CA1051008A - Thioamides - Google Patents

Abstract

A B S T R A C T

The invention relates to compounds of the formula:

1 wherein R stands for lower alkyl, aryl, heteroaryl, benzyl, heteroarylloweralkyl, phenoxyloweralkyl, phenylthio-loweralkyl, 4-amino-1-butyl and suitably protected derivatives, .alpha.-aminobenzyl and protected derivatives such as the carbamates (benzyl, trichloroethyl and methoxymethyl) and aldehyde and ketone adducts, .alpha.-hydroxybenzyl and protected derivatives, .alpha.-carboxy-benzyl and protected derivatives, .alpha.-sulfobenzyl and protected derivatives, the radical R5O-, R5S, or R5R6N-, wherein R5 and R6 may be the same or different and each be taken from the group lower alkyl, aryl, arylloweralkyl and heteroaryl and additionally, in the case of R5R6N-, R5 and/or R6 may be hydrogen;
R1 is hydrogen or a cleavable radical such as lower-alkoxymethyl, acyloxymethyl, loweralkylthiomethyl, loweralkyl, 2,2,2-trichloroethyl, benzyl, substi-tuted (nitro, methoxy or halo) benzyl, benzhydryl, phenacyl or trialkylsilyl;
R2 is hydrogen or methoxy;
R3 stands for lower alkyl, aryl, arylloweralkyl, heteroaryl, and the radicals R5O-, R5S-, R5R6N-, or R5R6NR7N-wherein R5 and R6 have the same meaning set forth above; and R7 has the same meaning as R5 or R6 including hydrogen, and R4 has the same meaning as R5 or R6 including hydrogen.
The novel compounds are useful intermediates in the preparation of cephalosporins and penicillins.

Description

1~5~
In copending Application Serial No. ~ ~iled 3JIq~ there is disclosed novel azetidinone imidoyl-disulfides which are useful as i.ntermediates for preparing 3-iodocephams which are themselves useful in preparin~ certain cephalosporin derivatives.
The azetidinone imidoyldisulfides prepared in accordance with the present invention correspond to the general formula:

RCONH~ S - C ~ 3 \ R
N ~

COORl , 10 which is taken to also represent the two double bond isomers: .

R2 H / NR4 R2 H ~ NR
RCONH ~ S - S - C \ RCON

COOR
. la lb In the above ~ormula:
R stands ~or lower alkyl, aryl, heteroaryl, benzyl, hetero-arylloweralkyl, phenoxyloweralkyl, phenylthioloweralkyl, 4-amino-1-carboxy-1-butyl and suitably protected derivatives.
~-aminobenzyl and protected derivatives such as the carbamates ~enzyl, trichloroethyl and methoxymethyl)and aldehyde and ketone adducts, ~-hydroxybenzyl and protected derivatives, a-carboxybenzyl and protected derivatives, ~-sul~obenzyl and protected derivatives, R50-, R5S-, R5R6N-, , ~.

l~S~Q~
wherein R5 and R6 may be the same or di~ferent and each be taken from the ~roup lower alkyl, aryl, aryl-loweralkyl and heteroaryl, and in the case where R
stands ~or R5R6N-, R5 and/or R6 may be hydrogen;
R is hydrogen or a cleavable radical such as loweralkoxy- ;~ ;
methyl, acyloxymethyl, loweralkylthiomethyl, lower alkyl,

2,2,2-trichloroethyl, benzyl, substituted (nitro, methoxy or halo)benzyl, benzhydryl, phenacyl, or trialkylsilyl; ~ ~
R is hydrogen or methoxy; ; ~;
R stands for lower alkyl, aryl, arylloweralkyl, heteroarylt R O-, R5S~ R5R6N- or R5R6NR7N
wherein R5 and R6 have the same meaning as set ~orth above; and R7 has the same meaning as R5 or R6 including hydrogen, and P.4 has the same meaning as R5 or R6 including hydrogen.
The novel azetidinone imidoyldisulfides are prepared by heating a penicillirl sull'oxide (either the ~- or ~-sulfoxides or a mixture can be used) of the formula;
R H

V

~OOR

wherein R, R and R are aæ previously defined, with a -thio-amide of the formula: S

wherein R3 and R4 are as previously defined.
The reaction is carried in the presence of a suitable inert solvent such as for example dioxane or toluene. As an example of suitable thioamides, there may be mentioned thio-acetamide, thiobenzamide, thiourea, thiosemicarbazide, thio-carbamates and dithiocarbamates.

