CN106117148B - A kind of preparation and purification technique of Lopinavir - Google Patents
A kind of preparation and purification technique of Lopinavir Download PDFInfo
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- CN106117148B CN106117148B CN201610439389.9A CN201610439389A CN106117148B CN 106117148 B CN106117148 B CN 106117148B CN 201610439389 A CN201610439389 A CN 201610439389A CN 106117148 B CN106117148 B CN 106117148B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of preparation and purification technique of Lopinavir, belong to pharmaceutical synthesis field, comprising: which Lopinavir crude product is dissolved in methanol, water is added for the first time after being cooled to 0~5 DEG C, water continues to be cooled to -5~-15 DEG C after adding, and carries out first time insulated and stirred, isolates supernatant after standing, water is added dropwise second into supernatant, after stirring to solid is precipitated；Carry out third time plus water, the specific steps of third time plus water are as follows: within interval time, water is added dropwise in a point several batches, and water carries out second of insulated and stirred after adding at 10~15 DEG C, isolates Lopinavir.For the purifying process using a small amount of methanol and a large amount of water as purification solvent, toxicity is low and at low cost；It can be by HPLC purity (peak area %) less than 99.5% using purifying process of the invention, preferably smaller than 99.1% and containing more than two contents be more than 0.1% single impurity Lopinavir purifying crude to all single impurity contents less than 0.1%, HPLC purity is greater than 99.5%, and purification process loss late is less than 10%.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation and purification technique of Lopinavir.
Background technique
Lopinavir, chemical name are (2S)-N- [(2R, 4S, 5S) -5- [[2- (2,6- dimethyl phenoxy) acetyl] ammonia
Base] -4- hydroxyl -1,6- diphenyl-hex- 2- yl] -3- methyl -2- (2- oxo -1,3- diazacyclo hex- 1- yl) butyramide, be
Abbott is based on the improved hiv protease inhibitor of new generation of Ritonavir design, in structure as shown in formula (I)
Lopinavir contains the chiral carbon of 4 S- configurations, and intermediate involved in synthesis process has diastereoisomer to deposit
In the increase that (in total about 10%) leads to amount of impurities, further results in the difficulty that quality controls in industrialized production and increase.It is former
Material medicine quality control meets national standard, and the single impurity content of Lopinavir USP standard requirements is largely no more than 0.1%, few
Number is no more than 0.2%, and total impurities are no more than 0.7%.
Lopinavir crude product is prepared using existing synthesis technology, after USP35 standard analysis, retention time (RT) 33 minutes
Or the impurity content of RRT0.74 is more than 0.3%, cannot be removed using conventional purification methods reduces the impurity, so that Lopinavir
Difficulty reaches USP standard requirements.
Summary of the invention
First aspect present invention technical problems to be solved are: the Lopinavir for being more than 0.3% containing single impurity is thick
Product, after purifying, all single impurity contents are less than 0.1%, to meet the requirement of USP35.
Second aspect of the present invention technical problems to be solved are to provide a kind of high yield, avoid using containing chlorine (Cl) reagent or
The preparation method of the Lopinavir of solvent.
The technical issues of to solve first aspect present invention, the invention provides the following technical scheme:
A kind of purifying process of Lopinavir comprising: Lopinavir (Formula II) crude product is dissolved in methanol, is cooled to
Water is added after 0~5 DEG C for the first time, water continues to be cooled to -5~-15 DEG C after adding, and carries out first time insulated and stirred, divides after standing
Supernatant is separated out, water is added dropwise second into supernatant, after stirring to solid is precipitated；Carry out third time plus water, third time plus water
Specific steps are as follows: within interval time, water are added dropwise in a point several batches, and water carries out second at 10~15 DEG C after adding and keeps the temperature
Stirring, isolates Lopinavir solid.
Further, the preparation of existing either method can be used in the Lopinavir crude product, such as IN2008CH01744 or
WO2006100552A1, the Lopinavir crude product are analyzed using USP35 method, and HPLC purity (peak area %) is less than
99.5%, preferably smaller than 99.1%, and contain the single impurity that more than two contents are more than 0.1%.
Further, the weight of the methanol is 10~20 times of Lopinavir (Formula II) crude product, preferably 15 times of weight.
Further, the weight that water is added for the first time is 6~15 times of Lopinavir (Formula II) crude product, preferably 9 times of weight.
Further, described second weight that water is added dropwise is the 30%~50% of Lopinavir (Formula II) crude product, preferably
40%.
Further, the third time adds the weight of water to be about 10 times of Lopinavir (Formula II) crude product, point several batches
The weight that water is added dropwise is respectively 1 times of Lopinavir (Formula II) crude product, 2 times, three times or four times.
Further, the time of the first time insulated and stirred can be within 60 minutes, when second of insulated and stirred
Between can be 60 minutes or more.
