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CAS No. : | 35179-98-7 | MDL No. : | MFCD00137995 |
Formula : | C4H7ClO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RTFGZMKXMSDULM-UHFFFAOYSA-N |
M.W : | 138.55 | Pubchem ID : | 5325479 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 28.9 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.06 cm/s |
Log Po/w (iLOGP) : | 1.99 |
Log Po/w (XLOGP3) : | 1.53 |
Log Po/w (WLOGP) : | 1.36 |
Log Po/w (MLOGP) : | 0.42 |
Log Po/w (SILICOS-IT) : | 0.64 |
Consensus Log Po/w : | 1.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.4 |
Solubility : | 5.53 mg/ml ; 0.0399 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.89 |
Solubility : | 1.81 mg/ml ; 0.013 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.09 |
Solubility : | 11.2 mg/ml ; 0.0805 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.27 |
Signal Word: | Danger | Class: | 3,8 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P370+P378-P403+P235-P405-P501 | UN#: | 2924 |
Hazard Statements: | H314-H226 | Packing Group: | Ⅲ |
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 |
---|---|---|
87% | With pyridine; In water; at 20℃; for 2h;Cooling; | General procedure: Mixing 1 mole of chloroalkyl chloroformate with 8 moles of alcohol,3 mols of pyridine was added dropwise under cooling with cold water.Stir at room temperature for 2 hours.Add 500mL of dichloromethane,And washed the organic layer twice with 2N hydrochloric acid,Then wash the organic layer once with water,Separate the organic layer,Anhydrous sodium sulfate was dried overnight.filter,The filtrate was evaporated to dryness of crude oil of intermediate (III),Can be used directly in the next reaction.The following intermediate (III) was prepared as described above,The product mass spectrum and yield are as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In di-isopropyl ether; water; acetonitrile; | EXAMPLE 24 To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone(0.50 g) and <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (2.9 g) was added acetonitrile (0.5 ml), and the mixture was stirred for 22 hours at 100 C. The reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate/acetone=1/1?acetone?acetone/ethanol=9/1?4/1), and the fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The elude was concentrated in vacuo, and the residue was dissolved in water(15 ml). The solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-ethoxycarbonyloxymethyl-1H-1,2,4-triazolium chloride (Compound 15, 0.14 g) as a white powder. 1H-NMR(d6-DSMO) delta: 0.97(3H,d,J=7 Hz), 1.22(3H,t,J=7 Hz), 3.60~4.08(4H,m), 4.18(2H,q,J=7 Hz), 4.63~4.73(1H,m), 4.87(1H,d,J=14 Hz), 5.10(1H,d,J=14 Hz), 6.13(1H,d,J=11H,z), 6.21(1H,d,J=11H,z), 6.65(1H,s), 6.96~7.04(1H,m), 7.24~7.37(2H,m), 7.82~7.95(5H,m), 8.78(1H,d,J=1H,z), 9.09(1H,s), 10.48(1H,s). | |
In di-isopropyl ether; water; acetonitrile; | Reference Example 33 To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone(0.50 g) and <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (2.9 g) was added acetonitrile (0.5 ml), and the mixture was stirred for 22 hours at 100 C. The reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate/acetone=1/1?acetone?acetone/ethanol=9/1?4/1), and the fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The elude was concentrated in vacuo, and the residue was dissolved in water(15 ml). The solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-ethoxycarbonyloxymethyl-1H-1,2,4-triazolium chloride (Compound 15, 0.14 g) as a white powder. 1H-NMR(d6-DSMO) delta: 0.97(3H,d,J=7 Hz), 1.22(3H,t,J=7 Hz), 3.60-4.08(4H,m), 4.18(2H,q,J=7 Hz), 4.63-4.73(1H,m), 4.87(1H,d,J=14 Hz), 5.10(1H,d,J=14 Hz), 6.13(1H,d,J=11H,z), 6.21(1H,d,J=11H,z), 6.65(1H,s), 6.96-7.04(1H,m), 7.24-7.37(2H,m), 7.82-7.95(5H,m), 8.78(1H,d,J=1H,z), 9.09(1H,s), 10.48(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; dichloromethane; | Combine chloromethyl chloroformate (19 mL) and ichloromethane (300 mL) and cool in an ice bath. Add dropwise over about i hour, a solution of ethanol (11.7 mL and triethylamine (30.7 mL) in dichloromethane (100 mL). After 3.5 hours, filter and concentrate the filtrate to give a residue. Partition the residue between diethyl ether and water. Separate the organic layer and dry over MgSOA, filter and evaporate in vacuo to give ethyl chloromethyl carbonate. | |
With N-ethyl-N,N-diisopropylamine; In ethanol; dichloromethane; | 6.19 Preparation of deprenyl-N-ethoxycarbonyloxymethyl, iodide salt To a solution of ethanol (360 mg, 0.808 mol) in dichloromethane (10 ml) was added diisopropylethylamine (1 g, 0.008 mol). The mixture was cooled to 0 C. and chloromethyl chloroformate (1 g, 0.008 mol) was added in a dropwise fashion. The mixture was stirred for one hour at room temperature and then was poured into water and separated. The organic layer was washed with aqueous hydrochloric acid (0.1N) and saturated aqueous sodium bicarbonate, dried (sodium sulfate), and concentrated in vacuo. Pure chloromethyl ethyl carbonate (500 mg) was obtained by distillation. | |
With pyridine; In ethanol; dichloromethane; | PREPARATION 77 Chloromethyl Ethyl Carbonate STR189 Ethanol (1.9 ml) was added in one portion to a cooled (0 C.) solution of chloromethyl chloroformate (4.2 g) in dichloromethane (20 ml). Pyridine (2.63 ml) was then added (CAUTION| EXOTHERMIC) and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with dichloromethane (100 ml), washed with ice-cold (0 C.) 0.5M hydrochloric acid then dried (MgSO4) and concentrated in vacuo to give the title compound as an oil, 0.17 g. 1 H-NMR (CDCl3): delta=5.70 (s,2H), 4.30-4.20 (q,2H), 1.35-1.25 (t,3H) ppm. |
In ethanol; | h) Ethyl chloromethyl carbonate. The compound was obtained from chloromethyl chloroformate and ethanol. 1 H NMR (60 MHz, CDCl3): delta1.25 (t, 3H, CH3), 4.25 (q, 2H, CH2), 5.70 (s, 2H, OCH2 Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.5% | In N-methyl-acetamide; | EXAMPLE 220 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[1-(ethoxycarbonyloxymethyloxy)-carbonyl]-biphenyl Prepared analogously to Example 215 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and <strong>[35179-98-7]1-(ethoxycarbonyloxy)-methylchloride</strong> in dimethylformamide. Yield: 38.5% of theory, Melting point: 123-125 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; | 27(a) Ethoxycarbonyloxymethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate Following a procedure similar to that described in Example 25(c), 0.69 g of the title compound was obtained as an oil from 0.55 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Example 25(b)], 0.30 g of <strong>[35179-98-7]ethoxycarbonyloxymethyl chloride</strong> and 0.50 g of potassium carbonate. Nuclear Magnetic Resonance Spectrum (CDCl3) delta ppm: 0.99 (3H, triplet, J=7 Hz); 1.23 (9H, singlet); 1.29 (3H, triplet, J=7 Hz); 1.64 (6H, singlet); 1.74-1.85 (2H, multiplet); 2.69 (2H, triplet, J=7.5 Hz); 4.21 (2H, quartet, J=7 Hz); 5.39 (1H, singlet); 5.52 (2H, singlet); 5.83 (2H, singlet); 6.97 (2H, doublet, J=8 Hz); 7.26-7.51 (5H, multiplet); 7.77 (1H, doublet, J=6.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
