Patent Grant
9630909
This application is a national stage filing of PCT application no. PCT/IN2014/000429, filed Dec. 31, 2014, which in turn claimed priority to and the benefit of priority to IN2823/CHE/2013, filed on Jun. 27, 2013, and IN4979/CHE/2013, filed on Nov. 4, 2013.
Processes for the preparation of nepafenac and intermediates thereof, as well as processes for the purification of nepafenac.
Nepafenac is a non-steroidal anti-inflammatory drug (NSAID) approved for ophthalmic use. Nepafenac is sometimes referred to as 2-amino-3-benzoylbenzeneacetamide and is structurally represented by Formula (I).
U.S. Pat. No. 4,313,949 discloses nepafenac and its preparation by treating 2-aminobenzophenone (II) with 2-(methylthio)acetamide (III) in the presence of t-butylhypochlorite to afford 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), which is subsequently reduced in the presence of Raney nickel and crystallized from isopropyl alcohol to afford nepafenac. This process is represented below in Scheme I.
U.S. Pat. No. 8,278,484 discloses a process for the preparation of nepafenac in which 2-aminobenzophenone (II) is treated with 2-(methylthio)acetamide (III) in the presence of N-chlorosuccinimide to afford 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), which is subsequently reduced in the presence of Raney nickel to afford nepafenac. This process is represented below in Scheme II.
Indian Publication No. 148/MUM/2011 discloses a process for the preparation of nepafenac in which 2-aminobenzophenone (II) is treated with 2-(methylthio)acetamide (III) in the presence of N-chlorophthalimide to afford 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), which is subsequently reduced in the presence of Raney nickel under hydrogen pressure to afford nepafenac.
A structurally similar impurity is also formed during the preparation of nepafenac. This impurity is known as 2-amino-3-benzoyl-5-chlorobenzeneacetamide and is represented below by Formula (Ia).
This impurity is difficult to remove by conventional purification methods. Moreover, U.S. Pat. No. 8,278,484 describes this impurity as causing “reproducibility problems” during the synthesis of nepafenac and also characterizes the formation of this impurity as a “drawback” suffered by the synthesis described in U.S. Pat. No. 4,313,949. Accordingly, there is a continuing need for new and improved processes for the preparation of nepafenac, as well as methods for removing, reducing, or eliminating the chlorinated impurities formed during the preparation of nepafenac from nepafenac compositions.
Some aspects of the present disclosure are to provide a process for the preparation of nepafenac.
One aspect provides a process for the preparation of 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), comprising: treating 2-aminobenzophenone (II) with 2-(methylthio)acetamide (III) in the presence of sulfuryl chloride to afford 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV).
One aspect provides a process for the preparation of nepafenac, comprising:
In some embodiments, the removing of the thiomethyl moiety is conducted under reducing conditions. In some embodiments, the reducing conditions comprise hydrogen gas and a catalyst. In some embodiments, the catalyst is Raney nickel, palladium on carbon, palladium oxide, or platinum oxide. In some embodiments, the catalyst is Raney nickel. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is platinum oxide. In some embodiments, the catalyst is palladium oxide. In some embodiments, the reducing conditions further comprise a solvent selected from the group consisting of diethyl ether, tetrahydrofuran, and diisopropylether. In some embodiments, the base is a trialkylamine, a dialkylamine, a cycloamine, or an N-alkylcycloamine. In some embodiments, the base is selected from the group consisting of: triethylamine, diisopropylamine, methylisopropylamine, N-methylmorpholine and mixtures thereof. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the treating of 2-aminobenzophenone (II) with 2-(methylthio)acetamide (III) occurs in a solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, diethyl ether, tetrahydrofuran, diisopropylether and mixtures thereof.
Some embodiments are directed to a process for the purification of a nepafenac composition containing a halogenated impurity, comprising: subjecting a nepafenac composition containing a halogenated impurity to reducing conditions, wherein the reducing conditions convert the halogenated impurity to nepafenac, and optionally crystallizing the resultant nepafenac composition. In some embodiments, the halogenated impurity is 2-amino-3-benzoyl-5-chlorobenzeneacetamide. In some embodiments, the reducing conditions comprise hydrogen gas and a catalyst. In some embodiments, the catalyst is Raney nickel, palladium on carbon, palladium oxide, or platinum oxide. In some embodiments, the reducing conditions further include a base. In some embodiments, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, diisopropylamine, methylisopropylamine and triethylamine. In some embodiments, the resultant nepafenac composition is crystallized and the crystallization is performed in a solvent comprising an alcohol. In some embodiments, the alcohol is methanol, ethanol, isopropanol or mixtures thereof. In some embodiments, the resultant nepafenac is crystallized from an isopropanol-water (9:1) mixture.
