Nothing Special   »   [go: up one dir, main page]

WO2009004653A2 - 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 - Google Patents

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 Download PDF

Info

Publication number
WO2009004653A2
WO2009004653A2 PCT/IN2008/000418 IN2008000418W WO2009004653A2 WO 2009004653 A2 WO2009004653 A2 WO 2009004653A2 IN 2008000418 W IN2008000418 W IN 2008000418W WO 2009004653 A2 WO2009004653 A2 WO 2009004653A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
tetrahydropyrimid
methylbutanoyl
hydroxy
dimethylphenoxyacetyl
Prior art date
Application number
PCT/IN2008/000418
Other languages
French (fr)
Other versions
WO2009004653A3 (en
Inventor
Debashish Datta
Vellanki Siva Rama Prasad
Arabinda Sahu
Balusu Raja Babu
Putta Subba Rayudu
Ravi Mastan Rao
Umamaheswara Rao Vasireddy
Nagamahesh Yarlagadda
Om Dutt Tyagi
Original Assignee
Matrix Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Matrix Laboratories Limited filed Critical Matrix Laboratories Limited
Publication of WO2009004653A2 publication Critical patent/WO2009004653A2/en
Publication of WO2009004653A3 publication Critical patent/WO2009004653A3/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06Heterocyclic 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
    • C07D239/08Heterocyclic 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
    • C07D239/10Oxygen or sulfur atoms

