NZ235529A - Azetidinone derivatives and their preparation - Google Patents
Azetidinone derivatives and their preparationInfo
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- NZ235529A NZ235529A NZ235529A NZ23552990A NZ235529A NZ 235529 A NZ235529 A NZ 235529A NZ 235529 A NZ235529 A NZ 235529A NZ 23552990 A NZ23552990 A NZ 23552990A NZ 235529 A NZ235529 A NZ 235529A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- 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
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Abstract
Compounds of formula I, consisting of the combination of formulae IA and IB: <IMAGE> in which: R1 denotes a hydrogen atom, a halogen atom, an alkyl radical, a trifluoromethyl radical, an alkoxy radical, a phenyl or benzyl radical (which are optionally substituted), a benzyloxy radical, a cyano radical, an alkoxycarbonyl radical, a carboxyl radical or an alkylamino radical, R2, different from R1, denotes a hydrogen atom, a halogen atom, an alkyl radical, a trifluoromethyl radical, an alkoxy radical, a phenyl or benzyl radical (which are optionally substituted), a benzyloxy radical, a cyano radical, an alkoxycarbonyl radical, a carboxyl radical or an alkylamino radical, each R3 denotes an alkyl radical or the two R3s form together and with the atoms of the dithioacetal functional group to which they are attached a 5- to 7-membered ring, R4 denotes an optionally substituted phenyl radical, a naphthyl radical or a furyl radical, each of R5 and R6, which are identical or different, denotes a hydrogen atom, an alkyl radical or an aryl radical (optionally substituted), and each R7 denotes a methyl radical or the two R7s form together and with the carbon atom to which they are attached a cyclohexane nucleus or a cyclopentane nucleus. The compounds of formula IA and IB are intermediates which are useful for the preparation of compounds of formulae XA and XB: Original abstract incomplete.
Description
New Zealand Paient Spedficaiion for Paient Number £35529
r>
Priority Diie{s):.
>5-
Complete Specification Filed:
r \ *'/~ ~f)<Cy-) ' C' t I ILf- ( 6 <.*jjl£
Pu&tfcaiton Date: .?.5.j\U8..1992*
P.O. Oourrsa*, 11&: y
23552C
NO DRAWINGS
NEW ZEALAND PATENTS ACT. 1953
No:
Date:
COMPLETE SPECIFICATION NEW 1/3,4—TRISUBSTITUTED 2-AZETIDINONE
DERIVATIVES, USEFUL AS INTERMEDIATES FOR THE SYNTHESIS
OF BETA-LACTAMS, AND PROCESS FOR THEIR ASYMMETRIC
SYNTHESIS
ADIR ET COMPAGNIE, a French body corporate, of 1 rue Carle HeDerTi, 92415, Courbevoie, Cedex, France hereby declare the invention for which $^e pray that a patent may be granted to njS/us, and the method by which it is to be performed, to be particularly described in and by the following statement
(followed by page la)
235 5 2
The present invention relates to new 1,3,4-trisubstituted 2-azetiainone derivatives and to the process for their asymmetric synthesis.
Beta-lactams constitute the most important class 5 of antibacterial agents known hitherto. It is also known that chiral 2-azetidinone derivatives are useful intermediates for the asymmetric synthesis of beta-lactam type antibiotics. A number of processes of enantioselective synthesis are described in the literature. Some of them 10 employ chiral Schiff bases as intermediates. Various asymmetry inducers have been proposed, such as D-threonine (A.K. Bose et al., Tetrahedron Lett., (1985), 26, p. 33-36) and D-glyceraldehyde (D.R. Wagle et al.; J. Org. Chem., (1988), 53, p. 4227-4236). 15 The compounds of the invention are very useful and interesting intermediates for the preparation of 3,4-disubstituted monobactams. in fact, the compounds of the present invention are prepared in a very good yield and in a stereoselective manner from inexpensive starting 20 materials. They originate from a process of synthesis which employs D-glucoasmine as asymmetry inducer, a readily available starting material. This process does not require any burdensome resolution stage.
Furthermore, on account of their chemical struc-25 ture, the compounds of the invention make it possible to apply an effective and original method for cleaving the chiral auxiliary in a single stage and obtaining quantitatively 3,4-disubstituted monobactams which are not substituted on the nitrogen in position 1. These latter 30 compounds constitute fundamental intermediates in the synthesis of antibacterial antibiotics.