~5~
The reaction temperature and t~me required ~or the reaction is determ:ined by the nature o~ -the penicillin sulfGxide 2, and the thioamide 3. Reaction temperatures of 80 to 130 have been found convenient, and times of 3 to 5 hours.
It is desirable to remove the water formed in the reaction, by azeotropic distillation or by the use of a Dean-Stark trap, o~
the use of drying agents such as a molecular sieve or magnasium sulfate.
The nature of the products formed is determined by the nature and purity of the penicillin sul~oxides 2, the thio~
amide 3, and the solvent used, the temperature and time of ~ ;
reac-tion, and the presence of impurities. The conjugate isomer la, is favoured by the presence o~ base and by extended reaction timesJ and lh can be converted to la on treatment with a suitable base such as triethylamine.
The aæetidinone disul~ides 1, are useful intermedi-ates and can be converted by known processes to penicillins and cephalosporins.
Thus, for example, the azetidinone disulfides lb, on treatment with an iodinating agent such as iodine and sulfenyl iodides, are converted to the respective 2-iodomethylpenams or the 3-iodocephams and these compounds are converted to cephalo- ; `
sporins by known processes.
The 3-iodocephams when treated with a base such as pyridine or picoline or collidine, undergo dehydroiodination to ~orm the ceph-3-ems, which are used for the preparation of the commercially important cephalexin.

~ .

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EXAMPLES ~ ;
The present invention will be more readily understood by referring to the following examples which are given only to illustrate the invention rather than limit its scope.

2-Oxo-3-Phenoxyacetamido-4 Acetimidoyldithio-a-Isopropenyl-azetidin-l-Acetic Acid, lb, (R - ~0CH2~4-*~-, Rl - H, R2 - H, ~
R3 = CH3, R4 H) .
__ _ _ ~
A mixture of anhydrous penicillin V sulfoxide (0.36 g.~ 0.001 mole, prepared by heating the hydrate to constan~
weight at 60C under vacuum over P205), and thioacetamide (0.08 9., ~0.001 mole) in purified dioxane (25 ml) was heated under reflux with stirring for 5 hrs in an oil-bath kept at 120. The clear reaction mixture was concentrated under vacuum to give a brown foam. The ir spectrum (CHC13): 3350, 1775,168~ .
1600 cm 1 and nmr spectrum (CDG13): signals at ~8.4, 8.0 (NH's and -COOH), multiplet at 7.5 to 6.9 (C6H5), signals at 5.68 (~-lactam Hs), 5.22 ( ~ CH2), 4.95 (-CHCQOH), 4.62 (-CH2), 2.5 ( ~ N~ ) and 1.9 ( ~CH2) are in agreement with the assignment.

Methyl 2-0xo-3-Phenoxyacetamido-4-Acetimidoyldithio-a-Isopropenylazetidin-l-Acetate~ lb (R ~OCH2~ t, Rl - CH3, R2 H, R3 - CH3, R4 ~ H~ and Methyl Penicillin Y
A mixture of methyl penicillin V sulfoxide (0.38 9., 0.001 mole) and thioacetamide (0.08 g., 0.001 mole) in purified dioxane (25 ml) was heated under reflux with stirring for 5 hrs, in an oil bath maintained at 120C. The clear reaction mixture was concentrated under vacuum ~o a brown foam. The ir spectrum (CHC13) showed strong sharp singlets at 1780~ 1745, and 1700 cm 1 with weaker absorptions at 1600 and 3400 cm 1.
The nmr spectrum (CDC13) indicated a mixture containing methyl 2-oxo~3-phenoxyacetamido-4-acetimidoyldithio-c~-isopropenyl-azetidin-l-acetate, lb, as the main product characterized by _ signals at ~5.22 and 5.1 ( ~CH2), 2.55 ( ~ CH3), and 1.92 ( ~C~l2) among others, and methyl penicillin V (estimated at C~l3 20~ and confirmed by thin layer chromatography characterized by its gem-dimethyl signals at ~1.65 and 1.5. In addition, there were trace amounts of methyl 4 phenoxyacetamidoisothiazol-3-one~ isopropenylacetate, characterized by its signals at ca.
~9.2 and 8.83.

