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BMS-663068 is an HIV-1 attachment inhibitor in development for the treatment of HIV-1 infection. BMS-663068 is a prodrug for BMS-626529 which binds to the viral envelope glycoprotein gp120 and interferes with attachment of the virus to the cellular CD4 receptor. Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted.
Fostemsavir (GSK3684934/BMS-663068) is an experimental HIVentry inhibitor and a prodrug of temsavir (BMS-626529). It is under development by [ViiV Healthcare / GlaxoSmithKline]] for use in the treatment of HIV infection. By blocking the gp120 receptor of the virus, it prevents initial viral attachment to the host CD4+ T cell and entry into the host immune cell; its method of action is a first for HIV drugs.[1] Because it targets a different step of the viral lifecycle, it offers promise for individuals with virus that has become highly resistant to other HIV drugs.[2] Since gp120 is a highly conserved area of the virus, the drug is unlikely to promote resistance to itself via generation of CD4-independent virus.[3]
Example 6Preparation of Compound I from Compound D′ (Example 5)
N-Benzoylpiperazine HCl, Compound Db, (11.73 g, 51.74 mmol) was added to a mixture of Compound D′ (14.83 g, 47.03 mmol) (prepared in Example 5) in dry THF (265 mL) and dry DMF (29.5 mL). NaOt-Bu, 30% w/w (52.3 mL, 147 mmol) was added dropwise (30 min.) keeping the temperature at 17-21° C. The resulting yellow slurry was stirred at 17-20° for 1 h more, then cooled to about 5° C. The mixture was slowly poured into cold water (90 mL) and the flask rinsed with additional water (10 mL). The pH of the resulting yellow solution was adjusted to 6-7 with slow addition (˜20 min., 5-12° C.) of 1 N HCl (105 mL). The resulting slurry was warmed and stirred at room temperature for 1.5 h. The slurry was filtered and the cake washed with water (2×60 mL) then dried in vacuo at 65-70° C. for 5 h giving 18.4 g Compound I as a white solid (82.6%), HPLC AP 99.4. 1H NMR (400 MHz, d6-DMSO): δ 2.48 (s, 3H), 3.43 (b, 4H), 3.67 (b, 4H), 3.99 (s, 3H), 7.45 (s, 5H), 7.88 (s, 1H), 8.24 (s, 1H), 9.22 (s, 1H), 12.39 (s, 1H). 13C NMR (100 MHz, d6-DMSO): 13.85, 40.65, 45.22, 56.85, 114.19, 121.02, 122.78, 123.65, 127.06, 128.42, 129.61, 129.70, 135.51, 138.59, 142.18, 149.23, 161.38, 166.25, 169.30, 185.51.
If necessary, the product could be further purified by recrystallization from acetic acid-water-ethanol, ethanol-water, or acetone-water. For example: A mixture of Compound I (25.0 g), glacial acetic acid (260 mL) and DI water (13.8 mL) was heated to 80° C. and held with stirring (overhead) until a solution was obtained (40 min.). The batch was cooled to 70° C. and seeded (0.5 g). With slow agitation (100 rpm), EtOH (300 mL) was added slowly (1 h), keeping the temperature at 70° C. The resulting slurry was kept at 70° C. for 1 h more with very slow stirring. The slurry was cooled to 20° C. over 2 hours and held at 20° C. for over 4 hours. The slurry was filtered, the wet cake washed with EtOH (125 mL), and the solid dried in vacuo at 70° C. (≧16 h), giving 22.6 g Compound I as a white solid (88.4%).
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel–Crafts acylation, Pictet–Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C–H bond, enabling a highly regioselective copper-mediated Ullmann–Goldberg–Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate
Attachment inhibitor BMS-663068 is currently in clinical development for the treatment of HIV infection. Key steps in the synthesis depicted are (1) a radical-mediated redox-aromatization to generate the 6-azaindole (B → C) and (2) the regioselective bromination of an N-oxide using PyBroP (D → E).
High regioselectivity was observed in the copper(I)-mediated Ullmann–Goldberg–Buchwald coupling (H → K) using the diamine ligand J (N1/N2 = 22:1), whereas a thermal SNAr reaction gave N1/N2 = 1:1. Alternative conditions for the bromination of the N-oxide D led mainly to deoxygenation.
Procedure: To a solution of the acid 6-81 (3.01 g, 10 mmol) and benzoylpiperazine hydrochloride (3.39 g, 15 mmol) in DMF (50 mL) was added triethylamine (10.1 g, 100 mmol, 10 eq.), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 5.75 g, 30 mmol) under N2 and the mixture stirred at room temperature for 22 h after sonication and at 40° C. for 2 h. The mixture was concentrated in vacuo to remove DMF and TEA, and to the residual solution was added water (200 mL) under stirring and sonication. The precipitates formed were collected, washed with water and dried in vacuo to obtain 2.8 g (5.9 mmol, Y. 59%) of the title compound IVc as off-white solid. The filtrate was extracted with CH2Cl2 (x2). The CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated to gum which was triturated with Et2O to obtain a solid. This solid was suspended and triturated with MeOH to obtain 400 mg of the title compound IVc as off-white solid. Total yield: 3.2 g (6.8 mmol, Y. 68%): MS m/z 474 (MH); HRMS (ESI) m/z calcd for C24H24N7O4 (M+H) 474.1890, found 474.1884 (Δ-1.2 ppm); 1H NMR (DMSO-d6) δ ppm 2.50 (3H, s, overlapped with DMSO peaks), 3.43 (4H, br, CH2N), 3.68 (4H, br, CH2N), 3.99 (3H, s, CH3O), 7.46 (5H, br. s, Ar—Hs), 7.88 (1H, s, indole-H-5), 8.25 (1H, s, indole-H-2), 9.25 (1H, s, triazole-H-5), 12.40 (1H, s, NH); 13C-NMR (DMSO-d6) δ ppm 13.78 ,40.58, 45.11, 56.78, 114.11, 120.95, 122.71, 123.60, 126.98, 128.34, 129.6, 135.43, 138.52, 142.10, 149.15, 161.29, 166.17, 169.22, 185.42; UV (MeOH) λ max 233.6 nm (ε 3.43×104), 314.9 nm (ε 1.73×104); Anal: Calc for C24H24N7O4.1/5H2O; C, 60.42; H, 4.94; N, 20.55, Found; C 60.42, H 5.03, N 20.65; KF (H2O) 0.75%.
This reaction can also be performed by use of HATU and DMAP to provide more consistent yield of the title compound: To a suspension of the acid 6-81 (15.6 mmol) and HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophos phonate] (8.90 g, 23.4 mmol; 1.5 eq.) in DMF (60 mL) and CH2Cl2 (60 mL) was added a mixture of DMAP (5.72 g, 46.8 mmol, 3 eq.) and benzoylpiperazine hydrochloride (5.30 g, 23.4 mmol; 1.5 eq.) in DMF (60 mL) at room temperature and the mixture was stirred under nitrogen atmosphere for 4 hrs. The mixture was concentrated in vacuo to remove CH2Cl2 and most of DMF, and to the residual solution was added water under stirring and sonication. The precipitates formed were collected, washed with water and dried in vacuo to obtain 5.38 g (11.4 mmol, Y. 72.8%) of the title compound IVc as off-white solid: HPLC >95% (AP, uv at 254 nm)
EXAMPLE 5Preparation of Ica, (Disodium Salt)
General Procedure: A suspension of IVc (0.24 g, 0.5 mmol) in anhydrous THF (4 mL) under nitrogen atmosphere was treated with sodium hydride (60% oil dispersion, 0.08 g, 2.0 mmol), and stirred until gas evolution ceased (approximately 5 minutes). The reaction mixture was treated with iodine (0.13 g, 0.5 mmol) and stirred for 2-3 minutes followed by addition of di-tert-butyl chloromethyl phosphate (1.6 g, 6.0 mmol, crude). A stream of nitrogen was allowed to pass over the reaction to facilitate the removal of much or all of the THF. The reaction mixture was stirred overnight. HPLC analysis of crude indicated starting IVc (ca. 56%) and desired adduct (ca. 32%).
