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Novel method for synthesizing Atazanavir

A new method and compound technology, which is applied in the field of chemical drug synthesis, can solve the problems of unsuitable industrial production requirements, many synthesis steps, and high total cost, and achieve the effects of low price, simple purification treatment, and reduced total cost

Inactive Publication Date: 2012-06-06
SHANGHAI ACEBRIGHT PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Although this route is milder than the reaction conditions of route 1 and 2, there are still many synthetic steps, and to obtain a high-purity product, the final product needs to be purified by silica gel column chromatography, and the yield is low, so that the total cost is still very high. Not suitable for industrial production needs

Method used

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  • Novel method for synthesizing Atazanavir
  • Novel method for synthesizing Atazanavir
  • Novel method for synthesizing Atazanavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: synthetic formula I compound

[0034]

[0035] a) Synthesis of compound 1:

[0036] Add p-bromobenzaldehyde (37g, 0.2mol) into methanol (500ml) dissolved with trimethyl orthoformate (31.8g, 0.3mol) and p-toluenesulfonic acid (0.38g, 2mmol), and stir at room temperature for 3 hours Sodium methoxide (0.43 g, 8 mmol) was added, the solution was concentrated after stirring for 1 hour, and the colorless oily liquid 1 was obtained by filtration, 44.96 g, yield 98%. 1 HNMR (CDCl 3 )δ: 7.49 (d, 2H, J = 8.7Hz), 7.33 (d, 2H, J = 8.7Hz), 5.36 (s, 1H), 3.30 (s, 6H).

[0037] b) Synthesis of compound 2:

[0038] Add compound 1 (44.89g, 195mmol) into tetrahydrofuran (40ml) dissolved with magnesium chips (5.11g, 212mmol), add a small amount of iodine, initiate under heating, and the solution turns brown; stir for 1 hour after initiation; Add the Grignard reagent dissolved in dibromopyridine (17.14ml, 177mmol) and Ni[dppp]Cl under ice bath 2 (1 g) in tetrahydrofur...

Embodiment 2

[0045] Embodiment 2: synthetic formula III compound

[0046]

[0047] At room temperature, sodium iodide (12.4g, 83mmol) was added into acetonitrile (250ml) dissolving 76mmol of compound of formula II (250ml), stirred for 30 minutes and then added MeCN solution (350ml) of 83mmol of compound of formula I dissolved, and continued to stir for 30 minutes , add sodium bicarbonate (12.7g, 152mmol), stir at room temperature for 12 hours and remove acetonitrile under reduced pressure, the system is diluted with ethyl acetate (800ml), washed twice with saturated potassium hydrogensulfate (300ml), washed with saturated brine (600ml) Wash once, dry, and concentrate to obtain the crude product, reflux with ethanol / water=1:2, the system gradually becomes transparent, cool down to room temperature, spin dry the ethanol under reduced pressure, extract the aqueous phase with ethyl acetate (200ml) three times, The organic phases were combined, dried and concentrated to obtain the compound o...

Embodiment 3

[0048] Embodiment 3: Synthesis of N-methoxycarbonyl-L-tert-leucine

[0049]

[0050] a) Synthesis of Compound 5:

[0051] Under ice bath, 3,3-dimethyl-butan-2-one (62.5ml, 0.5mol) was slowly added dropwise into a solution of potassium permanganate (158g, 1mol), sodium hydroxide (50g, 1.25mol) Aqueous solution (1L), stirred at 0°C for 1 hour, heated to 25°C and stirred for 2 hours; filtered the mixture with suction, washed the manganese dioxide residue with a small amount of hot water for 3 times, combined the filtrate and washing liquid, concentrated to 200ml, adjusted with 6N hydrochloric acid The concentrated solution was adjusted to a pH value of 3, extracted three times with ethyl acetate (100ml), combined the extracts, and dried with anhydrous sodium sulfate; the diethyl ether was drained, and the resulting oily product was distilled under reduced pressure, and fractions at 100°C / 30225kPa were collected to obtain Color oily liquid 5, 45.45g, yield 70%. 1 HNMR (CDCl ...

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Abstract

The invention discloses a novel method for synthesizing Atazanavir. The method comprises steps of: carrying out a nucleophilic substitution reaction on a compound shown as a formula I N-1-(t-butoxycarbony)-N-2-[4-(2-pyridyl) benzylidene]-hydrazine and a compound shown as a formula II (S)-4-chlorine-3-carbonyl-1-phenyl butane-2-tert-butyl carbamate to obtain an intermediate shown as a formula III; removing protective groups of the intermediate shown as a formula III and carrying out condensation reaction with N-methoxycarbonyl-L-tert-leucine to obtain an intermediate shown as a formula IV; carrying out a reduction reaction on the intermediate shown as the formula IV; and a reaction formula is shown as below. The synthetic method has advantages of mild reaction conditions, high security, simple operation, simple purification treatment on end product, high purity, stable quality, easily available raw material, low price and high overall yield, so as to substantially reduce cost and apply to demand of large-scale industrialized production.

Description

technical field [0001] The invention relates to a new synthesis method of HIV-1 protease inhibitor Atazanavir (Atazanavir), which belongs to the technical field of chemical drug synthesis. Background technique [0002] Atazanavir is an open-chain azapeptidomimetic compound and a novel HIV-1 protease inhibitor. Compared with other protease inhibitors, atazanavir has two significant advantages: firstly, it is the only protease inhibitor approved to be taken once a day, which will greatly simplify the dosage course; secondly, atazanavir has not been shown to increase the patient's Cholesterol and triglyceride levels, a challenge that all other protease inhibitors encounter to varying degrees. The structure of atazanavir is as follows: [0003] [0004] There are three main synthetic routes about atazanavir in the prior art: [0005] Route 1: Using p-bromobenzaldehyde as a raw material, the intermediate N-1-(tert-butoxycarbonyl)-N-2-[ (S)-1- ((R)-2-oxirane)-2-phenylethyl...

Claims

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Application Information

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IPC IPC(8): C07D213/42
CPCY02P20/55
Inventor 李金亮
Owner SHANGHAI ACEBRIGHT PHARMA GRP
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