US20130165650A1 - Process for the preparation of efavirenz - Google Patents
Process for the preparation of efavirenz Download PDFInfo
- Publication number
- US20130165650A1 US20130165650A1 US13/777,817 US201313777817A US2013165650A1 US 20130165650 A1 US20130165650 A1 US 20130165650A1 US 201313777817 A US201313777817 A US 201313777817A US 2013165650 A1 US2013165650 A1 US 2013165650A1
- Authority
- US
- United States
- Prior art keywords
- reaction
- efavirenz
- diphosgene
- organic solvent
- amount
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- NSVNQAXELSOMRW-ZDUSSCGKSA-N C[C@](O)(C#CC1CC1)C1=CC(Cl)=CC=C1N Chemical compound C[C@](O)(C#CC1CC1)C1=CC(Cl)=CC=C1N NSVNQAXELSOMRW-ZDUSSCGKSA-N 0.000 description 4
- IATBHACGYUTPII-AWEZNQCLSA-N C[C@@]1(C#CC2CC2)OC(=O)NC2=CC=C(Cl)C=C21 Chemical compound C[C@@]1(C#CC2CC2)OC(=O)NC2=CC=C(Cl)C=C21 IATBHACGYUTPII-AWEZNQCLSA-N 0.000 description 2
- JQMRNOQLHZTOFD-WZZOUBBWSA-N CC(=O)Cl.C[C@@]1(C#CC2CC2)OC(=O)NC2=CC=C(Cl)C=C21.C[C@](O)(C#CC1CC1)C1=CC(Cl)=CC=C1N.I.II.O.O=C=O Chemical compound CC(=O)Cl.C[C@@]1(C#CC2CC2)OC(=O)NC2=CC=C(Cl)C=C21.C[C@](O)(C#CC1CC1)C1=CC(Cl)=CC=C1N.I.II.O.O=C=O JQMRNOQLHZTOFD-WZZOUBBWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/70—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
Definitions
- the present invention is directed to a process for the preparation of Efavirenz.
- Efavirenz is a well known non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in the antiretroviral therapy of HIV-1. Efavirenz is on the market for this use since 1998.
- NRTI non-nucleoside reverse transcriptase inhibitor
- This intermediate (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol, as a free base, is reacted with a chloroformate derivative in basic conditions to give, after 1 to 6 hours reaction, an alkyl carbamate intermediate (reaction of the amine moiety of intermediate (II) with the chloroformate derivative) that is then cyclized to yield Efavirenz.
- the said reaction is performed in the presence of a weak base in an amount sufficient to neutralise the reaction mixture or in an up to 30% molar excess of such amount.
- a salt of intermediate of formula (II) is used, such a salt is preferably a mesylate salt.
- intermediate (II) salt is provisionally treated with a basic medium for a time sufficient to obtain the free base, before adding the diphosgene reagent.
- inventive process is performed starting from intermediate (II) free base. This allows to obtain Efavirenz with an improved purity profile.
- Intermediate (II) free base can be obtained by treating a salt of intermediate (II) such as mesylate salt—intermediate (II). 1,5 methansulphonic acid—with a base such as an hydroxide of an alkaline metal in an aqueous solution.
- a salt of intermediate (II) such as mesylate salt—intermediate (II). 1,5 methansulphonic acid—with a base such as an hydroxide of an alkaline metal in an aqueous solution.
- the reaction can be performed in an organic solvent at room temperature, as will be described in the experimental part of the present description.
- reaction of intermediate (II) free base to give Efavirenz can be performed without isolating the said intermediate, but just separating the organic layer containing the free base from the previous step and subjecting it to the subsequent step of reaction with diphosgene.
- the diphosgene has a formula Cl 3 CO—COCl and thus it can deliver two moles of phosgene per mole, according to the following reaction:
- diphosgene it can be used a stoichiometric amount of diphosgene or a slight excess up to a 30% molar excess, more preferably a 20 to 25% molar excess.
- this reaction can be performed in an organic solvent such as, for example but not limited thereto, an hydrocarbon selected from hexane, heptane and the like, an ether selected from diethylether, diisopropylether, tetrahydrofuran, dioxane and the like, chloroform, dichloromethane and the like, or a mixture of such solvents. More preferably, however, the reaction is conducted in a biphasic medium comprised of an organic solvent such as the one listed above and water. If the weak base is an inorganic base, water helps to solve the weak base and to promote the reaction.
