CA1076104A - Penicillin oxides - Google Patents

Abstract

PENICILLIN OXIDES
Abstract Compounds of the formula:

Description

1~76~0~
~ .: , ~, .
This invention relates to 6-(~-nitroso-N-acylamino)penicill-~i anic acid la-oxides and their derivatives. It further relates to -a process for preparing penicillin la-oxides in high yield.
- Compounds (I) according to this invention lS represented by :
~ 5 the following formula:
;..................................................................... ~ :
.; :.
NO
Acyl-~ ~.
S y CH2X -. ~ - . .
-~ (I) COB ~

1 0 ' " ' "
i ~
(where COB is carboxy or protected carboxy, and X is hydrogen or -`
a nucleophilic group).
Acyl in Compounds (I) contains up to 25 carbon atoms and includes conventional acyls used in the chemistry of penicillins -and cephalospDrins, and is exemplified by an inorganic acyl inclu-~; ding carbonic acyl (e.g. 2-8C alkoxycarbonyl, 8-15C aralkoxycar-bonyl, 6-llC aryloxycarbonyl), and organic acyl including 1-5C
alkanoyl, 3~8C cycloalkanoyl, 7-20C aralkanoyl, 7-lOC aroyl, 1-5C
alkylsulfonyl, 6-lOC arylsulfonyl, and 1-5C alkylphosphonyl.
These acyls, where possible, may have a hetero atom in the main nucleus, unsaturation, or substituent e.g. a halogen (e.g.
fluorine, chlorine, bromine), nitrogen function (e.g. amino, hydrazo, azido, 1-5C alkylamino, 6-lOC arylamino, 1-8C acylamino, 1-5C alkylideneamino, 1-8C acylimino, nitro), oxygen function (e.g. hydroxy, 1-5C alkoxy, 7-20C aralkoxy, 6-lOC aryloxy, 1-8C
acyloxy, oxo), sulfur function (e.g. mercapto, 1-5C alkylthio, 7-9C aralkylthio, 6-lOC arylthio, 1-8C acylthio, thioxo, sulfo, sulfonyl, sulfinyl, 1-5C alkoxysulfonyl, 6-lOC aryloxysulfinyl, carbon function (e.g. 1-5C alkyl, 1-5C alkenyl, 7-lOC aralkyl, 6-lOC aryl, carboxy, 2-6C carbalkoxy, carbamoyl, 1-8C alkanoyl, - 7r~

:' . .. :

1~761~
.. ,. .,` . ,.,~. . .. .
7-llC aroyl, 1-5C aminoalkyl, 7-lOC aralkanoyl, cyano), phosphorus ` function (e.g. phospho, phosphoroyl) or like substituents.
Representative Acyls include following groups:
1) 1-5C alkanoyl;
5 2) 2-5C haloalkanoyl; ~
3) azidoacetyl; ~-4) cyanoacetyl;
5) acyls of the formula:
Ar-CQQ'-Co-10 (where Q and Q' each is hydrogen or methyl; and -Ar is phenyl, dihydrophenyl, or a monocyclic heterocyclic ~,.,,, ~,. '-aromatic group containing 1 to 4 hetero atoms selected from :, . ~ ' :-.-.
~`~ nitrogen, oxygen, and/or sulfur atoms, each optionally sub-stituted by e.g. 1-5C alkyl, 1-5C alkoxy, halogen, trifluoro-^ 15 ~ methyl, hydroxy, cyano, aminomethyl, nitroso, and nitro).
6) acyls of the formula:
: : -Ar-G-CQQ'-CO- ;
(where G is oxygen or sulfur; and Ar, Q, and Q' are defined above);
,; .,, ,~, -` 20 7) acyls of the formula:
Ar-CHT-C0-~ ,.
(where Ar is defined above; and T is i) amino, ammonio, amino protected by an amino-protecting i~ group (including acyls e.g. benzyloxycarbonyl, 2-8C alkoxycarbonyl, ; 25 cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycar-. :- .: . .
bonyl, cyclopropylmethoxycarbonyl, methanesulfonylethoxycarbonyl, ~ -. . ~ :
~; 2,2,2-trichloroethoxycarbonyl, guanidylcarbonyl, substituted ureidocarbonyl, 1-5C alkanoyl, pyronecarbonyl, thiopyronecarbonyl, ; pyridonecarbonyl, and aromatic carbocyclic or heterocyclic acyl, i ~;
optionally substituted by e.g. halogen, trifluoromethyl, 1-5C alkyl, .. . . , , ., :: . , . :: . .. ' ~ ~0761!~34 i . . . .
...
r ' '1-5C aminoalkyl, 1-5C hydroxyalkyl; trityl, and other amino-protec-ting groups) or protected amino in the form of phthalimino or enamino derived from acetoacetates, acetylacetone, acetoacetoni- ~
- trile, and like protecting groups; ~-ii) hydroxy, 1-3C alkoxy, or 1-5C acyloxy; -iii) carboxy, 2-10C alkoxycarbonyl, indanyloxycarbonyl, .. ~ , . . -~ .
phenoxycarbonyl, dimethylphenoxycarbonyl, or like groups; or ~ -iv) azido, cyano, carbamoyl, sulfo, 1-5C alkoxysulfonyl, 1-3C alkoxyphosphonyl, or like groups), 8) 3-5C 2-syndon-3-alkanoyl;
9) 6-8C (2- or 4-pyridon-1-yl)alkanoyl;
10) 5-aminoadipoyl, 5-aminoadipoyl protected at the amino or carboxy; ~ ~ -;~ 11) acyls of the formula:
~', ~' .
L-O-CO-:- .. .
(where L is an easily removable 1-10C hydrocarbyl e.g. 2,2,2-tri-chloroethyl, isobornyl, t-butyl, l-methylcyclohexyl, 2-alkoxy-t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzhydryl), and the like acyls. ~-, :
Typical examples of Ar in the said definition include furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, `~ pyrazinyl, pyridazinyl, triazinyl, and dihydrophenyl, each option-ally may be substituted by e.g. halogen, 1-5C alkyl, hydroxy, aminomethyl, or 1-3C alkoxy.
Preferable Acyls are those of naturally occuring penicillins i.e. phenylacetyl or phenoxyacetyl.
COB in Compounds (I) is carboxy or protected carboxy. Repre-sentatives of them include those constituting esters [1-5C alkyl . , , - , : ... . . . .

