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SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

February 28, 2018 11:59 am / 1 Comment on SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

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SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

WO-2018032356, Pharmaresources (Shanghai) Co Ltd

CHEN, Ping; (CN).
PENG, Shaoping; (CN).
LI, Yinqiang; (CN).
LI, Dafeng; (CN).
DONG, Xuejun; (CN)

Process for the preparation of lactone derivatives and their intermediates are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir . Represents a first filing from Pharmaresources (Shanghai) Co Ltd and the inventors on this API. Gilead Sciences , following its acquisition of Pharmasset , has developed and launched sofosbuvir, a pure chiral isomer of PSI-7851, a next-generation HCV uracil nucleotide analog polymerase inhibitor prodrug for once-daily oral use.

Hepatitis C virus (HCV) infection represents a global health thereat in need of more effective treatment options. The World Health Organization (WHO) estimates that 130-170 million of individuals worldwide have detectable antibodies to HCV and approximately 60-85％of this population develops into chronic disease, leading to liver cirrhosis (5-25％) and hepatocellular carcinoma (1-3％) and liver failure. While there were existing therapeutics including pegylated interferon- (Peg-IFN) and ribavirin (RBV) , they are suboptimal due to various adverse effects, intolerability, low efficacy and slow response in reducing the viral loads across the multiple genotypes (1-6) of HCV. Therefore, there is an urgent and enormous need to develop more effective and efficacious novel anti-HCV therapies.

During the past decade, there have been a variety of small molecule agents as direct-acting antivirals (DAAs) targeting HCV viral replication via action on both structural and nonstructural proteins (NS3-5) have been launched inmarket or in late-stage clinical development. Among the DAAs reported, Soforsbuvir (brand name Sovaldi) targeting NS5B protein from Gilead was approved by FDA in 2003 for HCV genotypes 2 and 3 (in combination with Ribavin) . In 2014, a combination of Sofosbuvir with viral NS5A inhibitor Ledipasvir (brand name Harvoni) was approved. This combination provides high cure rates in people infected with HCV genotype 1, the most common subtype in the US, Japan, and much of the Europe, without the use of interferon, and irrespective of prior treatment failure or the presence of cirrhosis. Compared to previous treatment, Sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a 2-4 fold reduced duration of therapy.

Sofosbuvir is a prodrug using the ProTide biotechnology strategy. It is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis.

Due to the tremendous success in Sorosbuvir-based oral therapy, there remains a need for a more efficient method for making sofosbuvir-like anti-hepatitis C virus agents, including sofosbuvir and intermediates thereof. A variety of methods describing different synthetic approaches for substituted lactone (VI) shown below, a key intermediate for Sofosbuvir and its like anti-viral drugs have been published.

WO2008045419 reported a seven-step synthesis (Scheme 1) for the γ-lactone intermediate. When chiral glyceraldehyde used as the starting material, two new chiral centers were generated following Witting reaction and dihydoxylation. After cyclic sulfonate formed, the fluoro subsititution was introduced stereospecifically by a SN2 reaction with HF-Et3N. Lactonization was achieved under the acid conditions followed by hydroxy protecting step to give the desired intermediate. The main disadvantage of this approach is that considerable quantities of both solid and acidic liquid wastes were produced during the process which is very difficult to handle with (e.x. filtration) and/or contributes to the enviroment pollution upon disposal.

Scheme 1

In a similar process reported in CN105418547A (Scheme 2) , the Witting product was epoxidized followed by ring-opening fluorolation by HF-Et₃N or other fluoro-containing reagents, significant amount of regioisomer was observed which was difficult to remove from the oily mixture.

Scheme 2

US20080145901 reported an enzymetic approach to the γ-lactone intermediate (scheme 3) . Treatment of ethyl 2-fluoro-propinate with chiral glyceraldehyde to form the aldol adducts consisting the mixture of four disteroisomers. The disteroisomers were selectively hydrolyzed by enzyme and the major isomer was obtained. After lactonization and hydroxyl protecting, other two isomers were removed by recrystallization.

WO2008090046 reported a similar synthesis as described in Scheme 3.2-fluoro-propionic acid was converted to diffirent bulky ester or amide and reacted with chiral glyceraldehydes. The mixture of the disteroisomers were purified by recrystallization to obtain the pure isomer. By using the method described in Scheme 3, the γ-lactone can be scale up to kilogram quantities but the de value of the final product can not achieve desired level.

Scheme 3

In WO2014108525, WO2014056442 and CN105111169, diffirent auxiliaries were used in the Aldol Reaction to improve the disteroisomeric selectivity (Scheme 4) . The process was shortened to 3～4 steps and the de value was increase significantly.

Scheme 4

Examples

Example 1： preparation of 2-fluoropropanoyl chloride (3)

Chlorosulfonic acid (660 mL, 10 mol, 20 eq) was added to a solution of phthaloyl dichloride (1.4 L, 10 mol, 20 eq) and ethyl-2-fluoropropanoate (600 g, 5 mol) at room temperature. The solution was heated at 120 ℃ for 4 hs. 2- (R) -fluoropropanoyl chloride was distilled from the reaction mixture under reduced pressure and recovered as a colourless oil (320 g, 58.2％) . ¹H-NMR (CDCl₃， 400 MHz) ： δ 5.08 (dq, J ＝ 48.8, 6.8 Hz, 1 H) , 1.63 (dd, J ＝22.8, 6.8 Hz, 3 H) .

Example 2： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (4)

n-Butyl lithium (2.5 M in hexane, 30 mL, 75 mmol, 1.1 eq) was added to a solution of 4-(R) -4-isopropyl-2-oxazolidinone (8.8 g, 68.2 mmol, 1 eq) in dry THF (80 mL) at -50 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (6.8 mL, 0.9 eq) was added, and the solution was stirred for 4 hs at -50 ℃. The reaction was then quenched with a saturated solution of NH₄Cl (50 mL) , extracted with MTBE (80 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (Hexane/EtOAc＝ 10/1) and recovered as a brown oil (9 g, 74.8％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 6.00 (dm, J ＝ 49.2Hz, 1 H) , 4.27 -4.53 (m, 3 H) , 2.43 (dm, J ＝ 52.6 Hz, 1 H) , 1.63 (td, J ＝ 23.2Hz, 3 H) , 0.92 (dq, J ＝ 17.8 Hz, 6 H) .

[0206]

Example 3： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (5)

[0207]

n-Butyl lithium (2.5 M in hexane, 75 mL, 187 mmol, 1.1eq) was added to a solution of 4- (S) -4-isopropyl-2-oxazolidinone (22 g, 170 mmol, 1 eq) in dry THF (200 mL) at -50 ℃ under N₂ atomosphere. After 30 min 2-fuoropropanoyl chloride (17 mL, 153 mmol, 0.9 eq) was added, and the solution was stirred for 1 h at -50 ℃. After the starting material was completely consumed, the reaction was then quenched with a saturated solution of NH₄Cl (125 mL) , extracted with MTBE (200 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc＝ 10/1) and recovered as a brown oil (34 g, 83.3％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 5.93 (dm， J ＝ 48.8 Hz, 1 H) , 4.19 -4.17 (m, 3H) , 2.35 (dm, J ＝ 52.8 Hz , 1 H) , 1.55 (td, J ＝ 23.6 Hz, 3 H) , 0.85 (dq, J ＝ 18 Hz, 6 H) .

Example 4： preparation of (4R) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (6)

n-Butyl lithium (2.5 M in hexane, 13.5 mL, 33.74 mmol, 1.1 eq) was added to a solution of (R) -4-phenyloxazolidin-2-one (5 g, 30.67 mmol, 1 eq) in dry THF (75 mL) at -50 ℃ under N₂ atomosphere. After 30 minutes, 2-fuoropropanoyl chloride (3.75 g, 33.74 mmol) was added, and the solution was stirred for 1 h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃(sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (4 g, 55％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.35-7.21 (m, 5 H) , 5.99-5.84 (md, 1 H) , 5.42-5.33 (dd, 1 H) , 4.72 (dd, 1 H) , 4.31 (m, 1 H) , 1.50 (m, 3 H) .

Example 5： preparation of (4s) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7)

n-Butyl lithium (2.5 M in hexane, 67.5 mL, 169 mmol, 1.1 eq) was added to a solution of (s) -4-phenyloxazolidin-2-one (25 g, 153 mmol, 1 eq) in dry THF (375 mL) at -60 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (18.7 g, 169 mmol) was added, and the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (16.5 g, 45.4％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.36-7.20 (m, 5 H) , 5.95-5.80 (md, 1 H) , 5.42-5.30 (dd, 1 H) , 4.71 (dd, 1 H) , 4.30 (m, 1 H) , 1.51 (m, 3 H) .

Example 6： preparation of (4S) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (8)

n-Butyl lithium (2.5 M in hexane, 54.7 mL, 137 mmol, 1.1eq) was added to a solution of (S) -4-benzyloxazolidin-2-one (22 g, 124 mmol, 1eq) in dry THF (220 mL) at -60 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (15.2 g, 137 mmol) was added dropwisely below -50 ℃ , after adding the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc) and recovered as a brown oil (25.8 g, 82.7％) . ¹H-NMR(400 MHz, CDCl₃ ) ： δ 7.29-7.13 (m, 5 H) , 6.01-5.81 (qd, 1 H) , 4.71-4.58 (md, 1 H) , 4.29-4.04 (m, 2 H) , 3.32-3.16 (dd, 1 H) , 2.79-2.74 (m, 1 H) , 1.51 (m, 3 H) .

Example 7： preparation of (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (9)

Use the procedure described in Example 6, (R) -4-benzyloxazolidin-2-one as the start material to give the desired compound (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (yield: 85％) . ¹H-NMR (400 MHz, CDCl₃ ) ： δ 7.27 -7.12 (m, 5 H) , 6.00-5.83 (qd, 1 H) , 4.72-4.55 (md, 1 H) , 4.27-4.03 (m, 2 H) , 3.32 -3.16 (dd, 1 H) , 2.79 -2.72 (m, 1 H) , 1.53 (m, 3 H) .

[0221]

Example 8： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (10)

[0222]

[0223]

n-Butyl lithium (2.5 M in hexane, 48 mL) was added to a solution of (R) -4-isopropyl-5,5-diphenyloxazolidin-2-one (28.1 g) in dry THF (150 mL) at -65 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (16.4 g, 1.5 eq) was added dropwisely below -60 ℃. After adding the solution was stirred for 2 h at -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The crude product was recrystalized in (DCM/PE) to give (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (30 g, 85％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.50 -7.26 (m, 10 H) , 5.89 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.37 (dd, J ＝ 70.8, 3.4 Hz, 1 H) , 2.00 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.70 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.12 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.83 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0224]

Example 9： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11)

[0225]

[0226]

Use the procedure described in Example 8 and (S) -4-isopropyl-5, 5-diphenyloxazolidin-2-one as the start material to give the desired compound (4S) -3- (2-fluoropropanoyl) -4-isopropyl- 5,5-diphenyl oxazolidin-2-one (yield: 82％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.51 -7.27 (m, 10 H) , 5.90 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.38 (dd, J ＝ 70.8, 3.4 Hz, 1H) , 2.01 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.71 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.13 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.84 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0227]

Example 10： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12)

[0228]

[0229]

Method A: TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (10.3 mL, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.2 g, yield: 80％, purity: 97.2％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.89 (dddd, J ＝ 17.1, 10.5, 6.5, 0.8 Hz, 1 H) , 5.42 (d, J ＝17.2 Hz, 1 H) , 5.30 (d, J ＝ 10.1 Hz, 1 H) , 4.68 (dd, J ＝ 14.8, 6.5 Hz, 1 H) , 4.44 (d, J ＝ 4.0 Hz, 1 H) , 4.32 (t, J ＝ 8.5 Hz, 1 H) , 4.24 (dd, J ＝ 9.1, 3.4 Hz, 1 H) , 3.61 (d, J ＝ 6.5 Hz, 1 H) , 2.37 (dd, J ＝ 7.0, 4.1 Hz, 1 H) , 1.73 (s, 1.5 H) , 1.67 (s, 1.5 H) , 0.92 (ddd, J ＝ 7.8, 5.6, 2.4 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) : -158.3 ppm.

[0230]

Method B: TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, (-) -spartein (14.5 g, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with NH₄Cl (sat 50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (9.4 g, yield: 75％, purity: 96.5％) .

[0231]

Example 11： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (13)

[0232]

[0233]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.4 g, yield: 83％, purity: 92.8％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.92 (d， J ＝ 1.1 Hz， 1 H) ， 5.44 (d, J ＝ 17.2 Hz, 1 H) , 5.34 -5.28 (m, 1 H) , 4.73 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.43 (m, 1 H) , 4.37 -4.30 (m, 1H) , 4.27 -4.21 (m, 1 H) , 2.43 -2.31 (m, 1H) , 1.77 (s, 1.5 H) , 1.71 (s, 1.5 H) , 0.91 (dd, J ＝ 12.1, 7.0 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -159.1ppm.

[0234]

Example 12： preparation of (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one

[0235]

[0236]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4S) -4-benzyl-3-(2-fluoro propanoyl) oxazolidin-2-one (8) (12.3 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, TMEDA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at -78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL*2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (13 g, yield: 86％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 7.38 -7.27 (m, 3 H) , 7.22 (d, J ＝ 6.8 Hz, 2 H) , 5.96 (dddd, J ＝ 17.0, 10.5, 6.2, 1.2 Hz, 1 H) , 5.47 (d, J ＝ 17.2 Hz, 1 H) , 5.35 (d, J ＝ 10.5 Hz, 1 H) , 4.75 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.66 (td, J ＝ 7.1, 3.6 Hz, 1 H) , 4.23 (dd, J ＝ 16.3, 5.0 Hz, 2 H) , 3.33 (dd, J ＝ 13.3, 3.3 Hz, 1 H) , 2.76 (dd, J ＝13.3, 10.0 Hz, 1 H) , 1.81 (s, 1.5 H) , 1.76 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0237]

Example 13： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0238]

[0239]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, Et₃N (12.5 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (12 g, yield: 83％, purity: 90.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.43 -7.30 (m, 5 H) , 5.81 (dddd, J ＝ 17.0, 10.5, 6.3, 1.1 Hz, 1 H) , 5.46 (dd, J ＝ 8.4, 5.1 Hz, 1 H) , 5.37 (dt, J ＝ 17.2, 1.2 Hz, 1 H) , 5.23 (d, J ＝ 10.4 Hz, 1 H) , 4.74 (t, J ＝ 8.7 Hz, 1 H) , 4.64 (dd, J ＝ 13.5, 6.3 Hz, 1 H) , 4.31 (dd, J ＝ 8.9, 5.2 Hz, 1 H) , 1.60 (s, 1.5H) , 1.55 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0240]

Example 14： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0241]

[0242]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoro propan oyl) -4-phenyloxazolidin-2-one (6) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, DIPEA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (11.1 g, yield: 77％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.44 -7.29 (m, 5 H) , 5.74 -5.63 (m, 1 H) , 5.48 (dd, J ＝ 8.4, 5.3 Hz, 1 H) , 5.35 -5.26 (m, 1 H) , 5.15 (d, J ＝ 10.5 Hz, 1 H) , 4.73 (t, 1 H) , 4.52 (dd, J ＝ 14.8, 6.2 Hz, 1 H) , 4.28 (dd, J ＝ 8.9, 5.3 Hz, 1 H) , 1.68 (s, 1.5 H) , 1.63 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -161.93 ppm.

[0243]

Example 15： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one

[0244]

[0245]

Method 1: LiHMDS (1 M in THF, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry THF (100 mL) at -20 ℃ under N₂ atomosphere. After 1.5 hs, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -20 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step. m/z (ES+) : 412 [M+H] +.

[0246]

Method 2: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5g, 2eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (40 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (17.82 g, yield: 88％ (Internal standard yield) .

[0247]

Method 3: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, DIPEA (13 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (16.2 g, yield: 80％ (Internal standard yield ) .

[0248]

Method 4: (C₆H₁₂) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (14.6 g, yield: 80％ (Internal standard yield ) .

[0249]

Example 16： preparation of (3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydro furan-2 (3H) -one

[0250]

Method 1:

[0251]

[0252]

N-Bromosuccinimide (19.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in DME/H₂O (4: 1, 130ml) at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (bromomethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18a) . ¹H-NMR (400 MHz, CDCl₃) : δ 4.62 -4.53 (m, 1 H) , 4.37 (dd, J ＝ 3.0, 1.9 Hz, 1 H) , 3.73 (dd, J ＝ 10.1, 8.7 Hz, 1 H) , 3.60 (ddd, J ＝ 10.1, 5.8, 1.9 Hz, 1 H) , 2.59 (dd, J ＝ 2.5, 1.7 Hz, 1 H) , 1.67 (d, J ＝ 22.7 Hz, 3 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -172.248 ppm.

[0253]

Alternative Method 1a: Br₂ (17.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in MeCN/H₂O (4: 1, 130 mL) between -5 ℃ to -10 ℃ and stirred for 2 hs . After the reaction was complete, Na₂S₂O₃ (10％, 20 ml) was added and stirred for 0.5 h at rt then separated . The water phase was re-extracted by DCM (50 mL *2) , the combine organic phase was concentrated, dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to used in the next step.

[0254]

Alternative Method 1b: N-chlorosuccinimide (13.3 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in 100ml CH3CN at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (chloromethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18b) , m/z (ES+) : 183 [M+H] +.

[0255]

The related lactone 18a or 18b (0.14eq) was dissolved in EtOH (104 mL) , then KOH (30％in H₂O, 50 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into the mixture and reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (yield: 80～85％) . m/z (ES+) : 165 [M+H] +. ¹H-NMR (400 MHz, MeOD) : δ 4.34 (ddd， J ＝ 8.0， 4.2， 2.3 Hz， 1 H) , 4.02 (ddd, J ＝ 17.6, 15.2, 5.1 Hz, 2 H) , 3.74 (dd, J ＝ 13.0, 4.2 Hz, 1 H) , 1.60 (s, 1.5 H) , 1.54 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, MeOD) : -172.47 ppm.

[0256]

Method 2:

[0257]

[0258]

Osmium tetroxide (OsO4) (0.1 equiv) was added in one portion to a stirring solution of the (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in acetone/water (8: 1 ratio) under nitrogen. After 5 min, NMO (N-methylmorpholine N-oxide, 60％by weight in water, 1.1 equiv) was added in one portion and stirred for 24 h. The resulting reaction mixture was concentrated under reduced pressure and immediately purified via column chromatography to obtain the desired lactone (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (21) , yield: 87％, m/z (ES+) : 165 [M+H] +.