- an organic solvent such as, for example but not limited thereto, an hydrocarbon selected from hexane, heptane and the like, an ether selected from diethylether, diisopropylether, tetrahydrofuran, dioxane and the like, chloroform, dichloromethane and the like, or a mixture of such solvents. More preferably
- the ratio between the organic solvent and the water phase can range between 0.3:1 to 1:0.3.
- the organic solvent is a mixture of tetrahydrofuran and heptane in a ratio of between 0.8:1 and 1:0.8, more preferably about 1:1.
- the reaction can be performed in the presence of a weak base.
- a weak base is preferably an inorganic weak base such as a carbonate or a hydrogencarbonate of an alkaline or earth-alkaline metal.
- the weak base has the function to capture hydrogen chloride that is delivered by the reacting diphosgene, according to the reaction scheme shown above, and not to catalyse the reaction. Therefore, the amount of weak base will depend on the amount of diphosgene used and will be an amount sufficient to keep the reaction medium neutral, that is about the stoichiometric amount with respect to the amount of diphosgene, or up to 30% molar excess amount.
- the weak base is sodium hydrogencarbonate.
- the reaction can be performed at temperatures chosen in the range from 0° C. to 50° C., preferably 10° C. to 40° C., more preferably 18° C. to 30° C., even more preferably at around room temperature.
- the reaction is accomplished by adding diphosgene to the reaction mixture containing intermediate (II) free base in an organic solvent or a biphasic medium as described above containing the said weak base. It has been surprisingly found that the purity profile of the final product Efavirenz can be improved if such an addition is made in a short time, the only limit being just the exothermal behavior of the reaction, in order to operate in the temperature ranges depicted above.
- reaction to complete in a very short time, namely less than 1 hour, more particularly between 20 and 40 minutes. Typically, in about 30 minutes the reaction is complete.
- Diphosgene can be prepared by known methods of photochloruration (use of chlorine gas under irradiation) starting from methyl chloroformate CH 3 O—COCl. It has been seen that the presence of dichloromethyl chloroformate in a too high amount is detrimental to the purity of Efavirenz. It is therefore preferable that the amount of dichloromethyl chloroformate in diphosgene is not higher than 0.3% by weight, as detected by GC/TCD chromatography.
- the presence of residual chlorine in diphosgene can promote the formation of impurities in the subsequent reaction to give Efavirenz. Therefore, it is preferable that the color characteristics of diphosgene (which is a measure of the amount of chlorine present in the substance) is classified as GY4 score.
- diphosgene with such a color characteristics, it is possible to degasing diphosgene, for example by bubbling nitrogen in diphosgene at 60-70° C. for about 4 hours.
- Efavirenz contains no more than 10 ppm of p-chloroaniline (determined by HPLC), as this substance is classified cancerogenic. This can be accomplished by using intermediate (II) wherein p-chloroaniline is comprised in no more than 200 ppm (determined by HPLC).
- the mixture was stirred by keeping the temperature at 15-25° C.
- the pH was adjusted to >9 with about 690 ml of 30% NaOH in water (1.5 eq).
- the organic solution was distilled under reduced pressure at 60-70° C. in a 30 l glass lined reactor to give a residual 6.0 l volume.
- 15.8 l of heptanes were added, then it is re-distilled under reduced pressure at 60-70° C. to a residual 8.0 l volume.
- 13.8 l of heptanes were added and the THF content was checked by GC to be less than 0.1%.
- the obtained suspension was added with 220 ml of THF and the resulting slurry was heated to 70-80° C. until a clear solution was observed, then the temperature was allowed to reach 48-52° C.
- the solution was seeded with 4 g of Efavirenz Form 1; the suspension was stirred by keeping the temperature at 40-50° C. for at least 1 hour, then it was cooled in about 2 hours to ⁇ 5/ ⁇ 20° C. and stirred at this temperature for 1 hour.
- the slurry was then filtered and the wet cake was washed for three times at ⁇ 5/ ⁇ 20° C. with 3.0 l of heptanes each.
- the solid was dried in stove under vacuum at 85° C. for at least 8 hours, obtaining a weight dry product of 1350 g.
- the final product was obtained in a 93% yield and a HPLC purity higher than 99.8%.
- Efavirenz obtained according to the prior art method disclosed in WO 98/34928 has a HPLC purity of 96%, while Efavirenz synthesized as described in WO 06/029079 was obtained in a 78-90% yield.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the preparation of Efavirenz, (4S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, of formula (I):
comprising reacting the intermediate of formula (II):
as a free base or a salt thereof, with diphosgene (TCMCF, trichloromethylchloroformate) Cl3CO—COCl in an organic solvent or in a biphasic medium comprised of an organic solvent and water, preferably but not mandatorily in the presence of a weak base in an amount sufficient to neutralize the reaction mixture or in an up to 30% molar excess of such amount.
