* 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.
Reference：
[1] Journal of the American Chemical Society, 1917, vol. 39, p. 2437
2
[ 10268-12-9 ]
[ 52913-11-8 ]
Yield
Reaction Conditions
Operation in experiment
91%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16 h;
(3-Amino-phenyl)-acetic acid methyl ester: To a solution of (3-Nitro-phenyl)-acetic acid methyl ester (0.50 g; 2.55 mmol) in methanol (30.0 ml.) was added palladium on carbon (10percent w/w) (0.20 g; 0.19 mmol) portion wise under nitrogen atmosphere. The reaction mixture was hydrogenated under hydrogen atmosphere (bladder pressure) at RT for 16 h. The reaction mixture was filtered through celite, washed with methanol (75 mL) and the filtrate was concentrated to afford (3- Amino-phenyl)-acetic acid methyl ester 0.40 g (91 percent) as a brown solid. HPLC MS (Agilent - Waters Xbridge C8 (50x4.6 mm, 3.5 pm); 2.0 mlJmin; 220nm; buffer A: 0.1percent TFA/H20, buffer B: 0.1percent TFA/ACN; (0.0-8.0min 5percent-100percent buffer B; 8.0-8.1 min 100percent buffer B; 8.1-8.5min 100percent-5percent buffer B; 8.5-10.Omin 5percent-5percent buffer B): (M+H) 166.0; Rt. 1.39 min.
Reference：
[1] Patent: WO2016/50359, 2016, A1, . Location in patent: Page/Page column 97
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1206 - 1217
[3] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 10, p. 1601 - 1608
[4] Patent: WO2011/60196, 2011, A1, . Location in patent: Page/Page column 142
[5] Patent: WO2013/131408, 2013, A1, . Location in patent: Page/Page column 71
[6] Patent: WO2014/99633, 2014, A2, . Location in patent: Page/Page column 96
3
[ 67-56-1 ]
[ 14338-36-4 ]
[ 52913-11-8 ]
Yield
Reaction Conditions
Operation in experiment
87%
for 2 h; Heating / reflux
(3-Amino-phenyl)-acetic acid methyl ester (3a). Thionyl chloride (4.8 mL, 66.16 mmol) was carefully added drop wise to MeOH (100 mL) at 0 0C. To the resulting solution was added a suspension of 3-amino-phenylacetic acid (5.0 g, 33.08 mmol) in MeOH (100 mL) and the reaction mixture was refluxed for 2 h. Then MeOH was distilled off and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The phases were separated and the organic phase was washed with sat. aq. NaHCO3, dried (Na2SO4) and evaporated which gave the title compound (4.77, 87percent).
87%
Stage #1: at 0℃; for 2 h; Heating / reflux Stage #2: With water; sodium hydrogencarbonate In ethyl acetate
(3-Amino-phenyl)-acetic acid methyl ester (40a); Thionyl chloride (4.8 mL, 66.16 mmol) was carefully added drop wise to MeOH (100 mL) at 0 0C. To the resulting solution was added a suspension of 3-amino-phenylacetic acid (5.0 g, 33.08 mmol) in MeOH (100 mL) and the reaction mixture was refluxed for 2 h. Then MeOH was distilled off and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The phases were separated and the organic phase was washed with sat. aq. NaHCO3, dried (Na2SO4) and evaporated to give 4.77 (87percent) of the title compound.
83%
at 0℃; for 4 h;
3-AMINOPHENYLACETIC acid (15.5 g, 0.10 mol) was suspended in methanol (150 mL) and cooled to 0 °C. Thionyl chloride (11.2 ML, 0.15 mol) was added dropwise under stirring. A clear orange solution was obtained, which was stirred for 4 hours, then evaporated. The solid residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate (150 mL) and the organic phase washed with saturated sodium bicarbonate (100 mL), and brine and dried (Na2SO4). Methyl 3-aminophenylacetate was isolated as a brown oil. (14. 1g, 83percent). 1H NMR (500 MHz, CDC13) 8 7.12 (1H, dd), 6.7-6. 6 (3H, m), 3.71 (3H, s), 3.55 (2H, s). Methyl (3-Methanesulfonylamino-phenyl)-acetate : Methyl 3-aminophenylacetate
83%
Stage #1: at 0℃; for 4 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
Methyl 3-aminophenylacetate:; 3-Aminophenylacetic acid (15.5 g, 0.10 mol) was suspended in methanol (150 mL) and cooled to 0 °C. Thionyl chloride (11.2 mL, 0.15 mol) was added dropwise under stirring. A clear orange solution was obtained, which was stirred for 4 hours, then evaporated. The solid residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate (150 mL) and the organic phase washed with saturated sodium bicarbonate (100 mL), and brine and dried (Na2S04). Methyl 3-aminophenylacetate was isolated as a brown oil. (14.1g, 83percent). 1H NMR (500 MHz, CDC13) 8 7.12 (1H, dd), 6.7 - 6.6 (3H, m), 3.71 (3H, s), 3.55 (2H, s).
