(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide a key levetiracetam intermediate

(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide 

methyl (±)-(R,S)-alpha-ethyl-2-oxo-l -pyrrolidine acetate with (+)-(R)-(l-phenylethyl)- amine in toluene in the presence of a base such as sodium hydride or methoxide; crystallization- induced dynamic resolution of the resultant (±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

(R)-(+)-1-Phenylethylamine

 33978-83-5
1-​Pyrrolidineacetic acid, α-​ethyl-​2-​oxo-​, methyl ester











1004767-60-5
1-​Pyrrolidineacetamide​, α-​ethyl-​2-​oxo-​N-​[(1R)​-​1-​phenylethyl]​-
(±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide


Example 1

(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide. 

In a 100 ml reactor equipped with mechanical stirring, thermometer and bubble condenser, 13.4 g of (±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (71.6 mmol), 8.8 g of (+)-(R)-(l-phenylethyl)-amine (72.5 mmol) and 45 ml of tetrahydrofuran were charged. 3.4 g of NaH (60% dispersion in mineral oil, 85.6 mmol) was added in small portions under nitrogen atmosphere. Reaction mixture was maintained at room temperature for about 2 h. Then, it was heated up to 35⁰C and kept under stirring overnight. Reaction was controlled by TLC (Rf = 0.5, AcOEt/silica gel).

At reaction completed, one night at 35°C temperature, reaction mixture was cooled to room temperature and 30 ml of water was slowly charged. It was transferred into a separatory funnel and was diluted with 30 ml of water and 80 ml of dichloromethane. Phases were separated and the aqueous one was washed with 50 ml of dichloromethane. Collected organic phases were washed with an aqueous acid solution, dried on Na₂SO₄, filtered and concentrated under vacuum. 19.5 g of an oil residue was obtained which slowly solidified. Solid was suspended in 20 ml of a hexane/dichloromethane 9/1 v/v mixture. It was then filtered, washed with 10 ml of the same solvent mixture and dried at 40⁰C to give 12.1 g of the title compound (44.1 mmol, 61.6% yield) as dry solid.

¹H NMR (400.13 MHz, CDCl₃, 25 ⁰C): δ (ppm, TMS)
7.35-7.19 (1OH, m),
6.49 (2H, br s),
5.09-5.00 (2H, m),
4.41 (IH, dd, J = 8.3, 7.4 Hz),
4.36 (IH, dd, J = 8.6, 7.1 Hz),
3.49 (IH, ddd, J = 9.8, 7.7, 6.6 Hz),
3.41 (IH, ddd, J = 9.8, 7.7, 6.2 Hz),
3.30 (IH, ddd, J = 9.6, 8.3, 5.5 Hz),
3.13 (IH, ddd, 9.7, 8.5, 6.1 Hz), 2.47-2.38 (2H, m), 2.41 (IH, ddd, J = 17.0, 9.6, 6.3 Hz), 2.26 (IH, ddd, 17.0, 9.5, 6.6 Hz), 2.10-1.98 (2H, m), 2.01-1.89 (IH, m), 1.99-1.88 (IH, m), 1.98-1.85 (IH, m), 1.88-1.78 (IH, m), 1.75- 1.62 (IH, m), 1.72-1.59 (IH, m), 1.45 (3H, d, J = 7.1 Hz), 1.44 (3H, d, J = 7.1 Hz), 0.90 (3H, t, J = 7.4 Hz), 0.86 (3H, t, J = 7.4 Hz).  

¹³C NMR (100.62 MHz, CDCl₃, 25 ⁰C): δ (ppm, TMS)
176.05 (CO), 176.00 (CO), 169.08 (CO),
168.81 (CO), 143.59 (C_quat),
143.02 (C_quat), 128.66 (2 x CH), 128.55 (2 x CH),
127.33 (CH), 127.19 (CH), 126.05 (2 x CH),
125.80 (2 x CH), 56.98 (CH), 56.61 (CH),
48.90 (CH), 48.84 (CH), 44.08 (CH₂),
43.71 (CH₂), 31.19 (CH₂), 31.07 (CH₂), 22.08 (CH₃),
22.04 (CH₃), 21.21 (CH₂), 20.68 (CH₂),
18.28 (CH₂), 18.08 (CH₂), 10.50 (CH₃), 10.45 (CH₃).

Example 2 (±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 1).

In a 500 ml reactor equipped with mechanical stirring, thermometer and condenser, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 0⁰C temperature under nitrogen atmosphere, 9.5 g of NaH (60% mineral oil suspension, 237.50 mmol) was added in small portions. At the same temperature, 190.0 g of a toluene solution of (±)-(R,S)- alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 35°C and maintained in that condition till complete disappearing of methyl ester reagent (about 14 h; checked by HPLC).

At reaction completed, reaction mixture was cooled and when room temperature was reached, 100 ml of water was slowly charged. Aqueous phases were separated and extracted with toluene (2 x 75 ml). Collected organic phases were treated with acid water till neuter pH. Solvent was evaporated and residue was suspended in about 100 ml of heptane for about 30 minutes. Product was isolated by filtration and dried in oven at 40⁰C temperature under vacuum overnight to give 45.2 g of the title compound (164.54 mmol, 83.2% yield, d.e. 0.0%) as white dusty solid.


 Example 3

(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 2).

In a 500 ml reactor equipped with mechanical stirring, thermometer and Dean-Stark distiller, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 0⁰C temperature, 42.7 g of sodium methoxide (30% solution in methanol, 237.14 mmol) was added under nitrogen atmosphere. At the same temperature, 190.0 g of a toluene solution of (±)- (R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 65- 70⁰C and maintained in that condition till complete disappearing of methyl ester reagent (about 4 h; checked by HPLC). After a work-up carried out according to the procedure described in example 2, 40.2 g of the title compound (146.53 mmol, 74.1% yield, d.e. 0.0%) as white dusty solid was obtained.

http://www.google.com/patents/WO2008012268A1?cl=en

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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/

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

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GSK 2636771

Company: GlaxoSmithKline
Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial
Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta.
Medicinal chemistry tidbits: The GSK team seemed boxed in because in 3 out of 4 animals used in preclinical testing, promising drug candidates had high clearance. It turned out that a carbonyl group that they thought was critical for interacting with the back pocket of the PI3K-beta enzyme wasn’t so critical after all. When they realized they could replace the carbonyl with a variety of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown) is the tris salt of GSK2636771.
Status in the pipeline: Phase I clinical trials..........http://cenblog.org/the-haystack/2012/03/liveblogging-first-time-disclosures-from-acssandiego/
CARMEN
Posted By Carmen Drahl on Mar 24, 2012

Phone: 202-872-4502

Fax: 202-872-8727 or -6381

1372540-25-4
1H-​Benzimidazole-​4-​carboxylic acid, 2-​methyl-​1-​[[2-​methyl-​3-​(trifluoromethyl)​phenyl]​methyl]​-​6-​(4-​morpholinyl)​-
2-Methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid
GSK2636771 is a potent, orally bioavailable, PI3Kβ-selective inhibitor, sensitive to PTEN null cell lines.
Formula:C₂₂H_22F3N₃O₃
M.Wt:433.43
SEE AT
http://newdrugapprovals.org/2015/03/19/gsk-2636771/
 ............

WO2012047538

http://www.google.com/patents/WO2012047538A1?cl=en
Example 31

Preparation of 2-methyl- 1 - { [2-methyl-3-(trifluoromethyl)phenyllmethyl| -6-(4-morpholiny0- 1 H-benzimidazole-4-carboxylic acidAn aqueous solution of 2 N LiOH (1.2 mL) was added to a solution of methyl 2-methyl- 1- {[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylate, prepared as described in Example 30 (180 mg, 0.4 mmol) in THF (10 mL) and stirred at 50° C for 1 h. When TLC showed no starting material remaining, the mixture was cooled to rt and THF was removed under reduced pressure. The pH of the mixture was acidified to pH 3. The suspension was filtered and the filtrate was collected, and washed with water (lOmL) to give the product as a white solid (152 mg, yield 88%).
1H NMR (300 MHz,DMSO-d₆):
δ ppm 2.46 (s, 3H), 2.54 (s, 3H), 3.10 (t, 4H, J=4.8 Hz), 3.73 (t, 4H, J=4.8 Hz), 5.63 (s, 2H), 6.37 (d, IH, J=7.8 Hz), 7.26 (t, IH, J=7.8 Hz), 7.35 (d, IH, J=2.4 Hz), 7.44 (d, IH, J=2.4 Hz), 7.62 (d, IH, J=7.8 Hz);
LC-MS: m/e = 434 [M+l]


SEE AT
http://newdrugapprovals.org/2015/03/19/gsk-2636771/





SEE AT
http://newdrugapprovals.org/2015/03/19/gsk-2636771/









SEE AT
http://newdrugapprovals.org/2015/03/19/gsk-2636771/