CA1202959A - Process for the preparation of penam derivatives - Google Patents
Process for the preparation of penam derivativesInfo
- Publication number
- CA1202959A CA1202959A CA000419908A CA419908A CA1202959A CA 1202959 A CA1202959 A CA 1202959A CA 000419908 A CA000419908 A CA 000419908A CA 419908 A CA419908 A CA 419908A CA 1202959 A CA1202959 A CA 1202959A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- group
- alkyl
- ester
- forming
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Display Devices Of Pinball Game Machines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
The preparation of a penam derivative of formula (I):
(I) wherein RA is hydrogen or a group of formula (Ia):
(Ia) wherein X is -C02R1, or S03R1; R is C1-6 alkyl, aryl, or heterocyclyl; R1 is hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolyscable ester-forming radical; which process comprises reacting a compound of formula (II):
(II) wherein RB is a removable acyl group which protects the amino function or a group of formula (IIa):
(IIa) wherein Y is -C02RX or -S03RX; n is one and m is zero or one; R is as defined with respect to formula (I) above and wherein any reactive groups may he protected;
Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol
The preparation of a penam derivative of formula (I):
(I) wherein RA is hydrogen or a group of formula (Ia):
(Ia) wherein X is -C02R1, or S03R1; R is C1-6 alkyl, aryl, or heterocyclyl; R1 is hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolyscable ester-forming radical; which process comprises reacting a compound of formula (II):
(II) wherein RB is a removable acyl group which protects the amino function or a group of formula (IIa):
(IIa) wherein Y is -C02RX or -S03RX; n is one and m is zero or one; R is as defined with respect to formula (I) above and wherein any reactive groups may he protected;
Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol
Description
RJB/~.1133 ~ ~9~
This invention relates to a process for the preparation of antibacterially active penam derivatives having a ~X-methoxy substituent.
The present invention provides a process for the preparation of a penam derivative of formula (I):
R .NH - ~ -S 1 3 I ~ CH3 (I) ~ N ~
O \ 2 wherein RA is hydrogen or a group of formula (Ia):
. R.~H.C0- (Ia) .~
~Z~;~959 ~ 2 --1 wherein X is -C02Rl, or S03Rl; R is Cl_6 alkyl, aryl, or heterocyclyl; Rl i~ hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolysable ester-forming radical; which process comprises reacting a compound of formula (II):
(O)nSR (O) . ~ m R~.NH ~-S CH3 I ~ CH3 (II) /
wherein RB is a removable acyl group which protects the amino function or a group of formula (IIa):
R.CIH.CO- (IIa) wherein Y is -CO2RX or -S03RX; n is one and m is zero or one; R is as defined with respect to formula (I) above and wherein any reactive groups may be protected;
Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol and thereafter if necessary carrying out one or more of the following steps:
(i) removal of any blocking or protecting group;
(ii) converting a compound wherein m is one to the compound wherein m is zero;
12~295~
1 (iii) converting a group Rx into a group Rl;
(iv) converting the product to a pharmaceutically acceptable salt or ester thereof.
Suitahle examples of the group R include Cl_6 alkyl; an optionally substituted 5-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen; phenyl;
mono-substituted phenyl where the substituent is halogen, hydroxy, Cl_6 alkoxy, nitro, amino, Cl_6 lo alkyl, Cl_6 haloalkyl, C1_6 alkylcarbonyloxy, or Cl_6 alkyl sulphonylamino (for example -NHS02CH3); or di-substituted phenyl where the substituents are selected from hydroxy, halogen, methoxy, acetoxy and amino.
Suitably R is phenyl; mono substituted phenyl where the substituent is fluorine, chlorine, hydroxy, methoxy, nitro, amino, acetoxy or trifluoromethyl; or di-substituted phenyl where the substituents are selected from acetoxy, hydroxy, and methoxy.
Suitable Cl_6 alkyl groups for the groups R and include methyl, ethyl, n- and iso-propyl, n-, iso_, sec- and tert-butyl.
Suitable 5-membered heterocyclic rings for the group R include furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, iso-thiazolyl, imidazolyl; each such group may be substituted by various groups for example halogen, hydroxy, amino, or Cl_6 alkyl. Particular examples of such groups include 2- or 3- thienyl and
This invention relates to a process for the preparation of antibacterially active penam derivatives having a ~X-methoxy substituent.
The present invention provides a process for the preparation of a penam derivative of formula (I):
R .NH - ~ -S 1 3 I ~ CH3 (I) ~ N ~
O \ 2 wherein RA is hydrogen or a group of formula (Ia):
. R.~H.C0- (Ia) .~
~Z~;~959 ~ 2 --1 wherein X is -C02Rl, or S03Rl; R is Cl_6 alkyl, aryl, or heterocyclyl; Rl i~ hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolysable ester-forming radical; which process comprises reacting a compound of formula (II):
(O)nSR (O) . ~ m R~.NH ~-S CH3 I ~ CH3 (II) /
wherein RB is a removable acyl group which protects the amino function or a group of formula (IIa):
R.CIH.CO- (IIa) wherein Y is -CO2RX or -S03RX; n is one and m is zero or one; R is as defined with respect to formula (I) above and wherein any reactive groups may be protected;
Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol and thereafter if necessary carrying out one or more of the following steps:
(i) removal of any blocking or protecting group;
(ii) converting a compound wherein m is one to the compound wherein m is zero;
12~295~
1 (iii) converting a group Rx into a group Rl;
(iv) converting the product to a pharmaceutically acceptable salt or ester thereof.
Suitahle examples of the group R include Cl_6 alkyl; an optionally substituted 5-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen; phenyl;
mono-substituted phenyl where the substituent is halogen, hydroxy, Cl_6 alkoxy, nitro, amino, Cl_6 lo alkyl, Cl_6 haloalkyl, C1_6 alkylcarbonyloxy, or Cl_6 alkyl sulphonylamino (for example -NHS02CH3); or di-substituted phenyl where the substituents are selected from hydroxy, halogen, methoxy, acetoxy and amino.
Suitably R is phenyl; mono substituted phenyl where the substituent is fluorine, chlorine, hydroxy, methoxy, nitro, amino, acetoxy or trifluoromethyl; or di-substituted phenyl where the substituents are selected from acetoxy, hydroxy, and methoxy.
Suitable Cl_6 alkyl groups for the groups R and include methyl, ethyl, n- and iso-propyl, n-, iso_, sec- and tert-butyl.
Suitable 5-membered heterocyclic rings for the group R include furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, iso-thiazolyl, imidazolyl; each such group may be substituted by various groups for example halogen, hydroxy, amino, or Cl_6 alkyl. Particular examples of such groups include 2- or 3- thienyl and
2-aminothiazolyl.
95~
1 Speci~ic examples of the group R include phenyl, 2- or 3- thienyl, p-hydroxyphenyl, p-aminophenyl and p-acetoxyphenyl.
Suitable acyl groups which protect the amino function for RB include, for example, the benzyloxycarbonyl group.
Suitable pharmaceutically acceptable salt-forming ions for the groups R1 and R2 include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylenediamine, l-ephenamine, N-ethyl-piperidine, N-benzyl-~-phenethylamine, dehydroabeityl-amine, N,N'-bisdehydroabietylethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with known penicillins.
The salt-forming ions included within the definition of the group RY include the above mentioned ions and also include other salt-forming ions which are not necessarily pharmaceutically acceptable.