The present invention relates more especially to compounds of general formulae IA and IB which form the general formula I:
0 < K ~
im
/
r3
in which
Rx denotes a hydrogen atom, a halogen atom, an alkyl radical containing 1 to 6 carbon atoms, a tri-fluoromethyl radical, an alkoxy radical containing 1 to 6 carbon atoms, a phenyl, phenoxy or benzyl radical (optionally substituted, on the benzene ring by one or more halogen atoms, alkoxy radicals containing 1 to 6 carbon atoms or.alkyl radicals containing 1 to 6 carbon atoms), a benzyloxy radical, a cyano radical, an alkoxy-carbonyl radical containing 2 to 7 carbon atoms, a car boxy radical or an alkylamino radical containing 1 to 6 carbon atoms (on condition, however, that in this case R2 never simultaneously denotes a hydrogen atom),
R2, different from Rlf denotes a hydrogen atom, a halogen atom, an alkyl radical containing 1 to 6 carbon atoms, a tr if luoromethyl radical, an alkoxy radical
235 52 9
containing 1 to 6 carbon atoms, a phenyl/ phenoxy or benzyl radical (optionally substituted on the benzene ring by one or more halogen atoms, alkoxy radicals containing 1 to 6 carbon atoms or alkyl radicals contain-5 ing 1 to 6 carbon atoms) , a benzyloxy radical, a cyano radical, an alkoxycarbonyl radical containing 2 to 7 carbon atoms, a carboxy radical or an alkylamino radical containing 1 to 6 carbon atoms (on condition, however, that in this case never simultaneously denotes a 10 hydrogen atom),
each R3 denotes an alkyl radical containing 1 to 6 carbon atoms or the two R3 form together and with the atoms of the dithioacetal functional group to which they are attached a ring containing 5 to 7 chain links, 15 R* denotes a phenyl radical (optionally substi tuted by one or more halogen atoms, by one or more alkyl radicals containing 1 to 6 carbon atoms or by an alkoxy radical containing 1 to 6 carbon atoms), a naphthyl radical or a furyl radical,
each of R3 and Rg, which are identical or dif ferent, denotes a hydrogen atom, an alkyl radical containing 1 to 7 carbon atoms or an aryl radical (optionally substituted by one or more halogen atoms, alkoxy radicals containing 1 to 6 carbon atoms or alkyl 25 radicals containing 1 to 6 carbon atoms),
and each R7 denotes a methyl radical or the two R7 form together and with the carbon atom to which they are attached a cyclohexane nucleus or a cyclopentane nucleus. 30 The present invention also relates to a process for the preparation of the compounds of general formula I,
in which the D-glueosamine compound of formula II:
CHaOH
N-
(ii)
OH
HO
MH2
is condensed either with an equimolar quantity of a compound of formula IIIA:
HS(CH2)aSH IIIA
in which n is equal to 2-4,
or with an at least double quantity of a compound of formula IIIa:
HSR'3 III3
in which R'a denotes an alkyl radical containing 1 to 6 carbon atoms, in the presence of concentrated hydrochloric acid,
to obtain a D-glucosamine derivative of formula
IV:
R3 S3 S S
—MH2-
K0-
(IV)
OH OH
CH2OH
in which R3 has the same meaning as in the case of formula I,
which is then reacted with a compotind of formula
V:
K3CO OCH3
ST — C — 97 (V>
in which the meaning of R7 remains identical with that given in the case of formula I, in the presence of para-toluenesulfonic acid,
to obtain a derivative of formula VI:
- o -
23S529
(VI)
in which R3 and R7 have the same meaning as in the case of formula I,
which is condensed with an aldehyde of formula
VII:
OHC _ y5
*6 R 4
i (VII)
R5 ^ =>'■
in which the meaning of R4, Rj and Rg is identical with that given in the case of formula I,
to obtain a Schiff base of formula VIII:
T ?=-
in which R3, R4, Rs, r^ and R7 have the same meaning as in the case of formula I,
which is next cyclized in the presence of tri-ethylamine with an acid chloride of formula IX:
31 (IX)
r
0 CI
in which Rx and R2 have the same meaning as in the case of formula I,
to obtain a mixture of monobactams of general formula IA and I3, which is next separated by crystal-10 lization and/or by preparative chromatography.
The monobactams XA and X3 are easily obtained from the compounds IA and IB/ by virtue of their nature and of an effective and original method of cleaving the chiral auxiliary:
33 v /?l2i (XA)
1 N'H
R5
R2
3 2
,/
R4
± m
R6
(xb)
In the case of the formulae xA and Xb tiie meaning of rlr r2, r«, r3 and re remains identical with that given in the case of formulae IA and I9. 20 in fact, by subjecting the compounds of formula
Ix to the action of n-butyllithium or of another
235529
chemically equivalent reactant, the compounds of formula XA are obtained almost quantitatively, as are the compounds of formula X3 from compounds Ia.
This original cleaving method also forms part of 5 the present invention.
The process described makes it possible to obtain the compounds IA and I3 in a very good yield. In fact, it involves a cycloaddition of "Staudinger type" of a ketene and of an imine, to obtain 1,3,4-trisubstituted 10 azetidinones.
The advantage of the present invention lies in the fact that the IA and I3 diastereoisomers prepared from D-glucosamine are obtained and separated easily. Furthermore, the intermediates prepared during the various 15 stages are obtained in yields which are generally higher than 90%. The chiral compounds of formula IV are easily obtained in crystalline form by treating D-glucosamine, in the presence of hydrochloric acid, with a thiol (compound of formula IIIa) or a dithiol (compound of 20 formula IIIA).
In the case of the preparation of the compounds of formula IV, the necessary quantity of D-glucosamine and of dithiol is equimolar. On the other hand, during the reaction of D-glucosamine with a thiol, the necessary 25 quantity of the latter compound for the reaction is twice molar. The yield of these reactions is of the order of 90%.
The compounds of formula IV are obtained in a 90% yield by reacting the compounds of formula VI with the 30 compounds of formula V in the presence of para-toluene-sulfonic acid.
To obtain the Schiff bases of formula VIII the compounds of formula VI are condensed with heating with an aldehyde of formula VTI in an aromatic organic solvent 35 such as toluene.
The compounds of formulae XA and XB are obtained from the compounds of the invention by virtue of £-elimination, hitherto unknown in this field. This operation is based on the special reactivity of the
-J
proton carried by the carbon of the "thioacetal" functional group. This cleaving method, which consists in treating the compounds of formulae IA and I3 with 2 equivalents of n-butyllithium or of some other equivalent chemical reactant, at a temperature between -20°C and -80°C, makes it possible to obtain the azetidinones XA and Xs quantitatively and very easily.
The following examples, given without any limitation being implied, illustrate the invention.
The melting points shown are measured in a Reichert hot-stage microscope. The proton and 13C nuclear magnetic resonance (NMR) spectra were recorded on a spectrometer BROKER (WP 200).
EXAMPLE 1
D-Glucosamine trimethvlene dithioacetal hydrochloride
HCl
CHpGH
50 g of D-glucosamine hydrochloride are dissolved in 200 ml of concentrated hydrochloric acid cooled to 0 °C 20 and saturated with gaseous hydrochloric acid.
ml of 1,3-propanedithiol and 50 ml of dichloromethane are added and the mixture is stirred for 2 hours at room temperature and is then left overnight at 60°C.