[0259]

15.1 g (92.3 mmol) (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydrofuran-2 (3H) -one (21) was dissolved in 25 mL pyridine and 11.1 g (96.9 mmol) methanesulfonyl chloride was slowly added dropwise at -25 degC. It was stirred for a day at -25 deg and a day at -10 deg. After adding 20 mL of ethyl acetate and 20 mL water, the solvent was removed on a rotary evaporator. After neutralization with dilute sodium hydrogen carbonate solution, the solvent was removed in vacuo again, the residue was digested with ethyl acetate, the eluate was dried with magnesium sulfate and concentrated in vacuo to dryness. Recrystallization from ethyl acetate/diethyl ether gave a colorless crystalline product ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate (18c) . Yield: 31 ％.

[0260]

33.8g of ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate was disslolved in EtOH (104 mL) , then KOH (16.8 g , 3 eq) in H₂O (52 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into, the mixture was reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (10.5 g, yield: 45％) .

[0261]

Alternative reagents and reactions to those disclosed above can also be employed. For example, 4-methylbenzene-1-sulfonyl chloride can be used instead of methanesulfonyl chloride. Moreover, primary alcohol can be converted to chloro or bromo by using Ph₃P/CCl4, PPh₃P/CBr₄, PPh₃/NCS, PPh₃/NBS, or PPh₃/C₂Cl₆ as a halogenation reagent. The desired product can be obtained in good yields using these reagents and reactions.

[0262]

Method 3: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methyl pent-4-enoyl) -4-isopropyloxazolidin-2-one (13) as starting material provides the desired compound 19 (yield: 63.2％)

[0263]

Method 4： Using a method analogous to that described as hereinabove and (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one (14) as starting material provides the desired compound 19 (yield: 71.8％)

[0264]

Method 5： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one (15) as the start material gives the desired compound 19 (yield: 65.7％)

[0265]

Method 6： Using a method analogous to that described as hereinabove and (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-oneas (16) starting material provides the desired compound 19 (yield: 59.5％)

[0266]

Method 7： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (17) as starting material gives the desired compound 19 (yield: 66.7％)

[0267]

Example 17: preparation of ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetra hydro fur an-2-yl) methyl benzoate

[0268]

[0269]

(3R, 4R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (19) (25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml of THF. 4- (Dimethylamino) -pyridine (8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0 ℃. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to 35-40 ℃ in the course of 2 hs. Upon completion of the reaction, water (100 mL) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 mL) . The combined organic phases were dried over Na₂SO₄ (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 ℃ and stirred for 60 min, then cooled down to 0 ℃ and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate (47.5 g, 82.6 ％yield) was obtained. ‘H-NMR (CDCl₃, 400 MHz) : 8.10 (d, 7＝7.6 Hz, 2H) , 8.00 (d, 7＝7.6 Hz, 2H) , 7.66 (t, 7＝7.6 Hz, IH) , 7.59 (t, 7＝7.6 Hz, IH) , 7.50 (m, 2H) , 7.43 (m, 2H) , 5.53 (dd, 7＝17.6, 5.6 Hz, IH) , 5.02 (m, IH) , 4.77 (dd, 7＝12.8, 3.6 Hz, IH) , 4.62 (dd, 7＝12.8, 5.2 Hz, IH) , 1.77 (d, 7＝23.2 Hz, 3H) .

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Novel Drug Approvals for 2017, A Review/Compilation

February 17, 2018 4:11 am / Leave a comment

CDSCO Image result for FDA EMA

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO, Novel Drug Approvals for 2017, A Review Compilation (USFDA, EMA, PMDA, CDSCO).

Any errors in this compilation, email amcrasto@gmail.com, Call +919323115463

Some gaps will be filled up soon keep watching……………..

INDEX, NAME (click on the title, it contains link)

SECTION A; USFDA Approvals

6 BENRALIZUMAB

17 DURVALUMAB

24 GUSELKUMAB

25 INOTUZUMAB OZOGAMICIN

26 LATANOPROSTENE

27 LETERMOVIR

28 MACIMORELIN ACETATE

36 OZENOXACIN

40 SARILUMAB

41 SECNIDAZOLE

48 VESTRONIDASE ALFA-VJBK

49 VELPATASVIR

50 VOXILAPREVIR

INDEX, FORMULATION NAME

USFDA

•Aliqopa (COPANLISIB) to treat adults with relapsed follicular lymphoma — a slow-growing type of nonHodgkin lymphoma (a cancer of the lymph system) — who have received at least two prior systemic therapies;

• ALUNBRIG, BRIGATINIB, To treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

• Austedo, Deutetrabenazine For the treatment of chorea associated with Huntington’s disease

• Bavencio (avelumab) for the treatment of patients 12 years and older with a rare and aggressive form of cancer called metastatic Merkel cell carcinoma, including those who have not received prior chemotherapy;

•BAXDELLA, Delafloxacin, BACTERIAL INFECTIONS

• Benznidazole to treat children ages 2 to 12 years with Chagas disease, a parasitic infection that can cause serious heart illness after years of infection, and can also affect swallowing and digestion. This is the first treatment approved in the United States for this rare disease;

• Besponsa (inotuzumab ozogamicin) for the treatment of adults with a type of cancer of the blood called relapsed or refractory B-cell precursor acute lymphoblastic leukemia;

•BEVYXXA, BETRIXABAN, For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness

• BRINEURA, CERLIPONASE ALFA, To treat a specific form of Batten disease

• Calquence (ACALABRUTINIB) to treat adults with mantle cell lymphoma who have received at least one prior therapy. Mantle cell lymphoma is a particularly aggressive cancer;

• DUPIXENT, (DUPILUMAB) To treat adults with moderate-to-severe eczema (atopic dermatitis)

• Emflaza (deflazacort) to treat patients age 5 years and older with Duchenne muscular dystrophy, a rare genetic disorder that causes progressive muscle deterioration and weakness;

• FASENRA, BENRALIZUMAB, For add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype

• Giapreza (angiotensin II), for the treatment of hypotension in adults with distributive or vasodilatory shock (dangerously low blood pressure despite adequate heart function) whose blood pressure remains low despite receiving fluids and treatment with drugs called vasopressors;

• HEMLIBRA EMICIZUMAB To prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

• Idhifa (enasidenib) for the treatment of adults with relapsed or refractory acute myeloid leukemia, a form of blood cancer, who have a specific genetic mutation;

• IMFINZI, DURVALUMAB To treat patients with locally advanced or metastatic urothelial carcinoma

• Ingrezza (valbenazine) to treat adults with tardive dyskinesia, a side effect of some antipsychotic medications whereby patients can experience uncontrollable stiff, jerky movements of their face and body, and other uncontrolled movements such as eye-blinking, sticking out the tongue, and arm-waving;

• KEVZARA SARILUMAB, RHEUMATOID ARTHRITIS

• KISQALI, RIBOCICLIB, To treat postmenopausal women with a type of advanced breast cancer

• Macrilen macimorelin acetate, For the diagnosis of adult growth hormone deficiency

• Mavyret (glecaprevir and pibrentasvir) to treat adults with chronic hepatitis C virus genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease, as well as those who are on hemodialysis;

• Mepsevii (vestronidase alfa-vjbk) to treat patients with Sly syndrome or mucopolysaccharidosis type 7 – a rare genetic disorder where an enzyme deficiency results in skeletal abnormalities, developmental delay, enlarged liver and spleen, and narrowed airways, which can lead to respiratory infections;

• Nerlynx (neratinib) for the extended adjuvant treatment — a form of therapy administered after an initial treatment to further lower the risk of the cancer coming back — of early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer;

• OCREVUS, OCRELIZUMAB, To treat patients with relapsing and primary progressive forms of multiple sclerosis

• OZEMPIC SEMAGLUTIDE To improve glycemic control in adults with type 2 diabetes mellitus

•PARSABIV, ETELCALCETIDE, To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis

• Prevymis (letermovir) for prevention of an infection called cytomegalovirus (CMV) in patients who are receiving a bone marrow transplant. CMV disease can cause serious health issues in these patients;

• Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis, commonly referred to as Lou Gehrig’s disease, a rare disease that attacks and kills the nerve cells that control voluntary muscles;

• RHOPRESSA, NETARSUDIL, To treat glaucoma or ocular hypertension

• Rydapt (midostaurin) to treat adults newly diagnosed with a form of blood cancer known as acute myeloid leukemia who have a specific genetic mutation called FLT3, in combination with chemotherapy;

• Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis, a chronic disorder in which the body’s immune system sends out faulty signals that speed growth of skin cells that then accumulate, causing red, flaky patches that can appear anywhere on the body;

•SOLOSEC, SECNIDAZOLE To treat bacterial vaginosis

• STEGLATRO ERTUGLIFLOZIN To improve glycemic control in adults with type 2 diabetes mellitus

• Symproic (Naldemedine) for the treatment of opioid-induced constipation in adults with chronic noncancer pain; • Tremfya (guselkumab) for the treatment of adults with moderate-to-severe plaque psoriasis;

• Trulance (plecanatide) to treat adults with chronic idiopathic constipation, which is a persistent condition of constipation due to unknown origin;

• TYMLOS, Abaloparatide, To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies

• Vabomere (vaborbactam and meropenem) for treatment of adults with complicated urinary tract infections, including pyelonephritis (kidney infection) caused by bacteria;

• Verzenio (abemaciclib) to treat adults who have hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy);

• Vosevi (sofosbuvir/velpatasvir/voxilaprevir) to treat adults with chronic hepatitis C virus genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis;

• VYZULTA LATANOPROSTENE To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

• Xadago (safinamide) as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes;

• XERMELO, TELOTRISTAT ETHYL combined with somatostatin analog (SSA) therapy to treat adults with carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled, and;

• XEPI OZENOXACIN TO TREAT IMPETIGO

•XERMELO, TELOTRISTAT ETHYL, To treat carcinoid syndrome diarrhea

• Zejula (niraparib) for the maintenance treatment (intended to delay cancer growth) of adults with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, whose tumors have completely or partially shrunk (complete or partial response, respectively) in response to platinum-based chemotherapy

USFDA

Advancing Health Through Innovation: 2017 New Drug Therapy Approvals Report (PDF – 2.8MB)

No.	Drug Name	Active Ingredient	Approval Date	FDA-approved use on approval date
46.	Giapreza	angiotensin II	12/21/2017 Press Release Drug Trials Snapshot	To increase blood pressure in adults with septic or other distributive shock
45.	Macrilen	macimorelin acetate	12/20/2017 Drug Trials Snapshot	For the diagnosis of adult growth hormone deficiency
44.	Steglatro	ertugliflozin	12/19/2017 Drug Trials Snapshot	To improve glycemic control in adults with type 2 diabetes mellitus
43.	Rhopressa	netarsudil	12/18/2017 Drug Trials Snapshot	To treat glaucoma or ocular hypertension
42.	Xepi	ozenoxacin	12/11/2017	To treat impetigo Drug Trials Snapshot
41.	Ozempic	semaglutide	12/5/2017 Drug Trials Snapshot	To improve glycemic control in adults with type 2 diabetes mellitus
40.	Hemlibra	emicizumab	11/16/2017 Press Release Drug Trials Snapshot	To prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.
39.	Mepsevii	vestronidase alfa-vjbk	11/15/2017 Press Release Drug Trials Snapshot	To treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome.
38.	Fasenra	benralizumab	11/14/2017	For add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype Drug Trials Snapshot
37.	Prevymis	letermovir	11/8/2017	To prevent infection after bone marrow transplant Drug Trials Snapshot
36.	Vyzulta	latanoprostene bunod ophthalmic solution	11/2/2017	To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Drug Trials Snapshot
35.	Calquence	acalabrutinib	10/31/2017	To treat adults with mantle cell lymphoma Press Release Drug Trials Snapshot
34.	Verzenio	abemaciclib	9/28/2017	To treat certain advanced or metastatic breast cancers Press Release Drug Trials Snapshot
33.	Solosec	secnidazole	9/15/2017	To treat bacterial vaginosis Drug Trials Snapshot
32.	Aliqopa	copanlisib	9/14/2017	To treat adults with relapsed follicular lymphoma Press Release Drug Trials Snapshot
31.	benznidazole	benznidazole	8/29/2017	To treat children ages 2 to 12 years old with Chagas disease Press Release Drug Trials Snapshot
30.	Vabomere	meropenem and vaborbactam	8/29/2017	To treat adults with complicated urinary tract infections Press Release Drug Trials Snapshot
29.	Besponsa	inotuzumab ozogamicin	8/17/2017	To treat adults with relapsed or refractory acute lymphoblastic leukemia Press Release Drug Trials Snapshot
28.	Mavyret	glecaprevir and pibrentasvir	8/3/2017	To treat adults with chronic hepatitis C virus Press Release Drug Trials Snapshot
27.	Idhifa	enasidenib	8/1/2017	To treat relapsed or refractory acute myeloid leukemia Press Release Drug Trials Snapshot
26.	Vosevi	sofosbuvir, velpatasvir and voxilaprevir	7/18/2017	To treat adults with chronic hepatitis C virus Press Release Drug Trials Snapshot
25.	Nerlynx	neratinib maleate	7/17/2017	To reduce the risk of breast cancer returning Press Release Drug Trials Snapshot
24.	Tremfya	guselkumab	7/13/2017	For the treatment of adult patients with moderate-to-severe plaque psoriasis Drug Trials Snapshot
23.	Bevyxxa	betrixaban	6/23/2017	For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness Drug Trials Snapshot
22.	Baxdela	delafloxacin	6/19/2017	To treat patients with acute bacterial skin infections Drug Trials Snapshot
21.	Kevzara	sarilumab	5/22/2017	To treat adult rheumatoid arthritis Drug Trials Snapshot
20.	Radicava	edaravone	5/5/2017	To treat patients with amyotrophic lateral sclerosis (ALS) Press Release Drug Trials Snapshot
19.	Imfinzi	durvalumab	5/1/2017	To treat patients with locally advanced or metastatic urothelial carcinoma Web Post Drug Trials Snapshot
18.	Tymlos	abaloparatide	4/28/2017	To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies Drug Trials Snapshot
17.	Rydapt	midostaurin	4/28/2017	To treat acute myeloid leukemia Press Release Chemistry Review(s) (PDF) Drug Trials Snapshot
16.	Alunbrig	brigatinib	4/28/2017	To treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Drug Trials Snapshot
15.	Brineura	cerliponase alfa	4/27/2017	To treat a specific form of Batten disease Press Release Drug Trials Snapshot
14.	Ingrezza	valbenazine	4/11/2017	To treat adults with tardive dyskinesia Press Release Chemistry Review(s) (PDF)Drug Trials Snapshot
13.	Austedo	deutetrabenazine	4/3/2017	For the treatment of chorea associated with Huntington’s disease Drug Trials Snapshot, Chemistry Review(s) (PDF)
12.	Ocrevus	ocrelizumab	3/28/2017	To treat patients with relapsing and primary progressive forms of multiple sclerosis Press Release Drug Trials Snapshot
11.	Dupixent	dupilumab	3/28/2017	To treat adults with moderate-to-severe eczema (atopic dermatitis) Press Release Drug Trials Snapshot
10.	Zejula	niraparib	3/27/2017	For the maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers Press Release Drug Trials Snapshot
9.	Symproic	naldemedine	3/23/2017	For the treatment of opioid-induced constipation Drug Trials Snapshot
8.	Bavencio	avelumab	3/23/2017	To treat metastatic Merkel cell carcinoma Press Release Drug Trials Snapshot
7.	Xadago	safinamide	3/21/2017	To treat Parkinson’s disease Press Release Drug Trials Snapshot Chemistry Review(s) (PDF)
6.	Kisqali	ribociclib	3/13/2017	To treat postmenopausal women with a type of advanced breast cancer Drug Trials Snapshot
5.	Xermelo	telotristat ethyl	2/28/2017	To treat carcinoid syndrome diarrhea Press Release Drug Trials Snapshot
4.	Siliq	brodalumab	2/15/2017	To treat adults with moderate-to-severe plaque psoriasis Press Release Drug Trials Snapshot
3.	Emflaza	deflazacort	2/9/2017	To treat patients age 5 years and older with Duchenne muscular dystrophy (DMD) Press Release Drug Trials Snapshot
2.	Parsabiv	etelcalcetide	2/7/2017	To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis Drug Trials Snapshot
1.	Trulance	plecanatide	1/19/2017	To treat Chronic Idiopathic Constipation (CIC) in adult patients. Press Release Drug Trials Snapshot

* This information is currently accurate. In rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status of its application as a novel new biologics license application (BLA). For instance, new information may become available which could lead to a reconsideration of the original designation or status. If changes must be made to a drug’s designation or the status of an application as a novel BLA, the Agency intends to communicate the nature of, and the reason for, any revisions as appropriate.

