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Chemical Structure| 98760-08-8
Chemical Structure| 98760-08-8
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Product Details of [ 98760-08-8 ]

CAS No. :98760-08-8 MDL No. :MFCD00671705
Formula : C15H21NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :NVPOUMXZERMIJK-STQMWFEESA-N
M.W : 263.33 Pubchem ID :9813904
Synonyms :

Calculated chemistry of [ 98760-08-8 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.53
Num. rotatable bonds : 7
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 73.35
TPSA : 50.86 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.03 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.79
Log Po/w (XLOGP3) : 2.64
Log Po/w (WLOGP) : 2.52
Log Po/w (MLOGP) : 1.93
Log Po/w (SILICOS-IT) : 2.83
Consensus Log Po/w : 2.54

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.91
Solubility : 0.326 mg/ml ; 0.00124 mol/l
Class : Soluble
Log S (Ali) : -3.36
Solubility : 0.115 mg/ml ; 0.000438 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.87
Solubility : 0.0359 mg/ml ; 0.000136 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.13

Safety of [ 98760-08-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 98760-08-8 ]

* 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 [ 98760-08-8 ]

[ 98760-08-8 ] Synthesis Path-Downstream   1~85

  • 1
  • ((S)-1-benzylallyl)carbamic acid tert-butyl ester [ No CAS ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
98.7% With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 2h; 1.6 Example 1 (6) Tert-butyl (S)-1-phenyl-3-butene-2-carbamate 6 (103 g, 0.416 mol), m-chloroperbenzoic acid (215.4 g, 1.248 mol), dichloromethane (300 ml) The mixture was allowed to react for 2 h at normal temperature and pressure. After the reaction was completed, it was extracted with diethyl ether (2 x 150 ml), washed with saturated sodium carbonate (2 x 150 ml) and brine (2 x 150 ml), dried, filtered and concentrated under reduced pressure to give a white solid (2R, 3S)-1,2 - Epoxy-3-tert-butoxycarbonylamino-4-phenylbutane 7 (108 g, 98.7%).
97.8% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 1h; 1.6 6th step (2R, 3S) - 1,2-epoxy-3 - (tert-butoxycarbonylamino) - 4-phenyl-butane 7 The (S) - 3 - (tert-butoxycarbonylamino) - 4 phenyl-1-butene 6 (91.5g, 0 . 37mol) dissolved in methylene chloride solution (200 ml), to control the temperature to 0 °C, slowly dropping catalyst m-CPBA (25.9g, 0 . 15mol), after the completion of the dropping, stirring the mixture at room temperature for reaction to 1h. Tracking TLC after complete reaction of raw materials, mixed liquid ethyl ether dilution, respectively for 10% Na2SO3, saturated NaHCO3, saturated salt water washing, drying, filtering, concentrating under reduced pressure, to obtain white solid (2R, 3S) - 1,2-epoxy-3 - (tert-butoxycarbonylamino) - 4-phenyl-butane 7 (95.3g, 97.8%)
82% With 3-chloro-benzenecarboperoxoic acid In dichloromethane
80% With C90H69FeO6; butyraldehyde In 1,2-dichloro-ethane at 35 - 45℃; for 6h; 4 Preparation of (1S,2R)-1-epoxyethyl-2-phenylethylcarbamic acid tert-butyl ester 6 mmol of the compound of formula (IV)36 mmol of freshly distilled butyraldehyde,And 0.18 mmol of catalyst 2 (R2 = Me) and 50 mL of dichloroethane were added,The dry air was passed at a flow rate of 15 mL / min,The reaction was stirred at 35 ~ 45 for 6h,Stop the reaction,The reaction mixture was washed with saturated sodium bicarbonate solution,The aqueous layer was extracted, the aqueous layer was extracted with ether,The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure.The crude product was recrystallized from a mixture of ethyl acetate and petroleum ether,The compound of formula (I), in 80% yield,Ee value of 98.2%.
With 3-chloro-benzenecarboperoxoic acid
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; Yield given;
With 3-chloro-benzenecarboperoxoic acid
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 25℃;
Multi-step reaction with 2 steps 1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / <i>tert</i>-butyl alcohol / 24 h / 20 °C 2: triphenylphosphine; diethylazodicarboxylate

Reference: [1]Current Patent Assignee: SHANGHAI INSTITUE OF TECHNOLOGY - CN104803954, 2018, B Location in patent: Paragraph 0045; 0051; 0058; 0065
[2]Current Patent Assignee: SHANGHAI INSTITUE OF TECHNOLOGY - CN105348224, 2016, A Location in patent: Paragraph 0052; 0053
[3]Reddy, G. Vidyasagar; Iyengar [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 2, p. 130 - 132]
[4]Current Patent Assignee: CHINA STATE SHIPBUILDING CORPORATION LIMITED - CN106905264, 2017, A Location in patent: Paragraph 0014; 0030-0031
[5]Getman, Daniel P.; DeCrescenzo, Gary A.; Heintz, Robert M.; Reed, Kathryn L.; Talley, John J.; et al. [Journal of Medicinal Chemistry, 1993, vol. 36, # 2, p. 288 - 291]
[6]Rich; Vara Prasad; Sun; Green; Mueller; Houseman; MacKenzie; Malkovsky [Journal of Medicinal Chemistry, 1992, vol. 35, # 21, p. 3803 - 3812]
[7]Esler, William P.; Das, Chittaranjan; Wolfe, Michael S. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 8, p. 1935 - 1938]
[8]McConnell, Rose M.; Inapudi, Kalyani; Kadasala, Naveen; Yarlagadda, Karthika; Velusamy, Priya; McConnell, James S.; McConnell, Matthew S.; Trana, Carol; Green, Adam; Sayyar, Kelley [Medicinal Chemistry, 2012, vol. 8, # 6, p. 1146 - 1154,9]
[9]Jaudzems, Kristaps; Tars, Kaspars; Maurops, Gundars; Ivdra, Natalija; Otikovs, Martins; Leitans, Janis; Kanepe-Lapsa, Iveta; Domraceva, Ilona; Mutule, Ilze; Trapencieris, Peteris; Blackman, Michael J.; Jirgensons, Aigars [ACS Medicinal Chemistry Letters, 2014, vol. 5, # 4, p. 373 - 377]
  • 2
  • [ 132234-31-2 ]
  • [ 98760-08-8 ]
  • [ 132259-52-0 ]
YieldReaction ConditionsOperation in experiment
87% With triethylamine In methanol Heating;
With triethylamine In di-isopropyl ether for 24h; Heating;
  • 3
  • [ 98760-08-8 ]
  • [ 147976-16-7 ]
YieldReaction ConditionsOperation in experiment
71% With boron trifluoride-tetrahydrofuran complex In acetonitrile at 60℃; for 5h; (4 s,5 s)-4-Benzyl-5-(chloromethyl)oxazolidin-2-one (14) Acetonitrile (15 mL), and boron trifluoride-THF complex (1.0 equiv., 0.70 g) were added to compound tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1) (1.31 g, 5 mmol). The mixture was stirred at 60 °C for ca. 5 h. This reaction mixture was quenched with water and extracted with dicholormethane (DCM). The organic layer was combined, dried over Na2SO4, and purified by flash column chromatography on silica gel (hexane:ethyl acetate1:2) to furnish (4S,5S)-4-benzyl-5-(hydroxymethyl)oxazolidin-2-one as a white solid (0.74 g, 71%).
With water; 3-chloro-benzenecarboperoxoic acid 1.) CH2Cl2, reflux, 60 h, 2.) CH2Cl2, CHCl3; Yield given. Multistep reaction;
  • 4
  • [ 136630-87-0 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
100% With potassium hydroxide In methanol for 3h; Ambient temperature;
  • 5
  • [ 98760-08-8 ]
  • [ 147240-29-7 ]
  • [ 160978-16-5 ]
YieldReaction ConditionsOperation in experiment
82% With diethylaluminium chloride; potassium hexamethylsilazane In tetrahydrofuran at -78℃;
With diethylaluminium chloride; potassium hexamethylsilazane 1.) THF, toluene, -78 deg C, 10 min, 2.) THF, toluene, heptane, -74 deg C, 10 min; Yield given. Multistep reaction;
  • 6
  • [ 165727-45-7 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; In methanol; EXAMPLE 5 Process for Producing (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2 -hydroxy-4-phenylbutane (0.40 g) and potassium carbonate (0.37 g) were added to methanol (8 ml), and they were stirred at room temperature for 6 hours. The inorganic salt was removed from the reaction mixture by the filtration and then the filtrate was analyzed by HPLC to confirm that intended (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (0.35 g) was obtained in a yield of 100%. The filtrate was concentrated under reduced pressure. Water was added to the residue. After the extraction with methylene chloride, the obtained methylene chloride layer was washed with 20% aqueous citric acid solution.
95% With potassium carbonate; citric acid; In ethanol; n-heptane; water; toluene; Example 24 Process for producing (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (5.29 g) and potassium carbonate (4.88 g) were added to an ethanol:water (97:3) mixed solution (106 ml). The mixture was stirred at 33 C. for 7 hours, and a 10% citric acid aqueous solution(67.8 g)was added there to. After ethanol was distilled off under reduced pressure, toluene (93 ml) was added to conduct extraction. Further, the organic layer was washed with water (93 ml), and then concentrated. To the residue was added a heptane:toluene (4:1) mixture (112 ml). The heating was conducted at 50 C. over 1 hour, and the stirring was further conducted at 50 C. for 1 hour. Subsequently, cooling was conducted to -10 C. over 5 hours, and stirring was further conducted at -10 C. for 8 hours. Crystals were collected by filtration, washed with heptane, and then dried under reduced pressure to obtain desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (4.39 g) in a yield of 95%.
95% With potassium carbonate; In ethanol; water; Example 25 Process for producing (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (3.57 g) and potassium carbonate (3.29 g) were added to an ethanol:water (97:3) mixed solution (35.7 ml). The mixture was stirred at 27 C. for 22 hours and further at 33 C. for4 hours. A11.3% citric acid aqueous solution (40.3 g) was added thereto, and the cooling was then conducted to -10 C. Crystals were collected by filtration, washed with water (35.7 ml), and dried under reduced pressure to obtain desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.88 g) in a yield of 95%.
92% With potassium hydroxide; In ethanol; at 5℃; for 1h; Compound 7 (3.0 g, 10.0 mmol) and KOH (1.68 g, 30.0 mmol) was addedrespectively to 20 mL ethanol and cooled to ca. 5 C. With stirring, KOH in ethanol was gradually added to the mixture. The reaction was stirred for another 1 h and then concentrated in a vacuum. The crude mixture was dissolved in 40 mL ethyl acetate, washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated in a vacuum to give a white solid (2.42 g, 92%).
85% With potassium carbonate; In methanol; hexane; water; ethyl acetate; Example 23 Process for producing (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (0.40 g) and potassium carbonate (0.37 g) were added to methanol (8 ml), and the mixture was stirred at room temperature for 6 hours. The inorganic salt was filtered off from the reaction solution, and the filtrate was then concentrated under reduced pressure. To the residue was added water, and the solution was extracted with methylene chloride. The resulting methylene chloride layer was washed with a 20% citric acid aqueous solution, and the solvent was then distilled off under reduced pressure. Ethyl acetate (2 ml) was added to the residue. The mixture was heat-dissolved, and crystallized by being cooled to room temperature. Further, n-hexane (4 ml) was added thereto, and the resulting mixture was stirred while being cooled with ice. Crystals were separated, and dried to obtain the crystals (0.30 g) of desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane in a yield of 85%. 1H-NMR(CDCl3) deltappm: 1.38 (s, 9H), 2.73-2.81 (m, 2H), 2.84-3.01 (m, 3H), 3.69 (bs, 1H), 4.54 (d, J=8.2 Hz, 1H), 7.21-7.31 (m, 5H) mass spectrum m/e: 286 (M+Na+)

  • 7
  • [ 162536-40-5 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydroxide; In water; isopropyl alcohol; at 0℃; for 4h;Product distribution / selectivity; To (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (45.1 g) obtained in Example 3 were added isopropanol (120 ml) and water (45 ml), and the mixture was cooled to 0C. 29%. Aqueous sodium hydroxide solution was added, and the mixture was stirred for 4 hours. Aqueous citric acid solution (a mixed solution of citric acid (6.73 g) and water (14 ml)) was added to the reaction mixture, and acetone (35 ml) and water (59.5 ml) were further added. A seed crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was added, and this mixture was stirred for 1 hour. Water (200 ml) was added dropwise to the mixture over 1 hour, and the mixture was stirred overnight. The slurry solution was filtered, and the crystals were washed twice with aqueous acetone solution (a mixed solution of acetone (50 ml) and water (350 ml)). Wet crystals were dried under reduced pressure at room temperature to give (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane as white crystals (37.1 g, 100 wt%, yield 93%). As a result of HPLC analysis, it was found that the peak area ratio of the compound was 99.9%, and the diastereomer ((2S,3S)-form) was not detected.
