Process for preparing cyclopropylacetylene

Details Process for preparing cyclopropylacetylene Process for preparing cyclopropylacetylene

1999-09-01

2001-03-27

Padmanabhan, Sreeni (Department: 1621)

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

Organic compounds

Oxygen containing

C568S343000, C568S364000, C585S359000, C585S534000, C585S538000

Reexamination Certificate

active

06207864

ABSTRACT:

This is the U.S. National Stage Application of PCT/EP98/00927 filed Feb. 18, 1998.
The present invention relates to an improved process for the halogenation of cyclopropylmethyl ketone using dihalo-triorganophosphoranes, to the halogenation products obtained in said process, and to a process for the preparation of cyclopropylacetylene by dehydrohalogenation of said halogenation products.
Cyclopropylacetylene is disclosed by PCT/WO 96/22955 as an intermediate for an inhibitor of the HIV reserve transkriptase. The Human Immuno Deficiency Virus is the cause of the Acquired Immune Deficiency Syndrome (AIDS). The viral HIV reserve transkriptase is a key enzyme for replication of the HI Deficiency Virus in the host organism.
Since the key enzyme is inhibited by inhibitors of which cyclopropylacetylene is an intermediate, cyclopropylacetylene is of great significance in the preparation of medicamants to combat AIDS.
PCT/WO 96/22955 discloses a process for the preparation of cyclopropylacetylene by cyclization of 5-halo-1-pentyne using strong bases such as butyllithium in an aprotic solvent followed by quenching of the resulting lithium salt with a proton source such as ammonium chloride.
J. Amer. Chem. Soc. 94, 1158 (1972) describes a process for the preparation of cyclopropylacetylene, in which cyclopropylmethyl ketone is chlorinated with phosphorus pentachloride and the 1,1-dichloro-1-cyclopropylethane isolated from the chlorination product is then dehydrochlorinated with sodium amide in liquid ammonia to form cyclopropylacetylene.
Synthesis 1972, 703 reveals that the chlorination of cyclopropylmethyl ketone with phosphorus pentachloride only takes place without appreciable opening of the cyclopropane ring if carried out using purified, acid-free phosphorus pentachloride.
In order to prevent opening of the cyclopropane ring during chlorination, the processes described in SU 555,079, SU 578,293, and SU 572,445 effect chlorination in the presence of an organic base such as pyridine or N,N-diethylaniline.
The aforementioned chlorinations of cyclopropylmethyl ketone with phosphorus pentachloride suffer from the drawback that the phosphorus pentachloride, which is extremely sensitive to hydrolysis, can only be handled in absolute absence of moisture and must be used in equimolar amounts. Furthermore, said chlorinations produce phosphorus oxychloride, which must be removed by hydrolysis, since it can be removed from the chlorination product by distillation either not at all or only with great difficulty.
U.S. Pat. No. 3,715,407 discloses a process for the chlorination of ketones using molar excesses, based on the ketone, of dichloro-triorganophosphorane prepared in situ from triorganophosphane oxide and phosgene. This process suffers from the drawback that the triorganophosphane oxide must be used in large excess over the ketone. Owing to the poor solubility of triorganophosphane oxide, large quantities of solvent are necessary to carry out the reaction, and continuous operation of the process involves considerable technical problems.
It is an object of the invention, therefore, to overcome the above drawbacks.
Accordingly, we have found a novel and improved process for the halogenation of cyclopropylmethyl ketone with at least one dihalo-triorganophosphorane of the general formula I
R
3
PHal
2
  (I),
in which the radicals R can be the same or different and denote a saturated or unsaturated aliphatic C
1
-C
20
hydrocarbon radical, a phenyl or (C
1
-C
4
alkyl)phenyl radical, which may be optionally substituted by one or two fluorine, chlorine and/or nitro groups, preferably in ortho and/or para position relative to the phosphorus atom, 4-chloro-, 4-fluoro-, or 4-nitro-substituted phenyl radicals being particularly preferred, P stands for phosphorus and Hal denotes chlorine, bromine, or iodine, at a temperature of from 80° to 130° C., where the dihalo-triorganophosphorane of the general formula (I) is synthesized in situ from triorganophosphane oxide or triorganophosphane sulfide of the general formula II
