NUCLEOSIDE CYCLICPHOSPHATES

Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure: 3. A composition for the treatment and/or prophylaxis of any of the viral agents disclosed herein said composition comprising a pharmaceutically acceptable medium selected from among an excipient claim 1 , carrier claim 1 , diluent claim 1 , and equivalent medium and the compound of .4. A composition for the treatment and/or prophylaxis of any of the viral agents disclosed herein said composition comprising a pharmaceutically acceptable medium selected from among an excipient claim 2 , carrier claim 2 , diluent claim 2 , and equivalent medium and the compound of .5. A use of the compound of in the manufacture of a medicament for the treatment of any condition the result of an infection by hepatitis C virus claim 1 , West Nile virus claim 1 , yellow fever virus claim 1 , dengue virus claim 1 , rhinovirus claim 1 , polio virus claim 1 , hepatitis A virus claim 1 , bovine viral diarrhea virus or Japanese encephalitis virus.6. A use of the compound of in the manufacture of a medicament for the treatment of any condition the result of an infection by hepatitis C virus claim 2 , West Nile virus claim 2 , yellow fever virus claim 2 , dengue virus claim 2 , rhinovirus claim 2 , polio virus claim 2 , hepatitis A virus claim 2 , bovine viral diarrhea virus or Japanese encephalitis virus.7. A method of treatment in a subject in need thereof claim 2 , which comprises:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'administering a therapeutically effective amount of the compound of to the subject.'}8. A method of treatment in a subject in need thereof claim 2 , which comprises:{'claim-ref': {'@idref': 'CLM-00002', 'claim 2'}, 'administering a therapeutically effective amount of the compound of to the subject.'}11. A ...

Synthesis of purine nucleosides

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 181.-. (canceled)83. The compound according to claim 82 , wherein the compound is at least 98% of the Sstereoisomer represented by the formula (S-4) and not more than 2% of the Rstereoisomer represented by the formula (R-4).84. The compound according to claim 82 , wherein the compound is at least 99% of the Sstereoisomer represented by the formula (S-4) and not more than 1% of the Rstereoisomer represented by the formula (R-4).85. A pharmaceutical composition comprising the compound according to and a pharmaceutically acceptable medium.86. A pharmaceutical composition comprising the compound according to and a pharmaceutically acceptable medium.87. A pharmaceutical composition comprising the compound according to and a pharmaceutically acceptable medium.88. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the compound according to .89. The method according to further comprising administering to the human another antiviral agent.90. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the compound according to .91. The method according to further comprising administering to the human another antiviral agent.92. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the compound according to .93. The method according to further comprising administering to the human another antiviral agent. The right of priority is claimed to U.S. Provisional Patent Application Nos. 61/179,923, filed May 20, 2009, and 61/319,513, filed Mar. 31, 2010, the subject matter ...

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 181.-. (canceled)83. The compound according to claim 82 , wherein LG′ is p-nitrophenoxide claim 82 , p-chlorophenoxide claim 82 , o-chlorophenoxide claim 82 , 2 claim 82 ,4-dinitrophenoxide claim 82 , or pentafluorophenoxide.84. The compound according to claim 82 , wherein LG′ is p-nitrophenoxide.85. The compound according to claim 82 , wherein LG′ is p-chlorophenoxide.86. The compound according to claim 82 , wherein LG′ is o-chlorophenoxide.87. The compound according to claim 82 , wherein LG′ is pentafluorophenoxide.88. A process for preparing the compound according to claim 82 , which comprises:{'sub': '2', 'sup': i', 'i, 'reacting (LG′)P(O)(LG), wherein LG and LG′ are independently leaving groups, with isopropyl-alanate and a first base to obtain (LG′)P(O)(LG)(NHAla-Pr), followed by reacting (LG′)P(O)(LG)(NHAla-Pr) with phenol and a second base.'}89. A process for preparing the compound according to claim 82 , which comprises:{'sub': '2', 'reacting (LG′)P(O)(LG), wherein LG and LG′ are independently leaving groups, with phenol and a first base to obtain (LG′)P(O)(LG)(OPh), followed by reacting (LG′)P(O)(LG)(OPh) with isopropyl-alanate and a second base.'}90. A process for preparing the compound according to claim 82 , which comprises:{'sub': '2', 'reacting (LG′)P(O)(LG), wherein LG and LG′ are independently leaving groups, with a combination of isopropyl-alanate, phenol, and at least one base.'}91. A process for preparing the compound according to claim 82 , which comprises:{'sub': '2', 'sup': i', 'i, 'reacting (PhO)P(O)(LG), wherein LG and LG′ are independently leaving groups, with isopropyl-alanate and a first base to obtain (PhO)P(O)(LG)(NHAla-Pr), ...

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 170.-. (canceled)72. A pharmaceutical composition comprising the crystalline compound according to and a pharmaceutically acceptable medium.73. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the crystalline compound according to .74. The method according to further comprising administering to the human another antiviral agent.76. The process according to further comprising:grinding the first composition into a powder; andallowing the powder to stand in an open vessel.78. The process according to further comprising heating the suspension.79. The process according to further comprising cooling the suspension. This application is a continuation-in-part of U.S. patent application Ser. No. 12/783,680 filed on May 20, 2010, which claims priority to U.S. 61/179,923, filed May 20, 2009 and U.S. 61/319,513, filed on Mar. 31, 2010. Priority is claimed to U.S. 61/319,513, filed on Mar. 31, 2010 and U.S. 61/319,548, filed Mar. 31, 2010.Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for ...

