ethyl(4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate synthesis

Yield:1059630-08-8 98%

Reaction Conditions:

with sodium carbonate in tetrahydrofuran at 25; for 1.33333 h;Product distribution / selectivity;

Steps:

3

Example 3: Production of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indoIe-2(9bH)-carboxylate; (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first optaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-Z>]indole (36.0 g, 0.142mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lη-pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-*]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice- water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3- b]indole-2(9bH)-carboxylate). ¹H NMR (CDCl₃, 300 MHz): 1.20-1.35 (m,3H), 1.73- 1.85 (m, IH), 1.85-1.99 (m, IH), 3.22-3.52 (m, 3H), 3.52-3.66 (m, IH), 3.66-3.95 (Br, IH), 3.95-4.21 (m, 4H), 6.60 (t, J = 7.7 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 7.20 (d, J = 8.1 Hz, IH).[0084] Alternative to the use of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro- lH-pyrido[4,3-Z>]indole (Compound of Formual 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N₂ inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na₂CO₃ (2.88 g, 27.17 mmol), and 25 mL of TηF. To the yellow reaction mixture at 25 ⁰C (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of TηF dropwise over ca 70 minutes. The batch is stirred at 25 ⁰C for another 10 min, and is checked by ηPLC. Less than 2% of the starting material is observed by ηPLC, and the desired product is registered at ca. 98%. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly TηF). To the batch is then added 37.5 mL ofη₂O, and the resultant mixture shows pH >9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H₂O. After drying in a vacuum oven at 58 ⁰C for ca. 16 h, 3.9442 g of a yellow solid is obtained (98% yield). ¹H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99% purity. LC-MS showed a peak with M/e = 326 (M+ 1).

References:

WO2008/112280,2008,A1 Location in patent:Page/Page column 85-86