CN104098509B - A kind of method for preparing A type atazanavir sulfate - Google Patents
A kind of method for preparing A type atazanavir sulfate Download PDFInfo
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- CN104098509B CN104098509B CN201310128459.5A CN201310128459A CN104098509B CN 104098509 B CN104098509 B CN 104098509B CN 201310128459 A CN201310128459 A CN 201310128459A CN 104098509 B CN104098509 B CN 104098509B
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- atazanavir
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- atazanavir sulfate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
Abstract
The invention discloses a kind of method for preparing A type atazanavir sulfate, it comprises the following steps：Atazanavir free alkali is added in organic solvent, prepares settled solution；Described organic solvent is selected from least one of dimethyl sulfoxide (DMSO), esters solvent and ether solvent；Temperature is controlled at 10~65 DEG C, the concentrated sulfuric acid is added dropwise in the settled solution prepared to step a)；Drop finishes, insulated and stirred 0.5~10 hour；Cooling, filter, wash, dry.The present invention is by selecting specific solvent; realize with simplest operation, prepare high-purity A type atazanavir sulfate in high yield, and short preparation period, cost are cheap, without special installation and harsh conditions and operation; the big production of scale is especially suitable for, there is practical value.
Description
Technical field
The present invention relates to a kind of method for preparing A type atazanavir sulfate, belong to technical field of organic chemistry.
Background technology
Atazanavir is a kind of oral hiv protease inhibitor, is developed and listed by Bristol-Myers Squibb Co., obtained within 2003
U.S. FDA approval listing is obtained, the sharp Chinese mugwort of trade name is appropriate.
Novartis disclosed in the patent WO9740029 of application in 1997 one group of heterocycle azepine with antiviral activity oneself
Alkane derivatives, including atazanavir, Bristol-Myers Squibb Co. discloses in the patent WO9936404 of application in 1998
Sulfuric acid atazanavir.
At present, the report on sulfuric acid atazanavir crystal formation mainly has A types, c-type, E3 types, H1 types, Type B, p-type and without fixed
Shape is several, and wherein A types, c-type and E3 types are applied by Bristol-Myers Squibb Co., and A types are non-solvent compound crystal formation, and c-type is
Hydrate crystal forms, E3 types are the solvate containing 3 molecules of ethanol.
A kind of method for preparing A type atazanavir sulfate is disclosed in Chinese patent ZL200580022550.2, it is adopted
The solution of atazanavir free alkali and Part I sulfuric acid is set to react at relatively high temperatures with acetone, ethanol equal solvent, when
During the formation of atazanavir vitriol, the multistage is divided to add the other concentrated sulfuric acid to have with increased speed according to cubic equation
The formation atazanavir vitriol of effect, then form A type atazanavir vitriols through drying.This method is preparing A
Poisonous and harmful substance is easily produced during type atazanavir sulfate（Genotoxicity impurity）, in addition, this method is when being added dropwise sulfuric acid
Mode is added dropwise using the cubic equation multistage, operation is more loaded down with trivial details, is also unfavorable for industrialized production.
The content of the invention
In view of the above-mentioned problems existing in the prior art, it is an object of the invention to provide a kind of scale simple to operate, suitable
The method for preparing high-purity A type atazanavir sulfate.
For achieving the above object, the technical solution adopted by the present invention is as follows：
A kind of method for preparing A type atazanavir sulfate, comprises the following steps：
A) atazanavir free alkali is added in organic solvent, prepares settled solution；Described organic solvent is selected from diformazan
Base sulfoxide（DMSO）, at least one of esters solvent and ether solvent；
B) control temperature that the concentrated sulfuric acid is added dropwise in the settled solution prepared to step a) at 10~65 DEG C；
C) drop finishes, insulated and stirred 0.5~10 hour；
D) cool, filter, wash, dry, produce A type atazanavir sulfate.
As a kind of preferred scheme, described organic solvent is to include dimethyl sulfoxide (DMSO)（DMSO）Mixed solvent.
As further preferred scheme, the dimethyl sulfoxide (DMSO) of the in the mixed solvent（DMSO）Shared volume content is 1%
~30%.
As a kind of preferred scheme, described esters solvent is selected from ethyl acetate, isopropyl acetate, butyl acetate, acetic acid
At least one of isobutyl ester, methyl acetate.
As further preferred scheme, described esters solvent is selected from least one of ethyl acetate, isopropyl acetate.
As a kind of preferred scheme, described ether solvent be selected from isopropyl ether, methyl tertiary butyl ether(MTBE), glycol dimethyl ether,
At least one of ether, tetrahydrofuran.
As further preferred scheme, described ether solvent is selected from glycol dimethyl ether.
As a kind of preferred scheme, the molar concentration of the concentrated sulfuric acid is 16~20mol/L.
As a kind of preferred scheme, the mol ratio of sulfuric acid and atazanavir free alkali is 0.8:1~1.5:1.
As further preferred scheme, the mol ratio of sulfuric acid and atazanavir free alkali is 0.95:1~1.05:1.
Compared with prior art, the present invention is by selecting specific solvent（Selected from dimethyl sulfoxide (DMSO), esters solvent and ethers
At least one of solvent）, realize with simplest operation（The concentrated sulfuric acid need not be added dropwise using the cubic equation multistage）, high receive
Rate（Molar yield is up to 90%~94%）Prepare high-purity（HPLC purity ＞ 99.5%, maximum single miscellaneous ＜ 0.1%）A type atazanavirs
Sulfate, and short preparation period, cost are cheap, and without special installation and harsh conditions and operation, it is big to be especially suitable for scale
Production, has practical value.
Brief description of the drawings
Fig. 1 is by the infrared of the A type atazanavir sulfate of present invention method acquisition（FTIR）Collection of illustrative plates；Test-strips
Part is：Analyzed using the Spectrum65 types infrared spectrophotometer of Perkin Elmer companies, tested with pellet technique,
Scanning range is 400~4000 wave numbers, instrumental resolution 4cm-1。
Fig. 2 is the means of differential scanning calorimetry of the A type atazanavir sulfate obtained by present invention method（DSC）Figure
Spectrum；Test condition is：Using the Q2000 differential scanning calorimeters of TA companies of the U.S.（DSC）；Temperature measurement range is 30~230
DEG C, heating rate is 10 DEG C/min, and air-flow uses nitrogen, gas flow 50mL/min.
Fig. 3 is the X-ray powder diffraction of the A type atazanavir sulfate obtained by present invention method（XRPD）Figure
Spectrum；Test condition is：Using the D8ADVANCE powder diffractometers of German Bruker-AXS companies, test parameter is：40KV,
40mA；Scanning range is 2~50 °；Step-length speed is 0.1 second/step.
Embodiment
The present invention is described in more detail with reference to the accompanying drawings and examples.
It is prepared for the commercially available prior art that can also refer to of atazanavir free alkali in embodiment.
Embodiment 1
Atazanavir free alkali (150g, 212.8mmol) is added and formed by 2250mL ethyl acetate and 150mL DMSO
In the mixed solvent, stirring heating under an argon, after system dissolved clarification, adding 1.5g activated carbon decolorizings, (system temperature is 50
~60 DEG C), filtering, settled solution is made；Control temperature that the concentrated sulfuric acid is added dropwise into the settled solution of preparation at 35 ± 5 DEG C
(11.82mL, 212.8mmol)；Drop finishes, insulated and stirred 1~2 hour；Slowly（About 30~60 minutes）0~15 DEG C is cooled to, mistake
Filter, filter cake are washed 2~3 times with ethyl acetate, are dried in vacuo 5~8 hours at 40~60 DEG C, are produced atazanavir sulfate
158g, molar yield 92.5%, HPLC purity ＞ 99.5%, maximum single miscellaneous ＜ 0.1%.
The FTIR collection of illustrative plates of the atazanavir sulfate that the present embodiment is obtained as shown in figure 1, DSC collection of illustrative plates as shown in Fig. 2
XRPD collection of illustrative plates is as shown in Figure 3；Because of the phase of above-mentioned TuPu method and the A type atazanavir sulfate described in patent WO9936404
Answer collection of illustrative plates consistent, therefore, the sample obtained by the present embodiment method is A type atazanavir sulfate.
Embodiment 2
Atazanavir free alkali (10g, 14.19mmol) is added and mixed by what 120mL ethyl acetate and 10mL DMSO were formed
In bonding solvent, stirring heating under an argon, after system dissolved clarification, adding 0.1g activated carbon decolorizings, (system temperature is 50~60
DEG C), filtering, settled solution is made；Control temperature at 35 ± 5 DEG C, into the settled solution of preparation be added dropwise the concentrated sulfuric acid (0.8mL,
14.4mmol)；Drop finishes, insulated and stirred 1~2 hour；Slowly（About 30~60 minutes）0~15 DEG C is cooled to, is filtered, filter cake second
Acetoacetic ester washs 2~3 times, is dried in vacuo 5~8 hours at 40~60 DEG C, produces atazanavir sulfate 10.6g, molar yield
For 93.0%, HPLC purity ＞ 99.5%, maximum single miscellaneous ＜ 0.1%.
The atazanavir sulfate that the present embodiment is obtained also has the FTIR collection of illustrative plates shown in Fig. 1, the figures of the DSC shown in Fig. 2
Spectrum and Fig. 3 shown in XRPD collection of illustrative plates, be A type atazanavir sulfate.
Embodiment 3
Atazanavir free alkali (10g, 14.19mmol) is added what is formed by 120mL isopropyl acetates and 10mL DMSO
In the mixed solvent, stirring heating under an argon, after system dissolved clarification, add 0.1g activated carbon decolorizings (system temperature 50~
60 DEG C), filtering, settled solution is made；Control temperature that the concentrated sulfuric acid is added dropwise into the settled solution of preparation at 35 ± 5 DEG C
(0.8mL, 14.4mmol)；Drop finishes, insulated and stirred 1~2 hour；Slowly（About 30~60 minutes）0~15 DEG C is cooled to, is filtered,
Filter cake is washed 2~3 times with isopropyl acetate, is dried in vacuo 5~8 hours at 40~60 DEG C, is produced atazanavir sulfate
10.3g, molar yield 90.4%, HPLC purity ＞ 99.5%, maximum single miscellaneous ＜ 0.1%.
The atazanavir sulfate that the present embodiment is obtained also has the FTIR collection of illustrative plates shown in Fig. 1, the figures of the DSC shown in Fig. 2
Spectrum and Fig. 3 shown in XRPD collection of illustrative plates, be A type atazanavir sulfate.
Embodiment 4
Atazanavir free alkali (10g, 14.19mmol) is added and formed by 150mL glycol dimethyl ethers and 8mL DMSO
In the mixed solvent, stirring heating under an argon, after system dissolved clarification, adding 0.1g activated carbon decolorizings, (system temperature is 50
~60 DEG C), filtering, settled solution is made；Control temperature that the concentrated sulfuric acid is added dropwise into the settled solution of preparation at 35 ± 5 DEG C
(0.8mL, 14.4mmol)；Drop finishes, insulated and stirred 1~2 hour；Slowly（About 30~60 minutes）0~15 DEG C is cooled to, is filtered,
Filter cake spent glycol dimethyl ether washs 2~3 times, is dried in vacuo 5~8 hours at 40~60 DEG C, produces atazanavir sulfate
10.7g, molar yield 94.0%, HPLC purity ＞ 99.5%, maximum single miscellaneous ＜ 0.1%.
The atazanavir sulfate that the present embodiment is obtained also has the FTIR collection of illustrative plates shown in Fig. 1, the figures of the DSC shown in Fig. 2
Spectrum and Fig. 3 shown in XRPD collection of illustrative plates, be A type atazanavir sulfate.
Embodiment 5
Atazanavir free alkali (10g, 14.19mmol) is added by 100mL glycol dimethyl ethers, 100mL ethyl acetate
The in the mixed solvent formed with 8mL DMSO, stirring heating under an argon, after system dissolved clarification, add 0.1g activated carbon decolorizings
(system temperature is at 50~60 DEG C), filtering, settled solution is made；Temperature is controlled at 35 ± 5 DEG C, into the settled solution of preparation
The concentrated sulfuric acid (0.8mL, 14.4mmol) is added dropwise；Drop finishes, insulated and stirred 1~2 hour；Slowly（About 30~60 minutes）It is cooled to 0~
15 DEG C, filtering, filter cake spent glycol dimethyl ether washs 2~3 times, is dried in vacuo 5~8 hours at 40~60 DEG C, produces A Zhana
Wei sulfate 10.3g, molar yield 90.4%, HPLC purity ＞ 99.5%, maximum single miscellaneous ＜ 0.1%.
The atazanavir sulfate that the present embodiment is obtained also has the FTIR collection of illustrative plates shown in Fig. 1, the figures of the DSC shown in Fig. 2
Spectrum and Fig. 3 shown in XRPD collection of illustrative plates, be A type atazanavir sulfate.
It is last it is necessarily pointed out that：Above example is served only for carrying out furtherly technical scheme
It is bright, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art makes according to the above of the present invention
Some nonessential modifications and adaptations belong to protection scope of the present invention.
Claims (4)
- A kind of 1. method for preparing A type atazanavir sulfate, it is characterised in that comprise the following steps：A) atazanavir free alkali is added in organic solvent, prepares settled solution；Described organic solvent is by esters solvent And the mixed solvent that at least one of ether solvent is formed with dimethyl sulfoxide (DMSO), and the dimethyl sulfoxide (DMSO) of the in the mixed solvent Shared volume content is 1%~30%；Described esters solvent is selected from ethyl acetate, isopropyl acetate, butyl acetate, acetic acid At least one of isobutyl ester, methyl acetate；Described ether solvent is selected from isopropyl ether, methyl tertiary butyl ether(MTBE), glycol dinitrate At least one of ether, ether, tetrahydrofuran；B) control temperature that the concentrated sulfuric acid is added dropwise in the settled solution prepared to step a) at 10~65 DEG C；The concentrated sulfuric acid rubs Your concentration be 16~20mol/L, and is 0.8 with the mol ratio of atazanavir free alkali:1~1.5:1；C) drop finishes, insulated and stirred 0.5~10 hour；D) cool, filter, wash, dry, produce A type atazanavir sulfate.
- 2. the method according to claim 1 for preparing A type atazanavir sulfate, it is characterised in that：Described esters are molten Agent is selected from least one of ethyl acetate, isopropyl acetate.
- 3. the method according to claim 1 for preparing A type atazanavir sulfate, it is characterised in that：Described ethers is molten Agent is selected from glycol dimethyl ether.
- 4. the method according to claim 1 for preparing A type atazanavir sulfate, it is characterised in that：Sulfuric acid and A Zhana The mol ratio of Wei free alkali is 0.95:1~1.05:1.
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| CN111349042B (en) * | 2018-12-20 | 2023-07-14 | 陕西理工大学 | Atazanavir single crystal and preparation method thereof |
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| CN102911113A (en) * | 2011-08-05 | 2013-02-06 | 浙江九洲药业股份有限公司 | Method for preparing atazanavir |
| CN102917695A (en) * | 2010-04-09 | 2013-02-06 | 百时美施贵宝公司 | Atazanavir sulfate formulations with improved ph effect |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102917695A (en) * | 2010-04-09 | 2013-02-06 | 百时美施贵宝公司 | Atazanavir sulfate formulations with improved ph effect |
| CN102911113A (en) * | 2011-08-05 | 2013-02-06 | 浙江九洲药业股份有限公司 | Method for preparing atazanavir |
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