Processes for preparing alkynyl ketones and precursors thereof

The present invention provides processes for making alkynyl ketones and precursors thereof, using less expensive reagents and/or hydrocarbon solvents and/or higher temperatures.

CROSS-REFERENCE TO RELATED APPLICATIONS 
This application is related to commonly owned copending Provisional 
Application Ser. No. 60/006,967, filed Nov. 20, 1995, and claims the 
benefit of its earlier filing date under 35 U.S.C. 119(e). 
FIELD OF THE INVENTION 
This invention relates to processes for making metallated alkynyl compounds 
and for making alkynyl ketones using the same. 
BACKGROUND OF THE INVENTION 
Alkali metal and alkaline earth metal acetylenes are useful precursors in 
the synthesis of organic compounds. These compounds typically are highly 
reactive with ketones, labile chlorides, and the like. For example, 
1-propynyl lithium (CH.sub.3 --C.ident.C--Li) is a useful precursor of 
2-phenethyl 1-propynylketone (PPK), an acetylenic ketone, which is 
employed in the synthesis of a protease inhibitor. 
Various techniques can be used to prepare propynyl lithium and other 
lithiated acetylenes. For example, the propynyl anion can be prepared by 
the reaction of propyne (CH.sub.3 --C.ident.CH) with an organolithium 
compound in a mixed hydrocarbon/ethereal solvent. See L. Brandsma, 
"Preparative Acetylenic Chemistry" (Elsevier 2d ed. 1988), page 24. U.S. 
Pat. No. 3,410,918 describes passing a gaseous mixture of propyne and 
allene through a slurry of lithium metal and sodium metal to produce 
propynyl lithium. 
These techniques can require expensive reagents, such as propyne, or 
reagents which are difficult to handle, particularly on a commercial 
scale, such as lithium metal, which is a pyrophoric solid. This can also 
limit the commercial viability of these and other prior processes. 
These processes also typically require an ethereal solvent, such as 
tetrahydrofuran (THF), to solubilize the resultant lithiated acetylene 
product. However, ethereal solvents such as THF can be expensive, 
particularly as the reaction is scaled up to commercial production levels. 
In addition, ethers such as THF are highly reactive with alkyl lithium 
starting reagents. Accordingly, these reactions typically require very low 
temperatures (-20.degree. C. and lower). However, many reactor systems in 
production facilities do not have the capability to cool to these 
temperatures, and installation of reactor systems capable of cooling to 
these low temperatures require increased capital investments. This can 
adversely impact commercial scale production of organic products from both 
an engineering and economic standpoint. 
Propynyl ketones can be prepared using a propynyl lithium precursor by a 
cationic exchange reaction with zinc chloride, followed by coupling of the 
propynyl anion with a derivative of a carboxylic acid in a 
hydrocarbon/ethereal solvent to yield the desired product. Typically, the 
reaction is conducted at a temperature ranging from about -20.degree. C. 
to about 0.degree. C. After addition is complete, the reaction is warmed 
to room temperature (about 20.degree. C.) for 30 minutes or more. See 
Brandsma, supra, page 105; L. Brandsma et al., J. Organometallic Chem. 
388: 289-294 (1988). 
Propynyl ketones, such as PPK, produced under these conditions can contain 
impurities. As a result, the product may require downstream purification, 
such as vacuum distillation at high temperatures. However, propynyl 
ketones such as PPK can rapidly decompose when heated above about 
150.degree. C. in an exothermic reaction. 
SUMMARY OF THE INVENTION 
A first aspect of the present invention is a process for making metallated 
acetylenes, in which a mixture of at least one acetylenic compound and at 
least one saturated or unsaturated hydrocarbon (which is different from 
the acetylenic compound) is contacted with an organometallating agent 
capable of deprotonating and metallating the acetylenic compound, such as 
an organolithium. An exemplary mixture is MAPP gas, a gaseous byproduct of 
butadiene production which includes propyne, allene, propene and saturated 
hydrocarbons, such as propane and butane. Another exemplary mixture 
includes propyne and a saturated hydrocarbon, such as propane. 