83%
at 0℃; for 4 h;
Methyl 3-aminophenylacetate: 3-Aminophenylacetic acid (15.5 g, 0.10 mol) was suspended in methanol (150 mL) and cooled to 0 °C. Thionyl chloride (11.2 mL, 0.15 mol) was added dropwise under stirring. A clear orange solution was obtained, which was stirred for 4 hours, then evaporated. The solid residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate (150 ML) and the organic phase washed with saturated sodium bicarbonate (100 mL), and brine and dried (Na2SO4). Methyl 3-aminophenylacetate was isolated as a brown oil. (14. 1g, 83percent).APOS;H NMR (500 MHz, CDCL3) 8 7.12 (1H, dd), 6.7- 6.6 (3H, m), 3.71 (3H, s), 3.55 (2H, s).
83%
at 0℃; for 4 h;
Example 15; 3-(Methanesulfonylamino)phenylacetic acid:; Step A: 3-Aminophenylacetic acid (15.5 g, 0.10 mol) was suspended in methanol (150 mL) and cooled to 0 °C. Thionyl chloride (11.2 mL, 0.15 mol) was added dropwise while stirring. A clear orange solution was obtained, which was stirred for 4 hours, then evaporated. The solid residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate (150 mL) and the organic phase washed with saturated sodium bicarbonate (100 mL), and brine and dried (Na2SO4) to afford methyl 3-aminophenylacetate as a brown oil. (14.1g, 83percent). 1H NMR (CDCl3) No. 7.12 (1H, dd), 6.7 - 6.6 (3H, m), 3.71 (3H, s), 3.55 (2H, s).
77%
for 18 h; Heating / reflux
Example 6; a) (3-f [5-(2-Methoxy-phenyl)-furan-2-carbonyl]-amino}- phenyl)-acetic acid (17); (i) (3-Amino-phenyl)-acetic acid methyl ester (15); 3-Aminophenylacetic acid (5 g, 33.1 mmol) was esterified with MeOH using Method B to give the title compound Yield: 4.22 g, 77percent; LC/MS tr 0.70 min; MS (ES+) m/z 166 (M+H); A solution of carboxylic acid (1 eq) was heated under reflux for 18 h with H2SO4 (0.5 vol) in MeOH or EtOH (25 vol). The solvent was evaporated in vacuo and the residue partitioned between DCM and aqueous sodium bicarbonate. The DCM layer was washed with brine, dried (Na2SO4), filtered and the solvent removed in vacuo to give the ester.
Reference：
[1] Patent: WO2009/53277, 2009, A1, . Location in patent: Page/Page column 52
[2] Patent: WO2008/107365, 2008, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2005/19190, 2005, A2, . Location in patent: Page/Page column 56
[4] Patent: WO2005/103050, 2005, A2, . Location in patent: Page/Page column 171
[5] Patent: WO2004/41813, 2004, A1, . Location in patent: Page 117
[6] Patent: WO2005/105780, 2005, A2, . Location in patent: Page/Page column 70
[7] Patent: WO2005/80367, 2005, A1, . Location in patent: Page/Page column 64; 70
[8] Journal of the American Chemical Society, 1917, vol. 39, p. 2437
[9] Patent: WO2011/38572, 2011, A1, . Location in patent: Page/Page column 61
[10] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3502 - 3522
[11] Patent: EP1486491, 2004, A1, . Location in patent: Page 60
4
[ 14338-36-4 ]
[ 52913-11-8 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sulfuric acid In methanol for 48 h; Heating / reflux
Step 1: Dissolve (3-Amino-phenyl)-acetic acid ((24),700mg, 4.63mmol) in MeOH (21mL) and add conc. sulfuric acid (0.27mL, 5.09mmol). Stir the reaction mixture for 2d under reflux. Cooled mixture to room temperature (rt), remove solvent under reduced pressure and prepurify the residue by flushing it over a short pad of silica gel using EtOAc. Remove solvent again and partitione the residue between EtOAc and saturated aqu. NaHCO3 (1+1). Extracte the aqueous layer 3 times with EtOAc, washe the combined organic layers with brine and dried with Na2SO4. Remove solvent under reduced pressure and dry the residue without further purification in oil pump vacuum to obtain product (25) as a light yellow oil (708mg, 92percent). 1H NMR (400MHz, CDCl3): 3.51 (s, 2 H); 3.67 (s, 3 H); 6.57 (dd, 1 H, J1 = 7.8Hz, J2 = 1.BHz); 6.60 (br.Ψt, 1 H, J = 1.8Hz); 6.65 (br.d, 1 H, J 7.8Hz); 7.08 (Ψt, 1 H, J = 7.8Hz).
92%
With sulfuric acid In methanol at 20℃; for 48 h; Heating / reflux
Dissolve (3-Amino-phenyl)-acetic acid ((22),700mg, 4.63mmol) in MeOH (2 1 mL) and add conc. sulfuric acid (0.27mL, 5.09mmol). Stir the reaction mixture for 2d under reflux. Cooled mixture to room temperature (rt), remove solvent under reduced pressure and prepurify the residue by flushing it over a short pad of silica gel using EtOAc. Remove solvent again and partition the residue between EtOAc and saturated aqu. NaHCO3 (1+1). Extracte the aqueous layer 3 times with EtOAc, washe the combined organic layers with brine and dried with Na2SO4. Remove solvent under reduced pressure and dry the residue without further purification in oil pump vacuum to obtain product (23) as a light yellow oil (708mg, 92percent). 1H NMR (400MHz, CDCl3): 3.51 (s, 2 H); 3.67 (s, 3 H); 6.57 (dd, 1 H, J1 = 7.8Hz, J2 = 1.8Hz); 6.60 (br.Ψt, 1 H, J= 1.8Hz); 6.65 (br.d, 1 H, J 7.8Hz); 7.08 (Ψt, 1 H, J= 7.8Hz).
