NZ248043A - 1-(4-hydroxy-3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methy l-5-benzenesulphonyl-1,3-pentadiene derivatives; methods of preparation - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £48043 248043 Patents Form 5 Priority Dciie{s): . 5l9l Complete Specifics-tion Filed: Class: '"J' '2 5 MAR'TO Publication Date: P.O. Journal, No: ....ISO Under the provisions of RoflW- lation 23 (1) the Coysfi£j;& Specification has been ante-dated to...s£l 19 31 A N.Z. No.

(Divided out of New Zealand NEW ZEALAND Patent Specification No. 240765) Patents Act 1953 COMPLETE SPECIFICATION NOVEL COMPOUNDS We, NEUROSEARCH A/S, a Danish company of Smedeland 26, DK-2600 Glostrup, Denmark do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (Followed by 1A) 248043 1A The present invention provides a compound of the following formula wherein R1 is alkyl, alkoxy, N02, NH2 or halogen.

In a further aspect the present invention provides a method for the preparation of a compound having the formula wherein R' is alkyl, alkoxy, "NO,, NH, or halogen, which method comprises the step of reacting a compound having the formula 12 3* OSiR R R wherein R1, R2 and R3 independently are C^- alkyl which may be branched or phenyl with a compound having the formula wherein R' is alkyl, alkoxy, NO,, NH2 or halogen. 2 248043 Background of "the invention USP 4,585,885 discloses a compound having the formula wherein R2 is an trialkylsiloxy group or an ether group, which is oxidized with, a percarboxylic acid to form a compound having the formula wherein R2 is as above.

This compound is then transformed into a compound having the formula wherein R3 is an alkylether or an hydroxy group.

This compound is then transformed into a Wittig compound which upon reaction with a compound having the formula will yield astaxanthin. 24 8 0 4 3 3 Detailed Description The novel process of the present invention is carried out much more convenient, in that it avoids the use of peracids and allows a much more direct approach to the production of astaxanthin.

The novel process and the novel intermediates of the invention are illustrated in the below scheme 1 well known compound of USP 4; 098,827 0 Step 1 TMSC1 (trimethylsilyl chloride) in triethylamine, methylenechloride 2 0 1) NaHMDS (in THF) Ph0 Step 2 2) 1Z_^N Novel Process 3) HOAc 3 HO Novel Compound 0 4 24 8 0 4 J Step 3 Ph^ NsO~Na+ (in HOAc) Novel Process Novel Compound Step 4 1) NaOCH, 2) Br. (in THF) SOnPh S02Ph Step 5 1) KOt-Bu (in hexane) Astaxanthin 24 8 04 3 The above scheme illustrate preferred reagents, solvents, " acids and bases of the processes of the invention.

However the NaHMDS (sodiumhexamethyldisilazane) of step 2 above may easily be substituted for other bases as for example KHMDS, LiHMDS, LDA (lithium diisopropyl amide), sodium-hydride, potassium t-butylat as well as several others.

The oxidizing agent of ^_step 2, trans-2-(phenylsulfonyl)-3-phenyloxaziridine (Ph-£-N-S02Ph), is a key element.of step 2. However, this oxidizing agent may be any oxaziridine having the below formula •so2R' wherein R1 is phenyl, phenyl substituted with a substituent which is stable under the conditions of reaction, C3_7-cyclo-alkyl, and wherein R2 independently signifies hydrogen or the same radical as R1, or wherein R1 and R2 together form a cyclic or bicyclic radical as for example camphorylsulfonyl-oxaziridine.

The acid of step 2 used to quench the reaction mixture may be any proton donor. Any protic compounds such as water, alcohols, and hydrogen-donating acids may be employed, however, it preferred that the quenching proton donor is at least slightly acidic in order to avoid the formation of strong base during the quenching step.

The phenylsulphinate employed in step 3 above may be substituted for any substituted derivative thereof. For example the phenyl group may be substituted with alkyl, alkoxy, NOz, and halogen. The acetic acid employed in this step 3 may be sub- 24 BB4J5 6 stituted by any organic acid, or any neutral organic solvent with addition of an acid, for example ethanol added hydrogen chloride may conveniently be employed instead.

