GB2036023A - Bicycloheptane derivatives - Google Patents
Bicycloheptane derivatives Download PDFInfo
- Publication number
- GB2036023A GB2036023A GB7940254A GB7940254A GB2036023A GB 2036023 A GB2036023 A GB 2036023A GB 7940254 A GB7940254 A GB 7940254A GB 7940254 A GB7940254 A GB 7940254A GB 2036023 A GB2036023 A GB 2036023A
- Authority
- GB
- United Kingdom
- Prior art keywords
- group
- general formula
- compound
- formula
- benzyl
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
Abstract
There are provided (2R,5R)-7- oxo-4-thia-1-aza-bicyclo-[3,2,0]- heptane derivatives of the general formula (1> <IMAGE> wherein R represents a hydrogen atom, or a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl or trimethylsilyl group or a group of the formula -CH(CH3) OCOOC2H5 and R1 represents a group of the formula CH2OH, CH2SH, CH2NH2, CHO, CH2OCOR2, CH2OR3, COOR2, CH2NHCOR2 or CH2SR4 wherein R2 represents an alkyl, aryl, aralkyl or heterocyclic group, R3 represents a lower alkyl, benzyl, trialkylsilyl or trityl group and R4 represents a five or six membered heterocyclic ring containing one or more heteroatoms or a benzyl, trityl or trialkylsilyl group. These compounds, which have antibacterial activity, may be prepared by methods described from esters of penicillanic acid 1-oxide.
Description
SPECIFICATION
Bicycloheptane derivatives
The invention relates to (2R, 5R)-7-oxo-4-thia-1 -aza-bicyclo-[3,2,O]-heptane derivatives, to processes for their preparation from esters of penicillanic acid 1-oxide, and to intermediate compounds obtained in the preparation. Reference is made first to the reaction scheme set out below.In the compounds illustrated, R represents a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, phalidyl, or trimethylsilyl group or a group of the formula -CH(CH3)OCOOC2H5; R, represents a group of the formula CH2OCOR2, CH2OR3,COOR2, CH2NHCOR2 or
CH2SR4 wherein R2 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group, R3 represents a lower alkyl (preferably t.butyl), benzyl, trialkylsilyl or trityl group and R4 represents a five or six membered heterocyclic ring containing one or more heteroatoms or a benzyl, trityl or trialkylsilyl group; R5 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group;X represents a hydrogen atom or an electron withdrawing group, for example one of the formula COOR2, CN or CONH2,
R2 being as above defined; and pH represents a phenyl group.
Reaction A comprises reacting compound (2) with an allenic compound of the formula
CHX = C = CHR, or with an acetylenic compound of the formula CX C-CH2R1, X and Rl being as above defined, by heating to from 500C to 1 200C in an inert solvent. Suitable inert solvents are benzene, toluene and dimethylformamide.
Reaction B comprises an isomerisation effected in an inert solvent at room temperature.
Dichloromethane is suitable as the inert solvent.
Reaction C comprises a reduction effected with phosphorus tribromide, preferably at from OOC to --400C and preferably in dimethylformamide.
Reaction D is an ozonolysis of both double bonds of compound (4) carried out at a temperature of from -200C two 7800 in a solvent such as dichloromethane, ethyl acetate or tetrahydrofuran.
Reaction E comprises a hydrolysis, usually carried out in methanol in the presence of silica gel or in mild basic conditions.
Reaction F comprises condensing compound (10) with a glioxylic acid ester of the formula
CHO.COOR wherein R is as above defined at a temperature of from 400C to 10000. Compound (12) is obtained as a mixture of its diastereoisomers.
Reaction G is a chlorination reaction. Suitable conditions for this are the use of thionyl chloride as chlorinating agent in the presence of a base such as pyridine at a temperature of from-20 C to +200C.
Compound (14) is obtained as a mixture of its diastereoisomers.
Reaction H comprises a condensation between compound (14) and triphenylphosphine carried out at a temperature not exceeding 500C and in the presence of a base. The reaction is usually carried out at room temperature, and pyridine and 2,6 - lutidine are preferred bases.
Reaction lisa ring closure effected simply by heating compond (16) art a temperature of from 200C to 1400C in an inert solvent such as toluene, benzene or ethyl acetate and in the presence of a catalytic amount of an organic base, preferably pyridine.
Reaction J comprises an ozonolysis carried out at a temperature of from 2000 to --780C in a solvent such as dichloromethane, ethyl acetate or tetrahydrofuran.
Reaction K is a reduction reaction effected under the same conditions as reaction C above.
Reaction L comprises a hydrolysis, usually carried out under the same conditions as reaction E above.
Reaction M comprises condensing compound (7) with a glioxylic acid ester of the formula
CHO.COOR wherein R is as above defined at a temperature of from 400C to 10000. Compound (11) is obtained as a mixture of its diastereoisomers.