79%
With HCl conc.; sodium hydrogencarbonate In methanol; hexane; ethyl acetate
Methyl-3-aminophenylacetate (1) To a solution of 3-aminophenylacetic acid (3 g, 19.85 mmol) in methanol (50 mL) at room temperature was added HCl conc. (37percent, 7.5 mL). The mixture was stirred 6 h at room temperature then treated with a saturated aqueous solution of NaHCO3. The solvent was removed under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude mixture was purified by flash chromatography using hexane/AcOEt (1:1) yielding 1 as a yellow oil (3.06 g, 79percent). 1H NMR: (300 MHz, CDCl3): 7.10 (t, J=8 Hz, 1H), 6.68-6.58 (m, 3H), 3.69-3.65 (m, 5H), 3.53 (s, 2H).
EXAMPLE 20 (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenylacetic acid (R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92g, 4.47mmol) was dissolved in THF (25ml) and treated with a solution of (3-aminophenyl)acetic acid methyl ester (670mg, 4.06mmol) in THF (5ml) followed by triethylamine (615mg, 6.09mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester.
With triethylamine; In tetrahydrofuran; water;
EXAMPLE 20 (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenylacetic acid (R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92 g, 4.47 mmol) was dissolved in THF (25ml) and treated with a solution of (3-aminophenyl)-acetic acid methyl ester (670 mg, 4.06 mmol) in THF (5ml) followed by triethylamine (615 mg, 6.09 mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20 ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1: 1 hexane: ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester.
With triethylamine; In tetrahydrofuran; water;
EXAMPLE 20 (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenylacetic acid (R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92g, 4.47mmol) was dissolved in THF (25ml) and treated with a solution of (3-aminophenyl)-acetic acid methyl ester (670mg, 4.06mmol) in THF (5ml) followed by triethylamine (615mg, 6.09mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester.
With triethylamine; In tetrahydrofuran; water;
EXAMPLE 20 (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenylacetic acid (R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92 g, 4.47 mmol) was dissolved in THF (25 ml) and treated with a solution of (3-aminophenyl)acetic acid methyl ester (670 mg, 4.06 mmol) in THF (5 ml) followed by triethylamine (615 mg, 6.09 mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20 ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester.
{3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-phenyl}-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99.9%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
<Example 4> {3-[2-(4-Adamantan-l-yl-phenoxy)-acetylarnino]-phenyl}-acetic acid methyl esterTo a solution of the (4-adamantan-l-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and (3-amino- phenyl>acetic acid methyl ester (LMJ-I-57) (124 mg, 0.75 mmol) in DMF (5.0 mL) were added l-[3- (dimemyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144 mg, 0.75 mmol), 1-hdroxylbenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and NJv[-diisopropylethylamine (DIPEA) (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine.The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (CH2Cl2 : MeOH = 4O-: l),gave. {3-[2-(4-adamantan-l-yl-phenoxy)tauacetylamino]-phenyl}.-acetic.acid.methyl . ester as a white solid (208.8 mg, 99.9% yield).1H-MdR (CDCl3, 300Hz) 8.27(1H, s, NH), 7.51(2H, m, aromatic), 7.23-7.35(3H, m, aromatic), 7.04(1H, d, J=7.2 Hz, aromatic), 6.91(2H m, aromatic), 4.55(2H, s, OCH2CO), 3.66(3H, s, COCH3), 3.60(2H, s,CH2COOCH3), 2.06(3H, m, adamantyl), 1.86(6H, m, adamantyl), 1.68-1.78(6H, m, adamantyl).
99.9%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and <strong>[52913-11-8](3-amino-phenyl)-acetic acid methyl ester</strong> (LMJ-I-57) (124 mg, 0.75 mmol) in DMF (5.0 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144 mg, 0.75 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and N,N-disopropylethylamine (DIPEA) (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (CH2Cl2:MeOH=40:1) gave {3-[4-adamantan-1-yl-phenoxy)-acetylamino]-phenyl}-acetic acid methyl ester as a white solid (208.8 mg, 99.9% yield). 1H-NMR (CDCl3, 300 Hz) 8.27 (1H, s, NH), 7.51 (2H, m, aromatic), 7.23-7.35 (3H, m, aromatic), 7.04 (1H, d, J=7.2 Hz aromatic), 6.91 (2H, m, aromatic), 4.55 (2H, s, OCH2CO), 3.66 (3H, s, COCH3), 3.60 (2H, s, CH2COOCH3), 2.06 (3H, m, adamantyl), 1.86 (6H, m, adamantyl), 1.68-1.78 (6H, m, adamantyl).
