NZ207193A - Preparation of chiral beta-lactams - Google Patents
Preparation of chiral beta-lactamsInfo
- Publication number
- NZ207193A NZ207193A NZ207193A NZ20719384A NZ207193A NZ 207193 A NZ207193 A NZ 207193A NZ 207193 A NZ207193 A NZ 207193A NZ 20719384 A NZ20719384 A NZ 20719384A NZ 207193 A NZ207193 A NZ 207193A
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- New Zealand
- Prior art keywords
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- general formula
- acid
- process according
- lower alkyl
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen 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
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
1. A process for the manufacture of chiral beta-lactams of the general formula see diagramm : EP0120289,P14,F1 wherein R**1 signifies a readily cleavable protecting group, R**2 signifies azido, phthalimido or the group ROCO-CH=C(CH3 )-NH-, R signifies lower alkyl and R**3 and R**4 each individually signify hydrogen or lower alkyl or together signify alkylene with a maximum of 6 carbon atoms, and the groups denoted by lower have a maximum of 4 carbon atoms, characterized by reacting a lactone of the general formula see diagramm : EP0120289,P14,F2 wherein R**3 and R**4 have the above significance, with an alkali metal periodate, reacting the resulting aldehyde of the general formula see diagramm : EP0120289,P14,F3 wherein R**3 and R**4 have the above significance, with an amine of the general formula H2 N-R**1 wherein R**1 has the above significance, and reacting the thus-obtained compound of the general formula see diagramm : EP0120289,P14,F4 wherein R**1, R**3 and R**4 have the above significance, in the presence of a base with a reactive derivative of a carboxylic acid of the general formula R**2-CH2 -COOH wherein R**2 has the above significance.
Description
New Zealand Paient Spedficaiion for Paient Number £07193
207 193
Priority Dare's): 2-^$.,
Complete Specification Filed: \
Class: .m3Sk£Q.}0».
Publication Date: ...MPCT.8W
P.O. Journal, No:
NO DRAWINGS
No.: Date:
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
PROCESS FOR THE MANUFACTURE OF CHIRAL g-LACTAMS
K/We. F. HOFFMANN-LA ROCHE S CO. AKTIENGESELLSCHAFT, of 124-184
Grenzacherstrasse, Basle, Switzerland, a Swiss company, '■&? PATENT OBana
■
1. 18 AUG 1987* I* fiEC&VEf, ^
hereby declare the invention for which dx/ we pray that a patent may be granted to SHeVus, and the method by which it is to be performed, to be particularly described in and by the following atatement: -
(followed by page la)
207
The present invention is concerned with a process for the manufacture of chiral 0-lactams, namely of those of the general formula
J
3 4 2 1
III
N
in which R~ signifies a readily cleavable
2
protecting group, R represents benzyloxy-
carbonylamino, azido, phthalimiao or the
6 7 5
group R R C=C R -NH-, wherein R represents lower alkanoyl, lower alkoxycarbonvl or benzoyl, R^ represents hydrogen, lower alkyl,
lower alkanoyl, lower alkoxycarbonyl or cyano and R^ represents hydrogen or lower 3 ^
alkyl, and R and R" each individually represent hydrogen or lower alkyl or together represent lower alkylene.
The process comprises reacting a lactone of the general formula
0 X R
II"
3 4
in which R and R have the significance given above,
with an alkali metal metaperiodate, reacting the thus-obtained aldehyde of the general formula w^-PATBrrofpq
J 8 AUG 1987 fiecbved
X
207193
X
°)U
in which R-* and have the significance given above,
with an amine of the general formula h^-r1 jv in which R"*" has the significance given above,
and reacting the thus—obtained compound of the general formula
V
13 4
in which R f R and R have the significance above,
in the presence of a base with a reactive derivative of a carboxyiic acid of the general formula
R2-CH2-C00H VI &Z.
2 . .. 18 AUG 1987
in which R has the significance ■ •
given above. £ rkBVED
207193
The lactone starting materials of general formula II used in the above process are novel compounds. By using these novel lactones the aldehydes of general formula I are obtained in a simple manner and in good yield. The latter are useful for the synthesis of antimicrobially active fl-lactams ana also for the manufacture cf chiral glycerine or of its acetonide and of analogues thereof. The latter products are useful, for example, in the synthesis of leucotriene (Nachr. Chem. Techn. Lab. 31, 19 83, No. 2, p. 117-20) of "Platelet Agrregation Factors" (Helv. Chim. Acta, 1982, p. 1059-84) or of (R)-y-amino-/3-hydroxybutyric acid (J. Am. Chem. Soc., 1980, 102/ p. 6304-11).
The term "lower alkyl" signifies a straight-chain or branched-chain saturated hydrocarbon group containing at most 4 carbon atoms such as methyl, ethyl, isopropyl and the like. The term "lower alkoxy", alone or in combinations such as in "lower alkoxycarbonyl", has an analogous significance. The term "lower alkylene" signifies a straight-chain or branched-chain hydrocarbon group containing at most 6 carbon atoms (e.g. tetramethylene or, preferably, pentamethylene). The term "lower alkenyl" signifies an olefinic hydrocarbon group which can be straight-chain or branched-chain and which preferably contains up to 8, especially up to 4 carbon atoms such as, for example, vinyl, 2-propenyl (allyl), 1-propenyl, isopropenyl, 2-methallyl, 1- or 2-butenyl, 1- or 2-hexenyl, 1- or 2-heptenyl, 1- or 2-octenyl etc. The term "lower alkanoyl" signifies alkanoyl groups derived from straight-chain or branched-chain saturated fatty acids containing at most 4 carbon atoms such as formyl and acetyl.
,6-Isopropylidene-L-gulonolactone (the lactone of 3 4
formula II in which R and R both represent methyl) is preferably used in the process provided by the invention. The reaction of a lactone starting material of formula II with an alkali metal metaperiodate is preferably carried out in an aqueous phase with the addition of sodium metaperiodate, especially at about -10°C to +40°C. Prior
207193
to this reaction the lactone of formula II can, if desired, be treated (at about 0-l0°C) with an alkali hydroxide (e.g. aqueous sodium hydroxide or potassium hydroxide) in order to cleave the lactone. The resulting open structure of the general formula
H0-
O. 0'
OH
CoX
VII
coo
- OH
0 M®
7 4 . -.
wherein R and R have the above signin-
cance and M represents an alkali metal cation,
is neutralized, for example with aqueous mineral acid (e.g. hydrochloric acid), and then, as above, reacted with the alkali metal metaperiodate.
The group ROCO-CH=C (CH_) -NH- in which R represents c /- 7
lower alkyl is a sub-group of the group R R C=CR -NH-.