When the group R2 represents a pharmaceutically acceptable in vivo hydrolysable ester-forming radical, such esters are those which hydrolyse readily in the human body to produce the parent acid, and include, for example, acyloxyalkyl groups such as acetoxymethyl, )2~5~
1 pivaloyloxymethyl, ~-acetoxyethyl, ~acetoxybenzyl and ~-pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and ~-ethoxy-carbonyloxyethyl; dialkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylamino-methyl or diethylaminoethyl; and lactone groups such as phthalidyl or dimethoxyphthalidyl.
The group Rl may be any of the ester-forming radicals as specified for the group R2 and in addition lo Rl may represent other pharmaceutically acceptable ester-forming groups such as alkyl, aryl or aralkyl groups any of which may be substituted. ~xamples of such groups include:
a) Cl_6 alkyl such as methyl, ethyl, n- and iso_ propyl, n-, sec-, iso_ and tert-butyl;
b) substituted Cl_6 alkyl wherein the substituent is at least one of: chloro, bromo, fluoro, nitro, C1_6alkoxy, Cl_6alkoxycarbonyl, cyano, Cl_6alkylthio, Cl_6alkylamino;
c) phenyl, benzyl or substituted phenyl or benzyl wherein the substituent is at least one of chloro, bromo, fluoro, Cl_6alkyl, Cl_6alkoxy, Cl_6alkanoyl, C1_6alkoxycarbonyl, nitro or di-(Cl_6)alkylamino.
Preferred ester-forming radicals Rl include Cl_6 alkyl, benzyl, phthalidyl, indanyl, phenyl and mono-, di-, and tri-~Cl_6)-alkyl substituted phenyl such as o-, m-, or p-~ethylphenyl, ethylphenyl, n- or lso-propylphenyl, or n-, sec-, iso_ or t-butylphenyl.
~2~il2959 1 Suitable carboxyl-blocking groups for ~he group RY are those which may be readily removed from the carboxylic acid under conventional conditions at a later stage oE the reaction. Such groups include benzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl,
95~
1 Speci~ic examples of the group R include phenyl, 2- or 3- thienyl, p-hydroxyphenyl, p-aminophenyl and p-acetoxyphenyl.
Suitable acyl groups which protect the amino function for RB include, for example, the benzyloxycarbonyl group.
Suitable pharmaceutically acceptable salt-forming ions for the groups R1 and R2 include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylenediamine, l-ephenamine, N-ethyl-piperidine, N-benzyl-~-phenethylamine, dehydroabeityl-amine, N,N'-bisdehydroabietylethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with known penicillins.
The salt-forming ions included within the definition of the group RY include the above mentioned ions and also include other salt-forming ions which are not necessarily pharmaceutically acceptable.
When the group R2 represents a pharmaceutically acceptable in vivo hydrolysable ester-forming radical, such esters are those which hydrolyse readily in the human body to produce the parent acid, and include, for example, acyloxyalkyl groups such as acetoxymethyl, )2~5~
1 pivaloyloxymethyl, ~-acetoxyethyl, ~acetoxybenzyl and ~-pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and ~-ethoxy-carbonyloxyethyl; dialkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylamino-methyl or diethylaminoethyl; and lactone groups such as phthalidyl or dimethoxyphthalidyl.
The group Rl may be any of the ester-forming radicals as specified for the group R2 and in addition lo Rl may represent other pharmaceutically acceptable ester-forming groups such as alkyl, aryl or aralkyl groups any of which may be substituted. ~xamples of such groups include:
a) Cl_6 alkyl such as methyl, ethyl, n- and iso_ propyl, n-, sec-, iso_ and tert-butyl;
b) substituted Cl_6 alkyl wherein the substituent is at least one of: chloro, bromo, fluoro, nitro, C1_6alkoxy, Cl_6alkoxycarbonyl, cyano, Cl_6alkylthio, Cl_6alkylamino;
c) phenyl, benzyl or substituted phenyl or benzyl wherein the substituent is at least one of chloro, bromo, fluoro, Cl_6alkyl, Cl_6alkoxy, Cl_6alkanoyl, C1_6alkoxycarbonyl, nitro or di-(Cl_6)alkylamino.
Preferred ester-forming radicals Rl include Cl_6 alkyl, benzyl, phthalidyl, indanyl, phenyl and mono-, di-, and tri-~Cl_6)-alkyl substituted phenyl such as o-, m-, or p-~ethylphenyl, ethylphenyl, n- or lso-propylphenyl, or n-, sec-, iso_ or t-butylphenyl.
~2~il2959 1 Suitable carboxyl-blocking groups for ~he group RY are those which may be readily removed from the carboxylic acid under conventional conditions at a later stage oE the reaction. Such groups include benzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl,
3,5-di-t-butyl-4-hydroxybenzyl, benzoylmethyl, p-nitro-benzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, allyl, acetonyl, diphenylmethyl, tri-phenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methyl-thiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula ~N=CHR
where R is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined above.
The carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular RY group, for example, acid- and base-catalysed hydrolysis, or by enzymically- catalysed hydrolysis, or by hydrogenation.
When it is desired to produce a compound of formula (I) wherein the group Rl is hydrogen or a salt-forming ion, by the process of this invention, a compound of formula (II) is employed wherein Rx is a blocking group. For the preparation of a compound of formula (I) wherein Rl is a pharmaceutically acceptable ester-forming radical, a compound of formula (II) is employed wherein Rx represents the desired Rl group.
When the group R represents p-hydroxyphenyl, it may if desired be protected by means of a group which is readily removed chemically after the process of the :~L202~9 1 invention. Such protectinq groups include benzyloxycarbonyl.
Suitable examples of the alkyl group R3 include C1_6 alkyl groups such as methyl, ethyl, n- or iso-propyl, and n-, sec-, lso_, or tert-butyl groups.
A preferred al~yl group for R3 is methyl.
Suitable examples of the aryl group R3 include phenyl, optionally substituted with Cl_6 alkyl, C1_6 alkoxy, halogen, or nitro. Preferred aryl groups for R3 include phenyl, o-, m- or ~-methylphenyl, o-, _- or p-nitrophenyl, in particular p-methylphenyl.
A suitable temperature range for the process of this invention is greater than ambient temperature, conveniently 50C to 100C, preferably at the reflux temperature of the solvent system employed. The time required for the reaction depends on the temperature - and the reagents employed. Generally, the reaction is complete within one hour. The methanol used in the process is conveniently employed as a solvent for the reaction mixtures. Other compatible co solvents may be additionally used if desired, for example, tetrahydro-furan.
The starting material for the process of this invention, ie compound of formula (II) above may suitably be prepared by oxidation of a compound of formula ~III):
1~29S9 RB-NH ~ ~ CH3 ~_ N ~ (III) wherein RB, RY and R3 are as defined with respect to formula (II) above.
The oxidation is suitably brought about using an organic per-acid as the oxidising agent. Suitable acids include m-chloroperbenzoic acid and equivalent reagents.
It is normal to carry out the oxidation in an inert solvent such as methylene chloride or the like at an ambient or depressed temperature, for example at -20C to +20C, more suitably at -12C to +5C, for example at about 0C.
The compound of formula (III) above where RB is not hydrogen, is disclosed, although not claimed, in US
Patent Wo 3,965,093. It may be prepared by acylation, under conventional conditions of the compound (III) where RB is hydrogen, ie a 6-amino compound of formula (IV) or a salt or ester thereof:
0 ~ (IV) ~2~2959 .