Definitions

  • This invention in general relates to the field of Human Immunodeficiency Virus (HIV) protease inhibitor. More particularly,' the present invention provides a novel' process for preparing an amorphous form of (2S,3S,5S)-2-(2,6r dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyr hexane (Lopinavir) and product thereof.
  • HSV Human Immunodeficiency Virus
  • Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle.
  • Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in Man, animals and plants.
  • HIV-I and HIV-2 human immunodeficiency viruses
  • HIV-I and HIV-2 human immunodeficiency viruses
  • HIV-1 human immunodeficiency virus
  • HIV-2 human immunodeficiency virus
  • I, II, IV and V human T-cell lymphotrophic viruses I, II, IV and V
  • HIV human immunodeficiency virus
  • a particularly effective and recently approved HIV protease inhibitor is (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3 -hydroxy-5 -(2-(I -tetrahydropyrimid-2-only)-3 - methylbutanoyl)-amino-l,6-diphenyl hexane, also known as Lopinavir.
  • Lopinavir is known to have ability of inhibiting HIV protease and the HIV infection.
  • Lopinavir is particularly effective for the inhibition of HIV protease and for the inhibition of HIV infection when co administered with Ritonavir.
  • US 5,914,332 patent discloses a process for the preparation of lopinavir.
  • This patent also discloses a process for the preparation of amorphous lopinavir, wherein lopinavir is crystallized from different combinations of solvents such as mixture of ethanol and water, isopropyl alcohol and water, acetone -and water & acetonitrile and water to obtain amorphous lopinavir.
  • solvents such as mixture of ethanol and water, isopropyl alcohol and water, acetone -and water & acetonitrile and water to obtain amorphous lopinavir.
  • the lopinavir obtained by using the solvent mixtures, disclosed in the product patent have the contamination with crystalline polymeric forms.
  • crystallization method gives mixture of crystalline forms along with amorphous form. It is difficult to get the pure amorphous form by the solvent crystallization as given in the prior art. Therefore, there is a need to provide a process for preparing an amorphous form of lopinavir free of any contaminations.
  • a process for preparing an amorphous form of (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3 -hy droxy-5 -(2-( 1 -tetrahydropyrimid-2-only)-3 - methylbutanoyl)-amino-l ,6-diphenyl hexane comprises of dissolving the 2S,3S,5S)-2- (2,6-dimethylpheno ' xyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyl hexane in a solvent system, distilling out the remaining solvent from the resultant solution employing a drying technique and isolating the pure amorphous form of (2S,3S,5S)-2-(
  • a process for preparing an amorphous form of (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydro ⁇ yrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyl hexane comprises of heating or drying the (2S s 3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l- tetrahydropyrimid-2-only)-3-methylbutanoyl)-amino-l,6-diphenyl hexane at high temperature and reduced pressure, cooling the resultant solution and isolating the pure amorphous form of (2S,3S,5S)-2 ⁇ (2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5- (2S,3S,5S)-2 ⁇ (2,6
  • Figure 1 is XRD pattern of lopinavir amorphous form.
  • the solvent system comprises an organic solvent/s or a mixture of water and water miscible organic solvent/s or a mixture of said organic solvent/s, water and water miscible organic solvent/s.
  • the organic solvent/s is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane, methyl ethyl ketone, dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide or mixture thereof.
  • Lopinavir is dissolved in a solvent to get clear solution, which is subjected to spray drying or other suitable drying technique to get lopinavir amorphous form.
  • the water miscible organic solvent/s is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane, dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide or mixture thereof.
  • Lopinavir is dissolved in a mixture of water and water miscible organic solvent to get a clear solution, optionally the clear solution is treated with carbon and filtered to get a clear filtrate, which is subjected to spray drying or other suitable drying technique to get lopinavir amorphous form with better yield and improved quality as compared to the prior art.
  • Lopinavir according to the process of the present invention can be dissolved in an organic solvent, mixture of water and water miscible solvents or mixtures thereof to get a clear solution.
  • the remaining solvent is distilled out by employing the different types of drying' techniques like spray drying, freeze drying or thin film drying to give amorphous lopinavir. Further, the solvent distillation can be optionally performed under reduced pressure. .
  • Another embodiment of the present invention relates to a novel process for the preparation of lopinavir amorphqus' form,- wherein lopinavir is heated at high temperature to melt the solid followed by cooling and drying to lopinavir amorphous form with higher yield.
  • a process for preparing lopinavir amorphous form comprises of heating at high temperature and reduced pressure, cooling and drying the resultant solution and isolating the pure amorphous form, wherein the temperature used for heating is in the range of 75-100°C.
  • the temperature used for drying is in the range of 60-80° C and the resultant solution is cooled up to the temperature between 20-40°C.
  • lopinavir is heated/dried to higher temperature to melt the solid to form the uniform liquid, which is subjected to cooling and drying to give lopinavir amorphous form.
  • Another aspect of the present invention is a process for the preparation of amorphous lopinavir, wherein lopinavir is subjected to drying at higher temperature, optionally under vacuum followed by cooling and isolation to give amorphous lopinavir.
  • Example- 1 Lopinavir (crude) 45 gm (0.071 moles) is dissolved in 135 ml of ethanol at 40-
  • the solution is filtered.
  • the filtered; solution is spray dried at a feed rate of 180-720 ml/hr while drying with nitrogen at a flow rate of 350-750 lts/hr to get 35 gm pure amorphous lopinavir.
  • Example-2 Lopinavir (crude) 45 gni (0.071 moles) is dissolved in 90 ml of methanol at
  • the solution is filtered.
  • the filtered solution is spray dried at a feed rate of 180-720 ml/hr while drying with nitrogen at flow rate of 350-750 lts/hr to get 38 gm pure amorphous lopinavir.
  • Example-3 Lopinavir (crude) 45 gm (0.071 moles) is dissolved in 90 ml acetone at 25-30°
  • the filtered solution is spray dried at a feed rate of 180- 720 ml/hr while drying with nitrogen at a flow rate of 350-750 lts/hr to get 40 gn ⁇ pure amorphous lopinavir.
  • Lopinavir (crude) 45 gm (0.071 moles) is dissolved in 160 ml isopropyl alcohol at 25-30° C and the solution- is filtered. The filtered solution is spray dried at a feed rate of 180-720 ml/hr while drying with nitrogen at a flow rate of 350-750 lts/hr to get 35 gm pure amorphous lopinavir.
  • Lopinavir 500gm is heated : .to 90° C, maintained at 90° C under vacuum, then it is cooled to 30-35° C under vacuum. The solid resultant obtained is milled to get the powder form. Powder form is then ⁇ ied under vacuum at 90° C, further cooled to 30- 35° C under vacuum to give amorphous lopinavir.
  • Lopinavir hydrate (50gm) is dried at 80° C under vacuum and then cooled to 30-35° C under vacuum. The solid product is milled to get the powder form. Powdered product thus obtained is dried further under vacuum at 80° C and then cooled to 30-35° C under vacuum to; give amorphous lopinavir.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed herein is a process for preparing an amorphous form of (2S,3 S5SS)- 2-(2,6-dimethylphenoxyacetyl)-amiho-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)- 3-methylbutanoyl)-amino-l,6-diphenyl hexane(Lopinavir), wherein lopinavir is dissolved in a solvent system, followed by removal of solvent employing drying technique and isolating the resultant pure amorphous form. Further process comprises of heating/drying the lopinavir at higher temperature to melt the solid and form uniform liquid, which is subjected to cooling arid drying to give amorphous lopinavir.