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 170.-. (canceled)73. The compound according to claim 71 , wherein the compound is crystalline. This application is a continuation-in-part of U.S. patent application Ser. No. 12/783,680 filed on May 20, 2010, which claims priority to U.S. 61/179,923, filed May 20, 2009 and U.S. 61/319,513, filed on Mar. 31, 2010. Priority is claimed to U.S. 61/319,513, filed on Mar. 31, 2010 and U.S. 61/319,548, filed Mar. 31, 2010.Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for Disease Control. According to the World Health Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their ...

METHODS FOR PREPARING SUBSTITUTED PYRIDINONE-CONTAINING TRICYCLIC COMPOUNDS

The present disclosure relates to novel, scalable methods of making substituted tricyclic compounds that are useful to treat and/or prevent HBV and/or HBV-HDV infection and related conditions in a subject. 2. The method of claim 1 , wherein R is tert-butyl or ethyl.3. The method of claim 1 , wherein [25] is hydrolyzed by contacting [25] with a first acid or first base claim 1 ,optionally the method further comprising treating the product of [25] hydrolysis with a second acid or second base to a pH of about 5 to about 6 so as to isolate free acid [26] and recrystallizing [26] from a solvent comprising at least one alcohol.4. The method of claim 3 , wherein at least one of the following applies:(a) the first acid comprises at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, and phosphoric acid;(b) the first base comprises at least one of LiOH, NaOH, and KOH; and(c) the first acid or first base is contacted with [25] in a molar ratio of 1:1 to about 3:1.56-. (canceled)8. The method of claim 7 , wherein at least one of the following applies:(a) the dehydrogenation reagent comprises at least one of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), p-chloranil, N-bromosuccinimide, iodine, and manganese dioxide;(b) the dehydrogenation reagent is contacted with [24] in a molar ratio of about 1:1 to about 3:1;(c) the dehydrogenation reagent is contacted with [24] at a temperature from about 20° C. to about 80° C.; and(d) the reaction mixture is further contacted with an acid about 10 hours to about 30 hours after the dehydrogenation reagent is contacted with 1241.911-. (canceled)13. The method of claim 12 , wherein at least one of the following applies:(a) [22] is contacted with [23] in a molar ratio of about 1:1 to about 1:5; and(b) [22] is contacted with [23] at a temperature from about 20° C. to about 100° C.14. (canceled)16. The method of claim 15 , wherein at least one of the following applies:(a) Z is a protecting group comprising at least one of ...

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 181.-. (canceled)83. The process of claim 82 , wherein Z is hydrogen.84. The process of claim 82 , wherein the leaving group is an aryloxide substituted with at least one electron withdrawing group.85. The process of claim 82 , wherein the leaving group is p-nitrophenoxide claim 82 , 2 claim 82 ,4-dinitrophenoxide claim 82 , or pentafluorophenoxide.86. The process of claim 82 , wherein no chromatography is performed.88. The process of claim 87 , wherein Z is hydrogen.89. The process of claim 87 , wherein the leaving group is an aryloxide substituted with at least one electron withdrawing group.90. The process of claim 87 , wherein the leaving group is p-nitrophenoxide claim 87 , 2 claim 87 ,4-dinitrophenoxide claim 87 , or pentafluorophenoxide.91. The process of claim 87 , wherein no chromatography is performed. The right of priority is claimed to U.S. Provisional Patent Application Nos. 61/179,923, filed May 20, 2009, and 61/319,513, filed Mar. 31, 2010, the subject matter of which is incorporated by reference in its entirety.Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 4.5 million infected people in the United States alone, ...

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 181.-. (canceled) The right of priority is claimed to U.S. Provisional Patent Application No. 61/179,923, filed May 20, 2009, and U.S. Provisional Patent Application No. 61/319,513, filed Mar. 31, 2010, the subject matter of which is incorporated by reference in its entirety.Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for Disease Control. According to the World Health Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-α alone or in combination with ...

PROCESSES FOR PREPARING ANTIVIRAL COMPOUNDS

The present disclosure provides processes for the preparation of a compound of formula: 1134.-. (canceled)136. The compound of claim 135 , wherein Z is bromo.138. (canceled) This application is a continuation of U.S. application Ser. No. 15/582,224, filed Apr. 28, 2017, which is a continuation of U.S. application Ser. No. 14/733,139, filed Jun. 8, 2015, now U.S. Pat. No. 9,670,187, which claims priority to and the benefit of U.S. Provisional Application No. 62/010,813, filed Jun. 11, 2014, each of which is hereby incorporated by reference in its entirety.The present disclosure relates generally to the field of organic synthetic methodology for the preparation of antiviral compounds and the synthetic intermediates prepared thereby.Hepatitis C is recognized as a viral disease of the liver. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.The compound of Formula (A) is known to exhibit antiviral properties (WO 2013/075029). Processes suitable for its production are disclosed herein.The present disclosure provides processes for making a compound of formula (A):or a salt or solvate thereof.In one embodiment, provided is a process for preparing a compound of formula (A):or a salt or solvate thereof, comprising the steps of:(a) contacting a compound of formula (I), stereoisomer thereof, or mixture of stereoisomers thereof:with a compound of formula (J) or salt thereof:under conditions sufficient to yield a compound of formula (G), stereoisomer thereof, or mixture of stereoisomers thereof:(b) contacting the compound of formula (G) with a compound of formula (H) or salt thereof:under conditions sufficient to yield a compound of formula (B), stereoisomer thereof, or mixture of stereoisomers thereof:(c) cyclizing a compound of formula ...

