Method for preparing proteasome inhibitor Oprozomib and analogs thereof

A proteasome inhibitor and analog technology, which is applied in the field of preparation of proteasome inhibitor oprozomib and its analogs, can solve the problems of complicated operation, prolonged production cycle, loss of synthesized peptide chains, etc., and achieves improved yield and purity , the effect of shortening the reaction cycle and reducing the production cost

Inactive Publication Date: 2016-09-21
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this methyl ester structure can present two problems in solid-phase peptide synthesis reactions
One is that when using acid to remove the protective group of the α-amino group in each cycle to extend the peptide chain, it is always accompanied by a small amount of benzyl ester bond connected between the peptide chain and the resin is broken by acid hydrolysis, and the so-called "rooted branch" phenomenon occurs , resulting in severe loss of the synthesized peptide chain
The second is that when the peptide chain is cut off from the resin, it needs to use relatively strong acidic conditions such as HF and TFA, which will also bring some side reactions and make the operation complicated.
[0012] Regardless of route 1 or route 2, the chiral partial racemization of amino acids is likely to be caused during the condensation of two amino acids, so that HPLC separation and purification are required in the last step of the reaction, resulting in prolongation of the production cycle and increase in cost

Method used

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  • Method for preparing proteasome inhibitor Oprozomib and analogs thereof
  • Method for preparing proteasome inhibitor Oprozomib and analogs thereof
  • Method for preparing proteasome inhibitor Oprozomib and analogs thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 N-Fmoc-O-methyl-L-serine tert-butyl alcohol ester

[0066]

[0067] Dissolve N-Fmoc-O-methyl-L-serine (1g, 2.93mmol) in 15mL of ethyl acetate, slowly add tert-butyl trichloroacetimide ester (1.28 g, 5.87mmol), the mixture was stirred at 25°C for 18 hours, the reaction was quenched with saturated sodium carbonate (20mL), the organic layer was separated, and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced The solvent was evaporated under pressure, and 1.13 g of white solid was obtained by column chromatography.

[0068] Yield: 97%; 1 H NMR (500MHz, CDCl 3 ): δ7.76(d, J=7.5Hz, 2H), 7.62(q, J=4.0Hz, 2H), 7.40(t, J=7.5Hz, 2H), 7.31(t, J=7.4Hz, 2H ), 5.66(d, J=8.0Hz, 1H), 4.417-4.331(m, 3H), 4.24(t, J=7.5Hz, 1H), 3.78(dd, J=9.5, 3.5Hz, 1H), 3.65 (dd, J=9.0, 3.0Hz, 1H), 3.37(s, 3H), 1.48(s, 9H).ESI-MS: m / z=398[M+1] + .

Embodiment 2

[0069] Example 2 O-methyl-L-serine tert-butanol ester

[0070]

[0071] The N-Fmoc-O-methyl-L-serine tert-butanol ester (1g, 2.52mmol) obtained in Example 1 was dissolved in 9mL of acetonitrile, and 1mL of diethylamine was added under an ice bath, and detected by thin layer chromatography, the reaction After completion, the solvent was recovered under reduced pressure, and the white solid crude product was 440 mg, which was directly used in the next step.

[0072] Yield: 100%; 1 H NMR (500MHz, CDCl 3 ): δ4.24(t, J=7.5,1H),3.81(dd,J=9.5,3.5Hz,1H),3.56(s,1H),3.67(dd,J=9.0,3.0Hz,1H), 3.37(s,3H), 3.12(s,1H), 1.47(s,9H).

Embodiment 3

[0073] Example 3 O-methyl-N-(2-methyl-5-thiazole)-L-serine tert-butyl ester

[0074]

[0075] Under ice-cooling, the amine obtained in Example 2 (440 mg, 2.5 mmol) and 2-methylthiazole-5-carboxylic acid (429 mg, 3 mmol) were dissolved in tetrahydrofuran (10 mL), and HOBt (135 mg, 3 mmol) and HBTU (1.1 g, 3mmol) was slowly added dropwise N,N-diisopropylethylamine ((1mL, 6mmol), raised to room temperature and reacted for 4 hours. Added 20mL of ethyl acetate and allowed to stand to separate the organic layer. Wash with ammonium solution, saturated sodium bicarbonate solution and saturated saline solution, dry over anhydrous sodium sulfate, filter, recover the solvent under reduced pressure to obtain a residue, and purify by silica gel column chromatography to obtain 0.6 g of white solid.

[0076] Yield: 80%; 1 H NMR (500MHz, CDCl 3 )δ8.04(s,1H),6.74(d,J=7.5Hz,1H),4.74-4.72(m,1H),3.81(dd,J=9.5,3.0Hz,1H),3.71(dd,J =9.5,3.0Hz,1H),3.35(s,3H),2.72(s,3H),1.48(s,9H).ESI-MS: m / z=30...

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Abstract

The invention provides a method for synthesizing a proteasome inhibitor Oprozomib and analogs thereof. The proteasome inhibitor Oprozomib is prepared through subjecting a dipeptide intermediate represented by a formula IV shown in the description to deprotection, and then, subjecting the de-protected dipeptide intermediate to a reaction with a peptide-terminated epoxy ketone fragment represented by a formula VIII shown in the description. The proteasome inhibitor Oprozomib synthesized by the method provided by the invention, i.e., an object compound is obtained through separately preparing the dipeptide intermediate and the peptide-terminated epoxy ketone fragment and finally carrying out condensation, the yield of synthesis is 42%, the racemization of amino acids is avoided, and meanwhile, HPLC purification for the end product is avoided, so that the reaction cycle is greatly shortened, the production cost is reduced, and the yield and purity of the product are improved. The proteasome inhibitor Oprozomib has a structural general formula shown in the description.

Description

technical field [0001] The invention belongs to a chemical synthesis method, in particular to a preparation method of a proteasome inhibitor oprozomib and analogs thereof. Background technique [0002] The molecular formula of Oprozomib is: O-methyl-N-[(2-methylthiazol-5-yl)carbonyl]-L-seryl-O-methyl-N-{(1S)-1-benzyl- 2-[(2R)-2-Methyloxirane-2-yl]-2-oxoethane}-L-serinamide, the chemical structure formula is: [0003] [0004] Oprozomib (ONX 0912) is an oral, highly selective 26S proteasome chymotrypsin-like activity inhibitor jointly developed by Amgen of the United States and Ono Pharmaceutical Company of Japan, which inhibits 20S proteasome β 5 / LMP 7 CT-L activity, IC 50 It is 36nM / 82nM. At present, the compound has entered phase II clinical research for the treatment of myeloma and mantle cell lymphoma. [0005] Currently, there are two routes for synthesizing Oprozomib and its analogues, the difference mainly lies in the key intermediates. [0006] One of the s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/083C07K1/06
CPCY02P20/55C07K5/1013
Inventor 刘滔傅利萍胡永洲董晓武李大强何若愚
Owner ZHEJIANG UNIV
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