* 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 Organic Chemistry, 2008, vol. 73, # 2, p. 618 - 629
2
[ 5351-07-5 ]
[ 2955-46-6 ]
Yield
Reaction Conditions
Operation in experiment
47%
With water; potassium hydroxide In ethylene glycol at 150℃; for 7 h;
Step 24b: 2-(4-Methoxyphenyl)-2-methylpropanoic acid (Compound 0803-27)To a solution of 2-(4-Methoxyphenyl)-2-methylpropanenitrile (compound 0802- 27) (1.63 g, 9.30 mmol) in ethylene glycol (3.40 mL) was added potassium hydroxide (1.29 g, 22.99 mmol) and water (0.46 mL). The reaction mixture was heated at 150°C for 7 h. The mixture was poured into water, adjusted to pH 2 with <n="79"/>concentrated hydrochloric acid. The mixture was filtered and the collected solid was washed with water and dried in vacuum to afford product 0803-27 (0.85 g, 47 percent) as a white solid: LCMS: 195 [M+l]+. 1H NMR (DMSO-d6): δ 1.44 (s, 6H), 3.73 (s, 3H), 6.88 (d, J= 9.2 Hz, 2H), 7.25 (d, J= 8.4 Hz, 2H), 12.23 (s, IH).
Reference：
[1] European Journal of Organic Chemistry, 2007, # 21, p. 3449 - 3462
[2] Patent: WO2009/36016, 2009, A1, . Location in patent: Page/Page column 77; 78
[3] Acta Chemica Scandinavica (1947-1973), 1954, vol. 8, p. 1203,1207[4] Acta Chemica Scandinavica (1947-1973), 1955, vol. 9, p. 210,214
[5] Journal of the American Chemical Society, 1956, vol. 78, p. 4801,4805
[6] Journal of the American Chemical Society, 1968, vol. 90, p. 2082 - 2096
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4567 - 4570
[8] Organic Letters, 2013, vol. 15, # 3, p. 690 - 693
[9] Angewandte Chemie - International Edition, 2017, vol. 56, # 23, p. 6544 - 6547[10] Angew. Chem., 2017, vol. 129, # 23, p. 6644 - 6647,4
3
[ 5351-07-5 ]
[ 942-54-1 ]
[ 2955-46-6 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With potassium hydroxide In water; ethylene glycol at 20 - 160℃; Stage #2: With hydrogenchloride In monoethylene glycol diethyl ether; water
A mixture of 2- (4-methoxyphenyl)-2-methylpropionitrile g, 2.04 mol), KOH (284.8 g, 5.08 mol), ethylene glycol (750 mL), and water (100 mL) was heated at 150-160 °C for 7 h in a 1L round-bottom flask equipped with a bump flask and fermentation lock, then allowed to cool and stand overnight. Heating was continued for an additional 7 hours, without any additional conversion being observed. The reaction was allowed to cool and poured into water (2 L), then acidified with stirring to pH 10-11 by addition of concentrated HCI (-250 mL). The resulting solution was extracted with isopropyl acetate (1x1 L, followed by 2x500 mL) and then filtered to remove a small quantity of a white precipitate. The reaction mixture was stirred vigorously and slowly acidified further to ca pH = 2 with concentrated HCl (-250 mL). The product started to precipitate at pH 6-7. The suspension was stirred for 30 minutes at ambient temperature then kept a refrigerator overnight. The mixture was filtered and the precipitate was washed with cold 1M HCl (500 mL), followed cold water (2x150 mL). The solid was dried under suction, follow by high vacuum (lyophilizer) overnight to give 2- (4-methoxyphenyl)-2-methylpropanoic (314 g, 80percent) as pale yellow-orange crystals containing approximately 2.0 percent of the mono-methyl impurity.
