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CAS No. : | 17407-56-6 | MDL No. : | MFCD00066442 |
Formula : | C5H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NGEWQZIDQIYUNV-SCSAIBSYSA-N |
M.W : | 118.13 | Pubchem ID : | 5289545 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 29.08 |
TPSA : | 57.53 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.67 cm/s |
Log Po/w (iLOGP) : | 0.93 |
Log Po/w (XLOGP3) : | 0.5 |
Log Po/w (WLOGP) : | 0.09 |
Log Po/w (MLOGP) : | 0.01 |
Log Po/w (SILICOS-IT) : | -0.3 |
Consensus Log Po/w : | 0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.76 |
Solubility : | 20.7 mg/ml ; 0.176 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.28 |
Solubility : | 6.23 mg/ml ; 0.0527 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.5 |
Solubility : | 374.0 mg/ml ; 3.17 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.46 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfuric acid; water monomer; NaNO2 at 60℃; Flow reactor; | |
80% | With sulfuric acid; NaNO2 In water monomer at 60℃; Inert atmosphere; | |
65% | With sulfuric acid; NaNO2 In water monomer at 0 - 20℃; for 12h; |
60% | With sulfuric acid; NaNO2 In water monomer at 0 - 5℃; for 2h; | 1.1.A PREPARATION 1 Synthesis of (2R)-2-hydroxy-3-methyl-butanoic acid Scheme 1, Step A. To a solution of water (45 mL) and sulfuric scid (4 mL; 75 mmol) at 0° C. is added D-valine (10 g; 85.4 mmol). To this solution is slowly added a solution of sodium nitrite (8.8 g; 128 mmol) in water (45 mL) over 2 h, keeping the temperature below 5° C. The mixture is allowed to warm slowly to room temperature. After 2 h, the mixture is extracted with diethyl ether (2*75 mL). The combined ether layers are washed with brine, dried (MgSO4), filtered, and concentrated to provide the title compound as a colorless oil (6.1 g, 60%). This material is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 12.38 (broad, 1H), 5.02 (broad, 1H), 3.70 (d, J=4.4 Hz, 1H), 1.92-1.85 (m, 1H), 0.86 (d, J=6.9 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H). |
47% | With sulfuric acid; NaNO2 In water monomer 1.) 0 deg C, 3 h, 2.) RT, 2 h; | |
40% | With NaNO2 In sulfuric acid at 0℃; for 2h; | |
With hydrogenchloride; silver(I) nitrite | ||
With hydrogenchloride; glacial acetic acid; NaNO2 | ||
With sulfuric acid; NaNO2 | ||
With sulfuric acid; NaNO2 In water monomer 1.) 0 deg C, 2.) 0 deg C to room temperature, 12 h; Yield given; | ||
With sulfuric acid; NaNO2 at 20℃; | ||
Stage #1: D-Val-OH With glacial acetic acid; NaNO2 In water monomer Stage #2: With potassium carbonate In methanol; water monomer | ||
With sulfuric acid; NaNO2 | ||
With sulfuric acid; NaNO2 In water monomer at 20℃; for 27h; Cooling with ice; | 1. 4.1 D-α-hydroxy acid 10(A-C, G) General procedure: A 60 ml of aqueous solution of sodium nitrite (20.7 g, 0.3 mol) was added into a stirred and ice-cooled solution of D-amino acids (9A-C, G, 50 mmol) in 1 M H2SO4 (100 ml, 0.1 mol) over 3 h, and the mixture was stirred for 24 h at room temperature until the completion of the reaction (monitored by ninhydrin). The mixture was adjusted to pH 6 with solid NaHCO3 and then to pH 3 with concentrated HCl followed by freeze-drying. The resulting residue was extracted with hot acetone (4×100 ml), and the extracts were concentrated and dried to offer colorless oil, to which ether (200 ml) was added and filtrated to remove insoluble solids, the filtrate was concentrated and re-crystallized in ether/hexanes mixture to afford 10(A-C, G) as white crystalline, yield 82%-92%. | |
With sulfuric acid; water monomer; NaNO2 at 20℃; for 10h; Cooling with ice; | ||
With water monomer; glacial acetic acid; NaNO2 at 0 - 20℃; for 24h; Inert atmosphere; | ||
230 g | With sulfuric acid; NaNO2 at 0 - 20℃; | 8-1 8-1) Synthesis of A-22-Int2 A-22-Intl (400 g, 3.42 mol) was placed into a 10-L, threenecked flask, and 0.5M H2SO4 (5.2 L) was added. The reaction was cooled to 0°C and then 2 mol/L NaNOz (2.6 L) was added drop wise, after the addition was completed; the reaction was stirred at room temperature overnight. After this time, the reaction mixture was extracted with ethyl acetate (EA) (3 x 3 L) . The combined EA extracts were dried over NazSCM, filtered and concentrated. The resulting crude solid was recrystallized from petroleum ether to afford compound A-22-Int2 (230 g) .1H NMR (400 MHz, CDCI3) data of A-22-Int2 is shown in Fig. 10. |
230 g | With sulfuric acid; NaNO2 at 0 - 20℃; | 8-1 8-1) Synthesis of A-22-Int2 A-22-Intl (400 g, 3.42 mol) was placed into a 10-L, threenecked flask, and 0.5M H2SO4 (5.2 L) was added. The reaction was cooled to 0°C and then 2 mol/L NaNOz (2.6 L) was added drop wise, after the addition was completed; the reaction was stirred at room temperature overnight. After this time, the reaction mixture was extracted with ethyl acetate (EA) (3 x 3 L) . The combined EA extracts were dried over NazSCM, filtered and concentrated. The resulting crude solid was recrystallized from petroleum ether to afford compound A-22-Int2 (230 g) .1H NMR (400 MHz, CDCI3) data of A-22-Int2 is shown in Fig. 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate In acetone for 4h; Reflux; | 22.4 Step 4: Preparation of (R)-ethyl 2-hydroxy-3-methylbutanoate; (R)-2-hydroxy-3-methyl-butyric acid (1 g, 8.4 mmol) is dissolved in acetone (50 ml). Thereto, K2CO3 (1.4 g, 10 mmol) and ethyl iodide (2.67 g, excess) are added, and the resulting mixture is refluxed for 4 hours. Then, the mixture is extracted with diethyl ether. The entire extracts are dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography to obtain the compound, (R)-ethyl 2-hydroxy-3-methylbutanoate (0.88 g, 72%). |
With triethylamine In ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: benzyl alcohol With toluene-4-sulfonic acid In benzene for 0.5h; Reflux; Stage #2: (R)-2-Hydroxy-3-methylbutyric acid In benzene Reflux; | 1.5 General procedure for the preparation of the D-a-hydroxy acid derivatives 11 (A-G) General procedure: Benzyl alcohol (1.2 equiv) and p-toluenesulfonic acid (0.1 equiv) were taken in benzene and refluxed for 0.5 h, then compounds 10(A-G) (1 equiv) was added, and continuously reflexed until the completion of the reaction (monitored by TLC: petroleum ether/ethyl acetate, 8:1; typically 4 h). The reaction mixture was washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Purification by flash column chromatography gave the desired compounds 11(A-G) as colorless oil. |