1 wherein R3 is as defined with respect to formula (II) above. Compounds of formula (IV) may be prepared from a Schiff's base derivative as described in US Patent No 3,965,093 or may be prepared by reacting a thiooxime compound of formula (V):
R3-S-N ~ S ~ 3 C02H (V ) (where R3 is as defined with respect to formula (II) above) with a tri(alkyl)phosphine or tri(aryl)phosphine, followed by treatment with an acid catalyst such as silica gel. That process is described in US Patent No 4,119,778 and in J Amer Chem Soc, 1977, _ , 5504.
The compounds of formula ~Il wherein RA is not hydrogen, which are prepared by the process of this invention have good antibacterial activity, as disclosed in British Patents Nos 1,538,051 and 1,538,0S2. The compounds of formula (I) wherein RA
is hydrogen are useful as chemical intermediates.
The following Examples illustrate the process of this invention.
gll.~2~59 . ~,.
~xample 1 Oxidation of Benz~ -methylthio-613-phen~lacetamido~
penicillanate A solution of benzyl ~-meth~lthio-6!3-phen~l-acetamidopenicillanate in methylene dichloride at ice-bath temperature was treated with a solution of m-chloroperbenzoic acid (1.1 eq) in methylene dichloride. After stirring at that temperature for 75 mins, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate, dried ~MgSO4) and evaporated. Chromatographic purification o~ the residue gave among others products, benzyl 6~-methyl-thio-613-phen~lacetamidopenicillanate-1-(S)-l-oxide (1) benzyl ~-methylsulphinyl-6~-phenylacetamido-penicillanate (2) and benzyl 6~-methylsulphinyl-613-phenylacetamidopenicillanate-l-(S)-l-oxide (3). These gave the following spectroscopic characteristics;
The oxide (1) ~ (CDC13) 1.06 and 1.57 (each 3H, s, gem Me2) 2.16 (3H, s, Me), 3.61 (2H, s, Ph.CH2.CO), 4.61 (lH, s, C.CH.N), 4.86 (lH, s, C.CH.S), 5.18 (2H, AB~, J 12Hz, CO2.CH2.Ph), 6.72 (lH, s, CO.NH.C), 7.30 and 7.34 (each 5H, s, aromatic H).
The penicillanate (2) max (CH2C12) 3400 (N-H), 1785 (~-lactam C=0), 1745 ~ester C=0) and 1690 (amide C=0) cm~l, S (CDC13) 1.32 and 1.39 (each 3H, s, gem Me2), 2.68 (3H, s, S(O)Me), 3.63 (2H, s, Ph.CH2C0), 4.49 (lH, s, N.CH.CO2), 5.13 (2H, s, CO2.CH2Ph), 6.01 (lH, s, C.CH.S), 7.35 and 7.37 (each 5H, s, aromatic H), and 7.51 (lH, s, CO.NH.C).
!
~v2sss The oxide (3) ~ max ( CHC13) 3450 and 3380 (N-H), 1790 (13-lactam C-0), 1755 (ester C=0), 1680 (amide C=0), and 1055 (S=0) Cm~1 S(CDC13) major isomer 1.06 and 1.58 (each 3H, S, ~ Me2), 2.57 (3H, S, S(O)Me), 3.59 (2H, S, Ph.CH2.CO), 4.74 (1H, S, N.CH,CO2), 5.20 (2H, ~Bq, J
12HZ, CO2 CH2.Ph), 5.22 (1H, S, C.CHS), 7.23 and 7.33 (each 5H, s, aromatic H), and 7.46 (lH, s, CO.NH.C).
Example 2 Thermol~sis of the Sulphoxide (2) in Methanol Benzyl 6~-methylsulphinyl-613-phenylacetamido-penicillanate (0.033g, 0.068 mmol) (prepared as in Example l) was dissolved in methanol (2. 5 ml) and the solution heated under reflux. A~ter 3 hours, when all starting material had been depleted (t~l.c), the solvent was removed under reduced pressure and the residue chromatoqraphed on silica gel to give benzyl 6~-methOXY-6I3-PhenY1aCetamidOPeniCi11anate (0.028 g, 90%) which was identical in all respects with an authentic sample (t.l.c., n.m.r., i.r.) (CDC13) 1.33 (6H, S, ~ Me2), 3.37 (3H, S, OMe), 3.60 (2H, s, Ph.CH2.C0), 4.37 (lH, s, C.CH.N), 5.16 (2H, S, CO2.CH2.Ph)r 5.46 (lH, s, C.CH.S), 6.50 (lH, s, CO.NH.C), and 7.30 and 7.35 (each 5H, S, aromatic H).
~Z~:95~
.
Example 3 Thermolysis of the Sulphoxide (3) in Methanol Benzyl 6~-methylsulphinyl-613-phenylacetamido-penicillanate-l-~S)-l-oxide (2.23g, 4.44 x 10-3 mol) (prepared as in Example 1) was taken up in methanol (100 ml) and the resul'ing solution heated under reflux. The progress of the reaction was monitored by t.l.c. and after 3.75 hours, when no starting material remained, the solvent was removed in vacuo and the residue chromatographed on silica gel to afford benæyl 6~-methoxy-613-phenyl-acetamidopenicillanate-l-(S)-l-oxide (1.98g, 95%), m.p. 123-124C (from CHC13-Et20~, V max (CH2C12) 3400 and 3300 (N-H), 1790 (~-lactam C=0), 1755 (ester C=0), 1685 ~amide C=0), and 1060 (S=0) cm~l, ~ (CDC13) 1.05 and 1.~9 (each 3H, s, gem Me2), 3.34 (3H, s, OMe), 3.63 ~2H, s, Ph.CH2.CO),
where R is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined above.
The carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular RY group, for example, acid- and base-catalysed hydrolysis, or by enzymically- catalysed hydrolysis, or by hydrogenation.
When it is desired to produce a compound of formula (I) wherein the group Rl is hydrogen or a salt-forming ion, by the process of this invention, a compound of formula (II) is employed wherein Rx is a blocking group. For the preparation of a compound of formula (I) wherein Rl is a pharmaceutically acceptable ester-forming radical, a compound of formula (II) is employed wherein Rx represents the desired Rl group.
When the group R represents p-hydroxyphenyl, it may if desired be protected by means of a group which is readily removed chemically after the process of the :~L202~9 1 invention. Such protectinq groups include benzyloxycarbonyl.
Suitable examples of the alkyl group R3 include C1_6 alkyl groups such as methyl, ethyl, n- or iso-propyl, and n-, sec-, lso_, or tert-butyl groups.
A preferred al~yl group for R3 is methyl.
Suitable examples of the aryl group R3 include phenyl, optionally substituted with Cl_6 alkyl, C1_6 alkoxy, halogen, or nitro. Preferred aryl groups for R3 include phenyl, o-, m- or ~-methylphenyl, o-, _- or p-nitrophenyl, in particular p-methylphenyl.
A suitable temperature range for the process of this invention is greater than ambient temperature, conveniently 50C to 100C, preferably at the reflux temperature of the solvent system employed. The time required for the reaction depends on the temperature - and the reagents employed. Generally, the reaction is complete within one hour. The methanol used in the process is conveniently employed as a solvent for the reaction mixtures. Other compatible co solvents may be additionally used if desired, for example, tetrahydro-furan.