Description
- This is a continuation of application Ser. No. 13/060,839, filed on Feb. 25, 2011, which is a 371 of PCT/EP09/00612, filed on Jan. 30, 2009.
- The present invention is directed to a process for the preparation of Efavirenz.
- Efavirenz is a well known non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in the antiretroviral therapy of HIV-1. Efavirenz is on the market for this use since 1998.
- Several processes are known in the prior art to produce this active substance that start from the intermediate of formula (II):
- This intermediate, (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol, as a free base, is reacted with a chloroformate derivative in basic conditions to give, after 1 to 6 hours reaction, an alkyl carbamate intermediate (reaction of the amine moiety of intermediate (II) with the chloroformate derivative) that is then cyclized to yield Efavirenz.
- Even if this kind of reaction allows to obtain Efavirenz with an acceptable impurities profile, it has some disadvantages due to the length of the reaction time and/or the quite complicate work-up, as the alkyl carbamate intermediate must be isolated or the reaction mixture must be at least separated and concentrated before undergoing the cyclization step. No one-step process using chloroformate derivatives has been proposed so far, nor thrichloromethylchloroformate (diphosgene) has been proposed as a reactant of choice in this process.
- It has now been surprisingly found that by reacting intermediate (II) with diphosgene in pretty neutral or slightly basic conditions, it is possible to obtain Efavirenz with a one-step process in a short time and with high yield and purity.
- A process is provided for the preparation of Efavirenz, (4S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-214-3,1-benzoxazin-2-one, of formula (I):
- comprising reacting the intermediate of formula (II):
- as a free base or a salt thereof, with diphosgene (TCMCF, trichloromethylchloroformate) Cl3CO—COCl in an organic solvent or in a biphasic medium comprised of an organic solvent and water. Preferably, the said reaction is performed in the presence of a weak base in an amount sufficient to neutralise the reaction mixture or in an up to 30% molar excess of such amount.
- If a salt of intermediate of formula (II) is used, such a salt is preferably a mesylate salt. In this case, intermediate (II) salt is provisionally treated with a basic medium for a time sufficient to obtain the free base, before adding the diphosgene reagent.
- More preferably, the inventive process is performed starting from intermediate (II) free base. This allows to obtain Efavirenz with an improved purity profile.
- Intermediate (II) free base can be obtained by treating a salt of intermediate (II) such as mesylate salt—intermediate (II). 1,5 methansulphonic acid—with a base such as an hydroxide of an alkaline metal in an aqueous solution. The reaction can be performed in an organic solvent at room temperature, as will be described in the experimental part of the present description.
- The reaction of intermediate (II) free base to give Efavirenz can be performed without isolating the said intermediate, but just separating the organic layer containing the free base from the previous step and subjecting it to the subsequent step of reaction with diphosgene.
- The diphosgene has a formula Cl3CO—COCl and thus it can deliver two moles of phosgene per mole, according to the following reaction:
- It can be used a stoichiometric amount of diphosgene or a slight excess up to a 30% molar excess, more preferably a 20 to 25% molar excess.
- As said above, this reaction can be performed in an organic solvent such as, for example but not limited thereto, an hydrocarbon selected from hexane, heptane and the like, an ether selected from diethylether, diisopropylether, tetrahydrofuran, dioxane and the like, chloroform, dichloromethane and the like, or a mixture of such solvents. More preferably, however, the reaction is conducted in a biphasic medium comprised of an organic solvent such as the one listed above and water. If the weak base is an inorganic base, water helps to solve the weak base and to promote the reaction.
- The ratio between the organic solvent and the water phase can range between 0.3:1 to 1:0.3.
- Preferably, the organic solvent is a mixture of tetrahydrofuran and heptane in a ratio of between 0.8:1 and 1:0.8, more preferably about 1:1.
- As said above, the reaction can be performed in the presence of a weak base. Such a weak base is preferably an inorganic weak base such as a carbonate or a hydrogencarbonate of an alkaline or earth-alkaline metal. It should be noted that the weak base has the function to capture hydrogen chloride that is delivered by the reacting diphosgene, according to the reaction scheme shown above, and not to catalyse the reaction. Therefore, the amount of weak base will depend on the amount of diphosgene used and will be an amount sufficient to keep the reaction medium neutral, that is about the stoichiometric amount with respect to the amount of diphosgene, or up to 30% molar excess amount.
