CN107674046A

CN107674046A - A kind of purification process of atazanavir epoxide intermediates

Info

Publication number: CN107674046A
Application number: CN201610615878.5A
Authority: CN
Inventors: 李涛
Original assignee: GYROCHEM (SHANGHAI PUYI) CO Ltd
Current assignee: GYROCHEM (SHANGHAI PUYI) CO Ltd
Priority date: 2016-08-01
Filing date: 2016-08-01
Publication date: 2018-02-09
Anticipated expiration: 2036-08-01
Also published as: CN107674046B

Abstract

The present invention relates to a kind of purification process of the phenyl butane (I) of 1,2 epoxy of atazanavir epoxide intermediates (2R, 3S), 3 t-butoxycarbonyl amino 4.This method is using the oily crude product of gained after reacting as raw material, using normal heptane as solvent recrystallization, can be with higher production capacity, purity is obtained more than 99.5%, it is single it is miscellaneous be less than 0.1% lenticular product, improved method is provided to the phenyl butane (I) of 3 t-butoxycarbonyl amino of industry law production (2R, 3S) 1,2 epoxy 4.

Description

A kind of purification process of atazanavir epoxide intermediates

Technical field

The present invention relates to anti-AIDS drug atazanavir intermediate technical field, more particularly to (2R, 3S) -1,2- rings The purification process of oxygen -3- t-butoxycarbonyl amino -4- phenyl butanes.

Background technology

Atazanavir (Atazanavir) is by Bristol-Myers Squibb Co.（BMS）A kind of new azepine peptides of exploitation HIV-1 protease inhibitors, it is the active drug for treating AIDS, is approved listing by U.S. FDA within 2003；And (2R, 3S)- 1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I) are one of important intermediates for synthesizing atazanavir.

(2R, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I) are usually with the chloro- 2- hydroxyls of (2R, 3S) -1- Base -3- t-butoxycarbonyl amino -4- phenyl butanes (II) are raw material, in the presence of the alkali of sodium hydroxide or potassium carbonate etc, Cyclization obtains in alcohol or acetone equal solvent, as EP1777213,J. Med. Chem.1994, 37(12), 1758 – Described in 1768 grade documents（Formula 1）.Because (2R, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I) are fat-soluble Good, fusing point is not also high, so the crude product (I) that reaction end post processing obtains is often colourless or pale yellow oil, places 2 Be possible to solidification within ~ 3 days and obtain waxy solid, it has not been convenient to the quality control of product, it is therefore desirable to further crystallization purifying ability Obtain white crystal.

Formula 1

In (2R, 3S) -1,2- epoxies -3- t-butoxycarbonyl amino -4- phenyl butanes (I) crude product according to contained by the difference of technique Impurity also difference, it in general can contain and non-reflect isomers (2S, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- benzene Base butane, residual solvent, water etc.；The purifying of (2R, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I), one As report have following several method：

1st, column chromatography is purified, and such as patent US2002/72621, US6348615 is reported.Although column chromatography purifying can obtain purity Very high product, but be not suitable for industrialized production and amplification.

2nd, the mixed solvent of acetone or alcohol and water recrystallize, as have respectively in patent EP1777213 acetone/water, isopropanol/ The recrystallization example of the systems such as water, due to the presence of water, cause product crystallization more difficult, it is necessary to add crystal seed, and it is long when Between low temperature crystallization can just obtain crystal, yield and purity will be almost.

3rd, n-hexane/water or n-hexane recrystallization, such as documentOrg. Proc. Res. Dev.2002, 6(3), 323 There is the report of n-hexane/water in -328.Comparatively this method is relatively good method, the yield of products obtained therefrom is in document 88%, purity 97%.

The content of the invention

It is contemplated that in a kind of atazanavir epoxide intermediates (2R, 3S) -1,2- epoxy -3- tertbutyloxycarbonyl ammonia The purification process of base -4- phenyl butanes (I).In summary document after the advantage and disadvantage of purification process, after the present invention is to react The oily crude product (I) of gained is raw material, and it is solvent recrystallization to select normal heptane, can be obtained purity with higher production capacity and be more than 99.5%, it is single it is miscellaneous be less than 0.1% lenticular product, (2R, 3S) -1,2- epoxy -3- tertbutyloxycarbonyl ammonia is produced to industry law Base -4- phenyl butanes (I) provide improved method.

The present invention includes following steps：

(1) it is dissolved in the oily crude product (I) of gained after reaction for raw material in a certain amount of normal heptane；

Preferably, the content of formula (I) is 90 ~ 98% in oily crude product, volume and the oily weight of crude product ratio of normal heptane used For 4:1~6:1..

(2) drier is added in step a solution, controls moisture；

Preferably, moisture is less than 0.01% in n-heptane solution.

(3) drier and concentrated solvent are filtered to remove, then will warm up backflow；

Preferably, drier includes anhydrous magnesium sulfate, molecular sieve；After concentrated solvent, the volume of normal heptane and oily are thick in system Products weight ratio is 3:1~4:1.

(4) mother liquor in step c is slowly cooled crystallization, obtains product.

Preferably, the temperature of cooling crystallization is -20 ~ 0 DEG C.

Contrast n-hexane makees the crystallization processes of solvent, and beneficial effects of the present invention are characterized in particular in：

1. the solvent of same weight, it is bigger than n-hexane production capacity that solvent is made using normal heptane.The boiling point of n-hexane is 69 DEG C, and positive heptan The boiling point of alkane is 98 DEG C, and equally in the case where being heated to reflux, n-heptane system can dissolve more substrates；According to embodiment result Calculate, often obtaining qualified (2R, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I) of 100G about needs 350mL or so normal heptane, and need 500mL or so with n-hexane.