Description

Process For Preparing An Amorphous Form Of (2S,3S,5S)-2-(2,6-
Dimethylphenoxyacetyl)-Amino-3-Hydroxy-5-(2-(l-Tetrahydropyrimid-2-Only)- 3-Methylbutanoyl)-Amino-l,6rDiphenyl Hexane And Product Thereof
Field of the Invention This invention, in general relates to the field of Human Immunodeficiency Virus (HIV) protease inhibitor. More particularly,' the present invention provides a novel' process for preparing an amorphous form of (2S,3S,5S)-2-(2,6r dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyr hexane (Lopinavir) and product thereof.
Background of the Invention Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in Man, animals and plants.
Some of the more important retroviruses form a pathological standpoint include human immunodeficiency viruses (HIV-I and HIV-2) which cause Acquired Immune Deficiency Syndrome (AIDS) in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia. Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective and recently approved HIV protease inhibitor is (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3 -hydroxy-5 -(2-(I -tetrahydropyrimid-2-only)-3 - methylbutanoyl)-amino-l,6-diphenyl hexane, also known as Lopinavir. Lopinavir is known to have ability of inhibiting HIV protease and the HIV infection. Lopinavir is particularly effective for the inhibition of HIV protease and for the inhibition of HIV infection when co administered with Ritonavir. US 5,914,332 patent discloses a process for the preparation of lopinavir. This patent also discloses a process for the preparation of amorphous lopinavir, wherein lopinavir is crystallized from different combinations of solvents such as mixture of ethanol and water, isopropyl alcohol and water, acetone -and water & acetonitrile and water to obtain amorphous lopinavir. The lopinavir obtained by using the solvent mixtures, disclosed in the product patent have the contamination with crystalline polymeric forms. The product patent suggests that, crystallization method gives mixture of crystalline forms along with amorphous form. It is difficult to get the pure amorphous form by the solvent crystallization as given in the prior art. Therefore, there is a need to provide a process for preparing an amorphous form of lopinavir free of any contaminations.
Objects and Summary of the Invention
It is a principal object of the present invention to provide a novel process for preparing a pure form of an amorphous (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)- amino-3-hydroxy-5-(2-(l-te1rahydropyrimid-2-only)-3-methylbutanoyl)-amino-l,6- diphenyl hexane (Lopinavir).
It is another object of the present invention to provide a process for preparing an amorphous (2S,3S,5S)-2-(256-dimethylphenoxyaceryl)-amino-3-hydroxy-5-(2-(l- tetrahydropyrimid-2-only)-3 -methylbutanoyl)-amino- 1 ,6-diphenyl hexane (Lopinavir) having improved stability.
It is the further object of the present invention to provide a process for preparing an amorphous (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3- hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3-methylbutanoyl)-amino-l,6-diphenyl hexane (Lopinavir) in higher yield and better quality. The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with a preferred embodiment of the present invention, there is provided a process for preparing an amorphous form of (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3 -hy droxy-5 -(2-( 1 -tetrahydropyrimid-2-only)-3 - methylbutanoyl)-amino-l ,6-diphenyl hexane comprises of dissolving the 2S,3S,5S)-2- (2,6-dimethylpheno'xyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyl hexane in a solvent system, distilling out the remaining solvent from the resultant solution employing a drying technique and isolating the pure amorphous form of (2S,3S,5S)-2-(2,6-dirnethylphenoxyacetyl)- amino-3 -hydroxy-5 -(2-( 1 -tetrahydropyrimidr2-'only)-3-methylbutanoyl)-amino- 1 ,6- diphenyl hexane, wherein the drying is performed employing spray drying, freeze drying or thin film drying to obtain the resultant amorphous without any contaminations .
In accordance with another preferred embodiment of the present invention, there is provided a process for preparing an amorphous form of (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydroρyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyl hexane comprises of heating or drying the (2Ss3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l- tetrahydropyrimid-2-only)-3-methylbutanoyl)-amino-l,6-diphenyl hexane at high temperature and reduced pressure, cooling the resultant solution and isolating the pure 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, wherein the heating/drying is performed until melt of the solid (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3 -hydroxy-5 -(2-( 1 -tetrahydropyrimid-2-only)-3 - methylbutanoyl)-amino-l,6-dipheήyl hexane to obtain pure amorphous form. Brief Description of the Drawing: Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures,, wherein: Figure 1 is XRD pattern of lopinavir amorphous form.
Detailed Description of the Present Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples. The present invention relates to process for the preparation of amorphous
(2SJ3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l- tetrahydropyrimid-2-only)-3 -me1hylbutanoyl)-arnino- 1 ,6-diphenyl hexane
(Lopinavir), wherein lopinavir is dissolved in a solvent system, removing the solvent to get lopinavir amorphous form with higher yield and improved quality. The solvent system according to the present invention comprises an organic solvent/s or a mixture of water and water miscible organic solvent/s or a mixture of said organic solvent/s, water and water miscible organic solvent/s.
According to the present invention, the organic solvent/s is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane, methyl ethyl ketone, dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide or mixture thereof. Lopinavir is dissolved in a solvent to get clear solution, which is subjected to spray drying or other suitable drying technique to get lopinavir amorphous form.
According to the present invention, the water miscible organic solvent/s is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane, dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide or mixture thereof. Lopinavir is dissolved in a mixture of water and water miscible organic solvent to get a clear solution, optionally the clear solution is treated with carbon and filtered to get a clear filtrate, which is subjected to spray drying or other suitable drying technique to get lopinavir amorphous form with better yield and improved quality as compared to the prior art.
