(2,5-dioxopyrrolidin-1-yl) acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compound was synthesized by the method of Scheme 5 using 2-naphthylacetic acid as J-COOH, D-leucinol as NH2—CH(R5)—CH(R4)—OH, D-leucine methyl ester as NH2—CH(R5)—COOCH3, and Boc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group was attached to the amino group of D-2-Nal by reaction of the compound of Example 35 with Ac-OSu in DMF. It was tested as described above with the results shown. The mass was analyzed as 635.9 (M+H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compound was synthesized by the method of Scheme 5 using 2-naphthylacetic acid as J-COOH, D-leucinol as NH2—CH(R5)—CH(R4)—OH, D-leucine methyl ester as NH2—CH(R5)—COOCH3, and Boc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group was attached to the amino group of D-2-Nal by reaction of the compound of Example 35 with Ac-OSu in DMF. It was tested as described above with the results shown. The mass was analyzed as 635.9 (M+H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Acetoxysuccinimide (98 mg, 0.624 mmol) was added to a solution of Example 20-5 (50 mg, 0.108 mmol) and TEA (0.747 ml, 5.39 mmol) in DMSO (2 ml) at RT. The reaction mixture was stirred at RT for 30 min then concentrated in vacuo to remove excess Et3N. The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier). The appropriate fractions containing product were combined then adsorbed onto a MeOH conditioned SCX column (5 g, BSA Varian brand). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded a yellow oil. Et2O was added to the oil then concentrated to dryness affording the title compound as a yellowish orange solid (30 mg, 55% yield). LCMS Rt=0.52 min (LCMS method Q); MS (M+1)=506.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br. s, 1H), 8.35 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.77 (d, J=9.09 Hz, 2H), 7.35 (d, J=9.60 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=2.02 Hz, 1H), 6.95 (dd, J=9.09, 2.53 Hz, 1H), 4.92-5.04 (m, 1H), 4.11 (t, J=6.32 Hz, 2H), 3.20-3.28 (m, 2H), 2.98 (s, 3H), 1.87-1.96 (m, 2H), 1.82 (s, 3H), 1.55-1.63 (m, 2H), 1.44-1.55 (m, 2H), 1.30 (s, 6H), 1.14 (s, 6H). then concentrated in vacuo to remove excess Et3N The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier) The appropriate fractions containing product The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH Evaporation of the solvent afforded a yellow oil then concentrated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Acetoxysuccinimide (98 mg, 0.624 mmol) was added to a solution of Example 20-5 (50 mg, 0.108 mmol) and TEA (0.747 ml, 5.39 mmol) in DMSO (2 ml) at RT. The reaction mixture was stirred at RT for 30 min then concentrated in vacuo to remove excess Et3N. The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier). The appropriate fractions containing product were combined then adsorbed onto a MeOH conditioned SCX column (5 g, BSA Varian brand). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded a yellow oil. Et2O was added to the oil then concentrated to dryness affording the title compound as a yellowish orange solid (30 mg, 55% yield). LCMS Rt=0.52 min (LCMS method Q); MS (M+1)=506.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br. s, 1H), 8.35 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.77 (d, J=9.09 Hz, 2H), 7.35 (d, J=9.60 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=2.02 Hz, 1H), 6.95 (dd, J=9.09, 2.53 Hz, 1H), 4.92-5.04 (m, 1H), 4.11 (t, J=6.32 Hz, 2H), 3.20-3.28 (m, 2H), 2.98 (s, 3H), 1.87-1.96 (m, 2H), 1.82 (s, 3H), 1.55-1.63 (m, 2H), 1.44-1.55 (m, 2H), 1.30 (s, 6H), 1.14 (s, 6H). then concentrated in vacuo to remove excess Et3N The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier) The appropriate fractions containing product The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH Evaporation of the solvent afforded a yellow oil then concentrated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compound was synthesized by the method of Scheme 5 using 2-naphthylacetic acid as J-COOH, D-leucinol as NH2—CH(R5)—CH(R4)—OH, D-leucine methyl ester as NH2—CH(R5)—COOCH3, and Boc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group was attached to the amino group of D-2-Nal by reaction of the compound of Example 35 with Ac-OSu in DMF. It was tested as described above with the results shown. The mass was analyzed as 635.9 (M+H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compound was synthesized by the method of Scheme 5 using 2-naphthylacetic acid as J-COOH, D-leucinol as NH2—CH(R5)—CH(R4)—OH, D-leucine methyl ester as NH2—CH(R5)—COOCH3, and Boc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group was attached to the amino group of D-2-Nal by reaction of the compound of Example 35 with Ac-OSu in DMF. It was tested as described above