- In a very preferred embodiment of the invention, the weak base is sodium hydrogencarbonate.
- The reaction can be performed at temperatures chosen in the range from 0° C. to 50° C., preferably 10° C. to 40° C., more preferably 18° C. to 30° C., even more preferably at around room temperature.
- The reaction is accomplished by adding diphosgene to the reaction mixture containing intermediate (II) free base in an organic solvent or a biphasic medium as described above containing the said weak base. It has been surprisingly found that the purity profile of the final product Efavirenz can be improved if such an addition is made in a short time, the only limit being just the exothermal behavior of the reaction, in order to operate in the temperature ranges depicted above.
- This allows the reaction to complete in a very short time, namely less than 1 hour, more particularly between 20 and 40 minutes. Typically, in about 30 minutes the reaction is complete.
- It has also been surprisingly found that the purity profile of the reaction can be further enhanced if ammonia is added before the work-up of the reaction mixture. As NH3 reacts with diphosgene to give urea, it avoids that residual thrichloromethylchloroformate could remain in the product. Typically, aqueous ammonium hydroxide is used.
- Diphosgene can be prepared by known methods of photochloruration (use of chlorine gas under irradiation) starting from methyl chloroformate CH3O—COCl. It has been seen that the presence of dichloromethyl chloroformate in a too high amount is detrimental to the purity of Efavirenz. It is therefore preferable that the amount of dichloromethyl chloroformate in diphosgene is not higher than 0.3% by weight, as detected by GC/TCD chromatography.
- Also the presence of residual chlorine in diphosgene can promote the formation of impurities in the subsequent reaction to give Efavirenz. Therefore, it is preferable that the color characteristics of diphosgene (which is a measure of the amount of chlorine present in the substance) is classified as GY4 score.
- To obtain diphosgene with such a color characteristics, it is possible to degasing diphosgene, for example by bubbling nitrogen in diphosgene at 60-70° C. for about 4 hours.
- It is also preferable that Efavirenz contains no more than 10 ppm of p-chloroaniline (determined by HPLC), as this substance is classified cancerogenic. This can be accomplished by using intermediate (II) wherein p-chloroaniline is comprised in no more than 200 ppm (determined by HPLC).
- The invention will be now further described by means of illustrative examples that are not intended to limit the scope of protection as defined by the appended claims.
- In a 30 l glass lined reactor the following substances were charged under nitrogen atmosphere:
-
- 2.0 kg of intermediate (II) 0.1,5 methansulphonic acid;
- 3.5 l of THF;
- 3.5 l of heptanes;
- 7.0 l of purified water.
- The mixture was stirred by keeping the temperature at 15-25° C. The pH was adjusted to >9 with about 690 ml of 30% NaOH in water (1.5 eq).
- The mixture was stirred at 20-25° C. until a clear solution was observed (two clear phases), then the layers were separated.
- To the organic phase containing intermediate (II) as free base as prepared above, an aqueous solution of 9.6 kg of 10% NaHCO3 (0.75 eq) was added. The resulting biphasic suspension was stirred by keeping the temperature at 15-25° C.
- To said mixture, 560 g of diphosgene (0.615 eq) were added and the biphasic solution was stirred at 20-25° C. for at least 10 minutes, then an “in process” control was carried out.
- When the reaction was complete (about 30 minutes) 140 ml (0.45 eq) of 30% NH4OH aqueous solution were added. The resulting solution was stirred for at least 1 hour, then the two phases were separated.
- To the organic phase 7.0 l of heptanes were added and the resulting mixture was washed twice with 3.5 l of purified water each, while keeping the temperature at 40-50° C. Then, the solution was treated with 100 g of charcoal, the dark slurry was aged at 40-50° C. for at least 30 minutes, then filtered in a SS filter. The exhausted charcoal was washed with 3.0 l of THF/heptanes (1:1 in volume).
- The organic solution was distilled under reduced pressure at 60-70° C. in a 30 l glass lined reactor to give a residual 6.0 l volume. To the obtained slurry 15.8 l of heptanes were added, then it is re-distilled under reduced pressure at 60-70° C. to a residual 8.0 l volume. Further 13.8 l of heptanes were added and the THF content was checked by GC to be less than 0.1%.
- The obtained suspension was added with 220 ml of THF and the resulting slurry was heated to 70-80° C. until a clear solution was observed, then the temperature was allowed to reach 48-52° C.