m) Ethyl methacryloyloxymethyl carbonate. The compound was obtained from <strong>[35179-98-7]ethyl chloromethyl carbonate</strong> and potassium methacrylate. IR (KBr): delta1772 (C=O, str), 1736 (C=O, str.), 1635 (C=C, str) cm-1 1 H NMR (300 MHz, CDCl3): delta1.27 (t, 3H, CH3), 1.92 (s, 3H, CH3 C=), 4.23 (q, 2H, CH2), 5.66 (m, 1H, CH2 =), 5.80 (s, 2H, --OCH2 O--), 6.20 (m, 1H, CH2 =). 13 C NMR (75 MHz, CDCl3): delta15.70 (CH3 CH2), 19.60 (CH3 C=), 65.72(CH2 O), 83.05 (--OCH2 O--), 127.76 (CH2 =), 135.40 (C=), 153.82 (C=O), 165.42 (C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 20 - 50℃; for 22h; | A solution of 1.028 g (1.29 mmol) of the diacid, 118.2 mg (0.32 mmol), and 2.7 mL (19.4 mmol) of triethylamine in 20 mL N-methylpyrrolidone (20 mL) was stirred at rt as 2.054 g (14.8 mmol) of <strong>[35179-98-7]carbonic acid chloromethyl ester ethyl ester</strong> was added. The mixture was stirred at 50 C for 22 h and cooled to rt before filtration through a membrane filter. The filtrate was purified by preparative HPLC and the pure product containing fractions were freeze-dried to obtain 284 mg (22%) of compound 34: 1H NMR (300 MHz, CDCk): 5 7.99 (d, J = 9.3 Hz, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 7.37 (br, 1H), 7.31 (br, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.94 (dt, J = 17.1 and 9.7 Hz, 1H), 5.60-5.74 (m, 4H), 5.15-5.44 (m, 5H), 5.00 (br, 1H), 4.65 (t, J = 7.1 Hz, 1H), 4.35-4.44 (m, 2H), 4.13-4.26 (m, 4H), 3.96-4.05 (m, 1H), 3.94 (s, 3H), 3.66-3.77 (m, 1H), 2.81-2.90 (m, 1H), 2.40-2.49 (m, 1H), 2.00-2.21 (m, 1H), 1.47-1.88 (m, 10H), 1.35 (d, J = 6.3 Hz,6H), 1.20-1.38 (m, 6H), 1.04 (s, 9H); 31P NMR (75 MHz, CDCb) 5 22.32 (-0.1P),21.78 (-0.9P); LC/MS: 1003 (M+ + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 2h; | The phosphinic acid (83mg, 0.102) was suspended in 1.5mL of DMF.chloromethyl ethyl chloroformate (142mg, 1.02mmol), triethylamine (213 (at)1,1.53mmol) and tetrabutyl ammonium iodide (TBAI) (9mg, 0.02mmol) wereadded. The solution was heated at 70C for 2 hours. The solution was cooledto room temperature, purified using a Reverse Phase Gilson HPLC to yieldcompound 39 .H NMR (300 MHz, CDsOD): 8 8.03 (d, J=8.8 Hz, 1H), 7.43 (s,2H) 7.33 (s, 1H), 7.03 (d, J=9.2 Hz, 1H), 5.98 (m, 1H), 5.95 (m, 1H), 5.60 (d, 2H),5.44 (s, 1H), 5.33 (dd, 1H), 5.17 (t, 1H), 4.87 (s, 1H), 4.52 (d, J=9.4,1H), 4.56 (t,1H), 4.47 (d, 2H), 4.27 (s, 1H), 4.24 (m, 3H), 3.94 (s, 3H), 2.66 (m, 1H), 2.58 (m,1H), 2.37 (m, 1H), 2.14 (m, 1H), 1.64 (m, 6H), 1.33 (d, 6H), 1.20 (t, 3H), 1.29 (d,6H), 1.04 (s, 9H). 31P (75 MHz, CDsOD): S(at) 53.082, 57.428. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver carbonate; In toluene; for 3h;Heating / reflux; | To a solution of ((R)-3~benzyloxycarbonylamino-2-hydroxy- EPO <DP n="23"/>propyO-cyclohexylmethyl-phosphinic acid (1.0 g, 2.71 mmol) and <strong>[35179-98-7]carbonic acid chloromethyl ester ethyl ester</strong> (1.13 g, 8.16 mmol) in toluene (60 mL) was added silver carbonate (2.26 g, 8.16 mmol). The reaction mixture was heated at reflux for 3h. The reaction mixture was then filtered and was concentrated in vacuo. Purification by gradient flash chromatography (methanol/methylene chloride) on a 35 g RediSep disposable column gave (3- benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid ethoxycarbonyloxymethyl ester (300 mg, 0.63 mmol). 1H-NMR(CDCl3, 300 MHz): delta 7.35 (m, 5H), 5.65 (m,2H), 5.45 (br s, IH), 5.10 (s, 2H), 4.2 (m, 2H), 3.45 (dd, IH), 3.20 (dd, IH), 2.01-1.55 (m, HH), 1.40-0.95 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With sodium hydroxide; In water; toluene; | EXAMPLE 2 Preparation of 4-fluoro-2-[[(4-methoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate To NaOH (0.26 g, 6.5 mmol) dissolved in H2 O (12 ml) 4-fluoro-2-[[(4-methoxy-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole (1.0 g, 3.3 mmol) and tetrabutylammoniumhydrogen sulfate (1.1 g, 3.2 mmol) were added under stirring. The mixture was stirred for about 5 min, at ambient temperature and then extracted 3 times with CH2 Cl2 (20 ml). After separation the combined CH2 Cl2 phases were dried over Na2 SO4, filtrated and the solvent evaporated off giving an oil. The residual oil was dissolved in toluene (30 ml). <strong>[35179-98-7]Chloromethyl ethyl carbonate</strong> (0.68 g, crude material) dissolved in dry toluene (3 ml) was added under a protective gas and under stirring. The mixture was stirred at ambient temperature over night. The toluene was evaporated off and the residual oil was chromatographed on a silica column using ethyl acetate as eluent. Crystallizing from ethyl acetate - diethyl ether gave the title compound (0.33 g, 25%). NMR data for the product is given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 100 ml of one-necked flask, 0.698g of material, 0.162g of potassium carbonate, 5 ml of N,N-dimethylacetamide were added in turn. The solution was stirred at room temperature for 20 minutes. Then 0.702g of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> was added and the mixture was reacted at 45-50C for 16 hours. After the reaction was completed, the mixture solution was filtered, and 30ml of water was added into the filtrate. The resulting mixture was extracted with 30ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.854g of oil, which was directly used in the next reaction without purification. 10ml of dioxane and 5ml of 4mol/L HCl were added and the resulting mixture was reacted at room temperature for 16 hours. The reaction was stopped and the solution was adjusted to pH 6-7 using aqueous sodium bicarbonate solution. The solution went turbid, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated to give 0.420g of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl] imidazole-5- carboxylic acid, 1-[(ethoxycarbonyl)oxy] methyl ester. 1H-NMR (CDCl3) delta H (ppm) 0.92(t,3H,J=17.5), 1,23(t,3H,J=14.0), 1.37(m,2H,J=34.2), 1.73(m,2H,J=30.8), 2.69(t,2H,J=15.5), 4.13(q,2H,J=15.7), 5.58(s,2H), 5,89(s,2H), 6,99-7.61(8H), 8.16(d,1H,J=6.1) ESI(-): 539.1 Mp:164.5-160C | ||