Lopinavir, according to the process of the present invention can be dissolved in an organic solvent, mixture of water and water miscible solvents or mixtures thereof to get a clear solution. The remaining solvent is distilled out by employing the different types of drying' techniques like spray drying, freeze drying or thin film drying to give amorphous lopinavir. Further, the solvent distillation can be optionally performed under reduced pressure. . Another embodiment of the present invention relates to a novel process for the preparation of lopinavir amorphqus' form,- wherein lopinavir is heated at high temperature to melt the solid followed by cooling and drying to lopinavir amorphous form with higher yield.
A process for preparing lopinavir amorphous form comprises of heating at high temperature and reduced pressure, cooling and drying the resultant solution and isolating the pure amorphous form, wherein the temperature used for heating is in the range of 75-100°C. The temperature used for drying is in the range of 60-80° C and the resultant solution is cooled up to the temperature between 20-40°C.
According to the present /invention, lopinavir is heated/dried to higher temperature to melt the solid to form the uniform liquid, which is subjected to cooling and drying to give lopinavir amorphous form.
Another aspect of the present invention is a process for the preparation of amorphous lopinavir, wherein lopinavir is subjected to drying at higher temperature, optionally under vacuum followed by cooling and isolation to give amorphous lopinavir.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
Example- 1 Lopinavir (crude) 45 gm (0.071 moles) is dissolved in 135 ml of ethanol at 40-
45° C and the solution is filtered. The filtered; solution is spray dried at a feed rate of 180-720 ml/hr while drying with nitrogen at a flow rate of 350-750 lts/hr to get 35 gm pure amorphous lopinavir.
Example-2 Lopinavir (crude) 45 gni (0.071 moles) is dissolved in 90 ml of methanol at
25-30° C and the solution is filtered. The filtered solution is spray dried at a feed rate of 180-720 ml/hr while drying with nitrogen at flow rate of 350-750 lts/hr to get 38 gm pure amorphous lopinavir.
Example-3 Lopinavir (crude) 45 gm (0.071 moles) is dissolved in 90 ml acetone at 25-30°
C and the solution is filtered. The filtered solution is spray dried at a feed rate of 180- 720 ml/hr while drying with nitrogen at a flow rate of 350-750 lts/hr to get 40 gnα pure amorphous lopinavir.
Example-4
Lopinavir (crude) 45 gm (0.071 moles) is dissolved in 160 ml isopropyl alcohol at 25-30° C and the solution- is filtered. The filtered solution is spray dried at a feed rate of 180-720 ml/hr while drying with nitrogen at a flow rate of 350-750 lts/hr to get 35 gm pure amorphous lopinavir.
Example-5
Lopinavir (500gm) is heated:.to 90° C, maintained at 90° C under vacuum, then it is cooled to 30-35° C under vacuum. The solid resultant obtained is milled to get the powder form. Powder form is then φied under vacuum at 90° C, further cooled to 30- 35° C under vacuum to give amorphous lopinavir.
Example-6
Lopinavir hydrate (50gm) is dried at 80° C under vacuum and then cooled to 30-35° C under vacuum. The solid product is milled to get the powder form. Powdered product thus obtained is dried further under vacuum at 80° C and then cooled to 30-35° C under vacuum to; give amorphous lopinavir.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for.practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We Claim:
1. A process for preparing an amorphous form of (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyl hexane comprising: a) dissolving the 2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy- 5~(2-(l -tetrahydropyrimid-2-only)-3-methylbutanoyl)-amino-l ,6-diphenyl hexane in a solvent system; b) distilling out the remaining solvent from the resultant solution employing a drying technique selected from spray drying, freeze drying or thin film drying; and c) isolating the pure amorphous form of (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)- 3-methylbutanoyl)-amino-l,6-diphenyl hexane.
2. The process according to claim I5 wherein the solvent system comprises an organic solvent/s or a mixture of water and -water miscible organic solvent/s or a mixture of said organic solvent/s, water and water miscible organic solvent/s.
3. The process according to claim 2, wherein the organic solvent is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane, methyl ethyl ketone, dimethyl formamide or dimethylacetamide or mixture thereof.
4. The process according to claim 2, wherein the water miscible organic solvent is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane, dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide or mixtures thereof.
5. The process according to claim 1, wherein the distillation of the solvent is carried out optionally under reduced pressure. 6. A process for preparing an amorphous form of (2S,3S,5S)-2-(2j,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-only)-3- methylbutanoyl)-amino-l,6-diphenyl hexane comprising: a) heating the (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5- (2-(l-tetrahydropyrimid-2-only)-3-methylbutanoyl)-amino-l,6-diphenyl hexane at high temperature and reduced pressure; b) cooling and drying the resultant solution; and c) isolating the pure amorphous form of (2S,3S,5S)-2-(2,6- drnieώylphenoxyacetyl)-armno-3-hydr^xy-5-(2-(l-tetrahydropyrimid-2-only)- 3-methylbutanoyl)-amino-l ,
6-diphenyl hexane.
7. The process according to claim 6, wherein the temperature used for heating is in the range of 75-100° C.
8. The process according to claim 6, wherein the drying is carried out at a temperature range of 60-80° C.
9. The process according to claim 6, wherein the resultant solution is cooled up to the temperature 20-40° C.
10. The process according to claim 6, wherein the process is optionally carried out under vacuum.
11. The process according to claim 6, wherein the heating is performed until melting of the solid (2S,3S,5S)-2-(;2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5- (2-( 1 -tetrahydropyrimid-2-only)-3 -rήethylbutanoyl)-amino- 1 ,6-diphenyl hexane to form a uniform liquid.
PCT/IN2008/000418 2007-07-04 2008-07-02 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 WO2009004653A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1438/CHE/2007 2007-07-04
IN1438CH2007 2007-07-04
IN409CH2008 2008-02-18
IN409/CHE/2008 2008-02-18

