A kind of synthetic method of MMAF intermediate pentapeptideTechnical field
The invention belongs to pharmaceutical intermediate synthesis technical field, especially a kind of synthetic method of MMAF intermediate pentapeptide.
Background technology
MMAF (Monomethyl Auristantin F) is a kind of antimitotic Auristantin derivative newly, C-terminal has the phenylalanine residue with electric charge, compared with not charged MMAE, the damage of its energy minimization cell-signaling pathways, minimizes cytotoxicity.
The market of antibody-drug conjugate agent (Antibody-drug conjugates, hereinafter referred to as ADCs medicine) is very huge, and Ge great drugmaker of the world does not stint huge fund and puts into the research and development of ADCs medicine.ADCs medicine is made up of recombinant antibodies, chemical drugs and " connector ".Chemical drugs MMAF as ADCs medicine integral part was subject to the favor of people in recent years, but condensing agent (as the diethyl phosphorocyanidate) price of technology of preparing use is at present high, yield is low, is difficult to the market requirement meeting MMAF.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of synthetic method of MMAF intermediate pentapeptide is provided, solve the problem that is difficult to prepare high purity MMAF intermediate pentapeptide and the high problem of manufacturing cost.
The present invention solves its technical problem and takes following technical scheme to realize:
A synthetic method for MMAF intermediate pentapeptide, comprises the following steps:
(1) with the Boc-N-Me-Val of Val-Dil-Dap-Phe-OMe and 3.0eq of 1eq for raw material, add methylene dichloride dissolve;
(2) at 0 DEG C, add the HOBT of the DIPEA of 3.0eq, EDCI and 1.1eq of 1.1eq, at 25 DEG C, stir 18h;
(3) thin up reaction system, is extracted with ethyl acetate, and the saturated NaCl of organic phase washs, through anhydrous Na2sO4drying, filters, obtains crude product after desolvation;
(4) crude product is carried out column purification and obtain MMAF intermediate pentapeptide.
And described step (2) has been come as condensing agent by adding EDCI and HOBT.
And the number of times that described step (3) is extracted with ethyl acetate is three times.
Advantage of the present invention and positively effect are:
1, this synthetic method is synthesized by adding condensing agent EDCI and HOBT, and its building-up process is simple, product be easy to purifying and product purity up to more than 95%, product yield up to 84%, far away higher than 60% yield of currently available products.
2, condensing agent EDCI and HOBT of this synthetic method use is with low cost, well below the price of existing condensing agent diethyl phosphorocyanidate (DEPC), reduces production cost.
Accompanying drawing explanation
Fig. 1 is synthesis route figure of the present invention.
Embodiment
Below in conjunction with accompanying drawing, invention is further described
A synthetic method for MMAF intermediate pentapeptide, as shown in Figure 1, comprises the following steps:
Step 1, by Val-il-Dap-Phe-OMe(4.9g, 7.74mmol) and Boc-N-Me-Val (5.36g, 23.22mmol) join in reaction flask, add methylene dichloride (DCM) (90mL) dissolve.
Step 2, above-mentioned reaction system is cooled to 0 DEG C, then N is added successively, N-diisopropylethylamine (DIPEA) (3.8mL, 23.22mmol), EDC hydrochloride (EDCI) (1.64g, 8.52mmol) with I-hydroxybenzotriazole (HOBT) (1.15g, 8.52mmol), after reinforced, reaction system stirs 18 hours at 25 DEG C.
Step 3, in reaction solution, add water, then use ethyl acetate (EA) (50mL) to extract three times; The saturated NaCl(100mL of organic phase) washing, through anhydrous Na2sO4drying, filter, desolvation obtains crude product.
Step 4, crude product is carried out the MMAF intermediate pentapeptide (N-Boc-Me-Val-Val-Dil-Dap-Phe-Ome) that column purification obtains 5.51g, yield 84%.
The MMAF intermediate pentapeptide (N-Boc-Me-Val-Val-Dil-Dap-Phe-Ome) that a process for preparing is carried out proton nmr spectra 1H NMR (300MHz, CDCl3) to detect, its detected result is:
1HNMR(CDCl3,300MHz):δ7.20–7.29(m,5H),6.99-7.08(m,1H),6.63-6.67(m,1H),4.68-4.86(m,3H),3.86-3.98(m,2H),3.80(s,1H),3.72(s,3H),3.31-3.46(m,11H),3.00–3.20(m,4H),2.89(s,3H),2.81(s,3H),2.37-2.45(m,4H),2.18–2.27(m,2H),1.47–1.56(m,11H),1.16-1.18(m,3H),0.78-1.07(m,18H).
Can find out, the purity of the MMAF intermediate pentapeptide (N-Boc-Me-Val-Val-Dil-Dap-Phe-Ome) that a process for preparing can reach more than 95%.
It is emphasized that; embodiment of the present invention is illustrative; instead of it is determinate; therefore the present invention is not limited to the embodiment described in embodiment; every other embodiments drawn by those skilled in the art's technical scheme according to the present invention, belong to the scope of protection of the invention equally.