Examples of amines of formula IV are those in which R^" represents one of the following groups:
- 2,4- or 3,4-di(lower alkoxy)benzyl; (a)
- di[4-(lower alkoxy)phenyl]methyl; (b)
1&Z. PATENT OTOCf
— ~
\ 18 AUG 1937 receive!-
2073
(c)
(d)
(e) or
(f)
g wherein R represents lower alkyl and n represents the number 0 or 1.
Lower alkyl is preferably methyl and lower alkoxy is preferably methoxy. Lower 2-alkenyl is preferably 2-propenyl (allyl).
The reaction of an aldehyde of formula I with an amine of formula IV is preferably carried out at about 0°C to room temperature and in an organic/aqueous two-phase system (e.g. in methylene chloride/water, chloroform/water, benzene/water and the like). This procedure is especially suitable when the previous manufacture of the aldehyde of formula I has been carried out in an aqueous phase, since the aldehyde need not be isolated, but can be reacted directly in the aqueous phase. On the other hand, if the aldehyde of formula I is isolated, this can also be reacted with an amine of formula IV in an organic solvent in the absence of water, for example in a halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-di-chloroethane and the like or in a hydrocarbon such as benzene, toluene and the like. The water formed during the reaction is preferably removed continuously, for example by working in the presence of a water-removing agent (e.g. in the presence of a suitable molecular sieve) or in the presence of other customary drying agents such as sodium sulphate, magnesium sulphate and the like, preferably at room temperature. patent
Mm ■ < 11
, 18 AUG 1987 becgved
4-(lower alkoxy)-phenyl;
lower 2-alkenyl;
CH2-CH(OR )
ch2CH2
[0]
n
2&71?3
The reaction of a reactive derivative of a carboxyiic acid of formula VI with the compound of formula V obtained is a cycloaddition which is familiar to a person skilled in the art. When a reactive derivative of a
2
compound of formula VI in which R represents azido, phthalimido or the group ROCO-CH=C(CH^)-NH- is used, the reactive derivative is preferably the corresponding carboxyiic acid halide, especially a carboxyiic acid chloride, a corresponding carboxyiic acid anhydride or a mixed anhydride (e.g. with trifluoroacetic acid, mesitylenesulphonic acid,, chioroformic acid ethyl ester, p-chlorobenzene sul-
phonic acid and the like), a corresponding carboxyiic acid
2
imidazolide and the like. Where R represents the group 5 6 7
R R C=CR —NH-, there can be used a carboxyiic acid salt of the compound of formula VI, especially an alkali metal salt (e.g. the potassium salt) or an ammonium salt derived from a tertiary amine, "together with a reactive organic sulphonic acid derivative, especially a reactive sulphonic acid derivative of the general formula
R9 - S02 - X VIII
wherein X represents halogen or the group
9 g
-OSO2-R in which R represents phenyl,
(lower alkyl)-phenyl, halo-phenyl, lower alkyl or halo-(lower alkyl).
The compounds of formula VTII in which X represents halogen,
Q
especially chlorine, and R represents phenyl, (lower alkyl)-phenyl or halo-phenyl such as p-toluenesulphonvl chloride, p—chlorobenzenesulphonyl chloride and benzenesulphony1 chloride are preferred sulphonic acid derivatives.
2
When R represents benzyloxycarbonylamino, there can be used an alkali metal salt of the compound of formula VT, especially the potassium salt, together with a sulphonic acid chloride of the general formula
9 "fjX PATENT 0"~- t
R - S02 - CI »' — ~ IX
; 18 AUG 1987 {
207 193
9
in which R has the above significance.
As the sulphonic acid chloride of formula IX there is preferably used p-chlorobenzenesulphonyl chloride or, less preferably, p-toluenesulphonyl chloride or methane-sulphonyl chloride.
When the compound of formula V is reacted with a reactive derivative of a carboxyiic acid of formula VI, the reaction is carried out in the presence of a base, for example a tertiary amine such as trie thy 1 amine or diisopropyleth-ylamine and conveniently in an inert organic solvent, especially an ether such as tetrahydrafuran, diethyl ether, t-butyl methyl ether, dloxan, ethylene glycol dimethyl ether or the like, a halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane or the like, acetonitrile, dime thy lformamide or the like. The reaction can be carried out in a temperature range of about -30°C to about +30°C.
The reaction of a reactive derivative of a compound of formula VI with an optically uniform compound of formula V yields a chiral 0-lactam. of formula III in which the substituents in the 3- and 4-position of the acetidi-none ring are cis-positioned to one another as expected. It has, however, surprisingly been found that the use of an optically active compound of formula V in the above cycloaddition induces two new optical centres in high optical yield, i.e. with high diastereoselectivity, to form only one of two possible diastereomeric products. In the product obtained the second possible cis-cycloaddition product, which would be diastereoisomeric to the product actually obtained, could not be detected.
t
C- The chiral &-lactams of formula III
A j '
j^can be used for the manufacture of antimicrobially active o J
lijfl-lactams, for example according to the Reaction Schemes I and II hereinafter:
Reaction Scheme I
o H
1.ts0ii,tiif-ii20
2. NalO.
"V
Clio
^DMD
s
DMU
l. PY2Q-2O7/UHF
2. CII2M2
>coocii3
<r~\
cii3-niinm dnu
COOCII
3 Cbz—MHw >COOCII
Cbz-Cl ^^
DMtt
ButyLene oxide
<e
\
PMU
cbz—mi coocii 1
Nil .Oil i
Cbz—NHv
>CO»ll2
\
1. Py.SOj
I. Il2/Pd-C
,o
11 w .CON1I, 3 v > 2
"SO
0
ii2N
c
N
OIM
-0—CONHv N
\ lo A on &
,C0MIU
iO-iH
Cleavage of possible protecting groups on
RlO
>hN
[\ I
N Lc—CO Nllv
11 r
Nw°°cr
Reaction Scheme II
* « hhq.h oh
7 DMB
Cbz ^"vi-jL^a^Cbz^"
J \
DMB
cho
DMB
Cbz h a 11 vNxi_L-- R
8
" H s cooca, " ,H ® COOCH3 * H 1 COOH1
• N
8 is- H
12
DM3
0 ^MB
Cbz"
h h 11
so. a
9 3-
el
»a 17 K,N_/ % -R1-1
\ 0
so,.
CSzr"1^
h h n^/ v
CS
0 h
16
H h k h
Cbz
•fv7 ',
rr
:h-noh
0 VDMB 0 OMB
14
"2Y
C CONH
II N
\»
,11
\--10 0
17 S°3H
H,N c
2 s/ s \
XjL
N L—<jj —CONH
.11
\ „„100 A M
° 18 ^S°3*
Ft = phthalimido
DMB = 2,4-dimethoxybenzyl (can be replaced by other protecting groups R1)
TsOH = p-toluenesulphonic acid THF = tetrahydrofuran
DMF = dimethylformamide
Py = pyridine
Py.SO^ = sulphur trioxide-pyridinium complex 10 COX = reactive derivative of a carboxyiic acid
(e.g. acid anhydride, acid amide, active ester,
such as benzthiazolyl ester)
R^ = hydrogen, lower alkyl (e.g. methyl), protected carboxy-<lower alkyl) (e.g. protected carboxy-15 methyl, protected 1-methyl-l-carboxy-ethyl).
