Desulfurization of penicillins to prepare azetidinones

A process for the Raney nickel desulfurization of penicillins is described. In the process of the invention, amino penicillanic acid or derivatives thereof are reacted with Raney nickel under controlled conditions of temperature and time to yield azetidinones which are useful as intermediates for the synthesis of monocyclic beta-lactam antibiotics.

SUMMARY OF THE INVENTION 
It has long been known that the reaction of penicillins of formula Ia with 
Raney nickel afford dethiopenicillins of formula IIa, according to the 
following reaction: 
##STR1## 
wherein R is as hereinafter described 
Examples of this reaction are described in E. Kaczka and K. Folkers, "The 
Chemistry of Penicillin", Princeton University Press, Princeton, N.J., 
1949, p. 243; E. Van Heyningen and L. K. Ahern, J. Med. Chem., 11, 933 
(1968); E. Duranti and P. Bonifazi, Synthesis, 494 (1977); S. Wolfe and S. 
K. Hasan, Chem. Commun., 833 (1970); and T. Kamiya, "Recent Advances in 
the Chemistry of .beta.-Lactam Antibiotics", The Chemical Society, p. 281 
(1977). 
In contrast to previous literature reports, it has now been found that the 
desulfurization of penicillins of formula I with Raney nickel, when 
carried out under the controlled conditions of the invention, affords 
principally azetidinones of formula III and compounds of formula II as 
byproducts, according to the following reaction scheme: 
##STR2## 
Thus, the present invention is directed to a process for the preparation of 
compounds of formula III 
##STR3## 
wherein R and R.sup.1 taken together are phthaloyl, or R.sup.1 is hydrogen 
and R is hydrogen or a group of the formula 
##STR4## 
wherein R.sup.2 is (a) hydrogen, lower alkyl, halomethyl or phenyl; 
(b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy or 
4-methoxybenzyloxy; 
(c) a group of the formula 
EQU R.sup.3 --(O).sub.m --CH.sub.2 -- 
wherein m is 0 or 1; and R.sup.3 is 1,4-cyclohexadienyl, phenyl or phenyl 
substituted with 1 or 2 substituents independently selected from the group 
consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, C.sub.1 
-C.sub.7 alkyl and C.sub.1 -C.sub.7 alkoxy; 
(d) a group of the formula 
##STR5## 
wherein R.sup.3 is as defined above; and W is hydroxy, protected hydroxy, 
carboxy, protected carboxy, amino, or a group of the formula 
##STR6## 
(e) a group of the formula 
EQU R.sup.4 CH.sub.2 -- 
wherein R.sup.4 is a heterocyclic group selected from 2-furyl, 
5-tetrazolyl, 1-tetrazolyl, 4-isoxazolyl, or pyridyl, 
which comprises reacting a compound of the formula I 
##STR7## 
with Raney nickel, when R and R.sup.1 are hydrogen, at a temperature in 
the range of about 60.degree. C. to about 100.degree. C. and a reaction 
time in the range of from about 15 to about 60 minutes, or when R and/or 
R.sup.1 are other than hydrogen, at a temperature in the range of from 
about 100.degree. C. to about 200.degree. C. and a reaction time in the 
range of from about 10 to about 40 minutes, and, in each instance, if 
desired, separating the resulting compound of formula III by 
recrystallization or the like. Alternatively, the reaction product of 
formula III may be utilized in situ. 
In the process of the invention, an acid addition salt of the compound of 
formula I, when R and R.sup.1 are hydrogen, can also be utilized. 
DETAILED DESCRIPTION OF THE INVENTION 
As used throughout the specification and the appended claims, the term 
"lower alkyl" denotes a straight-chain or branched-chain alkyl group which 
contains from 1 to 7 carbon atoms. Exemplary of lower alkyl groups are 
methyl, ethyl, propyl, isopropyl, butyl, tertiarybutyl, pentyl, hexyl, 
heptyl and the like. 