Intelligent gate driver for igbt

A reverse-conducting insulated gate bipolar transistor, particularly a bi-mode insulated gate transistor, is controlled by responding to an ON command by applying high-level gate voltage for a first period, during which a current is fed into a connection point, from which it flows either through the RC-IGBT or along a different path. Based hereon, it is determined whether the RC-IGBT conducts in its forward/IGBT or reverse/diode mode, and the RC-IGBT is either driven at high or low gate voltage. Subsequent conduction mode changes may be monitored in the same way, and the gate voltage may be adjusted accordingly. A special turn-off procedure may be applied in response to an OFF command in cases where the RC-IGBT conducts in the reverse mode, wherein a high-level pulse is applied for a second period before the gate voltage goes down to turn-off level.

PROCESSES FOR PREPARING ANTIVIRAL COMPOUNDS

The present disclosure provides processes for the preparation of a compound of formula: This application is a divisional of U.S. application Ser. No. 15/847,803, filed Dec. 19, 2017, which is a continuation of U.S. application Ser. No. 15/582,224, filed Apr. 28, 2017, now U.S. Pat. No. 9,890,134, which is a continuation of U.S. application Ser. No. 14/733,139, filed Jun. 8, 2015, now U.S. Pat. No. 9,670,187, which claims priority to and the benefit of U.S. Provisional Application No. 62/010,813, filed Jun. 11, 2014, each of which is hereby incorporated by reference in its entirety.The present disclosure relates generally to the field of organic synthetic methodology for the preparation of antiviral compounds and the synthetic intermediates prepared thereby.Hepatitis C is recognized as a viral disease of the liver. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.The compound of Formula (A) is known to exhibit antiviral properties (WO 2013/075029). Processes suitable for its production are disclosed herein.The present disclosure provides processes for making a compound of formula (A):or a salt or solvate thereof.In one embodiment, provided is a process for preparing a compound of formula (A):or a salt or solvate thereof, comprising the steps of:(a) contacting a compound of formula (I), stereoisomer thereof, or mixture of stereoisomers thereof:with a compound of formula (J) or salt thereof:under conditions sufficient to yield a compound of formula (G), stereoisomer thereof, or mixture of stereoisomers thereof:(b) contacting the compound of formula (G) with a compound of formula (H) or salt thereof:under conditions sufficient to yield a compound of formula (B), stereoisomer thereof, or mixture of stereoisomers thereof:(c) ...

PROCESSES FOR PREPARING ANTIVIRAL COMPOUNDS

The present disclosure provides processes for the preparation of a compound of formula: 155.-. (canceled)57. The method of claim 56 , wherein the reaction conditions of step (a) comprise a solvent selected from the group consisting of N claim 56 ,N-dimethylacetamide claim 56 , N claim 56 ,N-dimethylformamide claim 56 , and acetonitrile.58. The method of claim 56 , wherein the reaction conditions of step (a) comprise a temperature of from about 20° C. to about 80° C.59. The method of claim 56 , wherein the reaction conditions of step (a) comprise at least one of a palladium catalyst claim 56 , a carbonate salt claim 56 , and a phosphine reagent.60. The method of claim 56 , wherein the reaction conditions of step (b) comprise a brominating reagent selected from the group consisting of pyridiniumtribomide claim 56 , bromine claim 56 , and N-bromosuccinimide.61. The method of claim 56 , wherein the reaction conditions of step (b) comprise a solvent selected from the group consisting of dichloromethane claim 56 , methanol claim 56 , and a mixture thereof.62. The method of claim 56 , wherein the reaction conditions of step (b) comprise a temperature of about 20° C.64. The method of claim 63 , wherein Xis halo claim 63 , —OH claim 63 , or —S(O)R claim 63 , and Ris alkyl claim 63 , haloalkyl claim 63 , or aryl claim 63 , and the aryl is optionally substituted with halo claim 63 , alkyl claim 63 , or haloalkyl.65. The method of claim 63 , wherein the reaction conditions comprise a solvent selected from the group consisting of N claim 63 ,N-dimethylacetamide claim 63 , tetrahydrofuran claim 63 , 2-methyltetrahydrofuran claim 63 , N claim 63 ,N-dimethylformamide claim 63 , and aceteonitrile.66. The method of claim 63 , wherein the reaction conditions comprise a temperature of from about 20° C. to about 70° C.67134.-. (canceled)136. The compound of claim 135 , wherein Z is bromo.137. (canceled) This application claims priority to and the benefit of U.S. Provisional Application ...

NUCLEOSIDE PHOSPHORAMIDATES

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. 170.-. (canceled)72. The tablet of claim 71 , wherein the crystalline Sp-4 has further XRPD 2θ-reflections (±0.2°) at 8.2 claim 71 , 10.4 claim 71 , 17.2 claim 71 , 17.7 claim 71 , 18.0 claim 71 , 18.8 claim 71 , 19.4 claim 71 , 19.8 claim 71 , 20.1 claim 71 , 20.8 claim 71 , 21.8 and 23.74. The tablet of claim 71 , wherein at least 80% of the Sp-4 is the crystalline Sp-4 of .75. The tablet of claim 71 , wherein at least 90% of the Sp-4 is the crystalline Sp-4 of .76. A method of treating a hepatitis C virus infection comprising administering the tablet of to a subject in need thereof.77. A method of treating a hepatitis C virus infection comprising administering the tablet of in combination with another antiviral agent to a subject in need thereof.78. The method of claim 77 , wherein the another antiviral agent is a HCV NS3 protease inhibitor.79. The method of claim 77 , wherein the another antiviral agent is a HCV NS5A inhibitor.80. The method of claim 77 , wherein the another antiviral agent is a HCV NS3 protease inhibitor and a HCV NS5A inhibitor. This application is a continuation of U.S. patent application Ser. No. 13/925,078, filed Jun. 24, 2013, which is a continuation of U.S. patent application Ser. No. 13/076,552, filed Mar. 31, 2011, now U.S. Pat. No. 8,618,076, which claims priority to U.S. Provisional Application No. 61/319,548, filed Mar. 31, 2010 and which is a continuation-in-part of U.S. patent application Ser. No. 12/783,680, filed May 20, 2010, now U.S. Pat. No. 8,642,756, which claims priority to U.S. Provisional Application No. 61/179,923, filed May 20, 2009 and U.S. Provisional Application No. 61/319,513, filed Mar. 31, 2010, all of ...