Protecting group: e.g. t-butyl (cleavable with, for example, trifluoroacetic acid), benzyl and p-nitrobenzyl (cleavable with, for example, hydrogen and palladium-carbon), 2- (trixnethylsilyl) -ethyl 20 (cleavable with, for example, tetrabutylammonium fluoride)
R^"00 = hydrogen, lower alkyl (e.g. methyl), carboxy-(lower alkyl) (e.g. carboxymethyl, 1-methyl-l-carboxy-ethy1)
Cbz = carbobenzoxy (benzyloxycarbonyl)
R^ = carbamoy 1, carbamoyloxymethyl.
The cleavage of the DMB N-protecting group and of the groups (a), (b) and (c) mentioned above as N-protecting 30 groups is conveniently carried out by mild oxidation. A suitable oxidation agent is cerium ammonium nitrate (e.g. in aqueous acetonitrile or in aqueous acetone). 2,4- and 3,4-di(lower alkoxy)benzyl as well as di[4-(lower alkoxy)-phenyl]methyl groups can likewise be cleaved off with a 35 buffered peroxodisulphate (e.g. ammonium peroxodisulphate/ ammonia or potassium peroxodisulphate/dipotassium -hydrogen phosphate), the cleavage being carried out in water and under approximately neutral conditions. Di-{4-(lower alkoxy)-
(
.. ' '! ..
!
*•***•«. ,x-: v
phenyl>methyl groups can also be cleaved off acidolytically, for example by the action of trifluoroacetic acid, formic acid or aluminium chloride in an inert organic solvent such 5 as methylene chloride or anisole.
The groups (d), (e) and (f) mentioned above as N-protecting groups R^" are not cleavable per se, but can be cleaved off as follows:
(d) R^" = lower 2-alkenyl, can be converted into lower 1-alkenyl (e.g. -CH2-CH=CH2 CH=CH-CH3) .
This isomerization is advantageously carried out 15 using an isomerization catalyst, for example a palladium dihalide such as palladium dichloride, a tris(triphenyl-phosphine)-rhodium (I) halide such as the corresponding chloride or palladium-carbon and a protonic acid such as hydrochloric acid or phosphoric acid. The isomerization is advantageously carried out in an inert organic solvent such as ethanol, methylene chloride or mixtures thereof with water and at a temperature between about 50°C and the boiling point of the reaction mixture.
" Lower 1-alkenyl groups (e.g. 1-propenyl or vinyl)
are cleaved off oxidatively, especially by treatment with an alkali metal permanganate, for example potassium permanganate, preferably an aqueous solution of potassium permanganate. If desired, the oxidation can be carried out 30 with the aid of an alkali metal periodate (e.g. potassium periodate) in the presence of a catalytic amount of the mentioned alkali metal permanganate. The reaction is preferably carried out in an aqueous buffered medium,
especially an aqueous medium buffered to pH 7-8, but it can 35 also be carried out in a water-miscible organic solvent,
for example in acetone, dimethoxyethane, dioxan or tetrahydrofuran, with the addition of a weak organic base such as pyridine or in a mixture of one of these solvents with
(
*
the mentioned aqueous buffer. If desired, the reaction can also be carried out under phase transfer catalysis, i.e. in the presence of an aqueous or non-aqueous phase, for example the above aqueous buffer as well as a water-immiscible inert organic solvent such as, for example, methylene chloride or benzene. Conventional substances can be used as phase transfer catalysts, especially organic quaternary ammonium halides such as benzyltriethylammonium chloride, tetra-n-butylammonium bromide and cetyltrimethylammonium bromide. The oxidative cleavage of 1-alkenyl groups is preferably carried out at a temperature in the range between about 0°C and 25°C.
(e) : R1 = -CH2-CH (OR8) 2 k> -CI^-CHO —CO-CH (OH) 2.
The first step is preferably carried out using a tri(lower alkyl)iodosilane, especially trimethyliodo-silane, or p-toluenesulphonic acid. The reaction is preferably carried out in an inert organic solvent such as acetonitrile and at a temperature between about 0°C and 50 °C.
The second step (oxidation) is preferably carried out using selenium dioxide under acidic conditions (e.g. in the presence of acetic acid). The reaction is preferably carried out in an inert organic solvent such as dioxan and at a temperature between room temperature and the boiling point of the reaction mixture.
The dihydroxyacetyl group is preferably cleaved off with an aqueous strong base (e.g. with aqueous ammonia or aqueous alkali hydroxide) in an inert organic solvent (e.g. a halogenated hydrocarbon such as chloroform, carbon tetrachloride or methylene chloride) at a temperature between about 0°C and +50°C.
m
13
R
1
-CH2CH2-S
O ^"CH2CH2-f-<^>
0
^-CH=CH2
The first step, the oxidation of the phenylthio ethyl group to the phenylsulphinylethyl group, can be carried out by treatment with an organic or inorganic oxidizing agent. As oxidizing agents there can be used various compounds which readily yield oxygen such as, for example, 10 organic peroxides, for example monosubstituted organic peroxides such as alkyl or alkanoyl hydroperoxides
(e.g. t-butyl hydroperoxide, performic acid and peracetic acid) as well as phenyl-substituted derivatives of these hydroperoxides (e.g. cumene hydroperoxide and perbenzoic 15 acidl, If desired, the phenyl substituent can carry a further lower group (e.g. C^-C4 alkyl or alkoxy), halogen or carboxy- (e.g. 4-methylperbenzoic acid, 4-methoxyper-benzoic acid, 3-chloroperbenzoic acid and monoperphthalic acid). As oxidizing agents there can also be used various 20 inorganic oxidizing agents, for example hydrogen peroxide,
ozone, permanganates such as potassium or sodium permanganate, hypochlorites such as sodium, potassium or ammonium hypochlorite and peroxymonosulphuric acid and peroxydisulphuric acid. The use of 3-chloroperbenzoic acid is preferred. 25 The oxidation is advantageously carried out in an inert solvent, for example in an aprotic inert solvent such as tetrahydrofuran, dioxan, methylene chloride, chloroform,
ethyl acetate or acetone or in a orotic solvent such as water, a lower alkanol (e.g. methanol or ethanol) or a 30 lower alkanecarboxylic acid which is optionally halogenated (e.g. formic acid, acetic acid or trifluoroacetic acid). The reaction temperature ranges particularly between about -20°C and +75°C.
