(6R,10R)-6,10,14-trimetylpentadecan-2-one prepared from 6,10-dimetylundec-5-en-2-one or 6,10-dimetylundeca-5,9-dien-2-one

Patent metadata

Field	Value
Publication number	US-9452961-B2
Application number	US-201314652303-A
Country	US
Kind code	B2
Filing date	Dec 18, 2013
Priority date	Dec 18, 2012
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The present invention relates to a process of manufacturing (6R,10R)-6,10,14-trimetylpentadecan-2-one in a multistep synthesis from 6,10-dimetylundec-5-en-2-one or 6,10-dimetylundeca-5,9-dien-2-one. The process is very advantageous in that it forms in an efficient way the desired chiral product from a mixture of stereoisomers of the starting product.

First claim

The invention claimed is:

1. A process of manufacturing (6R,10R)-6,10,14-trimethylpentadecan-2-one in a multistep synthesis from 6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-one comprising the sequential steps of:
a) providing a mixture of (E)-6,10-dimethylundec-5-en-2-one and (Z)-6,10-dimethylundec-5-en-2-one or a mixture of (E)-6,10-dimethylundeca-5,9-dien-2-one and (Z)-6,10-dimethylundeca-5,9-dien-2-one;
b) separating one isomer of 6,10-dimethylundec-5-en-2-one or of 6,10-dimethylundeca-5,9-dien-2-one from the mixture of step a);
c) conducting asymmetric hydrogenation using molecular hydrogen in the presence of a chiral iridium complex and yielding (R)-6,10-dimethylundecan-2-one;
d) chemically transforming (R)-6,10-dimethylundecan-2-one to a mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and (R,Z)-6,10,14-trimethylpentadec-5-en-2-one;
e) separating one isomer of (R)-6,10,14-trimethylpentadec-5-en-2-one from the mixture obtained in step d); and
f) conducting asymmetric hydrogenation using molecular hydrogen in the presence of a chiral iridium complex and yielding (6R,10R)-6,10,14-trimethylpentadecan-2-one, wherein
step d) is practiced by:
d1) ethynylation of (R)-6,10-dimethylundecan-2-one using ethyne in the presence of a basic substance to yield (7R)-3,7,11-trimethyldodec-1-yn-3-ol; and
d2) hydrogenation of (7R)-3,7,11-trimethyldodec-1-yn-3-ol with molecular hydrogen in the presence of a Lindlar catalyst to yield (7R)-3,7,11-trimethyldodec-1-en-3-ol;

or step d) is practiced by:
d1′) vinylation of (R)-6,10-dimethylundecan-2-one by addition of a vinyl Grignard reagent to yield (7R)-3,7,11-trimethyldodec-1-en-3-ol;

followed by either
d3) reacting (7R)-3,7,11-trimethyldodec-1-en-3-ol with 2-methoxyprop-1-ene to yield a mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and (R,Z)-6,10,14-trimethylpentadec-5-en-2-one;
or

d3′) reacting (7R)-3,7,11-trimethyldodec-1-en-3-ol with an alkyl acetoacetate or diketene in the presence of a base and/or an acid to yield a mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and (R,Z)-6,10,14-trimethylpentadec-5-en-2-one.

2. The process according to claim 1 , which further comprises a step c o ) before step c):
c o ) forming of a ketal of the isomer of 6,10-dimethylundec-5-en-2-one or of 6,10-dimethylundeca-5,9-dien-2-one separated in step b), and wherein
the ketal of 6,10-dimethylundec-5-en-2-one or of 6,10-dimethylundeca-5,9-dien-2-one in step c) is asymmetrically hydrogenated and after the asymmetric hydrogenation the hydrogenated ketal is hydrolysed to the ketone thereby yielding (R)-6,10-dimethylundecan-2-one.

3. The process according to claim 1 , wherein the process further comprises a step f o ) before the step f) of:
f o ) forming a ketal of the isomer of (R)-6,10,14-trimethylpentadec-5-en-2-one separated in step e), and wherein
step f) comprises asymmetrically hydrogenating the ketal of (R)-6,10,14-trimethylpentadec-5-en-2-one and then subsequently after the asymmetric hydrogenation, hydrolysing the hydrogenated ketal to the ketone to thereby yield (6R,10R)-6,10,14-trimethylpentadecan-2-one.

4. The process according to claim 1 , wherein the asymmetric hydrogenation in step c) and/or step f) takes place in the presence of an additive which is selected from the group consisting of organic sulfonic acids, transition metal salts of organic sulfonic acids, metal alkoxides, aluminoxanes, alkyl aluminoxanes and B(R) (3-v) (OZ) v , wherein v stands for 0, 1, 2 or 3, R stands for F, a C 1-6 -alkyl, a halogenated C 1-6 -alkyl, an aryl or halogenated aryl group, and Z stands a C 1-6 -alkyl, a halogenated C 1-6 -alkyl, an aryl or halogenated aryl group.