Reaction N is a chlorination reaction. Suitable conditions for this are the use of thionyl chloride as chlorinating agent, in the presence of a base such as pyridine at a temperature of from-20 C to +200C. Compound (13) is obtained as a mixture of its diastereoisomers.
Reaction O is carried out in the same conditions as reaction H above, except that the temperature is from 40 C to 80 C.
Reaction P is an ozonolysis reaction carried out with the carbon-phosphorus double bond protected by protonation with a strong acid such as trifluoroacetic acid, deprotonation being effected at the end of the ozone treatment using sodium bicarbonate. The reaction temperature is desirably from --20"C to --780C.
Reactions Q, R and S are ozonolysis reactions carried out under the same conditions as reaction J above.
The preferred synthetic route is reactions A, B, J, K, L, M, N, O, P and I.
The invention provides compounds (1) in which R is as above defined or represents a hydrogen atom and in which R1 is as above defined or represents a group of the formula CH2OH, CH2SH, CH2NH2 or CHO. The additional compounds may be obtained simply by removal of the various protecting groups R2,R3 and R4, reduction of the group COOR2 or hydrolysis of the group COOR.
Compounds (1), which exist as E and Z isomers, are related to clavulanic acid (T. T. Howarth and A
G. Brown, J. Chem. Soc. Chem. Comm. 266, 1976). They have antibacterial activity.
The invention further provides the process outlined in the reaction scheme for obtaining the compounds (1).
The invention further provides compounds (3), (4) and (16) as herein defined, and the processes outlined in the reaction scheme for obtaining them.
The invention is illustrated by the following Examples.
EXAMPLE 1 4,B-01 '-methoxycarbon ylme thyl-2 '-methoxycarbonyl- vinylsulphinyll- 1 -(1 "-methoxycarbonyl-2"-methyl- all yl)aze tidin -2 -one Reaction A: (2), R5=CH3-(3). R1=X=COOCH3, R5=CH3
1.5 g of methylpenicillinate 1-oxide were dissolved in 30 ml of toluene. To the solution, 2.2 g of glutinic acid dimethyl ester were added and the resulting solution was treated at refluxing temperature for 4 hours. The highly predominant product was purified by column chromatography using benzene:ethyl acetate mixture to give 1.8 g of the title compound.
I.R. (CHCl3).#max: 1770, 1740 cm-,
P.M.R. (CDCI3) #: 2.00 (s,
2.93 (dd, J=1 4.0 and 5.0 Hz, a C(3)H),
3.40 (dd, J=1 4.0 and 2.0 Hz, p C(3)H),
3.88 (s, three CH3O)
5.00 (br.s,
and one of the vinylidene protons),
5.24 (br.s, C(4)H and one of the vinylidene protons),
EXAMPLE 2 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylsulphinyl)-1-(1"-methoxycarbonyl-2"-methyl prop-i-en yl)-azetidin-2-one Reaction B: (3), R1=X=COOCH3, R5=CH3o(4), R=X=COOCH3, R5=C H3 2.8g of 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylsulphinyl)-1-(1"methoxycarbonyl-2"-methyl-allyl)-azetine-2-one, prepared as described in Example 1, were dissolved in 50 ml of dichloromethane. 0.5 ml of triethylamine was added. The solution was left at room temperature for one night and then evaporated "in vacuo" twice from carbon tetrachloride. The residue consisted of the title compound in pure form and in quantitative yield.
I.R. (CHCl3), #max: 1775, 1725 cm-.
P.M.R (CDCl3) #: 2.12 and 2.30 (twos,
3.78 (s, three CH3O),
5.11 (br.s,C(4)H)
6.64 (s,=C-H).
EXAMPLE 3 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonylvinylsulphinyl)-1-methoxyoxalyl-azetidin-2-one
Reaction J: (4), R1=X=COOCH3, R5=CH3- > (5), R1=X=COOCH3, R5=CH3
1.8 g of 4ss-(1 '-methoxycarbonylmethyl-2'-methoxycarbonylvinylsulphinyl)- 1 -(1"- methoxyca rbonyl-2"-methyl-prop-1 -enyl)-azetidin-2-one, prepared as described in Example 2, were dissolved in 100 ml of methylene dichloride and cooled to-78 C. A flow of ozone in oxygen was bubbled through this solution until a blue colour appeared. The resulting ozonide was reduced by shaking with an aqueous solution of sodium pyrosulphite. The organic phase was dried over anhydrous sodium sulphate and evaporated "in vacuo" to give 1.4 g of the title compound.
I.R. (CHCl3),#max: 1830, 1720cm-.
P.M.R. (CDCI3) #: 3.70 (s, two CH3O) 3.88 (s, CH3O),
5.27 (dd, J=5.5 and 2.5 Hz, C(4)H),
6.65 (s, = C-H).
