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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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HS 10340


HS-10340

CAS 2156639-66-4

MF C26 H31 N7 O5
MW 521.57
1,8-Naphthyridine-1(2H)-carboxamide, N-[5-cyano-4-[[(1R)-2-methoxy-1-methylethyl]amino]-2-pyridinyl]-7-formyl-3,4-dihydro-6-[(tetrahydro-2-oxo-1,3-oxazepin-3(2H)-yl)methyl]-
(R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl)-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

CAS 2307670-65-9

Jiangsu Hansoh Pharmaceutical Group Co Ltd

Being investigated by Jiangsu Hansoh, Shanghai Hansoh Biomedical and Changzhou Hengbang Pharmaceutical ; in June 2018, the product was being developed as a class 1 chemical drug in China.

Useful for treating liver cancer, gastric cancer and prostate cancer.

Use for treating cancers, liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma and rhabdomyosarcoma

The fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
FGFR4, a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4’s own cells. The phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis. Recently, more and more studies have shown that about one-third of liver cancer patients with continuous activation of FGF19/FGFR4 signaling pathway are the main carcinogenic factors leading to liver cancer in this part of patients. At the same time, FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
The incidence of liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer. The onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market. It can only prolong the overall survival period of about 3 months, and the treatment effect is not satisfactory. Therefore, it is urgent to develop a liver cancer system treatment drug targeting new molecules. FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia. Such as target related side effects. Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
SYN

PATENT

WO2017198149

where it is claimed to be an FGFR-4 inhibitor for treating liver and prostate cancers, assigned to Jiangsu Hansoh Pharmaceutical Group Co Ltd and Shanghai Hansoh Biomedical Co Ltd .

PATENT

WO2019085860

Compound (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-) 1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (shown as Formula I). The compound of formula (I) is disclosed in Hausen Patent PCT/CN2017/084564, the compound of formula I is a fibroblast growth factor receptor inhibitor, and the fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor. The body includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.

[0003]
Example 1: Preparation of a compound of formula (I)

[0048]
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol

[0049]

[0050]
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .

[0051]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);

[0052]
MS m/z (ESI): 310.2 [M+H] + .

[0053]
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone

[0054]

[0055]
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).

[0056]
MS m/z (ESI): 336.2 [M+H] + .

[0057]
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate

[0058]

[0059]
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .

[0060]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);

[0061]
MS m/z (ESI): 456.2 [M+H] + .

[0062]
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis

[0063]

[0064]
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).

[0065]
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);

[0066]
MS m/z (ESI): 568.3 [M+H] + .

[0067]
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

[0068]

[0069]
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).

[0070]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);

[0071]
MS m/z (ESI): 522.2 [M+H] + .

PATENT

WO-2019085927

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019085927&tab=FULLTEXT

Novel crystalline salt (such as hydrochloride, sulfate, methane sulfonate, mesylate, besylate, ethanesulfonate, oxalate, maleate, p-toluenesulfonate) forms of FGFR4 inhibitor, particularly N-[5-cyano-4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-2-pyridyl]-7-formyl-6-[(2-oxo-1,3-oxazepan-3-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (designated as Forms I- IX), compositions comprising them and their use as an FGFR4 inhibitor for the treatment of cancer such as liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and glioma or rhabdomyosarcoma are claimed.

Example 1: Preparation of a compound of formula (I)
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);
MS m/z (ESI): 310.2 [M+H] + .
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).
MS m/z (ESI): 336.2 [M+H] + .
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);
MS m/z (ESI): 456.2 [M+H] + .
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);
MS m/z (ESI): 568.3 [M+H] + .
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);
MS m/z (ESI): 522.2 [M+H] + .

///////////HS-10340 , HS 10340 , HS10340, CANCER, Jiangsu Hansoh, Shanghai Hansoh Biomedical,  Changzhou Hengbang, CHINA,  liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma,  rhabdomyosarcoma

C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

CCS(=O)(=O)O.C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

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CS 3001


str1

CS-3001

BB 7, VX 033

CAS 2159116-56-8
Propanoic acid, 2-[[5-bromo-4-(3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydrobenzo[c]thien-1-yl)-4H-1,2,4-triazol-3-yl]thio]-2-methyl-
Molecular Weight, 478.37

C17 H18 Br F2 N3 O2 S2

CStone Pharmaceuticals Co Ltd, JUNE 2018 IND FILED CHINA

URAT1 inhibitor – useful for treating hyperuricemia and gout.

The compound was originally claimed in WO2017202291 , covering thiophene derivative URAT1 inhibitors, useful for treating hyperuricemia and gouty arthritis, assigned to Medshine Discovery Inc , but naming the inventors.and has been reported in some instances to be a URAT1 modulator. In June 2018, an IND application was filed in

Uric acid is a product of the metabolism of terpenoids in animals. For humans, due to the lack of uric acid enzymes that continue to oxidatively degrade uric acid, uric acid is excreted in the human body as the final product of sputum metabolism through the intestines and kidneys. Renal excretion is the main pathway for uric acid excretion in humans. The upper limit of the normal range of uric acid concentration in the human body is: male 400 μmol/L (6.8 mg/dL) and female 360 μmol/L (6 mg/dL). Abnormal uric acid levels in the human body are often due to an increase in uric acid production or a decrease in uric acid excretion. Conditions associated with abnormal levels of uric acid include hyperuricemia, gout, and the like.
Hyperuricemia refers to a disorder in which the metabolism of substances in the human body is disordered, resulting in an increase or decrease in the synthesis of uric acid in the human body, and an abnormally high level of uric acid in the blood. Gouty arthritis refers to the fact that when uric acid is more than 7 mg/dL in human blood, uric acid is deposited as a monosodium salt in the joints, cartilage and kidneys, causing excessive reaction (sensitivity) to the body’s immune system and causing painful inflammation. The general site of attack is the big toe joint, ankle joint, knee joint and so on. Red, swollen, hot, and severe pain in the site of acute gout attacks, usually in the midnight episode, can make people wake up from sleep. In the early stages of gout, the attack is more common in the joints of the lower extremities. Hyperuricemia is the pathological basis of gouty arthritis. The use of drugs to lower blood uric acid concentration is one of the commonly used methods to prevent gouty arthritis.
In Europe and the United States, the onset of hyperuricemia and gout disease is on the rise. Epidemiological studies have shown that the incidence of gouty arthritis accounts for 1-2% of the total population and is the most important type of arthritis in adult males. Bloomberg estimates that there will be 17.7 million gout patients in 2021. In China, the survey showed that among the population aged 20 to 74, 25.3% of the population had a high blood uric acid content and 0.36% had gout disease. At present, clinical treatment drugs mainly include 1) inhibition of uric acid-producing drugs, such as xanthine oxidase inhibitor allopurinol and febuxostat; 2) uric acid excretion drugs, such as probenecid and benzbromarone; 3) Inflammation inhibitors, such as colchicine. These drugs have certain defects in treatment, poor efficacy, large side effects, and high cost are some of the main bottlenecks in their clinical application. It has been reported that 40%-70% of patients with serum uric acid levels do not meet the expected therapeutic goals (<6mg/dL) after receiving standard treatment.
As a uric acid excretion agent, its mechanism of action is to reduce the reabsorption of uric acid by inhibiting the URAT1 transporter on the brush-like edge membrane of the proximal convoluted tubule. Uric acid is a metabolite of sputum in the body. It is mainly filtered by glomerulus in the original form, reabsorbed and re-secreted by the renal tubules, and finally excreted through the urine. Very few parts can be secreted into the intestinal lumen by mesenteric cells. The S1 segment of the proximal convoluted tubule is a site of uric acid reabsorption, and 98% to 100% of the filtered uric acid enters the epithelial cells through the uric acid transporter URAT1 and the organic anion transporter OAT4 on the brush epithelial cell border of the tubular epithelial cells. The uric acid entering the epithelial cells is reabsorbed into the capillaries around the tubules via the renal tubular basement membrane. The S2 segment of the proximal convoluted tubule is the site of re-secretion of uric acid, and the amount secreted is about 50% of the excess of the small filter. The uric acid in the renal interstitial enters the epithelial cells first through the anion transporters OAT1 and OAT3 on the basal membrane of the tubular epithelial cells. The uric acid entering the epithelial cells passes through another anion transporter MRP4 on the brush border membrane and is discharged into the small lumen. The S3 segment of the proximal convoluted tubule may be a reabsorption site after uric acid secretion, and the amount of reabsorption is about 40% of the excess of the microsphere filtration, and similar to the first step of reabsorption, URAT1 may be a key reabsorption transporter. Therefore, if the urate transporter URAT1 can be significantly inhibited, it will enhance the excretion of uric acid in the body, thereby lowering blood uric acid level and reducing the possibility of gout attack.
In December 2015, the US FDA approved the first URAT1 inhibitor, Zurampic (Leinurad). The 200 mg dose was approved in combination with xanthine oxidase inhibitor XOI (such as Febuxostat, etc.) for the treatment of hyperuricemia and gouty arthritis, but the combination was compared with the xanthine oxidase inhibitor alone. The effect is not very significant. The Zurampic 400 mg dose was not approved due to significant toxic side effects at high doses (the incidence of renal-related adverse events, especially the incidence of kidney stones). Therefore, the FDA requires the Zurampic label to be filled with a black box warning to warn medical staff Zulampic of the risk of acute kidney failure, especially if it is not used in conjunction with XOI. If the over-approved dose uses Zurampic, the risk of kidney failure is even greater. high. At the same time, after the FDA asked for the listing of Zurampic, AstraZeneca continued its investigation of kidney and cardiovascular safety. Therefore, the development of a new type of safe blood-supplemented uric acid drug has become a strong demand in this field.
WO2009070740 discloses Leinurad, which has the following structure:
SYN
PATENT

WO-2019101058

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019101058&tab=FULLTEXT&maxRec=1000

Novel crystalline forms of URAT1 inhibitor (designated as Forms A and B) are claimed. The compounds are disclosed to be useful for treating hyperuricemia and gouty arthritis.

Novel crystalline forms of a URAT1 inhibitor, designated as Forms A and B, and their preparation.