with the results shown. The mass was analyzed as 635.9 (M+H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: t-BOCValAlaAsp-p-nitroanilide (174 mg, 0.33 mmole) was dissolved in neat TFA (5 mL) and stirred at room temperature for 1 hour. The TFA was removed in vacuo and the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo. This dissolution with CH2Cl2 and subsequent evaporation repeated two more times. The residue was dissolved in dioxane/water (5 mL, 4:1) and treated with acetic acid N-hydroxysuccinimide ester (63 mg, 0.40 mmole) and NaHCO3 (139 mg, 1.65 mmole). After 18 hours, the mixture was diluted with 1N HCl (25 mL) and extracted three times with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder: mp 196°-200° C. (dec.); 1H NMR (DMSO-d6) δ 0.80 (d, J=6.6 Hz, 3H), 0.82 (d, J=5.1 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 1.85 (s, 3H), 1.85-2.0 (m, 1H), 2.60 (dd, J=7.5, 16.6 Hz, 1H), 2.75 (dd, J=6.2, 16.6 Hz, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 4.6-4.7 (m, 1H), 7.8-7.9 (m, 3H), 8.11 (d, J=6.8 Hz, 1H), 8.21 (d, J=9.3 Hz, 2H), 8.27 (d, J=7.2 Hz, 1H), 10.51 (s, 1H), 12.45 (br s, 1H); MS (LSIMS) m/e 488 (6, M+ +Na), 466 (23, M+ +1), 449 (7) 328 (15), 213 (44), 142 (100); [α]D20 -24.9° (c=1.0, DMF); Analysis calculated for C20H27N5O8 : C, 51.60; H, 5.85; N, 15.05; found: C, 50.16; H, 5.79; N, 14.06. The TFA was removed in vacuo the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo This dissolution with CH2Cl2 and subsequent evaporation The residue was dissolved in dioxane/water (5 mL, 4:1) After 18 hours extracted three times with ethyl acetate The combined extracts were dried with MgSO4 filtered concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The same compound was also prepared by a different route. Thus, H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml Triton B, evaporated to dryness, and the residue re-evaporated twice with DMF (100 ml each). The residue was then stirred with Ac-OSu (16.9 g, 95.4 mmol) in 150 ml DMF for 20 hours. N-Methylmorpholin was added from time to time in order to maintain the reaction slightly basic. Removal of the solvent and extraction of the product into EtOAc followed by washing with small volumes of 10% HOAc, H2O (the product is water soluble, use a small volume of H2O), dried over Na2SO4, evaporation to dryness again gave a clear oil (14.5 g, Ac-Ser(Bzl)-OH). The compound failed to crystallize. It was thus dissolved in a mixture of MeOH and H2O (300 ml:30 ml), titrated to pH 7.0 with 20% Cs2CO3 and evaporated to a solid mass. The salt was re-evaporated twice more with DMF and stirred with benzyl bromide (15.4 g, 91 mmol) in 250 ml DMF for 18 hours. On evaporation of the solvent, the residue was taken up in H2O (600 ml) and the oily product formed was extracted into EtOAc. It was washed with H2O, dried over Na2SO4 and evaporated to a syrup which on seeding crystallized immediately. It was recrystallized from EtOAc and petroleum ether to yield, 10.42 g (32.2% overall); mp 89°-91°. The same compound was also prepared by a different route evaporated to dryness the residue re-evaporated twice with DMF (100 ml each) to maintain the reaction slightly basic Removal of the solvent and extraction of the product into EtOAc by washing with small volumes of 10% HOAc, H2O (the product dried over Na2SO4, evaporation to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml of Triton B (40% methanolic solution of Trimethylbenzylammonium Hydroxide), evaporated to dryness and the residue re-evaporated twice with DMF (250 ml each). The oily residue was taken up in DMF (250 ml) and stirred with Ac-OSu (16.5 g, 95.4 mmol) for 5 hr. A few ml (~5 ml) of NMM was added to bring the reaction to slightly basic conditions during this period of time. Acetic acid (~5 ml) was then added and the solvents removed by evaporation, leaving an oily residue which was partitioned between 5% HOAc and EtOAc. The aqueous layer was extracted once more with EtOAc and the combined EtOAc solution washed twice with small volumes of H2O, dried over Na2SO4, and evaporated to approximately 300 ml (1/3 of original volume). Crystalline product formed immediately when DCHA was added to a slightly basic condition (~35 ml). The crude material (32.5 g, mp 135°- 145°) was recrystallized from EtOH (150 ml) and ether (900 ml): evaporated to dryness the residue re-evaporated twice with DMF (250 ml each) the reaction to slightly basic conditions during this period of time the solvents removed by evaporation leaving an oily residue which was partitioned between 5% HOAc and EtOAc The aqueous layer was extracted once more with EtOAc the combined EtOAc solution washed twice with small volumes of H2O dried over Na2SO4 evaporated to approximately 300 ml (1/3 of original volume)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.27 