~07~ 4 (e.g. methyl, ethyl, trichloroethyl, t-butyl esters), 7-20C ar-alkyl (e.g. benzyl, methoxybenzyl, nitrobenzyl, diphenylmethyl, trityl esters), 6-12C aryl (e.g. phenyl and naphthyl esters), metal (e.g. trimethylsilyl, methoxydimethylsilyl, trimethylstannyl esters), and other esters], acid anhydrides, salts (e.g. sodium) potassium, magnesium, aluminum salts), thiol esters, amides, hydrazides, :
azides, and other derivatives of carboxy groups. COB can, where possible, have substituents referred to above e.g. halogen, sulfur-, , ~ ~-, .
~ oxygen-, nitrogen-, carbon-, or other functions or can be unsatura-.. ~ . .
~ 10 ted.
~ , . .. ..
~ Among these protected carboxy, important groups for COB are -; ~
~, .. . . .
those inert to the reaction and removable after the reaction with- ~ -out adverse effect on the other part of the molecule (e.g. 1-3C ~
. . . - .
haloalkyl, 2-10C acylalkyl, 2-7C alkoxya~kyl, 2-7C acyloxyalkyl, ~- 15 7-20C aralkyl esters, 2-6C dialkylhydrazides, alkali metal salts, ^~!

- and 1-12C alkylamine salts). ~
; . .
; The protecting group in COB has no meaning other than protec-;~ tion and deprotection, and wide variation can be possible without ~ -:, ...
$~
changing the gist of this invention.
Preferable COB groups include benzhydryloxycarbonyl, benzyloxy-carbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and ,.' . "," ~"' .
; 2,2,2-trichloroethoxycarbonyl, `~
X in Compounds (I) is hydrogen or nucleophilic group. The nucleophilic group can be halogen, acyloxy, hydroxy, mercapto, 1-3C alkylthio, 1-6C arylthio including heteroaromatic thio repre-sented by partial formula:
' ., ':', Ar-S- ~ ;

(where Ar is defined above) ~
: ' .: .
and other nucleophilic groups bound to methyl at position 3 of cephem ring in known cephalosporins. It can be exemplified by .

~ ':- , . ., - , , . . .:
.. . ; ", , ,, , , , . , ~ .
:. ~ ' ', ' ' ' ," ', ' :' . ': , : :' . . .
i, . . . . . . . .