The technical issues of to solve second aspect of the present invention, the invention provides the following technical scheme:
A kind of Lopinavir, structural formula preparation method as shown in formula (I)
The specific steps of the preparation method include: in the reaction vessel, under nitrogen protection, to put into dimethyl formyl
Compound shown in amine, formula (II), stirring and dissolving put into compound shown in formula (III) later, and 1- hydroxy benzenes is put into after being cooled to 0 DEG C
And triazole (HOBT), stirring it is complete it is molten after, put into the dimethyl formamide solution of dicyclohexylcarbodiimide (DCC), three second be added
Amine controls interior warm 25 DEG C of insulated and stirreds and reacts to end of reaction
Further, compound shown in the formula (II), compound, HOBT, DCC shown in formula (III), between triethylamine
Molar ratio are as follows: 1:1:3:2:2.
The invention has the following advantages that
The purifying process of Lopinavir provided by the present invention is using a small amount of methanol and a large amount of water as purification solvent, toxicity
It is low and at low cost；It can be by HPLC purity (peak area %) less than 99.5%, preferably smaller than using purifying process of the invention
99.1% and Lopinavir purifying crude to all single impurity for being more than 0.1% single impurity containing more than two contents contain
Amount is greater than 99.5% less than 0.1%, HPLC purity (peak area %), and purification process loss late is less than 10%.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, disclose further below some non-
Limiting embodiment, the present invention is described in further detail.
The preparation method of 1 Lopinavir crude product of embodiment
Dimethylformamide 147kg is put into a kettle, puts into compound 20kg shown in formula (II), and stirring is complete molten, throws
Enter compound 9kg nitrogen charging shown in formula (III) and be cooled to 0 DEG C of reinforcement nitrogen protection, put into HOBT 18.2kg, stirring it is complete it is molten after, throw
Enter DCC solution (DCC18.6kg/ dimethylformamide 8kg) and 25 DEG C of insulated and stirred reactions 12 of temperature in triethylamine 9.2kg control are added
Hour, HPLC tracks reaction end.(appearance or peak area accounting can not carry out at next step raw material less than 0.05%
Reason), after fully reacting, drinking water 200kg, ethyl acetate 200kg is added in 25 DEG C or so of temperature in control, is controlled interior 25 DEG C of temperature, is stirred
After mixing 30 minutes, stratification retains organic layer, and aqueous layer with ethyl acetate (100kg × 2) extraction is associated with several layers of, has several layers of
Successively with concentrated hydrochloric acid 30kg, 60kg water, 10% sodium bicarbonate aqueous solution 105kg, 105 grams of 5% sodium-chloride water solution washings, 60kg
Anhydrous magnesium sulfate is dry, controls interior temperature≤50 DEG C of vacuum distillations, obtains yellow oil.72kg acetic acid second is added into grease
Ester opens stirring, and heating water bath is to flowing back, and confirmation is completely dissolved, (if there is insoluble matter, should filter while hot), and normal heptane is added
66kg, insulated and stirred 30 minutes, slow cooling to room temperature crystallization, slow cooling was to 0 DEG C, insulated and stirred 2 hours, filtering, filter cake
It is sprinkled and is washed with 40kg ice normal heptane and ethyl acetate mixtures (weight ratio 1:1), take out filter cake, weighing is put into hot-air oven, controls
It is warm in baking oven≤45 DEG C, Lopinavir crude product 20kg is dried to obtain, carries out efficient liquid phase HPLC detection according to the method for USP35:
1 Lopinavir crude product HPLC testing result of table (treatment channel explanation: 2998Ch1 [email protected])
| Retention time (minute) | Area (microvolt * seconds) | % area | Highly (microvolt) | |
| 1 | 9.617 | 6416 | 0.04 | 763 |
| 2 | 10.309 | 5133 | 0.03 | 920 |
| 3 | 16.313 | 10764 | 0.06 | 871 |
| 4 | 26.947 | 20939 | 0.12 | 1789 |
| 5 | 31.566 | 34069 | 0.20 | 1918 |
| 6 | 33.857 | 57759 | 0.34 | 2580 |
| 7 | 38.593 | 22754 | 0.13 | 1249 |
| 8 | 46.674 | 16893135 | 99.07 | 338611 |
The purifying process of 2 Lopinavir crude product of embodiment
Put into 310kg methanol Lopinavir crude product 20kg stir confirmation in 60 minutes it is complete it is molten after, stirring is cooled to 0~5
DEG C, Quan Ronghou is cooled to 0~5 DEG C, is added water 179kg, and water continues to be cooled to -10 DEG C after adding, and insulated and stirred 10~30 minutes,