The term "C.sub.1 -C.sub.7 alkoxy" denotes a lower alkyl radical attached 
to the remainder of the molecule by oxygen. Exemplary of C.sub.1 -C.sub.7 
alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 
pentoxy, hexoxy, heptoxy and the like. "Halomethyl" refers to 
chloromethyl, bromomethyl or iodomethyl or di or tri halomethyl radicals. 
Representative of substituted phenyl groups are 4-hydroxyphenyl, 
3-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-chlorophenyl, 3,6-dichlorophenyl, 
3,4-dichlorophenyl, 3-bromophenyl, 3-chloro-4-hydroxyphenyl, 
3-chloro-4-methylphenyl, 4-tert-butylphenyl, 3,4-dimethylphenyl, 
4-ethylphenyl, 3-nitrophenyl, 4-trifluoromethylphenyl, 
3-methoxy-4-chlorophenyl, 4-iodophenyl, 2-chloro-3-cyanophenyl, 
4-cyanophenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl, 
2-propyl-4-methoxyphenyl, and the like. 
The term "protected amino" as employed in the above definition has 
reference to an amino group substituted with one of the commonly-employed 
amino blocking groups such as tert-butoxycarbonyl, benzyloxycarbonyl, 
4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 
2,2,2-trichloroethoxycarbonyl or 1-carbomethoxy-2-propenyl formed with 
methyl acetoacetate. Amino protecting groups such as those described by J. 
W. Barton in "Protective Groups in Organic Chemistry", J. F. W. McOmie, 
Ed., Plenum Press, New York, N.Y. (1973), Chapter 2 shall be recognized as 
suitable. 
The terms "protected hydroxy" and "protected carboxy" have reference to 
readily-cleavable groups such as formyloxy, chloroacetoxy, benzyloxy, 
benzhydryloxy, trityloxy, 4-nitrobenzyloxy, trimethylsilyloxy, 
phenacyloxy, tert-butoxy, methoxymethoxy, tetrahydropyranyloxy and the 
like. Other hydroxy protecting groups including those described by C. B. 
Reese in "Protective Groups in Organic Chemistry", supra, Chapter 3 shall 
be considered as within the term "protected hydroxy" as used herein. 
Representative of the group 
##STR8## 
wherein R.sup.3 is as above, and W is hydroxy or protected hydroxy, are 
2-(4-methoxyphenyl)-2-benzyloxyacetyl, 2-phenyl-2-benzhydryloxyacetyl, 
2-(4-chlorophenyl)-2-formyloxyacetyl, 
2-(2-chloro-4-hydroxyphenyl)-2-hydroxyacetyl, and the like. Representative 
of such groups when W is amino or protected amino are 
2-phenyl-2-(4-methoxybenzyloxycarbonylamino)acetyl, 
2-(1,4-cyclohexadien-1-yl)-2-benzhydryloxycarbonylaminoacetyl, 
2-(4-hydroxyphenyl)-2-(tert-butoxycarbonylamino)acetyl, 
2-(3-nitrophenyl)-2-(2,2,2-trichloroehoxycarbonylamino) acetyl, 
2-phenyl-2-aminoacetyl and 2-(2-bromo-4-methoxyphenyl)-2-aminoacetyl. When 
W is carboxy or protected carboxy, exemplary acyl groups are 
2-(1,4-cyclohexadienyl)-2-carboxyacetyl, 2-phenyl-2-carboxy-acetyl, 
2-(4-cyanophenyl)-2-(tert-butoxycarbonyl) acetyl, 
2-(4-trifluoromethylphenyl)-2-(4-nitrobenzyloxycarbonyl)acetyl, 
2-phenyl-2-(2,2,2-trichloroethoxycarbonyl)acetyl, 
2-(4-ethylphenyl)-2-(tert-butoxycarbonyl)acetyl, and the like. 
In the formulas presented herein, the various substituents are illustrated 
as joined to the penicillanic acid nucleus by one of the following 
notations: a solid line ( ) indicates a substituent which is in the beta 
orientation, that is, above the plane of the molecule, and a dotted line ( 
- - - ) or (.tbd.) indicates a substituent which is in the alpha 
orientation, that is, below the plane of the molecule. 
