GSK2248761A , IDX899, Fosdevirine,

Fosdevirine; IDX899; IDX-899; GSK2248761; cas 1018450-26-4; GSK-2248761, IDX 12899

[R(P)]-(2-Carbamoyl-5-chloro-1H-indol-3-yl)[3-(2-cyanovinyl)-5-methylphenyl]phosphinic acid methyl ester

Phase II clinical trials for the treatment of HIV infection

Idenix (Originator)

Fosdevirine, also known as GSK2248761 and IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor having an EC50 of 11 nM against the Y181C/K103N double mutant. GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

IDX-12899 is a non-nucleoside reverse transcriptase inhibitors (NNRTI) originated by Idenix (acquired by Merck & Co.). It had been in phase II clinical trials for the treatment of HIV infection. However, in 2010, the compound was placed on clinical hold by the FDA. In 2009, the compound was licensed by Idenix to GlaxoSmithKline for the treatment of HIV infection on a worldwide basis.

PATENT

WO2008/042240 A2, 2008, Compound III

compound 66a: racemic form

5-chloro-3-[ methyl 3-((Zζ)-2-cyanovinyl)-5-methylphenyl] phosphinoyl-l//-indole-2- carboxamide.

[00258] Compound 66a was synthesized according to method AL. White solid, ¹H NMR (CDCl₃, 300 MHz) δ 2.40 (s, 3H), 3.88 (d, J= 11.7 Hz, 3H), 5.89 (d, J= 16.5 Hz, IH), 5.97 (brs, IH), 7.33-7.67 (m, 7H), 10.46 (s, IH), 10.89 (brs, IH), ³¹P NMR (CDCl₃, 121.49 MHz) δ 31.54. MS (ES⁺) m/z = 414 (MH⁺).

Example 8

Preparation of Compound HI

305

1 (-)cιnchonιdιne, Acetone

2 1N HCI₁ EtOAc

Compound 302

[00348] A suitable reactor was charged Compound 301 (10Og, 0.23mol) and tetrahydrofuran (IL). The resulting solution was chilled between -90° to -100°C under nitrogen using a LN₂ / IPA slush bath, then was treated with n-butyl lithium (2.5M in Hexanes, 99ml, 0.25mol) added over 10 minutes. To this was added diethyl chlorophosphite (37.1g, 0.24mol) over 10 minutes. HPLC (Method 001, RT = 18.9 min) showed no starting material and ca. 85% product. The reaction was then diluted with ethyl acetate (IL) and was allowed to warm to -4O⁰C. The mix was then treated with hydrochloric acid (0.5M, 590ml) and was allowed to warm to ambient temperature and stir for 30 minutes. The resulting layers were separated and the aqueous extracted with ethyl acetate (500ml). The organics were combined and washed with brine (500ml) dried over sodium sulfate, filtered and concentrated to an oil. 88% HPLC AUC (Method 20, RT = 5.8 min) 115g, >100% yield due to impurities and solvent. Used as is in the next step. Compound 303

