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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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GST-HG-121


GST-HG-121

mw 431.4

C23 H29 N07

Fujian Cosunter Pharmaceutical Co Ltd

Preclinical for the treatment of hepatitis B virus infection

This compound was originally claimed in WO2018214875 , and may provide the structure of GST-HG-121 , an HBsAg inhibitor which is being investigated by Fujian Cosunter for the treatment of hepatitis B virus infection; in June 2019, an IND application was planned in the US and clinical trials of the combination therapies were expected in 2020. Fujian Cosunter is also investigating GST-HG-131 , another HBsAg secretion inhibitor, although this appears to be being developed only as a part of drug combination.

WO2017013046A1

PATENT

WO2018214875

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214875&_cid=P21-KB0QYA-12917-1

Example 6

 

 

 

Step A: Maintaining at 0 degrees Celsius, lithium aluminum hydride (80.00 g, 2.11 mol, 2.77 equiv) was added to a solution of 6-1 (100.00 g, 762.36 mmol, 1.00 equiv) in tetrahydrofuran (400.00 mL). The solution was stirred at 10 degrees Celsius for 10 hours. Then, 80.00 ml of water was added to the reaction solution with stirring, and 240.00 ml of 15% aqueous sodium hydroxide solution was added, and then 80.00 ml of water was added. The resulting suspension was stirred at 10 degrees Celsius for 20 minutes, and filtered to obtain a colorless clear liquid. Concentrate under reduced pressure to obtain compound 6-2.

 

1 H NMR (400 MHz, deuterated chloroform) δ = 3.72 (dd, J = 3.9, 10.2 Hz, 1H), 3.21 (t, J = 10.2 Hz, 1H), 2.51 (dd, J = 3.9, 10.2 Hz, 1H ), 0.91(s, 9H)

 

Step B: Dissolve 6-2 (50.00 g, 426.66 mmol) and triethylamine (59.39 mL, 426.66 mmol) in dichloromethane (500.00 mL), di-tert-butyl dicarbonate (92.19 g, 422.40 mmol) Mol) was dissolved in dichloromethane (100.00 ml) and added dropwise to the previous reaction solution at 0 degrees Celsius. The reaction solution was then stirred at 25 degrees Celsius for 12 hours. The reaction solution was washed with saturated brine (600.00 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and spin-dried, and then recrystallized with methyl tert-butyl ether/petroleum ether (50.00/100.00) to obtain compound 6-3 .
1 H NMR (400 MHz, deuterated chloroform) δ 4.64 (br s, 1H), 3.80-3.92 (m, 1H), 3.51 (br d, J = 7.09 Hz, 2H), 2.17 (br s, 1H), 1.48 (s, 9H), 0.96 (s, 9H).

 

Step C: Dissolve thionyl chloride (100.98 ml, 1.39 mmol) in acetonitrile (707.50 ml), 6-3 (121.00 g, 556.82 mmol) in acetonitrile (282.90 ml), and drop at minus 40 degrees Celsius After adding to the last reaction solution, pyridine (224.72 mL, 2.78 mol) was added to the reaction solution in one portion. The ice bath was removed, and the reaction solution was stirred at 5-10 degrees Celsius for 1 hour. After spin-drying the solvent under reduced pressure, ethyl acetate (800.00 ml) was added, and a solid precipitated, which was filtered, and the filtrate was concentrated under reduced pressure. Step 2: The obtained oil and water and ruthenium trichloride (12.55 g, 55.68 mmol) were dissolved in acetonitrile (153.80 ml), and sodium periodate (142.92 g, 668.19 mmol) was suspended in water (153.80 ml ), slowly add to the above reaction solution, and the final reaction mixture is stirred at 5-10 degrees Celsius for 0.15 hours. The reaction mixture was filtered to obtain a filtrate, which was extracted with ethyl acetate (800.00 mL×2). The organic phase was washed with saturated brine (800.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Column purification (silica, petroleum ether/ethyl acetate = 50/1 to 20/1) gave compound 6-4.

 

1 H NMR (400 MHz, deuterated chloroform) δ 4.49-4.55 (m, 1H), 4.40-4.44 (m, 1H), 4.10 (d, J = 6.15 Hz, 1H), 1.49 (s, 9H), 0.94 (s,9H).