Reference：
[1] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1942, p. 392[2] Chem.Abstr., 1945, p. 1620
16
[ 108-95-2 ]
[ 2955-46-6 ]
Reference：
[1] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1942, p. 392[2] Chem.Abstr., 1945, p. 1620
17
[ 55770-61-1 ]
[ 2955-46-6 ]
Reference：
[1] Acta Chemica Scandinavica (1947-1973), 1954, vol. 8, p. 1203,1207[2] Acta Chemica Scandinavica (1947-1973), 1955, vol. 9, p. 210,214
18
[ 2955-46-6 ]
[ 29913-51-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 20 - 180℃; for 5 - 23 h;
Step 4 a,a-Dimethyl 4-methoxyphenylacetic acid (108 g; 0.556 mol) was heated with pyridineNo.HCl (324 g; 2.80 mol) to 180 °C for 5 hours. The reaction mixture was allowed to cool to ca 90 °C, then added to an equal volume of 10percent aqueous sodium hydroxide and chipped ice to give a basic solution. The aqueous solution was washed with diethyl ether, then acidified to pH = 3 with 85percent H3P04. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were concentrated in vacuo to give a solid, which was recrystallized from water to give a,a-dimethyl 4-hydroxyphenylacetic acid. Alternate procedure a,a-Dimethyl 4-methoxyphenylacetic acid (100 g; 0.515 mol) and pyridineNo.HCl (297 g; 2.57 mol) were heated with stirring at 180 °C for 5 hours. The reaction mixture was allowed to cool to room temperature and then stand overnight. After 18 hours, the reaction was re-heated such that it was homogeneous for the purpose of sampling and then cooled to ~100°C and poured onto a mixture of 1L chipped-ice and 10percent aqueous NaOH (1.5 L). The aqueous layer was extracted with diethyl ether, then acidified with 85percent aqueous H3P04 to pH = 3 (@130 mL), and then extracted with EtOAc (500 mL, followed by 250 mL). The combined organic extracts were concentrated in vacuo to give a solid, which was crystallized from hot water. Once crystals had significantly established stirring was started at a rate so as to maintain mobility of the entire precipitate and then continued overnight. The mixture was cooled in a fridge for 2 hours prior to collection of the crystals by filtration. The crystals were washed with a minimum amount of cold water (~100 mL), and then dried, first under suction and then under high vacuum (lyophilizer) to give a,a-dimethyl 4- hydroxyphenylacetic acid (76.3 g, 82percent) as a tan crystalline solid.
76%
at 180℃; for 5 h;
Step 24c: 2-(4-Hydroxyphenyl)-2-methylpropanoic acid (Compound 0804-27)A mixture of 2-(4-Methoxyphenyl)-2-methylpropanoic acid (compound 0803- 27) (0.85 g, 4.38 mmol ) and pyridine hydrochloride (2.82 g, 24.40 mmol) was heated at 180°C for 5 h, The reaction mixture was then cooled to room temperature and adjusted to pH 6 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and concentrated to afford desired product 0804-27 (0.61 g, 76 percent) as a colorless oil: LCMS: 181 [M+l]+. 1H NMR (400 MHz, DMSO-d6): δ 1.41 (s, 6H), 6.70 (d, J= 8.8 Hz, 2H), 7.13 (d, J= 8.8 Hz, 2H), 9.28 (s, IH), 12.16 (s, IH).
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 26, p. 4508 - 4521
[2] Patent: WO2005/121102, 2005, A2, . Location in patent: Page/Page column 25-26
[3] Patent: WO2009/36016, 2009, A1, . Location in patent: Page/Page column 78c
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4567 - 4570
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 6129 - 6152
[6] Patent: WO2013/19682, 2013, A1, . Location in patent: Page/Page column 87
With water; potassium hydroxide; In ethylene glycol; at 150℃; for 7h;
Step 24b: 2-(4-Methoxyphenyl)-2-methylpropanoic acid (Compound 0803-27)To a solution of 2-(4-Methoxyphenyl)-2-methylpropanenitrile (compound 0802- 27) (1.63 g, 9.30 mmol) in ethylene glycol (3.40 mL) was added potassium hydroxide (1.29 g, 22.99 mmol) and water (0.46 mL). The reaction mixture was heated at 150C for 7 h. The mixture was poured into water, adjusted to pH 2 with <n="79"/>concentrated hydrochloric acid. The mixture was filtered and the collected solid was washed with water and dried in vacuum to afford product 0803-27 (0.85 g, 47 %) as a white solid: LCMS: 195 [M+l]+. 1H NMR (DMSO-d6): delta 1.44 (s, 6H), 3.73 (s, 3H), 6.88 (d, J= 9.2 Hz, 2H), 7.25 (d, J= 8.4 Hz, 2H), 12.23 (s, IH).