USFDA 2017
2017/12/21	Angiotensin II	Giapreza	La Jolla Pharmaceutical
2017/12/20	Ertugliflozin	Steglatro	Merck Sharp Dohme
2017/12/20	Macimorelin acetate	Macrilen	Aeterna Zentaris GmbH
2017/12/18	Netarsudil mesylate	Rhopressa	Aerie Pharmaceuticals
2017/12/11	Ozenoxacin	Xepi	Ferrer Internacional S.A.
2017/12/5	Semaglutide	Ozempic	Novo Nordisk Inc
2017/11/16	Emicizumab	Hemlibra	Genentech	BLA
2017/11/15	Vestronidase alfa	Mepsevii	Ultragenyx Pharmaceutical	BLA
2017/11/14	Benralizumab	Fasenra	AstraZeneca AB	BLA
2017/11/8	Letermovir	Prevymis	Merck Sharp Dohme
2017/11/2	Latanoprostene bunod	Vyzulta	Bausch & Lomb Incorporated
2017/10/31	Acalabrutinib	Calquence	AstraZeneca Pharmaceuticals LP
2017/9/28	Abemaciclib	Verzenio	Eli Lilly
2017/9/15	Secnidazole	Solosec	Symbiomix Therapeutics
2017/9/14	Copanlisib	Aliqopa	Bayer Healthcare Pharmaceuticals
2017/8/29	Benznidazole		Chemo Research
2017/8/29	Meropenem – Vaborbactam	Vabomere	Rempex Pharmaceuticals
2017/8/17	Inotuzumab ozogamicin	Besponsa	Wyeth Pharmaceuticals	BLA
2017/8/3	Glecaprevir – Pibrentasvir	Mavyret	AbbVie
2017/8/1	Enasidenib	Idhifa	Celgene Corporation
2017/7/18	Sofosbuvir – Velpatasvir – Voxilaprevir	Vosevi	Gilead Sciences
2017/7/17	Neratinib maleate	Nerlynx	Puma Biotechnology
2017/7/13	Guselkumab	Tremfya	Janssen Biotech	BLA
2017/6/23	Betrixaban	Bevyxxa	Portola Pharmaceuticals
2017/6/19	Delafloxacin meglumine	Baxdela	Melinta Therapeutics
2017/5/22	Sarilumab	Kevzara	Sanofi Synthelabo	BLA
2017/5/5	Edaravone	Radicava	Mitsubishi Tanabe Pharma America
2017/5/1	Durvalumab	Imfinzi	AstraZeneca UK	BLA
2017/4/28	Abaloparatide	Tymlos	Radius Health
2017/4/28	Midostaurin	Rydapt	Novartis Pharmaceuticals
2017/4/28	Brigatinib	Alunbrig	Ariad Pharmaceuticals
2017/4/27	Cerliponase alfa	Brineura	BioMarin Pharmaceutical	BLA
2017/4/11	Valbenazine	Ingrezza	Neurocrine Biosciences
2017/4/3	Deutetrabenazine	Austedo	Teva Pharmaceuticals
2017/3/28	Ocrelizumab	Ocrevus	Genentech	BLA
2017/3/28	Dupilumab	Dupixent	Regeneron Pharmaceuticals	BLA
2017/3/27	Niraparib	Zejula	Tesaro
2017/3/23	Naldemedine tosylate	Symproic	Shionogi
2017/3/23	Avelumab	Bavencio	EMD Serono	BLA
2017/3/23	Safinamide mesylate	Xadago	Newron Pharmaceuticals
2017/3/21	Ribociclib	Kisqali	Novartis Pharmaceuticals
2017/2/28	Telotristat ethyl	Xermelo	Lexicon Pharmaceuticals
2017/2/15	Brodalumab	Siliq	Valeant Pharmaceuticals	BLA
2017/2/9	Deflazacort	Emflaza	Marathon Pharmaceuticals
2017/2/8	Etelcalcetide hydrochloride	Parsavib	KAI Pharmaceuticals
2017/1/19	Plecanatide	Trulance	Synergy Pharmaceuticals

1 Abaloparatide

RADIUS

str1

Tymlos

FDA 4/28/2017

To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot

Image result for Abaloparatide

link……..https://newdrugapprovals.org/2018/02/13/abaloparatide-%D0%B0%D0%B1%D0%B0%D0%BB%D0%BE%D0%BF%D0%B0%D1%80%D0%B0%D1%82%D0%B8%D0%B4-%D8%A3%D8%A8%D8%A7%D9%84%D9%88%D8%A8%D8%A7%D8%B1%D8%A7%D8%AA%D9%8A%D8%AF-%E5%B7%B4%E7%BD%97%E6%97%81/

2 Abemaciclib

ELI LILLY

Verzenio	abemaciclib	FDA 9/28/2017	To treat certain advanced or metastatic breast cancers Press Release Drug Trials Snapshot

LINK https://newdrugapprovals.org/2015/10/19/abemaciclib-bemaciclib/

3 Acalabrutinib

Calquence		FDA APPROVED 10/31/2017	To treat adults with mantle cell lymphoma Press Release Drug Trials Snapshot

Image result for Acalabrutinib

LINK……….https://newdrugapprovals.org/2018/02/02/acalabrutinib-acp-196-%D0%B0%D0%BA%D0%B0%D0%BB%D0%B0%D0%B1%D1%80%D1%83%D1%82%D0%B8%D0%BD%D0%B8%D0%B1-%D8%A3%D9%83%D8%A7%D9%84%D8%A7%D8%A8%D8%B1%D9%88%D8%AA%D9%8A%D9%86%D9%8A%D8%A8-%E9%98%BF/

4 Angiotensin II

LA JOLLA

Giapreza	angiotensin II	12/21/2017	To increase blood pressure in adults with septic or other distributive shock Press Release Drug Trials Snapshot

Image result for angiotensin II Image result for GIAPREZA

LINK https://newdrugapprovals.org/2017/12/22/fda-approves-drug-giapreza-angiotensin-ii-to-treat-dangerously-low-blood-pressure/

5 AVELUMAB

MERCK

Image result for AVELUMAB

Bavencio		FDA 3/23/2017	To treat metastatic Merkel cell carcinoma Press Release Drug Trials Snapshot

LINK…..https://newdrugapprovals.org/2017/03/24/fda-approves-first-treatment-bavencio-avelumabfor-rare-form-of-skin-cancer/

6 BENRALIZUMAB

ASTRA ZENECA

Fasenra benralizumab

FDA 11/14/2017

For add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype
Drug Trials Snapshot

Image result for BENRALIZUMAB

7 Benznidazole

CHEMO RESEARCH

Image result for BENZNIDAZOLE

benznidazole		FDA 8/29/2017	To treat children ages 2 to 12 years old with Chagas disease Press Release Drug Trials Snapshot

LINK…https://newdrugapprovals.org/2017/08/30/fda-approves-first-u-s-treatment-benznidazole-for-chagas-disease/

8 BETRIXABAN

PORTOLA PHARMA

Image result for betrixaban

Bevyxxa		FDA 6/23/2017	For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness Drug Trials Snapshot Chemistry Review(s) (PDF)

Image result for betrixaban

LINK…….https://newdrugapprovals.org/2013/03/05/phase-3-portola-pharma-betrixaban-long-acting-oral-direct-factor-xa-inhibitor/

9 BRIGATINIB

Figure imgf000127_0001

TAKEDA

Image result for BRIGATINIB

Alunbrig		FDA 4/28/2017	To treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Drug Trials Snapshot

LINK..https://newdrugapprovals.org/2017/01/20/brigatinib-%D0%B1%D1%80%D0%B8%D0%B3%D0%B0%D1%82%D0%B8%D0%BD%D0%B8%D0%B1-%D8%A8%D8%B1%D9%8A%D8%BA%D8%A7%D8%AA%D9%8A%D9%86%D9%8A%D8%A8-%E5%B8%83%E6%A0%BC%E6%9B%BF%E5%B0%BC/

10 BRODALUMAB

VALEANT PHARMA

Siliq		FDA 2/15/2017	To treat adults with moderate-to-severe plaque psoriasis Press Release Drug Trials Snapshot

Image result for BRODALUMAB

LINK ,,,,https://newdrugapprovals.org/2017/02/16/fda-approves-new-psoriasis-drug-siliq-brodalumab/

11 CERLIPONASE ALFA

Image result Image result for cerliponase alfa

Brineura		FDA 4/27/2017	To treat a specific form of Batten disease Press Release Drug Trials Snapshot

LINK….https://newdrugapprovals.org/2017/04/28/fda-approves-first-treatment-for-a-form-of-batten-disease-brineura-cerliponase-alfa/

12 Copanlisib

Aliqopa		FDA APPROVED 9/14/2017	To treat adults with relapsed follicular lymphoma Press Release Drug Trials Snapshot

Copanlisib dihydrochloride.png

Image result for copanlisib

LINK…..https://newdrugapprovals.org/2017/11/20/copanlisib/

13 DEFLAZACORT

MARATHON PHARMA

Image result for deflazacort

Emflaza		FDA 2/9/2017	To treat patients age 5 years and older with Duchenne muscular dystrophy (DMD) Press Release Drug Trials Snapshot

LINK……https://newdrugapprovals.org/2017/02/17/deflazacort/

14 DELAFLOXACIN

Baxdela		FDA APPROVED 6/19/2017	To treat patients with acute bacterial skin infections

Image result for delafloxacin

LINK……..https://newdrugapprovals.org/2018/01/25/delafloxacin/

15 Deutetrabenazine

TEVA

Image result for deutetrabenazine

LINK……………https://newdrugapprovals.org/2015/08/15/sd-809-deutetrabenazine-nda-submitted-by-teva/

Austedo		FDA 4/3/2017	For the treatment of chorea associated with Huntington’s disease Drug Trials Snapshot Chemistry Review(s) (PDF)

16 DUPILUMAB

SANOFI/REGENERON

Image result for DUPILUMAB

Dupixent	FDA	3/28/2017	To treat adults with moderate-to-severe eczema (atopic dermatitis) Press Release Drug Trials Snapshot

LINK…….https://newdrugapprovals.org/2017/03/29/fda-approves-new-eczema-drug-dupixent-dupilumab/

17 DURVALUMAB

ASTRA ZENECA

Image result for DURVALUMAB

Imfinzi

durvalumab FDA 5/1/2017To treat patients with locally advanced or metastatic urothelial carcinoma
Web Post
Drug Trials Snapshot

18 EDAVARONE

MITSUBISHI TANABE

Radicava		FDA 5/5/2017	To treat patients with amyotrophic lateral sclerosis (ALS) Press Release Drug Trials Snapshot

Image result for EDARAVONE

LINK………https://newdrugapprovals.org/2017/05/06/fda-approves-drug-to-treat-als-radicava-edaravone-%D1%8D%D0%B4%D0%B0%D1%80%D0%B0%D0%B2%D0%BE%D0%BD-%D8%A5%D9%8A%D8%AF%D8%A7%D8%B1%D8%A7%D9%81%D9%88%D9%86-%E4%BE%9D%E8%BE%BE%E6%8B%89%E5%A5%89/

19 EMICIZUMAB

ROCHE

Image result for EMICIZUMAB

Hemlibra	emicizumab	FDA 11/16/2017	To prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors. Press Release Drug Trials Snapshot

LINK https://newdrugapprovals.org/2017/11/17/fda-approves-new-treatment-hemlibra-emicizumab-kxwh-to-prevent-bleeding-in-certain-patients-with-hemophilia-a/

Image result for EMICIZUMAB

20 Enasidenib

Image result for Enasidenib

Idhifa		FDA 8/1/2017	To treat relapsed or refractory acute myeloid leukemia Press Release Drug Trials Snapshot

LINK……https://newdrugapprovals.org/2017/08/02/enasidenib-%D1%8D%D0%BD%D0%B0%D1%81%D0%B8%D0%B4%D0%B5%D0%BD%D0%B8%D0%B1-%D8%A5%D9%8A%D9%86%D8%A7%D8%B3%D9%8A%D8%AF%D9%8A%D9%86%D9%8A%D8%A8-%E4%BC%8A%E9%82%A3%E5%B0%BC%E5%B8%83/

21 Ertugliflozin

MERCK

Image result for ERTUGLIFLOZIN

Steglatro	ertugliflozin	FDA 12/19/2017	To improve glycemic control in adults with type 2 diabetes mellitus Drug Trials Snapshot

LINK https://newdrugapprovals.org/2014/02/10/ertugliflozin/

Image result for ERTUGLIFLOZIN

22 ETELCALCETIDE

Amgen

Parsabiv		FDA APPROVED 2/7/2017	To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis Drug Trials SnapshotSYNTHESIS LINK……..https://cen.acs.org/articles/96/i4/the-year-in-new-drugs-2018.html

SYNTHESIS LINK……..https://cen.acs.org/articles/96/i4/the-year-in-new-drugs-2018.html

23 GLECAPREVIR

ABBVIE

Mavyret	glecaprevir and pibrentasvir	FDA 8/3/2017	To treat adults with chronic hepatitis C virus Press Release Drug Trials Snapshot

LINK https://newdrugapprovals.org/2016/10/05/glecaprevir-abt-493/

24 GUSELKUMAB

JOHNSON AND JOHNSON

Tremfya

guselkumab

FDA 7/13/2017

For the treatment of adult patients with moderate-to-severe plaque psoriasis
Drug Trials Snapshot

Image result for GUSELKUMAB

25 Inotuzumab ozogamicin

PFIZER

Image result for inotuzumab ozogamicin

Besponsa		FDA 8/17/2017	To treat adults with relapsed or refractory acute lymphoblastic leukemia Press Release Drug Trials Snapshot

LINK….https://newdrugapprovals.org/2015/10/23/fda-grants-breakthrough-status-for-pfizers-leukaemia-drug-inotuzumab-ozogamicin/

26 LATANOPROSTENE

VALEANT

Image result for LATANOPROSTENE

latanoprostene bunod ophthalmic solution

FDA 11/2/2017

To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Drug Trials Snapshot

LINK https://newdrugapprovals.org/2014/09/27/nicox-stock-leaps-on-positive-ph-iii-glaucoma-drug-data-%E8%8B%B1%E6%96%87%E5%90%8D%E7%A7%B0/

27 LETERMOVIR

MERCK

Image result for LETERMOVIR

Prevymis		FDA 11/8/2017	To prevent infection after bone marrow transplant Drug Trials Snapshot

LINK https://newdrugapprovals.org/2016/05/16/letermovir-aic-246/

28 Macimorelin acetate

AETERNA ZENTARIS

Macrilen	macimorelin acetate	FDA 12/20/2017	For the diagnosis of adult growth hormone deficiency Drug Trials Snapshot

LINK https://newdrugapprovals.org/2014/01/07/aeterna-zentaris-submits-new-drug-application-to-fda-for-macimorelin-acetate-aezs-130-for-evaluation-of-aghd-2/

29 MEROPENEM

Image result for MEROPENEM

30 MIDOSTAURIN

NOVARTIS

Chemistry Review(s) (PDF)

Image result for MIDOSTAURIN

Rydapt		FDA 4/28/2017	To treat acute myeloid leukemia Press Release Drug Trials Snapshot

LINK…….https://newdrugapprovals.org/2017/04/29/fda-approves-new-combination-treatment-for-acute-myeloid-leukemia-rydapt-midostaurin/

31 Naldemedine

FDA 3/23/2017, Symproic, For the treatment of opioid-induced constipation

Image result for naldemedine

LINK……..https://newdrugapprovals.org/2018/01/24/naldemedine-%E3%83%8A%E3%83%AB%E3%83%87%E3%83%A1%E3%82%B8%E3%83%B3%E3%83%88%E3%82%B7%E3%83%AB%E9%85%B8%E5%A1%A9/

32 NERATINIB MALEATE

PUMA BIOTECH

Image result for NERATINIB

Nerlynx	FDA	7/17/2017	To reduce the risk of breast cancer returning Press Release Drug Trials Snapshot

LINK…https://newdrugapprovals.org/2014/04/11/neratinib-hki-272-puma-presents-positive-results-from-phase-ii-trial-of-its-investigational-drug-pb272/

33 NETARSUDIL

Rhopressa		FDA APPROVED 12/18/2017	To treat glaucoma or ocular hypertension

Image result for Netarsudil

LINK……https://newdrugapprovals.org/2018/01/29/netarsudil/

34 NIRAPARIB

TESARO

Zejula	FDA	3/27/2017	For the maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers Press Release Drug Trials Snapshot

Figure imgf000023_0001

LINK…https://newdrugapprovals.org/2016/12/22/niraparib-mk-4827/

35 OCRELIZUMAB

ROCHE

Ocrevus	FDA	3/28/2017	To treat patients with relapsing and primary progressive forms of multiple sclerosis Press Release Drug Trials Snapshot

Image result for ocrelizumab

LINK..https://newdrugapprovals.org/2017/03/30/fda-approves-new-drug-to-treat-multiple-sclerosis-ocrevus-ocrelizumab/

36 OZENOXACIN

MEDIMETRIX

Image result for ozenoxacin

LINK https://newdrugapprovals.org/2014/03/28/ozenoxacin-in-phase-3-topical-formulation-in-the-treatment-of-impetigo/

Image result for ozenoxacin

Xepi	ozenoxacin	FDA 12/11/2017	To treat impetigo Drug Trials Snapshot

37 Pibrentasvir

ABBVIE

Mavyret	glecaprevir and pibrentasvir	FDA 8/3/2017	To treat adults with chronic hepatitis C virus Press Release Drug Trials Snapshot

LINK https://newdrugapprovals.org/2016/06/08/abt-530-pibrentasvir/

38 PLECANATIDE

Plecanatide 普卡那肽 ليكاناتيد плеканатид

SYNERGY PHARMA

Image result for PLECANATIDE

Trulance		FDA APPROVED 1/19/2017	To treat Chronic Idiopathic Constipation (CIC) in adult patients. Press Release Drug Trials Snapshot

LINK ….https://newdrugapprovals.org/2016/04/21/plecanatide-%E6%99%AE%E5%8D%A1%E9%82%A3%E8%82%BD-%D9%84%D9%8A%D9%83%D8%A7%D9%86%D8%A7%D8%AA%D9%8A%D8%AF-%D0%BF%D0%BB%D0%B5%D0%BA%D0%B0%D0%BD%D0%B0%D1%82%D0%B8%D0%B4/

39 RIBOCICLIB

NOVARTIS

2D chemical structure of 1374639-75-4

Structure..link for correct structure

Kisqali		FDA 3/13/2017	To treat postmenopausal women with a type of advanced breast cancer Drug Trials Snapshot

Image result for RIBOCICLIB

LINK https://newdrugapprovals.org/2015/10/19/ribociclib/

40 SARILUMAB

SANOFI /REGENERON

Kevzara	sarilumab	FDA 5/22/2017	To treat adult rheumatoid arthritis Drug Trials Snapshot

LINK https://newdrugapprovals.org/2013/11/25/late-stage-success-for-sanofiregeneron-ra-drug-sarilumab/

Image result for SARILUMAB

41 SECNIDAZOLE

SYMBIOMIX

Solosec	FDA	9/15/2017	To treat bacterial vaginosis Drug Trials Snapshot

Image result for SECNIDAZOLE

link….https://newdrugapprovals.org/2017/11/03/secnidazole-%D1%81%D0%B5%D0%BA%D0%BD%D0%B8%D0%B4%D0%B0%D0%B7%D0%BE%D0%BB-%D8%B3%D9%8A%D9%83%D9%86%D9%8A%D8%AF%D8%A7%D8%B2%D9%88%D9%84-%E5%A1%9E%E5%85%8B%E7%A1%9D%E5%94%91/

42 SAFINAMIDE

NEWRON PHARMA

Image result for safinamide

Chemistry Review(s) (PDF) for correct structure

Xadago		FDA 3/21/2017	To treat Parkinson’s disease Press Release Drug Trials Snapshot

LINK…https://newdrugapprovals.org/2017/03/22/fda-approves-drug-xadago-safinamide-%D1%81%D0%B0%D1%84%D0%B8%D0%BD%D0%B0%D0%BC%D0%B8%D0%B4-%D8%B3%D8%A7%D9%81%D9%8A%D9%86%D8%A7%D9%85%D9%8A%D8%AF-%E6%B2%99%E9%9D%9E%E8%83%BA-to-treat-parkins/

