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Structure of 25691-37-6 * Storage: {[proInfo.prStorage]}
* 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 pyridine In water; N,N-dimethyl-formamide at 20℃; Stage #2: With [bis(acetoxy)iodo]benzene In water; N,N-dimethyl-formamide for 4 h;
To a solution of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2g, 8. lmmol) in DMF: water (l : l,v/v, 18ml) was added pyridine (1.3ml, 16.2mmol). The resulting reaction mixture was stirred at room temperature for 5-10 minutes. Iodobenzene diacetate (3.92g, 12. lmmol) was added and further stirred for 4 hours. After completion of reaction D.M. water (100ml) was added and the resulting mixture was extracted with ethyl acetate (3 x 100ml). The combined organic extracts was washed with D.M. water (100ml), brine (100ml), dried over sodium sulphate and concentrated under vacuo to get the desired crude product. The crude product was purified by triturating with diethyl ether. Evaporation of the product fractions gave l .lg (yield, 62percent) of desired compound as brown solid. LC-MS: m/z = 219.1(M+H). [
62%
With pyridine; [bis(acetoxy)iodo]benzene In water; N,N-dimethyl-formamide at 20℃; for 4 h;
[00383] Step 1 : Preparation of (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid [00384] To a solution of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2g, 8. lmmol) in DMF: water (l : l,v/v, 18ml) was added pyridine (1.3ml, 16.2mmol). The resulting reaction mixture was stirred at room temperature for 5-10 minutes. Iodobenzene diacetate (3.92g, 12. lmmol) was added and further stirred for 4 hours. After completion of reaction D.M. water (100ml) was added and the resulting mixture was extracted with ethyl acetate (3 x 100ml). The combined organic extracts was washed with D.M. water (100ml), brine (100ml), dried over sodium sulphate and concentrated under vacuo to get the desired crude product. The crude product was purified by triturating with diethyl ether. Evaporation of the product fractions gave l .lg (yield, 62percent) of desired compound as brown solid. LC-MS: m/z = 219.1(M+H).
62%
Stage #1: With pyridine In water; N,N-dimethyl-formamide at 20℃; Stage #2: for 4 h;
To a solution of (S)-5-amino-2-(tert-butoxycarbo- nylamino)-5-oxopentanoic acid (2 g, 8.1 mmol) in DMF:water (1:1, v/v, 18 ml) was added pyridine (1.3 ml, 16.2 mmol). The resulting reaction mixture was stirred at room temperature for 5-10 minutes. Iodobenzene diacetate (3.92 g, 12.1 mmol) was added and further stirred for 4 hours. After completion of reaction D.M. water (100 ml) was added and the resulting mixture was extracted with ethyl acetate (3x1 00 ml). The combined organic extracts was washed with D.M. water (100 ml), brine (100 ml), dried over sodium sulphate and concentrated under vacuo to get the desired crude product. The crude product was purified by triturating with diethyl ether. Evaporation of the product fractions gave 1.1 g (yield, 62percent) of desired compound as brown solid. LC-MS:mlz=219.1 (M+H).
450 g
With [bis(acetoxy)iodo]benzene In tetrahydrofuran; water; ethyl acetate at 0 - 20℃; Large scale
Butyloxycarbonyl-L-glutamine 1.2KG, add ethyl acetate 8 liters, tetrahydrofuran 2 liters, water 5 liters, cooled to 0-5 ° C, add iodobenzene diacetate 4.5KG, at room temperature for 12-24 hours, The reaction was completed, the aqueous layer separated, the organic layer washed three times with water, the organic layer was iodobenzene recovery, the combined aqueous layer, vacuum distilled water and absolute ethanol stirred and filtered, washed twice with ethanol, drained, dried at 60 , To obtain N2-tert-butoxycarbonyl-L-2,4-diaminobutyric acid 450 g.