With pyridine hydrochloride; at 20 - 180℃; for 5 - 23h;Product distribution / selectivity;
Step 4 a,a-Dimethyl 4-methoxyphenylacetic acid (108 g; 0.556 mol) was heated with pyridineNo.HCl (324 g; 2.80 mol) to 180 C for 5 hours. The reaction mixture was allowed to cool to ca 90 C, then added to an equal volume of 10% aqueous sodium hydroxide and chipped ice to give a basic solution. The aqueous solution was washed with diethyl ether, then acidified to pH = 3 with 85% H3P04. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were concentrated in vacuo to give a solid, which was recrystallized from water to give a,a-dimethyl 4-hydroxyphenylacetic acid. Alternate procedure a,a-Dimethyl 4-methoxyphenylacetic acid (100 g; 0.515 mol) and pyridineNo.HCl (297 g; 2.57 mol) were heated with stirring at 180 C for 5 hours. The reaction mixture was allowed to cool to room temperature and then stand overnight. After 18 hours, the reaction was re-heated such that it was homogeneous for the purpose of sampling and then cooled to ~100C and poured onto a mixture of 1L chipped-ice and 10% aqueous NaOH (1.5 L). The aqueous layer was extracted with diethyl ether, then acidified with 85% aqueous H3P04 to pH = 3 (@130 mL), and then extracted with EtOAc (500 mL, followed by 250 mL). The combined organic extracts were concentrated in vacuo to give a solid, which was crystallized from hot water. Once crystals had significantly established stirring was started at a rate so as to maintain mobility of the entire precipitate and then continued overnight. The mixture was cooled in a fridge for 2 hours prior to collection of the crystals by filtration. The crystals were washed with a minimum amount of cold water (~100 mL), and then dried, first under suction and then under high vacuum (lyophilizer) to give a,a-dimethyl 4- hydroxyphenylacetic acid (76.3 g, 82%) as a tan crystalline solid.
76%
With pyridine hydrochloride; at 180℃; for 5h;
Step 24c: 2-(4-Hydroxyphenyl)-2-methylpropanoic acid (Compound 0804-27)A mixture of 2-(4-Methoxyphenyl)-2-methylpropanoic acid (compound 0803- 27) (0.85 g, 4.38 mmol ) and pyridine hydrochloride (2.82 g, 24.40 mmol) was heated at 180C for 5 h, The reaction mixture was then cooled to room temperature and adjusted to pH 6 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and concentrated to afford desired product 0804-27 (0.61 g, 76 %) as a colorless oil: LCMS: 181 [M+l]+. 1H NMR (400 MHz, DMSO-d6): delta 1.41 (s, 6H), 6.70 (d, J= 8.8 Hz, 2H), 7.13 (d, J= 8.8 Hz, 2H), 9.28 (s, IH), 12.16 (s, IH).
To a solution of methyl 2-(4-methoxyphenyl)acetate (10.0 g, 48.00 mmol) in MeOH (20 mL) was added dropwise a solution of NaOH (7.69 g, 192.3 mmol) in water (50 mL). The reaction mixture was stirred at rt for 6 h. The MeOH was distilled off at reduced pressure and water (25 mL) was added. The aqueous layer was washed with Et20 and then acidified to pH=4 using 6.0 M HC1. The resultant precipitate was filtered, washed with hexanes, and dried. The resultant solid was dissolved in CH2CI2 (150 mL) and cooled to -78 C followed by the addition of BBr3 (1.0 M solution in CH2C12) (72.0 mL, 72.00 mmol) over 30 min. After the completion of the addition, the temperature was raised to 0 C, and the reaction mixture was stirred for an additional 30 min. Water was slowly added and the organic layer was separated, dried over Na2S04; and concentrated to provide the title compound (4.30 g, 50%). lU NMR (400 MHz, DMSO-d6) delta ppm 12.17 (br s, 1H), 9.31 (s, 1H), 7.14 (d, 2H), 6.71 (d, 2H), 1.42 (s, 6H).