86% | With thionyl chloride In benzene at 20 - 100℃; Inert atmosphere; | |
78% | With thionyl chloride In benzene for 40h; Heating; |
With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In water at 35℃; biosynthesis by Proteus vulgaris (potassium phosphate buffer pH 7.0); | ||
With benzylviologen cation radical In water at 25℃; cell free extract of Proteus vulgaris (potassium phosphate buffer pH 7.0), Vmax; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sulfuric acid In methanol for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogenchloride at 60℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride In acetic acid at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | ||
at 20℃; for 0.5h; | ||
In methanol; diethyl ether at 20℃; for 0.0833333h; |
In diethyl ether at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sulfuric acid In water at 90℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In benzene for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With enniatin synthetase from Fusarium sambucinum BBA 63933; ATP; magnesium chloride In water; glycerol at 27℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With enniatin synthetase from Fusarium scirpi ETH 1536; ATP; magnesium chloride In water; glycerol at 27℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With enniatin synthetase from Fusarium sambucinum BBA 63933; ATP; magnesium chloride In water; glycerol at 27℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With enniatin synthetase from Fusarium sambucinum BBA 63933; ATP; magnesium chloride In water; glycerol at 27℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 mg | With sodium hydrogencarbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (R)-2-Hydroxy-3-methylbutyric acid With benzotriazol-1-ol; 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Stage #2: (1R,2R)-1,2-diaminocyclohexane In tetrahydrofuran at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With BIS-TRIS buffer; Lactobacillus paracasei DSM 20207 In water at 42℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: allyl alcohol; 5-isopropyl-[1,3]dioxolane-2,4-dione With hydroquinidine anthraquinone-1,4-diyl diether In diethyl ether at -78℃; for 6h; Stage #2: With water Further stages. Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: (R)-2-Hydroxy-3-methylbutyric acid With caesium carbonate In N,N-dimethyl-formamide at 0℃; for 0.666667h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 15h; Inert atmosphere; | |
58% | Stage #1: (R)-2-Hydroxy-3-methylbutyric acid With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide Inert atmosphere; | Benzyl (2R)-2-hydroxy-3-methylbutanoate (7) To a (2R)-2-hydroxy-3-methylbutanoic acid (2.95 g, 25 mmol) in dry DMF (17mL, 1.5M) is slowly added powdered Cs2CO3 (4.0 g, 0.5 eq) in portions at roomtemperature. The mixture was allowed to stir for 30 min. before the addition ofbenzyl bromide (3.3 mL, 1.1 eq). The mixture was allowed to stir overnightbefore the reaction mixture was filtered, washing with 20% EtOAc/40-60petroleum ether (100 mL). The filtrate was washed with aq. half-saturatedNH4Cl solution (3 x 50 mL), half sat. NaHCO3 (1 x 50 mL), and the organic layers werecombined and concentrated in vacuo. Residual benzyl alcohol was removed by azeotropic rotaryvacuum distillation with H2O (2 x 25 mL), and the organic residue was azeotropically dried with toluene (25 mL). The resulting oil (3.0g, 58% yield) was sufficiently pure for the next step. Ananalytically pure sample could be obtained by flash column chromatography (silica gel, 5% to10% EtOAc/40-60 petroleum ether). |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24h; | ||
1.3 g | With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 16h; | a DBU (1.021 niL, 6.77 mmol) was added to a solution of (R)-2-hydroxy-3- methylbutanoic acid (0.8 g, 6.77 mmol) and benzyl bromide (1.390 g, 8.13 mmol) in DMF (10 mL) and the resulting yellowish solution was stirred at rt for 16 h. The mixture was then taken up in EtOAc (50 mL) and water (30 ml) and the organic layer was separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried (MgS04), filtered and concentrated to give a clear oil. The residue was purified by flash chromatography (10%EtOAc/Hexanes). A clear oil corresponding to Cap L-32 step a (1.3 g) was recovered. NMR (400MHz, CDCI3) δ 7.44 - 7.31 (m, 5H), 5.30 - 5.17 (m, 2H), 4.10 (dd, J=6.1, 3.4 Hz, 1H), 2.73 (dd, J=6.1, 1.9 Hz, 1H), 2.11 (dtd, J=13.8, 6.9, 3.5 Hz, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H);13C NMR (101MHz, CDCI3) δ 174.8, 135.2, 128.6 (s, 2C), 128.5, 128.4 (s, 2C), 75.0, 67.3, 32.2, 18.8, 15.9 |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 64h; | B1.a a) (R)-benzy 2-hydroxy-3-methybutanoate To D-apha-hydroxyisovaeric acid (5 g, 42.3 rnmoD in DMF (50 mD were added benzybromide (6.00 m, 50.8 mmd) and DBU (6.38 m, 42.3 mmd) and the reaction mixture was stirred for 64h at RT. The sdvent was evaporated and the residue was taken up in AcOEt/water. The organic phase was dried over Na2SO4, fHtered and evaporated. The crude product was purified by flash cdumn chromatography on sHica g& (cyciohexane/AcOEt: 1/0 to 9/1) to afford (R)-benzy 2-hydroxy-3-methybutanoate. M/z = 209 [M+H]+, Rt = 0.95 mm (UPLC Method B2), 1H NMR (400 MHz, DMSO-d3) O ppm: 746-7.29 (rn, 5H), 5.35 (d, IH), 5.14 (d, 2H), 3.87 (dd, IH), 2.00-190 (m, IH), 088 (d. 3H). 0.82 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | In hexane at 0℃; for 1.33333h; | 4 To a solution of (R)-2-hydroxy-3-methylbutanoic acid (5.0 gm, 42.2 mmol) in methanol was added a solution of TMS CH2N2 (2M) in hexane (65 mL), at 0° C., over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The reaction was concentrated with a bath temperature of 20° C. and vacuum greater than 50 mm Hg. Purification via silica gel chromatography using 2-100% EtOAc in hexanes gave the ester as a yellow oil (438 mg, 12.7 mmol, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ 5.30 (d, J=5.1 Hz, 1H), 3.81 (t, J=0.8 Hz, 1H), 3.63H), 1.94-1.86 (m, 1H), 0.88-0.82 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N,N'-carbonyldiimidazole / tetrahydrofuran / 4 h / 20 °C 1.2: 54 mg / tetrahydrofuran / 30 h / 20 °C 2.1: 100 percent / H2 / Pd/C / methanol / 2 h 3.1: 2-chloro-1-methylpyridinium iodide; triethylamine / CH2Cl2 / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N,N'-carbonyldiimidazole / tetrahydrofuran / 4 h / 20 °C 1.2: 54 mg / tetrahydrofuran / 30 h / 20 °C 2.1: 100 percent / H2 / Pd/C / methanol / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: H2 / Pd(OH)2/C / methanol / 0.75 h / 2327.23 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4: 7.0 g / CH2Cl2 / 14 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4: 7.0 g / CH2Cl2 / 14 h / 20 °C 5: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 17 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 16 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 22 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 38 percent / tetrahydrofuran / 1 h / -20 °C 18.1: 92 percent / Dess-Martin periodinane / CH2Cl2 / 1.5 h 19.1: 93 percent / Super-Hydride / CH2Cl2; tetrahydrofuran / 2 h / -78 °C 20.1: t-BuOK / tetrahydrofuran / 0.5 h / -20 °C 20.2: 86 percent / t-BuOK / tetrahydrofuran / 1 h / -20 °C 21.1: 86 percent / CSA / methanol / 2 h | ||
