JPS59210087A - Manufacture of carbapenem - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention has the formula: %Formula% However, 'Au cyclopentylene, cyclohexylene or H
C+-04 alkylene (one or more CI C
(optionally substituted with 4 alkyl group), and R1
4 is a quaternary atom bonded to A by a quaternary nitrogen atom
Represents a nitrogen-containing aromatic or non-aromatic heterocycle; the 2-position of
A new method for producing carbapenem derivatives with substituents
purpose. The carbapenem derivatives produced by the method of the present invention are
April 9, 1982, March 8, 1983 and 1, respectively.
U.S. Patent Application No. 366.9 filed June 18, 1982
No. 10, No. 471,379 and Juice No. 1389,652
Inside, co-workers Choung' [J, Kim and Pete]
Disclosed by r F, Misco, Jr.,
four disclosures in each of those applications.
It is included in this specification layer for reference. 366,91 o-+-: and part 1
No. 1 filed on March 8, 1983, issued in the U.S.
4.71. ．． No. 379, this is the West German open bamboo license application mirror 3.
This is a partial navy continuous application corresponding to No. 312,533.
Formula, provided that R8 is hydrogen, and R1 is hydrogen; the substituent is
or has a substituent: alkyl, a
alkenyl and alkynyl, having 1-10 carbon atoms
;cycloalkyl and cycloalkylalkyl, cyclo
having 3-6 carbon atoms in the alkyl ring and the alkyl moiety
having 1-6 carbon atoms in minutes; phenyl; aryl moiety
Minutes are phenyl and former aliphatic moiety td 1-6 charcoal
Aralkyl, aralkenyl and hyaralkyl having elementary atoms
Nyl; heteroaryl, heteroaralkyl, heterosyl
Ril and Hiheterocyclylalkyl, in the ten-pointed Heterocyclylalkyl part
Heteroatoms of from 1-4 oxygen, nitrogen or sulfur atoms
Seven selected from the group consisting of:
having an alkyl moiety of 1-6 carbon atoms;
selected from the group; and related to the above groups.
one or more substituents include amino acid halo, hydroxyl,
ClCa atom which may be substituted with carboxy or carboxyl
Lucil OR3 10δNR"R4 - and NR3R4 NR3R4 802NR3R' 1 -NHCNR3R' C02R3 10j -OCR3 S R3 t S R9 1 SR9 1 CN N3 105O3R3 -O8O2R3 NR3S 02 R' -NR 3C=NR4 3 NR3C02R' N02 selected from the group consisting of
and hydrogen; alkyl, alkenyl and alkynyl, 1-
having 10 carbon atoms; cycloalkyl, cycloalkyl
Kylalkyl and alkylcycloalkyl, cycloalkyl
have 3-6 carbon atoms and in the alkyl moiety
having 1-6 carbon atoms; phenyl; the aryl moiety is
phenyl, the aliphatic part has 1-6 carbon atoms
aralkyl, aralkenyl and aralkenyl; and
heteroaryl, heteroaralkyl, heterocyclyl and
and heterocyclylalkyl, in the raw form 1 heterocyclic moiety
The terror atom is 1. 4 (oxygen, nitrogen or sulfur atom of H6?
selected from the group consisting of -n bonded to the heterocyclic moiety;
is selected from the group consisting of; or
R3 and R4 are nitrogen atoms, at least one of which is bonded)
May form partially 5-membered or 6-negative nitrogen-containing double arms
It is R91d except that it has 11 potassium in hydrogen.
, as defined for R3; or R1 and R8 together are C2 CIO alkyritene or
is C2 CIO alkyritene substituted with hydroxy
represents; A is cyclopentelene, cyclohexylene
Also kicz C6 alkylene (one or more C
optionally substituted with I C4 alkyl);
R2 also represents a counter anion when R2 is hydrogen or a protecting group.
Provided that hydrogen, anion tli or normal
is an easily removable carboxyl protecting group;
is bonded to A, l~, in which case the quaternary F.' ammonium group is
with or without substituents forming
d-represents a polynomial aromatic heterocyclic group;
In the method for producing Organism a and its pharmaceutically acceptable Hayabusa,
The following reaction scheme: ■ Kirene 8
Carbapenem antibiotics by H 1'A A and their pharmaceutically acceptable
Discloses a method for producing salt. U.S. Patent No. 389,652 and June 7, 1983
U.S. Patent Application No. 499,690, a partial continuation of the patent application filed in Japan.
is the formula, R8 hydrogen, RI U hydrogen; substituent
or has no 1d, 'f4'tfj group: a
alkyl, alkenyl and arginyl, 1-10 carbons
having atoms; cycloalkyl and cycloalkyl alkyl;
cycloalkyl, cycloalkyl, has 3 6 carbon atoms
and having 1-6 carbon atoms in the alkyl moiety [2;
Nyl: aryl moiety i) phenyl, aliphatic moiety
] -64f) ``aralkyl, aralkyl'' having a carbon atom
Lukenyl and hyaralkynyl: heteroaryl, heteroaryl
ralkyl, heterocyclyl and heterocyclylalkyl
, the hetero atoms in the above hetero apex are 1-4 oxygen,
selected from the group consisting of nitrogen, sulfur atoms, and
The argyl moiety bonded to the monkey moiety is 1-6i β1.
Ai - has an elementary atom; it's all good! ) 1 selected from scratch
and one or more related to the above groups.
The substituents are independently amine, halo, and bidroquine (substituted with bowtunorboxyl).
may be 108O3R"OS 02R3 -NR35O□R4NR"C02R'NO2; in relation to the above-mentioned substituents, the radicals R3 and R4 are independently hydrogen; alkyl, alkenyl
and alkynyl, having 1-10 carbon atoms; cyclo
Alkyl, cycloalkylalkyl and alkylcyclo
Alkyl, having 3-6 carbon atoms in the cycloalkyl ring
and has 1-6 carbon atoms in the alkyl moiety;
phenyl; the aryl part is phenyl and the aliphatic part-1
- aralkyl, aralkenyl and aralkyl having 6 carbon atoms
and aralkenyl: and heteroaryl, heteroaralkyl
heterocyclyl and heterocyclylalkyl, above
1 dl of heteroatoms in the hetero-0 ring moiety - 4 oxygen, nitrogen
or a yellow atom at position r, and the hetero
The alkyl moiety attached to the ring has 1-6 carbon atoms.
childless; chosen from the tears of
R3 and R4 are at least one of the nitrogens to which they are bonded.
Forms 5-membered or 6-negative nitrogen-containing heterocycles in cotton and produces 4%
R9 is similar to R3 except that it cannot be compared to hydrogen.
and R1 and R8 together are CCIO alkylidene or hydrogen.
Represents C2 CIO alkylidene substituted with droxy
Eagle; R5 has a substituent and has no substituent
: alkyl, alkenyl and alkynyl, 1-10
having a carbon atom; cycloalkyl and cycloalkyl
alkyl, having 3-6 carbon atoms in the cycloalkyl ring
and having 1-6 carbon atoms in the alkyl moiety; phenyl
R; the aryl part is phenyl and the aliphatic part is 1-6
aralkyl, aralkenyl and aralkyl having 5 carbon atoms
Ralkynyl; heteroaryl, heteroaralkyl, hetero
Rosyclyl and hyterocyclylalkyl, the above heteml
Heteroatoms in the monkey part are 1-4 oxygen, nitrogen or sulfur
selected from the group consisting of atoms and attached to the heteml ring moiety;
the associated alkyl moiety has 1-6 carbon atoms
; It is selected from the group consisting of;
5 groups may be amine, fluoro, chloro, carbon, etc.
Substituted with ruboxyl, hydroxy or d-carbamoyl
C+ Cs alkyl which may be present; fluoro, chloro or habromo; 10R3; 0CO2R3; 10COR3; 10CONR3R4; 13R3 ; 5O3R3: C02R"C0NR3R';-CN; or 1-3 fluoro, chloro, bromo, CI C6 a
Lukiru, -〇R3, -NR3R', S 03 'R3
, -CO2R3 or -CONR3R' (However, R3, R
4 and R9 are R5file groups as defined above
) optionally substituted with phenyl;
Substituted with 1-3 carefully selected substituents
It's okay. Forming divalent phenylene spanning CI C4 alkylene
A can represent a group; A is cyclopentylene, cyclohexylene or id:c2
C6 alkylene (one or more C1C4 alkylene)
R2 is a counter ion when R2 is hydrogen or a holding group;
hydrogen, an anion with one charge or normal
is an easily removable carboxyl protecting group; thus
A, in which quaternary ammonia, z, , jij
-, with or without substituents
, -1 represents 8 bifurcated polycyclic non-aromatic heteroterms:
Method for producing bapenem antibiotic eta and its pharmaceutically acceptable substance
In the method, the following reaction scheme: 1'B 1B and its g (acceptable above)
Discloses a method for producing salt. To elaborate on the scheme of the prior art in Section 7, starting price ■
is diphenylchloro in the presence of a ring group in an inert organic solvent.
Reacts with phosphate to give intermediate ■. Next, the intermediate ■
in an inert organic solvent in the presence of a base to form the formula H8-A-O
Reacts with the mercaptan reagent of I (to give intermediate ■.
The intermediate ■ is then treated with methane in an inert organic solvent in the presence of a base.
Acylated with sulfonyl chloride to form intermediate ■, which
reacts with an iodide ion source in an inert organic solvent to form an intermediate
Give 11. Intermediate ■ is prepared as desired in an inert organic solvent in the presence of silver ions.
The product BiA or I'B is quaternized by reacting with an amine of
, which is then unblocked to create the corresponding accent base
Formula IA or IBQ carbapenem with the
I can do it. There are several disadvantages to the process described above. For example, this program
The process has multiple steps, which advantageously reduces the number of steps.
I can do a little. The overall reaction yield was also low, and the quaternization process was not completed.
This study has been carried out on carbapenem compounds. (1)
With fewer reaction steps, (2) gives a higher yield, and (3)
) First, a quaternary amine is formed and then the carcinase is absorbed in the synthetic body membrane.
(4) For example, a sterically hindered atom
Various amines such as amines and amines with low PKb values
to more easily form quaternary amine products using
A novel process for producing compounds of formula IA or IB that can
It was desired to have a home base. In the present invention, R8 is hydrogen, and R1 is hydrogen; with and without substituents.
: alkyl, alkenyl and alkynyl, 1-10
having a carbon atom; cycloalkyl and cycloalkyl
alkyl, 3-6 carbon atoms and alkyl in the cycloalkyl ring
7; phenyl;
Aryl moiety is phenyl and aliphatic moiety]-6
aralkyl, aralkenyl and aralkyl having 5 carbon atoms
Ralkynyl; heteroaryl, heteroaralkyl, hetero
rosyclyl and hiheterocyclylalkyl, heteromorphs of the above
1-4 oxygen, nitrogen or sulfur atoms in the moiety
A group sword consisting of children is selected, and connected to the hetero instep part.
the associated alkyl moiety has 1-6 carbon atoms
selected from the group consisting of
C+ C6 alkylno\ro0R3 -OCNR3R,4 1 -CNR"R' NR3R4 -8O2NR"R' 1 -NHCNR'R' 1 R3CNR4- C02R3 N0 1 QCR3 5R3 -R9 1 -S R' 1 〇CN selected from the group consisting of: are independently hydrogen; alkyl, alkenyl
and alkynyl, having 1-10 carbon atoms; cyclo
Argyl, cycloalkylalkyl and alkylcyclo
alkyl, 3-6 carbon atoms in the cycloalkyl ring and
Having 1-6 carbon atoms in the alkyl moiety: phenyl:
The aryl part is phenyl and the aliphatic part is 1-
Aralkyl, aralkenyl and aralkyl having 6 carbon atoms
Aralkenyl; and heteroaryl, heteroaralkyl
, heterocyclyl and heterocyclylalkyl, above
The heteroatoms in the terocyclic moiety include 1-4 oxygen, nitrogen or
selected from the group consisting of sulfur atoms, and the heterocyclic moiety
the alkyl moiety attached has 1-6 carbon atoms
to a force selected from the group consisting of; or with R3;
R' is 5 with the moiety to which at least one is attached
or 6-membered nitrogen heterocycle:
R@ is constant with respect to BS except that it cannot be hydrogen.
or R1 and R8 together represent C2-Cl0 alkyl
Lyden or C2-Cl0hydroxyl(substituted alkylide)
Ad: cyclopentylene, cyclohegylene
(r: J-, C2-C6 alkylene (1 or 2
(Optionally substituted with the above C, -C4 alkyl group)
; R2 is also a counter anion when R2 is hydrogen or a protecting group
Provided that hydrogen, anionic charge or normal
is an easily removable carboxyl protecting group; it is attached to A through its ring nitrogen, with the quaternary
quaternized nitrogen-associated aromatic group forming a monium group or
Two carbapenem derivatives which are non-aromatic heterocycles or their
In the method for producing a pharmaceutically acceptable salt, (wherein R1 and R8 are as defined above, R2'
is a common easily removable carboxyl protecting group,
L is a normal leaving group) intermediate of the formula % (where A and R14 are as defined above and 0 is a pair
thiol compound (which is an anion) in an inert solvent,
Presence of base (However, R1, R8, R'', A-, R'' and X (E) are
producing carbapenem products (as defined above)
and, if desired, remove the carboxyl protecting group R21.
, a corresponding deprotected compound of formula I, or a pharmaceutically acceptable salt thereof.
provide a method for According to the present invention, an intermediate of formula (1) and a method for producing such an intermediate
is also provided. Carbapenem compounds of formula I are potent antibacterial agents or
It is a useful intermediate in the production of antibacterial substances. The compound of general formula I above has a carbapenem nucleus,
Therefore, 1-calper 2-benem-3-carboxylic acid derivative
It can be called. Alternatively, the compound has a group
7-oxo-1-azabisi
Chlo(3,2,0)hept-2-ene-2-carboxylic acid
It can be called a derivative. The present invention is based on the 5,6-proton
What is the relative stereochemistry of? It encompasses compounds that are both trans and trans.
However, the preferred compound is chenamycin.
It has a 5R,68 () lance) stereochemistry as in The compound of formula I has no substituents in the 6-position.
or other carbapenem derivatives.
It may be substituted with a substituent more disclosed. Change
Specifically, R8 may be hydrogen and R1 is
Hydrogen or, for example, European Patent Application No. 38,869
A non-hydrogen substituent (see the definition of R6)
). Or again, R8 and R1 are together
is substituted with 02-C, alkylidene or e.g. hydroxy.
C2-Cl0 alkylidene. To elaborate on the definitions of R' and R8: (a) After "alkyl", "alkenyl" and
and “alkynyl group diI(・ke straight chain or branched copper 1-1
0 carbon atoms, preferably 1-6, most preferably
A group having 1-4 carbons (atoms);
Substituents (e.g. cycloargylalkyl, or heteroara
(as in aralkil or aralkil), in the case of a
Alkyl, alkenyl and alkynyl groups are preferably ],
, -6, most preferably 1-4 carbon atoms
Ru. (b) ``heteroaryl 1-4 0, N or
Mono-, bi-, polycyclic aromatic heterocyclic groups containing S atoms
preferably a 5- or 6-membered heterocyclic ring, such as a chain ring;
ru, frill, thiadiazolyl, oxadiazolyl, tri
Azolyl, inthiazolyl, thiazolyl, imidazolyl
, isoxazolyl, tetrazolyl, oxazolyl, pyri
Zyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyro
Lyle and pyrazolyl are obtained. (C) “Heterocyclyl’ means 1-4 0, N or
Mono-, bi- and polycyclic saturated or unsaturated containing S atoms
including non-aromatic heterocyclic groups; preferably 5- or 6-membered heterocyclic groups;
A quick analogy for morpholinyl, piperazinyl, piperidine
, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.
. (d) “Halo” means chloro, bromo, fluoro and iodine.
and preferably chloro or bromo. The term “common easily removable carboxyl protecting group” refers to
, to protect the carboxyl group in the process of the chemical reaction below.
refers to the known ester group used in
If desired, use a method that does not cause any decomposition to the rest of the molecule.
e.g. chemical or enzymatic hydrolysis, under mild conditions.
treatment with chemical reducing agents, UV irradiation or catalytic hydrogenation
It can be removed depending on the of the ester protecting group
Examples include benzhydryl, p-nitrobenzyl, 2-na
phthylmethyl, allyl, benzyl, trichloroethyl,
Silyl e.g. trimethylsilyl, zenaacyl, p-methane
Toxybenzyl, acetonyl, 0-nitrobenzyl, 4
-pyridylmethyl and Ct-C, alkyl e.g. methyl
, ethyl or "-butyl." Protecting groups like this
contains groups that are hydrolyzed under biochemical conditions, such as piva
loyloxymethyl, acetoxymethyl, phthalidyl,
Included are indanyl and methoxymethyl. particularly advantageous
Carboxyl protecting groups can be easily removed by catalytic hydrogenolysis.
p-Nitrobenzyl and Pd(Pe3)4 contact reaction
The allele can be removed depending on the situation. The pharmaceutically acceptable salts mentioned in the preamble include non-toxic acid addition salts.
Examples include mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, and phosphoric acid.
, salts with sulfuric acid end and organic acids such as maric acid, acetic acid,
Citric acid, succinic cloth, benzoic acid, ammonium tartrate, fumaric acid,
mandelic acid, ascorbic acid, lactic acid, gluconic acid and
Salts with malic acid are included. Form of polyaddition salt form of formula ■
The compound can also be written as (however, Xθ indicates the aeon of resistance)
It is. What about anti-anion XO? ¥? Pharmaceuticals for therapeutic membrane administration
The formula is selected to provide an acceptable salt.
