric acid was added to the obtained residue to adjust the pH to 4, and then extraction with ethyl acetate (100 ml × 2) was carried out. The obtained organic layer was dried over anhydrous sodium chloride and then anhydrous sodium sulfate in this order, then dried, and the solvent was distilled off under reduced pressure to obtain 59.8 g of the objective compound as a black solid.
59.8 g Stage #1: (S)-2-acetoxypropanoyl chloride; N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine -2,3-diamine With pyridine at -20 - 20℃; for 0.5h; Stage #2: With water; sodium hydroxide In ethanol for 6.5h; Reflux; 12.1 Step 1: Synthesis of (S)-1-[3-methyl-6-(trifluorom- ethyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethanol j1180] 37.7 g of N2-methyl-5-(trifluoromethyl)pyridine-2, 3-diamine was dissolved in 150 ml of pyridine, and 32.8 g of(S)-(-)-2-acetoxypropionyl chloride was added at -20° C. Afier the addition, the reaction mixture was stirred at room temperature for 30 minutes. Afier the stirring, the solvent was evaporated from the reaction mixture under reduced pressure. The resulting residue was dissolved in 150 ml of ethanol, and 39.4 ml of a 1OM sodium hydroxide aqueoussolution was added at room temperature. After the addition,the reaction mixture was stirred under reflux with heating for 2 hours. Afier the stirring, 20 ml of a 1OM sodium hydroxide aqueous solution was added to the reaction mixture at room temperature. Afier the addition, the reaction mixture was stirred under reflux with heating for 4.5 hours. After the reaction, the solvent was evaporated from the reaction mixture under reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid to adjust the aqueous solution to have a pH of 4, and extracted with ethyl acetate (100 mlx2). The resulting organic layer was dehydrated with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 59.8 g of the desired (5)-i -[3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethanol as a black solid.11181] ‘H-NMR(CDC13): ö8.65 (s, 1H), 8.23 (s, 1H), 5.20 (brs, 1H), 3.97 (s, 3H), 2.99 (brs, 1H), 1.75 (d, J=6.3 Hz, 3H).
59.8 g Stage #1: (S)-2-acetoxypropanoyl chloride; N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine -2,3-diamine With pyridine In N,N-dimethyl-formamide at -20 - 20℃; for 0.5h; Stage #2: With water; sodium hydroxide In ethanol at 20℃; for 6.5h; Reflux; 1.1 Step 1: (S) -1 - [3-methyl-6- (trifluoromethyl) -3H-imidazo [ 4,5-b] pyridin-2-yl] ethanol 37.7 g of N 2 -methyl-5- (trifluoromethyl) pyridine-2,3-diamine (S) - (-) - 2-acetoxypropionyl chloride was added at -20 ° C. to a mixed solution of 150 ml of N, N-dimethylformamide and 150 ml of pyridine. After the addition was completed, the reaction mixture was stirred at room temperature for 30 minutes. After completion of stirring, the solvent was distilled off under reduced pressure.The obtained residue was dissolved in 150 ml of ethanol, and 39.4 ml of 10 mol / L sodium hydroxide aqueous solution was added at room temperature. After completion of the addition, the reaction mixture was stirred under heating reflux for 2 hours. After completion of stirring, the reaction mixture 20 ml of 10 mol / L sodium hydroxide aqueous solution was added to the mixture at room temperature. After completion of the addition, the reaction mixture was stirred under heating reflux for 4.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. 12 mol / L hydrochloric acid was added to the obtained residue to adjust the pH to 4, and then extraction with ethyl acetate (100 ml × 2) was carried out. The obtained organic layer was dried over anhydrous sodium chloride and then anhydrous sodium sulfate in this order, then dried, and the solvent was distilled off under reduced pressure to obtain 59.8 g of the objective compound as a black solid.