The starting material for the process of this invention, ie compound of formula (II) above may suitably be prepared by oxidation of a compound of formula ~III):
1~29S9 RB-NH ~ ~ CH3 ~_ N ~ (III) wherein RB, RY and R3 are as defined with respect to formula (II) above.
The oxidation is suitably brought about using an organic per-acid as the oxidising agent. Suitable acids include m-chloroperbenzoic acid and equivalent reagents.
It is normal to carry out the oxidation in an inert solvent such as methylene chloride or the like at an ambient or depressed temperature, for example at -20C to +20C, more suitably at -12C to +5C, for example at about 0C.
The compound of formula (III) above where RB is not hydrogen, is disclosed, although not claimed, in US
Patent Wo 3,965,093. It may be prepared by acylation, under conventional conditions of the compound (III) where RB is hydrogen, ie a 6-amino compound of formula (IV) or a salt or ester thereof:
0 ~ (IV) ~2~2959 .
1 wherein R3 is as defined with respect to formula (II) above. Compounds of formula (IV) may be prepared from a Schiff's base derivative as described in US Patent No 3,965,093 or may be prepared by reacting a thiooxime compound of formula (V):
R3-S-N ~ S ~ 3 C02H (V ) (where R3 is as defined with respect to formula (II) above) with a tri(alkyl)phosphine or tri(aryl)phosphine, followed by treatment with an acid catalyst such as silica gel. That process is described in US Patent No 4,119,778 and in J Amer Chem Soc, 1977, _ , 5504.
The compounds of formula ~Il wherein RA is not hydrogen, which are prepared by the process of this invention have good antibacterial activity, as disclosed in British Patents Nos 1,538,051 and 1,538,0S2. The compounds of formula (I) wherein RA
is hydrogen are useful as chemical intermediates.
The following Examples illustrate the process of this invention.
gll.~2~59 . ~,.
~xample 1 Oxidation of Benz~ -methylthio-613-phen~lacetamido~
penicillanate A solution of benzyl ~-meth~lthio-6!3-phen~l-acetamidopenicillanate in methylene dichloride at ice-bath temperature was treated with a solution of m-chloroperbenzoic acid (1.1 eq) in methylene dichloride. After stirring at that temperature for 75 mins, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate, dried ~MgSO4) and evaporated. Chromatographic purification o~ the residue gave among others products, benzyl 6~-methyl-thio-613-phen~lacetamidopenicillanate-1-(S)-l-oxide (1) benzyl ~-methylsulphinyl-6~-phenylacetamido-penicillanate (2) and benzyl 6~-methylsulphinyl-613-phenylacetamidopenicillanate-l-(S)-l-oxide (3). These gave the following spectroscopic characteristics;
The oxide (1) ~ (CDC13) 1.06 and 1.57 (each 3H, s, gem Me2) 2.16 (3H, s, Me), 3.61 (2H, s, Ph.CH2.CO), 4.61 (lH, s, C.CH.N), 4.86 (lH, s, C.CH.S), 5.18 (2H, AB~, J 12Hz, CO2.CH2.Ph), 6.72 (lH, s, CO.NH.C), 7.30 and 7.34 (each 5H, s, aromatic H).
The penicillanate (2) max (CH2C12) 3400 (N-H), 1785 (~-lactam C=0), 1745 ~ester C=0) and 1690 (amide C=0) cm~l, S (CDC13) 1.32 and 1.39 (each 3H, s, gem Me2), 2.68 (3H, s, S(O)Me), 3.63 (2H, s, Ph.CH2C0), 4.49 (lH, s, N.CH.CO2), 5.13 (2H, s, CO2.CH2Ph), 6.01 (lH, s, C.CH.S), 7.35 and 7.37 (each 5H, s, aromatic H), and 7.51 (lH, s, CO.NH.C).
!
~v2sss The oxide (3) ~ max ( CHC13) 3450 and 3380 (N-H), 1790 (13-lactam C-0), 1755 (ester C=0), 1680 (amide C=0), and 1055 (S=0) Cm~1 S(CDC13) major isomer 1.06 and 1.58 (each 3H, S, ~ Me2), 2.57 (3H, S, S(O)Me), 3.59 (2H, S, Ph.CH2.CO), 4.74 (1H, S, N.CH,CO2), 5.20 (2H, ~Bq, J
12HZ, CO2 CH2.Ph), 5.22 (1H, S, C.CHS), 7.23 and 7.33 (each 5H, s, aromatic H), and 7.46 (lH, s, CO.NH.C).
Example 2 Thermol~sis of the Sulphoxide (2) in Methanol Benzyl 6~-methylsulphinyl-613-phenylacetamido-penicillanate (0.033g, 0.068 mmol) (prepared as in Example l) was dissolved in methanol (2. 5 ml) and the solution heated under reflux. A~ter 3 hours, when all starting material had been depleted (t~l.c), the solvent was removed under reduced pressure and the residue chromatoqraphed on silica gel to give benzyl 6~-methOXY-6I3-PhenY1aCetamidOPeniCi11anate (0.028 g, 90%) which was identical in all respects with an authentic sample (t.l.c., n.m.r., i.r.) (CDC13) 1.33 (6H, S, ~ Me2), 3.37 (3H, S, OMe), 3.60 (2H, s, Ph.CH2.C0), 4.37 (lH, s, C.CH.N), 5.16 (2H, S, CO2.CH2.Ph)r 5.46 (lH, s, C.CH.S), 6.50 (lH, s, CO.NH.C), and 7.30 and 7.35 (each 5H, S, aromatic H).
~Z~:95~
.
Example 3 Thermolysis of the Sulphoxide (3) in Methanol Benzyl 6~-methylsulphinyl-613-phenylacetamido-penicillanate-l-~S)-l-oxide (2.23g, 4.44 x 10-3 mol) (prepared as in Example 1) was taken up in methanol (100 ml) and the resul'ing solution heated under reflux. The progress of the reaction was monitored by t.l.c. and after 3.75 hours, when no starting material remained, the solvent was removed in vacuo and the residue chromatographed on silica gel to afford benæyl 6~-methoxy-613-phenyl-acetamidopenicillanate-l-(S)-l-oxide (1.98g, 95%), m.p. 123-124C (from CHC13-Et20~, V max (CH2C12) 3400 and 3300 (N-H), 1790 (~-lactam C=0), 1755 (ester C=0), 1685 ~amide C=0), and 1060 (S=0) cm~l, ~ (CDC13) 1.05 and 1.~9 (each 3H, s, gem Me2), 3.34 (3H, s, OMe), 3.63 ~2H, s, Ph.CH2.CO),
4.64 (lH, s, N.CH.CO2), 4.93 (lH, s, C.CH.S), 5.21 (2H, ABq, J 12Hz, CO2.CH2.Ph), 7.05 (lH, s, CO.NH.C), and 7.29 and 7.35 (each 5H, s, aromatic H), m/e 470 (M+) and 91 (C7H7+t base peak). (Found : C, 61.44; H, 5.70;
N, 5.80; S, 6.44; M+, 470.1532. C24H26N206S requires C, 61.26; H, 5.57; N, 5.95; S, 6.81%; Ml 470.1511).