Several crude reaction mixtures (a total of 6.7 mmol based on starting material IVc) were re-dissolved in dichloromethane, combined, concentrated in vacuo to remove any remaining THF. The residue was suspended in dichloromethane and TFA (1:1, approximately 40 mL total volume). The mixture was stirred for 1.5-2 hours and then solvent was removed in vacuo. The residue was suspended in dichloromethane and extracted into water (approximately 60 mL) made weakly basic with solid or aqueous sodium bicarbonate. The aqueous layer was reduced in volume by rotary evaporator if required and the solution was loaded onto a C-18 reverse phase column (approximately 80 g of C-18, YMC ODS-Aq, 50 micron) and eluted with water, followed by water containing 2.5% acetonitrile. Fractions containing pure product were pooled and organic solvent was removed by rotary evaporator. Purified product was recovered after lyophilization to give 1.00 g (1.30 mmol, 19% over 2 steps) of the title compound Ica (disodium salt) as an off-white powder: HPLC purity>99% AP at 254 nm (gradient 0-100% B/A; A 10% CH3CN-90% H2O-0.1% TFA, B 90% CH3CN-10% H2O-0.1 % TFA, gradient time 4 min, column YMC ODS-Aq 4.6×50 mm 3 micron); MS-ESI— m/z 482 (M−H minus 2Na)−; HRMS (ESI) m/z calcd for C25H27N7O8P (M+H minus 2Na)+584.1659, found 584.1651 (Δ-1.3 ppm); 1H NMR (D2O, 500 MHz) δ ppm 2.53, 2.54 (3H, 2s), 3.56 (2H, s, CH2N), 3.72 (2H, br.s, CH2N), 3.78, 3.83 (2H, 2br.s, CH2N), 3.94, 3.96 (2H, 2br.s, CH2N), 4.14 (3H, s, CH3O), 5.38, 5.40 (2H, 2d, J=11 Hz), 7.45-7.59 (5H, m, Ar—Hs), 8.07, 8.09 (1H, 2s, indole-H-5), 8.64, 8.67 (1H, 2s, indole-H-2), 8.87, 8.89 (1H, 2s, triazole-H-5); 13C NMR (125.7 MHz, D2O) δ ppm 15.43 (N-Me), 44.03, 44.47, 44.66, 45.05, 48.20, 48.82, 49.60, 50.23, 59.78 (OMe), 75.81 (NCH2O), 115.6, 126.0, 127.2, 129.6, 131.0, 131.7, 132.1, 133.5, 136.8, 147.6, 150.1, 154.2, 164.8, 170.4, 175.8, 189.2; UV (H2O) λmax 220 nm (ε 3.91×104), 249 nm (ε 2.00×104), 303 nm (ε 1.60×104); Anal: Calc for C25H24N7O8PNa2. 8H2O. 0.2NaHCO3; C, 38.39; H, 5.14; N, 12.44, P, 3.93, Na, 6.42 Found; C, 38.16; H, 4.81; N, 12.43, P, 3.72, Na, 6.05; KF (H2O) 17.3%. A less pure fractions were collected to obtain 0.22 g (0.29 mmol, Y. 4%) of the title compound Ica (disodium salt): HPLC purity>95% (AP at 254 nm).
EXAMPLE 7Preparation of Crystalline Ic (Free Acid Mono-Hydrate)
To a mixture of IVc (600 mg, 1.27 mmol) in anhydrous THF (10 ml) in an oven-dried round bottle flask under nitrogen at r.t. was added NaH (153 mg, 6.38 mmol, dry powder, 95%), and the white suspension stirred until no gas evolution was observed. The mixture was then added I2 (375 mg, 1.48 mmol), and stirred at r.t. for 3 h. To the reaction mixture was added NaH (153 mg, 6.38 mmol, dry powder, 95%), and the mixture stirred for about 5 to 10 min. The crude chloromethyl di-tert-butylphosphate (2.0 g, about 1.6 ml, 7.79 mmol) was added to the mixture, which was then stirred at r.t. for 15 h. LCMS analysis of the reaction showed a >97% conversion of the starting material. After evaporation of the volatiles, the residue was added CH2Cl2 (10 ml), cooled in an ice-water bath, slowly added TFA (10 ml) and stirred at r.t. for 3 h. The reaction mixture was then evaporated, and the residue partitioned between CH2Cl2 (50 ml) and H2O (50 ml). The CH2Cl2 layer was poured into the reaction flask that contained some undissolved brownish solid, and this mixture was extracted with a dilute aqueous NaHCO3 solution (50 ml). The aqueous mixture was purified by reverse phase preparative HPLC (solvent A: 10% MeOH-90% H2O-0.1% TFA; solvent B: 90% MeOH-10% H2O-0.1% TFA; start % B=0, final % B=100; gradient time=6 min; flow rate=45 ml/min; column: phenomenex-Luna 30×50 mm, S5; fraction collected: 3.65 to 4.05 min). The fractions collected were evaporated to dryness, and the residue dried under high vacuum to obtain the acid Ic as a pale yellow solid (356.6 mg); 1H NMR: (500 MHz, CD3OD) δ 9.05 (s, 1H), 8.46 (s, 1H), 8.04 (s, 1H), 7.47 (b s, 5H), 5.93 (d, J=12, 2H), 4.10 (s, 3H), 4.00-3.40 (b s, 8H), 2.53 (s, 3H); 19F NMR analysis showed that the material contained residual TFA, (the percentage was not quantified); Analytical HPLC method: Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 mL/min, Column: Xterra MS C18 7u 3.0×50 mm, LC/MS: (ES+) m/z (M+H)+=584, HPLC Rt=0.983.
172.2 mg of the purified acid Ic was dissolved in 1 ml of H2O and then about 0.3 ml of absolute EtOH (200 proof) was added. The mixture was left standing in a refrigerator (temperature about 3° C.) overnight, after which time, crystalline material was observed. The mixture was then warmed to ambient temperature, diluted with H2O to a volumn of 3 mL, and then 20 mL of MeCN was added slowly. Following the completion of addition, the mixture was stirred at r.t. for 2 h and then filtered. The solid collected (90 mg) was dried in vacuo, and then under high vacuum. This material was shown by powder x-ray studies to be crystalline; Elemental Analysis calculated for C25H26N7O8P.H2O: C 49.92; H 4.69; N 16.30; observed: C 49.66; H 4.62; N 15.99; mp=205° C. (measured by differential scanning calorimetry). The 1H NMR pattern for crystalline material was compared with that from the purified acid and both were consistent with the structure.
EXAMPLE 10Preparation of Icb (mono tromethamine salt): [3-[(4-benzoylpiperazin-1-yl)(oxo)acetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2, 3-c]pyridin-1-yl]methyl dihydrogen phosphate, 2-amino-2-(hydroxymethyl)propane-1,3-diol salt (1:1). The sequence of reactions is described in Scheme for Example 10.
Scheme for Example 10
Preparation of di-tert-butyl chloromethyl phosphate
A mixture of tetrabutylammonium di-tert-butyl phosphate (57 g, 0.126 mol, Digital Specialty Chemicals) and chloroiodomethane (221 g, 1.26 mol) was stirred at room temperature for four hours before the volatiles were removed under vacuum. 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate in vacuo and removal of remaining volatiles using a vacuum pump provided di-tert-butyl chloromethyl phosphate as a light brown or yellow oil, which was utilized in the next step without further purification.