Reference：
[1] Synthetic Communications, 2004, vol. 34, # 6, p. 1049 - 1056
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 15, p. 4650 - 4656
[3] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 1, p. 161 - 175
[4] Patent: WO2014/151472, 2014, A1, . Location in patent: Paragraph 00340-00341
[5] Patent: WO2016/40315, 2016, A1, . Location in patent: Paragraph 00383; 00384
[6] Patent: US2016/130239, 2016, A1, . Location in patent: Paragraph 0699; 0700
[7] Journal of Organic Chemistry, 2014, vol. 79, # 20, p. 9567 - 9577
[8] Journal of the American Chemical Society, 1997, vol. 119, # 17, p. 4086 - 4087
[9] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 9, p. 1152 - 1158
[10] Synthesis (Germany), 2017, vol. 49, # 8, p. 1857 - 1866
[11] Patent: CN106916111, 2017, A, . Location in patent: Paragraph 0056; 0057; 0058; 0077
Reference：
[1] Justus Liebigs Annalen der Chemie, 1970, vol. 731, p. 152 - 180
7
[ 82911-69-1 ]
[ 25691-37-6 ]
[ 117106-21-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 1, p. 161 - 175
8
[ 28920-43-6 ]
[ 25691-37-6 ]
[ 117106-21-5 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 14, p. 4347 - 4354
9
[ 25691-37-6 ]
[ 92235-34-2 ]
Yield
Reaction Conditions
Operation in experiment
54%
With sodium hydrogencarbonate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 12 h;
[00202] (S)-tert-Ruiy\ (2-Oxopyrrolidin-3-yl)carbamate (126) To a solution of 0.60 g (2.75 mmol) of BOC-L-DAB-OH in 275 mL of DMF at a 10 mM concentration were added 1.22 g (2.75 mmol) of BOP and 1.16 g (20.0 mmol) of sodium bicarbonate. After 12 h stirring at room temperature, the mixture was concentrated to a small volume (around 5 mL) under reduced pressure. The concentrated mixture was diluted with water and saturated sodium bicarbonate solution (1 : 1, 100 mL) and extracted with three 100- mL portions of EtOAc. The combined organic extracts were washed with 200 mL of water and 200 mL of brine, dried over Na2S04, filtered, and concentrated under reduced pressure to afford a residue that crystallized upon trituration in 100 mL of ether and filtered to afford 126 as a colorless solid: yield 296 mg (54percent); mp 161-164°C (lit/ 168 - 171 °C); silica gel TLC i? 0.55 (10: 1 DCM-MeOH); 'H NMR (CDC13) δ 1.42 (s, 9H), 1.93-2.01 (m, 1H), 2.60-2.70 (m, 1H), 3.28-3.42 (m, 2H), 4.05-4.20 (m, 1H), 5.25 (s, 1H) and 6.85 (br s, 1H); 1 C NMR (CDC13) δ 28.3, 30.0, 39.2, 51.7, 79.9, 155.9 and 176.1.
Reference：
[1] Patent: WO2016/118877, 2016, A1, . Location in patent: Paragraph 00202
[2] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 18, p. 2753 - 2758
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3557 - 3571
4-[2-(3-acetoxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1<i>H</i>-cyclopenta[<i>a</i>]phenanthren-17-yl)-propionylamino]-2-<i>tert</i>-butoxycarbonylamino-butyric acid[ No CAS ]
With hydrogen; acetic acid;palladium dihydroxide; In methanol; water;
To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+H)+.
With hydrogen; acetic acid;20 % Pd(OH)2/C; In methanol; water; at 20℃;
To a suspension of Pd(OH)2, (20percent, 100 mg) , aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S) -4-amino-2- (tert- butoxycarbonylamino) butanoic acid (1 g, 4.48 mtalphaol) . The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixture was filtered through a pad of diatomaceous earth (CeI ite.(R).) , and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS : Anal. Calcd. for CnH22N2O4: 246; found: 247 (M+H) + .
With hydrogen; palladium(II) hydroxide; acetic acid; In methanol; at 20℃;
To a suspension Of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-sano~2-(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 nunol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for Cj ^22N2O4: 246; found: 247 (M+H)+.