43 Semaglutide

NOVO NORDISK

Image result for SEMAGLUTIDE

Ozempic	semaglutide	FDA 12/5/2017	To improve glycemic control in adults with type 2 diabetes mellitus Drug Trials Snapshot

LINK https://newdrugapprovals.org/2013/07/22/a-survey-of-promising-late-stage-diabetes-drugs/

Image result for SEMAGLUTIDE

44 SOFOSBUVIR

LINK https://newdrugapprovals.org/2013/12/11/us-approves-breakthrough-hepatitis-c-drug-sofosbuvir-all-about-drugs/

45 TELOTRISTAT ETHYL

LEXICON

LX1606 Hippurate.png

Xermelo		FDA 2/28/2017	To treat carcinoid syndrome diarrhea Press Release Drug Trials Snapshot

Image result for Lexicon Pharmaceuticals, Inc. STR1

46 VABORBACTAM

THE MEDICINES CO

Vabomere	meropenem and vaborbactam	FDA 8/29/2017	To treat adults with complicated urinary tract infections Press Release Drug Trials Snapshot

Image result for VABOMERE

LINK https://newdrugapprovals.org/2017/09/05/vaborbactam-%D0%B2%D0%B0%D0%B1%D0%BE%D1%80%D0%B1%D0%B0%D0%BA%D1%82%D0%B0%D0%BC-%D9%81%D8%A7%D8%A8%D9%88%D8%B1%D8%A8%D8%A7%D9%83%D8%AA%D8%A7%D9%85-%E6%B3%95%E7%A1%BC%E5%B7%B4%E5%9D%A6/

47 VALBENAZINE

NEUROCRINE

Image result for valbenazine

Chemistry Review(s) (PDF)

Image result for VALBENAZINE

Ingrezza		FDA 4/11/2017	To treat adults with tardive dyskinesia Press Release Drug Trials Snapshot

LINK…………..https://newdrugapprovals.org/2017/04/12/fda-approves-first-drug-ingrezza-valbenazine-to-treat-tardive-dyskinesia/

48 Vestronidase alfa-vjbk

ULTRAGENYX

Mepsevii	vestronidase alfa-vjbk	FDA 11/15/2017	To treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. Press Release Drug Trials Snapshot

Image result for vestronidase alfa-vjbk

LINK…https://newdrugapprovals.org/2017/11/16/fda-approves-mepsevii-vestronidase-alfa-vjbk-for-treatment-for-rare-genetic-enzyme-disorder/

49 VELPATASVIR

LINK https://newdrugapprovals.org/2016/07/30/velpatasvir-gs-5816-gilead-sciences-%D0%B2%D0%B5%D0%BB%D0%BF%D0%B0%D1%82%D0%B0%D1%81%D0%B2%D0%B8%D1%80-%D9%81%D8%A7%D9%84%D8%A8%D8%A7%D8%AA%D8%A7%D8%B3%D9%81%D9%8A%D8%B1-%E7%BB%B4%E5%B8%95/

50 VOXILAPREVIR

GILEAD

Image result for VOXILAPREVIR

Vosevi	sofosbuvir, velpatasvir and voxilaprevir	FDA 7/18/2017	To treat adults with chronic hepatitis C virus Press Release Drug Trials Snapshot

LINK https://newdrugapprovals.org/2017/07/19/voxilaprevir-%D9%81%D9%88%D9%83%D8%B3%D9%8A%D9%84%D8%A7%D8%A8%D8%B1%D9%8A%D9%81%D9%8A%D8%B1-%E4%BC%8F%E8%A5%BF%E7%91%9E%E9%9F%A6-%D0%B2%D0%BE%D0%BA%D1%81%D0%B8%D0%BB%D0%B0%D0%BF%D1%80%D0%B5%D0%B2/

SECTION B; EMA approvals

European Medicines Agency’s – Human medicines: Highlights of 2017

Advances in medicines authorizations are essential for public health as they have the potential to improve treatment of diseases. In 2017, EMA recommended 92 medicines for marketing authorization. Of these, 35 had a new active substance, which has never been authorized in the European Union (EU) before. Many of these medicines represent a significant improvement in their therapeutic areas; they include medicines for children, for rare diseases and advanced therapies42. Amongst the 35 new active substances (NAS) that EMA recommended, 11 were new drugs and biologics to treat cancer, 05 to treat neurological disorders, 04 for infectious diseases, 04 for immunology/rheumatology, 03 for endocrinology, 02 each for Uro-nephrology, haematology, and dermatology, 01 for Pneumonology, and 01 for hepatology/gastroenterology class of drugs.

EUROPE

2017/11/16	Niraparib	Zejula	Tesaro UK Limited	O	NME
2017/11/10	Adalimumab	Cyltezo	Boehringer Ingelheim International GmbH	B
2017/11/10	Miglustat	Miglustat Gen.Orph	Gen.Orph	G
2017/11/10	Ritonavir	Ritonavir Mylan	MYLAN S.A.S	G
2017/11/10	Padeliporfin	Tookad	STEBA Biotech S.A
2017/11/10	Guselkumab	Tremfya	Janssen-Cilag International N.V.		BLA
2017/9/27	Dupilumab	Dupixent	sanofi-aventis groupe		BLA
2017/9/21	Darunavir / Cobicistat / Emtricitabine / Tenofovir alafenamide	Symtuza	Janssen-Cilag International N.V.
2017/9/21	Atezolizumab	Tecentriq	Roche Registration Limited		BLA
2017/9/18	Avelumab	Bavencio	Merck Serono Europe Limited	O	BLA
2017/9/18	Entecavir	Entecavir Mylan	Mylan S.A.S	G
2017/9/18	Lacosamide	Lacosamide Accord	Accord Healthcare Ltd	G
2017/9/18	Midostaurin	Rydapt	Novartis Europharm Ltd	O	NME
2017/9/18	Telotristat ethyl	Xermelo	Ipsen Pharma	O	NME
2017/9/5	Trientine	Cuprior	GMP-Orphan SA
2017/9/5	Efavirenz / Emtricitabine / Tenofovir disoproxil	Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan	Mylan S.A.S	G
2017/8/24	Tivozanib hydrochloride monohydrate	Fotivda	EUSA Pharma (UK) Limited		NME
2017/8/24	Adalimumab	Imraldi	Samsung Bioepis UK Limited (SBUK)	B
2017/8/24	Nitisinone	Nitisinone MDK (previously Nitisinone MendeliKABS)	MendeliKABS Europe Ltd	G
2017/8/22	Ribociclib	Kisqali	Novartis Europharm Ltd		NME
2017/8/22	Cladribine	Mavenclad	Merck Serono Europe Limited
2017/7/26	Glecaprevir / Pibrentasvir	Maviret	AbbVie Limited		NME
2017/7/26	Sofosbuvir / Velpatasvir / Voxilaprevi	Vosevi	Gilead Sciences International Ltd		NME
2017/7/19	Insulin lispro	Insulin lispro Sanofi	sanofi-aventis groupe	B
2017/7/19	Patiromer sorbitex calcium	Veltassa	Vifor Fresenius Medical Care Renal Pharma France		NME
2017/7/17	Efavirenz / Emtricitabine / Tenofovir disoproxil	Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva	Zentiva k.s.	G
2017/7/17	Brodalumab	Kyntheum	LEO Pharma A/S		BLA
2017/7/17	beclometasone / formoterol / glycopyrronium bromide	Trimbow	Chiesi Farmaceutici S.p.A.
2017/7/13	Rituximab	Blitzima	Celltrion Healthcare Hungary Kft.	B
2017/7/13	Cariprazine	Reagila	Gedeon Richter
2017/7/10	Spheroids of human autologous matrix-associated chondrocytes	Spherox	CO.DON AG
2017/7/6	Cenegermin	Oxervate	Dompe farmaceutici s.p.a.	O	BLA
2017/6/29	Inotuzumab ozogamicin	Besponsa	Pfizer Limited	O	BLA
2017/6/23	Etanercept	Erelzi	Sandoz GmbH
2017/6/23	Sarilumab	Kevzara	Sanofi-Aventis Groupe		NME
2017/6/23	Dimethyl fumarate	Skilarence	Almirall S.A
2017/6/23	Carglumic acid	Ucedane	Lucane Pharma	G
2017/6/15	Rituximab	Rixathon, Riximyo B	Sandoz GmbH
2017/6/2	Pentosan polysulfate sodium	Elmiron	bene-Arzneimittel GmbH
2017/6/2	Nonacog beta pegol	Refixia	Novo Nordisk A/S		BLA
2017/5/30	Cerliponase alfa	Brineura	BioMarin International Limited	O E	BLA
2017/5/30	Nusinersen	Spinraza	Biogen Idec Ltd	O	NME
2017/5/24	Meningococcal group b vaccine (recombinant, adsorbed)	Trumenba	Pfizer Limited
2017/5/22	Ivabradine	Ivabradine Accord	Accord Healthcare Ltd	G
2017/5/8	Dinutuximab beta	Dinutuximab beta Apeiron	Apeiron Biologics AG	O E
2017/4/28	Emtricitabine – tenofovir disoproxil mixt	Emtricitabine/Tenofovir disoproxil Krka d.d.	KRKA, d.d., Novo mesto	G
2017/4/24	Parathyroid hormone	Natpar	Shire Pharmaceuticals Ireland Ltd	O C	BLA
2017/4/20	Edoxaban	Roteas	Daiichi Sankyo Europe GmbH
2017/3/22	Tofacitinib citrate	Xeljanz	Pfizer Limited		NME
2017/3/20	Umeclidinium	Rolufta	GlaxoSmithKline Trading Services Limited
2017/3/3	Chlormethine	Ledaga	Actelion Registration Ltd.	O
2017/2/27	Pregabalin	Pregabalin Zentiva	Zentiva k.s.	G
2017/2/17	Rituximab	Truxima	Celltrion Healthcare Hungary Kft.	B
2017/2/13	Etanercept	Lifmior	Pfizer Limited
2017/2/13	Baricitinib	Olumiant	Eli Lilly Nederland B.V.		NME
2017/1/19	Mercaptamine	Cystadrops	Orphan Europe S.A.R.L.	O
2017/1/18	Bezlotoxumab	Zinplava	Merck Sharp & Dohme Limited		NME
2017/1/11	Teriparatide	Movymia	STADA Arzneimittel AG	B
2017/1/11	Insulin glargine / lixisenatide	Suliqua	Sanofi-Aventis Groupe
2017/1/9	Insulin aspart	Fiasp	Novo Nordisk A/S
2017/1/9	Tadalafil	Tadalafil	Mylan S.A.S	G
2017/1/9	Tenofovir alafenamide	Vemlidy	Gilead Sciences International Ltd
2017/1/4	Lonoctocog alfa	Afstyla	CSL Behring GmbH		BLA
2017/1/4	Darunavir	Darunavir Mylan	Mylan S.A.S.	G
2017/1/4	Insulin glargine	Lusduna	Merck Sharp & Dohme Limited	B
2017/1/4	Teriparatide	Terrosa	Gedeon Richter Plc.	B

SECTION B; EMA Approvals

Combined drugs USFDA+EMA +PMDA list are listed below. trying to simplify search

1 Abaloparatide USFDA

2 Abemaciclib USFDA

3 ACALABRUTINIB USFDA

3A ALOFISEL EMA

3B AMENAMEVIR JAPAN

4 ANGIOTENSIN II USFDA

4A Atezolizumab EMA

5 AVELUMAB USFDA+EMA

6 BENRALIZUMAB USFDA+EMA

6A BARICITINIB JAPAN

7 BENZNIDAZOLE USFDA

8 BETRIXABAN USFDA

9 BRIGATINIB USFDA

10 BRODALUMAB USFDA+EMA

10A BUROSUMAB EMA

10B CARIPRAZINE HYDROCHLORIDE EMA

11 CERLIPONASE ALPA USFDA+EMA

12 COPANLISIB USFDA

13 DEFLAZACORT USFDA

14 Delafloxacin USFDA

15 Deutetrabenazine USFDA

16DUPILUMAB USFDA+EMA

17 DURVALUMAB USFDA

18 EDAVARONE USFDA

19 EMICIZUMAB USFDA

20 Enasidenib USFDA

21 ERTUGLIFLOZIN USFDA

22 ETELCALCETIDE USFDA

22A FORODESINE JAPAN

22B FLUCICLOVINE EMA

23 GLECAPREVIR USFDA+EMA

24 GUSELKUMAB USFDA+EMA

25 INOTUZUMAB OZOGAMICIN USFDA+EMA

26 LATANOPROSTENE USFDA

27 LETERMOVIR USFDA+EMA

27A Utetium lu 177 dotatate EMA

28 MACIMORELIN ACETATE USFDA

29 MEROPENEM USFDA

30 MIDOSTAURIN USFDA+EMA

31 NALDEMEDINE USFDA

32 NERATINIB USFDA

33 NETARSUDIL USFDA

34 NIRAPARIB USFDA+EMA

34A NONACOG EMA

34B NUCINERSEN EMA +Japan

35 Ocrelizumab USFDA+EMA

35A OXERVATE EMA

36 OZENOXACIN USFDA

36A PATIROMER EMA

36B PADELIPORFIN EMA

36C PEMAFIBRATE JAPAN

37 PIBRENTASVIR USFDA+EMA

38 PLECANATIDE USFDA

38A PRALATREXATE JAPAN

39 RIBOCICLIB USFDA+EMA

39A ROLAPITANT EMA

39BRURLOCTOCOG EMA

40 SARILUMAB USFDA+EMA

41 SECNIDAZOLE USFDA

42 SAFINAMIDE USFDA

43 SEMAGLUTIDE USFDA+EMA

43A SODIUM ZIRCONIUM CYCLOCYLICATE EMA

44 SOFOSBUVIR USFDA+EMA

44A SPHEROX EMA

45 TELOTRISTAT ETHYL USFDA+EMA

45A TIVOZANIB EMA

45B TOFACITINIB EMA

45C TRUMENBA EMA

46 VABORBACTAM USFDA

47 VALBENAZINE USFDA

48 VESTRONIDASE ALFA-VJBK USFDA

49 VELPATASVIR USFDA+EMA

50 VOXILAPREVIR USFDA+EMA

Drugs EMA list missed out in usfda list

3A ALOFISEL

link………https://newdrugapprovals.org/2018/03/02/alofisel-darvadstrocel-cx-601/

4A Atezolizumab

WILL BE UPDATED

10A BUROSUMAB

WILL BE UPDATED

10B CARIPRAZINE HYDROCHLORIDE

WILL BE UPDATED

22B FLUCICLOVINE

Image result for FLUCICLOVINE

LINK https://newdrugapprovals.org/2016/05/28/fda-approves-new-diagnostic-imaging-agent-fluciclovine-f-18-to-detect-recurrent-prostate-cancer/

SEE EMA

Axumin : EPAR – Summary for the public

EN = English

06/07/2017

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004197/human_med_002100.jsp&mid=WC0b01ac058001d124

Marketing-authorisation holder	Blue Earth Diagnostics Ltd
Revision	0
Date of issue of marketing authorisation valid throughout the European Union	22/05/2017

Contact address:

Blue Earth Diagnostics Ltd
215 Euston Road
London NW1 2BE
United Kingdom

27A Lutetium lu 177 dotatate

WILL BE UPDATED

34A NONACOG

WILL BE UPDATED

34B NUCINERSEN

EMA AND JAPAN 2017 APPROVED

Image result for Nusinersen sodium

LINK …….https://newdrugapprovals.org/2018/03/14/nusinersen-sodium-%E3%83%8C%E3%82%B7%E3%83%8D%E3%83%AB%E3%82%BB%E3%83%B3%E3%83%8A%E3%83%88%E3%83%AA%E3%82%A6%E3%83%A0/

35A OXERVATE

WILL BE UPDATED

36A PATIROMER

WILL BE UPDATED

36B PADELIPORFIN

NAME	Tookad
AGENCY PRODUCT NUMBER	EMEA/H/C/004182
ACTIVE SUBSTANCE	padeliporfin di-potassium
INTERNATIONAL NON-PROPRIETARY NAME(INN) OR COMMON NAME	padeliporfin
THERAPEUTIC AREA	Prostatic Neoplasms
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CODE	L01XD07
ADDITIONAL MONITORING	This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring.

MARKETING-AUTHORISATION HOLDER	STEBA Biotech S.A
REVISION	0
DATE OF ISSUE OF MARKETING AUTHORISATION VALID THROUGHOUT THE EUROPEAN UNION	10/11/2017

Contact address:

STEBA Biotech S.A
7 place du theatre
L-2613 Luxembourg
Luxembourg

Image result for PADELIPORFIN

38A PRALATREXATE

Japan approved 2017

2017/7/3

PMDA

JAPAN

Pralatrexate

Difolta

Mundipharma

NME

LINK https://newdrugapprovals.org/2018/03/16/pralatrexate-%E3%83%97%E3%83%A9%E3%83%A9%E3%83%88%E3%83%AC%E3%82%AD%E3%82%B5%E3%83%BC%E3%83%88/

39A ROLAPITANT

WILL BE UPDATED

39B RURLOCTOCOG

WILL BE UPDATED

43A SODIUM ZIRCONIUM

WILL BE UPDATED

44A SPHEROX

WILL BE UPDATED

45A TIVOZANIB

Image result for TIVOZANIB EMA

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC.

Treatment of advanced renal cell carcinoma

Fotivda : EPAR -Product Information

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004131/WC500239035.pdf

str6

Tivozanib is synthesized in three main steps using well defined starting materials with acceptable
specifications.
Adequate in-process controls are applied during the synthesis. The specifications and control methods for
intermediate products, starting materials and reagents have been presented. The critical process
parameters are duly justified, methodology is presented and control is adequate.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on
chemistry of new active substances. Potential and actual impurities were well discussed with regards to
their origin and characterised.
The active substance is packaged in a low-density polyethylene (LDPE) bag which complies with the EC
directive 2002/72/EC and EC 10/2011 as amended.