The degradation of the phenylsulphinylethyl group to the vinyl group is conveniently carried out by heating to about 100-200°C, preferably in an aprotic organic solvent
.X
such as hexamethylenephosphoric acid triamide, dimethyl sulphoxide or dimethylformamide, benzene or toluene. The reaction can be accelerated by the addition of an acceptor 5 for the phenylsulphonic acid formed during the reaction,
especially suitable acceptors being trimethyl phosphite or propiolic acid esters such as, for example, methyl propio-late.
The vinyl group is cleaved off as described above under (d) .
The reaction steps set forth in Scheme II can be carried out as follows:
A compound of formula 1 is obtained by the mild acidic hydrolysis of a compound of formula Ilia. The hydrolysis of a compound of formula Ilia can be carried out, for example, by treating the compound of formula Ilia 20 with an acid in the presence of water and optionally a water-miscible solvent such as acetone, tetrahydrofuran, dioxan, dimethyl sulphoxide, dimethylformamide or the like. As acids there come into consideration, for example, mineral acids such as hydrochloric acid and sulphuric acid, or 25 organic acids such as p-toluenesulphonic acid, pvridinium p-toluenesulphonate or the like, or sulphonated ion exchangers . Depending on the conditions used the dioxolan ring is also cleaved during this reaction, there being obtained a compound of formula 2.
3y treating a compound of formula 1 or 2 with an agent yielding the group Cbz there is obtained a compound of formula 3 or 4. Benzyl cnloroformate is, for example, a suitable agent yielding the group Cbz. This reaction is 35 conveniently carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloroform and the like, and conveniently in the presence of an acid-binding agent such as butylene oxide, triethylamine, quinuclidine etc. The reaction is con-
■> ' V
•v o
f i
.» 4*". »-
venientlv carried out at room temperature.
The hydrolysis of a compound of formula 3 to give a compound of formula 4 is preferably carried out under mild acidic conditions. In a preferred embodiment the desired reaction is carried out by trans-acetalization in a lower alcohol such as methanol or ethanol and in the presence of a suitable acidic catalyst. Suitable catalysts are, for example, sulphonated ion exchangers, pyridinium p-toluenesulphonate, p-toluenesulphonic acid and the like. This reaction is preferably carried out at room temperature. The hydrolysis can, however, also be carried out readily in the presence of water and a water-miscible solvent such as tetrahydrofuran, dioxan, dimethyl sulphoxide, dimethylformamide or the like.
The cleavage of the diol grouping in a -compound of formula 4 is carried out according to methods which are known per se and which are familiar to any person skilled in the art, and can be accomplished, for example, using sodium periodate in water, if desired, this reaction can be carried out in the presence of a solubilizer such as tetrahydrofuran, dioxan, methanol, ethanol or the like.
This reaction yields an aldehyde of formula 5.
The reduction of an aldehyde of formula 5 to give a primary alcohol of formula 6 is also carried out according to methods which are known per se and which are familiar to any person skilled in the art, for example by treatment with sodium borohydride in a lower alcohol such as ethanol, isopropanol or the like.
By reacting a compound of formula 6 with chloro-sulphonyl isocyanate in an inert organic solvent there is obtained a compound of formula 7. Suitable solvents are, for example, ethers such as diethyl ether, t-butyl methyl ether and ethylene glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, aceto-
*
nitrile, dimethylformamide, dimethyl sulphoxide, acetone and the like. The reaction is preferably carried out in a temperature range of about 0°C to about room temperature.
By cleaving off the protecting group denoted by DMB (or other protecting groups R^*) from a compound of formula 7 there is obtained a corresponding compound of formula 8. This cleavage is carried out under the con-10 ditions described above.
The compounds of formula 8 in which R^ represents carbamoyl can be obtained by oxidizing an aldehyde of formula 5 according to methods known per se to give a car-15 boxylic acid of formula 11, esterifying the carboxyiic acid of formula 11, for example with methyl iodide in the presence of potassium carbonate, cleaving off the protecting group denoted by DMB in the manner described above from the resulting compound of formula 12 and treating 20 the resulting compound of formula 13 with ammonia. -
The compounds of formula 8 in which R^ represents carbamoyl can, however, also be obtained by treating a compound of formula 5 with hydroxylamine, converting the 25 resuling oxime of formula 14 in a manner known per se into the nitrile of formula 15, cleaving off therefrom the protecting group denoted by DMB as described above and saponifying the nitrile group in the resulting compound of formula 16 to the carbamoyl group in a manner known per se.
By treating a compound of formula 8 with sulphur trioxide or a suitable complex of sulphur trioxide there is obtained a compound of formula 9. Suitable sulphur trioxide complexes are, for example, complexes with pyri-35 dine, trimethylamine, picoline, dimethylformamide and the like. An ether such as dioxan, pyridine, acetonitrile, dimethylformamide or the like is conveniently used as the solvent. The preferred solvent is acetonitrile. The reaction is preferably carried out at a temperature between
0 ?
about 0°C and 80°C.
By cleaving off the protecting group denoted by Cbz from a compound of formula 9 there is obtained a compound of formula 10, The benzyloxvcarbonvl group Cbz can be cleaved off, for example, hydrogenolytically, for example by treatment with elemental hydrogen in the presence of palladium-on-carbon.
By acylating a compound of formula 10 with a reactive function derivative of a carboxyiic acid of the general formula
H2N
C - COOH
N
\r10
wherein R^ has the above significance,
and cleaving off protecting groups which may be present on R^"° there is finally obtained the desired target compound of formula 18. The compound of formula X must be suitably protected when R^"00 in formula 18 signifies hydrogen or carboxy-(lower alkyl); the protecting group is removed after the acylation has been carried out. As reactive functional derivatives of compounds of formula X there can be used, for example, corresponding acid anhydrides, mixed anhydrides, benzthiazolyl thioesters and the like.
The target compounds of formula IB are valuable 35 antibiotics having antibacterial activity which can be used in human medicine for the control and prophylaxis of infectious diseases.
If
"r
S'
o
207193
The conversion of the compounds of formula III in
2
which R represents benzyloxycarbonylamino into anti-microbially valuable 0-lactari antibiotics is described, for example, in New Zealand Patent Specifications Nos. 201660 and 210362 and in New Zealand Patent Specification No. 205246. The cleavage of in the meaning "benzyl" which is thereby necessary is carried out in the same manner as when R^" represents "2,4- or 3,4-di(lower alkoxy)benzyl", i.e. oxidatively with the aid of a buffered peroxodisulphate such as potassium peroxodisulphate/dipotassium hydrogen sulphate.
However, the benzyl group can also be cleaved off reductive ly by the action of an alkali metal (e.g. sodium or lithium) in liquid ammonia.