With hydrogen; acetic acid;20% palladium(II) hydroxide on carbon; In methanol; water; at 20℃;
To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temperature. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+H]+.
With hydrogen; acetic acid;20% palladium hydroxide on carbon; In methanol; at 20℃;
Cap- 125/BocHN OH [00221] To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temperature. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC-MS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+FTf .
With hydrogen; acetic acid;20% palladium hydroxide-activated charcoal; In methanol; at 20℃;
To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixture was filtered through a pad of diatomaceous earth (Celite.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for CnH22 204: 246; found: 247 (M+H)+.
With hydrogen; palladium(II) hydroxide; acetic acid; In methanol; at 20℃;
To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) inmethanol (15 mL) was added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (1g, 4.48 mmol). The reaction waspurged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixturewas filtered through a pad of diatomaceous earth (Celite®), and the volatile component was removed in vacuo. Theresulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+H)+.
With hydrogen; acetic acid;palladium dihydroxide; In methanol;
To a suspension Of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon <n="105"/>room temp. The reaction mixture was filtered through a pad of diatomaceous earth(Celite ), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+H)+.
With hydrogen; acetic acid;palladium(II) hydroxide; In methanol; at 20℃;
To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixture was filtered through a pad of diatomaceous earth (Celite.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+H)+.
2-<i>tert</i>-butoxycarbonylamino-4-[2-(3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1<i>H</i>-cyclopenta[<i>a</i>]phenanthren-17-yl)-propionylamino]-butyric acid[ No CAS ]
[3-<i>tert</i>-butoxycarbonylamino-4-(3,6-dihydro-2<i>H</i>-pyridin-1-yl)-4-oxo-butyl]-(4-chloro-benzyl)-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached 1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled {-15 1C) water/MeOH (12 mL each} solution of (S) -4-araino-2- (tert -butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol) . A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr . Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ~ 1.0 and then heated for 2 hr at 40 "C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex .(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S) -2-ataunino-4- (diethylamino) butanoic acid as an off-white solid (1.73 g) .
NaCNBH3 ( 1.60 g, 24.2 mmol) was added in batches to a chilled (-15 0C) water/MeOH (12 mL each) solution of (S)-4-ammo-2-(terf-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached - 1.0 and then heated for 2 hr at 400C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified withDOWEX.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml OfNH4OH and 282 ml of water) to afford intermediate (S)-2-amino~4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (~15°C) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop- wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached - 1.0 and then heated for 2 hr at 400C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 niL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX.(R). 5OWX8-1OO ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-ammo-4-(dieiotahylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (-15 °C) water/MeOH (12 mL each) solution of (5)-4-amino-2-(?ert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HC1 until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 MHCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX.(R). 50WX8-100 ion- exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)- 2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
[00196] NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (-15 °C) water/MeOH (12 mL each) solution of (5)-4-amino-2-(?ert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HC1 until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 MHCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX.(R). 50WX8-100 ion- exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)- 2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (-15 °C) water/MeOH (12 mL each) solution of (5)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HC1 until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex .(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
1.73 g
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (?15 °C) water/MeOH (12 mL each) solutionof (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirredat ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirredfor 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentratedHCl until its pH reached ? 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and theresidue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile componentwas removed in vacuo and the residue was purified with Dowex ® 50WX8-100 ion-exchange resin (column was washedwith water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) toafford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (-15 "C) water/MeOH (12 mL each) solution of (5)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex .(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml OfNH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
With hydrogenchloride; ammonium hydroxide; NaCNBH3; In 1,4-dioxane; methanol; water;
