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Wednesday 22 July 2015

Verubecestat (MK-8931


Verubecestat.pngV1

Verubecestat (MK-8931)

Merck Alzheimer's drugs Verubecestat (MK-8931) is an oral β- amyloid precursor protein cleaving enzyme (BACE1 or β-secretase enzyme) inhibitor, is currently in Phase III clinical trials

Verubecestat MK 8931, MK-8931, SCH 900931  
2-Pyridinecarboxamide, N- (3 - ((5R) -3-amino-5,6-dihydro-2,5-dimethyl-1 , 1-dioxido-2H-1,2,4-thiadiazin-5-yl) -4-fluorophenyl) -5-fluoro- N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide  
CAS : 1286770-55-5  
Mechanism: Oral β- amyloid precursor protein cleavage enzyme (BACE) inhibitors Indications: Alzheimer's disease Development progress: phase III clinical  

Companies: Merck

Verubecestat (MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE) 1 and BACE2 in development by Merck for the treatment of Alzheimer's Disease. MK-8931 is a beta-secretase 1 (BACE1) inhibitor in phase III development for the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's disease at Merck & Co. The company is also conducting phase II/III trials for the treatment of Alzheimer's type dementia.
Smiles: C [C @] 1 (CS (= O) (= O) N (C (= N1) N) C) c2cc (ccc2F) NC (= O) c3ccc (cn3) F  

COSY PREDICT V0COSY
https://www.google.co.in/patents/CN102639135A?cl=en  

Scheme 3b:
Figure CN102639135AD00931
The amine A (Scheme 3a, step 4) (13.7 g) in n-butanol (150 mL) was added a slurry solution of cyanogen bromide (5M, in MeCN). The resulting mixture was heated to reflux for 4 hours. The mixture was concentrated to 1/3 of original volume. To this mixture was added Et20 (200 mL). The resulting solid was removed by filtration, and the solid was washed with Et20 (2x). The solid was partitioned between EtOAc and saturated Na2CO3 (aq). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 10.6 g Scheme 10:
Figure CN102639135AD00982
The nitro compound (Scheme 3b) (2. 50 g, 6. 0 mmol) of Et0H (150 mL) was degassed (To this solution was bubbled with nitrogen time 3 min). To this solution was added Pd / C (10% w / w, 50% water, 698 mg). The mixture was placed in a nitrogen atmosphere. Exhaust, and backfilled with H2 (3x). The obtained mixture at room temperature, followed by stirring under H2 balloon for 2 hours. Bubbling nitrogen gas, and the mixture was purged, filtered through Celite, and concentrated.Small plug filtered through a silica gel column, eluting with EtOAc, and the product was purified to give the aniline (2. 2g, 97%).

   
SEE PATENT http://www.google.co.in/patents/WO2011044181A1?cl=en


  veb  


SNAPSHOT WP_000366  

SYNTHESIS CONSTRUCTION
  V9
AND
 V8
ON RXN WITH WITH BuLi GIVES V7THIS GIVES
 V6
THIS ON TREATMENT WITH BrCN V5
ON BOC2O TREATMENT GIVES V4
GIVES ON HYDGN
 V2
 REACTION WITH
 V3
 GIVES FINAL COMPD Verubecestat V1


 1H NMR PREDICT V0 V01H GRAPH V01H 13C NMR PREDICT

  V013C GRAPH V013C


Updated.......WATCH OUT FOR MORE
https://www.google.co.in/patents/US8729071?cl=en


Steps 1-4:
These steps were performed using similar procedures to those described in steps 1-4 of Scheme 1a.
Step 5:
To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH2Cl2 (200 mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resulting solution was stirred at RT for 2.5 days. Additional benzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution was stirred at RT for an additional 2 hours. The solution was then concentrated in vacuo.
A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200 mL). To this solution was added Na2CO3 (s) (1.52 g, 14 mmol). The resultant mixture was stirred at RT for 45 min. After that time, a slight excess of HOAc was added to the solution. The mixture was then concentrated. The residue was partitioned between CH2Cl2 and ½ sat. NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The thiourea (˜4.9 g) was carried onto the next reaction without further purification.
Step 6:
Example 15 was prepared using a method similar to that described in Scheme 1a step 6.
To a shiny of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN). The resultant mixture was heated to reflux for 4 hours. The mixture was concentrated to ⅓ of the original volume. To the mixture was added Et2O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et2O (2×). The solid was partitioned between EtOAc and sat. Na2CO3 (aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 10.6 grams of Ex. 15. This material was converted to the t-butyl carbamate using a procedure similar to that described in Scheme 3.
Step 7:
A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39 mL, 8.30 mmol), Pd2(dba)3 (0.634 g, 0.692 mmol), John-Phos (0.413 g, 1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51 mL) was degassed (vacuum/N2). The mixture was then stirred at 65° C. under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was then dissolved in methanol (76 mL) and the resulting solution was charged with hydroxyl amine hydrochloride (2.16 g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 40 min. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/heptane) to afford the amino pyridine (0.880 g, 34%).
To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15, 1.5 g, 3.3 mmol), Pd2(dba)3 (305 mg, 0.3 mmol), (2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodium tert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol), and toluene (21 mL). The mixture was evacuated under vacuum and back-filled with N2 (3×). The mixture was stirred at 60° C. for 1 h. After filtration through celite, the filtrate was concentrated. The crude residue was dissolved in 36 mL of methanol, and hydroxyl amine hydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol) were added. The reaction was stirred for 35 min and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic portions were dried over magnesium sulfate and concentrated. The crude residue was purified by a flash silica column (50% ethyl acetate/hexane) to get an aminopyridine product (730 mg, 68%).
A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH (150 mL) was degassed by bubbling N2 through the solution for 3 min. To this solution was added Pd/C (10% w/w, 50% H2O, 698 mg.). The mixture was placed under an atmosphere of N2. The atmosphere was evacuated and back-filled with H2 (3×). The resulting mixture was stirred at RT under a H2 balloon for 2 h. The mixture was purged by bubbling N2 through it, filtered through Celite and concentrated. The product was purified by filtering through a small plug of silica gel column eluting with EtOAc to afford the aniline (2.2 g, 97%).

ENTRY 25 MH+: 410.0, HPLC1.79 min, LCMSMETHOD D
Method D:
  • Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM
Mobile phase: A: 0.05% Trifluoroacetic acid in water
    • B: 0.05% Trifluoroacetic acid in acetonitrile
Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2 min, 5:95 (A:B) for 1.2 min.
Flow rate: 1.0 mL/min
UV detection: 254 and 220 nm
Mass spectrometer: Agilent 6140 quadrupole


सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

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