Multi-step reaction with 20 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 50 percent / tetrahydrofuran / 1 h / -20 °C 18.1: t-BuOK / tetrahydrofuran / 0.5 h / -20 °C 18.2: 86 percent / t-BuOK / tetrahydrofuran / 1 h / -20 °C 19.1: 86 percent / CSA / methanol / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 19 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 38 percent / tetrahydrofuran / 1 h / -20 °C 18.1: 92 percent / Dess-Martin periodinane / CH2Cl2 / 1.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 21 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 38 percent / tetrahydrofuran / 1 h / -20 °C 18.1: 92 percent / Dess-Martin periodinane / CH2Cl2 / 1.5 h 19.1: 93 percent / Super-Hydride / CH2Cl2; tetrahydrofuran / 2 h / -78 °C 20.1: t-BuOK / tetrahydrofuran / 0.5 h / -20 °C 20.2: 86 percent / t-BuOK / tetrahydrofuran / 1 h / -20 °C | ||
Multi-step reaction with 19 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 50 percent / tetrahydrofuran / 1 h / -20 °C 18.1: t-BuOK / tetrahydrofuran / 0.5 h / -20 °C 18.2: 86 percent / t-BuOK / tetrahydrofuran / 1 h / -20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 18 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 38 percent / tetrahydrofuran / 1 h / -20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 20 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 38 percent / tetrahydrofuran / 1 h / -20 °C 18.1: 92 percent / Dess-Martin periodinane / CH2Cl2 / 1.5 h 19.1: 93 percent / Super-Hydride / CH2Cl2; tetrahydrofuran / 2 h / -78 °C | ||
Multi-step reaction with 18 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 50 percent / tetrahydrofuran / 1 h / -20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 23 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 38 percent / tetrahydrofuran / 1 h / -20 °C 18.1: 92 percent / Dess-Martin periodinane / CH2Cl2 / 1.5 h 19.1: 93 percent / Super-Hydride / CH2Cl2; tetrahydrofuran / 2 h / -78 °C 20.1: t-BuOK / tetrahydrofuran / 0.5 h / -20 °C 20.2: 86 percent / t-BuOK / tetrahydrofuran / 1 h / -20 °C 21.1: 86 percent / CSA / methanol / 2 h 22.1: 87 percent / DMAP / tetrahydrofuran; dimethylformamide / 18 h / 20 °C | ||
Multi-step reaction with 21 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C 15.1: 91 percent / TBAF; AcOH / tetrahydrofuran / 9 h 16.1: 91 percent / DMSO; Et3N; SO3*Py / CH2Cl2 / 2 h / 20 °C 17.1: 50 percent / tetrahydrofuran / 1 h / -20 °C 18.1: t-BuOK / tetrahydrofuran / 0.5 h / -20 °C 18.2: 86 percent / t-BuOK / tetrahydrofuran / 1 h / -20 °C 19.1: 86 percent / CSA / methanol / 2 h 20.1: 87 percent / DMAP / tetrahydrofuran; dimethylformamide / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 15 steps 1.1: 85 percent / iPr2NEt / CH2Cl2 / 52 h / 20 °C 2.1: 87 percent / DIBAL-H / tetrahydrofuran / 3 h / 0 °C 3.1: oxalyl chloride; DMSO; diisopropylethylamine / CH2Cl2 / -55 - 130 °C 4.1: 7.0 g / CH2Cl2 / 14 h / 20 °C 5.1: 90 percent / TMSCl / tetrahydrofuran; diethyl ether / 3.5 h / -78 °C 6.1: KHMDS / tetrahydrofuran; toluene / 0.5 h / -78 °C 6.2: 80 percent / trans-2-phenyl-sulfonyl-3-phenyloxaziridine / tetrahydrofuran; toluene / 3 h / -78 °C 7.1: 94 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 8.1: 86 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / 0 °C 9.1: 88 percent / DMAP / CH2Cl2 / 12 h / 0 °C 10.1: H2 / Pd(OH)2/C / methanol / 6 h / 20 °C / 760.05 Torr 11.1: 2.86 g / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 12.1: 91 percent / DIBAL-H / toluene; tetrahydrofuran / 1 h / -78 °C 13.1: 84 percent / I2; imidazole; PPh3 / toluene / 1.5 h / 0 °C 14.1: t-BuLi; HMPA / tetrahydrofuran; pentane / 1 h / -78 °C 14.2: 81 percent / tetrahydrofuran; pentane / 2 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 65 percent / Et3N, DMAP / CH2Cl2 / 6 h / Ambient temperature 2: 75 percent / HCl / tetrahydrofuran; H2O / 3 h / Ambient temperature 3: KBH4 / methanol / 10 h / 0 °C 4: 58 percent / H2SO4 / H2O / 0.5 h / 90 °C | ||
Multi-step reaction with 5 steps 1: Et3N, DMAP / CH2Cl2 / 6 h / Ambient temperature 2: 98 percent / TFA / CH2Cl2 / 78 h / Heating 3: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 4: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 5: 1M H2SO4 / 36 h / Heating | ||
Multi-step reaction with 5 steps 1: Et3N, DMAP / CH2Cl2 / 6 h / Ambient temperature 2: TiCl4 / -40 °C 3: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 4: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 5: 1M H2SO4 / 36 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Cl2CHOCH3 / CH2Cl2 / 1.) room temperature, 20 min, 2.) 50-55 deg C, 30 min 2: Et3N, DMAP / CH2Cl2 / 6 h / Ambient temperature 3: 98 percent / TFA / CH2Cl2 / 78 h / Heating 4: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 5: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 6: 1M H2SO4 / 36 h / Heating | ||
Multi-step reaction with 6 steps 1: Cl2CHOCH3 / CH2Cl2 / 1.) room temperature, 20 min, 2.) 50-55 deg C, 30 min 2: Et3N, DMAP / CH2Cl2 / 6 h / Ambient temperature 3: TiCl4 / -40 °C 4: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 5: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 6: 1M H2SO4 / 36 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 2: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 3: 1M H2SO4 / 36 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 98 percent / TFA / CH2Cl2 / 78 h / Heating 2: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 3: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 4: 1M H2SO4 / 36 h / Heating | ||