In the case of compound intermediates, X○ may be a toxic anion.
stomach. In this case, the ions are then removed or
can be substituted with a possible anion to produce the therapeutically active end product.
Rukoto can. An acidic or basic group is present in the R1 group or in the fourth group.
When present on the graded R14 radical, the present invention
A suitable base or acid salt of these functional groups, e.g.
Acid addition salts for acidic groups and metal salts for acidic groups (e.g.
Sodium, potassium, calcium and aluminum
ammonium salts and non-toxic amines (e.g.
Alkylamine, flocaine, shhenzylamine, 1-
Ephenamine, N-benzyl-β-phenethylamine,
N,N'-dibenzylethylenediamine, etc.)
Included. R2 is hydrogen, anionically charged or physiologically hydrolyzable
Compounds of formula I which are ester groups have a
Together with the salts obtained, it is useful as an antibacterial agent. of the remainder of formula I
The compounds are useful intermediates and
Can be converted into compounds. In a preferred embodiment of the invention R8 is hydrogen, and
Included within this subclass are compounds of formula I where R1 is hydrogen, CI(sCHz -,
So, preferred compounds have absolute configurations 5R, 6B, 8R.
ing. In another preferred embodiment, R1 and R8 together form the formula I
alkylene or cycloalkylene radical in the compound of
Cal A is or C2-06 alkylene (one or more cl-
(optionally substituted with a c4 alkyl substituent)
Ru. Preferred Alt+2ffl group: cyclopentylene
(R10, R11, RI2 and R1g are each independently water
or auto-C4 alkyl). are doing. having a cycloalkylene or branched alkylene A substituent
In the case of certain compounds of formula I, one or more further
Symbolic carbon atoms may appear and form diastereoisomers.
It is possible. The present invention includes diastereoisomers
Mixtures as well as individual purified diastereoisomers are included.
It is good. The quaternized R14 substituent has at least one nitrogen in the ring.
Contains an elementary atom and is bonded to A via the nitrogen of the ring
It has a C substituent that forms a quaternary ammonium group.
(may be) chino, bis- or polycyclic aromatic or non-aromatic
It can be a heterocyclic group. One preferred class of RI4 substituents is represented by the general formula
This general formula has at least one ring in the ring.
contains a nitrogen atom and is bonded to A via the ring nitrogen.
In this case, substituted or unsubstituted to form a quaternary ammonium group.
If-converted mono-, bis-, or poly-JX7 heteroaryl
The foundation shall be laid. Heteroaryl groups are CI -C4 alkyl, hydroxy, amino, carbo
-C4 alkyl directly converted to xy or muro, c:l -
C6 cycloalkyl, CI-C4 alkoxy, c,
-C4 alkylthio, amino, -04 alkylami
-, di(c, -C, alkyl)amino, halo, C1-C
4-alkanoylamino, CI-C4alkanoylamino
xy, carboxy, -C-OCl-C4 alkyl, hydro
roxy, amidino, guanidino, trifluoromethyl,
fx=ru, 1, 2 or 143 amines, halo, hydroxy
sil, trifluoromethyl, C, -C4 alkyl or C
, -04 phenyl substituted with alkoxy group, heteroa
Ryl and heteroaralkyl (in the heterocyclic moiety mentioned above)
Group of heteroatoms consisting of 1-4 O, N or S atoms
and attached to the heteroalkyl moiety
The alkyl moiety has 1-6 carbon atoms).
It may be substituted with a substituent. The heteroaryl group attached to M substituent A can be quaternized
Nitrogen atom (carbon atom of alkylene or cycloalkylene group)
directly attached to the child) and, in some cases,
one or more additional heteroatoms selected from O, N or S
is a 5- or 6-membered aromatic heterocyclic group containing more than
is preferable. Generally, it is bonded to A via a quaternized nitrogen.
Both heteroaryl groups are biologically active molecules.
Although found to produce rubapenem derivatives,
Preferred embodiments include the following (a) to (g):
Compounds representing the selected groups are covered. (a
) to (g) groups, provided that R5, R6 and R7 are independently water.
Element; C1-C4 alkyl: hydroxy, amino, carbo
c, -C4 alkyl substituted with xy or halo: C
3-C6 cycloalkyl: C1-C4 alkoxy; C,
-C4 alkylthio; amino: C1-C4 alkylami
Nonidi(c, -C, alkyl)amino; halo; C1-C
4-alkanoylamino; C1-C4 alkano? yloxy; carboxy; -C-OCI-C4 alkyl
;hydroxy; amidino; guanidino; trifluorome
thyl; phenyl: 1.2 or 3 amino, halo, hydro
Roxyl, trifluoromethyl, c, -C4 alkyl or
is Cm-C, phenyl substituted with alkoxy; and
Teroaryl and heteroaralkyl, in the above heterocyclic moieties
Heteroatoms of from 1-4 oxygen, nitrogen or sulfur atoms
selected from the group consisting of
The alkyl moiety in question has 1-6 carbon atoms: selected from or BS, R6 or R? 2 of them
together form a fused saturated carbocycle, a fused aromatic carbocycle, a fused
Even if it forms a fused saturated carbocyclic ring or a fused heteroaromatic ring
Good: one or more substituents on a carbon atom in the formula
Optionally substituted, the substituents are independently C, -C4
Alkyl: hydroxy, amino, carboxy or halogen
Ct-C4 alkyl substituted with C3-c6 cyclo
Alkyl; C1-C4 alkoxy; cl-C4 alkyl
Lucio: amino; cl-C4 alkylamino; C1'-
C4 alkanoyl substituent; Carboxy: ~Cx-C
4 alkyl: hydroxy; amidino; guanidino; tri
fluoromethyl; phenyl: 1.2 or 3 aminos;
Halo, hydroxyl, trifluoromethyl, C1-C
. Fe substituted with argyl or ci-C4 alkoxy group
nyl and heteroaryl or heteroaralkyl, as defined above.
Complex 1 ((Heteroatoms fd in 9: I-4 nitrogen, nitrogen
or a sulfur atom, and the heteroatom is
The alkyl part combined with the largyl part is 1-6w
or optional substitution selected from;
to form a fused carbon 9 or heterocycle: where l-11 or more substituents on the carbon atoms
Optionally substituted, the substituents are independently cl-c,
Alkyl; hydroxy, amino, carboxy or halogen
c, -C4 argyl substituted with C3-C6'/c
Roalkyl; Auto-04 Arcogysi: Auto-C4γ Lugil
thio; amino; cm -C4 algylamino; di(c,
-C4 argyl) amino; halo: Ct-C4 alkanoyl
Ruamino: cl-C4 alkanoyloxy: Carboquine
; C-0C1-C<alkyl;hydroxy; amidi
guanidino; trifluoromethyl; phenyl: 1.
2 or id 3 amino, halo, hydroxyl, to
Lifluoromethyl, C, -C4 alkyl or C, -C4
Phenyl substituted with alkoxy group; and heteroaryl
or heteroaralkyl, a heteroatom in the above heterocyclic moiety
from the group consisting of 1-4 nitrogen, nitrogen or sulfur atoms
selected and combined with the heteroaralkyl moiety
The alkyl moiety has 1-6 carbon atoms selected from:
or optionally substituted fused carbocyclic or heterocyclic ring
forming: in which one or more substituents are substituted on the carbon atom.
The substituents may be independently substituted with C1-C4 atom.
hydroxy, amino, carboxy or herogen
CI -C4furkyl substituted with; C3-C6cyc
Loalkyl; auto-04 alkoxy: C1-C4 alkyl
Lucio; amino, C□-C. alkylaminodi(CI-C4alkyl)ami7;
Halo; c1 ”'C4 alkanoylamino; C1-C4
Alkanoyloxy:carboxy:-1!5-OCI-
C4 alkyl; hydroxy; amidino: guazinino;
Lifluoromethyl; 112 or 3 amines, halo, hydrogen
Droxyl, trifluoromethyl, auto-C4 alkyl or
is phenyl substituted with Cl-C4 alkoxy group;
and heteroaryl or heteroaralkyl, above 'fJ
The heteroatoms in the ring moiety include 1-4 oxygen, nitrogen or
selected from the group consisting of sulfur atoms and said heteroaralkyl
The alkyl part that is joined to the le part has 1-6 carbons.
or optionally substituted;
form a combined carbon ring or ring element; where XFiOlS or NR (R is Cx -C4 full
or phenyl), and the above group is
may be substituted with one or more substituents
, the substituents are independently Cr-C4 alkyl:hydroxy
, amino, carboxy or halogen substituted -
04 alkyl: C3-c'6 cycloalkyl 5ex-c
4 alkoxy: C1-04 alkylthio; amino: C1
-C4 alkylamino; di(CI-04 alkyl)ami
ノ; eight days + C1-C4 alkanoylamino: auto -C
4-alkanoyloxy; carboxy; “-C-OCl
-C4 alkyl: hydroxy: amidino; guanidino
;trifluoro)'ti#;7xnyl;1.2 or it3
amino, hydroxyl, trifluoromethyl
, c, -C, alkyl or cl-C4 flukoxy group
substituted phenyl: and heteroaryl or heteroaryl
rukyl, the heteroatoms in the above heterocyclic moiety contain 1-4
selected from the group consisting of nitrogen, nitrogen or sulfur atoms;
The alkyl moiety combined with the teroaryl moiety is 1-
having 6 carbon atoms;
jM optionally substituted to form a fused carbocycle or heterocycle; in the formula
, X is 0, S or NR (R is ci-C4 alkyl or
phenyl), and the above group has one or more carbon atoms on the carbon atom.
may be substituted with one or more substituents, and the substitution
The groups are independently cl-c, alkyl; hydroxy, amino
, C, -C4 alkyl substituted with carboxy or halogen
Kyl; C3-C6 cycloalkyl; CI-C4 alco
Xy: C1-C4 alkylthio; Amino: C1-C
4-alkylamino; di(auto-04alkyl)amino:
Halo: C1-C4 Alkanoylamino: C, -C4 Al
Kanoyloxy; Carboxy: -C-OCI-C4a
Rukyl; Hydroxy; Amidino; Guanidino; Triful
Oromethyl; Phenyl; 1.2 or 3 aminos, 8 days
, hydroxyl, trifluoromethyl, Cl-C4al
Phenyl substituted with Kyl or CI-C4 alkoxy group
; and heteroaryl or heteroaralkyl, the above complex
Heteroatoms in the ring moiety are 1-4 hydroxyl, nitrogen is sulfur
atoms selected from the group consisting of
The alkyl moiety associated with contains 1-6 carbon atoms.
has; selected from: and where R is Cl-Ca
alkyl or phenyl, on the carbon atom of the group d-
may be substituted with one or more substituents,
The substituents are independently Ct-c4 alkyl; hydroxy;
cl-C substituted with amino, carboxy or halogen
, alkyl; C3-C6 cycloalkyl; cl -c4
Alkoxy; C1-C4 alkylthio; Amino: C
1-C4 alkylamino; di(C,-c4 alkyl)a
Mino: Halo: C, -c4 Alkanoylamino: C1-C
4-alkanoyloxy: carboxy; -C-OCl-
C4 alkyl: hydroxy; amidino; guanidino:
Lifluoromethyl: phenyl: 1.2 and ij: 3 pieces
amino, octane, hydroxyl, trifluoromethyl,
C, -c4 alkyl or cl'-c4 alkoxy group I
N-substituted phenyl; and heteroaryl or heteroaryl
ralkyl, the heteroatoms in the above heterocyclic moiety are 1-4
selected from the group consisting of 1p atoms, nitrogen or sulfur atoms, and
The alkyl moiety combined with the heteroaryl moiety is
having 1-6 carbon atoms; selected from;
be. Among the above subclasses, preferred compounds include substituted hams.
and (a) R'' and R8 become -g, and (b)
R8 is hydrogen and R1 is hydrogen, CH3CH2-1
A compound with an absolute configuration of 5 R% 68%
It is a compound having 8R. A particularly preferred embodiment of the present invention is 11 (wherein R5, R6 and R7 are independently hydrogen, C1-C
Substituted with 4 alkyl, auto-04 alkoxy, hydroxy group
C. -C4 alkyl, auto-04 alkylthio, amino, carbon
one selected from the group consisting of carboxy and carbamoyl;
The method for producing a compound of AI represented by the group
consists of Within this subclass, preferred compounds have substituent A
, and (a) R'' and R8 together (b)
R8 is hydrogen, R1 is hydrogen, CH3CH2-,
compound, preferably having the absolute configurations 5R, 6B, 8R.
It is a compound that The most preferred embodiment of the present invention is 11 (wherein R11, , R6 and R7 are independently hydrogen, Cl
-C4 alkyl, c, -c, alkoxy, hydroxy group
auto-C4 alkyl, C1-C4 alkyl substituted with
selected from the group consisting of
This method consists of a method for producing a compound of formula (1) represented by the following group. Within this subclass, preferred compounds are or (b) R8 is hydrogen, R1 is hydrogen, CR3CR
2-1. Particularly preferred is that R8 is water.
compound in which R1)H is CR3C)I-, preferably absolutely
Arrangement 5R. 68, a compound with SR. A second preferred embodiment of the invention comprises a process for preparing compounds of formula I as described below. Within this subclass, preferred compounds are those in which substituent A is
and (a) R' and R8 together, (b)
R' is hydrogen, R' is hydrogen, CHsCH2-1
It is a certain compound. Particularly preferred is when R8 is hydrogen.
, #5R, 68,8R. Consists of the method for producing the compound of 2) represented by a nium group.
. Preferred compounds (d: substituent A
and (b) Rδyb"Water IA 'tl'A'J R'
Id, hydrogen, CR3CH! −, is a compound that is
. In particularly preferred compounds, R8 has hydrogen in absolute configuration @5R,6
It is a compound having S and 8R. The most preferred M form of the present invention represents the formula % and R2 is hydrogen, an anionic charge or a normal
It is an easily removable carboxyl protecting group (where R2 is water).
In the case of basic or protective groups, counter anions are also present): Compounds of:
From the method for producing acid addition salts that are acceptable for production of mulberry products,
Become. Other preferred classes of quaternized R4 substituents have the general formula:
However, R16 has or does not have a substituent:
alkyl, alkenyl and alkynyl, 1-10 carbons
Cycloalkyl and cycloalkylalkyl atoms
3-6 carbon atoms in the cycloargyl ring and alkyl
having 1-6 carbon atoms in the group: phenyl; alkyl
The le moiety is phenyl and the aliphatic moiety is 1-6 carbon atoms.
Aralkyl, aralkenyl and aralkyl having elementary atoms
Nyl; heteroaryl, heteroaralkyl, heterosyl
lyl and heterocyclylalkyl, in the above heterocyclic moiety
Heteroatoms consist of 1-4 rope, nitrogen or sulfur atoms.
an atom selected from the group consisting of
The group consisting of: the lukyl moiety has 1-6 carbon atoms
and the above R16 group is selected from amino, fluorine,
Oro, chloro, carboxyl, hydroxy or hacarbamo
C, -c6 alkyl optionally substituted with yl;
-NR'R': R3C0NR4-; -NR'C02R';-NR'C0NR'R' -CN: or 1-3 fluoro, chloro, bromo, c, -Cg a
Lukil, -0R3, -NRBR', -S 03 R',
-CO2R3 or -CONR3R' (or R6 substitution
R3, R4 and R9 in the group are as defined above)
1-3 substituents independently selected from the group consisting of
to 75 which may contain or contain and via the ring nitrogen A
, forming a quaternary ammonium group.
, with or without substituents, mono-, bi-
- or polycyclic non-aromatic (other aromatic or non-aromatic rings)
(represents a heterocyclic group which may be fused)
Divalent phnylene or C]-Ca alkyl forming a polycyclic group
It is also possible to represent a ren group. The heterocyclic group is saturated or
May be unsaturated (having 1-2 double bonds)
, and contains up to two other heteroatoms other than the quaternary nitrogen
81, and the other heteroatoms are O, S
(Choose from Q臘, N1N Rl 6 or NR1?R18
[However, m1l-J: 0, ■ or 2, and R15 is
Hydrogen, self-06 alkyl which may have a substituent, or
is phenyl which may have a substituent, and R and B
18 -C which may have a substituent independently of
6 alkyl or phenyl which may have a substituent
]. In a preferred embodiment, a non-aromatic 4-7 membered, preferably 5-16-membered, 0
-2 double bonds and O, S(0)m, N, NR”
or NRIT Rl11 (where m is 0.1 or 2)
, R16 is hydrogen, independently -OR", -NR'R
', -CO2R3, oxo, phenyl, fluoro,
rioo, pro%, -S 03 Rs and (FCONR3R
' is substituted with 1-2 substituents selected from
may be self-C6 alkyl, or independently C, -C, alkyl
Kill, -ORku-NR"R', Fluoro, Chloro, But
Lomo, -8O3Rku -Co2R" and -CONR3
substituted with 1-3 substituents selected from R'
R” and R18 are each independently phenyl.
