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Reference：
[1] Organic Process Research and Development, 2015, vol. 19, # 1, p. 132 - 138
[2] Organic Process Research and Development, 2015, vol. 19, # 1, p. 132 - 138
[3] Organic Process Research and Development, 2015, vol. 19, # 1, p. 132 - 138
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Reference：
[1] Organic Process Research and Development, 2015, vol. 19, # 1, p. 132 - 138
[00277] In a 5L RB flask dissolved t-butyl glycine (74 g, 0.56 mol, 1.02 eq.) in saturated sodium bicarbonate (11 vol). Cyclopentyl 2,5-dioxopyrrolidin-l-yl carbonate (126 g, 0.55 mol, 1 eq.) was dissolved in acetone (5.5 vol) and the solution slowly added via addition funnel at room temperature to the solution of the glycine. The reaction mixture was stirred at room temperature until complete (approximately 4 hours). The acetone was removed under reduced pressure and the remaining aqueous solution was extracted with 30% ethyl acetate in hexanes (thrice, 5.5 vol each). The organic layers were discarded. The pH of EPO <DP n="293"/>the aqueous layer was adjusted to 2 with 2 N HCl and then extracted with ethyl acetate(thrice, 5.5 vol). The combined organic layers were dried (Na2SO4), filtered, and the solvent removed under reduced pressure to provide a clear oil the slowly crystallized. The crude product was crystallized from hexanes/ethyl acetate to provide (S)-2- (cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid as a white solid (82 g). The mother liquid was stripped and a second crop of crystals obtained (combined yield 105.54 g, 79% yield).
With triethylamine; In tetrahydrofuran; water; at 18 - 22℃; for 2.5h;
THF (350 mL) was added to a flask containing carbonic acid cyclopentyl ester 2,5- DIOXO-PYRROLIDIN-1-YL ester (9.00 g; 39.6 MMOL) and TERT-BUTYL GLYCINE (6.24 g; 47.5 MMOL) resulting in a suspension. Distilled water (100 mL) was added with vigorous stirring. A small amount of solid remained undissolved. Triethylamine (16.6 mL; 119 MMOL) was then added resulting in a homogenous solution which was stirred at R. T. After 2.5 h, the THF was evaporated and the aqueous residue diluted with water (100 mL). The reaction was rendered basic by the addition of 1 N NAOH (25 ML-FINAL pH >10). The solution was washed with EtOAc (2X 200 mL) and the aqueous phase acidified with 1 N HCI (ca. 70 mL-final pH <2). The turbid solution was extracted with EtOAc (200 + 150 mL). The extract was dried (MGS04) and evaporated to give carbamate 4a as a white solid (8.68 g).
With triethylamine; In tetrahydrofuran; water; at 20℃; for 2.5h;
THF (350 mL) was added to a flask containing <strong>[128595-07-3]carbonic acid cyclopentyl ester 2,5-dioxo-pyrrolidin-1-yl ester</strong> (9.00 g; 39.6 mmol) and tert-butyl glycine (6.24 g; 47.5 mmol) resulting in a suspension. Distilled water (100 mL) was added with vigorous stirring. A small amount of solid remained undissolved. Triethylamine (16.6 mL; 119 mmol) was then added resulting in a homogenous solution which was stirred at R.T. After 2.5 h, the THF was evaporated and the aqueous residue diluted with water (100 mL). The reaction was rendered basic by the addition of 1 N NaOH (25 mL-final pH >10). The solution was washed with EtOAc (2×200 mL) and the aqueous phase acidified with 1 N HCl (ca. 70 mL-final pH <2). The turbid solution was extracted with EtOAc (200+150 mL). The extract was dried (MgSO4) and evaporated to give carbamate 2a as a white solid (8.68 g).
With triethylamine; In tetrahydrofuran; water; at 20℃; for 2.5h;
The P3 carbamate fragment 1a was prepared as described in WO 03/064416. THF(350mL) was added to a flask containing <strong>[128595-07-3]carbonic acid cyclopentyl ester 2,5-dioxo-pyrrolidin-1-yl ester</strong> (Q.OOg; 39.6mmol) and terf-butyl glycine (6.24g; 47.5mmol)resulting in a suspension. Distilled water (100mL) was added with vigorous stirring. Asmall amount of solid remained undissolved. Triethylamine (16.6ml 119mmol) wasthen added resulting in a homogenous solution which was stirred at R.T. After 2.5h,the THF was evaporated and the aqueous residue diluted with water (100ml_). Thereaction was rendered basic by the addition of 1 N NaOH (25mL - final pH >10). Thesolution was washed with EtOAc (2 x 200ml_) and the aqueous phase acidified with 1N HCI (ca. 70ml final pH <2). The turbid solution was extracted with EtOAc (200 + 150mL). The extract was dried (MgSO4) and evaporated to give carbamate 1a as a white solid (8.68g).