83% With sodium hydroxide; In water; isopropyl alcohol; at 0℃; for 8.5h;Product distribution / selectivity; The organic layer (26.5 g) obtained in Comparative Example 2, step (2'g), was concentrated under reduced pressure, isopropanol (2 ml) was added to the residue, and the mixture was concentrated again to dryness. Isopropanol (21.8 ml) and water (3.0 ml) were added to the residue and the mixture was cooled to 0C. Then, 6 M aqueous sodium hydroxide solution (2.7 ml) and water (1.2 ml) were added to the solution, and the mixture was reacted for 8.5 hours. An aqueous solution (36.6 ml) of citric acid (351 mg) was added to the reaction mixture, and the mixture was cooled from 0C to -10C over 3 hours. A seed crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was added, and the mixture was stirred at -10C for 3 days and filtered. The obtained crystals were dried under reduced pressure to give adhesive orange crystals (2.47 g). As a result of HPLC analysis, it was found that the content of the object compound, (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane, was 2.07 g, 83.8 wt%, and the yield was 83%. In addition, the crystals contained 0.071 g of a diastereomer ((2S,3S)-form)), and the diastereomer ratio (2R,3S)/(2S,3S) was 96.7/3.3. Moreover, the peak area ratio of other byproduct was 10% relative to the object compound, (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane.
81.4 mg (93.5%) With potassium carbonate; citric acid; In methanol; water; ethyl acetate; Example 6 Production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (100 mg) and potassium carbonate (91.5 mg) were added to methanol (2.0 ml) for agitation at ambient temperature for 4 hours. Aqueous 10% citric acid solution (0.204 ml) and water (0.408 ml) were added to the resulting mixture, from which the solvent was evaporated under reduced pressure. To the residue were added water (1 ml) and ethyl acetate (1 ml) for extraction; the organic phase was concentrated under reduced pressure, to afford (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {(2R,3S) yield: 81.4 mg (93.5%)}. 1H-NMR (CDCl3, 300 MHz) delta ppm: 1.38 (s, 9H), 2.59 (bs, 1H), 2.69 (t. J=4.4 Hz, 1H), 2.83-3.04 (m, 3H), 4.12 (bs, 1H), 4.48 (bs, 1H), 7.17-7.37 (m, 5H) Mass spectrum m/e: 286 (M+Na+)
191 mg (71.6%) With potassium carbonate; citric acid; In ethanol; water; Example 7 Production of crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane To (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 300 mg; (2S,3S) content of 6.67 mg} obtained in the same manner as in Example 1 were added ethanol (3.40 ml), water (0.109 ml) and potassium carbonate (755 mg), for agitation at ambient temperature for 5 hours and further agitation at 30 C. for one hour. After cooling to 5 C., aqueous 17.5% citric acid solution (3.99 g) was added. After phase separation at 0 C., the ethanol layer was cooled to -10 C., followed by addition of the seed crystal and overnight agitation, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered, to afford (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. {(2R,3S) yield: 191 mg (71.6%) The dried crystal was analyzed by HPLC. (2R,3S): (2S,3S)-96.8:3.2.
64.2 mg (75%) With sodium hydroxide; In water; acetone; Example 8 Production of crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Acetone (0.8 ml) and aqueous 2.5 mol/l sodium hydroxide solution (0.2 ml) were added to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 97.8 mg; (2S,3S) content of 2.2 mg} obtained in the same manner as in Example 1, for agitation at ambient temperature for 2 hours and 50 minutes. The resulting mixture was separated into phases. To the resulting acetone layer was added water (1.18 ml), which was then cooled to -10 C., followed by addition of the seed crystal and overnight agitation, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered, to recover the crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {(2R,3S) yield: 64.2 mg (75%)}. The dried crystal was analyzed by HPLC. (2R,3S): (2S,3S)=97.9:2.1.

  • 9
  • [ 4630-82-4 ]
  • [ 98760-08-8 ]
  • [ 3931-52-0 ]
  • (S,S,S)-1-[2-(N-t-butoxycarbonyl)amino-2-benzyl-1-hydroxypropyl]-N-methyl-N-benzylaminocyclohexylcarbonylimide [ No CAS ]
  • (S,S,R)-1-[2-(N-t-butoxycarbonyl)amino-2-benzyl-1-hydroxypropyl]-N-methyl-N-benzylaminocyclohexylcarbonylimide [ No CAS ]
  • 10
  • [ 99113-35-6 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
88% With triphenylphosphine; diethylazodicarboxylate In chloroform for 50h; Heating;
27% With triphenylphosphine; diethylazodicarboxylate
With triphenylphosphine; diethylazodicarboxylate In chloroform for 36h; Heating; Yield given;
Multi-step reaction with 3 steps 1: p-TsOH; pyridine / CH2Cl2 / 20 °C 2: CH2Cl2 / 20 °C 3: 99 percent / K2CO3 / methanol / 20 °C
Multi-step reaction with 2 steps 1: Et3N / toluene / 0 - 20 °C 2: 22.5 mg / aq. NaOH / toluene / 2 h / 20 °C
Multi-step reaction with 2 steps 1: pyridine / methanol; water / 24.5 h / -10 - 5 °C 2: potassium hydroxide / methanol / 1 h / 0 °C

  • 11
  • [ 78-81-9 ]
  • [ 98760-08-8 ]
  • [ 160232-08-6 ]
YieldReaction ConditionsOperation in experiment
100% In isopropyl alcohol; at 20℃; A mixture of tert-butyl(S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (25.0 g) (6.1) and isobutylamine (10.0 eq) in isopropanol (150 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 6.2 quantitative. The crude product was dried under high vacuum and used as such in the next step.
100% In isopropyl alcohol; at 60℃; for 6h; i-BuNH2 (5.851 g, 80 mmol) was added to a stirred solution of(2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane (8) (1.053 g,4.0 mmol) in i-PrOH (20 mL) and the mixture was warmed at60 C. After 6 h the solvent and the excess of i-BuNH2 wereremoved under reduced pressure and the product (9) was obtainedas white solid in quantitative yield (1.340 g, 4.0 mmol). [a]D20+7.0(c, 1.0, CHCl3); Rf 0.35 (CHCl3/CH3OH 9:1); 1H NMR (500 MHz,CDCl3) dH (ppm) 7.25 (m, 5H), 4.71 (d, J = 8.4 Hz, 1H), 3.80 (m,1H), 3.48 (dd, J1 = 10.8 Hz, J2 = 6.3 Hz, 1H), 3.02 (d, J = 4.7 Hz, 1H),2.99 (d, J = 4.7 Hz, 1H), 2.87 (dd, J1 = 13.7 Hz, J2 = 7.9 Hz, 1H), 2.70(m, 2H), 2.45 (m, 2H), 1.73 (m, 1H), 1.35 (s, 9H), 0.93 (d,J = 6.6 Hz, 6H). 13C NMR (125 MHz, CDCl3): d (ppm) 155.9, 137.9,129.5, 128.4, 126.3, 79.4, 70.6, 57.9, 54.1, 51.4, 36.7, 28.33, 28.27,20.53, 20.51. Anal. Calcd for C19H32N2O3: C, 67.82; H, 9.59; N,8.33; Found C, 67.7; H, 9.7; N, 8.3.
100% In isopropyl alcohol; at 60℃;Inert atmosphere; i-BuNH2 (8.0?mL, 80?mmol) was added to a stirred solution of (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane 15 (1.053?g, 4.0?mmol) in i-PrOH (20?mL). The mixture was warmed at 60?C. After 6?h the solvent and the excess of i-BuNH2 were removed under reduced pressure. The product 16 was obtained as white solid in quantitative yield. 1H and 13C NMR spectra were consistent to literature data.8
97.63% at 65 - 75℃; for 3h; A mixture of (2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane (II) (100 g) and isobutyl amine (III) (277.9 g) was heated at 65-75C for 3 hours. After completion of the reaction, Isobutyl amine was distilled out completely from reaction mixture at 75-85C. The residue was cooled below 50C and Methanol (200 ml) was added. The mixture was heated at 60-70C to make a clear solution. The solution was cooled at 25-35C and added to water (1000 ml) and stirred for 2 hours. The product was filtered and washed with water (2 X 50 ml) to get wet cake.The wet cake was re-slurried in water (1500 ml), stirred for 2 hours and filtered. The wet cake was washed with water (2 X 50 ml). Solid was dried in air tray dryer for 2 hours at 25-35C and then at 65-75C for 12 hours to give the title product (124.0 g)Yield: 97.63%
97.87% at 65 - 70℃; (0109) Isobutylamine (1 1 1.03 g,1.519 mol) was charged to (2S,3S)-l,2-Epoxy-3-(Boc- (0110) Amino)-4-Phenylbutane (20.0 g, 0.0759 mol) at room temperature. Reaction mass heated to 65-70C and stirred for 3-4 hours for the completion of reaction. Distilled the reaction mass completely under vacuum. Charged methanol (20.0 mi) and charge water (200.0 ml) at 50-55C. Cool the reaction mass to 25-35uC and stir for 2-3 hours. Filtered the solid under vacuum and washed with water (40.0 ml). Dried the wet compound at 5()-55C and obtained the compound tert-Butyl (2S,3R)-3-hydroxy-4- (isobutylamino)- 1 -phenylbutan-2-ylcarbamate. (0111) Yield: 97.87% (0112) Purity: 98.55% (by HPLC) (0113) Purification: tert-Butyl(2S,3R)-3-hydroxy-4-(isobutylamino)- 1 -phenylbutan-2-yl carbamate compound (VI) (5.0 g) was stirred in Diisopropylether (50 ml) at 65-70C for 30-60 minutes. Cooled the reaction mass to room temperature and stirred for 30-45 minutes. Filtered the solid under vacuum and washed with Diisopropyl ether ( 10.0 ml) and dried at 50-55C. (0114) Yield: 78.0 % (0115) Purity: 99.32 %, Dibenzyl impurity (VIII): 0.51 % (by HPLC)
95.7% In neat (no solvent); at 50 - 60℃; for 2h;Reflux; (2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane (40 g, 0.15 moles) was added to isobutyl amine (80 mL, 0.78 moles) in several portions at 50C to 60C. The solution was heated under reflux for 2 hours and isobutyl amine was removed under reduced pressure. Water (200 mL) was added to the residue and the mixture was stirred. The product obtained was filtered, washed with water and dried under vacuum to obtain tert-buiyl [(2S,3R)-3-hydroxy-1-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate as white powder. Yield: 49.1 g (95.7%)HPLC Purity: 96%
85% In ethanol; at 80℃; for 3h; To a stirred solution of epoxide 17 (5.00 g,18.98 mmol) in ethanol (140 ml) was added isobutylamine (19.0 ml, 189.9 mmol ) and the reaction mixture was heated to 80 C and stirred for 3 h at that temperature. Upon cooling to rt, the solvents were concentrated off and the residue was triturated with hexanes (3 x 30 mL) to afford amino alcohol 18 (5.43g, 85%) as a white solid: 1H NMR (400 MHz, CDCl3): delta 7.31-7.21 (m, 5H), 4.73-4.70 (m, IH), 3.81 (bs, IH), 3.48-3.46 (m, IH), 3.01-2.96 (m, IH), 2.88-2.86 (m, IH), 2.70-2.68 (m, 2H), 2.42 (m, 2H), 1.75-1.60 (m, 2H), 1.44 (s, 9H), 0.92 (d, J= 5.0 Hz, 2H); MS (ESI) m/z 336 [C19H32N2O3 + H] +.
83% In acetonitrile; at 80℃; for 5h; (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamic acid tert-butyl ester (1) (Belling Technology Co., Ltd.) (20.0 g, 75.94 mmol), acetonitrile 80 mL and Isobutylamine (19.02 mL, 189.46 mmol) was added to a 200 mL eggplant-shaped flask, and the mixture was stirred at 80 C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Crude with ethyl acetate /The white target product (21.2 g, 83%) was obtained after recrystallization from n-hexane (1:9), and the white target product was Intermediate 2,
83% In acetonitrile; at 80℃; for 5h; (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamic acid tert-butyl ester(raw material 1,75.94 mmol), acetonitrile 80 mL and isobutylamine (189.46 mmol)It was added to a 200 mL eggplant-shaped flask, and the reaction was stirred at 80 C for 5 hours.After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure.The crude product was recrystallized from a mixture of ethyl acetate and n-hexane (yield: 1:9) to afford white product, Intermediate 2 (21.2 g, 83%).
83% In acetonitrile; at 80℃; for 5h; Tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (20.0 g, 75.94 mmol), Acetonitrile 80 mL and isobutylamine (19.02 mL, 189.46 mmol) were placed in a 200 mL eggplant-shaped flask, and the mixture was stirred at 80 C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate / n-hexane (1: 9) to give the title compound (21.2 g, 83%) as the desired product as the intermediate b1, LC-MS (ESI, M+H+) m/ z 337.2.
Heating / reflux; Example 1 : Preparation of (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester. To 154.4 Kg isobutylamine, (1-Oxiranyl-2 phenyl-ethyl)-carbamic acid tert-butyl ester (53. 3 Kg) was added, and then the solution was heated under reflux. Under reduced pressure, isobutylamine was removed from the reaction mixture, and then replaced by toluene.
Description of the chemical reactions for scheme 1; (1 -Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester (2); This compound was synthesized from the commercially available (1-oxiranyl-2-phenyl- ethyl)-carbamic acid tert-butyl ester (1 ), which was reacted with isobutylamine thereby forming the amino alcohol 2. <n="20"/>1 Ng, J. S.; Przybyla, C. A.; Zhang, S. Method of preparing retroviral protease inhibitor intermediates via diasterereomer purification. PCT Int. Appl. 1996, WO 9622275.
