Patent DE-102011088854-A1 (DE)
Title: Preparing O-amino-hydroxy-octadec-en-yl phosphate useful for preparing sphingosine-1-phosphate, comprises oxidizing substituted oxazolidin-yl-methanol derivative and reacting substituted carbaldehyde derivatives with alkyne compounds
Inventor: QUINT STEPHAN
IPC: C07D263/02
Filed: 2011-12-16
Abstract: Preparing O-2-amino-3-hydroxy-octadec-4-en-1-yl phosphate or its stereoisomers and/or its derivatives, comprises: (e) oxidizing substituted oxazolidin-4-yl-methanol derivatives (V) using oxalyl chloride, dimethyl sulfoxide and Hunig's base (less than 5.5 equivalents) at a temperature of not less than -70[deg] C to obtain substituted oxazolidine-4-carbaldehyde derivatives (VI); and (f) reacting (VI) with 1-alkyne compounds (VIII) (at least 1.5 equivalents) and a base to obtain substituted 1-oxazolidin-4-yl-alk-2-yn-1-ol derivatives (VIIa), and purifying (VIIa) by distilling unreacted (VIII). Preparing O-2-amino-3-hydroxy-octadec-4-en-1-yl phosphate or its stereoisomers and/or its derivatives, comprises: (e) oxidizing substituted oxazolidin-4-yl-methanol derivatives of formula (V) using oxalyl chloride, dimethyl sulfoxide and Hunig's base (less than 5.5 equivalents) at a temperature of not less than -70[deg] C to obtain substituted oxazolidine-4-carbaldehyde derivatives of formula (VI); and (f) reacting (VI) with 1-alkyne compounds of formula (H-CC-R3) (VIII) (at least 1.5 equivalents) and a base to obtain substituted 1-oxazolidin-4-yl-alk-2-yn-1-ol derivatives of formula (VIIa), and purifying (VIIa) by distilling unreacted (VIII). Pg : protecting group; either R1, R2 : 1-6C alkyl or phenyl (both optionally substituted) or H; or R1+R2 : 4-6C cycloalkyl (optionally substituted); and R3 : alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, aryl-alkynyl, alkylaryl, alkenylaryl or alkynyl-aryl (all optionally substituted and all optionally comprise several N, O or S in its carbon skeleton). An independent claim is also included for preparing sphingosine-1-phosphate or its stereoisomers and/or its derivatives, comprising (i) converting L-serine to (S)-methyl 2-amino-3-hydroxypropanoate (Xa) or its salts, (ii) protecting the amino functional group of (Xa) or its salts to obtain (S)-methyl 2-amino-3-hydroxypropanoate derivatives of formula (HO-CH 2-CH(NH-Pg)-C(=O)-O-CH 3) (Xb), (iii) protecting the primary hydroxy group and the amino group of (Xb) to obtain substituted (S)-oxazolidine-4-carboxylic acid ester compounds of formula (Xc), (iv) reducing (Xc) to obtain substituted (R)-1-oxazolidin-4-yl-methanol derivatives of formula (Xd), (v) oxidizing (Xd) using oxalyl chloride, dimethyl sulfoxide and Hunig's base (less than 5.5 equivalents) at a temperature of not less than -70[deg] C to obtain substituted (S)-oxazolidine-4-carbaldehyde derivatives of formula (Xe), (vi) reacting (Xe) with 1-pentadecyne (1.5 equivalents) and a base to obtain (VIIb), (vii) partially deprotecting (VIIb) to obtain (2S,3R)-2-amino-octadec-4-yne-1,3-diol derivatives of formula (HO-CH 2-CH(NH-Pg)-CH(OH)-CC-C 1 3H 2 7) (Xf), (viii) reducing the triple bond of (Xf) to a trans double bond to obtain (E)-(2S,3R)-2-amino-octadec-4-ene-1,3-diol derivatives of formula (HO-CH 2-CH(NH-Pg)-CH(OH)-CH=CH-C 1 3H 2 7) (Xg), (ix) phosphorylating the primary hydroxy group of (Xg) to obtain phosphoric acid (E)-(2S,3R)-2-amino-3-hydroxy-octadec-4-enyl ester dimethyl ester derivatives of formula (P(O-CH 3) 2(=O)-O-CH 2-CH(NH-Pg)-CH(OH)-CH=CH-C 1 3H 2 7) (Xh), and (x) deprotecting (Xh) to obtain sphingosine-1-phosphate, and purifying the obtained sphingosine-1-phosphate by distilling unreacted 1-pentadecyne. [Image] [Image].