Stand -OR', -NR"R',"C02R',
-oxo, phenyl, fluoro, chloro, bromo, -
8OsR” and (J-CONR3R’)
C, -C, which may be substituted with 1-2 substituents
alkyl or independently -OR', -NR'R', full
oro, chloro, bromo, -803R'', -CO2R2 and
1-3 locations selected from
C, -C6 alkyl which may be substituted with a substituent
：Karl m element iNR"MatahaNR"R" Group inside] R' and
as defined above with respect to the substituent
containing 0-2 further heteroatoms selected from
The figure shows an N-containing complex cell. (CC) substituted with 1-3 substituents independently selected from
It is possible to exchange. (a) to (cc) are (a) Ct-Cs alkyl, (in some cases fluoro
, chloro, bromo, -OR', -0COR", -0C
ONR"R', -oxo, -NR"R', -NR"C
OR', -NR"C0NR3R', -NR"5O2R'
, -8R'', -8O3R'', -Co2R' and -CO
with 1-2 substituents independently selected from NR"R'
(b) Cz-Ca alkenyl (substituted): (b) Cz-Ca alkenyl (if
Depending on the fluoro, ri0 mouth, pro%, -0Rs, -0
COR", -0CONRJR', -oxo, -NR"
R',-NR"C0R--NR'C0NR'R--N
R"802R',-3R", -8O3R3, -CO
1 independently selected from 2R3 and -C0NR3R'
-substituted with two substituents): (c) C2-c, alkynyl (in some cases, fluorocarbon
b, chloro, b o%, -OR", -0COR", -
0CONR"R', -oxo, -NR3R4, -NR'
C0R4, -NR"C0NR"R'. -NR"5O2R', -8R" % -8O3R"
, -Co2R' and H-CONR'R'
(d) C3-Cs+cycloalkyl (substituted with 1-2 substituents selected by
fluoro, chloro, bromo, -OR', -0COR3,
-ocoNr<'n', -oxo, -NR"R',
-NR3R', -NR"COR', -NR"C0NR
JIR', -NR'SO,R', -8R', -8
O3R', -Co2R' and -〇〇NRJR'
(substituted with 1-2 independently selected substituents)
; (e) cycloalkylalkyl, 3 in the cycloalkyl ring
-6 carbon atoms and 1-6 carbon atoms in the alkyl moiety
(in some cases, fluoro, chloro, butyl)
Lomo, -OR'. -0COR', -00ONR3R', -oxo, -N
R'R', -NR'COR"1-NR3CONR'R
', -NRaSO2R', -8R'. -8O3R3, -CO2B" and -CONR'R'?
substituted with 1-2 substituents independently selected from
): (f) heteroaryl, the heteroatoms are 1-4;
selected from the group consisting of oxygen, nitrogen or sulfur atoms (where
Depending on the case, fluoro, chloro, bromo, -OR",
-0COR", -0CONR"R', -oxo, -N
RsR"1-NR"COR', --NR'C0NR'R
', -NR"5OZR number, -8R",
-8O3R', -CO2R" and -CONR"R
' substituted with 1-2 substituents independently selected from
): Preferred heteroaryl groups are 5- or 6-membered aromatic
Is an aromatic heterocycle: selected from the group consisting of elementary or sulfur atoms
and the alkyl moiety has 1-6 carbon atoms, (
In some cases, fluoro, rioo, 7"lomo, -OR"
, -0COR3, -0CONR"R', -oxo, -
NR'R', -NR3COR', -NR3CONR
'R', -NR'5OzR', -8R', -8
O3R", -CO2R" and U-CONR3R'
substituted with 1-2 independently selected substituents
): A preferred heteroaryl is one in which the heteroaryl group is 5-
or a 6-membered aromatic heterocycle, and the alkyl moiety is 1-
having 2 carbon atoms: (h) heterocyc
lyle, heteroatoms are 1-4 oxygen, nitrogen or sulfur atoms
selected from the group consisting of (in some cases fluoro,
Chloro, bu0mo, -OR') -0COR3, -0cO
N;1j1F,', -oxo, -NR"R', -
NR3COR', -NR'C0NR"R"1-NR"5
O2R', -8R"%-8O3R",-CO2R"
and 1 independently selected from -CONR3R'
- substituted with two substituents): preferred heterones
Kryl is a 5- or 6-membered saturated or unsaturated ring; (i
) Heterocyclyl, heteroatoms are 1-4 oxygen, nitrogen
or a sulfur atom and an alkyl moiety
has 1-6 carbon atoms (sometimes fluorocarbon
bro, chloro, bromo, -0R1, -0COR", -0
CONR'R', -oxo, -NR"R4, -NR3
COR', -NR'C0NR3R', -NRjSO2
R', -8R'', -80,R', -CO2R'
1-2 independently selected from and
(substituted with R substituents): preferred heterocyclyl
Rualkyl is a 5- or 6-membered saturated heterocyclyl moiety
or heterocyclylalkyl which is an unsaturated ring; ('') fluoro, chloro or haplomo; (k) -OR": (1) -0COzR"; (m) -ocoRs. (n)-00ONR'R': (o)-080zR': (p)OXO; (q) -NR"R': (r) R3C0NR4-H (s) -NR"C02R': (t)- N
R3CONR"R': (u) -N R'802 R'; (v) -8
R3: (ff) -8O3R"; (j!) -CO2R": (aa) -CONR3R';(bb)-CN; and (CC) phenyl (in some cases, 1-3 phenyl
fluoro, chloro, bromo, c, -C6 alkyl, -OR
', -NR'R', -8O3R3, -CO2R" or -
The R3, R4 and R9 substituents mentioned above are related to the substituent R1.
It is the same as what has been determined. The ring is a non-aromatic heterocyclic group. This ring, however, is saturated or
can also be an unsaturated carbocyclic ring, preferably O-, N
180) rn %NR” or N-R17RI 11
4-7 shellfish containing 1-3 heteroatoms selected from
heterocyclic (saturated or unsaturated) ring or 01S(0)
, N, selected from NRI' or fiNR'Jrs
5-6 shellfish heteroatoms containing 1-3 heteroatoms are also aromatic.
group ring (in the above formula, m, RII, R, and R11 are
to be fused to another ring.
is also possible. The R16 substituent of the non-aromatic R14 group has (1) a P substituent.
optionally cl-C, 5 alkyl A/, C2-Cl0
Alknyl, C2-CIO alkynyl, C3-c6
Chloalkyl, C3-cs cycloalkyl-at-C
6 alkyl, phenyl, phenyl-06 alkyl,
Phenyl-C2-C6 alkenyl, phenyl-C2-c
6 alkynyl, heteroaryl, alkyl moiety is 1-6
heteroaralkyl, alkyl moiety having 4 carbon atoms
heterocyclyl or heterocyclyl having 1-6 carbon atoms
rosyclylalkyl, or (2) divalent phenylene, or
Self -C4 ring is bonded to a bridged ring polycyclic group such as quinuclidi
It is one of the following: hetero ant
(or of the heteroaryl part of a heteroaralkyl)
The substituents are 1,000,000,000, containing 1-4 0, N1 or Fis atoms.
-, be or polycyclic aromatic heterocyclic group: preferred
is a 5- or 6-membered heterocyclic ring such as chenyl, furyl
, thiadiazolyl, oxadiazolyl, triazolyl,
Isothiazolyl, thiazolyl, imidazolyl, isoxa
Zolyl, tetrazolyl, oxacylyl, pyridyl, pyra
Dinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrrolyl
It is lazolyl. heterocyclyl (or heterocyclyl
The substituents on the heterocyclyl part of alkyl are 1-4 0
, mono-, bi- or polycyclic saturated containing N or S atoms
or an unsaturated non-aromatic heterocyclic group; preferred is 5-
or 6-@ all heterocyclic rings such as morpholinyl, piperazinyl,
piperidinyl, pyrazolinyl, pyrazolidinyl, imida
Zolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl
It's Niru. RI' Ft, mM is alkyl, alkenyl, alkynyl
cycloalkyl, cycloalkylalkyl, phenyl
phenyl, phenylalkyl, phenylalkenyl, phenyl
alkynyl, heteroaryl, heteroaralkyl, heteroaryl
In the case of rosyclyl or heterocyclylalkyl groups,
The following groups are independently selected from (a) to (,) below.
It may be replaced with 1-3 substituents. (a) to (,) are (a) -C6 alkyl, optionally a substituent;
, preferably l-3 amino, fluoro, chloro, carbon
Having a ruboxyl, hydroxy or carbamoyl group:
(b) fluoro, chloro or bromo; (C) -
0R3; (d) -0CO2R"; (e) -0COR3: (f) -0CONI?3R'; (g) -0802R3: (h) -oxo(i) -N R'R'; (D R"C0NR '-; (k) -NR'C02R';(1)-NR'C0NR"R';li?1)-NR'5O2R': (n) -S R';(o)-8OR': ( (Q)-8O3R": (r)-CO2R";(S)-CONR3R':(t)-CN;
Mo, self -C6 full k, -OR person-NR'R', -
8O3R", -COzR" Also bar C0NR'R'
La Nakatachi Shite Sen &su; hl - substituted with 3 substituents
However, in relation to the above-mentioned B 16 N: substituent
and R3 and R4 are independently hydrogen; alkyl, alkenyl
and alkynyl, having 1-10 carbon atoms;
loalkyl, cycloalkylalkyl and alkylcyclo
loalkyl, 3-6 carbon atoms in the cycloalkyl ring and
and has 1-6 carbon atoms in the alkyl moiety; phenyl
; the aryl part is phenyl and the aliphatic part is 1
- aralkyl, aralkenyl and aralkyl having 6 carbon atoms
and aralkenyl; and heteroaryl, heteroaralkyl
heterocyclyl and heterocyclylalkyl, groups of
Heteroaryl and heterocyclyl groups or moieties are R16
the same as defined above for
The alkyl moiety combined with the kryl moiety has 1-6
having a carbon atom; or R3 and R4;
together with nitrogen, at least one of which is bonded (
atoms) together with the 5-statement is a 6-membered (defined above for R6
form a nitrogen-containing heterocyclic ring (identical to
and R9 may be defined above for R3.
(However, it cannot be hydrogen). most preferred
The new R111 substituent is Ct-C6 alkyl, especially methyl
It is. R'6 divalent phenylene or Ct-C6 alkylene group
Constructed if . A particularly preferred embodiment of the present invention is [wherein Y is hydrogen, C1-C6 alkyl, hydroxy,
-S C1-C6 alkyl, carboxyl, carbamoy
chloro, bromo, iodo, fluoro or phenyl
A process for producing a compound of formula I shown in [1]. child
Among the subclasses of 4), it is a compound with more
A preferred compound is A or A is -CI42CR2-.
and (a) R'' and R8 together (b) R' is hydrogen and R1 is hydrogen, CHs
This is a compound that shows CR2-1. It is a compound that exhibits the absolute (steric) configuration 51?
, 68°8R. An even more preferred embodiment of the invention consists of a process for preparing a compound of formula I as shown below. This preference
n is 2.3 or 4), and more
A preferred compound is A is -CH2CH2-1-CI-1
2CH2CH2+, -CHCH2-1 occupancy H3 The preferred compound is -CR2CR2-, and (
a) R' and R6113 (b) R8 is hydrogen and R1 is hydrogen Cf(3
CH2-17>-, any compound. H Particularly preferred is when R8 is hydrogen and R1 is CR3C
A compound in which H-, particularly in the absolute (steric) configuration 5
It is a compound having R,68,8R. An even more preferred embodiment of the present invention is [wherein Y is hydrogen, -C6 alkyl, hydroxy,
-S et -Cs alkyl, carboxyl, carbamo
yl, chloro, bromo, iodo, fluoro or phenyl
This method consists of a method for producing a compound of formula (1) shown in [1]. Within this preferred subclass, preferred compounds are those in which A is
-CHx CR2- and to the historical power or (b)
It is a compound of any of the following. It is a compound with a particular absolute (steric) configuration of 5R,6
S. consists of Within this preferred subclass, preferred compounds are those in which A is
-(C1-12) -(in the formula, n is 2.3 or 4
), and the most preferred is a compound in which -CHz
or (b) R6 is hydrogen and R1 is hydrogen, CHs
Any compound exhibiting a power of CHz −1. H Particularly preferred is when R6 is hydrogen and R1 is CR3
A compound that is CH-, with a particular absolute (steric) configuration 5
It is a compound with R% 68% 8R. The most preferred embodiment of the invention represents the formula (both oisomers) and R2 is hydrogen, aniozoyl or
A carbonyl protecting group that can be easily removed, provided that R2 is water.
In the case of an elementary or protective group, a counter ion is also present],
and a method for producing a pharmaceutically acceptable acid addition salt thereof.
Certain products within formula I include optical isomers as well as their
that it can be formed as a mixture of epimers.
8 You will be enlightened. This invention is within the scope of its patent rights.
It also includes all mixtures of optical isomers and epimers.
To be. For example, the substituent at the 6-position is hydroxyethyl
, the substituent is either R or 5r2tit.
can also be produced, and the resulting isomers as well as their
Mixtures of pimers are included within the invention. The process of the invention uses an intermediate of formula
Patent Application No. 38,869, disclosed therein.
It can be manufactured by the general method described in . L
(in European Patent Application No. 38,869 “Xo
(expressed as ) common leaving groups, e.g. chloro, bro
Mo, iodine, benzenesulfonyluene, p-)luene
Sulfonyloxy, p-nitrobenzenesulfonyloxy
methane sulfonyl, trifluoromethanesul
Honylno-1-gin, Jingenogishiphoscinyloxy or σ
:I] di(trichloroethoxy). Preferred
The groups are gin-ae/gyishi-sei and nyloxy. Intermediate 62 formula n of formula IV [however, R1, fN3 and R21 are as in Sadatsuru above
) is reacted with a suitable acylating agent: Ro-L.
and generally formed within the device. L is diphenoxy
Preferred intermediates in phosphinyloxy are ketoesters.
Le ■ inert organic 'kf! :J^An example is methylene chlora.
in acetonitrile or dimethylformamide.
Equimolar i1t of zincenyl chlorophosphate and base example
Eha diisopropylethylamine, triethylamine,
In the presence of 4-dimethylaminopyridine etc., about -20'C
The reaction is carried out at a temperature of from +40°C, most preferably at about 0°C.
Let me be 9? A: I can. Intermediate 1■ optionally d;,:
In the method of the present invention, it is possible to
or normally used as starting material without layering
. In the process of the invention, carbapenem intermediate IV is prepared by formula C+
4', Aa cyclohentylene, cyclohexylene, X
j: C2-C6 fullkylene (1 or u2
Above c. -c4 may be substituted with an alkyl group
), Tatsumomo f mashiri cyclobenzene, cycloheki
Shirenmataha RIG R12 1 (R10, R11, RI2 and RIB are each 3"1
Hydrogen or C. - monoalkyl), and ρ is strong n, - combined
For example, n C I- ', B r-
, Cl3 SO3- , CF3SO3- or C J
L3−(=)−8 03− and 1<
14 Phantom, quaternized nitrogen-containing aromatic or non
quaternary amine thiol compound of
Make it react. This reaction is carried out using an inert solvent such as acetonitrile.
acetonitrile-dimethylformamide, tetrahydrol, acetonitrile-dimethylformamide,
Dorofuran, Tetrahydrofuran - ■■201 Acetoni
Performed in the presence of a base in TriluH20 or acetone
do. The base character 6t is not critical. However, t [2 good
The results for non-nucleophilic tertiary amine bases, e.g.
Lopylethylamine, 1,8-diazabicyclo (5.
4.0) Undec-7-ene, 1,5-diazabisic
[430] Non-5-ene or tri(CI-C,
4) Argylamines such as triethylamine, tri-
obtained when using butylamine or tripropylamine.
It is being The reaction between intermediate ■ and thiol ■ takes place over a wide range of temperatures.
Ability to perform over a range, e.g. -15°C to room temperature
preferably in the range of about -15°C to +15°C
It is carried out at a humidity of H, most preferably around O'C. By reaction between quaternary amine thiol ■1 and intermediate 1■
soil in the manufactured carbapenem product, in combination with
[For example, (C6HsO)++ P 02■, C
of the anion combined with 10 or quaternary thiol]
It has a counter-anion, which can be used by other counter-anions in a conventional manner.
On, for example, with anion that is more pharmaceutically acceptable.
, can be replaced with this staircase. Alternatively, the following unblocking
The counter anion may be removed during the removal step. quaternized cal
Bapenem compound and counteranion form an insoluble product
If the product is crystallized in its formed form, it can be purified by filtration.
It may be collected in Following formation of the desired carbapenem product, optionally
If you trace the carboxyl protecting group R2' of compound I',
methods, such as solvolysis, chemical synthesis or hydrogenation.
The ability to remove it is the ability of the mouth. p-nitrobenzyl
, benzyl, benzhydryl or 2-naphthylmethyl
If various protecting groups are used, they can be removed by catalytic hydrogenation.
and a suitable solvent such as dioxane-water-ether
Tanol, tetrahydrophthene-diethyl ether Ruba
Zur7ar, tetrahydrofuran-9A dipotassium hydrogen oxide
Intermediate I' in aqueous solution - isogelobanol etc. from 1 to
Under a hydrogen pressure of 4 atmospheres, a hydrogenation catalyst, e.g.
In the presence of aluminum, palladium hydroxide, platinum oxide, etc.
Can be processed in about 0.24 to 4 hours at temperatures between 50℃ and 50℃.
Ru. When H21 is a protecting group such as 0-nitrobenzyl, it is removed.
Photolysis can also be used for blocks. 2,2.2-)!
Protecting groups such as J dichlorotyl can be removed by mild zinc reduction.