With pyridine; In dichloromethane; at 0 - 20℃; for 4h;
Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0 C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of METHANESULFONYL chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0 C for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), 1N HCL (2 x 100 mL) and brine. Dried over MGS04. Solvent was evaporated to reveal methyl 3- (methanesulfonyl) phenylacetate. (3.36 g, 100%). 1H NMR (500 MHz, CDC13) 8 7.32 (1H, dd), 7.2-7. 1 (3H, m), 6. 57 (1H, s), 3.72 (3H, s), 3 64 (2H, s), 3.02 (3H, s).
100%
With pyridine; In dichloromethane; at 0 - 20℃; for 4h;
Methyl (3-Methanesulfonylamino-phenyl)-acetate:; Methyl 3- aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0 C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0 C for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), IN HCI (2 x 100 mL) and brine. Dried over MgS04. Solvent was evaporated to reveal methyl 3-(methanesulfonyl)phenylacetate. (3.36 g, 100%). ¹H NMR (500 MHz, CDC13) No. 7.32 (lH, dd), 7.2 - 7.1 (3H, m), 6.57 (lH, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
100%
With pyridine; In dichloromethane; at 0 - 20℃; for 4h;
Methyl 3- (methanesulfonyl) phenylacetate : Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 ML) and cooled to 0 C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 ML, 16.8 mmol). The mixture was stirred at 0 C for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), IN HCI (2 x 100 mL) and brine. Dried over MgS04. Solvent was evaporated to reveal methyl 3- (methanesulfonyl) phenylacetate. (3.36 g, 100%).'H NMR (500 MHz, CDCl3) S 7.32 (1H, dd), 7.2-7. 1 (3H, m), 6.57 (1H, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
100%
With pyridine; In dichloromethane; at 0 - 20℃; for 4h;
Step B: Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0 C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0 C for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), IN HCI (2 x 100 mL) and brine. Dried over MgS04. Solvent was evaporated to afford methyl 3- (methanesulfonylamino) phenylacetate. (3.36 g, 100%). ¹H NMR (CDC13) 8 7.32 (1H, dd), 7.2 - 7.1 (3H, m), 6.57 (1H, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
75%
With pyridine; In dichloromethane; at 5 - 20℃; for 17h;
(3-Methanesulfonylamino-phenyl)-acetic acid methyl ester (3b). Methanesulfonyl chloride (0.47 rnL, 6.07 mmol) was added to a solution of the amine 2i (Ig,6.06 mmol) and pyridine (1 mL, 12.4 mmol) in CH2Cl2 (6 mL) at 5 0C. The reaction mixture was then stirred at r.t. for 17 h. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel (Hep:EtOAc 2.5:1) which gave the title compound (1.1 g,75%).
75%
With pyridine; In dichloromethane; at 5 - 20℃; for 17h;
(3-Methanesulfonylamino-phenyl)-acetic acid methyl ester (40b); Methanesulfonyl chloride (0.47 mL, 6.07 mmol) was added to a solution of 40a (Ig, 6.06 mmol) and pyridine (1 mL, 12.4 mmol) in CH2Cl2 (6 mL) at 5 0C. The reaction mixture was then stirred at r.t. for 17 h. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel (Hep:EtOAc 2.5:1) to give 1.1 g (75%) of the title compound.
With pyridine; In dichloromethane; at 0℃; for 1h;
Methyl 2-(3-aminophenyl)acetate (300 mg, 1.82 mmol),Pyridine (160 mg, 2.00 mmol) was dissolved in dichloromethane (10 mL)Methanesulfonyl chloride (230 mg, 2.00 mmol) was slowly added dropwise to the reaction mixture at 0 C. After 1 hour, TLC monitored the end of the reaction. The reaction mixture was poured into ice water, the organic phase was separated, the aqueous phase was extracted with methylene chloride. Methyl phenyl)acetate (450 mg, crude) was obtained as a pale yellow oil.
With pyridine; acetic anhydride; In dichloromethane; at 20℃; for 0.5h;
To a solution of the compound prepared in Reference Example 9 (820 mg) in methylene chloride (5 mL) were added pyridine (802 mul) and acetic anhydride (517 mul) under an atmosphere of argon and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the crude acetyl compound. The solution of the crude acetyl compound in anhydrous THF (3mL) was cooled with ice cooling under an atmosphere of argon. To the solution was added borane - dimethylsulfide complex (2M THF solution; 4.97 mL) and the mixture was stirred at room temperature for 1 hour and then stirred at 60 degrees for 15 hours. After cooling the reaction mixture by ice, To the reaction mixture were added methanol and hydrogen chloride in dioxane. The mixture was stirred at 60 degrees for 30 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 8 : 1) to give the title compound (320 mg) having the following physical data. TLC: Rf 0.49 (hexane : ethyl acetate = 2 : 1); NMR (CDCl3): delta 7.12 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.55-6.48 (m, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.15 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).
