* 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.
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
A) (S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with Q dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2- amino-l-methyl-ethyl)-carbamic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, / 5 = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
36%
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water
A) ((S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2-amino-l-methyl-ethyl)-carbarnic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
With sodium hydroxide In methanol; water at 20℃; for 20 h; Inert atmosphere; Cooling with ice
To a solution of (S)-1,2-diaminopropane dihydrochloride (16 g, 109 mmol) in MeOH (64 mL) and water (16 mL) was added di-tert-butyl dicarbonate (28.5 g, 131 mmol) in MeOH (16 mL). The resulting solution was cooled in an ice bath, and 4N NaOH (35 mL, 140 mL) was added dropwise over 2 h. The mixture was allowed to warm to rt and stirred for a total of 20 h. The reaction was filtered, and the filtrate concentrated to remove MeOH. 200 mL EtOAc, 200 mL water, and 16 mL 1M HCl were added sequentially. The layers were separated and the aqueous layer washed with EtOAc (200 mL). The combined organic extracts were washed with 0.04M HCl (208 mL). The organic phase was separated and discarded. The aqueous phases were combined, adjusted to pH=14 with 10N NaOH (20 mL), and extracted with DCM (400 mL*2). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the desired product as a clear oil (8.0 g, 42percent). MS (ESI): mass calcd. for C8H18N2O2, 174.1; m/z found, 175.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 5.01 (br s, 1H), 3.24-3.09 (m, 1H), 3.09-2.95 (m, 1H), 2.92-2.84 (m, 1H), 1.45 (s, 9H), 1.35-1.19 (m, 2H), 1.07 (d, J=6.4 Hz, 3H).
Reference：
[1] Patent: US2014/275096, 2014, A1, . Location in patent: Paragraph 0126; 0147
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 257 - 261
[3] European Journal of Pharmacology, 2015, vol. 765, p. 551 - 559
3
[ 15967-72-3 ]
[ 121103-15-9 ]
[ 146552-71-8 ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
A) (S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with Q dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2- amino-l-methyl-ethyl)-carbamic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, / 5 = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
36%
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water
A) ((S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2-amino-l-methyl-ethyl)-carbarnic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
Reference：
[1] Journal of Combinatorial Chemistry, 2010, vol. 12, # 2, p. 248 - 254
7
[ 1299490-85-9 ]
[ 121103-15-9 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7312 - 7315
8
[ 1299491-18-1 ]
[ 121103-15-9 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7312 - 7315
[2] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7312 - 7315
9
[ 24424-99-5 ]
[ 121103-15-9 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7312 - 7315
[2] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7312 - 7315
(5)-(-)-l,2-Diaminopropane dihydrochloride (6.94 g, 47.2 mmol) was suspended in 300 mL of dry CH2Cl2, treated with l,8-diaxabicyclo[5,4,0]undec-7-ene (15.5 mL, 103.8 <n="104"/>mmol), and cooled to 0 0C under an atmosphere of N2. Di-tert-butyl dicarbonate (10.29 g, 47.2 mmol) was dissolved in 100 mL of dry CH2Cl2 and was slowly added into the reaction via cannula. The reaction was kept cool for another hour before allowing it to warm to ambient temperature overnight. The reaction was then treated with 200 mL of acetic acid (10%), and the layers were separated. The organic layer was dried overNa2SO4, filtered, and concentrated under reduced pressure to give a white solid (5.51 g). This material was suspended in 50 mL of HCl/ethanol (3.0 M) and heated to 60 0C for 30 minutes. The solution was allowed to cool to ambient temperature, and the white precipitate was filtered off to cleanly give back (5)-(-)-l,2-diaminopropane dihydrochloride (2.0Og, 13.6 mmol). This material was resubmitted to the reaction conditions, and the aqueous phases from both reactions were combined and made basic with concentrated ammonium hydroxide, until the pH ~11. The aqueous layer was extracted with CH2Cl2 (6 x 150 mL). The combined organic layers were washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure to give a light yellow oil (2.40 g). Chromatography (SiO2, 40-60% CMA/CHC13) afforded tert- butyl (25)-2-aminopropylcarbamate (2.14 g) as a light yellow oil.