Product details

Name	Fotivda
Agency product number	EMEA/H/C/004131
Active substance	tivozanib
International non-proprietary name(INN) or common name	tivozanib hydrochloride monohydrate
Therapeutic area	Carcinoma, Renal Cell
Anatomical therapeutic chemical (ATC) code	L01XE

Publication details

Marketing-authorisation holder	EUSA Pharma (UK) Limited
Revision	0
Date of issue of marketing authorisation valid throughout the European Union	24/08/2017

Contact address:

EUSA Pharma (UK) Limited
Breakspear Park, Breakspear Way
Hemel Hempstead, HP2 4TZ
United Kingdom

LINK………https://newdrugapprovals.org/2018/02/26/tivozanib-%E3%83%86%E3%82%A3%E3%83%9C%E3%82%B6%E3%83%8B%E3%83%96%E5%A1%A9%E9%85%B8%E5%A1%A9%E6%B0%B4%E5%92%8C%E7%89%A9/

45B TOFACITINIB

WILL BE UPDATED

45C TRUMENBA

WILL BE UPDATED

SECTION C JAPANFORODOS

SECTION C New Drugs JAPAN

https://www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0002.html

FY 2017 (April – November)

JAPAN 2017

2017/9/27	Avelumab (genetical recombination)	Bavencio	Merck Serono	BLA
2017/9/27	Glecaprevir – pibrentasvir mixt	Maviret	Abbvie	NME
2017/9/27	Daratumumab (genetical recombination)	Darzalex	Janssen Pharmaceutical	BLA
2017/9/27	Belimumab (genetical recombination)	Benlysta	GlaxoSmithKline	BLA
2017/9/27	Bezlotoxumab (genetical recombination)	Zinplava	MDS	BLA
2017/9/27	Palbociclib	Ibrance	Pfizer	NME
2017/9/27	Lonoctocog alfa (genetical recombination)	Afstyla	CSL Behring	BLA
2017/9/27	Rupatadine fumarate	Rupafin	Teikoku seiyaku	NME
2017/9/27	Sarilumab (genetical receombination)	Kevzara	Sanofi	BLA
2017/9/27	Flutemetamol (18F)	Vizamyl	Nihon Medi-Physics	NME
2017/7/3	Nusinersen sodium	Spinraza	Biogen Japan
2017/7/3	Romidepsin	Istodax	Celgene	NME
2017/7/3	Pralatrexate	Difolta	Mundipharma	NME
2017/7/3	Amenamevir	Amenalief	Maruho	NME
2017/7/3	Baricitinib	Olumiant	Lilly	NME
2017/7/3	Pemafibrate	Parmodia	Kowa	NME
2017/3/30	Human prothrombin complex, freeze-dried concentrated	Kcentra	CSL Behring
2017/3/30	Ixazomib citrate	Ninlaro	Takeda	NME
2017/3/30	Forodesine hydrochloride	Mundesine	Mundipharma
2017/3/30	Aflibercept beta (genetical recombination)	Zaltrap	Sanofi
2017/3/30	Hydromorphone hydrochloride	Narusus, Narurapid	DaiichiSankyo-pp
2017/3/30	Naldemedine tosylate	Symproic	Shionogi	NME
2017/3/30	Guanfacine hydrochloride	Intuniv	Shionogi

3B AMENAMEVIR

Originally developed by Astellas, the drug was licensed to Maruho. Amenamevir treats herpes zoster by inhibiting the activity of the helicase-primer enzyme during viral DNA replication and blocking the virus’s proliferation.

Amenalief® is an oral film-coated tablet containing 200 mg of amenamevir per tablet. Recommended dose of 1 day, 400mg each time, after meals.

LINK https://newdrugapprovals.org/2018/03/12/amenamevir-%E3%82%A2%E3%83%A1%E3%83%8A%E3%83%A1%E3%83%93%E3%83%AB/

22A FORODESINE HYDROCHLORIDE

LINK https://newdrugapprovals.org/2018/03/06/forodesine-hydrochloride/

6A BARICITINIB JAPAN

Originally developed by Incyte, Baricitinib was later licensed to and for sale by Lilly under the trade name Olumiant®. Baricitinib is an irreversible inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2). Olumiant® is approved for the treatment of mild to moderate rheumatoid arthritis in adult patients who are not responsive or intolerant to other anti-arthritic drugs. This product can be used alone or in combination with methotrexate.

Olumiant® is a film-coated tablet containing 2 mg or 4 mg per tablet. Recommended oral dose is 4mg daily, with meals or fasting food, you can take any time period.

2017/7/3PMDA Baricitinib Olumiant Lilly

LINK https://newdrugapprovals.org/2013/06/17/lilly-and-partner-incyte-corp-have-presented-more-promising-data-on-their-investigational-jak-inhibitor-baricitinib-for-rheumatoid-arthritis/

36C PEMAFIBRATE

LINK https://newdrugapprovals.org/2016/04/24/pemafibrate/

SECTION D

CDSCO INDIA

http://www.cdsco.nic.in/forms/list.aspx?lid=2034&Id=11 http://www.cdsco.nic.in/forms/list.aspx?lid=2034&Id=11

KEEP WATCHING UNDER CONSTRUCTION AND WILL BE PASTED SOON………………………………………..

REFERENCES

1 http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/01/news_detail_002886.jsp&mid=WC0b01ac058004d5c1

2 http://www.ema.europa.eu/docs/en_GB/document_library/Report/2018/01/WC500242079.pdf

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

amcrasto@gmail.com

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

////////EMA APPROVALS, USFDA Approvals, ACALABRUTINIB, AVELUMAB, BETRIXABAN, BRODALUMAB, COPANLISIB, DEFLAZACORT, Delafloxacin, Deutetrabenazine, DUPILUMAB, ETELCALCETIDE, Naldemedine, NETARSUDIL, NIRAPARIB, Ocrelizumab, PLECANATIDE, RIBOCICLIB, SAFINAMIDE, TELOTRISTAT ETHYL, VALBENAZINE, CERLIPONASE, BRIGATINIB, MIDOSTAURIN, Abaloparatide, BENZNIDAZOLE, NERATINIB, inotuzumab ozogamicin, Enasidenib, LETERMOVIR, GLECAPREVIR, PIBRENTASVIR, VOXILAPREVIR, SOFOSBUVIR, EDAVARONE, abemaciclib, ANGIOTENSIN II, VESTRONIDASE, macimorelin acetate, ERTUGLIFLOZIN, SEMAGLUTIDE, EMICIZUMAB, eu 2017, fda 2017, BENRALIZUMAB, DURVALUMAB, GUSELKUMAB, LATANOPROSTENE, OZENOXACIN, SARILUMAB, SECNIDAZOLE, BENRALIZUMAB, TIVOZANIB, SARILUMAB, FLUCICLOVINE,

FDA approves Vosevi for Hepatitis C

July 19, 2017 12:54 am / 1 Comment on FDA approves Vosevi for Hepatitis C

FDA approves Vosevi for Hepatitis C

07/18/2017

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis.

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. Vosevi is a fixed-dose, combination tablet containing two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir. Vosevi is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and develop complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Vosevi was evaluated in two Phase 3 clinical trials that enrolled approximately 750 adults without cirrhosis or with mild cirrhosis.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5 or 6 all received Vosevi.

The second trial compared 12 weeks of Vosevi with the previously approved drugs sofosbuvir and velpatasvir in adults with genotypes 1, 2 or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

Results of both trials demonstrated that 96-97 percent of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history.

The most common adverse reactions in patients taking Vosevi were headache, fatigue, diarrhea and nausea.

Vosevi is contraindicated in patients taking the drug rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Vosevi.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted approval of Vosevi to Gilead Sciences Inc

//////////////Vosevi, Gilead Sciences Inc, Priority Review, Breakthrough Therapy designations, fda 2017, sofosbuvir, velpatasvir , voxilaprevir, Hepatitis B

LUPIN LIMITED, WO 2016181313, NEW PATENT, SOFOSBUVIR

November 22, 2016 10:30 am / Leave a comment

WO2016181313, A PROCESS FOR THE PREPARATION OF SOFOSBUVIR INTERMEDIATES & ITS POLYMORPH

LUPIN LIMITED [IN/IN]; Kalpataru Inspire 3rd Floor, Off Western Express Highway Santacruz (East) Mumbai 400 055 (IN)

SINGH, Girij, Pal; (IN).
SRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

Image result for lupin pharmaceuticals

SUCCESS QUOTIENT: Lupin chairman DB Gupta (sitting) with managing director Kamal K Sharma (centre), directors Vinita Gupta (right) and Nilesh Gupta.

The present invention provides a novel process for preparation N-[(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2) and resolving the formula 2 in the presence base to form N-[(S)-(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2′).

Sofosbuvir is chemically named as (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4- dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2yl)methoxy)-(phenoxy)phosphorylamino)propanoate and is represented by the following chemical structure:

Formula 1

PCT publications WO2011123645 and WO2010135569 describes process for preparation of compound of formula 2′ by reacting isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate and pentaflurophenol in the presence of base.

Formula 2′

Example-1:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium hydride

10.2g of sodium hydride was dissolved in 100 ml anhydrous THF. This solution was slowly added to a solution of pentafluorophenol (50g) in THF (100ml), Reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained solid was dried under vacuum at 45-50°C (yield=55g, confirmed by IR)

Example-2:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium methoxide

2,3,4,5, 6-pentafluorophenol (lOg) was dissolved in methanol (100ml), solution was cooled to 5-10°C. To this was added a solution of sodium methoxide in methanol. The reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained residue was striped with toluene. Obtained solid was dried under vacuum at 45-50°C (yield=l lg)

Example 3:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium hydroxide

2,3,4,5, 6-pentafluorophenol (lOOg) dissolved in methanol (—ml), solution was cooled to 5-10°C. To this was added a solution of sodium hydroxide (— g) in methanol. The reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained residue was striped with dichloromethane. Obtained solid was dried under vacuum at 45-50°C (yield=— g)

Example 4:

Preparation of (2S)-isopropyl-2-((chloro(phenoxy)posphoryl)amino)propanoate:

phenyl phosphodichloridate (30.6g) was dissolved in dichloromethane , to this was added a solution of 1-alanine isopropyl ester free base (19.16g) in dichloromethane at-60°C under nitrogen. Solution of triethylamine (20.7ml) was added to above reaction mass. Reaction mass was stirredat -60°C for 30 min and then temperature was raised to 25 °C. Reaction mass was stirred at 20-25 °C for 60 min & filtered and washed with dichloromethane. Clear filtrate was distilled under reduced pressure obtained residue was stirred with diisopropyl ether & filtered. Clear filtrate was distilled under reduced pressure to get (2S)-isopropyl-2-((chloro(phenoxy)posphoryl)amino)propanoate compound.

Example 5:

Preparation of isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (formula 2):

(Formula 2)

Obtained (2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate (1.2 mol eq.) was dissolved in dichloromethane and cooled to 0-5°C under nitrogen atmosphere. To this was added solution of sodium 2,3,4,5,6-pentaflurophemolate (1 mol eq.) in tetrahydrofuran . Temperature of reaction mass was raised to 25°C and reaction mass was stirred for 3 hrs. After completion of reaction, reaction mass was distilled under reduced pressure & obtained residue was dissolved I ethyl acetate. Ethyl acetate layer was washed with water, dried over sodium sulfate & distilled off under reduced pressure. Diisopropyl ether was added to obtained residue and stirred for 60 min at 25 °C, obtained mass was filtered & washed with diisopropyl ether. Solid product was dried under vacuum at 40-45 °C .(yield=20g, enantiomer purity=93.45%)

Example 6:

Preparation of (S)-isopropyl 2-(((S)- (perfluorophenoxy)phenoxy)phosphoyl)amino)propanoate (Formula 2′):

Formula 2′

(2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate (1.2 mol eq.) was dissolved in tetrahydrofuran (3.5 volumes). The reaction mass was cooled to -10°C. Solution of sodium salt of pentafluorophenol (1 mol eq.) in tetrahydrofuran (3.5 volumes) was added dropwise to the reaction mass at -10°C. After completion of the reaction solvent was distilled off. Ethyl acetate and water were added to the reaction mass. Reaction mass was stirred, ethyl acetate layer was separated and washed with sodium bicarbonate solution and brine. Ethyl acetate layer was concentrated under reduced pressure. Reaction mass was stripped with n-hepatane to get crude product. Crude product was dissolved in Methyl tert-butyl ether and n-heptane (1 : 1 ratio). The pH of reaction mass was adjusted to pH 8 by using triethylamine. Reaction mass was stirred overnight. Solid mass was filtered and washed with a mixture of methyl tertiary-butyl ether: n-heptane (1 : 1). The obtained product was dissolved in ethyl-acetate and washed with water and 20% brine solution. Ethyl acetate layer was separated; solvent was distilled off under reduced pressure. Reaction mass was stripped with diisopropyl ether. Di-isopropyl ether was added to the reaction mass. Reaction mass was stirred at 45-50°C. Reaction mass was cooled to 5-10°C and stirred. The titled compound was isolated by filtration and washed with di-isopropyl ether. The titled compound was dried under reduced pressure at 40°C. Yield 66.81%.

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Vinita Gupta, CEO, Lupin Pharmaceuticals Inc

Desh Bhandu Gupta- Founder and chairman of Lupin Limited

////////////LUPIN LIMITED, WO 2016181313, NEW PATENT, SOFOSBUVIR

LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

February 8, 2016 5:52 am / Leave a comment

(WO2016016865) A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE

LUPIN LIMITED [IN/IN]; 159 CST Road, Kalina, Santacruz (East), State of Maharashtra, Mumbai 400 098 (IN)

ROY, Bhairab, Nath; (IN).
SINGH, Girij, Pal; (IN).
SHRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

The present invention pertains to process for preparing nucleoside phosphoramidates and their intermediates. Phosphoramidates 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. One of the recently approved phosphoramidate by USFDA is Sofosbuvir [1190307-88-0]. Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis C. The present invention provides novel intermediate, its process for preparation and use for the preparation of Sofosbuvir. The present invention also gives one pot process for preparation of Sofosbuvir.

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. There are limited treatment options for individuals infected with hepatitis C virus. The current approved therapeutic option is the use of immunotherapy with recombinant interferon- [alpha] alone or in combination with the nucleoside analog ribavirin.

US 7964580 (‘580) is directed towards novel nucleoside phosphoramidate prodrug for the treatment of hepatitis C virus infection.

US’580 patent claims Sofosbuvir and rocess for preparation of Sofosbuvir of Formula 1.

Formula 1

Process for preparation of Sofosbuvir as per US ‘580 patent involve reaction of compound of Formula 4″ with a nucleoside 5’

Compound 4″ nucleoside 5′

Wherein X’ is a leaving group, such as CI, Br, I, tosylate, mesylate, trifluoroacetate, trifluroslfonate, pentafluorophenoxide, p-nitro-phenoxide.

Objects of the invention

The object of the present invention is to provide a novel intermediate of Formula 2

Formula 2

wherein X’ is a leaving group selected from 1-hydroxybenzotriazole, 5-(Difluoromethoxy)-lH-benzimidazole-2-thiol, 2-Mercapto-5-methoxybenzimidazole, cyanuric acid, 2-oxazolidinone, 2-Hydroxy Pyridine. The above leaving group can be optionally substituted with n-alkyl, branched alkyl, substituted alkyl; cycloalkyl; halogen; nitro; or aryl, which includes, but not limited to, phenyl or naphthyl, where phenyl or naphthyl are further optionally substituted with at least one of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ alkoxy, F, CI, Br, I, nitro, cyano, Ci-C₆ haloalkyl, -N(R^r)2, Ci-C₆ acylamino, -NHS0₂Ci-C₆ alkyl, -S0₂N(R^r)₂, COR^1″, and -S0₂Ci-C₆ alkyl; (R^r is independently hydrogen or alkyl, which includes, but is not limited to, Ci-C₂o alkyl, Ci-Cio alkyl, or Ci-C₆ alkyl, R¹” is -OR¹ or -N(R^r)₂).

Another object of the present invention is to provide a process to prepare the intermediate of Formula 2.

Another object of the present invention is use of the intermediate of Formula 2 in the preparation of Sofosbuvir of Formula 1.

Formula 1

Example 1:

Process for the preparation of S-oxazolidinone derivative of Formula 2

Step-1 Preparation of phosphorochloridate solution:

Dichloromethane (DCM 400ml) was charged in round bottom flask flushed with nitrogen. Phenyl phosphodichloridate (18.30ml) was added in one portion in the flask. The flask was cooled to -60°-70°C with a dry ice-acetone bath. Solution of L-alanine isopropyl ester hydrochloride (20.6gm)) in DCM (50ml) was added to the reaction flask. To this was added a solution of triethylamine (11.20ml) in MDC (100 ml) was added over a course of 60 minutes, while maintaining internal temperature below -70 °C throughout the addition. After completion of reaction, temperature of reaction mass was raised to room temperature.

100ml THF was charged in another round bottom flask flushed with nitrogen followed by the addition of S-4-phenyloxazolidnone (lOgm). Triethyl-amine (11.2ml) & LiCl (2.85gm) were added to the above flask. The reaction mass was stirred for 15-30 min at room temperature and was cooled to 0-5 °C. Phosphorochloridate solution from step-1 was added drop- wise to the reaction flask in 15-45 min maintaining reaction temperature at 0-5 °C. The reaction mass was stirred for 30-60min at 0°-5°C. The reaction progress was monitored on thin layer chromatography. After completion of the reaction, the reaction temperature was raised to room temperature. Agitation was resumed for an additional 30min. The reaction mass was filtered and concentrated under reduced pressure. To this was added diisopropyl ether (400ml) and aqueous saturated ammonium chloride solution and reaction mass was stirred for 10-15 minutes. Organic layer was separated and was washed with water (100ml) & dried over sodium sulfate and concentrated under vacuum. Cyclohexane (50ml) was charged to the obtained oily mass and reaction mass was stirred till solid precipitated out. Solid was filtered and washed with cyclohexane and dried under vacuum (8.80gm MP 56.5°-56.6°C). The obtained product was characterized by mass, NMR & IR. 1H NMR (DMSO-d₆) δ 1.142 -1.18

(m, 9H), 3.85-3.92 (m, 1H), 4.72-4.89(m, 2H), 5.31-5.32(d, 1H), 6.25-6.3 (m, 1H), 6.95-7.31 (m, 10H); MS, m/e 433 (M+l) ⁺

Example 2: Process for the preparation of 2-hydroxy pyridine derivatives of formula 2:

Anhydrous dichloromethane (DCM) 700ml was charged in round bottom flask flushed with nitrogen. The flask was cooled to -60° to -70°C in a dry ice acetone bath. Phenyl phosphodichloridate (76.04 gm) was added in one portion in the flask at -65°C. Solution of L-alanine isopropyl ester hydrochloride (60.56 gm) in DCM (50 ml) was added to the reaction mass. Solution of triethylamine (72.44gm) in DCM (50ml) was added to the reaction mass over a course of 60 minutes, while maintaining internal temperature below -70°C throughout the addition. The resulting white slurry was agitated for additional 60 minutes. Then the temperature of reaction mass was raised to room temperature. Reaction mass was stirred for 60 min & TLC was checked. Reaction mass was filtered and rinsed with anhydrous dichloromethane (2 XI 00 mL). The filtrate was concentrate under vacuum to 20 V and reaction mass was filtered, washed with DCM (15ml). The filtrate was transferred to RBF. The reaction mass was cooled to 0°-10°C. A solution of 2-hydroxy-3-nitro-5- (trifluoromethyl) pyridine (15.gm) in DCM (100ml) & triethyl amine (21.89gm) was added to the reaction mass. Temperature of reaction mass was raised to 20-30°C. Reaction mass was stirred overnight. Reaction was monitored using TLC. After completion, the reaction mass was filtered and washed with DCM (30ml). Filtrate was washed with water (150 ml x 2). Organic layer was concentrated under vacuum and degased. Diisopropyl ether (200ml) was charged to reaction mass and reaction mass was stirred for 15 minutes , filtered and washed with methyl ter-butyl ether (MTBE 30ml). Filtrate was concentrated under vacuum and dried. (8.68gm, MP-125.5°-131.5°C). Obtained compound was characterized by Mass, NMR & IR. 1H NMR (DMSO-d₆) δ 1.07 -1.27 (m, 9H), 4.04-4. l l(m, 1H), 4.73-4.79(m, 1H), 6.76-7.43 (m, 5H), 9.00-9.02 (d, 2H); MS, m/e 478 (M+l) ⁺; FTIR, 1203, 1409, 1580, 1732, 3217.