500 ml of water are added and the dichloro methane, which contains the excess 1,3-propanedithiol, is then separated off. Further washing with 100 ml of
23 5 5
dichloromethane is carried out twice.
The aqueous phase is neutralized with lead carbonate. It is filtered on a Biichner and two washings with 100 ml of water are carried out. The material is 5 then concentrated under vacuum. 500 ml of boiling ethanol are added and the solution is filtered on a Biichner. After cooling, the crystals obtained are filtered off and then rinsed with ethanol (0°C).
Yield: 83%
: Melting point: 115-117°C (ethanol).
EXAMPLE 2
3,4:5,6-Di-O-isopropvlidene-D-qlucosamine tri-methvlene dithioacetal
U°\
17 g of the compound of Example 1 are dissolved 15 in 45 ml of dimethylformamide and 50 ml of 2,2-dimethoxy-propane. 5 g of para-toluenesulfonic acid are added. The solution is heated to 70 °C for 1 hour 30 minutes in a Bitchi* rotary evaporator under a vacuum of 30 cm Hg, and then, after rapid cooling, 200 ml of hexane, 20 g of 20 sodium bicarbonate and 10 g of ice are added and stirring is applied. 3 extractions with hexane are carried out.
The hexane solution is dried and evaporated to dryness. The product obtained crystallizes easily from cold hexane.
Yields 91%
Melting points 79-80*C (hexane)
Rotatory power: (c=l.3% in CHC13):
[a]f = + 89.4#
■:y
EXAMPLE 3
Preparation of 2-f3fl-methoxv-2-oxo-43-stvrvl-l-azetidinvl)-2-deoxv-2-dithianvl-3.4:5.6-di-O-isopropvli-dene-D-qlucose f1^
/ / /
and of 2-( 3a-methoxv-2-oxo-4ct-stvrvl-l-
azetidinyl) -2-deoxv-2-dithianyl-3,4:5,6-di-Q-isopropvli-dene-D-qlucose (2)
9' 8*
7 g of the compound of Example 2 and 2.52 ml of cinnamaldehyde are dissolved in 6 ml of anhydrous 10 toluene. The mixture is heated to 60"C for 20 minutes and then the water formed is removed by entrainment with toluene under low pressure. The inline thus formed is diluted in 15 ml of anhydrous toluene, and 6.7 ml of triethylamine and 2.2 ml of methoxyacetyl chloride are 15 added. The solution is stirred for 45 minutes at room temperature. The reaction mixture is then poured onto a saturated aqueous solution of ammonium chloride at 0°C. The organic phase is taken up with dichloromethane and is
- IX -
r- 7-
0 3 0
washed successively with a saturated aqueous solution of sodium chloride, is dried over magnesium sulfate, filtered and evaporated down under reduced pressure. Crystallization from a hexane-dichloromethane mixture 5 enables 4.8 g of the 3,3,4£ isomer to be isolated. The mother liquors are chromatographed on silica preparative plates using a mixture of ethyl acetate and hexane (4:6 V/V) as eluent to separate the 3a,4a and 3^,4,8 isomers.
Yield: 3a,4a isomer: 34%
3^,40 isomer: 57%
Physicochemical constants:
A. 2-f 3fl-Methoxv-2-oxo-4g-stvrvl-l-azetidinvl 1 -2-deoxv-2-dithianvl-3.4:5,6-di-Q-isopropvlidene-D-qlucose f1^
- Melting point: 206 °C (hexane-dichloromethane) Rotatory power: (c=l% CHC13):
[a]l° = -101.6°
Elemental analysis:
C% H% N% S%
Theory: 60.53 6.96 2.61 11.97 Found: 60.41 6.80 2.63 12.06 Proton nuclear magnetic resonance (solvent:
CDCli). S ppm:
1.20-1.28-1.36-1.53 (12H, CH3i,opr, 4s); 1.9-2.2 (2H,Hg.,m); 25 2.7 (2H,H8./m); 2.9-3.2 (2H,Ha.,m); 3.46 (3H,OCH3/s);
3.8-4.4 (7H, Hr_6>/m); 4.57 (lH,H4,dd, J*_3=5Hz, J4.5=9Hz); 4.76 (1H,H3,d,J3_4=5Hz); 6.45 (lH,dd,H3, J5.4=9Hz, J3.6=16Hz); 7.3-7.6 (5H,CHa,m) .
13C nuclear magnetic resonance spectrum (solvent: CDC1-.1 30 6 ppm:
.2 (CE3iaapx); 25.6 (C9.); 26.4 (CH31aopE); 26.6 (CH31aopr); 27 (CH3i80pt); 27.2 (Ce.); 44.4 (C2.)? 54.1 (Cr); 58.7 (0CH3); 62.3 (C<); 67.7 (Cs.)? 76.9 77.3 79 (C3.,C4.,C5.); 85.4 (c3); 109 110 (C7.)? 126 126.9 128.1 128.6 134.9 35 (CHafCsrCs); 136.4 (Ca); 168.9 (CO).
B. 2~< 3a-Methoxv-2-oxo-4a-stvrvl-l-azetidinYl\-2-deoxv-2-dithianvl-3.4:5.6-di-O-isopropvlidene-D-glucose (2)
- Melting point: 155*C (hexane dichloromethane)
S - 12 -
Rotatory power: (c=l% CHC13):
[ct ]D° = +114.7°
- Elemental analysis:
C% H% N% S%
Theory: 60.53 6.96 2.61 11.97 Found: 60.51 7.25 2.53 12.04 Proton nuclear magnetic resonance spectrum (solvent: CDCl^ S pom:
1.35-1.36-1.49-1.58 (12H,CH311lopr,4s), 1.9-2.2 (2H,m,H9.,m); 10 2.5-2.7 (2H,H8.,m); 3.09 (2H,H8.,m) ; 3.46 (3H,OCH3,s); 3.62 (1H,H4., dd, J4..3.=8Hz, J*._5.=8Hz) ? 3.90-4.22 (4H,Hr, H3.,H6.,m); 4.60 (1H, H2.,dd, J2._3.=1.5Hz, J2._r=llHz); 4.69-4.78 (2H, H3, dd, J3.4=5Hz, H4, dd, J4_3=5Hz, J4_5=10Hz); 4.91 (1H,H3., dd/ J3..2>=1. 5Hz, J3._4.=8Hz); 6.61 (1H/ 15 Hj,,dd, J5_4=10Hz, Js_6=15.5Hz) ; 6.72 (lH,H6/d, Js_s=15.5Hz) ; 7.3-7.5 (5H/ CHa/m).