59.8 g Stage #1: (S)-2-acetoxypropanoyl chloride; N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine -2,3-diamine With pyridine at -20 - 20℃; for 0.5h; Stage #2: With sodium hydroxide In ethanol; water for 6.5h; Reflux; 1.1 Synthesis of (S) -1- [3-methyl-6- (trifluoromethyl) -3H-imidazo [4,5-b] pyridin-2-yl] ethanol N2-methyl-5- (trifluoromethyl) pyridine-2,3-diamine37.7 g and pyridine 150 ml, 32.8 g of (S) - (-) - 2-acetoxypropionyl chloride was added at -20 ° C. After the addition was completed, the reaction mixture was stirred at room temperature for 30 minutes. After completion of stirring, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 150 ml of ethanol, and 39.4 ml of 10 mol / L sodium hydroxide aqueous solution was added at room temperature. After completion of the addition, the reaction mixture was stirred under heating reflux for 2 hours. After completion of the stirring, 20 ml of a 10 mol / L sodium hydroxide aqueous solution was added to the reaction mixture at room temperature. After completion of the addition, the reaction mixture was stirred under heating reflux for 4.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. 12 mol / L hydrochloric acid was added to the obtained residue to adjust the pH to 4, and then extraction with ethyl acetate (100 ml × 2) was carried out. The obtained organic layer was dried over anhydrous sodium chloride and then anhydrous sodium sulfate in this order, then dried, and the solvent was distilled off under reduced pressure to obtain 59.8 g of the objective compound as a black solid.
59.8 g Stage #1: (S)-2-acetoxypropanoyl chloride; N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine -2,3-diamine With pyridine at -20 - 20℃; for 0.5h; Stage #2: With sodium hydroxide In water at 20℃; for 6.5h; Reflux; 12.1 Step 1: Synthesis of (S)-1-[3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethanol 37.7 g of N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine was dissolved in 150 ml of pyridine, and 32.8 g of (S)-(-)-2-acetoxypropionyl chloride was added at -20°C. Was added. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. After completion of stirring, the solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was dissolved in 150 ml of ethanol, and 39.4 ml of 10M sodium hydroxide aqueous solution was added at room temperature.Was added. After the addition was completed, the reaction mixture was stirred with heating under reflux for 2 hours. After completion of stirring, 20 ml of a 10 M aqueous sodium hydroxide solution was added to the reaction mixture at room temperature. After the addition was completed, the reaction mixture was stirred with heating under reflux for 4.5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. Concentrated hydrochloric acid was added to the obtained residue to adjust the pH of the aqueous solution to 4, and then the mixture was extracted with ethyl acetate (100 ml×2). The obtained organic layer was dehydrated and dried in this order with saturated saline and then with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.59.8 g of the desired product, (S)-1-[3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethanol, was obtained as a black solid.

  • 89
  • N<SUP>3</SUP>-methyl-6-(trifluoromethyl)pyridine-3,4-diamine [ No CAS ]
  • [ 36394-75-9 ]
  • (S)-1-[3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl]ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
3 g Stage #1: N<SUP>3</SUP>-methyl-6-(trifluoromethyl)pyridine-3,4-diamine; (S)-2-acetoxypropanoyl chloride With pyridine at -20 - 20℃; for 0.333333h; Stage #2: With water; sodium hydroxide In ethanol for 3h; Reflux; 13.1 Step 1: Synthesis of (S)-1-[3-methyl-6-(trifluorom- ethyl)-3H-imidazo[4,5-c]pyridin-2-yl]ethanol 11188] 3.34 g of N3-methyl-6-(trifluoromethyl)pyridine-3, 4-diamine was dissolved in 20 ml of pyridine, and 2.89 g of (S)-(-)-2-acetoxypropionyl chloride was added at -20° C. Afier the addition, the reaction mixture was stirred at room temperature for 20 minutes. Afier the stirring, the solvent was evaporated from the reaction mixture under reduced pressure. The resulting residue was dissolved in 20 ml of ethanol, and 3.5 ml of a 1OM sodium hydroxide aqueous solution was added at room temperature. After the addition, the reaction mixture was stirred under reflux with heating for one hour. After the stirring, 1.8 ml of a 1 OM sodium hydroxide aqueous solution was added to the reaction mixture at room temperature. Afier the addition, the reaction mixture was stirred under reflux with heating for 2 hours. Afier the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (50 mlx2). The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography using n-hexane/ ethyl acetate (with a gradient of 100:0 to 50:50) as the eluent to obtain 3.0 g of the desired product as a pale pink solid. 11189] Melting point: 97-100° C.11190] ‘H-NMR (CDC13): ö8.84 (s, 1H), 8.04 (d, J=0.7 Hz, 1H), 5.31-5.14 (m, 1H), 4.02 (s, 3H), 3.03 (d, J=7.2 Hz, 1H), 1.78 (d, J=6.5 Hz, 3H).