Some embodiments are directed to a process for the preparation of 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), comprising: treating 2-aminobenzophenone (II) with 2-(methylthio)acetamide (III) in the presence of sulfuryl chloride and a base to afford 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV). In some embodiments, the base is a trialkylamine, a dialkylamine, a cycloamine, or an N-alkylcycloamine. In some embodiments, the treating occurs at about −30° C.
Some embodiments are directed to a process for the preparation of nepafenac, comprising:
Some embodiments are directed to a process for the preparation of nepafenac, comprising:
Some embodiments are directed to a process for the preparation of nepafenac, comprising:
Some embodiments are directed to a process for the purification of a nepafenac composition containing a halogenated impurity, comprising: subjecting a nepafenac composition containing a halogenated impurity to reducing conditions, wherein the reducing conditions convert the halogenated impurity to nepafenac.
Some embodiments are directed to a process for the purification of a nepafenac composition containing a chlorinated impurity, comprising: hydrogenating a nepafenac composition containing a chlorinated impurity, wherein the hydrogenating converts the chlorinated impurity to nepafenac.
Some embodiments are directed to a process for the purification of a nepafenac composition containing a chlorinated impurity, comprising:
Some embodiments are directed to a process for the purification of a nepafenac composition containing a chlorinated impurity, comprising:
Scheme III below represents other embodiments in the present disclosure.
The present disclosure is directed to a process for the preparation of nepafenac, wherein 2-aminobenzophenone of Formula (II) is treated with 2-(methylthio)acetamide of Formula (III) in the presence of sulfuryl chloride to yield 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide of Formula (IV), which upon reduction affords nepafenac, represented by Formula (I). See, e.g., Scheme III above.
The present disclosure also relates to a process for the purification of nepafenac to remove a structurally similar impurity, wherein the nepafenac containing the structurally similar impurity compound is subjected to hydrogenation in the presence of a catalyst and a base, followed by isolation, to afford nepafenac. The obtained nepafenac of formula (I) is optionally subjected to crystallization in a mixture of alcohol and water to obtain a purified nepafenac. In some embodiments, the structurally similar impurity is a halogenated impurity, particularly one which contains a halogenated aromatic ring. In some embodiments, the halogenated impurity is 2-amino-3-benzoyl-5-chlorobenzeneacetamide.
One embodiment of the present disclosure is to provide an improved process for the preparation of nepafenac comprising the steps of:
The reaction of 2-aminobenzophenone of Formula (II) with 2-(methylthio)acetamide of Formula (III) is carried out in the presence of sulfuryl chloride and a base, preferably an organic base in a chlorinated solvent, at a temperature in the range of about −40° to about 0° C., preferably about −30° C., for a period of about 30 minutes to about 2 hours to afford a 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide of formula (IV). The 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide of formula (IV) is then reduced in the presence of a catalyst under hydrogen pressure in a suitable solvent, such as an ether and water solvent, at a temperature in the range of about 20° C. to about 35° C. and the reaction mixture is stirred for a period of 10 minutes to 60 minutes to afford nepafenac of formula (I). One of skill in the art will readily understand that a 2-(alkylthio)acetamide may be utilized in place of the specifically exemplified 2-(methylthio)acetamide. Moreover, a skilled artisan will readily recognize that alternative sources of hydrogen may be utilized in place of hydrogen gas in the reduction reaction described above. Such alternative sources include, but are not limited to, hydrazine, dihydronapthalene, dihydroanthracene, isopropanol, formic acid, and the like. Alternative hydrogen sources for reduction reactions are well-known in the synthetic arts.
According to the present disclosure, the base that is utilized in the reaction of 2-aminobenzophenone of Formula (II) with 2-(methylthio)acetamide of Formula (III) in the presence of sulfuryl chloride may be selected form organic amines such as trialkylamines, dialkylamines, monoalkylamines, cycloamines, and N-alkylcycloamines. As used herein, “alkyl” refers to C1-C6 linear and branched alkyl groups. As used herein, “cycloamine” refers to dialkylamines in which two of the alkyl groups are taken together to form a nitrogen-containing heterocyle (such as morpholine, piperidine, piperazine, pyrrolidine, imidazole, and pyridine). Non-limiting examples of trialkylamines include triethylamine and diisopropylethylamine. Non-limiting examples of dialkylamines include diisopropylamine and methylisopropylamine. Non-limiting examples of N-alkylcycloamines include N-methylmorpholine, N,N-dimethylpiperazine, N-methylpiperazine, and N-methylpyrollidine. A skilled artisan will readily understand that mixtures of the aforementioned bases can be utilized.