3-(4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzoylamino)phenylacetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In dichloromethane; at 20℃;
General procedure: To a stirred solution of 12e (62 mg, 0.4 mmol) in CH2Cl2 (5 mL) were added a solution of 18 (133 mg, 0.4 mmol) in CH2Cl2 (3 mL) and then pyridine (0.067 mL, 0.8 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with 1 M NaOH aq, water, brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to yield methyl ester (120 mg, 63%); TLC Rf = 0.14 (n-hexane/EtOAc, 7:3); 1H NMR (300 MHz, CDCl3) delta 7.60-7.38 (m, 4H), 7.32 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.92-6.77 (m, 4H), 6.74-6.66 (m, 2H), 4.70-4.60 (m, 1H), 4.26 (dd, J = 9.6, 5.4 Hz, 1H), 4.14 (dd, J = 11.4, 6.6 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H), 3.39 (dd, J = 11.4, 3.0 Hz, 1H), 3.26 (dd, J = 11.4, 7.8 Hz, 1H), 2.91 (s, 3H), 2.51 (s, 3H).CommentTo a stirred solution of methyl ester (120 mg, 0.25 mmol) described above in MeOH (4 mL) and THF (4 mL) was added 5 M NaOH aq (2 mL). After stirring for 1 h at room temperature, the reaction mixture was diluted with 2 M HCl aq and extracted with EtOAc (×2). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to give a crude product, which was washed with EtOAc/n-hexane to yield 4a (85 mg, 73%) as a pale blue powder
With pyridine; In dichloromethane; at 0℃; for 0.25h;
To a solution of the compound prepared in Reference Example 9 (165 mg) in methylene chloride (2 mL) was added pyridine (161 mul) under an atmosphere of argon. To the mixture was added dropwise a solution of the compound prepared in Reference Example 8 (350 mg) in methylene chloride (2.5 mL) under ice cooling and the mixture was stirred at 0 degrees for 15 minutes. To the mixture was added methanol and water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give the title compound (447 mg) having the following physical data. TLC: Rf 0.23 (hexane : ethyl acetate = 2 : 1).
3-((4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)benzyl)amino)phenylacetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In 1,1-dichloroethane; at 20℃; for 1h;
To a solution of the compound prepared in Reference Example 22 (270 mg) and the compound prepared in Reference Example 9 (180 mg) in dichloroethane (5 mL) was added acetic acid (0.097 mL) and sodium triacetoxyborohydride (462 mg) at room temperature and the mixture was stirred for 1 hour. To the reaction mixture was added water and then the mixture was extracted with ethyl acetate, The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give the title compound (330 mg) having the following physical data. TLC: Rf 0.46 (toluene : ethyl acetate = 1 : 9); NMR (300 MHz, CDCl3): delta 7.32-7.24 (m, 2H), 7.12 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.88-6.80 (m, 2H), 6.72-6.60 (m, 3H), 6.58-6.50 (m, 2H), 4.68-4.58 (m, 1H), 4.25 (s, 2H), 4.26-4.17 (m, 1H), 4.15-4.05 (m, 1H), 4.00-3.92 (m, 1H), 3.67 (s, 3H), 3.53 (s, 2H), 3.39 (dd, J = 11.7, 2.7 Hz, 1H), 3.25 (dd, J = 11.7, 6.6 Hz, 1H), 2.90 (s, 3H).
With sulfuric acid; In methanol; for 48h;Heating / reflux;
Step 1: Dissolve (3-Amino-phenyl)-acetic acid ((24),700mg, 4.63mmol) in MeOH (21mL) and add conc. sulfuric acid (0.27mL, 5.09mmol). Stir the reaction mixture for 2d under reflux. Cooled mixture to room temperature (rt), remove solvent under reduced pressure and prepurify the residue by flushing it over a short pad of silica gel using EtOAc. Remove solvent again and partitione the residue between EtOAc and saturated aqu. NaHCO3 (1+1). Extracte the aqueous layer 3 times with EtOAc, washe the combined organic layers with brine and dried with Na2SO4. Remove solvent under reduced pressure and dry the residue without further purification in oil pump vacuum to obtain product (25) as a light yellow oil (708mg, 92%). 1H NMR (400MHz, CDCl3): 3.51 (s, 2 H); 3.67 (s, 3 H); 6.57 (dd, 1 H, J1 = 7.8Hz, J2 = 1.BHz); 6.60 (br.Psit, 1 H, J = 1.8Hz); 6.65 (br.d, 1 H, J? 7.8Hz); 7.08 (Psit, 1 H, J = 7.8Hz).
92%
With sulfuric acid; In methanol; at 20℃; for 48h;Heating / reflux;
Dissolve (3-Amino-phenyl)-acetic acid ((22),700mg, 4.63mmol) in MeOH (2 1 mL) and add conc. sulfuric acid (0.27mL, 5.09mmol). Stir the reaction mixture for 2d under reflux. Cooled mixture to room temperature (rt), remove solvent under reduced pressure and prepurify the residue by flushing it over a short pad of silica gel using EtOAc. Remove solvent again and partition the residue between EtOAc and saturated aqu. NaHCO3 (1+1). Extracte the aqueous layer 3 times with EtOAc, washe the combined organic layers with brine and dried with Na2SO4. Remove solvent under reduced pressure and dry the residue without further purification in oil pump vacuum to obtain product (23) as a light yellow oil (708mg, 92%). 1H NMR (400MHz, CDCl3): 3.51 (s, 2 H); 3.67 (s, 3 H); 6.57 (dd, 1 H, J1 = 7.8Hz, J2 = 1.8Hz); 6.60 (br.Psit, 1 H, J= 1.8Hz); 6.65 (br.d, 1 H, J ? 7.8Hz); 7.08 (Psit, 1 H, J= 7.8Hz).
