CN116239503A - Preparation method and application of lopinavir impurity T - Google Patents

Preparation method and application of lopinavir impurity T Download PDF

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CN116239503A
CN116239503A CN202211499304.8A CN202211499304A CN116239503A CN 116239503 A CN116239503 A CN 116239503A CN 202211499304 A CN202211499304 A CN 202211499304A CN 116239503 A CN116239503 A CN 116239503A
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compound
lopinavir
impurity
ethyl acetate
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张祖良
田磊
王尧
王哲
王志邦
柏俊
谢大卫
蔡玉磊
程俊
卢云霞
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Anhui Baker Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a preparation method of lopinavir impurity T, which comprises the steps of firstly protecting compound 1 by hydroxy to generate compound 2, then deprotecting compound 2 by amino to generate compound 3, then condensing compound 3 by CDI to generate compound 4, and finally deprotecting compound 4 by hydroxy to obtain lopinavir impurity T; the invention provides a new thought for synthesizing lopinavir impurity T, the synthetic route has simple and mild reaction conditions, and higher yield and purity, can meet the preparation requirement of the impurity, and has important significance for the research of lopinavir.

Description

Preparation method and application of lopinavir impurity T
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method and application of lopinavir impurity T.
Background
Lopinavir (Lopinavir), developed by Abbot corporation in the united states, approved by the FDA in the united states at month 3 in 1996, marketed first in the united states, and subsequently marketed as Lopinavir/ritonavir complex formulation at month 9 in 2000. In 2007, the Chinese market is called chocolate ganoderma (kalett), and is mainly used for treating AIDS clinically. Wherein the cultural name is (2S, 3S, 5S) -2- (2, 6-dimethyl phenoxy acetyl) amino-3-hydroxy-5- [2S- (1-tetrahydropyrimidine-2-ketone) -3-methyl butyryl ] amino-1, 6-diphenyl n-hexane, and the structural formula is as follows:
Figure BDA0003966099990000011
lopinavir is a protease inhibitor of human immunodeficiency diseases HIV-1 and HIV-2. The mechanism of action is to block the cleavage of the gag-pol polyprotein, resulting in the production of immature, non-viable viral particles. Lopinavir, ritonavir and other antiretroviral drugs are used in combination to treat HIV-1 infection. Patent WO9721685 discloses a preparation method thereof, and the synthetic route is as follows:
Figure BDA0003966099990000012
n, N ' - (2S, 2' S,3' S,5' S) -5,5' -carbonylbis (aminodiyl) bis (3-hydroxy-1, 6-diphenylhexane-5, 2-diyl) bis [2- (2, 6-dimethylphenyloxy) acetamide ] (hereinafter referred to as lopinavir impurity T) is an impurity in lopinavir production, and has important significance for quality control and impurity study of lopinavir. However, the prior art does not disclose a preparation method of lopinavir impurity T, so that there is an urgent need in the art to provide a novel preparation method of lopinavir impurity T without similar article report.
Disclosure of Invention
The invention aims to provide a preparation method and application of lopinavir impurity T, which are used for solving the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a preparation method of lopinavir impurity T comprises the steps of firstly protecting compound 1 through hydroxyl to generate compound 2, then deprotecting compound 2 through amino to generate compound 3, then condensing compound 3 through CDI to generate compound 4, and finally deprotecting compound 4 through hydroxyl to obtain lopinavir impurity T, wherein the synthetic route is as follows:
Figure BDA0003966099990000021
wherein X is chlorine or bromine.
As a further scheme of the invention: the method specifically comprises the following steps:
s1: protection: under the conditions of strong alkali and N, N-dimethylformamide solvent, the compound 1 reacts with benzyl halide at room temperature, and after the reaction is finished, the compound 2 is obtained through extraction, evaporation and recrystallization;
s2: deprotection: under the condition that dichloromethane is used as a solvent and is acidic, deprotecting the amino of the compound 2 obtained in the step S1, and distilling, washing and spin-drying after the reaction is finished to obtain a compound 3;
s3: condensation: under alkaline condition and with N, N-dimethylformamide as solvent, reacting the compound 3 obtained in the step S2 with a condensation reagent N, N' -carbonyl diimidazole, and separating the reaction end by water washing, distillation and column chromatography to obtain a compound 4;
s4: deprotection: under the condition that ethanol is a solvent and 10% palladium carbon is a catalyst, the compound 4 obtained in the step S3 is deprotected by ammonium formate, and lopinavir impurity T is obtained after the reaction is completed and suction filtration, distillation and column chromatography separation are carried out.
As a further scheme of the invention: the strong alkali in the step S1 is any one of sodium hydroxide, potassium hydroxide and sodium hydride; the benzyl halide is any one of benzyl chloride and benzyl bromide; the recrystallization solvent is any one of methanol, ethanol, isopropanol and ethyl acetate or any one of mixed solvents of methanol and water, ethanol and water, isopropanol and water, ethyl acetate and n-hexane and ethyl acetate and n-heptane.
As a further scheme of the invention: the acid in the step S2 is any one of hydrochloric acid, sulfuric acid and trifluoroacetic acid.
As a further scheme of the invention: the alkali used in the alkaline condition in the step S3 is any one of diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate and potassium carbonate; the feeding mole ratio of the compound 3 to the condensing agent N, N' -carbonyl diimidazole is (2-2.5) to 1; the purification method of the compound 4 is column chromatography, and the eluent adopts n-hexane and ethyl acetate= (5:1) - (1:1).
As a further scheme of the invention: the molar ratio of the compound 4 to the ammonium formate in the step S4 is 1:
(3-6), wherein the mass ratio of the compound 4 to the palladium carbon of 10% is 1:0.1-0.8; the purification method of lopinavir impurity T is column chromatography, and the eluent adopts n-hexane and ethyl acetate= (5:1) - (1:1).
As a further scheme of the invention: the invention also discloses the application of the lopinavir impurity T prepared by the method in detecting and/or controlling the quality of lopinavir.
Compared with the prior art, the invention has the beneficial effects that: the preparation of lopinavir impurity T is completed by applying a new synthetic route; the synthesis method has the advantages of easily obtained starting materials, simple and mild reaction conditions, higher yield, simple reaction operation, safe and environment-friendly reaction; the synthesis of the lopinavir impurity T solves the dilemma of difficult purchase in the market, and the prepared lopinavir impurity T has high purity, meets the requirement of the work for analyzing the lopinavir impurity and has important significance for the quality research of lopinavir.
Drawings
Fig. 1 is a synthetic route diagram of lopinavir impurity T according to the embodiment of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of lopinavir impurity T prepared in the embodiment of the invention;
FIG. 3 is a nuclear magnetic carbon spectrum of lopinavir impurity T prepared in the embodiment of the invention;
FIG. 4 is an LC-MS spectrum of lopinavir impurity T prepared in the examples of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1, the invention discloses a preparation method of lopinavir impurity T, which specifically comprises the steps of firstly protecting compound 1 by hydroxyl to generate compound 2, then deprotecting compound 2 by amino to generate compound 3, then condensing compound 3 by CDI to generate compound 4, and finally deprotecting compound 4 by hydroxyl to obtain lopinavir impurity T, wherein specific examples are as follows:
example 1
S1: protection: naH (1.5 g,36.6 mmol) was added to a 250ml reaction flask, DMF100ml was stirred at 0-10℃for 10min, compound 1 (20 g,36.6 mmol) was added, stirring was carried out at 0-30℃for 30min, bnBr (7.5 g,43.9 mmol) was slowly added dropwise, the reaction was stirred at room temperature for 4h after the dropwise addition was completed, and TLC monitored for reaction (n-hexane: ethyl acetate=1:1). After the reaction, the reaction mixture was poured into 200ml of water, and 100ml of ethyl acetate was added thereto, followed by stirring and standing for separation. The ethyl acetate layer was washed with 100 ml.times.2 water and evaporated to dryness under reduced pressure at 45℃to give 23g of an oil. And adding 30ml of isopropanol into the obtained solid, heating, refluxing, dissolving, cooling to 0-10 ℃, preserving heat, stirring for 1h, carrying out suction filtration, and evaporating the filter cake at the temperature of less than or equal to 45 ℃ under reduced pressure to obtain 8.3g of white solid of the compound 2, wherein the yield of the obtained compound 2 is 78.5%.