The chiral aldehyde of formula I obtained in the process of the invention can be converted into chiral glycerine or its acetonide or analogues thereof, i.e. into compounds of the general formula
R12 r13
o
A
14
R OCH2
XI
UZPAmrri
18 AUG mi BEcevso
12 13
in which R and R each individually represent hydrogen or together represent"
R3 R4
3 4
the group wherein R and R"
each individually represent hydrogen or lower alkyl or together represent lower alkylene 14
and where further R represents a hydroxyl protecting group. This process comprises reacting the aldehyde
XVmv*—-
f
; x
,r~.
■'/ !• .a
of formula I obtained in the above manner with an alkali r,14
metal borohydride, introducing the protecting group R
3 4
and, if desired, hydrolyzing off the group R
Sodium borohydride or potassium borohydride is preferably used as the alkali metal borohydride. The reaction is preferably carried out in an aqueous phase at about 0°c to room temperature. In the resulting alcohol of 10 the general formula
XII
3 4
in which R and R has the significance given above,
1 4
the hydroxy protecting group R is now introduced. Therefor primarily the following groups come into consideration: alkanoyl groups with up to 20 carbon atoms, e.g. acetyl, 20 myristyl, palmityl, stearyl, arachyl; alkyl groups with up to 2 0 carbon atoms, e.g. methyl, n-tetradecyl, n-hexadeqyi# n-octadecyl, n-eicosyl; or the cholins-phosphoryl group.
These groups are introduced with the aid of the corresponding acid halogenide, preferably the chloride, or the 25 corresponding alkyl halogenide, particularly the bromide or chloride, or, in the case of the choline-phosphoryl group,
by reaction with phosphorous trichloride and choline. If
3 4
required, the group can subsequently be hydrolyzed off, for example, with p-toluenesulphonic acid, hydrochloric 30 acid or sulphuric acid in an aqueous phase, optionally in admixture with a water-miscible inert organic solvent such as tetrahydrofuran or dioxan.
The lactone starting materials of formula II above 35 can be prepared in a simple and efficient manner from L-
ascorbic acid, for example by catalvtically hydrogenating the latter (e.g. in the presence of palladium-carbon). The L-gulonic and y-lactone obtained is converted into the
■> \-
- 2U -
desired lactone of formula II by reaction with a ketal or acetal of the general formula r15-o r3 xttt
\ / mI
c r15-O^ ^R4
3 4
in which R and R have the significance given above and R^ represents lower alkyl.
A preferred method for the preparation of 5,6-isopropyli-
dene-L-gulonolactone (the lactone of formula II with in 3 4
which R and R both represent methyl) comprises reacting L-gulonic acid y-lactone with isopropenyl methyl ether or 2,2-dimethoxy-propane. The conversion of L-gulonic acid 15 y-lactone into the lactone starting material of formula II is catalyzed by the addition of an acid (e.g. p-toluene-sulphonic acid). The reaction is preferably carried out at a low temperature (e.g. about 0-15°C).
The following Examples illustrate the invention.
Example 1
218 g of 5,6-isopropylidene-L-gulonolactone are suspended in 1000 ml of water in a 10 1 sulphonation flask provided with a stirrer, thermometer, dropping funnel, 10 glass electrode and cooling bath (-15°C, ice-methanol).
140 ml of 50% aqueous potassium hydroxide are added dropwise at +3°C within 30 minutes. The ice-bath is removed and the mixture is stirred at room temperature for 15"minutes. (The pH is held basic and the completion of the reaction is 15 controlled by means of thin-layer chromatography). The brown solution is adjusted to pH 7.0 with aqueous hydrochloric acid while cooling with ice. The yellow solution obtained is cooled to -10°C and treated dropwise within 1 hour with a solution of 427 g of sodium metaperiodate 20 (2.0 mol) in 3000 ml of water. During the treatment the temperature should not rise above +10°C. The pH is held at 5.0 by the addition of saturated aqueous sodium carbonate solution. Traces of iodine which may be present are destroyed by the addition of sodium thiosulphate. At the end 25 of the addition the pH is adjusted to 7.0 with saturated aqueous sodium bicarbonate solution. The solution obtained contains crude (S)-glyceraldehyde acetonidej it is treated at +12°C with 1000 ml of methylene chloride and in an argon atmosphere while stirring vigorously with a solution 30 of 155 g (0.93 mol) of 2,4-dimethoxybenzylamine in 250 ml of methylene chloride. After standing at room temperature for 30 minutes, the phases are separated and the aqueous phase is extracted with 1000 ml of methylene chloride. The combined organic phases are dried over 150 g of magnesium 35 sulphate. The organic solution is filtered and the drying agent is rinsed with 300 ml of methylene chloride. The
combined organic solutions are evaporated to about 1 1 at 37°C/0.8 irtmHg. This solution is placed in a 2.5 1 sul-phonation flask provided with a stirrer, thermometer, 5 calcium chloride tube, dropping funnel and ice-methanol cooling bath. 174 ml (124.4 g; 1.23 mol) of triethylamine are added thereto. After cooling to 0°C, a solution of 207.5 g of phthaloylglycyl chloride (0.93 mol) in 300 ml of methylene chloride is added dropwise within 45 minutes, 10 whereby the temperature should not rise higher than +10°C. The mixture is now stirred at room temperature for 2 hours. The mixture is transferred into a separating funnel and washed in succession three times with lOO ml of water, once with 300 ml of aqueous IN hydrochloric acid, twice with 300 15 ml of saturated aqueous sodium bicarbonate solution, once with 500 ml of water and finally once with 500 ml of saturated aqueous sodium chloride solution. The organic phase is dried over 150 g of sodium sulphate, filtered and the filtrate is evaporated to dryness. The dark yellow viscous 20 foamy oil obtained is dissolved in 800 ml of ethyl acetate. The solution is partially concentrated (to about 500 ml) and brought to crystallization in the cold. There are obtained 237 g (53%) of N-[(3S,4S)-cis-1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-25 azetidinyl]-phthalimide as light yellowish crystals of melting point 155°C.
The 5,6-isopropylidene-L-glulonolactone used as the starting material can be prepared as follows:
231 g of crystalline L(+)-ascorbic acid in 1700 ml of water are catalytically hydrogenated in a 3 1 flask (75 g of 10% Pd/C; 65°C; 4 bar H2 pressure; 30 hours). The solution is filtered and the filtrate is evaporated to 35 dryness at 50°C/12 mmHg. The crystalline residue obtained is suspended in 200 ml of boiling methanol. The suspension
m
o
W 10
IS
** A "
?■' f' v'
23 -
is cooled and filtered. There are obtained 221.6 g (94.8%) of L-gulonic acid y-lactone as colourless crystals of melting point 183-184°C. The mother liquor is diluted with 100 ml of ethyl acetate and left to stand in the cold for 12 hours. There is obtained a further 1 g of product, the total yield thus being 222.6 g (95.3%).
