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CAS indexed 214 chemical substances from this document.
CAS subject entries for this document include: Alcohols, preparation; Amides, preparation; Amines, preparation; and 5 additional concepts | |
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CAPLUS COPYRIGHT 2008 ACS on STN
| TITLE:
| A process for resolving racemic mixtures and a diastereoisomeric complex of a resolving agent and an enantiomer of interest |
| INVENTOR(S):
| Napolitano, Elio; Fiaschi, Rita; Bechini, Chiara; Brunetto, Gabriella |
| PATENT ASSIGNEE(S):
| Abiogen Pharma S.p.A., Italy |
| SOURCE:
| PCT Int. Appl., 104pp. CODEN: PIXXD2 |
| LANGUAGE:
| English |
PATENT INFORMATION: PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- -------------------- --------
WO 2007088571 A2 20070809 WO 2007-IT67 20070201
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH,
CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD,
GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN,
KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK,
MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO,
RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT,
TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
RW: AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE,
IS, IT, LT, LU, LV, MC, NL, PL, PT, RO, SE, SI, SK, TR, BF, BJ,
CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG, BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW, AM, AZ, BY,
KG, KZ, MD, RU, TJ, TM
ABSTRACT:
A process for resolving a compd. in racemic form comprising the following steps is described: (a) reacting an org. acid or base compd. in racemic form with a resolving agent, (b) forming a diastereoisomeric complex of the resolving agent and an enantiomer of interest, (c) sepg. the enantiomer of interest from the obtained diastereoisomer, wherein such a process is characterized in that said resolving agent is a compd. of formula (I; C* = a chiral center; n, p = 0-1; R1 = C1-3 alkyl; R2 = CO2H, NH, NH2, Ph, or CH2OH; or R1, C* and R2 form a nitrogenous five-membered ring; R3 = C:O or CH2; R4 = H or CH2; CR = C6-C12 arom. group optionally substituted with one or more halogens; A = a substituent selected from the group consisting of CH2, SO2 and C:O; with the proviso that when n = 0 and p = 1, R1 = C1-C3 alkyl and R2 = CH2OH, Ph, COOH or R1, C*, N and R4 form a five-membered ring). A diastereoisomeric complex between the resolving agent of formula I and the enantiomer of interest is also described. The process according to the invention allows acid and basic racemic mixts. to be sepd. A group of resolving agents has been identified and synthesized from L-amino acids such as L-alanine, L-valine, and L-proline, whose structure results from the combination of three different structural elements: (a) a chiral center formable from enantiomerically pure compds., which are com. available in both enantiomeric forms and at low costs; (b) a functional group (an acid or a basic group) capable to allow the conjugation with the components of the racemic mixt.; and (c) a group capable of imparting crystallinity and allowing the modulation of the soly. of the diastereoisomeric conjugates. Thus, a soln. of tert-butoxycarbonyl-L-alanine in THF was cooled to 0.degree., treated sequentially with N-methylmorpholine and tert-Bu chloroformate, stirred at room temp. for 6 h, treated with 1,1'-biphenyl-4-amine, and stirred for one night at room temp. to give 95% [(1S)-1-(1,1'-biphenyl-4-ylcarbamoyl)ethyl]carbamic acid (II). A soln. obtained by adding in portions acetyl chloride to MeOH was cooled 0.degree., treated with II, heated to reflux in order to bring all components to soln., and then left at room temp. for a night to give, after workup, 95.9% 2-amino-N-(1,1'-biphenyl-4-yl)propionamide (III). A soln. of racemic tetrahydrofuran-2-carboxylic (1 g) in 10 mL Et2O was treated with the amine III (1.15 g) and heated to give a soln., which was slowly left to be cooled. The formed ppt. was filtered and washed by small portions of ether to give 1.4 g (R)-tetrahydrofuran-2-carboxylic acid-III salt in 85% yield. E.e. of the free acid was 95% which is comparable to the optical purity obtained by enzymic resoln.
Updated 1/25/2008 1:13:48 PM