S2: deprotection of amino group: into a 250ml reaction flask was charged compound 2 (15 g,23.6 mmol), dichloromethane 120ml, the solution was stirred at room temperature, trifluoroacetic acid (29.6 g,259.1 mmol) and dichloromethane 15ml were added dropwise at 25-30℃and the reaction was incubated at 25-30℃for 2h, and TLC monitored for reaction (n-hexane: ethyl acetate=3:1). After the reaction is finished, evaporating the mixture to dryness under reduced pressure at the temperature of less than or equal to 45 ℃, adding 100ml of ethyl acetate into the residue, stirring and dissolving the mixture, and sequentially using 10% NaHCO 3 150g, washing with 150g of water, and evaporating ethyl acetate phase at 45 ℃ or lower under reduced pressure to obtain 12.1g of compound 3, wherein the yield of the obtained compound 3 is 96.0%.
S3: condensation: into a 100ml reaction flask was charged compound 3 (10.0 g,18.6 mmol), DMF20ml, the solution was stirred, CDI (1.3 g,8.3 mmol) and DIPEA (2.4 g,18.6 mmol) were added, and the reaction was stirred at room temperature under nitrogen overnight. After the reaction, 100ml of ethyl acetate, 100ml of water, stirring, standing and separating, 100ml of organic phase water, 100ml of saturated saline water, and the organic phase is not more than 45 ℃ and evaporated to dryness under reduced pressure, and the remainder is subjected to column chromatography (n-hexane: ethyl acetate=1:1), 13.2g of a bubble solid of the compound 4 is obtained, and the yield of the obtained compound 4 is 64.4%.
S4: hydroxy deprotection: into a 250ml reaction flask was charged compound 4 (5 g,4.5 mmol), ethanol 50ml, water 2.5g, the solution was stirred, ammonium formate (1.3 g,20.5 mmol), 10% Pd/C0.5g, under nitrogen protection, the temperature was raised and the reflux reaction was monitored by TLC (n-hexane: ethyl acetate=3:1). The raw materials are reacted completely, cooled to room temperature, filtered by diatomite, leached by a little ethanol of filter cake, the filtrate is evaporated to dryness under reduced pressure, and the residue is added with 50ml of dichloromethane for dissolution, and sequentially added with saturated 10% NaHCO 3 50g, 50g of saturated saline water, and the dichloromethane phase is less than or equal to 45 DEG CAfter evaporation to dryness under reduced pressure, column chromatography (n-hexane: ethyl acetate=1:1) gave lopinavir impurity T3.7 g in 88.6% yield and 97.4% purity.
The lopinavir impurity T obtained in the synthesis process is tested, the test results are shown in figures 2-4, and the related data are as follows:
referring to fig. 2, nuclear magnetic hydrogen spectrum related data: 1 H NMR(600MHz，DMSO-d 6 )δ:7.47(d，J＝9.5Hz，2H)，7.25(d，J＝4.4Hz，8H)，7.22-7.11(m，8H),7.06(d，J＝6.9Hz，4H)，7.01(d，J＝7.5Hz，4H)，6.93(m，2H),5.62(d，J＝8.6Hz，2H)，5.04(d，J＝5.6Hz，2H)，4.22(m，2H)，4.08-3.98(m，6H)，3.70(d，J＝6.6Hz，2H)，2.81(d，J＝7.5Hz，4H)，2.68-2.61(m，4H)，2.13(s，12H)，1.40-1.37(q，4H)；
referring to fig. 3, nuclear magnetic carbon spectrum related data: 13 C NMR(600MHz,DMSO-d 6 )δ166.8,156.6,154.1,138.7，138.2,129.8,128.9,128.7,128.4,127.6,127.5,125.5,125.3,123.8,69.8,67.7,52.5,46.6,39.9,39.5,38.7,38.5,37.2,15.5；
referring to fig. 4, LC-MS related data thereof: LC-MS (m/z): 919.5[ M+H ]] + ，941.5[M+Na] + 。
Example 2
The differences from example 1 are: the molar ratio of the compound 3 to the condensing agent N, N' -Carbonyldiimidazole (CDI) fed in the step S3 was 2:1, and the yield of the compound 4 was 63.5%.