Example 4 Oxidation of Benzyl 613-[2-(2-methylphenoxycarbonyl)-2~
(3-thienyl)acetamido]-6~-(4-methylpheny])thio-penicillanate (7) Benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6~-(4-methylphenyl)thio-penicillanate in methylene dichloride at 0C was treated with a solution of m-chloroperbenzoic acid (1.1 eq) in methylene dichloride. ~lork-up as described in Example 1 gave, among other products benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)-acetamido]-6~-(4-methylphenyl)-sulphinylpenicillanate ~4) and benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]~ (4-methyl~henyl)sulphinyl-penicillanate-l-oxide (5). These gave the following spectral characteristics;
The penicillanate (4) ~ (CDC13) inter alia 1.30 (s, gem Me2), 2.10 and 2.37 (each s~ 2xPh.Me), 4.44 (s, N.CH.C), 4.89 (S.CO.CH.CO), 5.17 (s, CO2CH2.Ph), 6.07 (s, C.CH.S), and 6.9-7.6 (m, CO.NH.C and aromatic H).
The oxide (5) ;~ max (CHC13) 3240 (N-H, 1795 (13-lactam C=0), 1745 (ester C=0), and 1680 (amide C=0) cm~l, ~ (CDC13) 1.10 and 1.24 (each 3H, s, ~ e2), 2.12 and 2.32 (each 3H, s, 2xPh.Me), 4.66 (lH, s, N.CH.C), 5.20 (lH, s, CO.CH.CO), 5.24 (2H, ABq, J 12 Hz, CO2CH2.Ph), 5.35 (lH, s, C.CH.S), and 7.0-7.5 (17H, m, CO.NH.C and aromatic H).
s9 Example 5 Ther~olysis of the Sulphoxide (4) in Methanol A solution of benzyl 6~-[2-(2-methylpheno~y-carbonylj-2-(3-thienyl)-acetamido]-6~-(4-methylphenyl)-sulphinylpenicillanate (prepared as in Example 4) in methanol was heated under reflux. After 7.5 hours, the solvent was evaporated in vacuo and the residue chromatoyraphed on silica gel to give, among other products, benzyl 6t3-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6~-methoxypenicillanate. It exhibited the following characteristics;
V max (CH2C12) 3400 (N-H), 1780 (~-lactam C=0), 1745 (ester C=0), and 1700 (amide C=0) cm~l, ~(CDC13) 1.34 (6H, s, gem Me2), 2.12 (3H, s, Ph.Me), 3.46 (3H, s, OMe), 4.47 (lH, s, N.CH.CO2), 5.08 (lH, s, C.CH.S),
N, 5.80; S, 6.44; M+, 470.1532. C24H26N206S requires C, 61.26; H, 5.57; N, 5.95; S, 6.81%; Ml 470.1511).
Example 4 Oxidation of Benzyl 613-[2-(2-methylphenoxycarbonyl)-2~
(3-thienyl)acetamido]-6~-(4-methylpheny])thio-penicillanate (7) Benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6~-(4-methylphenyl)thio-penicillanate in methylene dichloride at 0C was treated with a solution of m-chloroperbenzoic acid (1.1 eq) in methylene dichloride. ~lork-up as described in Example 1 gave, among other products benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)-acetamido]-6~-(4-methylphenyl)-sulphinylpenicillanate ~4) and benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]~ (4-methyl~henyl)sulphinyl-penicillanate-l-oxide (5). These gave the following spectral characteristics;
The penicillanate (4) ~ (CDC13) inter alia 1.30 (s, gem Me2), 2.10 and 2.37 (each s~ 2xPh.Me), 4.44 (s, N.CH.C), 4.89 (S.CO.CH.CO), 5.17 (s, CO2CH2.Ph), 6.07 (s, C.CH.S), and 6.9-7.6 (m, CO.NH.C and aromatic H).
The oxide (5) ;~ max (CHC13) 3240 (N-H, 1795 (13-lactam C=0), 1745 (ester C=0), and 1680 (amide C=0) cm~l, ~ (CDC13) 1.10 and 1.24 (each 3H, s, ~ e2), 2.12 and 2.32 (each 3H, s, 2xPh.Me), 4.66 (lH, s, N.CH.C), 5.20 (lH, s, CO.CH.CO), 5.24 (2H, ABq, J 12 Hz, CO2CH2.Ph), 5.35 (lH, s, C.CH.S), and 7.0-7.5 (17H, m, CO.NH.C and aromatic H).
s9 Example 5 Ther~olysis of the Sulphoxide (4) in Methanol A solution of benzyl 6~-[2-(2-methylpheno~y-carbonylj-2-(3-thienyl)-acetamido]-6~-(4-methylphenyl)-sulphinylpenicillanate (prepared as in Example 4) in methanol was heated under reflux. After 7.5 hours, the solvent was evaporated in vacuo and the residue chromatoyraphed on silica gel to give, among other products, benzyl 6t3-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6~-methoxypenicillanate. It exhibited the following characteristics;
V max (CH2C12) 3400 (N-H), 1780 (~-lactam C=0), 1745 (ester C=0), and 1700 (amide C=0) cm~l, ~(CDC13) 1.34 (6H, s, gem Me2), 2.12 (3H, s, Ph.Me), 3.46 (3H, s, OMe), 4.47 (lH, s, N.CH.CO2), 5.08 (lH, s, C.CH.S),
5.23 (2HI s, C~2.CH2.Ph), 5.64 (lH, s, CO2.CH.CO),
6.9-7.7 (12H, m, aromatic H), and 7.85 (lH, s, CO.NH.C).
Example 6 Thermolysis of the Sulphoxide (5) in Methanol Benzyl 6~-[2-(2-methylphenoxycarbonyl-2-(3-thienyl)acetamido3-6~-(4-methylphenyl)sulphinylpeni-cillanate-l-oxide (0.059g, 8.22x10-5 mol) (prepared as in Example 4) was taken up in methanol (5 ml) and the solution heated under reflux. After 12 hours, the solvent was removed under reduced pressure and the residue chromatographed on silica gel to give, as the first eluted product benzyl-6~-methoxy-6t3-[2-(2-methyl-phenoxycarbonyl)-2-(3-thienyl)acetamido]penicillanate-1-(S)-l-oxide (0.016g, 32%), V max (CHC13) 3400 (N-H), 1790 (13-lactam C=0), 1745 br (ester C=0's), and 1690 i~Q29S9 (amide C=0) cm~l, (CDC13), 1.06 and 1.58 (each 3H, s, gem Me2), 2.03 and 2~11 (3H, each s, CO2.Ph.Me), 3.45 and 3.46 (3H, each s, OMe), 4.61 (lH, s, N.CH.CO2), ~.95 and 4.98 (lH, each s, C.CH.S), 5.01 and 5.08 (lH, each s, CO2.CH.C0), 5.17 (lEI, d, J llHz, CO2.CHH.Ph), 5.31 (lH, dd, J 11 and 1.5Hz, CO2.CHH.Ph),6.98 and 8.02 (lH, each s, CO.NH.C), and 7.0-7.6 (12H,m, aromatic H).