[0230]
Step D: Dissolve 6-5 (100.00 g, 657.26 mmol) in acetonitrile (1300.00 mL), add potassium carbonate (227.10 g, 1.64 mol) and 1-bromo-3-methoxypropane (110.63 g, 722.99 Millimoles). The reaction solution was stirred at 85 degrees Celsius for 6 hours. The reaction solution was extracted with ethyl acetate 600.00 ml (200.00 ml×3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain compound 6-6.

[0231]
1 H NMR (400 MHz, deuterated chloroform) δ 9.76-9.94 (m, 1H), 7.42-7.48 (m, 2H), 6.98 (d, J=8.03 Hz, 1H), 4.18 (t, J=6.53 Hz , 2H), 3.95 (s, 3H), 3.57 (t, J = 6.09 Hz, 2H), 3.33-3.39 (m, 3H), 2.13 (quin, J = 6.34 Hz, 2H).

[0232]
Step E: Dissolve 6-6 (70.00 g, 312.15 mmol) in methylene chloride, add m-chloroperoxybenzoic acid (94.27 g, 437.01 mmol), and the reaction was stirred at 50 degrees Celsius for 2 hours. After cooling the reaction solution, it was filtered, the filtrate was extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution 2000.00 ml (400.00 ml × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A brown oil was obtained. After dissolving with as little methanol as possible, a solution of 2 mol per liter of potassium hydroxide (350.00 ml) was slowly added (exothermic). The dark colored reaction solution was stirred at room temperature for 20 minutes, and the reaction solution was adjusted to pH 5 with 37% hydrochloric acid. It was extracted with ethyl acetate 400.00 ml (200.00 ml×2), and the organic phase was washed with saturated brine 200.00 ml (100.00 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 6-7.

 

1 H NMR (400 MHz, deuterated chloroform) δ 6.75 (d, J = 8.53 Hz, 1H), 6.49 (d, J = 2.89 Hz, 1H), 6.36 (dd, J = 2.82, 8.60 Hz, 1H), 4.07 (t, J = 6.40 Hz, 2H), 3.82 (s, 3H), 3.60 (t, J = 6.15 Hz, 2H), 3.38 (s, 3H), 2.06-2.14 (m, 2H).

 

Step F: Dissolve 6-7 (33.00 g, 155.48 mmol) in tetrahydrofuran (330.00 mL), add paraformaldehyde (42.02 g, 466.45 mmol), magnesium chloride (29.61 g, 310.97 mmol), triethylamine (47.20 g, 466.45 mmol, 64.92 mL). The reaction solution was stirred at 80 degrees Celsius for 8 hours. After the reaction was completed, it was quenched with 2 molar hydrochloric acid solution (200.00 ml) at 25°C, then extracted with ethyl acetate 600.00 ml (200.00 ml×3), and the organic phase was washed with saturated brine 400.00 ml (200.00 ml×2). Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The residue was washed with ethanol (30.00 ml) and filtered to obtain a filter cake. Thus, compound 6-8 is obtained.

 

1 H NMR (400 MHz, deuterated chloroform) δ 11.29 (s, 1H), 9.55-9.67 (m, 1H), 6.83 (s, 1H), 6.42 (s, 1H), 4.10 (t, J=6.48 Hz , 2H), 3.79 (s, 3H), 3.49 (t, J = 6.05 Hz, 2H), 3.28 (s, 3H), 2.06 (quin, J = 6.27 Hz, 2H)

 

Step G: Dissolve 6-8 (8.70 g, 36.21 mmol) in N,N-dimethylformamide (80.00 mL), add potassium carbonate (10.01 g, 72.42 mmol) and 6-4 (11.13 g) , 39.83 mmol), the reaction solution was stirred at 50 degrees Celsius for 2 hours. The reaction solution was quenched with 1.00 mol/L aqueous hydrochloric acid solution (200.00 mL), and extracted with ethyl acetate (150.00 mL×2). The combined organic phase was washed with water (150.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-9.
1 H NMR (400 MHz, deuterated chloroform) δ 10.31 (s, 1H), 7.34 (s, 1H), 6.57 (s, 1H), 4.18-4.26 (m, 3H), 4.07 (dd, J=5.33, 9.60Hz, 1H), 3.88(s, 4H), 3.60(t, J=5.96Hz, 2H), 3.39(s, 3H), 2.17(quin, J=6.21Hz, 2H), 1.47(s, 9H) , 1.06 (s, 9H).