Example 3
The differences from example 1 are: the differences from example 1 are: the molar ratio of the compound 3 to the condensing agent N, N' -Carbonyldiimidazole (CDI) fed in step S3 was 2.5:1, and the yield of the compound 4 was 63.1%.
Example 4
The differences from example 1 are: the purification method of compound 4 described in step S3 was column chromatography, eluting with n-hexane to ethyl acetate=5:1, and yielded compound 4 in a yield of 62.8%.
Example 5
The differences from example 1 are: the purification method of compound 4 described in step S3 was column chromatography, eluting with n-hexane to ethyl acetate=3:1, and the yield of compound 4 was 63.6%.
Example 6
The differences from example 1 are: the molar ratio of the compound 4 to the ammonium formate in the step S4 is 1:3, and the yield of lopinavir impurity T is 87.1% and the purity is 97.2%.
Example 7
The differences from example 1 are: the molar ratio of the compound 4 to the ammonium formate in the step S4 is 1:6, and the yield of lopinavir impurity T is 85.5% and the purity is 96.8%.
Example 8
The differences from example 1 are: the mass ratio of the compound 4 to the 10% palladium carbon in the step S4 is 1:0.5, and the yield of lopinavir impurity T is 86.7% and the purity is 97.1%.
Example 9
The differences from example 1 are: the feeding mass ratio of the compound 4 to 10% palladium carbon in the step S4 is 1:0.8, and the yield of lopinavir impurity T is 85.3% and the purity is 96.5%.
Example 10
The differences from example 1 are: the purification method of lopinavir impurity T in the step S4 is column chromatography, and eluent adopts normal hexane to ethyl acetate=5:1, so that the yield of lopinavir impurity T is 86.9% and the purity is 97%.
Example 11
The differences from example 1 are: the purification method of lopinavir impurity T in the step S4 is column chromatography, and the eluent adopts n-hexane to ethyl acetate=2.5:1, so that the yield of lopinavir impurity T is 84.9% and the purity is 96.6%.
As can be seen from the above description, the above embodiments of the present invention achieve the following technical effects:
as is clear from comparison of examples 1, 2 and 3, in the condensation reaction, the molar ratio of the compound 3 to the condensing agent N, N' -Carbonyldiimidazole (CDI) is limited to the range preferable in the present application, which is advantageous in improving the yield of the condensation reaction product.
As is clear from comparison of examples 1, 4 and 5, the amount of n-hexane/ethyl acetate as an eluent for purification of the compound 4 in the condensation reaction is limited to the preferred range of the present application, which is advantageous in improving the yield of the condensation reaction product.
Comparing examples 1,6 and 7, it is understood that in the hydroxy deprotection reaction, the molar ratio of compound 4 to ammonium formate is limited within the preferred range of the present application, which is advantageous for improving the yield and purity of lopinavir impurity T.
Comparing examples 1, 8 and 9, it is found that the ratio of the mass of the compound 4 to the mass of the 10% palladium on carbon in the hydroxyl deprotection reaction is limited within the preferred range of the present application, which is advantageous for improving the yield and purity of lopinavir impurity T.
Comparing examples 1, 10 and 11, it is found that limiting the amount of n-hexane/ethyl acetate used as an eluent for purifying lopinavir impurity T in the hydroxy deprotection reaction within the preferred ranges of the present application is advantageous for improving the yield and purity of lopinavir impurity T.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments, and any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (10)

1. A preparation method of lopinavir impurity T is characterized in that firstly, compound 1 is protected by hydroxyl to generate compound 2, then compound 2 is deprotected by amino to generate compound 3, then compound 3 is condensed by CDI to generate compound 4, and finally compound 4 is deprotected by hydroxyl to obtain lopinavir impurity T, and the synthetic route is as follows:
Figure FDA0003966099980000011
wherein X is chlorine or bromine.