Example 1: Preparation of a compound of formula (I)
synthetic route:
Step 1: Synthesis of Compound 2
In a three-necked flask (10 L), 4.5 L of dimethyl sulfoxide was added, and potassium t-butoxide (836.66 g, 7.46 mol, 2 eq) was added with stirring, and stirring was continued for 10 minutes until the dissolution was clear, and then cooled to an ice water bath. The internal temperature of the reaction solution was 20-25 °C. To the above solution, a solution of Compound 1 (500.05 g, 3.73 mol, 1 eq) in dimethyl sulfoxide (500 mL) was added dropwise, and the mixture was stirred for 30 minutes, and then carbon disulfide (283.86 g, 3.73 mol, 1 eq) was added dropwise thereto. ), after the completion of the dropwise addition, the reaction was stirred for 30 minutes. Further, ethyl bromoacetate (1250 g, 7.46 mol, 2 eq) was added dropwise thereto, and the mixture was stirred for further 2 hours. Finally, potassium carbonate (515.52 g, 7.46 mol, 1 eq) was added, and the temperature was raised to an internal temperature of 65 ° C, and the reaction was further stirred for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was diluted with ethyl acetate (10 L), and then 1M hydrochloric acid (2 L) and water (2 L) were added and stirred for 10 minutes, and the mixture was allowed to stand. The aqueous layer was separated and the organic phase was washed with water (2L×3). The combined aqueous layers were extracted with ethyl acetate (3L). All organic phases were combined and washed with saturated brine (2 L×2). The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, and then filtered, and then evaporated. On the same scale, 6 batches were fed in parallel, and the combined black and red oily products were obtained. After the crude product was allowed to stand for 72 hours, a large amount of solid was precipitated, ethanol (2 L) was added thereto, stirred for 30 minutes, filtered, and the cake was collected and dried in vacuo to give Compound 2. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 4.32 (Q, J = 7.2 Hz, 2H), 4.19 (Q, J = 7.2 Hz, 2H), 3.56 (S, 2H), 3.25 (T, J = 6.8Hz , 2H), 3.19 (t, J = 14.4 Hz, 2H), 2.26-2.17 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); MS m/z = 364.8 [M+H] + .
Step 2: Synthesis of Compound 3
Compound 2 (241.00 g, 0.66 mol) was dissolved in ethanol (1 L) and placed in an autoclave (5 L), and Raney nickel (120 g) was added under argon atmosphere, followed by the addition of ethanol (2 L). The autoclave was charged and replaced with argon three times, then replaced with hydrogen three times, hydrogen was charged to a pressure of 2.0 MP in the autoclave, stirred and heated to an internal temperature of 85 ° C for 28 hours. The reaction was stopped, the reaction system was cooled to room temperature, the reaction solution was filtered, and the filter cake was washed three times with ethanol, 0.5 L each time. The filtrates were combined and then dried to give compound 3. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 7.09 (S, IH), 4.26 (Q, J = 7.2 Hz, 2H), 3.20 (T, J = 6.8Hz, 2H), 3.12 (T, J = 14.4Hz , 2H), 2.20-2.10 (m, 2H), 1.30 (t, J = 6.8 Hz, 3H); MS m/z = 247.0 [M+H] + .
Step 3: Synthesis of Compound 4
Compound 3 (406.2 g, 1.65 mol, 1 eq) was dissolved in acetonitrile (6 L), then N-bromosuccinimide (1484.2 g, 6.60 mol, 4 eq) was slowly added, and the obtained reaction mixture was at 23 to 25 ° C. The reaction was stirred for 12 hours. After the reaction was completed, the reaction liquid was concentrated to about 1.0 L. The solid was removed by filtration, and a saturated solution of sodium hydrogensulfite (1 L) was added to the filtrate and stirred for 10 min. Add acid ethyl ester and extract three times, 2L each time. The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Petroleum ether (3 L) was added to the residue, and the mixture was stirred at 30 ° C for 30 minutes. After filtration, the filter cake was washed 5 times with petroleum ether, 200 mL each time, until no product remained in the filter cake. Combine all the organic phases and spin dry to obtain a crude product. Petroleum ether (100 mL) was added to the crude product, stirred well, filtered, and filtered, and then dried in vacuo. . 1 H NMR (400 MHz, CDCl3 . 3) [delta]: 4.24 (Q, J = 7.2 Hz, 2H), 3.19 (T, J = 6.8Hz, 2H), 2.95 (T, J = 14.4Hz, 2H), 2.17-2.07 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).
Step 4: Synthesis of Compound 5
Compound 4 (340.21 g, 1.05 mol), cyclopropylboronic acid (108.12 g, 1.26 mol), anhydrous potassium phosphate (444.98 g, 2.10 mol), palladium acetate (12.03 g, 53.58 mmol) and 2-dicyclohexyl Phospho-2′,4′,6′-triisopropylbiphenyl (23.86 g, 50.05 mmol) was added to a mixed solvent of toluene and water (10:1, 3.4 L/340 mL), and the reaction flask was replaced with nitrogen. After that, place it in an oil bath. The reaction solution was heated at an internal temperature of 80 ° C, and the reaction was stirred at this temperature for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and tris-thiocyanic acid (6.51 g, suspended in ethanol (34 mL)) was added to the reaction mixture and stirred for 0.5 hour. On a similar scale (300.00 g of compound 4), 5 batches were fed in parallel and combined. After filtration, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (250mL). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield crude crude oil. After the crude product was allowed to stand for 20 hours, a yellow solid was precipitated, and petroleum ether (3 L) was added thereto and stirred for 1 hour. Filtration and drying of the filter cake in vacuo gave compound 5. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 4.29 (Q, J = 7.2 Hz, 2H), 3.23 (T, J = 6.4Hz, 2H), 3.16 (T, J = 14.8 Hz, 2H), 2.24-2.18 (m, 2H), 1.95-1.85 (m, 1H), 1.35 (t, J = 6.8 Hz, 3H), 1.09-1.07 (m, 2H), 0.77-0.75 (m, 2H).
Step 5: Synthesis of Compound 6
Compound 5 (619.27 g, 2.16 mol) was added to a mixed solution of ethanol and water (3 L/3 L) of sodium hydroxide (173.55 g, 4.33 mol), and the reaction liquid was heated to an internal temperature of 60 ° C to stir the reaction 3 hour. After the reaction was completed, the reaction solution was cooled to room temperature. On a similar scale (750.17 g of compound 5), 1 batch was fed in parallel and combined. The combined reaction solution was extracted with petroleum ether (4 L). The organic phase was separated and the organic phase was backwashed twice with water (1.5L x 2). The aqueous phases were combined and concentrated under reduced pressure to remove ethanol. Water was added to the aqueous phase to dilute to 13 L, and then slowly added with dilute hydrochloric acid (3 M) to adjust to pH = 2, and a large amount of pale yellow solid precipitated. Filter and filter cake with water (3.0L x 2). After draining, the filter cake was collected and dried under vacuum at 60 ° C to give Compound 6. . 1 H NMR (400 MHz, DMSO-D . 6 ) [delta]: 12.79 (brs, IH), 3.23 (T, J = 14.8 Hz, 2H), 3.07 (T, J = 6.8Hz, 2H), 2.27-2.20 (m, 2H), 2.19-2.02 (m, 1H), 1.09-1.04 (m, 2H), 0.68-0.66 (m, 2H).
Step 6: Synthesis of Compound 7
Compound 6 (641.27 g, 2.48 mol), triethylamine (754.07 g, 7.45 mol) and diphenyl azide (1025.34 g, 3.73 mol) were added to t-butanol (6.5 L) with stirring. The reaction solution was heated in a 100 ° C oil bath for 16 hours. After the reaction was completed, it was cooled to room temperature. On a similar scale (650.00 g of compound 6), 4 batches were fed in parallel and combined. The reaction mixture was combined and concentrated under reduced pressure to remove t-butyl alcohol. The remaining black residue was dissolved with ethyl acetate (10L). Dry with an appropriate amount of anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude brown solid. Petroleum ether (8 L) was added to the crude product and stirred for 2 hours. After filtration, the filter cake was rinsed with petroleum ether (1 L) in portions, and the filter cake was vacuum dried in a vacuum oven at 60 ° C to obtain Compound 7. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 6.31 (brs, IH), 3.11 (T, J = 14.8 Hz, 2H), 2.66 (T, J = 6.8Hz, 2H), 2.23-2.15 (m, 2H) , 1.82-1.75 (m, 1H), 1.51 (s, 9H), 0.94-0.90 (m, 2H), 0.68-0.65 (m, 2H).
Step 7: Synthesis of Compound 8
Compound 7 (1199.17 g, 3.64 mol) was added to ethyl acetate (2 L), and then stirred and then ethyl acetate (4L, 16. The reaction solution was reacted at 15 ° C for 2.5 hours, and then placed in a 40 ° C warm water bath to continue the reaction for 2 hours. After the reaction was completed, a large amount of dark red solid precipitated. Filter and filter cake was rinsed with ethyl acetate (2.0 L). The filter cake was dried under vacuum in a vacuum oven at 60 ° C to give compound 8. . 1 H NMR (400 MHz, DMSO-D . 6 ) [delta]: 3.17 (T, J = 14.8 Hz, 2H), 2.82 (T, J = 6.8Hz, 2H), 2.25-2.15 (m, 2H), 2.00-1.94 ( m, 1H), 0.99-0.95 (m, 2H), 0.58-0.54 (m, 2H); MS m/z = 229.8 [M+H-HCl] + .
Step 8: Synthesis of Compound 9
In a 3 L three-necked flask, Compound 8 (301.25 g) was added to tetrahydrofuran (600 mL), and the mixture was cooled to an internal temperature of 0 to 10 ° C under ice-cooling. Diisopropylethylamine (635.72 g) was added dropwise, and after completion of the dropwise addition, the ice water bath was removed, and the mixture was stirred at an internal temperature of 10 to 15 ° C for about 10 minutes. Filter and filter cake was washed with tetrahydrofuran (100 mL x 2). The filtrates were combined to give a solution A for use.
Tetrahydrofuran (2 L) was added to a 5 L reaction flask containing thiophosgene (257.48 g). The mixture was stirred and cooled to an internal temperature of 0 to 10 ° C in an ice water bath, and the solution A was slowly added dropwise thereto, and the dropwise addition was completed within about 5.5 hours, and stirring was continued for 10 minutes. After the reaction was completed, it was filtered, and the filter cake was washed with tetrahydrofuran (150 mL × 2). The filtrate was combined and concentrated under reduced pressure to remove solvent. Tetrahydrofuran (400 mL) was added to the residue, which was dissolved to give a solution B.
The hydrazine hydrate (112.94 g) was added to tetrahydrofuran (2.5 L), and the mixture was cooled to an internal temperature of 5 to 10 ° C under ice-cooling. Solution B was added dropwise, and the addition was completed for about 2 hours, and stirring was continued for 10 minutes. After the reaction was completed, the reaction was stopped. The ice water bath was removed, N,N-dimethylformamide dimethyl acetal (333.45 g) was added, and the mixture was heated to an internal temperature of 60 to 65 ° C, and the reaction was stopped after the heat retention reaction for 3 hours.
The reaction solution was dried to dryness, and ethyl acetate (2 L) and purified water (1L) were added to the residue, and the mixture was stirred. The pH was adjusted to 5-6 with 10% hydrobromic acid, stirring was continued for 5 minutes, and allowed to stand for 10 minutes. Dispense and separate the aqueous phase. The organic phase was washed with pure water (500 mL x 2). The combined aqueous phases were extracted with EtOAc (1 mL). The desiccant was removed by filtration, and the filtrate was concentrated to dryness to dryness. n-Heptane (2.0 L) and tert-butyl methyl ether (150 mL) were added to the crude product, and the mixture was stirred ( stirring speed 550 rpm) for 18 hours. Filter and filter cake was washed with n-heptane (150 mL). The filter cake was collected and the filter cake was dried under vacuum at 60 ° C to give compound 9. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 7.82 (S, IH), 3.20 (T, J = 14.8 Hz, 2H), 2.74 (T, J = 6.8Hz, 2H), 2.28-2.10 (m, 2H) , 1.98-1.82 (m, 1H), 1.06-1.02 (m, 2H), 0.75-0.71 (m, 2H); MS m/z = 313.9 [M+H] + .
Step 9: Synthesis of Compound 10
Acetonitrile (3 L) was placed in a 5 L three-necked flask. Compound 9 (303.25 g) and potassium carbonate (261.83 g) were added first with stirring. Further, methyl 2-bromoisobutyrate (203.85 g) was added, and the reaction system was replaced with nitrogen, and then heated to an internal temperature of 60 to 65 ° C, and the reaction was kept for about 2 hours. After the completion of the reaction, the heating was stopped, and the mixture was naturally cooled to 15 to 20 ° C under stirring. Filter and filter cake was washed with ethyl acetate (100 mL x 3). The filtrate was combined and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography (mobile phase: ethyl acetate / n-heptane = 1:5 to 2:1). . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 8.20 (S, IH), 3.68 (S, 3H), 3.19 (T, J = 14.4Hz, 2H), 2.57 (T, J = 6.8Hz, 2H), 2.22 -2.12 (m, 2H), 1.93-1.83 (m, 1H), 1.67 (s, 6H), 1.08-1.03 (m, 2H), 0.73-0.69 (m, 2H); MS m/z = 414.0 [M +H] + .
Step 10: Synthesis of Compound 11
Acetonitrile (3.17 L) was placed in a 5 L three-necked flask. Under stirring, compound 10 (317.22 g) and thiocarbonyldiimidazole (26.94 g) were added, and the mixture was stirred at 16 to 20 ° C for 5 minutes. N-bromosuccinimide (158.60 g) was added and stirred for about 30 minutes with heat. After the reaction was over, the reaction was stopped. Filtration and concentration of the filtrate under reduced pressure afforded crude crude. The crude product was purified by column chromatography (EtOAc:EtOAc:EtOAc This crude product was dissolved in ethyl acetate (3.50 L) and washed with purified water (700 mL×4). The organic phase was separated and the organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated to dryness to give Compound 11. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 3.73 (S, 3H), 3.22 (T, J = 14.4Hz, 2H), 2.53 (T, J = 6.8Hz, 2H), 2.24-2.14 (m, 2H) , 1.95-1.91 (m, 1H), 1.71 (d, J = 4.4 Hz, 6H), 1.11-1.07 (m, 2H), 0.78-0.74 (m, 2H); MS m/z = 491.7 [M+H ] + ,493.7[M+H+2] + .
Step 11: Synthesis of a compound of formula (I)
Tetrahydrofuran (1.2 L) was added to a 5 L reaction flask, and Compound 11 (243.03 g) was added with stirring. After the solution was dissolved, pure water (1.2 L) was added, and then lithium hydroxide monohydrate (125.46 g) was added, and the mixture was stirred at 20 to 25 ° C for about 2.5 hours. After the reaction was completed, the reaction was stopped. The reaction solution was concentrated under reduced pressure at 40 ° C to remove organic solvent. Pure water (1 L) was added to the residue, and the mixture was extracted with t-butyl methyl ether (300 mL). The aqueous phase was placed in a 10 L three-necked flask and cooled to 5 to 10 ° C in an ice bath. The pH was adjusted to 2 to 3 with a 40% hydrobromic acid solution, and a large amount of a pale yellow solid precipitated. Stirring was continued for 30 minutes, and the pH was again measured to be 2-3. Stirring was continued for 20 minutes and filtered. The filter cake was washed with pure water (150 mL x 3). The filter cake was collected, pure water (1500 mL) was added, and the mixture was beaten at room temperature for 1 hour. After filtration, the filter cake was washed with pure water (150 mL × 2), and the filter cake was collected and dried under vacuum at 40 ° C for 3 hours to obtain a compound of the formula (I). . 1 H NMR (400 MHz, the CD . 3 the OD) [delta]: 3.27 (T, J = 15.6Hz, 2H), 2.60-2.47 (m, 2H), 2.27-2.17 (m, 2H), 2.10-2.03 (m, IH) , 1.68 (d, J = 1.2 Hz, 6H), 1.15.10.10 (m, 2H), 0.80-0.71 (m, 2H); MS m/z = 477.99 [M+H] + , 480.1 [M+H+ 2] + .
Example 2: Preparation of Form A of Compound of Formula (I)
The compound of the formula (I) (50 mg) was added to a glass bottle, and methanol (0.4 mL) was added thereto, followed by stirring to a suspension or a solution. The suspension sample was placed in a thermomixer (40 ° C), shaken at 40 ° C for 60 hours, and then centrifuged to collect a sample. The above-mentioned lysed sample was volatilized at room temperature, centrifuged, and the sample was collected. The above sample was dried in a vacuum oven (40 ° C) overnight, and its crystalline form was examined by XRPD to obtain a crystal form of the final product having a crystalline form of the compound of the formula (I).
The compound of the formula (I) (50 mg) was added to a glass bottle, and ethyl acetate (0.4 mL) was added and stirred to a suspension or a solution. The suspension sample was placed in a thermomixer (40 ° C), shaken at 40 ° C for 60 hours, and then centrifuged to collect a sample. The above-mentioned lysed sample was volatilized at room temperature, centrifuged, and the sample was collected. The above sample was dried in a vacuum oven (40 ° C) overnight, and its crystalline form was examined by XRPD to obtain a crystal form of the final product having a crystalline form of the compound of the formula (I).
Example 3: Preparation of Form B of Compound of Formula (I)
The compound of the formula (I) (50 mg) was added to a glass bottle, tetrahydrofuran (0.4 mL) was added, and the mixture was stirred to dissolve. The above-mentioned lysed sample was volatilized at room temperature, centrifuged, and the sample was collected. The collected sample was dried in a vacuum oven (40 ° C) overnight, and its crystalline form was examined by XRPD to obtain a crystalline form of the final product in the form of Form B of the compound of formula (I).
Example 4: Solubility test of Form A of the compound of formula (I)
1. Preparation of diluent and mobile phase
Diluent: Accurately measure 300mL of pure water and 100mL of pure acetonitrile, mix in a 1L glass bottle, ultrasonic degassing for 10 minutes and then set aside.
Mobile phase A: 0.1% phosphoric acid aqueous solution

