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Tivicay|Dolutegravir|度鲁特韦|GSK1349572(抗艾重磅新药)

(2013-11-05 21:29:00)
标签:

度鲁特韦

dolutegravir

gsk1349572

分类: 合成工艺

Dolutegravir (trade name:  Tivicay, also known as S/GSK1349572, GSK1349572, Chinese Name:度鲁特韦,德罗格韦) was approved by the US Food and Drug Administration (FDA) in August 12, 2013 for use in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children aged 12 years and older weighing at least 40 kg (approx. 88 lbs).

A once-daily integrase inhibitor, dolutegravir was developed by ViiV Healthcare, a joint venture between GlaxoSmithKline, Pfizer and Shionogi. Dolutegravir is viewed by analysts as a potential multibillion-dollar-a-year seller

Tivicay|Dolutegravir|度鲁特韦|GSK1349572(抗艾重磅新药)

Synthesis of Dolutegravir (S/GSK1349572, GSK1349572), HIV/AIDS Drug From Shionogi and GlaxoSmithKline 艾滋病重磅新药Dolutegravir的制备方法:

Tivicay|Dolutegravir|度鲁特韦|GSK1349572(抗艾重磅新药)

Full Experimental Procedures for the Preparation of Dolutegravir (S/GSK1349572, GSK1349572), HIV/AIDS Drug From Shionogi and GlaxoSmithKline

1) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound YP-2). To a slurry of 2000 g of 3-Hydroxy-2-methyl-4-pyrone (Compound YP-1, 1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K 2 CO 3 (1.2 eq.). The mixture was stirred at 80 0 C for 5 h and cooled to 13°C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound P-2 as oil. Without further purification, compound YP-2 was used in the next step. 1 H NMR(300 MHz, CDCl3 ) δ 7.60 (d, J = 5.7 Hz, 1 H), 7.4-7.3 (m, 5H), 6.37 (d, J = 5.7 Hz, 1 H), 5.17 (s, 2H), 2.09 (s, 3H).

2) Synthesis of 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound P-3). To 904 g of the crude compound YP-2 was added 5.88 L of THF and the solution was cooled to -600 C. 5.00 L of 1.0 M of Lithium bis(trimethylsilylamide) in THF(1.25 eq.) was added dropwise for 2 h to the solution of compound 2 at -60 0 C. Then, a solution of 509 g of benzaldehyde(1.2 eq.) in 800 ml. of THF was added at -60 0 C and the reaction mixture was aged at -60 0 C for 1 h. The THF solution was poured into a mixture of 1.21 L of conc.HCl, 8.14 L of ice water and 4.52 L of EtOAc at less than 2 0 C. The organic layer was washed with 2.71 L of brine (twice) and the aqueous layer was extracted with 3.98 L of EtOAc. The combined organic layers were concentrated. To the mixture, 1.63 L of toluene was added and concentrated (twice) to provide toluene slurry of compound P-3. Filtration, washing with 0.90 L of cold toluene and drying afforded 955 g of compound YP-3 (74% yield from compound P-1 ) as a solid. 1 H NMR(300 MHz, CDCl3 ) δ 7.62 (d, J = 5.7 Hz, 1 H), 7.5-7.2 (m, 10H), 6.38 (d, J = 5.7 Hz, 1 H), 5.16 (d, J = 11.4 Hz, 1 H), 5.09 (d, J = 11.4 Hz, 1 H), 4.95 (dd, J = 4.8, 9.0 Hz, 1 H), 3.01 (dd, J = 9.0, 14.1 Hz, 1 H), 2.84 (dd, J = 4.8, 14.1 Hz, 1 H).