81%
17A Methyl 3-aminophenylacetate Following the process described in example 9 (point A), starting from 3-aminophenylacetic acid, the title compound was prepared as a yellowish oil (81% yield). 1H N.M.R. (300 MHz, CDCl3) delta ppm: 3.52 (s, 2H); 3.67 (s, 3H); 3.68 (s, 2H); 6.55 (m, 2H); 6.65 (d, 1H); 7.09 (t, 1H).
79%
With HCl conc.; sodium hydrogencarbonate; In methanol; hexane; ethyl acetate;
Methyl-3-aminophenylacetate (1) To a solution of 3-aminophenylacetic acid (3 g, 19.85 mmol) in methanol (50 mL) at room temperature was added HCl conc. (37%, 7.5 mL). The mixture was stirred 6 h at room temperature then treated with a saturated aqueous solution of NaHCO3. The solvent was removed under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried(MgSO4) and evaporated. The crude mixture was purified by flash chromatography using hexane/AcOEt (1:1) yielding 1 as a yellow oil (3.06 g, 79%). 1H NMR: (300 MHz, CDCl3): 7.10 (t, J=8 Hz, 1H), 6.68-6.58 (m, 3H), 3.69-3.65 (m, 5H), 3.53 (s, 2H).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
(ii) f3- [ (5-Bromo-furan-2-carbonyl)-amino]-phenylj-acetic acid methyl ester (16); Methyl ester (15) (1 g, 6.06 mmol) was coupled to 5-bromo- furan-2-carboxylic acid (1.16 g, 6.07 mmol) using Method C to give the title compound Yield: 1.83 g, 89% ; LC/MS tr 1.34 min; MS (ES+) m/z 338,340 (M+H); C); To a stirred solution of carboxylic acid (1 eq) and amino acid ester (1 eq) in DMF (20 vol) was added DIPEA (1 eq) followed by TBTU (1 eq). The reaction was stirred overnight, or until complete by LC/MS, at room temperature. To the reaction mixture was added EtOAc (30 vol) and the organic layer was washed with 2M HCl (2 x 50 vol), brine (2 x 50 vol), saturated aqueous NaHC03 (2 x 50 vol) and brine (2 x 50 vol). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo to give the product.
Step 2: (The following reaction is done in an anhydrous N2 atmosphere.) Dissolve EDC hydrochloride (187mg, 0.98mmol) and triethylamine (0.14mL, 1.00mmol) in anhydrous dichloromethane (3.5mL) and stir for 5min at rt. Added 3-(2,3,4-Trimethoxy-phenyl)-propionic acid (234mg, 0.97mmol) and DMAP (12mg, 0.10mmol) and stir for 10min. Added ester (25) (107mg, 0.65mmol) and stir the reaction solution overnight at rt. Hydrolize the reaction solution with saturated aqu. NH4Cl followed by water, separate layers, extracte aqu. layer with dichloromethane (3 times) and washe the combined organic layers with water and brine and dry with Na2SO4. Remove solvent under reduced pressure. Purify crude product by preparative radial chromatography (silica gel 60PF, EtOAc/CyH 1+1) to obtain product (26) as a white solid (209mg, 83%). [K. C. Nicolaou; P. S. Baran; Y.-L. Zhong; K. Sugita; J. Am. Chem. Soc.;2002;124; 10; 2212-2220]. 1H NMR (400MHz, CDCl3): 2.62 (t, 2 H, J = 7.5Hz); 2.95 (t, 2 H, J = 7.5Hz); 3.58 (s, 2 H); 3.67 (s, 3 H); 3.82 (s, 3 H); 3.84 (s, 3 H); 3.91 (s, 3 H); 6.59 (d, 1 H, J = 8.6Hz); 6.86 (d, 1 H, J = 8.6Hz); 6.98 (br.d, 1 H, J = 7.8Hz); 7.32 (Psit, 1 H, J= 7.8Hz); 7.38 (br.d, 1 H, J = 7.8Hz); 7.41 (br.s, 1 H).
83%
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve EDC hydrochloride (187mg, 0.98mmol) and triethylamine (0.14mL, 1.00mmol) in anhydrous dichloromethane (3.5mL) and stir for 5min at rt. Added 3-(2,3,4-Trimethoxy-phenyl)-propionic acid (234mg, 0.97mmol) and DMAP (12mg, 0.10mmol) and stir for 10min. Add ester (23) (107mg, 0.65mmol) and stir the reaction solution overnight at rt. Hydrolize the reaction solution with saturated aqu. NH4Cl followed by water, separate layers, extracte aqu. layer with dichloromethane (3 times) and washe the combined organic layers with water and brine and dry with Na2SO4. Remove solvent under reduced pressure. Purify crude product by preparative radial chromatography (silica gel 60PF, EtOAc/CyH 1+1) to obtain product (24) as a white solid (209mg, 83%). []. 1H NMR (400MHz, CDCl3): 2.62 (t, 2 H, J = 7.5Hz); 2.95 (t, 2 H, J = 7.5Hz); 3.58 (s, 2 H); 3.67 (s, 3 H); 3.82 (s, 3 H); 3.84 (s, 3 H); 3.91 (s, 3 H); 6.59 (d, 1 H, J = 8.6Hz); 6.86 (d, 1 H, J = 8.6Hz); 6.98 (br.d, 1 H, J = 7.8Hz); 7.32 (Psit, 1 H, J= 7.8Hz); 7.38 (br.d, 1 H, J = 7.8Hz); 7.41 (br.s, 1 H).