A solution of 221.6 g of L-gulonic acid y-lactone in 2000 ml of dimethylfontiamide is cooled to 10°C in a 3.5 1 sulphonation flask provided with a stirrer, thermometer, dropping funnel, calcium chloride tube and ice-bath and treated with 1.8 g of p-toluenesulphonic acid monohydrate. This solution is treated dropwise at +10°C with 116.6 g (154.5 ml; 1.61 mol) of freshly distilled isopropenyl methyl ether. The clear solution obtained is stirred at 25°C for 24 hours. The thus-obtained colourless solution is treated with 220 g of sodium carbonate and the resulting suspension is stirred for 2 hours. The suspension is filtered and the solution obtained is concentrated at 40°C/ 0.2 mxtiHg. The light yellowish crystalline residue obtained is treated with 300 ml of toluene and stirred with a spatula while cooling with ice. The crystals formed are filtered off under suction, washed with a small amount of ethanol and a large amount of n-hexane and dried at room temperature under greatly reduced pressure. There are obtained 191.6 g (70.9%) of 5,6-isopropylidene-L-gulonolactone of melting point 167-168°C.
Example 2
43.6 g (0.2 mol) of 5,6-isopropylidene-L-gulonolactone are dispersed in 200 ml of water and treated portionwise with 85.5 g (0.4 mol) of sodium metaperiodate within 30 minutes under pH control (pH 5.5 by the addition of aqueous saturated sodium carbonate solution). The suspension ob-
^ - 24 -
tained is stirred at room temperature for 2 hours, saturated with sodium chloride and precipitated sodium iodate is removed by filtration. The pH of the filtrate is 5 adjusted to 7.0. The aqueous solution of (S)-glyceralde-hyde acetonide can be processed further as described in Example 1 or can be isolated as follows:
The aqueous solution is extracted in succession five 10 times with 200 ml of methylene chloride each time and four times with 200 ml of methyl acetate each time. The combined organic solutions are dried over magnesium sulphate and evaporated. The residue is distilled (boiling point at 35 mniHg = 64-66°C) , there being obtained 2.67 g of (S)-- 15 glyceraldehyde acetonide having a purity of 84% and 16.1 g of (S)-glyceraldehyde acetonide having a purity of 98%. The total yield amounts to 18 g (0.138 mol, 69%) of pure (S) -glyceraldehyde acetonide.
Example 3
21.8 g (0.1 mol) of 5,6-isopropylidene—L-gulonolactone are dispersed in 100 ml of water and treated at 0°C with 15 ml of 50% aqueous potassium hydroxide. After stirring 25 for 15 minutes, the solution is neutralized to pH 7 with 3N aqueous hydrochloric acid and subsequently cooled to -10°C. The solution is treated dropwise with a solution of 44.9 g (0.21 mol) of sodium metaperiodate in 400 ml of water. After 1 hour, the pH is adjusted to 7 by the 30 addition of saturated aqueous sodium bicarbonate solution. The solution contains (S)-glyceraldehyde and, after filtration, is processed directly:
The solution obtained is treated dropwise with a sol-35 ution of 16.12 g (0.4 mol) of sodium borohydride in 700 ml of water. The temperature is held at 20°C by cooling with ice. After stirring for 6 hours, excess sodium borohydride i
is destroyed by the slow addition of 200 ml of acetone.
After 20 minutes, excess acetone is removed by evaporation under reduced pressure and the aqueous phase obtained is extracted three times with 100 ml of methylene chloride. The organic phase is dried over sodium sulphate and evaporated. There are obtained 6.9 g (52%) of (R)-glycerine acetonide which, for purification, is distilled at 170°C/40 mmHg.
There are obtained 5.3 g (40.1%) of pure (R)-glycerine acetonide. = ~10.9° (c = 1 in methanol).
Example 4
If 3,4-dimethoxybenzylamine (veratrylamine) is used in Example 1 in place of 2,4-dimethoxybenzylamine, there is obtained under otherwise identical conditions N-[(3S,4S)-cis-1-(3,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide with an IR spectrum (KBr) 1766, 1720 cm"1.
If benzylamine is used in Example 1 in place of 2,4-dimethoxybenzylamine, there is obtained under otherwise identical conditions N-[(3S,4S)-cis-l-benzyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide of melting point 128-129°C.
If 4-methoxyarriline (p-anisidine) is used in
Example 1 in place of 2,4-dimethoxybenzylamine, there is obtained under otherwise identical conditions N-[(3S,4S)-cis-1-(4-methoxyphenyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide of melting point 64.7°C; [a]^° = +20.3° (c = 1 in methanol).
If 4-methoxybenzylamine is used in Example 1 in place of 2,4-dimethoxybenzylamine, there is obtained under otherwise identical conditions N-[(3S,4S)-cis-1-(4-methoxybenzyl)-
26 -
4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide having an IR spectrum (KBr): 1766, 1721 cm-1; [a]^° = +63.8° (c = 1 in chloroform).
Elemental analysis:
Calculated: C 66.05f H 5.54; N 6.42%.
Found: C 65.82; H 5.61; N 6.29%.
Example 5
a) 12 g (92.16 mmol) of (S)-glyceraldehyde acetonide are dissolved in 200 ml of methylene chloride, treated firstly with 60 g of magnesium sulphate and then dropwise over a period of 10 minutes with 5.26 g (92.16 mmol) of 3-amino-l-propene in 50 ml of methylene chloride and the suspension is stirred at room temperature for 5 hours. The magnesium sulphate is filtered off and the clear colourless solution is evaporated on a rotary evaporator. 14.6 g (86.3 mmol; 93.6%) of pure (S)-glyceraldehyde acetonide allylimine are obtained.
b) 8.64 g (51.1 mmol) of (S)-glyceraldehyde acetonide allylimine are dissolved in 400 ml of methylene chloride, treated firstly with 10.32 g (102.2 mmol) of triethylamine and then with 10.79 g (51.1 mmol) of potassium N-(1-methyl-2-methoxycarbonylvinyl)aminoacetate, the suspension is cooled to 0°C and treated dropwise within 5 minutes with 9.74 g (51.1 mmol) of p-toluenesulphonyl chloride in 50 ml of methylene chloride. The cooling bath is removed, the mixture is stirred at room temperature for 8 hours, treated with 200 ml of water, the organic phase is separated and evaporated. The crude product is chromatographed on silica gel while eluting with hexane/ethyl acetate (8:2). There are obtained 13.0 g (40.0 mmol; 78%) of methyl (Z)-3-[[(3S,4S)-l-allyl-2-[(R)-
2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-
butenoate as an oil which solidifies slowly upon standing. A product of melting point 98°C is obtained by crystallization from ether/hexane.
