Sunday 29 March 2015

SAXAGLIPTIN


SAXAGLIPTIN

Saxagliptin
CAS No.:361442-04-8
Synonyms:
  • Saxagliptin 15ND2;
  • Onglyza;
Formula:C18H25N3O2
Exact Mass:315.19500
Molecular Weight:315.41000

SMILES:

C1[C@@H]2C[C@@H]2N([C@@H]1C#N)C(=O)[C@H](C34CC5CC(C3)CC(C5)(C4)O)N

13c nmr predict

Saxagliptin, (1S,3S,5S)-2-(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile of the following chemical structure:
Figure US08410288-20130402-C00001

is a dipeptidyl peptidase IV (DPP4) inhibitor. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.
Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. No. 6,395,767. In addition, U.S. Pat. No. 7,420,079 discloses Saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as Saxagliptin monohydrate.
U.S. 2009/054303 and the corresponding WO 2008/131149 application disclose several crystalline forms of Saxagliptin and of Saxagliptin salts. The crystalline forms of Saxagliptin reported in that patent application are a monohydrate (denoted there as form H-1), a hemihydrate (denoted there as form H0.5-2), a dihydrate (denoted form H2-1) and an anhydrous form (denoted there as N-3).
WO 2005/117841 (the '841 application) describes the cyclization of Saxagliptin to form the therapeutically inactive cyclic amidine. The '841 application reports that such cyclization can occur both in solid state and solution state.
WO 2010/115974 discloses Forms: I-S, HT-S, IV-S, and HT-IV-S of Saxagliptin hydrochloride.




Org. Process Res. Dev.200913 (6), pp 1169–1176
DOI: 10.1021/op900226j





Abstract Image
The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin (1), is described from the two unnatural amino acid derivatives 2 and 3. After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4. Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1. While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9. Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.
Monohydrate 1 was isolated as a white solid (58.2 kg, 88%). 


1 H NMR (400 MHz, CD2Cl2- d6) δ 5.25 (dd, J1 ) J2 ) 1.0 Hz, 1H), 4.93 (dd, J1 ) 10.6 Hz, J2 ) 2.3 Hz, 1H), 3.55-3.50 (m, 1H), 3,35 (s, 1H), 2.45 (ddd, J1 ) 16.1 Hz, J2 ) 10.9 Hz, J3 ) 5.6 Hz, 1H), 2.25 (dd, J1 ) 13.6 Hz, J2 ) 2.5 Hz, 1H), 2.18-2.10 (m, 2H), 1.83-1.42 (m, 15H), 1.40-1.27 (m, 3H) 1.0-0.87 (m, 2H) 


13C NMR (100 MHz, CD2Cl2) δ 173.43, 120.15, 68.83, 60.90, 46.57, 45.51, 45.08, 45.01, 41.62, 38.15, 37.92, 37.35, 35.88, 30.98, 30.93, 30.80, 18.00, 13.69. 


MS (FAB) m/z 316 [M + H]+




1H NMR PREDICT

Saxagliptin NMR spectra analysis, Chemical CAS NO. 361442-04-8 NMR spectral analysis, Saxagliptin H-NMR spectrum


13C NMR PREDICT
Saxagliptin NMR spectra analysis, Chemical CAS NO. 361442-04-8 NMR spectral analysis, Saxagliptin C-NMR spectrum


..................

http://www.google.com/patents/WO2012162507A1?cl=en
 two amino acid derivatives (A) and (B), described in further detail hereinbelow, coupled in the presence of a coupling reagent. The amide coupling of (S)-a[[(l,l-dimethyleethoxy)carbonyl]amino]-3- hydroxytricyclo [3.3.1.1]decane-l-acetic acid (A) and (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide (B), subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin (C).
Figure imgf000002_0001





synthetic route is disclosed as follows:
Figure imgf000011_0001


Figure imgf000012_0001

Scheme-IV
Figure imgf000015_0001


Scheme-V
Figure imgf000016_0001

Figure imgf000017_0001



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Savage, Scott A., et al., "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor", Organic Process Research & Development, 2009, vol. 13, pp. 1169-1176.

