The synthetic method of n-boc-dolaproine and boc-dap DCHA

Abstract

The invention discloses a method for synthesizing N-Boc-Dolaproine and Boc-DapDCHA. The synthesis method comprises the following steps: step 1, and synthesis by Reformatsky reaction under the activation of zinc powder, wherein X is Cl, Br or I, and R is an alkane or alkene; step 2, obtaining through methylation; and step 3, N-Boc-Dolaproine is obtained through hydrolysis reaction. Applying the technical scheme of the present invention, the yield of each step of the reaction is relatively good, and the intermediates are all easy to purify, the process route used in the method is relatively short, the material price is relatively low, the synthesis process is simple to operate, and the production cost is further reduced. Can be applied to industrial production.

Description

technical field

[0001] The invention relates to the technical field of medicine and chemical industry, in particular to a method for synthesizing N-Boc-Dolaproine and Boc-DapDCHA. Background technique

[0002] Dolastatin 10 (Dolastatin 10, with the following structural formula) is a marine natural product, which was originally isolated from the Indian Ocean shellless mollusk Dolabella auricularia by Pettit et al. in 1987, and its absolute synthesis was determined by total synthesis. structure. It is an effective inhibitor of microtubule assembly and a pentapeptide with significant antitumor activity. It is mainly used for the treatment of solid tumors such as small cell lung cancer, ovarian cancer, melanoma and prostate. Despite satisfactory preclinical results, dolastatin 10 has been withdrawn from phase II human cancer clinical trials as a single agent due to toxic side effects. Therefore, the structural modification of Dolastatin 10 has become a research hotspot. Multi...

Examples

Embodiment 1

[0051] Synthesis of compound 3:

[0052] X=I, R=cyclopropyl, solvent is dioxane

[0053] Add 20 volumes of dioxane and 3.0 equivalents of zinc powder to the glass bottle, then replace the air until the oxygen content is ≤1.0%, then add 0.5 equivalents of trimethylchlorosilane dropwise, and raise the temperature of the system to 50~60°C. Stir the reaction for 2-3 hours. Then the system was cooled to 30~35°C, and 1.0 equivalent of N-Boc-L-prolinaldehyde dioxane solution was added dropwise to the reaction system, and stirred for 25 minutes. Then slowly add 0.8 equivalent of compound 2 in dioxane solution dropwise to the system, first drop about 20% compound 2 solution, after stirring for 0.5~1h, continue to drop the remaining compound 2 solution. The temperature was controlled at 30° C., and the reaction was continued for 4 hours. HPLC tracking, until the remaining compound 2 is less than 5%. The reaction system was quenched with saturated ammonium chloride, and the organic p...

Embodiment 2

[0055] Synthesis of compound 3:

[0056] X=Cl, R=cyclohexane, the solvent is 2-methyltetrahydrofuran

[0057] Add 20 volumes of 2-methyltetrahydrofuran and 3.0 equivalents of zinc powder to the glass bottle, then replace the air until the oxygen content is ≤1.0%, and then add 0.5 equivalents of trimethylchlorosilane dropwise; raise the temperature of the system to 50~60°C , stirring and reacting for 2 to 3 hours. Then the system was cooled to 30~35°C, and 1.0 equivalent of N-Boc-L-prolinaldehyde solution in 2-methyltetrahydrofuran was added dropwise to the reaction system, and stirred for 25 minutes. Then slowly add 0.8 equivalent of compound 2 in 2-methyltetrahydrofuran solution dropwise to the system, first drop about 20% compound 2 solution, after stirring for 0.5~1h, continue to drop the remaining compound 2 solution. The temperature was controlled at 30° C., and the reaction was continued for 4 hours. HPLC tracking, until the remaining compound 2 is less than 5%. The ...

Embodiment 3

[0059] Synthesis of compound 3:

[0060] X=Br, R=cyclohexane, solvent is tetrahydrofuran. Among them, Zn: 1.0 equivalent, dropping temperature: 10~20°C.

[0061]Add 20 volumes of tetrahydrofuran and 1.0 equivalent of zinc powder to the glass bottle, then replace the air until the oxygen content is ≤1.0%, and then add 0.5 equivalent of trimethylchlorosilane dropwise; raise the temperature of the system to 40~50°C, and stir the reaction for 1 ~2 hours. Then the temperature of the system was lowered to 10~20°C, and 1.0 equivalent of N-Boc-L-prolinaldehyde tetrahydrofuran solution was added dropwise to the reaction system, and stirred for 20~25min. Then slowly add 0.8 equivalent of compound 2 in tetrahydrofuran solution dropwise to the system, first drop about 20% compound 2 solution, after stirring for 0.5~1h, continue to drop the remaining compound 2 solution. Control the temperature at 30°C and continue the reaction for 3 to 4 hours. HPLC tracking, until the remaining compo...

technical field

[0001] The invention relates to the technical field of medicine and chemical industry, in particular to a method for synthesizing N-Boc-Dolaproine and Boc-DapDCHA. Background technique

[0002] Dolastatin 10 (Dolastatin 10, with the following structural formula) is a marine natural product, which was originally isolated from the Indian Ocean shellless mollusk Dolabella auricularia by Pettit et al. in 1987, and its absolute synthesis was determined by total synthesis. structure. It is an effective inhibitor of microtubule assembly and a pentapeptide with significant antitumor activity. It is mainly used for the treatment of solid tumors such as small cell lung cancer, ovarian cancer, melanoma and prostate. Despite satisfactory preclinical results, dolastatin 10 has been withdrawn from phase II human cancer clinical trials as a single agent due to toxic side effects. Therefore, the structural modification of Dolastatin 10 has become a research hotspot. Multi...

Examples

Embodiment 1

[0051] Synthesis of compound 3:

[0052] X=I, R=cyclopropyl, solvent is dioxane

[0053] Add 20 volumes of dioxane and 3.0 equivalents of zinc powder to the glass bottle, then replace the air until the oxygen content is ≤1.0%, then add 0.5 equivalents of trimethylchlorosilane dropwise, and raise the temperature of the system to 50~60°C. Stir the reaction for 2-3 hours. Then the system was cooled to 30~35°C, and 1.0 equivalent of N-Boc-L-prolinaldehyde dioxane solution was added dropwise to the reaction system, and stirred for 25 minutes. Then slowly add 0.8 equivalent of compound 2 in dioxane solution dropwise to the system, first drop about 20% compound 2 solution, after stirring for 0.5~1h, continue to drop the remaining compound 2 solution. The temperature was controlled at 30° C., and the reaction was continued for 4 hours. HPLC tracking, until the remaining compound 2 is less than 5%. The reaction system was quenched with saturated ammonium chloride, and the organic p...

Embodiment 2

[0055] Synthesis of compound 3:

[0056] X=Cl, R=cyclohexane, the solvent is 2-methyltetrahydrofuran

[0057] Add 20 volumes of 2-methyltetrahydrofuran and 3.0 equivalents of zinc powder to the glass bottle, then replace the air until the oxygen content is ≤1.0%, and then add 0.5 equivalents of trimethylchlorosilane dropwise; raise the temperature of the system to 50~60°C , stirring and reacting for 2 to 3 hours. Then the system was cooled to 30~35°C, and 1.0 equivalent of N-Boc-L-prolinaldehyde solution in 2-methyltetrahydrofuran was added dropwise to the reaction system, and stirred for 25 minutes. Then slowly add 0.8 equivalent of compound 2 in 2-methyltetrahydrofuran solution dropwise to the system, first drop about 20% compound 2 solution, after stirring for 0.5~1h, continue to drop the remaining compound 2 solution. The temperature was controlled at 30° C., and the reaction was continued for 4 hours. HPLC tracking, until the remaining compound 2 is less than 5%. The ...

Embodiment 3

[0059] Synthesis of compound 3:

[0060] X=Br, R=cyclohexane, solvent is tetrahydrofuran. Among them, Zn: 1.0 equivalent, dropping temperature: 10~20°C.

[0061]Add 20 volumes of tetrahydrofuran and 1.0 equivalent of zinc powder to the glass bottle, then replace the air until the oxygen content is ≤1.0%, and then add 0.5 equivalent of trimethylchlorosilane dropwise; raise the temperature of the system to 40~50°C, and stir the reaction for 1 ~2 hours. Then the temperature of the system was lowered to 10~20°C, and 1.0 equivalent of N-Boc-L-prolinaldehyde tetrahydrofuran solution was added dropwise to the reaction system, and stirred for 20~25min. Then slowly add 0.8 equivalent of compound 2 in tetrahydrofuran solution dropwise to the system, first drop about 20% compound 2 solution, after stirring for 0.5~1h, continue to drop the remaining compound 2 solution. Control the temperature at 30°C and continue the reaction for 3 to 4 hours. HPLC tracking, until the remaining compo...

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