2. The method for preparing lopinavir impurity T according to claim 1, which is characterized by comprising the following steps:
s1: protection: under the conditions of strong alkali and N, N-dimethylformamide solvent, the compound 1 reacts with benzyl halide at room temperature, and after the reaction is finished, the compound 2 is obtained through extraction, evaporation and recrystallization;
s2: deprotection: under the condition that dichloromethane is used as a solvent and is acidic, deprotecting the amino of the compound 2 obtained in the step S1, and distilling, washing and spin-drying after the reaction is finished to obtain a compound 3;
s3: condensation: under alkaline condition and with N, N-dimethylformamide as solvent, reacting the compound 3 obtained in the step S2 with a condensation reagent N, N' -carbonyl diimidazole, and separating the reaction end by water washing, distillation and column chromatography to obtain a compound 4;
s4: deprotection: under the condition that ethanol is a solvent and 10% palladium carbon is a catalyst, the compound 4 obtained in the step S3 is deprotected by ammonium formate, and lopinavir impurity T is obtained after the reaction is completed and suction filtration, distillation and column chromatography separation are carried out.
3. The method for preparing lopinavir impurity T according to claim 2, wherein the strong base in step S1 is any one of sodium hydroxide, potassium hydroxide and sodium hydride; the benzyl halide is any one of benzyl chloride and benzyl bromide; the recrystallization solvent is any one of methanol, ethanol, isopropanol and ethyl acetate or any one of mixed solvents of methanol and water, ethanol and water, isopropanol and water, ethyl acetate and n-hexane and ethyl acetate and n-heptane.
4. The method for preparing lopinavir impurity T according to claim 2, wherein the acid in step S2 is any one of hydrochloric acid, sulfuric acid and trifluoroacetic acid.
5. The method for preparing lopinavir impurity T according to claim 2, wherein the base used in the alkaline condition in step S3 is any one of diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate and potassium carbonate.
6. The method for preparing lopinavir impurity T according to claim 2, wherein the feeding molar ratio of said compound 3 to said condensing agent N, N' -carbonyldiimidazole in step S3 is (2-2.5) to 1.
7. The method for preparing lopinavir impurity T according to claim 2, wherein the purification method of compound 4 in step S3 is column chromatography, and the eluent is n-hexane: ethyl acetate= (5:1) - (1:1).
8. The method for preparing lopinavir impurity T according to claim 2, wherein the feeding molar ratio of the compound 4 to the ammonium formate in the step S4 is 1:3-6, and the feeding mass ratio of the compound 4 to 10% palladium carbon is 1:0.1-0.8.
9. The method for preparing lopinavir impurity T according to claim 2, wherein the purification method of lopinavir impurity T in step S4 is column chromatography, and the eluent is n-hexane to ethyl acetate= (5:1) - (1:1).
10. Use of lopinavir impurity T prepared by the preparation process as defined in any one of claims 1-9 for detecting and/or controlling lopinavir quality.
CN202211499304.8A 2022-11-28 2022-11-28 Preparation method and application of lopinavir impurity T Pending CN116239503A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100317855A1 (en) * 2007-06-08 2010-12-16 V Raghava Reddy Ambati Process for the preparation of substantially pure (2s,3s,5s)-5-amino-2-n,n-dibenzylamino-3-hydroxy-1,6-diphenylhexane
CN106117148A (en) * 2016-06-17 2016-11-16 厦门市蔚嘉化学科技有限公司 A kind of preparation and purification technique of Lopinavir
WO2019186522A1 (en) * 2018-03-30 2019-10-03 Laurus Labs Limited An improved process for preparation of lopinavir and its intermediates thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100317855A1 (en) * 2007-06-08 2010-12-16 V Raghava Reddy Ambati Process for the preparation of substantially pure (2s,3s,5s)-5-amino-2-n,n-dibenzylamino-3-hydroxy-1,6-diphenylhexane
CN106117148A (en) * 2016-06-17 2016-11-16 厦门市蔚嘉化学科技有限公司 A kind of preparation and purification technique of Lopinavir
WO2019186522A1 (en) * 2018-03-30 2019-10-03 Laurus Labs Limited An improved process for preparation of lopinavir and its intermediates thereof

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CHITTURI, SREENIVASA RAO等: "Impurity profile study of lopinavir and validation of HPLC method for the determination of related substances in lopinavir drug substance", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 48, no. 5, pages 1430 - 1440, XP025874131, DOI: 10.1016/j.jpba.2008.09.015 *
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