5. The process according to claim 1 , wherein the separation of isomers in step b) and/or e) is done by distillation.

6. The process according to claim 5 , wherein the distillation is done in the presence of a cis/trans isomerization catalyst.

7. The process according to claim 1 , which further comprises isomerizing residual isomer in the presence of a cis/trans isomerization catalyst, and respectively adding the isomerized residual isomer to the corresponding mixture of isomers provided by steps a) and d).

8. The process according to claim 1 , wherein the chiral iridium complex in steps c) and/or f) is a chiral iridium complex of formula (III-0)

wherein
P-Q-N stands for a chelating organic ligand comprising a stereogenic centre or has planar or axial chirality and has a nitrogen and phosphorous atom as binding site to the iridium centre of the complex;
Y 1 , Y 2 , Y 3 and Y 4 independently from each other are hydrogen atoms, C 1-12 -alkyl, C 5-10 -cycloalkyl, or aromatic group; or at least two of Y 1 , Y 2 , Y 3 and Y 4 form together at least a two-valent bridged group of at least 2 carbon atoms; with the proviso that Y 1 , Y 2 , Y 3 and Y 4 are not all hydrogen atoms; and
Y ⊖ is an anion selected from the group consisting of halide, PF 6 − , SbF 6 − , tetra(3,5-bis(trifluoromethyl)phenyl)borate (BAr F − ), BF 4 − , perfluorinated sulfonates, ClO 4 − , Al(OC 6 F 5 ) 4 − , Al(OC(CF 3 ) 3 ) 4 − , N(SO 2 CF 3 ) 2 − N(SO 2 C 4 F 9 ) 2 − and B(C 6 F 5 ) 4 − .

9. The process according to claim 1 , wherein the chiral iridium complex in steps c) and/or f) is a chiral iridium complex of formula (III)

wherein
n is 1, 2 or 3;
X 1 and X 2 are independently from each other hydrogen atoms, C 1-4 -alkyl, C 5-7 -cycloalkyl, adamantyl, phenyl optionally substituted with one to three C 1-5 -alkyl, C 1-4 -alkoxy, C 1-4 -perfluoroalkyl groups and/or one to five halogen atoms, benzyl, 1-naphthyl, 2-naphthyl, 2-furyl or ferrocenyl;
Z 1 and Z 2 are independently from each other hydrogen atoms, C 1-5 -alkyl or C 1-5 -alkoxy groups or Z 1 and Z 2 stand together for a bridging group forming a 5 to 6 membered ring;
Y ⊖ is an anion selected from the group consisting of halide, PF 6 − , SbF 6 − , tetra(3,5-bis(trifluoromethyl)phenyl)borate(BAr F − ), BF 4 − , perfluorinated sulfonates, ClO 4 − , Al(OC 6 F 6 ) 4 − , Al(OC(CF 3 ) 3 ) 4 − , N(SO 2 CF 3 ) 2 − N(SO 2 C 4 F 9 ) 2 − and B(C 6 F 6 ) 4 − ;
R 1 represents either phenyl or o-tolyl or m-tolyl or p-tolyl or a group of formula (IVa) or (IVb) or (IVc):

wherein R 2 and R 3 represent either both H or a C 1-4 -alkyl group or a halogenated C 1-4 -alkyl group or represent a divalent group forming together a 6-membered cycloaliphatic or an aromatic ring which optionally is substituted by halogen atoms or by C 1-4 -alkyl groups or by C 1∝ -alkoxy groups;
R 4 and R 5 represent either both H or a C 1-4 -alkyl group or a halogenated C 1-4 -alkyl group or a divalent group forming together a 6-membered cycloaliphatic or an aromatic ring which optionally is substituted by halogen atoms or by C 1-4 -alkyl groups or by C 1-4 -alkoxy groups;
R 6 and R 7 and R 8 represent each a C 1-4 -alkyl group or a halogenated C 1-4 -alkyl group;
R 9 and R 19 represent either both H or a C 1-4 -alkyl group or a halogenated C 1-4 -alkyl group or a divalent group forming together a 6-membered cycloaliphatic or an aromatic ring which optionally is substituted by halogen atoms or by C 1-4 -alkyl groups or by C 1-4 -alkoxy groups; and
wherein

the symbol * represents a stereogenic centre of the comple

Assignees

• Dsm Ip Assets Bv

Inventors

• Bonrath Werner
• Netscher Thomas
• Medlock Jonathan Alan
• Stemmler René Tobias
• Tschumi Johannes
• Verzijl Gerardus Karel Maria
• De Vries Andreas Hendrikus Maria

Classifications

• C07C45/71

  being hydroxy groups · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07F9/5045

  Complexes or chelates of phosphines with metallic compounds or metals · CPC title

• C07C45/62

  by hydrogenation of carbon-to-carbon double or triple bonds · CPC title

• C07F15/0033

  Iridium compounds · CPC title