2H-​Pyran-​4-​carboxamide, 4-​amino-​N-​[(1S,​2E)​-​4-​(2,​3-​dihydro-​1H-​indol-​1-​yl)​-​1-​ethyl-​4-​oxo-​2-​buten-​1-​yl]​tetrahydro-​, hydrochloride (1:1)

COMPD A

DATA FOR A

HCL SALT CAS 1613458-78-8

BASE CAS 1613458-70-0

C20 H27 N3 O3 . Cl H

MW OF BASE…..357.45

4-amino-N-[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l- yl]tetrahydr -2H-pyran-4-carboxamide hydrochloride

2H-​Pyran-​4-​carboxamide, 4-​amino-​N-​[(1S,​2E)​-​4-​(2,​3-​dihydro-​1H-​indol-​1-​yl)​-​1-​ethyl-​4-​oxo-​2-​buten-​1-​yl]​tetrahydro-​, hydrochloride (1:1)

DATA FOR A

WO 2014091443

http://www.google.com/patents/WO2014091443A1?cl=en

synthesis

Intermediate 1

1,1-dimethylethyl ((l -l-{[methyl(methyloxy)amino]carbonyl}propyl)carbamate

To a solution of (2,S)-2-({[(l,l-dimethylethyl)oxy]carbonyl}amino)butanoic acid (2.50 g, 12.3 mmol) in THF (15.0 mL) was added Ι,Γ-carbonyldiimidazole (2.39 g, 14.8 mmol) portionwise over about 10 min. After stirring 30 min at RT, a solution of Ν,Ο- dimethylhydroxylamine hydrochloride (1.32 g, 13.5 mmol) and DIPEA (2.36 mL, 13.5 mmol) in DMF (4.0 mL) was added. The reaction mixture was stirred for 2 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HC1 (2 x 20 mL), saturated aq. NaHC03 (2 x 20 mL), and brine (20 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (2.60 g, 88%) as a clear, colorless oil. LC-MS m/z 247 (M+H)+, 0.94 min (ret time).

Intermediate 2

1,1-dimethylethyl [(lS -l-formylpropyl] carbamate

To a solution of L1AIH4 (0.453 g, 11.9 mmol) in Et20 (20 mL) at 0 °C was added dropwise a solution of 1, 1-dimethylethyl ((l,S)-l-{[methyl(methyloxy)amino]carbonyl}- propyl)carbamate (2.67 g, 10.8 mmol) in Et20 (15 mL). The reaction mixture was stirred for 30 min at 0 °C and quenched with EtOAc (6.5 mL) followed by 5% aq. potassium bisulfate (6.5 mL). The reaction mixture was washed with 1 M aq. HC1 (3 x 10 mL), saturated aq. NaHC03 (3 x 10 mL), and brine (10 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound as a clear, colorless oil.

Intermediate 3

methyl (2E V)-4-({ [(1 , l-dimethylethyl)oxy] car bonyl} amino)-2-hexenoate

To a stirred solution of methyl (triphenylphosphoranylidene) acetate (4.35 g, 13.0 mmol) in Et20 (25 mL) at RT was added a solution of Intermediate 2 in Et20 (15 mL). The reaction mixture was stirred at RT overnight. The solid was removed by filtration and the solution was concentrated in vacuo. Purification via flash column chromatography (0-50% EtOAc/hexanes) afforded the title compound (1.44 g, 55% over two steps) as a clear, colorless oil. LC-MS m/z 244 (M+H)+, 0.98 min (ret time). Intermediate 4

(2E,4S)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-2-hexenoic acid

Li OH (2.95 g, 123 mmol) was added to a solution of methyl (2£, S 4-({[(1, 1- dimethylethyl)oxy]carbonyl}amino)-2-hexenoate (6 g, 24.66 mmol) in THF (50 mL), MeOH (10.00 mL), and water (50.0 mL). The reaction was stirred overnight at RT. After 18.5 h, the reaction mixture was concentrated under reduced pressure to remove the THF and MeOH. Water (40 mL) was added, and aqueous mixture was adjusted to pH = 3 with 6 M aq. HC1, as measured by pH paper. EtOAc (80 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over Na2S04, concentrated under reduced pressure, and dried under high vacuum, giving 6.09 g of the title compound. LC-MS m/z 230 (M+H)+, 0.77 min (ret time).