Other 2-hydroxy pyridine derivatives of Formula 2 were prepared by following the process disclosed in example 2-

2-Hydroxy-5-fluoropyridine derivative of Formula 2;-1H NMR (DMSO-d₆) δ 1.09 -1.23 (m, 9H), 3.02-3.06 (m, lH), 3.85-4.01 (m,lH), 4.79-4.87(m, 1H), 6.4-6.52 (m,lH), 7.10-7.89 (m,6H); MS, m/e 383 (M+l) ⁺,

2-Hydroxy-5-nitropyridine derivative of Formula 2:- 1H NMR (DMSO-d₆) δ 1.06 -1.22 (m, 9H),4.0-4.02 (m,lH), 4.7-4.8(m,lH), 6.5-6.6 (m,lH),7.12-7.42 (m,6H),8.66-8.68 (d, lH),9.07-9.13(d,lH); MS, m/e 410 (M+l) ⁺

2-Hydroxy-3, 5-dinitropyridine derivative of Formula 2:- 1H NMR (DMSO-d₆) δ 1.11 -1.24 (m, 9H), 3.04-3.09(m,lH), 4.8-4.86(m,lH), 7.09-7.39 (m,5H),8.97-9.06 (d,2H)

Example 3: Process for the preparation of Sofosbuvir by coupling of isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione :

To a solution of l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (0.2gm) in THF (4 ml), tert- butylmagnesium chloride (0.80ml, 1.7 M solution in THF) was added dropwise at room temperature and reaction mass was stirred for 30 minutes. A solution of pyridine derivative from example 2 (0.36gm) in THF (4ml) was added dropwise to the reaction mass at room temperature. Completion of reaction was monitored using TLC. After completion of reaction, reaction mass was quenched by using saturated ammonium chloride solution (10ml). Reaction mass was extracted with ethyl acetate (50ml). Organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel & obtained solid product was characterized. MS, m/e 530.2 (M+l) ⁺.

/////////LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

SOFOSBUVIR HPLC

November 3, 2015 6:09 am / Leave a comment

SEE http://www.google.co.in/patents/US20100298257

Example 28

Chemical Purity Determination by HPLC
Various HPLC conditions can be used to determine the chemical purity of the compounds disclosed herein. One such example is disclosed above in relation to the thermodynamic aqueous solubility studies. Another example is disclosed below.
HPLC Conditions:
- LC: Waters Alliance 2695 Separations Module, Waters 2996 PDA detector and Waters Empower 2 Software (Version 6.00)
- Column: Phenomenex Luna C18(2); 4.6×50 mm; 3 μm
- Flow rate: 1.2 mL/min
- Injection Volume: 10 μL
- Mobile phase: Solvent A: 95% Water with 5% Methanol and 10 mM Ammonium Acetate; pH˜5.3
- Gradient Solvent B: MeOH with 10 mM Ammonium Acetate hold at 0% B 3 min
  - 0-47% B 3-4 min
  - hold at 47% B 4-10 min
  - 47%-74% B 10-11 min
  - hold at 74% B 11-13.5 min
  - return to 0% B 13.5-13.6 min
  - hold at 0% B 13.6-15.5 min
Under these conditions, the purity of 4, R_P-4, and S_P-4 was determined to be ˜99.6, ˜99%, and ˜99.5%, respectively. It is noted that higher purities can be realized by optimizing the methods disclosed above.
Inspection of the XRPD diffractograms shows that the two crystalline single diastereoisomers gave clearly different XRPD patterns. Additionally, there was a clear difference in the melting point of the two crystalline diastereoisomers, with R_P-4 having a considerably higher onset than S_P-4 (136° C. vs. 94° C.).
Example 29Additional Separation Methods
The following SFC separation (conditions listed below) yielded adequate separation of a mixture of the diastereomers, R_P-4 and S_P-4.


Preparative Method:	Analytical Method:

Chiralpak AS-H (2 × 25 cm) SN# 07-8656	Chiralpak AS-H (25 ×
	0.46 cm)
20% methanol/CO₂(100 bar)	20% methanol/CO₂(100 bar)
50 ml/min, 220 nm.	3 ml/min, 220 nm.
Conc.: 260 mg/30 ml methanol,
inj vol.: 1.5 ml

The following SFC separation (conditions listed below) yielded adequate separation of a mixture of the diastereomers, R_P-4 and S_P-4.


Preparative Method:	Analytical Method:

Chiralpak IA(2 × 15 cm) 802091	Chiralpak IA(15 × 0.46 cm)
30% isopropanol(0.1% DEA)/CO₂,	40% methanol(DEA)/CO₂, 100 bar
100 bar
60 mL/min, 220 nm.	3 mL/min, 220 nm.
inj vol.: 2 mL, 20 mg/mL methanol

TABLE 16

Summary of results from the batch characterization of R_P-4, 4, and S_P-4.
Analysis	R_P-4	4	S_P-4

Proton NMR	Single diastereoisomer	1:1 Mixture of	Single diastereoisomer
		diastereoisomers
XRPD	Crystalline – different	Amorphous	Crystalline – different
DSC	from S_P-4	Endotherm; 59° C.	from R_P-4
	Endotherm; melt – 136° C.		Endotherm; melt – 94° C.
TGA	No wt loss,	No wt loss, decomposition	No wt loss,
	decomposition >240° C.	>240° C.	decomposition >240° C.
IR	See above	See above	See above
Aq Solubility	1.58	6.11	5.65
(mg · ml⁻¹)
HPLC Purity	96.9%	99.6%	99.5%
40° C./75% RH	No form change	Deliquescence inside 1.5 h	Deliquescence inside 4.5 h
25° C./53% RH	—	Deliquescence	No form change
GVS	Non-hygroscopic up to 90%	—	Non-hygroscopic up to 60%
	RH		RH

Aqueous solubility was determined by suspending a sufficient amount of compound in water to give a maximum final concentration of ≧10 mg.ml⁻¹of the parent free-form of the compound. The suspension was equilibrated at 25° C. for 24 hours then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg.ml⁻¹in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.

TABLE 14

HPLC Method Parameters for Solubility Measurements


Type of method:	Reverse phase with gradient elution
Column:	Phenomenex Luna, C18 (2) 5 μm 50 × 4.6 mm
Column Temperature	25
(° C.):
Standard Injections (μl):	1, 2, 3, 5, 7, 10
Test Injections (μl):	1, 2, 3, 10, 20, 50
Detection:	260, 80
Wavelength,
Bandwidth (nm):
Flow Rate (ml · min⁻¹):	2
Phase A:	0.1% TFA in water
Phase B:	0.085% TFA in acetonitrile
	Time (min)	% Phase A	% Phase B
Timetable:	0.0	95	5
	1.0	80	20
	2.3	5	95
	3.3	5	95
	3.5	95	5
	4.4	95	5

[0306]

Analysis was performed under the above-noted conditions on an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SR1.

TABLE 15

Aqueous solubility result for R_P-4, 4, and S_P-4.
	pH of Unfiltered
Sample ID	mixture	Solubility/mg · ml⁻¹	Comments

R_P-4	7.12	1.58	Suspension
4	7.03	6.11	Residual solid
S_P-4	6.88	5.65	Residual solid

FIG 1

Chemical structures of RBV, BOC, TVR, and VRT-127394. Shown are the chemical structures of the anti-HCV drugs RBV {1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide)} (A), BOC {(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S)-2(tertbutylcarbamoylamino)-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide} (B), TVR {(3S,3aS,6aR)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1, 2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide} (C), and VRT-127394 (R diastereoisomer of TVR) (D).

Blank plasma samples used for matrix effect (ME) assessment and for the preparation of calibration and control samples were obtained from citrated blood (1,850 × g, 10 min, +4°C, Beckman J6B centrifuge) collected from Vaquez disease patients on the occasion of their regular phlebotomy.

The blank plasma used for the preparation of the calibration and quality control (QC) samples was acidified with 10% FA (50 μl of 10% FA added to 950 μl of plasma). The acidification of plasma aims at preventing the conversion of TVR to its epimer VRT-127394 that occurs in vivo and in vitro. (Tibotec-Janssen, personal communication).

Equipment.The LC system used consisted of Rheos Allegro quaternary pumps equipped with an online degasser and an HTS PAL autosampler (CTC Analytics AG, Zwingen, Switzerland) controlled by Janeiro-CNS 1.1 software (Flux Instruments AG, Thermo Fischer Scientific Inc., Waltham, MA). Separations were done on a Hypercarb 3-μm column (2.1 mm ID by 100 mm; Thermo Fischer Scientific) placed in a column oven thermostat regulated at +80°C (HotDog 5090; ProLab GmbH, Reinach, Switzerland). The chromatographic system was coupled to a triple-stage quadrupole quantum mass spectrometer (Thermo Fischer Scientific) equipped with an electrospray ionization (ESI) Ion Max interface and operated with the Xcalibur software package (version 2.0; Thermo Fischer Scientific).

READ T……http://aac.asm.org/content/57/7/3147.full

READ

http://www.us.edu.pl/uniwersytet/jednostki/wydzialy/chemia/acta/ac14/zrodla/14_AC14.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291777/

UPDATE………….DEC2015

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

Step (a):

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ8.25 & 7.94 (1: 1);

¹ HNMR (CDCl ₃ , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

¹³ C NMR (CDCl ₃ , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ3.54ppm;

¹³ C NMR (CDCl ₃ , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

¹ HNMR (CDCl ₃ , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(4) nucleophile as NaN ₃ , phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN ₃ (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N ₃ ).

¹ HNMR (CDCl ₃ , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

³¹ PNMR- (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

¹ HNMR (CDCl ₃ , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(2) X is N ₃

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

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Gilead’s HCV drug Sovaldi gets Europe OK

January 20, 2014 12:00 pm / 4 Comments on Gilead’s HCV drug Sovaldi gets Europe OK

Gilead's HCV drug Sovaldi gets Europe OK

Gilead Sciences’ closely-watched hepatitis C drug Sovaldi has been given the green light in Europe.

The European Commission has granted marketing authorisation for Sovaldi (sofosbuvir) 400mg tablets

which, as part of HCV combination therapy with peg-interferon and ribavirin, offers cure rates of around 90% in previously-untreated adults. However, most significant is that the once-daily nucleotide analogue polymerase inhibitor is the first all-oral treatment option for up to 24 weeks for patients unsuitable for interferon.

SYNTHESIS

sofosbuvir » All About Drugs

http://www.allfordrugs.com/tag/sofosbuvir/‎

by ANTHONY MELVIN CRASTO – in 1,319 Google+ circles

ALL ABOUT DRUGS BY DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER HELPING … US Approves Breakthrough Hepatitis C Drug,Sofosbuvir.

US Approves Breakthrough Hepatitis C Drug, Sofosbuvir » All About Drugs

December 11, 2013 1:02 am / 51 Comments on US Approves Breakthrough Hepatitis C Drug, Sofosbuvir » All About Drugs

SOFOSBUVIR

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US Approves Breakthrough Hepatitis C Drug, Sofosbuvir » All About Drugs

AND ALSO

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SEE………………….http://orgspectroscopyint.blogspot.in/2015/02/sofosbuvir-visited.html

READ ABOUT SYNTHESIS BY CLICKING ABOVE LINK

Sofosbuvir

Sovaldi

M.Wt: 529.45

Formula: C22H29FN3O9P

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

A prodrug of 2′-deoxy-2′-alpha-F-2′-beta-C-methyluridine 5′-monophosphate.
GS-7977, PSI-7977

GS 7977
GS-7977
PSI 7977
PSI-7977
Sofosbuvir
Sovaldi
UNII-WJ6CA3ZU8B

CAS Registry Number :1190307 -88-0

http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf

Indications: Chronic hepatitis C (HCV GT1, GT2, GT3, GT4)
Mechanism: nucleoside NS5B polymerase inhibitor
approved Time: December 6, 2013
,U.S. Patent Number: 7964580,8415322,8334270,7429572;, patent validity: March 26, 2029 (U.S. Patent No.: 7,964,580 and 8,334,270), April 3, 2025 (U.S. Patent No.: 7,429,572 and 8,415,322)

US patent number 7964580, US patent number 8415322, US patent number 8334270,US patent number 7429572 Patent Expiration Date: March 26, 2029 for US patent number 7964580 and 8334270 (2028 in EU)； April 3, 2025 for US patent number 7429572 and 8415322

Sales value (estimated): $ 1.9 billion (2014), 6600000000 USD (2016)

Drug Companies: Gilead Sciences, Inc. (Gilead Sciences)

WASHINGTON, Dec. 6, 2013 (AP) — Federal health officials have approved a highly anticipated hepatitis C drug from Gilead Sciences Inc. that is expected to offer a faster, more palatable cure to millions of people infected with the liver-destroying virus.

The Food and Drug Administration said Friday it approved the pill Sovaldi in combination with older drugs to treat the main forms of hepatitis C that affect U.S. patients.

Current treatments for hepatitis C can take up to a year of therapy and involve weekly injections of a drug that causes flu-like side effects. That approach only cures about three out of four patients. Sovaldi is a daily pill that in clinical trials cured roughly 90 percent of patients in just 12 weeks, when combined with the older drug cocktail.http://www.pharmalive.com/us-approves-breakthrough-hepatitis-c-drug

The end of October 2013 saw a nod from the FDA given to Gilead’s New Drug Application for Sofosbuvir, a much needed treatment for hepatitis C.
As a nucleotide analogue, Sofosbuvir is designed as a once daily treatment.
There are roughly 170 million cases of hepatitis C around the world.
A report in the Journal of the American Medical Association on August 28, 2013 revealed that the Sofosbuvir and Ribavirin combination treatment effectively cured many patients with the Hepatitis C Virus.
The Sofosbuvir and Ribavirin drug combination was void of interferon-based treatments, which many patients are resistant too.
More than 3 million Americans have chronic Hepatitis C Virus, and 22 percent of these patients are African American.

Sofosbuvir (brand names Sovaldi and Virunon) is a drug used for hepatitis C virus (HCV) infection, with a high cure rate.^[1]^[2] It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.^[3]

Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic Hepatitis C.^[4]

In 2013, the FDA approved sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4.^[4] Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, compared to 24 weeks for treatment of genotype 3. The label furhter states that sofosbuvir in combination with ribavirin may be considered for patients infected with genotype 1 who are interferon-ineligible.^[5] Sofosbuvir will cost $84,000 for 12 weeks of treatment and $168,000 for the 24 weeks, which some patient advocates have criticized as unaffordable.