 

Step H: Dissolve 6-9 (15.80 g, 35.95 mmol) in dichloromethane (150.00 mL) and add trifluoroacetic acid (43.91 mL, 593.12 mmol). The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-10.
1 H NMR (400 MHz, deuterated chloroform) δ 8.40 (s, 1H), 6.80 (s, 1H), 6.51 (s, 1H), 4.30 (br d, J = 12.35 Hz, 1H), 4.04-4.11 ( m, 3H), 3.79 (s, 3H), 3.49 (t, J = 5.99 Hz, 2H), 3.36 (br d, J = 2.93 Hz, 1H), 3.28 (s, 3H), 2.06 (quin, J = 6.24Hz, 2H), 1.02(s, 9H).

 

Step I: Dissolve 6-10 (5.00 g, 15.56 mmol) in toluene (20.00 mL) and add 6-11 (8.04 g, 31.11 mmol). The reaction solution was stirred at 120 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was quenched with water (100.00 mL), extracted with ethyl acetate (100.00 mL×2), the combined organic phases were washed with water (80.00 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column. Then purified by high-performance liquid chromatography (column: Phenomenex luna C18 250*50 mm*10 microns; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-70%, 25 minutes) Compound 6-12 is obtained.

 

1 H NMR (400 MHz, deuterated chloroform) δ 7.95 (s, 1H), 6.59 (s, 1H), 6.40 (s, 1H), 5.15-5.23 (m, 1H), 4.35-4.41 (m, 2H) , 4.08-4.19 (m, 2H), 3.94-4.00 (m, 2H), 3.72 (s, 3H), 3.61-3.67 (m, 1H), 3.46 (dt, J=1.96, 5.99Hz, 2H), 3.27 (s, 3H), 3.01-3.08 (m, 1H), 2.85-2.94 (m, 1H), 1.97-2.01 (m, 2H), 1.18-1.22 (m, 3H), 1.04 (s, 9H).

 

Step J: Dissolve 6-12 (875.00 mg, 1.90 mmol) in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and add tetrachlorobenzoquinone (1.40 g, 5.69 mmol). The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase. Add 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) to the organic phase, stir at 10-15 degrees Celsius for 20 minutes, and separate the liquid. Wash the organic phase with 2 mol/L aqueous hydrochloric acid solution (60.00 mL×2), separate the liquid, and separate the water phase A 2 mol/L aqueous sodium hydroxide solution (200.00 ml) and dichloromethane (200.00 ml) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-13.

[0243]
1 H NMR (400 MHz, deuterated chloroform) δ 7.98-8.78 (m, 1H), 6.86 (s, 1H), 6.43-6.73 (m, 2H), 4.41-4.48 (m, 1H), 4.28-4.38 ( m, 2H), 4.03-4.11 (m, 2H), 3.93 (br s, 1H), 3.80 (s, 3H), 3.47-3.52 (m, 3H), 3.29 (s, 3H), 2.06 (quin, J = 6.24 Hz, 2H), 1.33 (t, J = 7.15 Hz, 2H), 0.70-1.25 (m, 10H).

[0244]
Step K: Dissolve 6-13 (600.00 mg, 1.31 mmol) in methanol (6.00 mL), and add 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 equiv). The reaction solution was stirred at 15 degrees Celsius for 0.25 hours. The reaction solution was adjusted to pH=3-4 with a 1.00 mol/L hydrochloric acid aqueous solution, and then extracted with dichloromethane (50.00 mL×3). The organic phases were combined, washed with saturated brine (50.00 mL), and dried over anhydrous sodium sulfate. , Filtered and concentrated under reduced pressure to obtain Example 6.

[0245]
ee value (enantiomeric excess): 100%.