3) Synthesis of 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound YP-4). To a solution of 882 g of compound YP-3 (1.0 eq.) in 8.82 L of THF were added 416 g of Et 3 N(1.5 eq.) and 408 g of methanesulfonyl chloride(1.3 eq.) at less than 300 C. After confirmation of disappearance of compound P-3, 440 ml. of NMP and 1167 g of DBU(2.8 eq.) were added to the reaction mixture at less than 300 C and the reaction mixture was aged for 30 min. The mixture was neutralized with 1.76 L of 16% sulfuric acid and the organic layer was washed with 1.76 L of 2% Na2SO3 aq. After concentration of the organic layer, 4.41 L of toluene was added and the mixture was concentrated (tree times). After addition of 4.67 L of hexane, the mixture was cooled with ice bath. Filtration, washing with 1.77 L of hexane and drying provided 780 g of compound YP-4 (94% yield) as a solid. 1 H NMR(300 MHz, CDCl3 ) δ 7.69 (d, J = 5.7 Hz, 1 H), 7.50-7.25 (m, 10H), 7.22 (d, J = 16.2 Hz, 1 H), 7.03 (d, J = 16.2 Hz, 1 H), 6.41 (d, J = 5.7 Hz, 1 H), 5.27 (s, 2H).

4) Synthesis of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid (compound YP-5). To a mixture of 822 g of compound YP-4 (1.0 eq.) and 1 1.2 g of RuCl3 -nH2O(0.02 eq.) in 2.47 L of MeCN, 2.47 L of EtOAc and 2.47 L of H2O was added 2310 g of NalO4 (4.0 eq.) at less than 250 C. After aging for 1 h, 733 g of NaCIO2 (3 eq.) was added to the mixture at less than 250 C. After aging for 1 h, precipitate was filtered and washed with 8.22 L of EtOAc. To the filtrate, 1.64 L of 50% Na 2 S 2 0 3 aq, 822 ml. of H2O and 630 ml. of coc.HCl were added. The aqueous layer was extracted with 4.11 L of EtOAc and the organic layers were combined and concentrated. To the residue, 4 L of toluene was added and the mixture was concentrated and cooled with ice bath. Filtration, washing with 1 L of toluene and drying provided 372 g of compound YP-5 (56% yield) as a solid. 1 H NMR(300 MHz, CDCl3 ) δ 7.78 (d, J = 5.7 Hz, 1 H), 7.54-7.46 (m, 2H), 7.40-7.26 (m, 3H), 6.48 (d, J = 5.7 Hz, 1 H), 5.6 (brs, 1 H), 5.31 (s, 2H).

5) Synthesis of 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2- pyridinecarboxylic acid (compound YP-6). A mixture of 509 g of compound YP-5 (1.0 eq.) and 407 g of 3-amino-propane-1,2-diol(2.5 eq.) in 1.53 L of EtOH was stirred at 65 0 C for 1 h and at 80 0 C for 6 h. After addition of 18.8 g of 3-Amino-propane-1,2-diol(0.1 eq.) in 200 ml. of EtOH, the mixture was stirred at 80 0 C for 1 h. After addition of 18.8 g of 3-amino- propane-1 ,2-diol (0.1 eq.) in 200 ml. of EtOH, the mixture was stirred at 80 0 C for 30 min. After cooling and addition of 509 ml. of H 2 O, the mixture was concentrated. To the residue, 2.54 L Of H 2 O and 2.54 L of AcOEt were added. After separation, the aqueous layer was washed with 1.02 L of EtOAc. To the aqueous layer, 2.03 L of 12% sulfuric acid was added at less than 12 0 C to give crystal of compound YP-6. Filtration, washing with 1.53 L of cold H 2 O and drying provided 576 g of compound YP-6 (83% yield) as a solid. 1 H NMR(300 MHz, DMSO-d6) δ 7.67 (d, J = 7.5 Hz, 1 H), 7.5-7.2 (m, 5H), 6.40 (d, J = 7.5 Hz, 1 H), 5.07 (s, 2H), 4.2-4.0 (m, 1 H), 3.9-3.6 (m, 2H), 3.38 (dd, J = 4.2, 10.8 Hz, 1 H), 3.27 (dd, J = 6.0, 10.8 Hz, 1 H).