2-[5-(4-amino-1<i>H</i>-pyrrolo[3,2-<i>c</i>]pyridin-2-yl)-6-benzyloxy-3'-(<i>tert</i>-butoxycarbonylamino-methyl)-biphenyl-3-yl]-2-methyl-propionic acid[ No CAS ]
2-[6-benzyloxy-3'-(<i>tert</i>-butoxycarbonylamino-methyl)-5-(4-chloro-1-methanesulfonyl-1<i>H</i>-pyrrolo[3,2-<i>c</i>]pyridin-2-yl)-biphenyl-3-yl]-2-methyl-propionic acid methyl ester[ No CAS ]
2-{5-(4-amino-1<i>H</i>-pyrrolo[3,2-<i>c</i>]pyridin-2-yl)-3'-[3-(2,6-difluoro-phenyl)-ureidomethyl]-6-hydroxy-biphenyl-3-yl}-2-methyl-propionic acid[ No CAS ]
A mixture of 2- (4-methoxyphenyl)-2-methylpropionitrile g, 2.04 mol), KOH (284.8 g, 5.08 mol), ethylene glycol (750 mL), and water (100 mL) was heated at 150-160 C for 7 h in a 1L round-bottom flask equipped with a bump flask and fermentation lock, then allowed to cool and stand overnight. Heating was continued for an additional 7 hours, without any additional conversion being observed. The reaction was allowed to cool and poured into water (2 L), then acidified with stirring to pH 10-11 by addition of concentrated HCI (-250 mL). The resulting solution was extracted with isopropyl acetate (1x1 L, followed by 2x500 mL) and then filtered to remove a small quantity of a white precipitate. The reaction mixture was stirred vigorously and slowly acidified further to ca pH = 2 with concentrated HCl (-250 mL). The product started to precipitate at pH 6-7. The suspension was stirred for 30 minutes at ambient temperature then kept a refrigerator overnight. The mixture was filtered and the precipitate was washed with cold 1M HCl (500 mL), followed cold water (2x150 mL). The solid was dried under suction, follow by high vacuum (lyophilizer) overnight to give 2- (4-methoxyphenyl)-2-methylpropanoic (314 g, 80%) as pale yellow-orange crystals containing approximately 2.0 % of the mono-methyl impurity.
With pyridine; hydrogenchloride; sodium chloride; In tetrahydrofuran; dichloromethane;
EXAMPLE 10 Synthesis of 4-(2'-Carboxy-2'-methylpropylmercapto)phenyl 2-(4'-Methoxyphenyl)isobutyrate (308) A solution of 2-(4'-methoxyphenyl)isobutyric acid (1.5 g, 7.7 mmol) in CH2 Cl2 was treated with a 2.0M oxalyl chloride solution in CH2 Cl2 (7.7 mL, 15.4 mmol) and a drop of DMF. After stirring overnight at room temperature, the volatiles were removed under vacuum and the residue dissolved in dry THF. The resulting solution of 2-(4'-methoxyphenyl)isobutyryl chloride was added to a stirred solution of V (2.68 g, 7.7 mmol) and pyridine (0.73 g, 9.3 mmol) in THF and stirred overnight. The reaction mixture was concentrated under vacuum, the residue dissolved in ether and washed with H2 O. The organic layer was washed subsequently with dilute HCl, dilute bicarbonate, H2 O and dried over anhydrous MgSO4. The product was isolated by preparative HPLC to afford 1.1 g (27%) of the benzyloxymethyl protected ester. The benzyloxymethyl group was removed by treatment with 40 mL of 6N HCl/40 mL of THF for 1 hour. Saturated NaCl was added, the reaction mixture extracted with ether, washed with dilute bicarbonate solution, dried over anhydrous MgSO4 and evaporated to give 0.75 g (89%) of 4-(2'-carboxy-2'-methylpropylmercapto)phenyl 2-(4'-methoxyphenyl)isobutyrate. 1 H NMR (CDCl3) delta1.27 (s, 6H), 1.68 (s, 6H), 3.14 (s, 2H), 3.81 (s, 3H), 6.86-6.93 (m, 4H, ArH), 7.35-7.38 (m, 4H, ArH); 13 C NMR (CDCl3) delta24.36, 26.22, 43.75, 45.08, 45.91, 55.16, 114.00, 122.04, 126.93, 131.85, 134.10, 136.18, 150.02, 158.69, 175.79, 182.77.