1~6104 ~:
halogen (e.g. chlorine, bromine, fluorine), acyloxy (e.g. formyl- -oxy, acetyloxy, propionyloxy, benzoyloxy, sulfonyloxy, carbonic or suIfuric acyloxy), 1-3C alkoxy (e.g. methoxy, ethoxy, butoxy), arylthio (e.g. phenylthio, nitrophenylthio, tolylthio, 1,3,4- -;~ 5 thiadiazolylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 2-hydroxy-methyl-1,3,4-thiadiazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,2,3-triazol-5-ylthio, pyridazin-3-ylthio, 1-bxidopyridin-2-yl-thio) or ~ like nucleophiles.
`;~ Preferable X groups include hydrogen, chlorine, 1-5C alkanoyl-oxy, 1,3,4-thiadiazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, and l-methyltetrazol-5-ylthio.
When a group Acyl, X, or Cos is unstable under the reaction condition, it can be protected prior to and deprotected after the reaction to avoid unfavorable side reactions. -~; 15 Typical and specific examples of Compounds (I) are:
6~-(N-nitroso-phenylacetamido)-2a-methyl-2~-chloromethylpenam- `

4-carboxylic acid diphenylmethyl ester la-oxide, ~;
` 6~-(N-nitroso-phenylacetamido)-2a-methyl-2~-acetoxymethylpenam-4-carboxylic acid 2,2,2-trichloroethyl ester la-oxide, ` 20 6~-(N-nitroso-phenoxyacetamido)penicillanic acid diphenylmethyl ester la-oxide, 6~-(N-nitroso-phenoxyacetamido)-2a-methyl-2~-chloromethylpenam-4-carboxylic acid diphenylmethyl ester la-oxide, 6~-(N-nitroso-phenoxyacetamido)-2a-methyl-2~-acetoxymethylpenam-: . ~
4-carboxylic acid diphenylmethyl ester la-oxide, and 6~-(N-nitroso-phenoxyacetamido)-2a-methyl-2~-acetoxymethylpenam-4-carboxylic acid benzyl ester la-oxide.

- Starting materials for preparing Compounds (I) can be prepared by treating a 6-acylaminopenicillanic acid or its derivative with a nitroso-introducing reagent (particularly nitrogen dioxides i.e.

~' ''' ';
` `'' ~ ' ' ' '' : , ~L~76~
` dinitrogen tetraoxide, dinitrogen trioxide, nitrosyl halide, alkyl ~` nitrite). -~
- Compounds (I) can be prepared, for example, by the action of an oxidizing reagent on the starting material (II), 6-(~-nitroso-~-acylamino)-penicillanic acid or its derivative, according to the ; following scheme:

',' O '. '' ,NO ,NO ~
;~ Acyl-~ ~ ~ CH2X oxidation_~ ~ ~ CH X
O CH3 o~~~N
(II) COs (where COB and X are defined above).
Said oxidizing reagent is that oxidizable a sulfide to give a sulfoxide, for example, organic or inorganic peracids of oxido-15 reduction potential higher than ~ 0.7 (especially m-chloroperben- `
", , .
` zoic acid, perbenzoic acid, monoperphthalic acid, peracetic acid, periodic acid), or their salts, hydrogen peroxide, urea peroxide, -. ~ ,~. ., , ~
nickel peroxide, and like oxidative reagents, if required in the : .. . ..
presence of catalyzer (e.g. wolfrumates for hydrogen peroxide).
The reaction is preferably carried out in a solvent (particu-larly hydrocarbon-, halohydrocarbon-, ether-, ester-, ketone-, nitrohydrocarbon-, water-, alcohol- solvents or their mixtures), ........ .... ..................................................................... .. ... ... ......... .
especially methylene chloride.
Under more drastic conditions, sulfones can be obtained as by- ;
. . .
~5 products.
- Usually, a temperature over 50 C should be avoided to minimize -formation of azo compounds by removal of acyl.
The reaction completes usually within 0.5 to 10 hours. The products can be isolated by conventional methods. As the products are unstable, they are preferably stored after removing the nitroso : -, . ' . ' ' ', , ' ~ , ... ..
- , , - , ' ' ' . i ' ' : ' ' ' ~ ' '' ' ' "

group by successive reduction.
~ Compounds (I) can be used for preparing penicillin la-oxides : ~ (III) difficulty prepared until this invention. The process comprises treatment of Compound (I) with a reducing reagent cap-j~ 5 able of removing N-nitroso to NH without causing undesirable changes .
on other parts of the molecule (particularly, reducing metals e.g.
aluminum, zinc, tin, or iron, and acid; hydrosulfite; boranic acid derivatives; and like reagents~ according to the following reaction scheme:
; ~
` 10 ' ~ ,~ 0 Acyl- ~ CH2X Acyl-NH~ ~ \ / CH2X
o ~ - N~ Y CH3 ~3 Cos COB
(I) (III) '". `' :
15 (where COB and X are defined above) ` The reaction is carried out in a solvent as described above in relation to the preparation of Compounds (I), and it generally ~-~ completes within 0.1 to 5 hours at room temperature to 0 C.
.:
-`~ The products can be isolated by conventional manners from the reaction mixture.
.~ .
These two reactions can be carried out in one and same reac-tion vessel without separation and purification of the intermediates (I) for convenient procedures and safer handling of unstable inter-mediates. Thus, Compounds (III) are now preparable from Compounds (II) in more than 60% over-all yield, by simple treatment.
, Compounds (III) (and therefore Compounds (I)) are useful for -` preparing known antibacterial cephalosporins including cefalotin and cefazolin, by successive treatment with e.g. benzothiazol-2-thiol;
halogen; and then heating, to give recyclized cephem compounds.
Thus, the reactions constitute a synthesis of expensive cephalos-,', ' '~',' 1~7~ 4 porins from less expensive penicillins.
The following examples are provided to illustrate this inven- `
tion in detail, but they are not intended to restrict the scope ~-thereof. Elemental analyses and physical constants of the products : ,: .:
are not contradictory to given structures.
;~ Example 1.
. ~ ~
Table I shows examples of reaction conditions, and Tables II
A to C show physical constants o~ the products.
: ~; ....
- Among them, the first example is described below to show more ;~i 10 detailed procedures. Other examples are carried out analogously.
: :
;: : ' . :
(The first example in Table I) ~
'! . . . .
~ (1) To a solution of benzhydryI 6-phenylacetamido-2~-chloro-.~. ;,. ... ..
methyl-2a-methylpenam-3a-carboxylate (11.6 g) in methylene chlor- ~
15 ide (25 ml) are added sodium acetate (5 g) and nitrogqn dioxide - - .
: ~ ~
(2 ml), and the mixture stirred at 0C for 40 minutes. The reac-tion mixture is poured into ice water containing sodium hydrogen ~. .
~ carbonate and extracted with methylene chloride. The extract is ? ". ;~ , ' ` ,' ', . . . .
washed with water, dried, and concentrated to give diphenylmethyl 6-(N-nitroso-N-phenylacetylamino)-2~-chloromethyl-2a-methylpenam-;. :
3a-carboxylate (11.8 g). -~ (2) To a solution of the product (11.8 g) prepared above (1) .~, in methylene chloride (120 ml) is added m-chloroperbenzoic acid . .
(4.5 g) at O C, and the mixture stirred for 2 hours. The reaction . '.
mixture is poure~ into ice-water and extracted with methylene chlor-ide. The extract is washed with cold lN-sodium carbonate solution ~ . .
~ and water, dried, and concentrated to give diphenylme~hyl 6-(N-: nitroso-N-phenylacetylamino)-2~-chloromethyl-2a-methylpenam-3a-.. ~ :
carboxylate la-oxide (11.2 g).
(3) To a solution of the product (11.2 g) prepared above (2) ~-..

,, .
, ~L~7~
in methylene chloride (200 ml) are added acetic acid (20 ml) and zinc powder (8 g), and the mixture stirred at 0C for 1 hour.
; After filtering off the insoluble material, the methylene chloride ~-~` layer is washed with water, dried, and concentrated to give diphenylmethyl 6~-phenylacetamido-2~-chloromethyl-2a-methylpenam-3a-carboxylate la-oxide (9.59 g). This product is chromatographed on 10% water-silica gel (200 g) to give pure product (6.32 g).

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Claims (18)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula I

or of the formula III

wherein Acyl is phenylacetyl or phenoxyacetyl: X is hydrogen chlorine or alkanoloxy of 1 to 5 carbon atoms and COB is carboxy or protected carboxy which comprises selecting a process from the group of processes consisting of:
a) when a compound of formula I is required:
oxidizing a compound of the formula II

wherein Acyl, X and COB are as defined above, with an oxidizing reagent;
b) when a compound of formula III is required:
(i) treatlng a compound of formula I

wherein Acyl, X and COB are as defined above, with a reducing agent; or (ii) treating a compound of formula II

wherein Acyl, COB and X are as defined above, with an oxidizing reagent, followed by reductive removal of the nitroso group with a reducing agent.

2. A process for preparing compounds of formula I according to claim 1, wherein the oxidizing reagent is m-chloroperbenzoic acid, perbenzoic acid, monoperphthalic acid, peracetic acid, periodic acid, hydrogen peroxide, urea peroxide, or nickel peroxide.