[00349] A suitable reactor was charged with Compound 302 (111 g, estimated 0.18mol), iodocinnamonitrile (47.1g, 0.175mol), triethylamine (29.3ml, 0.21mol) and toluene (800ml). The resulting mix was degassed by sparging with a stream of nitrogen for 10 minutes at ambient temperature, after which time tetrakis(triphenylphosphine) palladium(O) (10. Ig, 0.0088mol) was added. The mix was sparged for an additional 5 minutes, then was heated to 80°C for 2 hours. HPLC (Method 20, RT = 6.5 min) showed a complete reaction. The mix was cooled to ambient and was filtered through celite and washed with ethyl acetate (400ml). The combined organics were washed with brine (2 x 500ml) then dried over sodium sulfate, filtered and concentrated to a volume of 350ml. The concentrate was cooled to O⁰C and was stirred for 1 hour, during which time the product crystallized. The solids were filtered and washed with hexane:toluene (2:1, 150ml). Dried to leave 95g, 90% yield, HPLC AUC 98% (Method 20). Used as is in the next reaction. [00350] 303: C₂₉H₂₆ClN₂O₆PS 597.02gmol^“‘ m/z (ESI+): 597.0 (MH⁺, 100%), 599.0 (MH⁺, 35%) ¹H NMR δ_H (400 MHz, CDCl₃): 1.38, 1.48 (2 x 3H, 2 x t, COOCH₂CH₃, POOCH₂CH₃), 2.41 (3Η, s, Ar-CH₃), 4.09-4.16 (2Η, m, POOCH₂CH₃), 4.52 (2H, q, COOCH₂CH₃), 5.93 (IH, d, CH=CHCN), 7.33-7.38 (3Η, m, CH=CHCN, 2 x Ar-H), 7.52 (2Η, t, 2 x Ar-H), 7.64 (1Η, t, Ar-H), 7.74, 7.77 (2 x 1Η, 2 x d, 2 x Ar-H), 7.85 (1Η, d, Ar- H), 7.94 (1Η, dd, Ar-H), 8.08 (2Η, d, 2 x Ar-H) ¹H NMR δ_H (400 MHz, d6-DMSO): 1.26, 1.33 (2 x 3H, 2 x t, COOCH₂CH₃, POOCH₂CH₃), 2.34 (3Η, s, Ar-CH₃), 3.95-4.10 (2Η, m, POOCH₂CH₃), 4.40 (2H, q, COOCH₂CH₃), 6.52 (IH, d, CH=CHCN), 7.52 (1Η, dd, Ar-H), 7.60-7.84 (8Η, m, CH=CHCN, 7 x Ar-H), 8.07 (3 x 1Η, m, 3 x Ar-H)

Compound 304

[003511 A suitable reactor was charged with Compound 303 (537g, 0.90mol) and methylene chloride (2.0L). The resulting solution was cooled to O⁰C, and was treated with bromotrimethylsilane (45Og, 2.9mol) added over 15 minutes. The reaction was then warmed to 40⁰C for 1.5 hours. ΗPLC (Method 20, RT = 4.4 min) indicated a complete reaction. The excess TMSBr was stripped under vacuum (40 – 45°C) and the resulting sticky solid was resuspended in DCM (2.5L) and chilled to 0⁰C. Oxalyl chloride (156ml, 1.8mol) was added over 15 minutes, followed by N,N-dimethylformamide (13.7ml, 0.18mol) both added at O⁰C. Gas evolution was observed during the DMF addition. After 1 hour, ΗPLC (Method 20, RT = 6.2 min, sample quenched with anhydrous methanol prior to injection) showed a complete reaction. The solvents were stripped again to remove residual oxalyl chloride and the mix resuspended in chilled methanol (3.0L) at 0° – 5°C, and then was allowed to warm to ambient. After two hours, HPLC indicated a complete reaction (HPLC Method 20, RT = 6.2 min). The solution was concentrated to a volume of 1.5L, and the resulting thin slurry was cooled to 0°C, and was diluted with an aqueous solution of sodium bicarbonate (126g, 3L water). After 2 hours at 5⁰C, the product was filtered and washed with cold water / methanol (2:1, 1.5L) then dried to leave 50Og Compound 304. HPLC (Method 20) purity 92% used as is.

Compound 305

[00352] A suitable reactor was charged with Compound 304 (ca. 28Og, 0.48mol) and tetrahydrofuran (2.8L). The resulting solution was then cooled to 5°C and was treated with lithium hydroxide monohydrate (45g, 1.07mol) added in one portion. The reaction was allowed to warm to ambient, during which time the color lightened and a white precipitate formed. After overnight stirring, HPLC indicated an incomplete reaction (Method 20, product RT = 4.3, partially deprotected RT = 5.1, major impurity RT = 3.8). An additional 10% LiOH-H₂O was added, but after 10 hours, the partially deprotected intermediate remained at 5%, and the impurity peak at 3.8 minutes had increased to ca. 25%. The reaction was cooled to 5⁰C and was acidified with hydrochloric acid (5N, 280ml) then was diluted with ethyl acetate (2L). The layers were separated and the aqueous extracted with ethyl acetate (500ml). The combined organics were washed with brine (IL) and dried with sodium sulfate, then concentrated to leave a crude oily solid, Compound 305. Ca. 300g, HPLC AUC 57%.