For example, remove 2.0 mL of phosphoric acid into 2000 mL of water, sonicate for 10 minutes, mix, and let cool to room temperature as mobile phase A.

Mobile phase B: acetonitrile.
2. Preparation of the reference solution (using the A crystal form itself as a control sample)
Accurately weigh 5 mg of Form A, place it in a sample vial, add 10 mL of diluent, sonicate for 5 minutes, then cool to room temperature and mix well, and mark it as working reference solution STD-1.
Accurately weigh 5 mg of Form A, place it in a sample vial, add 10 mL of diluent, sonicate for 5 minutes, then cool to room temperature and mix well, and mark it as working reference solution STD-2.
3. Preparation of linear solution
The above working reference solution STD-1 was diluted 1 time, 10 times, 100 times, 1000 times and 2000 times, and recorded as linear solutions L1, L2, L3, L4 and L5.
4. Solubility test
Accurately weigh 6mg of A crystal form into 8mL glass bottle, then accurately add 3mL different solvent (0.1N hydrochloric acid solution, 0.01N hydrochloric acid solution, purified water, pH3.8 buffer solution, pH4.5 buffer solution, pH5 .5 buffer solution, pH 6.0 buffer solution, pH 7.4 buffer solution, pH 6.8 buffer solution), made into a suspension. A stir bar was added to the above suspension, and the mixture was thoroughly stirred at 37 ° C in the dark. After stirring, the solids in the pH 7.4 buffer solution and the pH 6.8 buffer solution were all dissolved, and 6 mg of the A crystal form was accurately weighed, added to the buffer solution, and thoroughly stirred again to prepare a suspension. After stirring for 4 hours and 24 hours, the sample was centrifuged, and the solution was filtered through a filter and the concentration thereof was measured by HPLC. The HPLC analysis method is shown in Table 3.
Table 3: HPLC analysis methods

////////////CS-3001, BB 7, VX 033, CHINA, PRECLINICAL, CStone Pharmaceuticals, URAT1 inhibitor,  hyperuricemia, gout

O=C(O)C(C)(C)Sc4nnc(Br)n4c2sc(c1CC(F)(F)CCc12)C3CC3

TL 487


str1

TL-487

CAS  1469746-55-1
2-Butenamide, N-[3-cyano-7-ethoxy-4-[(4-phenoxyphenyl)amino]-6-quinolinyl]-4-(dimethylamino)-, (2E)-
Molecular Weight, 507.58, MF C30 H29 N5 O3

Teligene Inc(2E)-N-[3-Cyano-7-ethoxy-4-[(4-phenoxyphenyl)amino]-6-quinolinyl]-4-(dimethylamino)-2-butenamide

(E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide

Maleate in anhydrous or monohydrate CAS, 2326561-36-6, AND 2326561-38-8 form are BTK and HER-2 kinase inhibitor useful for treating cancer

Useful for treating breast cancer, ovary cancer and colon cancer. are BTK and HER-2 kinase inhibitor useful for treating cancer.

Anticancer protein kinase inhibitor

The compound was originally claimed in WO2013152135 , and may provide the structure of TL-487 , a small molecule inhibitor to HERs, being investigated by Teligene for the treatment of breast cancer; in July 2016, the company intended to develop the product as a class 1.1 chemical drug in China.

PATENT

US 20150057312

PATENT

WO2013152135

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013152135&tab=PCTDESCRIPTION&queryString=%28ET%2Fkinase%29+&recNum=8&maxRec=4574

PATENT

WO-2019096327

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019096327&redirectedID=true

Novel crystalline maleate salt of (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (first disclosed in WO2013152135) and its hydrates (monohydrate) and anhydrates, process for its preparation, composition comprising it and its use for treating cancers such as breast cancer, ovary cancer, colon cancer, prostate cancer, kidney cancer, bladder cancer, stomach cancer, lung cancer, mantle cell lymphoma and multiple myeloma are claimed. The compound is disclosed to be an irreversible inhibitor to BTK and Her-2 (also known as Erb-2 or neu).

(E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide is mentioned in WO2013152135 and corresponds to the compound of the Formula I:
Formula I
Compounds derived from 3-cyanoquinoline have been shown to have anti-tumor activity, which may make them useful as chemotherapeutic agents in treating various cancers, including but not limited to, pancreatic cancer, melanoma, lymphatic cancer, parotid tumors, Barrett’s esophagus, esophageal carcinomas, head and neck tumors, ovarian cancer, breast cancer, epidermoid tumors, cancers of major organs, such as kidney, bladder, larynx, stomach, and lung, colonic polyps and colorectal cancer and prostate cancer. Examples of compounds derived from 3-cyanoquinoline are disclosed and shown to possess anti-tumor activity in many literatures. One limitation of certain 3-cyanoquinoline compounds is that they are not water soluble in a free base form.
The crystalline form of a particular drug as a salt, a hydrate and/or any polymorph thereof is often one important determinant of the drug’s ease of preparation, stability, water solubility, storage stability, ease of formulation and in-vivo pharmacology. It is possible that one crystalline form is preferable over another where certain aspects such as ease of preparation, stability, water solubility and/or superior pharmacokinetics are deemed to be critical. Crystalline forms of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide salts that possess a higher degree of water solubility than the free base but are stable fulfill an unmet need for stable, crystalline, water-solubl
Example 1. (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide sulfate
95%ethanol (4.0 ml) was added to (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , followed sulfuric acid (101.9 mg, 1.04 mmol, 1.05 eq) in 95%ethanol (1.0 ml) was added dropwise to the reaction mixture. Then an amount of precipitate was founded. Another 95% (60 ml) was added to the reaction mixture and the reaction mixture was heated to 70℃. Filtered and the filtrate was heated to 70℃ again. Then the reaction mixture was cooled to room temperature and The reaction mixture was crystallized at -10℃ for 41.5h. Filtered the precipitated solid and dried at 40℃ under vacuum for 1 hour to get the title compound (260 mg) as a yellow solid.
X-ray detection shows an amorphous structure to the compound as FIG. 9.
Example 2. Synthesis of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide hydrochloride
95%ethanol (5.0 ml) was added to (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , followed hydrochloric acid (38.0 mg, 1.04 mmol, 1.05 eq) in 95%ethanol (1.0 ml) was added dropwise to the reaction mixture. The reaction mixture was heated to 70℃. Filtered and the filtrate was crystallized under -10℃ for 44.5h. Filtered the precipitated solid and dried at 40℃ under vacuum for 1 hour to get the title compound (96 mg) as a yellow solid.
X-ray detection shows an amorphous structure to the compound in FIG. 6.
Example 3. Synthesis of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide malate
(E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , L-malic acid (139.4 mg, 1.04 mmol, 1.05 eq) and 95%ethanol (5.0 ml) was added to a 50 ml round-bottom flask. The reaction mixture was heated to 70℃. Filtered and the filtrate was crystallized under -10℃ for 45.5h. A little of precipitate was founded and then the reaction mixture was evaporated under vacuum at 40℃ to give the target (370 mg) as a yellow solid.
X-ray detection shows an amorphous structure to the compound in FIG. 8
Example 4: synthesis of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide citrate
To a solution of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , citric acid (198.8 mg, 1.04 mmol, 1.05 eq) and 95%ethanol (5.0 ml) . The reaction mixture was heated to 70℃. Filtered and the filtrate was crystallized under -10℃ for 45h. A little of precipitate was founded and then the reaction mixture was evaporated under vacuum at 40℃ to give the target compound (610 mg) as a yellow solid.
X-ray detection shows an crystalline structure to the compound in FIG. 7.
Example 5: Preparation of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate monohydrate.
(E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide free base (0.091 kg) is rinsed with a 10%solution of USP purified water in n-propanol (0.082 kg, 0.10 L) followed by the addition of water: n-propanol solution (0.74 kg, 0.90 L) . Maleic acid is added (1.01 equiv) and the mixture is rinsed with 10%water: n-propanol (0.082 kg, 0.10 L) . The mixture is quickly heated to 50-60 ℃ and held for a minimum of 15 min. until a solution is obtained. The hot solution is clarified through a pre-heated 50-60 ℃, 0.2 Mm filter cartridge and the filtrates are collected in a preheated 45-55℃, 2 L multi-neck flask. The filter cartridge is rinsed through with 10%water: n-propanol pre-heated to 45-55 ℃ (0.082 kg, 0.10 L) . The solution is cooled over at least one hour to 40 ℃ and held at that temperature for 12 hours then cooled to room temperature (25 ℃) over a minimum of four hours and held at that temperature for at least two hours. The mixture is filtered on a 12.5 cm diameter Buchner funnel for 5 min., then rinsed and washed with prefiltered10%water: n-propanol solution (2 x 0.12 kg, 2 x 0.15 L) . The cake is dammed and suction maintained until dripping essentially stops, about 1 h.
PXRD is shown in FIG. 1.
Example 6: The product from Example 1 is dried (50 ℃, 10 mm Hg, 24 h) to give crystalline, anhydrous (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate.
PXRD is shown in FIG. 3.
Example 7: Preparation of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate monohydrate.
To a solution of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (38.0 g, 75.0 mmol, 1.0 eq) and n-propanol/H 2O (380 ml, V: V=9: 1) . maleic acid (8.7 g, 75.0 mmol, 1.0 eq) in n-propanol/H 2O (76 ml, V: V=9: 1) was added to the reaction mixture. An amount of precipitate was founded, then the reaction mixturewas heated to 65 ℃. The solid was dissolved completely, then the reaction mixture was cooled to room temperature and stand for 20 hours. Filtered and filtrate was evaporated under vacuum to get the crude product.
The crude product (14.0 g) was recrystallized in n-propanol/H 2O (240 ml, V: V=9: 1) at 70℃. The solid was dissolved completely, then the reaction mixture was cooled to room temperature and stand for 20.5 hours. Filtered and wash the cake with n-propanol/H 2O (20 ml, V: V=9: 1) to get target product (12.9 g, wet) .
PXRD as FIG. 1.
Example 8: crystalline, anhydrous (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate.
To a solution of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (21.5 g, 42.4 mmol, 1.0 eq) and ethanol (300 ml) . maleic acid (5.2 g, 44.8 mmol, 1.05 eq) was added to the reaction mixture. An amount of precipitate was founded, then the reaction mixture was heated to 70 ℃. Another ethanol (1980 ml) was added to the reaction mixture in several times and the reaction temperature was keep at 70 ℃. Filtered and filtrate was cooled to room temperature, stop stirring and stand for 16-20 hours. Filtered and the solid was dried at room temperature for 24 hours to get the title compound.

