Organic compounds -- part of the class 532-570 series – Organic compounds – Halogen containing
Reexamination Certificate
2001-04-05
2003-03-04
Siegel, Alan (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Halogen containing
C585S312000, C585S317000, C585S359000
Reexamination Certificate
active
06528693
ABSTRACT:
DESCRIPTION
This invention concerns a process for preparing cyclopropylethyne as well as a process for preparing intermediates for making cyclopropylethyne.
Cyclopropylethyne is used, for example, as an intermediate in the synthesis of the important HIV reverse transcriptase inhibitor of the following structure:
There are two main syntheses for cyclopropylethyne already disclosed in the literature. These are:
1. Chlorination of cyclopropyl methyl ketone with phosphorus pentachloride to give 1,1-dichloro-1-cyclopropylethane followed by dehydrochlorination with a strong base
2. Reaction of 5-chloro-1-pentyne with 2 equivalents of butyl lithium to effect cyclisation.
Whilst these methods work well on a laboratory scale, manufacture on a production scale is difficult. The intermediate, 1,1-dichloro-1-cyclopropylethane produced in the first literature route is a very labile molecule and is thermally and hydrolytically unstable. For example, whilst chlorination of cyclopropyl methyl ketone with phosphorus pentachloride proceeds quite well even on a large scale, the isolation of the 1,1-dichloro-1-cyclopropylethane from the reaction mixture (which necessarily contains phosphorus oxychloride) can lead to extensive decomposition of the product. The phosphorus oxychloride may be removed by decomposition with water. Such a process is very exothermic and unless the reaction mixture is kept cool the product is decomposed by both aqueous acids and alkalis. The cooling requirements on a plant scale would be enormous. This leads to a very high capital investment in plant. If the feed time is extended to overcome the deficiencies in the cooling systems, decomposition also occurs and leads to very low yields of the target compound.
It is also possible to remove the phosphorus oxychloride by fractional distillation. However, in a conventional pot still, extensive decomposition due to ring opening can occur resulting in low yields.
Once the required 1,1-dichloro-1-cyclopropylethane has been obtained in a pure form, dehydrochlorination to give the required compound can also lead to problems. As stated above, the compound is both thermally unstable and also unstable to alkalis. Thus to effect dehyrochlorination, a hindered base in a dipolar aprotic solvent is required so that elimination rather than substitution is the major synthetic pathway. Because of the stoichiometry of the process at least two equivalents of expensive base are required. This seriously increases the cost of manufacture.
The method of manufacture where 5-chloro-1-pentyne is ring closed by means of at least 2 equivalents of n-butyl lithium also works quite well in the laboratory. However, the cost of n-butyl lithium makes manufacture by this route an expensive option. Furthermore, specialised plant is required to handle the pyrophoric concentrated solutions that an efficient synthesis dictates.
WO98/40333A (BASF Aktiengesellschaft) discloses a process for halogenating cyclopropylmethyl ketone with at least one dihalogen triorganophosphorane as well as a process for converting the halogenated cyclopropyl methyl ketone into cyclopropylacetylene.
A first object of this invention is to provide a process for preparing an intermediate for preparation of cyclopropylethyne, which is both thermally and hydrolytically stable and does not involve use of expensive pyrophoric reagents.
A second object of this invention is to provide an improved process for preparing cyclopropylethyne.
It has been surprisingly found that a suitable intermediate for use in preparing cyclopropylethyne is 1-chloro-1-cyclopropylethene.
According to a first aspect of this invention there is provided a process for preparing 1-chloro-1-cyclopropylethene comprising treating 1-cyclopropylethanone with dichlorotriaryl phosphorane or dichlorotriakyl phosphorane in the presence of a base in an inert solvent characterised in that the base is a tertiary amine.