6) Synthesis of methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2- pyridinecarboxylate (compound YP-7). To a slurry of 576 g of compound YP-6 (1.0 eq.: 5.8% of H2O was contained) in 2.88 L of NMP were added 431 g of NaHCO3 (3.0 eq.) and 160 ml. of methyl iodide(1.5 eq.) and the mixture was stirred at room temperature for 4 h. After cooling to 5 0 C, 1.71 L of 2N HCI and 1.15 L of 20% NaClaq were added to the mixture at less than 10 0 C to give crystal of compound YP-7. Filtration, washing with 1.73 L of H 2 O and drying provided 507 g of compound YP-7 (89% yield) as a solid. 1 H NMR(300 MHz, DMSO- d6) δ 7.59 (d, J = 7.5 Hz, 1 H), 7.40-7.28 (m, 5H), 6.28 (d, J = 7.5 Hz, 1 H), 5.21 (d, J = 5.4 Hz, 1 H), 5.12 (d, J = 10.8 Hz, 1 H), 5.07 (d, J = 10.8 Hz, 1 H), 4.83 (t, J = 5.7 Hz, 1 H), 3.97 (dd, J = 2.4, 14.1 Hz, 1 H), 3.79 (s, 3H), 3.70 (dd, J = 9.0, 14.4 Hz, 1 H), 3.65-3.50 (m, 1 H), 3.40-3.28 (m, 1 H), 3.26-3.14 (m, 1 H).

7) Synthesis of methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2- pyridinecarboxylate (compound YP-8). To a mixture of 507 g of compound YP-7 (1.0 eq.) in 5.07 L of MeCN, 5.07 L of H 2 O and 9.13 g of AcOH(0.1 eq.) was added 390 g of NaIO 4 (1.2 eq.) and the mixture was stirred at room temperature for 2 h. After addition of 1.52 L of 10% Na 2 S 2 0 3 aq., the mixture was concentrated and cooled to 10 0 C. Filtration, washing with H 2 O and drying provided 386 g of compound YP-8 (80% yield) as a solid. 1 H NMR(300 MHz, DMSO-d 6 ) δ 7.62 (d, J = 7.5 Hz, 1 H), 7.42-7.30 (m, 5H), 6.33 (d, J = 6.0 Hz, 2H), 6.29 (d, J = 7.5 Hz, 1 H), 5.08 (s, 2H), 4.95-4.85 (m, 1 H), 3.80 (s, 3H), 3.74 (d, J = 5.1 Hz, 2H).

8) Synthesis of (4R,12aS)-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H- pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (compound YP-9). After dissolution of a mixture of 378 g of compound YP-8 (1.0 eq.) in 3.78 L of MeOH by heating, the solution was concentrated. To the residue, 1.51 L of toluene was added and the mixture was concentrated. To the residue, 1.89 L of toluene, 378 ml. of AcOH and 137 g of {R)-3-Amino-butan-1-ol(1.3 eq.) were added and the mixture was heated to 90 0 C, stirred at 90 0 C for 2.5 h and concentrated. To the residue, 1.89 L of toluene was added and the mixture was concentrated. The residue was extracted with 3.78 L and 1.89 L of CHCI3 and washed with 2 x 1.89 L of H 2 O. The organic layers were combined and concentrated. To the residue, 1.89 L of EtOAc was added and the mixture was concentrated. After addition of 1.89 L of EtOAc, filtration, washing with 1.13 L of EtOAc and drying provided 335 g of compound YP-9 (83% yield) as a solid. 1 H NMR(300 MHz, CDCl3 ) δ 7.70-7.58 (m, 2H), 7.40-7.24 (m, 3H), 7.14 (d, J = 7.5 Hz, 2H), 6.47 (d, J = 7.5 Hz, 1 H), 5.35 (d, J = 10.2 Hz, 1 H), 5.28 (d, J = 10.2 Hz, 1 H), 5.12 (dd, J = 3.9, 6.3 Hz, 1 H), 5.05-4.90 (m, 1 H), 4.07 (dd, J = 3.9, 13.5 Hz, 1 H), 4.00-3.86 (m, 3H), 2.23-2.06 (m, 1 H), 1.48 (ddd, J = 2.4, 4.5, 13.8 Hz, 1 H), 1.30 (d, J = 6.9 Hz, 3H).