3.0 g Stage #1: N<SUP>3</SUP>-methyl-6-(trifluoromethyl)pyridine-3,4-diamine; (S)-2-acetoxypropanoyl chloride With pyridine at -20 - 20℃; for 0.333333h; Stage #2: With sodium hydroxide In water at 20℃; for 3h; Reflux; 13.1 Step 1: Synthesis of (S)-1-[3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl]ethanol 3.34 g of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine was dissolved in 20 ml of pyridine, and 2.89 g of (S)-(-)-2-acetoxypropionyl chloride was added at -20°C. Was added. After the addition was complete, the reaction mixture was stirred at room temperature for 20 minutes. After completion of stirring, the solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was dissolved in 20 ml of ethanol, and 3.5 ml of 10M aqueous sodium hydroxide solution was added at room temperature.It was After the addition was completed, the reaction mixture was stirred with heating under reflux for 1 hour. After completion of stirring, 1.8 ml of 10M aqueous sodium hydroxide solution was added to the reaction mixture at room temperature. After the addition was completed, the reaction mixture was stirred with heating under reflux for 2 hours. After completion of the reaction, 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml×2). The obtained organic layer was dehydrated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue isPurification by medium pressure preparative liquid chromatography eluting with n-hexane-ethyl acetate (gradient of 100:0 to 50:50) gave 3.0 g of the desired product as a pale pink solid.
  • 90
  • [ 36394-75-9 ]
  • Levorphanol [ No CAS ]
  • C22H29NO4*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: (S)-2-acetoxypropanoyl chloride; Levorphanol With triethylamine In dichloromethane at 0 - 5℃; for 2h; Stage #2: With hydrogenchloride In 1,4-dioxane 3-(Acetyl-OCH(CH3)C(O))-levorhanol 30: To a solution 0-acetyl lactyl chloride (0.098 mL, 0.78 mmol) in CH2CI2 (2 mL) was added to a solution of levorphanol 1 (0.1 g, 0.39 mmol) and trimethylamine (0.22 mL, 1 .56 mmol) in CH2CI2 (6 mL) at 0-5°C. After the addition, the reaction mixture was stirred at 5°C for 2 hours. Solvent was evaporated under reduced pressure. The residue was dissolved in CH2CI2 (100 mL) and washed with 5% aqueous NaHCO3 (2 x 60 mL), brine (1 x 60 mL). The CH2CI2 part was dried over anhydrous Na2504 and evaporated to dryness. The crude product was purified by preparative HPLC and converted to the corresponding hydrochloride salt 30 (0.115 g, 72%) by treatment with 2N HCI in dioxane.
  • 91
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • [ 50709-36-9 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 200 mg, 528 muiotaetaomicron) in tetrahydrofuran (2.0 ml) was treated at 0C with N,N-diisopropylethylamine (260 mu, 1.5 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (73 mu, 580 mumol) and stirred at 0C for 1 h. (2,6- Dichlorophenyl)hydrazine hydrochloride (1: 1) (124 mg, 581 muiotaetaomicron) was added in portion and the resulting mixture was stirred at 0C for 1.5 h, overnight at RT, 2 h at refluxed temperature and 4 h at 100C under microwave irradiation. The reaction mixture was evporated and the residue was purified by preparative HPLC (Method 4) affording 123 mg (38% of th.) of the title compound. LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 619.0 [M+H]+-NMR (400 MHz, DMSO-d6) delta [ppm]: 7.86-7.55 (m, 7H), 6.95-6.84 (m, 1H), 5.87-5.71 (m, 1H), 5.22-5.04 (m, 2H), 4.37-4.22 (m, 1H), 4.10-3.77 (m, 2H), 1.84-1.69 (m, 3H), 1.55 (d, 3H).