In isopropyl alcohol; for 1h;Heating / reflux; Step 1: To a solution of 1000 mL of isobutylamine and 1000 mL of isopropanol at room temperature was added 500 g of the commercially-available epoxide (9), and the resulting mixture was heated to reflux for 1 hour. After cooling, the mixture was concentrated under vacuum, and the residue was triturated with 1000 mL of heptane. The resulting precipitate was recovered by filtration, washed with heptane, and dried to provide 625 g of the aminoalcohol (10).

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  • 12
  • [ 98760-08-8 ]
  • [ 198904-85-7 ]
  • [ 198904-86-8 ]
YieldReaction ConditionsOperation in experiment
75% In isopropyl alcohol;Heating / reflux; Synthesis of tert-butyl 2-((2S,3S)-3-(tert-butoxyearbonylammo)-2-hydroxy-4-phenylbutyl)-2-(4-(pyndin-2-yl)b enzyl)hydrazinccarboxylate (XV, YIa = YIb = H).; A mixture of tert-butyl (S)-1-((R)-oxian-2-yl)-2-phenylthylcarbamate XIV (1.18 g. 4.48 mmol), XIII, Y1a = Y1b = H (1.23 g, 4.11 mmol) and isopropanol (15 mL) was kept at reflux under nitrogen overnight. The solvent was removed in a rotary evaporator and the residue was purified by chromatography on silica (100 g) with 8:2 dichloromethane/ethyl acetate to give product XV, wherein Y1a = Y1b = II (1.74 g, 75%).
62.5% In isopropyl alcohol; for 24h;Reflux; Step 1: Synthesis of tert -butyl 2-((2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4- phenylbutyl)-2-(4-(pyridin-2-yl)benzyl)hydrazinecarboxylate:A stirred solution of tert-butyl 2-(4-(pyridin-2- yl)benzyl)hydrazinecarboxylate (about 1.3 g, 4.347 mmol) and tert-butyl (S)-1-((R)- oxiran-2-yl)-2-phenylethylcarbamate (about 1.7 g, 6.521 mmol) in Isopropanol was refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture brought to room temperature and water (23 ml) was added and stirred at same temperature for about 16 hours. Resulting solid precipitation was filtered and washed with water (23 ml), cold methyltertiarybutyl ether (3 ml) then dissolved in acetonitrile, water (35 ml) was added and filtered, the resulting solid purified by silica gel column (100-200 mesh, elution: 20% EtOAc in Hexane) to afford the title compound as an off white solid. Wt:1.5 g; Yield: 62.5 %; NMR (300 MHz, CDCI3): delta 8.69 (d, 1H, J = 4.5 Hz,), 7.95 (d, 2H, J = 8.1 Hz), 7.76-7.69 (m, 2H), 7.41 (d, 2H, J = 8.1 Hz), 7.25-7.23 (m, 6H), 5.25 (s, 1H), 5.12 (d, 1H, J =9.3 Hz), 4.54 (s.1H).4.07-3.94 (m, 2H), 3.68-3.55 (m, 2H).2.95-2.80 (m, 3H), 2.46 (d, 1H, J= 10.2 Hz), 1.38 (s, 9H), 1.32 (s, 9H); Mass: [M+H}+ 563 (3%), [M+Na) + 585 (100%).
N-1 -(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)-benzyl]-hydrazine (II) (100 g, 0.33 mole) and (2R)-[(rS)-Boc-amino-2'-phenylethyl]oxirane (I) (102.8 g, 0.39 mole) were added in IPA (400mL), and heated to reflux for 30 hours. Water (50 mL) was added slowly and stirred at 60 - 70C for 2 hours. Cooled to 15 - 20C and solid was filtered, washed with a mixture of IPA and water. Wet solid was crystallized from methanol-water, to give 160 g of hydroxy compound (III).
  • 13
  • [ 98760-08-8 ]
  • (9S,12S,15S)-15-Amino-12-((S)-sec-butyl)-11,14-dioxo-2-oxa-10,13-diaza-tricyclo[15.2.2.13,7]docosa-1(20),3(22),4,6,17(21),18-hexaene-9-carboxylic acid methyl ester; hydrochloride [ No CAS ]
  • (9S,12S,15S)-15-((2S,3S)-3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butylamino)-12-((S)-sec-butyl)-11,14-dioxo-2-oxa-10,13-diaza-tricyclo[15.2.2.13,7]docosa-1(20),3(22),4,6,17(21),18-hexaene-9-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With TEA In methanol for 24h; Heating;
  • 14
  • [ 98760-08-8 ]
  • (9S,12S,15S)-9-Amino-12-((S)-sec-butyl)-10,13-dioxo-2-oxa-11,14-diaza-tricyclo[15.2.2.13,7]docosa-1(20),3,5,7(22),17(21),18-hexaene-15-carboxylic acid methyl ester; hydrochloride [ No CAS ]
  • (9S,12S,15S)-9-((2S,3S)-3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butylamino)-12-((S)-sec-butyl)-10,13-dioxo-2-oxa-11,14-diaza-tricyclo[15.2.2.13,7]docosa-1(20),3,5,7(22),17(21),18-hexaene-15-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With TEA In methanol for 24h; Heating;
  • 15
  • [ 98760-08-8 ]
  • [(1S,2R)-1-Benzyl-3-((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butylsulfanyl)-2-hydroxy-propyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With triphenylsilanethiol; caesium carbonate In methanol at 20℃;
  • 16
  • [ 98760-08-8 ]
  • (S)-2-[((R)-5,5-Dimethyl-thiazolidine-4-carbonyl)-amino]-3-methyl-butyric acid methyl ester [ No CAS ]
  • [ 359690-94-1 ]
YieldReaction ConditionsOperation in experiment
90% With triethylamine In methanol at 80℃; for 24h;
  • 17
  • [ 98760-08-8 ]
  • [ 100-46-9 ]
  • [ 143577-00-8 ]
YieldReaction ConditionsOperation in experiment
82% In isopropyl alcohol at 50℃;
47% With pyridine In isopropyl alcohol for 16h; Reflux; Procedure for the synthesis of compounds 1a-15a (procedure A) General procedure: Tert-butyl ((S)-1-((S)-oxiran-2-yl)-2-phenylethyl)carbamate or tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1.0 equiv.), corresponding amine (1, 1.1 or 2 equiv.), and a catalytic amount of pyridine in n-propanol, isopropanol or ethanol were refluxed for 16 h. Then, the solvent was evaporated and the resulting residue was purified by flash column chromatography using a mixture of DCM and MeOH (gradient or isocratic purification).
In isopropyl alcohol for 16h; Heating;
  • 18
  • [ 102123-74-0 ]
  • [ 98760-08-8 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
(2S,3S) compound/((2S,3S) compound) + (2R,3S) compound: 99.7percent (3S)-1-Chloro-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane content: less than 0.1 area percent (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane: less than 0.1 area percent (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane: less than 0.1 area percent Mean crystal grain diameter: ca 300 to 400 mum
  • 19
  • [ 200616-28-0 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate In methanol at 20℃;
  • 20
  • [ 78-81-9 ]
  • [ 98760-08-8 ]
  • [ 160232-08-6 ]
YieldReaction ConditionsOperation in experiment
94.67% In isopropyl alcohol at 20 - 30℃; Preparation of tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(-4-nitrophenyl)sulfonyl]-amino]propyl]carbamate (7) A mixture of isobutyl amine (1000 mL, 9.981 mol), IPA (200 mL, 1.0 volume) and200 g (0.759 mol) of 3 was stirred for 12-14 h at 20-30 °C. After completion ofreaction (TLC), volatiles were removed under vacuum. Water (1000 mL) was addedto the residue followed by stirring for 2 h, and subsequent filtration resulted to affordintermediate 6, after drying at 50-60 °C in air oven over a period of 10-12 h. Driedsolid was then mixed with DCM (740 mL), TEA (115 mL, 0.835 mol) at 15-25 °Cfollowed by slow addition of 4-nitrobenzenesulfonyl chloride solution (168 g,0.759 mol, in 300 mL of DCM) at 15-25 °C. Resulted reaction mixture was stirredfor 1-2 h at 15-25 °C. After reaction completion (TLC), volatiles were evaporatedunder vacuum completely. Water (1500 mL) and sodium hydroxide solution(200 mL; 0.700 mol) was added to distilled residue followed by stirring for 2 h. Theresulting aqueous slurry was filtered, washed with water and dried in air oven at55-60 °C over a period of 10-12 h to yield the intermediate 7.
93% In isopropyl alcohol at 80℃; for 2.5h; 1 EXAMPLE 1; tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate To a solution of (2R,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (10 g) in 2-propanol (100 mL) was added isobutylamine (11.4 mL, 3 equivalents), and the mixture was heated at 80° C. for 2.5 hours. After evaporation of the solvents, 11.86 g (93%) of the amine was produced in pure enough form for use in the next step. 1H NMR (300 MHz, CDCl3) δ ppm 0.90 (d, J=1.47 Hz, 3H), 0.92 (d,J=1.47 Hz, 3H), 1.35 (s, 9H), 1.59 (s, 1H), 1.70 (m, 1H), 2.41 (d, J=6.99 Hz, 2H), 2.68 (d,J=4.78 Hz, 2H), 2.88 (d, J=8.09 Hz, 1H), 2.97 (d,J=4.41 Hz, 1H), 3.01 (d, J=4.78 Hz, 1H), 3.45 (q, J=5.52 Hz, 1H), 3.80 (s, 1H), 4.68 (d, J=8.09 Hz, 1H), 7.21 (m, 3H), 7.29 (m, 2H).
In isopropyl alcohol at 80℃; for 2.5h;
  • 21
  • [ 98760-08-8 ]
  • [ 105-53-3 ]
  • [ 193338-94-2 ]
YieldReaction ConditionsOperation in experiment
82% With sodium ethanolate In ethanol at 0 - 25℃;
With sodium ethanolate In ethanol at 0 - 25℃; for 18.1666h; 92.A ethyl (5S)-3-(4-bromobenzyl)-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-2-oxotetrahydro-3-furancarboxylate EXAMPLE 92A ethyl(5S)-3-(4-bromobenzyl)-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-2-oxotetrahydro-3-furancarboxylate A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with a solution of NaOEt (13.5 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 18 hours. The reaction was re-cooled to 0° C. and treated with a solution of 4-bromobenzyl bromide (9.5 g, 38.0 mmol) in ethanol (40 mL), stirred at 50° C. for 3 hours, cooled to 0° C. and adjusted to neutral pH by addition of 4N HCl. The ethanol was removed under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (22.4 g), which was used without further purification.
  • 22
  • [ 98760-08-8 ]
  • [ 918127-15-8 ]
YieldReaction ConditionsOperation in experiment
69% Stage #1: (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane With sodium azide; ammonium chloride In methanol at 64℃; for 3h; Stage #2: With triphenylphosphine In acetonitrile for 3h; Heating;
  • 23
  • [ 1003888-36-5 ]
  • [ 98760-08-8 ]
  • C35H40N4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% In isopropyl alcohol at 80℃; for 27h; Compound 10Compound 9 (248.2 mg, 0.7 mmol) and tert-butyl (S)-l-((R)-oxiran-2-yl)-2- phenylethylcarbamate purchased from Kaneka Corporation (177.0 mg, 0.7 mmol) were dissolved in isopropanol and heated to 800C. The reaction mixture was stirred for 27 h before it was cooled to r.t. and concentrated. The resulting solid was crystallized in hexane and purified using silica gel chromatography (20-50% ethyl acetate/hexane) to give Compound 10 as a yellow solid (18.815g, 31.5 mmol, 68%). Mass spectrum: (M+H)+ = 597.1.
  • 24
  • [ 98760-08-8 ]
  • [ 1385766-21-1 ]
YieldReaction ConditionsOperation in experiment
90.3% With sodium azide; ammonium chloride In methanol Reflux; 4.1.1 tert-Butyl (2S,3S)-4-azido-3-hydroxy-1-phenylbutan-2-ylcarbamate (7) To a solution of compound 6 (770 mg, 2.93 mmol) in methanol (20 mL) was added NH4Cl (282 mg, 5.27 mmol), NaN3 (457 mg, 7.03 mmol). The mixture was heated to reflux overnight and then the solvent was concentrated under reduced pressure. Water (30 mL) was added into the reaction. The solution was extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by diluted HCl, saturated NaHCO3, saturated brine twice (15 mL × 2) by turns. Then the organic layers were dried over Na2SO4, filtered and evaporated to give the residue, which was purified by silica gel chromatography to afford 7 (810 mg, 90.3 %). 1H NMR (300 MHz, CDCl3): δ 7.29-7.27 (m, 5H), 4.60 (d, J=8.4 Hz, 1H), 3.82-3.78 (m, 2H), 3.42-3.37 (m, 3H), 2.90-2.93 (m, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 156.1, 137.8, 129.4, 128.5, 126.3, 79.8, 72.1, 55.1, 53.8, 38.2, 28.2; LCMS (ESI): 306.7 [M+H]+; HRMS: calcd for C15H22N4O3Na 329.1590, found C15H22N4O3Na 329.1602; [α]D19=-51.5° (c 1.000, MeOH).