9) Synthesis of (4R,12aS)-9-bromo-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (compound YP-10). To a slurry of  332 g of compound YP-9 (1.0 eq.) in 1.66 L of NMP was added 191 g of NBS(1.1 eq.) and the mixture was stirred at room temperature for 2 h. After addition of 1.26 L of H2O, the mixture was stirred for 30 min. After addition of 5.38 L of H 2 O and aging of the mixture at 10 0 C for 30 min and at 5 0 C for 1 h, filtration, washing with 1.33 L of cold H 2 O and drying provided 362 g of compound YP-10 (89% yield) as a solid.1 H NMR(300 MHz, CDCl3 ) δ 7.69-7.63 (m, 2H), 7.59 (s, 1 H), 7.38-7.24 (m, 3H), 5.33 (d, J = 10.2 Hz, 1 H), 5.25 (d, J = 9.9 Hz, 1 H), 5.12 (dd, J = 3.9, 5.7 Hz, 1 H), 5.05-4.90 (m, 1 H), 4.1 1 (dd, J = 3.9, 13.2 Hz, 1 H), 4.02-3.88 (m, 3H), 2.21-2.06 (m, 1 H), 1.49 (ddd, J = 2.4, 4.5, 14.1 Hz, 1 H), 1.31 (d, J = 6.9 Hz, 3H).

10) Synthesis of (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7- [(phenylmethyl)oxy]-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazine-9-carboxamide (compound YP-11). Under carbon monooxide atmosphere, a mixture of 33.5 g of compound YP-10 (1.0 eq.), 34.8 ml. of i-Pr2NEt(2.5 eq.), 14.3 ml_ of 2,4- difluorobenzylamine(1.5 eq.) and 4.62 g of Pd(PPh3)4 (0.05 eq.) in 335 ml. of DMSO was stirred at 90 0 C for 5.5 h. After cooling, precipitate was filtered and washed with 50 ml. of 2-propanol. After addition of 502 ml. of H 2O and 670 ml. of AcOEt to the filtrate, the organic layer was washed with 335 ml. of 0.5N HClaq. and 335 ml. of H2O and the aqueous layer was extracted with 335 ml. of AcOEt. The organic layers were combined and concentrated. To the residue, 150 ml. of 2-propanol was added and the mixture was concentrated. After addition of 150 ml. of 2-propanol, concentration, cooling to 20 0 C and filtration, crude crystal of compound P-11 was obtained. After dissolution of the crude crystal in 380 ml. of acetone by heating, precipitate was filtered and the filtrate was concentrated. After addition of 200 ml. of EtOH, concentration, addition of 150 ml. of EtOH, concentration, cooling and filtration, crude crystal of compound P-11 was obtained. After dissolution of the crude crystal in 450 ml. of acetone by heating, the solution was concentrated. To the residue, 150 ml. of 2-propanol was added and the mixture was concentrated (twice). After cooling of the residue, filtration, washing with 2-propanol and drying provided 34.3 g of compound YP-11 (84% yield) as a solid. 1 H NMR(300 MHz, CDCI 3 ) δ 10.40 (t, J = 6.0 Hz, 1 H), 8.35 (s, 1 H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J = 9.9 Hz, 1 H), 5.26 (d, J = 10.2 Hz, 1 H), 5.15 (dd, J = 3.9, 5.7 Hz, 1 H), 5.05-4.90 (m, 1H), 4.64 (d, J = 5.4 Hz, 2H), 4.22 (dd, J = 3.9, 13.5, 1 H), 4.09 (dd, J = 6.0, 13.2 Hz, 1 H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1 H), 1.50 (ddd, J = 2.4, 4.5, 14.1 Hz, 1 H), 1.33 (d, J = 7.2 Hz, 3H).