The second eluted product was benzyl 6~-methoxy-6~-[2-methoxycarbonyl-2-(3-thienyl)acetamido]peni-cillanate-l-(S)-l-oxide (0.009g, 20~ ~ax (CHC13) 3390 (N-H), 1790 (13-lactam C=0), 1740 and 1730 (ester C=0) and 1690 (amide C=0~ cm~l, S(CDC13) 1.05 and 1.57 (each 3H, s, gem Me2), 3.42 and 3.45 (3H, each s, OMe), 3 77 (3H, s, CO2Me), 4.60 and 4.63 (lH, each s, N.CH.CO2), 4.71 and 4.83 (lH, each s, C.CH.S), 4.91 and 4.94 (lH, each s, CO2.CH.CO), 5.17 (lH, dd, J 12 and 2Hz, C02.CHH.Ph), 5.31 (lH, d, J 12Hz, CO2.CHH.Ph),
Example 6 Thermolysis of the Sulphoxide (5) in Methanol Benzyl 6~-[2-(2-methylphenoxycarbonyl-2-(3-thienyl)acetamido3-6~-(4-methylphenyl)sulphinylpeni-cillanate-l-oxide (0.059g, 8.22x10-5 mol) (prepared as in Example 4) was taken up in methanol (5 ml) and the solution heated under reflux. After 12 hours, the solvent was removed under reduced pressure and the residue chromatographed on silica gel to give, as the first eluted product benzyl-6~-methoxy-6t3-[2-(2-methyl-phenoxycarbonyl)-2-(3-thienyl)acetamido]penicillanate-1-(S)-l-oxide (0.016g, 32%), V max (CHC13) 3400 (N-H), 1790 (13-lactam C=0), 1745 br (ester C=0's), and 1690 i~Q29S9 (amide C=0) cm~l, (CDC13), 1.06 and 1.58 (each 3H, s, gem Me2), 2.03 and 2~11 (3H, each s, CO2.Ph.Me), 3.45 and 3.46 (3H, each s, OMe), 4.61 (lH, s, N.CH.CO2), ~.95 and 4.98 (lH, each s, C.CH.S), 5.01 and 5.08 (lH, each s, CO2.CH.C0), 5.17 (lEI, d, J llHz, CO2.CHH.Ph), 5.31 (lH, dd, J 11 and 1.5Hz, CO2.CHH.Ph),6.98 and 8.02 (lH, each s, CO.NH.C), and 7.0-7.6 (12H,m, aromatic H).
The second eluted product was benzyl 6~-methoxy-6~-[2-methoxycarbonyl-2-(3-thienyl)acetamido]peni-cillanate-l-(S)-l-oxide (0.009g, 20~ ~ax (CHC13) 3390 (N-H), 1790 (13-lactam C=0), 1740 and 1730 (ester C=0) and 1690 (amide C=0~ cm~l, S(CDC13) 1.05 and 1.57 (each 3H, s, gem Me2), 3.42 and 3.45 (3H, each s, OMe), 3 77 (3H, s, CO2Me), 4.60 and 4.63 (lH, each s, N.CH.CO2), 4.71 and 4.83 (lH, each s, C.CH.S), 4.91 and 4.94 (lH, each s, CO2.CH.CO), 5.17 (lH, dd, J 12 and 2Hz, C02.CHH.Ph), 5.31 (lH, d, J 12Hz, CO2.CHH.Ph),
7.02 and 8.17 (lH, each s, CO.NH.C), and 7.1-7.5 (8H, m, aromatic H).
Example 7 Oxidation of Benzyl-6!3-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6~-methylthiopenicillanate The above penicillanate in methylene dichloride at 0~C was treated with a solution of m-chloroperbenzoic acid (1.1 eq) in methylene dichloride. Work-up as described in Example 1 gave, among other products, benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl) acetamido]-6d~methylsulphinylpenicillanate (6) and benzyl 6~-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)-acetamido]-~-methylsulphinylpenicillanate-l-oxide (7). These gave the following characteristics;
~2!11 Z~5g .
The penicillanate (6) ~ (CDC13) 1.3 br (6H, s, gem Me2), 2.05 (3H, s, Ph.Me), 2.70 (3H, s, S(0)Me), 4.50 (lH, s, N.CH.C), 5.05 (lH, s, CO.CH.C0), 5.10 (2H, s, CO2.CE~2Ph), 6.03 (lH, s, C.CH.S), 7.0-7.6 (12H, m, aromatic H), and ~.30 br (lH, s, CO.NH.C).
The oxide (7) ~ (CDC13) 1.00 and 1.50 (each 3H, s, gem Me2), 2.05 (3H, s, Ph.Me), 2.53 and 2.74 (3H, each s, S(0)Me), 4.65 and 4.78 (lH, each s, N.CH.C), 5.00-5.35 (4H, m, CO2.C~2.Ph, CO.CH.C0, and C.CH.S), and 6.90-7.60 (lH, m, C~.NH.C and aromatic H).
Example 8 Thermolysis of the Sulphoxide (6) Benzyl 613-~2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6 -methylsulphinylpenicillanate (0.090g, 0.144 mmol) ~prepared as in Example 7) was dissolved in methanol (5 ml) and the solution heated under reflux for 1 hour. The solvent was then-removed under reduced pressure and the residue chromato~raphed on silica gel to give Benzyl 6a-methoxy-6!3-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-penicillanate (0.075g, 90%).
Example 9 Oxidation of the mono-Sulphoxide (1) Benzyl 6a methylthio-6!3-phenylacetamido-penicillanate-l-(S)-l-oxide (0.179g) in methylene dichloride (10 ml) at 0C was treated with m-chloroper-benzoic acid (0.076 g) in methylene dichloride for 45 mins. Work-up and chromatography, as described in Example 1 gave the bis-sulphoxide (3) (0.052 g).
Example 10 Reaction of Benzyl 6p~- Methoxy-6,!3[2(2-methyl-phenoxycarbonyl)-2-(3-thienyl) acetamido] penicillanate -l-(S)-l-oxide with Phosphorous Tribromide Benzyl-6~-methoxy-6~-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]penicillanate-1-(S)-l-oxide (0.063g, 0.103 mmol) (prepared as in Example 6) was taken up in dimethylformamide (1 ml), the solution cooled in an ice bath, and phosphorous tribromide (0.043 g, 0.159 mmol) added in one portion. Progress of the reaction was monitored (t.l.c) and after 55 mins, when all reactant had been depleted, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (2x), followed by saturated brine. The separated organic layer was dried (r1gso4)~ and evaporated to give as residue benzyl 6~-methoxy-6!3-[2-(2-methylphenoxy-carbonyl)-2-(3-thienyl)acetamido]penicillanate (0.058g, 95%) which was identical in all respects (t.l.c., n.m.r., i.r.) with an authentic sample.
Example 11 Reaction of the Sulphoxide (3) with Methanol Benzyl ~-methylsulphinyl-6!3-phenylacetamido-penicillanate-l-(S)-l-oxide (prepared as in Example 1) was taken up in methanol and the homogeneous solution allowed to stand at 25C. Progress of the reaction was monitored by t.l.c. and after 12 days, when no reactant remained, the methanol ~as removed under reduced pressure. Examination of the residue (n.m.r. i.r. and t.l.c) showed only the presence of benzyl 6~-methoxy-6~3-phenylacetamidopenicillanate-1-(S)-l-oxide.
~959 Example 12 Reaction of the Sulphoxide (3) with Methanol in the presence of Triethylamine A solution oE benzyl ~-methylsulphinyl-6!3-phenyl-acetamido-l-(S)l-oxide (prepared as in Example 1) (0,050 9, 9.96x10-5 mmol) in methanol (3 ml) was stirred with triethylamine (0.01g, 14 ~1, 9.96x10-5 mmol) at room temperature. After 24 hours the methanol was removed in vacuo the residue taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The separated organic phase was dried (MgSO4) and evaporated to give a residue which was subjected to purification by silica gel column chromatography. The first-eluted product was identical in all respect (i.r., n.m.r., t.l.c.) to the [6~-methoxypenicillin sulphoxide of Example 11 (0.019 g, 40~). The second~eluted component was methyl 6~-methoxy-6~-phenylacetamidopenicillanate-l-(S)-l-oxide (0.008g, 23%); max (CHC13) 3400 (N-H), 1790 (!3-lactam C=0), 1750 (ester C=0) and 1680 (amide C=0)cm~l, (CDC13) 1.23 and 1.66 (each 3H, s, gem Me2), 3.40 (3H, s, OMe), 3.66 (2H, s, Ph.CH2.C0), 3.80 (3H, s, CO3Me), 4.59 (lH, s, N.CH.C), 4.98 (lH, s, C.CH.S), 6.50 br (lH, s, CO.NH.C), and 7.2-7.4 (5H, m, aromatics).