Example 19 Methyl 2-[3-[3-[N-[3-[N-methyl-N-(3,5-dimethylphenyl)carbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl] acetate (1-19) Compound S19 (3.15 g) was dissolved in tetrahydrofuran (150 ml). N,N'-Carbonyldiimidazole (1.26 g) was added to the solution under ice cooling. The mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure. 2.03 g of the residue was dissolved in toluene (100 ml). Methyl 2-(3-aminophenyl)acetate (1.15 g) was added to the solution and the solution was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed successively with 1N HCl, water and brine, then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50:1), obtaining 0.86 g of the compound (1-19) as crystals. 1 H-NMR (CDCl3)delta: 2.34 (6H, s), 3.26-3.66 (6H, m), 3.56 (2H, s), 3.66 (3H, s), 3.85 (2H, s), 4.08 (2H, s), 4.43 (2H, s), 5.69 (1H, brs), 6.79-7.41 (17H, m)
Example 27 Methyl 2-[3-[3-[N-[2-[N-methyl-N-(3-methylphenyl)carbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl] acetate (1-27) Compound S20 (1.0 g) was dissolved in tetrahydrofuran (20 ml). N,N'-Carbonyldiimidazole (0.38 g) was added to the solution. The mixture was stirred for 15 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in toluene (30 ml). Methyl 2-(3-aminophenyl)acetate (0.69 g) was added to the solution. The mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue was partitioned between chloroform and 1N HCl. The two layers were separated. The organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform/methanol=50:1). The elude was concentrated and the residue was crystallized from n-hexane/ethyl acetate/diethyl ether, obtaining 0.8 g of the compound (1-27) as crystalline powder. mp 133-135 C. 1 H-NMR (CDCl3)delta: 2.40 (3H, s), 3.23 (3H, s), 3.27 (3H, s), 3.49 (1H, d), 3.55 (2H, s), 3.66 (3H, s), 3.95 (2H, s), 4.42 (2H, s), 4.68 (1H, d), 6.60 (1H, d), 6.87 (1H, d), 6.98 (1H, t), 7.03-7.06 and 7.14-7.38 (14H, m), 7.69 (1H, d) MS (m/z): 666 (M+1)+
methyl 2-[3-[3-[N-[3-[N-methyl-N-(3-methylphenyl)carbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; chloroform; toluene;
Example 15 Methyl 2-[3-[3-[N-[3-[N-methyl-N-(3-methylphenyl)carbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl]acetate (1-15) Compound S23 (3.0 g) was dissolved in tetrahydrofuran (300 ml). N,N'-Carbonyldiimidazole (1.23 g) was added to the solution under ice cooling. The mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure. 2 g of the residue was dissolved in toluene (150 ml). Methyl 2-(3-aminophenyl)acetate (1.16 g) was added to the solution and the solution was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The resulting solution was washed successively with 1N HCl, water and brine, then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30:1) and crystallized from ethyl acetate/diethyl ether, obtaining 0.57 g of the compound (1-15) as crystalline powder. 1 H-NMR (CDCl3)delta: 2.38 (3H, s), 3.25 (3H, s), 3.31 (3H, s), 3.55 (2H, s), 3.66 (3H, s), 3.85 (2H, d), 4.08 (2H, s), 4.43 (2H, s), 5.80 (1H, brs), 6.79-6.99 and 7.13-7.40 (18H, m)
methyl 2-[3-[3-[N-[3-[N-ethyl-N-(3,5-dimethylphenyl)carbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; chloroform; toluene;
Example 12 Methyl 2-[3-[3-[N-[3-[N-ethyl-N-(3,5-dimethylphenyl)carbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl]acetate (1-12): Compound S29 (1.0 g) was dissolved in tetrahydrofuran (20 ml). N,N'-Carbonyldiimidazole (0.36 g) was added to the solution. The mixture was stirred for 15 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in toluene (30 ml). Methyl 2-(3-aminophenyl)acetate (0.70 g) was added to the resulting solution. The mixture was refluxed for 3 hours and concentrated under reduced pressure. The residue was partitioned between chloroform and 1N HCl. The two layers were separated. The organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform/methanol=50:1). The elude was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diethyl ether, obtaining 0.4 g of the compound (1-12) as crystalline powder. mp 104-106 C. 1 H-NMR (CDCl3)delta: 1.14 (3H, t), 2.35 (6H, s), 3.24 (3H, s), 3.54 (2H, s), 3.65 (3H, s), 3.75 (2H, q), 3.86 (2H, s), 4.08 (2H, s), 4.38 (2H, s), 5.84 (1H, brs), 6.79 (1H, d), 6.89 (2H, s), 6.91 (1H, d), 6.99 (1H, d), 7.03 (1H, s), 7.14-7.37 (11H, m) MS (m/z): 694 (M+1)+
N-(3-Cyanophenyl)-N-methyl-2-[3-[N-(2-aminoacetyl)-N-(N-methyl-N-phenylcarbamoylmethyl)amino]phenoxy]acetamide[ No CAS ]