R
3
PA   (II),
in which R is as defined above with respect to formula I and A denotes oxygen or sulfur, using a halogenating agent, wherein the triorganophosphane oxide or triorganophosphane sulfide is used in catalytic amounts.
In the process of the invention dichloro-triorganophosphoranes of the general formula I are preferably synthesized in situ, particular preference being given to dichlorotriphenylphosphorane, a dichloro-tri(C
6
-C
8
alkyl)phosphorane, dichloro-tri(4-chlorophenyl)phosphorane, dichloro-tri(4-fluorophenyl)phosphorane, dichloro-tri(4-nitrophenyl)phosphorane, or mixtures thereof.
Suitable halogenating agents for use in the process of the invention are known per se and are described, for example, in Houben-weyl, Methoden der organischen Chemie, Vol. E2, 872 (1982). We prefer to use a chlorinating agent in the process of the invention, examples of which are chlorine, oxalyl chloride, thionyl chloride, phosgene, diphosgene or triphosgene, of which phosgene is preferred.
The halogenation of the cyclopropylmethyl ketone is preferably carried out at a temperature of from 90° to 120° C., more preferably from 90° to 100° C., and under a pressure of from 0.8 to 1.5 bar, preferably under standard pressure, the halogenating agent being used in a molar ratio of from 0.5:1 to 2:1 and preferably from 0.5:1 to 1.0:1 and the triorganophosphane oxide or triorganophosphane sulfide is used in equimolar amounts, preferably catalytic amounts ranging from 0.5 to 5 mol % and more preferably from 1.0 to 2.5 mol %, based, in each case, on the cyclopropylmethyl ketone.
A particularly recommendable routine for carrying out the halogenation is to place the halogenating agent in the reactor and then add a solution of triorganophosphane oxide or triorganophosphane sulfide in cyclopropylmethyl ketone. Alternatively, only a portion of the total amount of halogenating agent is initially placed in the reactor, the remainder thereof being added after the solution of triorganophosphane oxide or triorganophosphane sulfide in cyclopropylmethyl ketone has been added. This routine is particularly recommended when phosgene is used as halogenating agent.
Another possibility is to place from 5 to 25 wt %, preferably from 15 to 25 wt %, of the total amount of triorganophosphane oxide or triorganophosphane sulfide in cyclopropylmethyl ketone in the reactor, to add the chlorinating agent, and then to add the remainder of the solution. It is of course possible, if desired, to place all of the solution of triorganophosphane oxide or triorganophosphane sulfide in cyclopropylmethyl ketone in the reactor as initial batch.
The process of the invention may be carried out batchwise or continuously, preference being given to continuous operation for economical reasons.
Triorganophosphane oxides can be prepared, for example, by the method described in Houben-Weyl, Methoden der organischen Chemie, Vol. E2 (1982), page 2.
A mixture of tri(C
6
-C
8
alkyl)phosphane oxides is marketed, for example, by Cytec Industries Inc., N.J., USA under the Trade Name Cyanex
á
923.
Triorganophosphane sulfides can be prepared, for example, by the process described in Houben-weyl, Methoden der organischen Chemie, Vol. E2 (1982), page 79.
The process of the invention for the halogenation of cyclopropylmethyl ketone is preferably carried out in the absence of solvent. However, the process of the invention may, if desired, be carried out in an inert solvent having a boiling point preferably above 110° C. and in which the dihalo-triorganophosphorane is soluble.
Suitable solvents are, for example, halogenated aromatic hydrocarbons such as chlorobenzene, 1-methylnaphthalene, xylene, or mesitylene, of which xylene and mesitylene are preferred.
By-products formed in the process of the invention for the halogenation of cyclopropylmethyl ketone are triorganophosphane oxides or triorganophosphane sulfides of formula II, from which the halogenation product can be separated by distillation.
The process of the invention for haloge

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