2. crystallization effect is more preferable, product quality is more preferably.It was found that the content of solvent reclaimed water has a great influence to crystallization, and Solubility of the water in normal heptane（0.010%, 25 DEG C）Compare n-hexane（0.011%, 25 DEG C）Smaller, this is just easier normal heptane Crystallization；It is all the crude product that purity is 92% according to embodiment result, purity more than 99.0% is once can reach with n-hexane crystallization, it is single Miscellaneous less than 0.2%, and once can reach purity more than 99.5%, list miscellaneous less than 0.1% with normal heptane crystallization.

3. it is amid all these factors, that recrystallisation solvent replaces n-hexane to improve (2R, 3S) -1,2- rings with normal heptane The crystallization production capacity of oxygen -3- t-butoxycarbonyl amino -4- phenyl butanes (I), and be advantageous to the lifting of product quality.

Embodiment

In order to be more clearly understood that the technology contents of the present invention, described in detail especially exemplified by following examples.

Embodiment 1：

150g raw materials (2R, 3S) -1- chlorine-2-hydroxyl -3- t-butoxycarbonyl amino -4- phenyl butanes (II) are dissolved in 500mL third In ketone, 1mol/L NaOH aqueous solution 100mL, stirring at normal temperature 2 hours are added；After the completion of TLC monitoring reactions, concentration removes big Part acetone, and be extracted with ethyl acetate twice；The organic phase aqueous citric acid solution of merging, water, saturated common salt water washing, do It is dry, filter and concentrate, obtain the faint yellow oily crude products (2R, 3S) of 130g -1,2- epoxy -3- t-butoxycarbonyl amino -4- benzene Base butane (I), thick yield 98.7%, HPLC purity 92%, maximum single miscellaneous 1.0%.

Embodiment 2：

Above-mentioned (2R, 3S) -1,2- epoxies -3- t-butoxycarbonyl aminos -4- phenyl butanes (I) crude products of 50g are taken, are dissolved in In 250mL normal heptanes, and anhydrous magnesium sulfate drying 1h is added, the water content in water content detection system is 0.008%；It is filtered to remove After anhydrous magnesium sulfate, system is concentrated into 150mL or so, reclaims the normal heptane steamed, now system has solid precipitation, is heated to Backflow makes its dissolving；By system slow cooling to room temperature, then it is positioned in -10 DEG C of refrigerators 4 hours, separates out a large amount of white crystals. Filter, wash and dry, obtain 44g white crystals (2R, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I), yield 88.0%, HPLC purity 99.8%, maximum single miscellaneous 0.08%.

¹H NMR (300 MHz, CDCl₃) δ 7.30–7.24 (m, 5H), 4.53 (s, 1H), 4.11 (s, 1H), 3.01–2.85 (m, 3H), 2.70 (dd, J = 8.8, 4.4Hz, 1H), 2.58 (s, 1H), 1.39 (s, 9H); ¹⁹F NMR (300 MHz, CDCl₃): δ –195.2 (d, J = 49.3Hz, 1F).

MS (ESI) m/z = 286.1 (M+Na⁺).

Embodiment 3：

Above-mentioned (2R, 3S) -1,2- epoxies -3- t-butoxycarbonyl aminos -4- phenyl butanes (I) crude products of 50g are taken, are dissolved in In 400mL n-hexanes, and anhydrous magnesium sulfate drying 1h is added, the water content in water content detection system is 0.011%；It is filtered to remove After anhydrous magnesium sulfate, system is concentrated into 250mL or so, reclaims the n-hexane steamed, now system has solid precipitation, is heated to Backflow makes its dissolving；By system slow cooling to room temperature, then it is positioned in -10 DEG C of refrigerators 8 hours, separates out a large amount of white crystals. Filter, wash and dry, obtain 40g white crystals (2R, 3S) -1,2- epoxy -3- t-butoxycarbonyl amino -4- phenyl butanes (I), yield 80.0%, HPLC purity 99.2%, maximum single miscellaneous 0.15%.

Spectral data is shown in embodiment 2.

In this description, the present invention is described with reference to its specific embodiment.But it is clear that it can still make various Modification and conversion are without departing from the spirit and scope of the present invention.Therefore, specification is considered as illustrative and non-limiting 's.

Claims

1. a kind of purification process of atazanavir epoxide intermediates, refer specifically to (2R, 3S) -1,2- epoxy -3- tertiary butyloxycarbonyls Base amino-4-phenyl butane (I), this method comprises the following steps：

A) it is dissolved in the oily crude product (I) of gained after reaction for raw material in a certain amount of normal heptane；

B) drier is added in step a solution, controls moisture；

C) drier and concentrated solvent are filtered to remove, then will warm up backflow；

D) mother liquor in step c is slowly cooled crystallization, obtains product

。

2. according to the method described in claim 1a, it is characterised in that the content of formula (I) is 90 ~ 98% in oily crude product, institute It is 4 with the volume and oily weight of crude product ratio of normal heptane:1~6:1.

3. according to the method described in claim 1b, it is characterised in that moisture is less than 0.01% in n-heptane solution.

4. according to the method described in claim 1c, it is characterised in that drier includes anhydrous magnesium sulfate, molecular sieve；Concentrate molten After agent, the volume of normal heptane and oily weight of crude product ratio are 3 in system:1~4:1.

5. according to the method described in claim 1d, it is characterised in that the temperature of cooling crystallization is -20 ~ 0 DEG C.