tert-butyl (2S)-2-[(3-nitroquinolin-4-yl)amino]propylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃;
A solution of tert-bvAy (25)-2-aminopropylcarbamate (2.14 g, 12.28 mmol) in 120 mL of dry CH2Cl2 was cooled to 0 0C and treated with 3-chloro-4-nitroquinoline (2.56 g, 12.28 mmol) and triethylamine (3.4 mL, 25 mmol) under an atmosphere of N2. The reaction was allowed to slowly warm to ambient temperature overnight. It was then treated with 100 mL of H2O (2x) followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-bvlambday (25)-2-[(3- nitroquinolin-4-yl)amino]propylcarbamate (4.10 g) as a bright yellow solid.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 0℃; for 2.0h;
Example 23; (1 IS)-I l-Methyl-9-(methylsulfonyl)-8,9,10,l l-tetrahydropyrazino[r,2':l,2]imidazo[4,5- c] quinolin-6-amine; Part A; (£)-(-)- 1,2-Diaminopropane (2.00 g, 13.6 mmol) and l,8-diaxabicyclo[5.4.0]undec- 7-ene (DBU) (4.46 mL, 28.8 mmol) were dissolved in dichloromethane (50 mL) and the solution was cooled to 0 0C under N2. In another flask, di-tert-butyl dicarbonate (2.96 g, 13.6 mmol) was dissolved in dichloromethane (50 mL), and the solution was slowly added to the reaction mixture via cannula. After stirring for 2 hours, the reaction mixture was treated with H2O (50 mL) and the layers were separated. The organic portion was discarded and the aqueous portion was made basic by the addition of 3 mL of concentrated, aqueous NH4OH solution and then extracted with CH2Cl2 (5 x 250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 7% MeOHZCHCl3 saturated with concentrated, aqueous NH40H solution) afforded tert-bupsilontyl (25)-2-aminopropylcarbamate (0.50 g) as a colorless liquid.
Part B; A suspension of 3-chloro-4-nitroquinoline (3.04 g, 14.5 mmol) in dichloromethane(150 mL) was treated with triethylamine (4.5 mL, 32.02 mmol) and the reaction mixture was cooled to 0 C under an atmosphere of N2. In a separate flask, tert-bntyl (2S)-2- aminopropylcarbamate (2.79 g, 16.0 mmol) was dissolved in dichloromethane (50 mL) and the solution was added into the reaction via cannula. The reaction was allowed to EPO <DP n="141"/>slowly warm to ambient temperature overnight. The reaction mixture was then washed successively with water (2 x 150 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to yield tert-butyl (2S)-2-[(3-nitroquinolin-4- yl)amino]propylcarbamate (5.04 g) as a bright yellow solid.