[00353] The crude product was taken up in acetonitrile (1.2L) at 4O⁰C, and the product triturated w/ water (1.2L). The resulting slurry was cooled to 5⁰C and was allowed to granulate for 30 minutes, after which time the product was filtered and washed with ACN:H₂O (1 :1, 100 ml). Ca. 103g, 88% by HPLC. The product was then recrystallized from 360ml ACN at 40⁰C and 360ml water as before. Filtered, washed and dried to leave 75g Compound 305. HPLC AUC 97%. Used as is in the next step.

Compound 306 (chiral resolution)

[00354] A suitable reactor was charged with Compound 305 (28Og, 0.66mol) and acetone (4.2L). The resulting thin slurry was then treated with (-)-cinchonidine (199g, 0.66mol) added in one portion. After one hour, a solution had formed, and after an additional hour, a white solid precipitated, and the mix was left to stir for an additional two hours (four hours total) after which time the solids were filtered, washed with acetone (200ml) and dried to leave 199g Crude Compound 306 cinchonidine salt. HPLC showed an isomer ratio of 96:4.

[00355] The crude salt was then slurried in ethyl acetate (3L) and hydrochloric acid (IN, 3L). The two phase solution was vigorously stirred for 2 hours at ambient temperature. The layers were separated, and the aqueous extracted with ethyl acetate (3L). The organics were combined, dried with sodium sulfate, and concentrated to leave the free base Compound 306, 107g, 95:5 by chiral HPLC.

[00356] The crude Compound 306 was then suspended in acetone (1.07L) and treated with (-)-cinchonidine (76g, 0.26 mol.) After 4 hours total stir time (as above) the solids were filtered, washed with acetone (200ml) and dried to leave 199g of the salt. HPLC 98.6:1.4.

[00357] The salt was broken by dissolving in ethyl acetate (3L) and hydrochloric acid (IN, 3L). The two phase solution was stirred for 2 hours at ambient temperature. The layers were separated, and the aqueous extracted with ethyl acetate (2L). The organics were combined, dried with sodium sulfate, and concentrated to leave the free base Compound 306, 98g, 98.6:1.4 by chiral HPLC. 70% recovery of the desired isomer, 35% yield from the racemic Compound 306. #6: C₂₀H₁₆ClN₂O₄P 414.78gmol^“‘ m/z (ESI+): 415.1 (MH⁺, 100%), 417.0 (MH⁺, 35%) [α]_D ²⁵ : -47.51 (c, 10.66mgml^“‘ in EtOAc) [Opposite enantiomer [α]_D ²⁵ : +47.26 (c, 9.60mgml^“‘ in EtOAc)] ¹H NMR δ_H (400 MHz, d6-DMSO): 2.33 (3 H, s, Ar-CH₃), 3.71 (3H, d, CH₃OP), 6.50 (1Η, d, CH=CHCN), 7.36 (1Η, dd, H-6), 7.57 (1Η, d, H-I), 7.66-7.71 (2Η, m, H-4, Ar-H_orth_o), 7.67 (1Η, d, CH=CHCN), 7.84 (IH, d, Ar-H_ortho), 7.98 (1Η, s, Ar-H_para), 12.97 (1Η, s, N-H), 14.38 (1Η, br-s, COOH) Multiple δc values indicate splitting of carbon signal due to P. ¹³C NMR δc (100 MHz, d6-DMSO): 20.68 (Ar-CH₃), 51.70 (CH₃OP), 98.15 (CH=CHCN), 102.33, 103.85, 1 14.98, 120.91 (3 x Q, 118.47 (CN), 125.39 (C), 126.78 (Q, 127.74, 127.86 (C- H_ortho), 129.78, 129.88 (Q, 131.25 (Q, 132.06 (Q, 133.44, 133.55 (Q, 133.89, 134.05 (Q, 134.62, 134.75 (Q, 135.47, 135.66 (Q, 138.78, 138.91 (Q, 149.62 (CH=CHCN), 160.40 (C=O) ³¹P NMR δ_P (162 MHz, d6-DMSO): 33.50 (IP, s)