Processes for preparing antiviral compounds

The present disclosure provides processes for the preparation of a compound of formula: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

PROCESSES FOR PREPARING ANTIVIRAL COMPOUNDS

The present disclosure provides processes for the preparation of a compound of formula: 13.-. (canceled)5. The method of claim 4 , wherein X is bromo and Y is bromo.6. The method of claim 4 , wherein the reaction conditions comprise a solvent selected from the group consisting of dichloromethane claim 4 , 2-methyltetrahydrofuran claim 4 , tetrahydrofuran claim 4 , isopropyl acetate claim 4 , ethyl acetate claim 4 , tert-butyl methyl ether claim 4 , cyclopentyl methyl ether claim 4 , dimethylformamide claim 4 , acetone claim 4 , methyl ethyl ketone claim 4 , and methyl isobutyl ketone.7. The method of claim 4 , wherein the reaction conditions comprise a temperature of from about 10° C. to about 60° C. or from about 10° C. to about 30° C.8. The method of claim 4 , wherein the reaction conditions comprise a base.9. The method of claim 8 , wherein the base is a phosphate salt or a carbonate salt.10. The method of claim 4 , comprising contacting a compound of formula (I) claim 4 , stereoisomer thereof claim 4 , or mixture of stereoisomers thereof claim 4 , with a salt of compound of formula (J).11. The method of claim 10 , wherein the salt of the compound of formula (J) is a potassium claim 10 , a sodium claim 10 , or a cesium salt.13. The method of claim 12 , wherein the salt of a compound of formula (H) is a potassium claim 12 , a sodium claim 12 , or a cesium salt. This application is a continuation of U.S. application Ser. No. 16/404,550, filed May 6, 2019, which is a divisional of U.S. application Ser. No. 15/847,803, filed Dec. 19, 2017, now abandoned, which is a continuation of U.S. application Ser. No. 15/582,224, filed Apr. 28, 2017, now U.S. Pat. No. 9,890,134, which is a continuation of U.S. application Ser. No. 14/733,139, filed Jun. 8, 2015, now U.S. Pat. No. 9,670,187, which claims priority to and the benefit of U.S. Provisional Application No. 62/010,813, filed Jun. 11, 2014, all of which are hereby incorporated by reference in their entireties.The present ...

Nucleoside cyclicphosphates

Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure:

Synthesis of purine nucleosides

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

Crystalline (S) -isopropyl 2 - (((S) - (((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-DIHYDROPYRIMIDIN- 1- (2 H) -yl) - 4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate

Purine nucleoside phosphoramidate

Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Purine nucleoside phosphoramidate

Disclosed herein is a compound represented by formula 1 or its hydrate thereof in crystalline or crystal-like form.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Synthesis of purine nucleosides

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

Stereoselective synthesis of phosphorus containing actives

Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphorainidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Stereoselective synthesis of phosphorous containing actives

N- [(2'r) -2'-deoxy-2'-fluoro-2' -methyl-p-phenyl-5' -uridylyl] -l-alanine 1-methylethyl ester and process for its production

Disclosed herein are processes for preparing a compound represented by formula 4 and which comprises: a) reacting an isopropyl-alanate, A, a di-X'-phenylphosphate, B, 2'-deoxy-2'-fluoro-2'-C-methyluridine, 3, and a base to obtain a first mixture comprising 4, or the phosphorous-based diastereomer thereof; b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4, or the phosphorous-based diastereomer thereof, and a protected side product, wherein the protecting compound is t-butyl-dimethyl-silyl-chloride; and c) subjecting the second mixture to crystallization, chromatography, or extraction in order to obtain 4, or the phosphorous-based diastereomer thereof.

Nucleoside cyclicphosphates

Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure: Formula (I)

Crystalline form of sofosbuvir

Crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1-(2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

And process for the preparation of n-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester

Nucleoside cyclicphosphates

Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure: Formula (I)

Stereoselective synthesis of phosphorus containing actives

Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same. A process for preparing a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I is disclosed: 1 which comprises a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or a diastereomerically enriched compound of formula II wherein Group is as defined herein, W is an aryl or -CCH 2 )nSC(O)C(CH 3 )m(CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3, and LG is a leaving group; b) optionally deprotecting the compound obtained in step a) and c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the active.

Nucleoside phosphoramidates

PROCEDURE FOR PREPARATION OF N-[(2'R) -2'-DEOXY-2'-fluoro-2'-fluoro-2'-METHYL-P-FENYL-5'-URYLYL] -METHYL-PYTHYL]

Αποκαλύπτονται εις το παρόν φωσφοραμιδικά νουκλεοζιδίων του χημικού τύπου 4 και η χρήση αυτών ως παράγοντες για αγωγή ιικών παθήσεων. Αυτές οι ενώσεις είναι αναστολείς της RNA-εξαρτώμενης ιικής αντιγραφής του 5 RNA και είναι χρήσιμοι ως αναστολείς της πολυμεράσης NS5B του HCV, ως αναστολείς της αντιγραφής του HCV και για αγωγή της λοίμωξης από ηπατίτιδα C σε θηλαστικά. Αποκαλύπτεται επίσης και διεργασία για παρασκευή της ένωσης που αναπαρίσταται από τον χημικό τύπο 4• (Χημικός Τύπος 4) όπου το Ρ* αναπαριστά χειρόμορφο άτομο φωσφόρου, η οποία περιλαμβάνει: α) αντίδραση ισοπροπυλ-αλανικού, (Χημικός Τύπος Α), δι-Χ'-φαινυλφωσφορικού (Χημικός Τύπος Β), 2'-δεοξυ-2f-φθορο-2'-C-μεθυλουριδίνης, (Χημικός Τύπος 3), και βάσης για να ληφθεί πρώτο μείγμα που περιλαμβάνει το 4• όπου το Χ είναι βάση συζεύγματος ενός οξέος, το n είναι 0 ή 1, και το X' είναι αλογόνο, β) αντίδραση του πρώτου μείγματος με μια προστατευτική ένωση για να ληφθεί ένα δεύτερο μείγμα που περιλαμβάνει το 4• και γ) υποβολή κατά προαιρετικό τρόπο του δεύτερου μείγματος σε κρυστάλλωση, χρωματογραφία ή εκχύλιση προκειμένου να ληφθεί το 4. The phosphoramid nucleoside nucleosides of the formula 4 and their use as agents for the treatment of viral diseases are disclosed herein. These compounds are RNA-dependent viral replication inhibitors of 5 RNAs and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication, and for the treatment of hepatitis C infection in mammals. Also disclosed is a process for preparing the compound represented by Formula 4 • (Formula 4) wherein P * represents a chiral phosphorus atom, comprising: a) an isopropyl-alanate reaction, (Formula A), di-X; '-phenylphosphate (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4 • wherein X is the base of a conjugate of a acid, n is 0 or 1, and X 'is halogen; b) reaction of the first mixture with a protecting compound to obtain a second ...

Nucleoside cyclicphosphates

Methods for preparing substituted pyridinone-containing tricyclic compounds

Tablet comprising (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2h)-yl) Crystalline -4-fluoro3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Un comprimido que comprende (S)-isopropilo 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihidropirimidin-1(2H))-il)-4- fluoro-3-hidroxi-4-metiltetrahidrofuran-2-il)metoxi)(fenoxi)fosforil)amino)propanoato cristalino representado por la Fórmula Sp-4: **(Ver fórmula)** que tiene reflexiones XRPD 2θ (± 0,2º) en 6,1, 8,2, 10,4, 12,7, 17,2, 17,7, 18,0, 18,8, 19,4, 19,8, 20,1, 20,8, 21,8 y 23,3. A tablet comprising (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H))- crystalline yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate represented by Formula Sp-4: **(See formula)** having XRPD reflections 2θ (±0.2º) at 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20, 1, 20.8, 21.8 and 23.3.

Processes to prepare antiviral compounds

Un método de preparación de un compuesto de fórmula (A): **Fórmula** o una de sus sales o sus solvatos, que comprende las etapas de: (a) poner en contacto un compuesto de fórmula (I): **Fórmula** o un estereoisómero o una mezcla de estereoisómeros del mismo, con un compuesto de fórmula (J) o una sal del mismo:**Fórmula** en condiciones suficientes para producir un compuesto de fórmula (G):**Fórmula** o un estereoisómero o una mezcla de estereoisómeros del mismo, (b) poner en contacto el compuesto de fórmula (G) con un compuesto de fórmula (H) o una sal del mismo:**Fórmula** en condiciones suficientes para producir un compuesto de fórmula (B): **Fórmula** o un estereoisómero o una mezcla de estereoisómeros del mismo, (c) ciclar un compuesto de fórmula (B) en condiciones suficientes para producir un compuesto de fórmula (C): **Fórmula** (d) deshidrogenar el compuesto de fórmula (C) en condiciones suficientes para dar lugar a un compuesto de fórmula (D): **Fórmula** en el que las condiciones de reacción de la etapa (d) comprenden un aditivo seleccionado entre el grupo que consiste en una base de carbonato, una amina, un ácido y una sal de acetato, por ejemplo el aditivo es ácido acético, (e) desproteger el compuesto de fórmula (D) en condiciones suficientes para dar lugar a un compuesto de fórmula (E) o una de sus sales:**Fórmula** y (f) poner en contacto el compuesto de fórmula (E) con un compuesto de fórmula (F): **Fórmula** en condiciones suficientes para producir un compuesto de fórmula (A), o un estereoisómero o una mezcla de estereoisómeros del mismo, en el que PG es un grupo protector de amina, X e Y están seleccionados cada uno independientemente entre el grupo que consiste en halo, -OSO2R, -OP(O)OR y -OP(O)(OR)2, donde R es alquilo, haloalquilo, arilo o arilo sustituido. A method of preparing a compound of formula (A): ** Formula ** or one of its salts or solvates, comprising the steps of: (a) contacting a compound of formula (I): ** Formula ** or a ...

N-[(2'R)-2 '-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl] -L-alanine 1-methylethyl ester and process for its production

Abstract Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropyl-alanate, (Formula A), a di-X' phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

N- [(2'r) -2'-deoxy-2'-fluoro-2' -methyl-p-phenyl-5' -uridylyl] -l-alanine 1-methylethyl ester and process for its production

Disclosed herein are processes for preparing a compound represented by formula 4 and which comprises: a) reacting an isopropyl-alanate, A, a di-X'-phenylphosphate, B, 2'-deoxy-2'-fluoro-2'-C-methyluridine, 3, and a base to obtain a first mixture comprising 4, or the phosphorous-based diastereomer thereof; b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4, or the phosphorous-based diastereomer thereof, and a protected side product, wherein the protecting compound is t-butyl-dimethyl-silyl-chloride; and c) subjecting the second mixture to crystallization, chromatography, or extraction in order to obtain 4, or the phosphorous-based diastereomer thereof.