Multi-step reaction with 4 steps 1: TiCl4 / -40 °C 2: 99 percent / H2 / Pd/C / ethyl acetate / 2.5 h / 2585.7 Torr 3: 51 percent / Na, liquid NH3 / tetrahydrofuran / 0.01 h 4: 1M H2SO4 / 36 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 78 percent / SOCl2 / benzene / 40 h / Heating 2: 99 percent / 2,6-lutidine / CH2Cl2 / 0.5 h / -78 °C 3: 78 percent / 2,6-lutidine / 1,2-dichloro-ethane / 18 h / 70 °C 4: H2, (+)-camphorsulfonic acid / 10percent Pd/C / methanol / 7 h / 2585.7 Torr 5: hydroxybenzotriazole (HOBT), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), N-methylmorpholine (NMM) / N,N-dimethyl-acetamide / 64 h / Ambient temperature 6: sodium cyanoborohydride, AcOH / acetonitrile; H2O / 1 h / 0 °C | ||
Multi-step reaction with 7 steps 1: 78 percent / SOCl2 / benzene / 40 h / Heating 2: 99 percent / 2,6-lutidine / CH2Cl2 / 0.5 h / -78 °C 3: 95 percent / proton sponge / 1,2-dichloro-ethane / 18 h / 70 °C 4: 73 percent / NaBH4 / dimethylformamide; H2O 5: H2, (+)-camphorsulfonic acid / 10percent Pd/C / methanol / 7 h / 2585.7 Torr 6: hydroxybenzotriazole (HOBT), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), N-methylmorpholine (NMM) / N,N-dimethyl-acetamide / 64 h / Ambient temperature 7: sodium cyanoborohydride, AcOH / acetonitrile; H2O / 1 h / 0 °C | ||
Multi-step reaction with 10 steps 1: thionyl chloride / benzene / 20 - 100 °C / Inert atmosphere 2: 2,6-dimethylpyridine / dichloromethane / 0.5 h / -78 °C / Inert atmosphere 3: 2,6-dimethylpyridine / 1,2-dichloro-ethane / Inert atmosphere; Heating 4: toluene-4-sulfonic acid / Inert atmosphere 5: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6: trifluoroacetic acid / dichloromethane / 6 h / 0 - 20 °C / Inert atmosphere 7: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C / 760.05 Torr 8: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 48 h / 20 °C / Inert atmosphere 9: sodium cyanoborohydride; acetic acid / water; acetonitrile / 0 - 20 °C / Inert atmosphere 10: tetrabutyl ammonium fluoride / tetrahydrofuran / 5 h / 0 - 20 °C / Inert atmosphere |
Multi-step reaction with 11 steps 1: thionyl chloride / benzene / 20 - 100 °C / Inert atmosphere 2: 2,6-dimethylpyridine / dichloromethane / 0.5 h / -78 °C / Inert atmosphere 3: 2,6-dimethylpyridine / 1,2-dichloro-ethane / Inert atmosphere; Heating 4: toluene-4-sulfonic acid / Inert atmosphere 5: triethylamine / acetonitrile / 20 °C 6: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 7: trifluoroacetic acid / dichloromethane / 6 h / 0 - 20 °C / Inert atmosphere 8: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C / 760.05 Torr 9: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 48 h / 20 °C / Inert atmosphere 10: sodium cyanoborohydride; acetic acid / water; acetonitrile / 0 - 20 °C / Inert atmosphere 11: tetrabutyl ammonium fluoride / tetrahydrofuran / 5 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 78 percent / SOCl2 / benzene / 40 h / Heating 2: 99 percent / 2,6-lutidine / CH2Cl2 / 0.5 h / -78 °C 3: 78 percent / 2,6-lutidine / 1,2-dichloro-ethane / 18 h / 70 °C 4: H2, (+)-camphorsulfonic acid / 10percent Pd/C / methanol / 7 h / 2585.7 Torr 5: hydroxybenzotriazole (HOBT), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), N-methylmorpholine (NMM) / N,N-dimethyl-acetamide / 64 h / Ambient temperature | ||
Multi-step reaction with 6 steps 1: 78 percent / SOCl2 / benzene / 40 h / Heating 2: 99 percent / 2,6-lutidine / CH2Cl2 / 0.5 h / -78 °C 3: 95 percent / proton sponge / 1,2-dichloro-ethane / 18 h / 70 °C 4: 73 percent / NaBH4 / dimethylformamide; H2O 5: H2, (+)-camphorsulfonic acid / 10percent Pd/C / methanol / 7 h / 2585.7 Torr 6: hydroxybenzotriazole (HOBT), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), N-methylmorpholine (NMM) / N,N-dimethyl-acetamide / 64 h / Ambient temperature | ||
Multi-step reaction with 8 steps 1: thionyl chloride / benzene / 20 - 100 °C / Inert atmosphere 2: 2,6-dimethylpyridine / dichloromethane / 0.5 h / -78 °C / Inert atmosphere 3: 2,6-dimethylpyridine / 1,2-dichloro-ethane / 12 h / 85 °C / Inert atmosphere 4: toluene-4-sulfonic acid / 4 h / 20 °C / Inert atmosphere 5: trifluoroacetic acid / dichloromethane / 1.5 h / 0 °C / Inert atmosphere 6: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 760.05 Torr 7: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C / Inert atmosphere 8: L-Selectride / tetrahydrofuran / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 78 percent / SOCl2 / benzene / 40 h / Heating 2: 99 percent / 2,6-lutidine / CH2Cl2 / 0.5 h / -78 °C 3: 78 percent / 2,6-lutidine / 1,2-dichloro-ethane / 18 h / 70 °C 4: H2, (+)-camphorsulfonic acid / 10percent Pd/C / methanol / 7 h / 2585.7 Torr | ||
Multi-step reaction with 5 steps 1: 78 percent / SOCl2 / benzene / 40 h / Heating 2: 99 percent / 2,6-lutidine / CH2Cl2 / 0.5 h / -78 °C 3: 95 percent / proton sponge / 1,2-dichloro-ethane / 18 h / 70 °C 4: 73 percent / NaBH4 / dimethylformamide; H2O 5: H2, (+)-camphorsulfonic acid / 10percent Pd/C / methanol / 7 h / 2585.7 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Py 2: (i) PCl5, (ii) /BRN= 3562296/, Et3N 3: H2 / Pd 4: N2H4*H2O / ethanol / Heating | ||
Multi-step reaction with 4 steps 1: Py 2: (i) PCl5, Et2O, (ii) /BRN= 3562296/, Et3N, THF 3: H2 / PdO / ethanol 4: N2H4*H2O / ethanol / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: Py 2: (i) PCl5, (ii) /BRN= 3562296/, Et3N 3: H2 / Pd | ||
Multi-step reaction with 3 steps 1: Py 2: (i) PCl5, Et2O, (ii) /BRN= 3562296/, Et3N, THF 3: H2 / PdO / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Py 2: (i) PCl5, (ii) /BRN= 3562296/, Et3N 3: H2 / Pd 4: NH3 / methanol | ||
Multi-step reaction with 4 steps 1: Py 2: (i) PCl5, Et2O, (ii) /BRN= 3562296/, Et3N, THF 3: H2 / PdO / ethanol 4: NH3 / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HCl 2: (i) carbonyldiimidazole, THF, (ii) /BRN= 2525872/ 3: H2 / Pd-C / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: HCl 2: (i) carbonyldiimidazole, (ii) H2, Pd-BaSO4 | ||
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 24 h / 20 °C 2: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h / -40 °C 3: palladium on activated charcoal; hydrogen / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: HCl 2: (i) carbonyldiimidazole, THF, (ii) /BRN= 2525872/ 3: H2 / Pd-C / tetrahydrofuran 4: (i) carbonyldiimidazole, THF, (ii) /BRN= 2390203/ 5: HCl / acetic acid 6: (i) carbonyldiimidazole, THF, (ii) /BRN= 6129780/ | ||