EXAMPLE4 4-( 1 '-methoxycarbonylmethyl-2 '-methoxycarbonylvinylthioJ- 1 -methoxyoxalyl-azetidine-2-one
Reaction K: (5), R1=X=COOCH3,R5=CH3- > (6) R1=X=COOCH3, R5=CH3
A solution of 1.5 g of 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylsulphinyl)-1methoxyalyl-azetidin-2-one, prepared as described in Example 3, in 10 ml of anhydrous dimethylformamide was cooled to-20 C and 0.6 ml of phosphorus tribromide was added under stirring. After 10 minutes, the mixture was poured into ethyl acetate and washed twice with water. The organic layer was dried over anhydrous sodium sulphate and evaporated "in vacuo" to give 1.1 g of the title compound.
P.M.R. (CDCI3): 3.76 a (s, two CH3O), 3.97 a (s, CH3O),
5.65 a (dd, J=5.5 and 2.5 Hz, C(4)H),
6.20 #(s,=C-H).
EXAMPLE 5 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylthio)-azetidin-2-one
Reaction L: (6), R2=X=COOCH3,R5=CH3- > (7),R1=X=COOCH3
A solution of 1.6 g of 4ss-(1 '-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylthio)-1 - methoxyoxalyl-azetidin-2-one, prepared as described in Example 4, in 50 ml of methanol was left overnight under vigorous stirring together with 5 g of silica gel. After filtering off the insoluble material, the methanolic solution was evaporated and the residue chromatographed on silica gel, eluting with benzene: ethylacetate mixture, to give 0.8 g of the title compound.
I.R. (CHCl3), #max: 1780, 1740, 1715 cm-
P.M.R. (CDCI3) #: 3.70 (s, two CH3O), 3.83 (s, -CH2C=C), 5.11 (br.s, C(4)H), 5.77 (s, =0-H).
EXAMPLE 6 4ss-(1'-methoxycarbonylacetylthio-azetidin-2-one
Reaction Q:(7).R1=X=COOCH3- > (10),R1=COOCH3
A solution of 0.250g of 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylthio)-azetidin2-one, prepared as described in Example 5, in 30 ml of dichloromethane was cooled to-78 C and a flow of ozone in oxygen was bubbled through this solution until a blue colour appeared. The mixture shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate.
The title compound was obtained in a yield of 0.150 g.
P.M.R. (CDCI3): 3.67 # (s, CO-0H2-CO0C(H3), 3.81 a(s,0H30), 5.35 a (br.s, C(4)H).
EXAMPLE 7 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylthio)-1-(1"-methoxycarbonyl-2"-methyl-prop 1 -enylJ-azetidin-2-one Reaction C: (4), Rt=X=COOCH3, R5=CH3o(8), R1=X=COOCH3, Rs=CH3 1.3 g of 4p-( 1 '-methoxycarbonylmethyl-2'-methoxycarbonyl-vinyl-sulphinyl)-1-(1"- methoxycarbonyl-2"-methyl-prop-1-enyl)-azetidin-2-one, prepared as described in Example 2, were dissolved in 20 ml of anhydrous dimethylformamide and cooled to-20 C. 0.5 ml of phosphorus tribromide were added and the mixture left under stirring and cooling for 30 minutes. Ethyl acetate was added and the organic phase was washed twice with water and dried over anhydrous sodium sulphate.
After evaporation "in vacuo", 1.0 g of the title compound were obtained.
P.M.R. (CDCI3) #: 2.03 (s, 3 H,
2.26 (s, 3 H,
3.32 (m, J=3Hz, 5 Hz, 2H, H-3) 3.70-3.80(11 H, CH2COOCH3, = CHCOOCH3,
5.50 (dd, J=3 Hz, 5 Hz, 1 H, H-4) 5.97(s, 1H,=CH)
EXAMPLE 8 4ss-methoxycarbonylacetylthio-1-methoxyoxalyl-azetidin-2-one
Reaction D: (8), R1=X=COOCH3, R5=CH3e(9), R,=COOCH3, R5CH3 A solution of 0.450 g of 4p-(1 '-methoxywarbonylmethyl-2'-methoxycarbonyl-vinylthio)-1 -(1"- methoxycarbonyl-2"-methyl-prop-1-enyl)-azetidin-2-one, prepared as described in Example 7, in 50 ml of dichloromethane was cooled to-78 C and a flow of ozone in oxygen was bubbled through it until a blue colour appeared.The ozonide was reduced by shaking the organic phase with a solution of sodium pyrosulphite. After drying over anhydrous sodium sulphate and evaporating "in vacuo", 0.280 g of the title compound were obtained.