In contrast with prior processes, the process in accordance with this 
aspect of the invention uses a relatively inexpensive reagent (the 
acetylenic compound mixture) as a starting reagent. Further, the process 
eliminates the use of reagents which are difficult to handle, particularly 
on a commercial scale, such as lithium metal. Accordingly, the process can 
improve the commercial viability of preparing metallated acetylenic 
compounds on a large scale. 
From the literature, it would be expected that an organolithium would 
deprotonate other unsaturated hydrocarbons present in the mixture, not 
just propyne. See L. Brandsma, "Preparative Acetylenic Chemistry" 
(Elsevier 2d ed. 1988), page 233, which states that butyllithium can 
metallate allenes. Surprisingly, however, the inventors have not observed 
allenyl and/or propenyl derived products. 
A second aspect of the present invention is a process for making metallated 
acetylenes, in which a relatively pure acetylenic compound or a mixture 
thereof with at least one saturated or unsaturated hydrocarbon (such as 
MAPP gas) is reacted with an organometallating agent capable of 
deprotonating and metallating the acetylenic compound, such as an 
organolithium, in a hydrocarbon solvent. As noted above, prior processes 
typically require an ethereal solvent to solubilize the metallated 
compound. However, ethers such as THF are highly reactive with 
organolithium starting reagents, and processes using ethereal solvents 
require very low reaction temperatures (-20.degree. C. and lower). 
In contrast, in this aspect of the invention, ethereal solvents, and 
accordingly low reaction temperatures, are eliminated. This can improve 
economies of synthesis, both with regard to the cost of materials and 
specialized equipment required to conduct synthesis at extremely low 
temperatures. 
A third aspect of the invention is a process for preparing acetylenic 
ketones in which a metallated acetylene is reacted with transition metal 
halide or other suitable transition metal derivative (optionally) and with 
a derivative of carboxylic acid to form a reaction product. The inventors 
have found that the reaction product includes unreacted reagents, such as 
unreacted carboxylic acid derivatives, in addition to the acetylenic 
ketone. The inventors have also found that the unreacted reagents can 
participate in undesirable side reactions and thus adversely impact purity 
of the recovered ketone. For example, unreacted carboxylic acid 
derivatives can cleave ethereal solvents in the presence of catalytic 
amounts of zinc halide, particularly at work-up temperatures currently 
recommended in the literature. 
In this aspect of the invention, the reaction product is treated under 
conditions sufficient to minimize or eliminate formation of impurities by 
unreacted starting reagents during work-up of the reaction product and 
recovery of the acetylenic ketone. Suitable neutralizing agents are added 
to the reaction product to neutralize unreacted reagents at temperatures 
below which the unreacted reagents can form impurities. This can provide a 
three to four fold reduction of impurities in the recovered acetylenic 
ketone. Because the recovered product is purer, additional downstream 
purification steps can be minimized or eliminated. This is advantageous 
because downstream purification, such as distillation, can increase 
production costs and time and adversely affect product quality. 
DETAILED DESCRIPTION OF THE INVENTION 
The term "metallated acetylenes" as used herein refers to compounds of the 
formula R--C.ident.C--M, in which R is hydrogen, alkyl, cycloalkyl, aryl, 
alkylaryl, arylalkyl, silyl or heteroaromatic, and M is an alkali or 
alkaline earth metal, such as, but not limited to, lithium, sodium, and 
magnesium. As used herein, the term "alkyl" refers to C1 to C10 linear or 
branched alkyl, such as, but not limited to, methyl, ethyl, propyl, butyl, 
isopropyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, and the like. The 
term "aryl" as used herein refers to C6 to C10 cyclic aromatic groups such 
as phenyl, naphthyl, and the like and includes substituted aryl groups 
such as tolyl. The term "cycloalkyl" as used herein refers to C3 to C8 
cyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 
and the like. The term "silyl" as used herein refers to C1 to C10 
organosilicon groups, such as trimethylsilyl and the like. The term 
"heteroaromatic" as used herein refers to C4 to C10 heteroaromatic groups, 
such as pyridinyl, furanyl thiophenyl, and the like. 