Preparation of IIc: (3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate
NaH (2.6 g, 10.3 mmol, 95% in oil, Seq.) was added slowly into a suspension of IVc (10.0 g, 21.1 mmol) in dry THF (100 ml) and the mixture was allowed to stir for 0.5 hour at room temperature. A solution of iodine (5.27 g, 20.8 mmol) dissolved in dry THF (10 ml) was added slowly into the stirring solution at a rate which prevented foaming or a violent reaction. The resultant mixture was stirred for an additional 3 hours before a second 2.6 g portion of NaH was introduced. After 15 minutes at ambient temperature di-tert-butyl chloromethyl phosphate, the entire batch of di-tert-butyl chloromethyl phosphate, obtained from step one, was added. After stirring for 16 hours, the reaction mixture was poured into iced NH4OAc (30%) (120 ml), followed by extraction with EtOAc (3×300 ml). The combined organic extracts were washed with water (100 ml) and then brine (100 ml), dried over Na2SO4, and concentrated under vacuum to afford a residue, which was purified by silica gel chromatography (elution with EtOAc/Et3N (50/1) and then EtOAc/MeOH (100/1)) to give 8.0 g (˜75% AP, ˜41% yield) of diester IIc as a light yellow solid.
Preparation of Icb (mono L tromethamine salt): [3-[(4-benzoylpiperazin-1-yl)(oxo)acetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate, 2-amino-2-(hydroxymethyl)propane-1,3-diol salt (1:1)
500 mg (˜p75 AP, 0.54 mmol) of diester IIc was dissolved in a mixture of water (2.5 ml) and acetone (2.5 ml). The resulting mixture was stirred at 40° C. for 16 hours to complete the solvolysis. To this reaction mixture was added 3.0M aqueous TRIS (mono tromethamine) solution to adjust pH to 3.32. Acetone (30 ml) was slowly added to the reaction mixture in 1 hour.* After complete addition of acetone, the solution was stirred overnight to complete the crystallization of Icb. The solid was collected by filtration and rinsed with 20:1 acetone-water (2×5 mL). The white crystalline solid was dried under house vacuum under nitrogen atomosphere at 50° C. for 24 h to afford 290 mg of Icb (>98.5 AP).
*After adding about 15 and 20 ml of acetone, the reaction mixture was seeded with crystalline Icb.
Obtained via other process (hydrolysis with TFA in methylene chloride), salt Icb is ˜1 molar mono tromethamine salt with 0.47% of water, 0.1% of acetone and 0.05% of methanol. 1H NMR (500 MHz, d6-DMSO, 30° C.) δ8.77 (s, 1H), 8.48 (s, 1H), 8.00 (s, 1H) 7.44 (b, 5H), 5.42 (d, 2H, J=15 Hz), 4.02 (s, 3H), 3.70-3.30 (m, 8H), 3.41 (s, 6H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3, 30° C.) δ184.8, 169.0, 165.8, 160.3, 150.4, 146.2, 143.2, 135.4, 129.4, 128.9, 128.2, 127.7, 126.9, 123.2, 122.2, 112.9, 72.3, 60.7, 59.0, 56.7, 13.4. MS m/z: (M-trisamine+H)+ calcd for C25H27N7O8P 584.2, found 584.0. Anal. Calcd. C, 49.11; H, 5.37; N, 15.76; P, 4.32; found: C, 48.88; H, 5.28; N, 15.71; P, 4.16. M.P. 201-205° C.
EXAMPLE 13Alternate preparation of Icb (Pro-drug of IVc)
To a 10 L reactor equipped with an overhead stirrer, thermocouple, distillation apparatus, and nitrogen inlet was charged IVc (200.00 g, 422.39 mmol), Cs2CO3 (344.06 g, 1.06 mol), KI (140.24 g, 844.81 mmol) and NMP (1.00 L, 10.38 mol). The reaction was stirred at room temperature resulting in a light brown heterogeneous suspension. Di-tert-butyl chloromethyl phosphate (273.16 g, 1.06 mol) was added via addition funnel and the reaction mixture was heated to 30° C. for 16-24 hours with stirring after which time the reaction was cooled to 5° C. To the reaction was added DCM (1.5 L) then the reaction was slowly quenched with water (3.5 L) maintaining the reaction temperature under 20° C. resulting in a biphasic mixture. The product rich bottom layer was separated, washed with water (3.5 L×3), then transferred back to the reactor. The solution was concentrated under vacuum to a volume of 1 L keeping the temperature below 25° C. IPA was added (2 L) then the reaction was concentrated under vacuum to a volume of 2 L keeping the temperature below 25° C. The reaction was then seeded with IIc (0.200 g), stirred overnight at room temperature resulting in a slurry. The slurry was filtered and the wet cake was washed with MTBE (1 L), dried in a vacuum oven at 50° C. overnight resulting in a yellow/white powder (207.1 g, 70%). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.42 (s, 5H), 5.95 (d, J=14.2 Hz, 2H), 4.06 (s, 3H), 3.97-3.36 (m, 8H), 2.50 (s, 3H), 1.27 (s, 18H); 3C NMR (100 MHz, CDCl3) δ 184.64, 170.65, 165.91, 161.60, 150.82, 145.38, 141.89, 134.96, 130.20, 129.59, 128.68, 127.58, 127.10, 124.77, 122.64, 115.22, 83.90, 83.83, 73.69, 73.63, 56.95, 46.04, 41.66, 29.61, 29.56, 13.90; ES+ MS m/z (rel. intensity) 696 (MH+,10), 640 (MH+-isobutylene, 30), 584 (MH+-2 isobutylene, 100).
To a 10 L 4 neck reactor equipped with a thermocouple, overhead stirrer, condenser and nitrogen inlet was added IIc (200.24 g, 287.82 mmol), acetone (800.00 ml, 10.88 mol) and water (800.00 ml, 44.41 mol). The reaction was heated to 40° C. and stirred for 18-24 hours. The reaction was cooled to 20° C. then tromethamine (33.62 g, 277.54 mmol) was added. The reaction was heated to 40° C. then stirred for an additional hour until all solids were dissolved. The reaction was cooled to 20° C. then filtered through a 10 micron cuno filter into a 10 L 4 neck reactor equipped with a thermocouple, overhead stirrer, and nitrogen inlet. Acetone (3 L) was added rapidly, followed by seeding with Icb (0.500 g), then additional acetone (3 L) was added. The reaction was stirred at room temperature overnight resulting in a slurry then filtered. The wet cake was washed with acetone (800 ml) then dried in a vacuum oven at 50° C. overnight resulting in a fluffy white powder (165.91 g, 82%).
Supplementary Information:
Isolation of the Free-Acid Intermediate IC:
In a 250 mL 3 neck reactor equipped with a thermocouple, overhead stirrer, condenser and nitrogen inlet was added IIc (10.0 g, 14.37 mmol), acetone (40.00 ml, 544.15 mmol) and water (40.00 ml, 2.22 mol). The reaction was heated to 40° C. and stirred for 14-24 hours. The reaction was cooled to 20° C. then stirred for three hours, resulting in a slurry. The slurry was filtered, then the wet cake washed with acetone (40.00 ml) then dried in a vacuum oven at 50° C. overnight resulting in a fluffy white powder (7.00 g, 83%). NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.47 (s, 1H), 8.06 (s, 1H), 7.45 (s, 5H), 5.81 (d, J=12.3 Hz, 2H), 4.03 (s, 3H), 3.91-3.19 (m, 8H), 2.39 (s, 3H); 13C NMR (500 MHz, DMSO-d6) δ 185.20, 169.32, 165.85, 160.75, 150.51, 146.30, 143.24, 135.53, 129.74, 129.22, 128.46, 127.34, 127.09, 123.67, 122.73, 113.94, 72.90 (d, 2JC-P=5 Hz), 57.01, 45.2 (bs), 40.8 (bs), 13.66. ES+ MS m/z (rel. intensity) 486 (MH+−H3PO4, 100).
Ripasudil hydrochloride hydrate (Glanatec® ophthalmic solution 0.4 %; hereafter referred to as ripasudil) is a small-molecule, Rho-associated kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compound, which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm’s canal.
As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogues (which increase uveoscleral outflow) and β blockers (which reduce aqueous production).
The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy.
K-115 is a Rho-kinase inhibitor as ophthalmic solution originally developed by Kowa and D Western Therapeutics Institute (DWTI). The product candidate was approved and launched in Japan for the treatment of glaucoma and ocular hypertension in 2014.