The compounds prepared by the process of the present invention, that is, 
the compounds of formula III are useful as intermediates in the synthesis 
of monocyclic beta-lactam antibiotics. Exemplary of such monocyclic 
beta-lactam antibiotics is nocardicin characterized by the formula 
##STR9## 
The compounds of formula III are also useful as intermediates in the 
preparation of the antibiotic sulfazecin characterized by the formula 
##STR10## 
Norcardicin and sulfazecin of formulas IV and V may be prepared from a 
compound of formula III via a 2-azetidinone intermediate of the formula 
##STR11## 
wherein R.sup.2 is as above. 
The 2-azetidinone intermediate of formula VI may be prepared according to 
procedures disclosed in Example 5. 
The starting materials, that is, compounds of the formula 
##STR12## 
wherein R and R.sup.1 are as described above, are penicillins and are well 
known in the art and may be prepared according to methods well known in 
the art such as are reviewed in Flynn, "Cephalosporins and Penicillins", 
Academic Press, New York and London (1972) pp. 27-91. Of particular note 
are pages 27-37 which disclose the preparation of 6-amino penicillanic 
acid by biological methods and pages 39-70 which disclose the preparation 
of 6-amino penicillanic acid by chemical methods. Also of note are pages 
74-91 which disclose acylation of the amino group of 6-amino penicillanic 
acid to yield acylated moieties corresponding to various 
naturally-occurring and synthetically-prepared penicillins. 
In the process of the present invention, a compound of the formula 
##STR13## 
wherein R and R.sup.1 are as described above, is reacted with Raney 
nickel, when R and R.sup.1 are hydrogen, at temperatures in the range of 
about 60.degree. C. to about 100.degree. C., and a reaction time is in the 
range of about 15 to about 60 minutes, or when R and/or R.sup.1 are other 
than hydrogen, at a temperature in the range of about 100.degree. C. to 
about 200.degree. C. and a reaction time in the range of about 10 to about 
40 minutes so as to yield a compound of the formula 
##STR14## 
wherein R and R.sup.1 are as above. 
The reaction, when R and/or R.sup.1 in formula I are other than hydrogen, 
is preferably carried out at temperatures in the range of from about 
140.degree. C. to about 180.degree. C., most preferably at a constant 
temperature of about 165.degree. C. The reaction time, when R and/or 
R.sup.1 in formula I are other than hydrogen, is preferably carried out in 
the range of from about 15 to about 25 minutes, most preferably about 20 
minutes. 
In a most preferred embodiment, a compound of the formula 
##STR15## 
wherein R and R.sup.1 are hydrogen, is reacted with Raney nickel at a 
temperature in the range of about 60.degree. C. to about 100.degree. C., 
and a reaction time in the range of from about 15 minutes to about 60 
minutes. 
The reaction, wherein R and R.sup.1 in formula I are hydrogen, is 
preferably carried out at a temperature in the range of about 70.degree. 
C. to about 85.degree. C., most preferably at a constant temperature of 
about 75.degree. C. The reaction time is preferably in the range of about 
25 to about 35 minutes, most preferably about 30 minutes. 
The Raney nickel utilized in the process of the invention is preferably of 
the W-2, W-4 or Type 28, most preferably of the type prepared according to 
Example 4 of the present invention. Furthermore, the reaction may be 
carried out in any polar solvent, preferably in aqueous solution. 
The examples which follow further illustrate the invention. All 
temperatures are in degrees centigrade unless otherwise stated.

