(4R)-3-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-thiazolidine-4-carboxylic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution in DMF (10 mL) of N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid (777 mg, 3.33 mmol), prepared as in Example 164A, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (602 mg, 3.69 mmol), and ethyl dimethylaminopropyl carbodiimide hydrochloride (709 mg, 3.70 mmol) was added N,O-dimethylhydroxylamine hydrochloride (357 mg, 3.66 mmol) and 4-methylmorpholine (0.44 mL, 4.01 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and extracted with aqueous 1M H3PO4 (2×), saturated aqueous NaHCO3 (2×), and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (2:1 hexane-ethyl acetate) gave N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid-N-methoxy-N-methyl amide (605 mg) as a thick yellow oil. extracted with aqueous 1M H3PO4 (2×), saturated aqueous NaHCO3 (2×), and brine The organic phase was dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The desired compound was prepared by coupling of N-tert-butoxycarbonyl-(R)-(−) thiazolidine-4-carboxylic acid, prepared as in Example 164A with [4-amino-2-phenylbenzoyl]methionine methyl ester (compound 8) according to the method of Example 163D.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3.0 g (12.9 mmol) of Boc-Thz-OH and 2.15 ml (15.5 mmol) of triethylamine in 25 ml of DMF, 2.02 ml (15.5 mmol) of isobutyl chloroformate was added dropwise at -15° C. After stirring for 10 min at that temperature. 4.06 ml (38.7 mmol) of tert-butylamine was added. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling, concentrated under reduced pressure, diluted with 50 ml of ethyl acetate, washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure to give 3.13 g (Y. 84%) of Boc-Thz-NH-tBu which was convened to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 2-5 of Example 3. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling concentrated under reduced pressure diluted with 50 ml of ethyl acetate washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively dried over Na2SO4 evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3.0 g (12.9 mmol) of Boc-Thz-OH and 2.15 ml (15.5 mmol) of triethylamine in 25 ml of DMF, 2.02 ml (15.5 mmol) of isobutyl chloroformate was added dropwise at -15° C. After stirring for 10 min at that temperature. 4.06 ml (38.7 mmol) of tert-butylamine was added. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling, concentrated under reduced pressure, diluted with 50 ml of ethyl acetate, washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure to give 3.13 g (Y. 84%) of Boc-Thz-NH-tBu which was convened to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 2-5 of Example 3. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling concentrated under reduced pressure diluted with 50 ml of ethyl acetate washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively dried over Na2SO4 evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A was prepared from (4R)-3-(tert-butoxycarbonyl)-1,3-thiazolidine-4-carboxylic acid (5.30 g, 22.7 mmol) and Meldrum's acid according to the previously described procedure used for Example 1C, giving the title compound as yellow solid (7.31 g, 89%). LCMS m/z 358 (M−H). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 5.88 (m, 1H), 4.80–4.51 (m, 3H), 369 (m, 1H), 3.05 (m, 1H), 2.0–1.8 (m, 3H), 1.8–1.7 (m, 6H), 1.44 (s, 5H), 1.38 (s, 4H) ppm.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Deprotection of 94 mg of the compound obtained by the process 1 was performed similarly to that in Example 30 (Process 2), and the obtained product was dissolved in 3 ml of DMF and neutralized with 88.9 μl of triethylamine under ice cooling. To the neutralized solution, 164 mg of Boc-Thz-OH, 108 mg of HOBt and 147 mg of EDC hydrochloride were added and the resultant mixture was stirred for 2 hr. The reaction mixture was treated similarly to that in Example 132 (Process 1) to give 50 mg of the title compound. The reaction mixture was treated similarly to that in Example 132 (Process 1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Deprotection of 94 mg of the compound obtained by the process 1 was performed similarly to that in Example 30 (Process 2), and the obtained product was dissolved in 3 ml of DMF and neutralized with 88.9 μl of triethylamine under ice cooling. To the neutralized solution, 164 mg of Boc-Thz-OH, 108 mg of HOBt and 147 mg of EDC hydrochloride were added and the resultant mixture was stirred for 2 hr. The reaction mixture was treated similarly to that in Example 132 (Process 1) to give 50 mg of the title compound. The reaction mixture was treated similarly to that in Example 132 (Process 1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a methylene chloride solution containing 300 mg of Boc-Thz-OH, 358 μl of triethylamine, 358 mg of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate and 153 μl of piperidine were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process 3) to give 300 mg of the title compound. were added under ice cooling The reaction mixture was treated similarly to that in Example 33 (Process 3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a methylene chloride solution containing 0.30 g of Boc-Thz-OH, 0.12 ml of 2-amino-2-methyl-1-propanol and 0.29 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process 3) to give 190 mg of the title compound. were added The reaction mixture was treated similarly to that in Example 33 (Process 3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a methylene chloride solution containing 0.30 g of Boc-Thz-OH, 0.12 ml of 2-amino-2-methyl-1-propanol and 0.29 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process 3) to give 190 mg of the title compound. were added The reaction mixture was treated similarly to that in Example 33 (Process 3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution in DMF (10 mL) of N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid (777 mg, 3.33 mmol), prepared as in Example 164A, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (602 mg, 3.69 mmol), and ethyl dimethylaminopropyl carbodiimide hydrochloride (709 mg, 3.70 mmol) was added N,O-dimethylhydroxylamine hydrochloride (357 mg, 3.66 mmol) and 4-methylmorpholine (0.44 mL, 4.01 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and extracted with aqueous 1M H3PO4 (2×), saturated aqueous NaHCO3 (2×), and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (2:1 hexane-ethyl acetate) gave N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid-N-methoxy-N-methyl amide (605 mg) as a thick yellow oil. extracted with aqueous 1M H3PO4 (2×), saturated aqueous NaHCO3 (2×), and brine The organic phase was dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The desired compound was prepared by coupling of N-tert-butoxycarbonyl-(R)-(−) thiazolidine-4-carboxylic acid, prepared as in Example 164A with [4-amino-2-phenylbenzoyl]methionine methyl ester (compound 8) according to the method of Example 163D.