Intermediate 5

1,1-dimethylethyl [(lS,2E)-4-(2,3-dihydro-li -indol-l-yl)-l-ethyl-4-oxo-2-buten-l- yl] carbamate

A solution of 50 wt% *T3P in EtOAc (22.00 mL, 37.0 mmol) was added dropwise via addition funnel to a solution of (2£,,4,S)-4-({[(l, l-dimethylethyl)oxy]carbonyl}- amino)-2-hexenoic acid (5.65 g, 24.64 mmol), 2,3-dihydro-lH-indole (2.76 mL, 24.64 mmol), and Et3N (11 mL, 79 mmol) in CH2C12 (90 mL) at 0 °C (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 30 min, the reaction was quenched by dropwise addition of saturated aq. NaHC03 (50 mL). The layers were separated, and the reaction was washed with 10% citric acid (1 x 50 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 7.21 g (89%) of the title compound. LC-MS m/z 331 (M+H)+, 1.05 (ret time). Intermediate 6

[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l-yl]amine

trifluoroacetate

TFA (25 mL, 324 mmol) was added to a solution of 1, 1-dimethylethyl [(1^,2£)-4- (2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l-yl]carbamate (7.21 g, 21.82 mmol) in CH2C12 (25 mL). The reaction was stirred at RT. After 3.5 h, CH2C12 (200 mL) was added, and the reaction was concentrated under reduced pressure and dried under high vacuum. LC-MS m/z 231 (M+H)+, 0.69 (ret time).

Intermediate 7

1,1-dimethylethyl [4-({[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten- l-yl]amino carbonyl)tetrahydro-2H-pyran-4-yl]carbamate

A solution of 50 wt% UT3P in EtOAc (1.3 mL, 2.184 mmol) was added dropwise to a solution of [(l,S’,2£)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l-yl]amine trifluoroacetate (500 mg, 1.452 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2H- pyran-4-carboxylic acid (356 mg, 1.452 mmol), and Et3N (1 mL, 7.21 mmol) in CH2C12 (5 mL) at 0 °C (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 1 h 20 min, the reaction mixture was washed with saturated aq. NaHC03 (1 x 5 mL) and 10% citric acid (1 x 5 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 251 mg (38%) of the title compound. LC-MS m/z 458 (M+H)+, 0.96 (ret time).

Example 1

4-amino-N-[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l- yl]tetrahydr -2H-pyran-4-carboxamide hydrochloride

A solution of concentrated aq. HCI (0.23 mL, 2.76 mmol) was added to a solution of 1,1-dimethylethyl [4-({[(l^,2£)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten- l-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.549 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65 °C (bath temp) for 1 h 45 min. The solvent was evaporated under reduced pressure. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65 °C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 193.3 mg (89%) of the title compound. LC-MS m/z 358 (M+H)+, 0.68 (ret time).

1H MR (400 MHz, METHANOL-^) δ ppm 8.14 (br. s., 1 H); 7.25 (d, J=7.03 Hz, 1 H); 7.18 (t, J=7.53 Hz, 1 H); 7.02 – 7.09 (m, 1 H); 6.83 (dd, J=15.18, 6.65 Hz, 1 H); 6.49 (d, 7=14.8 Hz, 1 H); 4.56 (d, 7=7.28 Hz, 1 H); 4.22 (br. s., 2 H); 3.95 (d, 7=7.53 Hz, 1 H); 3.88 – 3.94 (m, 1 H); 3.71 – 3.78 (m, 2 H); 3.23 (br. s., 2 H); 2.39 – 2.46 (m, 2 H); 1.79 – 1.86 (m, 2 H); 1.75 (s, 1 H); 1.72 (d, 7=8.28 Hz, 1 H); 1.00 (t, 7=7.40 Hz, 3 H)

CELECOXIB

CELECOXIB

169590-42-5
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Celecoxib)