13C nuclear magnetic resonance spectrum (solvent: CDC1,) S ppms
(CH3iaopt); 25.3 25.6 (C9.,Ca.); 25.9 (CH3isopr)? 26.1 (Ca.) ? 20 26.3 (CH3isopr); 27.5 (CH3iaopr); 43.7 (C2.); 51.8 (Cv); 58.6 (OCH3)? 63 (C4); 67.5 (C6.); 77.1 77.7 78.5 (C3., C4., C5.); 85.3 (C3); 109.4 (C7.)? 109.9 (C7.); 123.9 126.6 128.1 128.6 135.8 (CHa, Cs, C6); 136.2 (Ca); 167.8 (CO). EXAMPLE 4
3 fl-Methoxv-4 fl-stvrvl-2-azetidinone
2.6 g of the 2-(3^-methoxy-2-oxo-4,5-styryl-l-azetidinyl)-2-deoxy-2-dithianyl-3,4:5,6-di-O-isopropyli-dene-D-glucose compound of Example 3 are dissolved in 60 ml of anhydrous tetrahydrofuran.
8 ml of n-butyllithium (1.2M in hexane) cure added slowly at -40#C. The solution is stirred for 20 minutes and is then poured onto a saturated aqueous solution of ammonium chloride at 0"C. The pH is returned to 7 by
235 5
adding acetic acid. The organic phase is separated off and washed with a saturated aqueous solution of sodium chloride and is dried over anhydrous magnesium sulfate, filtered and then evaporated down. The residue is chroma-5 tographed on a silica column using a mixture of ethyl acetate and of hexane (3:7 V/V) as eluant to obtain the pure expected product.
Yield: 90%
Melting point: 126 °C (hexane-dichloromethane) 10 Rotatory power (c=l% in CHC13):
[a]f = +10.0°
- Elemental analysis:
C% H% N%
Theory: 70.91 6.45 6.89 15 Found: 70.87 6.35 6.57
Proton nuclear magnetic resonance spectrum (solvent: CDC1-.) S ppms
3.44 (3H,OCH3,m); 4.38 (lH,H4,dd, J4.3=4.8Hz, J4_5=8.3Hz); 4.64 (lH,H3,dd,J3.4=4.8Hz, J^^Hz); 6.26 (1H,HS,J5_4=8.3Hz, 20 J5-6=16Hz) ; 6.56 (1H,NH) ; 6.65 (lH,^, J8.5=16Hz) ; 7.2-7.5 (5H,CHpjj,m).
13C nuclear magnetic resonance spectrum (solvent: CDC1,1 5 ppm:
56.9 (C4); 58.5 (CH30); 86.8 (C3); 125.04 (C6); 126.7 25 (CHpjj); 128.1 (CHa); 128.7 (CHa); 134.8 (C5); 136.36 (C^);
168 (CO).
EXAMPLE 5
3a-Methoxv-4g-stvrvl-2-azetidinone
This compound was prepared from 2- (3a-methoxy-2-30 oxo-4a-styryl-l-azetidinyl) -2-deoxy-2-dithianyl-3,4:5,6-di-O-isopropylidene-D-glucose according to the process described in Example 4.
23552
Rotatory power (c=l% in CHC13):
[a]o° = -10.0°
EXAMPLE 6
3.4:5,6-Di-O-isopropvlidene-D-qlucosamine diethyl dithioacetal STAGE A
D-Glucosamine diethyl dithioacetal hydrochloride
-2^5 -2*5
HO-
■MK2
■OH •OH
CH2OH
HC1
g of D-glucosamine hydrochloride are dissolved in 80 ml of concentrated hydrochloric acid, cooled to 0*C and saturated with gaseous hydrochloric acid. 100 mg of Aliquat 336* (Aldrich) and 30 ml of ethyl thiol are added. The mixture is left at 0°C for 2 hours and then at room temperature overnight.
Dichloromethane is added and the organic phase which contains the excess ethylthiol is separated off. Two more washings with dichloromethane sure carried out. Methylene chloride is added and the organic phase which contains the excess ethylthiol is separated off. Two more washings with dichloromethane are carried out.
The aqueous phase is neutralized using lead carbonate. It is filtered on a Buchner. The water is stripped off tinder vacuum. The residue is taken up with ethanol. After being filtered on a Buchner, the solution containing the expected product is evaporated to dryness. Melting point: 75-76"C (ethanol)
235529
STAGE B
The residue obtained in the preceding stage is dissolved in 20 ml of dimethylformamide. 3,4:5,6-Di-0-isopropylidene-D-glucosamine diethyl dithioacetal is then obtained according to the process described in Example 2. Overall yield: 59%.
EXAMPLE 7
Preparation of 2-f3fl-methoxv-2-oxo-4fl-stvrvl-l-azetidinvl) -2-deoxv-3,4:5,6-di-O-isopropvlidene-D-glucose diethyl dithioacetal f 3 >
CH30
235529
and of 2- ( 3a-methoxv-2-oxo-4a-stvrvl-1-
azetidinvl \ -2-deoxv-3 .4:5,6-di-O-isooropvlidene-D-glucose diethyl dithioacetal (4)
CH3O
/
H5C2
\
O -A.