In one aspect of the invention, metallated acetylenes are prepared by the 
reaction of an organometallating agent capable of deprotonating and 
metallating the acetylenic compound with a mixture comprising at least one 
acetylenic compound and at least one other hydrocarbon which is different 
from the acetylenic compound. Exemplary organometallating agents include 
without limitation organoalkali metal compounds, organoalkaline earth 
metal compounds, organomagnesium halides, and the like. Organoalkali metal 
compounds, such as organolithium and organosodium, generally can be 
described by the formula R.sup.1 --M, in which R.sup.1 is alkyl, 
cycloalkyl, aryl, alkylaryl, or arylalkyl, each of which is defined above 
with regard to R, and M is alkali metal, such as lithium or sodium. 
Organoalkaline earth metal compounds, such as dialkylmagnesium, generally 
can be described by the formula M(R.sup.1).sub.2, in which each R.sup.1 is 
as defined above and M is alkaline earth metal, such as magnesium. 
Organomagnesium halide can generally be described as a Grignard reagent 
R.sup.1 MgX, in which R.sup.1 is as defined above and X is halide. 
The acetylenic compound may be any compound which includes a reactive 
acetylenic linkage --C.ident.CH, and generally can be described by the 
formula R--C.ident.CH, wherein R is as defined above. 
The acetylenic compound is provided as a component of a mixture with at 
least one other hydrocarbon which is different from the acetylenic 
compound. The other hydrocarbon can be a saturated or unsaturated, 
branched or linear hydrocarbon. 
An exemplary mixture includes allene (H.sub.2 C:C:CH.sub.2) and/or propene. 
Saturated linear or branched C1 to C4 hydrocarbons can also be present in 
the mixture, including, for example, propane and butane. Advantageously, 
the mixture is a gaseous mixture comprising propyne and allene known as 
MAPP gas. MAPP gas is widely available commercially as a by-product of the 
manufacture of butadiene, and is generally used as a welding fuel gas. 
The composition of the mixture can vary, so long as the mixture includes 
acetylenic compound in an amount sufficient to produce lithiated 
acetylenic compound. Suitable MAPP gases comprise about 2% to about 40% 
propyne and about 1% to about 40% allene. The MAPP gas can also include 
about 1% to about 20% propene. Commercially available MAPP gas also 
typically includes about 20% to about 60% saturated C1 to C4 hydrocarbons, 
principally propane and butane, as diluents. Surprisingly, no allenyl or 
propenyl derived products are observed when using MAPP gas. 
Another exemplary mixture comprises propyne and at least one saturated 
hydrocarbon, for example about 15% or less propane. 
The mixture of acetylenic compound and at least one saturated and/or 
unsaturated hydrocarbon is contacted with the organometallating agent in a 
mixed ethereal/hydrocarbon solvent at a temperature of less than or about 
-20.degree. C. The mixture can be added to the organometallating agent 
(such as a solution of alkyllithium), the organometallating agent added to 
the mixture, or the reagents added to a reaction vessel substantially 
simultaneously. The reaction product, which includes metallated acetylenic 
compound, can be allowed to reach room temperature after the reaction is 
complete, and the metallated acetylenic compound can be recovered using 
conventional techniques. 
Suitable hydrocarbon solvents include, but are not limited to, alkanes, 
cycloalkanes and aromatic solvents, such as alkanes and cycloalkanes 
containing five to ten carbon atoms, such as pentane, hexane, cyclohexane, 
methylcyclohexane, heptane, methylcycloheptane, octane, decane and the 
like, and aromatic solvents containing six to ten carbon atoms such as 
toluene, ethylbenzene, p-xylene, m-xylene, o-xylene, n-propylbenzene, 
isopropylbenzene, n-butylbenzene, t-butylbenzene, and the like, and 
mixtures thereof. Suitable ethereal solvents include, but are not limited 
to, diethyl ether, dibutyl ether, tetrahydrofuran (THF), 
2-methyltetrahydrofuran, methyl tert-butyl ether, and the like, and 
mixtures thereof. 