EXAMPLE 1 
Desulfurization of Sodium 6-Aminopenicillanate with Raney Nickel Catalyst 
A solution of 6-aminopenicillanic acid (64.8 g, 0.3 mol) and sodium 
bicarbonate (25.9 g, 0.3 mol) in water (750 ml) was poured into a 
well-stirred suspension of Raney nickel prepared as described in Example 4 
(650 g) in water (1,350 ml) and placed in a preheated bath (76.degree.) 
with vigorous stirring for 35 minutes. The reaction mixture was then 
cooled immediately, filtered and washed with a small amount of water. To 
the combined filtrate was added sodium bicarbonate (51.8 g, 0.62 mol) and 
benzyl chloroformate (60 ml, 0.42 mol) in acetone (60 ml). The resulting 
mixture was stirred vigorously for 3 hours. The reaction mixture, after 
washing with dichloromethane (3.times.750 ml), was acidified to pH 3 with 
concentrated hydrochloric acid at 0.degree. C. and stirred at room 
temperature for 1 hour. Filtration of the solid gave 30.2 g (31%) of the 
mixture of [1R, 3S]-alpha-( 
1-methylethenyl)-2-oxo-3-amino-1-azetidineacetic acid and [1R, 
3S]-alpha-(1-methylethenyl)-2-oxo-3-amino-1-azetidineacetic acid as 
N-carbobenzoxy derivative. Based on the nmr signals (CDCl.sub.3) at 2.0 
and 1.2 ppm, the crude product contained [1R, 
3S]-alpha-(1-methylethyl)-2-oxo-3-amino-1-azetidineacetic acid and [1R, 
3S]-alpha-(1-methylethenyl)-2-oxo-3-amino-1-azetidineacetic acid in a 
one-to-one ratio. The mixture crystallized from methyl alcohol-water and 
repeated recrystallization from chloroform gave the N-carbobenzoxy 
derivative of [1R, 
3S]-alpha-(1-methylethenyl)-2-oxo-3-amino-1-azetidineacetic acid in 97% 
purity, mp 151.degree.-152.degree.. 
C.sub.16 H.sub.18 N.sub.2 O.sub.5 : Calculated: C, 60.37; H, 5.70; N, 8.80. 
Found: C, 60.10; H, 5,81; N, 8.80. 
EXAMPLE 2 
Desulfurization of Potassium 6-Phenylacetamidopenicillanate with Raney 
Nickel 
To a solution of potassium 6-phenylacetylaminopenicillanate (11.5 g, 0.03 
mol) in water (600 ml) was added Raney nickel prepared as described in 
Example 4 (72 g), and the mixture was placed in a preheated oil bath 
(165.degree.) with vigorous stirring for 15 minutes. The reaction was then 
cooled immediately, filtered and washed with water. The combined filtrates 
were acidified to pH 2 with concentrated hydrochloric acid and extracted 
with ethyl acetate (3.times.200 ml). The extract was washed with water, 
dried over sodium sulfate and evaporated in vacuo to give 6.4 g of an oil; 
tlc [silica]; ethylacetate:acetic acid:water, 60:3:1; two major spots with 
R.sub.f 0.31 
([1R,3S]-alpha-(1-methylethyl)-2-oxo-3-[phenylacetyl-amino]-1-azetidineace 
tic acid) and 0.18 
([1R,3S]-alpha-(1-methylethenyl)-2-oxo-3-[phenylacetylamino]-1-azetidineac 
etic acid)]. 
To the mixture of 
[1R,3S]-alpha-(1-methylethyl)-2-oxo-3-[phenylacetylamino]-1-azetidineaceti 
c acid and 
[1R,3S]-alpha-(1-methylethenyl)-2-oxo-3-[phenylacetylamino]-1-azetidineace 
tic acid in dichloromethane (60 ml), a solution of diphenyldiazomethane in 
dichloromethane was added portionwise until the purple color persisted and 
stirred for 3 hours at room temperature. The excess of 
diphenyldiazomethane was then decomposed with acetic acid, and the organic 
solutions were washed with 5% sodium bicarbonate, water, dried over sodium 
sulfate and evaporated to dryness. The oily residue obtained was purified 
on preparative High-performance liquid chromatography [silica, ethyl 
acetate-hexane, 1:1; R.sub.f 0.14] and crystallized from ethyl 
acetate-hexane (1:1) to give 5.2 g (35%) of the inseparable benzhydryl 
esters of 
[1R,3S]-alpha-(1-methylethyl)-2-oxo-3-]phenylacetyl-amino]-1-azetidineacet 
ic acid and 
[1R,3S]-alpha-(1-methylethenyl)-2-oxo-3-[phenylacetyl-amino]-1-azetidineac 
etic acid in 6 to 4 ratio based on the nmr analysis. These esters can be 
used directly for subsequent reactions such as isomerization, epoxidation 
or bromination to give the separate mixture of products and the unreacted 
benzhydryl ester of 
[1R,3S]-alpha-(1-methylethyl)-2-oxo-3-[phenylacetylamino]-1-azetidineaceti 
c acid. 