Interferon-free therapy for treatment of hepatitis C eliminates the substantial side-effects associated with use of interferon. Up to half of hepatitis C patients cannot tolerate the use of interferon.^[6]

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate.^[7] Sofosbuvir is anucleotide analog inhibitor of the hepatitis C virus (HCV) polymerase.^[8] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

The New Drug Application for Sofosbuvir was submitted on April 8, 2013 and received the FDA’s Breakthrough Therapy Designation, which grants priority review status to drug candidates that may offer major treatment advantages over existing options.^[9]

On 6^th December 2013, the U.S. Food and Drug Administration approved sofosbuvir for the treatment of chronic hepatitis C.^[10]

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.^[11]^[12] It has shown clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.^[13]

Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.^[14]^[15]

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.^[16] Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3.^[17] This represents a substantial pricing increase from previous treatments consisting of interferon and ribavirin, which cost between $15,000 and $20,000.^[18] The price is also significantly higher than that of Johnson & Johnson‘s recently approved drug simeprevir (Olysio), which costs $50,000 and also treats chronic hepatitis C.^[18] The high cost of the drug has resulted in a push back from insurance companies and the like, includingExpress Scripts, which has threatened to substitute lower priced competitors, even if those therapies come with a more unfriendly dosing schedule.^[18] Other treatments that have recently entered the market have not matched the efficacy of sofosbuvir, however, allowing Gilead to set a higher price until additional competition enters the market.^[18] Patient advocates such as Doctors Without Borders have complained about the price, which is particularly difficult for underdeveloped countries to afford.^[19]

sofosbuvir

News: United States to approve potent oral drugs for hepatitis C, Sara Reardon, Nature, 30 October 2013
Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA (October 2010). “Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus”. J. Med. Chem. 53 (19): 7202–18.doi:10.1021/jm100863x. PMID 20845908.
“PSI-7977”. Gilead Sciences.
Tucker M (December 6, 2013). “FDA Approves ‘Game Changer’ Hepatitis C Drug Sofosbuvir”. Medscape.
“U.S. Food and Drug Administration Approves Gilead’s Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C – See more at: http://www.gilead.com/news/press-releases/2013/12/us-food-and-drug-administration-approves-gileads-sovaldi-sofosbuvir-for-the-treatment-of-chronic-hepatitis-c#sthash.T9uTbSWK.dpuf”. Gilead. December 6, 2013.
“Sofosbuvir is safer than interferon for hepatitis C patients, say scientists”. News Medical. April 25, 2013.
Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA (November 2010). “Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977”. J. Biol. Chem. 285 (45): 34337–47.doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890.
Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
“FDA Advisory Committee Supports Approval of Gilead’s Sofosbuvir for Chronic Hepatitis C Infection”. Drugs.com. October 25, 2013.
“FDA approves Sovaldi for chronic hepatitis C”. FDA New Release. U.S. Food and Drug Administration. 2013-12-06.
Murphy T (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”.Bloomberg Businessweek.
Asselah T (January 2014). “Sofosbuvir for the treatment of hepatitis C virus”. Expert Opin Pharmacother 15 (1): 121–30. doi:10.1517/14656566.2014.857656. PMID 24289735.
“AASLD 2012: Sofosbuvir and daclatasvir dual regimen cures most people with HCV genotypes 1, 2, or 3”. News. European Liver Patients Association. 2012-11-21.
AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (January 2013). “Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C”.N. Engl. J. Med. 368 (1): 34–44. doi:10.1056/NEJMoa1208953. PMID 23281974.
CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
Campbell T (December 11, 2013). “Gilead’s Sofosbuvir Gets New Name, Price, Headaches”. The Motley Fool.
Cohen, J. (2013). “Advocates Protest the Cost of a Hepatitis C Cure”. Science 342 (6164): 1302–1303. doi:10.1126/science.342.6164.1302. PMID 24337268. edit

The chemical structure

GS-7977, (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin^l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, available from Gilead Sciences, Inc., is described and claimed in U.S. Patent No. 7,964,580. (See also US 2010/0016251, US 2010/0298257, US 201 1/0251 152 and US 2012/0107278.) GS-7977 has the structure:

GS-7977 can be crystalline or amorphous. Examples of preparing crystalline and amorphous forms of GS-7977 are disclosed in US 2010/0298257 (US 12/783,680) and US 201 1/0251 152 (US 13/076,552),

Chemical Synthesis of Sofosbuvir_Sovaldi_GS-7977_PSI-7977_Hepatitis C_Gilead

Commerically available isopropylidine protected D-glyceraldehyde was reacted with (carbethoxyethylidene)triphenylmethylphosphorane gave the chiral pentenoate ester YP-1. Permanganate dihydroxylation of YP-1 in acetone gave the D-isomer diol YP-2. The cyclic sulfate YP-3 was obtained by first making the cyclic sulfite with thionyl chloride and then oxidizing to cyclic sulfate with sodium hypochlorite. Fluorination of YP-3 with triethylamine-trihydrofluoride(TEA-3HF) in the presence of triethylamine, followed by the hydrolysis of sulfate ester in the presence of concentrated HCl provided diol YP-4 which was benzoylated to give ribonolactone YP-5. Reduction of YP-5 with Red-Al followed by chlorination with sulfuryl chloride in the presence of catalytic amount of tetrabutylammonium bromide yielded YP-6. The conversion of YP-6 to benzoyl protected 2′-deoxyl-2′-alpha-F-2′-Beta-C-methylcytidine (YP-7) was achieved by using O-trimethyl silyl-N4-benzoylcytosine and stannic chloride. Preparation of the uridine nucleoside YP-8 was accomplished by first heating benzoyl cytidine YP-7 in acetic acid then treating with methoanolic ammonia to provide YP-8 in 78% yield.

The phosphoramidating reagent YP-9 was obtained by first reacting phenyldichlorophosphate with L-Alanine isopropyl ester hydrochloride and then with pentafluorophenol. Isolation of single Sp diastereomer YP-9 was achieved via crystallization-induced dynamic resolution in the presence of 20% MTBE/hexane at room temperature.

The uridine nucleoside YP-8 was treated with tert-butylmagnesium chloride in dry THF, followed by pentafluorophenyl Sp diastereomer YP-9 to furnish the Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate (Sovaldi, sofosbuvir, GS-7977, PSI-7977)。

…………

US 7429572

US 8415322

US 7964580

US 8334270B

WO 2006012440

WO 2011123668

US8334270

/US20080139802

……………………………………………

In US 20050009737 published Jan. 13, 2005, J. Clark discloses fluoro-nucleoside derivatives that inhibit Hepatitis C Virus (HCV) NS5B polymerase. In particular, 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-faran-2-yl)-1H-pyrimidin-2-one (18) was a particularly potent inhibitor of HCV polymerase as well as the polymerase of other Flaviviridae.

In WO2006/012440 published Feb. 2, 2006, P. Wang et al disclose processes for the preparation of 18. Introduction of the cytosine is carried out utilizing the Vorbruggen protocol. In US 20060122146 published Jun. 8, 2006, B.-K. Chun et al. disclose and improved procedures for the preparation of the 2-methyl-2-fluoro-lactone 10. In the latter disclosure the nucleobase is glycosylated by reacting with ribofuranosyl acetate which is prepared by reduction of 10 with LiAlH(O-tert-Bu)₃followed by acetylaton of the intermediate lactol which was treated with an O-trimethylsilyl N4-benzoylcytosine in the presence of SnCl₄to afford the O,O,N-tribenzoylated nucleoside.

……………………………………………………………….

http://www.google.nl/patents/US20080139802

The present process as described in SCHEME A and the following examples contain numerous improvements which have resulted in higher yields of the desired nucleoside. The asymmetric hydroxylation of 22 was discovered to be best carried out with sodium permanganate in the presence of ethylene glycol, sodium bicarbonate in acetone which afforded the diol in 60-64% on pilot plant scale. The sodium permanganate procedure avoids introduction of osmium into the process stream. Further more the stereospecific hydroxylation can be accomplished without using an expensive chiral ligand. The requisite olefin is prepared from (1S,2S)-1,2-bis-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethane-1,2-diol (20) (C. R. Schmid and J. D. Bryant, Org. Syn. 1995 72:6-13) by oxidative cleavage of the diol and treating the resulting aldehyde with 2-(triphenyl-λ⁵-phosphanylidene)-propionic acid ethyl ester to afford 22.

(i) NaIO₄, NaHCO₃, DCM; (ii) MeC(═PPh₃)CO₂Et; (iii) acetone-NaMnO₄(aq), ethylene glycol, NaHCO₃, −10 to 0° C.; aq. NaHSO₃(quench); (iv) i-PrOAc, MeCN, TEA, SOCl₂; (v) i-PrOAc, MeCN, NaOCl; (vi) TEA-3HF, TEA; (vii) HCl (aq)-BaCl₂-aq; (viii) (PhCO)₂O, DMAP, MeCN, (ix) RED-AL/TFE (1:1), DCM; (x) SO₂Cl₂-TBAB, DCM; (xi) 32, SnCl₄-PhCl; (xii) MeOH-MeONa

EXAMPLE 3 (2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (24)

A suspension of 22 (10 kg, CAS Reg. No. 81997-76-4), ethylene glycol (11.6 kg), solid NaHCO₃(11.8 kg) and acetone (150 L) is cooled to ca.-15° C. A solution of 36% aqueous NaMnO₄(19.5 kg) is charged slowly (over 4 h) to the suspension maintaining reaction temperature at or below −10° C. After stirring for 0.5 h at −10° C., an aliquot of the reaction mixture (ca. 5 mL) is quenched with 25% aqueous sodium bisulfite (ca. 15 mL). A portion of resulting slurry is filtered and submitted for GC analysis to check the progress of the reaction. When the reaction is complete, the reaction mixture is quenched by slow addition (over 40 min) of cooled (ca. 0° C.) 25% aqueous NaHSO₃(60 L). The temperature of the reaction mixture is allowed to reach 4° C. during the quench. CELITE® (ca. 2.5 kg) is then slurried in acetone (8 kg) and added to the dark brown reaction mixture. The resulting slurry is aged at RT to obtain light tan slurry. The slurry is filtered, and the filter cake is washed with acetone (3×39 kg). The combined filtrate is concentrated by vacuum distillation (vacuum approximately 24 inches of Hg; max pot temperature is 32° C.) to remove the acetone. The aqueous concentrate is extracted with EtOAc (3×27 kg), and the combined organic extracts were washed with water (25 L). The organic phase is then concentrated by atmospheric distillation and EtOAc is replaced with toluene. The volume of the batch is adjusted to ca. 20 L. Heptane (62 kg) is added and the batch cooled to ca. 27° C. to initiate crystallization. The batch is then cooled to −10° C. After aging overnight at −10° C., the product is filtered, washed with 10% toluene in heptane and dried at 50° C. under vacuum to afford 6.91 kg (59.5%) of 24 (CARN 81997-76-4) as a white crystalline solid.

EXAMPLE 4 (3R,4R,5R)-3-Fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-dihydro-furan-2-one (10)

steps 1 & 2—A dry, clean vessel was charged with 24 (6.0 kg), isopropyl acetate (28.0 kg), MeCN (3.8 kg) and TEA (5.4 kg). The mixture was cooled to 5-10° C., and thionyl chloride (3.2 kg) was added slowly while cooling the solution to maintain the temperature below 20° C. The mixture was stirred until no starting material was left (GC analysis). The reaction was typically complete within 30 min after addition is complete. To the mixture was added water (9 kg) and after stirring, the mixture was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a mixture of water (8 kg) and saturated NaHCO₃(4 kg) solution. To the remaining organic phase containing 36 was added MeCN (2.5 kg) and solid NaHCO₃(3.1 kg). The resulting slurry was cooled to ca. 10° C. Bleach (NaOCl solution, 6.89 wt % aqueous solution, 52.4 kg, 2 eq.) was added slowly while cooling to maintain temperature below 25° C. The mixture was aged with stirring over 90-120 min at 20-25° C., until the reaction was complete (GC analysis). After completion of the reaction, the mixture was cooled to ca. 10° C. and then quenched with aqueous Na₂SO₃solution (15.1% w/w, 21 kg) while cooling to maintain temperature below 20° C. The quenched reaction mixture was filtered through a cartridge filter to remove inorganic solids. The filtrate was allowed to settle, and phases are separated and the aqueous phase is discarded. The organic layer was washed first with a mixture of water (11 kg) and saturated NaHCO₃solution (4.7 kg), then with of saturated NaHCO₃solution (5.1 kg). DIPEA (220 mL) was added to the organic phase and the resulting solution was filtered through CELITE® (bag filter) into a clean drum. The reactor was rinsed with isopropyl acetate (7 kg) and the rinse is transferred to the drum. The organic phase was then concentrated under vacuum (25-28 inches of Hg) while maintaining reactor jacket temperature at 45-50° C. to afford 26 as an oil (˜10 L). Additional DIPEA (280 mL) was added and the vacuum distillation was continued (jacket temperature 50-55° C.) until no more distillate was collected. (batch volume ca. 7 L).

step 3—To the concentrated oil from step 2 containing 26 was added TEA (2.34 kg) and TEA-trihydrofluoride (1.63 kg). The mixture was heated to 85° C. for 2 h. The batch was sampled to monitor the progress of the reaction by GC. After the reaction was complete conc. HCl (2.35 kg) was added to the mixture and the resulting mixture heated to ca. 90° C. (small amount of distillate collected). The reaction mixture was stirred at ca. 90° C. for 30 min and then saturated aqueous BaCl₂solution (18.8 kg) was added. The resulting suspension was stirred at about 90° C. for 4 h. The resulting mixture was then azeotropically dried under a vacuum (9-10 inches of Hg) by adding slowly n-propanol (119 kg) while distilling off the azeotropic mixture (internal batch temperature ca. 85-90° C.). To the residual suspension was added toluene (33 kg) and vacuum distillation was continued to distill off residual n-propanol (and traces of water) to a minimum volume to afford 28.

step 4—To the residue from step 3 containing 28 was added MeCN (35 kg) and ca. 15 L was distilled out under atmospheric pressure. The reaction mixture was cooled to ca. 10° C. and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 40° C. The batch was aged at ca. 20° C. and the progress of the benzoylation is monitored by HPLC. After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE® pad (using a nutsche filter) to remove inorganic salts. The solid cake was washed with EtOAc (38 kg). The combined filtrate and washes were washed successively with water (38 kg), saturated NaHCO₃solution (40 kg) and saturated brine (44 kg). The organic phase was polish-filtered (through a cartridge filter) and concentrated under modest vacuum to minimum volume. IPA (77 kg) was added to the concentrate and ca. 25 L of distillate was collected under modest vacuum allowing the internal batch temperature to reach ca. 75° C. at the end of the distillation. The remaining solution was then cooled to ca. 5° C. over 5 h and optionally aged overnight. The precipitate was filtered and washed with of cold (ca. 5° C.) IPA (24 kg). The product was dried under vacuum at 60-70° C. to afford 6.63 kg (70.7% theory of 10 which was 98.2% pure by HPLC.

EXAMPLE 1 Benzoic acid 3-benzoyloxy-5-(4-benzoylamino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl ester (14)

Trifluoroethanol (4.08 kg) is added slowly to a cold solution (−15° C.) of RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at or below −10° C. After warming up to RT (ca. 20° C.), the modified RED-AL reagent mixture (30.1 kg out of the 37.6 kg prepared) is added slowly to a pre-cooled solution (−15° C.) of fluorolactone dibenzoate 10 (10 kg) in DCM (94.7 kg) while maintaining reaction temperature at or below −10° C. After reduction of the lactone (monitored by in-process HPLC), a catalytic amount of tetrabutylammonium bromide (90 g) is added to the reaction mixture. Sulfiiryl chloride (11.86 kg) is then added while maintaining reaction temperature at or below 0° C. The reaction mixture is then heated to 40° C. until formation of the chloride is complete (ca. 4 h) or warmed to RT (20-25° C.) and stirred over night (ca. 16 h). The reaction mixture is cooled to about 0° C., and water (100 L) is added cautiously while maintaining reaction temperature at or below 15° C. The reaction mixture is then stirred at RT for ca. 1 h to ensure hydrolytic decomposition of excess sulfuryl chloride and the phases are separated. The organic layer is washed with a dilute solution of citric acid (prepared by dissolving 15.5 kg of citric acid in 85 L of water) and then with dilute KOH solution (prepared by dissolving 15 kg of 50% KOH in 100 L of water). The organic phase is then concentrated and solvents are replaced with chlorobenzene (2×150 kg) via atmospheric replacement distillation. The resulting solution containing 30 is dried azeotropically.

A suspension of N-benzoyl cytosine (8.85 kg), ammonium sulfate (0.07 kg) and hexamethyldisilazane (6.6 kg) in chlorobenzene (52.4 kg) is heated to reflux (ca. 135° C.) and stirred (ca. 1 h) until the mixture becomes a clear solution. The reaction mixture is then concentrated in vacuo to obtain 32 as a syrupy liquid. The anhydrous solution of 30 in chlorobenzene (as prepared) and stannic chloride (28.2 kg) is added to this concentrate. The reaction mixture is maintained at about 70° C. until the desired coupling reaction is complete (ca. 10 h) as determined by in-process HPLC. Upon completion, the reaction mixture is cooled to RT and diluted with DCM (121 kg). This solution is added to a suspension of solid NaHCO₃(47 kg) and CELITE® (9.4 kg) in DCM (100.6 kg). The resulting slurry is cooled to 10-15° C., and water (8.4 kg) is added slowly to quench the reaction mixture. The resulting suspension is very slowly (caution: gas evolution) heated to reflux (ca. 45° C.) and maintained for about 30 min. The slurry is then cooled to ca. 15° C. and filtered. The filter cake is repeatedly reslurried in DCM (4×100 L) and filtered. The combined filtrate is concentrated under atmospheric pressure (the distillate collected in the process is used for reslurrying the filter cake) until the batch temperature rises to about 90° C. and then allowed to cool slowly to about −5° C. The resulting slurry is aged for at least 2 h at −5° C. The precipitated product is filtered and washed with IPA (30 kg+20 kg), and oven-dried in vacuo at about 70° C. to afford 8.8 kg (57.3%) of 1-(2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-β-D-ribofuranosyl)-N-4-benzoylcytosine (14, CAS Reg No. 817204-32-3) which was 99.3% pure.

EXAMPLE 2 4-Amino-1-(3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (18)

A slurry of 14 (14.7 kg) in MeOH (92.6 kg) is treated with catalytic amounts of methanolic sodium methoxide (0.275 kg). The reaction mixture is heated to ca. 50° C. and aged (ca. 1 h) until the hydrolysis is complete. The reaction mixture is quenched by addition of isobutyric acid (0.115 kg). The resulting solution is concentrated under moderate vacuum and then residual solvents are replaced with IPA (80 kg). The batch is distilled to a volume of ca. 50 L. The resulting slurry is heated to ca. 80° C. and then cooled slowly to ca. 5° C. and aged (ca. 2 h). The precipitated product is isolated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70° C. in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure.

………………………………………………………………………

https://www.google.com/patents/US8334270

EXAMPLE 4 Preparation of 2′-deoxy-2′-fluoro-2′-C-methyluridine

2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1.0 g, 1 eq) (Clark, J., et al., J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10 ml of anhydrous pyridine and concentrated to dryness in vacuo. The resulting syrup was dissolved in 20 ml of anhydrous pyridine under nitrogen and cooled to 0° C. with stirring. The brown solution was treated with benzoyl chloride (1.63 g, 3 eq) dropwise over 10 min. The ice bath was removed and stirring continued for 1.5 h whereby thin-layer chromatography (TLC) showed no remaining starting material. The mixture was quenched by addition of water (0.5 ml) and concentrated to dryness. The residue was dissolved in 50 mL of dichloromethane (DCM) and washed with saturated NaHCO₃aqueous solution and H₂O. The organic phase was dried over NaSO₄and filtered, concentrated to dryness to give N⁴,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, Yield: 91%).

N⁴,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After cooling and standing at room temperature (15° C.), most of the product precipitated and then was filtered through a sintered funnel. White precipitate was washed with water and co-evaporated with toluene to give a white solid. The filtrate was concentrated and co-evaporated with toluene to give additional product which was washed with water to give a white solid. Combining the two batches of white solid gave 1.50 g of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (Yield: 91%).

To a solution of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60%).

Example numbers 13-54 and 56-66 are prepared using similar procedures described for examples 5-8. The example number, compound identification, and NMR/MS details are shown below:

entry 25

entry 251H NMR (DMSO-d₆) δ 1.13-1.28 (m, 12H), 3.74-3.81 (m, 2H), 3.95-4.08 (m, 1H), 4.20-4.45 (m, 2H), 4.83-4.87 (m, 1H), 5.52-5.58 (m, 1H),5.84-6.15 (m, 3H), 7.17-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57(m, 1H), 11.50 (s. 1H); MS, m/e 530.2 (M + 1)+

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Synthesis of diastereomerically pure nucleotide phosphoramidates.