Example 6
1.7 g (10 mmol) of (S)-glyceraldehyde acetonide allylimine are dissolved in 80 ml of methylene chloride, 10 treated firstly with 3.03 g (30 mmol) of triethylamine and then with 2.6 g (10 mmol) of potassium N-(l-methyl-2-benzoyl-vinyl)aminoacetate and the suspension is cooled to 0°C. 2.85 g (15 mmol) of p-toluenesulphonyl chloride in 10 ml of methylene chloride are added dropwise thereto, the mixture 15 is stirred at room temperature for 5 hours, washed with 100 ml of water and evaporated. The crude product is purified on silica gel using hexane/ethyl acetate (7:3) for the elution. There are obtained 1.5 g (4.04 mmol; 40%) of (3S,4S)-1-ally1-3—[[(Z)-2-benzoyl-1-methylvinyl] amino]-4-20 [(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidinone as a pure oil which crystallizes out from a mixture of ether and hex-ane and then has a melting point of 154-156°C.
Example 7
1.7 g (10 mmol) of (S)-glyceraldehyde acetonide allylimine are dissolved in 80 ml of methylene chloride and treated firstly with 3.03 g (30 mmol) of triethylamine and then with 2.8 g (10 mmol) of potassium N-(2,2-diethoxycar-30 bonylvinyl)aminoacetate. 2.85 g (15 mmol) of p-toluenesulphonyl chloride in 20 ml of methylene chloride are then added dropwise to the solution which is cooled in ice and the mixture is stirred at room temperature for 5 hours. The mixture is subsequently washed with 100 ml of water, the 35 organic phase is evaporated and the crude product obtained is chromatographed on silica gel while eluting with hexane/
y.s'
ethyl acetate (7:3). There are obtained 1.15 g (2.9 mmol; 29%) of pure diethyl [[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]-malonate as an oil.
IR spectrum (film): bands, inter alia, at 1755, 1740, 1700, 1660 and 1600 cm
Example 8
3.75 g (13.44 mmol) of (S)-glyceraldehyde acetonide (2,4-dimethoxybenzyl)imine [obtained from (S)-glyceraldehyde acetonide and 2,4-dimethoxybenzylamine in a manner analogous to that described in Example la)] are dissolved in 150 ml of 15 methylene chloride and treated with 3.25 g (32.25 mmol) of triethylamine. 3.40 g (16.12 mmol) of potassium N-(l-methyl-
2-methoxycarbonylvinyl)aminoacetate are added and the suspension is cooled to 0°C. 3.40 g (16.12 mmol) of pr-toluene-sulphonyl chloride in 50 ml of methylene chloride are added
dropwise thereto within 5 minutes and the mixture is stirred at room temperature for 15 hours. After washing with 100 ml of water and evaporating the organic phase, the residue is purified by chromatography on silica gel using hexane/ethyl acetate- (7:3) as the eluting agent. There are obtained 3.45 g 25 (7.94 mmol; 59%) of pure methyl (Z)-3-[ [ (3S,4S)-1- (2,4-
dimethoxybenzyl)-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-
3-azetidinyl]amino]-2-butenoate as an oil which solidifies slowly. After crystallization from ether/hexane, the product has a melting point of 121°C.
Example 9
2.8 g (10 mmol) of (S)-glyceraldehyde acetonide (2,4-dimethoxybenzyl)imine are dissolved in 125 ml of methylene 35 chloride and treated with 3.03 g (30 mmol) of triethylamine. 2.6 g (10 mmol) of potassium N-(1-methyl-l-benzoyl-vinyl)-
it
'7 V\.
V../'
aminoacetate are then added and the suspension is stirred strongly at 0°C. 2.35 g (15 mmol) of p-toluenesulphonyl chloride in 50 ml of methylene chloride are slowly added 5 dropwise thereto and the mixture is stirred at room temperature for 5 hours. The mixture is then treated with 100 ml of water, the organic phase is separated and evaporated. The residue is chromatographed on silica gel using hexane/ethyl acetate (7:3) as the eluting agent. There are obtained 1.4 g 10 (2.91 mmol; 29%) of pure (3S,4S)-3-[[(Z)-2-benzoyl-l-methyl-vinyl]amino]-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidinone which crystallizes out from ether/hexane and then has a melting point of 177-179°C.
Example 10
6.48 g (20 mmol) of methyl (Z)-3-[[(3S,4S)-1-allyl-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-amino]-2-butenoate are dissolved in 40 ml of acetone and treated with 3.80 g (20 mmol) of p-toluenesulphonic acid monohydrate in 20 ml of acetone. The clear solution is stirred at room temperature for 15 minutes and then treated slowly with 120 ml of ether. The precipitated product is filtered off and dried. There are obtained 6.4 g (15.3 mmol; 77%) of pure (3S,4S)-cis-3-amino-l-allyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone p-toluenesulphonate of melting point 165°C.
Identical products are obtained when (3S,4S)-1-allyl-30 3-[ [ (Z)-2-benzoyl-l-methylvinyl]amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and diethyl [[[(3S,4S)-1-allyl-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azeti-dinyl]amino]methylene]malonate are subjected to the same reaction conditions. The yields lie between 75% and 80%.
x
m
Example 11
g of anhydrous magnesium sulphate and 17.7 g 5 (71.6 mmol) of potassium N-carbobenzoxyglycinate are dispersed in 400 ml of methylene chloride. After adding 20 ml (143 mmol) of triethylamine/ the suspension obtained is stirred vigorously at room temperature for 1.5 hours and subsequently cooled to 5°C. The suspension is treated with 10 10.0 g (35.8 mmol) of (S)-glyceraldehyde acetonide (2,4-
dimethoxybenzyl)imine [prepared from 2,4-dimethoxybenzylamine and (S)-glyceraldehyde acetonide in 20 ml of methylene chloride]. 15.1 g (71.6 mmol) of p-chlorobenzenesulphonyl chloride in 50 ml of methylene chloride are subsequently 15 added dropwise at 5°C within 45 minutes. The suspension is stirred at room temperature for 3 hours and filtered. The filtrate is evaporated, the yellow-brown oil obtained is dissolved in 300 ml of ethyl acetate and washed in succession twice with 100 ml of IN aqueous hydrochloric acid, twice 20 with 100 ml of 5% aqueous sodium bicarbonate solution and once with 100 ml of aqueous sodium chloride solution. The organic phase is evaporated and the oily yellow residue is crystallized by adding 300 ml of ether at 0°C. There are obtained 10.5 g (62%) of benzyl (3S,4S)-cis-1-(2,4-dimethoxy-25 benzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-azetidinecarbamate of melting point 113-114°C.
Example 12
When allylamine is used in Example 11 in place of
2,4-dimethoxybenzylamine, there are obtained in the same manner, after chromatography on silica gel (0.040 to 0.063 mm), 7.05 g (67%) of benzyl (3S,4S)-cis-l-allyl-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-azetidinecarbamate of melting point 35 94-96°C.