EXAMPLE 3 
Desulfurization of Potassium 6-Phenoxyacetamidopenicillanate with Raney 
Nickel 
The desulfurization method described for potassium 
6-phenylacetylpenicillanate was followed. Thus, 5.7 g (38%) of the 
inseparable benzhydryl esters of 
[1-R,3S]-alpha-(1-methylethyl)-2-oxo-3-[phenoxyacetylamino]-1-azetidineace 
tic acid and 
[1-R,3S]-alpha-(1-methylethenyl)-2-oxo-3-[phenoxyacetylamino]-1-azetidinea 
cetic acid in the ratio of 6.4 to 3.6, respectively (silica; 
ethylacetate:Hexane, 1:1; R.sub.f 0.22) was obtained from potassium 
6-phenoxyacetylaminopenicillanate (12.03 g, 0.03 mol) and Raney nickel 
prepared as described in Example 4 (72 g). 
EXAMPLE 4 
Preparation of Raney Nickel 
120 gallons of water was metered into a 500-gallon kettle. The water was 
agitated, and over approximately 10 minutes, 63 gallons (400 lbs as 100% 
NaOH) of caustic soda, 50%, were metered in. The temperature rose to about 
70.degree. C. during the caustic soda addition. When necessary, steam may 
be applied to heat contents of kettle to 70.degree. C. 
With a scoop, 400 lbs. of nickel aluminum alloy which consists of aluminum 
49.9%, nickel 49.9% and iron 0.43% was slowly sprinkled into a kettle. The 
powder was added slowly to minimize foaming and to maintain the 
temperature at a maximum of 100.degree. C. A small stream of water may 
also be added to the kettle to help control the temperature and maintain 
volume during the nickel aluminum alloy addition. The nickel aluminum 
alloy muxt be added over a one and one half to two-hour period. During the 
addition of the nickel aluminum alloy, it may be necessary to balance the 
stream of water flow and the steam to the jacket in order to maintain the 
temperature and not to exceed 100.degree. C. 
The jacket steam pressure was adjusted to 25-30 psig and heated to 
110.degree. C. The temperature was maintained at 110.degree. C. for one 
hour. This hold time is critical to the formation of the desired catalyst. 
Extending or shortening this one-hour digestion period may lead to 
formation of an undesirable type of catalyst. 
The jacket steam pressure was increased to 55-60 psig, and the water was 
evaporated over about a one hour period. The batch temperature reached 
approximately 125.degree.-130.degree. C. over this one hour period. 
The reaction mixture was quenched by metering 150 gallons of filtered city 
water into a kettle. The reaction was agitated for 10 minutes. The 
agitator was turned off, and the Raney nickel catalyst was allowed to 
settle for 15 minutes. A steam syphon system was used to separate the 
supernatant liquid through the 55-gallon steel drum trap number 2 into the 
sewer. While making the separation, the pH should be taken with hydrion 
paper at the drum trap and recorded on a log sheet, pH will be initially 
over 13. 
The above step was repeated three times with 150 gallons of filtered city 
water. The total volume of wash water was 600 gallons. 