g (0.011 mol) of N-hydroxysuccinimide were initially introduced into 10 ml of ethyl acetate, a solution of 3.22 g (0.012 mol) of diphenyl chlorophosphate in 10 ml of ethyl acetate was added and then a solution of 2.53 g (0.025 mol) of triethylamine in 10 ml of ethyl acetate was added dropwise in the course of 10 minutes, the temperature rising to 41° C. A thick, white suspension resulted, which was treated with a solution of 0.6 g (0.01 mol) of acetic acid in 10 ml of ethyl acetate and heated at 45°-55° C. for 16 hours. After ending of the reaction, the solid was filtered off and washed with 2×3 ml of ethyl acetate. The combined filtrates were evaporated in vacuo and the semicrystalline residue which remained was washed by stirring with 20 ml of ethanol for 30 minutes. The white solid thus obtained was filtered off, washed with 2×3 ml of ethanol, sucked dry and then washed by stirring with 10 ml of isopropanol. After filtering off, washing with 2×2 ml of isopropanol and drying in vacuo, 1.1 g (70%) of white acetic acid succinimidyl ester were obtained. rising to 41° C A thick, white suspension resulted heated at 45°-55° C. for 16 hours After ending of the reaction the solid was filtered off washed with 2×3 ml of ethyl acetate The combined filtrates were evaporated in vacuo the semicrystalline residue which remained was washed The white solid thus obtained was filtered off washed with 2×3 ml of ethanol sucked dry washed by stirring with 10 ml of isopropanol After filtering off washing with 2×2 ml of isopropanol drying in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: t-BOCValAlaAsp-p-nitroanilide (174 mg, 0.33 mmole) was dissolved in neat TFA (5 mL) and stirred at room temperature for 1 hour. The TFA was removed in vacuo and the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo. This dissolution with CH2Cl2 and subsequent evaporation repeated two more times. The residue was dissolved in dioxane/water (5 mL, 4:1) and treated with acetic acid N-hydroxysuccinimide ester (63 mg, 0.40 mmole) and NaHCO3 (139 mg, 1.65 mmole). After 18 hours, the mixture was diluted with 1N HCl (25 mL) and extracted three times with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder: mp 196°-200° C. (dec.); 1H NMR (DMSO-d6) δ 0.80 (d, J=6.6 Hz, 3H), 0.82 (d, J=5.1 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 1.85 (s, 3H), 1.85-2.0 (m, 1H), 2.60 (dd, J=7.5, 16.6 Hz, 1H), 2.75 (dd, J=6.2, 16.6 Hz, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 4.6-4.7 (m, 1H), 7.8-7.9 (m, 3H), 8.11 (d, J=6.8 Hz, 1H), 8.21 (d, J=9.3 Hz, 2H), 8.27 (d, J=7.2 Hz, 1H), 10.51 (s, 1H), 12.45 (br s, 1H); MS (LSIMS) m/e 488 (6, M+ +Na), 466 (23, M+ +1), 449 (7) 328 (15), 213 (44), 142 (100); [α]D20 -24.9° (c=1.0, DMF); Analysis calculated for C20H27N5O8 : C, 51.60; H, 5.85; N, 15.05; found: C, 50.16; H, 5.79; N, 14.06. The TFA was removed in vacuo the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo This dissolution with CH2Cl2 and subsequent evaporation The residue was dissolved in dioxane/water (5 mL, 4:1) After 18 hours extracted three times with ethyl acetate The combined extracts were dried with MgSO4 filtered concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The same compound was also prepared by a different route. Thus, H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml Triton B, evaporated to dryness, and the residue re-evaporated twice with DMF (100 ml each). The residue was then stirred with Ac-OSu (16.9 g, 95.4 mmol) in 150 ml DMF for 20 hours. N-Methylmorpholin was added from time to time in order to maintain the reaction slightly basic. Removal of the solvent and extraction of the product into EtOAc followed by washing with small volumes of 10% HOAc, H2O (the product is water soluble, use a small volume of H2O), dried over Na2SO4, evaporation to dryness again gave a clear oil (14.5 g, Ac-Ser(Bzl)-OH). The compound failed to crystallize. It was thus dissolved in a mixture of MeOH and H2O (300 ml:30 ml), titrated to pH 7.0 with 20% Cs2CO3 and evaporated to a solid mass. The salt was re-evaporated twice more with DMF and stirred with benzyl bromide (15.4 g, 91 mmol) in 250 ml DMF for 18 hours. On evaporation of the solvent, the residue was taken up in H2O (600 ml) and the oily product formed was extracted into EtOAc. It was washed with H2O, dried over Na2SO4 and evaporated to a syrup which on seeding crystallized immediately. It was recrystallized from EtOAc and petroleum ether to yield, 10.42 g (32.2% overall); mp 89°-91°. The same compound was also prepared by a different route evaporated to dryness the residue re-evaporated twice with DMF (100 ml each) to maintain the reaction slightly basic Removal of the solvent and extraction of the product into EtOAc by washing with small volumes of 10% HOAc, H2O (the product dried over Na2SO4, evaporation to dryness