Synthesis of 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol_Industrial additives

Background and overview^[1]

7,8-Difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol is the synthetic intermediate of Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza viruses. It can target the key link of influenza virus replication and inhibit it from obtaining the CAP structure at the 5′ end of the host mRNA from the host cell, thus inhibiting the transcription of the influenza virus’s own mRNA. Since there is no protease with a similar mechanism in host cells, this drug will theoretically not have an impact on host cells.

Preparation^[2]

Step 1: Preparation of compound I (N,N-diethyl-3,4-difluorobenzamide)

Put 31.62g 3,4-difluorobenzoic acid, 500ml methylene chloride, 5ml N’N-dimethylformamide into the reaction bottle, stir at room temperature, drop in 48.22g oxalyl chloride, stir for 1 hour at room temperature after dripping, reduce Evaporate the solvent to dryness, add 200 ml of methylene chloride to dissolve the remaining oil, and directly drop it into the diethylamine aqueous solution (dissolve 60.81g of potassium carbonate and 26.26g of diethylamine hydrochloride in 200 ml of water). After the dripping is completed, stir at room temperature and separate the organic layer. The phases were extracted with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 39.23g of oil. Yield 92.1%, ¹HNMR (MHz, CDCl₃) δ7.13～7.25 (m, 3H), 3.52 (brm, 2H), 3.27 (brm, 2H ), 1.21(brm, 3H), 1.16(brm, 3H); MS(ESI)m/z(M+H)⁺：214.2

Step 2: Preparation of compound II (N,N-diethyl-2-aldehyde-3,4-difluorobenzamide)

Put 26.00g N, N-diethyl-3,4-difluorobenzamide, 250ml tetrahydrofuran, and 18.42g tetramethylethylenediamine into the reaction bottle, cool to -80°C, and drip in 84ml 1.6M Butyllithium, stir for 1 hour after dripping, add 22.30g N’N-dimethylformamide dropwise, remove the refrigerant after dripping, and react for half an hour, quench the reaction with dilute hydrochloric acid, separate the organic layer, and use ethyl acetate for the aqueous phase Extract, combine the organic layers, and evaporate to dryness under reduced pressure to obtain 29.50 g of oil, with a yield of 100%. ¹HNMR (MHz, CDCl₃) δ10.33 (s, 1H), 7.41～7.46 (m, 1H), 7.03～7.07 (m, 1H), 3.56 (q, J=7.2Hz, 2H), 3.06 (q, J=7.2Hz, 2H), 1.30 (t, J=7.2Hz, 2H), 1.02 (t, J=7.2Hz, 2H); MS (ESI )m/z(M+H)⁺：242.1

Step 3: Preparation of compound III (4,5-difluoro-3-hydroxyisobenzofuran-1(3H)-one)

Put 29.50g N, N-diethyl-2-aldehyde-3,4-difluorobenzamide and 200ml 6M hydrochloric acid into the reaction bottle, heat it to 100°C, stir for 2.5h, and extract with 100mlX4 dichloromethane. The organic layer was separated, washed with purified water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 20.98g of brown solid, with a yield of 92.4%. ¹HNMR (MHz, CDCl₃) δ7.66～7.70 (m, 1H), 7.40～7.50 (m, 1H), 6.78 (s, 1H), 4.54 (brs, 1H); (MS-ESI)m/z(M-H)^–：185.0

Step 4: Preparation of compound IV (4,5-difluoro-3-phenylthioisobenzofuran-1(3H)-one)

Put 20.00g 4,5-difluoro-3-hydroxydiethanolaminoisobenzofuran-1(3H)-one, 200ml toluene, 14.08g diphenyl disulfide, and 16.92g triphenylphosphine into the reaction bottle , 2.04g p-toluenesulfonic acid, stir at 60°C for 24 hours, cool to room temperature, wash with 100ml×41M sodium hydroxide, purified water, saturated brine, dry over anhydrous sodium sulfate, filter and evaporate to dryness under reduced pressure, add n-heptane to the obtained solid alkane, beat at room temperature, filtered, rinsed with n-heptane, evaporated to dryness under reduced pressure and dissolved to obtain 27.1g of white solid, with a yield of 90.1%. ¹HNMR (MHz, CDCl₃) δ7.44～7.53 (m, 4H), 7.22～7.36 (m, 3H), 6.76 (s, 1H)

Step 5: Preparation of compound V (3,4-difluoro-2-phenylthiomethylbenzoic acid)

Put 12.46g aluminum trichloride and 100ml toluene into the reaction bottle and cool it to 0℃ while stirring and drop in the toluene solution of 1,1,3,3-tetramethyldisiloxane (12.55g dissolved in 50ml toluene) After the dripping, the temperature was raised to room temperature and stirred for 30 minutes. Dissolve 20.00g of 4,5-difluoro-3-phenylthioisobenzofuran-1(3H)-one in 50ml of toluene and slowly drip it into the reaction system and stir at room temperature for 3 hours. , drop into the sulfuric acid aqueous solution, separate the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, filter and evaporate to dryness under reduced pressure. Add n-heptane to the obtained solid, beat in an ice-water bath, filter, rinse with n-heptane, and dry to obtain 18.21g of white solid, yield 91.7%. ¹HNMR (MHz, CDCl₃) δ7.84～7.88(m, 1H), 7.34～7.37(m, 2H), 7.27(m, 1H), 7.25 (m, 2H), 7.13 (m, 1H), 4.60 (ds, 2H); MS (ESI) m/z (M-H) ^–: 279.0

Step 6: Preparation of compound VI (7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazepam-11-one)

Put 20g 3,4-difluoro-2-phenylthiomethylbenzoic acid and 100g polyphosphoric acid into a 100ml reaction bottle and stir at 120°C for 4 hours. After cooling, add ice water dropwise, extract with ethyl acetate, and add hydrogen carbonate. Wash with sodium aqueous solution, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, use n-heptane to dry, beat with n-heptane, cool and filter to obtain 17.2 g of solid, yield 92%. ¹HNMR (MHz, CDCl₃) δ8.18～8.22(m, 1H), 7.35～7.45(m, 3H), 7.27～7.32(m, 1H) , 7.17～7.12 (m, 1H), 4.14 (ds, 2H); MS (ESI) m/z (M+H)⁺: 263.1

Step 7: Preparation of compound VII (7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol)

Put 15g of 7,8-difluoro-6,11-dihydrodiphenyl into the reaction bottle.�[b, e] Thiazin-11-one, 50 ml ethanol, 5 ml water, cool down in an ice-water bath, add sodium borohydride several times, slowly add acetone after the reaction is complete, evaporate the solvent to dryness under reduced pressure, and add purified water Beat, filter, and dry to obtain a solid, 14.8 g of 8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol, with a yield of 97%. ¹HNMR (MHz, CDCl₃) δ7.44～7.50 (m, 1H), 7.11～7.22 (m, 4H), 6.99～7.06 (m, 1H) , 6.10 (d, J=3.2Hz, 1H), 4.70 (dd, J=14.4; 1.2Hz1H), 4.20 (dd, J=14.4; 1.2Hz, 1H), 2.68 (d, J=3.6Hz, 1H) ;MS(ESI)m/z(M+H-H₂O)⁺: 247.1.

Main reference materials

[1] CN201810997345.7 Xofluza sulfur-containing heterocyclic compound, its intermediates and preparation method of Japan Tosoh matting agent

[2] CN110143941 – A synthesis method of baloxavir malpol ester intermediate