According to a second aspect of this invention there is provided a process for preparing cyclopropylethyne comprising the steps of preparing 1-chloro-1-cyclopropylethene by chlorinating 1-cyclopropylethanone with dichlorotriarylphosphorane or dichlorotriakylphosphorane in the presence of a base in an inert solvent and dehydrochlorinating the 1-chloro-1-cyclopropylethene with a strong base in an inert solvent, characterised in that the base in the chlorination stage is a tertiary amine.
The 1-chloro-1-cyclopropylethene used in the process of the second aspect of the invention may be that prepared by the process of the first aspect of the invention.
A benefit of using 1-chloro-1-cyclopropylethene is that, in principle, only one equivalent of strong base is required to bring about the dehydrochlorination. Furthermore, this base does not need to be an expensive alkali metal salt of a hindered tertiary alcohol. Simple hydroxides of alkali metals will suffice to bring about the transformation. The literature indicates that this intermediate may be prepared in reasonable yield by the mono-dehydrochlorination of 1,1-dichloro-1-cyclopropylethane; an intermediate which has already been stated to be difficult to manufacture on a large scale. A better synthesis of 1-chloro-1-cyclopropylethene was therefore sought.
It is known that acetyl ketones will react with dichlorotriphenylphosphorane to afford the corresponding gem dichlorides. (U.S. Pat. No. 3,715,407). The reaction in the case of cyclopropyl methyl ketone has the complication that the cyclopropane ring is ruptured during the course of the reaction with the formation of compounds which were identified as dichloropentenes. It was considered that these by-products were formed by adventitious hydrogen chloride in the reaction mixture and that the inclusion of an organic base would prevent this side reaction occuring. When this experiment was carried out, the amount of ring opened dichloropentenes was greatly reduced from an experiment which did not contain base. We were surprised to find that only minor amounts of 1,1-dichloro-1-cyclopropylethane were formed but that 1-chloro-1-cyclopropylethene was formed in good yield. Furthermore, the amount of ring opened dichloropentenes were greatly reduced from an experiment which did not contain base. A convenient synthesis of the desired intermediate was thus opened to us.
wherein R is an aryl group or an alkyl group.
The dichlorothiarysphohranes or the dichlorotrialkylphosphoranes may be prepared by reaction of the appropriate triarylphosphine or triarylphosphine oxide or trialkylphosphine or trialkylphosphine oxide with a chlorinating agent such as chlorine or phosgene. The chlorination stage may be carried out catalytically in situ particularly if phosgene is used. 1-100 mol % of trisubstituted phosphine or its oxide may be used. Less than 25 mol % of triarylphosphine or its oxide or trialkylphosphine or its oxide may be sufficient to bring about the transformation with 1-10 mol %, more preferably about 6 mol %, being close to the optimum in terms of yield and reaction velocity.
The organic base that is required for good reaction can be any base which does not react with phosgene or dichlorotriarylphosphorane or dichlorotrialkylphosphorane. In practice this means that tertiary amines are probably most suitable as the organic base. Pyridine and quinoline are particularly suitable since they appear to be inert to the phosgenation reaction conditions. Other tertiary amines such as triethylamine which may be used are less suitable since they can preferentially react with phosgene under the reaction conditions to give carcinogenic carbamoyl chlorides such as diethyl carbamoyl chloride. The production of even minor amounts of such carcinogens precludes the use of such tertiary amines in large scale manufacture.
As already described the thermal and hydrolytic stability of 1-chloro-1-cyclopropylethene is much greater than 1,1-dichloro-1-cyclopropylethane. This means that the work-up of the product is much simpler. The product may be distilled directly from the reaction mixture or quenched on to aqueous alkali and then phase separat
Cremins Peter John
Gandy Robert
Timms Allan Williams
Drinker Biddle & Reath LLP
Great Lakes (UK) Limited
Siegel Alan
LandOfFree
Preparation of cyclopropylethyne and intermediates for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation of cyclopropylethyne and intermediates for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of cyclopropylethyne and intermediates for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3077289