Olefination process to itaconate and succinate derivatives

Details Olefination process to itaconate and succinate derivatives Olefination process to itaconate and succinate derivatives

2002-07-18

2004-06-15

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S105000, C560S121000, C560S123000, C560S124000, C560S127000, C560S190000

Reexamination Certificate

active

06750363

ABSTRACT:

The invention described herein relates to a novel olefination process which is useful for making certain itaconate and succinate derivatives.
It is desirable in a number of instances to be able to have an efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (I), and/or succinate derivatives of formula (II) and/or (III):
wherein “R*” is a sterically bulky group.
Of particular interest to us is the provision of compounds of the formula (IV), (V) and (VI), especially (IV) and (V):
wherein R is aryl, C
3-8
cycloalkyl, C
1-10
alkyl, (aryl)C
1-10
alkylene, (C
3-8
cycloalkyl)C
1-10
alkylene, heterocyclyl, (heterocyclyl)C
1-10
alkylene, (aryl)C
3-8
cycloalkylene, (C
3-8
cycloalkyl)arylene or (C
1-10
alkylaryl)C
1-10
alkylene,
wherein “aryl” is a mono- or bicyclic partially or fully unsaturated carbocyclic ring system containing from 4 to 10 atoms, such as phenyl or naphthyl, or a partially or fully unsaturated mono- or bicyclic heterocyclic moiety having up to 10 atoms in the ring system and with up to 4 hetero-atoms in the said ring system each independently selected from N, O and S, said carbocyclic ring system and heterocyclic moiety being optionally substituted by one or more substituents each independently selected from halogen, NO
2
, NH
2
, CO
2
R
9
, phenyl, C
1-6
alkyl(optionally substituted by one or more halogen), and C
1-6
alkoxy(optionally substituted by one or more halogen), and “heterocyclyl” is a 3- to 8-membered mono or bicyclic saturated heterocyclic group having from 1 to 4 ring hetero-atoms each independently selected from N, O and S, optionally substituted by one or more substituents each independently selected from halogen, NO
2
, NH
2
, CO
2
R
9
, phenyl, C
1-6
alkyl(optionally substituted by one or more halogen), and C
1-6
alkoxy(optionally substituted by one or more halogen);
R
1
is C
1-6
alkoxy,
R
2
is OH or O
−
M
+
;
R
9
is H or C
1-6
alkyl; and M
+
is the cation of a metal such as sodium, lithium or potassium, or is a protonated amine moiety such as (mono-, di- or tri-C
1-10
alkyl)ammonium, (mono-, di- or tri-C
3-10
cycloalkyl)ammonium, (C
1-10
alkyl)
n1
(C
3-10
cycloalkyl)
n2
ammonium, anilinium, benzylammonium, triethanolammonium, or (S)-&agr;-methylbenzylammonium, where n1 and n2 are each independently selected from 1 or 2 with the proviso that the sum of n1 and n2 is not greater than 3;
Alkyl groups, and groups containing alkyl moieties such as alkoxy and alkylene groups, can be straight chain or branched if the number of carbon atoms allows,
Halogen means fluorine, chlorine or bromine,
Cycloalkyl groups attached to an ammonium moiety can contain 1, 2, or 3 rings, where the number of carbon atoms allows, for example adamantanammonium.
Production of compounds related to (IV), (V) and (VI) has been disclosed previously, e.g. by Owton et al, in Synthetic Communications, 23(15), 2119-2125 (1993), M J Burk et al, Angew. Chem. Int. Edn. (Eng.) (1998) 37, 13/14, 1931-1933, Monsanto, U.S. Pat. No. 4,939,288, and by Chirotech Technology Ltd. in International Patent Application publication no. WO 99/31041. Known olefination reactions leading to systems related to (IV), generally result in poor E/Z selectivity, (for a review of the Stobbe condensation, see Org. React. 1951, 6, 1-73). Where selectivity has been controlled, however, for example by the use of phosphorus reagents, the substitution pattern is different from that required by us in formula (IV)(e.g. Monsanto, Owten, supra).
The products of the Owten chemistry are exemplified by compounds of the formula (VII):
on which we attempted hydrolysis of the ethyl ester using conventional chemistry. In our hands this resulted in scrambling of the olefinic moiety resulting overall in a mixture of stereoisomers and regioisomers.
