TITLE OF THE INVENTION
Novel process for the preparation of a-chlorovinyl, a,a -dichloro, and acetylenes from ketones FIELD OF THE INVENTION
An improved process to convert ketones to the corresponding a-chlorovinyl and a,a-dichloro compounds. More specifically, the present invention is directed at a process to convert ketones to corresponding acetylenes with corresponding a-chlorovinyl and a,a-dichloro compounds as intermediates.
BACKGROUND OF THE INVENTION
A class of compounds which have considerable synthetic utility are a-chlorovinyl and a,a-dichloro compounds. These compounds may then be converted to the corresponding acetylenes, furthering their synthetic utility. This includes their use in polymer chemistry as well in the preparation of pharmaceuticals. The overall process is depicted in figure 1.
Figure 1 o ci c ci R' R~,,,, R' + R R' i ketone, I a-chlorovinyl, 2 a,a-dichloro, 3 acetylene, 4 Examples of commercially useful acetylenes which are valuable for the preparation of active pharmaceuticals include 3,3-dimethyl-l-butyne, which has been used as a key raw material for terbinafine (5) (for instance, US Patent 5,817,875) and cyclopropylacetylene, which is a key raw material for Efavirenz (6) (for instance, US Patent 6,297,410). A box is placed around the acetylenic moiety in these pharmaceuticals as depicted in figure 2.
Figure 2 HCI
5, Terbinafine 6, Efavirenz The use of the highly toxic and corrosive chlorinating agent phosphorus pentachloride (PC15) for a transformation of this type is known. For instance, T.L. Jacobs provides a review in Organic Reactions, Vol. 5, Chapter 1. However, the PC15 reagent suffers from many disadvantages.
These include the cost of this reagent coupled with the fact that only two of the five chlorine atoms are used. An even greater disadvantage, especially on an industrial scale, is the fact that the granular PCl5 tends to sublime and agglomerate to a hard, solid mass upon storage, which makes it very difficult to load this reagent into a reactor. A further disadvantage of using PC15 reacts on exposure to moisture in the atmosphere to generate hydrogen chloride gas.
Specific examples of the preparation of 3,3-dimethyl-l-butyne (tert-butylacetylene) from pinacolone (R = tert-butyl, R' = hydrogen) using PC15 include work done by P.D. Bartlett and L.J. Rosen (J. Am. Chem. Soc., 64, p. 543, 1942) and P.J. Kocienski (J. Org.
Chem., 39, p.3285, 1974). Likewise, a description of the process used for the preparation of cyclopropylacetylene from cyclopropyl methyl ketone using PC15 is described in Synlett, 1999, pp.1948 to 1950 by Schmidt et al.
The isolation of 3,3-dimethyl-l-butyne by the process described by Bartlett and Rosen and Kocienski was accomplished using fractional distillation which would require specialized equipment for further scale-up. Thus, a more facile and industrially acceptable process to isolate the acetylenic compound from the reaction mixture would be advantageous.
A substitute to the PCl5 reagent is described in US Patent 3,715,407 whereby dichlorophosphoranes having the formula R3PC12 were used. This reagent was obtained by the reaction of phosgene with phosphine oxide having formula R3PO. However, this method suffers from the severe disadvantage that it employs phosgene, which is a highly poisonous gas being used as a chemical warfare agent. Very recently, the use of this type of reagent was described in US Patent 6,207,864 B 1 for the preparation of the key intermediate cyclopropylacetylene from cyclopropyl methyl ketone. Briefly cyclopropylacetylene is disclosed in PCT/WO
96/22955 as an intermediate for a pharmaceutical (Efavirenz), which acts as an inhibitor of the HIV reverse transcriptase enzyme. This is a key enzyme for the replication of the Human Immuno Deficiency virus that is the cause of Acquired Immune Deficiency (AIDS) syndrome. The method again uses dihalotriorganophosphoranes prepared from triorganophosphane oxides or triorganophosphane sulfides and a chlorinating agent of which the toxic phosgene is preferred.
Therefore, an industrially acceptable and general process, which overcomes the deficiencies of the prior art, was required for the conversion of ketones to the corresponding a-chlorovinyl and a,a-dichloro compounds and, optionally, their further conversion to their corresponding acetylenes.
To overcome the difficulties associated with prior art processes for these reactions, alternative chlorinating reagents were examined. No reaction was obtained when ketones having general formula 1(figure 3) were treated with phosphorus oxychloride (POC13) in the absence a base.
Addition of a base produced an unidentified phosphonate intermediate which did not undergo elimination. Surprisingly, the addition of a copper catalyst such as cuprous chloride to the phosphorus oxychloride and base mixture efficiently converted the ketone to a mixture of a-chlorovinyl (2) and a,a-dichloro (3) compounds as depicted in figure 3. These results were similar to the results obtained using phosphorus pentachloride.
Figure 3 0 POC13, Base Ci CI CI
Copper catalyst ketone, 1 a-chlorovinyl, 2 a,a-dichloro, 3 In figure 3, R is a cyclic or acyclic C, to C6 alkyl, aryl, or C7 to Clo aralkyl. R' is hydrogen, cyclic or acyclic C1 to C6 alkyl, aryl, or C7 to C10 aralkyl. Most preferably, R is a tert-butyl, phenyl, or cyclopropyl.
SUMMARY OF THE INVENTION
According to one aspect of the invention there is provided a process for the conversion of a ketone of general formula (1) R' R
(1) wherein R is a cyclic or acyclic C, to C6 alkyl, aryl, or C7 to Clo aralkyl and R' is hydrogen, cyclic or acyclic C1 to C6 alkyl, aryl, or C7 to Clo aralkyl, to a-vinylchloride of formula (2) and/or an a,a-dichloro of formula (3) CI CI CI
R)~ R, R~~ R1 (2) (3) wherein the process comprises using phosphorus oxychloride in the presence of a trialkylamine base and a catalyst.
According to another aspect of the invention there is provided a process for the conversion of a ketone (1) R' (1) wherein R is a cyclic or acyclic C1 to C6 alkyl, aryl, or C7 to Clo aralkyl and R' is hydrogen, cyclic or acyclic C1 to C6 alkyl, aryl, or C7 to C10 aralkyl, to an a-vinylchloride (2) and a,a -dichloro (3) CI CI CI
R' R~'C R' (2) (3) wherein the process comprises using phosphorus oxychloride in the presence of a trialkylamine base and a catalyst in an inert organic solvent.
Preferably, the trialkylamine base is selected from the group consisting of triethylamine, tripropylamine and tributylamine. Most preferably, the base is triethylamine.
Preferably, the trialkylamine base and ketone have an equivalent ratio ranging from 0.05:1 to 5:1. More preferably, the trialkylamine base and ketone have an equivalent ratio ranging from 0.1:1 to 1:1. Most preferably, the trialkylamine base and ketone have an equivalent ratio of 0.2:1.
Preferably, the catalyst is selected from the group consisting of cuprous acetate and cuprous chloride. More preferably, the catalyst is cuprous chloride.
Preferably, the inert organic solvent is selected from the group consisting of C5 to Clo cyclic and acyclic hydrocarbon. More preferably, the inert organic solvent is selected from the group consisting of hexane, heptane and cyclohexane. Most preferably, the inert organic solvent is hexane.
According to yet another aspect of the invention there is provided a process for the isolation of an acetylene of general formula (4) R' ~
(4) wherein R is a cyclic or acyclic C1 to C6 alkyl, aryl, or C7 to Clo aralkyl and R' is hydrogen, cyclic or acyclic C1 to C6 alkyl, aryl, or C7 to Clo aralkyl, comprising the steps of:
(i) treating an a-chlorovinyl (2) and/or an a,a-dichloro (3) Ci CI CI
R~ R' R~~ R' (2) (3) compound in an alkyl sulfoxide or sulfone solvent in the presence of a strong base; and (ii) extracting the resulting acetylene (4) by using an organic extraction solvent.
Preferably, the alkyl sulfoxide solvent for step (i) is dimethylsulfoxide.
Preferably, the strong base is potassium tert-butoxide.
Preferably, the organic extraction solvent is a organic solvent of C5 to Clo.
Preferably, the organic solvent of C5 to Cto is heptane.
Preferably, the a-vinylchloride is 2-chloro-3,3-dimethyl-l-butene. Preferably, the a,a-dichloro compound is 2,2-dichloro-3,3-dimethylbutane. Preferably, the acetylene is 3,3-dimethyl-l-butyne, 1-phenyl-l-propyne, or phenylacetylene.
According to yet another aspect of the invention there is provided a process for the preparation of an intermediate in the preparation of terbinafine comprising the steps of:
(i) preparing 3,3-dimethyl-2-chloro-l-butene and 3,3-dimethyl-2,2-dichlorobutane using the process as described previously;
(ii) dehydrohalogenation of the 3,3-dimethyl-2-chloro-l-butene and 3,3-dimethyl-2,2-dichlorobutane using a strong base in an alkyl sulfoxide or sulfone solvent;
and (iii) isolating the resulting 3,3-dimethyl-l-butyne by extraction in an organic extraction solvent wherein said solvent is a hydrocarbon being from 5 to 10 carbon atoms.
Preferably, the strong base is potassium tert-butoxide. Preferably, the alkylsulfoxide is dimethylsulfoxide.
Preferably, the phosphorus oxychloride is added stepwise. Preferably, the phosphorus oxychloride and the base are added stepwise.
In another aspect of this invention, the a-chlorovinyl and/or a,a-dichloro compounds are converted to their corresponding acetylenes.
DETAILED DESCRIPTION OF THE INVENTION
The use of the readily available and inexpensive reagent phosphorus oxychloride, instead of phosphorus pentachloride, offers numerous advantages on an industrial scale.
For instance, it is much less difficult to handle since it is a non-volatile liquid. Also, relative to phosphorus pentachloride, it uses two of the three available chlorine atoms present on the molecule and is less expensive. The use of these reagents for this type of transformation is unprecedented in chemical literature.
It has been discovered that the effective stoichiometries of phosphorus oxychloride are 0.5 equivalents to 1.5 equivalents, more preferably 0.7 to 0.9 equivalents, most preferably 0.8 equivalents.
The preferred catalysts are salts of copper (I) and copper (II) such as cuprous acetate or cuprous chloride, most preferably cuprous chloride. The preferred stoichiometry of base is 0.05 to 0.6 equivalents, more preferably 0.1 to 0.3 equivalents, most preferably 0.2 equivalents.
The reaction is typically conducted at 70 to 110 C, more preferably at 80 to 100 C, even more preferably at 90 to 95 C. The reaction can be conducted neat or in the presence of a non-reactive solvent such as a C5 to C10 cyclic or acyclic hydrocarbon, for instance hexane, heptane or cyclohexane. When conducted in the presence of an inert solvent, the most preferred solvent is a C5 to C10 hydrocarbon, for instance heptane.
For the reaction, the ketone, base, copper catalyst and, optionally the solvent, are mixed whereupon the phosphorus oxychloride reagent is added portionwise over time.
This is done since a strongly exothermic reaction may occur which could pose a safety hazard. For instance, in the preparation of 3,3-dimethyl-2-chloro-l-butene and 3,3-dimethyl-2,2-dichlorobutane from pinacolone using the phosphorus oxychloride, triethylamine and cuprous chloride combination, a delayed exothermic reaction was noted which could have possibly led to runaway reaction conditions on further scale-up. It was discovered that by using a portionwise mode of addition of the phosphorus oxychloride reagent, these conditions were avoided and the reaction was intrinsically safe. In another embodiment, the base together with the phosphorus oxychloride reagent are added in a portionwise manner.
In another aspect of this invention, the a-chlorovinyl and a,a-dichloro compounds are converted to the acetylenic compound by treatment with a strong base, preferably a metal alkoxide, most preferably tert-butoxide, in alkyl sulfoxide and sulfone solvents such as dimethyl sulfoxide and sulfolane, most preferably dimethylsulfoxide. This process is depicted in figure 4 below.
Figure 4 cl C CI 1.Strong base R' ~ R' R' R R alkyl sulfoxide or sulfone solvent acetylene, 4 a-chlorovinyl, 2 a,a-dichloro, 3 2. Extraction in solvent The advantage of this type of elimination process is that it allows the convenient isolation of the acetylenic compound in a cyclic or acyclic C5 to Clo hydrocarbon solvent, most preferably hexane or heptane. Thus, the reaction is quenched using water and the acetylenic compound is extracted into the C5 to Clo hydrocarbon solvent. The residual by-products and alkyl sulfoxide or sulfone solvent are readily removed from the C5 to Clo hydrocarbon solvent containing the acetylene compound by washing with water and / or brine. This process greatly simplifies some of the processes of the prior art, for instance the process described by P.J.
Kocienski (J. Org.
Chem., 39, p.3285, 1974) for the isolation of 3,3-dimethyl-l-butyne, which was accomplished using fractional distillation of the compound from the dimethylsulfoxide solvent.
The following examples exemplify various aspects of the invention.
Example 1 Preparation of 3,3-Dimethyl-l-butyne from pinacolone Part A: Preparation of 3,3-dimethyl-2-chloro-l-butene and 3,3-dimethyl-2,2-dichlorobutane A round bottom flask was charged with cuprous chloride (14.7 g, 0.100 mol), pinacolone (200.00 g, 1.997 mol), and (40.42 g triethylamine, 0.399 mol) and the mixture was stirred and heated under a nitrogen atmosphere to 75 C. The flask is then charged with a portion of the phosphorus oxychloride (60.7 g, 0.396 mol) and heated to 90 to 95 C and maintained at this temperature for about 2 hours whereupon the mixture was cooled to 70 to 75 C and another portion of phosphorus oxychloride (30.40 g, 0.198 mol) was added (note: in this case, non-portionwise addition of the phosphorus oxychloride led to a delayed exotherm, see Disclosure section). The reaction mixture was then re-heated to 90 to 95 C and maintained at this temperature for about 2 hours. Similarly, two additional portions of phosphorus oxychloride (2 X 60.70 g, 2 X 0.396 mol; total phosphorus oxychloride = 1.386 mol) were added at which point H NMR
indicated that the reaction was complete. The temperature was decreased to 55 C and heptanes (400 mL) was added followed by the slow addition of water (200 mL) while controlling the temperature between 50 to 60 C. This process took about 1 hour whereupon the mixture was cooled to 20 to 25 C and the layers were split. The organic layer was washed with water (200 mL) and brine (300 mL). The weight of the organic layer was 500 g and it was comprised of 130 g of 3,3-dimethyl-2-chloro-l-butene (55.0% yield from pinacolone) and 71 g of 3,3-dimethyl-2,2-dichlorobutane (23.0% yield from pinacolone). The overall yield was 78% from pinacolone.
Part B: Preparation of 3,3-dimethyl-l-butyne from 3,3-dimethyl-2-chloro-l-butene and 3,3-dimethyl-2,2-dichlorobutane A round bottom flask was charged with potassium tert-butoxide (157 g, 1.40 mol) and dimethylsulfoxide (235 mL) and the temperature increased to 42 C. The mixture was cooled with stirring and under nitrogen to about 20 C whereupon a 195 g portion of the solution from part "A" above was added dropwise while maintaining the temperature below 30 C. H NMR
analysis of this solution demonstrated that it contained about 50.7 g of 3,3-dimethyl-2-chloro-l-butene (0.427 moL) and 27.7 g of 3,3-dimethyl-2,2-dichlorobutane (0.179 moL).
After a period of time, a further portion of potassium tert-butoxide (17.5 g, 0.156 mol) was added and the reaction maintained at room temperature. Water was added while keeping the temperature below 30 C and the layers separated. The organic layer was sequentially washed with water (3 X 235 mL) and brine (1 x 235 mL). This provided a pale, light brown solution weighing 306 g of which 11% (w/w) was 3,3-dimethyl-l-butyne (33.7 g, 53% yield).
Example 2 Preparation of Phenylacetylene from acetophenone Part A: Preparation of a-chlorostyrene from acetophenone To a stirred mixture of cuprous chloride (0.60 g, 0.0061 mol), triethylamine (1.3 g, 0.013 mol), and phosphorus oxychloride (5.2 g, 0.034 mol) in heptanes (15 mL) at 25 C was added acetophenone (5.0 g, 0.042 mol). The resulting mixture was heated to 95-100 C
for 20 hours.
The reaction mixture was cooled to 45-50 C and then slowly quenched with water (ca. 25 mL).
The organic layer was washed with water (10 mL) and brine (10 mL), dried over (MgSO4), and evaporated to give 5.4 g of the a-chlorostyrene product (93% yield).
Part B. Preparation of phenylacetylene from a-chlorostyrene The vinyl chloride (5.4 g, 0.039 mol) in heptanes (20 mL) mixture produced above was added dropwise to a solution of potassium tert-butoxide (7.4 g, 0.066 mol) in dimethylsulfoxide (20 mL) at a rate such that the temperature was maintained below 30 C. The reaction mixture was stirred at 20-25 C for a further 3 hours and quenched by the slow addition of water (30 mL) while maintaining the temperature below 30 C. The organic layer was washed with water (2 X
mL) and brine (1 X 15 mL) and then evaporated to dryness to provide 2-g of phenyl acetylene (50% yield).
Example 3 Preparation of 1-Phenyl-l-propyne from propiophenone Part A: Preparation of 1-chloro-l-phenyl-l-propene from propiophenone To a stirred mixture of copper (I) chloride (0.60 g, 0.0061 mol), triethylamine (1.1 g, 0.011 mol) and phosphorus oxychloride (4.5 g, 0.030 mol) in heptanes (20 mL) was added propiophenone (5.0 g, 0.037 mol). The resulting mixture was then cooled to 45-50 C and slowly quenched with water (ca. 25 mL) while maintaining the internal temperature below 60 C. The organic layer was washed successively with water (20 mL) and brine (20 mL), dried over MgSO4, and evaporated to dryness to provide 1-chloro-l-phenyl-l-propene (4.8 g, 86%) as a yellow oil.
Part B. Preparation of 1-phenyl-l-propyne from 1-chloro-l-phenyl-l-propene The vinyl chloride compound from part `A' above (4.8 g, 0.030 mol) in heptanes (20 mL) was added dropwise to a solution of potassium tert-butoxide (5.8 g, 0.050 mol) in dimethylsulfoxide (20 mL) at a rate such that the temperature was maintained below 30 C. The reaction mixture was stirred at 20-25 C for a further 2 hours and then quenched by the slow addition of water (30 mL) while maintaining the temperature below 30 C. The organic layer was washed with water (2 X 15 mL) and brine (1 X 15 mL) and then dried over Na2SO4 and evaporated to dryness to provide 2.7 g of 1-phenyl-l-propyne (77% yield).
Example 4 Preparation of 2-chloro-2-cyclopropyl- I -propene from cycloprop lY methyl ketone A 500 mL round bottom flask was charged with cuprous chloride (1.8 g, 0.018 moL), heptanes (60 mL), tripropylamine (51 g, 0.356 moL), phosphorus oxychloride (14.4 g, 0.094 moL), and cyclopropyl methyl ketone and heated with stirring and under nitrogen to 95 C.
After heating for about 20 hours at this temperature another portion of cuprous chloride (3.2 g, 0.032 moL) was added and heating was continued. After a further 20 hours, the reaction mixture was cooled to 60 to 65 C and then slowly quenched with saturated aqueous sodium bicarbonate.
The organic layer was washed with brine (50 mL). This provided 57 g of an organic layer which contained, by H NMR analysis, about 1.9 g (16% yield from cyclopropyl methyl ketone) of 2-chloro-2-cyclopropyl-l-propene.
While the foregoing provides a detailed description of a preferred embodiment of the invention, it is to be understood that this description is illustrative only of the principles of the invention and not limitative. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.