With sodium azide; ammonium chloride In ethanol; water at 85℃; for 16h; 26 To a solution of epoxide 28 (4.0 g, 15.2 mmol) in EtOH (48 mL) and water (6 ml) were added ammonium chloride (1.62 g, 30.4 mmol) and sodium azide (2.0 g, 30.4 mmol). The reaction mixture was heated at 85 0C for 16 h. The mixture was cooled to 25 0C and the solvents were evaporated under reduced pressure. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with water and brine, and dried over Na2SO4. Evaporation under reduced pressure gave a white solid (4.8 g).
  • 27
  • [ 7535-56-0 ]
  • [ 98760-08-8 ]
  • 28
  • [ 102123-74-0 ]
  • [ 98760-08-8 ]
  • 29
  • [ 259752-50-6 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In tetrahydrofuran; methanol at 25℃; for 20h; 5 Example 5; (2R, 3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-epoxide Example 5 (2R, 3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-epoxide A mixture composed of 1.0 mmol (0.401 g) of (2S, 3S)-1-acetoxy-3-(t-butoxycarbonylamino)-2-methanesulfonyloxy-4-phenylbutane, 2.2 mmol (0.304 g) of potassium carbonate, 10 ml of methanol and 10 ml of tetrahydrofuran was stirred at 25° C. for 20 hours.. Thereafter, 10 ml of ethyl acetate and 10 ml of water were added for extraction of the product.. The organic layer was separated, dried and the solvent was distilled off under reduced pressure to give a crude product.. Purification by silica gel column chromatography gave 0.236 g (90%) of (2R, 3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-oxirane. 1H-NMR (400 MHz, CDCl3) δ 1.38 (5, 9H), 2.76-2.81 (m, 2H), 2.83-2.99 (m, 3H), 3.76 (br s, 1H), 4.45 (br, 1H), 7,21-7.33 (m, 5H) 13C-NMR (100 MHz, CDCl3) δ 28.26, 37.58, 46.91, 53.03, 53.20, 80.03, 126.68, 128.55, 129.46, 136.69, 155.21.
90% With potassium carbonate In tetrahydrofuran; methanol at 20 - 30℃; for 15h; Inert atmosphere; 23 Example 23 Preparation of tert-butyl N-{(1S)-1-[(2R)oxiran-2-yl]-2-phenylethyl}carbamate 6 To a suitable reactor was added 5 (2 g, 4.98 mmol), THF (20 mL), MeOH (20 mL), and K2CO3 (1.5 g, 10.96 mmol) at 20-30° C. under N2. The mixture was stirred at 20-30° C. for 15 hr. The mixture was filtered, and the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil. After being purified by flash column chromatography, 6 was obtained as a white solid in 90% yield. 1H NMR (400 MHz, CDCl3) δ 7.35-7.23 (m, 5H), 4.51 (br s, 1H), 4.14 (br d, J=6.8 Hz, 1H), 3.04-2.96 (m, 2H), 2.90 (dd, J=13.2, 7.6 Hz, 1H), 2.71 (t, J=4.4 Hz, 1H), 2.60 (br s, 1H), 1.41 (s, 9H)
  • 30
  • [ 98760-08-8 ]
  • [ 110207-94-8 ]
  • [ 850426-66-3 ]
YieldReaction ConditionsOperation in experiment
In ethanol at 50℃; for 15h; 6.a a) (2R, 3S)-3-amino-1- (3-isopropyl-benzylamino)-4-phenyl-butan-2-ol dihydrochloride; A solution of 700 mg (2.7 mmol) tert-butyl (S- (R, R) (-)- (1-oxiranyl-2-phenylethyl)-carbamate and 470 mg (3.3 mmol) 3-iso-propylbenzylamine in 10 ml EtOH is heated for 15 h at 50°C. Evaporation of the solvent and purification by column chromatography (silica gel, DCM/MeOH 9: 1) afforded 820 mg of [ (1S, 2R)-1-benzyl-2-hydroxy-3- (3-iso-propyl- benzylamino)-propyl]-carbamic acid ter-butyl ester as a colourless solid. This material is dissolved in 10 mi 4N HCI in dioxane, stirred for 2 h at ambient temperature and all volatiles removed in vacuo to give 643 mg desired compound.
  • 31
  • [ 98760-08-8 ]
  • [ 162536-72-3 ]
YieldReaction ConditionsOperation in experiment
With lithium azide; ammonium chloride In ethanol; water at 75℃; for 2h; 274.A EXAMPLE 274A; (2R,3S)-3-amino-1-azido-4-phenylbutan-2-ol A solution of (2R,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (1.17 g) in ethanol:water (45 mL, 4:1) was treated with lithium azide (1.09 g, 5 equivalents) and NH4Cl (1.19 g, 5 equivalents), stirred at 75° C. for 2 hours and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated. A solution of the residue in dichloromethane/trifluoroacetic acid (40 mL, 1:1) was stirred at 25° C. for 1 hour and concentrated to give the title compound.
  • 32
  • [ 98760-08-8 ]
  • [ 198904-85-7 ]
  • [ 198904-86-8 ]
YieldReaction ConditionsOperation in experiment
57% In isopropyl alcohol; at 65℃; for 16h; EXAMPLE 7A Tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate A solution of Example 4B (0.84 g, 2.8 mmol) in isopropanol (9 mL) was treated with (2S,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (0.74 g, 1 equivalent), stirred at 65 C. for 16 hrs and cooled to room temperature. The mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were concentrated. Ether was added to precipitate the solid which was filtered to give 0.8 g (57%) of the title compound.
35 - 57% In isopropyl alcohol; at 65 - 85℃; for 16h;Product distribution / selectivity; Example 7A; tert-butyl 2-f (2S, 3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2- pyridinyl) benzyl] hydrazinecarboxylate; A solution of Example 4B (0.84 g, 2.8 mmol) in isopropanol (9 mL) was treated with (2S, 3)-3-N-tert-butoxycarbonylamino-1, 2-epoxy-4-phenylbutane (0. 74 g, 1 equivalent), stirred at 65C for 16 hrs and cooled to room temperature. The mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were concentrated. Ether was added to precipitate the solid which was filtered to give 0. 8 g (57%) of the title compound.; Example 191A; ter-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2- pyridinyl) benzyl] hydrazinecarboxylate; (2S, 3S)-3-N-tert-butoxycarbonylamino-1, 2-epoxy-4-phenylbutane (3 g, 0.011 mol) in isopropanol (50 mL) was combined with Example 4B (3.41 g, 1 equivalent), stirred at 85C for 16 hrs. The mixture was cooled to room temperature, evaporated and partitioned between CHC13 and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil which was crystallized by trituration with diethyl ether, filtered, and dried in vacuo to give 2.27 g (35%) of the title compound.
35% In isopropyl alcohol; at 85℃; for 16h; EXAMPLE 191A Tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate (2S,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (3 g, 0.011 mol) in isopropanol (50 mL) was combined with Example 4B (3.41 g, 1 equivalent), stirred at 85 C. for 16 hrs. The mixture was cooled to room temperature, evaporated and partitioned between CHCl3 and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil which was crystallized by trituration with diethyl ether, filtered, and dried in vacuo to give 2.27 g (35%) of the title compound.
YieldReaction ConditionsOperation in experiment
7.94g (80.2%) Example 20 Purification of (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane and production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2-Propanol (25.3 ml) and water (8.5 ml) were added to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 11.28 g; (2S,3S) content of 1.55 g} obtained by the same method as in Reference Example 3, to prepare a slurry, followed by addition of potassium chloride (329 mg) at 70 C., which was then agitated for 15 hours and cooled to 20 C. over 2.5 hours. The slurry was filtered at 20 C., to remove insoluble matters. 2-Propanol (58.7 ml) and water (3.2 ml) were added to the resulting mother liquor, followed by cooling at 4 C. and addition of aqueous 4 mol/l sodium hydroxide solution (14.1 ml), for agitation at 4 C. for 2.5 hours. The reaction solution was analyzed by HPLC. The objective (2R,3S) compound was at 93.6% (HPLC area ratio). The reaction was quenched by addition of aqueous 0.85% citric acid solution (142 g). After cooling from 27 C. to -10 C. for 2.5 hours, the addition of the seed crystal and overnight agitation enabled the crystallization of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered; to the resulting crystal was added water (56.4 ml), to prepare a slurry, followed by agitation at 20 C. for one hour; the slurry was filtered and dried, to afford the crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {(2R,3S) recovery yield of 7.94g (80.2%)}. The dried crystal was analyzed by HPLC. (2R,3S):(2S,3S)=98.1:1.9. Additionally, (2R,3S) purity was at 97.6% (HPLC area ratio).
  • 34
  • [ 67-63-0 ]
  • [ 162536-40-5 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; citric acid; Example 9 Production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2-Propanol (342 ml) and aqueous 2.5 mol/l sodium hydroxide solution (85.8 ml) were added to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 40.6 g; (2S,3S) content of 1.66 g} obtained in the same manner as in Example 1, for agitation at 0 C. for 1.5 hours. Aqueous 13.8% citric acid solution (99.5 g) was added to the resulting mixture, and then, 2-propanol was evaporated under reduced pressure. To the resulting residue was added toluene (342 ml) for extraction; and the organic layer was concentrated under reduced pressure, to afford (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (37.2 g) {the total yield of (2R,3S) and (2S,3S): 98.3%}, which was then analyzed by HPLC. (2R,3S): (2S,3R)=96.1:3.9.
2.4 g (96.2%) With sodium hydroxide; citric acid; In water; Example 18 Production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2-Propanol (12.9 ml) and aqueous 6.08 mol/l sodium hydroxide solution (2.94 g) were added to a solution containing (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane obtained in Example 17 {(2R,3S) content of 2.79 g; (2S,3S) content of 83.9 mg}, for agitation at 4 C. for 15 hours. The resulting solution was analyzed by HPLC, which indicates that the objective (2R,3S) compound was at 94.0% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 4.4% citric acid solution (20.9 g), the reaction solution was cooled from 25 C. to -10 C. over 2.3 hours; then, the seed crystal was added, followed by addition of water (19.2 ml) for overnight agitation, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. By filtration of the resulting slurry, the crystal of the objective (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was obtained {(2R,3S) yield: 2.4 g (96.2%)}. The dried crystal was then analyzed by HPLC. (2R,3S): (2S,3S)=97.9:2.1. Additionally, the purity of (2R,3S) was at 95.4% (HPLC area ratio).
With sodium hydroxide; citric acid; In water; Example 26 Production of Crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane The solution of (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 5.99 g; (2S,3S)content of 80 mg} obtained in the same manner as in Example 22 was concentrated, and then 2-propanol (30.8 ml) and water (10.3 ml) were added to the resulting residue. After cooling to 4 C., 4 mol/l sodium hydroxide solution (7.7 ml) was added, followed by agitation at 4 C. for 70 minutes. The reaction solution was analyzed by HPLC. The objective (2R,3S) compound was at 97.1% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 1.5% citric acid solution, the resulting mixture was cooled to -3 C., followed by the addition of the seed crystal and agitation for 30 minutes. The mixture was cooled to -10 C. over 1 hour and was agitated for 2 hours, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. After filtration of the resulting slurry, water (61.6 ml) was added to the resulting crystal, for preparing slurry, which was then agitated at ambient temperature for 30 minutes, to filtrate the slurry. The resulting crystal was dried to obtain the objective crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {the yield of (2R,3S): 4.92 g (93.5%)}. The dry crystal was analyzed by HPLC. (2R,3S):(2S,3S)=97.9:2.1. Additionally, the purity of (2R,3S) was 98.3% (HPLC area ratio).
  • 35
  • [ 67-63-0 ]
  • [ 165727-45-7 ]
  • [ 77-92-9 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
87% With sodium hydroxide; In water; EXAMPLE 12 Process for Producing (2S,3S)-3-tert-butoxycarbonylamino-1,2-eoxy-4-phenylbutane 2-Propanol (2.4 ml) was added to (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (300 mg). After cooling to 4 C., 4 mol/l aqueous sodium hydroxide solution (0.375 ml) and water (0.225 ml) were added to the obtained mixture, and they were stirred at 4 C. for 7 hours. 13.7% aqueous citric acid solution (695 mg) was added to the reaction mixture. After the extraction with tert-butyl methyl ether, the obtained organic layer was washed with water and analyzed by HPLC to find that intended (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (230 mg)was obtained in an yield of 87%.
