Amide boronic acid ester for detecting the purity of bortezomib intermediate, preparation method and application thereof

An amide boronate and leucine boronate technology, applied in the field of medicine, can solve the problems of interference analysis and detection, instability, and inability to detect the optical purity of products, and achieve high optical purity, short reaction time, sensitivity and accuracy. high degree of effect

Active Publication Date: 2016-06-08
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Description
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Problems solved by technology

However, (R)-leucine borate itself is unstable, and the degradation product after the C-B bond is easily oxidized in the gas phase and in the air will interfere with the analysis and detection. Therefore, the method in the literature cannot accurately determine the optical properties of the product Purity is tested

Method used

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  • Amide boronic acid ester for detecting the purity of bortezomib intermediate, preparation method and application thereof
  • Amide boronic acid ester for detecting the purity of bortezomib intermediate, preparation method and application thereof
  • Amide boronic acid ester for detecting the purity of bortezomib intermediate, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: the synthesis of formula B compound:

[0057] The compound of formula A1 (200mg, 0.8mmol, 1eq) was weighed and placed in a 25mL single-necked bottle. The temperature was cooled in an ice bath, and regular dichloromethane (8 mL) was added. Then p-bromobenzoyl chloride (263mg, 1.2mmol, 1.5eq) was weighed and added to the reaction flask. Triethylamine (0.22 mL, 1.6 mmol, 2.0 eq) was measured and added dropwise to the reaction. The reaction lasted for about 10 minutes, and when the reaction was over, a white solid precipitated out, and 244 mg of the white solid was obtained by filtration, and another 70 mg was obtained by column chromatography of the mother liquor, which was identified as the compound of formula B1 by 1HNMR and ESI-MS, and the reaction was quantitatively completed.

[0058] R f =0.4(PE / AE=2:1)

[0059] 1 HNMR (CDCl 3 ,400MHz):δ7.65(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),7.04(brs,1H),3.08-3.02(m,1H),1.73-1.64( m,1H),1.52(t,J=7.2Hz,2H),1.27(s,6H)...

Embodiment 2

[0061] Embodiment 2: the synthesis of formula IIb+II'b mixture:

[0062] Weigh the compound of formula B1 (317mg, 0.80mmol, 1eq) and dissolve it in THF (4mL), add (+)-pinanediol (272mg, 1.60mmol, 2eq), and react at room temperature for 2 hours to obtain IIb+II'b mixture (230mg, 64%).

[0063] 1 HNMR (CDCl 3 ,400MHz):δ7.64,7.63(d,J=8.0Hz,2H),7.55(d,J=8.4Hz,2H),6.70,6.59(brs,1H),4.36-4.27(m,1H), 3.36-3.19(m,1H),2.40-2.28(m,1H),2.26-2.13(m,1H),2.09-1.97(m,1H),1.95-1.80(m,2H),1.78-1.61(m ,1H),1.61-1.51(m,2H),1.44,1.42(s,3H),1.41-1.33(m,1H),1.29(s,3H),0.95(d,J=6.4Hz,6H), 0.86(s,3H).

[0064] MS(ESI,m / z):446.1([M( 79 Br)-H] + ),448.1([M( 81 Br)-H] + ).

Embodiment 3

[0065] Embodiment 3: the synthesis of formula IIb compound:

[0066] The compound of formula Ib (90mg, 0.3mmol, 1eq) was weighed and placed in a 25mL single-necked bottle. The temperature was cooled in an ice bath, and regular dichloromethane (3 mL) was added. Then weigh p-bromobenzoyl chloride (99mg, 0.45mmol, 1.5eq) and add it into the reaction flask. Measure Et 3 N (84 μL, 0.6 mmol, 2.0 eq), was added dropwise to the reaction. The reaction was about 5 minutes, and the reaction ended. Direct concentration, dry loading, column chromatography. The target product (133 mg, yield 99%, ee value 97.0%) was obtained.

[0067] 1 HNMR (CDCl 3 ,400MHz):δ7.64(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),6.64(brs,1H),4.34-4.29(m,1H),3.29-3.21( m,1H),2.40-2.29(m,1H),2.22-2.13(m,1H),2.07-1.99(m,1H),1.95-1.82(m,2H),1.78-1.67(m,1H), 1.59-1.51(m,2H),1.44(s,3H),1.38-1.33(m,1H),1.29(s,3H),0.95(d,J=6.8Hz,6H),0.86(s,3H) .

[0068] MS(ESI,m / z):446.1([M( 79 Br)-H] + ),448.1([M( 81 Br)-H] + ).

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Abstract

The present invention relates to an amide borate for detecting bortezomib intermediate purity, wherein the amide borate is a compound having the following structure formula, the compound is an optically pure compound II or a diastereoisomer II', and X is fluorine, chlorine, bromine or iodine. According to the present invention, the amide borate is used for rapid detection of the optical purity of the bortezomib key intermediate (R)-leucine borate, wherein the fluorescent chromophore protection group is introduced into the (R)-leucine borate with the simple one-step chemical reaction to obtain the amino borate derivative having strong ultraviolet absorption, wherein the derivative can be provided for quantitatively and rapidly detecting the optical purity through HPLC. The method has characteristics of simple process operation, high sensitivity and high accuracy.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an amide borate, a preparation method and an application thereof. It is also an analysis method for a bortezomib intermediate, and a method for preparing high-purity bortezomib through quality control of the intermediate. Background technique [0002] Bortezomib, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarboxy)amino]propyl]amino] Butyl] boronic acid, structural formula is as follows: [0003] [0004] Bortezomib is a new type of anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. It is a synthetic, highly selective and reversible inhibitor of chymotrypsin-like activity of the 26S proteasome, mainly by blocking a variety of intracellular regulation of apoptosis. The degradation of apoptosis and signaling proteins leads to the death of tumor cells. The FDA approved bortezomib in 2003 for the treatment of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/04G01N30/02
Inventor 林国强赵俊田平宗在伟孙彩云赵宇
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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