[ 52913-11-8 ]
[ 530-62-1 ]
methyl 2-[3-[3-[N-[3-[N-(3-cyanophenyl)-N-methylcarbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethyl acetate; toluene;
Example 13 Methyl 2-[3-[3-[N-[3-[N-(3-cyanophenyl)-N-methylcarbamoylmethyloxy]phenyl]-N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido]phenyl]acetate (1-13) Compound S33 (1.0 g) was dissolved in tetrahydrofuran (30 ml). N,N'-Carbonyldiimidazole (0.5 g) was added to the solution. The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The resulting solution was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Toluene (40 ml) and methyl 2-(3-aminophenyl)acetate (0.7 g) were added to the residue. The resulting mixture was refluxed for 1 hour. Ethyl acetate (150 ml) was added to the reaction mixture. The resulting solution was washed successively with 1N HCl, water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform/methanol=20:1), obtaining 0.7 g of the compound (1-13) as white powder. mp 86-90 C. 1 H-NMR (CDCl3)delta: 3.24 (3H, m), 3.33 (3H, s), 3.52 (2H, s), 3.64 (3H, s), 3.84 (2H, d), 4.09 (2H, s), 4.47 (2H, brs), 6.06 (1H, brs), 6.84-7.01 (4H, m), 7.11-7.36 (9H, m), 7.60-7.65 (4H, m), 7.89 (1H, s)
With potassium hydroxide; ethanethiol; In hydrogenchloride; diethyl ether; hexane; water; sodium nitrite;
3-Ethylthiophenylacetic acid To a solution of methyl 3-aminophenylacetate (102 g, 0.62 mole) in 1N HCl (1600 ml) cooled in an ice bath was added NaNO2 (42.7 g, 0.62 mole) portionwise and the solution stirred for 20 minutes. A solution of potassium ethanethiolate was prepared by adding ethanethiol (202 ml, 2.73 mole) dropwise over 10 minutes to a solution of 87.5% KOH (159 g, 2.48 mole) in water (1.2 l) at 0 C. The diazonium salt solution was then added via cannula to the solution of potassium ethanethiolate and the reaction mixture was stirred 30 minutes in an ice bath. Diethyl ether (~ 1.5 l) was added and the mixture was stirred 1.5 hours at room temperature. The ether layer was separated, the aqueous phase further extracted with diethyl ether (3*700 ml), and the combined ether solutions concentrated. The residue was eluted from silica gel with ethyl acetate:hexane (1:19) to give a mixture of methyl 3-ethylthiophenylacetate 1 H NMR (DMSO-d6, 200 MHz) delta: 1.21 (t, J=7 Hz, 3H, ethyl CH3), 2.95 CH2), 3.60 (s, 3H, OCH3), 3.65 (s, 2H, ArCH2), 7.02-7.44 (m, Ar), and methyl phenylacetate (85.9 g). The esters (84 g) were hydrolyzed in a solution of methanol (500 ml) and 6.25N NaOH (100 ml) stirred overnight at room temperature. The solution was concentrated in vacuo to remove the methanol, the remaining solution acidified with concentrated HCl and the resulting solid was extracted into diethyl ether. The ether solution was washed with brine (3*100 ml), dried (Na2 SO4) and concentrated. Vacuum distillation (0.5 mm Hg) gave a distillate (100-115 C.) of phenylacetic acid and a residue of 3-ethylthiophenylacetic acid. The residue in the flask solidified upon cooling to give 3-ethylthiophenylacetic acid (49.8 g). Mp=49-51 C. 1 H NMR (DMSO-d6, 200 MHz) delta: 1.21 (t, J=7 Hz, 3H, CH3), 2.95 (q, J=7 Hz, 2H, SCH2), 3.54 (s, 2H, ArCH), 7.01-7.28 (m, 4H, Ar), 12.33 (br s, 1H, CO2 H). Mass spectrum (CI-CH4): 197 (M+1, 100%).
Methyl 3-aminophenylacetate may be prepared in a fashion similar to that described in Example 10.sctn.A, but starting from 37.1 g of methyl 3-nitrophenylacetate in solution in 550 cm3 of methanol and 2 g of palladinized charcoal. 28.2 g of methyl 3-aminophenylacetate are thus obtained in the form of a dark yellow liquid used as it is in subsequent syntheses. Methyl 3-nitrophenylacetate may be prepared according to the method described by SEGERS and A. BRUYLANTS, Bul. Soc. Chim. Belg., 64, 87, (1955).
(RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid[ No CAS ]
[ 52913-11-8 ]
(RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 7 Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide The procedure described in Example 1 was repeated, except that dihydropyran (0.4 ml) and methyl m-aminophenylacetate (604 mg) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (893 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (624 mg). IR numax cm-1 (neat): 3336, 1723, 1691, 1346, 1167 Fab-MS m/z: 497 (MH+), 413
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