In 2002, the compound was licensed to Kowa Pharmaceutical by D Western Therapeutics Institute (DWTI) in Japan for the treatment of glaucoma. The compound is currently in phase II clinical trials at the company for the treatment of age-related macular degeneration and diabetic retinopathy.
Use of (S)-(-)-1-(4- fluoro-5-isoquinoline-sulfonyl)-2-methyl-1,4-homopiperazine (ripasudil hydrochloride, first disclosed in WO9920620), in the form of eye drops, for the treatment of retinal diseases, particularly diabetic retinopathy or age-related macular degeneration.
Follows on from WO2012105674 by claiming a combination of the same compound. Kowa, under license from D Western Therapeutics Institute, has developed the Rho kinase inhibitor ripasudil hydrochloride hydrate (presumed to be Glanatek) as an eye drop formulation for the treatment of glaucoma and ocular hypertension which was approved in Japan in September 2014..
The company is also developing the agent for the treatment of diabetic retinopathy, for which it is in phase II trial as of October 2014.
…………………….
A Practical Synthesis of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate, the key intermediate of Rho-kinase inhibitor K-115
Synthesis (Stuttgart) 2012, 44(20): 3171
practical synthesis of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate has been established for supplying this key intermediate of Rho–kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama–Mitsunobu cyclization of a N-nosyl diamino alcohol starting from the commercially available (S)- or (R)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility.
The including prevention and treatment cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, cerebrovascular disorders such as cerebral edema, the present invention relates to a salt thereof or isoquinoline derivatives useful as therapeutic agents, particularly glaucoma.
(S) – (-) -1 – (4 – fluoro-iso-5 – yl) sulfonyl – 2 – methyl -1,4 – diazepane the following formula (1):
It is a compound represented by the particular it is a crystalline water-soluble, not hygroscopic, because it is excellent in chemical stability, it is useful as a medicament has been known for its hydrochloride dihydrate ( refer to Patent Documents 1 and 2). -5 Isoquinoline of these – the sulfonamide compounds, that prophylactic and therapeutic agents for cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, cerebrovascular disorders such as cerebral edema, is useful as a therapeutic agent for preventing and glaucoma in particular is known (1-5 see Patent Document 1).
Conventionally, for example, a method of manufacturing by the method described in Patent Document 1, as shown in the following production process has been reported preparation of said compound (Production Method 1-A).
That is, (S)-1-tert-butoxycarbonyl – 3 – by reacting the presence of triethylamine in methylene chloride-fluoro-isoquinoline (2) – methyl -1,4 – diazepane and 5 (3) – chloro-sulfonyl -4 by adding trifluoroacetic acid in methylene chloride compound (the first step), obtained following (4) to synthesize a compound (4) by deprotection to (second step) the desired compound (1) This is a method of manufacturing.
It is also an important intermediate for preparing the compound (1) (S)-1-tert-butoxycarbonyl – 3 – methyl-1 ,4 – diazepane to (3), for example, in the following manner (; see JP Production Process 1-B) that can be produced is known.
Further, on the other hand, the compound (1) (see Patent Document 1) to be manufactured manufacturing routes such as: Any (Process 2) are known.
WO 1999/20620 pamphlet WO 2006/057397 pamphlet WO 1997/028130 pamphlet JP Patent Publication No. 2006-348028 JP Patent Publication No. 2006-290827
However, it is possible to produce in the laboratory of a small amount scale, but you place the point of view for mass industrial production, environmentally harmful halogenated hydrocarbon solvent in the compound of the above-mentioned process for producing 1-A is ( problem because it is carried out coupling step (3) and 2), giving significant adverse environmental exists. Therefore, solvent of halogenated hydrocarbon other than those listed to the specification of the patent document 1, for example, I tried actually dioxane, tetrahydrofuran and the like, but the present coupling reaction will be some progress indeed, Problems reaction is not completed raw material remained even after prolonged reaction time, yield undesirably stays in at most 30% was found. Furthermore, it is hard to decompose in the environment, elimination is also difficult to dioxane is not preferred irritating to humans, and are known as compounds that potentially harmful brain, kidney and liver .
When we actually produced compound (3) by the above production method 1-B, can be obtained desired compound in good yield merged with reproducibility is difficult has further been found that. That is, in the production path, 1,4 – and is used sodium hydride with dimethyl sulfoxide in forming a diazepane ring, except that I actually doing this step, Tsu than the reproducibility of the desired compound It could not be obtained in high yield Te. Also, that this is due to the synthetic route through the unstable intermediate, that it would be converted into another compound easily found this way. limitations and potential problems of the present production process is exposed since this stability may affect the reproducibility of the reaction.
Meanwhile, an attempt to carry out mass production is actually in the Process 2, it encounters various problems. For example, it is stored as an impurity whenever I repeat step, by-products formed in each stage by tandem production process ranging from step 8 gave more complex impurity profile. Depending, it is necessary to repeat a complicated recrystallization purity obtained as a medicine until the purification, the yield in the laboratory be a good overall yield is significantly reduced in the mass production of actual example be away, it does not have industrial utility of true was found. It can be summarized as follows: Considering from the viewpoint of GMP process control required for pharmaceutical production these problems.
Requires control process and numerous complex ranging 1) to 8 step, 3 2) third step – amino-1 – in the step of reacting a propanol, a difficult to remove positional isomers are mixed, 3) The fourth step water is mixed by the minute liquid extraction operation at the time of return to the free base from oxalate require crystallization purification by oxalate in the removal of contaminants of positional isomers, in 4) fifth step, 5) sixth step The Mitsunobu by reproducibility poor require water control in the Mitsunobu reaction used in the ring closure compounds to (1) compounds in (6), 6) ring closure reaction, departing management of the reagent added or the like is generated, in 7) Seventh Step it takes a complicated purification in impurity removal after the reaction, resulting in a decrease in isolated yield. These are issues that must be solved in order to provide a stable supply of raw material for pharmaceuticals high chemical purity is required.
Thus, gentle salt thereof, or the environment isoquinoline derivative comprising a compound represented by the formula (1), the present invention provides a novel production method having good reproducibility and high purity easily and in high yield I intended.
As a result of intensive studies in view of such circumstances, the present inventors, in the manufacturing process of the final target compound shown by the following expression
(Wherein represents a fluorine, chlorine, bromine or iodine,may,R 3 and 1, R 2 R represents a C 1-4 alkyl group be the same or different from each other, and P, X 1 is a protecting group shows a, 0 to m represents an integer of 3, 0 to n is. represents an integer of 3)
Is a urea-based solvents nitrile solvents, amide solvents, sulfoxide or solvents, the solvent may be preferably used in the coupling step of the compound (III) and (II) are generally very short time With these solvents It has been found that can be converted to the desired product quantitatively. It is possible to carry out the coupling step Volume scale while maintaining a high yield by using these solvents, there is no need to use a halogenated hydrocarbon solvent to give significant adverse environment. In consideration of the process such as removal of the solvent after the reaction was further found that acetonitrile is the best among these solvents. Also, since by using hydrochloric acid with ethyl acetate solvent in step deprotection can be isolated as crystal of hydrochloride desired compound (I), without going through the manipulation of solvent evaporation complicated , it has been found that it is possible to obtain the object compound (I) is a simpler operating procedure. Since there is no need to use a halogenated hydrocarbon solvent in this deprotection step further, there is no possibility of harming the environment.
It has been found that it is possible in mass production of (II), leading to the target compound purity, in high yield with good reproducibility as compared with the conventional method compounds are important intermediates in the coupling step further. That is, was it possible to lead to the intermediate high purity and in high yield by eliminating the production of a harmful halogenated hydrocarbon solvent to the environment in this manner. 1,4 addition – in order to avoid the problems encountered in the reaction using sodium hydride in dimethyl sulfoxide in forming the diazepane ring, in order to allow the cyclization reaction at mild conditions more, as a protecting group By performing the Mitsunobu reaction using Noshiru group instead of the carbobenzyloxy group, in addition to one step shorten the manufacturing process of the whole, without deteriorating the optical purity was successfully obtained the desired compound desired.