  • 36
  • active charcoal [ No CAS ]
  • sodium methylate methanol [ No CAS ]
  • [ 34557-54-5 ]
  • [ 99113-35-6 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In tetrahydrofuran; n-heptane 5 N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenyl Butane Example 5 N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenyl Butane To a solution of the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-Butanol obtained in Reference Example 2 and dissolved in tetrahydrofurane 750 ml were added methane sulfonylchoride 63.25 g at 15-20° C. and then triethylamine 55.83 g and the solution was stirred at 15-25° C. for 1 hr. The reaction solution was washed with an aqueous 5% sodium bicarbonate solution to separate an organic phase, which was washed with an aqueous 10% sodium chloride solution. To the separated organic phase was added a 28% sodium methylate methanol solution 96.5 g at -5° C. to 5° C. and stirred at 0° C. to 10° C. for 30 min. The reaction solution was diluted with water and adjusted with 6N-HCl to pH6.5-7.5 to separate an organic phase, which was distilled to remove the solvent. The concentrated residue was mixed with n-heptane, stirred at the ambient temperature for 1 hr to deposit crystals, which were filtered to remove. The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 1.1 g, stirred at the ambient temperature for 30 min and filtered to remove the active charcoal. The filtrate was cooled down to -20° C. to deposit crystals, which were filtered and dried in vacuum to obtain an object product, namely the N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenyl-butane(98.6% according to the HPLC area ratio)99.46 g. The diol compound and the 1,2-disulfonate compound contained in a concentration of 0.5% or less in the object product according to the HPLC area ratio respectively. 12.3 g of the object product was lost into the filtered liquid.
  • 37
  • aqueous potassium hydroxide [ No CAS ]
  • aqueous sodium hypochlorite [ No CAS ]
  • [ 3236-56-4 ]
  • [ 98760-08-8 ]
  • sodium hydrogensulfite [ No CAS ]
  • (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With potassium hydroxide; cyfluthrin In hexane; water; ethyl acetate; acetonitrile 9 Production of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid EXAMPLE 9 Production of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid To dry crystals of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (18.0 g, (2R,3S):(2S,3S)=98.1:1.9) obtained in the same manner as in Reference Example 5 was added acetonitrile (54.0 ml) and then boron trifluoride-ether complex (8.63 g) was added. The mixture was stirred at 70° C. for 12 hr. The mixture was cooled to room temperature, and water (18 ml) was added. The mixture was then adjusted to pH=7.0 with 8N potassium hydroxide solution and sodium hydrogencarbonate (14.4 g) was added. The mixture was cooled to 0° C. TEMPO (0.103 g) was added, and 12% aqueous sodium hypochlorite solution (106 g) was added dropwise over 1.5 hr. After the completion of the reaction, the mixture was stirred at 0° C. for 3 hr and sodium hydrogensulfite (7.12 g) was added to the reaction mixture. To this solution was added potassium hydroxide (14.8 g) and the mixture was stirred at 50° C. for 17 hr. The reaction mixture was cooled to room temperature and adjusted to pH=10 with 6N aqueous hydrochloric acid solution. A solution of di-tert-butoxycarbonate (23.0 g) in acetonitrile (35.6 ml) was added, and the mixture was stirred at 40° C. for 12 hr while maintaining at pH=10 with 8N aqueous potassium hydroxide solution. The reaction mixture was adjusted to pH=2.0 with 6N aqueous hydrochloric acid solution and the organic layer and aqueous layer were partitioned. The aqueous layer was extracted three times with ethyl acetate (55.0 ml, 27.5 ml, 27.5 ml) and the ethyl acetate layer and the organic layer partitioned earlier were combined. The organic layer was adjusted to pH=10 with 1N aqueous sodium hydroxide solution and back extracted. The resulting organic layer was back extracted with aqueous sodium hydroxide solution (pH=10, 55.0 ml). The two aqueous layers were combined and adjusted to pH=1.7 with 6N aqueous hydrochloric acid solution, and the aqueous layer was extracted twice with ethyl acetate (55.0 ml, 55.0 ml). The solvent of this solution was removed under reduced pressure, and ethyl acetate (81 ml) and hexane (115 ml) were added, dissolved with heating at 65° C. and cooled to 5° C. over 6 hr. The mixture was stirred at 5° C. for 7 hr, and the obtained crystals were collected by filtration. The crystals were dried under reduced pressure to give the objective (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (7.89 g, yield 39%).
  • 38
  • [ 98760-08-8 ]
  • [ 105-53-3 ]
  • [ 98737-33-8 ]
YieldReaction ConditionsOperation in experiment
With sodium In ice-water; ethanol 1.e 1e 1e 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-ethoxycarbonyl-dihydrofuran-2-(3H)-one 3.4 g of sodium are added in portions to a solution of 26 ml of malonic acid diethyl ester in 260 ml of abs. ethanol When the sodium has been consumed (approximately 1.5 h) a solution of 13 g of 2(R)-[1(S)-(Boc-amino)-2-phenylethyl]-oxirane in 100 ml of ethanol is added dropwise over the course of 10 min. After stirring for 5 h at RT, the reaction mixture is poured onto 1.5 liters of ice-water and adjusted to pH 4 with 10% citric acid. After extracting four times with ether, the combined organic phases are washed in succession twice with saturated aqueous sodium hydrogen carbonate solution, once with brine, again with saturated aqueous sodium hydrogen carbonate solution, with water and again with brine. After concentrating the solvent, the title compound is obtained by column chromatography (SiO2, hexane/ethyl acetate: 4/1). TLC Rf (C)=0.22; FAB-MS (M+H)+ =378.
With sodium In ice-water; ethanol 1 1 e) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-carbethoxy-dihydrofuran-2-(3H)-one 1 e) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-carbethoxy-dihydrofuran-2-(3H)-one 3.4 g of sodium are added in portions to a solution of 26 ml of malonic acid diethyl ester in 260 ml of absolute ethanol. When the sodium has been consumed (about 1.5 hours), a solution of 13 g of 2(R)-[1(S)-(Boc-amino)-2-phenylethyl]-oxirane in 100 ml of ethanol is added dropwise in the course of 10 minutes. After being stirred for 5 hours at room temperature, the reaction mixture is poured onto 1.5 liters of ice-water and adjusted to pH 4 with 10% citric acid. After extraction four times with ether, the combined organic phases are washed in succession twice with saturated aqueous sodium hydrogen carbonate solution, once with brine, again with saturated aqueous sodium hydrogen carbonate solution, with water and again with brine. After evaporation of the solvent, the title compound is obtained by column chromatography (SiO2, hexane/ethyl acetate: 4/1). TLC Rf (C)=0.22; FAB-MS (M+H)+ =378.
  • 39
  • [ 103127-52-2 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate; 3-chloro-benzenecarboperoxoic acid In dichloromethane 1.d 1d 1d 2(R)-[1(S)-(Boc-amino)-2-phenylethyl]-oxirane A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added over the course of 15 min at from 0° to 5° C. to a solution of 1.45 g of N-Boc-1-phenyl-3-buten-2(S)-amine in 20 ml of methylene chloride. The batch is stirred for 18 h at that same temperature and is then stirred for a further 8 h, with heating to RT, to complete the reaction and poured onto ice-cold 10% sodium carbonate solution. The aqueous phase is extracted three times with ether.
  • 40
  • [ 259752-50-6 ]
  • (2R,3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-oxirane [ No CAS ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
0.236 g (90%) With potassium carbonate In tetrahydrofuran; methanol; water; ethyl acetate 5 (2R,3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-epoxide Example 5 (2R,3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-epoxide A mixture composed of 1.0 mmol (0.401 g) of (2S,3S)-1-acetoxy-3-(t-butoxycarbonylamino)-2-methanesulfonyloxy-4-phenylbutane, 2.2 mmol (0.304 g) of potassium carbonate, 10 ml of methanol and 10 ml of tetrahydrofuran was stirred at 25° C. for 20 hours. Thereafter, 10 ml of ethyl acetate and 10 ml of water were added for extraction of the product. The organic layer was separated, dried and the solvent was distilled off under reduced pressure to give a crude product. Purification by silica gel column chromatography gave 0.236 g (90%) of (2R,3S)-3-(t-Butoxycarbonylamino)-4-phenylbutane 1,2-oxirane. 1H-NMR (400 MHz, CDCl3) δ 1.38 (s, 9H), 2.76-2.81 (m,2H), 2.83-2.99 (m, 3H), 3.76 (br s, 1H), 4.45 (br, 1H), 7,21-7.33 (m, 5H) 13C-NMR (100 MHz, CDCl3) δ 28.26, 37.58, 46.91, 53.03, 53.20, 80.03, 126.68, 128.55, 129.46, 136.69, 155.21.
  • 41
  • [ 3468-17-5 ]
  • [ 98760-08-8 ]
  • C24H31N3O3 [ No CAS ]
  • 42
  • [ 1028634-77-6 ]
  • [ 98760-08-8 ]
  • [ 1028634-74-3 ]
YieldReaction ConditionsOperation in experiment
In toluene at 80℃; for 48h; 2 Example 2 - Preparation of t-Boc-protected compound (6); In a 250 ml round bottom flask 11,3 g of epoxide (10), and 18.5 g of compound (9), prepared as described in example 1, were heated at 80°C for 48 hours in toluene (110 ml). The reaction mixture was then cooled and filtered. The solid was washed with toluene and dried to give 13.8 g of an off-white product.
  • 43
  • [ 2740-83-2 ]
  • [ 98760-08-8 ]
  • [ 388071-74-7 ]
YieldReaction ConditionsOperation in experiment
70% In isopropyl alcohol; at 75℃; for 9h; To a solution of tert-butyl {(S)-1-[(S)-oxiran-2-yl]-2-phenylethyl}carbamate (7) (0.13 mmol, 34.2 mg) in iPrOH (2 mL), 3-(trifluoromethyl)benzylamine (8) (0.36 mmol, 0.05 ml) was added at 23 C. The resulting mixture was heated at 75 C. for 9 h. [0105] Isopropanol was removed under reduced pressure and the residue was purified by silica gel column chromatography (1-3% MeOH/CH2Cl2) to furnish tert-butyl {(2S,3R)-3-hydroxy-1-phenyl-4-[(3-(trifluoromethyl)-benzylamino]butan-2-yl}carbamate in 70% yields (39.9 mg).
In isopropyl alcohol; at 20 - 65℃;Inert atmosphere; EXAMPLE 9; 9.1: Base; N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide9.1.1: tert-Butyl[(1S,2R)-1-benzyl-2-hydroxy-3-[3-(trifluoromethyl)benzyl]-amino}propyl]carbamate Poured, over 20 min, into a suspension, under argon, of 10 g of tert-butyl [S-(R,R)]-(-)-(1-oxiranyl-2-phenylethyl)carbamate in 100 cm3 of 2-propanol is a solution of 6.5 cm3 of 3-(trifluoromethyl)benzylamine in 20 cm3 of 2-propanol at a temperature close to 20 C. The reaction mixture is heated at a temperature of 65 C. for 20 h. It is then cooled in order to be concentrated using a rotary evaporator under reduced pressure (5 kPa). The 20 g of colorless oil obtained are purified by flash chromatography over silica (column: 400 g; particle size: 15-40 mum; flow rate: 20 cm3/min; eluant: 100% dichloromethane to 95% dichloromethane/5% methanol gradient over 140 min). After concentrating the fractions under reduced pressure, 11 g of tert-butyl[(1S,2R)-1-benzyl-2-hydroxy-3-[3-(trifluoromethyl)benzyl]amino}propyl]carbamate are obtained in the form of a white solid. LC-MS-DAD-ELSD: 439(+)=(M+H)(+); 483(-)=(M+formic acid-H)(-) NMR: For this batch, all the signals are broad with: 1.22 (s, 9H) 2.25 (m, 1H) 2.38-2.65 (partially masked m, 3H) 2.99 (m, 1H) 3.51-3.65 (m, 2H) 3.80 (m, 2H) 4.83 (d, J=6.3 Hz, 1H) 6.61 (d, J=9.1 Hz, 1H) 6.99-7.30 (m, 5H) 7.48-7.80 (m, 4H).
In isopropyl alcohol; for 16h;Reflux; c) [(1S,2R)-1-Benzyl-2-hydroxy-3-(3-trifluoromethyl-benzylamino)-propyl]-carbamic acid tert-butyl ester A mixture of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (183 mg, 0.695 mmol) and (3-(trifluoromethyl)phenyl)methanamine (305 mg, 1.74 mmol) in 2-propanol (4 mL) was refluxed for 16 hr. The reaction mixture was cooled to room temperature and all volatiles were removed under reduced pressure. The residue was poured into 20 mL 1 M KHSO4 and extracted with DCM (2*15 mL). The organic layers were concentrated and the residue was used without further purification in the subsequent step. MH+: 439.3
In isopropyl alcohol; for 16h;Reflux; c) [(IS ,2R)- 1 -B enzyl-2-hydroxy-3 -(3 -trifluoromethyl-benzylamino)-propyl] -carbamic acid tert-butyl ester; A mixture of tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate (183 mg, 0.695 mmol) and (3-(trifluoromethyl)phenyl)methanamine (305mg, 1.74 mmol) in 2-propanol (4 mL) was refluxed for 16 hr. The reaction mixture was cooled to room temperature and all volatiles were removed under reduced pressure. The residue was poured into 20 mL 1 M KHS04 and extracted with DCM (2 x 15 mL). The organic layers were concentrated and the residue was used without further purification in the subsequent step. MH+: 439.3

  • 44
  • [ 98760-08-8 ]
  • [ 198904-85-7 ]
  • [ 1140968-73-5 ]
  • [ 198904-86-8 ]
  • 45
  • [ 98760-08-8 ]
  • [ 589-15-1 ]
  • [ 105-53-3 ]
  • [ 854757-12-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane; diethyl malonate With sodium ethanolate In ethanol at 0 - 25℃; for 18.1667h; Stage #2: 1-bromomethyl-4-bromobenzene In ethanol at 0 - 50℃; for 3h; Stage #3: With hydrogenchloride In ethanol; water at 0℃; 92.A A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with a solution of NaOEt (13.5 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 18 hours. The reaction was re-cooled to 0° C. and treated with a solution of 4-bromobenzyl bromide (9.5 g, 38.0 mmol) in ethanol (40 mL) was, stirred at 50° C. for 3 hours, cooled to 0° C. and adjusted to neutral pH by addition of 4N HCl. The ethanol was removed under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (22.4 g), which was used without further purification.
  • 46
  • [ 98760-08-8 ]
  • [ 52199-24-3 ]
  • [ 105-53-3 ]
  • [ 854753-93-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane; diethyl malonate With sodium ethanolate In ethanol at 0 - 25℃; for 3.16667h; Stage #2: 2-[(4-bromomethyl)phenyl]pyridine In ethanol at 0 - 25℃; for 16h; Stage #3: With hydrogenchloride; lithium hydroxide; water more than 3 stages; 1.A A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with sodium ethoxide (17 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 2 hours, treated with additional diethyl malonate (0.58 mL, 3.4 mmol) and stirred for 1 hour. The reaction was cooled to 0° C., and solid 2-[4-(bromomethyl)phenyl]pyridine (9.43 g, 38.0 mmol) was added in four increments over 10 minutes. To this suspension was added ethanol (20 mL) and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was treated with LiOH monohydrate (4.6 g, 109.6 mmol) solution in water (30 mL), stirred at 25° C. for 16 hours, cooled to 0° C., adjusted to pH 5 by addition of 4N HCl and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (100 mL) was heated at reflux for 16 hours, cooled to 25° C. and concentrated to afford the title compound (21.4 g).
  • 47
  • [ 78-81-9 ]
  • [ 98760-08-8 ]
  • [ 98-68-0 ]
  • [ 159006-03-8 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: isobutylamine; (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane In isopropyl alcohol at 80℃; for 2h; Stage #2: 4-methoxy-phenyl-sulphonyl chloride With triethylamine In dichloromethane at 25℃; for 1h; 521.A tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propylcarbamate To a solution of (2R,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (0.2 g, 0.76 mmol) in 2-propanol (4 mL) was added the isobutylamine (1.5 mL, 20 equivalents), and the mixture was heated at 80° C. for 2 hours. The solvents were evaporated, and the crude residue was dissolved in dichloromethane (8 mL) and treated with triethylamine (0.32 mL, 3 equivalents) and p-methoxybenzenesulfonyl chloride (0.173 g, 1.1 equivalents) and the mixture is stirred at 25° C. for 1 h. The solvents were evaporated and the crude residue was purified using 0.5% methanol/dichloromethane to give 0.356 g (92%) of the title compound.
  • 48
  • [ 98760-08-8 ]
  • [ 52199-24-3 ]
  • [ 105-53-3 ]
  • tert-butyl (1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane; diethyl malonate With sodium ethanolate In ethanol at 0 - 25℃; for 3.166h; Stage #2: 2-[(4-bromomethyl)phenyl]pyridine In ethanol at 0 - 25℃; for 16.166h; Stage #3: With hydrogenchloride; lithium hydroxide more than 3 stages; 1.A tert-butyl (1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate EXAMPLE 1A tert-butyl(1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate A solution of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with sodium ethoxide (17 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 2 hours, treated with additional diethyl malonate (0.58 mL, 3.4 mmol) and stirred for 1 hour. The reaction was cooled to 0° C., and solid 2-[4-(bromomethyl)phenyl]pyridine (9.43 g, 38.0 mmol) was added in four increments over 10 minutes. To this suspension was added ethanol (20 mL) and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was treated with LiOH monohydrate (4.6 g, 109.6 mmol) solution in water (30 mL), stirred at 25° C. for 16 hours, cooled to 0° C., adjusted to pH 5 by addition of 4N HCl and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (100 mL) was heated at reflux for 16 hours, cooled to 25° C. and concentrated to afford the title compound (21.4 g).
  • 49
  • [ 1146967-64-7 ]
  • [ 98760-08-8 ]
  • [ 1146967-61-4 ]
YieldReaction ConditionsOperation in experiment
75% In isopropyl alcohol at 65℃; for 15h; 5.1 Epoxide 10a (1.83 g, 6.95 mmol) was added to a pressure flask containing a solution of amine 11a (1.14 g, 13.9 mmol) in isopropanol (33.0 mL). The reaction was then sealed and heated to 65 0C for 15 hours. After cooling to room temperature, the reaction was concentrated to dryness and purified by silica gel column chromatography on an ISCO system (0-10% MeOHZCFI2Cl2) to afford amino alcohol 12a (1.80 g, 75%) as a white solid. MS (ESI) 346.4 [(M + H)+].
  • 50
  • [ 98760-08-8 ]
  • [ 165331-67-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane With lithium azide; ammonium chloride In ethanol; water at 75℃; for 2h; Stage #2: With trifluoroacetic acid In dichloromethane at 25℃; for 1h; 274A Example 274A(2R,3S)-3-amino-1-azido-4-phenylbutan-2-olA solution of (2R,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (1.17 g) in ethanol:water (45 mL, 4:1) was treated with lithium azide (1.09 g, 5 equivalents) and NH4Cl (1.19 g, 5 equivalents), stirred at 75° C. for 2 hours and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated. A solution of the residue in dichloromethane/trifluoroacetic acid (40 mL, 1:1) was stirred at 25° C. for 1 hour and concentrated to give the title compound.
  • 51
  • [ 872703-56-5 ]
  • [ 98760-08-8 ]
  • [ 857904-19-9 ]
YieldReaction ConditionsOperation in experiment
62.8% In isopropyl alcohol for 16h; Reflux; 9.3 Step 3: Synthesis of methyl (S)-l -(2-benzyl-2-((2S S)-3-(tert- bιιtoxycarbonylami o)-2 ιydroxy-4ψhenylbι^tΛ1)hydrazinyl)-3 -dimethyl- l - oxobu tan -2 -y lea rba mate: A stirred solution of (S)-methyl l -(2-benzylhydrazinyl)-3,3-dimethyl- l - oxobutan-2-ylcarbamate (step 2, about 2. 1 g, 7.167 n mol) and tert-butyl (S)- 1 -((R)- oxiran-2-yl)-2-phenylethylcarbamate (about 2.82 g, 10.750 mmol) in isopropanol (20 ml) was refluxed for about 16 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated and the resulting crude was purified by silica gel column ( 100-200 mesh, elution: 30% EtOAc in Hexane) to afford the title compound as an off white solid. Wt:2.5 g; Yield: 62.8 %; NMR (300 MHz, CDCI3): δ 7.36-7. 12 (m, 10H), 6.26 (s, 1 H), 5.21 (d, 1 H), 5.05 (d, 1 H, J = 9.3 Hz), 4.69 (s, 1 H), 4.07 (d, 1 H, J = 13.8 Hz), 3.85 (d, 1 H, J = 13.8 Hz), 3.66 (s, 3H), 3.58- 3.42 (m, 3H), 2.95-2.83 (m, 3H), 2.59-2.5 1 (m, 1 H), 1.37 (s, 9H), 0.72 (s, 9H); Mass: [M+H]+ 556 (25%), [M+Na]+ 579 ( 100%); BR (KBr, cm 1 ): 3401 , 3294, 2978, 2964, 1695, 1655, 1509, 1457, 1446, 1367, 1326, 1246, 1 171 , 1 154, 1018, 794, 747,698; M.R: 1 81.8 UC - 184.9 X.
  • 52
  • methyl N-[(1S)-2,2-dimethyl-1-[N'-({4-[2-(morpholin-4-yl)ethoxy]phenyl}methyl)hydrazinecarbonyl]propyl]carbamate [ No CAS ]
  • [ 98760-08-8 ]
  • [ 1350924-13-8 ]
YieldReaction ConditionsOperation in experiment
50% In isopropyl alcohol for 12h; Reflux; 27.1 Step 1: Synthesis of methyl N-[(lS)-l-(N'-[(2Sl3S)-3-([(tert- butoxy)carbonyl)amino}-2-hydroxy-4-phenylbutyl]-N'-{{4-[2-(morpholin-4- yl )ethoxy) phenyl Jmethy I )h hy I propyl) carbamate:IPA (30 ml) was added to a mixture of (S)-l-((R)-oxiran-2-yl)-2- phenylethylcarbamate (0.626 g) and methyl N-[(lS)-2,2-dirnethyl-l-[N'-({4-[2- (moipholin-4-yl)ethoxy]phenyl }methyl)hydrazinecarbonyl]propyl]carbamate (Intermediate 15, 1.0 g) and the reaction mixture was stirred for 12 hours at refluxed temperature. After completion of the reaction (monitored by TLC), cooled the reaction mixture to room temperature, poured into an ice cold water, and collected the solid by filtration and dried the compound to get pure 800 mg of product (50 % Yield). NMR (300 MHZ, CDC1?): δ 7.14-7.31 (7H. m), 6.84 (2H, d, J = 8.4 Hz), 6.52 (1H, brs), 5.30 (1H, d, J = 9.0 Hz), 5.08 (1H, d, J = 9.0 Hz), 4.70 (1H, brs), (4.06-4.10 (2H, m), 3.65-4.00 (5H, m), 3.64 (3H, s), 3.4-3.6 (2H, m), 2.77-2.81 (5H, m), 2.56-2.59 (4H, m), 1.36 (9H, s), 0.78 (9H, s); Mass: [M++H] 685 (100%).
  • 53
  • [ 1313358-60-9 ]
  • [ 98760-08-8 ]
  • [ 1313358-61-0 ]
YieldReaction ConditionsOperation in experiment
90% In isopropyl alcohol for 16h; Reflux; 10.4 Step 4:Synthesis of methyl ' o)-2-hydroxy-4-phenylbuty)hydrazny)-3oxobu tan-2-ylca rbamate :A stirred solution of (S)-methyl l -(2-(biphenyl-4-ylmethyl)hydrazinyl)-3,3- dimethyl- l -oxobutan-2-ylcarbamate (step 3, about 1 .5 g, 4.065 mmol) and tert-butyl(S)- l -((R)-oxiran-2-yl)-2-phenylethylcarbamate (about 1 .06 g, 4.065 mmol) in isopropanol (30 ml) was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was brought to room temperature and ice was added then the solid formed was filtered, washed with water and dried under vacuum. Wt: 2.3 g; Yield: 90%; NMR (300 MHz, CDCI3): δ 7.59-7.50 (m,4H), 7.49-7.3 1 (m, 5H), 7.29-7. 13 (m, 5H), 6.44 (s, 1 H), 5.27 (d, 1 H, J = 9.3 Hz), 5. 10 (d, 1 H), 4.76 (s, 1 H), 4. 12 (d, 1 H, J = 13.5 Hz), 3.89 (d, 1 H, 13.5 Hz), 3.64 (s, 3H), 3.7 1 -3.47 (m, 3H), 2.98-2.83 (m, 3H), 2.64-2.57 (m, 1 H), 1.36 (s, 9H), 0.7 1 (s, 9H); Mass: [M+Na]+ 655 ( 100%); IR (KBr, cm" 1 ): 3397, 3030, 2965, 1692, 1655, 15 13, 1456, 1392, 1367, 1428, 1 17 1 , 1053, 1020, 762, 747; M.R: 199.5 °C -201 °C.
  • 54
  • [ 1313358-65-4 ]
  • [ 98760-08-8 ]
  • [ 1313358-66-5 ]
YieldReaction ConditionsOperation in experiment
44% In isopropyl alcohol for 16h; Reflux; 11.6 Step 6: Synthesis of (S) methyl -l-(2-((2S,3S)-3-(tert-butoxycarbonylamino)-2- hydrox -4^henylbut}'l)-2-(4-(pyridin-2-yl)benzyl)hydrazinyl)-4-methyl-l- oxopentan-2-ylcarbamate :A stirred solution of (S)-methyl 4-methyl-l-oxo-l-(2-(4-(pyridin-2- yl)benzyl)hydrazinyl)pentan-2-ylcarbamate (step 5, about 2.4 g, 6.486 mmol) and tert-butyl (S)-l-((R)-oxiran-2-yl)-2-phenylethylcarbamate (about 1.7 g, 6.486 mmol) in Isopropanol (40 ml) was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the solvent was cooled to room temperature and poured in to an ice water, the resulting solid title compound was filtered and dried under vacuum. Wt:1.5 g; Yield: 44%; NMR (300 MHz, CDCh): δ 8.67 (d, 1H, J = 4.8 Hz).7.93 (d, 2H, J = 8.1 Hz), 7.81-7.68 (m, 2H), 7.41 (d, 2H, J = 7.8 Hz), 7.38-7.11 (m, 6H), 6.80 (s, 1H), 5.10 (d, 1H, J = 9.3 Hz), 4.90-4.70 (m, 3H), 4.12 (d, 1H, J = 13.5 Hz), 3.80-3.78 (m, 2H), 3.77-3.62 (m, 1H), 3.61 (s, 3H), 3.58-3.46 (m, 1H), 2.98-3.86 (m.2H), 2.63-2.52 (m, 1H), 1.37 (s, 9H), 1.30-1.11 (m, 3H), 0.79-0.64 (m, 6H); Mass: [M+H]+634 (100%); IR (KBr, cm"1): 3373, 3263, 2958, 1691, 1516, 1467, 1366, 1284, 1249, 1171, 1052, 1018, 779, 751; M.R: 176.4 °C -183.1 °C.