With potassium carbonate; In N,N-dimethyl acetamide; at 20 - 50℃; for 16.3333h; | To a 100 ml of one-necked flask, 0.698 g of material, 0.162 g of potassium carbonate, 5 ml of N,N-dimethylacetamide were added in turn. The solution was stirred at room temperature for 20 minutes. Then 0.702 g of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> was added and the mixture was reacted at 45-50 C. for 16 hours. After the reaction was completed, the mixture solution was filtered, and 30 ml of water was added into the filtrate. The resulting mixture was extracted with 30 ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.854 g of oil, which was directly used in the next reaction without purification.10 ml of dioxane and 5 ml of 4 mol/L HCl were added and the resulting mixture was reacted at room temperature for 16 hours. The reaction was stopped and the solution was adjusted to pH 6-7 using aqueous sodium bicarbonate solution. The solution went turbid, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated to give 0.420 g of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(ethoxycarbonyl)oxy]methyl ester.1H-NMR (CDCl3) delta H (ppm) 0.92 (t, 3H, J=17.5), 1.23 (t, 3H, J=14.0), 1.37 (m, 2H, J=34.2), 1.73 (m, 2H, J=30.8), 2.69 (t, 2H, J=15.5), 4.13 (q, 2H, J=15.7), 5.58 (s, 2H), 5.89 (s, 2H), 6.99-7.61 (8H), 8.16 (d, 1H, J=6.1)ESI(-): 539.1Mp: 164.5-160 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00376] A mixture of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (0. 556 g, 4 mmol) and sodium iodide (600 mg, 4 mmol) in acetone was stirred at room temperature for 1 h. To that mixture was added CsHCO3 (0.776 g, 4 mmol) and compound 102 (1. 33 g, 4 mmol), respectively. The resulting mixture was stirred at room temperature for 16 h. After removing the solvent under reduced pressure, the residue was partitioned between ethyl acetate and 10% citric acid. The organic phase was separated, dried over MGS04, and concentrated. The resulting residue was purified by silica gel chromatography, eluting with hexane : ethyl acetate (5: 5) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium IODIDE (25 MG) was dissolved in acetonitrile (0. 15 mL) in which had been dissolved <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (22 mg) [Z. Li et al. , Bioorg. Med. CHEM. LETT., 7,2909 (1997)], and the solution was stirred for four hours under dark room conditions at room temperature. Next, the solution was added to DMF (0. 30 mL) in which had been dissolved BOC--ALA-HIS (TRT) (30 mg) and DIISOPROPYLETHYLAMINE (0. 019 ML), and stirring was further carried out for 3 days at room temperature. After that, ethyl acetate (30 mL) was added to the solution obtained, and the solution was washed with a sodium hydrogencarbonate aqueous solution (5 mL) twice and a sodium chloride aqueous solution (5 ML) once. After the washing, drying was carried out with sodium sulfate, concentration was carried out under reduced pressure, the concentrate was dissolved in a mixed liquid of acetonitrile and water (1: 4), and then freeze drying was carried out, thus obtaining A white powder (approximately 55 mg). The powder was treated for 30 minutes with TFA (1.2 ML) CONTAINING 2% TRIISOPROYLSILANE and 2% water, and then washing was carried out three times with ether (10 mL). The residue was dissolved in a mixed solution of acetonitrile and water (1: 4), and then freeze drying was carried out, thus obtaining 28 mg of crude product. The crude product obtained was subjected to HPLC (with an ODS column) with the undermentioned conditions using water- acetonitrile containing 0. 1T TFA as an eluent, the fraction containing THE TARQET COMPOUND (ss-ALA-HIS-OCH2-OCO-OCH2CH3) was isolated using the absorbance at 220 nm as an indicator, and freeze drying was carried out, thus obtaining a white powder (19 mg) of P-ALA-HIS-OCH2-OCO-OCH2CH3 (TFA salt). This powder was dissolved in a 0. 05 M HC1 aqueous solution containing 5% acetonitrile, and freeze drying was again carried out, whereby the target compound (-ALA-HIS-OCH2-OCO-OCH2CH3 2HC1) WAS obtained as a white powder (11 mg, 52T yield). LT;HPLC CONDITIONS GT; Column : Cosmosil 5C18-MS 10 x 250 mm Eluent : Solution A: Water containing 0. 1% TFA Solution B: Acetonitrile containing 0. 1% TFA Concentration gradient Time (min) 0 20 25 Solution B % 5 15 95 Flow rate : 2.5 ML/MIN -H NMR (400 MHz, DMSO-d6, 25C) : No. 1. 23 (3H, t, J = 7.1 Hz), 2.46-2. 58 (2H, m), 2. 88-2. 98 (2H, m), 3.07 (1H, dd, J = 8.8 and 15.1 Hz), 3.16 (1H, dd, J = 5.7 and 15. 1 Hz), 4.19 (2H, q, J = 7.1 Hz), 4.58-4. 66 (1H, m), 5.69 (1H, d, J = 6.1 Hz), 5.72 (1H, d, J = 6. 1 HZ), 7.44 (1H, s), 7. 87 (3H, br), 8.87 (1H, d, J = 7.2 Hz), 9. 01 (1H, S), 14.35 (2H, br) ; DUC NOR (100 MHz, DMSO-DS, 25C) : 8 13.9, 25. 6,31. 8,34. 9, 51.3, 64.5, 82.4, 117. 2, 128.6, 133.9, 153.1, 169. 3, 169. 8; ESI-MS: m/z 329 (M+H) ; calculated for CL3H2LN406 : 329. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 404-((R)-3-(Bis-ethoxycarbonyloxymethoxy-phosphoryl)-2-[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl esterA solution of intermediate 22.2 (100 mg) in abs. DMPU (0.3 mL) and NEt3 (68 muL) was stirred for 10 min at RT. Then, <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (650 mg, prepared as described in WO2004092189) and NaI (29 mg) were added at RT, and the reaction mixture was stirred overnight at 50 C. The reaction mixture was diluted with H2O and the aq. phase extracted with toluene. The combined organic layers were dried over Na2SO4 and concentrated to dryness. CC (EA) gave 19 mg of the desired product.LC-MS: tR=0.97 min; [M+H]+: 822.32. | ||
Example 40: 4-((R)-3-(Bis-ethoxycarbonyloxymethoxy-phosphoryl)-2-[4-((S)-3- methoxy-pyrrolidin-l-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-propionyl)-piperazine- 1-carboxylic acid butyl ester:A solution of intermediate 22.2 (100 mg) in abs. DMPU (0.3 mL) and NEt3 (68 muL) was stirred for 10 min at RT. Then, <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (650 mg, prepared as described in WO2004092189) and NaI (29 mg) were added at RT, and the reaction mixture was stirred overnight at 500C. The reaction mixture was diluted with H2O and the aq. phase extracted with toluene. The combined organic layers were dried over Na2SC^ and concentrated to dryness. CC (EA) gave 19 mg of the desired product. <n="84"/>LC-MS: tR = 0.97 min; [M+H]+: 822.32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 59: 4-{(R)-3-[Bis-(ethoxycarbonyloxymethoxy)-phosphoryl]-2-[(2-pheiiyl- thiazole^-carbony^-aminoj-propionylj-piperaziiie-l-carboxylic acid butyl ester A solution of Example 9 (100 mg) and NEt3 (0.08 mL) in DMPU (0.35 mL) was stirred for 10 min at RT. Then, NaI (35 mg) and <strong>[35179-98-7]carbonic acid chloromethyl ester ethyl ester</strong> (0.76 mg, prepared as described in WO2004092189) were added. The mixture was stirred overnight at 500C under argon. The reaction mixture was washed with H2O and the aq. phase extracted with toluene (3x). The combined org. phases were dried over Na2Stheta4 and concentrated to dryness. CC purification (EA/[CH2Cl2/Me0H 8:2] 1:0 to 3:1) gave 55 mg of the desired product. LC-MS: tR = 1.07 min; [M+H]+: 729.28. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In acetone; for 24h;Inert atmosphere; Reflux; | Y. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid ethoxycarbonyloxymethyl ester (R4=H; R7=-CH2OC(O)OCH2CH3) <strong>[35179-98-7]Chloromethyl ethyl carbonate</strong> (54 mg, 387 nmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 mumol) and Et3N (35 muL, 254 mumol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