According to the present disclosure, the solvent for the reaction of 2-aminobenzophenone of Formula (II) with 2-(methylthio)acetamide of Formula (III) in the presence of sulfuryl chloride may be selected from chlorinated solvents such as dichloromethane (or “DCM”), dichloroethane, or chloroform, as well as ether solvents such as diethyl ether, tetrahydrofuran or diisopropylether. Additional solvents include those suitable for aromatic acylation reactions.
According to the present disclosure, the catalyst for the reduction of 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide may be a metal catalyst such as Raney nickel, Palladium on carbon, Palladium oxide, or Platinum oxide. The solvent used in the reduction of 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide may be selected from an ether solvent such as without limitation, diethyl ether, tetrahydrofuran, or diisopropylether. Other solvents include those that are compatible with catalytic reductions, mixtures thereof, and aqueous mixtures thereof. Such solvents include, but are not limited to, alcohols exemplified by methanol, ethanol, isopropanol and n-butanol.
Another embodiment of the present disclosure relates to an improved process for the purification of nepafenac containing the structurally similar impurity comprising the steps of:
According to the present disclosure, impure nepafenac, which is containing 2-amino-3-benzoyl-5-chlorobenzene acetamide as a halogenated impurity in the range of, for example, about 0.3% to about 0.7%, is hydrogenated in the presence of a catalyst and a base in a solvent at about 40-45° C. under 5-7 psi hydrogen pressure until effective reaction completion, or for about about 6-15 hours, about 8-10 hours, or about 12-13 hours. After the effective completion of the reaction, the catalyst is filtered and the filtrate is concentrated to afford nepafenac. This is then optionally subjected to further purification by crystallization from an appropriate solvent. Crystallization solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol, n-butanol, or mixtures thereof, as well as alcohol-water mixtures. A 9:1 ratio of alcohol to water has proven useful in practice, with 9:1 isopropanol:water being particularly preferred.
According to the present disclosure, the catalyst for use during the removal of the halogenated impurity may be selected from metal catalyst such as without limitation, palladium on carbon, or platinum oxide. Palladium on carbon is particularly preferred. The base for use during the removal of the halogenated impurity is one that is suitable for use during catalytic reductions, and may be selected without limitation from bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, diisopropylamine, methylisopropylamine and triethylamine. Organic amines such as trialkylamines, dialkylamines, monoalkylamines, cycloalkylamines, and N-alkylcycloamines as previously described above are particularly preferred. Moreover, a skilled artisan will readily recognize that alternative sources of hydrogen as described above may be utilized in place of hydrogen gas in the reduction reaction.
According to the present disclosure, the solvent for for use during the removal of the halogenated impurity includes, but is not limited to those that are suitable for use during catalytic reductions. These include alcohols such as methanol, ethanol, isopropanol and n-butanol, ethers such as diethyl ether and tetrahydrofuran, and esters such as ethyl acetate.
Additional aspects of the detailed disclosure are repeated and further enumerated as follows:
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
To a suspension of 2-aminobenzophenone (75 g) and 2-(methylthio)acetamide (22 g) in methylene dichloride (450 mL) was added dropwise a solution of sulfuryl chloride (25 g) in methylene chloride (300 mL) at −30° C. over a period of 30 min. The resulting mixture was stirred for 30 min at −30° C.; followed by the slow addition of triethylamine (76 g) at −30° C. and the reaction mixture was maintained for 60 minutes at the same temperature. The reaction mixture temperature was then raised to room temperature and the reaction was quenched with water (500 mL). The aqueous layer was separated and extracted twice with methylene chloride (2×200 mL). The combined organic layer was concentrated under reduced pressure to afford a residue that was subsequently dissolved in isopropyl alcohol (1940 mL) at 65°-70° C. The solution was allowed to cool to room temperature and stirred for 30 min. The resultant solid was filtered, washed with isopropyl alcohol (150 mL) and dried at 50-55° C. in a hot air oven to afford 2-amino-3-benzoyl-α-(methylthio)phenylacetamide (26 g) as a yellow solid.