  • 55
  • [ 98760-08-8 ]
  • [ 77-76-9 ]
  • [ 1352280-28-4 ]
YieldReaction ConditionsOperation in experiment
59% With magnesium sulfate; toluene-4-sulfonic acid; lithium iodide In toluene at 75℃; for 6h; Representative procedure for the cascade reaction of epoxides 3 to iodo-N,O-acetonide aminals 7. General procedure: To a solution of 3b (0.100 g, 0.465 mmol) in dry toluene (5 mL) was added LiI (0.156 g, 1.16 mmol), TsOH·H2O (0.035 g, 0.186 mmol), 2,2-dimethoxypropane (2.8 mL), and anhydrous MgSO4 (0.279 g, 2.33 mmol) was added. The reaction was heated to 75 °C and allowed to stir for 6 h. The reaction was then allowed to cool to room temperature and filtered. The filtrate was evaporated, and the residue dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate, water, and brine. The solution was then dried with magnesium sulfate and filtered. The crude product was purified via column chromatography (12:1 hexanes:EtOAc) to afford 7b (121 mg, 68%) as a colorless solid.
  • 56
  • [ 98760-08-8 ]
  • [ 635728-49-3 ]
  • 57
  • [ 4897-50-1 ]
  • [ 98760-08-8 ]
  • [ 1418733-36-4 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran for 48h; Reflux;
In ethanol at 80℃; for 0.5h; Microwave irradiation; General experimental procedure General procedure: General experimental procedure. Briefly, a 50 mL round-bottomed wascharged with 3.8 mmol of (2R,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane(I), amines (3.8 mmol), 5 mL of ethanol, and the contents werestirred under microwave irradiation for 30 min at 300 W/80 C. Thereaction mixture was then allowed to attain room temperature, and thesolvent was concentrated under reduced pressure. Thus, obtained crudeproduct was recrystallized from ethyl acetate and hexane (1:9) and usedfor the next steps. In the next step, a 100 mL round-bottom flask, theobtained BOC protected intermediate (2.0 mmol) was dissolved in 20mL of dichloromethane (DCM) and treated with trifluoracetic acid (TFA)(3 mL, 15% of DCM) slowly. The reaction mixture was stirred at roomtemperature for 4 h and after completion of the reaction, excess of DCMand TFA were removed under reduced pressure. The reaction mixturewas adjusted pH, 8-9 using 1 N NaOH, and then extracted with ethylacetate(3x25 mL) and washed with brine solution (3x15 mL). Theorganic layer was dried over anhydrous sodium sulfate and the excess ofethylacetate was removed under reduced pressure to afford the deprotectedintermediates, which was used as such for the next step of theprocedure. Next, acid (1.5 mmol) and triethylamine (TEA) (4.5 mmol)was dissolved in 20 mL of DCM and the contents were stirred for 30 minat room temperature, followed by the addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCHCl) (3.0 mmol). After 30 min. stirring,hydroxybenzotriazole (HOBt) (3.0 mmol) was added followed bythe addition of deprotected intermediate (1.0 mmol) at 0 C. The contentswere initially stirred at 0 C for 30 mins. And then at room temperaturefor 24 h. After completion of the reaction, excess DCM wasremoved under reduced pressure and the final coupling product wasextracted with ethylacetate (3x25 ml). The organic layer was dried overanhydrous sodium sulfate, the solvent was removed, and the product was purified by column chromatography (70: 30, hexane: ethylacetate).
  • 59
  • [ 74702-89-9 ]
  • [ 98760-08-8 ]
  • [ 1422208-38-5 ]
  • 60
  • [ 288-32-4 ]
  • [ 98760-08-8 ]
  • C18H25N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 4.2.9 N1-((R)-1-(4-Fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(1H-pyrazol-1-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (20) General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added pyrazole (51 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product 19 used without further purification. To a solution of the product (99 mg, 0.30 mmol) in DMF (8 mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 mg, 0.27 mmol), DIPEA (99 μL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4 and evaporated to give the residue, which was purified by silica gel chromatography to afford 20 (149 mg, 91.3 %).
  • 61
  • [ 288-88-0 ]
  • [ 98760-08-8 ]
  • C17H24N4O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 4.2.9 N1-((R)-1-(4-Fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(1H-pyrazol-1-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (20) General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added pyrazole (51 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product 19 used without further purification. To a solution of the product (99 mg, 0.30 mmol) in DMF (8 mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 mg, 0.27 mmol), DIPEA (99 μL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4 and evaporated to give the residue, which was purified by silica gel chromatography to afford 20 (149 mg, 91.3 %).
  • 62
  • [ 25222-43-9 ]
  • [ 98760-08-8 ]
  • C19H27N3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1.0h; General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added pyrazole (51 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product 19 used without further purification. To a solution of the product (99 mg, 0.30 mmol) in DMF (8 mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 mg, 0.27 mmol), DIPEA (99 muL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4 and evaporated to give the residue, which was purified by silica gel chromatography to afford 20 (149 mg, 91.3 percent).
  • 63
  • [ 37622-90-5 ]
  • [ 98760-08-8 ]
  • [ 1470073-14-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 4.2.9 N1-((R)-1-(4-Fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(1H-pyrazol-1-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (20) General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added pyrazole (51 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product 19 used without further purification. To a solution of the product (99 mg, 0.30 mmol) in DMF (8 mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 mg, 0.27 mmol), DIPEA (99 μL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4 and evaporated to give the residue, which was purified by silica gel chromatography to afford 20 (149 mg, 91.3 %).
  • 64
  • [ 98760-08-8 ]
  • [ 288-94-8 ]
  • C16H23N5O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 4.2.12 N1-((R)-1-(4-Fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(1H-tetrazol-1-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (23) and N1-((R)-1-(4-fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(2H-tetrazol-2-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (24) General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added tetrazole (53 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product used without further purification. To a solution of the product (100 mg, 0.30 mmol) in DMF (8mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 g, 0.27mmol), DIPEA (99 μL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4, filtered and evaporated to give the residue, which was purified by silica gel chromatography to afford 23 (68 mg, 41.3 %) and 24 (74 mg, 45.4 %)
  • 65
  • [ 288-13-1 ]
  • [ 98760-08-8 ]
  • [ 1470073-07-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 4.2.9 N1-((R)-1-(4-Fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(1H-pyrazol-1-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (20) General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added pyrazole (51 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product 19 used without further purification. To a solution of the product (99 mg, 0.30 mmol) in DMF (8 mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 mg, 0.27 mmol), DIPEA (99 μL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4 and evaporated to give the residue, which was purified by silica gel chromatography to afford 20 (149 mg, 91.3 %).
57 mg With sodium carbonate In N,N-dimethyl-formamide at 110℃; for 1h; Microwave irradiation; 1.1 The epoxy compound(2S, 3S) -1,2-epoxy-3- (N-tert-butoxycarbonylamino) -4-Phenylpropane(50 mg, 0.19 mmol)Dissolved in 2mL DMF,To the system was added pyrazole (13 mg, 0.19 mmol)Catalytic amount of sodium carbonate.And reacted at microwave at 110 ° C for 1 hour.At the end of the reaction, 25 mL of water was added to the system,Ethyl acetate extraction (25 mL x 2),Combine organic phase,Saturated brine (25 mL),Dried over anhydrous sodium sulfate,filter,concentrate,A white solid(2S, 3S) -1-benzyl-2-hydroxy-3-pyrazolyl carbamate57 mg
  • 66
  • [ 288-94-8 ]
  • [ 98760-08-8 ]
  • C16H23N5O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 4.2.12 N1-((R)-1-(4-Fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(1H-tetrazol-1-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (23) and N1-((R)-1-(4-fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-1-phenyl-4-(2H-tetrazol-2-yl)butan-2-yl)-5-(N-methylmethylsulfonamido)isophthalamide (24) General procedure: To a solution of compound 6 (131 mg, 0.50 mmol) in DMF (2 mL) was added tetrazole (53 mg, 0.75 mmol), K2CO3 (138 mg, 1.00 mmol). The mixture was heated at 100 °C for 1 h. Reaction mixture was cooled, ice cold water (30 mL) was added and then extracted with EtOAc twice (30 mL × 2) and the combined organic layers were washed by saturated brine (30 mL). Then the organic layers were dried over Na2SO4, filtered and evaporated to afford the crude product used without further purification, To a solution of CF3COOH (1 mL) in CH2Cl2 (4 mL) was added the remaining solid (92 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 h, and then it was concentrated under reduced pressure to afford the crude product used without further purification. To a solution of the product (100 mg, 0.30 mmol) in DMF (8mL) was added 3-[(R)-1-(4-fluorophenyl)ethylaminocarbonyl]-5-[methyl (methylsulfonyl)amino]benzoic acid (106 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol), HOBt (37 g, 0.27mmol), DIPEA (99 μL, 0.60 mmol) was added and the mixture was allowed to react overnight at room temperature. Then the resulting mixture was diluted by 50 mL EtOAc and washed with dilute HCl aqueous solution (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL) sequentially. The organic layers were dried over Na2SO4, filtered and evaporated to give the residue, which was purified by silica gel chromatography to afford 23 (68 mg, 41.3 %) and 24 (74 mg, 45.4 %)
  • 68
  • [ 24812-90-6 ]
  • [ 98760-08-8 ]
  • (2S,3R)-3-(3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutylamino)-4-methoxybenzoic acid methyl ester [ No CAS ]
  • 69
  • [ 98760-08-8 ]
  • [ 52568-28-2 ]
  • [(1S,2R)-1-benzyl-2-hydroxy-3-(1-methyl-1-pyridin-2-ylethylamino)propyl]carbamic acid tert-butyl ester [ No CAS ]
  • 70
  • [ 99980-40-2 ]
  • [ 98760-08-8 ]
  • [(1S,2R)-1-benzyl-2-hydroxy-3-(1-methyl-1-pyridin-3-ylethylamino)propyl]carbamic acid tert-butyl ester [ No CAS ]
  • 71
  • [ 98760-08-8 ]
  • [ 29490-19-5 ]
  • [ 1346158-03-9 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine; In methanol; at 20℃; for 2h; <strong>[29490-19-5]2-mercapto-5-methyl-1,3,4-thiadiazole</strong> 4 (1.5 mmol),triethylamine (TEA) (1.6 mmol) and epoxide 1 (1.6 mmol)were dissolved in methanol (10 mL) and stirred at roomtemperature for 2 hours. After this period, the solvent wasremoved by evaporation and the crude product was purifiedby crystallization in methanol/water (7:3). Yield 80%, mp114-116C, 1H-NMR (DMSO-d6) : 7.26 (t, 2H, J = 7.3;Ph); 7.19-7.13 (m, 3H; Ph); 6.76 (d, 1H, J = 8.7; NH); 5.54(d, 1H, J = 6.2; OH); 3.66-3.54 (m, 3H; H3, H2 and H4b);3.21 (dd, 1H, 1J = 13.0; 2J = 8.2; H4a); 3.05 (dd, 1H, 1J =14.1; 2J = 2.8; H1b); 2.66 (s, 3H; CH3); 2.56 (dd, 1H, 1J =13.8; 2J = 10.1; H1a); 1.26 (s, 9H; Boc), 13C-NMR (DMSOd6): 165.9 (C17); 165.0 (C18); 155.3 (C=O); 139.3 (C11);129.3 (C13 and C15); 127.9 (C12 and C16); 125.7 (C14);77.6 (C(Boc)); 71.7 (C3); 56.2 (C2); 39.2 (C4); 35.9 (C1);28.2 (CH3(Boc)); 15.2 (CH3(Het)), MS (ESI+) m/z (relintensity): 418.1 (M+ + Na, 100%), C18H25N3O3S2.
  • 72
  • [ 165727-45-7 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
74% With sodium hydroxide; In methanol; ethanol; at 0 - 20℃; for 4.5h; 100 mL of absolute ethanol was added to the crude product obtained in the above Example 5, cooled to 0 C, and 50 mL of sodium hydroxide (55 mmol) in methanol was slowly added dropwise. After the dropwise addition in 0.5 h, the temperature was naturally raised to room temperature and stirring was continued. 4h, the reaction was stopped, the solvent was evaporated under reduced pressure, and 100 mL of distilled water and 100 mL of dichloromethane were added to the residue, and the mixture was stirred for 0.5 hr. The mixture was allowed to stand, the aqueous layer was separated, and the aqueous layer was washed with dichloromethane. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to give crystals crystals crystals crystals crystals crystals crystals (IV) Compound], the ee value was 97.2%.
  • 73
  • tert-butyl (4S,5R)-4-benzyl-5-(chloromethyl)-2-oxooxazolidine-3-carboxylate [ No CAS ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
95% With potassium hydroxide In ethanol at 5℃; for 0.5h; tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-phenylethyl)carbamate (1) Compound 11 (10.0 g, 31.0 mmol) and KOH (5.25 g, 93.0 mmol) were added respectively to 25 mL ethanol and cooled to ca. 5 °C. With stirring, KOH in ethanol was gradually added to the mixture. Then after 30 min the reaction mixture was concentrated in a vacuum, dissolved in 100 mL ethyl acetate, and washed with water (30 mL) and brine (30 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated in a vacuum to give a colorless liquid (7.75 g, 95%), which could also be solidified at 20 °C to afford the title product as a white solid.