At room temperature, 1.64g (4mmoL) of IV1, 0.8g (8mmoL) of triethylamine were added to 12ml of N-methylpyrrolidone, stirred for 30 min, then 2.2g (16 mmol) of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> was added, the reaction was performed at 70C under stirring for 2 h, cooled, added with 300ml of 1% citric acid water solution and 500ml of diethyl ether, stirred, layered, the water layer was extracted with diethyl ether twice, the organic layers were combined, dried, separated by column chromatography, eluted with MeOH: CH2Cl2=1:30, to obtain 0.92 g of I6. 1H-NMR (DMSO-d6, 400MHz)delta: 7.86 (s, 1H), 7.50(d, 2H), 7.02(d, 2H), 6.30(s, 2H, NH2), 5.47-5.78(m, 4H), 4.24(m, 4H), 4.28(t, 2H), 4.09 (t, 2H), 3.95(m,2H), 3.83 (s, 3H), 1.30(m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 20[(Ethoxycarbonyl)oxy]methyl trans-4-[(R or 1 )-l-(6-[4-(difluoromethyl)pyridin-2-yl] 4-methyl-2,3'-bipyridin-6'-yl)-l-hydroxyethyl]cyclohexanecarboxylate; 0This example describes the procedure for conversion of (Al) to (C) as shown in Scheme 8. A mixture of trans-A-[{R or 15)-l-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'- bipyridin-6'-yl)-l-hydroxyethyl]cyclohexanecarboxylic acid (200 mg, 0.414 mmol), potassium carbonate (115 mg, 0.829 mmol), and sodium iodide (31 mg, 0.21 mmol) in DMF (3 mL) was stirred at 20C. After 30 minutes, <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (55 mg, 0.39 mmol) was added and the reaction mixture was stirred at 20C. After 16 hours, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (4 x 20 mL). The organic layer was separated, washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue. The residue was purified by silica gel chromatography (0-100% ethyl acetate in hexanes, linear gradient) to afford[(ethoxycarbonyl)oxy]methyl trans-4-[(R or lS)-l-(6-[4-(difluoromethyl)pyridin-2-yl]amino}- 4-methyl-2,3'-bipyridin-6'-yl)-l-hydroxyethyl]cyclohexanecarboxylate. The product was dissolved in acetonitrile (2 mL) and diluted with water (6 mL). The resulting suspension was frozen and lyophilized to afford [(ethoxycarbonyl)oxy]methyl trans-4-[(R or l<S)-l-(6-[4- (difluoromethyl)pyridin-2-yl]amino} -4-methyl-2,3'-bipyridin-6'-yl)- 1 - hydroxyethyljcyclohexanecarboxylate. MS ESI calc'd. for C30H35F2N4O [M + H]+ 585, found 585. 1H NMR (500 MHz, DMSO-d6) delta 10.00 (s, 1H), 9.13 (d, J= 2.0 Hz, 1H), 8.39 - 8.35 (m, 2H), 8.32 (s, 1H), 7.68 (d, J- 8.5 Hz, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 7.09 (t, J= 55.5 Hz, 1H), 7.02 (d, J= 5.0 Hz, 1H), 5.64 (s, 2H), 5.07 (s, 1H), 4.13, (q, J= 7.0 Hz, 2H), 2.34 (s, 3H), 2.22 - 2.15 (m, 1H), 1.96 - 1.90 (m, 1H), 1.88 - 1.70 (m, 3H), 1.43 (s, 3H), 1.32 - 1.10 (m, 8H). rhSyk IC50 = 14 nM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; | J. (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-methyl)-N'-oxalylhydrazino]-2-hydroxy-propionic Acid Ethoxycarbonyloxymethyl Ester A mixture of (R)-3-[N'-t-butoxyoxalyl-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (270 mg, 580 mumol), <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (160 mg, 1.16 mmol), NaI (174 mg, 1.2 mmol) and 2,6-dimethylpyridine (620 mg, 5.8 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL) and the mixture was then extracted with EtOAc (3*30 mL). The combined organic layers were washed with saturated aqueous NaCl (2*30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude Compound 1 (300 mg) was used without purification. LC-MS: 569 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h; | To a solution of (2R,4R)-4-(t-butoxyoxalylamino)-5-(3?-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid (100 mg, 220 mumol) and <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (61 mg, 440 mol) in DMF (3 mL) was added 2,6-lutidine (72 mg, 660 mumol) and NaI (33 mg, 220 mumol). After stirring at room temperature for 24 hours, the mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with saturated aqueous NaCl (2×70 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product which was further purified by preparative TLC (PE:EtOAc=2:1) to yield Compound 1 (40 mg) as a yellow solid. LC-MS: 572[M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56 mg | With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; | Example 3K (R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid Ethoxycarbonyloxymethyl Ester 2,6-Lutidine (407 mg, 3.8 mmol) was added to a solution of (R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (200 mg, 380 mmol), <strong>[35179-98-7]carbonic acid chloromethyl ester ethyl ester</strong> (105 mg, 760 mumol) and NaI (114 mg, 760 mumol) in DMF (10 mL). The mixture was stirred overnight at room temperature. Water (30 mL) was added and the mixture was extracted with EtOAc (3*40 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (MeCN-H2O (0.1% TFA); Gradient 60-70) to yield the title compound as a white solid (56 mg). LC-MS: 630.1 [M+H]+. 1H-NMR: (CD3OD-d4, 400 MHz) delta 1.24 (t, J=5.9 Hz, 3H), 3.30-3.33 (m, 2H), 4.17-4.32 (m, 4H), 4.45 (t, J=4.2 Hz, 1H), 5.78 (br, 2H), 7.20-7.28 (m, 1H), 7.57-7.29 (m, 10H), 7.92-7.95 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 4G (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid Ethoxycarbonyloxymethyl Ester A mixture of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (17.9 mg, 129 mumol) and NaI (19.4 mg, 129 mumol) in acetone (0.7 mL, 10 mmol) was heated at 65 C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 muL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (5.8 mg, purity 94%). MS m/z [M+H]+ calc'd for C25H25ClFN3O9, 566.13. found 566. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5 mg | With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 8h; | Example 5H (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic Acid Ethoxycarbonyloxymethyl Ester To a solution of (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 mumol) in dry DMF (10 mL) was added <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (69 mg, 503 mumol), NaI (101 mg, 670 mumol) and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (15 mL) was added and the mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1?1:100) to yield the title compound as a white solid (9.5 mg). LC-MS: 627.9 [M+H]+. 1H NMR: (CDCl3, 400 MHz) delta 1.25 (t, J=7.1 Hz, 3H), 3.44 (br, 2H), 4.17-4.35 (m, 4H), 4.50 (s, 1H), 5.75-5.78 (m, 2H), 7.10 (t, J=9.3 Hz, 1H), 7.28-7.40 (m, 1H), 7.42-7.52 (m, 7H), 7.87 (s, 2H), 8.37 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
170 mg | With 2,6-dimethylpyridine; sodium iodide; at 50℃; for 4h; | Example 7J (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(1H-tetrazole-5-carbonyl)-hydrazino]-2-hydroxypropionic acid ethoxycarbonyloxymethyl ester To a suspension of lithium (R)-3-(2-(1-allyl-1H-tetrazole-5-carbonyl)-1-((5'-chloro-2'-fluorobiphenyl-4-yl)methyl)hydrazinyl)-2-hydroxypropanoate (250 mg, 526 mumol) in <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (2 mL) was added NaI (158 mg, 1.1 mmol) and 2,6-lutidine (113 mg, 1.1 mmol). The resulting mixture was stirred at 50 C. for 4 hours, cooled to room temperature, then poured into water (10 mL). The resulting solution was extracted with EtOAc (2*10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=4:1?3:1?2:1) to yield Compound 1 as a yellow solid (170 mg). LC-MS: 577 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 8E (R)-3-[N-(3'-Chlorobiphenyl-4-ylmethyl)-N'-(3-ethoxycarbonyloxymethoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid A mixture of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (22.7 mg, 164 mumol) and NaI (24.5 mg, 164 mumol) in acetone (2.0 mL, 27 mmol) was stirred at 60 C. for 1 hour, then cooled to room temperature and added to a mixture of (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (30.0 mg, 54.5 mumol) and cesium carbonate (17.8 mg, 0.054.5 mumol) in acetone (1 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated, dissolved in AcOH (2 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and concentrated. Zinc (178 mg, 2.7 mmol) and AcOH (1.0 mL, 18 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse phase preparative HPLC to yield the title compound (2.2 mg). MS m/z [M+H]+ calc'd for C24H24ClN3O9, 534.12. found 534.