The amount of ether present in the solvent can vary depending, for example, 
on the solubility of the reagents and/or the resultant metallated 
acetylenic compound, the temperature of the reaction, and the like. 
Exemplary solvents include mixed ethereal/hydrocarbon solvents of 
tetrahydrofuran and hexane, methyl tert-butyl ether and hexane, and the 
like. 
An exemplary reaction in accordance with this aspect of the invention is 
illustrated below: 
##STR1## 
Metallated acetylenic compounds of the formula R--C.ident.C--M described 
above, in which R and M are as defined above, can also be prepared in the 
absence of an ethereal solvent and/or at increased temperatures relative 
to conventional processes. In this aspect of the invention, a suitable 
source of an acetylenic compound is reacted with an organometallating 
agent as described above, such as an alkyllithium. Suitable acetylenic 
compound sources include relatively pure acetylenic compounds of the 
formula R--C.ident.CH, as defined above, such as propyne gas. The 
acetylenic compound can also be provided as a mixture of the acetylenic 
compound with at least one other hydrocarbon as described above, for 
example, MAPP gas and propyne/propane mixtures. 
The acetylenic compound can be added to the organometallating agent (such 
as a hydrocarbon solution of an alkyllithium), the organometallating agent 
can be added to the acetylenic compound, or the reagents added to a 
reaction vessel substantially simultaneously. The hydrocarbon solvent can 
be any of the hydrocarbon solvents described above. In addition, the 
reaction can be conducted at a temperature of at least about 0.degree. C. 
or higher. 
An exemplary reaction in accordance with this aspect of the invention is 
illustrated below: 
##STR2## 
Metallated acetylenic compounds produced in accordance with the present 
invention can be further reacted with suitable reagents, such as 
derivatives of carboxylic acid and salts thereof, to form acetylenic 
ketones of the formula RC.ident.CC(.dbd.O)R.sup.2. A metallated acetylene 
(prepared as described above or by other processes) is optionally reacted 
with transition metal halide or other suitable transition metal derivative 
in the presence of an ethereal cosolvent. The acetylenic organometallic 
compound is then reacted with a derivative of carboxylic acid of the 
formula R.sup.2 COX or a salt thereof. The reaction takes place at a 
temperature less than or about -20.degree. C. for a period sufficient to 
produce acetylenic ketone. See L. Brandsma, Preparative Acetylenic 
Chemistry (Elsevier 2d ed. 1988), page 105; L. Brandsma, et al., J. 
Organometallic Chem. 388, 289-294 (1988). 
Exemplary transition metal halides include, but are not limited to, zinc 
chloride, zinc bromide, manganese chloride, cadmium chloride, and the 
like. Other transition metal derivatives can also be used. 
R.sup.2 is selected from the group consisting of alkyl, aryl, alkylaryl, 
arylalkyl, or cycloalkyl (each as defined above) and X is halogen, C1 to 
C10 alkoxy, anhydride, or NR.sup.3 R.sup.4, wherein each R.sup.3 and 
R.sup.4 is independently selected from alkyl, aryl, alkylaryl, arylalkyl, 
cycloalkyl (each as defined above), C1 to C10 alkoxy, or R.sup.3 and 
R.sup.4 together represent a heterocyclic group (such as imidazole, 
triazole, oxazolidiene, and the like). The transition metal halide, or 
other suitable transition metal derivative, is an optional reagent, and 
the metallated acetylene can be reacted directed with a derivative of 
carboxylic acid or a salt thereof. 