[0312] In a 5L RB flask dissolved t-butyl glycine (74 g, 0.56 mol, 1.02 eq.) in saturated sodium bicarbonate (11 vol). Cyclopentyl 2,5-dioxopyrrolidin-l-yl carbonate (126 g, 0.55 mol, 1 eq.) was dissolved in acetone (5.5 vol) and the solution slowly added via addition funnel at room temperature to the solution of the glycine. The reaction mixture was stirred at room temperature until complete (approximately 4 hours). The acetone was removed under reduced pressure and the remaining aqueous solution was extracted with 30% ethyl acetate in hexanes (thrice, 5.5 vol each). The organic layers were discarded. The pH of the aqueous layer was adjusted to 2 with 2 N HCl and then extracted with ethyl acetate (thrice, 5.5 vol). The combined organic layers were dried (Na2SO4), filtered, and the solvent removed under reduced pressure to provide a clear oil the slowly crystallized. The crude product was crystallized from hexanes/ethyl acetate to provide (S)-2-(cyclopentyloxycarbonylamino)-3,3- dimethylbutanoic acid as a white solid (82 g). The mother liquid was stripped and a second crop of crystals obtained (combined yield 105.54 g).
To a solution of L-tert-leucine (2 g, 15.25 mmol) dissolved in CH3CN (50 mL) was added TMSCN (7.06 mL, 56.41 mmol) and stirred for 15 min. The reaction mixture was heated to75 C for 30 min. Cyclopentyl chloroformate (2.83 g, 19.06 mmol) was added to the reaction mixture and the reaction mixture was heated at80 C overnite, concentrated in vacuo. The residue was treated with MeOH (40 mL), stirred for 10 min, and concentrated in vacuo. The residue was adjusted pH to 8.5, and extracted with Et20(2x200mL). The aqueous layer was acidified to pH 3 and extracted withCH2CI2 (2x200mL). The combined extract was dried(MgS04), and concentrated in vacuo. The residue was recrystallized from minimal amount of Et20/hexanes to afford the product 3.48 g (94%):'H NMR (500 MHz, methanol-d4) S ppm 1.00 (s, 9 H), 1.59 (m, 2 H), 1.73 (m, 4 H), 1.84 (dd, J=5. 95,3. 20 Hz, 2 H), 3.98 (s, 1 H), 5.02(m, 1 H).
94%
Step 63d: Preparation of (L)-2-Cyclopentyloxycarbonylamino-3,3-dimethyl-butyric Acid To a solution of L-tert-leucine (2 g, 15.25 mmol) dissolved in CH3CN (50 mL) was added TMSCN (7.06 mL, 56.41 mmol) and stirred for 15 min. The reaction mixture was heated to 75 C. for 30 min. Cyclopentyl chloroformate (2.83 g, 19.06 mmol) was added to the reaction mixture and the reaction mixture was heated at 80 C. overnite, concentrated in vacuo. The residue was treated with MeOH (40 mL), stirred for 10 min, and concentrated in vacuo. The residue was adjusted pH to 8.5, and extracted with Et2O (2*200 mL). The aqueous layer was acidified to pH 3 and extracted with CH2Cl2 (2*200 mL). The combined extract was dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from minimal amount of Et2O/hexanes to afford the product 3.48 g (94%): 1H NMR (methanol-d4) ppm 1.00 (s, 9H), 1.59 (m, 2H), 1.73 (m, 4H), 1.84 (dd, J=5.95, 3.20 Hz, 2H), 3.98 (s, 1 H), 5.02 (m, 1 H).
In tert-butylaminoacetic acid; sodium hydrogencarbonate; acetone;
Preparation of (S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid In a 5 L RB flask dissolved t-butyl glycine (74 g, 0.56 mol, 1.02 eq.) in saturated sodium bicarbonate (11 vol). Cyclopentyl 2,5-dioxopyrrolidin-1-yl carbonate (126 g, 0.55 mol, 1 eq.) was dissolved in acetone (5.5 vol) and the solution slowly added via addition funnel at room temperature to the solution of the glycine. The reaction mixture was stirred at room temperature until complete (approximately 4 hrs). The acetone was removed under reduced pressure and the remaining aqueous solution was extracted with 30% ethyl acetate in hexanes (thrice, 5.5 vol each). The organic layers were discarded. The pH of the aqueous layer was adjusted to 2 with 2 N HCl and then extracted with ethyl acetate (thrice, 5.5 vol). The combined organic layers were dried (Na2SO4), filtered, and the solvent removed under reduced pressure to provide a clear oil the slowly crystallized. The crude product was crystallized from hexanes/ethyl acetate to provide (S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid as a white solid (82 g). The mother liquid was stripped and a second crop of crystals obtained (combined yield 105.54 g).
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