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | With pyridine; sodium iodide; In N,N-dimethyl-formamide; at 30℃; for 15h; | A suspension Compound 2 (150 mg, 0.3 mmol), <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (84 mg, 0.6 mmol), NaI (15 mg, 0.6 mmol), and pyridine (96 mg, 1.2 mmol) in DMF (20 mL) was stirred for 15 hours at 30 C. The reaction was quenched with water (15 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were concentrated in vacuo and purified by column chromatography (petroleum ether/EtOAc=3:1) to yield the title compound as an off-white solid (10 mg). LC-MS: 611 [M+H]+. 1H NMR (400 MHz, CDCl3): delta 1.33 (t, J=7.2 Hz, 3H), 2.03-2.08 (m, 1H), 2.30-2.34 (m, 1H), 3.05 (d, J=6.4 Hz 2H), 4.26 (q, J=7.2 Hz, 2H), 4.48 (br, 1H), 4.75 (br, 1H), 5.68-5.70 (m, 1H), 5.81-5.83 (m, 1H), 6.88 (d, J=8.8 Hz, 1H), 7.28-7.34 (m, 7H), 7.42-7.53 (m, 4H), 7.96-7.99 (t, J=6.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13 mg | With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 50℃; for 15h; | Example 9B (2R,4R)-5-(3'-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)amino]pentanoic Acid Ethoxycarbonyloxymethyl Ester A solution of (2R,4R)-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)amino]pentanoic acid (253 mg, 0.5 mmol), <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (69 mg, 0.5 mmol), 2,6-lutidine (165 mg, 1.5 mmol) and NaI (150 mg, 1 mmol) in DMF (20 mL) was stirred for 15 hours at 50 C. The mixture was quenched with water (20 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were collected and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc=3:1) to yield the title compound as a white solid (13 mg). LC-MS: 608.8 [M+H]+. 1H NMR: (CDCl3, 400 MHz) delta 1.27 (t, J=8.0 Hz, 3H), 2.03-2.33 (m, 2H), 3.02-3.05 (m, 2H), 4.18 (q, J=8.0 Hz, 2H), 4.49 (br, 1H), 4.85 (br, 1H), 5.57-5.76 (m, 2H), 7.03 (d, J=12 Hz, 1H), 7.25-7.40 (m, 4H), 7.42-7.51 (m, 3H), 7.53-7.61 (m, 3H), 7.93 (d, J=8.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With 2,6-dimethylpyridine; sodium iodide; at 50℃; for 6h; | To a mixture of Compound 3 (80 mg, 160 mumol) and <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (1.0 ml) were added NaI (48 mg, 0.32 mmol) and lutidine (52 mg, 480 mumol). The mixture was stirred at 50 C. for 6 hours. The mixture was then cooled to room temperature, diluted with water (15 ml), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (silica gel: 200-300 mesh; elute with PE:EtOAc from 4:1 to 1:1) to yield Compound 4 (60 mg) as a light yellow solid. LC-MS: 591 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
190 mg | With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; | Example 7E (2R,4R)-5-(3?-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-methoxyisoxazole-5-carbonyl)-amino]pentanoic Acid Ethoxycarbonyloxymethyl Ester [0418] [0419] To a stirred solution of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (0.2 mL, 1.1 mmol) in DMF (1 mL) was added dropwise a solution of (2R,4R)-4-(t-butoxycarbonylamino)-5-(3?-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid (400 mg, 960 mumol) in DMF (6 mL) at room temperature. NaI (432 mg, 2.88 mmol) and DIPEA (0.5 mL, 2.88 mmol) were added and the resulting mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated aqueous NaCl (2×50 mL) and water (2×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The product was purified by column chromatography (petroleum ether:EtOAc, 15:1-6:1) to yield Compound 1 as a white solid (190 mg). LC-MS: 544 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.1g, 0.2mmol)And triethylamine (114 muL, 0.8 mmol)Dissolved in N,N-dimethylformamide (0.6 mL),And added tetrabutylammonium bromide (132 mg, 0.4 mmol) thereto.a solution of N,N-dimethylformamide (0.2 mL),After the mixture was stirred at 10 C for 0.5 hours,Chloromethylethyl carbonate (34 mg, 0.25 mmol) was added dropwise to the system.A solution of N,N-dimethylformamide (0.2 mL).The reaction solution was stirred at 10 C for 3 hours.After completion of the reaction, the mixture was diluted with ethyl acetate (40 mL) and filtered.The filtrate was concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (petroleum ether /Purified with ethyl acetate (v/v) = 2/1)The title compound was obtained as a white solid (85 mg, 73%). | |
85 mg | Step 2) (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl ethyl carbonate To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (114 muL, 0.8 mmol) in DMF (0.6 mL) was added a solution of TBAB (132 mg, 0.4 mmol) in DMF (0.2 mL). The reaction was stirred at 10 C. for 30 min, followed by dropwise addition of a solution of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (34 mg, 0.25 mmol) in DMF (0.2 mL). The mixture was stirred at 10 C. for another 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (85 mg, 73%). The title compound was characterized by LC-MS and 1H NMR as shown below: LC-MS (ESI, pos. ion) m/z 592.0 [M+H]+; 1H NMR (400 MHz, CDCl3) delta 1.05-1.10 (t, J=7.4 Hz, 3H), 1.25-1.32 (t, J=7.2 Hz, 3H), 1.85-1.97 (m, 2H), 3.09-3.16 (m, 2H), 4.18-4.25 (q, J=7.1 Hz, 2H), 6.29 (s, 2H), 6.51 (s, 1H), 7.04-7.10 (m, 1H), 7.46-7.51 (d, J=8.5 Hz, 2H), 7.57-7.63 (d, J=8.5 Hz, 2H), 7.70-7.77 (m, 1H), 7.86 (s, 1H), 8.67-8.70 (d, J=2.1 Hz, 1H), 8.83-8.85 (d, J=2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To a solution of LB-100 (150 mg, 0.56 mmol) in DMF (5 mL) is added Cs2CO3 (546 mg, 1.7 mmol) at room temperature. After stirring for 5 min., <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (232 mmg, 1.7 mmol) is added. The resulting mixture is stirred at room temperature overnight. Water (10 ml) is added, the mixture is extracted with ethyl acetate (5×10 ml). The organic phase is dried over MgSO4, filtered and the solvent is removed. The residue is titrated with hexane, and filtered to give white solid (124 mg, 60% yield). 1HNMR (CDCl3) 1.23 (t, 3H), 1.52 (d, 2H), 1.84 (d, 2H), 2.28-2.52 (m, 7H), 2.84 (d, 1H), 3.18 (d, 1H), 3.36-3.52 (m, 3H), 3.72 (m, 1H), 4.20 (q, 2H), 4.80 (s, 1H), 5.00 (s, 1H), 5.62 (d, 1H), 5.80 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | To the mixture of the acid in methylene chloride is added TEA (1 mmol) followed by the alkyl chloride (1.5 mmol). The reaction mixture is stirred overnight at room temperature and evaporated to dryness. The product is purified by column chromatography and recrystallization to afford the pure prodrug. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;Inert atmosphere; | ELQ-300 (0.85 g, 1.8 mmol), tetrabutylammonium iodide (1.33 g, 3.6 mmol) and potassium carbonate (0.50 g, 3.6 mmol) were dissolved anhydrous dimethylformamide (8 ml) in a flame-dried round bottom flask at 60 C under inert atmosphere. <strong>[35179-98-7]Chloromethyl ethyl carbonate</strong> (0.5 g, 3.6 mmol) was added dropwise and the reaction stirred under inert atmosphere at 60 C for two hours, at which point reaction completion was confirmed by thin layer chromatography. After cooling to room temperature, the reaction solvent was removed under reduced pressure and the mixture taken up in water (10 ml) and extracted with dichloromethane (3 x 20 ml). Combined organic layers were washed with brine (10 ml), dried over MgS04, and the dichloromethane evaporated under reduced pressure. The resulting crude product was purified by flash chromatography (EtOAc/DCM) to yield the title compound, ELQ- 331, as a white crystalline solid (560 mg, 54%). 1H NMR (400 MHz, DMSO-d6): delta = 7.98 (s, 1H), 7.57 (s, 1H), 7.44 (m, 4H), 7.21 (m, 4H), 5.76 (s, 2H), 5.35 (s, 2H), 4.03 (s, 3H), 2.44 (s, 3H), 1.11 (t, 3H, J = 7.1 Hz); M.P. (C): 103.5-103.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
386 mg | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;Cooling with ice; | Probucol (520mg, lmmol) was dissolved in DMF (IOml), was added sodium carbonate (an Ig) was added <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (145mg, 1.15mmol) under ice cooling, followed by stirring at room temperature for 5 hours, 30 ml of water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporation, the residue was purified by column chromatography to give a white solid (386mg) |
386 mg | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;Cooling; | Probucol (520 mg, 1 mmol) was dissolved in 10 ml DMF. Afier adding 1 g sodium carbonate, the mixture was stirredunder the chilled water condition, then adding compound (111-1) (145 mg, 1.15 mmol) and then being incubated with stirring at room temperature. 5 hours later, 30 ml distilled water was added to the mixture and the mixture was then extracted with ethyl acetate. The organic phase was sepa20 rated, dried by anhydrous sodium sulfate and then beingfiltered. Rotary evaporators was used to treat the filtrate. The residue was purified by column chromatography and finally got compound (11-1) (386 mg, white solid).?H NMR (400 MHz, CDC13) oe 7.44 (s, 4H), 6.75 (s, 2H),5.07 (s, 1H), 4.23 (q, J=8.4 Hz, 2H), 1.42 (s, 42H), 1.31 (t,J=8.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A: 4-(2-{2-chloro-4-[ 6-(4-fluorophenyl)-4-[ (2R)-l-[ (4-methoxybenzyl)oxy]-3-(2-[2- (2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l-oxopropan-2-yl] (0270) thieno[2,3-d]pyrimidin-5-yl]-3-methylphenoxy}ethyl)-l-[(ethoxycarbo (0271) methylpiperazin-l-ium trifluoroacetate (0272) To the solution of 200 mg compound obtained in Step A of Example 1 (0.201 mmol, 1 eq.) and 56 mg <strong>[35179-98-7]ethyl chloromethyl carbonate</strong> (0.402 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.201 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/H20 (0.5 mL/L) as eluents. Compound of Step A was obtained as trifiuoroacetate salt. HRMS calculated for C59H59ClFN6OioS: 1097.3680; found 1097.3694 (M) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
260 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | 216 mg etomidate (CAS: 56649-48-0) was dissolved in 20 mL of DMF, 165 mg of <strong>[35179-98-7]ethyl chloromethyl carbonate</strong> was added, 275 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, poured into 150 mL of water and extracted with 100 mL of dichloromethane. The organic layer was separated and dried over anhydrous sodium sulfate overnight. The filtrate was filtered the next day and concentrated under reduced pressure to give a yellow oil which was subjected to column chromatography. Colorless oil 260 mg, yield: 81.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | To DMF (10 mL) were added <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (0.66 g, 4.77 mmol),potassium carbonate (1.00 g, 7.16 mmol) and (2S,3S)-3-((2-bromo-6-(5-chlorothiophen-2-yl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid (1.10 g, 2.39 mmol) andthe mixture was stirred at rt overnight. To the reaction mixture was added water (40 mL), and theresulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layerswere washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 1511) to give the title compound as a light yellow solid (0.90 g, 67 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a solution of (2S,3S)-3-((2-bromo-5-fluoro-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid (2.00 g, 4.69 mmol) in DMF (20 mL) wereadded potassium carbonate (2.02 g, 14.20 mmol) and <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (0.79 g, 5.70mmol), and the mixture was stirred at rt overnight. To the reaction mixture was added water (50mL), and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combinedorganic layers were washed with saturated brine (100 mL x 3), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silicagel column chromatography (PE/EtOAc (v/v) = 511) to give the title compound as a light yellowsolid (0.48 g, 69 % ).MS (ESI, pos. ion) m/z: 527.7 [M+Ht;1H NMR (400 MHz, CDCb) 8 (ppm): 7.84-7.81 (m, 1H), 7.57 (d, J = 5.0 Hz, 1H), 7.20-7.14(m, 1H), 6.02 (d, J = 5.7 Hz, 1H), 5.77 (d, J = 5.6 Hz, 1H), 4.45 (d, J = 5.2 Hz, 1H), 4.24 (q, J =7.1 Hz, 2H), 2.50 (d, J = 5.4 Hz, 1H), 2.03 (d, J = 2.3 Hz, 1H), 1.91 (d, J = 2.4 Hz, 1H), 1.81 (m,1H), 1.72 (m, 4H), 1.65- 1.57 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). |
69% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | (2S,3S)-3-((2-bromo-5-fluoro-6-(2-thienyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2- Formic acid (2.00 g, 4.69 mmol) was dissolved in DMF (20 mL)Add potassium carbonate (2.02 g, 14.20 mmol)And <strong>[35179-98-7]chloromethylethyl carbonate</strong> (0.79g, 5.70mmol),The resulting mixture was stirred at room temperature overnight.Add water (50 mL) to the reaction solution.Extracted with ethyl acetate (50 mL×3).The combined organic phases were washed with saturated brine (100 mL×3).Dry over anhydrous sodium sulfate, filter,The filtrate was concentrated under reduced pressure.The residue obtained was subjected to silica gel column chromatography(Petroleum ether / ethyl acetate (nu / nu) = 5 / 1) purification,The title compound is a pale yellow solid(1.70 g, 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 35 - 50℃; | R = Et. (5g, 16mmol) and DIEA PMPA anhyride (Hunig ' s base) (11. 5 ml, 66mmol)In an anhydrous DMF (50 ml). Furthermore, by adding bischloromethylbiphenyl carbonate (49mmol), Then rapidly while mechanically stirring the suspension, is heated up to 50 C under argon. 