///////////////TL-487, PRECLINICAL, CHINA, breast cancer, ovary cancer, olon cancer,  BTK, HER-2 kinase inhibitor,

CN(C)C\C=C\C(=O)Nc3cc4c(Nc2ccc(Oc1ccccc1)cc2)c(cnc4cc3OCC)C#N

Quisapride Hydrochloride


STR1

Quisapride Hydrochloride

(R) – quinuclidine-3-5 – ((S) -2 – (( 4 – amino-5-chloro-2-ethoxy benzoylamino) methyl) morpholino) hexanoate

IND Filed china

A 5-HT4 agonist potentially for the treatment of gastrointestinal motility disorders.

SHR-116 958, SHR 116958

CAS 1132682-83-7 (Free)

Shanghai Hengrui Pharmaceutical Co., Ltd.

CAS 1274633-87-2 (dihcl)

  • (3R)-1-Azabicyclo[2.2.2]oct-3-yl (2S)-2-[[(4-amino-5-chloro-2-ethoxybenzoyl)amino]methyl]-4-morpholinehexanoate hydrochloride (1:2)
  • SHR 116958
  • C27 H41 Cl N4 O5 . 2 Cl H,
    4-Morpholinehexanoic acid, 2-[[(4-amino-5-chloro-2-ethoxybenzoyl)amino]methyl]-, (3R)-1-azabicyclo[2.2.2]oct-3-yl ester, hydrochloride (1:2), (2S)-

STR1

5-HT is a neurotransmitter Chong, widely distributed in the central nervous system and peripheral tissues, 5-HT receptor subtypes at least seven, and a wide variety of physiological functions of 5-HT receptor with different interactions related. Thus, the 5-HT receptor subtypes research is very necessary.

The study found that the HT-5 4 receptor agonists useful for treating a variety of diseases, such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, postoperative intestinal infarction, central nervous system disorders, Alzheimer’s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure , arrhythmias, intestinal pseudo-obstruction, gastroparesis, diabetes and apnea syndrome.

The HT-5 4 receptor agonists into benzamides, benzimidazole class and indole alkylamines three kinds, which benzamides derivatives act on the neurotransmitter serotonin in the central nervous system by modulation, It showed significant pharmacological effect. The role of serotonin and benzamides derivatives and pharmacologically related to many diseases. Therefore, more and more people will focus on the human body produce serotonin, a storage position and the position of serotonin receptors, and to explore the relationship between these positions with a variety of diseases.

Commonly used in clinical cisapride (cisapride) and Mosapride (Tony network satisfied) is one of the novel benzamides drugs.

These drugs mainly through the intestinal muscle between the excited 5-HT neurofilament preganglionic and postganglionic neurons 4 receptor to promote the release of acetylcholine and enhancing cholinergic role in strengthening the peristalsis and contraction of gastrointestinal smooth muscle. In large doses, it can antagonize the HT-53 receptors play a central antiemetic effect, when typical doses, through the promotion of gastrointestinal motility and antiemetic effect. These drugs can increase the lower esophageal smooth muscle tension and promote esophageal peristalsis, improving the antrum and duodenum coordinated motion, and promote gastric emptying, but also promote the intestinal movement and enhanced features, increase the role of the proximal colon emptying, It is seen as the whole digestive tract smooth muscle prokinetic effect of the whole gastrointestinal drugs.

Mainly used for reflux esophagitis, functional dyspepsia, gastroparesis, postoperative gastrointestinal paralysis, functional constipation and intestinal pseudo-obstruction patients. Since there is slight antagonism cisapride the HT-5 3 and anti-D2 receptor, can cause cardiac adverse reactions, prolonged QT occurs, and therefore, patients with severe heart disease, ECG QT prolonged, low potassium, and low blood magnesium prohibited drug. Liver and kidney dysfunction, lactating women and children is not recommended. Due to increase between drug diazepam, ethanol, acenocoumarol, cimetidine and ranitidine the absorption of anticholinergic drugs may also antagonize the effect of this product to promote peristalsis of the stomach, should be aware of when using these, such as when diarrhea should reduce, anticoagulant therapy should pay attention to monitoring the clotting time. Mosapride selective gastrointestinal tract the HT-5 4 receptor agonists, there is no antagonism of D2 receptors, does not cause QT prolonged, reduce adverse reactions, mainly fatigue, dizziness, loose stools, mild abdominal pain , the efficacy of cisapride equivalent clinical effect broader Puka cisapride (prucalopride, Pru) of benzimidazole drugs, with high selectivity and specificity of the HT-5 4 receptor, increasing cholinergic neurotransmitters quality release, stimulate peristalsis reflex, enhance colon contraction, and accelerate gastric emptying, gastrointestinal motility to promote good effect, can effectively relieve the patient’s symptoms of constipation, constipation and for treatment of various gastrointestinal surgery peristalsis slow and weak, and intestinal pseudo-obstruction.

WO2005068461 discloses as the HT-5 4 receptor agonists benzamides compounds, particularly discloses compounds represented by the formula:

ATI-7505

ATI-7505 is stereoisomeric esterified. Cisapride analogs, safe and effective treatment of various gastrointestinal disorders, including gastroparesis, gastroesophageal reflux disease and related disorders. The drug can also be used to treat a variety of central nervous system disorders. ATI-7505 for the treatment or prevention of gastroesophageal reflux disease, also taking cisapride significantly reduced side effects. These side effects include diarrhea, abdominal cramps and blood pressure and heart rate rise.

Further, the compounds and compositions of this patent disclosure also useful in treating emesis and other diseases. Such as indigestion, gastroesophageal reflux, constipation, postoperative ileus, and intestinal pseudo-obstruction. In the course of treatment, but also taking cisapride reduce the side effects.

ΑΉ-7505 as the HT-5 4 receptor ligands may be mediated by receptors to treat the disease. These receptors are located in several parts of the central nervous system, modulate the receptor can be used to affect the CNS desired modulation.

ATI-7505 contained in the ester moiety does not detract from the ability of the compounds to provide treatment, but to make the compound easier to serum and / or cytosolic esterases degraded, so you can avoid the drug cytochrome P450 detoxification system, and this system with cisapride cause side effects related, thus reducing side effects.

The HT-Good 5 4 receptor agonists and should the HT-5 4 receptor binding powerful, while the other hardly shows affinity for the receptor, and show functional activity as agonists. They should be well absorbed from the gastrointestinal tract, metabolically stable and possess desirable pharmacokinetic properties. When targeting the receptor in the central nervous system, they should cross the blood-free, selectively targeting peripheral nervous system receptors, they should not pass through the blood-brain barrier. They should be non-toxic, and there is little proof of side effects. Furthermore, the ideal drug candidate will be a stable, non-hygroscopic and easily formulated in the form of physical presence.

Based on the HT-5 4 receptor agonists current developments, the present invention relates to a series of efficacy better, safer, less side effects of the benzamide derivatives.

Synthesis

STR1

PATENT

WO 2009033360

Example 3

(R) – quinuclidine-3-5 – ((S) -2 – (( 4 – amino-5-chloro-2-ethoxy benzoylamino) methyl) morpholino) hexanoate

 

REFERENCES

China Pharmaceuticals: Asia Insight: China Has R&D

pg.jrj.com.cn/acc/Res/CN_RES/…/cd837477-44e9-4f98-a2b9-97620cd64576.pdf

Nov 6, 2012 – levofolinate, sevoflurane inhalation, ambroxol hydrochloride, ioversol, etc ….. dextromethorphan hydrochloride 复方沙芬那敏. 3.2 …… quisapride.

Pharmazie (2011), 66(11), 826-830

//////SHR-116 958, SHR 116958, Quisapride Hydrochloride, preclinical

Cl.Cl.Clc1cc(c(OCC)cc1N)C(=O)NC[C@H]4CN(CCCCCC(=O)O[C@H]3CN2CCC3CC2)CCO4

Tianagliflozin IND filed by Tianjin Institute of Pharmaceutical research


str1

SCHEMBL9611990.png

str1

Tianagliflozin,

taigeliejing, 6-deoxydapagliflozin

Molecular Formula: C21H25ClO5
Molecular Weight: 392.8732 g/mol

IND Filing…Tianjin Institute of Pharmaceutical research

Tianjin Institute Of Pharmaceutical Research,

(3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methyloxane-3,4,5-triol

1-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-b-D-glucopyranose
D-​Glucitol, 1,​5-​anhydro-​1-​C-​[4-​chloro-​3-​[(4-​ethoxyphenyl)​methyl]​phenyl]​-​6-​deoxy-​, (1S)​-

1[4Chloro3(4ethoxybenzyl)phenyl]1,6dideoxyβdglucopyranose

6-deoxydapagliflozin
A SGLT-2 inhibitor potentially for the treatment of type 2 diabetes.

 

CAS N. 1461750-27-5

SCHEMBL9611990.png

str1

 https://static-content.springer.com/image/art%3A10.1007%2Fs00706-013-1053-0/MediaObjects/706_2013_1053_Fig1_HTML.gif

The structures of dapagliflozin and 6-deoxydapagliflozin (1)

,deletion of the 6-OH in the sugar moiety of dapagliflozin led to the discovery of a more potent SGLT2 inhibitor, 6-deoxydapagliflozin (1, ). In an in vitro assay, 1 was a more active SGLT2 inhibitor, with IC 50 = 0.67 nM against human SGLT2 (hSGLT2), as compared with 1.1 nM for dapagliflozin, leading to the identification of 1 as the most active SGLT2 inhibitor discovered so far in this field. Also in an in vivo assay, 1 also introduced more urinary glucose in a rat urinary glucose excretion test (UGE) and exhibited more potent blood glucose inhibitory activity in a rat oral glucose tolerance test (OGTT) than dapagliflozin.