P.M.R. (CDCI3)a: 3.08 (dd, J=4 Hz, 14 Hz, 1 H, H(3) a)
3.55 (dd, J=5 Hz, 14Hz, 1 H, H(3) p) 3.70(s,2 H, CH2COOCH3)
3.80 (s, 3 H, CH2COOCH3)
3.97 (s,3 H, COCOOCH3) 5.82 (dd, J=5 Hz, 4 Hz, 1 H, C(4)H)
EXAMPLE 9 4ss-Methoxycarbonylacetylthio-azetidin-2-one
Reaction E: (9), R=COOCH3, R5=CH3- > (10), R1=COOCH3
To a solution of 0.380 of 4ss-methoxycarbonylacetylthio-1-methoxyoxalyl-azetidin-2-one, prepared as described in Example 8, in 50 ml of methanol, 2 g of silica gel were added and the resulting mixture was left under stirring for 60 minutes. After filtering off the insoluble material, the residue obtained by evaporation consisted of 0.210 g of the title compound.
P.M.R. (CDCI3): identical to spectrum of Example 6.
EXAMPLE 10 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonylvinylthio)-1-(1"-methoxycarbonyl-1" hydroxymethyl)-azetidin-2-one Reaction M: (7), R1=X=COOCH3- > (11), R=X=COOCH3, R=CH3
1.8 ml of methyl glioxylate (freshly prepared by ozonolysis of dimethyl fumarate) were dissolved in 50 ml of benzene and the solution was refluxed for 30 minutes through a Dean-Stark apparatus. After cooling to 50 C 0.8 g of 4ss-( 1 '-methoxycarbonyl methyl-2'-methoxyca rbonyl-vi nylthio)-azetidin-2- one, prepared as described in Example 5, was added and the resulting solution refluxed again at boiling temperature for 3 hours. After a short chromatography on silica gel for the purification of the product from the excess of methyl glioxylate, 1.7 g of the title compound as a mixture of its diastereoisomers were obtained.
P.M.R. (CDCl3): 3.75, 3.90 and 3.95 # (three s, three CH30), 5.38 8 (s,
5.40 8 (br.s,
C(4)H),
6.00 8 (s, =0-H) EXAMPLE 11 4ss-Methoxycarbonylacetylthio-1-(1'-methoxycarbonyl-1'-hydroxymethyl)-azetidin-2-one
Reaction F: (10), R1=COOCH3e(12), R1=COOCH3, R=CH3
A solution of 0.450 g of freshly prepared methyl glioxylate in 30 ml of benzene was boiled through a Dean-Stark apparatus for 30 minutes. 0.200 g of 4ss-methoxy-carbonylacetylthio-azetidin-2-one, prepared as described in either of Examples 6 or 9, was added and the mixture was maintained at boiling temperature for 3 hours.After a short column chromatography for the purification from the excess of methyl glioxylate, 0.1 0 g of the title compound was obtained.
P.M.R. (CDCI3): 3.76 8 (s, CO-CH2-COOCH3): 3.90 and 3.94 8 (two s, two CH3O), 5.60 S (s,
5.72 S (br.s, C(4)H).
EXAMPLE 12 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinyl-thio)(-1-(1"-methoxycarbonyl-1"
chloromethyl)-azetidin-2-one
Reaction N: (11), R1=X=COOCH3, R=CH3- > (13), R1=X=COOCH3, R=CH3
To a solution of 0.200 g of 4ss-(1 '-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylthio)-1 -1"- methoxycarbonyl-1 "-hydroxymethyl)-azetidin-2-one, prepared as described in Example lOin 3 ml of anhydrous tetrahydrofuran cooled to 0 C,0.047 ml of pyridine and 0.042 ml of thionyl chloride were added under stirring. The mixture was left under stirring for 30 minutes, whereafter the insoluble material (pyridine hydrochloride) was filtered off and the resulting solution was evaporated "in vacuo at 30 C. The residue was 0.180 g of the title compound as a mixture of its diastereoisomers.
I.R.(CHCl3). #max: 1780, 1745, 1715 cm-,
P.M.R. (CDCI3) b: 3.74, 3.75 and 3.92 (three s, three CH3O),
5.30 (br.s C(4)H), 5.91(s, CHCI), 6.10(s, =0-H).
EXAMPLE 13 4p-methoxycarbonylacetylthio- 1 -(1 '-methoxy-carbonyl- 1 '-chloromethyl)-azetidin-2-one
Reaction S:(13),R1=X=COOCH3,R=CH3- > (14),R1=COOCH3,R=CH3
A solution of 0.1 50 g of 4ss-(1 '-methoxylcarbonylmethyi-2'-methoxycarbonyl-vinylthio)-1 -(1"- methoxycarbonyl-1 "-chloromethyl)-azetidin-2-one, prepared as described in Example 12, in 10 ml of dichloromethane was cooled to-78 C and a flow of ozone in oxygen was bubbled until a blue colour was observed. The mixture was then shaken with an aqueous solution of sodium pyrosulphite and, after drying over anhydrous sodium sulphate, evaporated "in vacuo" to give 0.090 g of the title compound.