A) (S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with Q dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the sub-title compound (211 mg, 36 % yield) and the by-product ((S)-2- amino-l-methyl-ethyl)-carbamic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) delta(ppm) 1.09 (d, 3H, / 5 = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
36%
A) ((S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the the sub-title compound (211 mg, 36 % yield) and the by-product ((S)-2-amino-l-methyl-ethyl)-carbarnic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) delta(ppm) 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
6-(4-((S)-4-((E)-2-(5-chlorothiophen-2-yl)-ethenesulfonyl)-2-methyl-6-oxopiperazin-1-ylmethyl)-piperidin-1-yl)-2-methyl-2H-pyridazin-3-one[ No CAS ]
6-(4-((S)-4-((E)-2-(5-chlorothiophen-2-yl)-ethenesulfonyl)-5-methyl-2-oxopiperazin-1-ylmethyl)-piperidin-1-yl)-2-methyl-2H-pyridazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 16. i) 6-(4-{(S)-4-[(E)-2-(5-chloro-thiophen-2-yI)-ethenesulfonyl]-2-methyl-6-oxo- pip erazin-1 -ylmethyl} -piperidin-1 -yl)-2-methyI-2H-pyridazin-3 -one and ii) 6-(4-{(S)-4-[(E)-2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-5-methyl-2-oxo-pipera- zin-l-ylmethyl}-piperidin-l-yl)-2-methyl-2H-pyridazin-3-oneA) i) ((S)-2-{ri-(l-methyl-6-oxo-l,6-dihvdro-pyridazin-3-yl)-piperidin-4-ylmethyn- amino) -propyl)- carbamic acid tert-butyl ester and ) ((S)- 1 -methyl-2- { [".-( l-niethyl-6-oxo- 1 ,6-dihvdro-pyridazin-3-yl)-piperidin-4- ylmethyll-aminol-ethvD-carbamic acid tert- butyl ester. To a solution of ((S)-2-amino-propyl)-carbamic acid tert-butyl ester (1.27 g, 7.12 rnmol) in anhydrous dichloromethane (37 mL) was added l-(l-methyl-6-oxo-l,6-dihydro-pyridazin- 3-gammal)-piperidine-4-carbaldehyde (1.25 g, 5.65 mmol) under nitrogen. After stirring the resulting mixture at room temperature for 40 minutes, sodium triacetoxyborohydride (3.2 g, 15 mmol) was added and the mixture was stirred for 90 minutes. The reaction flask was cooled to 0 C, and the reaction mixture was quenched by adding water. Dichloromethane was evaporated under reduced pressure and the aqueous phase was freeze dried over night. The residue was suspended in dichloromethane, filtered and the solution was evaporated to dryness. The crude product was purified by column chromatography on silica gel using dichloromethane / methanol (100 : 10 and 100 : 20) as eluent to give 2.14 g (99 %) of the sub-title products as a mixture. The mixture was used in the next step without separation of the two sub-title products.B) iH(SV2-|(2-chloro-aceryl)-ri-('l-methyl-6-oxo-l,6-dihvdro-pyridazin-3-yl)- piperidin-4-ylmethvn-amino}-propyl)-carbamic acid tert-butyl ester and ii) (fS)-2- { (2- chloro- acetyl)- Fl-(I -methyl- 6- oxo -1,6- dihydro-pyridazin- 3 - gammal)- piperidin-4-ylmethyl1-ammo)-l-memyl-ethyl)-carbamic acid tert-butyl esterTo a solution of the sub-title products from step A, i.e. i) ((S)-2-[l-(l-methyl-6-oxo-l,6- dihydro-pyridazm-3-yl)-piperidin-4-ylmethyl]-amino}-propyl)-carbamic acid tert-butyl ester and ii) ((S)-l-methyl-2-[l-(l-methyl-6-oxo-l,6-dihydro-pyridazin-3-yl)-piperidin-4- ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester, (1.7 g, 4.8 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (1.7 mL, 12 mmol) at 0 0C dropwise under nitrogen. A solution of bromoacetyl chloride (0.66 g, 5.8 mmol) in anhydrous dichloromethane (7 mL) was added at 0 C dropwise to the mixture, and the reaction mixture was stirred at room temperature for 1 hour. The reaction flask was cooled to 0 0C, and water/dichloromethane was added. The organic phase was separated, washed with brine, dried