I can leave. Allyl protecting groups are used for platinum compounds and triphenylphos
Example of a catalyst consisting of a mixture with a sphine in an aprotic solvent
For example, tetrahydrofuran, methylene chloride or diene
Can be removed using chill ether. Similarly, other
Conventional carboxyl protecting groups are removed by methods well known to those skilled in the art.
It is possible to leave. Finally, R2′ is physiologically hydrolyzed.
The resulting esters such as acetoxymethyl, phthalidyl,
Dandanil, hivaloyloxymethyl, methoxymethyl, etc.
Compounds of formula I' which are (as described above)
Because tel hydrolyzes in vivo under physiological conditions, it provides protection.
It can be administered to a subject without removing the base. R1 and/or R8 substituent or quaternary bonded to substituent A
Possibility of nucleophilic substituent RI4 interfering with the intended reaction pathway
If it contains a certain functional group, it can be used as a normal blocking group.
Therefore, the desired group can be protected and the block removed.
It should be understood that the functional groups of suitable blog
Introduction and removal of base groups are well within the skill of those skilled in the art.
This is a well-known fact. As with other β-lactam antibiotics, of general formula I
For purposes of this invention, compounds are essentially non-chlorinated compounds.
The equivalent pharmaceutically acceptable salt may be modified by known methods.
Can be exchanged. For example, a compound of formula I in which R2 is an anionic charge may be
and then an equivalent amount of a pharmaceutically acceptable inert solvent.
A (I) acid can be added. The desired acid addition salt is
By conventional methods such as solvent precipitation, freeze drying, etc.
It is recoverable. Other basic or acidic compounds in the compound of formula I
Pharmaceutically acceptable base additions if functional groups are present
Salts and acid addition salts can be similarly prepared by known methods. A compound of 2, where R2 is hydrogen or an anionic charge, or
The pharmaceutically acceptable salt thereof can also be prepared by a conventional method.
Corresponding compounds that are physically hydrolysable ester groups
or R2 can be converted into
Compounds of formula I which are protecting groups are defined by R2 being hydrogen, anionic charge or
is a physiologically hydrolyzable ester group versus JIU
, or a pharmaceutically acceptable salt thereof.
be. Some thiol intermediates of formula
la ~ III b\rjll C [wherein, Rlo R11, RI2 and R13 are each
independently hydrogen or C, -C4 alkyl]
a heteroaromatic amine (as defined above) of the formula
or a non-aromatic heterocyclic amine (as defined above) of the formula
, and can be produced by reacting with a strong acid. reaction is inert
Organic solvents, preferably hamethylene chloride, benzene,
The presence of non-polar solvents such as xylene, toluene, etc.
It can be carried out under or in the absence. amine and sulfy
If the reagent is a liquid or if a solid amine is used as a liquid sulfuric acid
If the solvent is soluble in the reagent, perform the reaction without using an additional solvent.
It is preferable to The particular strength m used in the reaction is not critical, but for example
Hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluene
Strong acids such as sulfonic acid, trifluoromethanesulfonic acid, etc.
It can be an inorganic or organic acid. The formation of the quaternary amine thiol intermediate
It can be carried out at temperatures in the range of about 100°C. preferred temperature
degrees are generally in the range of about 50-70°C. The sulfide reagent, aromatic amine and acid are preferably
Using approximately equimolar amounts of sulfide and acid,
for amines in excess, e.g. 1 mole of sulfide or
2 to 3 moles of amine relative to acid are used. @The quaternary amine thiol intermediate is the pair with which it is combined.
Let's have an anion and it depends on the particular acid used
I'll settle for that. Of course, at this point the next carbape
Rely on conventional methods for use in reactions with NEM intermediates■
can be replaced with a different counteranion. R1 is hydrogen, anionically charged or physiologically hydrolyzable
Novel carbapenem derivatives or their formulations
Tolerable salts are compatible with various Gram-positive and Gram-negative bacteria.
It is a powerful antibiotic with activity against
They are used, for example, as growth-promoting animal feed additives, food preservatives, and
Industrial applications, e.g. water-based paints and paper mill whites
A disinfectant that suppresses the growth of harmful bacteria in water, and a medical
Destroys or inhibits the growth of harmful bacteria in medical and dental equipment
It can be used as a samurai disinfectant. But this
These are caused by Gram-positive or Durham-negative bacteria.
Particularly useful in treating infectious diseases of humans and other animals
. The pharmaceutically active compounds of the invention can be used alone.
Or, in addition to the active carbapenem ingredient,
Mulberry silk composition containing a pharmaceutically acceptable carrier or diluent
It can also be prescribed as a product. Compounds can be prepared by various means.
can be administered. The means of primary interest are oral
, local or parenteral (intravenous or intramuscular injection)
include. The pharmaceutical composition can be in solid form, e.g. capsules,
Tablets, powders, etc. or liquid forms such as solutions, suspensions, etc.
can be an emulsion. Injectable compositions (preferred route of administration)
is the 9i position in the ampoule or multi-dose container - Ej,i
Prescription agents such as suspending agents, stabilizers and
It can contain a dispersant. The composition is in ready-to-use form
However, during administration with a suitable vehicle e.g. sterile water, regeneration is necessary.
It may be in powder form. The dosage for administration depends on the particular compound used,
the particular composition, route of administration, host characteristics and treatment;
depending on the specific site and microorganism
. So, the selection of the particular preferred dosage and application route is
It is left to the discretion of the doctor. However, in general the compound is about 5-5-2O0/9z day
Can be administered parenterally or orally to mammalian hosts in the
can. Dosing is generally divided into doses, with 3 seconds
It is carried out ~4 times/day. The following example is for illustrative purposes only and does not limit the scope of this opening song 4.
It is not determined. Example 1 Preparation A, 1-(2-mercaptoethyl)pyridiniummethane
Pyridine (8.0 mA, 0.099 m
o l) methanesulfone/i? (1,95me,
Pyridinium produced by feeding 0.03 mol)
Ethylene is added to the pyridine suspension of mumethane sulfonate.
Ruphide (1,96yqA, 0.033mol)
added. The resulting mixture was stirred at 55°C for 16 hours,
Concentrate under reduced pressure to form a thick syrup and mix with several mL of water.
. This solution was applied to a μmbond-apak C-18 column.
(40X16m) Pour on top and elute with water.
Freeze-dried colorless syrup 65.9 (91%)
I got it. ir (film) Imax: 2300-2600 (br
, SH), ], 635 (pyridinium), 1490
, 1200 (sulfonate). 1]-068,1060,1045,791,780cm
, “Hmr(DMSO-d6)δ:2.3
2(3H2SpcH3sO3-), 2.61. 2.70, 2.73, 2.82 (B part of IH, A2B system
, SH), 3.07 (2Hp rn (at D20, 3.
08(2) Lt,! =6.5142)), cn2s),
4.76 (2H,t, J=6.5H2, Cl42N+
), 8.19 (20, m. y(m) of pyridinium, 8.6 (LH, m, pyridinium
■(0), 9.08 (2J(,dd,,J=
6.8Hz, J=1.4I-1z, pyridinium
110), /IV(H20)λmax:206
(ε5230), 258 (ε3760) mμ. Method Crude 1-(2-mercaptoethyl)pyridinium methane
Palm chit Ruphonate (9,1,0,04m01)
(permutit) S-ICI"" column (2,5
X41c'In). Column at 0.5mL/m
in. Elute with water at a rate of
7.0g of yellow syrup, freeze-dried and used in the next step.
(100%) was obtained. xHm r (D20) δ: 3.22 (2H, m, C
H25), 4.88 (m. CHIN), 8.18 (2H, m: pyridinium
) 1m ), 8.7 ([1゜m, Hp of pyridinium)
,9. oppm (zH, my pyridinium J(O). Method B I-Pyridine (5-5niL, 7QmmOl) cooled in a water bath
) to pyridine hydrochloride (4.05g, 35mmol I
) and ethylene sulfide (2.1 mL, 35 mmol
) was added. Heat the mixture to 65°C and stir for 75 minutes
A two-phase system was created. The light phase is removed and the remaining oil is
Wash with gel (5 x 10 mL) and reduce the pressure to high vacuum to form the title.
The compound (90-100%) was obtained and used in the next step. OH1-NEt(iPr)2 4-NEt(iPr)2 (M( '' p-nitrobenzyl 6α-(1-(R)-hydroxyethyl
Chil]-3,7-thioxo-1-azabicyclo(3,2
,0) Hebutane-2-calhoki'/shi) (6,09g
, 17.5 mm o I) of acetonitrile (2
0 mL) solution was cooled to +5°C under nitrogen atmosphere and diluted with
Sopropylethylamine (3.65 mL, 21.0
mmol) and diphenylchlorophosphate (4,34
mI. 210 mmol). generation mixture
The mixture was stirred for 30 minutes at 5°C, cooled to -5°C and
-(2-mercaptoethyl)pyridinium chloride (
4,:l, 24 mmol) of N,N-dimethylforma
Mid (10m L) i? Diisopropyl from i & Bi Ichidekien
Ethylamine (3.65mL, 21.0mmol)
Processed one after another. The reaction mixture was stirred at 0°C for 1 hour,
The mixture was cooled to -30°C and stirred for an additional 15 minutes. solid
Each door was washed with cold (-30°C) acetonitrile. 5
．． 7'# (65%), 1r (nu, jol) max:
3300 (OH), 1775 (β-lactam C-0)
, 1690 (C-0 of PNB ester), 1630 (PNB ester)
Lysinium), 1605 (Phenyl of PNB ester)
, 1515 (No2), 1335cm-” (NO2)
,”)(mr(DMSO-d6)δ: 1.17 (
3H, d, J=6. I H2, (J(scH□H)
, 3.2-3.75 (5H, H-4, H-6, CI-(
28), 3.75-4.5 (2H11(-5,C)(
3CHOH), 4.92 (2H, br t, J
=6.5H2. CI-h N+), 5.18 (IH, d, J=4.9H
z, 0I-1), 5.37 (center of AB9, La,
b ; 14.2 Hz PN B cnz), 7.
69 (2H, d, J=8.7Hz, Ho of PNB)
, 8.24 (d, J=8.7Hz. Hm of I'NB), 8.0-8.4 (4H, Hm of PNB
m, Hm of pyridinium. 8.66 (IH, m, Hp of pyridinium), 9.17
(2H,brd,J=5.5Hz,pyridinium)(
o), P solution and washing solution were combined and mixed with ether (150 mL).
It was diluted with Decant the supernatant and thoroughly remove the gum.
Dissolve K in water (40 mL) containing acetonitrile.
As a solution, a p-bondapak C-18 column (
3×10σ) was injected apically. Column with 10%-acetonylate
Tolyl - 90% water (150 mL) and 50% acetonitol
Elution was carried out with a mixture of Li#-50% water (100 mL). suitable
Combine the desired fractions and remove acetonitrile under vacuum.
After removal, it was frozen and flaked to obtain a yellowish powder. N
MR results show that the title compound contains some p-nitrobenzyl.
3-(2-(1-pyridinium)ethylthio]-6α-
C1-(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo(3,2,0)hept-2-ene-2-ka
Mixed with lupogishile-todiphenylposphere-1 (2:
1) showed that it exists. Powder (minimum amount
) Dissolved in water, column of Balmchit S-I C1-
(],,55221m passed by water. Appropriate frac
1.8g (20%) of the title compound was obtained by freeze-drying the
? I got hit. 4) NEt (i, Pr)2 p-nitrobenzyl 6α-C1-(x<)-hydroxy
shiconityl)-3,7-thioxo-1-azabicyclo(
3,2,0)hebutane-2-carboxylene)(0,1
74 g, 0.50 mmol) of acetonitrile (2 mL
) The solution was cooled to 0 °C under nitrogen atmosphere and diisopropyl
Ethylamine (0,105rnL, 0.60mm o
l') and U diphenylchlorophosphate-1.(0,
124m LXQ, 5Q mm o l)
It was processed immediately. 3 o 'A+J
o “C” to add 1-(2-mercaptoethyl)pi
Lysinium meta 7'A sulfonate (0,170,9,0
,72mmo] ) of acetonitrile (0.6mJ,
) solution and diisopropylethylamine/(o, 105
rnL, 0.60 mtn o l) one after another.
Ta. The reaction mixture was stirred at 0 °C for 15 min and cooled (o'c).
Diluted with water (7 mL) and prepared μmbondapak C-1.
Inject onto the top of a No. 8 column (1.5 x 6.4 cm). mosquito
Rum was mixed with acetonitrile (25-50%) and water (75-5%).
0%) mixture to melt gf0. appropriate fraction
are combined and cooled after removing the acetonitrile under vacuum.
0.33 g (92%) of a dry yellowish powder was obtained:
ir(KBr)vmaX=3600~3000(0■(
), 1765 (C of β-rakkum = 0), 1.690 (
I) C of NB ester; 0), 1625 (pyridinium
), 1585 (phenyl), 1.510 (NO2), 1
330 (NO2), 885 sure-"(NO,,),'Hm
r(DMSO-d6)δ: 1.1.6(3H,d, J
=6.2Hz, CH3CHO)I), 4.87(2H
, brt, J=6.611z, CHzS), 5.37(
Center of AB, ja, b”14-3Hz, PNB
CH2), 6.7-7.5 (phenyl), 7.68
(d, J=8.8Hz, PNB rio),
&23 (dz J -&8 ■I ZyPNB Hm
), 8.0-8.3(m, of pyridinium)-1m),
8.4-8.8 (IH, pyridinium r■p), 9.
09 (2H, dd, J=6.7l-1z. J=1.3Hz, pyridinium no). p in moist tetrahydrofuran (10 nlL)
-=trobenzyl 3-(2-(1-pyridinium)ethyl
[ruthio]-6α-[1-(λ)-hydroxyethyl]-
7-oxo-1-azabicyclo(3,2,0)hept-
2-ene-2-carboxylate diphenyl phosphate
(0.16 g, 0.22 mmol) in a solution of
Le (10nlT, ): - Basic potassium phosphate - Water p6
Nato! J c, b, -ha7'7-pH7,4(16
mL, 0.05 M) and 10% palladium on charcoal.
(0.16 g) was added. The resulting mixture was heated at 25°C.
Hydrogenated at 40 psi for 1 hour. Separate the two phases and organic phase
was extracted with water (2 x 3 mL), the aqueous solutions were combined, and ether
(2 x 10 mL) and remove traces of organic solvent under vacuum.
After removal with μ-bondapak C-18 column
(1,5×6.23) was injected on top. fill the column with water
After lyophilization of appropriate fractions, yellowish color appears.
A powder was obtained. o, o62y (84%), + 1r (KBr), n
ax: 3700-3000 (OH), 1755 (β-La
C=0), 1630 (pyridinium), 159
0-” (carboxylate), 'Hmr (D20):
1.22 (3H, d, J=6.4Hz, Cll3
Cnon), 2.92(d, J=9.1H2,T(-4
), 2.97 (d, J-9, IHz, H-4), 3-2
0(dd, J=2.5)Lz, J-6,1Hz. H-6) 33.44 (t, J=6.014z, C, I-
Iz S), 3.93 (dd. J = 9.1 Hz y J = 2-5 Hz t H
-5) p 482 (ts J-6,0Hz. CH2N) p 8.04 ("t pyridinium
Hrn) p 8-5 (ms pyridinium Hp
), 8.82(dd, J=3.2'Hz, J
=1-NJz). UV (Hz 0) 2rr, 8x: 259 (ε5800
), 296 (ε7030) “U・”, = 13・5” (3
Buffer at 6.8℃, pH 7.4
Measured at a concentration of 10 M (hereinafter abbreviated as “to conditions”)
) Method ■3 p-nitrobenzyl 3-(2-(1-pyridium)ethyl
[ruthio]-6α-[1-(dan)-hydroxyethyl]-
7-oxo-1-azabicyclo(3,2,0)hept-
2-ene-2-carboxylate chloride (5,77
g, 11.4 mmol) of -basic soluble potassium
- Sodium hydroxide buffer (170 mL, 0.2
M, pH 7,22) solution was added with tetrahydrofuran (30 m
L), Nythea b (3 omL) and 1°% para on charcoal
Dium (5.7 g) was added. The obtained dl (compound 2
Hydrogenate for 1 hour at 2°C and 40 psj, then apply to Celite pad.
I stagnated. The pad was washed with water (2 x 15 mL). Combines Oki liquid and washing liquid.
and diluted with ether (100 mL). Separate the aqueous phase
Wash with ether (3x100mL)
After removing the solvent for about 1 hour in a direct atmosphere, remove the p-bo
Ndapak C-18 column (4,5×20 mer) top
injected into. Column with water and acetonitrile (1%)
Freezing of the appropriate fractions eluted in a mixture with water
2-48 g of the title compound as a yellowish powder upon drying
(65%) and nine analytical data were prepared using the method π′11.
It was identical to that of compound 1. Example 2 Cold 3.5-#tidine (2°51 mT, 0.022 mo
l) to stance/l/phonic acid (0.65 mL, 0.01
．． in 3,5-lutidine prepared by adding nN
in a suspension of 3,5-lutidinium methanesulfonate.
Ethylene sulfide (0,655mL, 0.011
mol) was added. ? 4) Place the prepared mixture in a nitrogen atmosphere.
Stir at 55°C for 24 hours, cool to 23°C, and add water.