I-
/
207793
Claims (10)
- WHAT WE CLAIM IS: rocess for the manufacture of chiralp-lactams of the general formula P. 0X, R' ~0 \r1 III in which R represents a readily cleavable protecting group, R2 represents benzyloxycarbonylamino, azido, phthalimido or the group r g n ^ R R C=C R —NH-, wherein R represents lower alkanoyl, lower alkoxycarbonyl or benzoyl, represents hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano and R^ represents hydrogen or lower 3 4 alkyl, and R and R each individually represents hydrogen or lower alkyl or together represent lower alkylene, which process comprises reacting a lactone of the general formula II 3 4 m which R and R have the significance given earlier in this claim, with an alkali metal metaperiodate, reacting the thus-obtained aldehyde of the general formula HX PATBJT' 18 AUG 1987 R" X o H , R OHC in which R^ and R^ have the significance given earlier in this claim, with an amine of the general formula HJN-R1 IV in which R1 has the significance given earlier in this claim, and reacting the thus-obtained compound of the general formula 13 4 in which R r R and R have the significance given earlier in this claim, in the presence of a base with a reactive derivative of a carboxyiic acid of the general formula r2-ch2-cooh VI 2 in which R has the significance given earlier in this claim. - 33 - 207 1?3
- 2. A process according to claim 1, wherein a reactive derivative of a carboxyiic acid of formula VI in which R2 represents azido, phthalimido or the group ROCO-CH=C(CH^)-NH-, wherein R represents lower alkyl, is used.
- 3. A process according to claim 1 or claim 2, wherein 5,6-isopropylidene-L-gulonolactone is used as the starting material of general formula II.
- 4. A process according to any one of claims 1-3 , wherein the reaction of a chiral aldehyde of formula I with an amine of formula IV is carried out in an organic/aqueous two-phase system.
- 5. A process according to claim 4, wherein methylene chloride is used as the organic component of the organic/ aqueous two-phase system.
- 6. A process according to any one of claims 1-5, wherein an amine of formula IV in which R1 represents one of the following groups: 2,4- or 3,4-di(lower alkoxy)benzyl; (a) di-[4-(lower alkoxy)phenyl]methyl; (b) 4-(lower alkoxy)-phenyl; (c) lower 2-alkenyl; (d) CH2-CH(OR8)2; (e) CH-CH--S —V/\> ; (f) 2 2c5ln W q wherein R represents lower alkyl and n represents the number 0 or 1, is used. or PATENT on^Ct 18 AUG 1987 RECEIVED
- 7. A process according to any one of claims 2-6, wherein the acid chloride of the carboxyiic acid of formula VI / . / * is used.
- 3. A process according to any one of claims 2-7, wherein a reactive derivative of phthaloylglycine is used.
- 9. A process according to claim 1, substantially as G hereinbefore described with particular reference to any one of the foregoing Examples 1 and 4 to 12.
- 10. A chiral 0-lactam of the general formula (III) as defined in claim 1, whenever prepared by a process according to any one of the preceding claims. -34- 207 7^3 DATED THIS ^ DAY OF |»#7 a. J. PARK & SON AGENTS FOR THF APPLICANTS © — NX PATENT - 18 AUG 1987 ...... "becbveo j
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH106183 | 1983-02-25 | ||
| CH3384 | 1984-01-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ207193A true NZ207193A (en) | 1987-10-30 |
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ID=25683311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ207193A NZ207193A (en) | 1983-02-25 | 1984-02-17 | Preparation of chiral beta-lactams |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0120289B1 (en) |
| AT (1) | ATE34389T1 (en) |
| AU (1) | AU570032B2 (en) |
| CA (1) | CA1224789A (en) |
| DE (1) | DE3471306D1 (en) |
| DK (1) | DK36784A (en) |
| IL (1) | IL71006A (en) |
| NZ (1) | NZ207193A (en) |
| PH (1) | PH20100A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1251454A (en) * | 1983-01-20 | 1989-03-21 | Gerard Schmid | PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMES |
| DK411384A (en) * | 1983-10-03 | 1985-04-04 | Hoffmann La Roche | PROCEDURE FOR THE PREPARATION OF AZETIDINE UNDIVERIVES |
| IL101052A (en) * | 1991-02-28 | 1997-03-18 | Lilly Co Eli | Process for producing glyceraldehyde- 3-pentanide |
| WO2013173672A1 (en) | 2012-05-18 | 2013-11-21 | Array Biopharma Inc. | Method for the preparation of thiadiazoles |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2541438A1 (en) * | 1975-09-17 | 1977-03-31 | Basf Ag | Odoriferous dioxolane aldehydes prepn. - by hydroformation of vinyl dioxolanes; for detergents, perfumes, soaps, etc. |
| US4111958A (en) * | 1977-06-03 | 1978-09-05 | Pfizer Inc. | Ascorbic acid synthesis |
| CA1262128A (en) * | 1981-08-27 | 1989-10-03 | Christian N. Hubschwerlen | .beta.-lactams |
| EP0096296B1 (en) * | 1982-06-03 | 1987-07-29 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | 1-sulfo-2-oxoazetidine derivatives |
| CA1204746A (en) * | 1982-08-19 | 1986-05-20 | Hoffmann-La Roche Limited | .beta. LACTAMS |
| CA1251454A (en) * | 1983-01-20 | 1989-03-21 | Gerard Schmid | PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMES |
-
1984
- 1984-01-26 DK DK36784A patent/DK36784A/en not_active Application Discontinuation
- 1984-02-06 CA CA000446804A patent/CA1224789A/en not_active Expired
- 1984-02-17 NZ NZ207193A patent/NZ207193A/en unknown
- 1984-02-20 AU AU24745/84A patent/AU570032B2/en not_active Ceased
- 1984-02-20 IL IL71006A patent/IL71006A/en not_active IP Right Cessation
- 1984-02-21 DE DE8484101813T patent/DE3471306D1/en not_active Expired
- 1984-02-21 AT AT84101813T patent/ATE34389T1/en not_active IP Right Cessation
- 1984-02-21 EP EP84101813A patent/EP0120289B1/en not_active Expired
- 1984-02-24 PH PH30297A patent/PH20100A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL71006A (en) | 1988-10-31 |
| EP0120289A2 (en) | 1984-10-03 |
| DK36784A (en) | 1984-08-26 |
| IL71006A0 (en) | 1984-05-31 |
| AU2474584A (en) | 1984-08-30 |
| DK36784D0 (en) | 1984-01-26 |
| DE3471306D1 (en) | 1988-06-23 |
| EP0120289A3 (en) | 1985-01-23 |
| AU570032B2 (en) | 1988-03-03 |
| CA1224789A (en) | 1987-07-28 |
| PH20100A (en) | 1986-09-24 |
| EP0120289B1 (en) | 1988-05-18 |
| ATE34389T1 (en) | 1988-06-15 |
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