Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1998-02-04
2003-07-01
Morris, Patricia L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S310000, C544S318000
Reexamination Certificate
active
06586594
ABSTRACT:
This invention relates to a process for the preparation of alcohols by the addition of organometallic reagents to ketones. More particularly, this invention relates to the reaction of 1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone derivatives with organometallic compounds derived from alpha-haloalkylpyrimidines to form tertiary alcohols.
The reaction of organometallic compounds derived from alkyl halides with aldehydes and ketones to form secondary and tertiary alcohols, respectively, is well established in the field of organic chemistry. Many different metals and metal derivatives have been reported as being useful in this type of reaction, including lithium, magnesium, aluminium, tin and zinc, together with salts thereof. For example, A. R. Gangloff et al, J. Org. Chem., 57, 4797-4799 (1992) discloses that 2-(bromomethyl)-4-carbethoxy-1,3-oxazole reacts with zinc dust to form an organozinc derivative which undergoes nucleophilic addition to aldehydes and ketones. Also, Chollet et al, Synth. Comm., 19 (11 and 12), 2167-2173 (1989) reports the reaction of organozinc derivatives of bromoesters with aldehydes and ketones.
Certain compounds prepared according to the present process are disclosed in European Patent Application Publication numbers 0357241 and 0440372.
It has now been surprisingly found that certain 1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone derivatives may be reacted with organometallic compounds derived from certain alpha-haloalkylpyrimidine derivatives to form tertiary alcohols in good to excellent yields and with high stereoselectivity using reaction conditions that are particularly suitable for the bulk synthesis of the product.
This finding has been found to be particularly useful for the synthesis of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-1,2,4-triazol-1-yl)butan-2-ol, a key intermediate for the preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound having antifungal activity. The syntheses of both of these compounds have been described in European Patent Application Publication number 0440372. In this Application, (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is prepared by the chromatographic separation of the two pairs of enantiomers obtained from the addition of an organolithium derivative of 4-chloro-6-ethyl-5-fluoropyrimidine to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone at from −70 to −50° C. The best stereoselectivity that has been obtained in this addition is a 1.1:1 molar ratio in favour of the 2R,3S/2S,3R enantiomeric pair with the total isolated yield of all four stereoisomers being only about 50%, the low yield being thought to be due to a competing enolisation reaction. These factors, coupled with the need to operate the addition reaction at very low temperatures and under very dilute conditions, together with the difficulty in separating approximately equimolar amounts of the two pairs of enantiomers at the end of the reaction with the 2R,3R/2S,3S enantiomeric pair being unwanted, mean that the process is extremely unsuitable for the economic preparation of the required 2R,3S/2S,3R intermediate on a large scale.
In contrast, for example, it has now been found that a 9:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol and a 65% isolated total yield of all the enantiomers (as the hydrochloride salts) can be obtained under the reaction conditions according to the present invention that are highly suitable for large scale synthesis of the product.
However, higher isolated yields have been obtained and higher molar ratios (both in situ and in respect of isolated product) have been determined by varying the reaction conditions in accordance with the present invention.
Similar results have been obtained with a range of alpha-haloalkyl-pyrimidine substrates.
Considerable economic advantages result from the yields and stereospecificity achieved.
The present invention provides a process for the preparation of a compound of the formula:
or an acid addition or base salt thereof, wherein
R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and trifluoromethyl;
R
1
is C
1
-C
6
alkyl; and
“Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo, oxo, benzyl and benzyloxy,
comprising reaction of a compound of the formula:
wherein R is as previously defined for a compound of the formula (I), with a compound of the formula:
wherein R
1
and “Het” are as previously defined for a compound of the formula (I) and X is chloro, bromo or iodo, in the presence of zinc, iodine and/or a Lewis acid and an aprotic organic solvent: said process being optionally followed by formation of an acid addition or base salt of the product.
Optionally, lead can also be present in the reaction, either as the metal per se or in the form of a suitable salt, e.g. a lead (II) halide. It can be added separately or be inherently present in the zinc used.
In the above definitions, alkyl and alkoxy groups containing three or more carbon atoms may be straight- or branched-chain and “halo” means fluoro, chloro, bromo or iodo.
Preferably, R is phenyl optionally substituted by 1 to 3 halo substituents.
More preferably, R is phenyl substituted by 1 or 2 substituents each independently selected from fluoro and chloro.
Yet more preferably, R is phenyl substituted by 1 or 2 fluoro substituents.
Most preferably, R is 2,4-difluorophenyl.
Preferably, R
1
is C
1
-C
4
alkyl.
More preferably, R
1
is methyl or ethyl.
Most preferably, R
1
is methyl.
Preferably, “Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from halo, oxo and benzyl.
More preferably, “Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from fluoro, chloro, oxo and benzyl.
Yet more preferably, “Het” is pyrimidinyl substituted by 1 to 3 substituents each independently selected from fluoro and chloro.
Preferred examples of “Het” include pyrimidin-4-yl, 4-chloro-5-fluoropyrimidin-6-yl, 5-fluoropyrimidin-4-yl, 2-chloro-5-fluoropyrimidin-6-yl, 2,4-dichloro-5-fluoropyrimidin-6-yl, 4-chloropyrimidin-6-yl and 1-benzyl-5-fluoropyrimidin-6-on-4-yl.
Most preferably, “Het” is 4-chloro-5-fluoropyrimidin-6-yl.
Preferably, X is bromo or iodo.
Most preferably, X is bromo.
The compound of the formula (II) may be an enolisable ketone. Most preferably, the compound of formula (II) is 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone.
Preferably the compound of the formula (III) is selected from 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine, 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine, 6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine, 4-(1-bromoethyl)pyrimidine, 4-(1-bromoethyl)-6-chloropyrimidine, 4-(1-bromoethyl)-5-fluoropyrimidine and 1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one.
Most preferably, the compound of the formula (III) is 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine.
The reaction is carried out in the presence of a suitable aprotic organic solvent such as tetrahydrofuran, toluene, 1,2-dimethoxyethane or methylene chloride, or a mixture of two or more thereof. It is highly desirable to dry the solvent before use to remove substantially all traces of water. Drying can be achieved using a desiccant such as magnesium sulphate, sodium sulphate or molecular sieves, by distillation from a metal such as lithium, sodium or potassium or by azeotropic distillation.
The preferred solvent for the reaction is tetrahydrofuran.
It is also preferable to carry out the reaction under a dry, inert atmosphere such as by using dry nitrogen or argon gas.
The zinc used in the reaction may be zinc powder derived from a commercial source or it may be freshly generated in situ by the reduction of a zinc halide (e.g. zinc chloride) using lithiu
Butters Michael
Harrison Julie Ann
Pettman Alan John
Djuardi, Ph.D Elsa
Morris Patricia L.
Pfizer Inc.
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