(5 mL) and ether (5 mL). organic layer
The aqueous solution was diluted with ether (6 x 4 mL) except for
Washed. Remove traces of ether under vacuum and remove solution /J
-bondapak C-18 column (2,5X
6.0 crn) was introduced at the top. Elute the column with water and
A colorless syrup is obtained by freeze-drying the essential fraction.
Ta. 24g (91%): ir (film) I/max: 25
20 (8TI). 1628 (pyridinium), 1,600,1495,1
325,1305°1283.1200 (Sulfone)
), 1040,938,765°680cm-1;
'Hmr(DMSOds) δ;2.31 (3
H,s, CH35Os-), 2.47(6H,s,
chi on pyridinium, ). 2.57, 2.66, 2.69, 2.78 (I
H, A, 2 B part of yarn, SH). 3.06(2I■,m((2)-J with DzO addition,
t, J-6,5Hz)). CH2S), 4.65 (2I■, t, J=6.5H1
,C11,,N+),8.34(H(,s,pyridinium)
I(P), 8.79(2)(, 'S, Pyridinium
Ho): UV (H20)' max
: 271 (ε4860) m/7° Elemental analysis 2 calculated value
(as C16H17NO382” 0.5Hz O)
C44,09, H6,66, H5,14, S23.54
: Actual value: C44, 26°116.49. H5, 17,
S24.18゜diethyl]-7-oxo-1-azabisi
Chlo(3,2,0)hept-2-ene-2-carboxy
Rate diphenylphosphate (phO) 2PO Nitrogen atmosphere IJ1 (p-nitrobenzyl 6α-
(1-■-Hydroxyethyl)-3,7-thioxo 1
-azabicyclo(3,2,0)butane-2-carboxy
Sylate (0,523,!i'. 1.50 mmol) in acetonitrile (6,0 mL
) diisopropylethylamine (0,
314mL, 1.8mm01), then diphenylc
Rolophosphate (0,373g, ], 8mm
o l) and stirred the reaction mixture for 30 min.
, 1-(2-mercaptoethyl)-3,5-dimethylpi
Lysinium methanesulfonate (0,493,9,18
7 mmol) in acetonitrile (1.9 mL)
Then, diisopropylethylamine (0,314 mL
, 1.8 mmol). reaction mixture
Stir at 0°C for 1 hour and add cold (0°C) water (26rrlL)
diluted with μ-bondapak C-18 column (7
, Ox 3.5cm) Injected at the top and 25-5
Eluted with a mixture of 0% acetonitrile-75-50% water.
After lyophilization of the appropriate fractions, 1.01. ! 7
(90%) of the title compound as a yellowish powder.
is. 1r (KBr) max: 3700-3100 (O
)I). 1778 (β-lactam C=0), 1700 (PNB
Ester C-0) l], 635 (pyridinyl
um), 1595 (phenyl), 1521 (NOz)
, 1335 (NO2), 895□-' (NO□), 'H
mr(■)MSOd6)δ:1.16(3H,d,J
=6.11(z, CH3CHOH). 2.43 (S, birinidiram'2 CH3), 4-
．． 75 (2H, m. C1f2N), 5.38 (ABO center +
i a , B = -14,3Hz pP N T3
CH2), 6.6-7.5 (IOH, nn, phenyl)
, 7.70 (2H. d, J-8, 7J (Z, HO of PNB), 8.0-
8.5 (3H, m, Hp of pyridinium, Hm of PNB
), 8.82 (2H,s, 1-1 o of pyridinium
), UV (B20)λmax:270(ε11
570), 30G (ε7343) mfz0 elemental analysis: total
Calculated value (C37B58N30to 8: [' -Hz O
): C58,03,B5.26. B5.48.
S4.18; Actual jHti: C57,98, B5.0
5, B5.22, S4.34°H p in water-containing tetrahydrofuran (36 mJ,)
-=trobenzyl 3-(2-(1-(3,5-dimethyl
Pyridinium))ethylguo)-6a-41-(n)-
Hydroxyethyl]d-oxo-niazabicyclo(3
,2,0) hept-2-ene-2-carboxylate di
Phenyl phosphate (0,600g, 0.80m
ether (36 mL) p mL to the bath solution of mo I)
Phosphorous potassium - water intoxication) IJum buffer (
0,05M, pH 7,4,44rnL) and 1 on charcoal
0% palladium (0.60 g) was added. the resulting mixture
40psi. Hydrogenation was performed at 23° C. for 1.25 hours. Take out the organic layer
Extracted with buffer (2×5 mL). bring the water layers together
, filtered with Celite pad, ether (4omr, )
Wash with care to remove traces of organic solvent.
, μm Bondapak C-18 column (2,5X 10
．． 0cm) and eluted the column with water, using a suitable filter.
As a yellowish powder due to freeze-drying of
0.18 fl (64%) of the compound was obtained. 1r(K13r)ν :3700-3100(01
(), 1760aX (C=O of β-lactam), 1595cm-' (carbo
xylate). 'Hmr (B20) δ: 1.21 (3H, d, J=6.
3Hz, CH3CHOH). 2.45 (6H,s, CH3 on pyridinium), 2.
81 (d, J-9, 2Hz, H-4), 2.96 (d,
J=9.2Hz, )-1-4), 3.22(dd, J=
2.6Hz, J=6.2Hz, T-1-6), 3.40
(t, J-6,2Hz, C1hS), 3.84
(d d , J-9,2Hz, J-2,6H2s) I
-5), 4.15 (m, CH3C OH),
4.71(', J=6.2Hz. CfJzN), 8.21(H(,s, pyridinium
Hp ), 8.46(2)(, S, pyridinium
Ho), Uv(B20)λmax=279(
68345), 296(ε7714)m, (α]o +
40.7(C0,53,T(20), tl =16.9
h (measured under condition A). Example 3 Zinio)ethylcothio)-6-(1-(R)-hydroxy
Chetrifluoromethanesulfonic vinegar (1,327 mL,
0.015 m01) to a drop of 3-pyridine methanol (
2,9], m L zo, 030m01), and the following
to ethylene sulfide (0.89 mL, 0.015 mo
l) was added. The resulting homogeneous mixture was incubated for 20 hours under N250
Heated to -70°C (oil bath). The reaction mixture was then diluted with water (1
5 mL) and extracted with CH2Cl2 (5 x 5 mL).
I put it out. The aqueous phase was concentrated in vacuo and applied to a C18 reverse phase column. I4 zOg4 was eluted, and the relevant fractions were evaporated to a pale color.
A yellow oil was obtained. This material should be chromatographed again.
After drying in vacuum (P2O3), an almost colorless oil was obtained.
(4,5 tl, 94%) obtained as 75-11 thick oil
It was. ir (film) ν 3450 (S, 0) 1), 2
560 (W. mix' 3J () cm-1; ') (m r (d6-aceto
) δ: 9.10-8.05 (m. 4H, aromatic), 5.01 (t, J = 5.5H1
, 2T, I, N-CH2). 4.93 (S, 2H, -CH20H), 4.4.3 (b
rs, IH, -0H). 3.43-3.18 (m, 2H, 8-CH2), 2.3
4-2.10 (m, IH. s■q). Phosphate
)-hydroxyethyl)-3,7-thioxo-1-aza
Bicyclo[3,2,0)-hebutane-2-carboxylene
(0,174 F. 0.50 mm0]) in 2 mL of anhydrous acetonitrile.
The solution was diisopropylethylamine (0
,096mL. 0.55 mm Ol) It's okay. Next Nijifeni
(0.114 mL, 0.55 mmo
1) was added dropwise and the reaction was stirred at 0°C for 30 minutes. Next, 3-hydroxymethyl-1-(2-mercaptoethyl
) Pyridinium trifluoromethanesulfonate (0
, 223 g, Q, 7Qmmo I) of acetonitrile
(0.50 mL) solution was further diisopropylethyl alcohol.
Min (0.122 mL, 070 mmol) was added. anti
The reaction mixture was kept at 0°C for 30 minutes and then concentrated in vacuo to remove the remaining
Add yellow gum to I20 (sufficient alcohol to help dissolve the gum).
Setonitrile was added. This solution
was used on a Cl11 reverse phase column and the column was washed with 15% acetate.
Elution was performed with Nitrile-I20. Freezing of related fractions
The product (0,305,9°81%) was converted into a base by drying.
It is advantageous as a yellow solid. 1r(KBr)ν :3420(1)r,
OH), 1775 (β-aX lactam Co), 1695 (-CO2PNB)
CM-';'Hmr (d6-acetone), δ: 9
．． 44-7.72 (m, 8I-1, aromatic). 7.22-6.91 (m, ], CD(, diphenyl
Phosph x-)). 5.53, 5.27 (ABQ, J=14T-1z, 2H
, benzyl), 5.04 (t, J=7.4Hz, 2H,
N-Cl 2), 4.75 (s, 2H. CH2011), 4.5-3.1. (m, 8H), 1.
21(d, J=6.3Hz, 3H, C1'(Me, ).C0(5dan, 6dan)-3((2-(3-hydroxymethyl
p-nitrobenzyl 2-ene-2-carboxylate (5 cold, 6 days)-3-(:2-(3
-hydroxymethylpyridinio)ethylthio)-6-(
1-(R)-hydroxyethyl]-7-oxo-1-a
Zabicyclo [3゜2.0)-hept-2-ene-2-ka
Ruboxylate diphenyl phosphate (0,145g
+0.194 mmol) of 1120 containing 10
Add 6.0 mL of photo7.7x to mL of THI” solution.
Buffer (0.05M, pi-1,7,4), 0.1
45.9 10% palladium (charcoal) and 10 mL of
- added. The mixture was hydrogenated at 40 psi for 1 hour (
Par r ) l, then pi with celite pad
. Wash the fitter cake with Ensign's H2O and ether.
, the aqueous phase was separated and extracted with ether (3x). Cool the aqueous solution to 0°C and add p11 to pH 7.4 buffer.
7.0 Toshida. After removing the remaining volatile components in vacuo, C18
A reverse phase column was used and the column was eluted with water. Relationship 7
Freeze-drying of lactone gives the product as a pale yellow solid (36
~, 51%) was obtained, and further purification by reverse phase HPLC yielded a solid.
A pure product (31, m9.41%) was obtained. 1r (KBr) '3300 (br, OH
), 1755 (β-maX' lactam Co), 1590 (-C02-'')z-
';'Hnmr (D20) δ: 8.78-7.9
4 (m, 4H, aromatic), 4.83 (t, ,
T=6.0) (Z.2H,N-CH2), 4. ．． 83(S, 2T(, Cl4
20f(), 4.16(d of q, J=J'=6.2H2
, IH, H-1'), 3.98 (d, t, J-9,1
Hz, , J' = 2.6Hz, 11
-1, Tl-5), 3.75-3.20
(m. 3H), 3.20-2.65 (m, 2H), 1.22 (
d, Yi=6.4Hz. 3H, C1 (Me); UV (I (20) λ: 294
(C761-4). aX 266 (ε6936). nm; tl (pi 7.4, 36.8°C) 14.
, Oh. Example 4 4-pyridinemethano in CN2 C12 of CF3SO30 JOr(!
0 to mol (], 635, 0.015 mol,)
℃ One section of N2 with trifluoromethanesulfone F+'2
<, 1.3271 rrp, 0.015 mol) was added.
4-Pyridine methanol (], 635r,
0.0], 5rnol,) for the time being;
Then, remove the solvent under reduced pressure to obtain an oil. to this oil
Ethylene sulfite (0,891me, 0.015
) was added to form a homogeneous mixture at about 60°C (oil
It was heated for 3 hours...1 in the bath). Pour the reaction mixture into 15 ml of N2
0, and the aqueous solution was purified with CHs CC12 (5X5).
, cleanliness). Isamu, remaining in the air, Kashiwa Yumyo, Jojiden, Suiyu
The solution was applied to a CI8 six-phase column. , solution at HzO,
By evaporating the Wl fraction, oil was obtained, and P in the air was obtained.
The product (4,64 f
, 97%] was obtained. ir (film) νmax: 3455 (s, OH)
, 2565v, SH)m-' : 'Hnmr(C
1,,110)n')δ:9.07.8,],8(A
Bq, J=6.8)]z, 4'H, aromatic], 5.
03 (s, 2N. CH20H), 4.96 (, t, J=6.51-1
7. , 2]-1,N-CH□), 409(br s,
],]H,-0H,3,53,1,(m, 21+
, S-CI-12), 2.25 (br s,
I H, -8l-1). 5ml! p-2L loben in water acetonitrile
Zyl (5R. OS) -6-[], -(]dan]-bitroxyethyl
-3,7-dioxo-1-azabicyclo[3,2,
0]] Pengkun-2-carboxylene (0,341',
], Ommol) was diluted with nitrogen gas at 0°C.
Isopropylethylamine (0,1,91πe. ], 1rnmo]) - oil 1
Phenylchlorophosphate (0,228 nte, ],
1 rnmol) was added. The resulting lion-gold solution
Incubate at 0°C for 40 minutes ['j::lj, stir and incubate. to this solution]
, 4-hydroxymethyl- in mA of acetonitrile
1-(2-mercaptomethyl)pyridinium trifluoro
Lomethane sulpone-1- (0,447 g', 1.4 m
mol) solution of i+isobrobylethyl
Amine (0,1,91i/, 1.1 m+iol)
Additional saw. Aka-nii (IjJ's cam is anti-Jr'r, V17 go
Mo・1 also put out 41+. 20 minutes at 0℃, anti-h1゛
, the mixture was cured 11 times, and 22:9:Qυ1゛ was extracted. Residue
Minimum dipping fl+)7se) 2) Lil 1"20 (1:
1) When i'C is used for LCts pure phase column.
Ta. 25 acetonitrile) l=-N20 solution
Ri, Ryl fraction's meki torture, clean, f.
Hard I^ and (. Te raw J′Jν(lin・(0,353y, section 47)
! 7 et off/(. 1r(1(Br)νmaX: 3240(br, 011
),], 775 (β~lactam CO), 1695
(C07PNB)/M-';'I(nmr(d6
-acetone) δ: 9,24 7.84 (m, 811
．． ”) 7.4-6.9 (m, 10)
I, Jife, := Lusulpo: 71. Phossoate],
5.52.5.54 (ABq, J-], /!H7,2!
", Pencil, ), 5.15-4.1 (m, 4H)
, 4.45-3.05 (, m, 7.8), 1.35 (
d, J-6, 6Hz, 3H, (J4Me). p-nitrobenzyl (5 shaku, 6 to)-3-C2-(4-
ethylthio]-6-41
-(R,)-hydroxyethyl]-7-ogiso], -
Azabicyclo[3,2,0]]hepto-2-en-2-
carboxylate diphenylphosphe) (0,311,
0,465 mrnol) and 10% palladium on charcoal.
(0,3!M) of 117 phosphate buffers (
0.05M, pH 7.4), 5 ml of T H1” and
10- in ether at 40 psi for 125 hours.
Hydrogenated for a while. Apply the mixture to a celite pad.
The aqueous phase was washed with ether (3X) and the pH was adjusted to
, 7, 4 buffer to adjust the pH of the aqueous solution to 7.0.
Adrenal L-/'r. Removal of residual volatile components in vacuum, water dissolution
Liquid IC! There were 8 columns. 2thiacetonitrile H
A yellowish brown solid was obtained by dissolution at 20°C and extraction drying.
Obtained. This material is romatographed again on a C18 reversed phase.
/ Hz O) desired product (0,060f, 36ch)
Obtained as a pale yellow solid. 1r()(Br)νmax=3400(br,OH),
1755 (β-lactam CO), 1590 (-CO2
-)CTn-'; J(,nrnr(D20)δ:
8.73.7.96 (ABq, L-6,8] Jz,
4H, Chikazoku), 4.93 (s, 2H, CI]-z
OH), 4.77 (t, J=6.0Hz. 2)1. N-CH2), 4.15 (q dr J
-J'-6,31 (z, January. H-1',), 3.96 (d of t, J=9.2Hz,
J' = 2.68. z, 1. ) (. H-5), 3.65-3.20 (m, 3H,), 3.1
-3-2.62 (rn, 2H), 1.21 (d,
J-6,3Hz, 3H,C)LMe) : nv(
H2O,) 2maX :295(ε('+880),
256 (ε5595), 224 (ε8111) nm;
t' (pTI7.4.36.8℃) 14.5 h
, lwo' M+r Example 5 Cold 2-methylpyridine (2,17 ml!, 0.022
mo1. ) to Meku77/I, fonic acid (0,65d, 0
．． 010 rno] ) prepared by adding 2-methyl
Viridinium mekun 2, 2-methyl pyridine of sulfonate
Ethylene sulfide (0,655ml!,0
．． 011 mol) at λ/. Place the reaction mixture in a nitrogen atmosphere
Below, it was heated at 55℃ for 21 hours, cooled to 23℃ and poured with water (55℃).
This aqueous solution was diluted with ether (6X 4++
+/ ) [2.
While pulling the pressure, μ-bondapakC-18) Force 7
M(2,5X], O,Om)]JJI/(jlEAL
,*. Elute the column with water and remove 4 of the appropriate outside fractions.
11 2.1:1 (85 section) of title compound suggestion l was obtained by drying.
It was done. Effect (film) νn1aX=2520(s■-1), 1
623 (pyridinium), 1574.1512.148
5.1412.1195 (Sulfone-1゛9.1038
m-','Hmr (DMSO-d60D20)δ
: 2.37 (3H,s, CH3SO3-), 2.
83 (3H.S, CIT3 on pyridinium), 3.09 (2H
, J = 6.9 Hz. C) T2S), 4.71 (2H,,t, J=6.9H
7, CH12N"), 793 (2) 1. m, pyridine
Hm of pyridinium), 8.44 (IH,m, Hm of pyridinium), 8.44 (IH,m,
H, p), 8.89 (LH, m, Ho of pyridinium)
, u v (I420 )λn1aX=266(ε35
50) mμ0 phase 4) NEt(iPr)Z p-nitrobenzyl-6α-[1
-()e)-Hydroxyethyl)-3,7-shiogiso
1-Asahicyclo(3,2,0)butane-2-calpho
Gysylate (0,523 g, 1.50 mmol)
Cold (0°C) acetonitrile (6d) PM with diisofurobi
Ruethylamine (0,314 m/!, 1.80 r
nmo, l) and diphenylchlorophosphate.
(0,373 mA, 1.80 rnmol) was added.
Ta. The reaction mixture was finger pressed at 0°C for 30 min to form 1-(2-
Mercabutethynolly 2-methylpyridinium methane
of sulfonate (0,530?, 2.16 mmol)
in acetonitrile (18rne) solution, then diisopropylene.
Pyrethylamine ((1314mIV, 1.8 mm
o1). The reaction mixture was incubated at 0°C for 1 hour.
Press and rinse with cold (0°C) water (267ml)!! -
bondapak C-18 column (3.5
7. Ocm Tsuki'KZF Ida O25'l= 7 se
) 2) 'J k-75 water and 50 water-acetoni
Elution of the column with Tolyl-50% water yields the Sekipo fraction.
After dry cooking, it becomes a yellowish powder for 1.06S.
'(96% one title compound was obtained. 1r(KBr, lνmax: 3650-3100(
OH), 177° (C-0 of β-lactam), 1695
and 1690 (C=O in PNB), 1.630 (
Pyridinium, ), 1595 (phenyl), 1518
(N'O□), :I-335 (NO2), 890 ty
n-' (NO2), January mr (DIVISO, d
6) δ: 1.15 (3,f(d, -6,1Hz
. Cl-13C]lOH,), 2.87(s, pyridine
Cl-13 on Ni, 3.6-4.4 (2B,,
ITI, )1. -5. CH3Cdan011), 4.
75 (2), Lrn. CF1□N+), 5.37 (center of A-Bq, J=
14Hz, PNB Cl2), 6.5-7.4 (10
H,rn, phenyl), 7.70 (2H,.d,J=8.8Hz,PNB)io),8.0
(2H, m, Hp of pyridinium), 8.24 (2H,
d, J=8.8Hz, Hm of PNB), 8.50
(1) J, m, Hp of pyridinium), 8.95 (]
)Lbrd. :L-6,I I:1. z, pyridinium9. q-1
o ), u v (] I12 ) λn, aX ”265
(ε11.990), 314 (C8020,) ml'
. C1 3 and □ 2 I (:2~nee tree-↓younime?, -7
- E 1η) and W - Ou Issodai 1) -) □ 35
p- in OH Mizotsu/ζtetrahuman I Gofran (34rne)
2-l-obenzyru-3-42-(1-(2-methylpyri)
Zinium))ethylthio]-6α-CI-(R)-hydro
[oxyethyl]-7-oxo-1-asabicyclo(3,
2,0) Hept-2-ene-2-carboxylate diphenate
phenyl phosphate (0,669,0,90 mmol
), ether (34 onions), -basic potassium phosphate
Mu sodium hydroxide buffer (0.15M, 16
．． 5me, pH 7,22) and 10% palladium on charcoal.
(0,66f) was added. The product mixture was heated to 40 psi
, and hydrogenated at 23° C. for 1 hour. Excluding the organic layer,
Extracted with tel. (2x6m) Combine the water layer with Celite.
Passed through a pad for 1-1 hours, washed with ether (40 ml),
Remove traces of organic solvent by vacuuming, and remove μmbond.
One column of apak C-18 (2,5X 10ff+
) 11-i. Column elution with water, suitable for flushing
The title compound is formed as a yellowish powder by drying.
Product o, o9sr (3i%) was obtained. 1r (KBr) νmax: 3650-3100 (OH
), 1755 (β-Rakum C-0), 1630 (Pi
lysinium), 1590 cm-' (carboxylene
], 'H, mr (D20.) δ: 1.20 (3
H, d, ? 6.3Hz, CH3CHO)] ), 2
．． 83 (S, CTJs on pyridinium), 2.7-
3.1 (5H, XH-4, on pyridinium) CH3)
, 3.1. -3.7 (3H, m, CH2S, H-
6), 3.90 (d d, J=9.1.Hz, J
=2.6Hz, H, -5), 3.1 (m. CH3CHOH), 4.78 (t, J=6.2Hz, (
JhN''), 7.8 (2H,m, Hm of pyridinium)
, 8.3 (IH, m, pyridinium up), 8.
65 (IH, 171, Ho of pyridinium), uv (
I(20)λm&x: 268 (ε9.350), 29
6 (ε8840) mμ, [α], +41° (CO, 5,
H20), tt=ls, Qh (measured under condition A) 0 Example 6 3-(2-(1-(4-methylpyridinium))ethyl
Chi-cooled 4-picoline (2,14me, 0.022m
ol) to methanesulfonic acid C0,65me, 0.010
4-picolinium methane prepared by adding mol)
Ethylene sulfate is added to the carving solution in 4-picoline of sulfonate.
Add Fido (0,655 mL O, 011 mol)
Ta. The reaction mixture was stirred at 55°C for 24 hours under nitrogen atmosphere.
, cooled to 23°C and mixed with water (5me) and ether (10ml).
) was diluted with After removing the organic layer, the aqueous layer was diluted with ether (5X
5 m/) to remove traces of ether under reduced pressure.
After that, add a μm Pondapak C-18 column (2.5× 1
0cm) added to ljl. 15 Thiacetonitrile 8
Elution of the column with a mixture of 5 and
Colorless syrup 2.66r (100%)
) occurred. ir (film) νmax: 2500 (SIN)
, 1640 (pyridinium), 1572.1520.1
478.1200 (sulfonate), 1040.833
and 768Crn-', l) 1mr (DMS O-d
6) δ: 231 (3...S, Cout5O3-), 2.6
2(s, CH3 on pyridinium), 2.2-2.9(
4H, SR, CHs on pyridinium), 3.
04 (2H, m, CH2S), 4.68 (2H,
t, two 6.4H, Z, CH2N+), 8.01
(2H, d, J=6.6 Hz+ pyridinium,
Hm), 8.89 (2H,d, ,I-6,6H,z
. Pyridinium HO), u v (H20)λrnax
=256 (ε4100), 221 (ε7544) mμ0 p-) luenesulfonic acid (1,72f, 0.01 m
4-pico into a benzene (6,5+++/) suspension of
Added Rin (1,17 melo, 012 m1) and added
The mixture was poured at 23°C for 30 minutes under a nitrogen atmosphere, and then
Tyrene sulfide (0.65ml1.0.011mol
) and stirred at 75°C for 24 hours. Furthermore, ethylene
Add sulfide (0.65 mJ, 0.011 mol)
Stirring was continued for an additional 24 hours at 75°C. reaction mixture
was cooled to 23°C, water (5rn1.) and ether (8rn1.
Diluted with ml. Take out the aqueous layer and ether (3X8+
Wash with ++I water and remove traces of organic and dissolved materials under 1.7 cm.
and the compound with μ-bondapak C-1,80
Chromatographically fractionated using water as an eluent to produce one-color syrup.
2.945' (90%) of the title compound was obtained. Title (film) shi, aX: 2510 (SH), 16
40 (pyridinium), 1595.1582.1475
．． 1200 (sulfonate), 1031.1010.8
18 cm −', J(rnr (DMSO, d6)
δ: 2.29 (3H4s, CH3 on pyridinium
), 2,61 (s, C)b Ph ), 2.4-2
．． 8 (4f(.SH,CH3P h ), 3.03 (2H,m[:
Produced by the addition of DzO, J=6.4Hz, 3
．． 04], CH2S), 4.68 (2]1.t
. L-6,4Hz, CH2N+), 711.7.49(
4)-1,2d, J=7.9Hz, fx=)b)
, 8.00 (2H, d, J=6.5Hz, Pyrigini
)tm), 8.89 (2H,d, p 6.5
Hz, pyridinium 110), uv(H2O)λma
x: 256 (ε4315), 222 (ε17045
) Fnμ. p-nitrobenzyl 6α-C1,-(R)-hydroxy
ethyl)-3,”/-dioxo-1-asabicyclo(3
,2,0) to butane-2-carboxylate (0,52
The chamber was kept under a nitrogen atmosphere of 2r, 1.5mrrol).
Setonitrile (6 m/cold (0°C) solution, diisopropylene
Pyrethylamine (0,314ml, 1.8mmol
) wo, then diphenylchlorophosphate (0,37
3m1. ．． 1.9 mmol) was added. reaction mixture
After stirring for 45 minutes, 1-(2-mercaptoethyl)-4
-methylpyrinidinium methanesulfone) (0,53
9f, 2.16 mmol) of acetonitrile (1,
8 m/) solution was added dropwise and then diisopropylethylamine
(034J, 1.8 rr+mo 1)
. The reaction mixture was stirred at 0 °C for 1 h and cooled (OC) water (24
1rd2) and 7z-bondapak C-
A mixture of 25 thiacetonitrile and 75 thiacetonitrile in water was poured onto a 113 column (2,5X 8.5α)
(100TnIj), then 50% acetonitrile-50
Dissolve 1iifEt using a mixture of % water (100ml)
, freeze-dried fractions, yellowish powder
A four F compound of 0.9N7 (83 excellent) was obtained. 1r(KBr)νmax: 3700-2800(O
H), 1770 (β-lactam C-0), 1700 (
PNB Nisder's C-〇), 1640 (Pirisicum),
1595 (phenol), 1520 (NOx), 134
0 (2 NOs, -1(NOz) of 890,'I(m
r(DMSO,d6)δ: ],, 16 (3H,d
, Eero, 2Hz. C183C'H,OH), 2.61 (S, pyridine
CH3), 3.1-37 (3H,'m,
H,-6,CH2S), 3.7-4.4 (2H,m
. H-5, CPbCdanOH), 4.79 (2]i(, b
rt, J-6,3Hz. CH2N+), 5.1-7 (d, J=4.9Hz,
0)1. ), 5.37 (A, B C1O center,
J = 14.1H, z, CH2 of PNB), 6
．． 7-7.4 (IOH, m, Funininori, 7.69
(21-1, d, stop y8.8Hz, HO of PNB), 8
．． 00 (2I-(, d, positive-6,5HZ, pyridinium
im), 8.23 (2H, d, length -8,8Hz
, Hm of PNB], 8.92 (2H, d, J=
6.5H7,, pyridinium [o), uv (Hz O
) λmax: 262 (ε10835), 311 (ε
9670) mμ. Elemental analysis two calculated values (C36H36N3
0+oSP・1.5H20): C5684, H5
, 17, N 5.52. S 4.21; Actual value: C
56,89,H5,13,N 5.19. S4
−． 4],. p-Nitrobenzyl 3-C2-(1,-(4-methyl
pyridinium))ethylthio]-6α-(:1-1)-
Hydroxyethyl]-7-oxo-1-asabicyclo(
3,2,0) hept-2-ene-2-carboxylate
diphenylphos-7a) (0,587f, 0.80
Tetrahydrofuran (3 mmo 1 ) containing water
Add ether (30fn, m-based phosphoric acid) to the solution (0me).
Lithium-sodium hydroxide buffer (0,1,5M
, 1/I7 Go, pH, 7, 22 and 10 parts on charcoal.
Radium (0,597) was added. , the resulting mixture
Hydrogenate at 40 pS and 1.23°C for 125 hours. organic
Remove the layer and extract with buffer (2×6 ml). Combine the aqueous extracts, pass through a Celite pad once, and
Clean with 3 x 20 m/liter to remove traces of organic solvent.
Vacuum with a tank pump and add p-bondapak.
Pour into a column of C-18 (2,5X 10tyn) m
. Elution of the column with water and freeze drying of the relevant fractions.
0.136 (49
%) was obtained: 1r(KBr)νmax: 3700-3000(0
) T), 1700 (β-lactam C=0), 1642
(pyridinium), 1592z-” (carboxylene)
),' )1m r (D20 )δ:1.19(
3I (, t, J-6, 3Hz, CH3CHOH), 2.
59 (3H. S, Pyridinium Ten CI-(3), 2.84 (d,
Engineering = 9.1Hz. ■-4), 2.90 (d, length-9, 1Hz, H,-
4), 3.0-3.6 (3H1m, CHz S,
H-6), 3.86 (dd, length-9,1, H, z,
J-2,6Hz. -5), 4.12 (+71.C needle IOH,), 4.
5-4.9 (CH, 2N+・HOD masked)
), 7.80 (2H, d, P6.6Hz. Hm of pyridinium), 8.58 (2H, d, J = 6
．． 6H,z, pyridinium HO), u v (H
20) λ: 256(ε55]0), aX 262(ε5360), 296(ε7050)rn, [
αゎ +208゜(CO, 48, H2O), t+-1
2.8h (measured under condition A). Example 4 - Mercaptopyridine (5,55f, 50.0 mm
ol ;, Aldrich) % abs, Et
OH (50me) melt angle ￥L/ta0 insoluble gun with celite
Then, remove the juice. Heat the juice to redissolve it,
When cooled to about 50°C, methyl iodide A- (3.17 mg, 5
1.0 mmol; Aldrich)
Ta. Shio 5 compound i was cooled and crystallized. One type of parody
6.779 (
26.7 mmol, 1%! rate 53.5'%): lHm r (D20) δ: 2.70 (3H,s
, -8CHs)'lyhi765-7.77 8,
35 8.48 ppm (411, AZBZ type, Rikika
family)TS);1r(Nujol)νmax: 1
615.1585 (aromatic) and 780cIn-';
uv(H,20)λmax: 227(C2,02X
10') and 298 nm (C1,64X104). Conohydrogen iodide N%', m (6,33f 125.Om
Dissolve mol) in water (40-), remove insoluble matter e,
NaOH tablet in P solution of water (10 tnl) θ at 00~5℃
(57) was added, extracted with Et20 (3X25ml),
The aqueous layer was saturated with NaC1.
Clean with line (x2), dry% (Jv+g 5O4)
and evaporated to give 2922 of the Title 1 compound as an oil.
(23.4 mmol) to obtain a total yield (50 h) ζ: 'H-mr (CDC13) δ: 2.48 (3H-
, S, -3CH3) and 7.0:3-7. :1.3-
8.38 8.481') pm (4H, A2B2 type, aromatic
aromatic group-Its); ir (film) ν8.11aX=
1580 and 800cm0* The manufacturing method for this compound is K
ing and Ware, Luli Prefecture Soc, 8
73 (1939), and this document
I was wondering about the method. 4-Methylthiopyridine (2,7!M, 22.Ommo
l) is cooled in an ice bath with methanesulfone W < 0
．． 65mf! , 105 mmol) was added slowly.
. Add ethylene sulfide* (0.66mp,
11.0rnmol, Aldrich) was added,
The mixing tube was heated to 50-60°C for 21 hours. reaction progress
As the line progresses, the solid becomes a solution. After cooling, pour the reaction mixture into water.
Dissolve in (5ml)! SaseEt20 (5X4m/ri/i/
, +1 purification. You are the only one. Pass the water layer with Celite for i/-1
2. Reverse-phase silica gel column chromatography of J' solution
(C18rnicro bondapak 10?)
Therefore, elute with H2O and make a lees and a1om/! each of
Fractions were collected. Combine fractions 2 and 3
and repurified using a reverse phase column. Fraction 2 is viscous
1.258 S' (4,48mrnol) as oil
, yield 426%) to give the title compound: 'Hmr (DMSO-d6.CFT-20) δ: 232
(3H. s, M e S Off' ), 2.72 (3,H,
s, -8M, e), 2.68 (11(. m, SH), 2.9-3.2 (3H, m, -CH2
S-), 4.59 (2■-1°t, J=6.4H
z, -CH2NO), 7.97 (2TL "d"
, positive-7,2Hz2aromatic-H3)26 and 8.72pp
m(2H, “d”・positive −7, 2, +717. aromatic −
H5); 1r (neat) max: 1630.1
200 (br, -8030), 7,85 and 770
cm-'0*iri well 1 was distilled prior to well 1. CO2PNB (5μ) p-nitrobenzyl 3,7-thioxo (6S
)-((IR)-hydroxyethyl]-1-azabicic
(to [3,2,9]]butane-2)-carboxylate
(475■, 1.36 mmol) and diisopropylene
Pyrethylamine (0.24d, 1..4mmol)
of CHsCN (5 ml!) solution at 0° to 5°C.
, diphenylchlorophosphate (0,
29yd, 1.41 mmol) was added. tearful hardware
Finger press for 30 minutes at 0°-5°C. This mixture contains CH3C
4-Methylthio-N-(2-
Mercaptoethyl)pyridinium methanesulfone) (
678, 1.45 mmol; 60% pure] oil
The suspension II compound was then diisopropylethylamine (0,2
4ml1.1.4mmol) was added. Mixture from 00 to
The mixture was stirred at 5° C. for 1 hour. There is a golden tinge to the club activities that add heat.
A sedimentation occurred. Separate this precipitate and add cold CHsCN.