(A) 1-(4'-methoxy-phenyl)-2-bromo-2-methyl-propan-1-one (3.2 g; 0.012 moles) is added under nitrogen and under stirring to a solution of ZnBr2 (25 g; 0.11 moles) in methanol (9 ml) maintained at 85 C. The reaction mixture is maintained at 85 C. and under stirring for 2 hours. The reaction mixture is then cooled to room temperature, poured into water and extracted with methylene chloride (2*50 ml). The collected organic extracts are dried on Na2 SO4, filtered and the solvent is evaporated to afford a residue which according to the I.R. and N.M.R. analysis contains the methyl ester of the 2-(4'-methoxy-phenyl)-2-methyl-propionic acid. The residue is dissolved in a 30% solution of NaOH (10 ml) in methanol (100 ml). The mixture is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is extracted with water (100 ml)-methylene chloride (100 ml) mixture. The aqueous phase is separated, acidified with conc. HCl and extracted with methylene chloride. The organic extract is dried on sodium sulphate. The evaporation of the solvent under vacuum leaves a residue which by crystallization from petroleum ether/ether affords the 2-(4'-methoxy-phenyl)-2-methyl propionic acid (1.05 g; 0.05 moles) (yield 45%). M.p. 75-77 C.
4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenol; Step 1.; To a 2M solution of LDA in heptane (commercial rade; 66.2 ml) at 0C, under nitrogen, it was added 4-methoxyphenyl acetic acid (5.5 g; 33.09 mmol). After stirring at 0C for 40 minutes it was added iodomethane (13. 18 ml ; 211. 78 mmol). Allowed to warm to rt and stirred additional 30 minutes. The reaction mixture was then added to 200 ml of saturated ammonium chloride. Extracted 3x150 ml of ethyl ether. The aqueous phase was acidified with 1N HCl and extracted 2x150ml with ethyl ether. The latter organic phases were dried over sodium sulfate and concentrated to afford 5. 8 g of an oil which corresponded to a 2.5:1 mixture of 2-(4-methoxyphenyl)-2-methylpropanoic acid (bis-methylation product) to 2- (4-methoxyphenyl)propanoic acid (monomethylation product) which was used in the next step without any further purification.
With isopropylmagnesium bromide; triphenylphosphine; cobalt(II) chloride; In tetrahydrofuran; at 20℃; for 18h;Green chemistry;
General procedure: The iPrMgBr (excess in THF) was added to a mixture of alpha,alpha-dimethyl phenylacetic acids (1 mmol), cobalt salt (10 mol%), ligand (20 mol%) in dried THF (3 mL), the reaction mixture was stirred at room temperature for 18 h. After that, the mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and dichloromethane to give the corresponding products.
To a solution of methyl 2-(4-methoxyphenyl)acetate (10.0 g, 48.00 mmol) in MeOH (20 mL) was added dropwise a solution of NaOH (7.69 g, 192.3 mmol) in water (50 mL). The reaction mixture was stirred at rt for 6 h. The MeOH was distilled off at reduced pressure and water (25 mL) was added. The aqueous layer was washed with Et20 and then acidified to pH=4 using 6.0 M HC1. The resultant precipitate was filtered, washed with hexanes, and dried. The resultant solid was dissolved in CH2CI2 (150 mL) and cooled to -78 C followed by the addition of BBr3 (1.0 M solution in CH2C12) (72.0 mL, 72.00 mmol) over 30 min. After the completion of the addition, the temperature was raised to 0 C, and the reaction mixture was stirred for an additional 30 min. Water was slowly added and the organic layer was separated, dried over Na2S04; and concentrated to provide the title compound (4.30 g, 50%). lU NMR (400 MHz, DMSO-d6) delta ppm 12.17 (br s, 1H), 9.31 (s, 1H), 7.14 (d, 2H), 6.71 (d, 2H), 1.42 (s, 6H).
With water; sodium hydroxide; In methanol; for 2h;Reflux;
to the step (3) the resulting rearrangement product with a 250 ml methanol and 150 ml water with 5.8 g of sodium hydroxide mixed solution, stir at reflux 2 h, until the disappearance of the rearrangement product. Reduced pressure to remove the methanol, added to the reaction solution in the 500 ml water and 100 ml ethyl acetate, aqueous layer, the aqueous layer with concentrated hydrochloric acid to PH=1 - 2, a large number of solid separated out, the solid filtering, the filter cake is washed with water. Finally the ethyl acetate to alpha - (4 - fluorophenyl) recrystallization of isobutyric acid, dried to obtain 10.2 g product, yield 90%.
methyl 3-[(2R)-4-amino-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate, hydrochloric acid[ No CAS ]
methyl 3-{(2R,4S)-7-methoxy-4-[2-(4-methoxyphenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoate[ No CAS ]
methyl 3-{(2R,4R)-7-methoxy-4-[2-(4-methoxyphenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25.01%; 31.3%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;
To <strong>[2955-46-6]2-(4-methoxyphenyl)-2-methylpropanoic acid</strong> (53.3 mg, 0.274 mmol) in N,N-dimethylformamide (1 mL) was added HATU (139 mg, 0.366 mmol). The mixture was stirred for 5 minutes at room temperature, followed by the addition of Example 24C (80 mg, 0.229 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.120 mL, 0.686 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse-phase preparative HPLC on a Phenomenex Luna C8(2) 5 mum 100 AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). The fractions collected was concentrated and the residue purified by chromatography, eluting with 5-20% tert-butyl methyl ether in heptane. Example 24D was obtained as the first eluting isomer. (28 mg, 25.01%). 1H NMR (400 MHz, CDCl3) delta 8.09-8.00 (m, 2H), 7.58-7.45 (m, 2H), 7.37-7.30 (m, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.98-6.91 (m, 2H), 6.53 (dd, J=8.5, 2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 5.49 (d, J=6.8 Hz, 1H), 5.00 (dt, J=6.8, 3.0 Hz, 1H), 4.71 (dd, J=11.7, 2.0 Hz, 1H), 3.98 (s, 3H), 3.82 (s, 3H), 3.78 (d, J=1.1 Hz, 3H), 2.33 (dt, J=14.2, 2.3 Hz, 1H), 2.17-2.05 (m, 1H), 1.62 (s, 3H), 1.59 (s, 3H); MS(ESI+): m/z=489.8 (M+H); analytical chiral SFC analysis of the compound (column: ChiralCel OJ-H, eluting with 5-30% methanol:CO2 over 10 minutes, 3 mL/min, 150 bar) showed single peak at 3.77 minutes. Example 24 E (35 mg, 31.3%) was obtained as the second eluting isomer. Chiral SFC showed single peak at 5.047 min. HTP-TFA/(APCI+) 490 (M+1)+.
methyl 4-[(2R,4R)-4-amino-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate hydrochloride[ No CAS ]
methyl 4-{(2R,4R)-7-methoxy-4-[2-(4-methoxyphenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 60℃; for 4h;
2-(4-Methoxyphenyl)-2-methylpropanoic acid (37.1 mg, 0.191 mmol) was dissolved in N,N-dimethylformamide (0.5 mL) and pyridine (0.5 mL). Example 1C (39.8 mg, 0.114 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37.7 mg, 0.197 mmol) were added and the reaction mixture was stirred at 60 C. for 4 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase preparative HPLC on a Phenomenex Luna C8(2) 5 mum 100 AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A), to provide the title compound (19.7 mg, 35%). 1H NMR (501 MHz, DMSO-d6) delta 8.03-7.97 (m, 2H), 7.61-7.56 (m, 2H), 7.48 (d, J=8.8 Hz, 1H), 7.29-7.22 (m, 2H), 6.90-6.85 (m, 2H), 6.80 (dd, J=8.5, 1.0 Hz, 1H), 6.46-6.40 (m, 2H), 5.43-5.27 (m, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.69 (s, 3H), 2.13-2.06 (m, 1H), 2.05-1.95 (m, 1H), 1.47 (s, 6H); MS (ESI-) m/z 488 (M-H)-.
methyl 5-[(3-phenylpropyl)amino]pentanoate[ No CAS ]
methyl 5-[2-(4-methoxyphenyl)-2-methylpropanoyl](3-phenylpropyl)amino}pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
To a solution of <strong>[2955-46-6]2-(4-methoxyphenyl)-2-methylpropanoic acid</strong> (27.3 mg, 0.140 mmol) and 1 -[bis(dimethylamino)methylene] - 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (53.4 mg, 0.140 mmol, HATU) in N,N-dimethylformamide (3 mL) was added diisopropylethylamine (0.025 mL 0.140 mmol). The resulting solution was stirred at room temperature for 10 minutes. Then Example 70-Step 1 (35 mg, 0.140 mmol) was added in one portion. The solution was stirred at room temperature overnight. It was diluted with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine 3 times, dried over anhydrous Na2504, filtered andconcentrated to give a residue which was purified by flash column chromatography on silica gel (loaded directly with CH2C12) eluted with hexanes and ethyl acetate (0-50%) to give the titled compound (50 mg, 0.117 mmol, 84% yield). LC-MS (ESI) m/z 426.2 (M+H), RT = 1.944 minutes.
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