Exemplary acid derivatives include, but are not limited to, hydrocinnamoyl 
chloride, acetyl chloride, benzoyl chloride, Weinreb amide of 
hydrocinnamic acid (in which X is N(OCH.sub.3)CH.sub.3), and the like, 
although other acid derivatives or their salts can be used. 
Exemplary acetylenic ketones include, without limitation, 2-phenethyl 
1-propynylketone (PPK), phenyl propynyl ketone, cyclohexyl 1-butynyl 
ketone, isopropyl 1-butynyl ketone, cyclohexyl 2-trimethylsilylethynyl 
ketone, and the like. 
After the reaction is substantially complete, the reaction product, which 
includes acetylenic ketone and unreacted starting reagents such as acid 
derivative, is treated to neutralize and thus reduce or minimize unreacted 
starting reagents. During the neutralization step, the reaction product is 
maintained at reduced temperatures of less than about 0.degree. C., 
preferably between about -20.degree. C. and about 0.degree. C., to 
minimize the reactivity of unreacted starting reagents and thus improve 
the purity of the recovered ketone. The reaction product can be warmed up 
to about 0.degree. C. for not more than 1 hour during the neutralizing 
step. 
The types and quantities of unreacted starting reagents present in the 
reaction product can be determined using conventional techniques, and 
suitable neutralizing agents can be added to the reaction product as 
needed in amounts sufficient to substantially neutralize unreacted 
reagents. For example, exemplary neutralizing agents for neutralizing acid 
derivative include, without limitation, alkali and alkaline earth metal 
hydroxides (such as sodium hydroxide NaOH, potassium hydroxide KOH, 
calcium hydroxide Ca(OH).sub.2 and the like), ammonium hydroxide, alkali 
and alkaline earth metal carbonates or bicarbonates (such as potassium 
carbonate K.sub.2 CO.sub.3, sodium bicarbonate NaHCO.sub.3, and the like), 
water, or other suitable agents known in the art for quenching acid. Other 
neutralizing agents may be added to the reaction product as well, 
depending upon the unreacted starting agents present. 
Neutralizing unreacted reagents at low temperatures prior to work-up and 
recovery of the acetylenic ketone can improve the purity of the recovered 
product to at least about 80% purity, and more preferably at least about 
90% purity, and higher. In contrast, following conventional techniques, 
the recovered product has a purity of only about 80% (as illustrated in 
comparative example 2 below), and the product requires downstream 
purification steps. Further, the process of the invention can provide 
improved purity with improved yield (at least about 75% yield and higher). 
An exemplary reaction in accordance with this aspect of the invention is 
illustrated below: 
##STR3## 
The following examples further illustrate the invention.

EXAMPLE 1 
To a 250 ml 3-neck flask under argon is added 50 grams 24% w/w 
n-Butyllithium (n-BuLi) (0.19 mol). The flask is then cooled to below 
-20.degree. C. followed by addition of 75 ml THF. To this solution cooled 
to below -20.degree. C. is added MAPP gas (about 50 grams or until all 
n-BuLi is consumed). In another 500 ml 3-neck flask under argon 86 ml of 
THF is added. At 0.degree. C. 25.5 grams ZnCl.sub.2 (0.19 mol) is added. 
The propynyllithium slurry is then added to the flask containing 
ZnCl.sub.2 and stirred for 30 minutes. This solution is then cooled to 
-20.degree. C. and 26.3 grams hydrocinnamoyl chloride (0.16 mol) is added 
and solution is stirred for 1 hour at 0.degree. C. After workup and 
concentration at reduced pressure 2-phenethyl 1-propynylketone is obtained 
in 78% yield and 93% purity. 
Comparative Example 2 
To 250 ml 3-neck flask under argon is added 50 grams 24% w/w n-BuLi (0.19 
mol). Flask is then cooled to below -20.degree. C. followed by addition of 
75 ml THF. To this solution cooled to below -20.degree. C. is added MAPP 
gas (about 50 grams or until all n-BuLi is consumed). In another 500 ml 
3-neck flask under argon is added 86 ml of THF. At 0.degree. C., 25.5 
grams ZnCl.sub.2 (0.19 mol) is added. The propynyllithium slurry is then 
added to the flask containing ZnCl.sub.2 and stirred for 30 minutes. To 
this solution at 0.degree. C. is added 26.3 grams hydrocinnamoyl chloride 
(0.16 mol) followed by warming to 20.degree. C. or higher. After workup 
and concentration at reduced pressure 2-phenethyl 1-propynylketone is 
obtained in 70% yield and 80% purity. 
EXAMPLE 3 
To 250 ml 3-neck flask under argon is added 50 grams 24% w/w n-BuLi (0.19 
mol). Flask is then cooled to below -20.degree. C. followed by addition of 
75 ml THF. To this solution cooled to below -20.degree. C. is added 
propyne until all n-BuLi is consumed. In another 500 ml 3-neck flask under 
argon is added 86 ml of THF. At 0.degree. C. 25.5 grams ZnCl.sub.2 (0.19 
mol) is added. The propynyllithium slurry is then added to the flask 
containing ZnCl.sub.2 and stirred for 30 minutes. This solution is then 
cooled to -20.degree. C. and 26.3 grams hydrocinnamoyl chloride (0.16 mol) 
is added and solution is stirred for 1 hour at 0.degree. C. After workup 
and concentration at reduced pressure 2-phenethyl 1-propynylketone is 
obtained in 78% yield and 93% purity. 
EXAMPLE 4 
To 500 ml 3-neck flask under argon is added 50 grams 24% w/w n-BuLi (0.19 
mol). To this solution was added 150 ml hexane and cooled to 0.degree. C. 
followed by addition of MAPP gas (about 50 grams or until all n-BuLi is 
consumed). At 0.degree. C. 75 ml THF followed by 25.5 grams ZnCl.sub.2 
(0.19 mol) is added and stirred for 30 minutes. This solution is then 
cooled to -20.degree. C. and 26.3 grams hydrocinnamoyl chloride (0.16 mol) 
is added and solution is stirred for 1 hour at 0.degree. C. After workup 
and concentration at reduced pressure 2-phenethyl 1-propynylketone is 
obtained in 78% yield and 90% purity. 
EXAMPLE 5 
To 250 ml 3-neck flask under argon is added 50 grams 24% w/w n-BuLi (0.19 
mol). Flask is then cooled to below -20.degree. C. followed by addition of 
130 ml THF. To this solution cooled to below -20.degree. C. is added 
propyne until all n-BuLi is consumed. At 0.degree. C., 25.5 grams 
ZnCl.sub.2 (0.19 mol) is added and stirred for 30 minutes. This solution 
is then cooled to -20.degree. C. and 26.3 grams hydrocinnamoyl chloride 
(0.16 mol) is added and solution is stirred for 1 hour at 0.degree. C. 
After workup and concentration at reduced pressure 2-phenethyl 
1-propynylketone is obtained in 78% yield and 93% purity. 
EXAMPLE 6 
To 250 ml 3-neck flask under argon is added 50 grams 24% w/w n-BuLi (0.19 
mol). Flask is then cooled to below -20.degree. C. followed by addition of 
75 ml THF. To this solution cooled to below -20.degree. C. is added 
propyne until all n-BuLi is consumed. In another 500 ml 3-neck flask under 
argon is added 70 ml of THF followed by 39.5 grams hydrocinnamoyl chloride 
(0.285 mol). At 0.degree. C. the propynyllithium slurry is then added to 
the flask containing hydrocinnamoyl chloride and is stirred for 1 hour at 
10.degree. C. After workup and concentration at reduced pressure 
2-phenethyl 1-propynylketone is obtained in 78% yield and 80% purity. 
The foregoing examples are illustrative of the present invention and are 
not to be construed as limiting thereof. The invention is defined by the 
following claims, with equivalents of the claims to be included therein.