I.R.(CHCl3)#max: 1785,1750cm-,
P.M.R. (CDCI3) 8: 3.66
3.85 and 3.92 (two s, two CH3O), 5.75 (br.s, C(4)H),
EXAMPLE 14 4ss-Methoxycarbonylacetylthio-1-(1'-methoxy-carbonyl-1'-triphenylphosphoranylidenemethyl)
azetidin-2-one
Reaction H: (14), R1=COOCH3, R-CH3- > (16), R1=COOCH3, R=CH3
A solution of 0.210 g of 4ss-methoxycarbonylacetylthio-1-( 1 -methoxycarbonyl-1 -chloromethyl)azetidin-2-one, prepared as described in Example 13, in 8 ml of anhydrous tetrahydrofuran, containing 0.038 ml of pyridine and 0.250 g of triphenylphosphine, was left overnight at room temperature after a gentle heating. After purification over silica gel, the title compound was obtained in a yield of 0.120 g.
I.R.(CHCl3),#max: 1755(large) cm-,
P.M.R. (CDCI3) 8: 3.60 and 3.74 (two, CH3O), 5.80 (br.s, C(4)H), 7.1-8.1 (m, 306H5 groups).
EXAMPLE 15 4ss-(1'-methoxycarbonylmethyl-2'-methoxy-carbonyl-vinyltyhio)-1-(1"-methoxycarbonyl-1"-triphenyl
phosphoranylidenemethyl)-azetidin-2-one
Reaction O:(13), R1=X=COOCH3, R=CH3- > (15),R1=X=COOCH3,R=CH3
A solution of 0.200g of 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylthio)-1-(1"
methoxycarbonyl-1"-chloromethyl)-azetidin-2-one, prepared as described in Example 12, in 4 ml of tetrahydrofuran and 4 ml of dioxane, containing 0.047 ml of pyridine and 0.300 g of triphenylphosphine, was heated at 65 C for 4 hours. After purification over silica gel, the title compound was obtained in a yield of 0.220 g.
I.R.(CHCl3),#max: 1755 (large), 1715cm-, P.M.R.(CDCl3)#: 3.65 and 3.72 (two s, two CH3O)
5.45(br.s, C(4)H),6.68(s,=C-H), 7.2-8.0 (m, 3 C6H5 groups).
EXAMPLE 16 4/s-Methoxycarbonylacetylthio- 1-(1 '-methoxy-carbonyl- 1 '-triphenylphosphoranylidenemethyl)azetidin-2-one
Reaction P: (15, R,=X=COOCH3, R=CH3o(16), R1=COOCH3, R5CH3
A solution of 0.100 g of 4-( 1 -methoxycarbonylmethyl-2-methoxycarbonyl-vinylthio)- 1 -(1 - methoxycarbonyl- 1 -triphenylphosphora nylidene methyl)-azetidin-2-one, prepared as described in
Example 15, in 6 ml of dichloromethane was cooled to-20 C and 7 ml of a 1 0% solution of trifluoroacetic acid in dichloromethane were added. A flow of ozone in oxygen was bubbled for one minute, the solution degassed with nitrogen and 0.2 ml of trimethylphosphite were added.The resulting solution was shaken with a saturated solution of sodium bicarbonate and dried over anhydrous sodium sulphate, to give 0.060 g of the title compound.
I.R. (CHCl3)#max: 1755(large)cm-.
EXAMPLE 17 2-(Methoxycarbonyl-(2R,5R)-E-3-methoxycarbonyl-methylene-7-oxo-4-thia-1-aza-bicycol-[3,2,0]
heptane
Reaction l: (16), R1=COOCH3, R=CH3- > (1), R,=COOCH3, R=CH3, E and Z isomers
0.080 g of 4p-methoxycarbonylacetylthio-1- (1 -methoxy-carbonyl-1 - triphenylphosphoranylidenemethyl)-azetidin-2-one, prepared as described in either of Examples 14 or 16, was dissolved in 3 ml of toluene and heated at 1200C for 30 minutes. The product was purified from triphenyl phosphine oxide by a short column chromatography, giving 0.036 g of a mixture of the title compound and its Z isomer. Purification of the highly predominant component (E isomer) was effected by thin layer chromatography.