Compound HI

[00358] A suitable reactor was charged with Compound 306 (0.63g, O.OOHmol) and 1 ,2-dimethoxyethane (10ml.) The mix was treated with 1,1-carbonyldiimidazole (0.47g, 0.0028mol) added in one portion, and the mix was allowed to stir at ambient temperature until gas evolution ceased (ca. 1.5 hours.) The solution was then cooled to 5⁰C, and was sparged with ammonia gas for 5 minutes. HPLC (Method 20, product RT=5.0 min) showed a complete reaction after one hour at ambient. The reaction was quenched by the addition of 1Og crushed ice, and was concentrated under reduced pressure to remove the DME. The resulting slurry was stirred for one hour at 5⁰C to granulate the product. The solids were filtered and dried to leave pure Compound III ((2-Carbamoyl-5-chloro-4-fluoro-lH-indol-3- yl)-[3-((E)-2-cyano-vinyl)-5-methyl-phenyl]-(S)-phosphinic acid methyl ester) as a white solid 0.56g, 89% yield. HPLC (Method 20) chemical purity 98.5%. Chiral purity 97%. [00359] A suitable reactor was charged with Compound 306 (1Og, 0.024mol) and 1,2- dimethoxyethane (150ml). The mix was treated with 1,1-carbonyldiimidazole (7.8g, 0.048mol) added in one portion, and the mix was allowed to stir at ambient temperature until gas evolution ceased. The solution was then cooled to 5°C, and was sparged with ammonia gas for 5 minutes. HPLC (Method 20, product RT=5.0 min) showed a complete reaction after one hour. The reaction was quenched by the addition of lOOg crushed ice, and was concentrated under reduced pressure to remove the DME. The resulting oily solid (in water) was diluted with methanol (20ml) and stirred for one hour at 5⁰C to granulate the product. The solids were filtered and dried to leave pure Compound III ((2-Carbamoyl-5- chloro-4-fluoro-lH-indol-3-yl)-[3-((E)-2-cyano-vinyl)-5-methyl-phenyI]-(S)-phosphinic acid methyl ester). 9.8g, 98% yield. HPLC (Method 20) chemical purity 99.5%. Chiral purity 94.3%.

Compound III: C₂₀Hi₇ClN₃O₃P 413.79gmol^“‘ m/z (ESI+): 414.1 (MH⁺, 100%), 416.1 (MH⁺, 35%)

v_max (KBr disc) (cm^“1) 1620.0 (amide I), 1670.6 (amide II), 2218.7 (CN), 3125.5, 3291.9 (N-H)

[α]_D ²⁰ : -75.08 (c, 9.04mgmr’ in CHCl₃)

m.p.: 144- 148⁰C transition to opaque semi-solid, 209-210⁰C melts

Elemental analysis: C₂₀H₁₇ClN₃O₃P calculated C 58.05%, H 4.14%, N 10.15%, Cl 8.57%, P 7.49%. Found C 58.13%, H 4.08%, N 10.16%, Cl 8.69%, P 7.44% 

¹H NMR δ_H (400 MHz, d6-DMSO): 2.32 (3H, s, Ar-CH₃), 3.74 (3Η, d, CH₃OP), 6.52 (1Η, d, CH=CHCN), 7.30 (1Η, dd, H-6), 7.53-7.58 (3Η, m, H-4, H-7, H-6′), 7.68 (1Η, d, CH=CHCN), 7.73 (IH, s, H-4′), 7.75 (1Η, d, H-2′), 8.02, 10.15 (2 x 1Η, 2 x s, NH₂), 12.80 (1Η, s, N-H) Multiple δ_c values indicate splitting of carbon signal due to P. 

¹³C NMR δ_c(100 MHz, d6-DMSO): 20.77 (Ar-CH₃), 51.75, 51.81 (CH₃OP), 98.39, 98.91 (C-3), 98.44 (CH=CHCN), 1 15.05 (C-7), 1 18.53 (CN), 119.96 (C-4), 124.73 (C-6), 126.68 (C-5), 127.15, 127.26 (C-2′), 129.25, 129.35 (C-9), 131.37 (C-4′), 132.45, 134.04 (C-I ‘), 132.69, 132.80 (C-6′), 133.92 (C-8), 134.30, 134.44 (C-3′), 139.33, 139.46 (C-5’), 139.96, 140.17 (C-2), 149.55 (CH=CHCN), 160.65 (C=O)

 ³¹P NMR δ_P (162 MHz, d6-DMSO): 33.72 (IP, s)

PATENT

http://www.google.ch/patents/WO2009120914A1?cl=en&hl=de

(2-carbamoyl-5-chloro-lH-indol-3-yl)-[3-((E)-2-cyano-vinyl)-5-methyl-phenyl]- (7?)-phosphinic acid methyl ester (I):

Figure 7 provides an infrared spectrum of Form I.

Paper

Development of an Efficient Manufacturing Process to GSK2248761A API

Celine Bret^†§, Elaine Smith^†, Erica Vit^†§, Jerome F. Hayes^*† , John D. Hayler^† , Alan Ironmonger^†, David Pascoe^†, Neil Hodnett^†, Jonathan Stanway^†, Stephen Etridge^†, Alistair Stewart^‡⊥, Jingyang Wang^‡⊥, Benjamin A. Mayes^‡⊥, and Adel Moussa^‡⊥

^† GlaxoSmithKline, Medicines Research Center, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.

^‡ Merck & Co. Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00357

*E-mail: Jerome.Hayes@gsk.com.

Amidation of indole 2-carboxylate 1 with ammonia gas via the imidazolide 2 gave GSK2248761A API 3, which was in development for the treatment of HIV. Three significant impurities, namely the phosphinic acid 4, the N-acyl urea 8, and the indoloyl carboxamide 6, were formed during the reaction, and the original process was unable to produce API within clinical specification when run at scale. Investigation into the origin, fate, and control of these impurities led to a new process which was able to produce API within clinical specification.

Development and Scale-Up of a Manufacturing Route for the Non-nucleoside Reverse Transcriptase Inhibitor GSK2248761A (IDX-899): Synthesis of an Advanced Key Chiral Intermediate

Richard Bellingham^†§, Gary Borrett^†, Guillaume Bret^†§, Bernadette Choudary^†§, David Colclough^†§, Jerome Hayes^† , John Hayler^† , Neil Hodnett^†, Alan Ironmonger^*†, Augustine Ochen^†, David Pascoe^†, John Richardson^†§, Erica Vit^†§, François-René Alexandre^‡ , Catherine Caillet^‡∥, Agnès Amador^‡∥, Stéphanie Bot^‡, Séverine Bonaric^‡∥, Daniel da Costa^‡, Marie-Pierre Lioure^‡, Arlène Roland^‡∥, Elodie Rosinovsky^‡∥, Christophe Parsy^‡∥, and Cyril B. Dousson^‡

^† GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

^‡ Merck & Co., Inc.,126 East Lincoln Avenue, Rahway, New Jersey 07065, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00356

*E-mail: Alan.2.Ironmonger@gsk.com.

Abstract

A new and improved synthetic route to an intermediate in the synthesis of the phosphinate ester GSK2248761A is described. In the key step, we describe the first process-scale example of a palladium-catalyzed phosphorus–carbon coupling to give the entire backbone of GSK2248761A in one telescoped stage in 65% average yield on a 68 kg scale. This unusual chemistry enabled the route to be reduced from six chemistry stages to four and eliminated a number of environmentally unfriendly reagents and solvents.

REFERENCES

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/////////////GSK2248761A , IDX899, Fosdevirine, PHASE 2

CC1=CC(=CC(=C1)C=CC#N)P(=O)(C2=C(NC3=C2C=C(C=C3)Cl)C(=O)N)OC