Multi-step reaction with 8 steps 1: HCl 2: (i) carbonyldiimidazole, THF, (ii) /BRN= 2525872/ 3: HCl / acetic acid / Ambient temperature 4: DCC / CH2Cl2 5: HCl / acetic acid 6: (i) carbonyldiimidazole, THF, (ii) /BRN= 2390203/ 7: HCl / acetic acid 8: (i) carbonyldiimidazole, THF, (ii) /BRN= 6129780/ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: HCl 2: (i) carbonyldiimidazole, THF, (ii) /BRN= 2525872/ 3: H2 / Pd-C / tetrahydrofuran 4: (i) carbonyldiimidazole, THF, (ii) /BRN= 2390203/ 5: HCl / acetic acid | ||
Multi-step reaction with 7 steps 1: HCl 2: (i) carbonyldiimidazole, THF, (ii) /BRN= 2525872/ 3: HCl / acetic acid / Ambient temperature 4: DCC / CH2Cl2 5: HCl / acetic acid 6: (i) carbonyldiimidazole, THF, (ii) /BRN= 2390203/ 7: HCl / acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine In ethyl acetate; N,N-dimethyl-formamide | 61.3 Step 3 Step 3 To a stirred solution of L-prolyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamide from the previous step (0.23 g, 0.62 mmol, HPLC RT=2.77 min), 2R-hydroxy-3-methylbutyric acid acid (77 mg, 0.65 mmol), and HOBT hydrate (99 mg, 0.65 mmol) in DMF (4 mL) was added EDC (0.16 g, 0.82 mmol). Diisopropylethylamine was then added in portions (0.1 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 2 h, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash chromatography using EtOAc as eluant. N-(2R-Hydroxy-3-methylbutanoyl)-L-prolyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamide was obtained as a colorless gum (TLC Rf=0.7 (EtOAc); HPLC RT=3.21 min; LC-MS m/z=468). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen; In toluene; | EXAMPLE 3 In a 200 ml-volume autoclave whose atmosphere had been displaced with nitrogen were charged 11.5 g (0.1 mol) of 3-methyl-2-oxobutanoic acid and 100 ml of toluene, and 88 mg (0.090 mmol) of [Ru((-)-T-BINAP)](ClO4)2 as prepared in Reference Example 2 was added thereto to effect hydrogenation at a temperature of 60 C. and a hydrogen pressure of 50 kg/cm2 for 20 hours. After completion of the reaction, the solvent was removed by distillation, and the residue was extracted with an alkali. The aqueous layer was neutralized and extracted with diethyl ether. The extract was concentrated and dried to obtain 8 g of (R)-3-methyl-2-hydroxybutanoic acid having a melting point of 63 to 65 C. The optical rotation [alpha]D25 of the resulting alcohol was +10.65 (CHCl3). In the light of the optical rotation available in the literature, [alpha]D25 =+16.9 (CHCl3), the optical purity of the product was found to be 63%ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | 4.a Production of (S)-1,2-Bis-(diphenylphosphino)-3-methyl-butane (a) (R)-1,2-Dihydroxy-3-methyl-butane was produced analogous to the S-isomer (see Example 3(a)) starting from (R)-2-hydroxy-isovaleric acid. The yield was 86.5% of theory Rotary value [α]D20 =-10.0° (c=1/CHCl3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water at 110℃; for 24h; | 2 A sample of compound 1 (100 μg) was treated with 6 N HCl at 110 0C for 24 h. The hydrolysate was concentrated to dryness, reconstituted in 100 μL H2O and then analyzed by chiral HPLC [column, Chirobiotic TAG (4.6 x 250 mm), Supelco; solvent, MeOH-10 mM NH4OAc (40:60, pH 5.23): flow rate, 0.5 niL/min; detection by ESIMS in positive ion mode (MRM scan)]. L-Thr, L-Leu, L-Pro, iV,iV-Me2-L-Val and iV-Me-D-Phe eluted at tR 7.2, 9.0, 14.4, 27.0 and 45.4 min, respectively. The retention times (fo, min; MRM ion pair, parent→product) of the authentic amino acids were as follows: L-Thr (7.2; 120→74), L-α//o-Thr (7.5), D-Thr (8.6;), D-α//o-Thr (11.9), L-Pro (14.4; 116→70), D-Pro (39.5), L-Leu (9.0; 132→86), D-Leu (20.6), N- Me-L-Phe (25.0; 180→134), iV-Me-D-Phe (45.4), A^iV-Me2-L- VaI (27.0; 146→100), and A^V-Me2-D-VaI (69.8). The assignment of L-Thr was confirmed by co-injection of the hydrolysate with L-α//o-Thr and L-Thr. The MS parameters used were as follows: DP 31.0, EP 8.0, CE 17.3, CXP 3.1, CUR 35, CAD Medium, IS 4500, TEM 750, GSl 65, GS2 65. L-AIa was also detected in positive ion mode, at fo 8.0, but with slightly different MS conditions. The retention times (tR, min; MRM ion pair, parent→product) of the authentic standards were as follows: L-AIa (8.0; 90→44), D- AIa (14.6). The MS parameters used were as follows: DP 21.0, EP 8.0, CE 15.0, CXP 5.0, CUR 50, CAD Medium, IS 4500, TEM 750, GSl 65, GS2 65. Asp was only detected weakly in positive ion mode and consequently negative ion mode was used with the same LC conditions. L-Asp eluted at tR 6.1 min, indicating that the configuration of the Asn unit was L. The retention times (tR, min; MRM ion pair, parent→product) of the authentic standards were as follows: L-Asp (6.1; 132→88), D- Asp (6.8). The MS parameters used were as follows: DP -30.0, EP -5.0, CE -18.5, CXP -13.0, CUR 30, CAD High, IS -4500, TEM 750, GSl 65, GS2 65.A sample of compound 3 was treated with 6 N HCl at 110 0C for 24 h. The hydrolysate was concentrated to dryness, reconstituted in 100 μL H2O and then analyzed by chiral HPLC [column, Chirobiotic TAG (4.6 x 250 mm), Supelco; solvent, MeOH-10 mM NH4OAc (40:60, pH 5.33): flow rate, 0.5 niL/min; detection by ESIMS in positive ion mode (MRM scan)]. N-Me-L-GIu, L-IIe, L- Leu, L-Pro and N-Me-D-Phe eluted at tR 6.0, 8.3, 8.6, 13.3 and 41.7 min, respectively. The retention times (tR, min; MRM ion pair, parent→product) of the authentic standards were as follows: N-Me-L-GIu (6.0; 162→44), N-Me-D-GIu (15.8), L-IIe (8.3; 132→86), L- α//o-Ile (8.5), D-α//o-Ile (19.6), D-IIe (22.2), L-Leu (8.6; 132→86), D-Leu (19.8), L- Pro (13.3; 116→70), D-Pro (35.2), N-Me-L-Phe (23.2; 180→134), and N-Me-D-Phe (41.7). To further separate the isobaric He and Leu units, different LC conditions were employed [column, Chirobiotic TAG (4.6 x 250 mm), Supelco; solvent, MeOH-10 mM NH4OAc (90:10, pH 5.65); flow rate, 0.5 niL/min; detection by MS (MRM scan)]. L-IIe and L-Leu eluted at tR 12.3 and 13.1 min, respectively. The retention times (tR, min; MRM ion pair, parent→product) of the authentic amino acid standards were as follows: L-IIe (12.3; 132→86), L-α//o-Ile (13.4), D-α//o-Ile (57.5), D-IIe (70.5), L-Leu (13.1; 132→86), and D-Leu (51.7). The MS parameters used were as follows: DP 31.0, EP 8.0, CE 17.3, CXP 3.1, CUR 35, CAD Medium, IS 4500, TEM 750, GSl 65, GS2 65.Hmpa in the hydrolysate of compound 3 was detected in negative ion mode [column, Chirobiotic TAG (4.6 x 250 mm), Supelco; solvent, MeOH-10 mM NH4OAc (40:60, pH 5.35); flow rate, 0.5 niL/min; detection by ESIMS in negative ion mode (MRM scan)]. The MS parameters used