/
C2H5
(41
These compounds were prepared from the compound obtained in Example 6 and according to the process described in Example 3.
Phys icochemical constants:
A. 2- (3g-Methoxv-2-oxo-4g-stvrvl-l-azetidinyl ^ -2-deoxv-3,4:5,6-di-0-isopropvlidene-D-glucose diethyl dithioacetal (3)
- Melting point: 71-73.5°C (acetone-water)
- Rotatory power: (c=0.98% CHC13)
[a]f = -117.5°
- Elemental analysis:
C% H%
Theory: 60.95 7.49 Found: 60.98 7.48
N% 2.54 2.71
S% 11.62 11.62
Proton nuclear magnetic resonance spectrum (solvent: CDCl-») 8 ppm:
1.19-3.33 (18H CH3i,opt. + 2CH-.CH... m); 2.6-2.85 (4H 2S-CH7CH,. m); 3.40 (3H,0Me,s); 3.7 (IH/H^t, J4.>3.=J4,i3.=7Hz); 3.89—4.17 (4H/H3.pk',s',6**,®) r 4.33 (1H/Hg>^/ d/ «Jj.mig.j5=9.5Hz); 4.62 (lH,H4/dd, J^^SHz, J4>3=9Hz) ; 4.65-4.68 (2H,H3/H3.,m); 6.4 (lH,H3,dd, J3 6=16Hz, J3 4=9Hz) ; 6.63 (lH,Ha, J8-3=l6Hz,d); 25 7.18—7.43 (5H arom,m)
235529
B. 2-( 3a-Methoxv-2-oxo-4a-stvrvl-l-azetidinvl 1 -2-deoxv-3,4:5.6-di-Q-isopropvlidene-D-qlucose diethyl dithioacetal (4)0
Melting point: 81-848C (acetone-water) 5 - Rotatory power: (c=1.15% CHC13)
[a]g° = +106°
- Elemental analysis:
C% H% N% S%
Theory: 60.95 7.49 2.54 11.62 10 Found: 60.76 7.53 2.65 11.63
Proton nuclear magnetic resonance spectrum (g<*>lvent: CDC1,) S ppm:
1.2 f 6H.2CH,CH,S.t\: 1.32;1.39;1.42;1.58 (12H,CH3(isope.4s); 2.57-2.75 (4H/2S-CH2CH3/m); 3.5 (3H,OCH3,s); 3.6 (1H,H4., 15 t, J4. S.=JV v=7.5Hz); 3.93-4.23 (5H,H1.(2.i5.i5,.(6.b,m); 4.7 (2H, H3, H4/s broad); 4.95 (lH,H3.,dd,J3.4.=7.5 Hz J3.2.=2Hz); 6.7-6.73 (2H, H5, Hg,s broad); 7.3-7.5 (5H arom,m). EXAMPLE 8
Preparation of 2--f4fl-r2-f 2-furvHvinvn-3fl-20 methoxv-2-oxo-l-azetidinvl1-2-deoxv-2-dithianvl-3.4:5.6-di-O-isopropylidene-D-qlucose (5^
and of 2—44a— T2-(2-furvl) vinyl"l-3a-methoxv-2-oxo-l-azetidinvl1.-2-deoxy-2-dithianvl-3.4:5.6-di-O-iso-25 propvlidene-D-qlucose (6^
23
CH30.
9* 8'
(6)
Both compounds were prepared according to the process described in Example 3, but using 3-(2-furyl)-acrylaldehyde instead of cinnamaldehyde. The isomers were 5 separated according to the method described in Example 3. Yield: 3a,4a isomer: 32.12%
3/3,40 isomer: 48.18%
Physicochemical constants
A. 2--f4fl-r2-f 2-Furvl1vinvn-3a-methoxv-2-oxo-l-aze-10 tidinvl T— 2-deoxy-2-dithianvl-3,4:5,6 -di-Q- isopropvl idene-D-qlucose (5^
Melting point: 185-188°C (methanol)
Rotatory power: (c= 2.28% CHC13) :
[a]f = -112.28°
- Elemental analysis
C% H% N% S%
Theory: 57.13 6.71 2.66 12.17 Found: 57.09 . 6.60 2.71 12.15 Proton nuclear magnetic resonance spectrum (solvent: 20 CDC1-.T S ppms
1.23; 1.28; 1.36; 1.53 (12H, 4CH3 Uopr., 4s): 1.91-2.11 (2H, Ha. m); 2.56-2.7 (2H, H7., m); 2.91-3.13 (2H, H7., m); 3.46 (3H, och3, s); 3.72-3.82 (1H, H,., m); 4.00-4.23 (4H, Hj., Hj., 2Hj., m) 4.42-4.51 (2H, H^, H4, m); 4.62-4.74 (2H, 25 H3, H3., m); 6.27 (1H, H8, dd, J8_9 * 3Hz); 6.29 (1H, Hj, dd Jj—5 = 16Hz; J3-4 3 9Hz); 6.37 (IB, Hg, dd, Jg—xo = 1.5 Hz,
O "7 r- «•
/.j 3 ^
_ 19 _ v
J8_9 = 3Hz); 6.46 (1H, Hs/ d J5.5 = 16Hz); 7.36 (1H, H10, d, Jg-io 1. 5Hz] .
B. 2--f 4a-F 2- ( 2-Furvl)vinvl 1 -3a-methoxv-2-oxo-l-aze-tidinvl>-2-deoxv-2-dithianvl-3 .4:5.6-di-O-isopropvlidene-D-qlucose (6 >
Rotatory power: (c= 1.16% CHC13):
[a]f = +110.68°
Elemental analysis:
C% H% N% S%
Theory: 57.13 6.71 2.66 12.17 Found: 57.09 6.58 2.72 12.14 Proton nuclear magnetic resonance spefft.mm fsolvent: CDC1,) S ppm:
1.31; 1.36; 1.48; 1.5 (12H, 4CH3isopr_, s); 1.93-2.10 (2H, Hg#/ m); 2.43-2.68 (2H, Hv/ m); 2.90-3.23 (2H, H7., m); 3.48 (3H, 0CH3, s); 3.63 (1H, H4., m); 3.86-4.20 (4H, H1>f Hs., 2Hg., m); 4.55 (1H, H2., dd); 4.60-4.70 (2H, H3, H«, m); 4.8 (1H, H3,, dd); 6.29-6.35 (4H, HjHgHaHg, m); 7.38 (1H, H10/ d, J9.10 = 15Hz).