SYNTHESIS

http://newdrugapprovals.org/2013/04/07/drug-spotlight-celecoxib-from-g-d-searle-company/

PAPER

http://pubs.acs.org/doi/abs/10.1021/op800158w

An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2 Inhibitor

Anumula Raghupathi Reddy ET AL

Department of Research and Development, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R R Dist-500 072, A.P., India

Org. Process Res. Dev., 2009, 13 (1), pp 98–101

DOI: 10.1021/op800158w
E-mail: prataprp@ drreddys.com. Fax: 914044346285. Telephone: 9989997176

HPLC 99.97%; regioisomer 0.03%; DSC 162.14 °C; Heavy metals <10 ppm;

M/S m/z 382 M+ + H;

IR (KBr) cm−1 3341, 3235 (N−H);

1H NMR, (DMSO-d6) δ 7.89 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H); 7.52 (s, NH2); 7.22 (m, 4H); 7.17 (s, 1H); 2.32 (s, 3H);

13C NMR (DMSO-d6) δ 20.7, 37.4, 106.1, 121.5, 125.3, 125.9, 126.8, 128.7, 129.4, 139.1, 141.1, 142.2, 144.0, 145.2, 267.4;

Anal. Calcd for C17H14F3N3O2S: C 53.53, H 3.69, N 11.01, S 8.39. Found: C 53.50, H 3.70, N 11.01, S 8.44.

An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.

HPLC Conditions:

Column: Kromasil 100 C18, 250 mm × 4.6 mm × 5 μm

Wavelength: 258 nm

Flow: 0.8 mL/min

Temperature: 25 °C

Injection load: 10 μL

Run time: 60 min

Mobile phase A: buffer (1.36 g potassium dihydrogen phosphate and 0.22 g octane-1-sulfonic acid sodium salt in 1 L of milli-Q water. pH adjusted to 3.3 with dilute H3PO4)

Mobile phase B: acetonitrile and water in the ratio of 7:3

Gradient program: time (min): 0 8 20 30 42 45 60

% of mobile phase A: 50 50 10 5 5 50 50

% of mobile phase B: 50 50 90 95 95 50 50

Retention time of celecoxib: 29.2 min

Retention time of regioisomer: 30.9 min

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Celecoxib extraction
Celecoxib was extracted from Celebra™ 100
mg and 200 mg capsules. Ten capsules were
crushed to fine powder, using agate mortar and
pestle, transferred to a 50 ml volumetric flask
and diluted to volume with methanol. The solution
was shaked for 5 min and filtered. The
residue was recrystallized from acetonitrile after
evaporation of the solvent in a water bath at 50
°C, under a stream of nitrogen.



Thin layer Chromatography (TLC) In this procedure it was used silica gel 60 F254 plates (20 x 20 cm) with a thickness of 0.25 mm. All plates used were commercially prepared by MERCK (lot # 040422153). The mobile phase used to develop the system consisted of chloroform-ethyl acetate-ether (10:5:1, v/v/v). Just in order to verify the selectivity of the proposed system, another COX-2 inhibitor (rofecoxib) with similar properties was used. 20 µl of celecoxib reference substance and extracted from tablets and rofecoxib solutions (50 µg.ml–1) were spotted on the TLC plates, and transferred to a developing tank containing the mobile phase. The plate was then examined under UV light (254 and 365 nm).

Thin-layer chromatography One of the most effective screening methods is the thin-layer chromatography (TLC), which is the simplest of all the widely used chromatographic methods to perform. In the determination of this method, different chromatography systems were tested and analyzed according to the classification proposed by Moffat 13, which divide the drugs in three categories: acid, basic and neutrals based on their polarity and acid characteristics. This procedure is important in
order to increase the information obtained only by changing the mobile phase, and thus resulting in a significant change in selectivity. These chromatographic systems consisted of mixtures of the following solvents: chloroformacetonitrile, ethyl acetate, acetone and methanol, in different concentrations. Nevertheless, all the mobile phases tested were not adequate for the proper identification of the drug. With the objective to develop more reliable chromatographic method, a modification in the system tested was proposed, in order to improve the chromatographic resolution. The mobile phase used consisted of chloroform-ethyl acetate-ether (10:5:1 v/v/v). The system was chosen due to its sensitivity, simplicity and efficacy
The preference to use commercially prepared silica gel plates was due to its durability and homogeneity of the absorbent layer. A sample solution of the working standard and the drug sample (50 (µg ml–1) were spotted onto a silica gel plate with a micropipette and the chromatogram was developed by placing the plate in a tank containing the mobile phase. Following development the individual solute spots were identified under UV lamp (254 and 365 nm). The spots in the drug sample and the working standard presented similar Rf values. The Rf value obtained for drug sample and the working standard were 0.45 and for rofecoxib 0.32.


NMR

The spectrum shown in Figure 3 possesses two characteristic sharp singlet peaks at 2.3 and3.3 ppm that belong to the methyl and sulfonamide protons of celecoxib. The spectrum also reveals peaks from 7.3 to 7.9, which is due to the protons of aromatic groups. The characteristics peaks from the working standard agree well with those observed in the samples, considering the fact that a constant shift is observed in all peaks 11, 12.

UV

IR
1150 - 1350 S = O stretching (sulfonamide group)
1550 - 1600 N - H stretching
3300 - 3500 NH2 stretching

1H NMR PREDICT







13 C NMR





(4) (a) Matsuo, M.; Tsuji, K.; Konishi, N.; Nakamura, K. EP patent 0,418,845, A1, 1990. (b) Matsuo, M.; Tsuji, K.; Konishi, N.; Ogino, T. EP patent 0,554,829, A1, 1993. (c) Nishiwaki, T. Bull. Chem. Soc. Jpn. 1969, 42, 3024. (d) Soliman, R.; Feid-allah, H. J. Pharm. Sci. 1980, 70, 602. (e) Wright, J. B.; Dulin, W. E.; Markillie, J. H. J. Med. Chem. 1963, 7, 102. (f) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039. (g) Szabo, G.; Fischer, J.; Kis-Varga, A.; Gyires, K. J. Med. Chem. 2008, 51, 142. (h) Oh, L. M. Tetrehedron Lett. 2006, 47, 7943.

(5) Talley, J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J.; Malecha, J. W.; Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto, M. J.; Rogers, R. S.; Carter, J. S. US patent 5,466,823, 1995.

(6) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347.


 7 Talley, J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J.; Malecha, J. W.; Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto, M. J.; Rogers, R. S.; Carter, J. S.; Docter, S. H.; Yu, S. S. US patent 6,586,603, B1, 2003.

 (8) (a) O′ Shea, P. ; Tillyer, R. D. ; Wang, X. ; Clas, S. D. ; Dalton, C. US patent 6,150,534, 2000. (b) O′ Shea, P. ; Tillyer, R. D. ; Wang, X. ; Clas, S. D. ; Dalton, C. US patent 6,232,472, 2001.

(9) (a) Zhi, B. ; Newaz, M. US patent 5,,892,053, 1999. (b) Zhi, B. ; Newaz, M. US patent 5,910,597, 1999.

10(a) Letendre, L. J.; McGhee, W. D.; Snoddy, C.; Klemm, G.; Graud, H. T. US patent 7,141,678, 2006. (b) Letendre, L. J.; McGhee, W. D.; Snoddy, C.; Klemm, G.; Graud, H. T. US patent 2007/0,004, 924 A1, 2007.
(11) ICH harmonized tripartite guideline, Impurities in New Drug Substances Q3A (R2), current step 4 version dated 25 October2006.
(12) Ahlstrom, M. M.; Ridderstrom, M.; Zamora, I.; Luthman, K. J. Med. Chem. 2007, 50, 4444. (13) Soliman, R. J. Med. Chem. 1979, 22, 321.


SYNTHESIS

  +GIVES........CELECOXIB

EUCLISES PHARMACEUTICALS, INC.; MARTINEZ, Eduardo, J.; TALLEY, John, J.; JEROME, Kevin, D.; BOEHM, Terri, L. Patent: WO2014/12074 A2, 2014 ; Location in patent: Paragraph 00209; 00210 


2

+




+


Reddy, Anumula Raghupathi; Sampath, Alla; Goverdhan, Gilla; Yakambaram, Bojja; Mukkanti, Kagga; Reddy, Padi Pratap Organic Process Research and Development, 2009 , vol. 13, # 1 p. 98 - 101

3
Prabhakaran, Jaya; Underwood, Mark D.; Parsey, Ramin V.; Arango, Victoria; Majo, Vattoly J.; Simpson, Norman R.; Van Heertum, Ronald; Mann, J. John; Kumar, J.S. Dileep Bioorganic and Medicinal Chemistry, 2007 , vol. 15, # 4 p. 1802 -

4
Li, Feng; Nie, Jing; Sun, Long; Zheng, Yan; Ma, Jun-An Angewandte Chemie - International Edition, 2013 , vol. 52, # 24 p. 6255 - 6258

5
Synlett, , vol. 1997, # 4 p. 375 - 377

6Tetrahedron Letters, , vol. 52, # 45 p. 6000 - 6002


7 

Bioorganic and Medicinal Chemistry Letters, , vol. 21, # 22 p. 6636 - 6640

COCK WILL TEACH YOU NMR

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tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine- 6(5H)-carboxylate.

Synthesis of tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate. To a slurry of 2-chloro-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (106.1 g, 517 mmol, commercially available from D-L Chiral Chemicals, ST-0143) and N,N-diisopropylethylamine (80 g, 108 mL, 621 mmol, 1.2 eq) in DCM (1 L) was added a solution of di-tert-butyl dicarbonate (119 g, 543 mmol, 1.05 eq) in

DCM (100 mL) via an addition funnel within 1 hr. The reaction mixture became a clean solution and the solution thus obtained was stirred at room temperature for an additional hour and monitored using LCMS. Upon completion, the reaction mixture was concentrated. The residue was dissolved in EtOAc (1 L) and washed with water (3 x 300 mL), washed with brine (300 mL) and dried over MgSOzt. The solvent was evaporated under vacuum to give the title compound as an off- white solid (139 g, yield: 100%).

 ^lH NMR (400MHz ,CDC1₃) δ ppm 

1.49 (9H, s),  9 Tert butyl methyls protons

2.97 (2H, t, J= 5.9 Hz), BOC N CH2 CH2 AR

3.73 (2H, t, J= 6.0 Hz), BOC N-CH2 -AR

4.57 (2H, s),Boc-N-CH2-CH2.Ar

7.17 (1H, d, J= 8.0 Hz), 

7.38 (1H, d, J= 8.0 Hz) ppm;

5-iodo-A^-((lr,4r)-4-methylcyclohexyl)pyridine-2,4- diamine. N4-((lr,4r)-4-Methylcyclohexyl)pyridine-2,4-diamine

5-iodo-A^-((lr,4r)-4-methylcyclohexyl)pyridine-2,4- diamine. N4-((lr,4r)-4-Methylcyclohexyl)pyridine-2,4-diamine

PATENT WO2012129344

http://www.google.com/patents/WO2012129344A1?cl=en

STEP A

4-Chloropyrimidine-2-amine (commercially available from Sigma-Aldrich, St. Louis, MO) (1000 g, 7.72 mol, 1.0 eq), trans- 4-methylcyclohexylamine hydrochloride (commercially available from TCI America, M1780) (1500 g, 10.03 mol, 1.3 eq) and TEA (3.23 L, 23.2 mol, 3.0 eq) were mixed together in n-butanol (8 L). The reaction mixture was heated at reflux for 36 hours and monitored using LCMS. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (8 L) and extracted with EtOAc (2 x 10 L). The organic layers were combined, dried over Na2S04, and concentrated under reduced pressure to give the title compound (1770 g) which was us

STEP B

Synthesis of 5-iodo-A^-((lr,4r)-4-methylcyclohexyl)pyridine-2,4- diamine. N4-((lr,4r)-4-Methylcyclohexyl)pyridine-2,4-diamine (1770 g, 8.58 mol, 1.0 eq) was dissolved in anhydrous DMF (8 L). To this solution under N2 atmosphere at 10 °C was added NIS (1.93 kg, 8.58 mol, 1.0 eq) in portions over 10 minutes. Upon completion of the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. Upon completion, the reaction mixture was cooled using an ice bath, quenched with saturated aqueous sodium carbonate (5 L) and extracted with EtOAc (2 x 15 L). The combined organic extracts were washed with saturated aqueous sodium carbonate (2 x 5 L), water (3 x 2 L), dried over Na2S04, and concentrated under reduced pressure. The residue was purified using column chromatography eluting with 25% to 40% EtOAc in hexanes to provide the title compound (1.47 kg, 57% over two steps). 