3. A process for preparing compounds of formula I according to Claim 1, wherein the reaction is carried out in methylene chloride.

4. A process for preparing compounds of formula I according to claim 1, wherein CoB is benzhydryloxycarbonyl, benzyloxy-carbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, or 2,2,2-trichloroethoxycarbonyl.

5. A process for preparing 6.beta.-(N-nitroso-phenylacetamido)-2.alpha.-methyl-2.beta.-chloromethylpenam-4-carboxylic acid diphenylmethyl ester 1.alpha.-oxide according to claim 1, wherein Acyl is phenylacetyl, X is chlorine and COB is benzhydryloxycarbonyl.

6. A process for preparing 6.beta.-(N-nitroso-phenylacetamido)-2.alpha.-methyl-2.beta.-acetoxymethylpenam-4-carboxylic acid 2,2,2-trichloroethyloxycarbonyl ester 1.alpha.-oxide according to claim 1, wherein Acyl is phenylacetyl, X is acetoxy and COB is 2,2,2-trichloroethoxycarbonyl.

7. A process for preparing 6.beta.-(N-nitroso-phenoxyacetamido) penicillanic acid diphenylmethyl ester 1.alpha.-oxide accordlng to claim 1, wherein Acyl is phenoxyacetyl, X is hydrogen and COB is benzhydryloxycarbonyl.

8. A process for preparing 6.beta.-(N-nitroso-phenoxyacetamido)-2a-methyl-2.alpha.-chloromethylpenam-2-carboxylic acid diphenylmethyl ester 1.alpha.-oxide according to claim 1, wherein Acyl is phenoxyacetyl X is ahlorine and COB is benzhydryloxycarbonyl.

9. A process for preparing 6B-(N-nitroso-phenoxyacetamido)-2.alpha.-methyl-2.beta.-acetoxymethylpenam-4-carbaxylic acid dlphenylmethyl ester la-oxide according to claim 1, wherein Acyl is phenoxy-acetyl, X is acetoxy and COB is benzhydryloxycarbonyl.

10. A process for preparing 6.beta.-(N-nitroso-phenoxyacetamido)-2.alpha.-methyl-2.beta.-acetoxymethylpenam-4-carboxylic acid benzyl ester 1.alpha.-oxide according to claim 1, wherein Acyl is phenoxyacetyl, X is acetoxy and COB is benzyloxycarbonyl.

11. A process for preparing the compounds af formula III according to claim 1, wherein the reducing agent in step (i) is zinc in the presence of acetic acid.

12. Compounds of the formula I

where Acyl is phenylacetyl or phexonyacetyl, X is hydrogen, chlorine or alkanoyloxy of 1 to 5 carbon atams and COB is carboxy or protected carboxy when prepared by the process of claim 1.

13. Compounds according to claim 2 wherein COB is benzhydryloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxy-carbonyl, p-nitrobenzyloxycarbonyl, or 2,2,2-trichloroethoxy-carbonyl7 when prepared by the process of Claim 4.

14. 6.beta.-(N-nitroso-phenylacetamido)-2a methyl-2.beta.-chloromethyl-penam-4-carboxylic acid diphenylmethyl ester 1.alpha.-oxide when prepared by the process of claim 5.

15. 6.beta.-(N-nitroso-phenylacetamido)-2.alpha.-methyl-2.beta.-acetoxymethyl-penam-4-carboxylic acid 2,2,2-trichloroethyloxycarbonyl ester 1.alpha.-oxide when prepared by the process of claim 6.

16. 6.beta.-(N-nitroso-phenoxyacetamido)penicillanic acid diphenylmethyloxycarbonyl ester 1.alpha.-oxide when prepared by the process of claim 7.

17. 6.beta.-(N-nitroso-phenoxyacetamido)-2.alpha.-methyl-2.beta.-chloromethyl-penam-4-carboxylic acid diphenylmethyl ester 1.alpha.-oxide when prepared by the process of claim 8.

18. 6.beta.-(N-nitroso-phenoxyacetamido)-2.alpha.-methyl-2.beta.-acetoxymethyl-penam-4-carboxylic acid diphenylmethyl ester 1.alpha.-oxide when prepared by the process of claim 9.

l9. 6.beta.-(N-nitroso-phenoxyacetamido)-2.alpha.-methyl-2.beta.-acetoxymethyl-penam-4-carboxylic acid benzyl ester 1.alpha.-oxide when prepared by the process of claim 10.