Astakolactin is a sesterpene from the Ionian Sea near Greece possessing considerable biological properties. Hence, that’s why the authors decided to synthesize it, and also why the we’re all interested in its structure. In the conclusion of this paper, no biological studies were performed, but the characterization matches that of the natural product, which is a big deal.
Paul Murray Catalysis Consulting helps companies to save money and resources through more efficient chemical processes.
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Dr Paul Murray is a world leading consultant scientist, providing expertise and training in the fields of Catalysis, Design of Experiments and Principal Component Analysis. Paul is an experienced scientist with an additional expertise in automation, multivariate data analysis, process development and problem solving. Paul has a proven track record of the timely delivery of innovative solutions to client projects resulting in significant reductions in costs and resources to customers.
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The development and optimisation of challenging catalytic reactions.
The use of Principal Component Analysis (PCA) to optimise ligand and solvent selection.
The use of advanced experimental design linking DoE with PCA for efficient…
I am seated left with DR PAUL MURRAY, DR JOHN KNIGHT, DR WILL WATSON, At Scientific Update Organic Process Research and Dev Conference, NCL, PUNE ,INDIA, 5 TH DEC 2014
OK it was an extended time away from posting — I totally blame the Turkey, Ham, Beer, Stuffing, Pie — at least I have tapered off over the years.
So what’s sitting on my desk — after several pontifications, I have gotten back to thinking about how chemists think about their chemistry and where it can go in flow processes — so, OK, retrosynthesis — but I often think in classes of fragments and what they can do (think of it as a review on enaminone transformations so to speak). In this case, Ian Baxendale got me thinking about ynones or alpha, beta-acteylenic ketones — used quite a bit right? furans, flavones, pyrazoles, pyrimidines and heck back at Bayer I used them in a number of dipolarcycloadditions and intramolecular cyclizations to isoxazoles and pyrroles……you get the point……if interested in a nice article on using a flow approach to ynones and…
APD334, an orally available agonist of the S1P1 receptor, is an internally discovered investigational drug candidate intended for the potential treatment of a number of conditions related to autoimmune diseases, including multiple sclerosis, psoriasis and rheumatoid arthritis. S1P1 receptors have been demonstrated to be involved in the modulation of several biological responses, including lymphocyte trafficking from lymph nodes to the peripheral blood. By isolating lymphocytes in lymph nodes, fewer immune cells are available in the circulating blood to effect tissue damage. We have optimized APD334 as a potent and selective small molecule S1P1 receptor agonist that reduces the severity of disease in preclinical autoimmune disease models.
Autoimmune diseases are characterized by an inappropriate immune response against substances and tissues that are normally present in the body. In an autoimmune reaction, a person’s antibodies and immune cells target healthy tissues, triggering an inflammatory response. Reducing the immune and/or inflammatory response is an important goal in the treatment of autoimmune disease.
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid of Formula (la):
The present invention relates to processes and intermediates useful in the preparation of of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol- 3-yl)acetic acid of Formula (la) or salts thereof, an SlPl receptor modulator that is useful in the treatment of SlPl receptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g. , acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g. , as may occur in inflammation, tumor development and atherosclerosis).
BACKGROUND OF THE INVENTION
SlPl receptor agonists have been shown to possess at least immunosuppressive, antiinflammatory, and/or hemostatic activities, e.g. by virtue of modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and/or enhancing vascular integrity. Accordingly, SlPl receptor agonists can be useful as immunosuppressive agents for at least autoimmune diseases and disorders, inflammatory diseases and disorders (e.g. , acute and chronic inflammatory conditions), transplant rejection, cancer, and/or conditions that have an underlying defect in vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis) with fewer side effects such as the impairment of immune responses to systemic infection.
The sphingosine-1 -phosphate (SIP) receptors 1-5 constitute a family of G protein- coupled receptors containing a seven-transmembrane domain. These receptors, referred to as SlPl to S1P5 (formerly termed endothelial differentiation gene (EDG) receptor-1, -5, -3, -6, and -8, respectively; Chun et al., Pharmacological Reviews, 54:265-269, 2002), are activated via binding by sphingosine-1 -phosphate, which is produced by the sphingosine kmase-catalyzed phosphorylation of sphingosine. SlPl, S1P4, and S1P5 receptors activate Gi but not Gq, whereas S1P2 and S1P3 receptors activate both Gi and Gq. The S1P3 receptor, but not the SlPl receptor, responds to an agonist with an increase in intracellular calcium.
In view of the growing demand for S 1P1 agonists useful in the treatment of S 1P1 receptor-associated disorders, the compound (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid of Formula
(la):
has emerged as an important new compound, see PCT patent application, Serial No.
PCTVUS2009/004265 hereby incorporated by reference in its entirety. Accordingly, new and efficient routes leading to (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid of Formula (la), salts, and intermediates related thereto are needed. The processes and compounds described herein help meet these and other needs.
Example 7: Preparation of (i?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)) and L-Arginine Salt of (JR)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)).
Method 1
Preparation of (/?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)) and L-Arginine Salt Thereof.
Step A: Preparation of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta [b] indol-3-yl)acetic acid.
To a solution of rac-ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetate (20.00 g, 41.19 mmol) in acetonitrile (185 ml) in a 500 mL three-neck RBF equipped with magnetic stir bar, N2 inlet, thermocouple, and condenser was added potassium phosphate buffer (15 ml, 1.0 M, pH = 7.80) and followed by addition of lipase B, Candida antarctica, immobilized recombinant from yeast (1.0 g, 5865 U/g, 5865 U). The resultant yellow suspension was stirred at about 40 °C under N2 for 16 hours. To the mixture, 1 M citric acid was added to adjust the pH to 3.96 which was then filtered on a Whatman filter cup. The solids were washed with ACN (3 x 15 mL). The combined filtrate and washings were concentrated at about 30 °C under vacuum to give an orange residue, which was partitioned between EtOAc (60 mL) and brine (60 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with H20 (2 x 80 mL), brine (2 x 80 mL), dried over Na2S04, decanted, and concentrated at 30 °C under vacuum to give an orange oil, which was dried under vacuum at room temperature overnight to give a light orange oil (22.203 g) containing (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta|¾]indol-3- yl)acetic acid. The crude was assayed to be 41.41 wt % (9.194 g) with 99.42% ee.
Step B: Preparation of L-Arginine Salt of (i?)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)).
To the crude (21.837 g) (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (41.41 %w/w; 9.043 g, 19.77 mmol) containing the (5)-isomer as the ester impurity in a 200 mL round bottom flask was added IPA (150.72 mL). The mixture was heated at 60 °C under N2 till the oily residue dissolved completely. The resultant orange solution was heated at about 60 °C for 5 min. Seeds of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetate (362 mg) were added. The seeds were suspended in the orange solution. A 2.27 M aqueous solution of L-arginine (8.709 mL, 3.44 g, 19.77 mmol) pre-warmed to about 60 °C was added into the mixture dropwise over 30 min. A light yellow precipitate formed gradually during the addition. The suspension was stirred for about an additional 30 min. The temperature of the suspension was allowed to drop at about 0.4 °C per minute to room temperature. The mixture was agitated occasionally at room temperature overnight. The suspension was filtered and the cake was washed with IP A (3 6 mL) and EtOAc (3 x 15 mL). The filter cake was dried at room temperature under vacuum overnight to give L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate as a white solid (11.631 g, 44.7%): HPLC 99.38 Area %, 99.6 % ee. TGA, PXRD, PLM, SEM and DSC indicated the solid as a non-solvated, crystalline compound with an average aggregates size of 18.05 microns and a melting point of 202.69 °C.
Preparation of (l?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)).
Additional procedures to prepare (R)-2-(7-(4-Cyclopentyl-3- (1xiiluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)) using other lipases were utilized, for example, the following were shown to hydrolyze rac-ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetate to (R)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)). General hydrolysis conditions and % enantiomeric excess (% ee) are shown below for the following enzymes, lipase B Candida Antarctica, lipase Mucor miehei (MML), and P. fluorescens.