Publications (2)

Publication Number Publication Date
WO2009004653A2 true WO2009004653A2 (en) 2009-01-08
WO2009004653A3 WO2009004653A3 (en) 2009-02-26

Family

ID=40010634

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000418 WO2009004653A2 (en) 2007-07-04 2008-07-02 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

Country Status (1)

Country Link
WO (1) WO2009004653A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8445506B2 (en) 2009-02-06 2013-05-21 Hetero Research Foundation Polymorphs of lopinavir
US9096556B2 (en) 2011-05-27 2015-08-04 Hetero Research Foundation Amorphous ritonavir co-precipitated
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5914332A (en) * 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5914332A (en) * 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STONER, ERIC J. ET AL: "Synthesis of HIV Protease Inhibitor ABT-378 (Lopinavir)" ORGANIC PROCESS RESEARCH & DEVELOPMENT , 4(4), 264-269 CODEN: OPRDFK; ISSN: 1083-6160, 2000, XP002505235 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8445506B2 (en) 2009-02-06 2013-05-21 Hetero Research Foundation Polymorphs of lopinavir
US9096556B2 (en) 2011-05-27 2015-08-04 Hetero Research Foundation Amorphous ritonavir co-precipitated
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

Also Published As

Publication number Publication date
WO2009004653A3 (en) 2009-02-26

Similar Documents

Publication Publication Date Title
EP2438062B1 (en) Process for the preparation of amorphous raltegravir potassium
WO2017203395A1 (en) Crystalline forms of tenofovir alafenamide hemi fumarate
US8329740B2 (en) Polymorphs of sunitinib malate
US8598341B2 (en) Process for etravirine intermediate and polymorphs of etravirine
WO2012066565A2 (en) Asenapine maleate amorphous and crystalline form and process for preparation thereof
WO2009004653A2 (en) 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
US9624207B2 (en) Polymorphs of azilsartan medoxomil
US20140350270A1 (en) Crystalline Darunavir
WO2012014149A1 (en) N-methylformamide solvate of dasatinib
US10300044B2 (en) Polymorphic forms of methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate and salts thereof
AU2008209271B9 (en) A novel crystalline mycophenolate sodium polymorph and processes to manufacture same
CN100410248C (en) Modifications of the trometamol salt of R-thioctic acid as well as a process for their production
EP3242876A1 (en) An improved process for the preparation of lurasidone and its intermediate
WO2019171222A1 (en) Crystalline forms of venetoclax
WO2012019862A1 (en) Process for making linezolid
WO2017118447A1 (en) A preparation method of amorphous apremilast
WO2016042576A1 (en) Co-crystal of sofosbuvir and amino acid and process for preparation thereof
CN106432253B (en) A kind of Wei Patawei novel crystal forms and preparation method thereof
US8318930B2 (en) Process for preparing polymorphic forms of (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one
WO2003027106A1 (en) Process for the preparation of crystalline polymorph ii of lamivudine
US7183442B2 (en) Purification method of terephthal aldehyde
CA2549871A1 (en) Novel polymorphs of atovaquone and process of preparation thereof
CN108341841B (en) Salt of tenofovir alafenamide and aspartic acid
US20240199615A1 (en) Novel crystalline polymorphs of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and process for preparation thereof
WO2021024135A1 (en) An improved process for preparation of methyl (2e)-2-(2-{[6-(2-cyanophenoxy)pyrimidin-4-yl]oxy}phenyl)-3-methoxyacrylate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08808135

Country of ref document: EP

Kind code of ref document: A2

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08808135

Country of ref document: EP

Kind code of ref document: A2