were as follows: DP -35.0, EP -8.0, CE -17.9, CXP -1.7, CUR 40, CAD Medium, IS -4500, TEM 750, GSl 65, GS2 65. (2^3S)-HmPa from the hydrolysate eluted at tR 6.4 min. The retention times (tR, min; MRM ion pair, parent→product) of the authentic standards were as follows: (2S,3R)-Hmpa (6.0; 131→85), (2S,3S)-Umpa (6.2; 131→85), (2R,3S)-Hmpa (6.4; 131→85), (2R,3R)-Hmpa (7.0; 131→85). The hydrolysate was examined under different HPLC conditions in order to confirm this assignment [column, Chiralpak MA (+) (4.6 x 50 mm), Daicel Chemical Industries, Ltd.; solvent, 2 mM CuSO4-CH3CN (85:15); flow rate, 1.0 niL/min; detection by UV absorption at 254 nm]. (2^3S)-HmPa from the hydrolysate eluted at tR 15.4 min. The retention times (tR, min) of the authentic standards were as follows: (2R5SS)-HmPa (15.4), (2R,3R)- Hmpa (17.9), (25,3R)-HmPa (22.7), (25,3S)-HmPa (27.5). Under these conditions, all other units eluted at tR <6.5 min.EXAMPLE 3BASE HYDROLYSIS TO DETERMINE CONFIGURATION OF HIVA UNITSThe acid hydrolysate of compound 1 was analyzed by chiral HPLC [column, Chirobiotic TAG (4.6 x 250 mm), Supelco; solvent, MeOH-10 mM NH4OAc (60:40, pH 5.63); flow rate, 0.5 niL/min; detection by ESIMS in negative ion mode (MRM scan)]. Both L-Hiva and D-Hiva were detected at tR 6.0 and 6.4 min, respectively. The retention times (tR, min; MRM ion pair, parent→product) of the authentic standards were as follows: L-Hiva (6.0; 117→71), D-Hiva (6.4). A sample of compound 1 (100 μg) was suspended in 80 μL MeOH-0.5 N NaOH (1:1) and left to stand at room temperature for 72 h. The solution was neutralized by the addition of 20 μL 1 N HCl, and was then analyzed by chiral HPLC-MS.Only L-Hiva was detected at tR 6.0 min. The retention times (tR, min; MRM ion pair, parent→product) of the authentic standards were as follows: L-Hiva (6.0; 117→71), D-Hiva (6.4). The MS parameters used were as follows: DP -30.0, EP -3.0, CE -17.3, CXP -2.0, CUR 45, CAD Medium, IS -4500, TEM 650, GSl 50, GS2 25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran at 20℃; for 2h; | 65.1 Example 65 Synthesis of Compound (II-23) [Show Image] Step (1): Compound 23a + Compound 23b → Compound 23c; Compound 23a (4 g, 33.9 mmol) was dissolved in tetrahydrofuran (50 mL). While stirring, a tetrahydrofuran solution (30 mL) of diphenyldiazomethane 23b (6.91 g, 35.6 mmol) was added drop-wise thereto. After the reaction solution was stirred at room temperature for two hours, the solvent was evaporated under reduced pressure. n-Hexane (100 mL) was then added to the residue. The resulting solid was filtrated, and then washed with n-hexane to yield Compound 23c (8.25 g, 86%) as a solid. 1H-NMR (CDCl3) δ(delta): 7.36-7.29 (10H, m), 6.96 (1H, s), 4.16 (1H, d, J = 3.2 Hz), 2.67 (1H, br s), 2.23-2.13 (1H, m), 1.02 (3H, d, J = 7.0Hz), 0.77 (3H, d, J = 7.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 20℃; | Allyl (R)-2-hydroxy-3-methylbutanoate (13). To a solution of D-valic acid 33 (1.2 g, 10.2 mmol) andTBAI (0.75 g, 2.0 mmol) in dry DMF (25 mL) were added allyl bromide (1.8 mL, 20.3 mmol) and K2CO3(2.8 g, 20.3 mmol) at room temperature. After stirring overnight, the reaction mixture was quenched with 1N HCl and extracted with Et2O. The combined organic layer was washed with brine, driedover MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography(EtOAc/Hexane = 1:20) to give 1.5 g (93%) of ester 13 as a colorless oil. [α]D20 = +24.77 (c 1.00, CHCl3);1H-NMR (800 MHz, CDCl3) δ 5.84 (ddt, J = 17.1, 10.6, 5.9 Hz, 1H), 5.26 (dd, J = 17.2, 1.3 Hz, 1H), 5.18(dd, J = 10.4, 1.1 Hz, 1H), 4.61 (dd, J = 13.1, 5.9 Hz, 1H), 4.57 (dd, J = 13.2, 5.9 Hz, 1H), 3.98 (d, J = 3.9 Hz,1H), 2.87 (s, 1H), 2.01 (dtd, J = 13.9, 6.9, 3.7 Hz, 1H), 0.94 (d, J = 7.3 Hz, 3H), 0.79 (d, J = 7.2 Hz, 3H);13C-NMR (200 MHz, CDCl3) δ 174.4, 131.4, 118.9, 74.9, 65.8, 32.0, 18.6, 15.8; IR (thin film, neat) νmax3516, 2968, 1743, 1468, 1372, 1197, 1130, 933 cm-1; LR-MS (ESI+) m/z 181 (M + Na+); HR-MS (ESI+)calcd for C8H14NaO3 (M + Na+) 181.0835; found 181.0834. |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; at 110℃; for 15h; | Compound 1 (1.5 mg) was hydrolyzed with 6 M HCl (0.5 mL) at 110 C for 15 h. After concentration to dryness, the residue was dissolved in MeOH (200 muL) and subjected to HPLC analysis. In the same manner, compound 2 was hydrolyzed. HPLC analysis of the depsipeptide hydrolysates was performed using a ligand-exchange-type chiral column: Phenomenex Chirex 3126 (d)-penicillamine, 4.6×250 mm; mobile phase 2-propanol in 2 mM aqueous CuSO4; flow rate 1 mL/min, UV 235 nm. The 2-hydroxyisovaleric acid standard was purchased from Aldrich. Two mobile phase conditions were employed due to the large retention time differences of the standard samples: (1) 15% 2-propanol in 2 mM aqueous CuSO4, N-Me-l-Val and N-Me-d-Val (tR 7.0 min, peaks were superimposed), N-Me-l-Phe (tR 26.6 min), N-Me-d-Phe (tR 30.8 min), l-Hiv (tR 40.0 min), and d-Hiv (tR 67.4 min); (2) 5% 2-propanol in 2 mM aqueous CuSO4, N-Me-l-Val (tR 11.0 min), N-Me-d-Val (tR 13.9 min). Hydrolyzates of 1 and 2 contained N-Me-l-Val, N-Me-l-Phe, and d-Hiv. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; at 110℃; for 15h; | Compound 1 (1.5 mg) was hydrolyzed with 6 M HCl (0.5 mL) at 110 C for 15 h. After concentration to dryness, the residue was dissolved in MeOH (200 muL) and subjected to HPLC analysis. In the same manner, compound 2 was hydrolyzed. HPLC analysis of the depsipeptide hydrolysates was performed using a ligand-exchange-type chiral column: Phenomenex Chirex 3126 (d)-penicillamine, 4.6×250 mm; mobile phase 2-propanol in 2 mM aqueous CuSO4; flow rate 1 mL/min, UV 235 nm. The 2-hydroxyisovaleric acid standard was purchased from Aldrich. Two mobile phase conditions were employed due to the large retention time differences of the standard samples: (1) 15% 2-propanol in 2 mM aqueous CuSO4, N-Me-l-Val and N-Me-d-Val (tR 7.0 min, peaks were superimposed), N-Me-l-Phe (tR 26.6 min), N-Me-d-Phe (tR 30.8 min), l-Hiv (tR 40.0 min), and d-Hiv (tR 67.4 min); (2) 5% 2-propanol in 2 mM aqueous CuSO4, N-Me-l-Val (tR 11.0 min), N-Me-d-Val (tR 13.9 min). Hydrolyzates of 1 and 2 contained N-Me-l-Val, N-Me-l-Phe, and d-Hiv. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: (R)-2-Hydroxy-3-methylbutyric acid; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide for 24h; Stage #2: With water; potassium carbonate In methanol at 0 - 20℃; for 2.5h; | 3 (R)-TBS-Protected Alcohol 972b (R)-TBS-Protected Alcohol 972b: (0151) The compound was prepared according to J. Chem. Soc., Perkin Trans. 