and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane / methanol (100 : 4) as eluent to give 0.91 g (42 %) of the sub-title products as a mixture. The mixture was used in the next step without separation of the two the sub-title products.C) i) N-f(S)-2-amino-l-methyl-ethyl)-2-chloro-N-ri-("l-methyl-6-oxo-l,6-dihvdro- pyridazin-3-yl)-piperidin-4-ylmemyl"l-acetamide hydrochloride andii) N-rfS)-2-amino-propyl)-2-chloro-N-ri-(l-methgammal-6-oxo-l,6-dihvdro-pyridazin- 3-yl)-piperidin-4-ylmethyll-acetamide hydrochlorideTo a solution of the sub-title products from step B, i.e. i) ((S)-2- {(2-chloro- acetyl)- [1 -(I - methyl- 6-oxo- 1 ,6-dihydro-pyridazin- 3 -yl)-piperidin-4-ylmethyl]- amino } -propyl) -carbamic acid tert-butyl ester and ii) ((S)-2-{(2-chloro-acetyl)-[l-(l-methyl-6-oxo-l,6-dihydro- pyridazin-3-yl)-piperidin-4-ylmethyl]-amino}- l-methyl-ethyl)-carbamic acid tert-butyl ester, (0.91 g, 1.99 ralphamol) in methanol (25 mL) was added a saturated methanolic hydrogen chloride (50 mL) at 0 0C. After stirring at room temperature for 11 hour, the solution was evaporated to dryness to give 0.73 g (93 %) of the sub-title products. The mixture of the sub -title products was used in the next step without separation of the two sub-title products.D) i) 2-Methyl- 6- F4-f (S)- 2-methyl-6-oxo-piperazin- 1 - ylmethvD-piperidin- 1 -yl1-2H- pyridazin-3-one and ) 2-methyl-6-r4-((S)-5-methyl-2-oxo-piperazin-l-ylmethyl)-piperidin-l-ylI-2H- pyridazin-3-oneTo a solution of the sub-title products from step C, i.e. i)iV-((S)-2-amino-l-methyl-ethyl)- 2-chloro-iV-[l-(l-methyl-6-oxo-l,6-dihydro-pyridazin-3-yl)-rhoirhoeridin-4-ylmethyl]- acetamide hydrochloride and ii) iV-((S)-2-amino-propyl)-2-chloro-iV-[l-(l-methyl-6-oxo- l,6-dihydro-pyridazin-3-yl)-piperidin-4-ylmethyl]- acetamide hydrochloride, (0.73 g, 1.86 rnmol) in anhydrous N,Lambda/"-dimethylformamide (9 mL) was added triethylamine (2 mL) at 0 ? C under nitrogen. After stirring at room temperature for 8 hours, the solution evaporated to dryness and the crude product was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (5 : 95 to 40 : 60) as eluent to give 30 mg (5 %) of the sub-title products. The mixture of the sub-tit...
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;
C) ( (S)-2-(4-( l-Methyl-6-oxo-1,6-dihvdro-pyridazin-3-yl)-benzylamino)-propyl)-carbamic acid tert-butyl ester: To a solution of 4-(l-methyl-6-oxo-l,6-dihydro-pyridazin-3-yl)benzaldehyde (300 mg, 1.40 mmol) from step B in dry dichloromethane was added ((S)-2-amino-propyl)carbamic acid tert-butyl ester (211 mg, 1.21 mmol) from step A. Acetic acid (160 muL, 2.80 mmol) was added dropwise under stirring followed by addition of sodium triacetoxyborohydride (712 mg, 3.36 mmol) and stirring over night at room temperature. Purification by preparative HPLC gave a mixture of products with the sub-title compound (120 mg, 23 %) being the major product. The material was used directly in the next step.
23%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;
C) { (S)-2-[4-(l -Methyl-6-oxo-l ,6-dihvdro-pyridazin-3-yl)-benzylamino1-propyl } - carbamic acid tert-butyl ester: To a solution of 4-(l-methyl-6-oxo-l,6-dihydro-rhoyridazin-3-yl)benzaldehyde (300 mg, 1.40 mmol) from step B in dry dichloromethane was added ((S)-2-amino-propyl)carbamic acid tert-butyl ester (211 mg, 1.21 mmol) from step A. Acetic acid (160 muL, 2.80 mmol) was added dropwise under stirring followed by addition of sodium triacetoxyborohydride (712 mg, 3.36 mmol) and stirring over night at room temperature. Purification by preparative HPLC gave a mixture of products with the sub-title compound (120 mg, 23 %) being the major product. The material was used directly in the next step.