REFERENCES
US639576716 Feb 200128 May 2002Bristol-Myers Squibb CompanyCyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US699518327 Jul 20047 Feb 2006Bristol Myers Squibb CompanyAdamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US718684628 Mar 20056 Mar 2007Bristol-Myers Squibb CompanyProcess for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein
US721470223 May 20058 May 2007Bristol-Myers Squibb CompanyReacting the amide compound with phosphorus oxychloride in an organic solvent; treating the reaction mixture with water to form (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile-hydrochloride
US72235732 May 200529 May 2007Bristol-Myers Squibb CompanyEnzymatic ammonolysis process for the preparation of intermediates for DPP IV inhibitors
US742007918 Nov 20032 Sep 2008Bristol-Myers Squibb CompanyIntermediates for making 1(alpha-amino-1-(cyclopropyl-fused pyrrolidinylcarbonyl)methyl)-3-hydroxyadamantanes, e.g., methyl 3-hydroxy-<a-oxotricyclo[3.3.1.13,7]decane-1-acetate
US747081011 Jan 200530 Dec 2008Bristol-Myers Squibb CompanySuch as 1-dodecane-thiotrifluoroacetate; alkyl/arylthiol is treated with trifluoroacetic anhydride in presence of pyridine, solvent (dichloromethane), and dimethylaminopyridine (DMAP) as catalyst; for protection of amino acids
US774108212 Apr 200522 Jun 2010Bristol-Myers Squibb CompanyProcess for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
US794365618 Apr 200817 May 2011Bristol-Myers Squibb CompanyCrystal forms of saxagliptin and processes for preparing same
US200600359548 Aug 200516 Feb 2006Sharma Padam NAmmonolysis process for the preparation of intermediates for DPP IV inhibitors
WO2001068603A25 Mar 200120 Sep 2001Bristol Myers Squibb CoCyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use
WO2008131149A218 Apr 200830 Oct 2008Squibb Bristol Myers CoCrystal forms of saxagliptin and processes for preparing same
WO2010115974A19 Apr 201014 Oct 2010Sandoz AgCrystal forms of saxagliptin
WO2011140328A15 May 201110 Nov 2011Teva Pharmaceutical Industries Ltd.Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof

Citing PatentFiling datePublication dateApplicantTitle
US8748631 *24 May 201210 Jun 2014Apicore, LlcProcess for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
US20130023671 *24 May 201224 Jan 2013Apicore, LlcProcess for preparing saxagliptin and its novel intermediates useful in the synthesis thereof

REFERENCES
  • 1. Scott A. Savage, Gregory S. Jones, Sergei Kolotuchin, Shelly Ann Ramrattan, Truc Vu, and Rebert E. Waltermire (2009) Preparation of Saxagliptin, a Novel DPP-IV Inhibitor, Organic Process Research & Development., 13, 1169-1176.
  • 2. Santosh K. Sing, Narendra Manne and Manojit Pal, (2008) Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors. Beilstein Journal of Organic Chemistry, 4, No. 20.
  • 3. U.S. Pat. No. (2010) 0274025 A1.
  • 4. U.S. Pat. No. (2006) 0035954 A1.
  • 5. U.S. Pat. No. (2005) 0090539 A1.
  • 6. Organic letters. (2001) Vol. 3, No.5, Page: 759-762
  • 7. Tetrahedron 59 (2003) 2953-2989







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Wednesday 25 March 2015

GSK 923295, a CENP-E Inhibitor


GSK-923295A
1088965-37-0
Synonym: GSK-923295; GSK 923295; GSK923295.