^-NMR (300 MHz, DMSO-d6) 

δ ppm 0.85 (3H, d, J= 7.2 Hz), 

0.98 (1H, dd, J= 12.9, 2.7 Hz), 

1.41 – 1.27 (3H, m), 

1.66 (2H, d, J = 12.3 Hz), 

1.78 (2H, d, J= 12.3 Hz), 

3.85 (1H, m), 

5.48 (1H, d, J= 8.1 Hz), 

6.16 (2H, br s), 

7.86 (1H, S)


MS 333 M+1

CS 3150

CS-3150,  (XL550)

CS 3150, angiotensin II receptor antagonist,  for the treatment or prevention of such hypertension and heart disease similar to olmesartan , losartan, candesartan , valsartan,  irbesartan,  telmisartan, eprosartan,

 Cas name 1H-​Pyrrole-​3-​carboxamide, 1-​(2-​hydroxyethyl)​-​4-​methyl-​N-​[4-​(methylsulfonyl)​phenyl]​-​5-​[2-​(trifluoromethyl)​phenyl]​-​, (5S)​-

CAS 1632006-28-0 for S conf

MF C22 H21 F3 N2 O4 S

MW 466.47

(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

CAS 1632006-28-0 for S configuration

1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, CAS 880780-76-7

(+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-82-4

(-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-83-5

WO 2014168103

WO 2008126831

WO2008 / 126831 (US Publication US2010-0093826)http://www.google.co.in/patents/EP2133330A1?cl=en

WO 2015012205

WO 2006012642..compound A;..http://www.google.com/patents/WO2006012642A2?cl=en

WO2006 / 012642 (US Publication US2008-0234270)

WO 2015030010…http://www.google.com/patents/WO2015030010A1?cl=en

• Originator Exelixis
• Developer Daiichi Sankyo Company..
  

  Daiichi Sankyo Company,Limited, 第一三共株式会社

• Class Antihypertensives; Small molecules
• Mechanism of Action Mineralocorticoid receptor antagonists 

SEE

http://newdrugapprovals.org/2015/03/13/cs-3150-angiotensin-ii-receptor-antagonist-for-the-treatment-or-prevention-of-such-hypertension-and-heart-disease/

WO 2014168103

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014168103

(8-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl
ethyl acetate (240 mL), was mixed tetrahydrofuran (80 mL) and oxalyl chloride 20.72 g (163 mmol), and cooled to 10 ~ 15 ℃ was. Then the resulting solution was added while keeping the 10 ~ 15 ℃ Example (8-1) and stirred for about 1 hour by heating to 15 ~ 20 ℃. After stirring, acetonitrile (120 mL) and pyridine 2.46 g (31 mmol) was added and the reaction mixture was concentrated under reduced pressure (120 mL), acetonitrile (200 mL) was added and further concentrated under reduced pressure (120 mL).

　After completion concentration under reduced pressure, acetonitrile (200 mL) was added and cooled to 10 ~ 15 ℃ (reaction 1).

　Acetonitrile (240mL), pyridine 12.39 g (157 mmol), 4- were successively added (methylsulfonyl) aniline 26.85 g (157 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.

　The resulting reaction solution in acetonitrile (40 mL), 2 N hydrochloric acid water (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. Again, 2N aqueous hydrochloric acid to the organic layer (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. After filtering the resulting organic layer was concentrated under reduced pressure (400 mL). Water (360 mL) was added to the concentrated liquid, after about 1 hour stirring, the crystals were filtered, washed with 50v / v% aqueous acetonitrile (120 mL), wet product of the title compound (undried product, 62.02 g) and obtained. 1 H NMR (500 MHz, DMSO-D 6 ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H) 

(8-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A)) 　( the resulting wet product crystals 8-2), t- butyl methyl ether (200 mL), acetonitrile (40 mL), 48w / w potassium hydroxide aqueous solution (16 g) and water (200 mL) was added, I was stirred for about 2 hours at 25 ~ 35 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (120 mL), ethanol (240 mL) was added and further concentrated under reduced pressure (120 mL). After completion concentration under reduced pressure, ethanol (36 mL), and heated in water (12 mL) was added 35 ~ 45 ℃, while maintaining the 35 ~ 45 ℃ was added dropwise water (280 mL), and was crystallized crystals. After cooling the crystal exudates to room temperature, I was filtered crystal. Then washed with crystals 30v / v% aqueous ethanol solution (80 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystalline (26.26 g, 89.7% yield). Moreover, the enantiomers of the resulting crystals was 0.3%. 

1 H NMR (400 MHz, CDCl 3 ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, M), 7.77 ~ 7.90 (6H, M). 

(8-4) (S)-1-(2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3- HPLC method for measuring the amount enantiomer carboxamide (%) 　and collected the title compound of about 10 mg is, what was the 10 mL was diluted with 50v / v% aqueous acetonitrile to obtain a sample solution.

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(Example 12) (S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A)) Preparation of 2 

(12-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H – pyrrole-3-carboxylic acid
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 10.00 g (16 mmol) in t- butyl methyl ether (90 mL), water (10 mL) 36w / w% aqueous hydrochloric acid ( 5 mL) was added and stirring at room temperature and separated. The resulting organic layer was concentrated under reduced pressure (30 mL), was added ethyl acetate (50 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (30 mL). 

(12-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl
ethyl acetate (50 mL), was mixed with tetrahydrofuran (20 mL) and oxalyl chloride 5.18 g (41 mmol), and cooled to 0 ~ 5 ℃ was.Then the resulting solution was added in Examples while maintaining the 0 ~ 5 ℃ (12-1), and the mixture was stirred for 6 hours at 0 ~ 10 ℃. After stirring, acetonitrile (30 mL) and pyridine 0.62 g (8 mmol) was added and the reaction mixture was concentrated under reduced pressure (30 mL), acetonitrile (50 mL) was added, and further concentrated under reduced pressure (30 mL).

　After concentration under reduced pressure end, is added acetonitrile (10 mL) and oxalyl chloride 0.10 g (1 mmol), and cooled to 0 ~ 5 ℃ (reaction 1).

　Acetonitrile (30mL), pyridine 3.15 g (40 mmol), 4- were successively added (methylsulfonyl) aniline 6.71 g (39 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.

　Insolubles from the resulting reaction solution was filtered, washed with acetonitrile (10 mL), and stirred for about 2 hours the addition of water (15 mL), followed by dropwise addition of water (75 mL) over about 1 hour . After about 1 hour stirring the suspension was filtered crystals were washed with 50v / v% aqueous acetonitrile (20 mL), wet product of the title compound (undried product, 15.78 g) to give a. 1 H NMR (500 MHz, DMSO-D 6 ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H) 

(12-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A)) 　( the resulting wet product crystals 12-2), t- butyl methyl ether (50 mL), acetonitrile (10 mL), 48w / w potassium hydroxide aqueous solution (4 g) and water (50 mL) was added, 15 I was about 2 hours of stirring at ~ 25 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (30 mL), was added ethanol (60 mL), was further concentrated under reduced pressure (30 mL). After completion concentration under reduced pressure, ethanol (14 mL), after addition of water (20 mL), was added a seed crystal, and was crystallized crystals. After dropwise over about 1 hour water (50 mL), and about 1 hour stirring, and crystals were filtered off. Then washed with crystals 30v / v% aqueous ethanol solution (10 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystal (6.36 g, 87.0% yield). Moreover, the enantiomers of the resulting crystals was 0.05%. Enantiomers amount, I was measured by the method of (Example 8-4). 1 H NMR (400 MHz, CDCl 3 ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, m), 7.77 ~ 7.90 (6H, m).