~ .
2-Oxo-3-Phenoxyacetamido-4-(N-Phenylacetimidoyl)Dithio-~-Isopropenylazetidin-l-Acetic Acid, lb (R - ~OCH2fi~*, Rl - H, R H, R - CH3, R - ~) A mixture of anhydrous penicillin V sulfoxide (0.36 9., 0.001 mole) and thioacetanilide (0.15 9., 0.001 mole) in purified dioxane (25 ml) was heated under reflux with stirring for 5 hrs in an oil bath kept at 120. The clear reaction -~
mixture was concentrated under vacuum to a brown foam. The ir spectrum (CHC13): 3350, 1775, 1680, 1600 cm 1 and nmr spectrum 20 tcDcl3):- signals at ~10.25, 8.2 to 6.95 (m, C6H5, NH and COOH~, 5.65 (~-lactam protons), 5.2 ( ~ CH2), 4.95 (CHCOOH), 4.6 C~3 ( O CH2 ), 2.7 ( ~ CH )~ 1.92 ( ~ 2) are conslstent for the assigned structure.

Methyl 2~0xo-3-Phenoxyacetamido-4-(N-Phenylacetimidoyl)Dithio-~Isopropenylazetidin-l-Acetate, lb (R - ~OCH2~ t, R : CH3, R2 H, R3 - CH3, R4 A mixture of methyl penicillin V sulfoxide (0.38 9., 0.001 mole) and thioacetanilide (0.15 g., 0.001 mole) in puri-fied dioxane (25 ml) was heated under reflux with stirring for 5 hrs in an oil bath kept at 120C. The clear reaction mixture .~- .
- , . . . ....................... .
~ - , . , ~ .

~ 5~1~08 on concentration under vacuum gave a brown foam. The nmr spectrum (CDC13) indicated that the reaction was incomplete, about 20% of methyl penicillin V sulfoxide being present, along with methyl 2-oxo-3-phenoxyacetam;do-4-(N-phenylacet;midoyl)-dithio-~-isopropenylazetidin-l-acetate characterized by ~5.7 to 5.3 (m, ~-lactam protons), 5.2 and 5.05 ( ~CH2), 4.92 CH3 ;~

3) ( O CH2 ), 2.72 ( ~ ~ ) and 1.92 ( ~ CH2).
In a similar manner using solvents such as toluene, :~
dichloroethane, mesitylene, and thioamides such as thio-benzamide, N-methylthioacetamide, N-methylthiobenzamide, N-phenylthiobenzamide, thionicotinamide, thioison;cotinamide, 2- ;
th;azoleth;oacetamide and 2-thiazolethiobenzamide, and penicillin sulfoxides such as trichloroethyl penicillin V
sulfoxide, methoxymethyl penicillin V sulfoxide, p-nitrobenzyl penicillin V sulfoxide, penicillin G sulfoxide, methoxymethyl penicillin G sulfoxide, trichloroethyl penicill;n G sulfoxide, 6-phenoxyamidopen;cillin sulfoxide, methoxymethyl N-tmethoxy-methyloxycarbonyl)ampicillin sulfoxide, di(methoxymethyl~-carbenicillin sulfoxide, and 6-thien-2-ylacetamido-6-methoxy-penicillin sulfoxide: various azetidinone disulfides of formula1 are obtained, Methyl 2-Oxo-3-Phenoxyacetamido-4-~Aminoimidoyl)Dithio-a Isopropenylazetidin-l-Acetate, lb (R - ~OCH2~ , R - CH
R = H, R NH2, R - H) .
A mixture of methyl penicillin V sulfoxide (0.2 9., 0.00052 moles) and thiourea (0.04 g., 0.000052 moles) in puri fied dioxane (15 ml) with one drop of dimethylaniline was ``
heated under reflux with stirring for $ hrs in an oil bath kept 30 at 120C. The reaction mixture on concentration under vacuum ~-gave a brown foam. The nmr and ir spectra of the foam indi-.
.. . , . . :: :

0~
cated the presence of the desired compound. The ir spectrum showed strong absorptions at 1775, 1740, 1700 and 1600 cm 1.
_AMPLE 6 Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate from Methyl 2-Oxo-3-Phenoxyacetamido-4-(Aminoimidoyl)Dithio-~-Isopropenylazetidin-l-Acetate, lb (R - ~OCH2~NII, Rl = CH3, R2 - H, R3 - NH2~ R4 = H) The total crude product obtained in Exa~ple 5 was dissolved in methylene chloride (5 ml) and stirred with iodt?ne (0.13 g., 0.00052 moles) at ambient temperature for 16 hrs.
The reaction mixture was then concentrated to give a brown foam. The formation of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate in this reaction was shown by com-paring the nmr spectrum of the crude product with that of an authentic sample. A thin layer chromatogram using an authentic sample of the 3-iodocepham con~irmed its presence in the react-?on mixture.
_AMPLE 7 Dehydroiodination of Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate_Using P~ dine_in Benzene_ A solution of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate and pyridine in ben~ene was heated ;~
under reflux, in an oil-bath maintained at 90. Per~odically aliquots of the reaction mixture were removed and the progress of the reaction followed by analysing the nmr spectrum of the residue. The 3-iodocepham in the mixture is characterized by the C4-H singlet at ~4.9, the C6-H doublet at ~5.38 and the C~-CH2 quartet at ~2.95; the ceph-3-em is characterized by its C6-H doublet at ~5.05 and its C2-CH2 doublet at ~3.35. Any ceph-2-em produced is easily detected by its C3-CH3 singlet at ~1.92 and its C2-H signal at ~6.1. Xn all our experiments using pyridine as the base there were no detectable amounts of - 7 - ~ ?

