Dabrafenib mesylate, GSK 2118436 ダブラフェニブ 达拉菲尼,

DABRAFENIB

1195765-45-7

Benzenesulfonamide, N-​[3-​[5-​(2-​amino-​4-​pyrimidinyl)​-​2-​(1,​1-​dimethylethyl)​-​4-​thiazolyl]​-​2-​fluorophenyl]​-​2,​6-​difluoro-

N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

MW 519.56

MF C23 H20 F3 N5 O2 S2

• Dabarefenib
• Dabrafenib
• GSK 2118436
• Tafinlar

PAPER

ACS Medicinal Chemistry Letters (2013), 4(3), 358-362.

ACS Med. Chem. Lett., 2013, 4 (3), pp 358–362

DOI: 10.1021/ml4000063

http://pubs.acs.org/doi/abs/10.1021/ml4000063

http://pubs.acs.org/doi/suppl/10.1021/ml4000063/suppl_file/ml4000063_si_001.pdf

The title compound,N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenze

nesulfonamide was obtained (94 mg, 47% yield).

1H NMR

(400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 7.93 (d,J=5.2 Hz, 1 H), 7.55 – 7.70 (m, 1 H), 7.35 – 7.43 (m, 1 H), 7.31(t,J=6.3 Hz, 1 H), 7.14 – 7.27 (m, 3 H), 6.70 (s, 2 H),5.79 (d,J=5.13 Hz, 1 H), 1.35 (s, 9 H).

MS (ESI): 519.9 [M+H]+.

13C NMR (100 MHz, DMSO-d6) δ ppm 182.1, 164.0, 160.6, 159.4, 158.0, 154.9,

152.4, 145.8, 136.6, 135.1, 130.0,

128.4, 125.6, 124.7, 114.1, 113.9, 105.7, 38.3, 31.0.

see
http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/

Dabrafenib mesylate is a kinase inhibitor. The chemical name for dabrafenib mesylate is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt. It has the molecular formula C23H20F3N5O2S2•CH4O3S and a molecular weight of 615.68. Dabrafenib mesylate has the following chemical structure:

Dabrafenib mesylate is a white to slightly colored solid with three pKas: 6.6, 2.2, and -1.5. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

TAFINLAR (dabrafenib) capsules are supplied as 50-mg and 75-mg capsules for oral administration. Each 50-mg capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg of dabrafenib free base. Each 75-mg capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg of dabrafenib free base.

The inactive ingredients of TAFINLAR are colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Capsule shells contain hypromellose, red iron oxide (E172), and titanium dioxide (E171).

Dabrafenib mesylate

1195768-06-9 cas of mesylate

• COA (Certificate Of Analysis)
• HPLC
• Request NMR (NMR of exclusive products available upon request.)
• MSDS (Material Safety Data Sheet)

N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;methanesulfonic acid

Chemical structure

………………….

PATENT

http://www.google.com/patents/WO2009137391A2?cl=en

WO 2009137391

Example 58d: Λ/-{3-r5-(2-amino-4-pyrimidinvn-2-(1.1-dimethylethylV1.3-thiazol-4-yll-2- fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate

 MESYLATE

To a solution of Λ/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (204 mg, 0.393 mmol) in isopropanol (2 ml_), methanesulfonic acid (0.131 ml_, 0.393 mmol) was added and the solution was allowed to stir at room temperature for 3 hours. A white precipitate formed and the slurry was filtered and rinsed with diethyl ether to give the title product as a white crystalline solid (210 mg, 83% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1 H) 7.92 – 8.05 (m, 1 H) 7.56 – 7.72 (m, 1 H) 6.91 – 7.50 (m, 7 H) 5.83 – 5.98 (m, 1 H) 2.18 – 2.32 (m, 3 H) 1.36 (s, 9 H). MS (ESI): 520.0 [M+H]+.

see
http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/


see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/



Dabrafenib prediction
1H NMR PREDICT






13C NM PREDICT





see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/

INTERMEDIATES


Methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate; Methyl 3-(tert-butoxycarbonylamino)-2-fluorobenzoate

1195768-23-0

methyl 3-bromo-2-fluorobenzylate; PC3663; fluorobromobenzoic acid methyl ester;

3-bromo-2-fluorobenzoic acid methyl ester;

206551-41-9

SYN 1





GLAXOSMITHKLINE LLC; HOOS, Axel; GRESHOCK, Joel Patent: WO2014/66606 A2, 2014 ; Location in patent: Page/Page column 20; 24 ;


SYN  2








WO2011/47238 A1, ;



SYN 3



ACS Medicinal Chemistry Letters, , vol. 4, # 3 p. 358 - 362


SYN 4




ACS Medicinal Chemistry Letters, , vol. 4, # 3 p. 358 - 362

SYN 5


ACS Medicinal Chemistry Letters, , vol. 4, # 3 p. 358 - 362


SYN 6
WO2011/47238 A1, ;




see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/



updated

COSY NMR PREDICT

HMBC, HSBC NMR PREDICT

 UPDATES WATCH REGULARLY

WO2015003571

达拉菲尼甲磺酸盐的新晶型及其制备方法

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=A1F1236472ED5D758B64CA11358EBB6C.wapp1nC?docId=WO2015003571&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Brief Description

Figure 1 Form IV of the present invention an X-ray powder diffraction pattern.

Figure 2 is a schematic diagram Form IV of DSC language.

Figure 3 Form IV of the present invention TGA profiles.

Figure 4 is a dynamic water adsorption of Form IV of the invention, FIG.

Figure 5 Form IV of the present invention 1HNMR spectrum.

Figure 6 of the present invention, Form II X-ray powder diffraction pattern.

Figure 7 of the present invention, Form II TGA profiles.

Figure 8 Form III of the present invention an X-ray powder diffraction pattern.

Figure 9 Form V of the present invention, an X-ray powder diffraction pattern.

Figure 58a and in Example 10 in accordance with Patent Document WO2009 / 137391 or in CN200980126781.6

58d method described for the preparation of polymorph I of the known X-ray powder diffraction pattern.

Figure 11 is in accordance with Patent Document WO2009 / 137391 or CN200980126781.6 in the method of Example 58a and 58d described for the preparation of polymorph I of the known DSC pattern.

12 is in accordance with Patent Document WO2009 / 137391 or CN200980126781.6 in the method of Example 58a and 58d described for the preparation of polymorph I of the known TGA profiles.

Figure 13 is a known polymorph I in Comparative Example 1 in various stages XRPD comparison chart with the sample from top to bottom in the order of: Dara Phoenix free base hydrate, a known polymorph I in water was stirred for 15 After minutes to obtain a sample, and a known polymorph I.

Figure 14 Form IV in the present invention Comparative Example 1 each stage XRPD comparison chart with the sample from top to bottom in the order of: Form IV, Form IV in water with stirring for 15 minutes to obtain a sample, Form IV After stirring overnight in water to obtain a sample, as well as the free base of the hydrate Dara Phoenix. Figure 15 is a Comparative Form IV polymorph I of the known elution compared to the situation in Figure 1 (A to Form IV, ■ known Form 1).

Figure 16 is known in the polymorph I of Comparative Example 2 in various stages XRPD comparison chart (figure from top to bottom as follows: Form I is known API by "wet granulation" process of granulation (excluding section 3-step tablet) obtained by the sample, the known polymorphs I and amount of excipients formulated physically mixed formulation obtained sample, lactose monohydrate and microcrystalline cellulose according to Formulation physical sample after mixing, Dara Feeney free base hydrate, as well as known Form 1).

17 is a crystalline form IV according to the present invention in Comparative Example 2 in various stages XRPD comparison chart (from top to bottom as follows: In Form IV according to API "wet granulation" process of granulation (not included in Step 3 tableting) after the sample obtained, Form IV and excipients Formulation amount by physically mixing the obtained sample, the sample lactose monohydrate and microcrystalline cellulose according to Formulation after physical mixing, and Form IV).

full synthesis

see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/

see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/


see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/



see......http://newdrugapprovals.org/2015/03/19/dabrafenib-mesylate-gsk-2118436/

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