5% DMF inP. fluorescens 7.5 30 C 19-20 phosphate Buffer
Free enzyme (i.e., non-immoblized)
Each of the above enzymes provided the desired (R)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound of Formula (la)) with varying degrees of % ee.
Example 8: Preparation of L-Arginine Salt of (l?)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
Method 1
(R)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (174.7 mg, 0.381 mmol) was dissolved in EPA (1.57 mL) and L-arginine (66.4 mg, 0.381 mmol) was added as a solution in water (263 μΕ,). The homogeneous solution was warmed to 40 °C. After 15 min at this temperature, a precipitate had formed. The reaction mixture was warmed to 70 °C causing the precipitate to dissolve. The heat bath was turned off. A precipitate began to form at 40 °C and the reaction mixture was allowed to cool to about 28 °C before collecting the solids by filtration. The solids were washed with 14% water in EPA to give the L-arginine salt of (R)-2-(7-(4-cyclopentyl-3- (1riiluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (130 mg).
Method 2
Example 8: Preparation of L-Arginine Salt of (i?)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
Step A: Preparation of l-Cyclopentyl-2-(trifluoromethyl)benzene (Compound of Formula (lib)).
To a 50 L three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet, was added dry THF (35 L) and cooled to 0-5 °C. To the flask was added Iron (III) chloride (2.7 kg, 0.15 eq) portion wise over 30-60 min. and stirred for 15- 30 min. resulting in a clear greenish solution. Under a nitrogen atmosphere in a dry 100 gallon glass lined reactor was added THF (87.5 L) and magnesium turnings (4.05 kg, 1.5 eq), and cooled to 0-5 °C. To the THF and magnesium mixture was added the solution of FeCl3 in THF at a rate to maintain the internal temperature below 10 °C. To the resulting yellow/green mixture was added TMEDA (15.5 kg, 1.2 eq) at a rate to maintain the internal temperature below 20 °C. The resulting reaction mixture was heated to 40-45 °C for 1 hour and a mixture of 1 bromo-2-
(trifluoromethyl) benzene (25 kg, 1.0 eq) and bromocyclopentane (19.9 kg, 1.2 eq) was added to the reaction mixture at a rate to maintain an internal temperature below 25 °C. The resulting reaction mixture was allowed to stir at room temperature overnight and subsequently cooled to an internal temperature of 0-5 °C. To the resulting mixture was added 6 N HC1 (100 L, 1.5 h) at such a rate as to maintain the internal temperature below 15 °C (caution, very exothermic). After the quench, MTBE (200 L) was added and the reactor contents was stirred for 30 min. The phases were separated and the aqueous layer back extracted with MTBE (75 L). The combined organic layers were washed with H20 (50 L), brine (50 L) and dried (MgS04). The mixture was filtered through an in-line (1 micron) filter cartridge followed by an additional in-line (0.45 micron) filter cartridge into a clean dry reactor. The solvent was evaporated under vacuum (jacket < 30 °C) and co-evaporated with heptanes (2 x 25 L) to provide a viscous liquid. The viscous liquid was dissolved in heptanes (100 L) and passed through a silica plug (25 kg). The silica plug was eluted with heptanes (TLC, Rf ~ 0.8, silica gel, heptanes) and the fractions containing the product were evaporated to provide the title compound as a yellow liquid, 11.7 kg (49.2%), purity as determined by HPLC was 94.1%. Ή NMR conforms to reference standard.
Step B: Preparation of 4-(Chloromethyl)-l-cyclopentyl-2-(trifluoromethyl)benzene (Compound of Formula (He)).
To a 100 gallon glass lined reactor equipped with a stirrer was added concentrated sulphuric acid (48.6 L) and cooled to an internal temperature between about -5 to -10 °C under an atmosphere of N2. To the sulfuric acid was added thionyl chloride (26.99 kg, 2 eq) at a rate to maintain the internal temperature below -5 °C. To the resulting mixture 1,3,5-trioxane (15.3 kg, 1.5 eq) was added portion wise at a rate to maintain the internal temperature below -5 °C. After the addition of 1,3,5-trioxane, l-cyclopentyl-2-(trifluoromethyl) benzene (24.0 kg) was added drop wise over a period of approximately 2-3 hours. The reaction mixture was stirred at 0 °C for approximately 3-4 hours, allowed to warm to room temperature overnight and subsequently cooled to an internal temperature of 0-5 °C. To the resulting mixture was added water (316 L) drop wise over a period of approximately 5-6 hours (Note: Very exothermic). After the quench with water, the resulting aqueous mixture was extracted with MTBE (243 L and 123 L). The combined organics were washed with saturated NaHC03 (100 L), brine (100 L), water (100 L), brine (100 L), and dried (MgS04). The mixture was filtered through an in-line (1 micron) filter cartridge followed by an additional in-line (0.45 micron) filter cartridge into a clean dry reactor. The solvent was evaporated under vacuum (jacket < 30 °C) and further evaporated under vacuum at 35-40 °C. The resulting oil was distilled under high vacuum to provide the title compound as a yellow liquid, 24.8 kg (83%), purity as determined by HPLC was 99.47%. Ή
NMR conforms to reference standard.
Step C: Preparation of Ethyl 2-(2-Morpholinocyclopent-2-enylidene)acetate (Compound of Formula (Kg), Whe
Cyclopentanone (22.00 kg), morpholine (22.88 kg) and cyclohexane (43.78 kg) were charged to a 400 L glass-lined reactor equipped with overhead agitation, jacket temperature control, a nitrogen inlet, and a Dean-Stark trap. The reactor contents were heated to about 85 °C to 95 °C for approximately 26 h while removing water using the Dean-Stark trap. The reaction to form the enamine (i.e., 4-cyclopentenylmorpholine, Compound of Formula (lie) wherein R1 and R2 together with the nitrogen atom form a morpholine ring) is deemed complete when the morpholine amount is verified to be < 3% by GC peak area.
The reactor contents were cooled to about 60 °C and ethyl glyoxalate (Compound of Formula (ΠΤ) wherein R3 is ethyl; 58.74 kg, 50% solution in toluene) was added to the mixture slowly so as to maintain an internal temperature of < 80 °C. The reactor contents were heated to about 85 °C to 95 °C for at least 25 hours while removing water using the Dean-Stark trap. The reaction was deemed complete when the eneamine (i.e., 4-cyclopentenylmorpholine) amount by GC was verified to be less than 0.5% by GC peak area. The cyclohexane/toluene mixture was distilled under vacuum, ethanol (261.80kg) was charged to the reactor, and the resulting solution was again distilled under vacuum. Ethanol (34.76 kg) and water 44.00 kg) were charged to the reactor and the reactor contents stirred at 25 °C. The mixture was stirred further for 6 h at about 0-5 °C.
The resulting product slurry was collected by filtration, washed with aqueous ethanol (34.76 kg ethanol dissolved in 176.00 kg water). The filter-cake was further washed with water (110.00 kg), dried initially at approximately 36 °C for 1 hour under vacuum and subsequently at approximately 50 °C under vacuum for 17 h. The title compound was obtained as a tan solid (23.48 kg, 37.8% yield).