  • 92
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [2-(difluoromethoxy)phenyl]hydrazine [ No CAS ]
  • [ 36394-75-9 ]
  • (1S)-1-{3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: [2-(difluoromethoxy)phenyl]hydrazine In tetrahydrofuran at 20 - 100℃; Microwave irradiation; Inert atmosphere; 7A (1S)-1-{3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H- 1 ,2,4-triazol- 1 -yl } methyl)- 1 - [2-(difluoromethoxy)phenyl] - 1 H- 1 ,2,4-triazol-5-yl }ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in tetrahydrofuran (1.5 ml) was treated at 0°C with N,N-diisopropylethylamine (210 μ, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μ, 440 μιηο) and stirred at 0°C for 30 min. [2- (Difluoromethoxy)phenyl]hydrazine (75.9 mg, 436 μιηο) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 100°C under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 143 mg (58% of th.) of the title compound.LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 617.1 [M+H]+-NMR (400 MHz, DMSO-d6) δ [ppm] : 7.84-6.77 (m, 10H), 5.79-5.57 (m, 1H), 5.21-4.95 (m, 2H), 4.38-4.20 (m, 1H), 4.10-3.74 (m, 2H), 1.88-1.67 (m, 3H), 1.53 (d, 3H).
  • 93
  • [2-(trifluoromethoxy)phenyl]hydrazine hydrochloride [ No CAS ]
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • (1S)-1-{3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: [2-(trifluoromethoxy)phenyl]hydrazine hydrochloride In tetrahydrofuran at 20 - 120℃; Microwave irradiation; Inert atmosphere; 9A (1S)-1-{3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H- 1 ,2,4-triazol- 1 -yl } methyl)- 1 - [2-(trifluoromethoxy)phenyl] - 1 H- 1 ,2,4-triazol-5-yl } ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in tetrahydrofuran (3.0 ml) was treated at 0°C with N,N-diisopropylethylamine (210 μ, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μ, 440 μιηο) and stirred at 0°C for 30 min. [2- (Trifluoromethoxy)phenyl]hydrazine hydrochloride (1 :1) (99.6 mg, 436 μιηο) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 120°C under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 141 mg (56% of th.) of the title compound. LC-MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 635.3 [M+H]+
  • 94
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • [ 90824-33-2 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(2-sulfamoylphenyl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-hydrazino-benzenesulfonamide In tetrahydrofuran at 20 - 120℃; Microwave irradiation; Inert atmosphere; 11A ( 1 S)- 1 - [3-( { 3-(4-Chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl } methyl)- l-(2-sulfamoylphenyl)- 1H- 1 ,2,4-triazol-5-yl]ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -4,5-dihydro- lH-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in tetrahydrofuran (3.0 ml) was treated at 0°C with N,N-diisopropylethylamine (280 μ, 1.6 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μ, 440 μmol) and stirred at 0°C for 30 min. 2- Hydrazinylbenzenesulfonamide (81.6 mg, 436 μιηο) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 120°C under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 193 mg (76% of th.) of the title compound rotamers.LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 630.3 [M+H]+-NMR (400 MHz, DMSO-d6) δ [ppm] : 8.24-6.72 (m, 11H), 6.13-5.41 (m, 1H), 5.29-4.99 (m, 2H), 4.38-4.20 (m, 1H), 4.09-3.70 (m, 2H), 1.87 (br s, 3H), 1.48 (d, 3H).