With sodium hydroxide; In methanol; water; at 20℃; for 20h;Inert atmosphere; Cooling with ice;
To a solution of (S)-1,2-diaminopropane dihydrochloride (16 g, 109 mmol) in MeOH (64 mL) and water (16 mL) was added di-tert-butyl dicarbonate (28.5 g, 131 mmol) in MeOH (16 mL). The resulting solution was cooled in an ice bath, and 4N NaOH (35 mL, 140 mL) was added dropwise over 2 h. The mixture was allowed to warm to rt and stirred for a total of 20 h. The reaction was filtered, and the filtrate concentrated to remove MeOH. 200 mL EtOAc, 200 mL water, and 16 mL 1M HCl were added sequentially. The layers were separated and the aqueous layer washed with EtOAc (200 mL). The combined organic extracts were washed with 0.04M HCl (208 mL). The organic phase was separated and discarded. The aqueous phases were combined, adjusted to pH=14 with 10N NaOH (20 mL), and extracted with DCM (400 mL*2). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the desired product as a clear oil (8.0 g, 42%). MS (ESI): mass calcd. for C8H18N2O2, 174.1; m/z found, 175.2 [M+H]+. 1H NMR (500 MHz, CDCl3) delta 5.01 (br s, 1H), 3.24-3.09 (m, 1H), 3.09-2.95 (m, 1H), 2.92-2.84 (m, 1H), 1.45 (s, 9H), 1.35-1.19 (m, 2H), 1.07 (d, J=6.4 Hz, 3H).
(6S)-tert-butyl (2-((2-chloro-3-(trifluoromethyl)benzyl)amino)propyl) carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
A solution of <strong>[121103-15-9](S)-tert-butyl(2-aminopropyl)carbamate</strong> (4.0 g, 23 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde (4.8 g, 23 mmol) in DCE (100 mL) was stirred at rt for 2 h. Sodium triacetoxyborohydride (7.3 g, 34 mmol) was added at once and stirring continued overnight. Saturated aqueous NaHCO3 was added, and the resulting mixture was extracted with DCM (*2). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a clear oil. Purification by chromatography (SiO2; hex-60% EtOAc/hex) provided the desired product as a clear oil (7.2 g, 85%). MS (ESI): mass calcd. for C16H22ClF3N2O2, 366.1; m/z found, 367.2 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 7.72-7.56 (m, 2H), 7.35 (t, J=7.7 Hz, 1H), 4.94 (s, 1H), 3.99 (d, J=14.1 Hz, 1H), 3.90 (d, J=14.1 Hz, 1H), 3.29-3.14 (m, 1H), 3.11-2.99 (m, 1H), 2.84 (dd, J=11.1, 6.2 Hz, 1H), 1.44 (s, 9H), 1.11 (d, J=6.4 Hz, 3H).
2-fluoro-4-(5-fluoropyrimidin-2-yl)benzaldehyde[ No CAS ]
C19H22F2N4O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In ethanol; for 2.0h;Reflux;
A mixture of the intermediate 3 (0.40 g, 1.82 mmol) and <strong>[121103-15-9](S)-tert-butyl (2-aminopropyl)carbamate</strong> (intermediate 4, 0.32 g, 1.82 mmol, prepared according to literature: Pittelkow, M. et al Synthesis 2002, 2195-2202) in absolute ethanol (5 mL) containing 1 drop of glacial acetic acid was heated at reflux for two hours. After cooling to room temperature, solvent was removed in vacuo. The residue was dissolved in methanol (10 mL), cooled in an ice-water bath, treated with solid sodium borohydride (173 mg, 4.57 mmol) for 20 min. It was quenched by addition of water (20 mL). The mixture was extracted with ethyl acetate (25 mL x 3). The organic layer was dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the crude which was purified by flash column (silica gel, dichloromethane/methanol/NH40H = 97:3;0.1) to obtain intermediate 6 as an oil (0.5 g).