Nucleoside Phosphoramidates

Disclosed herein are nucleoside phosphoramidates Sp-4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. A process for producing Sp-4 is also disclosed.

Nucleoside cyclicphosphates.

Fosfato cíclico de derivados de nucleósidos para el tratamiento de infecciones virales en mamíferos, que es un compuesto, sus estereoisómeros, sales (sales por adición de ácidos o bases), hidratos, solvatos o sus formas cristalinas, representado por la siguiente estructura: (ver fórmulas (I)).

Processes for preparing antiviral compounds

The present disclosure provides processes for the preparation of a compound of formula: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

Synthesis of purine nucleosides

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodmgs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof(No suitable figure)

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphorainidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

N-[(2’r)-2’-deoxy-2’-fluoro-2’-methyl-p-phenyl-5’-uridylyl]-l-alanine 1-methylethyl ester and process for its production

Disclosed is the enantiomeric purification of (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester and its analogues as useful synthetic intermediates in the enantiomerically pure synthesis of sofosbuvir. Also disclosed are compounds of general formula C and C’, wherein R is a leaving group (LG’) selected from tosylate, camphorsulfonate, an aryloxide, or an aryloxide substituted with at least one electron withdrawing group, and preferably selected from p-nitrophenoxide, p-chlorophenoxide, o-chlorophenoxide, 2,4-dinitrophenoxide and pentafluorophenoxide.

(S) -2 - (((S) - (((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -4- Crystalline isopropyl fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate

(S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihidropirimidin-1(2H)-il)-4-fluoro-3-hidroxi-4-metiltetrahidrofuran-2-il) metoxi)(fenoxi)fosforil)amino)propanoato de isopropilo cristalino representado por la fórmula SP-4:**Fórmula** que tiene reflexiones 2θ (º) de XRPD a aproximadamente: 6,1, 8,2, 10,4, 12,7, 17,2, 17,7, 18,0, 18,8, 19,4, 19,8, 20,1, 20,8, 21,8, y 23,3. (S) -2 - (((S) - (((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro -3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) crystalline isopropyl propanoate represented by the formula SP-4: ** Formula ** having 2θ (º) reflections of XRPD at approximately : 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21 , 8, and 23.3.

Synthetic processes and intermediates

The invention provides synthetic processes and synthetic intermediate compounds that can be used to prepare therapeutic conjugates. The invention also provides methods for treating HBV and/or HDV infection in a human by administering a therapeutic conjugate prepared by the synthetic methods of the invention.

Crystalline forms 1 6 of (s) -isopropyl-2 - (((s) - (((2r.3r.4r.5r) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2h) -yl) -4-fluoro-3-hydroxy-4-methyl tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate; pharmaceutical composition and combination; and its use to treat a hepatitis c virus infection.

Forma cristalina de (s)-isopropil-2-(((s)-(((2r.3r.4r.5r)-5-(2,4-dioxo-3,4-dihidropirimidin-1(2h)-il)-4-fluoro-3-hidroxi-4-metiltetrahidrofuran-2-il)metoxi)(fenoxi)fosforil)amino)propanoato; proceso de preparación; composición farmacéutica; y su uso para tratar una infección por el virus de la hepatitis C. Crystalline form of (s) -isopropyl-2 - (((s) - (((2r.3r.4r.5r) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2h) -il ) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate; Preparation process; pharmaceutical composition; and its use to treat a hepatitis C virus infection.

Nucleoside cyclicphosphates

Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure: Formula (I)

Method for making monolithically integrated signal processing circuit having active and passive components

An optical signal processor is implemented as a monolithically integrated semiconductor structure having optical waveguide devices forming beam splitters, optical amplifiers and optical phase shifters. The monolithic structure photonically controls a phased-array microwave antenna. Phase-locked master and slave lasers generate orthogonal light beams having a difference frequency that corresponds to the microwave carrier frequency of the phased-array antenna. The lasers feed the signal processor, which performs beam splitting, optical amplifying and phase shifting functions. A polarizer and an array of diode detectors convert optical output signals from the signal processor into microwave signals that feed the phased-array antenna. The optical waveguides of the signal processor are fabricated in a single selective epitaxial growth step on a semiconductor substrate.

Health investigation in a circuit breaker

A health investigating arrangement (22) for a first unidirectional conducting element (MBD1) having a reverse blocking state, a forward conduction state and a faulty state comprises a voltage dividing circuit (26) in parallel with the element (MBD1), the circuit (26) comprises a first block (40) comprising a first component (R1) connected in series with a second block (42) comprising a second component (R2), the components having a relationship between each other dividing the reverse blocking state voltage down to a level that can be handled by a signal evaluating circuit. A junction between the blocks (40, 42) forms a health signal output providing a health signal (Vmon) capable of representing all states and the block (42) comprises a second unidirectional conducting element (D2) with opposite orientation compared with the first (MBDi) for removing the voltage division from the health signal when the first element is in the forward conduction state.

N- [(2'r) -2'-deoxy-2'-fluoro-2' -methyl-p-phenyl-5' -uridylyl] -l-alanine 1-methylethyl ester and process for its production

Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropylalanate, (Formula A), a di-X'-phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.