[0246]
SFC (Supercritical Fluid Chromatography) method: Column: Chiralcel OD-3 100 mm x 4.6 mm ID, 3 μm mobile phase: methanol (0.05% diethylamine) in carbon dioxide from 5% to 40% Flow rate: 3 ml per minute Wavelength: 220 nm.

[0247]
1 H NMR (400 MHz, deuterated chloroform) δ 15.72 (br s, 1H), 8.32-8.93 (m, 1H), 6.60-6.93 (m, 2H), 6.51 (br s, 1H), 4.38-4.63 ( m, 2H), 4.11 (br dd, J = 4.52, 12.23 Hz, 3H), 3.79-3.87 (m, 3H), 3.46-3.54 (m, 2H), 3.29 (s, 3H), 2.07 (quin, J = 6.24 Hz, 2H), 0.77-1.21 (m, 9H).

PATENT

WO-2020103924

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020103924&tab=FULLTEXT&_cid=P21-KB0QP8-09832-1

Novel crystalline forms of 11-oxo-7,11-dihydro-6H-benzo[f]pyrido[1,2-d][1,4]azepine, a hepatitis B surface antigen and HBV replication inhibitor, useful for treating HBV infection.

Hepatitis B virus, or hepatitis B for short, is a disease caused by Hepatitis B Virus (HBV) infection of the body. Hepatitis B virus is a hepatotropic virus, which mainly exists in liver cells and damages liver cells, causing inflammation, necrosis, and fibrosis of liver cells. There are two types of viral hepatitis, acute and chronic. Acute hepatitis B in most adults can heal itself through its own immune mechanism. But chronic hepatitis B (CHB) has become a great challenge for global health care, and it is also the main cause of chronic liver disease, cirrhosis and liver cancer (HCC). It is estimated that 2 billion people worldwide are infected with chronic hepatitis B virus, and more than 350 million people have developed into hepatitis B. Nearly 600,000 people die each year from complications of chronic hepatitis B. my country is a high incidence area of ​​hepatitis B. There are many patients with accumulated hepatitis B, and the harm is serious. According to data, there are about 93 million people with hepatitis B virus infection in China, and about 20 million of them are diagnosed with chronic hepatitis B, of which 10%-20% can evolve into cirrhosis and 1%-5% can develop into Liver cancer.

 

The key to the functional cure of hepatitis B is to remove HBsAg (hepatitis B virus surface antigen) and produce surface antibodies. HBsAg quantification is a very important biological indicator. In patients with chronic infection, few HBsAg reductions and seroconversion can be observed, which is the end point of current treatment.

 

The surface antigen protein of hepatitis B virus (HBV) plays a very important role in the process of HBV invading liver cells, and is of great significance for the prevention and treatment of HBV infection. Surface antigen proteins include large (L), medium (M) and small (S) surface antigen proteins, sharing a common C-terminal S region. They are expressed from an open reading frame, and their different lengths are determined by the three AUG start codons in the reading frame. These three surface antigen proteins include pre-S1/pre-S2/S, pre-S2/S and S domains. The HBV surface antigen protein is integrated into the endoplasmic reticulum (ER) membrane and is initiated by the N-terminal signal sequence. They not only constitute the basic structure of the virion, but also form spherical and filamentous subviral particles (SVPs, HBsAg), aggregated in the ER, host ER and pre-Golgi apparatus, SVP contains most S surface antigen proteins. The L protein is crucial in the interaction between viral morphogenesis and nucleocapsid, but it is not necessary for the formation of SVP. Due to their lack of nucleocapsid, the SVPs are non-infectious. SVPs are greatly involved in disease progression, especially the immune response to hepatitis B virus. In the blood of infected persons, the amount of SVPs is at least 10,000 times the number of viruses, trapping the immune system and weakening the body’s immune response to hepatitis B virus. HBsAg can also inhibit human innate immunity, can inhibit the production of cytokines induced by polysaccharide (LPS) and IL-2, inhibit the DC function of dendritic cells, and LPS interfere with ERK-1/2 and c-Jun N-terminal interfering kinase-1 2 Inducing activity in monocytes. It is worth noting that the disease progression of cirrhosis and hepatocellular carcinoma is also largely related to the persistent secretion of HBsAg. These findings indicate that HBsAg plays an important role in the development of chronic hepatitis.

 

The currently approved anti-HBV drugs are mainly immunomodulators (interferon-α and pegylated interferon-α-2α) and antiviral drugs (lamivudine, adefovir dipivoxil, entecavir, and Bifudine, Tenofovir, Kravudine, etc.). Among them, antiviral drugs belong to the class of nucleotide drugs, and their mechanism of action is to inhibit the synthesis of HBV DNA, and cannot directly reduce the level of HBsAg. As with prolonged treatment, nucleotide drugs show HBsAg clearance rate similar to natural observations.

 

Existing therapies in the clinic are not effective in reducing HBsAg. Therefore, the development of small molecule oral inhibitors that can effectively reduce HBsAg is urgently needed in clinical medicine.

 

Roche has developed a surface antigen inhibitor called RG7834 for the treatment of hepatitis B, and reported the drug efficacy of the compound in the model of woodchuck anti-hepatitis B: when using RG7834 as a single drug, it can reduce the surface of 2.57 Logs Antigen, reduced HBV-DNA by 1.7 Logs. The compound has good activity, but in the process of molecular synthesis, the isomers need to be resolved, which reduces the yield and increases the cost.

 

WO2017013046A1 discloses a series of 2-oxo-7,8-dihydro-6H-pyrido[2,1,a][2]benzodiazepine-3-for the treatment or prevention of hepatitis B virus infection Carboxylic acid derivatives. The IC 50 of Example 3, the highest activity of this series of fused ring compounds , is 419 nM, and there is much room for improvement in activity. The chiral centers contained in this series of compounds are difficult to synthesize asymmetrically. Generally, the 7-membered carbocyclic ring has poor water solubility and is prone to oxidative metabolism.
Example 1 Preparation of compound of formula (I)

 

[0060]

 

Step A: Maintaining at 0 degrees Celsius, to a solution of compound 1 (100.00 g, 762.36 mmol, 1.00 equiv) in tetrahydrofuran (400.00 mL) was added lithium aluminum hydride (80.00 g, 2.11 mol, 2.77 equiv). The solution was stirred at 10 degrees Celsius for 10 hours. Then, 80.00 ml of water was added to the reaction solution with stirring, and 240.00 ml of 15% aqueous sodium hydroxide solution was added, and then 80.00 ml of water was added. The resulting suspension was stirred at 10 degrees Celsius for 20 minutes, and filtered to obtain a colorless clear liquid. Concentrate under reduced pressure to obtain compound 2.
Step B: Dissolve compound 2 (50.00 g, 426.66 mmol) and triethylamine (59.39 mL, 426.66 mmol) in dichloromethane (500.00 mL), di-tert-butyl dicarbonate (92.19 g, 422.40 mmol) ) Was dissolved in dichloromethane (100.00 ml) and added dropwise to the previous reaction solution at 0 degrees Celsius. The reaction solution was then stirred at 25 degrees Celsius for 12 hours. The reaction solution was washed with saturated brine (600.00 ml), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and spin-dried, and then recrystallized from methyl tert-butyl ether/petroleum ether (50.00/100.00) to obtain compound 3.
Step C: Dissolve thionyl chloride (100.98 ml, 1.39 mmol) in acetonitrile (707.50 ml), compound 3 (121.00 g, 556.82 mmol) in acetonitrile (282.90 ml), and add dropwise at minus 40 degrees Celsius To the last reaction solution, after the dropwise addition, pyridine (224.72 mL, 2.78 mol) was added to the reaction solution in one portion. The ice bath was removed, and the reaction solution was stirred at 5-10 degrees Celsius for 1 hour. After spin-drying the solvent under reduced pressure, ethyl acetate (800.00 ml) was added, and a solid precipitated, which was filtered, and the filtrate was concentrated under reduced pressure. Step 2: The obtained oil and water and ruthenium trichloride (12.55 g, 55.68 mmol) were dissolved in acetonitrile (153.80 ml), and sodium periodate (142.92 g, 668.19 mmol) was suspended in water (153.80 ml ), slowly add to the above reaction solution, and the final reaction mixture is stirred at 5-10 degrees Celsius for 0.15 hours. The reaction mixture was filtered to obtain a filtrate, which was extracted with ethyl acetate (800.00 mL×2). The organic phase was washed with saturated brine (800.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Column purification (silica, petroleum ether/ethyl acetate = 50/1 to 20/1) gave compound 4.
Step D: Dissolve compound 5 (100.00 g, 657.26 mmol) in acetonitrile (1300.00 mL), add potassium carbonate (227.10 g, 1.64 mol) and 1-bromo-3-methoxypropane (110.63 g, 722.99 mmol) Mole). The reaction solution was stirred at 85 degrees Celsius for 6 hours. The reaction solution was extracted with ethyl acetate 600.00 ml (200.00 ml×3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain compound 6.

 

Step E: Compound 6 (70.00 g, 312.15 mmol) was dissolved in methylene chloride, m-chloroperoxybenzoic acid (94.27 g, 437.01 mmol) was added, and the reaction was stirred at 50 degrees Celsius for 2 hours. After cooling the reaction solution, it was filtered, the filtrate was extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution 2000.00 ml (400.00 ml × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A brown oil was obtained. After dissolving with as little methanol as possible, a solution of 2 mol per liter of potassium hydroxide (350.00 ml) was slowly added (exothermic). The dark colored reaction solution was stirred at room temperature for 20 minutes, and the reaction solution was adjusted to pH 5 with 37% hydrochloric acid. It was extracted with ethyl acetate 400.00 ml (200.00 ml×2), the organic phase was washed with saturated brine 200.00 ml (100.00 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7.

[0066]
Step F: Compound 7 (33.00 g, 155.48 mmol) was dissolved in tetrahydrofuran (330.00 mL), paraformaldehyde (42.02 g, 466.45 mmol), magnesium chloride (29.61 g, 310.97 mmol), triethylamine ( 47.20 g, 466.45 mmol, 64.92 mL). The reaction solution was stirred at 80 degrees Celsius for 8 hours. After the reaction was completed, it was quenched with 2 molar hydrochloric acid solution (200.00 ml) at 25°C, then extracted with ethyl acetate 600.00 ml (200.00 ml×3), and the organic phase was washed with saturated brine 400.00 ml (200.00 ml×2). Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The residue was washed with ethanol (30.00 ml) and filtered to obtain a filter cake. Thus, compound 8 is obtained.

 

Step G: Dissolve compound 8 (8.70 g, 36.21 mmol) in N,N-dimethylformamide (80.00 mL), add potassium carbonate (10.01 g, 72.42 mmol) and compound 4 (11.13 g, 39.83 Mmol), the reaction solution was stirred at 50 degrees Celsius for 2 hours. The reaction solution was quenched with 1.00 mol/L aqueous hydrochloric acid solution (200.00 mL), and extracted with ethyl acetate (150.00 mL×2). The combined organic phase was washed with water (150.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 9.

Step H: Compound 9 (15.80 g, 35.95 mmol) was dissolved in dichloromethane (150.00 mL), and trifluoroacetic acid (43.91 mL, 593.12 mmol) was added. The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10.

Step I: Compound 10 (5.00 g, 15.56 mmol) was dissolved in toluene (20.00 mL), and compound 11 (8.04 g, 31.11 mmol) was added. The reaction solution was stirred at 120°C for 12 hours under nitrogen protection. The reaction solution was quenched with water (100.00 mL), extracted with ethyl acetate (100.00 mL×2), the combined organic phases were washed with water (80.00 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column. Purified by high-performance liquid chromatography (column: Phenomenex luna C18 250×50 mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-70%, 25 minutes) Compound 12 is obtained.

Step J: Compound 12 (875.00 mg, 1.90 mmol) was dissolved in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and tetrachlorobenzoquinone (1.40 g, 5.69 mmol) was added. The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase. Add 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) to the organic phase, stir at 10-15 degrees Celsius for 20 minutes, and separate the liquid. Wash the organic phase with 2 mol/L aqueous hydrochloric acid solution (60.00 mL×2), separate the liquid, and separate the water phase A 2 mol/L aqueous sodium hydroxide solution (200.00 ml) and dichloromethane (200.00 ml) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 13.

Step K: Compound 13 (600.00 mg, 1.31 mmol) was dissolved in methanol (6.00 mL), and 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 equiv) was added. The reaction solution was stirred at 15 degrees Celsius for 0.25 hours. The reaction solution was adjusted to pH=3-4 with a 1.00 mol/L hydrochloric acid aqueous solution, and then extracted with dichloromethane (50.00 mL×3). The organic phases were combined, washed with saturated brine (50.00 mL), and dried over anhydrous sodium sulfate , Filtered and concentrated under reduced pressure to obtain the compound of formula (I). ee value (enantiomeric excess): 100%.

SFC (supercritical fluid chromatography) method:
Column: Chiralcel OD-3 100 mm x 4.6 mm size, 3 microns.
Mobile phase: methanol (0.05% diethylamine) in carbon dioxide, from 5% to 40%.
Flow rate: 3 ml per minute.
Wavelength: 220 nm.

////////////GST-HG-121, Fujian Cosunter,  Preclinical ,  hepatitis B,  virus infection

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)C

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)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

Hepatitis B


Hepatitis B


Key facts

  • Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease.
  • The virus is transmitted through contact with the blood or other body fluids of an infected person.
  • About 600 000 people die every year due to the consequences of hepatitis B.
  • Hepatitis B is an important occupational hazard for health workers.
  • Hepatitis B is preventable with the currently available safe and effective vaccine.


Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It is a major global health problem. It can cause chronic liver disease and chronic infection and puts people at high risk of death from cirrhosis of the liver and liver cancer.

More than 240 million people have chronic (long-term) liver infections. About 600 000 people die every year due to the acute or chronic consequences of hepatitis B.

A vaccine against hepatitis B has been available since 1982. Hepatitis B vaccine is 95% effective in preventing infection and its chronic consequences, and was the first vaccine against a major human cancer.

Geographical distribution

Hepatitis B virus can cause an acute illness with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain. Hepatitis B prevalence is highest in sub-Saharan Africa and East Asia. Most people in these regions become infected with the hepatitis B virus during childhood and between 5–10% of the adult population is chronically infected.

High rates of chronic infections are also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and the Indian subcontinent, an estimated 2–5% of the general population is chronically infected. Less than 1% of the population in western Europe and North America is chronically infected.

Transmission

In highly endemic areas, HBV is most commonly spread from mother to child at birth, or from person to person in early childhood.

Perinatal or early childhood transmission may also account for more than one third of chronic infections in areas of low endemicity, although in those settings, sexual transmission and the use of contaminated needles, especially among injecting drug users, are the major routes of infection.

The hepatitis B virus can survive outside the body for at least seven days. During this time, the virus can still cause infection if it enters the body of a person who is not protected by the vaccine.

The hepatitis B virus is not spread by contaminated food or water, and cannot be spread casually in the workplace.

The incubation period of the hepatitis B virus is 75 days on average, but can vary from 30 to 180 days. The virus may be detected 30 to 60 days after infection and persists for variable periods of time.

Symptoms

Most people do not experience any symptoms during the acute infection phase. However, some people have acute illness with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain.

In some people, the hepatitis B virus can also cause a chronic liver infection that can later develop into cirrhosis of the liver or liver cancer.

More than 90% of healthy adults who are infected with the hepatitis B virus will recover and be completely rid of the virus within six months.

Who is at risk for chronic disease?

The likelihood that infection with the hepatitis B virus becomes chronic depends upon the age at which a person becomes infected. Children less than 6 years of age who become infected with the hepatitis B virus are the most likely to develop chronic infections:

  • 80–90% of infants infected during the first year of life develop chronic infections;
  • 30–50%% of children infected before the age of 6 years develop chronic infections.

In adults:

  • <5% of otherwise healthy adults who are infected will develop chronic infection;
  • 15–25% of adults who become chronically infected during childhood die from hepatitis B-related liver cancer or cirrhosis.

Diagnosis

It is not possible, on clinical grounds, to differentiate hepatitis B from hepatitis caused by other viral agents and, hence, laboratory confirmation of the diagnosis is essential. A number of blood tests are available to diagnose and monitor people with hepatitis B. They can be used to distinguish acute and chronic infections.

Laboratory diagnosis of hepatitis B infection centres on the detection of the hepatitis B surface antigen HBsAg. WHO recommends that all blood donations are tested for this marker to avoid transmission to recipients.

  • Acute HBV infection is characterized by the presence of HBsAg and immunoglobulin M (IgM) antibody to the core antigen, HBcAg. During the initial phase of infection, patients are also seropositive for HBeAg.
  • Chronic infection is characterized by the persistence (>6 months) of HBsAg (with or without concurrent HBeAg). Persistence of HBsAg is the principal marker of risk for developing chronic liver disease and hepatocellullar carcinoma (HCC) later in life.
  • The presence of HBeAg indicates that the blood and body fluids of the infected individual are highly contagious

Treatment

There is no specific treatment for acute hepatitis B. Care is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids that are lost from vomiting and diarrhoea.

Some people with chronic hepatitis B can be treated with drugs, including interferon and antiviral agents. Treatment can slow the progression of cirrhosis, reduce incidence of HCC and improve long term survival. Treatment, however, is not readily accessible in many resource-constrained settings.

Liver cancer is almost always fatal and often develops in people at an age when they are most productive and have family responsibilities. In developing countries, most people with liver cancer die within months of diagnosis. In high-income countries, surgery and chemotherapy can prolong life for up to a few years.

People with cirrhosis are sometimes given liver transplants, with varying success.

Prevention

The hepatitis B vaccine is the mainstay of hepatitis B prevention. WHO recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.

The birth dose should be followed by 2 or 3 doses to complete the primary series. In most cases, 1 of the following 2 options is considered appropriate:

  • a 3-dose schedule of hepatitis B vaccine, with the first dose (monovalent) being given at birth and the second and third (monovalent or combined vaccine) given at the same time as the first and third doses of DTP vaccine; or
  • 4 doses, where a monovalent birth dose is followed by 3 monovalent or combined vaccine doses, usually given with other routine infant vaccines.

The complete vaccine series induces protective antibody levels in more than 95% of infants, children and young adults. Protection lasts at least 20 years and is possibly lifelong.

All children and adolescents younger than 18 years old and not previously vaccinated should receive the vaccine if they live in countries where there is low or intermediate endemicity. In those settings it is possible that more people in high risk groups may acquire the infection and they should also be vaccinated. They include:

  • people who frequently require blood or blood products, dialysis patients, recipients of solid organ transplantations;
  • people interned in prisons;
  • injecting drug users;
  • household and sexual contacts of people with chronic HBV infection;
  • people with multiple sexual partners, as well as health-care workers and others who may be exposed to blood and blood products through their work; and
  • travellers who have not completed their hepatitis B vaccination series should be offered the vaccine before leaving for endemic areas.

The vaccine has an excellent record of safety and effectiveness. Since 1982, over one billion doses of hepatitis B vaccine have been used worldwide. In many countries, where 8–15% of children used to become chronically infected with the hepatitis B virus, vaccination has reduced the rate of chronic infection to less than 1% among immunized children.

As of July 2011, 179 Member States vaccinate infants against hepatitis B as part of their vaccination schedules. This is a major increase compared with 31 countries in 1992, the year that the World Health Assembly passed a resolution to recommend global vaccination against hepatitis B. Furthermore, as of July 2011, 93 Member States have introduced the hepatitis B birth dose.

In addition, implementation of blood safety strategies, including quality-assured screening of all donated blood and blood components used for transfusion can prevent transmission of HBV. Safe injection – unnecessary as well as unsafe injections – practices can protect against HBV transmission. Furthermore, safer sex practices, including minimizing the number of partners and using barrier protective measures (condoms), protect against transmission.

WHO response

WHO is working in the following areas to prevent and control viral hepatitis:

  • raising awareness, promoting partnerships and mobilizing resources;
  • formulating evidence-based policy and data for action;
  • preventing of transmission; and
  • executing screening, care and treatment.

WHO also organizes World Hepatitis Day on July 28 every year to increase awareness and understanding of viral hepatitis.

 

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