Approximately 50% of the fresh Raney nickel catalyst was transferred via 
the steam syphon into the 55-gallon wash tank. An air motor was attached 
to the wash tank, and the agitator was started slowly to prevent the 
catalyst from overflowing. The filtered city water was turned on and the 
water flow rate adjusted to a rotometer reading of 110-120 mm, and the 
Raney nickel catalyst was washed continuously until the effluent was clear 
and the ph was between 9 and 10. The effluent from the wash tank through 
the drum trap number 1 should be checked at hourly intervals with hydrion 
paper and the pH recorded on a log sheet. 
The air motor was removed from the wash tank, and the catalyst was allowed 
to settle for 30 minutes. Using the steam syphon system, the supernatant 
liquid was separated off into drum trap number 2. The wash tank was tilted 
into the horizontal position, and the catalyst was poured into a tared 
20-gallon pot. All the catalyst fit into one pot. 
The excess water from the 20-gallon pot was ladled. The wet catalyst in the 
20-gallon pot was weighed, and the gross, tare and net weights were 
recorded on the log sheet. Sufficient water to cover the catalyst was 
added. The portion of the procedure beginning with the transfer of 50% of 
the fresh Raney nickel to the steam syphon through the addition of 
sufficient water to cover the catalyst was repeated with the remaining 50% 
of the fresh Raney nickel in the kettle. 
Once a week, the contents of drum traps numbers 1 and 2 were ladled into a 
tared pot, and the excess water was removed. The gross, tare and net 
weight of the pot was measured and recorded. Net weight and batch numbers 
of catalyst prepared during this period were recorded in the sludge 
recovery book. 
EXAMPLE 5 
Synthesis of 3-Carbobenzyloxyamino-2-Azetidinone 
30 g (0.073 mol) of a mixture of 
([1R,3S]-alpha-(1-methylethyl)-2-oxo-3L-carbobenzyloxyamino-1-azetidineace 
tic acid benzyl ester and [1R, 
3S]-alpha-(1-methylethenyl)-2-oxo-3-carbobenzyloxyamino-1-azetidineacetic 
acid benzyl ester in 600 ml of dichloromethane and 17 ml of triethylamine 
was refluxed (oil bath 80.degree. C. or steam bath) for 5 hours. The 
methylene chloride solution was washed successively with 1N hydrochloric 
acid, water, 5% sodium bicarbonate, water and dried over sodium sulfate. 
Removal of the solvent in vacuo gave 30 g of oil which was used for the 
next step without further purification. 
22 g (0.054 mol) of the azetidinones obtained from the foregoing step in 
120 of acetone and 3.77 g (0.021 mol) of potassium dihydrogen phosphate in 
40 ml of water was stirred and cooled to -3.degree. C. To this 
vigorously-stirred solution was added 4.28 g (0.027 mol) of potassium 
permanganate (pulverized in mortar) over a 10-minute period so that the 
temperature remained below 0.degree. C. After complete addition, the 
reaction mixture was stirred at 0.degree. C. for 30 minutes. Then added 
0.7 g (0.006 mol) of sodium bisulfite in 10 ml of water, and the reaction 
was stirred for 10 minutes. To this mixture was added 200 ml of 1N sodium 
carbonate and 300 ml of dichloromethane and stirred at 0.degree. C. for 30 
minutes. After the separation of dichloromethane layer, the reaction was 
further extracted two times with 150 ml of dichloromethane. The combined 
methylene chloride extract was filtered through Celite, and the filtrate 
was washed with water and dried over sodium sulfate. Removal of the 
solvent gave 21 g of oil which was crystallized from 50 ml of ethyl 
acetate. After cooling at 0.degree. C. overnight, the crystal was filtered 
and washed three times with 4 ml of cold ethyl acetate to give 1.56 g 
(33%) of 3-carbobenzyloxyamino-2-azetidinone. The mother liquor was 
stripped to dryness to give 15 g of oil which was crystallized from 120 ml 
of ethyl acetate-pet. ether (3:7) to give 8.6 g (65%) of the unreacted 
[1R, 3S]-alpha-(1-methylethyl)-2-oxo-3-carbobenzyloxyamino-1-azetidineceti 
c acid benzyl ester.