Step D: Preparation of Ζί/ZEthyl 2-(7-(Benzyloxy)-l,2-dihydrocyclopenta[b]indol- 3(4H)-ylidene)acetate
To a 400 L glass-lined reactor equipped with overhead agitation, jacket temperature control, and a nitrogen inlet was added (4-(benzyloxy)phenyl)hydrazine hydrochloride (21.08 kg, 1.000 mole equiv.), ethyl 2-(2-mo holinocyclopent-2-en lidene)acetate (22.02 kg, 1.104 mole equiv.), ethanol (51.2 kg, 2.429 mass equiv.), and acetic acid (36.8 kg, 1.746 mass eq.). After the reactor contents are allowed to stand for 10 minutes, agitation and then heating to 60°C to 65°C (60°C target) was started. While stirring at that temperature, samples of the reaction mixture were taken over intervals of approximately 30 minutes and analyzed by HPLC for (4-
(benzyloxy)phenyl)hydrazine, ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate, and hydrazone content. When (4-(benzyloxy)phenyl)hydrazine HPLC % area was < 1, TFA (11.6 kg, 101.7 mol, 1.200 mole equiv., 0.550 mass equiv.) was charged over approximately 1 hour while the stirred reaction mixture was maintained at 60°C ± 5°C with reactor jacket cooling. As stirring at 60°C to 65°C was continued, the hydrazone and imine content of the reaction mixture was monitored by HPLC. After stirring at 60°C to 65°C for at least 12 hours the imine content of the reaction mixture was < 5% area by HPLC, and the stirred reaction mixture was cooled to 20°C to 25°C over approximately 3 hours. Stirring was maintained at that temperature to allow isomerization of the Z isomer to the desired E isomer. The E isomer crystallizes from the reaction mixture. The Z isomer and E isomer % area content of the reaction mixture was monitored by HPLC during this period of stirring at 20°C to 25°C, which was continued until the Z-isomer content of the reaction mixture was < 15% area by HPLC.
The stirred reaction mixture was cooled (0°C to 5°C) over at least 2 hours and then filtered. The reactor was charged with ethanol (27.4 kg, 1.300 mass equiv.), which was stirred and chilled to 0°C to 5°C and then used in two approximately equal portions to slurry-wash the product filter cake twice. The reactor was charged with ethanol (13.8 kg, 0.655 mass equiv.), which was stirred and chilled to 0°C to 5°C and then used to wash the product filter cake by displacement. The reactor was charged with USP purified water (100 kg, 4.744 mass equiv.), and the temperature was adjusted to 20°C to 25°C. The USP purified water was then used in three approximately equal portions to wash the product filter cake three times, the first two by reslurrying and the third by displacement. The reactor was charged with ethanol (16.4 kg, 0.778 mass equiv.), stirred and chilled to 0°C to 5°C, and then used to wash the product filter cake by displacement. The washed product filter cake was dried under full vacuum first with a jacket temperature of 35°C for 1 hour and then with a jacket temperature of 50°C. While drying continues with a jacket temperature of 50°C, the product solids are turned over every 1 hour to 3 hours, and product samples are analyzed for loss on drying (LOD) every >4 hours. When LOD was < 1%, the product was cooled to < 30°C. The yield of the title compound was 13.06 kg (37.59 mol, 44.7%). Step E: Preparation of Ethyl 2-(7-Hydroxy-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetate.
To a 200 liter Hastelloy reactor was added ethyl 2-(7-(benzyloxy)-l ,2- dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (E/Z mixture, 12 kg), 10% Pd/C (50% wet with H20; 1.80 kg) and ethyl acetate (108 kg). The suspension was degassed 3x with N2 and triethylamine (1.76 kg) was added. To the resulting mixture was added formic acid (3.34 kg) while maintaining the internal temperature at below 35 °C. The reaction progression was followed by HPLC to monitor the complete consumption of starting material (i.e., E/Z mixture of ethyl 2-(7-(benzyloxy)-l ,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and the debenzylated intermediate. After approximately 30 minutes an additional amount of formic acid (0.50 kg) was added and the combined peak area of ethyl 2-(7-(benzyloxy)-l ,2- dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate and the related debenzylated intermediate was determined to be < 1 % area by HPLC. The reactor contents were filtered through a 1.2 μιη cartridge filter followed by an in-line 0.2 μπι inline polishing filter. To the filtrate was added water (60 kg) and the biphasic mixture was partitioned. The organics were separated and concentrated under vacuum at approximately 60°C ± 5°C to a minimum stir volume, ethyl acetate (21.6 kg) was added and the mixture was further concentrated under vacuum to a minimum stir volume. Once again ethyl acetate (16.8 kg) was charged to the crude mixture and the resulting solution was heated to approximately 60 °C. Heptanes (37.2 kg) were charged maintaining the internal temperature at 60 °C. The solution was slowly cooled to approximately 0 to 5 °C and approximately 2-3 hr to facilitate crystallization. The slurry was filtered, the filter cake was reslurried in heptanes (27.12 kg) and ethyl acetate (7.08 kg). The resulting suspension was filtered and the solids dried under vacuum at approximately 40 ± 5 °C (until the loss on drying (LOD) is < 1%) to afford the title compound (6.23 kg, 70.3 % yield) as a solid.
Step F: Preparation of ( ft^-Ethyl 2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (Compound of Formula (Ilk), Wher
To a 50 liter glass reactor containing ethyl 2-(7 -hydroxy- 1 ,2,3, 4- tetrahydrocyclopenta[b]indol-3-yl)acetate (2.000 kg, 1.000 equiv.) was added cesium carbonate
(3.266 kg, 1.300 equiv.) and acetonitrile (15.720 kg) under nitrogen. To the resulting mixture was added 4-(chloromethyl)-l-cyclopentyl-2-(trifluoromethyl)benzene (2.228 kg, 1.100 equiv.) over approximately one hour while maintaining the stirred reactor contents at 40°C ± 5°C. After the addition of 4-(chloromethyl)-l-cyclopentyl-2-(trifluoromethyl)benzene the reactor contents were heated to 65°C ± 5°C with stirring until the concentration of ethyl 2-(7-hydroxy-l , 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetate in the reaction mixture was less than 2.0 % area by
HPLC. The reaction mixture was cooled to 50°C ± 5°C and filtered under nitrogen through a fine filter cloth with suction to remove cesium salts (Note: ethyl 2-(7-(4-cyclopentyl-3-
(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate may precipitate below 30 °C). The filter cake was washed with fresh hot (50°C ± 5 °C) acetonitrile (5.658 kg divided in approximately three equal portions). The filtrates were returned to the reactor. The combined filtrates were concentrated by vacuum distillation with a jacket temperature of 60°C ± 10°C. To the reactor was added ethyl alcohol (3.156 kg) and once again concentrated with stirring by vacuum distillation with a jacket temperature of 60°C ± 10 °C. Once again, ethyl alcohol (3.156 kg) was added to the reactor and the contents were concentrated by vacuum distillation with a jacket temperature of 60 °C ± 10 °C to a reactor volume of approximately 14 L. The stirred reactor contents were cooled to 0 °C ± 5°C and the temperature maintained for 4 hours to facilitate the crystallization of the product. The resulting slurry was filtered. The filter cake was washed with cold 0 °C ± 5 °C ethyl alcohol (2 x 3.156 kg). The filter cake was dried under vacuum at 35 °C ± 5 °C until the weight loss over >1 hour was <2% to provide 3.0943 kg (81.0% yield) of the title compound as a solid.