General procedure: A mixture of the intermediate 3 (0.40 g, 1.82 mmol) and <strong>[121103-15-9](S)-tert-butyl (2-aminopropyl)carbamate</strong> (intermediate 4, 0.32 g, 1.82 mmol, prepared according to literature: Pittelkow, M. et al Synthesis 2002, 2195-2202) in absolute ethanol (5 mL) containing 1 drop of glacial acetic acid was heated at reflux for two hours. After cooling to room temperature, solvent was removed in vacuo. The residue was dissolved in methanol (10 mL), cooled in an ice-water bath, treated with solid sodium borohydride (173 mg, 4.57 mmol) for 20 min. It was quenched by addition of water (20 mL). The mixture was extracted with ethyl acetate (25 mL x 3). The organic layer was dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the crude which was purified by flash column (silica gel, dichloromethane/methanol/NH40H = 97:3;0.1) to obtain intermediate 6 as an oil (0.5 g).
5-amino-2-methylsulfanyl-1,3-thiazole-4-carboxylic acid[ No CAS ]
{(S)-2-[(5-amino-2-methylsulfanyl-1,3-thiazole-4-carbonyl)amino]propyl}-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.29 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; at 20℃; for 72.0h;
5-amino-2-methylsulfanyl--1,3-DMF solution of thiazole-4-carboxylic acid (1.50g) (33mL), was synthesized in US2010 / 22518A1 describedmethods ((S) -2- amino-propyl ) - carbamic acid tert- butyl ester (1.65 g), N, N-diisopropylethylamine (1.92 mL), and EDC hydrochloride (2.12 g) andHOBt monohydrate (1.49 g) was added, the reaction mixture It was stirred at room temperature for 3 days. Water was added to the reaction mixture,the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.The residue was purified by silica gel column chromatography, and purified by (solvent: hexane / ethyl acetate = 70 / 30-20 / 80) to give the titlecompound (2.29 g).MS (ESI) M / Z; 347 [M Tasu H] Tasu
With triethylamine; In dichloromethane; toluene; at 0 - 20℃; for 5.0h;
At 0 C,The hydrochloride salt of Compound B-3 (0.5 g, 2.4 mmol),Triethylamine (0.73g, 7.2mmol) was addedIn a solution of dichloromethane (10 ml),Add one step of the toluene solution of compound B-2.After the addition, the reaction was carried out at room temperature for 5 h.The reaction was quenched by the addition of water (10 ml).Extracted with dichloromethane (20ml × 3),Combine the organic phase,Dry over anhydrous sodium sulfate,Concentrate for column separation (eluent:Petroleum ether/ethyl acetate (v/v) = 4:1),Obtained 0.45 g of a white solid product.The yield was 80%.
(2R)-4-amino-2-(octanoylamino)-4-oxobutanoic acid[ No CAS ]
tert-butyl N-[(2S)-2-[[(2R)-4-amino-2-(octanoylamino)-4-oxo-butanoyl]amino]propyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 12.25h;
A mixture of (2R)-4-amino-2-(octanoylamino)-4-oxo-butanoic acid (50 mg, 194 pmol, 1 equiv.), EDCI (41 mg, 213 mitioI, 1 .1 equiv.), <strong>[121103-15-9]tert-butyl N-[(2S)-2-aminopropyl]carbamate</strong> (41 mg, 232 mitioI, 36 pL, 1 .2 equiv.) in DMF (2 mL) was cooled to 0 C. HOBt (29 mg, 213 mitioI, 1 .1 equiv.) and TEA (43 mg, 426 mitioI, 59 m_, 2.2 equiv.) was added to the mixture and the reaction mixture was stirred at 0 aC for 15 min and was stirred at 25 C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by prep-HPLC (column: Luna C18 100*30mm 5um;mobile phase: [water(0.1 %TFA)-ACN];B%: 25%-55%,12min) to give tert-butyl N-[(2S)-2-[[(2R)-4- amino-2- (octanoylamino)-4-oxo-butanoyl]amino]propyl]carbamate (40 mg, 50%) as a white solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
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