Nucleoside phosphoramidates

Disclosed herein are nucleoside phosphorainidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Nucleoside Cyclophosphates

Un compuesto de fórmula I-3:**Fórmula** o un estereoisómero, una sal, un hidrato, un solvato o una forma cristalina del mismo; en la que R1 es n-alquilo, alquilo ramificado, cicloalquilo, alcarilo, fenilo o naftilo, en donde el fenilo o naftilo está opcionalmente sustituido con al menos uno de F, Cl, Br, I, OH, OR', SH, SR', NH2, NHR', NR'2, heterociclo, alquilo C1-C6, alquenilo C1-C6 halogenado, alquinilo C2-C6, alquinilo C2-C6 halogenado, alcoxi C1-C6, alcoxi C1-C6 halogenado, CO2H, CO2R', CONH2, CONHR', CONR'2, CH>=CHCO2H o CH>=CHCO2R', en donde R' es un alquilo C1-C10 opcionalmente sustituido, cicloalquilo C3-C7, alquenilo C2-C10, alquinilo C2-C10, o alcoxialquilo C1-C10; R2 es H, un alquilo C1-C6, ciano, vinilo, O-(alquilo C1-C6), hidroxil-alquilo C1-C6, fluorometilo, azido, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, F, CI, Br o I; R3 es CH3, CH2F, CHF2 o CF3; X es F; R7 y R8 son independientemente H, F, Cl, Br, I, OH, OR', SH, SR', NH2, NHR', NR'2, NHR'2 +, NR'3 +, heterociclo, alquilo C1-C6, alquilo C1-C6 halogenado, alquenilo C2-C6, alquenilo C2-C6 halogenado, alquinilo C2-C6, alquinilo C2-C6 halogenado, alcoxi C1-C6, alcoxi C1-C6 halogenado, CO2H, CO2R', CONH2, CONHR', CONR'2, CH>=CHCO2H o CH>=CHCO2R'; Z es N o CR9; y R9 es H, F, OH, OR', NH2, NHR', NR'2, alquilo C1-C6 o alquilo C1-C6 halogenado; en donde R' es un alquilo opcionalmente sustituido, un cicloalquilo opcionalmente sustituido, un alquinilo opcionalmente sustituido, un alquenilo opcionalmente sustituido, un acilo opcionalmente sustituido o un alcoxialquilo opcionalmente sustituido, en donde para el caso de NR'2 o NHR'2 +, cada R' es independiente uno del otro o ambos R' se unen para formar un heterociclo que comprende al menos dos átomos de carbono, y en donde para el caso de NR'3+, cada R' es independiente uno del otro o al menos dos R' se unen para formar un ...

Security modes for a distributed routing table

A mesh is joined by a node, wherein the mesh includes a Distributed Routing Table (DRT) for determining addresses of nodes in the mesh. A DRT message is processed in accordance with a security mode of the DRT.

METHODS, METHOD FOR PREPARING A CRYSTALLINE FORM, CRYSTALLINE FORM, COMPOUNDS AND SALT

MÉTODOS, MÉTODO PARA PREPARAR UMA FORMA CRISTALINA, FORMA CRISTALINA, COMPOSTOS E SAL. A invenção fornece processos sintéticos e compostos intermediários sintéticos que podem ser usados para preparar conjugados terapêuticos. A invenção também fornece métodos para o tratamento de infecção por HBV e/ou HDV em um humano pela administração de um conjugado terapêutico preparado pelos métodos sintéticos da invenção. METHODS, METHOD FOR PREPARING A CRYSTALLINE FORM, CRYSTALLINE FORM, COMPOUNDS AND SALT. The invention provides synthetic processes and synthetic intermediates that can be used to prepare therapeutic conjugates. The invention also provides methods for treating HBV and/or HDV infection in a human by administering a therapeutic conjugate prepared by the synthetic methods of the invention.

N-[(2’r)-2’-deoxy-2’-fluoro-2’-methyl-p-phenyl-5’-uridylyl]-l-alanine 1-methylethyl ester and process for its production

Disclosed is a process for the synthesis of enantiomerically pure sofosbuvir (Sp-4) or its corresponding opposite phosphoramidate enantiomer (Rp-4), said process comprising reacting an enantiomerically purified isopropyl-alanylphosphoramidate of formula (C) (or C’ in the case of the preparation of Rp-4), with 2’-deoxy-2’-fluoro-2’-C-methyluridine of formula (3) and a base, where LG’ is a suitable leaving group such as an aryloxide substituted with at least one electron withdrawing group (e.g. p-nitrophenoxide, p-chlorophenoxide, o-chlorophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide etc.), wherein Z is hydrogen or a protecting group, and optionally subsequently deprotecting the product as necessary.

Stereoselective synthesis of phosphorus containing actives

Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same.

Synthetic processes and intermediates

The invention provides synthetic processes and synthetic intermediate compounds that can be used to prepare therapeutic conjugates. The invention also provides methods for treating HBV and/or HDV infection in a human by administering a therapeutic conjugate prepared by the synthetic methods of the invention.

N- [(2'r) -2'-deoxy-2'-fluoro-2' -methyl-p-phenyl-5' -uridylyl] -l-alanine 1-methylethyl ester and process for its production

Provided herein is a process for preparing the compound of formula Sp-4: (see formula Sp-4)

Synthesis of purine nucleosides

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

N-[(2’r)-2’-deoxy-2’-fluoro-2’-methyl-p-phenyl-5’-uridylyl]-l-alanine 1-methylethyl ester and process for its production

Disclosed is a crystalline compound represented by the formula Sp-4 which is (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate / (S)-2-{ [(2R,3R,4R,SR)-S-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy]-phenoxyphosphorylamino} -propionic acid isopropyl ester. Further disclosed is a composition comprising the crystalline compound Sp-4 which is the (S) phosphorus enantiomer of the compound (S)-2-{ [(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -propionic acid isopropyl ester and a pharmaceutically acceptable medium for the treatment of a hepatitis C virus infection.

