Synthesis method for valrubicin

A synthetic method, the technology of valrubicin, which is applied in the field of drugs for the treatment of BCG refractory bladder carcinoma in situ, can solve the problem of unstable polybrominated and bicinoid compounds, which are not suitable for industrial production of high-purity raw materials Medicine and other problems, to achieve the effect of high yield

Inactive Publication Date: 2014-04-02
深圳万乐药业有限公司
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Problems solved by technology

[0007] The above two synthetic methods finally condense the obtained intermediates (compounds 4 and 6) with sodium n-pentanoate to obtain compound 1. The inventors found it difficult to obtain the target compound 1 by repeating the bromination route according to the above method. The reason was analyzed Compound 5 may be prepared by bromination of compound 2. Since the ketone will exist in the form of enol at the same time, if it is not protected, it is prone to multi-bromination, thereby destroying the original structure; at the same time, Br- is an active halogenated group. In the reaction of synthesizing compound 6, it is easy to be substituted by trifluoroacetyl group, which leads to trifluoroacetylation of the α-position methyl hydrogen of the ketone and cannot be substituted by n-valeric acid
In another route of iodine substitution, the ketone, under the condition of CaO as the base, not only inactivates the activity of the carbonyl group, but also improves the activity of the α-position methyl hydrogen, making the α-position methyl hydrogen easy to be replaced, but in the actual experiment , under the action of CaO, compound 3 is unstable under alkaline conditions due to the strong alkalinity of CaO. 2 The effect is easy to lead to the phenomenon of desugaring, which greatly reduces the product yield and purity
The inventor repeated the above two methods, and the intermediate product was too complicated to be purified, which made it difficult to obtain the final product valrubicin
Thereby, the method of prior art is not suitable for industrialized production high-purity crude drug valrubicin

Method used

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  • Synthesis method for valrubicin
  • Synthesis method for valrubicin
  • Synthesis method for valrubicin

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Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1: the preparation of compound 7

[0024] Add daunorubicin hydrochloride (15.0g, 26.6mmol) into a 2L three-necked flask, then add 150ml of methanol and 300ml of 1,4-dioxane, stir and cool to 8±2°C under nitrogen protection, then add orthoformic acid Trimethyl ester (13.0g, 122mmol); bromine (5.1g, 31.9mmol) was diluted with about 15ml of dichloromethane and added dropwise to the reaction flask at 8±2°C. After dropping, the solution was stirred and reacted at 8±2°C under the protection of nitrogen for 2 to 3 hours, then quenched by adding propylene oxide (2.32g, 39.9mmol), and cooled to 0±2°C, adding 1350ml of isopropyl ether dropwise. Stir and crystallize at 0±2°C for 1 to 2 hours, suction filter under nitrogen protection, rinse the filter cake with an appropriate amount of isopropyl ether, drain it, and dry it in vacuum at room temperature for 2 to 4 hours to obtain compound 7 as a red solid powder with a yield of 18.0 g. The yield was 98.3%, and the produc...

Embodiment 2

[0025] Embodiment 2: the preparation of compound 5

[0026] Add compound 7 (20.0g, 29.0mmol) to a 5L three-necked flask, add 1000ml of acetone, stir and cool to 0±2°C under nitrogen protection, dilute 40% HBr (5.9g, 29.0mmol) with 10ml of water and dilute at 0 Add it dropwise to the reaction flask at ±2°C; after the drop is complete, the solution is stirred and reacted overnight at 0±2°C under the protection of nitrogen. The next day, add 2500ml of isopropyl ether dropwise, stir and crystallize at 0±2°C for 1-2 hours, suction filter under nitrogen protection, rinse the filter cake with an appropriate amount of isopropyl ether, drain it, and dry it in vacuum at room temperature for 2-4 hours to obtain Red solid powder compound 5, yield 18g, yield 96.5%, purity 95.1% (HPLC, area normalization method).

Embodiment 3

[0027] Embodiment 3: the preparation of compound 8

[0028] Add compound 5 (15.0g, 23.3mmol), sodium n-valerate (7.2g, 58.3mmol), 750ml of acetone and 7.5ml of water into a 1L three-necked flask, stir and heat to 60±2°C under nitrogen protection, and place at 60 Stir the reaction at ±2°C for 2-3 hours. Suction filtration while hot, the filtrate was concentrated to dryness under reduced pressure at 25±3°C, the concentrate was separated and purified by silica gel normal phase column chromatography, and eluted with dichloromethane:methanol=10:1 as the eluent, the collected purity was greater than 95% The eluate was concentrated to dryness under reduced pressure at 25±3°C to obtain red solid compound 8, yield 8.0g, yield 54.8%, purity 96.5% (HPLC, area normalization method); MS / ES+: (M+ h) + 628.28.

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Abstract

The invention provides a synthesis method for valrubicin. Daunorubicin is used as a starting material. The method comprises the following steps of selectively protecting carbonyls, performing bromination reaction, removing carbonyl protection, performing reaction with sodium n-valerate, and performing reaction with trifluoroaceticanhydride to obtain amide to prepare the valrubicin. Compared with the prior art, the synthesis method has the advantages that intermediate compounds 5 and 8 obtained by such a synthesis route are high in purity and low in impurity content, so that a target product valrubicin with purity of over 99 percent is prepared, and is high in yield and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing valrubicin, a drug for treating BCG refractory bladder carcinoma in situ. Background technique [0002] Valrubicin (Valrubicin) was originally developed by Anthra Pharmaceuticals in the United States and is now owned by Endo Pharmaceuticals. It was launched in the United States for the first time on September 3, 2009, mainly for the treatment of BCG-refractory bladder carcinoma in situ. The molecular formula of valrubicin is C 34 h 36 f 3 NO 13 , the chemical name is (2S-cis)-2-[1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo Generation-4-[[2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-α-L-lyxopyranyl]-oxygen]-2-naphthacene]-2 -Oxoethylvalerate, its structural formula is as follows: [0003] [0004] Valrubicin (Valrubicin, AD 32 ) is a semi-synthetic homologue of doxorubicin (Doxorubicin), which is a water-soluble anth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/252C07H1/00
Inventor 朱勇黄维宇陈齐阳李萍刘东华王庆秋张广明
Owner 深圳万乐药业有限公司
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