Given the fact that 6-dexoydapagliflozin (1) is a very promising SGLT2 inhibitor that could be used to treat type 2 diabetes, led to preclinical trials
str1
 Tianjin Institute Of Pharmaceutical Research,天津药物研究院

SPECTRAL DATA of Tianagliflozin

1 as a white solid (3.65 g, 93 %). R f = 0.35 (EtOAc);

m.p.: 148–149 °C;

1H NMR (400 MHz, DMSO-d 6): δ = 7.35 (d, 1H, J = 8.4 Hz), 7.25 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.4 Hz), 4.95 (d, 1H, J = 5.2 Hz, OH), 4.90 (d, 1H, J = 4.4 Hz, OH), 4.79 (d, 1H, J = 5.6 Hz, OH), 3.92–4.01 (m, 5H), 3.24–3.29 (m, 1H), 3.18–3.22 (m, 1H), 3.09–3.15 (m, 1H), 2.89–2.95 (m, 1H), 1.29 (t, 3H, J = 7.0 Hz, CH2 CH 3 ), 1.15 (d, 3H, J = 6.0 Hz, CHCH 3 ) ppm;

13C NMR (100 MHz, DMSO-d 6): δ = 156.85, 139.65, 137.82, 131.83, 131.16, 130.58, 129.52, 128.65, 127.14, 114.26, 80.71, 77.98, 75.77, 75.51, 74.81, 62.84, 37.55, 18.19, 14.62 ppm;

IR (KBr): v¯¯¯ = 3,564 (w), 3,385 (s), 2,981 (s), 2,899 (s), 2,861 (s), 1,613 (m), 1,512 (s), 1,477 (m), 1,247 (s), 1,102 (s), 1,045 (s), 1,012 (s) cm−1;

HR–MS: calcd for C21H29ClNO5 ([M + NH4]+) 410.1729, found 410.1724.

PATENT

 CN 103864737

http://www.google.com/patents/CN103864737A?cl=en

PATENT

WO 2014094544

http://www.google.com/patents/WO2014094544A1?cl=en

Figure imgf000032_0001

Figure imgf000028_0006
Figure imgf000029_0001

-27-

Figure imgf000030_0001
Figure imgf000030_0002

1 D1 -6 Optionally, the step (7 ‘) is the step (7’) in place:

LS l- [4 – D (I- Dl- 6)

Figure imgf000041_0001

A.

Figure imgf000041_0002

(DMSO-d 6, 400 MHz), δ 7.35 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J ‘. 2.0 Hz), 7.17 (dd, IH, / = 2.0 Hz and 8.4 Hz), 7.05 (d, 2H, J: 8.8 Hz), 6.79 (d, 2H, 8.8 Hz): 4.924,95 (m, 2H), 4,81 (d, IH, 6,0 Hz), 3.93- 3.99 (m, 5H), 3,85 (d, 1H, J = 10,4 Hz), 3,66 (dd, IH, 5,2 Hz and 11,6 Hz), 3.17-3,28 (m, 3H), 3.02-3.08 (m: IH), 1.28 (t, 3H, J = 7,0 Hz), 0,80 (s, 9H), -0.05 (s, 3H), -0.09 (s, 3H) .

PATENT

CN 104045614

[0066] The added 100mL dried over anhydrous methanol 0. 5g of sodium metal, nitrogen at room temperature with stirring, until the sodium metal disappeared. Followed by addition of 5. 2g (10mmol) of compound 6, stirring was continued at room temperature for 3 hours. To the reaction system was added 5g strong acid cation exchange resin, stirred at room temperature overnight, the reaction mixture until pH = 7. The resin was removed by suction, and the filtrate evaporated to dryness on a rotary evaporator, the residue was further dried on a vacuum pump to give the product I-D1-6, as a white foamy solid.

PATENT

 WO 2014139447

PATENT related

http://www.google.com/patents/WO2013044608A1?cl=en

http://link.springer.com/article/10.1007%2Fs40242-014-4043-9#/page-1

Med Chem. 2015;11(4):317-28.

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

Abstract

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

http://www.ncbi.nlm.nih.gov/pubmed/25557661

Paper

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

http://www.ingentaconnect.com/content/ben/mc/2014/00000010/00000003/art00009?crawler=true

CLIP

str1

A facile synthesis of 6-deoxydapagliflozin

Keywords. Carbohydrates Drug research Hydrogenolysis Dapagliflozin SGLT2 inhibitor

https://static-content.springer.com/image/art%3A10.1007%2Fs00706-013-1053-0/MediaObjects/706_2013_1053_Sch3_HTML.gif

The synthetic route to the target compound 1 is shown in Scheme 3. The starting material methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-αd-glucopyranoside (3) was prepared from commercially available methyl αd-glucopyranoside (2) according to a known method [5, 6].

Iodide 3 was reductively deiodinated to give 4 in 91 % yield under hydrogenolytic conditions using 10 % Pd/C as catalyst in the presence of Et3N as base in THF/MeOH at room temperature.

when the iodide 3 was treated with Barton–McCombie reagent (n-Bu3SnH/AIBN) [7] in toluene at room temperature no reaction occurred; however, when the reaction was carried out at elevated temperatures, such as reflux, a complex mixture formed with only a trace amount (3 %, entry 1) of the desired product 4.

When the iodide 3 was treated with LiAlH4 in THF at 0 °C to room temperature, another complex mixture was produced with only a trace amount (2 %, entry 2) of 4.

When Pd(OH)2 was used as the hydrogenolysis catalyst instead of 10 % Pd/C, the desired 4 was indeed formed (14 %, entry 4), but most of the starting material was converted to a few more polar byproducts, which were believed to result from the cleavage of at least one of the benzyl groups.

pdf available

Monatshefte für Chemie – Chemical Monthly

December 2013, Volume 144, Issue 12, pp 1903-1910

http://download.springer.com/static/pdf/721/art%253A10.1007%252Fs00706-013-1053-0.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs00706-013-1053-0&token2=exp=1458808857~acl=%2Fstatic%2Fpdf%2F721%2Fart%25253A10.1007%25252Fs00706-013-1053-0.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs00706-013-1053-0*~hmac=bd1c3c2bdc3712f5540267c99f732b2f7588020a868aa23021792a2a2a58d65e

////////IND Filing, SGLT-2 inhibitor, type 2 diabetes, Tianagliflozin, taigeliejing, 6-deoxydapagliflozin, 1461750-27-5

Clc1c(cc(cc1)C2[C@@H]([C@H]([C@@H]([C@H](O2)C)O)O)O)Cc3ccc(cc3)OCC

CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)C)O)O)O)Cl
c1(c(cc(cc1)C2OC(C(C(C2O)O)O)C)Cc3ccc(cc3)OCC)Cl

Shanghai Hengrui’s potent inhibitors of Human Uric Acid Transporter 1 (hURAT1)


CID 86294127.png

 MF C 1 4 H 1 2 BrNO 2 S
MW 338.21958 g / mol

1- (6-bromoquinolin-4-yl) sulfanylcyclobutane-1-carboxylic acid

CAS…….1638327-48-6

Cyclobutanecarboxyli​c acid, 1-​[(6-​bromo-​4-​quinolinyl)​thio]​-

COMING ………….

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MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

 

WO-2014183555-A1 / 2014-11-20

http://www.google.co.in/patents/WO2014183555A1?cl=en

PROCEDURE

6-bromo-quinoline-4-thiol

A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, using known methods “Bioorganic &

Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.

The second step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl carboxylate

Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were sequentially added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction solution was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.

MS m / z (ESI): 368.2 [M + l]

1H MR (400 MHz, CDCl 3 ) [delta] 8.67 (d, = 4.77 Hz, IH), 8.31 (d, = 2.13 Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H)

third step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the resulting A by thin layer chromatography in a developing solvent system, and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%.

MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

 

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

First step

6-bromo-quinoline-4-thiol

A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, a known method of “Bioorganic &

Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.

The second step

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl

Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.

MS m / z (ESI): 368.2 [M + l]

1H MR (400 MHz, CDC1 3) δ 8.67 (d, = 4.77Hz, IH), 8.31 (d, = 2.13Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H) Step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to the resulting thin layer chromatography using a developing solvent system A and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%. MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

CYCLOALKYL ACID DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL APPLICATION THEREOF

Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model

  • Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China

This Letter describes the Discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURATl). Lead generation via 3D pharmacophore Analysis and Optimization resulted in compound 41 . With an IC 50 of 33.7 nM, 41 Also Demonstrated good Oral Bioavailability in RAT (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).

Image for unlabelled figure

http://www.sciencedirect.com/science/article/pii/S0960894X1530353X

Map of Shanghai Hengrui Pharmaceutical Co. Ltd

//////// Shanghai Hengrui, inhibitors of Human Uric Acid Transporter 1 (hURAT1), 1- (6-bromoquinolin-4-yl) sulfanylcyclobutane-1-carboxylic acid

c13cc (ccc3nccc1SC2 (C (= O) O) CCC2) Br

 

Lefucoxib (乐福昔布)


CID 16730197.pngC3

 

Lefucoxib (乐福昔布)

5-(3,4-dimethyl-phenyl)-1-methanesulfonyl-3-trifluoromethol-pyrazole

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole

CAS 849048-84-6

Molecular Formula: C19H17F3N2O2S
Molecular Weight: 394.41069 g/mol

IND FILED

Prostaglandin G/H Synthase 2 (PTGS2; COX-2) Inhibitors

A COX-2 inhibitor potentially for the treatment of rheumatoid arthritis.

cyclooxygenase-2 (COX-2) inhibitor

National Center of Biomedical Analysis

Example 1

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1)

1- (3,4- two toluene-yl) -4,4,4-trifluoro-methyl – D-1,3-dione (IV1) of sodium metal was weighed 2.3g (0.1mol) was added 50ml of anhydrous toluene to prepare a sodium sand. After cooling, ethanol was added dropwise 12ml, and then heated at 60 ℃, complete reaction of sodium metal. After cooling to room temperature, was added 3,4-dimethylphenyl ethanone 23.8g (0.1mol) and trifluoroacetic ethyl acetate 20ml (0.2mol), reacted at 100 ℃ 5 hours. Toluene was distilled off under reduced pressure, a 10% aqueous hydrochloric acid was added, the pH was adjusted to 2-3, extracted with ethyl acetate, washed with water, dried over anhydrous MgSO4, ethyl acetate was distilled off under reduced pressure. Then under reduced pressure, distillation, collecting fractions 105-107 ℃ / 0.7mmHg, was 14.6g, 60% yield.

1- [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1) take the above-prepared substituted (IV1) 2.38g (0.01mol ), 15ml of ethanol, then added p-methanesulfonyl phenyl hydrazine salt alkoxide 2.3g (0.01ml). Was refluxed for 15 hours. Place the refrigerator overnight, the crystals were collected by filtration, recrystallized from ethanol, mp 129-31 ℃, to give 3.1 g.

Elemental analysis: C19H17F3N2O2S Calculated: C, 57.86; H, 4.34; N, 7.10 Found: C, 57.97; H, 4.29; N, 7.20MS (m / z): 395 (M + 1)

C4

 

CN101497585B Jan 31, 2008 Jan 12, 2011 中国科学院理化技术研究所 Method for photocatalytic synthesis of 1,3,5-trisubstituted-2-pyrazole derivative

What is SMU-B?


Figure CN101851237BD00291

cas 1253286-89-3

Spiro[3H-​indole-​3,​4′-​piperidin]​-​2(1H)​-​one, 5-​[6-​amino-​5-​[(1R)​-​1-​(2,​6-​dichloro-​3-​fluorophenyl)​ethoxy]​-​3-​pyridinyl]​-​1′-​methyl-

SMU-B

or is it

china 1

1253286-90-6

Spiro[3H-​indole-​3,​4′-​piperidin]​-​2(1H)​-​one, 6-​[6-​amino-​5-​[(1R)​-​1-​(2,​6-​dichloro-​3-​fluorophenyl)​ethoxy]​-​3-​pyridinyl]​-​1′-​methyl-

SMU-B

Abstract Image

A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4′-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (compound 5b or SMU-B) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models.

see..http://pubs.acs.org/doi/abs/10.1021/ml400203d

ACS Med. Chem. Lett., 2013, 4 (8), pp 806–810
DOI: 10.1021/ml400203d

cas 1253286-90-6

6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (compound 5b or SMU-B)

SEE

CN 101851237

南方医科大学

Figure CN101851237BD00142

1_4,3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-nitro-approved P set

 

Figure CN101851237BD00251

  obtained in Step 1-3 (IS) -I- (2,6- dichloro-3-fluorophenyl) ethanol (2. 09g, IOmmol) was dissolved in dry THF (80 ml). Then, at room temperature under a nitrogen atmosphere, a solution of 3-hydroxy-2-nitro-pyridine (1.54g, llmmol) and triphenylphosphine (3. 409g, 13mmol), and so is completely dissolved, cooled to 0 ° C, was added Diisopropyl azodicarboxylate (DIAD, 2.63g, 13mmol), After the addition, the mixture was stirred at 0 ° C for 16 hours, the solvent was removed by rotary evaporation and the oily residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate : 4/1) to give the desired product as a white solid (3. 046g, yield: 92%) o 1H-NMR (CDClySOOMHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), 6 . 10 (q, J = 6. 4Hz, 1H), 7. 09 (dd, J = 7. 6,8. 8Hz, 1H), 7. 21 (dd, J = 8. 4, I. 2Hz, 1H ), 7. 31 (dd, J = 4. 8,8. 8Hz, 1H),

7. 37 (dd, J = 4. 8,8. OHz, 1H), 8. 04 (dd, J = L 6,4. 4Hz, 1H). Mass spectrum m / z:. 330 94 [M + H, 35C1,35Cl], 332. 92 [M + H, 35Cl, 37Cl].