1 after time, reaction product is transparent, 35 C until the temperature is lowered. The reaction product is stirred for 48 hours. DMF on the evaporator is removed, the reaction product is CH2Cl2between and waterA distributor. CH2Cl2layer is dried with magnesium sulfate, filtered, then condensed in the evaporator. The residue is taken, then the glycopeptide (150g, SiO2) in methylene chloride. This is, respectively, 0, 3, 6, 9, 12, 15, 18%(v/v) methylene chloride in isopropanol 500 ml, then 21%, the elution 2000 ml. An appropriate fractionPool a, then evaporate and the desired product is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of <strong>[1190307-88-0]sofosbuvir</strong> (530 mg, 1.0 mmol, 1.0 eq.) in DMF(2 mL) cooled in an ice bath was added K2CO3 (138 mg, 1.0 mmol,1.0 eq.) followed with a 15 min?s stir. 1-chloroethyl- or methyl- carbonates(2.0 eq.) was added to the resulted mixture and stirred at roomtemperature for 12 h. The mixture was diluted with EA (50 mL) andthen washed with water (10 mL×3). The organic layer was dried overanhydrous Na2SO4, concentrated in vacuo and purified by silica gelchromatography to afford 8a-8b in 40% ? 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.9% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60℃; | Compound 7 (500 mg, 0.83 mmol), compound 11 (571.9 mg, 4.14 mmol), potassium carbonate (572.7 mg, 4.14 mmol) and potassium iodide (68.1 mg, 0.41 mmol) were added to the reaction flask, and 10 ml of DMF was added and heated to 60 C reactionThe reaction was completed by TLC, and the temperature was lowered to room temperature, diluted with excess water, extracted with ethyl acetate for 3-4 times, and the organic phases were combined and saturated.Wash with salt water, concentrate,Purification by silica gel column chromatography gave 99 mg of product.Yield: 16.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere; | Step 1 ((ethoxycarbonyl)oxy)methyl 4-((tert-butoxycarbonyl)amino)benzoate 14c 4-((tert-butoxycarbonyl)amino)benzoic acid 14a (4 g, 16.86 mmol, prepared by a known method disclosed in ""), potassium iodide (2.24 g, 13.49 mmol) and potassium carbonate (2.33 g, 16.86 mmol) were dissolved in 50 mL of N,N-dimethylformamide, followed by addition of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> 14b (3.5 g, 25.29 mmol, prepared by a known method disclosed in "") under argon atmosphere. After completion of the addition, the reaction solution was warmed up to 50C, stirred for 16 hours and cooled to room temperature. The reaction solution was added with 100 mL of ice water, and extracted with ethyl acetate (60 mL*3). The organic phases were combined, washed with 25 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system C to obtain the title compound 14c (5.3 g, yield: 88.0%). MS m/z (ESI): 340.5 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | 234 mg of (R) -2-fluoro-1- (1-phenethyl) -1H-imidazole-5-carboxylic acid (CAS: 2093287-75-1) was dissolved in 20 mL of DMF, and 138 mg of <strong>[35179-98-7]ethyl chloromethyl carbonate</strong> was added Then, 275 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered, it was poured into 150 mL of water and extracted with 100 mL of dichloromethane. The organic layer was separated and dried over anhydrous sodium sulfate overnight. The filtrate was filtered the next day and concentrated under reduced pressure to give a yellow oil. Column chromatography 242 mg of colorless oil was obtained, yield: 72.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | 234 mg of (R) -2-chloro-1- (1-phenethyl) -1H-imidazole-5-carboxylic acid (CAS: 2093287-74-0) was dissolved in 20 mL of DMF, and 138 mg of <strong>[35179-98-7]ethyl chloromethyl carbonate</strong> was added Then, 275 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered, it was poured into 150 mL of water and extracted with 100 mL of dichloromethane. The organic layer was separated and dried over anhydrous sodium sulfate overnight. The filtrate was filtered the next day and concentrated under reduced pressure to give a yellow oil. Column chromatography 242 mg of colorless oil was obtained, yield: 72.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.4% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | 295 mg of (R) -2-bromo-1- (1-phenethyl) -1H-imidazole-5-carboxylic acid (CAS: 2133363-72-9) was dissolved in 20 mL of DMF, and 138 mg of <strong>[35179-98-7]ethyl chloromethyl carbonate</strong> was added. Then, 275 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered, it was poured into 150 mL of water and extracted with 100 mL of dichloromethane. The organic layer was separated and dried over anhydrous sodium sulfate overnight. The filtrate was filtered the next day and concentrated under reduced pressure to give a yellow oil. Column chromatography 228 mg of colorless oil was obtained, yield: 57.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82 mg | Under a nitrogen atmosphere, a stirred mixture of 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]-N-(3-ethoxy-4,5-dihydroisoxazol-5-yl)-2-methyl-benzamide (200 mg) in N,N-dimethylformamide (1 .82 ml_) was cooled to 0C. After 5 min, sodium hydride (0.022 g, 60% suspension in oil) was added and the reaction mixture was allowed to warm up and to stir at ambient temperature. After 30 min, <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (0.104 g) was added and the reaction mixture was stirred for 2.5 hours. The reaction mixture was carefully quenched with water and diluted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed once with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by Combiflash chromatography (eluent: gradient Cyclohexane/Ethyl acetate 1 :0 to 70:30), to give 82 mg of the desired product A8 as a mixture of rotamers. 1H NMR (400 MHz, CDC ) d ppm 7.47 - 7.65 (m, 4 H) 7.32 (br s, 1 H) 6.09 - 6.78 (m, 1 H) 4.86 - 5.98 (m, 2 H) 4.04 - 4.33 (m, 5 H) 3.69 (br d, 1 H) 2.99 - 3.60 (m, 2 H) 2.36 (s, 3 H) 1.22 - 1.42 (m, 6 H). 19F NMR (377 MHz, CDCIs) d ppm -79.43 and -79.48 (m, 3 F) -1 13.54 (s, 1 F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | General procedure: A solution of N-[(2R)-3-(7-methyl-lH-indazol-5-yl)- l-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-l-oxopropan-2-yl]-4-(2-oxo-l,2-dihydroquinolin-3- yl)piperidine-l-carboxamide (162 mg, 254 pmol) in DMF (3.9 mL) was treated with lithium hexamethyldisilylamide (1.0 M in THF, 762 pL, 762 pmol) and stirred for 20 minutes. Chloromethyl pivalate (146 pL, 1,016 pmol) was added via syringe and the mixture was stirred for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200 pL), filtered with a syringe filter (45 pm), and the crude product mixture was purified by RP-FIPLC (method D), where the product fractions were combined and lyophilized to provide the pure product as a white solid consisting of a mixture of mono 1-alkylated and 2-alkylated indazole isomers (63.1 mg, 28.7%) and bis 1-alkylated and 2-alkylated indazole isomers (103.9 mg, 41.7%). The mixed fractions of both mono and bis targets were purified two additional times (method D) to provide the four title compounds as individual indazole isomers characterized below. {7-methyl-5-[(2R)-3-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-3-oxo-2-[4-(2-oxo-l,2-dihydroquinolin-3-yl)piperidine-l-carbonyl]amino}propyl]-lH-indazol-l-yl}methyl 2,2-dimethylpropanoate trifluoroacetate (1): (3 mg, 1.4%), XH NMR (300MHz, DMSO-ds) d = 11.76 (s, 1H), 8.10 (s, 1H), 7.85 - 7.51 (m, 2H), 7.51 - 7.34 (m, 2H), 7.33 - 7.04 (m, 3H), 6.81 (m, 1H), 6.54 (br d, 7=7.0 Hz, 4H), 6.39 (s, 2H), 4.76 (br d, 7=6.4 Hz, 1H), 4.25 - 3.96 (m, 2H), 3.02 - 2.81 (m, 6H), 2.78 - 2.60 (m, 8H), 2.45 - 2.32 (m, 3H), 2.31 - 2.16 (m, 2H), 2.07-1.89 (m, 4H), 1.75-1.49 (m, 3H), 1.45-1.03 (m, 5H), 1.00 (s, 9H). LC/MS method A: Rt = 3.55 mins., (M+H)+ = 753, purity = 91%. {7-methyl-5-[(2R)-3-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-3-oxo-2-[4-(2-oxo-l,2-dihydroquinolin- 3-yl)piperidine-l-carbonyl]amino}propyl]-2H-indazol-2-yl}methyl 2,2-dimethylpropanoate trifluoroacetate (2): (12 mg, 5.5%), XH NMR (300MHz, DMSO-ds) d = 11.75 (s, 1H), 8.39 (s, 1H), 7.64 (d, 7=6.4 Hz, 1H), 7.54 (s, 1H), 7.43 (t, 7=7.7 Hz, 1H), 7.39 - 7.37 (m, 1H), 7.26 (d, 7=8.2 Hz, 1H), 7.20 - 7.12 (m, 1H), 7.01 (s, 1H), 6.81 (br d, 7=5.9 Hz, 1H), 6.35 - 6.25 (m, 2H), 4.78 (br dd, 7=2.3, 5.3 Hz, 1H), 4.35 - 4.01 (m, 2H), 2.98 - 2.62 (m, 15H), 2.47 - 2.38 (m, 4H), 2.32 - 2.16 (m, 1H), 2.07 (m, 1H), 2.03 - 1.84 (m, 2H), 1.83 - 1.48 (m, 4H), 1.45 - 1.15 (m, 4H), 1.08 - 1.03 (m, 1H), 1.06 (s, 9H). LC/MS method A: Rt = 3.48 mins., (M+H)+ = 753, purity = 96%. {5-[(2R)-2-[4-(l-[(2,2-dimethylpropanoyl)oxy]methyl}-2-oxo-l,2-dihydroquinolin-3-yl)piperidine-l- carbonyl]amino}-3-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-3-oxopropyl]-7-methyl-lH-indazol-l- yljmethyl 2,2-dimethylpropanoate trifluoroacetate (3): (6 mg, 2.4%), XH NM R (300M Hz, DMSO-de) d = 8.11 (s, 1H), 7.72 (dd, 7=1.5, 7.9 Hz, 2H), 7.66 - 7.41 (m, 3H), 7.34 - 7.27 (m, 1H), 7.20 (s, 1H), 6.86 (br d, 7=6.4 Hz, 1H), 6.38 (s, 2H), 6.26 (br s, 2H), 4.77 (br d, 7=7.5 Hz, 1H), 4.32 - 3.97 (m, 2H), 3.46 (m, 4H), 3.02 - 2.83 (m, 7H), 2.80 - 2.66 (m, 7H), 2.46 - 2.12 (m, 3H), 2.11 - 1.84 (m, 1H), 1.83 - 1.52 (m, 4H), 1.51 - 1.16 (m, 6H), 1.09 (s, 9H), 0.98 (s, 9H). LC/MS method A: Rt = 4.27 mins., (M+H)+ = 867, purity = 95%. {5-[(2R)-2-[4-(l-[(2,2-dimethylpropanoyl)oxy]methyl}-2-oxo-l,2-dihydroquinolin-3-yl)piperidine-l- carbonyl]amino}-3-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-3-oxopropyl]-7-methyl-2H-indazol-2- yljmethyl 2,2-dimethylpropanoate trifluoroacetate (4): (38 mg, 15.2%), XH NMR (300MHz, DMSO-de) d = 8.40 (s, 1H), 7.75 (dd, 7=1.2, 7.6 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.43 (d, 7=8.6 Hz, 1H), 7.38 (s, 1H), 7.30 (t, 7=7.0 Hz, 1H), 7.02 (s, 1H), 6.86 - 6.82 (m, 1H), 6.31 - 6.23 (m, 4H), 4.77 (br d, 7=7.0 Hz, 1H), 4.07 (br dd, 7=5.9, 7.6 Hz, 2H), 3.58 - 3.47 (m, 4H), 2.98 - 2.62 (m, 14H), 2.47 - 2.37 (m, 4H), 2.47 - 2.37 (m, 1H), 2.25 (br dd, 7=1.8, 4.1 Hz, 2H), 1.97 (br d, 7=1.2 Hz, 1H), 1.78 - 1.60 (m, 4H), 1.30 - 1.20 (m, 2H), 1.09 (s, 9H), 1.04 (s, 9H). LC/MS method A: Rt = 4.25 mins., (M+H)+ = 867, purity = 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
231 mg | To a solution of [5-[4-[4-chloro-3-[(1 -cyanocyclopropyl)carbamoyl]phenyl]pyrazol-1 -yl]-1 -methyl-4- (trifluoromethyl)pyrazol-3-yl] 1 ,1 ,1 ,2,3,3,3-heptafluoropropane-2-sulfonate (500 mg, 0.732 mmol) in 2 ml DMF was added 35 mg sodium hydride (0.879 mmol, 1 .2 eq.). After 15 minutes at RT (room temperature), a solution of <strong>[35179-98-7]chloromethyl ethyl carbonate</strong> (209 mg, 1 .46 mmol, 2 eq.) in 0.5 ml DMF (dimethyl formamide) was added dropwise. The yellow suspension was stirred for 5 hours. The mixture was then extracted with ethyl acetate and washed with saturated aqueous NFUCI. After drying and evaporating the organic phase, the residue was purified by flash-chromatography to give 231 mg 5-[4-[4-chloro-3-[(1 -cyanocyclopropyl)-(ethoxycarbonyloxy methyl)carbamoyl]phenyl] pyrazol-1 -yl]-1 -methyl-4-(trifluoromethyl)pyrazol-3-yl] 1 ,1 ,1 ,2,3,3,3-heptafluoropropane-2-sulfonate as a white solid. 19F NMR (377 MHz, CDCI3) d ppm -167.00 (1 F) -71 .25 (s, 6 F) -56.22 (s, 3 F) LC-MS (Method A): tR = 1 .25 min, m/z = 829/31 [M+45 (HCOO )]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With sodium iodide In acetonitrile at 90℃; for 2h; | 6 Example 6 Synthesis of Compound 6 To a stirred solution of Itraconazole (1.0 g, 1.42 mmol, 1.0 eq.) in acetonitrile (20 mL) were added sodium iodide (318.6 mg, 2.13 mmol, 1.5 eq.) and chloromethyl ethyl carbonate (393 mg, 2.83 mmol, 2.0 eq.). The reaction was heated at 90° C. for 2 h. LCMS indicated that most of Itraconazole was consumed and the desired MS was formed. The reaction was cooled to room temperature, filtered and the filtrate was concentrated to give a residue, which was purified by silica gel chromatography (eluent: dichloromethane/methanol=50-20/1) to give 200 mg of the iodide salt. LCMS indicated that the purity was more than 90%. 200 mg of the iodide salt was dissolved in 100 mL of acetonitrile, then 30 g of Cl- ion exchange resin was added. The mixture was stirred at 15° C. for 16 h. ELSD indicated Cl- and no I-. The mixture was filtered and the filtrate was concentrated to give a residue, which was lyophilized to give 105.7 mg (8.4%) of Compound 6 (chloride salt) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.4% | With potassium carbonate In acetonitrile at 50℃; | 11 Example 11. Preparation of the compound of the present invention Dissolve 200 mg of dexmedetomidine free base in 10 mL of acetonitrile (MeCN),Add 208 mg of chloromethyl ethyl carbonate and 300 mg of anhydrous potassium carbonate,Stir overnight at 50°C.The reaction solution was cooled the next day, filtered, and the filtrate was evaporated to dryness under reduced pressure.Column chromatography (cyclohexane/ethyl acetate=5/1)171 mg of white solid was obtained, namely compound 6,Yield 56.4%. |
56.4 % | With potassium carbonate In acetonitrile at 50℃; | 11 Example 11. Preparation of the compound of the present invention Dissolve 200 mg of dexmedetomidine free base in 10 mL of acetonitrile (MeCN),Add 208 mg of chloromethyl ethyl carbonate and 300 mg of anhydrous potassium carbonate,Stir overnight at 50°C.The reaction solution was cooled the next day, filtered, and the filtrate was evaporated to dryness under reduced pressure.Column chromatography (cyclohexane/ethyl acetate=5/1)171 mg of white solid was obtained, namely compound 6,Yield 56.4%. |
Tags: 35179-98-7 synthesis path| 35179-98-7 SDS| 35179-98-7 COA| 35179-98-7 purity| 35179-98-7 application| 35179-98-7 NMR| 35179-98-7 COA| 35179-98-7 structure
[ 35180-01-9 ]
Chloromethyl isopropyl carbonate
Similarity: 0.88
[ 98298-66-9 ]
1-Chloroethyl isopropyl carbonate
Similarity: 0.79
[ 35180-01-9 ]
Chloromethyl isopropyl carbonate
Similarity: 0.88
[ 98298-66-9 ]
1-Chloroethyl isopropyl carbonate
Similarity: 0.79
[ 99464-83-2 ]
1-Chloroethyl cyclohexyl carbonate
Similarity: 0.68
[ 35180-01-9 ]
Chloromethyl isopropyl carbonate
Similarity: 0.88
[ 98298-66-9 ]
1-Chloroethyl isopropyl carbonate
Similarity: 0.79
[ 99464-83-2 ]
1-Chloroethyl cyclohexyl carbonate
Similarity: 0.68
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P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
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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