1, 1996, 1427-1433 while the analytics are compared to Analytics compared to: J. Org. Chem. 1989, 54, 2085-2091. (R)-2-Hydroxy-3-methylbutyric acid (not shown) (305 mg, 2.58 mmol, 1.00 eq.), TBS-Cl (934 mg, 6.20 mmol, 2.40 eq.) and imidazole (1.07 g, 12.4 mmol, 4.80 eq) were dissolved in 3.5 mL DMF at RT. The mixture was stirred 24 h. The mixture was diluted with 65 mL EtOAc, washed 3× with 10 mL sat. aq. citric acid, sat. aq. NaHCO3 and brine, dried over MgSO4 and concentrated. The resulting oil was dissolved in 22 mL MeOH and cooled to 0° C. 650 mg K2CO3 in 8 mL H2O were added and the mixture was stirred for 2.5 h at RT. The solution was adjusted to pH 4 (aq. HC 1 M) and the aq. phase was extracted with EtOAc (3×40 mL). The combined org. phase was dried over MgSO4 and concentrated. The colorless oil was purified by FC (hexane/EtOAc 6:1→4:1) to deliver (R)-TBS-protected alcohol 972b (339 mg, 57% over 2 steps) as a colorless oil. (0152) Rf: 0.25 (10% MeOH in CH2Cl2) (0153) [α]2D: +18.31 (c 0.942, CH2Cl2) (0154) 1H-NMR: (400 MHz, CDCl3) δ 4.05 (d, J=4.0 Hz, 1H), 2.16-2.01 (m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.95-0.91 (m, 12H), 0.09 (s, 6H). (0155) 13C-NMR: (101 MHz, CDCl3) δ 176.9, 76.7, 32.8, 25.7, 18.8, 16.7, -5.2. (0156) HR-MS: (ESI): m/z calc. for C11H23O3 Si [M-H]- 231.1422. found 231.1424. |
339 mg | Stage #1: (R)-2-Hydroxy-3-methylbutyric acid; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; Schlenk technique; Stage #2: With potassium carbonate In methanol; water at 0 - 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 2.1.B PREPARATION 2 Synthesis of methyl 4-[(1S)-1-[[(2R)-2-hydroxy-3-methyl-butanoyl]amino]ethyl]benzoate Scheme 1, Step B. A mixture of 4-[(1S)-1-aminoethyl]-benzoic acid, methyl ester (5.8 g; 49.1 mmol), (2R)-2-hydroxy-3-methyl-butanoic acid (9.3 g; 51.9 mmol), 1-hydroxybenzotriazole (0.82 g; 6.1 mmol), and triethylamine (22 mL; 158 mmol) in CH2Cl2 (120 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.2 g; 74.1 mmol). The cloudy mixture is stirred at room temperature overnight. The reaction mixture is washed with 1N HCl (2*150 mL) then brine. The organic layer is dried over MgSO4, filtered, concentrated, and dried under high vacuum to provide the title compound as a white solid (10.24 g, 75%). This material is used in the next step without further purification. MS (m/z): 280.0 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 8.14-8.12 (m, 1H), 7.87-7.84 (m, 2H), 7.45-7.43 (m, 2H), 5.35 (d, J=5.7 Hz, 1H), 5.00-4.95 (m, 1H), 3.79 (s, 3H), 3.64 (dd, J=4.0, 5.7 Hz, 1H), 1.93-1.89 (m, 1H), 1.36 (d, J=7.2 Hz, 3H), 0.81 (d, J=6.9 Hz, 3H), 0.65 (d, J=6.7 Hz, 3H). |
54% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; ethyl cyanoglyoxylate-2-oxime In N,N-dimethyl-formamide at 27℃; for 18h; Cooling with ice; | Step (i) To an ice-cooled solution of (2R)-2-hydroxy-3-methyl-butanoic acid (10.0 g, 84.7 mmol) and methyl (S)-4-(1-aminoethyl)benzoate (16.7 g, 93.1 mmol) in DMF (170 mL) was added EDC HCI (24.3 g, 127.0 mmol), ethyl (hydroxyimino)cyanoacetate (13.2 g, 93.1 mmol) and triethylamine (29.5 mL, 211.6 mmol). The mixture was stirred at RT for 18 hrs after which it was partitioned between EtOAc and water. The organics were separated, washed sequentially with 1 M HCI, sat. aq. NaHCO3 and brine, dried over MgSO4 and concentrated to afford Intermediate 1 , methyl 4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate (12.8 g, 45.9 mmol, 54% yield) as an orange solid. Data available in Table 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 mg; 4.3 mg | With hydrogenchloride; In water; at 110℃; for 24h;Sealed tube; Inert atmosphere; | 10 mg of 1bwas treated with 15 mL of 6 N HCl (pa) and heated at 110 C for 24 hin ampoules previously sealed under N2 gas. The resulting solutionwas added to 15 mL of H2O and then extracted three times with 15 mLdiethylether to obtain 5 mg of 2-hydroxy-3-methylbutyric acid. The aqueoussolution was then evaporated under vacuum to afford 4.3 mg of N-methylphenylalanine.2-Hydroxy-3-methylbutyricacid was then analyzed with GC-MS and further investigatedfor its absolute configuration by examination of its specific optical rotationvalue and menthyl ester derivatization.Moreover, the absolute configuration of N-methylphenylalanine was alsoanalyzed by examination of its specific optical rotation value and Marfeyderivatization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With 4-methyl-morpholine; dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 40℃; | 30 Example 30: 5-[4-((R)-2-Hydroxy-3-methyl-butyryl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide To (R)-(+)-2-Hydroxy-3-methylbuttyric acid (15 mg, 0.13 mmol), a solution containing HOBt*H2O (0.13 mmol), N-methylmorpholine and 0.01 mmol DMAP in 0.75 ml DMF was added and the mixture was stirred at RT until the acid had dissolved. Then 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide (Intermediate 5) (42 mg, 0.11 mmol) in 1 ml DMF was added, followed by 0.13 mmol EDC (neat). The tube was closed with a screw cap and shaken over night at 40 °C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to SFC purification to give the title compound as a colorless film (17 mg, 30%). 1 H NMR (DMSO-d6, 500 MHz) δ ppm 9.02 (t, 1 H), 8.1 (d, 1 H), 7.66 (d, 1 H), 7.02 (d, 1 H), 6.90 (d, 1 H), 6.68 (s, 1 H), 4.6 (bs, 1 H), 4.41 (d, 2H), 4.03 (d, 1 H), 3.82 (s, 3H), 3.7 (s, 2H), 3.6-3.4 (m, 4H), 2.45-2.3 (m, 4H), 1.89 (m, 1 H), 0.88 (d, 3H), 0.78 (d, 3H). LC/MS (Method 3); Rt = 1.26 min; detected mass: m/z = 447.20 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: (R)-2-Hydroxy-3-methylbutyric acid With 4-methyl-morpholine; dmap; benzotriazol-1-ol In N,N-dimethyl-formamide at 20 - 25℃; Stage #2: 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid (2-methoxy-pyridin-ylmethyl)amide hydrochloride With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 40℃; Sealed tube; | 30 Example 30: 5-[4-((R)-2-Hydroxy-3-methyl-butyryl)-piperazin-1 -ylmethyl]-thiophene-2- carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide Example 30: 5-[4-((R)-2-Hydroxy-3-methyl-butyryl)-piperazin-1 -ylmethyl]-thiophene-2- carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide To (R)-(+)-2-Hydroxy-3-methylbuttyric acid (15 mg, 0.13 mmol), a solution containing HOBt*H2O (0.13 mmol), N-methylmorpholine and 0.01 mmol DMAP in 0.75 ml DMF was added and the mixture was stirred at RT until the acid had dissolved. Then 5- piperazin-1 -ylmethyl-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide (Intermediate 5) (42 mg, 0.1 1 mmol) in 1 ml DMF was added, followed by 0.13 mmol EDC (neat). The tube was closed with a screw cap and shaken over night at 40 °C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to SFC purification to give the title compound as a colorless film (17 mg, 30%). 