To a solution of 2-amino-3-benzoyl-α-(methylthio)phenylacetamide (26 gm) in tetrahydrofuran (340 mL) and water (80 mL), Raney nickel (wet 208 g) was added at room temperature. The mixture was stirred for 15 min and filtered through a hyflo bed. The filtrate was concentrated under reduced pressure and the obtained solid was dissolved in isopropyl alcohol (780 mL) at about 75°-80° C. The solution was allowed to cool to room temperature and the resultant precipitate was filtered and dried at about 50-55° C. under reduced pressure to afford nepafenac as a yellow solid (13 g).
To a solution of nepafenac (17 g) containing 0.33% of 2-amino-3-benzoyl-5-chlorobenzeneacetamide in methanol (2550 mL) was added potassium carbonate (17 g) and 10% palladium on carbon (1.7 g). Hydrogen gas was then applied to the mixture at about 40-45° C. and 5-7 psi pressure for about 8-10 hours. After completion, the reaction mass was filtered and the filtrate was concentrated to afford nepafenac with 0.06% 2-amino-3-benzoyl-5-chlorobenzeneacetamide. This product was further purified by crystallization from an isopropanol-water mixture (9:1) to afford nepafenac as a yellow solid (8.0 g, purity 99.86% with 0.03% 2-amino-3-benzoyl-5-chlorobenzeneacetamide).
To a solution of nepafenac (0.50 g) containing 0.67% of 2-amino-3-benzoyl-5-chlorobenzeneacetamide in methanol (75 mL) was added potassium carbonate (0.50 mg) and 10% palladium on carbon (50 mg). Hydrogen gas was then applied to the mixture at about 40-45° C. and 5-7 psi pressure for 12-13 hours. After completion, the reaction mass was filtered and the filtrate was concentrated to afford nepafenac with 0.08% 2-amino-3-benzoyl-5-chlorobenzeneacetamide. This product was further purified by crystallization from an isopropanol-water mixture (9:1) to afford nepafenac as a yellow solid (0.3 g, purity 99.84%, with 0.03% 2-amino-3-benzoyl-5-chlorobenzeneacetamide).
To a solution of nepafenac (17 g) containing 0.33% 2-amino-3-benzoyl-5-chlorobenzeneacetamide in methanol (2550 mL) was added triethylamine (17 g) and 10% palladium on carbon (1.7 g). Hydrogen gas was then applied to the mixture at about 40-45° C. and 5-7 psi pressure for 8-10 hours. After completion, the reaction mass was filtered and the filtrate was concentrated to afford nepafenac (yield 11 g, purity 99.86% with 0.06% 2-amino-3-benzoyl-5-chlorobenzeneacetamide).
To a solution of nepafenac (1 g) containing 0.67% 2-amino-3-benzoyl-5-chlorobenzeneacetamide in methanol (150 mL) was added triethylamine (1 g) and 10% palladium on carbon (100 mg). Hydrogen gas was then applied to the mixture at about 40-45° C. and 5-7 psi pressure for 8-10 hours. After completion, the reaction mass was filtered and the filtrate was concentrated to afford nepafenac (yield 0.67 g, purity 99.89% with 0.01% 2-amino-3-benzoyl-5-chlorobenzeneacetamide).