Methyl iodide (56 muL, 0.90 mmol) was added and stirring was continued for 18 hr while allowing the bath to thaw to ambient condition. The reaction was quenched with water and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, and washed with methanol followed by compound elution with 2N NH3/Methanol. Removal of the volatile component in vacuo afforded Cap-75, contaminated with (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellow semi-solid (100 mg). The product was used as is without further purification. NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (~15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached~1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
With hydrogenchloride; ammonium hydroxide; NaCNBH3; In 1,4-dioxane; methanol; water;
Methyl iodide (56 muL, 0.90 mmol) was added and stirring was continued for 18 hr while allowing the bath to thaw to ambient condition. The reaction was quenched with water and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, and washed with methanol followed by compound elution with 2N NH3/Methanol. Removal of the volatile component in vacuo afforded Cap-75, contaminated with (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellow semi-solid (100 mg). The product was used as is without further purification. NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (~15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ~1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
With hydrogenchloride; ammonium hydroxide; NaCNBH3; In 1,4-dioxane; methanol; water;
Methyl iodide (56 muL, 0.90 mmol) was added and stirring was continued for 18 hr while allowing the bath to thaw to ambient condition. The reaction was quenched with water and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, and washed with methanol followed by compound elution with 2N NH3/Methanol. Removal of the volatile component in vacuo afforded Cap-75, contaminated with (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellow semi-solid (100 mg). The product was used as is without further purification. NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (~15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ~1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was elated with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
With hydrogenchloride; ammonium hydroxide; NaCNBH3; In 1,4-dioxane; methanol; water;
Methyl iodide (56 muL, 0.90 mmol) was added and stirring was continued for 18 hr while allowing the bath to thaw to ambient condition. The reaction was quenched with water and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, and washed with methanol followed by compound elution with 2N NH3/Methanol. Removal of the volatile component in vacuo afforded Cap-75, contaminated with (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellow semi-solid (100 mg). The product was used as is without further purification. NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (~15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ~1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (-15 °C) water/MeOH (12 mL each) solution of (5)-4-amino-2-(?ert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HC1 until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (-15 "C) water/MeOH (12 mL each) solution of (5)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex .(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml OfNH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (15° C.) water/MeOH (12 mL each) solution of (5)-4-amino-2-(tert-butoxycarbonylarnino)butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached 1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex.(R). 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).
With formaldehyd; hydrogen; acetic acid;palladium(II) hydroxide; In methanol; at 20℃;
To a suspension Of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0,5 mL) in methanol (15 mL) was added (S)-4-amino-2~(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temp. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal Calcd. for C j 1H22N2O4: 246; found: 247 (M+H)+.
With formaldehyd; hydrogen; acetic acid;palladium(II) hydroxide; In methanol; water; at 20℃;
To a suspension of Pd(OH)2, (20percent, 100 mg), aqueous formaldehyde (37percent wt, 4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added (S)-4-amino-2-(tert- butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol). The reaction was purged several times with hydrogen and was stirred overnight with an hydrogen balloon room temperature. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE.(R).), and the volatile component was removed in vacuo. The resulting crude material was used as is for the next step. LC/MS: Anal. Calcd. forCiiH22N204: 246; found: 247 (M+H)+.
(S)-tert-butyl 1-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]-pyridin-2-yl)pyridin-3-yl)methyl)-2-oxopyrrolidin-3-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaOH; NaBH(OAc)3; acetic acid; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Step 1.(S)-tert-butyl 1-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]-pyridin-2-yl)pyridin-3-yl)methyl)-2-oxopyrrolidin-3-ylcarbamate (107)To a suspension of 47 (230 mg, 0.51 mmol, scheme 15) in DCM (5.1 mL) were added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (224 mg, 1.03 mmol) and acetic acid (59 mul, 1.03 mmol).After stirring for 20 min at room temperature, NaBH(OAc)3 (326 mg, 1.54 mmol) was added.The reaction mixture was stirred for 16 h, quenched by addition of 1N NaOH, and concentrated.The solid was collected by filtration and purified by Biotage (SNAP 50 g cartridge; MeOH/DCM:0/100 to 20/80 over 20 CV), to afford the title compound 107 (120 mg, 0.19 mmol, 37percent yield). MS (m/z): 633.7 (M+H).
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