Ross BS, Reddy PG, Zhang HR, Rachakonda S, Sofia MJ.

J Org Chem. 2011 Oct 21;76(20):8311-9. doi: 10.1021/jo201492m. Epub 2011 Sep 26.

The HCV NS5B nucleoside and non-nucleoside inhibitors.

Membreno FE, Lawitz EJ.

Clin Liver Dis. 2011 Aug;15(3):611-26. doi: 10.1016/j.cld.2011.05.003. Review.

Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.

Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA.

J Med Chem. 2010 Oct 14;53(19):7202-18. doi: 10.1021/jm100863x.

Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977.

Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA.

J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26.

Michael J. Sofia,Donghui Bao, Wonsuk Chang, Jinfa Du, Dhanapalan Nagarathnam, Suguna Rachakonda, P. Ganapati Reddy, Bruce S. Ross, Peiyuan Wang, Hai-Ren Zhang, Shalini Bansal, Christine Espiritu, Meg Keilman, Angela M. Lam, Holly M. Micolochick Steuer, Congrong Niu, Michael J. Otto, and Phillip A. Furman; Discovery of a β-D-2^’-Deoxy-2^’-a-fluoro-2^’-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus; J. Med. Chem. 2010, 53, 7202–7218; Pharmasset, Inc.

Bruce S. Ross, P. Ganapati Reddy , Hai-Ren Zhang , Suguna Rachakonda , and Michael J. Sofia; Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates; J. Org. Chem., 2011, 76 (20), pp 8311–8319; Pharmasset, Inc.

Peiyuan Wang, Byoung-Kwon Chun, Suguna Rachakonda, Jinfa Du, Noshena Khan, Junxing Shi, Wojciech Stec, Darryl Cleary, Bruce S. Ross and Michael J. Sofia; An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase; J. Org. Chem., 2009, 74 (17), pp 6819–6824;Pharmasset, Inc.

Jeremy L. Clark, Laurent Hollecker, J. Christian Mason, Lieven J. Stuyver, Phillip M. Tharnish, Stefania Lostia, Tamara R. McBrayer, Raymond F. Schinazi, Kyoichi A. Watanabe, Michael J. Otto, Phillip A. Furman, Wojciech J. Stec, Steven E. Patterson, and Krzysztof W. Pankiewicz; Design, Synthesis, and Antiviral Activity of 2‘-Deoxy-2‘-fluoro-2‘-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication; J. Med. Chem., 2005, 48 (17), pp 5504–5508; Pharmasset, Inc

Harrison C. Patent battle lines drawn as sofosbuvir gains approval. , Nat Rev Drug Discov , Volume 13 , Issue 1 , 2013 Dec 31
Traynor K. Sofosbuvir approved for chronic hepatitis C infection. , Am J Health Syst Pharm , Volume 71 , Issue 2 , 2014 Jan 15
Benhamou Y. HCV F1/F2 patients: treat now or continue to wait. , Liver Int , Volume 34 Suppl 1 , 2014 Feb
Asselah T. HCV direct-acting antiviral agents: the best interferon-free combinations. , Liver Int , Volume 34 Suppl 1 , 2014 Feb
Marcellin P. Second-wave IFN-based triple therapy for HCV genotype 1 infection: simeprevir, faldaprevir and sofosbuvir. , Liver Int , Volume 34 Suppl 1 , 2014 Feb
Corouge M. Treatment of hepatitis C virus genotype 3-infection. , Liver Int , Volume 34 Suppl 1 , 2014 Feb
Osinusi A. IFNL4-ΔG Genotype is Associated with Slower Viral Clearance in Hepatitis C, Genotype-1 Patients Treated with Sofosbuvir and Ribavirin. , J Infect Dis , 2013 Dec 23
Alavian SM. Sofosbuvir has come out of the magic box. , Hepat Mon , Volume 13 , Issue 12 , 2013 Dec 16
Ferguson MC. Sofosbuvir with ribavirin is safe and effective in hepatitis C genotype 1 with unfavourable pretreatment characteristics. , Evid Based Med , 2013 Dec 12
Hunt S. Minimal Impact of Sofosbuvir and Ribavirin on Health Related Quality of Life in Chronic Hepatitis C (CH-C). , J Hepatol , 2013 Dec 10

SOVALDI is the brand name for sofosbuvir, a nucleotide analog inhibitor of HCV NS5B polymerase.

The IUPAC name for sofosbuvir 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)phosphorylamino)propanoate. It has a molecular formula of C₂₂H₂₉FN₃O₉P and a molecular weight of 529.45. It has the following structural formula:

SOVALDI™ (sofosbuvir) Structural Formula Illustration

Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2-7.7 at 37 oC and is slightly soluble in water.

SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

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J. Med. Chem. 2005, 48, 5504.
WO2008045419A1
CN201180017181

(WO2015139602) Sofosbuvir New Patent

(WO2015139602) 2′-SUBSTITUTED-2,2′-DEHYDRATED URIDINE OR 2′-SUBSTITUTED-2,2′-DEHYDRATED CYTIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF

ZHANG, Rongxia

A further object of the present invention to provide a method for preparing a compound of formula I.

The present invention provides a process for preparing a compound I 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-cytidine using the following formula or 2′-deoxy-2′-substituted 2′-2′-substituted nitrile or uridine 2′-deoxy-2′-substituted-2′-carbonitrile The method of cytidine compound,

2′-deoxy-2′-fluoro-2′-methyl-uridine (IIIa) is the preparation of anti-hepatitis C drugs Sofosbuvir key intermediate.

Sofosbuvir developed by Gilead Science Company, FDA on December 6, 2013 Sofosbuvir formally approved for the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is first used to treat certain types of HCV infection without the use of interferon effective and safe drugs. Clinical trials have shown, sofosbuvir can achieve very high proportion of sustained virologic response (clinical cure). More revolutionary breakthrough that, sofosbuvir without joint peginterferon α situation is still very significant effect, such as sofosbuvir ribavirin genotype 2 and genotype 3 patients with previously untreated chronic hepatitis C continued virological response rate of 100%. Sofosbuvir is a prodrug is metabolized in vivo to 2′-deoxy-2′-fluoro-2′-methyl-uridine-5′-monophosphate.

Currently reported 2′-deoxy-2′-fluoro-2′-methyl uridine synthetic methods are as follows:

In the literature (Journal of Medicinal Chemistry, 2005,48,5504) in order cytidine as a raw material, first selectively protected 3 ‘, 5′-hydroxyl group, and then oxidizing the 2′-hydroxyl to a carbonyl group, and the reaction of methyllithium get the 2’-hydroxyl compound, and then removing the protective group, use benzoyl protected 3 ‘, 5’-hydroxyl group, and then reacted with DAST fluorinated compound, followed by hydrolysis and aminolysis reaction products, such as the following Reaction Scheme. The method of route length, the need to use expensive silicon ether protecting group molecule relatively poor economy; conducting methylation time will generate a non-methyl enantiomer beta bits.

In Patent (WO2005003147, WO2006031725A2, US20040158059) using 2′-fluoro-2′-methyl – ribose derivative with N- benzoyl cytosine for docking the reaction, then after the hydrolysis, aminolysis reaction to obtain the final product, As shown in the following reaction scheme. Raw material of the process is not readily available, synthetic steps cumbersome, expensive; the reaction product obtained contained docking base for the alpha position isomers, need purification removed to form waste.

SUMMARY OF THE INVENTION

The present inventors have designed and synthesized a compound of formula I as shown, the compound may be a fluorinated or nitrile reaction of 2′-deoxy-2′-fluoro-2′-get-substituted uridine or 2 under appropriate conditions’ – 2′-deoxy-2′-fluoro-2′-deoxy-2′-substituted cytidine or nitrile uridine or 2′-substituted-2′-deoxy-2′-substituted-2′-cytidine nitrile compound; or a compound of formula I or a nitrile group by fluoro reaction, followed by deprotection reaction to give 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro–2 ‘- cytidine or 2′-substituted-2′-deoxy-2′-nitrile-substituted uridine or 2′-deoxy-2′-substituted-2′-cytidine compound nitrile group; or a compound of formula I through the opening cyclization reaction, and then through the group of fluoro or nitrile, and finally deprotection reaction to give 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-2’-substituted Cellular glycoside or 2 ‘substituted-2′-deoxy-2′-carbonitrile 2′-deoxy-uridine or 2′-substituted-2’-cytidine compound nitrile group; or a compound of formula I through a ring-opening reaction, and then 2 ‘- hydroxyl forming a leaving group, and then after a nitrile group or a fluorinated reaction, the final deprotection reaction of 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′- cytidine or 2′-fluoro-2′-substituted-2′-deoxy-2′-nitrile-substituted uridine or 2′-deoxy-2′-substituted-2’-cytidine nitrile compound.

It is therefore an object of the present invention is to provide a compound of the general formula I prepared 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-2′-substituted cytidine or 2′-substituted-2′-deoxy-2′-carbonitrile uridine or 2′-deoxy-2′-substituted-2′-carbonitrile The method of cytidine compound.

Example 1:

The 2′-C- methyl uridine (18.4g, 0.07mol), N, N’- carbonyldiimidazole (216.2g, 0.10mol), sodium bicarbonate (8.4g, 0.10mol) was suspended N, N- two dimethylformamide (50ml), the temperature was raised to 130 ℃, reaction for 4 hours, cooled and filtered to remove inorganic salts, the filtrate was added ethyl acetate (200ml), analyze the material at room temperature, suction filtered, washed with ethyl acetate cooled to, drying to give a yellow solid (19.9g, yield: 83%).

Ia: ¹ H NMR (300 MHz, CD ₃ OD): [delta] 7.80 (d, 1H, J = 7.5 Hz), 6.05 (d, 1H, J = 7.5 Hz), 5.91 (s, 1H), 4.34 (d, 1H, J = 4.8Hz), 4.07 (m, 1H), 3.56 (m, 2H), 1.63 (s, 3H); ESI-MS m / z (M + 1) 241.

Example 2:

The compound of Example 1 Ia (0.24g, 1mmol)) was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure, the residue was added acetone, beating, and filtered to give solid (0.18g, yield: 70%).

IIIa: ¹ H NMR (300 MHz, DMSO-d ₆ ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.

Example 3:

Compound Ib (0.45g, 1mmol) was dissolved in a mixture of dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2), dried over anhydrous dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the residue was subjected to column chromatography to give the product (0.36g, yield: 78%).

IIa: ¹ H NMR (400 MHz, CDCl ₃ and DMSO-d ₆ ): [delta] 7.99 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 7.34 ~ 7.61 (m, 7H ), 6.10 (brs, 1H), 5.64 (brs, 1H), 5.42 (d, J = 8.0Hz, 1H), 4.53-4.68 (m, 3H), 1.40 (d, J = 22.8Hz, 3H); ESI -MS m / z (M + 1) 469.

Example 4:

The compound of Example 3 IIa (0.47g, 1mmol) dissolved in 10% methanol solution of ammonia and stirred overnight, the solvent was removed under reduced pressure, and the residue was slurried in ethyl acetate, filtered to give a white solid (0.2g, yield : 77%).

Example 5:

Compound IVa (0.57g, 1mmol) was dissolved in dichloroethane (20ml) was added trifluoromethanesulfonic acid trimethylsilyl ester (1ml), was heated for 12 hours, cooled, and the reaction solution was concentrated dryness, added two dichloromethane (100ml) was dissolved, washed successively with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give an oil which was purified by column chromatography to give a white solid (0.3g, yield : 67%).

Ib: ¹ H NMR (300 MHz, CDCl ₃ ): δ7.96-8.10 (m, 6H), 7.41-7.65 (m, 9H), 7.32 (d, 1H, J = 5.4 Hz), 6.09 (d, 1H, J = 5.4Hz), 5.79 (m, 2H), 4.67 (m, 1H), 4.48 (m, 2H), 1.81 (s, 3H); ESI-MS m / z (M-1) 447.

Example 6:

N The compound of Example 1 Ia (1.3g, 5.4mmol) dissolved in dry, N- dimethylformamide (10ml) was added p-toluenesulfonic acid monohydrate (1.12g, 5.9mmol) and 3,4- dihydropyran (1.28ml, 14.04mmol), The reaction was stirred for 5 hours at room temperature, water was added and the methylene chloride solution was separated, the organic layer was concentrated and purified by silica gel chromatography to give the product 1.3g.

Ic: ¹ H NMR (300 MHz, CDCl ₃ ): [delta] 7.29 (m, 1H), 6.08 (m, 1H), 5.61 (m, 1H), 4.33-4.72 (m, 4H), 3.37-3.90 (m, 6H), 1.43-1.82 (m, 12H), 1.25 (s, 3H); ESI-MS m / z (M + 1) 427.

Example 7:

The solvent was removed, the residue was purified compound of Example 6 Ic (0.43g, 1mmol) was dissolved in 70% HF in pyridine was heated to 100 ~ 120 ℃, stirred for 5 hours, cooled, reduced pressure was purified through silica gel column to give a solid ( 0.18g, yield: 72%).

Example 8:

The compound of Example 6 Ic (50mg, 0.122mmol) was dissolved in methanol (1ml) was added 1N sodium hydroxide solution (0.2ml), stirred at room temperature overnight, water was added and the methylene chloride solution was separated, the organic layer was concentrated after purified by column chromatography to give the product (45mg, yield: 87%).

VA: ¹ H NMR (300 MHz, CDCl ₃ ): [delta] 7.89 (d, 1H, J = 4.5Hz), 6.01 (s, 1H), 5.95 (d, 1H, J = 4.5Hz), 5.65 (m, 2H ), 4.73 (m, 3H), 4.59 (m, 1H), 3.52-4.30 (m, 4H), 1.56-1.80 (m, 12H), 1.32 (s, 3H); ESI-MS m / z (M + 35) 461.

Example 9:

The mixture of Example 8 Compound Va (0.43g, 1mmol) was dissolved in dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2) and washed , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound IIb. Compound IIb is dissolved in methanol (10ml) was added p-toluenesulfonic acid (200mg), stirred for 6 hours at room temperature, the methanol was removed under reduced pressure, silica gel column chromatography to give the product IIIa (180mg, yield: 75%).

Example 10:

The 2′-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added N, N’- carbonyldiimidazole (0.194g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), was heated to 130 ℃, stirred for 4 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled, The solvent was removed under reduced pressure, the residue was added to acetone and filtered to obtain a solid IIIa (0.12g, yield: 60%).

Example 11:

The 2′-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate ( 55mg, 0.66mmol), was heated to 150 ℃, stirred for 6 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure The residue was added to acetone and filtered to obtain a solid IIIa (0.13g, yield: 65%).

Example 12:

Under nitrogen, the compound of Example 9 Example Va (4.26g, 10mmol) was dissolved in dry tetrahydrofuran (100ml) was added triethylamine (6g, 60mmol), cooled to -78 ℃, was added trifluoromethanesulfonic anhydride (4.23g , 15mmol), stirred for 1 hour, the reaction system was added saturated ammonium chloride solution, extracted three times with methylene chloride, organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product Vb ( 4g, yield: 72%). ESI-MS m / z (M-1) 557.

Compound Vb (4g) was dissolved in dry tetrahydrofuran, was added tetrabutylammonium fluoride (1.87g, 7.1mmol), warmed to reflux, cooled to room temperature after heating for 1 hour, water was added to the reaction system, and extracted with methylene chloride three times, the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product IIb (2.7g, yield: 88%). ESI-MS m / z (M-1) 427.

Compound IIb (2.7g) was dissolved in methanol (20ml) was added 3M hydrochloric acid (10ml), 50 ℃ stirred for 8 hours, and concentrated to give a solid, was added acetonitrile, beating, and filtered to give the product IIIa (1g, yield: 61%).

UPDATE DEC2015………….

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

Step (a):

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ8.25 & 7.94 (1: 1);

¹ HNMR (CDCl ₃ , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

¹³ C NMR (CDCl ₃ , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ3.54ppm;

¹³ C NMR (CDCl ₃ , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

¹ HNMR (CDCl ₃ , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

(4) nucleophile as NaN ₃ , phase transfer catalyst is TBAB

¹ HNMR (CDCl ₃ , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

³¹ PNMR- (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

¹ HNMR (CDCl ₃ , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(2) X is N ₃

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

//////

////////////////

amcrasto@gmail.com

Positive Review For Gilead’s Hep C Drug Sofosbuvir

October 24, 2013 7:20 am / 1 Comment on Positive Review For Gilead’s Hep C Drug Sofosbuvir

Sofosbuvir

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf –for cas no

The U.S. Food and Drug Administration (FDA) has issued a positive review for a highly anticipated hepatitis C drug from Gilead Sciences, saying the pill cures more patients in less time than currently available treatments.

The agency posted its review of Gilead’s sofosbuvir online ahead of a meeting Friday where government experts will vote on whether to recommend the drug’s approval.

http://www.dddmag.com/news/2013/10/positive-review-gileads-hep-c-drug?et_cid=3555713&et_rid=523035093&type=headline

old article cut paste

Jun. 7, 2013– Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted priority review to the company’s New Drug Application (NDA) for sofosbuvir, a once-daily oral nucleotide analogue inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The FDA grants priority review status to drug candidates that may offer major advances in treatment over existing options. Gilead filed the NDA for sofosbuvir on April 8, 2013, and FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of December 8, 2013.

The data submitted in this NDA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.

Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.^[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.^[2]

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.^[3]

Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.^[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.^[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.^[6]

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir (formerly GS-5885), and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.^[9]Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
“PSI-7977″. Gilead Sciences.
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347.doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
http://www.gilead.com/pr_1757156
AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.

Gilead Announces U.S. FDA Priority Review Designation for Sofosbuvir for the Treatment of Hepatitis C

June 11, 2013 3:18 am / Leave a comment

Sofosbuvir

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf –for cas no

Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.

About Gilead Sciences

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.^[3]

Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.^[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
“PSI-7977″. Gilead Sciences.
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347.doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
http://www.gilead.com/pr_1757156
AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.

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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO, Novel Drug Approvals for 2017, A Review Compilation (USFDA, EMA, PMDA, CDSCO).

Any errors in this compilation, email amcrasto@gmail.com, Call +919323115463

SECTION A; USFDA Approvals

6 BENRALIZUMAB

7 Benznidazole

15 Deutetrabenazine

17 DURVALUMAB

20 Enasidenib

24 GUSELKUMAB

25 Inotuzumab ozogamicin

26 LATANOPROSTENE

28 Macimorelin acetate

32 NERATINIB MALEATE

40 SARILUMAB

41 SECNIDAZOLE

43 Semaglutide