E Isomer
I.R.(CHCl3), #max: 1792, 1750, 1700cm-, P.M.R.(CDCl3)#: 3.31 (dd, J=16.5 and 4.0 Hz, α C(6)H),
3.86 (dd, J=1 6.5 and 2.0 Hz, P C(6)H),
3.91 and 3.92 (two s, two CH3O),
5.53 (dd, J=4.0 and 2.0 Hz, C(5)H),
5.64 (d, J=1.0 Hz, C(2)H),
6.29 (d, J=1.0 Hz, =0-H).
M.S.: m/e 257, 0355 (M+, calc. for C10H11NO5S 257, 0358);
m/e 215, 0253 (M-0H200, calc. for C8HgNO4S 215, 0252);
m/e 1 56, 01 19 (M-CH2CO-COOCH3, calc. for C6H6NO2S 156,0119).
EXAMPLE 18 2-Benzyloxycarbonyl-(2R,5R)-E-3-methoxycarbonylmethylene-7-oxo-4-thia-1-aza-bicyclo-[3,2,0]
heptane (16)R1=COOCH3,R=benzyl- > (1)R1=COOCH3,R=benzyl, E isomer
0.120g of 4ss-methoxycarbonylacetylthio-1-(1-benzyloxy-carbonyl-1triphenylphosphoranylidenemethyl)-azetidin-2-one, prepared as described in Examples 1 to 5, 10 and 12 to 14 or in Examples 1 to 5, 10, 12, 15 and 1 6 but using benzyl glioxylate in place of methyl glioxylate in Example 10, were dissolved in 4 ml of toluene and heated for 60 minutes at 1000C. The title compound was purified from POPh3 by short column chromatography to give 0.040 g of the pure compound.
P.M.R. (CDCI3) S: 3.22 (dd, J=2 Hz, 16 Hz, 1 H, H-6 p) 3.74 (dd, J=4 Hz, 16 Hz, 1 H, H-6) 3.77 (s, 3 H, CH3OCO) 5.18 (s, H, CH2Ph) 5.36 (dd, J=4 Hz, 2 Hz, 1 H, H-5
5.51 (d,J=1.5Hz,1H,H-2)
6.12 (d,J=1.5Hz,1H,=CH)
7.33 (m, 5 H,Ph)
Claims (22)
1. A compound of the general formula (1)
wherein R represents a hydrogen atom, or a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl or trimethylsilyl group or a group of the formula H(CH3) OCOOC2H5 and R, represents a group of the formula CH2OH, CH2SH, CH2NH2, CHO,
CH2OCOR2, CH2OR3, COOR2, CH2NHCOR2 or CH2SR4 wherein R2 represents an alkyl, aryl, aralkyl or heterocyclic group, R3 represents a lower alkyl, benzyl, trialkylsilyl or trityl group and R4 represents a five or six membered heterocyclic ring containing one or more heteroatoms or a benzyl,t trityl or trialkylsilyl group.
2. 2-Methoxycarbonyl-(2 R,5R)-E-3-methoxyca rbonyl-methylene-7-oxo-4-thia-1 -aza-bicyclo [3,2,0]-heptane.
3. 2-Benzyloxycarbonyl-(2R,5R)-E-3-methoxyca rbonyl-methylene-7-oxo-4-thia- 1 -aza-bicyclo [3,2,0]-heptane.
4.2-Carboxy-(2R,5R)-3-(ss-hydroxy-ethylidene)-7-oxo-4-thia-1-aza-bicyclo-[3,2,0]-heptane.
5.2-Carboxy-(2R,5R)-E-3-(ss-hydroxy-ethylidene)-7-oxo-4-thia-1-aza-bicvclo-[3.2.0]-hentane
6. 2-Carboxy-(2R,5R)-Z-3-(p-hyd roxy-ethylidene)-7-oxo-4-thia- 1 -aza-bicyclo[3,2,0]-heptane.
7. A method for the preparation of a compound according to claim 1, the method comprising heating to from 500C to 1200C in an inert solvent a compound of the general formula (2) as defined herein with an allenic compound of the formula CHX=C=CHR, or with an acetylenic compound of the formula CX~CCH2R,, X being as defined herein and R, being as defined in claim 1 other than a group of the formula CH2OH, C H2SH, CH2NH2 or CHO, isomerizing the resultant compound of the general formula (3) as defined herein in an inert solvent, converting the resultant compound of the general formula (4) as defined herein to a compound of the general formula (16) as defined herein by the following steps (a) to (e) carried out in that order, step (f) carried out after any of steps (b) to (e) or simultaneously with step (a) and step (g) carried out before or after step (a);
(a) ozonolysing in a solvent at from -200C to --780C the double bond of the substituent of the
general formula
(b) hydrolysing the resultant substituent of the general formula
(c) condensing the resultant 1 -unsubstituted azetidin-2-one with a glioxylic acid ester of the general formula CHO.COOR wherein R is as defined in claim 1 other than a hydrogen atom at a temperature of from 400C to 1000C, (d) chlorinating the resultant substituent of the general formula
(e) condensing the resultant substituent of the general formula
with triphenylphosphine at a temperature not exceeding 50 C and in the presence of a base, (f) ozonolysing the double bond of the substituent of the general formula
ozonolysis being effected under the conditions of step (a) unless carried out after step (e) in which
case the conditions additionally include protection of the carbon-phosphorus double bond by
protonation with a strong acid and deprotonation at the end of the reaction,
(g) reducing with phosphorus tribromide the sulphinyl group to a thio group and effecting a ring closure by heating the compound of the general formula (16) at a temperature of from 20 C to 140 C in an inert solvent in the presence of a catalytic amount of an organic base, and optionally removing the protecting group R2,R2 or R4 and/or hydrolysing the group COOR and/or reducing the group COOR2.