Example 7 Oxidation of Benzyl-6!3-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6~-methylthiopenicillanate The above penicillanate in methylene dichloride at 0~C was treated with a solution of m-chloroperbenzoic acid (1.1 eq) in methylene dichloride. Work-up as described in Example 1 gave, among other products, benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl) acetamido]-6d~methylsulphinylpenicillanate (6) and benzyl 6~-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)-acetamido]-~-methylsulphinylpenicillanate-l-oxide (7). These gave the following characteristics;
~2!11 Z~5g .
The penicillanate (6) ~ (CDC13) 1.3 br (6H, s, gem Me2), 2.05 (3H, s, Ph.Me), 2.70 (3H, s, S(0)Me), 4.50 (lH, s, N.CH.C), 5.05 (lH, s, CO.CH.C0), 5.10 (2H, s, CO2.CE~2Ph), 6.03 (lH, s, C.CH.S), 7.0-7.6 (12H, m, aromatic H), and ~.30 br (lH, s, CO.NH.C).
The oxide (7) ~ (CDC13) 1.00 and 1.50 (each 3H, s, gem Me2), 2.05 (3H, s, Ph.Me), 2.53 and 2.74 (3H, each s, S(0)Me), 4.65 and 4.78 (lH, each s, N.CH.C), 5.00-5.35 (4H, m, CO2.C~2.Ph, CO.CH.C0, and C.CH.S), and 6.90-7.60 (lH, m, C~.NH.C and aromatic H).
Example 8 Thermolysis of the Sulphoxide (6) Benzyl 613-~2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-6 -methylsulphinylpenicillanate (0.090g, 0.144 mmol) ~prepared as in Example 7) was dissolved in methanol (5 ml) and the solution heated under reflux for 1 hour. The solvent was then-removed under reduced pressure and the residue chromato~raphed on silica gel to give Benzyl 6a-methoxy-6!3-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-penicillanate (0.075g, 90%).
Example 9 Oxidation of the mono-Sulphoxide (1) Benzyl 6a methylthio-6!3-phenylacetamido-penicillanate-l-(S)-l-oxide (0.179g) in methylene dichloride (10 ml) at 0C was treated with m-chloroper-benzoic acid (0.076 g) in methylene dichloride for 45 mins. Work-up and chromatography, as described in Example 1 gave the bis-sulphoxide (3) (0.052 g).
Example 10 Reaction of Benzyl 6p~- Methoxy-6,!3[2(2-methyl-phenoxycarbonyl)-2-(3-thienyl) acetamido] penicillanate -l-(S)-l-oxide with Phosphorous Tribromide Benzyl-6~-methoxy-6~-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)acetamido]penicillanate-1-(S)-l-oxide (0.063g, 0.103 mmol) (prepared as in Example 6) was taken up in dimethylformamide (1 ml), the solution cooled in an ice bath, and phosphorous tribromide (0.043 g, 0.159 mmol) added in one portion. Progress of the reaction was monitored (t.l.c) and after 55 mins, when all reactant had been depleted, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (2x), followed by saturated brine. The separated organic layer was dried (r1gso4)~ and evaporated to give as residue benzyl 6~-methoxy-6!3-[2-(2-methylphenoxy-carbonyl)-2-(3-thienyl)acetamido]penicillanate (0.058g, 95%) which was identical in all respects (t.l.c., n.m.r., i.r.) with an authentic sample.
Example 11 Reaction of the Sulphoxide (3) with Methanol Benzyl ~-methylsulphinyl-6!3-phenylacetamido-penicillanate-l-(S)-l-oxide (prepared as in Example 1) was taken up in methanol and the homogeneous solution allowed to stand at 25C. Progress of the reaction was monitored by t.l.c. and after 12 days, when no reactant remained, the methanol ~as removed under reduced pressure. Examination of the residue (n.m.r. i.r. and t.l.c) showed only the presence of benzyl 6~-methoxy-6~3-phenylacetamidopenicillanate-1-(S)-l-oxide.
~959 Example 12 Reaction of the Sulphoxide (3) with Methanol in the presence of Triethylamine A solution oE benzyl ~-methylsulphinyl-6!3-phenyl-acetamido-l-(S)l-oxide (prepared as in Example 1) (0,050 9, 9.96x10-5 mmol) in methanol (3 ml) was stirred with triethylamine (0.01g, 14 ~1, 9.96x10-5 mmol) at room temperature. After 24 hours the methanol was removed in vacuo the residue taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The separated organic phase was dried (MgSO4) and evaporated to give a residue which was subjected to purification by silica gel column chromatography. The first-eluted product was identical in all respect (i.r., n.m.r., t.l.c.) to the [6~-methoxypenicillin sulphoxide of Example 11 (0.019 g, 40~). The second~eluted component was methyl 6~-methoxy-6~-phenylacetamidopenicillanate-l-(S)-l-oxide (0.008g, 23%); max (CHC13) 3400 (N-H), 1790 (!3-lactam C=0), 1750 (ester C=0) and 1680 (amide C=0)cm~l, (CDC13) 1.23 and 1.66 (each 3H, s, gem Me2), 3.40 (3H, s, OMe), 3.66 (2H, s, Ph.CH2.C0), 3.80 (3H, s, CO3Me), 4.59 (lH, s, N.CH.C), 4.98 (lH, s, C.CH.S), 6.50 br (lH, s, CO.NH.C), and 7.2-7.4 (5H, m, aromatics).
Claims (11)
IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a penam derivative of formula (I):
(I) wherein RA is hydrogen or a group of formula (Ia):
(Ia) wherein X is -C02Rl, or SO3Rl; R is C1-6 alkyl, aryl, or heterocyclyl; R1 is hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolysable ester-forming radical; which process comprises reacting a compound of formula (II):
(II) wherein RB is a removable acyl group which protects the amino function or a group of formula (IIa):
(IIa) wherein Y is -CO2Rx or -SO3Rx; n is one and m is zero or one; R is as defined with respect for formula (I) above and wherein any reactive groups may be pro-tected; Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol and thereafter if necessary carrying out one or more of the following steps:
(i) removal of any blocking or protecting group;
(ii) converting a compound wherein m is one to the compound wherein m is zero;
(iii) converting a group Rx into a group R1;
(iv) converting the product to a pharmaceutically acceptable salt or ester thereof.
(I) wherein RA is hydrogen or a group of formula (Ia):
(Ia) wherein X is -C02Rl, or SO3Rl; R is C1-6 alkyl, aryl, or heterocyclyl; R1 is hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolysable ester-forming radical; which process comprises reacting a compound of formula (II):
(II) wherein RB is a removable acyl group which protects the amino function or a group of formula (IIa):
(IIa) wherein Y is -CO2Rx or -SO3Rx; n is one and m is zero or one; R is as defined with respect for formula (I) above and wherein any reactive groups may be pro-tected; Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol and thereafter if necessary carrying out one or more of the following steps:
(i) removal of any blocking or protecting group;
(ii) converting a compound wherein m is one to the compound wherein m is zero;
(iii) converting a group Rx into a group R1;
(iv) converting the product to a pharmaceutically acceptable salt or ester thereof.