CENP-E Inhibitor

IUPAC/Chemical name: 
3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide
3-​chloro-​N-​[(1S)​-​2-​[[2-​(dimethylamino)​acetyl]​amino]​-​1-​[[4-​[8-​[(1S)​-​1-​hydroxyethyl]​imidazo[1,​2-​a]​pyridin-​2-​yl]​phenyl]​methyl]​ethyl]​-​4-​(1-​methylethoxy)​- Benzamide,
3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide
3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide
3-Chloro-N-[1-(N,N-dimethylglycinamido)-3-[4-[8-[1(S)-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2(S)-yl]-4-isopropoxybenzamide
C32H38ClN5O4
Exact Mass: 591.26123
Molecular Weight: 592.12822
Elemental Analysis: C, 64.91; H, 6.47; Cl, 5.99; N, 11.83; O, 10.81
Kinesin-like protein KIF11 inhibitor; Centromere protein E inhibitor
GSK-923295 is a novel antimitotic inhibitor of centromere-associated protein E (CENP-E) with potential anticancer activity. GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts.
GSK-923295, a small-molecule inhibitor of centromere associated protein (CENP), is in early clinical development at Cytokinetics for the treatment of refractory cancer. No recent development has been reported for early clinical research which had been ongoing at GlaxoSmithKline.
Clinical study showed that GSK923295  had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.
GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with Ki of 3.2 nM, and less potent to mutant I182 and T183. Phase 1.
The compound potently inhibits CENP-E ATPase activity and exerts broad-spectrum antiproliferative activity against cancer cells and xenografts. GSK-923295 has demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors.
Cytokinetics was developing GSK-923295, the lead from a series of small-molecule mitotic kinesin spindle protein inhibitors, for treating cancer including advanced solid tumors. However, since October 2014, the program was no longer listed on the Cytokinetics' website
In 2001, a strategic alliance was established between Cytokinetics and GlaxoSmithKline to discover, develop and commercialize novel small-molecule therapeutics targeting mitotic kinesins for applications in the treatment of cancer and other diseases.
.........................
PATENT
US8772507
http://www.google.com/patents/US8772507
1,1-Dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate
To a solution of 4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0° C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution and were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%). ESMS [M+H]+: 331.2.
1,1-Dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate
To a solution of 1,1-dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warm to RT over 5 h. The reaction was then concentrated in vacuo and product was triturated out of solution using ethyl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3×100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]+: 460.4.
1,1-Dimethylethyl {(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-d oxo-1,3-dihydro-21′-isoindol-2-yl)methyl]ethyl}carbamate
A solution of 1,1-dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (5 mol %) were stirred in anhydrous dioxane (300 mL) at 100° C. for 3 h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400 mL). The mixture was treated with N-bromosuccinimide (108.8 mmol) and stirred at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL). Precipate formed upon addition of hexanes (350 mL) and was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+H]+: 502.4.
1,1-Dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate
A mixture of 1,1-dimethylethyl{(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]+.
3-Chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide
A mixture of 1,1-dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4 M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness and redissolved in DMF (30 mL). To this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4 [(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na2SO4), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS (ES+) m/e 637 [M+H]+.
N-[(1S)-2-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide
A mixture of 3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57° C. overnight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound (1.67 g, 100%) as a pale yellow powder. MS (ES+) m/e 507 [M+H]+.
3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide
A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCI (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS (ES+) ink 592 [M+H]+.
......................
WO2005107762
https://www.google.im/patents/WO2005107762A2
Example 1

cheme E:
ide
NaHCOj, IPA 100 'C
1 , 1 -Dimethylethyl [( 1 S)-2-(4-bromophenyl)- 1 -(hydroxymethyl)ethyl]carbamate:
To a solution of 4-bromo-N-{[(l ,1 -dimethylethyl)oxy] carbonyl }-L- phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0 °C was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stiπed for an additional 2 h at 0 °C, The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stiπed at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%).
ESMS [M+H]+: 331.2.
1,1 -Dimethylethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]ethyl}carbamate:
To a solution of 1 ,1 -dimethylethyl [(lS)-2-(4-bromophenyl)-l -
(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0 °C was added dropwise diisopropyl azodi carboxyl ate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to wai to RT over 5h, The reaction was then concentrated in vacuo and product was tritarated out of solution usingl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3 x 100 mL), and dried to afford the title product as a white solid (57%).
ESMS [M+H]+: 460.4.
1 ,1 -Dimethylethyl {(15)-2-[4-(bromoacetyl)phenyl]-l -[(l,3-dioxo-l ,3-dihydro-2H-isoindol- 2-yl)methyl]ethyl}carbamate:
A solution of 1,1 -dimethyl ethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and /ra/?s--dichlorobis(triphenylphospine)palladιum(II) (5 mol%) were stiπed in anhydrous dioxane (300 mL) at 100 °C for 3h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400mL) and treated with N- bromosuccinimide (108.8 mmol) and stined at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL) and precipate formed upon addition of hexanes (350 mL). The precipitate was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+Η]+: 502.4. l,l-Dimethylethyl [(lS)-2-(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]carbamate:
A mixture of l!l-dimethylethyl{(lS)-2-{4-(biOinoacetyl)phenyl]-l-[(l,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), l-(2- amino-3-pyτidinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4,72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2S04), and concentrated to give the title compound (1.79 g, S7%) as a light pink solid. MS(ES+) m/e 541 [M+Η]+.
3-Chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-Λ]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l - methylethyl)oxy]benzamide:
A mixture of 1,1 -dimethylethyl [(15)-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-fl]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M ΗC1 in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness ,redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16,55 mmol) and pentafluorophenyl 3-chloro-4 [(l-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na SO ), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS(ES+) m/e 637 [M+H]+.
N-[(lS)-2-Amino-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]p>tidin-2- yl]phenyl}methyl)eth)'l]-3-chloro-4-[(l-methylethyl)oxy]benzamide:
A mixture of 3-chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2N-isoindol-2-yl)-l-
({4-[8-(l -hydiOxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l- methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57°C ovemight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound(1.67 g, 100%) as a pale yellow powder. MS(ES+) m/e 507 [M+H]+.
3-Chloro-N-[(15)-2-[(7VN-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l ,2- «]pyitdin-2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide:
A mixture ofN-[(lS)-2-amino-l-({4-[S-(l-hydroxyethyl)imidazo[l,2- α]pyridin-2-yl]phenyl)methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide (0.912 g, 1 ,80 mmol), EDCI (0.69 g, 3,6 mmol), NN-diisopropylethylamine (0.466 g, 3,6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Νa2S0 ), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound ( 0.515 g, 48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]+.

SEE
WO2008 / 138561
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Organic Process Research & Development (2010), 14(5), 1254-1263
Org. Process Res. Dev., 2010, 14 (5), pp 1254–1263
DOI: 10.1021/op100186c
http://pubs.acs.org/doi/abs/10.1021/op100186c
Abstract Image
The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel−Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.
1H NMR (400 MHz, CD3OD) δH 1.34 (6H, d, J = 6.0, (CH3)2), 1.59 (3H, d, J = 7.0, CH3CH), 2.21 (6H, s, N(CH3)2), 2.87−3.01 (4H, m, CH2Ph and CH2N(CH3)2), 3.49 (2H, m, CH2NPhthal), 4.50 (1H, m, CHNH), 4.70 (1H, m, (CH3)2CHO)), 5.49 (1H, q, J = 7.0, CHOH), 6.88 (1H, t, J = 7.0, H-j), 7.08 (1H, d, J = 7.5, H-b), 7.33−7.37 (3H, m, H-k and H-d), 7.63 (1H, dd, J = 7.5 and 2.0, H-c), 7.78 (1H, s, H-a), 7.83 (2H, d, J = 7.0, H-e), 8.09 (1H, m, H-h), 8.27 (1H, d, J = 8.0, H-i);
13C NMR (100 MHz, CD3OD) δC 22.2, 24.1, 39.3, 43.8, 46.1, 53.0, 63.7, 66.2, 73.0, 110.4, 113.8, 115.3, 121.2, 124.5, 126.1, 127.5, 128.4, 128.5, 130.6, 130.7, 133.3, 136.0, 139.4, 145.1, 146.1, 157.6, 168.5 and 173.6;
HRMS (ESI+) m/z calculated for [M+H]+ C32H39N5O4Cl 592.2691, found 592.2684.
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ACS Medicinal Chemistry Letters (2010), 1(1), 30-34
http://pubs.acs.org/doi/abs/10.1021/ml900018m
Abstract Image
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.
SEE
WO-2015037460
https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=F8D2DAAA427F9EBAB6B7CE67A7EE0772.wapp1nC?docId=WO2015037460&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText
Method for producing optically active 3-(biphenyl-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol
Process for preparing optically active 3-(biphenyl-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol, useful as an intermediate in the synthesis of pharmaceuticals described in WO2005107762 and WO2008138561 (such as GSK-923295 and tubulysin derivatives respectively). Appears to be a new area of interest to the assignee.
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WO2010118207
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010118207&recNum=278&docAn=US2010030350&queryString=%28SYK%29%2520&maxRec=1655
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