EXAMPLE 9
Preparation of 2--f 45- r 2-/2-furyl1vinyl!-33-methoxv-2-oxo-l-a^etidinvlV-2-deoxv-3 .4:5 .6-di-O-iso-propvlidene-D-glucose diethyl dithioacetal (7)
(7)
and of 2--f4a T 2- f 2-furvl)vinvl 1 -3a-methoxv-2-oxo-l-azet idinvl -2 -deoxv- 3,4:5.6-di-O-isopropylidene-D-qlucose diethyl <iit-hioacetal (8)
235529
CH3C.
(8)
These two compounds were prepared and separated according to the process described in Example 3, but using 3-(2-furyl)acrylaldehyde and 3,4:5,5-O-iso-propylidene-D-glucosamine diethyl dithioacetal.
- Yield: 3<s,4<* isomers 33.44%
3)9,40 isomer: 45.60%
Physicochemical constants
A. 2--T 4fl-r 2-f 2-Furvl) vinyl! -3 fl-methoxv^-oxo-l-
azetidinvl'V^-deoxv-S .4:5.6-di-O-isooropvlidene-D-qlucose diethyl dithioacetal (7)
Rotatory power:" (c= 1.87% CHC13:
[a]f = -128.87*
- Elemental analysis:
C% H%
Theory: 57.67 7.25 Foundt 57.60 7.18 Proton nuclear magnetic
N% S%
2.58 11.81 2.43 11.52 resonance spflptmm (solvent:
CDC1,> S ppm:
1.16-1.43 (18H, 6CH3, m); 2.56-2.86/ (4H, 2S-CH,-CH,. m); 3.46 (3H, 0CH3/ s); 3.7 (1H, H4., m); 3.86-4.16, (4H, Hr, H2., Hj., H,.., m); 4.25 (1H, Hg.b, dd) ? 4.31-4.70 (3H, H3/ Hj., rn); 6.27 (1H, H„, d Ja.B = 3Hz); 6\31 (1H, Ha dd, J3_i = 16Hz, J3.4 : 8Hz); 6.36 (1H, H,, dd; J3_10 = 1.5Hz Ja_9 = 3Hz); 6.44 (1H, Ha, d, J3_8 = 16Hz); 7.34 d,
J9.10 = 1.5Hz)
235 5
B. 2--f 4a f 2- ( 2-Furvl T vinvl 1 -3a-methoxv-2-oxo-l-aze-tidinvl >-2-deoxv-3,4:5.6-di-O-isopropvlidene-D-qlucose diethyl dithioacetal (8)
Rotatory power: (c= 2.13% CHC13) : 5 [a ]q5 = +60.09°
Elemental analysis:
C% H% N% S%
Theory: 57.67 7.25 2.58 11.81 Found: 57.49 7.18 2.45 11.76 10 Proton nuclear magnetic resonance (solvent:
CDCl^ S ppxn:
1.18-1.51, (18H, 6CH3, m); 2.53-2.71 (4H, 2S-CH-.-CH,. m); 3.46 (3H, 0CH3, s) 3.58 (1H, H4., m); 3.80-4.20 (5H, Hr, H2., Hs., 2Hg., m); 4.60-4.82 (2H, H3, Hw m); 4.90-5.03 15 (1H, H3. r dd); 6.29-6.38 (5H, H5, He, Ha, Hg, m); 7.38 (1H, H10,d, J9-10 = 1.5).
EXAMPLE 10
Preparation of 2- T 3fl-methoxv-4fl- (fl-methvlstvrvl) -2-oxo-l-azetidinvl1-2-deoxv-3.4:5,6-di-O-isopropvlidene-20 D-qlucose diethyl dithioacetal f91
and of 2-r3a-methoxv-4a-/fl-methylstvryl)-2-oxo-l-azetidinvl 1 -2—deoxv-3.4:5,6-di-O-isopropvlidene-D-alucose diethyl dithioacetal (10)
23 5 5 2
The two compounds were prepared from 3/4:5,6-di-O-isopropylidene-D-glucosamine diethyl dithioacetal and a-methylcinnamaldehyde, and were then separated according 5 to the process described in Example 3.
Yield: 3a,4a isomer: 13.40%
,40 isomer: 53.60%
Physicochemical constants
A. 2- r 3 6-Methoxv-4fl- ( fl-methvlstvrvl) -2-oxo-l-aze-10 tidinvl1-2-deoxv-3.4:5,6-di-Q-isopropvlidene-D-olucose diethyl dithioacetal (9)
- Rotatory power: (c = 1.25% CHC13):
[a]? = -53.84"
- Elemental analysis:
C% H% N% S%
Theory: 61.57 7.66 2.47 11.31 Found: 61.50 7.54 2.62 11.40 Proton nuclear magnetic resonance soe^+T™ (solvent: CDCli) f ppm>
1.1-1.4 (18H, 6CH3, m); 2.05 (3H, CH3, H7, s); 2.62-2.82 (4H, 2 S-CEL-CH,. m); 3.45 (3H, CDCH3/ s)? 3.75 (1H,, H4., m); 3.95 (1H, H^,. m); 4.09-4.35 (4H, Hr, Hj., Hg., H^, m); 4.61 (1H, H4, d, J4.3 = 5Hz); 4.75 (1H, H3., m); 4.82 (1H, H3, d J3.4: 5Hz); 6.6 (1H, Ho, s); 7.20-7.39 (5H, 1H, m). 25 B. 2- f3a-Methoxy-4a-(fl-methylstyiryl)-2-oxo-l-aze-tidinyl 1 -2-deoxy-3.4:5.6-di-q-isooroovlidene-D-glucose diethyl dithioacetal (10)
- Rotatory power: (c = 0.3% CHC13):
[a]f = +55.15*
r
235529
CH3O
The two compounds were prepared from 3,4:5,5-di-O-isopropylidene-D-glucosamine diethyl dithioacetal and a-methylcinnamaldehyde, and were then separated according 5 to the process described in Example 3.