  • 95
  • [ 4930-98-7 ]
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: pyrid-2-ylhydrazine In tetrahydrofuran at 20℃; Inert atmosphere; 12A (1S)-1-[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H- l,2,4-triazol-1-yl}methyl)-1-(pyridin-2-yl)-1H-l,2,4-triazol-5-yl]ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 200 mg, 528 μιηο) in THF (2.0 ml) was treated at 0°C with N,N-diisopropylethylamine (280 μ, 1.6 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (79 μ, 580 μιηο) and stirred at 0°C for 30 min. 2- Hydrazinylpyridine (63.4 mg, 581 μιηο) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 199 mg (68% of th.) of the title compound.LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 552 [M+H]+-NMR (500 MHz, DMSO-d6) δ [ppm]: 8.55-8.47 (m, 1H), 8.19-8.02 (m, 1H), 7.83-7.44 (m, 6H), 6.90 (d, 1H), 6.51 (q, 1H), 5.17-5.05 (m, 2H), 4.31 (m, 1H), 4.06-3.81 (m, 2H), 1.89 (s, 3H), 1.62 (d, 3H).
  • 96
  • [ 887266-57-1 ]
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -4,5-dihydro- lH-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 muiotaetaomicron) in THF (1.5 ml) was treated at 0C with N,N-diisopropylethylamine (210 mu, 1.2 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (55 mu, 440 muiotaetaomicron) and stirred at 0C for 30 min. 3-Fluoro-2- hydrazinylpyridine (55.4 mg, 436 muiotaetaomicron) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 152 mg (67% of th.) of the title compound.LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 570 [M+H]+ -NMR (400 MHz, DMSO-d6) delta [ppm]: 8.46 (br. d, 1H), 8.23-8.05 (m, 1H), 7.88-7.53 (m, 5H), 6.89 (d, 1H), 5.93 (q, 1H), 5.12 (m, 2H), 4.30 (m, 1H), 4.08-3.71 (m, 2H), 1.79 (s, 3H), 1.59 (d, 3H).
  • 97
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • [ 22841-92-5 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (3-chloro-2-pyridyl)hydrazine In tetrahydrofuran at 20℃; Inert atmosphere; 16A ( 1 S)- 1 - [3-( { 3-(4-Chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro- 1 H- l,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-l,2,4-triazol-5-yl]ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -4,5-dihydro- lH-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in THF (1.5 ml) was treated at 0°C with N,N-diisopropylethylamine (210 μ, 1.2 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (55 μ, 440 μιηο) and stirred at 0°C for 30 min. 3-Chloro-2- hydrazinylpyridine (62.5 mg, 436 μιηο) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 78.1 mg (34% of th.) of the title compound.LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 586 [M+H]+-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.59 (dd, 1H), 8.32 (dd, 1H), 7.83-7.48 (m, 6H), 6.89 (d, 1H), 5.87 (q, 1H), 5.12 (m, 2H), 4.42-4.21 (m, 1H), 3.98 (d, 1H), 3.85 (dd, 1H), 1.75 (s, 3H), 1.56 (d, 3H).
  • 98
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • [ 27032-63-9 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 muiotaetaomicron) in THF (1.5 ml) was treated at 0C with N,N-diisopropylethylamine (210 mu, 1.2 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (55 mu, 440 muiotaetaomicron) and stirred at 0C for 30 min. 5-Chloro-2- hydrazinylpyridine (62.5 mg, 436 muiotaetaomicron) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 165 mg (71% of th.) of the title compound.LC-MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 586 [M+H]+-NMR (400 MHz, DMSO-d6) delta [ppm] : 8.58 (d, 1H), 8.21 (dd, 1H), 7.89-7.54 (m, 5H), 6.90 (d, 1H), 6.46 (q, 1H), 5.23-5.00 (m, 2H), 4.31 (m, 1H), 4.12-3.76 (m, 2H), 1.92 (s, 3H), 1.61 (d, 3H).