- The solution was seeded with 4 g of Efavirenz Form 1; the suspension was stirred by keeping the temperature at 40-50° C. for at least 1 hour, then it was cooled in about 2 hours to −5/−20° C. and stirred at this temperature for 1 hour.
- The slurry was then filtered and the wet cake was washed for three times at −5/−20° C. with 3.0 l of heptanes each.
- The solid was dried in stove under vacuum at 85° C. for at least 8 hours, obtaining a weight dry product of 1350 g.
- The final product was obtained in a 93% yield and a HPLC purity higher than 99.8%.
- By comparison, Efavirenz obtained according to the prior art method disclosed in WO 98/34928 has a HPLC purity of 96%, while Efavirenz synthesized as described in WO 06/029079 was obtained in a 78-90% yield.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US13/777,817 US20130165650A1 (en) | 2009-01-30 | 2013-02-26 | Process for the preparation of efavirenz |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2009/000612 WO2010085978A1 (en) | 2009-01-30 | 2009-01-30 | Process for the preparation of efavirenz |
US201113060839A | 2011-02-25 | 2011-02-25 | |
US13/777,817 US20130165650A1 (en) | 2009-01-30 | 2013-02-26 | Process for the preparation of efavirenz |
Related Parent Applications (2)
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---|---|---|---|
PCT/EP2009/000612 Continuation WO2010085978A1 (en) | 2009-01-30 | 2009-01-30 | Process for the preparation of efavirenz |
US201113060839A Continuation | 2009-01-30 | 2011-02-25 |
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US20130165650A1 true US20130165650A1 (en) | 2013-06-27 |
Family
ID=40933506
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US13/060,839 Active 2029-07-23 US8420808B2 (en) | 2009-01-30 | 2009-01-30 | Process for the preparation of efavirenz |
US13/777,817 Abandoned US20130165650A1 (en) | 2009-01-30 | 2013-02-26 | Process for the preparation of efavirenz |
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US13/060,839 Active 2029-07-23 US8420808B2 (en) | 2009-01-30 | 2009-01-30 | Process for the preparation of efavirenz |
Country Status (4)
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---|---|
US (2) | US8420808B2 (en) |
EP (1) | EP2384324B1 (en) |
CN (1) | CN102272110A (en) |
WO (1) | WO2010085978A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015004686A3 (en) * | 2013-07-11 | 2015-06-11 | Laurus Labs Private Limited | A process for purification of efavirenz and intermediates thereof using chromatographic methods |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010115641A1 (en) * | 2009-04-09 | 2010-10-14 | Lonza Ltd | Process for the synthesis of chiral cyclic carbamates |
WO2012097511A1 (en) * | 2011-01-19 | 2012-07-26 | Lonza Ltd | Dmp-266 by cyclisation |
CN102617367A (en) * | 2012-03-08 | 2012-08-01 | 浙江江北药业有限公司 | Preparation method of (S)-5-chloro-alpha-(cyclopropylacetylene)-2-amino-alpha-(trifluoromethyl) phenylcarbinol crystals |
EP2944631A1 (en) | 2014-05-12 | 2015-11-18 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Improved process for the preparation of Efavirenz |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6028237A (en) * | 1996-12-16 | 2000-02-22 | Dupont Pharmaceuticals Company | Synthesis of cyclopropylacetylene |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998045278A1 (en) * | 1997-04-07 | 1998-10-15 | Du Pont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones via new intermediates |
-
2009
- 2009-01-30 WO PCT/EP2009/000612 patent/WO2010085978A1/en active Application Filing
- 2009-01-30 CN CN2009801543820A patent/CN102272110A/en active Pending
- 2009-01-30 US US13/060,839 patent/US8420808B2/en active Active
- 2009-01-30 EP EP09776351.0A patent/EP2384324B1/en active Active
-
2013
- 2013-02-26 US US13/777,817 patent/US20130165650A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6028237A (en) * | 1996-12-16 | 2000-02-22 | Dupont Pharmaceuticals Company | Synthesis of cyclopropylacetylene |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015004686A3 (en) * | 2013-07-11 | 2015-06-11 | Laurus Labs Private Limited | A process for purification of efavirenz and intermediates thereof using chromatographic methods |
Also Published As
Publication number | Publication date |
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US20110196151A1 (en) | 2011-08-11 |
EP2384324B1 (en) | 2014-04-02 |
CN102272110A (en) | 2011-12-07 |
EP2384324A1 (en) | 2011-11-09 |
US8420808B2 (en) | 2013-04-16 |
WO2010085978A1 (en) | 2010-08-05 |
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