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Bortezomib synthesis intermediate preparation method

A technology for bortezomib and intermediates, which is applied in the field of bortezomib synthesis intermediates, and can solve the problems of high content of deboronation by-products, low catalytic activity, immature process, etc.

Active Publication Date: 2015-08-26
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The Ellman method is condensed by isovaleraldehyde and the chiral ligand R-tert-butylsulfinamide, and then undergoes asymmetric addition with pinacol biboronic ester under the catalysis of (NHC) CuOt-Bu, and then hydrolyzes A method for preparing (R) 1-amino-3-methylbutylboronic acid pinacol ester hydrochloride (I), the method uses a single N-heterocyclic carbene tert-butoxide copper catalysis, and the catalytic activity is low, The addition reaction period is long, which leads to high content of deboronation by-products in the reaction solution, low yield, and poor stereoselectivity. It needs to be separated by column chromatography to improve the purity to meet the requirements of the next reaction. Therefore, this method is only in the experimental stage. Laboratory research stage, immature technology, not suitable for industrial production

Method used

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  • Bortezomib synthesis intermediate preparation method
  • Bortezomib synthesis intermediate preparation method
  • Bortezomib synthesis intermediate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1 Preparation of Icy.BF4

[0078] Add paraformaldehyde (12.6g), toluene (400ml), and cyclohexylamine (39.6g) into a 1000ml reaction bottle, react at room temperature for 1.5 hours, raise the temperature to 40°C, and add another portion of cyclohexylamine (39.6g) , then dropwise add tetrafluoroboric acid (40% HBF4, 88g) aqueous solution, add about 0.5 hours, stir for 10 minutes, cool down to 0°C, add glyoxal (58g), stir at 0-5°C for 2 hours, heat up to 20°C ℃, stirred at 20-25℃ for 3 hours, a large amount of solid precipitated out, cooled to 0-5℃ and stirred for 2 hours, filtered, washed the solid twice with water and twice with ether, drained, and air-dried indoors to obtain 82g of crude Icy.BF4.

[0079] Add crude Icy.BF4 (82g), dichloromethane (500ml), and ethyl acetate (500ml) into a 2000ml reaction flask, raise the temperature to reflux to dissolve the solid material, filter out the insoluble matter, and stir the filtrate at room temperature for 1 hour, 0-5 ...

Embodiment 2

[0080] Example 2 Preparation of (R)-1-N-(tert-butylsulfinyl)-3-methylbutylimine (b3)

[0081] In a 50L reactor equipped with a reflux condenser, sequentially add (R)-tert-butylsulfinamide (b2) (0.93Kg), dichloromethane (14.9Kg), isovaleraldehyde (b1) (1.02Kg) , anhydrous magnesium sulfate (5Kg), PPTS (0.094Kg), turn on the stirring water bath and raise the temperature to reflux, the temperature of the water bath is controlled at 47-50°C, the reflux reaction is 6 hours HPLC monitoring b2 disappears, drop to room temperature and filter, wash with dichloromethane Dehydrating agent, combined with dichloromethane solution, washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate for 3 hours, filtered, washed with dichloromethane, combined with dichloromethane solution, spin-dried at 40°C under reduced pressure , and then pumped under reduced pressure with a diaphragm pump for 3 hours. Obtain b3 (1.24Kg), yield 90%. This intermediate was directly use...

Embodiment 3

[0082] Example 3 Preparation of hydrochloride (I) of (R)-1-amino-3-methylbutylboronic acid pinacol ester

[0083] Add Icy.BF4 (0.062Kg), tetrahydrofuran (6.4Kg), potassium tert-butoxide (0.048Kg) into a 30L reactor, add CuCl (0.0192Kg), b4 (1.176Kg) and stir for 2 hours under the protection of argon , add b3 (0.72Kg) and methanol (122g), react at 20-25°C for 3 hours, TLC monitors the disappearance of raw material b3, absorb the reaction solution into a 50L separator, add ethyl acetate (16.2Kg) to dilute, and use pure Washed with water three times, dried overnight with anhydrous sodium sulfate (7.5Kg), filtered the next day, and the filtrate was concentrated to dryness at 34°C under reduced pressure to obtain a yellow oil b5 (1.07Kg), which was directly used in the next step without purification.

[0084] Dissolve b5 prepared in the previous step with dioxane (9.6Kg) and methanol (3.2Kg), transfer it to a 30L reactor, adjust the temperature to 20°C, add HCl dioxane solution (4M...

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Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation process of a bortezomib synthesis intermediate (R) 1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride. The preparation process comprises that in an ether and / or benzene solvent, (R)-1-N-(tert-butyl sulfinyl)-3-methylbutyl imine and bis borate are subjected to nucleophilic addition at a temperature of 0-30 DEG C in a reactor filled with argon gas or nitrogen gas under co-catalysis of an azacyclo carbene copper tert-butoxide coordination compound (NHC) CuOt-Bu and a proton donor to obtain the (R)-1-N-(tert-butyl sulfinyl)-3-methylbutylamine-1-boronic acid pinacol ester.

Description

Technical field: [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation process of (R) 1-amino-3-methylbutylboronic acid pinacol ester hydrochloride, a synthetic intermediate of bortezomib. Background technique: [0002] Bortezomib, chemical name [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)-amino] Propyl]amino]boronic acid, the trade name is Velcade, and its chemical structure is as follows: [0003] [0004] Bortezomib is a proteasome inhibitor developed by Millennium Corporation of the United States. It is the first dipeptide boronic acid proteasome inhibitor, which can reversibly bind to 26S proteasome, block protein degradation, and prevent malignant proliferation of tumor cells. Clinically for the treatment of multiple myeloma (MM). [0005] Bortezomib is a chiral dipeptide compound. The key to the synthesis of bortezomib is the synthesis of the chiral intermediate (R) 1-amino-3-methylb...

Claims

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Application Information

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IPC IPC(8): C07F5/04C07K5/078C07K1/02
CPCC07F5/022C07F5/04
Inventor 吕家森周微李万亮王国成
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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