  • 74
  • [ 37622-90-5 ]
  • [ 98760-08-8 ]
  • C21H29N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
81.2% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; Microwave irradiation; 50 Example 50 Epoxide Ib (52 mg, 0.2 mmol)And pyrazole-4-one (42 mg, 0.3 mmol)Was dissolved in 5 mL of DMF,Potassium carbonate (42 mg, 0.3 mmol) was added.Microwave reaction 100 ,1 hour.To the system was added 50 mL of water,Ethyl acetate extraction (50 mL x 2),Combine organic phase,Saturated brine washing,Dried over anhydrous sodium sulfate,filter,concentrate,The column chromatography gave white solid Ic (65 mg, yield: 81.2%, melting point: 102-104 ° C).The compound Ic (40 mg, 0.1 mmol)Was dissolved in 10 mL of anhydrous tetrahydrofuran,Two equivalents of triethylamine (40 [mu] L, 0.2 mmol) were added,Two equivalents of methanesulfonyl chloride (15 [mu] L, 0.2 mmol)Stir at room temperature for two hours.Methanol was added to quench the excess methanesulfonyl chloride,Continue to stir for half an hour,Recycle solvent column chromatography gave Compound Id (39 mg, yield: 81.3%, melting point: 144-146 ° C). Id(39mg0.08mmol)2mL DMF2(10mg0.16mmol)6050mL(50mL×2)Ie (30mg88.2%118-120) Compound Ie (30 mg, 0.07 mmol) was dissolved in 4 mL of dichloromethane,To the system was added 1 mL of trifluoroacetic acid,Room temperature reaction 2h.concentrate,The resulting amine did not proceed directly to the next reaction.The acid (30 mg, 0.08 mmol) was dissolved in 2 mL of DMF,EDCI (20 mg, 0.10 mmol) was added,HOBt (10 mg, 0.07 mmol),Stir at room temperature for 10 min.The amine obtained in the previous step was dissolved in 2 mL of DMF,DIPEA (50 [mu] l, 0.3 mmol) was added,This was added dropwise to the above reaction system,And then under microwave conditions 70 reaction 15min.To the system was added 30 mL of water,Ethyl acetate extraction (50 mL x 2),Combine organic phase,Dilute acid wash (25mL × 2),Saturated sodium bicarbonate (25 mL x 2),Saturated brine washing,Dried over anhydrous sodium sulfate,filter,concentrate,Column chromatography gave a white solid compound If (42 mg, yield: 85.7%, m.p .: 157-159 ° C).The compound [...] (42 mg, 0.06 mmol)Was dissolved in a mixed solvent of 20 mL (ethanol / water = 3/1, volume ratio)10 equivalents of ammonium chloride (30 mg, 0.6 mmol) were added successively,10 equivalents of zinc powder (40 mg, 0.6 mmol).Stir overnight at room temperature.Diatomaceous earth filtration,Anhydrous ethanol washing,The filtrate was decompressed and recovered directly after column chromatography.To give compound 50 (32 mg, yield: 82.0%).
  • 75
  • (1S,2S)-(1-benzyl-3-chloro-2-acetyloxypropyl)carbamate tert-butyl ester [ No CAS ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
98% With potassium hydroxide In tetrahydrofuran; ethanol at -15℃; for 2h; Inert atmosphere; 2.3 (3) (1S,2S)-(1-benzyl-3-chloro-2-acetyloxypropyl)carbamate tert-butyl ester 3 (50 g, 0.146 mil), ΚOΗ (16.7 g, 0.298 mol) THF (180 ml) and ethanol (100 ml) under nitrogen atmosphere. The reaction temperature was controlled at -15 ° C and stirred for 2 h. After completion of the reaction, the reaction mixture was extracted with ether (2 X 125 ml), dried, filtered and concentrated under reduced pressure to give white solid 4 (37.6 g, 98%).
  • 76
  • [ 110-85-0 ]
  • [ 98760-08-8 ]
  • di-tert-butyl ((2S,2′S,3R,3′R)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))dicarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% In isopropyl alcohol for 16h; Reflux; regioselective reaction; 2.1 4.1.2.1 Regioselective ring opening of (2R, 3S)-3-(N-BOC-amino)-1-oxirane-4-phenylbutane by piperazine to afford hydroxyethylamine intermediate 2 Epoxide 1 (2 eq, 6.97 mol) and piperazine (1 eq, 3.48 mol) were dissolved in isopropanol and the resulting reaction mixture was refluxed for 16 h, completion of reaction was monitored by TLC. After completion, the reaction mixture was cooled and the solvent was removed under reduce pressure to obtain compound 2 (93% yield) as solid. Compound 2, thus obtained was used for the next step without any column purification.
  • 77
  • 3,4-dichloro-N-isopropoxybenzenesulfonamide [ No CAS ]
  • [ 98760-08-8 ]
  • tert-butyl ((1S,2S)-3-((3,4-dichloro-N-isopropoxyphenyl)sulfonamido)-2-hydroxy-1-phenylpropyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With phosphazene base-P4-tert-butyl In tetrahydrofuran at 23℃; for 40h; Inert atmosphere;
  • 79
  • [ 78-81-9 ]
  • [ 98760-08-8 ]
  • tert-butyl [(1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propyl]-N-[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetone at 20 - 30℃; Preparation of tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(-4-nitrophenyl)sulfonyl]-amino]propyl]carbamate (7) A mixture of isobutyl amine (1000 mL, 9.981 mol), IPA (200 mL, 1.0 volume) and200 g (0.759 mol) of 3 was stirred for 12-14 h at 20-30 °C. After completion ofreaction (TLC), volatiles were removed under vacuum. Water (1000 mL) was addedto the residue followed by stirring for 2 h, and subsequent filtration resulted to affordintermediate 6, after drying at 50-60 °C in air oven over a period of 10-12 h. Driedsolid was then mixed with DCM (740 mL), TEA (115 mL, 0.835 mol) at 15-25 °Cfollowed by slow addition of 4-nitrobenzenesulfonyl chloride solution (168 g,0.759 mol, in 300 mL of DCM) at 15-25 °C. Resulted reaction mixture was stirredfor 1-2 h at 15-25 °C. After reaction completion (TLC), volatiles were evaporatedunder vacuum completely. Water (1500 mL) and sodium hydroxide solution(200 mL; 0.700 mol) was added to distilled residue followed by stirring for 2 h. Theresulting aqueous slurry was filtered, washed with water and dried in air oven at55-60 °C over a period of 10-12 h to yield the intermediate 7.
  • 80
  • [ 78-81-9 ]
  • [ 98760-08-8 ]
  • tert-butyl [(1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propyl]-N-[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate [ No CAS ]
  • [ 160232-08-6 ]
YieldReaction ConditionsOperation in experiment
80% In toluene at 20 - 30℃; Preparation of tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(-4-nitrophenyl)sulfonyl]-amino]propyl]carbamate (7) A mixture of isobutyl amine (1000 mL, 9.981 mol), IPA (200 mL, 1.0 volume) and200 g (0.759 mol) of 3 was stirred for 12-14 h at 20-30 °C. After completion ofreaction (TLC), volatiles were removed under vacuum. Water (1000 mL) was addedto the residue followed by stirring for 2 h, and subsequent filtration resulted to affordintermediate 6, after drying at 50-60 °C in air oven over a period of 10-12 h. Driedsolid was then mixed with DCM (740 mL), TEA (115 mL, 0.835 mol) at 15-25 °Cfollowed by slow addition of 4-nitrobenzenesulfonyl chloride solution (168 g,0.759 mol, in 300 mL of DCM) at 15-25 °C. Resulted reaction mixture was stirredfor 1-2 h at 15-25 °C. After reaction completion (TLC), volatiles were evaporatedunder vacuum completely. Water (1500 mL) and sodium hydroxide solution(200 mL; 0.700 mol) was added to distilled residue followed by stirring for 2 h. Theresulting aqueous slurry was filtered, washed with water and dried in air oven at55-60 °C over a period of 10-12 h to yield the intermediate 7.
  • 81
  • [ 6850-57-3 ]
  • [ 98760-08-8 ]
  • tert-butyl ((2S,3S)-3-hydroxy-4-((2-methoxybenzyl)amino)-1-phenylbutan-2-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
63.8% With pyridine In propan-1-ol for 16h; Reflux; Procedure for the synthesis of compounds 1a-15a (procedure A) General procedure: Tert-butyl ((S)-1-((S)-oxiran-2-yl)-2-phenylethyl)carbamate or tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1.0 equiv.), corresponding amine (1, 1.1 or 2 equiv.), and a catalytic amount of pyridine in n-propanol, isopropanol or ethanol were refluxed for 16 h. Then, the solvent was evaporated and the resulting residue was purified by flash column chromatography using a mixture of DCM and MeOH (gradient or isocratic purification).
  • 82
  • [ 98760-08-8 ]
  • [ 110207-94-8 ]
  • tert-butyl ((2S,3S)-3-hydroxy-4-((3-isopropylbenzyl)amino)-1-phenylbutan-2-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43.1% With pyridine In isopropyl alcohol for 16h; Reflux; Procedure for the synthesis of compounds 1a-15a (procedure A) General procedure: Tert-butyl ((S)-1-((S)-oxiran-2-yl)-2-phenylethyl)carbamate or tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1.0 equiv.), corresponding amine (1, 1.1 or 2 equiv.), and a catalytic amount of pyridine in n-propanol, isopropanol or ethanol were refluxed for 16 h. Then, the solvent was evaporated and the resulting residue was purified by flash column chromatography using a mixture of DCM and MeOH (gradient or isocratic purification).
  • 83
  • [ 39895-55-1 ]
  • [ 98760-08-8 ]
  • tert-butyl ((2S,3S)-4-((4-(tert-butyl)benzyl)amino)-3-hydroxy-1-phenylbutan-2-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With pyridine In propyl alcohol for 16h; Reflux; Procedure for the synthesis of compounds 1a-15a (procedure A) General procedure: Tert-butyl ((S)-1-((S)-oxiran-2-yl)-2-phenylethyl)carbamate or tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1.0 equiv.), corresponding amine (1, 1.1 or 2 equiv.), and a catalytic amount of pyridine in n-propanol, isopropanol or ethanol were refluxed for 16 h. Then, the solvent was evaporated and the resulting residue was purified by flash column chromatography using a mixture of DCM and MeOH (gradient or isocratic purification).
68.97% With pyridine In propyl alcohol for 16h; Reflux; 1.5 Step 1 General procedure: (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1,2-epoxy-4-phenylbutane or (2R,3S)-3-[(tert- butoxycarbonyl)amino]-1,2-epoxy-4-phenylbutane (1 eq.) and the appropriate amine (1-2 eq.) were dissolved in n- propanol or isopropanol. A catalytic amount of pyridine was added and the mixture was stirred at the reflux temperature for 16 hours. Then, the solvent was distilled off, and the obtained residue was purified by flash column chromatography using a mixture of dichloromethane (DCM) and methanol (isocratic or gradient separation).
  • 84
  • [ 98760-08-8 ]
  • [ 75-64-9 ]
  • tert-butyl ((2S,3S)-4-(tert-butylamino)-3-hydroxy-1-phenylbutan-2-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51.8% With pyridine In propan-1-ol for 16h; Reflux; Procedure for the synthesis of compounds 1a-15a (procedure A) General procedure: Tert-butyl ((S)-1-((S)-oxiran-2-yl)-2-phenylethyl)carbamate or tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1.0 equiv.), corresponding amine (1, 1.1 or 2 equiv.), and a catalytic amount of pyridine in n-propanol, isopropanol or ethanol were refluxed for 16 h. Then, the solvent was evaporated and the resulting residue was purified by flash column chromatography using a mixture of DCM and MeOH (gradient or isocratic purification).
  • 85
  • [ 98760-08-8 ]
  • [ 198904-85-7 ]
  • [ 437713-06-9 ]
YieldReaction ConditionsOperation in experiment
52.2 g With zinc dibromide In dichloromethane at 20 - 40℃; 1-6 Example 1 At room temperature, add 150ml of dichloromethane to the clean reactor, add 50g (0.167mol) of tert-butyl hydrazinocarboxylate of formula I and compound of formula II (2R, 3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane40g (0.152mol), then, then add 1.2g (0.0053mol) of zinc bromide in catalytic amount as a catalyst, slowly raise the temperature to 25-30 to carry out the addition reaction for 16-20 hours, After the reaction is complete, began to slowly cool down to 20°C, then add 36g (0.16mol) of zinc bromide, then, the temperature is raised to 30-40 °C to react, keep warm for 12 hours, after the end, then directly add 100ml to the reaction solution, wash with water twice, stand still and separate into layers, collect the organic phase and distill to remove the dichloromethane solvent, add 200ml n-hexane to slowly cool down to 05 and keep it at this temperature and stir to fill the analytical crystals for 1-2 hours, filter the wet product, control the temperature to dry at 40-50 °C, obtain the solid product of atazanavir main chain intermediate compound of formula V (1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane) 52.2g (0.144mol), HPLC purity is 99.85%.
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