| Number | Date | Country | Kind |
|---|---|---|---|
| 2823/CHE/2013 | Jun 2013 | IN | national |
| 4979/CHE/2013 | Nov 2013 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2014/000429 | 6/26/2014 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2014/207769 | 12/31/2014 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 5475034 | Yanni et al. | Dec 1995 | A |
| 6066671 | Yanni et al. | May 2000 | A |
| 6174878 | Gamache et al. | Jan 2001 | B1 |
| 6342524 | Hellberg et al. | Jan 2002 | B1 |
| 6395746 | Cagle et al. | May 2002 | B1 |
| 6403609 | Asgharian | Jun 2002 | B1 |
| 6551584 | Bandyopadhyay et al. | Apr 2003 | B2 |
| 6638976 | Gamache et al. | Oct 2003 | B2 |
| 6646001 | Hellberg et al. | Nov 2003 | B2 |
| 6646003 | Graff et al. | Nov 2003 | B2 |
| 6716830 | Cagle et al. | Apr 2004 | B2 |
| 6740664 | Cagle et al. | May 2004 | B2 |
| 7736624 | Marnett et al. | Jun 2010 | B2 |
| 7741359 | Wallace et al. | Jun 2010 | B2 |
| 7758778 | Persyn et al. | Jul 2010 | B2 |
| 7820195 | Kauper et al. | Oct 2010 | B2 |
| 7834059 | Wong | Nov 2010 | B2 |
| 7947295 | Chowhan et al. | May 2011 | B2 |
| 7964738 | Gately et al. | Jun 2011 | B2 |
| 8071648 | Wong | Dec 2011 | B2 |
| 8278484 | Suárez et al. | Oct 2012 | B2 |
| 8324281 | Wong | Dec 2012 | B2 |
| 20020022629 | Cagle et al. | Feb 2002 | A1 |
| 20020035264 | Kararli et al. | Mar 2002 | A1 |
| 20020037929 | Kapin et al. | Mar 2002 | A1 |
| 20020049255 | Gamache et al. | Apr 2002 | A1 |
| 20020103255 | Hellberg et al. | Aug 2002 | A1 |
| 20020107238 | Bandyopadhyay et al. | Aug 2002 | A1 |
| 20020183376 | Graff et al. | Dec 2002 | A1 |
| 20020193370 | Cagle et al. | Dec 2002 | A1 |
| 20030187072 | Kapin et al. | Oct 2003 | A1 |
| 20030207941 | Bingaman et al. | Nov 2003 | A1 |
| 20040132773 | Gamache et al. | Jul 2004 | A1 |
| 20040219220 | Sherry et al. | Nov 2004 | A1 |
| 20040224010 | Hofland et al. | Nov 2004 | A1 |
| 20040259765 | Bingaman | Dec 2004 | A1 |
| 20050143468 | Bingaman et al. | Jun 2005 | A1 |
| 20050187241 | Wen et al. | Aug 2005 | A1 |
| 20060100288 | Bague et al. | May 2006 | A1 |
| 20060257487 | Owen et al. | Nov 2006 | A1 |
| 20070043006 | Bingaman | Feb 2007 | A1 |
| 20070048373 | Chastain et al. | Mar 2007 | A1 |
| 20070116729 | Palepu | May 2007 | A1 |
| 20070166402 | Friedlaender et al. | Jul 2007 | A1 |
| 20070248645 | Bague et al. | Oct 2007 | A1 |
| 20070254841 | Ousler, III et al. | Nov 2007 | A1 |
| 20070297981 | Ousler, III et al. | Dec 2007 | A1 |
| 20070299124 | Ousler, III et al. | Dec 2007 | A1 |
| 20080031903 | Gambotto et al. | Feb 2008 | A1 |
| 20080038316 | Wong et al. | Feb 2008 | A1 |
| 20080039398 | Ousler, III et al. | Feb 2008 | A1 |
| 20080107738 | Philips et al. | May 2008 | A1 |
| 20080220079 | Chen et al. | Sep 2008 | A1 |
| 20080233053 | Gross et al. | Sep 2008 | A1 |
| 20080268020 | Philips et al. | Oct 2008 | A1 |
| 20090010850 | Ousler, III et al. | Jan 2009 | A1 |
| 20090018057 | Lambert et al. | Jan 2009 | A1 |
| 20090028955 | Philips et al. | Jan 2009 | A1 |
| 20090105245 | Bingaman | Apr 2009 | A1 |
| 20090111780 | Girodano | Apr 2009 | A1 |
| 20090136514 | Power | May 2009 | A1 |
| 20090209574 | Owen et al. | Aug 2009 | A1 |
| 20090312429 | Safanova et al. | Dec 2009 | A1 |
| 20090312575 | Suarez et al. | Dec 2009 | A1 |
| 20100093673 | Oronsky | Apr 2010 | A1 |
| 20100144719 | Kabra | Jun 2010 | A1 |
| 20100166874 | Malakhov et al. | Jul 2010 | A1 |
| 20100172969 | Dreu et al. | Jul 2010 | A1 |
| 20100172998 | Mathiowitz et al. | Jul 2010 | A1 |
| 20100173876 | Lichtenberger et al. | Jul 2010 | A1 |
| 20100183502 | Anderson | Jul 2010 | A1 |
| 20100184946 | Van Boxtel | Jul 2010 | A1 |
| 20100226997 | Bowman et al. | Sep 2010 | A1 |
| 20100234469 | Gavaldá Escudé et al. | Sep 2010 | A1 |
| 20100331430 | Olejnik | Dec 2010 | A1 |
| 20110015271 | Wong | Jan 2011 | A1 |
| 20110021443 | Lambert et al. | Jan 2011 | A1 |
| 20110129516 | Jacob et al. | Jun 2011 | A1 |
| 20110135743 | Chowhan et al. | Jun 2011 | A1 |
| 20120027716 | Stein et al. | Feb 2012 | A1 |
| 20120029084 | Wong | Feb 2012 | A1 |
| Number | Date | Country |
|---|---|---|
| 199916259 | Jul 1999 | AU |
| 2005311738 | Jun 2006 | AU |
| 2006244244 | Nov 2006 | AU |
| 2313386 | Jul 1999 | CA |
| 2414780 | Jan 2002 | CA |
| 2417282 | Feb 2002 | CA |
| 2418059 | Feb 2002 | CA |
| 2167524 | Aug 2002 | CA |
| 2483275 | Nov 2003 | CA |
| 2498191 | Apr 2004 | CA |
| 2527121 | Dec 2004 | CA |
| 2581126 | Apr 2006 | CA |
| 2578176 | May 2006 | CA |
| 2586074 | May 2006 | CA |
| 2607608 | Nov 2006 | CA |
| 2625568 | Apr 2007 | CA |
| 2628178 | May 2007 | CA |
| 2632568 | Jun 2007 | CA |
| 2672377 | Jul 2008 | CA |
| 2745123 | Jun 2010 | CA |
| 0716600 | Apr 2002 | EP |
| 1655021 | May 2006 | EP |
| 1929996 | Jun 2008 | EP |
| 1967212 | Sep 2008 | EP |
| 2123626 | Nov 2009 | EP |
| 2144599 | Aug 2010 | EP |
| 2016936 | Sep 2010 | EP |
| 9932104 | Jul 1999 | WO |
| 0115678 | Mar 2001 | WO |
| 0205815 | Jan 2002 | WO |
| 0213804 | Feb 2002 | WO |
| 0213805 | Feb 2002 | WO |
| 03092669 | Nov 2003 | WO |
| 2004022939 | Mar 2004 | WO |
| 2004027027 | Apr 2004 | WO |
| 2004112772 | Dec 2004 | WO |
| 2006037106 | Apr 2006 | WO |
| 2006050836 | May 2006 | WO |
| 2006050837 | May 2006 | WO |
| 2006050838 | May 2006 | WO |
| 2006060618 | Jun 2006 | WO |
| 2006082588 | Aug 2006 | WO |
| 2006121963 | Nov 2006 | WO |
| 2007042262 | Apr 2007 | WO |
| 2007061529 | May 2007 | WO |
| 2007067807 | Jun 2007 | WO |
| 2007070463 | Jun 2007 | WO |
| 2007087609 | Aug 2007 | WO |
| 2008014431 | Jan 2008 | WO |
| 2008084171 | Jul 2008 | WO |
| 2008153746 | Dec 2008 | WO |
| 2009007409 | Jan 2009 | WO |
| 2009059191 | May 2009 | WO |
| 2009103053 | Aug 2009 | WO |
| 2009105534 | Aug 2009 | WO |
| 2009141144 | Nov 2009 | WO |
| 2009150524 | Dec 2009 | WO |
| 2009151619 | Dec 2009 | WO |
| 2011053841 | May 2011 | WO |
| 2011068872 | Jun 2011 | WO |
| 2011084473 | Jul 2011 | WO |
| 2011098578 | Aug 2011 | WO |
| 2011106702 | Sep 2011 | WO |
| 2011109732 | Sep 2011 | WO |
| 2012009696 | Jan 2012 | WO |
| Entry |
|---|
| Savall et al, J. Org. Chem., 61, No. 24, 1996, 8696-97. |
| Marcin et al, Letters in Organic Chemistry, vol. 9, No. 7, 2012, 461-64(see the abstract only). |
| P.G. Gassman & G. Gruetzmacher, “Specific Ortho Alkylation of Aromatic Amines” Jan. 24, 1973; 95(2): 588-89. |
| P.G. Gassman et al., “Use of Halogen-Sulfide Complexes in the Synthesis of Indoles, Oxindoles, and Alkylated Aromatic Amines” Sep. 19, 1973; 95(19): 6508-09. |
| Number | Date | Country | |
|---|---|---|---|
| 20160214927 A1 | Jul 2016 | US |