Yield: 3a,4a isomer: 13.40%
,4/3 isomer: 53.60%
Physicochemical constants
A. 2-T 33-Methoxv—A3—(fl-methvlstvrvl)-2-oxo-1-aze-10 tidinvl 1 -2-deoxy-3 ,4:5, 6-di-0-isopropvlidene--D-qlucose diethyl dithioacetal (9)
- Rotatory power: (c = 1.25% CHC13):
[a]f = -53.84*
- Elemental analysis: 15 C% H% N% S%
Theory: 61.57 7.66 2.47 11.31 Found: 61.50 7.54 2.62 11.40 Proton nuclear magnetic resonance spectrum (solvent: CDC1,1 S ppm:
1.1-1.4 (18H, 6ch3, m); 2.05 (3H, CH3, H7, s); 2.62-2.82
(4H, 2 S-CHo-CH,. m); 3.45 (3H, 0CH3, s); 3.75 (1H,, H4., m); 3.95 (1H, H3., m); 4.09-4.35 (4H, Hx., H2., Ha</ H^, m) ; 4.61 (1H, H4/ d, J4.3 = 5Hz); 4.75 (1H, H3., m); 4.82 (1H, H3/ d J3_4: 5Hz); 6.6 (1H, Hg, s); 7.20-7.39 (5H, 1H, m). 25 B. 2-r3a-Methoxv-4a-( -methylstvrvl)-2-oxo-l-aze-tidinvl 1 -2-deoxy-3 ,4:5.6-di-O-isopropylidene-D-qlucose diethyl dithioacetal {10)
- Rotatory power: (c = 0.3% CHC13):
[a]^ =■ +55.15*
Claims (7)
1. Compounds of formula I, consisting of the set of the formulae IA and I3: *3 in which R, denotes a hydrogen atom, a halogen atom, an alkyl radical containing 1 to 6 carbon atoms, a tri-fluoromethyl radical, an alkoxy radical containing 1 to 6 carbon atoms, a phenyl, phenoxy or benzyl radical (optionally substituted on the benzene ring by one or more halogen atoms, alkoxy radicals containing 1 to 6 carbon atoms or alkyl radicals containing 1 to 6 carbon - 25 - O f atoms), a benzyloxy radical, a cyano radical, an alkoxy-carbonyl radical containing 2 to 7 carbon atoms, a carboxy radical or an alkylamino radical containing 1 to 6 carbon atoms (on condition, however, that in this case R2 never simultaneously denotes a hydrogen atom), R2/ different from R,, denotes a hydrogen atom, a halogen atom, an alkyl radical containing 1 to 6 carbon atoms, a trifluoromethyl radical, an alkoxy radical containing 1 to 6 carbon atoms, a phenyl, phenoxy or benzyl radical (optionally substituted on the benzene ring by one or more halogen atoms, alkoxy radicals containing 1 to 6 carbon atoms or alkyl radicals containing 1 to 6 carbon atoms), a benzyloxy radical, a cyano radical, an alkoxycarbonyl radical containing 2 to 7 carbon atoms, a carboxy radical or an alkylamino radical containing 1 to 6 carbon atoms (on condition, however, that in this case R1 never simultaneously denotes a hydrogen atom), each R3 denotes an alkyl radical containing 1 to 6 carbon atoms or the two R3 form together and with the atoms of the dithioacetal functional group to which they are attached a ring containing 5 to 7 members, R4 denotes a phenyl radical (optionally substituted by one or more halogen atoms, by one or more alkyl radicals containing 1 to 6 carbon atoms or by an alkoxy radical containing 1 to 6 carbon atoms), a naphthyl radical or a furyl radical, each of and Rg, which are identical or different, denotes a hydrogen atom, an alkyl radical containing 1 to 7 carbon atoms or an aryl radical (optionally substituted by one or more halogen atoms, j^lkoxy radicals containing 1 to 6 carbon atoms or alkyl "radicals containing 1 to 6 carbon atoms), , 11 and ^ / J each R7 denotes a methyl radical or the two R7 form together and with the carbon atom to which they are attached a cyclohexane nucleus or a cyclopentane nucleus.
2. A process for the preparation of the compounds of formulae XA and IB as claimed in claim 1, 23552 - 26 - wherein the D-glucosamine compound of formula II: 10 -:o :h (ii) is condensed either with an equimolar quantity of a compound of formula IIIA: HS(CH2)aSH IIIA in which n is equal to 2-4, or with an at least double quantity of a compound of formula IIIa: HSR'3 IIIB in which R'3 denotes an alkyl radical containing 1 to 6 carbon atoms, in the presence of concentrated hydrochloric acid to obtain a D-glucosamine derivative of formula IV: 15 s3 a3 —MH2 C*0 HO' OH OH CHjOH in which Rj has the same meaning as in the case of formula I, as claimed in claim 1, which is then reacted with a compound of formula V: - 27 - J<3SS-2,C r.-tCQ :c:-:3 (V) •• I I in which the meaning of R7 remains identical with that given in the case of formula I, as claimed in claim 1, in the presence of para-toluenesulfonic acid, to obtain a derivative of formula VI: =3 a 3 (VI) in which R3 and R7 have the same meaning as in the case of formula I, as claimed in claim 1, which is condensed with an aldehyde of formula VII: J 36 N y (vii) QKC 35 H4 in which the meaning of R*, R5 and R6 is identical with that given in the case of formula I, as claimed in claim 1, to obtain a Schiff base of formula VIII: - 28 - 235 5 (viii) in which R3/ R4, Rs, Rg and R7 have the same meaning as in the case of formula I, as claimed in claim 1/ which is next cyclized in the presence of tri-ethylamine with an acid chloride of formula IX: H2 Hi (ix) CI 10 15 in which R, and R2 have the same meaning as in the case of formula I, as claimed in claim 1, to obtain a mixture of monobactams of general formula IA and IB, which is next separated by crystallization and/or .by preparative chromatography. 3. Use of the compounds IA and IB/ as claimed in claim 1, as intermediates for the preparation of the monobactams XA and XB: r5 r2 Jtl 4.> 3 41 2 l nh / R6 (Xb) - 29 - R2 R1
3 2 mh e=c^ RU (Xfl) in which the meaning of R,, R2, Rw Rs and Rg remains identical with that given in the case of formla I as claimed in claim 1.
4. Use of the compounds of formulae IA and I3 for the preparation of the compounds XA and XS/ as claimed in claim 3, wherein the compounds of formulae IA and I3 are sxibjected to the action of n-butyllithium or of another equivalent chemical reactant, to obtain the compounds of formulae XA and XB.
5. Use of the compounds of formulae 1^ and Ig for the preparation of compounds X/\ and Xg as claimed in claim 3 or 4, wherein the compounds formulae IA and IB in solution in tetrahydrofuran or in smother equivalent organic solvent are subjected to the action of n-butyllithium at a temperature of between -20°C and -80°C, and the reaction mixture is then neutralized with the aid of an inorganic acid to obtain the compounds of formulae XA and X3.
6. Compounds of formula I as defined in claim 1 substantially as herein described with reference to the examples.
7. A process for the preparation of compounds as defined in claim 1 substantially as herein described with reference to the examples. ftfcFED TUB fth DAY S? A. J. PAilK. a SON FER jf AfiEMTS FOR THE APFUCAWW
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8913969A FR2653429B1 (en) | 1989-10-25 | 1989-10-25 | NOVEL DERIVATIVES OF AZETIDIN-2-ONE, 1,3,4-TRISUBSTITUES, INTERMEDIATES USEFUL FOR THE SYNTHESIS OF BETA-LACTAMS, AND THEIR ASYMMETRIC SYNTHESIS PROCESS. |
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|---|---|
| NZ235529A true NZ235529A (en) | 1992-08-26 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ235529A NZ235529A (en) | 1989-10-25 | 1990-10-01 | Azetidinone derivatives and their preparation |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0425378B1 (en) |
| JP (1) | JPH0725731B2 (en) |
| AT (1) | ATE113058T1 (en) |
| AU (1) | AU635975B2 (en) |
| CA (1) | CA2028458A1 (en) |
| DE (1) | DE69013461T2 (en) |
| DK (1) | DK0425378T3 (en) |
| ES (1) | ES2064692T3 (en) |
| FR (1) | FR2653429B1 (en) |
| IE (1) | IE903554A1 (en) |
| NZ (1) | NZ235529A (en) |
| OA (1) | OA09319A (en) |
| PT (1) | PT95671A (en) |
| ZA (1) | ZA908130B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4384998A (en) * | 1981-03-30 | 1983-05-24 | Merck & Co., Inc. | Synthesis of thienamycin from D-glucose |
| US4777252A (en) * | 1987-08-13 | 1988-10-11 | E. R. Squibb & Sons, Inc. | 2-oxo-1-[[(substituted sulfonyl)amino]-carbonyl]azetidines |
| EP0308867B1 (en) * | 1987-09-22 | 1995-07-26 | Shionogi Seiyaku Kabushiki Kaisha | Alkenylsilylazetidinone intermediates for carbapenems |
-
1989
- 1989-10-25 FR FR8913969A patent/FR2653429B1/en not_active Expired - Lifetime
-
1990
- 1990-10-01 NZ NZ235529A patent/NZ235529A/en unknown
- 1990-10-04 IE IE355490A patent/IE903554A1/en unknown
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- 1990-10-24 JP JP2286939A patent/JPH0725731B2/en not_active Expired - Lifetime
- 1990-10-24 AU AU64967/90A patent/AU635975B2/en not_active Ceased
- 1990-10-24 PT PT95671A patent/PT95671A/en not_active Application Discontinuation
- 1990-10-24 CA CA002028458A patent/CA2028458A1/en not_active Abandoned
- 1990-10-25 EP EP90403003A patent/EP0425378B1/en not_active Expired - Lifetime
- 1990-10-25 AT AT90403003T patent/ATE113058T1/en not_active IP Right Cessation
- 1990-10-25 OA OA59874A patent/OA09319A/en unknown
- 1990-10-25 DE DE69013461T patent/DE69013461T2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| ATE113058T1 (en) | 1994-11-15 |
| DE69013461T2 (en) | 1995-05-18 |
| ZA908130B (en) | 1991-07-31 |
| JPH03151382A (en) | 1991-06-27 |
| EP0425378B1 (en) | 1994-10-19 |
| AU635975B2 (en) | 1993-04-08 |
| AU6496790A (en) | 1991-05-02 |
| OA09319A (en) | 1992-09-15 |
| DK0425378T3 (en) | 1995-02-27 |
| FR2653429B1 (en) | 1991-12-20 |
| ES2064692T3 (en) | 1995-02-01 |
| FR2653429A1 (en) | 1991-04-26 |
| DE69013461D1 (en) | 1994-11-24 |
| CA2028458A1 (en) | 1991-04-26 |
| PT95671A (en) | 1991-09-13 |
| IE903554A1 (en) | 1991-05-08 |
| EP0425378A1 (en) | 1991-05-02 |
| JPH0725731B2 (en) | 1995-03-22 |
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