Use of the Monsanto chemistry gives products of the formula (VIII):
which has the wrong substitution pattern for our requirements.
We have discovered a new and efficient olefination method which can be used to make compounds of formula (IV) in good yield and with good trans-selectivity, and which products can then be asymmetrically reduced to give compounds of formula (V) and (VI). The olefination is base-catalysed and can be used with enolisable aldehydes or aldehyde derivatives without significant amounts of self-condensation products. We also surprisingly observe no substantial double bond migration to give deconjugated isomers of (IV) under the basic conditions, which would afford other geometric and regio-isomers, which is another significant problem with similar prior art olefinations.
Our olefination system is thus particularly useful when highly selective production of the compounds (IV), (V) and/or (VI) is required, or where separation of (IV), (V) and/or (VI) and/or the respective isomers thereof, may be difficult or undesirable, such as in processing to make pharmaceutical products and regulatory starting materials for such products.
Thus, according to the present invention, there is provided a process for the preparation of compounds of formula (IV) as defined above, comprising reaction of an aldehyde of formula RCHO, or a protected derivative thereof such as a hemiacetal or adduct thereof such as a bisulphite, wherein R is as defined above, with a phosphorus compound of formula (IX):
or a metal carboxylate salt thereof such as a sodium, lithium or potassium carboxylate salt thereof,
wherein R
1
is as defined above, and
“P” is a phosphonate moiety of formula —P(O)(OR
3
)(OR
4
), wherein R
3
and R
4
are either each independently selected from H, C
1-6
alkyl, benzyl and phenyl (optionally substituted by one or more C
1-6
alkyl), or R
3
and R
4
taken together are C
2-5
alkylene,
or “P” is a phosphorane moiety of formula —(PR
5
R
6
R
7
)
+
X
−
wherein R
5
, R
6
and R
7
are each independently selected from C
1-6
alkyl and phenyl, and X is bromine, chlorine or iodine, in the presence of a sodium, lithium or potassium C
1
-C
6
alkoxide base, in an inert solvent, and at a temperature of from −80° C. to 20° C.
Preferably the reaction time is less than 24 hours.
Preferably R is (aryl)C
1-10
alkylene or (C
3-8
cycloalkyl)C
1-10
alkylene.
More preferably R is phenylethyl, cyclohexylethyl or (2-methyl-1,1′-biphenyl-4-yl)ethyl.
Preferably R
1
is t-butoxy.
Preferably R
2
is OH, O
−
Li
+
, O
−
Na
+
, O
−
K
+
, O
−
cyclohexylammonium
+
, O
−
adamantanammonium
+
, O
−
triethanolammonium
+
or O
−
(S)-&agr;-methylbenzylammonium
+
.
Preferably the olefination reaction is carried out using the aldehyde RCHO or the sodium bisulphite adduct thereof RCH(OH)SO
3
−
Na
+
.
Preferably “P” is P(O)(OC
2
H
5
)
2
, P(O)(OCH
2
CH
2
O) or a triphenylphosphinium halide moiety.
More preferably P is P(O)(OC
2
H
5
)
2
.
Preferably the base is potassium t-butoxide, sodium t-butoxide or sodium methoxide.
When the base alkoxide and R
1
are different there is a possibility of transesterification taking place during the olefination reaction. We have found that this apparently has no detrimental effect on the course of the reaction at the olefination centre, in terms of stereochemistry, and may not be important with respect to the use made of the product, e.g. if it is used as an intermediate and the R
1
moiety is later removed, e.g. by displacement, hydrolysis or deprotection.
Preferably the olefination reaction solvent is anhydrous tetrahydrofuran, anhydrous toluene or R
1
H, where R
1
takes the meaning as specified above with respect to the compounds of formulae (IV), (V) and (VI), or a mixture thereof.
More preferably the reaction solvent is selected from tetrahydrofuran and toluene when the aldehyde RCHO is used as a substrate, and selected from tetrahydrofuran/t-butanol and toluene when the bisulphite adduct is used as substrate.
Preferably the reaction is carried out at a temperature from −20° C. to 10° C.
More preferably the reaction is carried out at a temperature from −10° C. to 10° C

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