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GSK3β inhibitor, AZD8926



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[4- [5-Fluoro-4- [3-tetr ahydropy r an-4-yl-2-(trifluor omethyl)imidazol-4-yl] -pyrimidin- 20 2-yl] aminophenyl]-(4-methylpiperazin-l-yl)-methanone 


 GSK3β inhibitor

AZD8926  is a potent glycogen synthase kinase-3β (GSK3β) inhibitor which has potential for treating several CNS disorders, such as Alzheimer’s disease (AD), schizophrenia, and chronic as well as acute neurodegenerative diseases






Abstract Image

Development of a new, safe, and scalable route to the GSK3β inhibitor, AZD8926, is presented.

In brief, the process constitutes of (i) a synthesis of 1-(pyran-4-yl)-2-trifluoromethyl-imidazole, 14; (ii) a Ziegler-type coupling of lithiated 14 with commercially available 2-chloro-5-fluoropyrimidine via 1,2-addition over the 3,4-C–N bond; (iii) a copper-catalyzed dehydrogenative aromatization using oxygen as the stoichiometric oxidant; and (iv) an aromatic C–N bond formation using either a Buchwald–Hartwig coupling or an acid-catalyzed amination. This process circumvents the main issue in the early-phase route, in which serious process safety constraints were associated with the hazardous properties of the structure, formation, and reduction of 5-methyl-4-nitroisoxazole, 2 (4200 J/g). The new process has been demonstrated on a multigram, 2-L scale. The overall yield was improved from 4 to 14%, and the number of steps decreased from 12 to 10

Org. Process Res. Dev.201317 (4), pp 672–678
DOI: 10.1021/op300365e

[4-[5-Fluoro-4-[3-tetrahydropyran-4-yl-2-(trifluoromethyl)imidazol-4-yl]-pyrimidin-2-yl]aminophenyl]-(4-methylpiperazin-1-yl)-methanone (9)

Ester Hydrolysis

The butyl-ester 17 (130 g, 0.25 mol) was mixed in 2-propanol (1040 mL) at 25 °C. KOH (4 M, 95 mL, 0.37 mol) was charged, and the reaction mixture was heated at 55 °C for 6 h. HCl (2 M, 189 mL, 0.38 mol) diluted with water (780 mL) was charged to the reaction solution over 45 min, while 55 °C was maintained. The slurry was cooled to 15 °C over 2 h and left for 1 h. The solids were collected, washed with water (380 mL), and dried at 55 °C with vacuum to give the butyl acid (122.8 g, 98% yield, corrected for 98.5 wt % 1H NMR assay) as a yellow solid. MS (ESI) m/z452 [M + H]+; 1H NMR (DMSO-d6) δ 1.88–1.94 (m, 2H), 2.10–2.18 (m, 2H), 3.23 (t, 2H, J = 11.4 Hz), 3.81 (dd, 2H, J = 11.6 and 4.0 Hz), 4.77–4.84 (m, 1H), 7.57 (d, 1H, J = 2.0 Hz), 7.78 (d, 2H, J = 8.8 Hz), 7.88 (d, 2H, J = 8.8 Hz), 8.83 (d, 1H, J = 1.6 Hz), 10.22 (s, 1H), 12.61 (br s, 1H); 13C NMR (DMSO-d6) δ 32.02, 55.96, 66.43, 118.08, 118.89 (CF3, JC,F = 267.9 Hz), 123.66, 127.43, 130.24, 132.45 (C–H, JC,F = 5.4 Hz), 136.48 (C–CF3, JC,F = 38.2 Hz), 144.08, 144.21 (C–C, JC,F = 12.6 Hz), 147.94 (C–H, JC,F = 24.4 Hz), 150.22 (C–F, JC,F = 251.9 Hz), 155.76 (C–N, JC,F = 3.1 Hz), 167.01; 99.8% HPLC purity. Reaction monitoring (acidt7.25 min) was conducted by HPLC analysis with UV detection at 292 nm. HRMS m/z found 452.1345 [M + H]+, C20H18N5O3F4 requires 452.1346.
EDCI Coupling