2. A process as claimed in claim 1 wherein R1 is hydrogen or a salt forming ion.
3. A process as claimed in claim 1 wherein R is a carboxyl blocking group.
4. A process as claimed in claims 1 or 3 wherein R is a pharmaceu-tically acceptable ester - forming radical.
5. A process as claimed in claim 1 wherein R is C1-6 alkyl; an optionally substituted 5-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen; phenyl; mono-substituted phenyl where the substituent is halogen, hydroxy, C1-6 alkoxy, nitro, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylcarbonyloxy, or C1-6 alkyl sulphonylamino;
or di-substituted phenyl where the substituents are selected from hydroxy, halogen, methoxy, acetoxy and amino.
or di-substituted phenyl where the substituents are selected from hydroxy, halogen, methoxy, acetoxy and amino.
6. A process as claimed in claim 5 wherein R is phenyl; mono-substi-tuted phenyl where the substituent is fluorine, chlorine, hydroxy, methoxy, nitro, amino, acetoxy or trifluoromethyl; or di-substituted phenyl where the substituents are selected from acetoxy, hydroxy, and methoxy.
7. A process as claimed in claim 6 in which R is 2-aminothiazoly or 2 or 3 thienyl.
8. A process as claimed in claim 1 wherein R3 is C1-6 alkyl.
9. A process as claimed in claim 8 wherein R3 is methyl.
10. A process for the preparation of a compound of formula (II) by oxidation of a compound of formula (III):
(III) wherein RB, RY and R3 are as defined with respect to formula (II) in claim 1.
(III) wherein RB, RY and R3 are as defined with respect to formula (II) in claim 1.
11. A process as claimed in claim 10 wherein the oxidation is brought about using an organic per-acid as oxidising agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8201754 | 1982-01-22 | ||
| GB8201754 | 1982-01-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1202959A true CA1202959A (en) | 1986-04-08 |
Family
ID=10527792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000419908A Expired CA1202959A (en) | 1982-01-22 | 1983-01-20 | Process for the preparation of penam derivatives |
Country Status (12)
| Country | Link |
|---|---|
| KR (1) | KR840003257A (en) |
| AT (2) | AT381095B (en) |
| CA (1) | CA1202959A (en) |
| DK (1) | DK23083A (en) |
| ES (2) | ES8407054A1 (en) |
| FI (1) | FI830193L (en) |
| GR (1) | GR77868B (en) |
| JO (1) | JO1228B1 (en) |
| MX (1) | MX155039A (en) |
| NO (1) | NO830184L (en) |
| PL (2) | PL240237A1 (en) |
| PT (1) | PT76127A (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE811314A (en) * | 1973-03-15 | 1974-08-20 | PROCESS FOR THE PREPARATION OF CEPHALOSPORINS AND PENICILLINS | |
| NZ195030A (en) * | 1979-10-09 | 1983-06-17 | Beecham Group Ltd | Preparation of 6 -methoxy-penam derivatives |
-
1983
- 1983-01-19 JO JO19831228A patent/JO1228B1/en active
- 1983-01-20 MX MX6997A patent/MX155039A/en unknown
- 1983-01-20 PL PL24023783A patent/PL240237A1/en unknown
- 1983-01-20 NO NO830184A patent/NO830184L/en unknown
- 1983-01-20 DK DK23083A patent/DK23083A/en not_active Application Discontinuation
- 1983-01-20 GR GR70301A patent/GR77868B/el unknown
- 1983-01-20 PL PL24419583A patent/PL244195A1/en unknown
- 1983-01-20 FI FI830193A patent/FI830193L/en not_active Application Discontinuation
- 1983-01-20 PT PT76127A patent/PT76127A/en unknown
- 1983-01-20 CA CA000419908A patent/CA1202959A/en not_active Expired
- 1983-01-21 AT AT0020483A patent/AT381095B/en not_active IP Right Cessation
- 1983-01-21 KR KR1019830000223A patent/KR840003257A/en not_active Application Discontinuation
- 1983-01-21 ES ES519191A patent/ES8407054A1/en not_active Expired
-
1984
- 1984-04-09 ES ES531428A patent/ES8506721A1/en not_active Expired
-
1985
- 1985-09-02 AT AT0256085A patent/AT384611B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI830193L (en) | 1983-07-23 |
| MX155039A (en) | 1988-01-22 |
| PT76127A (en) | 1983-02-01 |
| AT384611B (en) | 1987-12-10 |
| ATA256085A (en) | 1987-05-15 |
| ATA20483A (en) | 1986-01-15 |
| DK23083A (en) | 1983-07-23 |
| ES519191A0 (en) | 1984-08-16 |
| ES531428A0 (en) | 1985-07-16 |
| ES8506721A1 (en) | 1985-07-16 |
| ES8407054A1 (en) | 1984-08-16 |
| PL244195A1 (en) | 1984-09-10 |
| NO830184L (en) | 1983-07-25 |
| DK23083D0 (en) | 1983-01-20 |
| KR840003257A (en) | 1984-08-20 |
| PL240237A1 (en) | 1984-02-27 |
| JO1228B1 (en) | 1985-04-20 |
| GR77868B (en) | 1984-09-25 |
| FI830193A0 (en) | 1983-01-20 |
| AT381095B (en) | 1986-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4539149A (en) | β-Lactam antibacterial agents | |
| IE49881B1 (en) | B-lactam intermediates | |
| GB2129421A (en) | Derivatives of 6 beta -hydroxalkyl- penicillanic acids as beta -lactamase inhibitors | |
| EP0114752B1 (en) | Beta-lactam antibacterial agents | |
| JPH0217557B2 (en) | ||
| CA1202959A (en) | Process for the preparation of penam derivatives | |
| EP0131174B1 (en) | Substituted phenylglycine derivatives of beta-lactam antibiotics | |
| US4062842A (en) | Method for preparing 7-substituted cephalosporins and 6-substituted penicillins by replacement of sulfur-containing groups | |
| EP0115405B1 (en) | Process for the preparation of beta-lactam compounds | |
| US3968109A (en) | Production of 2-(thio substituted)cephalosporin sulfoxides and 2-(thio substituted)cephalosporins | |
| US4308259A (en) | Penicillin derivatives | |
| EP0114750A2 (en) | Beta-lactam antibacterial agents | |
| US3941779A (en) | Method for producing 2-(substituted thio)-3-cephem derivatives | |
| US4260625A (en) | Penicillins | |
| EP0066373B1 (en) | Beta-lactam derivatives, a process for their preparation and compositions containing them | |
| EP0114751B1 (en) | Beta-lactam antibacterial agents | |
| WO1984002911A1 (en) | beta-LACTAM ANTIBACTERIAL AGENTS | |
| EP0070103B1 (en) | Process for the preparation of penam derivatives | |
| EP0166377A1 (en) | Process for the preparation of beta-lactam compounds and intermediates therefor | |
| EP0167011A2 (en) | Beta-lactam compounds, intermediates thereof, their use in preparing beta-lactams having a diketopiperazine group | |
| IE53889B1 (en) | Beta-lactam antibacterial agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |