AU635975B2 - New 1,3,4-trisubstituted 2-azetidinone derivatives, useful as intermediates for the synthesis of beta-lactams, and process for their asymmetric synthesis - Google Patents
New 1,3,4-trisubstituted 2-azetidinone derivatives, useful as intermediates for the synthesis of beta-lactams, and process for their asymmetric synthesis Download PDFInfo
- Publication number
- AU635975B2 AU635975B2 AU64967/90A AU6496790A AU635975B2 AU 635975 B2 AU635975 B2 AU 635975B2 AU 64967/90 A AU64967/90 A AU 64967/90A AU 6496790 A AU6496790 A AU 6496790A AU 635975 B2 AU635975 B2 AU 635975B2
- Authority
- AU
- Australia
- Prior art keywords
- radical
- formula
- compounds
- denotes
- case
- 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.)
- Ceased
Links
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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
Form COMMONWEALTH OF AUSTRAL
A
PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: riority i oglated Art 608a e *0 5 Name of Applicant: *goo
S
'AJdress of Applicant: Actual Inventor O e Address for Service o •8 ADIR ET CCMPAGNIE 1 rue Carle Hebert 92415 Courbevoie Cedex, France ALICE GATEAU-OLESKER, STEPHANE GERO, JEANNINE CLEOPHAX and DANIEL MERCIER WATERMARK PATENT TRADEMARK ATTORNEYS.
LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: NEW 1,3,4-TRISUBSTITUTED 2-AZETIDINONE DERIVATIVES, USEFUL AS INTERMEDIATES FOR THE SYNTHESIS OF BETA-LACTAMS, AND PROCESS FOR HEIR ASYMMETRIC
SYNTHESIS
The following statement is a full description of this invention, including the best method of performing it known to US S r 1 The present invention relates to new 1,3,4trisubstituted 2-azetidinone derivatives and to the process for their asymmetric synthesis.
Beta-lactams constitute the most important class 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 employ chiral Schiff bases as intermediates. Various asymmetry inducers have been proposed, such as D-threonine Bose et al., Tetrahedron Lett., (1985), 26, p. 33-36) and D-glyceraldehyde 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 compounds constitute fundamental intermediates in the synthesis of antibacterial antibiotics.
Tho present invention relates more especially to compounds of general formulae I, and I, which form the general formula I: r i -2r r 2 R4 R2 R1 C= C 0 R6 0 TR
IA
R3 0 S
R
7 R3 R9 R4 R2*. R R2 1 42 RC R7 3 B O R6 0 Ig
N
R3 0 R S R7 R3 0 "0 ~in which RI 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, pherioxy or benzyl radical (optionally substituted on the benzene ring by one or more halogen atoms, alkoxy radicals containing 1 to 6 .10 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
R
2 never simultaneously denotes a hydrogen atom), Re, different from Ri, denotes a hydrogen atom, a halogen atom, an alkyl radical containing 1 to 6 carbon atoms, a trifluoromethyl radical, an alkoxy radical 3 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 containinq 1 to 6 carbon atoms (on condition, however, that in this case R, never simultaneously denotes a hydrogen atom), each R 3 denotes an alkyl radical containing 1 to 6 carbon atoms or the two R 3 form together and with the atoms of the dithioacetal functional group to which they are attached a ring containing 5 to 7 chain links,
R
4 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 Sradical or a furyl radical, each of Rs and R 6 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, alkoxy radicals containing 1 to 6 carbon atoms or alkyl radicals containing 1 to 6 carbon atoms), fee and each R, denotes a methyl radical or the two R 7 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-glucosamine compound of formula II: 0
(II)
OH
-0 NH2 4 is condensed either with an equimolar quantity of a compound of formula IIIA:
HS(CH
2 )nSH
III,
in which n is equal to 2-4, or with an at least double quantity of a compound of formula IIIr:
HSR'
3 I113 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:
R3 R3 .s s -NH2. (IV)
HO
OH
OH
15 in which R 3 has the same meaning as in the case of formula I, which is then reacted with a compound of formula Vs H3CO OCH3
(V)
R7 C R 7 in which the meaning of R 7 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: H2
(VI)
0
R
R7 in which R 3 and R 7 have the same meaning as in the 0 case ci: formula I, which is condensed with an aldehyde of formula
VII:
6..
0:0 OHC R6 0009 (V I R5 (V4I in which the meaning of R4, R 5 and RO is identical ****with that given in the case of formula I, to obtain a Schiff base of formula VIII: 0000 SC R 3 R7R S VI
I
0 0e 7 Ox R7 -6 in which R 3
R
4 Re and R7 have the same meaning as in the case of forinula I, which is next cyclized in the presence of triethylamine with an acid chloride of formula IX: R2 C (IX)
NCH(I
C
0 Cl in which R I and R 2 have the same meaning as in the case of formula I, to obtain a mixture of monobactams of general formula 'A and IB, which is next separated by crystallization and/or by preparative chromatography.
The monobactams X k and X. are easily obtained from the compounds I^ and by virtue of their nature and of an effective and original method of cleaving the chiral auxiliary: R5 R4
IY
SCC C See R4 2 R C2 R1 C
XB
0I2 1 NH In the case of the formulae XA and XB the meaning of RI, R 2
R
4 R, and RG remains identical with that given in the case of formulae I^ and ID.
In fact, by subjecting the compounds of formula I, to the action of n-butyllithium or of another 7 chemically equivalent reactant, the compounds of formula XA are obtained almost quantitatively, as are the compounds of formula Xg from compounds I
B
This original cleaving method also forms part of the present invention.
The process described makes it possible to obtain the compounds I^ and I B 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 azetidinones.
The advantage of the present invention lies in the fact that the IA.and IB diastereoisomers prepared from D-glu~samine 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 III) or a dithiol (compound of formula II).' 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 The compounds of formula IV are obtained in a yield by reacting the compounds of formula VI with the 30 compounds of formula V in the presence of para-tolueresulfonic acid.
To obtain the Schiff bases of formula VIII the compounds of formula VI are condensed with heating with an aldehyde of formula VII in an aromatic organic solvent such as toluene.
The compounds of formulae X, and X B are obtained from the compounds of the invention by virtue of p-elimination, hitherto unknown in this field. This operation is based on the special reactivity of the 8 proton carried by the carbon of the "thioacetal" functional group. This cleaving method, which consists in treating the compounds of formulae I, and IB with 2 equivalents of n-butyllithium or of some other equivalent preVr'ovLC chemical reactant, jat a temperature between -20°C and makes it possible to obtain the azetidinones X, and X, 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 "1C nuclear magnetic resonance (NMR) spectra were recorded on a spectrometer BRUKER (WP 200).
EXAMPLE 1 15 D-Glucosamine trimethylene dithioacetal hydrochloride
OH
H2 HC1
HO--
*5* 0 0 50 g of D-glucosamine hydrochloride are dissolved in 200 ml of concentrated hydrochloric acid cooled to O'C 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 0
C.
500 ml of water are added and the. dichloromethane, which contains the excess 1,3-propanedithiol, is R/_6 then separated off. Further washing with 100 ml of 9 dichloromethane is carried out twice.
The aqueous phase is neutralized with lead carbonate. It is filtered on a Bichner and two washings with 100 ml of water are carried out ,he material is then concentrated under vacuum. 500 ml of boiling ethanol are added and the solution is filtered on a Bichner.
After cooling, the crystals obtained are filtered off and then rinsed with ethanol Yield: 83% Melting point: 115-117 0 C (ethanol).
EXAMPLE 2 3,4:5,6-Di-O-isopropylidene-D-glucosamine trimethylene dithioacetal e n.
-NH2 So 0- 0 -0 Ox 17 g of the compound of Example 1 are dissolved in 45 ml of dimethylformamide and 50 ml of 2,2-dimethoxypropane. 5 g of para-toluenesulfonic acid are added. The solution is heated to 70"C for 1 hour 30 minutes in a Bichi rotary evaporator under a vacuum of 30 cm Hg, and then, after rapid cooling, 200 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.
Yield: 91% Melting 9oint: 79-80°C (hexane) Rotatory power: in CHCl 3 [a]0 89.4" 10 EX.AMPLE 3 Preparation of 2-f 38-methoxv-2-oxo-4 trL1-1az~tidinyl) -2-deoxv-2-dithianvl-3 .4:5,6-di-O-isopropylidene-D-rltucose 1_11.
0 7, 8' .3 91 at 4* 4 4 4e 0 4 J A 04 .444
A
6040 ~19 *000 and of -2-(3ca-methoxv-2-oxo-4ca-stvrv1-lazetidinvi) -2-deoxsy-2-dithianvl-3 6-di-O-isop~ropvlidene-D-cxlucose LZI 7, 44 81
S
7 g of the compound of Examile 2 and 2.52 ml of cinnamaldehyde are dissolved in 6 ml of anhydrous toluene. The mixture is heated to 600C for 20 minutes and then the water formed is removed by entrainment with toluene under low pressure. The imine thus formed is diluted in 1.5 ml of anhydrous toluene, and 6.7 ml of triethylamine and 2.2 ml of methoxyacetyl chloride are 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 0
C.
The organic phase is taken up with dichloromethane and is 11 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 enables 4.8 g of the 3p,4p8 isomer to be isolated. The mother liquors are chromatographed on silica preparative plates using a mixture of ethyl acetate and hexane 6 V/V) as eluent to separate the 3 a, 4 cz and 3fi,4i isomers.
Yield: 3cx,4cx isomer: 34% 3p,4p isomer: 57% Physicochemical constants: A. 38-Methoxv-2-oxo-48-stvrl--azetidinyl) -2-deoxv- 2-dithianvl,-3 6-di-0-isopropvlidene-D-cjlucose _(jj1 Melting point: 206 0 C (hexane-dichloroms-"tane) Rotatory power: (c1l% CHCl 3 _1 .6 D~ 116 Elemental analysis: C% H% N% S% 20 Theory: 60.53 6.96 2.61 11.97 Found: 60.41 6.80 2.63 12.06 Proton nuclear magnetic resonance spectrum (solvent: CPClIA, 6 ppM: 1.20-1.28-1.36-1.53 (12H, 1 4s); 1.-7 2.7 2.9-3.2 3.46 (.3H,OCH 3 1
S);
3.8-4.4 (7H, Hl 1 8 4.57 (lH,H4,ddJ4 3 =5Hz, J 4 5 =9Hz); 4,.76 (1H,H 3 ,d,J 3 .4=5Hz); 6.45 (1H,dd,H,,J 5 .4_=9Hz, J 5 8 a=l6Hz); 7.3-7.6 (5HOCHMI) 13,C uclear maarnetic resonance spectrum (solvent: CDC1.) 4.*
S
baa.
4 b.
4 *5 30 6RD 25.2 (CH 3 25.6 (C 9 26.4 (CH 3 1sopr) 26.6 27 (CH 3 27.2 44.4 (C 2 '11; 54.1 58.7
(OCH
3 62.3 67.7 76.9 77.3 79 (C 3
.,C
4
.,C
5 85.4 109 110 126 126.9 128.1 128.6 134.9 (CHph,C 5 1
C
8 136.4 (Cph); 168.9 (CO).
B. 2-(3a-Methoxv-2-oxo-4a-stVTyl--azetidinvl)-2deoxv-2-dithianyl-3 a1uc se k Melting point: 155*C (hexane dichioromethane) 12 Rotatory power: CHC1 3 CaD0= +114.70 Elemental analysis: C% H% NS% Theory: 60.53 6.96 2.61 11.97 Found: 60.51 7.25 2.53 12.04 Proton nuclear magnetic resonance spectrum (solvent: CDC1,) 6 'PPM: 1.35-1.36-1.49-1.58 (12H,CH 3 i 5 0 1.9-2.2 (2H,m,H, 1 1 m); 2.5-2.7 3.G9 3.46 (3H,OCH 3 3.62 (1HH' 4 1 dd,J4.- 3 J4...
5 =8Hz) 3.90-4.22 (4H,H 1 1 611 4.60 (IH, H 211 dd,J 2 31 =1.5Hz,, J 2111 11lHz) 4.69-4.78 (2H,H 3 ,dd,J 3 4 5HZ,H 41 ,dd, J 4 3 =5Hz, J 4 5 10Hz) 4.91 (1HH 3 dd,J 3121 1. 5Hz, J 31 -4,=8Hz) 6.61 (1H, :6,0.615 H5 dd,J5..
4 =i0Hz, J 5 a15.5HIz); 6.72 (1H,Ha,d,J6 8 5 =15.5Hz); 7.3-7.5 (5H, CHrh,m).
13 C nuclear magnetic resonance spectrum (solvent: CDC1,)
(CH
3 ±sopr); 25.3 25.6 25.9 (CH 3 26.1 &me 20 26.3 (CH 3 27.5 (CH 3 j, 0 p 43.7 (C 2 51.8 (C 1 58.6
(OCH
3 63 67.5 77.1 77.7 78.5 (C 31
C
4
C
5 85.3 109.4 (C 7 109.9 (C 7 123.9 126.6 128.1 fb 0Go 4128.6 135.8 (CH~hI C 5 CG); 136.2 (Cph); 167.8 (CO), EXAMPLE 4 38-Methoxy-48-styvl-2-azetidinone
CH
3
O
46 -a 1 2.6 g of the 2-(3p-methoxy-2-oxo-43-styryl-lazetidinyl) -2-deoxy-2-dithianyl-3 6-di-O-isopropylidene-D-glucose compound of Example 3 are dissolved in ml of anhydrous tetrahydrofuran.
8 ml of n-butyllithium-( 1.22 in hexante) are added slowly at -40*C. The solution is stirred for 20 minutes and is ther. poured onto a saturated aqueous solution of ammonium chloride at OOC. The pH is returned to 7 by 13 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 chromatographed 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: Melting point: 126*C (hexane-dichioromethane) Rotatory power in CHC1 3 +100 Elemental analysis: all C% H% N% *Theory: 70.91 6.45 6.89 Found: 70.87 6.35 6.57 PProton nuclear magnetic resonance spectrum (solvent: *00:CDCL~) 6 Dpm: 16 3.44 (3H,OCH 31 4.38 (1HIH 41 d, 4 =4.8Hz,J 4 4.64 (1H,H 3 ,dd,J 3 4 =4.8Hz,, J 3 6.26 (1H,H 5
,J
5 4 =8.3Hz,
J
5 -r=l6Hz); 6.56 (1H,NH); 6.65 (lH,H 6 1
J
8 6 5 =l6Hz); 7.2-7.5 1 3 C nuclear magtnetic resonance spectrum (solvent: CDCI.,;) 6S P~m 56.9 58.5 (CH 3 86.8 (C 3 125.04 (C 6 126.7 (CHph); 128.1 (CHph); 128.7 (CHph); 134.8 (C 5 136.36 (Cph); 168 (CO).
EXAMPLE 3c-!ethoxvy-4c-strl-2-azetidinone
CH
3 0/ This compound was prepared from 2-(3a-methoxy-2oxo-4cg-styryl-l-azetidinyl)-2-deoxy-2-dithiany1-3,4 :5,6di-O-isopropylidene-D-glucose according to the process described in Example 4.
14 Rotatory power in CHC1 3 -10.0 EXAMPLE 6 3,4:5,6-Di-O-isopropylidene-D-qlucosamine diethyl dithioacetal STAGE A D-Glucosamine diethyl dithioacetal hydrochloride C2H S S H2
HC
S...HO-
OH
.6 CH2OH g of D-glucosamine hydrochloride are dissolved in 80 ml of concentrated hydrochloric acid, cooled to O*C saturated with gaseous hydrochloric acid. 100 mg of Aliquat 3360 (Aldrich) and 30 ml of ethylthiol 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 are 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 Bchner. The water is stripped off under vacuum. The residue is taken up with ethanol. After being filtered on a Bichner, the solution containing the expected product is evaporated to dryness.
Melting point: 75-76°C (ethanol) 15 STAGE B S S
%NH
2 0 0 0*0 0 ,49:0 The residue obtained in the preceding stage is dissolved in 20 ml of dimethylformaiide. 3,4#:5,6-Di-Owoo: isopropylidene-D-glucosamine diethyl dithioacetal is then 0:00 5 obtained according to the process described in Example 2.
Overall yield: 59%.
EXAMPLE 7 Preparation of 2- (3B-methoxv--2-oxo-40-styrvl-lazetidinyl) -2-deoxv-3 diethyl dithioacetal (3) goo* 00 j3 4 6 0 0;.1 1 2 7' 45 SS 3 2 0
H
5
C
2 C2H 16 and of 2 -(3ca-methoxy-2-oxo-4a-stvr..i...
azetidinvi -2-deoxv-3 .4:5 6-di-O-isoy)ro~vlidene-D-grlucose diethyl dithicacetal (4) 46 0 [2 1.
S0 6 C2HS 0 fe *These compounds were prepared from the compound s obtained in Example 6 and according to the process 0:0* described in Example 3.
Physicochemical constants: A. 2- (28-Methoxv-2-oxo-48-stvrl.-1-azetidinvl) -2-deoMv- 3,4:5. 6-di-O-isopropylidene-D-glucose diethyl dithioacetal JUj M elting point: 71-73.5*C (acetone-water) Rotatory power: (c=0.98% CHC1 3 ego* -117-50 Elemental analysis: *to i5C
H%NS
0 Theory: 60.95 7.49 2.54 11.62 Found: 60.98 7.48 2.71 11.62 C. Proton nuclear macnetic resonance st~ectru (solvent: CDC13) 6 13pp1: 1.19-3.33 (18H CHU..p. 2CH3CH 2 in); 2.6-2.85 (4H 2S- CH2CH 3 3.40 (3HOMe,s); 3.7'(HH.tJ 9 5 4 3.89-4.17 (4HH 3 s, 4 6, 5 1, 6 4.33 (1H,H 6 'I d, B,6-b= 9 4.62-(H,vHA',dd,J.
3 5Hz,,J.
5 4.65-4.68 (2H,,H 31
H
31 1 m); 6.4 (1H,H 5 1 ,dd,J,.=16HzJ 5 6.63 J,.
5 =l6Hz,d); 7.18-7.43 (5H arom,m) 17 3 4:5, G-di-O-isopropvlidene-D-grlucose diethyl dithiaacetal LjjO Melting point: 81-84 0 C (acetone-water) Rotatory power: (c=1.15% CHCl 3 21 [D +1060 Elemental analysis: CH% N% S% Theory: 60.95 7A49 2.54 11.62 Found.- 60.76 7.53 2.65 11.63 Proton nuclear magnetic resonance spectrum (solvent:_ CDC1,A- E ppm: 1.2 (6H,2CHCH 2 1.32;1.39;1.42;1.58 (12H,C{ 3 ,j, 0 ,p,4s); 2.57-2.75 (4H,2S-CH,.CH 3 1 3.5 (3H-,OCH 3 3.6 (lH,H 4 t,J 4 5 .5Hz); 3.93-4.23 (5H,Hj, B'bIM) 4.7 (2H,
H
3
H
4 's broad); 4.95 (1H,H 3 1,dd,J 3 4 .5 Hz J 3 2 .=2Hz); mo 0 667-6.73 (2H, H 5 1 Hr 61 s broad); 7.3-7.5 (5H arom,m).
EXAMILB 8 *Pe p.ration of 2-j4a-r2- (2funvl )vinvl1-33methox-2-oxc--azetidinyfl-2-deoxv-2-dithianvl-3,.4 :5,6di-O-isopropvlidene-D-crlucose LU 7* 9 foo CH 6 0 8' 1-ztiivI.2dex--dt3ay- 44: Irpldn--lcs V.) 0
CH
3 O79 12 7' 2' -4' S 3' 0<7 9. 8' (6) a *to 41-01* Both compounds were prepared according to the
*S
*process described in Example 3, but using 3-(2-furyl)acrylaldehyde instead of cinnamaldehyde. The isomers wera too: 5 separated according to the method described in Example 3.
*too. Yield: 3a,4a isomer: 32.12% 3p,4p isomer: 48.18% Physicochemical constants A. 2-.48-r2-(2-Furvllvinvll-3B9-methoxv-2-oxo-l-azetidinvi 1-2-deoxv-2-dithianyl-3 4:5. 6-di-O-isotropvlidene- ,**%,D-glucose j Meilting point: 185-188 0 C (methanol) .Poo* Poo@. Rotatory power: 2.28% CHC1 3 X]2-1 -112.28* 15 Elemental analysis 0* C% H% N% S% Thoy 7.3 67 26 21 06 hoy 5.3 67 26 21 Found: 57.09 -6.60 2.71 12.15 Proton nuclear magnetic resonance spectrum (solvent: CDC1, 6pm: 1.23; 1.28; 1.36; 1.53 (1211, 4CH 3 illpl., 4 1.91-2.11 (211, He. in); 2.56-2.7 (2H, 117., mn); 2.91-3.13 (2H, HVI. Mn); 3.46 (311, OCH 3 3.72-3.82 (111, mn); 4.00-4.23 (4H, Hj., 115#, mn) 4.42-4.51 (2H1, H12', mn); 4.62-4.74 (211, H3, 113., mn); 6.27 (1H1, He, dd, J 89 3Hz); 6.29 (1H, H5~, dd Jj8= 16Hz; 9Hz); 6.37 (1H, H 9 dd, Jg- 10 1.5 Hz, 19 J89=3Hz) 6. 46 (l1H, Hp,, d J5-r 16Hz) 7. 36 1H, HI 0 *d, J-o=1. B. 2 -i4cr-r2-( 2-Furvl')vinvl1 -3a-methoxy-2-oxo-l-azetidir~1 ',.-2-deoxy-2-dithianvl-3 6-di-O-isopropylidene- D-cglucose, j(6, -Rotatory power: 1.16% CHC1 3 [a 2 +110.68* -Elemental analysis: C% H% N% S Theory; 57.13 6.71 2.66 12.17 Foundt 57.09 6.58 2.72 12.14 Proton nuclear macrnetic resonance spectrum (solvent: CDCl 3 q) 6 Dpm 1.31; 1.36; 1.48; 1.5 (12H, 4CH 3 1 1,93-2.10 (2H, 6.*15 in); 2.43-2.68 (2H, HP7I in); 2.90-3.23 (2H, H 7
M);
3.48 (3H, OCH 3 3.63 (1H, in); 3.86-4.20 (4H,
H
5 2H 6 in); 4.55 (1H, H 2 dd); 4.60-4.70 (2H, H 3
H
4 1 in); 4.8 (1H, H 3 dd); 6.29-6.35 (4H, H 5 in); 7.38 o :s(1H, H 10 d, J 9 10 15Hz) EXAMPLE 9 Preparation of 2-f48-r2-(2-furvl)vinvlI-3Bmethoxy-2-oxo-l-azetidinvfl-2-deoxy-3 6-di-O-isop~ror~yidene--ilucose-diethyl dithicacetal£2 6 S 4H 3 0 666 3 Ei5C2 (7) and of 2-f 4a r2- (2-f ugyl)vinyl I-3a-methoxv-2-oxo-1azetidinvl 1- 2-deany-3, 4: 5, 6 -di-O-isop~ropvlidene-D-ailucose diethyl dithicacetal M(j 20 CH' ~2 HS C2 C 2 H
S.
*0 0~I.
SS
S. *500 a a. S SeRe 0 E~ .5
S
*000 These two compounds were prepared and separated according to the process described in Example 3, but using 3-(2-furyl)acrylaldehyde and 3,4:5,6-0-iso- 5 propylidene-D-glucosamine diethyl dithioacetal.
Yield: 3ca, 4 a isomer: 33.44% 3fi,4fi isomer: 45.60% Physicochemical constants A. 2-f48-2-(2-Furyl)vinyll -38-methoxy-2-oxo-lazetidinv]A-2-deoxv-3 .4:5 5 4e** 0*sW 0@ 0@ S o 6 .545
S
0*S0 0S 0 diethyl dithioacetal 11 Rotatory power: 1.87% CHCl 3 -128.870 Elemental anal~ysis: Theory: 57.67 7.25 2.58 11.81 Founds 57.60 7.18 2.43 11.52 Proton nuclear magrnetic resonance spectrum (solvent: a 4 a 40 CDC3) Dy: 1.16-1.43 (18H, *6CH., mi); 2.56-2.86,, (4H, 2S-CH 2
-CH
3 in); 3.46 (3H, OCH 3 3.7 H 4 in); 3.86-4.16, (4H, H 1
H
2
H
5 Hetal in); 4.25 (1H, He'b, dd); 4.31-4.70 (3H, H 3
H
3
H
4 1 mn); 6.27 (1H, H 8 d J8- 3Hz); 6.31 (1H, H 5 dd, J- 16Hz, J3- 8Hz) 6.36 (1H1, H9, dd; Jq-.O~ 1.5Hz 3Hz); 6.44 Hts, d, J5-. 16Hz); 7.34 (1H, HI,, d, J930= 1. 5Hz) -21 B. 2 -14ck r2-(2 -Fur 1~inVlI-3a-methoxv-2-oxo-1-azediethyl dithioacetal I(aj Rotatory power: CHCl 3 5 +60.090
S.
A
**g
SO
0 4
S
S
.554
S
SO..
Se
S.
ASOS
0350
U
555.
0003
S
*0 0 4*35 0
S
COOS
S.
0
S
Elemental analysis: C% H% N% S Theory: 57.67 7.25 2.58 11.81 FounA 57.49 7.18 2.45 11.76 Proton nuclear magnetic resonance spectrum (solvent: CDCl 3 A~ S ppm: 1.18-1.51, (18H, 6CH 3 1 in); 2.53-2.71 (4H, 2S-CH2-CH 3 v in); 3.46 (3H, OCH 3 1 s) 3.58 (1H, H 4 3.80-4.20 (5H, H 1
H
2
H
5 2H6., mn); 4.60-4.82 (2H, H 3
H
4 mn); 4.90l-5.03 15 (1H, H 3 dd); 6.29-6.38 (5H, H 5
H
6 Hs, mn); 7,3i 'lHi,
H
10 Ji..
10 =4 EXAMPLE Preparation of 2-[r3g-inethoxv-4B- fB-iethvlstvrvl) 2-oxo-1-azetidinvl -2-deoxv-3,4:5,6-di-O-isopropylidene- D- alucose diethiyl dithioactalj CH30 4 6 0 0 1i2 1 U4 5 4' 7 s* 0 61 -0 C2KC(9 and of 2-f 3a-inethoxv-4a-( B-iethvlstvrvl) -2-oxo-1alzetidinvll1-2-deoxv-3 6-di-O-isotropylidene-D-atlucose diethyl dithioacetal (101) 22 7' O 0 6 HSC2 C2H(10) 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 to the process described in Example 3.
Yield: 3a,4a isomer: 13.40% 3p,4p isomer: 53.60% Physicochemical constants A. 2-r3B-Methoxv-4B -(B-methylstvrvl)-2-oxo-1-azetidinyll-2-deoxv-3,4:5.6-di--isopropvlidene-D-glucose diethyl dithioacetal Rotatory power: (c 1.25% CHC1 3 [a]D25 -53.840 SeeS
S
S
egee
S
S. I S I 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 spectrum (solvent: 20 1.1-1.4 (18H, 6CH., 2.05 (3H, CH 3
H
7 2.62-2.82 (4Hr 2. S-H,-CH3, 3.45 (3HI OCH3. 3.75 (1Hj, HV,, 3.95 (1H, Hi., in); 4.09-4.35 (4H, Hji, H 2
H
6 5, Hb m); 4.61 (1H, H 4 d, J4- 3 5Hz); 4.75 (1H, H 3 4.82 (1H,
H
3 d J3-4: 5Hz); 6.6 (1H, H 6 7.20-7.39 (5H, 1H, i).
B. 2-r3c-Methoxv-4ca-(B-methlstvrvl)-2-oxo-1-azetidiny ll-2-deoxve-3.4:5,6-di-O-isopropylidene-D-rlucose diethyl dithioacetal Rotatory power: (c 0.3% CHCl 3 +55.150 -23- Elemental analysis: C% NS Theory: 61.57 7.66 2.47 11.31 Found: 61.79 7.61 2.35 11.28 proton nuclear magnetic resonance spectrum (solvent: CDC,L_ 6 _pm: 1.1-1.5 (18H, 6CH 3 in); 2.05 (3H, H7, CH., 2.63-2.78 (4H, 2S-CH2-CH 3 in); 3.42 (3H, OCH 3 3.78 (1Hi, H 4 in) 3.80-4.21 (5H, HI., H 2
H
5 ,1 H 6 Hb' in); 4.68 (2H, H 3
H
4 Mn); 4.81 (1H, H 3 6.73 (1H, Hr 6 s) 7.21-7.39 (5H1, 1H1, &in).
*to so 00
Claims (3)
- 2. A process for the preparation of the compounds of formulae 1A and I n as claimed in claim 1, S- 26 wherein the D-glucosamine compound of formula II: 0 OH OH (II) 0 O H HO iH2 is condensed either with an equimolar quantity of a compound of formula III,: HS(CH 2 )nSH III, in which n is equal to 2-4, or with an at least double quantity of a compound of formula IIIB: d. 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: R 3 R3 Se* S S -NH2 (IV) HO-- OH -oH in which R 3 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 1 27 H 3 CO 0 CH 3 (V) R7-C R 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 VIi R3 R3 N H2 0a R? (VI) R7 At 0 V 66 .'-OX~RR7 in which R 3 and R 7 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:, 0eS tootanaScifbaeI)fruaII -28 C R II sR3 R 3 (VIII) R R7 0 00 o R7 in which R 3 R 4 R 5 ,r N and R 7 have the same meaning as in the case of formula 1, as claimed in claim 1, which is next cyclized in the presence of tri- ethylamine with an acid chloride of formula IX: R2 R1 (IX) in which R, and R 2 have the same meaning as in the case of formula 1. as claimed in claim 1, t ~o to obtain a mixture of monobac:tams- of general formula and 1. which is next separated by crystal- )ization and/or .by preparative chromato~graphy.
- 3. Use of the compounds of formulae IA and Ig for the preparation of the monolactams XA and Xe: R 4 o 2 R C~ C ^(XA) 4 S.R2 R i 0 ,,N(XB) 2 NH in which the meaning of R 1 R, R4, R and Re remains identical with that given in the case of formula I as claimed in claim 1, wherein the compounds of formulae IA and ls are subjected to the action of 2 equivalents of n-butyllithium or of another equivalent chemical reactant, to obtain the compounds of formula XA and Xs.
- 4. Process for the preparation of compounds XA and XB where XA and Xs, R 1 R 2 R 4 Rs and Re are as defined in claim 3, wherein the compounds of formula IA and Is in solution in tetrohydrofuran or in another equivalent organic solvent are subjected to the action of 2 equivalents of n-butyl-lithium at a temperature of between -20°C and and the reaction mixture is then neutralised with the aid of an inorganic acid to obtain the compounds of formulae XA and XB. DATED this llth day of February, 1993. WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA -29-
Applications Claiming Priority (2)
| 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. |
| FR8913969 | 1989-10-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6496790A AU6496790A (en) | 1991-05-02 |
| AU635975B2 true AU635975B2 (en) | 1993-04-08 |
Family
ID=9386756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU64967/90A Ceased AU635975B2 (en) | 1989-10-25 | 1990-10-24 | New 1,3,4-trisubstituted 2-azetidinone derivatives, useful as intermediates for the synthesis of beta-lactams, and process for their asymmetric synthesis |
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) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2091988A (en) * | 1987-08-13 | 1989-02-16 | E.R. Squibb & Sons, Inc. | 2-oxo-1-(((substituted sulfonyl)amino)carbonyl)-azetidines |
| AU2246688A (en) * | 1987-09-22 | 1989-03-23 | Shionogi & Co., Ltd. | Alkenylsilylazetidinone intermediates for carbapenems |
Family Cites Families (1)
| 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 |
-
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
- 1990-10-11 ZA ZA908130A patent/ZA908130B/en unknown
- 1990-10-24 AU AU64967/90A patent/AU635975B2/en not_active Ceased
- 1990-10-24 CA CA002028458A patent/CA2028458A1/en not_active Abandoned
- 1990-10-24 JP JP2286939A patent/JPH0725731B2/en not_active Expired - Lifetime
- 1990-10-24 PT PT95671A patent/PT95671A/en not_active Application Discontinuation
- 1990-10-25 DK DK90403003.8T patent/DK0425378T3/en active
- 1990-10-25 DE DE69013461T patent/DE69013461T2/en not_active Expired - Fee Related
- 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 EP EP90403003A patent/EP0425378B1/en not_active Expired - Lifetime
- 1990-10-25 ES ES90403003T patent/ES2064692T3/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2091988A (en) * | 1987-08-13 | 1989-02-16 | E.R. Squibb & Sons, Inc. | 2-oxo-1-(((substituted sulfonyl)amino)carbonyl)-azetidines |
| AU2246688A (en) * | 1987-09-22 | 1989-03-23 | Shionogi & Co., Ltd. | Alkenylsilylazetidinone intermediates for carbapenems |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE113058T1 (en) | 1994-11-15 |
| AU6496790A (en) | 1991-05-02 |
| PT95671A (en) | 1991-09-13 |
| JPH03151382A (en) | 1991-06-27 |
| IE903554A1 (en) | 1991-05-08 |
| DE69013461D1 (en) | 1994-11-24 |
| ZA908130B (en) | 1991-07-31 |
| FR2653429B1 (en) | 1991-12-20 |
| FR2653429A1 (en) | 1991-04-26 |
| JPH0725731B2 (en) | 1995-03-22 |
| DK0425378T3 (en) | 1995-02-27 |
| ES2064692T3 (en) | 1995-02-01 |
| NZ235529A (en) | 1992-08-26 |
| DE69013461T2 (en) | 1995-05-18 |
| OA09319A (en) | 1992-09-15 |
| EP0425378B1 (en) | 1994-10-19 |
| CA2028458A1 (en) | 1991-04-26 |
| EP0425378A1 (en) | 1991-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Boivin et al. | Iminyl, amidyl, and carbamyl radicals from O-benzoyl oximes and O-benzoyl hydroxamic acid derivatives | |
| JP5911447B2 (en) | Exo- and diastereo-selective synthesis of himbacine analogs | |
| KR950013767B1 (en) | Chiral azetidinone derivatives and method for preparing them | |
| Arrieta et al. | Reagents and synthetic methods. Part 67. Preparation of 4-unsubstituted. beta.-lactams from 4-acetoxyazetidin-2-ones. A formal approach to monobactams and nocardicins | |
| JPH0649674B2 (en) | Method for iodizing or brominating the α-methylene carbon atom of a secondary amide | |
| Hoffmann et al. | Chiral Organometallic Reagents, VIII. On the Configurational Stability of α‐Hetero‐Substituted Benzyllithium Compounds | |
| Alcaide et al. | Preparation of. alpha.-Methylene and. alpha.-Ethylidene. beta.-Lactams via the Ester Enolate-Imine Condensation Using. beta.-(Dialkylamino) Esters as Starting Materials: Scope and Synthetic Applications | |
| Osorio-Lozada et al. | Synthesis and determination of the absolute stereochemistry of the enantiomers of adrafinil and modafinil | |
| HU217088B (en) | Process for producing benzylidene derivatives | |
| Oppolzer et al. | An Efficient Enantioselective Synthesis of (—)‐Serricorole | |
| AU635975B2 (en) | New 1,3,4-trisubstituted 2-azetidinone derivatives, useful as intermediates for the synthesis of beta-lactams, and process for their asymmetric synthesis | |
| EP1529777A2 (en) | Process and oxazolidine intermediate for the synthesis of taxanes | |
| JP2787602B2 (en) | Isoxazoline derivative | |
| Batchelor et al. | Total syntheses of close analogues of the immunosuppressant FK506 | |
| Molina et al. | One-pot conversion of 4-aryl-3-butenylazides into benz [f] indoles by a consecutive staudinger reaction/aza Wittig reaction/intramolecular Diels-Alder cycloaddition process. | |
| Braverman et al. | Synthesis of mono-and disubstituted sulfines via β-elimination of chloroform from trichloromethyl sulfoxides | |
| Araki et al. | A new synthesis of pyrroles by the condensation of cyclopropenes and nitriles mediated by gallium (III) and indium (III) salts | |
| Rossi et al. | Stereoselective Synthesis of Naturally-Occurring 7-(Hetero) Aryl (2E, 4E, 6E)-2, 4, 6-Heptatrienamides and Their Structural Analogues | |
| Humber et al. | C-nucleosides. Part 1. Preparation of tiazofurin and N-substituted tiazofurins from benzyl (2′, 3′, 5′-tri-O-benzoyl-β-D-ribofuranosyl) penicillinate | |
| KR910005230B1 (en) | Process for producing azetidinones | |
| HU214086B (en) | Process for producing 3-isoxazolecarboxylic acid and intermediates thereof | |
| Viallon et al. | Thermal and acid-catalysed sigmatropic rearrangements of allylamino-methoxy-1, 2-benzoquinones | |
| Martín et al. | Stereocontrolled routes to derivatives of 3-alkoxycarbonyl-2-amino-4-aryl-5-cyano-6-phenyl-4H-pyrans | |
| Budnikova et al. | Synthesis of endocyclic enol methyl ethers of 3-acylthiotetronic acids and their reactions with amines | |
| HU216796B (en) | Process for producing 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine and its salts |