The butyl acid (112.6 g, 0.24 mol) was mixed in THF (675 mL) at 25 °C. N-Methyl-piperazine (29.3 mL, 0.26 mol), NMM (41 mL, 0.37 mol), and HOBt as a water solution (17 mL, 24.4 mmol, 19.4%) were added to the reaction solution. EDCI (72.7 g, 0.34 mol) dissolved in water (220 mL) was added over 10 min. The reaction mixture was heated at 45 °C for 1 h. EtOAc (675 mL) was added, and the reaction solution was heated at 55 °C. The lower water phase was separated off, and the organic phase was washed with 5% NaCl in water (225 mL), and then the organic solution was left stirring at 55 °C. Heptane (675 mL) was added over 1.5 h to initiate crystallization. The slurry was cooled to 5 °C over 8 h and left for at least 2 h. The solids were collected, washed with a cooled mixture of EtOAc and heptane (1:1, 600 mL), and dried at 60 °C with vacuum to give compound 9 (120.8 g, 89% yield, corrected for 96.1 wt % 1H NMR assay) as a light-yellow solid.
MS (ESI) m/z 534 [M + H]+;
1H NMR (DMSO-d6) δ 1.86–1.93 (m, 2H), 2.08–2.18 (m, 2H), 2.19 (s, 3H), 2.23–2.38 (m, 4H), 3.22 (t, 2H, J = 11.4 Hz), 3.34–3.68 (m, 4H), 3.80 (dd, 2H,J = 11.4 and 3.8 Hz), 4.77–4.88 (m, 1H), 7.35 (d, 2H, J = 8.8 Hz), 7.57 (d, 1H, J = 2.4 Hz), 7.70 (d, 2H, J = 8.8 Hz), 8.05 (d, 1H, J = 1.6 Hz), 10.04 (s, 1H);
13C NMR (DMSO-d6) δ 32.01, 45.57, 54.49 (piperazine), 55.96, 66.44, 118.65, 118.90 (CF3, JC,F = 267.8 Hz), 127.53, 127.89, 129.08, 132.39 (C–H, JC,F = 5.6 Hz), 136.42 (C–CF3, JC,F = 38.3 Hz), 141.07, 144.06 (C–C, JC,F = 12.5 Hz), 147.96 (C–H, JC,F = 24.7 Hz), 150.02 (C–F, JC,F = 251.2 Hz), 156.04 (C–N, JC,F = 2.9 Hz), 168.89; 99.6% HPLC purity.
Reaction monitoring (9t2.90 min) was conducted by HPLC analysis with UV detection at 292 nm.
HRMS m/z found 534.2250 [M + H]+, C25H28N7O2F4 requires 534.2241.

Scheme I:

Figure imgf000038_0001

Scheme 1

Anilines of formula (III) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process b). Compounds of formula (IV) and amines of formula (V) may be reacted together under standard Buchwald conditions as described in Process a.

A synthesis of pyrimidines of formula (IV) is described in Scheme 2(RX may be the same or different and is Q.βalkytyT should not be there

Figure imgf000039_0001

Scheme 2

Compounds of formula (V) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Compounds of formula (VI) in which R6 has the general structure Ra-CH-Rb (wherein Ra and Rb are as defined in formula I and Rx may be the same or different and is C1-6alkyl) and R9 is F may be prepared according to Scheme 3

Figure imgf000039_0002

(VI) (VIf)

Scheme 3

Example 104

[4- [5-Fluoro-4- [3-tetr ahydropy r an-4-yl-2-(trifluor omethyl)imidazol-4-yl] -pyrimidin- 20 2-yl] aminophenyl]-(4-methylpiperazin-l-yl)-methanone hydrochloride


Figure imgf000141_0002

The title compound was prepared in accordance with the general method E and work-up procedure B. The product was purified by flash chromatography (CH2Cl2MeOH 30:1, 20:1 then 15:1). Using 5-fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH- 25 imidazol-5-yl]pyrimidin-2-amme (obtained from Example 34(d)) (33 mg, 0.1 mmol), l-(4- bromobenzoyl)-4-methylpiperazine (0.027 g, 0.095 mmol), Cs2CO3 (65 mg, 0.2 mmol), Pd2(dba)3 (6.8 mg, 0.0075 mmol) and X-Phos (7 mg, 0.015 mmol), the base of the title compound (35 mg, 70%) was obtained as a solid. The hydrochloride was prepared in accordance with the method described in general method D. 1H NMR (DMSO-<fc, 300 MHz) δ 10.60 (br s, 1 H), 10.11 (s, 1 H), 8.82 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.56 (s, 1 H), 7.42 (d, J= 8.4 Hz, 2 H), 4.80 (t, 1 H), 3.80 (d, J= 8.4 Hz, 2 H), 3.22 (t, J= 11.5 Hz, 2 H), 3.2-3.0 (m, 2 H), 2.78 (s, 3 H), 2.2-2.1 (m, 2 H), 2.0-1.8 (m, 2 H); 6 Hydrogens were not assigned in the region 3.6 -2.2 ppm due to the presence of the water and DMSO peaks in this region; MS (ESI) m/z 534.5 (M+ 1); MS (ESI) m/z 532.5 (M-I).



Example 34 (d) 5-Fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH- imidazol-5-yl]pyrimidin-2-amine

Figure imgf000091_0001

The title compound was prepared in accordance with the general method B with the exception that guanidine carbonate was used. Using (2Z)-3-dimethylamino-2-fluoro-l-[l- (tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-5 -y l]prop-2-en- 1 -one (0.330 g, 1.0 mmol, obtained from Example 34(c)) and guanidine carbonate (0.45 g, 2.50 mmol). After purification by flash chromatography (heptane/EtOAc 1 :2), the title compound was obtained (0.170 g, 51 %) as a white solid.

1HNMR (CDCl35 300 MHz) δ 8.29 (s, 1 H)5 7.63 (d, J= 2.7 Hz, 1 H)5 5.10 (br.s., 2 H)5 4.88-4.76 (m, 1 H), 4.16-4.07 (m, 2 H)53.53-3.42 (m5 2 H)5 2.80-2.65 (m, 2 H), 1.89-1.81 (m, 2 H); MS (ES) m/z 332 (M+l).


(a) BhatR. V.; BuddS. L. Neurosignals 200211251
(b) BhatR. V.; Budd HaeberleinS. L.; AvilaJ. J. Neurochem. 2004891313

(c) JohanssonS.; JämsäA.; VasängeM.; WinbladB.; Luthman; CowburnR. F. Neurochemistry 200617907

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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