Nucleoside phosphoramidates

Methods for preparing substituted pyridinone-containing tricyclic compounds

The invention relates to novel, scalable methods of making substituted tricyclic compounds that are useful to treat and/or prevent HBV and/or HBV-HDV infection and related conditions in a subject.

N- [ (2 ` r) -2 ` -deoxy-2 ` -fluoro-2 ` -methyl-p-phenyl-5 ` -uridylyl] -l-alanine 1-methylethyl ester and process for its production

Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropyl-alanate, (Formula A), a di-X'-phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.

Processes for preparing antiviral compounds

Synthesis of substituted 1-aryl-1'-heteroaryl compounds and substituted 1,1'-biheteroaryl compounds, and analogues thereof

The present disclosure includes synthetic methods for preparing certain substituted 1-aryl-1'-heteroaryl and 1,1'-biheteroaryl compounds, which can be used to treat, ameliorate, and/or prevent hepatitis B virus (HBV) infections in a patient, in particular compound 2-((6-(2-chloro- 3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6- diazaspiro[3.4]octan-7-one.

Synthesis of substituted tricyclic amides and analogues thereof

The present disclosure includes synthetic methods for preparing certain substituted tricyclic amides, which can be used to treat, ameliorate, and/or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a subject.

Synthesis of substituted tetracyclic carboxylic acids and analogues thereof

The present disclosure includes synthetic methods for preparing certain substituted tetracyclic carboxylic acids, which can be used to treat, ameliorate, or prevent hepatitis B virus (HBV) infections in a patient.

Synthetic processes and intermediates

Infrared/optical imaging techniques using anisotropically strained doped quantum well structures

An imaging system for transferring an infrared (IR) image to a visible image. The imaging system includes a polarization rotator that rotates the polarization of a visible light beam in response to absorptions of radiation from the IR image. A polarizer outputs components of the visible light beam as a function of the amount of absorbed radiation from the IR image. The polarization rotator is formed from a multiple quantum well structure grown on a semiconductor substrate with a thermally induced uniaxial, in-plane, compressive strain. The multiple quantum well structure includes a heterostructure of undoped barrier layers and doped quantum well layers. The strain causes the quantum well layers to have anisotropic radiation absorption characteristics. In particular, orthogonal components of the visible light parallel to and perpendicular to the strain will experience different degrees of absorption. The dopant in the quantum well layers is sufficient to bleach the lowest exciton resonances, thereby reducing absorption of the light beam. IR absorption from the image decreases the bleaching and increases the ability of the quantum well layers to promote exciton transitions. As such, the polarization of the light beam rotates as a function of the amount of IR absorbed from the image.

Synthesis of substituted tricyclic amides and analogues thereof

Synthesis of substituted tricyclic amides and analogues thereof

The present disclosure includes synthetic methods for preparing certain substituted tricyclic amides, which can be used to treat, ameliorate, and/or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a subject.

Synthesis of substituted tricyclic amides and analogues thereof

The present disclosure includes synthetic methods for preparing certain substituted tricyclic amides, which can be used to treat, ameliorate, and/or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a subject.

Intelligent gate driver for igbt

Intelligent gate driver for igbt

A reverse-conducting insulated gate bipolar transistor (RC-IGBT), particularly a bi-mode insulated gate transistor (BIGT), is controlled by responding to an ON command by applying high-level gate voltage for a first period (51 ), during which a current is fed into a connection point, from which it flows either through the RC-IGBT or along a different path. Based hereon, it is determined whether the RC-IGBT conducts in its forward/IGBT or reverse/diode mode, and the RC-IGBT is either driven at high (a) or low (b) gate voltage. Subsequent conduction mode changes may be monitored in the same way, and the gate voltage may be adjusted accordingly (c, d). A special turn-off procedure may be applied in response to an OFF command in cases where the RC- IGBT conducts in the reverse mode, wherein a high-level pulse is applied for a second period (52) before the gate voltage goes down to turn-off level (b, c).

Procesos e intermedios sinteticos.

La invención proporciona procesos sintéticos y compuestos intermedios sintéticos que pueden usarse para preparar conjugados terapéuticos. La invención también proporciona métodos para tratar la infección por HBV y/o HDV en un ser humano mediante la administración de un conjugado terapéutico preparado mediante los métodos sintéticos de la invención.

Sintesis de amidas triciclicas sustituidas y analogos de las mismas.

La presente descripción incluye métodos de síntesis para preparar ciertas amidas tricíclicas sustituidas, las cuales pueden usarse para tratar, mejorar y/o prevenir infecciones por el virus de la hepatitis B (HBV) y/o el virus de la hepatitis D (HDV) en un sujeto.

Synthesis of substituted tricyclic amides and analogues thereof

The present disclosure includes synthetic methods for preparing certain substituted tricyclic amides, which can be used to treat, ameliorate, and/or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a subject.

Processes for preparing antiviral compounds

The present disclosure provides processes for the preparation of a compound of formula: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

Processes for preparing antiviral compounds

The present disclosure provides processes for the preparation of a compound of formula: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

Intelligent gate driver for IGBT

A reverse-conducting insulated gate bipolar transistor, particularly a bi-mode insulated gate transistor, is controlled by responding to an ON command by applying high-level gate voltage for a first period, during which a current is fed into a connection point, from which it flows either through the RC-IGBT or along a different path. Based hereon, it is determined whether the RC-IGBT conducts in its forward/IGBT or reverse/diode mode, and the RC-IGBT is either driven at high or low gate voltage. Subsequent conduction mode changes may be monitored in the same way, and the gate voltage may be adjusted accordingly. A special turn-off procedure may be applied in response to an OFF command in cases where the RC-IGBT conducts in the reverse mode, wherein a high-level pulse is applied for a second period before the gate voltage goes down to turn-off level.