1 H NMR (DMSO-d6, 500 MHz) δ ppm 9.02 (t, 1 H), 8.1 (d, 1 H), 7.66 (d, 1 H), 7.02 (d, 1 H), 6.90 (d, 1 H), 6.68 (s, 1 H), 4.6 (bs, 1 H), 4.41 (d, 2H), 4.03 (d, 1 H), 3.82 (s, 3H), 3.7 (s, 2H), 3.6-3.4 (m, 4H), 2.45-2.3 (m, 4H), 1 .89 (m, 1 H), 0.88 (d, 3H), 0.78 (d, 3H). LC/MS ( Method 3); Rt = 1 .26 min; detected mass: m/z = 447.20 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.67 h / 0 °C / Inert atmosphere 1.2: 15 h / 0 - 20 °C / Inert atmosphere 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 0 - 20 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 17 h / 0 - 20 °C / Inert atmosphere 5.1: hydrogenchloride / 1,4-dioxane / 6 h / 20 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 7.1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 6 h / 20 °C / Inert atmosphere 8.1: hydrogenchloride / 1,4-dioxane / 6 h / 20 °C / Inert atmosphere 9.1: 1-chloro-1-(dimethylamino)-2-methyl-1-propene / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 10.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18.5 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 11 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.67 h / 0 °C / Inert atmosphere 1.2: 15 h / 0 - 20 °C / Inert atmosphere 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 0 - 20 °C / Inert atmosphere 3.1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 2.5 h / 20 °C / Inert atmosphere 4.1: 1-chloro-1-(dimethylamino)-2-methyl-1-propene / dichloromethane / 0.33 h / 0 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 17 h / 0 - 20 °C / Inert atmosphere 6.1: hydrogenchloride / 1,4-dioxane / 6 h / 20 °C / Inert atmosphere 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 8.1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 6 h / 20 °C / Inert atmosphere 9.1: hydrogenchloride / 1,4-dioxane / 6 h / 20 °C / Inert atmosphere 10.1: 1-chloro-1-(dimethylamino)-2-methyl-1-propene / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 11.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18.5 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 9 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.67 h / 0 °C / Inert atmosphere 1.2: 15 h / 0 - 20 °C / Inert atmosphere 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 0 - 20 °C / Inert atmosphere 3.1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 2.5 h / 20 °C / Inert atmosphere 4.1: 1-chloro-1-(dimethylamino)-2-methyl-1-propene / dichloromethane / 0.33 h / 0 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 6.1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 6 h / 20 °C / Inert atmosphere 7.1: hydrogenchloride / 1,4-dioxane / 6 h / 20 °C / Inert atmosphere 8.1: 1-chloro-1-(dimethylamino)-2-methyl-1-propene / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 9.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18.5 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 20℃; for 2h; Inert atmosphere; | Tetrabutylammonium salts General procedure: The tetrabutylammonium salts were prepared by adding 1 equiv tetrabutylammonium hydroxide in methanol to a solution of corresponding carboxylic acid (1 equiv) in methanol [21]. The mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The resulting syrup was dried at high vacuum for 24 h, stored in the desiccators. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 110℃; for 24h; | Urumamide (1) (0.7 mg) was treated with 9 N HCl (100 L) for 24 h at 110 C. The hydrolyzed product was evaporated to dryness and could be separated into each component by HPLC. [Cosmosil 5C18-PAQ (4.6 × 250 mm); flowrate, 1.0 mL/min; detection at 215 nm; solvent H2O. Retention times (min) of components: N-Me-Ala (tR = 3.0 min), Pro(tR = 3.2 min), Val (tR = 3.4 min), N-Me-Val (tR = 3.7 min), Leu (tR = 4.8 min), N-Me-Ile (tR = 5.3 min), N-Me-Leu (tR =6.0 min)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 715.5 Step 5: Preparation of (R)-4-(6-(4-(2-hydroxy-3 -methylbutanoyl)piperazin- 1- yl)pyridin-3 -yl)-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1.5-alpyridine-3 -carbonitrile. A solution of 6-( 1 -(1 -(2-methoxyethyl)piperidin-4-yl)- 1H-pyrazol-4-yl)-4-(6-(piperazin- 1 -yl)pyridin-3 -yl)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile dihydrochloride (31mg, 0.053 mmol) in DMF (1.1 mL) was treated with D-alpha-Hydroxyisovaleric acid (7.5 mg, 0.064 mmol), HATU (24.2 mg, 0.0636 mmol) and DIEA (46.2 tL, 0.265 mmol). The resulting solution was stirred overnight at ambient temperature. The reaction mixture was diluted with 5% MeOHIDCM (20 mL) and washed with water (5 mL). The combined organic extracts were dried over anhydrous MgSO4, then filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (8% MeOHIDCM with 2% NH4OH(aq) as the eluent) to cleanly afford the title compound (20 mg, 62% yield). MS (apci) m/z = 611.9, 612.9 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; | 723.3 Step 3: Preparation of (R)-4-(6-(4-(2-hydroxy-3 -methylbutanoyl)piperazin- 1- yl)pyridin-3 -yl)-6-(2-methylthiazol-5-yl)pyrazolo[ 1 ,5-alpyridine-3-carbonitrile 2,2,2- trifluoroacetate. A solution of 6-(2-methylthiazol-5 -yl)-4-(6-(piperazin- 1 -yl)pyridin-3 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (42 mg, 0.0885 mmol) in DCM (3 mL)was treated with DIEA (61.7 tL, 0. 354 mmol), D-alpha-Hydroxyisovaleric acid (12.5 mg, 0.106mmol) and HATU (40.4 mg, 0.106 mmol). The resulting solution was stirred overnight at ambienttemperature. The reaction mixture was concentrated in vacuo, and the crude residue was purifiedby C18 reverse-phase chromatography (5-95% ACN/water with 0.1% TFA as the gradient eluent)to cleanly afford the title compound as the bistrifluoroacetate salt (15 mg, 28% yield). MS (apci)m/z = 502.2 (M+H). |
Tags: 17407-56-6 synthesis path| 17407-56-6 SDS| 17407-56-6 COA| 17407-56-6 purity| 17407-56-6 application| 17407-56-6 NMR| 17407-56-6 COA| 17407-56-6 structure
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P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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