11) Synthesis of (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (Dolutegravir) Under hydrogen atmosphere, a mixture of 28.0 g of compound P-11 (1.0 eq.) and 5.6 g of 10% Pd-C in 252 ml. of THF and 28 ml. of MeOH was stirred for 1 h. After precipitate (Pd-C) was filtered and washed with 45 ml. of THF, 5.6 g of 10% Pd-C was added and the mixture was stirred for 1.5 h under hydrogen atmosphere. After Pd-C was filtered and washed with 150 ml. of CHCI 3 /Me0H(9/1 ), the filtrate was concentrated. After dissolution of the residue in 1.38 L of EtOH by heating, the solution was gradually cooled to room temperature. After filtration, the filtrate was concentrated and cooled. Filtration, washing with EtOH and drying provided 21.2 g of compound 1a (92% yield) as a solid. 1 H NMR(300 MHz, DMSO-d6) δ 12.51 (s, 1 H), 10.36 (t, J = 5.7 Hz, 1 H), 8.50 (s, 1 H), 7.39 (td, J = 8.7, 6.3 Hz, 1 H), 7.24 (ddd, J = 2.6, 9.5, 10.8 Hz, 1 H), 7.12-7.00 (m, 1 H), 5.44 (dd, J = 3.9, 5.7 Hz, 1 H), 4.90-4.70 (m, 1 H), 4.65-4.50 (m, 1 H), 4.54 (d, J = 5.1 Hz, 2H), 4.35 (dd, J = 6.0, 13.8 Hz, 1 H), 4.10-3.98 (m, 1 H), 3.96-3.86 (m, 1 H), 2.10-1.94 (m, 1 H), 1.60-1.48 (m, 1 H), 1.33 (d, J = 6.9 Hz, 3H).

12). Synthesis of (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide sodium salt (Dolutegravir Sodium salt). After dissolution of 18.0 g of dolutegravir (1.0 eq.) in 54 ml_ of EtOH by heating, followed by filtration, 21.5 ml. of 2N NaOHaq.(1.0 eq.) was added to the solution at 80 0 C. The solution was gradually cooled to room temperature. Filtration, washing with 80 ml. of EtOH and drying provided 18.8 g of Dolutegravir Sodium salt (99% yield) as a solid. 1 H NMR(300 MHz, DMSO-d6 ) δ 10.70 (t, J = 6.0 Hz, 1 H), 7.89 (s, 1 H), 7.40-7.30 (m, 1 H), 7.25-7.16 (m, 1 H), 7.06-6.98 (m, 1 H), 5.22-5.12 (m, 1 H), 4.87-4.74 (m, 1 H), 4.51 (d, J = 5.4 Hz, 2H), 4.35-4.25 (m, 1 H), 4.16 (dd, J = 1.8, 14.1 Hz, 1 H), 4.05-3.90 (m, 1 H), 3.86-3.74 (m, 1 H), 2.00-1.72 (m, 1 H), 1.44-1.32 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3H).

References:

Johns, Brian Alvin; Kawasuji, Takashi; Taishi, Teruhiko; Taoda, Yoshiyuki ; Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity and their preparation; PCT Int. Appl., WO2006116764, 02 Nov 2006

Johns, Brian Alvin; Weatherhead, Jason Gordon;Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection; PCT Int. Appl., WO2010011812, 28 Jan 2010

Johns, Brian Alvin; Weatherhead, Jason Gordon; Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection;PCT Int. Appl., WO2010011819, 28 Jan 2010

Yoshida, Hiroshi; Taoda, Yoshiyuki; Johns, Brian Alvin; Synthesis of fused tricyclic carbamoylpyridone HIV integrase inhibitors and intermediates;PCT Int. Appl.,WO2010068253, 17 Jun 2010

Johns, Brian Alvin; Duan, Maosheng; Hakogi, Toshikazu;Processes and intermediates for fused tricyclic carbamoylpyridone HIV integrase inhibitors;PCT Int. Appl., WO2010068262, 17 Jun 2010

Sumino, Yukihito; Okamoto, Kazuya; Masui, Moriyasu; Yamada, Daisuke; Ikarashi, Fumiya;Preparation of compounds having HIV integrase inhibitory activity; PCT Int. Appl.,WO2012018065, 09 Feb 2012

Kawasuji, Takashi; Johns, Brian A.;Discovery of dolutegravir and S/GSK1265744: Carbamoyl pyridone HIV-1 integrase inhibitors;Abstracts, 64th Southeast Regional Meeting of the American Chemical Society, Raleigh, NC, United States, November 14-17 (2012), SERM-176.

Kawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Weatherhead, Jason G.; Akiyama, Toshiyuki; Taishi, Teruhiko; Taoda, Yoshiyuki; Mikamiyama-Iwata, Minako; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Garvey, Edward P.; Fujiwara, Tamio; Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles;Journal of Medicinal Chemistry (2013), 56(3), 1124-1135

Walmsley S et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – SINGLE (ING114467). 52nd ICAAC, 9-12 September 2012, San Francisco. Abstract H-556b.

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