Step G: Preparation of (!?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo
A 1.0 M buffer solution was prepared containing potassium phosphate monobasic (29.1 g, 0.0335 equiv.) in USP purified water (213 g) and potassium phosphate dibasic (368.2 g, 0.331 equiv.) in USP purified water (2.107 g). To a 50 liter glass reactor was added ethyl 2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate
(3.094 kg, 1.000 equiv.), Lipase B, Candida antarctica, immobilized (88.18 g, 293250 units/kg of ethyl ester starting material) and acetonitrile (22.32 kg). To the stirred contents of the reactor was added the previously prepared 1.0 M potassium phosphate buffer. The resulting mixture was stirred under nitrogen at a temperature of 40°C ± 5°C until the (R)-2-(7-(4-cyclopentyl-3-
(rrifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid concentration was >35% area as determined by HPLC (Note: although the reaction usually is complete after about 10 hours, the reaction mixture may be held at 40°C ± 5°C overnight). The stirred reactor contents were cooled to 25 °C ± 5°C and the pH was adjusted to between 4 and 5 by addition of a solution of citric acid (278.5 g, 0.228 equiv.) dissolved in USP purified water (1.454 kg). The reactor contents were filtered to remove immobilized lipase and phosphate and citrate salts. The reactor and solids were washed with acetonitrile (4.827 kg) and the combined filtrates were added backed into the reactor. The stirred reactor contents were concentrated to a volume of 1.0 L to 2.0 L by vacuum distillation at a jacket temperature of 55 °C ± 5°C. To the reactor was added ethyl acetate (5.582 kg) and USP purified water (6.188 kg). The contents were stirred at 20°C ± 5°C for at least 10 minutes and a solution of sodium chloride (1 kg) in USP purified water (1 kg) was added to facilitate phase separation. After phase separation was complete, the lower aqueous layer was drained. A solution of sodium chloride (5.569 kg) in USP purified water (12.38 kg) was divided in two approximately equal portions and the ethyl acetate phase was washed (2x). The ethyl acetate phase was transferred into a carboy and the reactor was rinsed with ethyl acetate (838.5 g) and added to the carboy containing the ethyl acetate phase. The reactor was washed sequentially with USP purified water (12.38 kg), acetone (4.907 kg), and ethyl acetate (838.5 g) and the ethyl acetate mixture from the carboy was transferred back to the reactor and concentrated with stirring to a volume of 1 L to 2 L by vacuum distillation at a jacket temperature of 55°C ± 5°C. To the reactor was added 2-propanol (14.67 kg) and after stirring the resulting mixture was concentrated to a volume of 1 L to 2 L by vacuum distillation at a jacket temperature of 55°C ± 5°C. To the reactor was added 2-propanol (7.333 kg) and heated with stirring at 60°C ± 5°C until the contents dissolved. The stirred reactor contents were cooled to 20°C ± 5°C and filtered through a medium-porosity fritted-glass filter to remove any inorganic solids to provide a 2-propanol solution containing 1.3188 kg of the title compound.
Step H: Preparation of L-Arginine Salt of (i?)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l ,2,3?4-tetrahydrocyclopenta [b] indol-3-yl)acetic acid
(Compound of For
To a 50 liter glass reactor containing the 2-propanol solution prepared in Step G of (R)- 2-(7-(4-cyclopen1yl-3-(trifluoromethyl)ben2yloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid (1.3188 kg, 1.000 equiv.) was added an additional amount of 2-propanol (6.3389 kg) to adjust the total volume to approximately 16.7 L/kg of (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. The reactor contents were stirred and heated to 60 °C ± 5 °C. To the reactor was added seed material (L- arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l , 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 26.4 g, 0.0145 equiv.). The reactor contents were stirred for approximately 5 minutes at 60 °C ± 5 °C and a solution of L-arginine (502.5 g, 1.000 equiv.) in USP purified water (1.27 kg) preheated to 60°C ± 5°C was added over approximately
1 hour while maintaining the stirred reactor contents at 60°C ± 5°C. The stirring of the reactor contents at 60°C ± 5°C was maintained for approximately 1 hour and then allowed to cool at an approximate rate of 0.2°C/min to 1.0°C/min. to a temperature of 25°C ± 5°C. Once at approximately 25°C the contents of the reactor were stirred for approximately 1 hour maintaining the temperature of 25°C ± 5°C. The resulting slurry was filtered and the filter cake was washed with 2- propanol (6.2511 kg divided in three approximately equal portions) and with ethyl acetate (13.560 kg divided in six approximately equal portions. The filter cake was dried under vacuum at 40°C ± 5°C (until the weight loss over >1 hour is <2%) to provide 1.657 kg of the title compound (32.9% yield) as a crystalline solid.
HPLC purity: 99.64 Area %; Enantiomeric purity: 99.3%; DSC melting onset temperature 203.46 °C; TGA Weight Loss out to ~1 10 °C was 0.05%. NMR confirms the structure of the L-salt.
Five additional lots of the L-arg salt have been prepared using substantially this same synthetic method as described above, the DSC melting onset temperatures for a sample from each of the lots is as follows: 203.96 °C, 203.00 °C, 203.11 °C, 203.79 °C and 203.97 °C; the TGA Weight Loss out to ~1 10 °C for a sample from each of the lots is as follows: 0.04%, 0.04%, 0.03%, 0.10%, and 0.12%.
Blinatumomab (AMG103) is a drug that has anti-cancer properties. It belongs to a new class of constructed monoclonal antibodies,bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the CD19 antigen present on B cells.[1]
The drug was developed by a German-American company Micromet, Inc. in cooperation with Lonza; Micromet was later purchases by Amgen, which has furthered the drug’s clinical trials. In July 2014, the FDA granted breakthrough therapy status to blinatumomab for the treatment of acute lymphoblastic leukemia (ALL).[2] In October 2014, Amgen’s Biologics License Application for blinatumomab was granted priority review designation by the FDA, thus establishing a deadline of May 19, 2015 for completion of the FDA review process.[3]
Structure and mechanism of action
Blinatumomab linking a T cell to a malignant B cell.
Blinatumomab enables a patient’s T cells to recognize malignant B cells. A molecule of blinatumomab combines two binding sites: a CD3site for T cells and a CD19 site for the target B cells. CD3 is part of the T cell receptor. The drug works by linking these two cell types andactivating the T cell to exert cytotoxic activity on the target cell.[4]CD3 and CD19 are expressed in both pediatric and adult patients, making blinatumomab a potential therapeutic option for both pediatric and adult populations.[5]
Therapeutic use
Clinical trials
In a phase 1 clinical study with blinatumomab, patients with non-Hodgkin’s lymphoma showed tumor regression, and in some cases complete remission.[6] There are ongoing phase 1 and phase 2 clinical trials of blinatumomab in patients with acute lymphoblastic leukemia (ALL).[7] One phase II trial for ALL reported good results in 2010 and another is starting.[8]
Adverse effects
Common side effects observed in Phase 2 trials are listed below; they were temporary and typically occurred during the first treatment cycle:[5]
Flu-like symptoms (i.e. fever, headache, and fatigue)
Tremor
Weight increase
Hypokalemia
Decrease of blood immunoglobulin
CNS effects were also observed during clinical trials and were treated via a lower dose of blinatumomab, administration of dexamethasone, or treatment discontinuation. Because the side effects were reversible, early monitoring for the CNS symptoms listed below is important:[5]
Mølhøj, M; Crommer, S; Brischwein, K; Rau, D; Sriskandarajah, M; Hoffmann, P; Kufer, P; Hofmeister, R; Baeuerle, PA (March 2007). “CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis”. Mol Immunol44 (8): 1935–43. doi:10.1016/j.molimm.2006.09.032. PMID17083975.
In October 2014, the US FDA issued a Warning Letter to the company Hikma Pharmaceuticals justified by deficiencies in the visual inspection of vials. Read more here.
In October 2014, the US FDA issued a Warning Letter to the company Hikma Pharmaceuticals because of deficiencies in the visual inspection of vials and environmental monitoring.
Already in a Warning Letter issued in 2011, a deficiency in the visual inspection was noted as the detection and evaluation of particulate matter failed to be sufficient. Now, the current complaint in the area of visual control explicitly refers to the qualification of staff for the performance of the manual visual inspection. Here, the FDA inspectors noticed that visible markings were present on the qualifcation test sets which enabled operators for visual inspection to recognize – thanks to these markings – vials with particles. The qualification of staff…
Cenacitinib CAS 2641636-52-2 MF C19H19F2N7O3 MW431.4 Urea, N-[(1R,2S)-2-fluorocyclopropyl]-N′-[5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]- N-{5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl}-N′-[(1R,2S)-2-fluorocyclopropyl]urea Janus kinase inhibitor, anti-inflammatory, VTX958, VTX 958, SB88R8KGL3 VTX958 for the Treatment of Moderately to Severely…
Branosotine CAS 2412849-26-2 MF C26H26FN7O MW471.5 g/mol 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-7-methoxy-3H-benzimidazole-5-carbonitrile 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-7-methoxy-1H-1,3-benzimidazole-5-carbonitrilesomatostatin receptor agonist (veterinary use), 4L2VN6D3D8Branosotine is a small molecule drug. The usage of the INN stem ‘-sotine’…
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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Blinatumomab linking a 
New Drug Approvals 