Step 4 and 5 above illustrate the utility of the novel intermediates of the invention produced by the novel processes of the invention for the production os astaxanthin.

Step 4 and step 5 above may conveniently be effected by use of the reagents indicated above. The principles of the processes are described in more detail in examples 5 and 6 of USP 4,049,718.

Examples The invention will now be described in greater detail with reference to the following examples, which are given by way of illustration only and are not to be construed as limiting. l-(3-oxo-2,6, 6-trimethyl-l-cyclohexen-l-yl )-3-methyl-3-trimethylsiloxy-1,4-pentadiene A solution of l-(3-oxo-2, 6, 6-trimethyl-l-cyclohexen-l-yl )-3-methyl-l,4-pentadiene-3-ol (2.34 g, 10 mmoles)(prepared as described in J. Org. Chem. 47, 2130-2134 (1982)) in methylenechloride is added triethylamine (2.08 ml, 15 mmoles), trimethylchlorosilane (1.9 ml, 15 mmoles), and N,N-dimethyl-4-aminopyridine (5 nig, catalytic amount). The mixture is stirred at room temperature for four hours, followed by concentration in vacuo and trituration with dry diethyl-ether. The suspension is filtered and the filtrate is concentrated in vacuo yielding the title compound as a slightly yellow oil. l-(4-hydroxy-3-oxo-2,6,6-trimethyl-l-cyclohexen-l-yl)-3-methyl-3-trimethylsiloxy-l, 4-pentadiene 248043 7 A solution of l-(3-oxo-2,6,6-trimethyl-l-cyclohexen-l-yl)-3-methyl-trimethylsiloxy-1,4-pentadiene (918 mg, 3 mmoles) in 10 ml absolute tetrahydrofurane at -20°C is slowly added sodium hexamethyldisilazane (4.5 ml 1M in THF, 4.5 mmoles) forming a violet solution of sodium-enolate. The mixture is stirred 30 minutes at -20°C, the temperature is lowered to -78°C and a solution of diphenyl-sulfonyloxaziridine (1.17 g, 4.5 mmoles) in 10 ml absolute tetrahydrofurane is added.

After stirring for 30 minutes glacial acetic acid (257 jil, 4.5 mmoles) is added and the mixture is concentrated in vacuo and the remanecens is subjected to column chromatography using methylenechloride/ethylacetate (95/5) as eluent. The fractions containing the product is concentrated in vacuo yielding the title compound as a yellow oil. l-(4~hydroxy-3-oxo-2,6,6-trimethyl-l-cyclohexen-l-yl)-3-methyl-5-benzenesulfonyl-l,3-pentadiene A solution of l-(4-hydroxy-3-oxo-2,6,6-trimethyl-l-cyclohexen-l-yl )-3-methyl-3-trimethylsiloxy-l, 4-pentadiene (200 mg, 0.62 mmol) in 1 ml glacial acetic acid is added benzene-sulfinic acid, sodium salt (153 mg, 0.93 mmoles) and the mixture is stirred overnight at ambient temperature. The mixture is concentrated in vacuo and the remanecens is taken up in 10 ml diethylether and 10 ml 1M sodium hydroxide. The aqueous layer is separated and extracted twice with 10 ml diethyl-, ether. The combined ether phases are dried and concentrated in vacuo yielding the title compound as a slightly yellow oil. 8

Claims (4)

WHAT WE CLAIM IS:

1. A compound having the formula 24 8 04 3 o wherein R' is alkyl, alkoxy, N02, NH2 or halogen.

2. A method for the preparation of a compound having the formula wherein R' is alkyl, alkoxy, "N02, NH2 or halogen, which method comprises the step of reacting a compound having the formula wherein R1, R2 and R3 independently are C1.6-alkyl which may be branched or phenyl with a compound having the formula 0 II wherein R' is alkyl, alkoxy, N02, NH2 or halogen. 4 i 9 24 8 0 & T " - /

3. A compound according to claim 1 substantially as herein described or exemplified.

4. A method according to claim 2 substantially as herein described or exemplified. NEUROSEARCH A IS By Their Attorneys HENRY HUGHES LTD Per: