Structure of 914777-33-6
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CAS No. : | 914777-33-6 |
Formula : | C21H20F2O3 |
M.W : | 358.38 |
SMILES Code : | O=C(C1=CC=C(F)C=C1)CCCC(CCCC(C2=CC=C(F)C=C2)=O)=O |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Step 1. Preparation of (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (A1) 5-(4-Fluorophenyl)-5-oxopentanoic acid (372.0 g, 1.77 mol) and 4-dimethylamino-pyridine (286.9 g, 2.35 mol) were dissolved in N,N-dimethylformamide (1770 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 6 C. (ice/water bath), trimethylacetyl chloride (290 mL, 2.35 mol) was added quickly drop-wise over 17 min to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature below 8.5 C. The mixture was stirred for 1 h at 9 C. (ice/water bath) then for 2 h at 20 C. (colorless solution with copious white thick precipitate). The mixture was charged with (S)-benzyl-2-oxazolidinone (313.5 g, 1.77 mol) and 4-dimethylaminopyridine (216.4 g, 1.77 mol) both as solids to afford a bright yellow colored suspension. The reaction was stirred at 27 C. for 3.3 h. The pale olive colored solution was poured into water (4300 mL) while stirring vigorously (an exotherm was detected to 39 C.), transferred with water (1000 mL) and stirred at room temperature for 2 h to afford a pale orange-brown solution with an off-white precipitate. The compound was filtered, transferred with water (2×300 mL), washed with water (400 mL) and air dried for 1.5 h to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (2600 mL, 4.0 mL/g theoretical yield) by heating to near reflux to afford a dark golden yellow colored solution. The mixture was cooled slowly from 81 C. to 74 C. in 20 min, a seed crystal was added and crystals began to precipitate. The mixture was cooled slowly to room temperature over 11 h, cooled to 2 C. in an ice/water bath and stirred for 3 h. The crystals were filtered, transferred with cold mother liquor (350 mL), washed with cold isopropanol (2×350 mL), air dried and vacuum dried to constant weight to afford (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (A1) (510.6 g, 78 % yield) as a white crystalline solid; m.p. 113.4+/-1.2 C.; Rf 0.37 (1:2 ethyl acetate-hexane); HPLC purity 99.7 A % (96.4 A % by NMR); 1H NMR (300 MHz, CDCl3) delta 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J=8.7 Hz, 2H), 4.72-4.64 (m, 1H), 4.25-4.15 (m, 2H), 3.32 (dd, J=13.3, 3.4 Hz, 1H), 3.12-3.01 (m, 4H), 2.78 (dd, J=13.3, 9.6 Hz, 1H), 2.15 (quint., J=7.2 Hz, 2H), ppm.In the synthesis of (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (A1), two side products are formed: The first of these, AI1, can be reduced with hydrogen in the presence of a chiral catalyst to produce AI4 which can be utilized in the synthesis of D2 using the procedure described in PCT WO2004 099132. Although AI1 and AI2 were isolated by chromatography from the reaction described above, if one wishes to make AI1 directly, one can react <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> with oxalyl chloride. The second by-product, AI2, if not removed, is subsequently reduced to AI3 in the following step. It then co-crystallizes with A2 from toluene/alkane solvents and remains an impurity in A2. It can be removed from A2 by crystallization from isopropanol/alkane. The analytical assessment of the products is by TLC or HPLC with the following results: A0-Rf 0.08 (1:2 ethyl acetate-hexane); HPLC RT 3.7 min; A1-Rf 0.37 (1:2 ethyl acetate-hexane); HPLC RT 7.4 min; A2-Rf 0.14 (1:2 ethyl acetate-hexane); HPLC RT 6.5 min; AI1-Rf 0.50 (1:2 ethyl acetate-hexane); HPLC RT 5.5 min; AI2-Rf 0.38 (1:2 ethyl acetate-hexane); HPLC RT 7.6 min; AI3-Rf 0.43 (2:1 ethyl acetate-hexane); HPLC RT 5.4 min. HPLC on Waters Xterra MS C18 (3.0×150 mm), 5 mum at 35 C. Mobile Phase (A): 0.1% Formic Acid in Water (HPLC grade) Mobile Phase (B): Acetonitrile (HPLC grade) Gradient Program: 25% B-initial conditions 25% to 100% B-11 min 100% to 25% B-0.4 min 25% B-3.6 min (flow increase to 1.75 mL/min) Detection: 254 nm Flow Rate: 1.0 mL/min Run Time: 15 min AI1 6-(4-fluorophenyl)-3,4-dihydro-2H-pyran-2-one. 1H NMR (CDCl3/300 MHz) 7.54(dd, 2H, J=5.1, 9.0 Hz), 7.01(dd, 2H, J=9.0, 9.0 Hz), 5.72(t, 1H, J=4.8 Hz), 2.68-2.63(m, 2H), 2.51-2.47(m, 2H). Mass spectrum, M+H=193. AI2 1,9-bis(4-fluorophenyl)nonane-1,5,9-trione, mp 97.1+/-0.7 C. 1H NMR (CDCl3/300 MHz) 7.92(dd, 4H, J=5.4, 9.0 Hz), 7.06(dd, 4H, J=9.0, 9.0 Hz), 2.92(t, 4H, J=6.9 Hz), 2.49(t, 4H, J=6.9 Hz), 1.95(sept, 4H, J=6.9 Hz). Mass spectrum, M+H=359. AI3 (1S,9S)-1,9-bis(4-fluorophenyl)nonane-1,5,9-triol. 1H NMR (CDCl3/300 MHz) 7.24(dd, 4H, J=5.4, 8.4 Hz), 6.98(dd, 4H, J=8.4, 8.4 Hz), 4.60(m, 2H), 3.52(m, 1H), 3.20-2.60(m, 2H), 1.80-1.20(m, 10H). Mass spectrum, M+H=365. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | 5-(4-Fluorophenyl)-5-oxopentanoic acid (372.0 g, 1.77 mol) and 4-dimethylamino- pyridine (286.9 g, 2.35 mol) were dissolved in LambdazetaN-dimethylformamide (1770 rnL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 6 0C (ice/water bath), trimethylacetyl chloride (290 mL, 2.35 mol) was added quickly drop-wise over 17 min to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature below 8.5 C. The mixture was stirred for 1 h at 9 C (ice/water bath) then for 2 h at 20 C (colorless solution with copious white thick precipitate). The mixture was charged with (S)-benzyl-2- oxazolidinone (313.5 g, 1.77 mol) and 4-dimethylaminopyridine (216.4 g, 1.77 mol) both as solids to afford a bright yellow colored suspension. The reaction was stirred at 27 C for 3.3 h. The pale olive colored solution was poured into water (4300 mL) while stirring vigorously (an exotherm was detected to 39 C), transferred with water (1000 mL) and stirred at room temperature for 2 h to afford a pale orange-brown solution with an off-white precipitate. The compound was filtered, transferred with water (2 x 300 mL), washed with water (400 mL) and air dried for 1.5 h to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (2600 mL, 4.0 mL/g theoretical yield) by heating to near reflux to afford a dark golden yellow colored solution. The mixture was cooled slowly from 81 C to 74 C in 20 min, a seed crystal was added and crystals began to precipitate. The mixture was cooled slowly to room temperature over H h, cooled to 2 C in an ice/water bath and stirred for 3 h. The crystals were filtered, transferred with cold mother liquor (350 mL), washed with cold isopropanol (2 x 350 mL), air dried and vacuum dried to constant weight to afford (4iotaS)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoylj-l,3- oxazolidin-2-one (Al) (510.6 g, 78 % yield) as a white crystalline solid; m.p. 113.4 + EPO <DP n="33"/>1.2 C; R/ 0.37 (1 :2 ethyl acetate-hexane); HPLC purity 99.7 A% (96.4 A% by NMR); 1H NMR (300 MHz, CDCl3) delta 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J= 8.7 Hz, 2H), 4.72-4.64 (m, IH), 4.25-4.15 (m, 2H), 3.32 (dd, J= 13.3, 3.4 Hz, IH), 3.12-3.01 (m, 4H), 2.78 (dd, J= 13.3, 9.6 Hz, IH), 2.15 (quint, J= 7.2 Hz, 2H) ppm. |
Tags: 914777-33-6 synthesis path| 914777-33-6 SDS| 914777-33-6 COA| 914777-33-6 purity| 914777-33-6 application| 914777-33-6 NMR| 914777-33-6 COA| 914777-33-6 structure
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