8. A method according to claim 7 wherein step (f) is carried out after step (e) and step (g) is carried out after step (a).
9.A method according to claim 7 substantially as described herein with reference to Examples 1 to 5, 10, 12 to 14 and 17, or to Examples 1 to 5, 10, 12 and 15 to 17, or to Example 18.
10. A compound of the general formula (3)
wherein R, represents a group of the formula CH20COR2, CH2OR3, COOR2, CH2NHCOR2 or CH2SR4 wherein R2 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group, R3 represents a lower alkyl (preferably t.butyl), benzyl, trialkylsilyl or trityl group and R4 represents a five or six membered heterocyclic ring containing one or more heteroatoms or a benzyl, trityl or trialkylsilyl group;
R5 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group; and X represents a hydrogen atom or an electron with drawing group, for example one of the form ula COOR2, CN or CONH2,
R2 being as above defined.
11. 4,B-( 1 '-methoxycarbonylmethyl-2'-methoxyca rbonyl-vinyisulphinyl)- 1 -(1 "-methoxyca rbonyl 2"-methylallyl)-azetidin-2-one.
1 2. A method for the preparation of a compound according to claim 10, the method comprising heating to from 500C to 1200C in an inert solvent a compound of the general formula (2) as defined herein with an allenic compound of the formula CHX=C=CHR, or with an acetylenic compound of the formula CX~CCH2R" X being as defined herein and R1 being as defined in claim 1 other than a group o-f the formula CH2OH, CH2SH, CH2NH2 or CHO.
13. A method according to claim 10 substantially as described herein with reference to Example 1.
14. A compound of the general formula (4)
wherein R, represents a group of the formula CH2OCOR2, CH2OR3, COOR2, CH2NHCOR2 or CH2SR4 wherein R2 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group, R3 represents a lower alkyl (preferably t.butyl), benzyl, trialkylsilyl or trityl group and R4 represents a five or six membered heterocyclic ring containing one or more heteroatoms or a benzyl, trityl or trialkylsilyl group;
R5 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group; and X represents a hydrogen atom or an electron withdrawing group, for example one of the formula COOR2, CN or CONH2,
R2 being as above defined.
15. 4ss-(1'-methoxycarbonylmethyl-2'-methoxycarbonyl-vinylsulphinyl)-1-(1"-methoxycarbonyl2"-methylprop-1-enyl)-azetidin-2-one.
16. A method for the preparation of a compound according to claim 14, the method comprising heating to from 50 C to 120 C in an inert solvent a compound of the general formula (2) as defined herein with an allenic compound of the formula CHX=C=CHR1 or with an acetylenic compound of the formula CX=C-CH2R1,X being as defined herein and R1 being as defined in claim 1 other than a group oftheformula0H2OH, CH2SH, CH2NH2 or CHO, and isomerizing the resultant compound of the general formula (3) as defined herein in an inert solvent.
17. A method according to claim 16 substantially as described herein with reference to Examples 1 and 2.
1 8. A compound of the general formula (1 6)
wherein R represents a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, or trimethylsilyl group or a group of the formula-CH(CH3)OCOOC2H5; R1 represents a group of the formula CH2OCOR2,CH2OR3, COOR2,CH2NHCOR2 or CH3SR4 wherein R2 represents an alkyl (preferably lower alkyl), aryl, aralkyl or heterocyclic group, R3 represents a lower alkyl (preferably t.butyl), benzyl, trialkylsilyl or trityl group and R4 represents a five or six membered heterocyclic ring containing one or more heteroatoms or a benzyl, trityl or trialkylsilyl group; and pH represents a phenyl group.
19. 4ss-methoxycarbonylacetylthio-1-(1'-methoxycarbonyl-1'triphenylphosphoranylidenemethyl)-azetidin-2-one.