(yellow oil is had on reaction vessel) stands 10 minutes, separates supernatant, and water 8kg stirring is slowly dropped into supernatant
It is precipitated to solid, confirmation solid is added portionwise water 200kg (20+40+60+80) after being precipitated again and added once, after adding every 10 minutes
10~15 DEG C insulated and stirred 1 hour, centrifuge rejection filter is put into wet product in hot-air oven, control in temperature 50~55 DEG C drying 48
Hour, 18.2kg is dried to obtain, carries out efficient liquid phase HPLC detection according to the method for USP35:
2 Lopinavir sterling HPLC testing result of table (treatment channel explanation: 2998Ch1 [email protected])
| Retention time (minute) | Area (microvolt * seconds) | % area | Highly (microvolt) | |
| 1 | 9.621 | 7261 | 0.04 | 903 |
| 2 | 10.263 | 4680 | 0.02 | 596 |
| 3 | 16.356 | 4674 | 0.02 | 280 |
| 4 | 27.660 | 9871 | 0.05 | 424 |
| 5 | 33.877 | 17326 | 0.09 | 598 |
| 6 | 46.702 | 18985086 | 99.77 | 376452 |
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (1)
1. a kind of purifying process of Lopinavir, characterized in that it comprises: Lopinavir crude product is dissolved in methanol, is dropped
Temperature continues to be cooled to -5~-15 DEG C after adding to water, water is added after 0~5 DEG C for the first time, carries out first time insulated and stirred, stands
After isolate supernatant, into supernatant, second is added dropwise water, after stirring to solid is precipitated；Carry out third time plus water, third time
Add the specific steps of water are as follows: within interval time, water is added dropwise in a point several batches, and water carries out second after adding at 10~15 DEG C
Insulated and stirred, isolates Lopinavir solid, and the weight of the methanol is 15 times of weight of Lopinavir crude product, the first time
The weight that water is added is 9 times of weight of Lopinavir crude product；Described second weight that water is added dropwise is Lopinavir crude product
40%；The third time adds the weight of water to be 10 times of Lopinavir crude product, and it is respectively Lip river that the weight of water, which is added dropwise, in a point several batches
1 times of that Wei crude product, 2 times, three times or four times.
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| CN106117148B true CN106117148B (en) | 2019-04-12 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903249B (en) * | 2019-12-20 | 2021-05-25 | 厦门蔚嘉制药有限公司 | Lopinavir prepared by one-pot method |
| CN111018791B (en) * | 2019-12-20 | 2021-05-25 | 厦门蔚嘉制药有限公司 | Novel method for preparing lopinavir |
| CN113512569B (en) * | 2021-03-12 | 2023-04-18 | 江苏阿尔法药业股份有限公司 | Enzymatic synthesis method of lopinavir intermediate |
| CN115108996A (en) * | 2022-07-27 | 2022-09-27 | 苏州健雄职业技术学院 | Novel lopinavir crystal form and preparation method thereof |
| CN116239503A (en) * | 2022-11-28 | 2023-06-09 | 安徽贝克制药股份有限公司 | Preparation method and application of lopinavir impurity T |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1208405A (en) * | 1995-12-13 | 1999-02-17 | 艾博特公司 | Retroviral protease inhibiting compounds |
| EP2393786B1 (en) * | 2009-02-06 | 2014-01-22 | Hetero Research Foundation | Novel polymorphs of lopinavir |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009004653A2 (en) * | 2007-07-04 | 2009-01-08 | Matrix Laboratories Limited | Process for preparing an amorphous form of (2s,3s,5s)-2-(2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(1-tetrahydropyrimid-2-only)-3-methylbutanoyl)-amino-1,6-diphenyl hexane and product thereof |
-
2016
- 2016-06-17 CN CN201610439389.9A patent/CN106117148B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1208405A (en) * | 1995-12-13 | 1999-02-17 | 艾博特公司 | Retroviral protease inhibiting compounds |
| EP2393786B1 (en) * | 2009-02-06 | 2014-01-22 | Hetero Research Foundation | Novel polymorphs of lopinavir |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis of ABT-378, an HIV Protease Inhibitor Candidate: Avoiding the Use of Carbodiimides in a Difficult Peptide Coupling;Eric J. Stoner，et al.;《Organic Process Research & Development》;19991231(第3期);第145-148页 |
| 洛匹那韦合成工艺研究;徐洪根等;《安徽医药》;20141231;第18卷(第4期);第610-613页 |
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Effective date of registration: 20200310 Address after: Tieshan town Xiaopai Road, Xinluo District, Longyan City, Fujian Province Patentee after: Fujian Weijia biomedical Co., Ltd Address before: Haicang District of Xiamen City, Fujian province 361006 Xinyang Street Weng Kok Road No. 289 Chong Building 717 unit Patentee before: XIAMEN CITY WEI JIA CHEMICAL TECHNOLOGY CO., LTD. |