  • 99
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • [ 23589-59-5 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (3-chloropyridin-4-yl)hydrazine In tetrahydrofuran at 20 - 150℃; for 6h; Inert atmosphere; Microwave irradiation; 20A ( 1 S)- 1 - [3-( { 3-(4-Chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro- 1 H- l,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-4-yl)-1H-l,2,4-triazol-5-yl]ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -4,5-dihydro- lH-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in THF (1.5 ml) was treated at 0°C with N,N-diisopropylethylamine (210 μ, 1.2 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (55 μ, 440 μιηο) and stirred at 0°C for 30 min. 3-Chloro-4- hydrazinylpyridine (62.5 mg, 436 μιηο) was then added and the resulting mixture was stirred 3 h at room temperature, followed by 3 h at 150°C in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 133 mg (57% of th.) of the title compound.LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 586 [M+H]+-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.97 (s, 1H), 8.78 (d, 1H), 7.84-7.58 (m, 5H), 6.89 (d, 1H), 5.88-5.72 (m, 1H), 5.13 (m, 2H), 4.40-4.20 (m, 1H), 4.09-3.79 (m, 2H), 1.76 (s, 3H), 1.56 (d, 3H).
  • 100
  • [ 153708-69-1 ]
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • [ 36394-75-9 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (3,5-dichloropyridin-4-yl)hydrazine In tetrahydrofuran at 20 - 150℃; for 6h; Inert atmosphere; Microwave irradiation; 21A ( 1 S)- 1 - [3-( { 3-(4-Chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro- 1 H- l,2,4-triazol-1-yl}methyl)-1-(3,5-dichloropyridin-4-yl)-1H-l,2,4-triazol-5-yl]ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in THF (1.5 ml) was treated at 0°C with N,N-diisopropylethylamine (210 μ, 1.2 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (55 μ, 440 μιηο) and stirred at 0°C for 30 min. 3,5-Dichloro-4- hydrazinylpyridine (77.6 mg, 436 μιηο) was then added and the resulting mixture was stirred 3 h at room temperature, followed by 3 h at 150°C in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 89.6 mg (33% of th.) of the title compound as a mixture of rotamers.LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 620 [M+H]+-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.99 (d, 1H), 7.80-7.51 (m, 5H), 6.88 (m, 1H), 5.81 (q, 1H), 5.15 (m, 2H), 4.43-4.21 (m, 1H), 4.11-3.74 (m, 2H), 1.77 (s, 3H), 1.57 (d, 3H).
  • 101
  • methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate [ No CAS ]
  • 4-chloro-3-hydrazinopyridine hydrochloride salt [ No CAS ]
  • [ 36394-75-9 ]
  • (1S)-1-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% Stage #1: methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate; (S)-2-acetoxypropanoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-chloro-3-hydrazinopyridine hydrochloride salt In tetrahydrofuran at 20 - 150℃; for 6h; Inert atmosphere; Microwave irradiation; 23A ( 1 S)- 1 - [3-( { 3-(4-Chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro- 1 H- l,2,4-triazol-1-yl}methyl)-1-(4-chloropyridin-3-yl)-1H-l,2,4-triazol-5-yl]ethyl acetate Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -4,5-dihydro- lH-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 μιηο) in THF (1.5 ml) was treated at 0°C with N,N-diisopropylethylamine (210 μ, 1.2 mmol) and (2S)-1- chloro-1-oxopropan-2-yl acetate (55 μ, 440 μιηο) and stirred at 0°C for 30 min. 4-Chloro-3- hydrazinylpyridine hydrochloride (78.4 mg, 436 μιηο) was then added and the resulting mixture was stirred 3 h at room temperature, followed by 3 h at 150°C in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 118 mg (51% of th.) of the title compound.LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 586 [M+H]+-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.97-8.65 (m, 2H), 8.01-7.46 (m, 5H), 6.89 (d, 1H), 5.75 (m, 1H), 5.12 (m, 2H), 4.36-4.20 (m, 1H), 4.14-3.76 (m, 2H), 1.79 (s, 3H), 1.55 (d, 3H).
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