20. A method for the preparation of a compound according to claim 18, the method comprising heating to from 50 C to 120 C in an inert solvent a compound of the general formula (2) as defined herein with an allenic compound of the formula CHX=C=CHR1 or with an acetylenic compound of the formula OX=-C-0H2R1, X being as defined herein and R, being as defined in claim 1 other than a group of the formula CH2OH, CH2SH, CH2NH2 or CHO, isomerizing the resultant compound of the general formula (3) as defined herein in an inert solvent, and converting the resultant compound of the general formula (4) as defned herein to a compound of the general formula (16) as defined herein by the following steps (a) to (e) carried out in that order, step (f) carried out after any of steps (b) to (e) or simultaneously with step (a), and step (g) carriedout betore or atter step (a):
(a) ozonolysing in a solvent at from-20 C to-78 C the double bond of the substituent of the
general formula
(b) hydrolysing the resultant substituent of the general formula
(c) condensing the resultant 1 -unsubstituted azetidin-2-one with a glioxylic acid ester of the general formula CHO.COOR wherein R is as defined in claim 1 other than a hydrogen atom at a temperature of from 40 C to 100 C.
(d) chlorinating the resultant substituent of the general formula
(e) condensing the resultant substituent of the general formula
with triphenylphosphine at a temperature not exceeding 500C and in the presence of a base, (f) ozonolysing the double bond of the substituent of the general formula
the ozonolysis being effected under the conditions of step (a) unless carried out after step (e) in
which case the conditions additionally include protection of the carbon-phosphorus double bond
by protonation with a strong acid and deprotonation at the end of the reaction,
(g) reducing with phosphorus tribromide the sulphinyl group to a thio group.
21. A method according to claim 20 wherein step (f) is carried out after step (e) and step (g) is carried out after step (a).
22. A method according to claim 20 substantially as described herein with reference to Examples 1 to 5, 10 and 12 to 14 or to Examples 1 to 5, 10, 12, 15 and 16.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7940254A GB2036023B (en) | 1978-11-24 | 1979-11-21 | Bicycloheptane derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7845966 | 1978-11-24 | ||
| GB7940254A GB2036023B (en) | 1978-11-24 | 1979-11-21 | Bicycloheptane derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2036023A true GB2036023A (en) | 1980-06-25 |
| GB2036023B GB2036023B (en) | 1983-03-02 |
Family
ID=26269721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7940254A Expired GB2036023B (en) | 1978-11-24 | 1979-11-21 | Bicycloheptane derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2036023B (en) |
-
1979
- 1979-11-21 GB GB7940254A patent/GB2036023B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2036023B (en) | 1983-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4331677A (en) | 7-Oxo-4-1-aza-bicyclo-[3,2,0]-heptane derivatives | |
| US4631150A (en) | Process for the preparation of penems | |
| Leanza et al. | An efficient synthesis of 2-substituted-thio-6-hydroxyethyl-penem-3-carboxylic acids via 2-thioxopenams | |
| EP0252744B1 (en) | 3-Beta-(3,4-disubstituted succinimido)azetidinones | |
| EP0013617B1 (en) | Penicillin derivatives, process for their preparation and pharmaceutical compositions containing certain of these compounds | |
| US4443373A (en) | Process for the production of antibiotic penems | |
| EP0171064A1 (en) | Azetidinone derivative and processes for production thereof | |
| EP0146730A1 (en) | Process for the production of penems | |
| NO167291B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PENEM RELATIONS. | |
| EP0013067A1 (en) | Bicyclic beta-lactam antibacterial agents, their use in pharmaceutical compositions, processes for their preparation and intermediates for use in such processes | |
| HU187807B (en) | Process for producing optically active penemes | |
| GB2036023A (en) | Bicycloheptane derivatives | |
| EP0278911B1 (en) | Bicyclic beta-lactam carboxylic acids | |
| US4647558A (en) | Antibacterial agents, their preparation and use | |
| US4444685A (en) | Stereospecific synthesis of thienamycin from penicillin | |
| US4525582A (en) | Silyl, benzyl, p-nitrobenyl, or methyl esters of diazoacetate, a synthon used in the conversion of penicillin to thienamycin | |
| US3951951A (en) | Azetidinones | |
| RU2049786C1 (en) | Method of synthesis of 2-methoxymethylpenems | |
| SU791244A3 (en) | Method of preparing oxazolinoazetidine compounds | |
| US5892036A (en) | Process for the preparation of 2-bromo- and 2-nitroxy derivatives of 3-bromo- and 3,3-dibromo-4-oxo-azetidines | |
| US5416208A (en) | Process for penems | |
| RU2175971C2 (en) | Method of preparing 2-halogenmethyl penems and 2-azitidinone derivatives as intermediate compounds | |
| JPH085853B2 (en) | Lactam compound and its manufacturing method | |
| SK13897A3 (en) | 3-bromo- and 3,3-dibromo-4-oxo-1-azetidines, method for preparation thereof and their use | |
| IE49408B1 (en) | Azetidinone derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19951121 |