  1_5,3_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -2_ atmosphere based grant given P

 

Figure CN101851237BD00252

to take steps 1-4 to get the 3 – [(lR) _l- (2,6_ dichloro-3-fluorophenyl) ethoxy] -2_ nitro than Li Jie (2. 649g, 8mmol) was dissolved in ethanol (15mL) was added iron powder (3. 575g, 64mmol) were mixed under nitrogen with vigorous stirring at 90 ° C oil bath, was added via syringe 0.8mL IM HCl (aq), after 10 minutes, was added 0. 8mL IMHCl (aq). Stirring was continued for 30 minutes, TLC showed the reaction. Cooled to room temperature, filtered through Celite, the filter residue washed with ethanol (3X IOmL). The combined organic phase was removed by rotary evaporation of the solvent gave the desired product as a light brown solid (2. 41g, yield: 100%) o 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 81 (d, J = 6. 8Hz, 3H ), 5. 03 (s, br, 2H), 6. 01 (q, J = 6. 8Hz, 1H), 6. 47 (dd, J = 4. 8,7. 6Hz, 1H), 6. 70 (d, J = 8. OHz, 1H), 7. 05 (t, J = 8. 8Hz, 1H), 7. 28 (dd, J = 4. 0,8. 0Hz, 1H), 7. 57 ( d, J = 5.2Hz, lH). Mass spectrum m / z:. 301 00 [M + H, 35Cl, 35Cl], 302. 77 [M + H, 35Cl, 37Cl].

  l-6,5_ desert _3_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -2_ atmosphere base than Li Jie

 

Figure CN101851237BD00261

The steps 1-5 obtained 3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-yl atmosphere than Li Jie (1.506g, 5mmol) dissolved in acetonitrile (20mL) in. Then, at 0 ° C and the degree of stirring in added portionwise N- bromosuccinimide (0.908g, 5. Lmmol), After the addition, stirring was continued for 30 minutes. The solvent was removed by rotary evaporation, the crude product was obtained as a white solid was the desired product (1.045g, yield: 55%) was purified by column chromatography on silica gel. 1H-NMR (⑶Cl3,500MHz): 8 (ppm) I. 81 (d, J = 6. 8Hz, 3H), 4 85 (s, br, 2H), 6 98 (q, J = 6. 8Hz.. , 1H), 6. 82 (d, J =

2. 0Hz, 1H), 7. 08 (t, J = 8. 4Hz, 1H), 7. 31 (dd, J = 4. 8,8. 8Hz, 1H), 7. 65 (d, J = 2 . OHz, 1H). Mass spectrum m / z:… 378 84 [M + H, 35Cl, 35Cl, 79Br], 380 82 [M + H, 35Cl, 35Cl, 81Br or 35Cl, 37Cl, 79Br], 382 80 [M + H, 35Cl , 37Cl, 81Bror 37Cl, 37Cl, 79Br].

Step 2, I ‘- methyl-5- (4,4,5,5-tetramethyl -I, 3,2- dioxolane boron-2-yl) spiro [indoline Spray – 3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00262

  2-1,5- bromo -I ‘- methyl-spiro [indoline-3,4’ – piperidin] _2_ one

 

Figure CN101851237BD00263

[0300] 5-bromo – indol-2-one (I. 272g, 6mmol) was suspended THF (15mL) at, and cooled to -78 ° C, added dropwise with stirring IM NaN (SiMe3) THF solution of 2 (30mL, 30mmol). After the addition was stirred at _78 ° C 30 min, then 2-chloro -N- (2- chloro-ethyl) -N- methyl-ethylamine hydrochloride solid (I. 155g, 6mmol). After the addition stirring was continued for 30 minutes, then warmed to room temperature and stirred for two days. TLC showed the reaction was completed, to the pink suspension was carefully added aqueous 4M hydrochloric acid (IOmL), and then adjusted with concentrated aqueous ammonia to pH ^ 9, and extracted with DCM (3 X 80mL). The organic phases were combined, dried (Na2SO4), and concentrated to give the crude product was purified by silica gel column chromatography (7M NH3 in methanol solution / DCM: 5/95) to give the desired product (I. 38g, yield: 78%) was purified. 1H-NMR (CD3ODjOOMHz):. 8 (ppm) I. 86-1 92 (m, 2H), I 94-1 98 (m, 2H), 2 44 (s, 3H), 2 62-…. 2. 68 (m, 2H), 2. 86-2. 91 (m, 2H), 6. 76 (d, J = 7. 6Hz, 1H), 7. 33 (dd, J = I. 2,7 . 6Hz, 1H), 7. 44 (d, J = I. 6Hz, 1H), 7. 81 (s, br, 1H). Mass spectrum m / z:. 294 99 [M + H, 79Br], 296 82 [M + H, 81Br]..

2-2, V – methyl-5- (4,4,5,5-tetramethyl–1,3,2_ dioxolane Borane _2_ yl) spiro [indoline – 3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00271

Under nitrogen, obtained in Step 2-1 to 5-bromo -I ‘- methyl-spiro [indoline-_3,4’ – piperidin] _2_ one (147. 6mg, 0. 5mmol) , the United pinacols drop acid unitary purpose (140mg, 0. 55mmol) and acetic acid Bell (147mg, I. 5mmol) in DMSO (0. 2ml) was added in PdCl2 (dppf) • CH2Cl2 (20. 4mg, 0. 025mmol ), to the resulting solution was bubbled with nitrogen for 2 minutes, and then stirred at 80 ° C of 16 hours. LC-MS showed completion of the reaction, after cooling to room temperature, water (2mL), extracted with DCM (3X5mL). The organic phases were combined, dried (Na2SO4), and concentrated to give the desired product (170mg, yield: 100%) o MS m / z:. 342 07 [M + H], 343. 08 [M + H, 100%], 344. 11 [M + H].

  Step 3,5_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3_ batch P fixed base] -I ‘- A group spiro [indoline-3,4 ‘- piperidin] -2_ one

The steps 1-6 5_ desert obtained _3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-yl batch atmosphere pyridine (75. 8mg , 0. 2mmol), I’- step 2_2 obtained methyl 5- (4,4,5,5-tetramethyl-l, 3,2-dioxolane Borane 2-yl) spiro [ indoline-3,4′-piperidin] -2-one (82mg, 0. 24mmol) and potassium carbonate (82. 9mg, 0. 6mmol) was dissolved in DME / water mixture solution (4 / 1,2. Oml ). Then, under nitrogen, was added Pd (PPh3) 4 (II. 6mg, 0. Olmmol), to the resulting mixture was bubbled with nitrogen for 2 minutes, and then stirred at 80 ° C of 18 hours. LC-MS showed completion of the reaction, after cooling to room temperature, water (5mL), extracted (3 X IOmL) with DCM. The organic phases were combined, dried (Na2SO4), and concentrated to give the crude product was purified by silica gel column chromatography (7M NH3 in methanol solution / DCM: 5/95) to give the desired product (88. 6mg, yield: 86%) was purified. 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), I 93-2 02 (m, 4H), 2 44 (s, 3H),…

2. 66-2. 72 (m, 2H), 2. 89-2. 93 (m, 2H), 4. 87 (s, br, 2H), 6. ll (q, J = 6. 4Hz, 1H ), 6. 88 (d, J =

8. OHz, 1H), 6. 94 (d, J = I. 2Hz, 1H), 7. 06 (t, J = 8. 4Hz, 1H), 7. 19 (dd, J = I. 2,8 . OHz, 1H),

7. 31 (m, 1H), 7. 36 (s, 1H), 7. 66 (s, br, 1H), 7. 80 (d, J = 2. OHz, 1H). Mass spectrum m / z:.. 515 05 [M + H, 35Cl, 35Cl], 517 03 [M + H, 35Cl, 37Cl].

  Example 2: 6_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3_ than Li Jie base] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00281

Step I, I ‘- methyl-6- (4,4,5,5-tetramethyl–I, 3,2- dioxolane boron-2-yl) spiro [indoline Spray – 3,4 ‘- piperidin] -2_ one

  1-1,6- bromo -I ‘- methyl-spiro [indoline-3,4’ – piperidin] -2_ one

 

Figure CN101851237BD00282

  As described in Example I steps 2-1 of the method from the commercially available 6-bromo – indol-2-one was prepared, Yield: 82%. Analysis of the data obtained the desired product are = 1H-Nmr (Cd3OdJOOmHz): 8 (ppm) 1.90-1.98 (m, 4H),

2. 44 (s, 3H), 2. 64-2. 68 (m, 2H), 2. 86-2. 92 (m, 2H), 7. 05 (d, J = 2. 0Hz, 1H), 7. 16-7. 21 (m, 2H), 7. 91 (s, br, 1H). Mass spectrum m / z: 295 00 [M + H, 79Br], 296 78 [M + H, 81Br]… [0312] 1-2, 1 ‘- methyl-6- (4,4,5,5-tetramethyl-_1,3,2_ dioxolane Borane _2_ yl) spiro [indoline – 3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00283

In the step 1-1 of the obtained 6-bromo -I ‘- methyl-spiro [indoline-_3,4’ – piperidin] -2_ ketone and commercially available linking pinacol boronic ester material, the method of Example I was prepared in accordance with steps 2-2, Yield: 95%. Analysis of the data obtained of the target product are as follows: Mass spectrum m / z:. 342 06 [M + H], 343 04 [M + H, 100%], 344. 12 [M + H]..

  Step 2,6_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3 ratio Li Jie base] -I ‘- methyl-spiro [indoline-3,4 ‘- piperidin] -2_ one

  Example I steps 1-6 to obtain 5-bromo -3 – [(IR) -I- (2,6- dichloro-3-fluorophenyl) ethoxy] -2-amino- pyridine, I obtained in Example 1-2 of the present embodiment in step ‘- methyl-6- (4,4,5,5-tetramethyl-l, 3,2-dioxolane-2-yl borane) spiro [indoline-_3,4 ‘- piperidin] -2-one, prepared as in Example I Step 3. Yield: 82%. 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), I. 91-1 95 (m, 2H), I 97-2 03 (m, 2H… ), 2. 45 (s, 3H), 2. 65-2. 72 (m, 2H), 2. 89-2. 95 (m, 2H), 5. 12 (s, hr, 2H),

6. 12 (q, J = 6. 4Hz, 1H), 6. 94-7. 00 (m, 3H), 7. 06 (t, J = 8. 4Hz, 1H), 7. 31 (m, 1H ), 7. 35 (d, J = 7. 2Hz, 1H), 7. 90 (d, J = 2. 0Hz, 1H), 9. 28 (s, br, 1H). Mass spectrum m / z:.. 515 05 [M + H, 35Cl, 35Cl], 517 03 [M + H, 35Cl, 37Cl].

5- [6-amino-5 – [(2,6-dichloro-3-fluorophenyl) methoxy] _3_ pyridinyl] -I’–methyl-spiro [indole: 3 [0317] Example morpholine-3,4 ‘- piperidin] -2-one

 

H2N N

 

Figure CN101851237BD00291
Figure CN101851237BD00292
Figure CN101851237BD00293

Step I, 5_ desert _3_ (2,6_ two gas -3- integrity oxy) _2_ atmosphere based grant given P

  1-1,2,6_ two gas acid gas _3_

 

Cl OF

Sodium hydroxide (13g, 325mmol) in water (IlOmL) was cooled to _5 ° C was added dropwise under vigorous stirring of liquid bromine (12. 5g, 78. 2mmol), added after the addition of pre-cooled to 10 ° C dioxane (75mL). The above mixture under vigorous stirring was added dropwise a pre-cooled to 5 ° C of I- (2,6- dichloro-3-fluorophenyl) ethanone (5g, 21. 2mmol) in dioxane (330mL) and water (90mL) was added. After the addition, at room temperature for 2 hours Lan Xiang, Xiang Lan then 90 C for 30 minutes. TLC was not shown with the S starting material disappeared, and was acidified with concentrated hydrochloric acid to PH~9. The resulting mixture was rotary evaporated to dryness, added water (20mL), and extracted with diethyl ether (2X80mL), the organic phases were combined, dried (Na2SO4), and concentrated to give an oily product solidified after cooling to a transparent, slightly yellow solid (3. 4g, Yield: 67%). 1H-Nmr (Cdci3AOOmHz):. 8 (ppm) 7. 21 (. Dd, J = 8. 0,8 8Hz, 1H), 7 35 (. Dd, J = 4. 4,9 2Hz, 1H), 9 . 79 (s, br, 1H). Mass spectrum m / z (ES “:. 207 11 [M_H, 35Clj35Cl], 209 10 [MH, 35Cl, 37Cl]..

  1-2,2,6–dichloro-3-fluoro-benzyl alcohol

 

^ Coh

F

[0325] To be filled with 2,6-dichloro-3-fluoro benzoic acid (3g, 14. 35mmol) added dropwise to the flask IM BH3. THF (43mL, 43mmol), added after the mixture was stirred under reflux for 24 hours. TLC showed the reaction was complete, methanol (50mL) to destroy excess borane, and the solvent was distilled off under reduced pressure and the resulting trimethyl borate, the process is repeated twice more to give a viscous product 2. I g, yield: 75% . 1H-Nmr (Cdci3JOOmHz): 8 (ppm) 2. 09 (t, J = 6. 4Hz, 1H), 4. 97 (d, J = 6. 4Hz, 2H), 7 09 (t, J = 8. . 8Hz, 1H), 7. 32 (dd, J = 4. 8,9. 1Hz, 1H). Mass spectrum m / z (ES-):.. 193 08 [M_H, 35Cl, 35Cl], 195 12 [MH, 35Cl, 37Cl].

  1-3,3_ (2,6-gas _3_ integrity oxy) _2_ nitro grant given P

 

Figure CN101851237BD00301

Following the procedure of steps 1-4 of Example I, was prepared from 2,6-dichloro-3-fluoro-benzyl alcohol and 3-hydroxy-2-nitropyridine prepared in yield (in this example embodiment steps 1_2) : 90%. 1H-Nmr (Cdci3AOOmHz): 8 (ppm) 5. 45 (s, 2H), 7 20, 7 37 (dd, J = 4. 8. (Dd, J = 8. 0,9 2Hz, 1H.). , 9. 2Hz, 1H), 7. 59 (dd, J = 4. 4,8. 4Hz, 1H),

7. 74 (dd, J = L 2,8. 4Hz, 1H), 8. 17 (dd, J = L 6,4. 4Hz, 1H). Mass spectrum m / z:. 316 89 [M + H, 35Cl, 35Cl], 318. 89 [M + H, 35Cl, 37Cl].

  1_4,3_ (2,6-gas _3_ integrity oxy) _2_ atmosphere based grant given P

 

Figure CN101851237BD00302

The method according to Example I step 1_5 from 3- (2,6-gas -3- integrity oxy) _2_ nitro Jie ratio 唳 preparation (in this case, steps 1-3), that Yield: 95% o 1H-Nmr (Cdci3JOOmHz):. 8 (ppm) 4 65 (s, br, 2H), 5 31 (s, 2H), 6 66 (dd, J = 5. 2,8.. . 0Hz, 1H), 7. 14 (dd, J = I. 2,8. 0Hz, 1H), 7. 18 (dd, J =

8. 4,9. 2Hz, 1H), 7. 37 (dd, J = 4. 8,8. 8Hz, 1H), 7. 73 (dd, J = I. 6,5. 6Hz, 1H). Mass spectrum m / z:. 286 95 [M + H, 35Cl, 35Cl], 288 85 [M + H, 35Cl, 37Cl]..

  1-5,5_ desert -3- (2,6-gas -3_ integrity oxy) ~ 2 ~ atmosphere based grant given P

 

Figure CN101851237BD00303

Following the procedure of Example I step 1_6 embodiment, starting from 3- (2,6-gas _3_ integrity yloxy) _2_ atmosphere group given the preparation of the batch P (in the example of the present embodiment in step 1-4), Yield: 60% o 1H-Nmr (Cdci3JOOmHz):. 8 (ppm) 4 68 (s, br, 2H), 5 28 (s, 2H), 7 21 (dd, J = 8. 0,8.. . 8Hz, lH), 7. 24 (dd, J = 2. OHz, 1H), 7. 39 (dd, J = 4. 8,

9. 2Hz, 1H), 7. 78 (d, J = 2. OHz, 1H). Mass spectrum m / z:. 364 83 [M + H, 35Cl, 36Cl, 79Br], 366 77 [M + H], 368 69 [M + H]…

  Step 2,5_ [6_ atmosphere base _5_ [(2,6_ two gas -3- gas) methoxy] -3_ than Li Jie base] -I-methyl-spiro [indoline _ 3,4 ‘- piperidin] -2-one

The present embodiment 5_ desert steps 1_5 obtained _3_ (2,6_ two gas _3_ integrity yloxy) pyridine ~ 2 ~ atmosphere, Examples 2-2 obtained in step I I ‘- methyl-5- (4,4,5,5-tetramethyl-borane _1,3,2- dioxolane-2-yl) spiro [indoline-_3,4’ – piperidine ] -2-one, prepared as in Example I Step 3. Yield: 85 V0o 1H-Nmr (Cdci3JOOmHz):.. 8 (ppm) I. 92-2 02 (m, 4H), 2. 43 (s, 3H), 2. 65-2 71 (m, 2H) , 2. 90-2. 91 (m, 2H), 4. 92 (s, br, 2H), 5. 52 (s, 2H), 6. 89 (d, J = 8. 4Hz, 1H), 6 . 90 (d, J = L 2Hz, 1H), 7. 06 (t, J = 8. OHz, 1H), 7. 21 (dd, J = L 2,8. OHz, 1H), 7. 31 ( m, 1H),

7. 37 (s, 1H), 7. 79 (s, br, 1H), 7. 80 (d, J = 2.0Hz, lH). MS m / z:. 501 06 [M + H, 35Cl, 35Cl], 503 04 [M + H, 35Cl, 37Cl]..

6- [6-amino-5 – [(2,6-dichloro-3-fluorophenyl) methoxy] _3_ pyridinyl] -I’- methyl-spiro [indole: 4 [0337] Example morpholine _3,4 ‘- piperidin] -2-one

 

Figure CN101851237BD00311
Figure CN101851237BD00312
Figure CN101851237BD00313

H2N N

  Following the procedure in Example I step of Example 3, the procedure of Example 3 to give 5-bromo-1-5 _3_ (2,6-dichloro-3-fluoro-benzyloxy) -2-amino-pyridine and Step 2 in Example I to give the embodiment 1-2 ‘- methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxolane Borane 2-yl) spiro [ indoline-3,4 ‘- piperidine] _2_ ester -one, yield:. 78 V0o 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 96-2 00 (m, 2H), 2. 01 -2. 12 (m, 2H), 2. 46 (s, 3H), 2. 66-2. 73 (m, 2H), 2. 90-2. 96 (m, 2H), 5. 30 (s , hr, 2H), 6. 94-7. 01 (m, 3H), 7. 07 (t, J =

8. 4Hz, 1H), 7. 30 (m, 1H), 7. 34 (d, J = 7. 2Hz, 1H), 7. 89 (d, J = 2. OHz, 1H), 8. 56 ( s, br, 1H). MS m / z:. 501 06 [M + H, 35Cl, 35Cl], 503 04 [M + H, 35Cl, 37Cl]..

  Example 5: 5_ [5_ atmosphere base -6- [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Batch-2-yl] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2-one

 

J0A = o

. | J: too

[0342] Step 1,5_ desert _2_ atmosphere base _3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Jie than exposure

 

Cl 6, / ISL / Br

xy

H2N N

  In at 0 ° C, NaH (80mg of NaH in mineral oil, 2mmol) force the mouth (1R) -1_ (2,6- dichloro-3-fluorophenyl) ethanol (418mg, 2mmol. See example Example I Step 1_3) in anhydrous THF (6mL) and stirred for half an hour, a solution of 2-amino-3,5-dibromo-pyrazine (506mg, 2mmol) in THF (6mL) was added. The resulting mixture was warmed to room temperature, heated under reflux for 20 hours. TLC showed the reaction was substantially complete. After cooling to room temperature, water was added (IOmL), the mixture was extracted three times with ethyl acetate (3x20mL), the organic phases were combined, dried, concentrated, and the residue to give 594mg product was purified by column chromatography (l-3Me0H inhexanes), yield: 78%. 1H-NMR (O) Cl3, 500MHz):. 8 (ppm) I. 83 (d, J = 7. 2Hz, 3H), 5. 12 (s, br, 2H), 6 73 (q, J = 6 . 8Hz, 1H), 7. 05 (t, J = 8. OHz, 1H), 7. 28 (dd, J = 4. 8,

8. 8Hz, 1H), 7. 58 (s, 1H). Mass spectrum m / z:. 379 83 [M + H, 35Cl, 35Cl, 79Br], 381. 81 [M + H, 35Cl, 35Cl, 81Br], 383 79 [M + H, 35Cl, 37Cl, 81Br]..

Step 2,5_ [5_ atmosphere base _6_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Batch-2-yl] -I ‘- A group spiro [indoline-3,4 ‘- piperidin] -2-one

  5_ bromide present embodiment obtained in step I _2_ amino _3_ [(IR) -I- (2,6_ dichloro _3_ fluorophenyl) ethoxy] pyrazine, implemented I’- methyl step 2-2 obtained in Example I-5 (4,4,5,5-tetramethyl -I, 3,2- dioxolane boron

2-yl) spiro [indoline-3,4 ‘- piperidin] -2-one, prepared as in Example I Step 3. Yield: 54%. 1H-NMR (CD3ODjOOMHz): 8 (ppm) I. 85 (d, J = 6. 8Hz, 3H), I 85-1 88 (m, 2H), I 97-2 04 (m, 2H…. ), 2. 46 (s, 3H), 2. 76-2. 82 (m, 2H), 2. 97-3. 02 (m, 2H), 6. 74 (q, J = 6. 4Hz, 1H ), 6. 85 (d, J = 8. OHz, 1H), 7. 15 (t, J = 8. 4Hz, 1H), 7. 41 (dd, J = 4. 8,9. 2Hz, lH) , 7. 54 (dd, J = I. 6,

8. OHz, 1H), 7. 69 (d, J = I. 8Hz, 1H), 7. 81 (dt, J = 2. 0,8. 0Hz, 1H), 7. 87 (s, 1H). Mass spectrum m / z:. 515 92 [M + H, 35Cl, 35Cl], 517. 90 [M + H, 35Cl, 37Cl].

Example 6: 6- [5-amino -6 – [(lR) -l_ (2,6- dichloro _3_ fluorophenyl) ethoxy] pyrazin-2-yl] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2-one

 

Figure CN101851237BD00321

The embodiment of Example 5, 5_ bromo obtained in step I _2_ amino _3_ [(IR) -I- (2,6_ dichloro _3_ fluorophenyl) ethoxy] pyrazine, Example I’- methyl-2 obtained in steps 1-2 6- (4,4,5,5-tetramethyl–I, 3,2- dioxolane boron-2-yl) spiro [indole morpholine -3,4’_ piperidin] -2-one, prepared as in Example I Step 3. Yield: 67% 0

1H-NMR (CD3ODjOOMHz): 8 (ppm) I. 85 (d, J = 6. 8Hz, 3H), I 88-1 96 (m, 4H), 2 48 (s… , 3H), 2. 76-2. 82 (m, 2H), 2. 98-3. 05 (m, 2H), 6. 75 (q, J = 6. 4Hz, 1H), 7. 16 (t , J = 8. 8Hz, 1H), 7. 31 (d, J = 2. OHz, 1H), 7. 36-7. 43 (m, 3H), 7. 88 (s, 1H).

Mass spectrum m / z:. 515 99 [M + H, 35Clj35Cl], 517 90 [M + H, 35Cl, 37Cl]..

SEE

Bioorganic & Medicinal Chemistry Letters (2014), 24(16), 3673-3682.

School of Pharmaceutical Sciences, Southern Medical University,

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.
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.
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.




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Zifaxaban, TY-602, Zhifeishaban 知非沙班……Tianjin Institute of Pharmaceutical Research China


 

zifa

 

Zifaxaban

Figure CN102464658AD00081

Zifaxaban

cas 1378266-98-8

rotation (-)

C20 H16 Cl N3 O4 S

C20H16ClN3O4 S, M = 429.87

Tianjin Institute of Pharmaceutical Research

Deep vein thrombosis; Lung embolism

Factor Xa antagonist

TY-602; zhifeishaban; zifaxaban

天津药物研究院

Chinese J Struc Chem. 2014, 33 (7), 1091-1095.

(S) -5- chloro -N- ((2- oxo _3_ (4_ (2_ oxo _2H_-1-yl) phenyl) oxazolidin-5 -1,3_ yl) methyl) thiophene-2-carboxamide

5-Chloro-N-(5S)-2-oxo-3-[4-(2-oxopyridin-1(2H)-yl)phenyl]oxazolidin-5-ylimethyllthiophene-2-carboxamide]

 

The title compound(zifaxaban 2, C20H16ClN3O4 S, Mr = 429.87) was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900(12), b = 13.086(3), c = 12.889(3) A, β = 100.86(3)°, V = 959.1(3) A3, Z = 2, Dc = 1.489 g/cm3, F(000) = 444, μ = 0.342 mm-1, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections(I > 2σ(I)).

The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation.

Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.

zifaxaban (first disclosed in CN102464658), useful for treating thromboembolic disorders. Zifaxaban, a factor Xa antagonist, is being developed by Tianjin Institute of Pharmaceutical Research, for treating deep vein thrombosis and pulmonary embolism (preclinical, as of November 2014). In May 2014, an IND was filed in China. In June 2014, the institute was seeking to outlicense this product.

In vivo within the cardiovascular, blood coagulation or blood analysis some have formed out of the process of forming a solid mass with the aggregation, called thrombosis, the formation of a solid mass called a thrombus blocks. Thrombosis is an abnormal flow of blood coagulation status due to platelet activation and coagulation factors are activated in accordance therewith.

The blood coagulation was originally a protective mechanism of the organism, there is a mutual antagonism in blood coagulation system and the anti-clotting system. Under physiological conditions, blood clotting factors continue to be activated to produce thrombin, fibrin formation trace, calm on the vascular endothelium, but these traces of fibrin and constantly being activated fibrinolytic system dissolution, while being activated coagulation factors are constantly mononuclear phagocyte system swallowed. The dynamics of the coagulation system and fibrinolysis system, which ensures the blood coagulation potential can also always ensure that the fluid state of the blood.

 Sometimes, however, in certain factors can promote the coagulation process, breaking the above dynamic balance triggered the coagulation process, the blood can form a thrombosis or embolism, such as leading to myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism and other thromboembolic disease.

Thromboembolic disease is cardiovascular disease against the most serious diseases, is the first killer of human health. In China, with the improvement and increased aging of the population’s living standards, the incidence of such diseases, mortality, morbidity is increasing every year.

The existing anti-thromboembolic diseases into anti-platelet drugs, anticoagulants and fibrinolytic drugs. Among them, the anti-clotting drugs are the main contents of antithrombotic therapy, mainly thrombin inhibitors and vitamin K antagonists. Heparin and low molecular weight heparin, represented by the presence of oral thrombin inhibitor invalid, non-selective inhibition and high risk of bleeding and other shortcomings. Although warfarin is representative of vitamin K antagonists can be administered orally, but there are narrow therapeutic index, high risk of bleeding and other shortcomings.

Studies have shown that the coagulation process is usually divided into intrinsic coagulation pathway and the extrinsic coagulation pathway. Coagulation process involves a lot of coagulation factors, coagulation factor activated are each the next inactive clotting factor precursor is converted into the activated form. Endogenous, exogenous pathway final summary, the blood coagulation factor X is converted to Xa.

Therefore, theoretically, the direct inhibition of ¾ factor activity should produce effective anti-clotting effect, without the side effects of thrombin inhibitors with. As direct inhibition) (a factor activity on normal hemostasis reaction / adjustment process produces minimal impact. For example, platelets remain low catalytic activity of thrombin on the ability to respond to, and thus does not affect the formation of platelet thrombi, so bleeding integrated minimize the risk of the levy.

  research also proved this point. Recently reported a variety of compounds can selectively inhibit efficient Xa, which play a preventive and / or treatment of thromboembolic disease effect (W003000256A1; CN00818966; US2007259913A1; US2007259913A1). Among them, rivaroxaban (Rivaroxaban) was listed in 2008 for hip or knee replacement surgery prophylaxis and treatment of venous thrombosis, with oral, fixed dose and other advantages.

  rivaroxaban drawback is the high price of raw materials, low yield preparation, purification of the product is difficult, high production costs. Patent CN00818966 8 reported rivaroxaban synthetic routes as follows:

4

Figure CN102464658AD00051

where the first reaction (Preparation of 4- (4-morpholino-3-yl) nitrobenzene) yield of only 17.6%, and rivaroxaban difficult purification.

 

Figure CN102464658AD00061

 

………………………………

Patent

http://www.google.com/patents/CN103232446A?cl=en

(S) -5- chloro -N- ((2- oxo-3- (4- (2_ oxo -2H- pyridin-1-yl) phenyl) -1, 3_ oxazolidine -5 – yl) methyl) thiophene-2-carboxamide.

[0011] Meanwhile, patent CN201110337461.4 described formula (I) Preparation of the compound:

[0012]

Figure CN103232446AD00041

 

……………………………………..

Patent

CN102464658

http://www.google.com/patents/CN102464658B?cl=en

Example 1

[0046] (S) -5- chloro -N- ((2- oxo-3- (4_ (2_ Batch oxo _2H_ piperidinyl) phenyl) _1,3_ oxazolidin-5-yl) methyl ) thiophene-2-carboxamide (II)

 

Figure CN102464658AD00081

[0048] A, 1- (4- amino-phenyl) -IH- pyridin _2_ -one (Compound VII) is

[0049] The reaction flask was charged with 104g of pyridine -2 (IH) – one (Compound IX), 200g of iodoaniline (compound VIII), 26gCuI, 151g of potassium carbonate, 18g8- hydroxyquinoline, 500mlDMF, nitrogen, heated to reflux, Insulation reaction was stirred 10h. Filtered hot, the filtrate evaporated under reduced pressure to make the solvent, the residue was added ethyl acetate, IL, 0 ° C incubated with stirring lh, filtered and the solid dried, 2L acetonitrile and purified to give 98g dark red solid. Refined liquor was concentrated to 500ml, the ice bath was stirred lh, filtered to give a dark red solid 19g. Total product were 117g, yield 68.9%.

[0050] 1H-NMR (DMSO-Cl6), δ (ppm):… 5 306 (s, 2H), 6 236 (d, 1H), 6 406 (d, 1H), 6 601 (d,. 2H), 6. 977 (d, 2H), 7. 459 (m, 2H).

[0051] B, (R) -2- (2- hydroxy-3- ((2-oxo–2H- pyridin-1-yl) phenyl) amino) propyl) isoindoline-1,3- -dione (Compound V) is

[0052] The reaction flask was added 40gl_ (4- aminophenyl) -IH- pyridin-2-one (Compound VII), 45g (S) _N_ glycidyl phthalimide (Compound VI), 300ml95% ethanol, heating to reflux, the gradual emergence of solid insulation mixing IOh, cooled to room temperature, filtered, and the filter cake washed with ethanol (150ml X 2), and dried to give an off-white solid 38g.

[0053] The mother liquor was taken, evaporated to dryness under reduced pressure, was added 15g (Q-N_ glycidyl phthalimide (Compound VII), 150ml95% ethanol, heated to reflux, stirred incubated 10h, concentrated under reduced pressure, cooled to room temperature , stirred at room temperature for 2h, washed with ethanol and dried to give an off-white solid 33g.

[0054] A total of an off-white solid 71g, yield of 84.8%, without purification, was used directly in the next step.

[0055] 1H-NMR (DMS0_d6), δ (ppm):… 3 053 (m, 1H), 3 194 (m, 1H), 4 644 (m, 2H), 4 020 (m, 1H). , 5. 168 (d, 1H), 5. 851 (t, 1H), 6. 230 (m, 1H), 6. 404 (d, 1H), 6. 665 (d, 2H), 7. 041 ( d, 2H), 7. 435 (m, 1H), 7. 537 (m, 1H), 7. 855 (m, 4H).

[0056] C, ⑶-2- ((2- oxo-3- (4- (2_ oxo _2H_ pyridyl) phenyl) oxazolidin _5_ -1,3_ yl) methyl ) Preparation of isoindoline-1,3-dione (Compound IV) of the

[0057] The reaction flask was charged 50g Compound V, 27gN, N’- carbonyldiimidazole (⑶I), 4_ catalytic amount of dimethylaminopyridine (DMAP), 150mlN, N- dimethylformamide (DMF), stirred for 90 temperature ° C, the reaction was kept for 8 hours to make the solvent was evaporated under reduced pressure, added to IL of water, stirred and dispersed, filtered, washed with water (150mlX “, washed with ethanol (100ml X 1), dried to give a white solid 48g, yield of 90%.

[0058] 1H-NMR (DMSo-CI6), δ (ppm):…. 3 984 (m, 3H), 4 251 (t, 1H), 4 968 (m, 1H), 6 301 (m, 1H), 6. 459 (d, 1H), 7. 423 (d, 2H), 7. 514 (m, 1H), 7. 615 (m, 3H), 7. 892 (m, 4H).

[0059] D, (S) -5- (aminomethyl) -3- (4- (2_ oxo _2H_-1-yl) phenyl) oxazolidin _2_ -1,3_ one hydrochloride (compound III) Synthesis of

[0060] The reaction flask was charged 50g compound IV, 200ml of ethanol, 60ml aqueous methylamine (40%), heated to reflux, stirred incubated 2h, cooled, evaporated under reduced pressure to make the solvent to give a sticky solid.

[0061] added to 300ml of ethanol, 20ml of hydrochloric acid, heated to reflux, stirred incubated lh, cooled to room temperature, incubated with stirring 2h, filtered, washed with ethanol, and dried to obtain;. 34 5g of white solid, yield 88.7%.

 1H-NMR (DMS0_d6), δ (ppm):…. 3 240 (m, 2H), 3 980 (m, 1H), 4 255 (m, 1H), 5 028 (m, 1H) , 6. 321 (m, 1H), 6. 475 (d, 1H), 7. 504 (m, 3H), 7. 634 (m, 3H), 8. 561 (s, 1H).

 Ε, (S) -5- chloro -N – ((2- oxo-3- (4- (2-oxo–2Η- pyridin-1-yl) phenyl) oxazolidin _1,3_ 5-yl) methyl) thiophene-2-carboxamide Preparation of thiophene (II) of

The reaction flask was charged 15g Compound III, 200ml of tetrahydrofuran, 40ml of water was added with stirring 6. 2g of sodium carbonate was added dropwise 10g5- chloro-thiophene-2-carbonyl chloride (Compound II-1) in tetrahydrofuran IOOml, 30~35 ° C insulation stirred 5h, point board to control the reaction was complete.

 to make the solvent was distilled off under reduced pressure, 50ml of water was added, stirring was filtered, the filter cake washed with water and dried to give 18. 5g of white solid.

 200ml of acetic acid and purified room temperature overnight, filtered, and the filter cake washed with ethanol and dried to give a white solid 16g, 80% yield.

Melting point: 204 8 ~205 8 ° C;

 1H-NMR (DMSo-CI6), δ (ppm):…. 3 623 (t, 2H), 3 893 (m, 1H), 4 230 (t, 1H), 4 871 (m, 1H), 6. 308 (t, 1H), 6. 468 (d, 1H), 7. 193 (d, 1H), 7. 426 (m, 2H), 7. 500 (m, 1H), 7. 637 (m, 4H), 8. 967 (t, 1H);

 MS (ESI): m / z = 430 (M + H);

 HPLC: rt (%) = 14. 38 (99. 62);

 [a] 20d = -37 6 ° (c 0. 3004, DMS0);

 

WO-2014183667Acetic acid solvate of oxazolidinone derivative, preparation method for the solvate, and application thereof

 

WO-2014183665Oxazolidinone derivative crystal form I and preparation method and use thereof

 

WO-2014183666Oxazolidinone derivate crystal form II, preparation method therefor, and application thereo

 

SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

/////////

 

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