. - ; . , ~

~ s~
the ceph-2-em isomer produced. The following tab1e summarizes the results of experiments in which the relative amount of pyridine was varied.

Dehydroiodination of 3-Iodocepham_Usin~ Pyridine In Benzene Mole Ratio of Yield of *
No. Pyridine Time of RefluxCeph-3-em IQ~)_ l. 2.5 equivalents 0.5 hr 45 2. 2.5 " l.0 hr 60 lO 3. 2.5 " 1.5 hr 67

4. S.0 equivalents 0.5 hr 50 ~:~

5. 5.0 " l.0 hr 66

6. 5O0 " 1.5 hr 80

7. S.0 " 3.0 hr ~lO0

8. lO equivalents 0.5 hr 60

9. lO " l.0 hr ~lO0 lO. lO , " 1.5 hr lO0 ~.
* There was no detectable trace of any ceph-2-em isomer in any of these experiments.

Claims (12)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. The process for the preparation of a compound of the formula:
1 wherein:
R stands for phenoxyloweralkyl;
R1 is hydrogen or lower alkyl;
R2 is hydrogen;
R3 stands for lower alkyl or amino; and R4 stands for hydrogen or phenyl, which comprises heating a penicillin sulfoxide of the general formula 2:
wherein R, R1 and R2 have the same meaning as set forth above, with a thioamide of the general formula:
3 wherein R3 and R4 have the same meaning as set forth above, in a suitable solvent.

2. The process of Claim 1, wherein penicillin V
sulfoxide is reacted with thioacetamide to form the 2-oxo-3-phenoxyacetamido-4-acetimidoyldithi o-a- isopropenylazetidin-l-acetic acid.

3. The process of Claim 1, wherein methyl penicillin V sulfoxide is reacted with thioacetamide to form the methyl 2-oxo-3-phenoxyacetamido-4-acetimidoyldithio-.alpha.-isopropenyl-azetidin-l-acetate.

4. The process of Claim 1, wherein penicillin V
sulfoxide is reacted with thioacetanilide to form the 2-oxo-3-phenoxyacetamido-4-(N-phenylacetimidoyl)dithio-.alpha.-isopropenyl-azetidin-l-acetic acid.

5. The process of Claim 1, wherein methyl penicillin V sulfoxide is reacted with thioacetanilide to form the methyl 2-oxo-3-phenoxyacetamido-4-(N-phenylacetimidoyl)dithio-.alpha.-iso-propenylazetidin-l-acetate.

6. The process of Claim 1, wherein methyl penicillin V sulfoxide is reacted with dimethylaniline to form the methyl Z-oxo-3-phenoxyacetamido-4-(aminoimidoyl)dithio-.alpha.- isopropenyl-azetidln-l-acetate.

7. The novel azetidinone imidoyldisulfides of the formula.

wherein:
R stands for phenoxyloweralkyl;

R1 is hydrogen or lower alkyli R2 is hydrogen;
R3 stands for lower alkyl or amino; and R4 stands for hydrogen or phenyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

8. The compound which is 2-oxo-3-phenoxyacetamido-4-acetimidoyldithio-.alpha.-isopropenylazetidin-l-acetic acid, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.

9. The compound which is methyl 2-oxo-3-phenoxy-acetamido-4-acetimidoyldithio-.alpha.-isopropenylazetidin-1-acetate, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

10. The compound which is 2-oxo-3-phenoxyacetamido-4-(N-phenylacetimidoyl)dithio-.alpha.-isopropenylazetidin-l-acetic acid, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

11. The compound which is methyl 2-oxo-3-phenoxy-acetamido-4-(N-phenylacetimidoyl)dithio-.alpha.-isopropenylazetidin-l-acetate, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

12. The compound which is 2-oxo-3-phenoxyacetamido-4-(aminooimidoyl)-.alpha.-isopropenylazetidin-l-acetate when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.