(After washing with 3dJ, a golden-tinged solid of 413■ was obtained.
. This was extracted from 101MeOH (5m6) in I (20).
341ii+ (0,618m
mol, 113 > rate 45.4%) of the title compound
Obtained: mp 118°-120°C; lHmr (DMSO
-d6. CFT-20) δ: ], , 16 (3H, d,
J=6.1Hz, 1'-CN5), 2.72(3H
, s, -8CHs), 3.1-3.7 (5H, m
), 3.7-4.3 (2H, m), 4.71 (2H, t
, J=6−3FIz+ −CHllN”), 5.15
'(IH, d, , Q4.9H, z, OH), 5.2
0-5.35-5.40-5.5! 5 (2H, AB
(1,C02CH,2-Ar), 7.70 (2H,
“d”. J-8,8)iz,=to7x=nil-Ls)
, 7.97 (2)1. d'. J=7.0Hz, pyridinio-)1. s), 8.25
(2H, “d”. J=8.8Hz,=trophenyl-H8), and 8.7
6ppm (2H, “d”, L-7, 1Hz, Pyridine
Nioh-H5); ir(Nujol)νmax
: 3250 (OH), 1775 (β-lactam),
1700 (ester) and 1625 cm −' (pi
uv(abs.EtOH)λ: 308℃m(C4,4'7xi
O');(α11)" 0aX + 24.8 (c O, 5, MeOH); elemental analysis
:Total qsen (C24H26N306 S2 C1・H20
): C50, 56, H4, 95, N 7.
37: Actual value: C50, 63, H4, 72, N689
(5R) p-nitrobenzyl 3-[2-(4-methylthi
e) Ethylthio 1-(6S)-[(IR)-hydroxy
ethyl]-7-oxo-1-azabicyclo[: 3.2
．． 0:) hept-2-ene-2-carboxylate
Lolide (380■, 0,688 mmol,) is T
HF (31,5 m/) and pH 7,40 phosphate
・Buffer (31.5ml: 0.05M Fish
er) and diluted with Et20 (31.5ml). A solution of 10% Pd-C (38079, Engelh
ard) on a parr shaker at 35 psi;
Hydrogenation was carried out manually for 1 hour. Pass the aqueous layer through Celite once.
Remove the catalyst and replace the pad with Ej20 (2X30
-). The aqueous layer was pulled under reduced pressure to remove the organic solvent.
K-i! / phase column chromatography (Cts m
1 cr. bondapak, 13? , Waters , As5o
It was purified by eluting with water. 307
Collect fractions with UV absorption of nm (approximately 1 t),
Freeze-dried as a yellowish powder of 127M (0,3
34 mmol, yield 48.5%) (7) The title compound was obtained.
: lJ(mr(D20.CFT-20)δ: 1.20
(3H,,d, J=6.4)(z, 1'-CH
5), 2.64 (3H,S, -8CH3), 2.81
(2H,m, -8CH2-), 3.19(II-T,
dd, J6. , =6.1Hz, J,, =2.6H
z, 6-H), 3.32 (2H2dd, J=11)iz
, J=5.5'Hz, 4-Hs), 3.92(IH
, dt, J=9.2Hz. J5-6=2.6Hz, 5-H), 4.1 (IH, m
, ], ]'-I-1), 4.61 (2H,t, J=
5.9H7,-CH2N''), 7.70(2H,-d''
. J=7. IHz, aromatic-H8), and 8.40
ppm (2H, -d'. J-7, 1Hz, aromatic -) is ) ; ir (
KBr, Tisf] νmax: a4oo(oH),
1750 (β-lactam). 1630 (pyridinium) and 1590ctn-' (carbohydrate).
uV(H20)λmax: 23
1 (ε9800) and 307 nm (ε25000); I
: α) D + 3.14 (CO, 5° mountain 0). Example 8 Pre-cooled (5°C) 3-methoxypyridine (698■, 6
．． 4nunol) to methanesulfone Wf (0,21
6rrd:, 3.05 mmol) and ethylene sulfur
(019fn/!, 3.2 mmol) was added dropwise.
. The mixture was then heated to 60°C for 18 hours and cooled to 20°C.
Cool 2, dilute with water (10me) and dilute with ether (3X10
ml). The aqueous phase is placed in a high vacuum for 15 minutes using the W1 pump.
It was pulled down and loaded onto a CI8 reverse phase column. title compound with water
The eluted related fractions are combined and evaporated under high vacuum.
The DI desired thiol (6,1,6■, yield 76.3%
) was obtained. i r (CH2C12) νmax: 2550 (W,
SH) and 1620.1600.1585cn1-'
(m, aromatic); IHmr(DMSOd6)δ:
8.90-7.90 (4) L m, C-H), 4.72
(2H, t. J7G, 6Hz, CPhN”), 4.01 (3H
,s, OCH3), 35-3.0 (m, hidden C
H25), 2.66 (IH, dd, J'-9,5Hz
. J = 7.5Hz, SR) and 2.31 p pm (
3H,s, CH3SO3-). -Hydroxyethyl]-7-okine-1-asabicyclo
(3゜□-N----1 Misaki---15□--121
，←−? To, you! - Two ≧ Luck 1 - Hini name Ni B yoi
knee? -Ding-η-Bippy Tsuboto and Fico ±4) Et
N(<)2 02PNB p-nitropencyl 6α-[1'-(1?,)-hydro
xyethyl)-3,7-thioxo-1-asabicyclo-
(3,2,0)-1\butane-2-carboxylene) (
1,04y, 3mmol) of acetonitrile (12rβ
] The cold (0°C) solution was diisopropylethylamine 7 (0
, 63m213.6mmol) and diphenyl
Phosph:r--) (0,75+d, 3.6 mm
ol) was treated with drop force 1 ratio-C and stirred at 0°C for 30 minutes.
Ta. The raw enol phosphate was converted into 1-(2-merca
(butethyl)-3-methoxypyridinium methanesulfonate
Nate (1°14ri, 4.30mrnol) (CH
3CN (7ra/)], diisopropylene
ruethylamine (, 0,63me, 4.30 rnmo
7. Stir for 30 minutes and heat to -10℃ for 30 minutes.
Cooled for a while. Separate the precipitated solid from the mixture and cool it.
Wash with acetonitrile (2 mg), dry, and prepare the title compound.
The product (1,32F, yield 82も) was obtained: 1r(nujol)z+rrlaX: 3320(rn
, OH), 1780°1765(s, β-lactam
C-0), 1700.1695 (m, ester C=0
) and 1520m-”(s, N02); IH,m
r(DMSOd6)δ: 9-01 (,H], b
s, H-3 aromatic), 8.75 (IH, bd, J-5
, 4Hz, 14-6 aromatic], 835-7.95 (
4H, m, H-aromatic), 7.70 (2H, d,
, p7.7Hz, H-aromatic], 5-37 (2H, ce
inter of A13q. Stop-131 (z, CH2PNB), 5°17 (LH
, d, left = 4.9H, z, OR), 4.87 (2H,
t, J=6.3T (Z, CH2N■), 4.35-
3.75 (2H, rn, 1■-5 and H-1'), 4
．． 00 (3H,s, 0CH3), 3.56 (t of
Part, L-6, 3H, Z, CH25), 3.5-3.
20 C3H. m, H-6, H-3) and 1.16 ppm (3H,
ci, J=6.1H,z. CH3CHO). p-Nitrobenzyl 3-[2-(3-methoxy-1-p-
Lysinium chloride]ethylthio]-6α-[1'-
(R)-Hydroxyethyl]-7-oxo-1-asabi
cyclo(3,2,0)-hept-2-ene-2-carbo
Xylate (600T9, ], 12 mmol)
of THF (25 m/liter solution, ether (25 m6.)
and pH 7.4 phosphate or buffer (0.11V
1. , 25 m/! ) in a parr shaker with 10% p
Hydrogenated on d/C(112) for 1 hour at 40 psi.
Ta. Dilute the mixture with ether 7 and harden the aqueous phase = +52
I passed f-1 on "f" paper. Water layer with ether (2X20+
＋jri, evacuated to a vacuum, and transferred to a silica gel reversed phase column.
I poured it. Mix the acetonitrile in Sections 2 and 5 with water.
The compound is eluted. Combine and preserve related fractions
Dry and dry to obtain a yellow solid, h plc and P i'i
! :=L, penemcarboxylate) (150g, 38
%) was obtained. :ir (nujol)shimaX17
50 (S, β-lactam C-0) and 1580>+-'
(s, carboxyv-)):”Hmr(DzO)δ:
8.55-8.30 C2H,m, H,-2,H,
-6 aromatic), 817-7.75 (2H, rn, H-3
, H-4 aromatic), 4.77 (2H, t.
Part 1 of 1,5 (, J = 6.311, z, ) (-1
,' ), 3.97 (3ls, OCH3), 385
．． 382 (2 lines, part of dt, positive -2.6Hz, I-
T, -5 part), 342 (2H, t, tongue = 5.9H
,z, CHz-3), 3.25 (IH, dd., J=6.1Hz, J=2.6Hz, H-6
), 2.99-2.60 (2H. 6, part of H-4) By 1. ．． 20ppm (3■
-Ld, J=6.4Hz, C133):”(H,20
, CO, 05) λmax ”290 (ε10517,
223(ε6643); tl(0,11VIpn
7.4 Phosphate, buffer, 37°C) 20h
Example 3 - Methylthiopyridine (2,00f, 0.016mo
Add 15 lN HCl to a solution of 1) in ether (10 mL).
Add mL and adjust the size of the border. Take out water 441]
- Rinse with 0 mL of ether, then let it emit.
. Talin monolayer hydrochloride in vacuum (P20=,
) to obtain a white P solid.・This solid hydrochloric acid
3-methylthiopyridine (], , 8El, 0.
015rr+ o l ) Fy ethylene sulfide (
Add 0.89rnL, 0.01.5mol, I4 yen etc.
The contaminated compound was heated at 55-65°C (oil bath 9) for 15 hours with N2T.
A cloudy, oily substance was spilled.
, 125mJ, N20 VC and CB'z C1
The aqueous phase precipitated in step 2 was concentrated to 25rnL, and a few drops of acetic acid were added.
Tonitrile was added to make the mixture homogeneous. A (f)
The aqueous solution was added to a C8 reverse phase column. using Hz O
Due to elution and evaporation of related horns, it becomes pale yellow and viscous.
The product (2,66f, 80 cracks) was produced as an oil.
tir(Filri νmax: 2440(br,
SI") cti-':' H, r+m r (d6-
DMSO+D20) δ:8.88-7.88(m,
4H. aromatic], 4.70 (t, J=6.5)Lz, 2H
, N-CH2), 3.08 (skewed t, positive-
6.5Hz, 2H,S-CH2,), 2.64C
s. 3H,S-Me). 1, J, A, 7: oltewiez and
C, N15i, J, Qg, chem. Prepared using the method of Dan A, 76-5 (1969,). 02PNB O2PNB p-2l-lovenzyl (51R,6S)-6-[1-(
R)-hydroxyethyl)-3,7-thioxo-1-a
ZabicycloC3,2,0]butane-2-carboxy
Rate 0.5222,], 50 rnmol,
) solution in aqueous acetonitrile (7 mL) was cooled to 0°C [
, diisopropylethylamine (0,287rn I
J, 1.65 mmol) was added. generate
Tanabe brown solution Nidiphenylchlorosulfonate (0,3
42rnL, 1.65mmn1) - drop to add λ, anti-L''
, the mixture was kept at 0°C for 30 minutes. Then diisopropylene
Ruethylamine (0,313 mL, 80 mr
nol), 3-me fhf) r-1-(2-me
Captoethyl pyridinium chloride (0,398
r,],, 80 mmol) of anhydrous DIVIF (
0.70m1. ) solution was added. Approximately 1 minute after completion of addition 1, precipitate precipitates from reaction mixture 1.
2. Further cooled to 10℃ KIO min 1b1 to form solid oren.
I calmed down the pain in Ji t1. This solid is seven tons) Ij
The mixture was ground with a sieve, and the residue was removed by filtration. This residue
Clean with acetonitrile, then with acetone, and then
Bovine P% (
0,45! M, 55゜) was I14. 4 ina 11 again
'J-1 liquid is irritated to make a yellow oil, and it is
Dissolve in setonitrile and cool at 0°C for 30 minutes to obtain A2. child
Further, 01397 Gu D (・mono
Shaiban 1--4 as a body: fc. Combined income 0.594? (72%). 1r (KBr) maX: 3345 (br, -0H),
1770 (β-lactam CO), 1680 (CO2
PNB )rrn-';')inmr(d,-DM
, SO δ: 8.98-7.96 (m, 4H,
aromatic), 8.20-7.65 (ABQ, J=7.
0Hz, 4H. PNB Aromatic 95.53-4.80 (m, 4H)
, 4.37-3.7 (m, 2H), 3.6-3.25 (
m, 6H), 2.66 (S, 3H, 5-Ivle),
1.16 (d, J-6,0Hz, 3H,CHMe
). [Nio]ethylthio”]-6-[1-1)-hydroxye
Chil]-7-oxo-1-azabicyclo[3,2,0)
Hept-2-ene-2-carboxylate 25m7! Sulfate buffer (0゜05M
, pH 7,4) in p-nitrobenzyl (5I,
6s)-3-[2-(3-methylthiopyridinio)ethyl
ruthio)-6-(1-(R)-hydroxyenal]-7
-oxo-1-azabicycloC3,2,0':lhept
-2-ene-2-carboxylate chloride F (0,5
51? , 1.0 mmol) and 10% parasitic acid on charcoal.
THF (5 ml
) and ether (25m/) to lie/7.・. 40
This mixture ¥/Ij (parr,) for 1 hour at psi
Hydrogenated. 'I'3PS of the reaction η di-compound with Celite
L, filter cake ■ (20 and ether and sweat)
and puζ. The aqueous layer was removed and further poured with ether (3X). in vacuum
Remove the remaining organic solvent by cooling the aqueous solution to 0 °C and saturated N
The pI-1 was adjusted to 70 with aHCO3 aqueous solution. Immediately
solution was applied to a CIR reverse phase column. Elution with H2O
and freeze-drying of related fractions to give a bright yellow solid 0
25g is obtained. This knowledge can be acquired using reverse phase hplc.
η”Jk product (0,2107
, 55 attacks). 1r (KBr) νmaX: 3400 (br, -0H
), 1755 (β-lactam CO), 1590 (CO
2) cm-'; 1)], nmr (D20) δ:
8.60-7.76 (, m, 4 ratio '3': T4'm
: ), 4.76 Ct. J=5.8Hz, 2I(,N'-CH2)) 4.1
3 (qσ)d, J=J'=6.3Hz, 1. H,
H-1'), 3.95 (t dr J=90Hz,
Do-2,8Hz, IJT, H-5), 3.45-
2.75 (m, 51"), 2.59 (s, 3H,
S-Me, ), 1.20 (d, positive = 6.4l-1
z, 3 CBMe); 11 V (H=O)λ
. , ax: 296 (ε8509), 273 (ε1300
5), 231 (ε1.1576) nm: tt(p)17
゜4. knee 36.8°C) 20h. Fruit 1h91j 10 A, 1-(2-mercaptoethyl)-2,6-dimethyl
Pyridinium methanesulfonate 2,6-dimethylpyridine (19.2ml, 0.165
moj) and methanesulfonic acid (3,27T11F, 0
．． 05011101. ) for 15 minutes.
1se, ethylene sulfide (4,1'Inrl, 0.0
70mo1). BS[fi1'il;j bottom,
Finger press at 100°C for 42 hours. After cooling to 25°C, the reaction mixture
The compound was dissolved in ether (45me) and water (,30+nl).
Dilute the two phases and dilute the organic layer with water (2 x 5 m
e) Extracted. Add the aqueous phase and add υ・1 with a Celite-exposed pad.
Washed with ether (2X15y+i) and dissolved in water.
To remove traces of conspiracy, use Shinsai Kai 94 and μ-bon + dap
akC-18 column (3, OX 12cm) J
I poured it into "L". 3 acetonitrile-97 water mixture
Freeze-drying of the solute I #1 [and 2
．． 59 impure Fj + 11 mixtures are served as syrup.
1are phplc (7z-bondapak C
-18) for Koma・jpI+ 0.90ii' (7%)
21 [1 compound was obtained: ir (film) vT
Tlax: 2520 (SI(>, 1640 and1
625 (pyridinium), 1585, 1490, 120
Qz-1 (sh*ne-)), 'Hm r' (D
MSO-d6 + D20) δ: 2.36 (3H,
s, CI-L3SO3-), 4.62 (,2)T,
, m, CH2N”), 7.74 (2)1.,
m, pyridinium)1m), 8.24 (IH,rr
+. Pyridinium 1(p), uv(H2O) rmx:
272 (4080) m 71. Phosphate 4) NEt(1Pr),. p-Nitropencyl 6α-[:1-(R)-hydroxy
ethyl]-3,7-shioquine-1-asabicyclo(3,
2,0)hebutane-2-carboxylate) (0,658
f, acetate kept under a nitrogen atmosphere of 1.89 mmol
Nitrile (6Ml) cold (diimpropyl ether in O1J solution)
Thylamine (0,394mg, 2.26mmol
) and diphenylchlorophosphate) (0,468mC
12.25 mmol) was added. 309 reaction mixture
1-(2-mercaptoethyl)-2,6-
Dimethylpyridinylam methanesulfonate (0,720
? , 2.73 mmol) of acetonyl-lyl (3 m
l) solution, then diisopropylethylamine (0,
394me, 2.26mmol) and Da1. J
Ta. The anti-Li”7 compound was stirred for 2 hours and cooled (
°C) water < 27me) diluted with 7z-bond
pak C-], 8 columns (2,5X 9.Q(:
rn) injected into /ζ. acetonitrile-water mixture
The elution used was 0.0%, and freeze-drying of appropriate fractions gH
(65%) of the title compound was obtained /ζ. 1r(KBr)vrl, 1. :3700-3000(O
H), 1765 (C=0 of β-lactam), 1690 (
PNB ester C=()], 1620 (pyridinium
], 1.590 (phenyl), 1517 (N02), 1
330 (NO2), 880cjn-' (NO2),”
Hmr(DMSO1d6)δ: 1.15 (3H,
d, J=6.2Hz. C CHOH), 2.7-3.7 (1), H, CH2
S, pyridinium (1) 2-(LJ(s, H-4
,H-6), 3.7 4.4 (211,C)L+CH
Oh. ■-5), 4.7 (2H, m, CHzN”), 5
．． 14. (IH, d, , J-4, 5Hz, OH), 5
．． 37 (AB (l center, history - 13,2Hz. PNB CH2), 6.7-7.5 (10H, m
, 7E=L), 75-8.7 (7H, pyridinium
, II' (plural) of PN'B, u v (H
20) Radiation ax: 274 (ε], 415()), 3
19(ε9445)mμO C,3-[2-(1-(2,6-dimethylbiricinium)
)) dried 1 to 1-eiko-2-9/ni ↓ knee η-R
-2 Nisa, -Heewa Seiwa Doo Tenorie p-Nitrobenge
3-C2-(], -(2,6-dimethylviridine)
um))ethylthio]-6α-[1-(It)-hydro
=vdiethyl]-7-oxo-1-arybicyclo(3
,2゜0,) to 7')-2-ene-2-carboxylate
Diphenyl phosphate (0,80?, ],,O
Tetrahydrofura containing water of 07rnrnol)
(42mE) For melting, needle (42rnsu, :”)
1^ Base - Skin intoxication Potassium - Ice 6: Ich sodium bag
Fur (0,15M, pH7,22,2,1tne)
and added 10% palladium (0,8Of) on charcoal.
. The resulting liquid mixture was diluted with Samurai IWl water at 40 psi and 23°C.
+ Gradually add 1 u' to a pot with a Celite pad.
Remove the IJ"・L-1 aqueous layer (extract liquid) and add
(50 rnl) to remove traces of solvus lumps.
Apply vacuum and remove the It-bondapak C-18 cap.
Ram (, 3, OX 10.2)] Injected into 11 and it is 7. Column of 5% acetonitrile-95% water/Irij
Due to the elution and drying of the related fractions, the color becomes yellowish.
The pjl record compound 0.2461i' (63 pieces) was used as a powder.
] was rejected. + r (KB r ) νmax : 3700
280 (1(O)l 3 ,] 750 (β-lac
Tam's C-0), 1.620 (pyridinium), 1.5
85ffi-' (carboxylate), I) (mr(
H20) δ: 1, . 23 (3H, d, J=6.41
1z, (J(sCH-011), 2.5-3.5(]
1) i, H-4, H-6, C■■2S, pyridinium
M + (D 2 CH3,), 3.8”-4,,4 (2H
, CH3cH,OH,H-5), 4.5-4.9 (C
H2N", 'HOD), 7.64 and 7.74
(2H, A sound 1s of A213 thread, Hr of pyridinium
n), 8.07.8.16.818 and 8.27
(I H. A2 B , p) B %j'1. pyridinium
−1p), uv(ToOJ 'rnax ”277(ε
9733), 300 (ε8271) mal, Ca':
] D"3+50.7 (CO, 48, H20), yJ,
e analysis: W(tJ,,4i/j-(C1s H22N2
04 S ・1.5H20,)C55,51,H
647, H7, 19; Actual value: C55, 14,) 1,6
．． 23.1'J6.4fi. Example trifluoromethanesulfonic acid (1,,381rl,0
0]5 mmol) under O'C, N2.
O-1-methylimikudull (4,0?), 0.03
mol) was added to -drops. Next, ethylene sulfide (0.9m!,, 0.015
), and the mixture was heated to 24 Ft under N2.
-' 1 hour at 55°C. Anti-LL, ete the mixture
(3X) and dissolve the residue in acetone, ΔI
and evaporated. This produces the product as a semi-crystalline solid (
4, 2F, 82%] was increased by +4F, making it possible to make it into history.
and decoction (used in the next reaction). ir (film) vmax: 2550 (W, 5h) cr
n-';'Hnmr(d6-acetone) δ: 7.97
(s, 2H), 466 (t, J=7) 1z, 2a
tyrene), 4.17 (s, 3H,, N-Me). 3.20 (d of t, J=7Hz, J'=9Hz, 2B,
methylene), 2.72 (s, 3H, S-Me), 2.2
0(t, J=9Hz, I)L-8H). 1. ilMH according to the following literature: A. Wohl
and W. B, p-nitrobenzyl (5R,6S)-3-['
2-(2p-nitrobenzyl(5R,6-)-6-[
1-(R,)-hydroxyethyl)-3,7-thioxo
-1-azabicyclo[3,2,0]]pentane-2-ka
Ruboxylate 1.4of. 4.0rnmol) of anhydrous acetonitrile c50ml
Add diisopropylethylamine (No. 076, 4) to the solution.
．． 4 mmol) dropwise, then add diphenylchlorophos
Nufa) (0.91me, 4.1mmol) was added.
I got it. N1: After stirring the mixture in both grooves for 1 hour, diimp
Lopylethylamine (0.7rye, 4.4 mmo
l) is added to λ, then 2-methylthio-3-methyl-1-
(2-norcatethyl)imikuzolium trifluoro
Methanesulfone) (2,0?,ri, 9 rnmol
) +7: j acetonitrile s (5mJ) one drop of i solution
added. Place the mixture at 15:00 at a constant temperature (keep N1,
Then, by decompression, we obtained the cam shape and l. This gum personal item 1
)Combed to 120Cts:ig! I got a phase kashikaram. ) hO1 then 20% acetonitrile-water, LH 30%
Elution with acetonitrinode-water, followed by 1 night, 1 message.
・Fraction brew &, v%i・Te pale yellow f2v・1 body
1r (K, Br, l ”max: 338.0 (br
,OH),]-770(β-lactam C0)tyn-'
' Hnmr (d6-7 setone) δ: 8.
35 (br, s + IH) + 824.7
．． 78 (AB q, J=8.81-1.z, 4H
，Yoshi? "li6'), 7.89(br,
s, IT-1), 7.25-6.91 (n]
, 1. OH, diphenyl phosphate), 550
゜5.25 (AB q, J=12Hz, 2H, Benji
Rick], 4.75-4.27 (m, 3FL), 4.
03 (S, 3H, N'-Me), 4. ．． 1.5-
2.75 (m, FH-li, 259 (S, 3■)),
5-IV4e), 1-. 22 (d. J=6.2l-1y, 3B, -CI-IMe
). C, (5R,6K)-3-[2-(2-methylthio-3
-methylimidazolio]ethylthio)-6-[1-(B
)-Hydroxyethyl]-7-Okin-Easabishik
B [3THF (70ml), ether (70me)
D and phosphate buffer (0.05M, pH 7
, 4), p-nitropencil (5dan, 6)
)-3-[2-(2-methylthio-3-methylimida
[zorio]ethylthio)-6-[1-(R)-hydroxy
ethyl]-7-oxo1 asabicyclo[3,2,(1
) hept-2-ene-2-carboxylate diphenyl
Dissolution of phosphate (1,2C1,1,56 mmol)
Add 1.22 of the 10-modulus palladium on the wood M to the liquid.
. This mixture was heated at 35 psi for 55 minutes (parr).
Hydrogenate the mixture, then rinse with a Cely pad.
1fDIL-, filter cake with H20 and ether
It was purified with. The aqueous phase was cooled to νυ, -(: 0°C,
The pH was adjusted to 7.0 with saturated aqueous NaHCOg solution. vacuum
In the middle, the remaining Aurimoto is removed using a C18 reversed-phase column.
added to. H20 and then 8-unit acetonitrile-Hz
Elution with O, lyophilization of relevant fractions
The furnace produced 0.259% solid. This substance/quality is stirrup
hplc Japanese powder, 'crime! Formed as a non-white solid
I picked up the objects (0, 11, 4f, 19ch). jr(KBr)νmax: 3420COH),
1750 (β-lactam co), 1590 (-CO20
) Cm-1; ' Rnmr (DzO) δ7.58 (
s, 2H), 4.52 (t, J-6Hz, 't, H),
4.28-3.82 (m, 2H), 3.90 (s,
3H,NM,e), 3.40-2.87('m,
5H), 2.40(s, 3H, SM, e), 1.
20 (d, !L=6.4Hz, 3I(, -CHMe
); uV (HzO) λmax: 297 (ε7572),
262(ε6259), 222(ε7955)nn]0
1112 Rum chloride 3-aminopyridine (1,50 ri, 0.016rno1
．． ) to 11i methanolic HCI of 15TnC.
5. Let the fermentation proceed as planned, and Halodorochlora
I turned it into an oily substance and ate it. Add 3-7 mins to this oily substance.
Pyridine (1-,321', 0.015 mol) and
Tyrene sulfide (0.89 ml, 0.015 mo
l) and the resulting mixture was heated at 60-65°C (
The mixture was heated to 2mt1111 in an oil bath]. IJF active member
Gotylene sulfide (0,89+++e. 0.015 mo1) is 55-65
65k at °C] Hg Ketao J” = V
2c12 Teipuri, then to R20 (25me)
Kashi, Ta. Apply the aqueous solution to a CI8 reverse phase column, and
It was melted at 20. Sword IP by evaporation of related fractions,
Viscous oil and 1. , raw Luci (1,26f, 44v)
IR (Film) νmax: 3180 (NR2)
Cm-';1)1. nmr(d6-DMSO)δ:
8.19-7.59 Cm, 4H, aromatic,), 4
．． 59 (t, J-6,2Hz, 2H,N-CHz
), 3.5 (br s, 2H, -NR2), 3
．． 20-2.77 (m, 3H). p-Nitropencyl (F5L6-do)-6 at 0°C under N2
-(1-(R)-hydroxyethyl)-37-thioxo
-1-azabicyclo(3,2,0)-hebutane-2-ka
ruboxylate (0,696?, 2.Qmmol)
Rabbit 171t, - drops in a+tonitrile (10ml) solution
Poly1” diisopropylethylamine ((1382me,
2.2rnrnol), then shift x-= )b
Ri o. Phosphe) (0,457ml, 2.2 rnm
ol) was added. After stirring 1+l for 30 minutes at 0℃, 3-A
Mino-1-(2-mercaptoethyl)pyridinium chloride
Ride (o4757.2.5 mmol) anhydrous DM
Ii' (1me) Diisopropylethate following the melting pond
Ruamine (0,435 m#, 2.5 mrnol
) is added. Reaction r1" compound ・O'c 1.5F to 1
After that, the soldiers Pft [7/(.Iυ et al.)]
A+tonitrino=H20C]: Combust to 1.3
, inverse A (add λp i.HzOl to 1 column and then 2()%
acetonitrile]”20 by h”f’:!ts then
[A beige solid is obtained by multiplying 1 fraction by 1 viscous shell.]
Then, the cow rJ(・object(0,73(1,50%)) is
P was received. 1r (KBr) ν: 3330 (br, 01
)1), 3180aX (br, NR2), 1770 (β-lactam co)
, 1690(-C(JzPNH)tyn-';'
Hnmr (d6-DIVl, SO) δ:8.29-
7.63 (m, 8-ajl,), 7.2-6.7
(m, 10H, diphenyl phosphate), 547
．． 5-18 (AB q, Heaven = 14H7,, 2H, Ben
Jirik), 4.73-4.45 (m, 3 ■ j), 4
．． 2-3.8(m, 1)(,), 3.6-2.6(
m, 8H), 1. ．． 15 (d. J=6.2Hz, 3)]', C)(-R11,e
). C, (5F,, 6D)-3-(2-(3-aminopi)
lysinio]ethylthio) -6-(1-(,R)-hydro
(oxyethyl)-phosphate Φ buffer (0,05
#i, p147.4), p-=toro in 20m1
53 6 S ) -3-(2-(3-
aminopyridinio]nigelthio)-6-(]-(]HJ
-Hydroxyethyl-7-oxo-1-azabicyclo(
32,0) Hept-2-ene-2-carboxylate di
Phenyl phosphate (0,730?, 1.0 mmo
l ) and wood's soil's 10-modulus palladium (,0,79)
Shio, compound TI-T, F (8 mA) and ether (
I added 20*/ri. Pour this mixture at 40 psi.
World: (parr) 7! □Nosoe power [1 Sea only 4 To D Shi
4-+,i',%l,fu
Filter cake with T-1, O and ether
? 'f' l, ko water ali ην, then ether
(, 2X) to remove the ti:ti+rm components.
Remove again in vacuo. Immediately transfer the aqueous solution to a C18 reverse phase column
and eluted with H2O. Freezing of relevant fractions
Dry, whiten, and remove the thick solid 0457, and transfer this substance to the reverse phase b.
The desired product (
0,1237, ·35chi,) was obtained. 1r(T(Br) νn,x: 3340(br,)
, 1750 (br. β-lactam co), 1580 (br, -CO20)
crn-';')lnmr(D20)δ: 8.0
7-7.59 (m, 4T-[, aromatic], 4.61
(b, J-58By, 2H, N-CHz), 414 (q
Lvt,, Stop-6,3Hz, LH,H-1,')
, 3.97 (J=9.2Hz. J'=2.6J(z, IH, H-5), 3.38(t,
J=5.8Hz, 2H. S-CH2), 3.24(d of d, Muro, 0I(z,
J-'=2.6Hz. IH, H-6), 3.17-2.57 (m, 2H, H-
4), 1.21. (d. J=6.3.T-Tz, 3I on CHMe
) ; uv(H2O) λ1TlaX :
299 (ε7949), 256 (ε8822)
nm; t+/2 (pJ(,7,4°368°C)18
．． 5h0 Example 13 and methanesulfonic acid (1,95td, 0.030mol)
of cold pyridine (7,83 m/!, 0.097
mol) and the resulting mixture was heated at 40°C for 15 min.
Push, dt-propylene sulfide (2,59+n
/! , 0.033 mol) under a nitrogen atmosphere.
It was pressed at 60°C for 90 hours. Pyridine is removed under Makabe.
and the residue was mixed with water] chromatography (hplc
. Made in Japan based on Prep, 13ondapak C-18)
did. The Kaburakiri fractions were combined and freeze-dried to obtain a non-e1
Cl-1-(2-mercapto-2-methy) as syrup
Ruethylpyridinium methanesulfonez, :zr(
15%) , :ir (film) νmaX:
2520 (SH), 1640 (pyridinium), 118
0 (s, Cl1l'SO3-), 1040<CHs
SOs-)cm-', J(mr (DMSOd6)
δ: 1.35 (d, , L-6,8)iz, 3H,
CH3CH3), 2.30(S, 3)LCH3SO3
-), 2.90 (d, , L-8,5Hz, IH, SH
), 3.2-3.7(m, C7(SH), 4.52
(d d, J, rn= ], 2.9Hz, J=8
．． 4) 1z, CHCH2N+),'+87 (dd,
Jgem-12,9Hz, J=6.0)T,z,
CTIC Dan, N+), 8.0-8.4 (m, 2H,
Pyridinium H, m), s, s-s, s(m, 1.
H, , Hp of pyridinilla A), 904 (dd, , J-
1,4'f(z, J=6.7Hz, 2H, pyridine
) (0), 11 V (,O20)λmax:
208 (ε5267), 259 (ε3338), elemental content
Analysis: Meter I1r1 (C9HI5NO3S2・2 O20
):C37,88,)■ 671-1 N
4. ．． 91, S22.47; Actual 11th investigation:
C37,49, H685, N486, S22.0
9 and dt-1--(2-mercapto-1-methyl
Ethyl pyridinium methanesulfonate 0.822 (
11%, l (also colorless syrup and 1-5) ;ir (film) νmax: 2500 (SH
), 1628 (pyridinium), 1180 (sulfone
), 1035 (sulfonate) L:Ty+-', 1
Hmr(D, MSOd6) δ: 1-, 69(d, J=6
．． 8Hz, 3H, CH3CHN"), 2.31. (s
, 3H. CO3S 03-), 3.0-3.3 (m, 2
a C)llz S), 4.2-5.2 (m. 1, H, CHN), 8.0-8.4 (m, 2
H, pyridinium Hm), 8.5-8.8 (rn,
LH, pyridinium H, p, ), 9.0-9.2
(m, 2H. Pyridinium Ho), uv(O20)λ□ax:2
09 (ε4987), 258 (ε3838). elemental analysis
: Total q value (C9Hl s NO3S2・1.5H20,
): C39,11, H656, N507; Actual value
:C39,3, H-5,92, N520 was obtained. 4) NEt(iPr),. (5th day, 6th day) Valanitrobenzyl 6-[1-(μ9-
hydroxyethyl]-3,7-thioxo-1-azabisi
Chlo(3,2,0)hebutane-2-carpooxylate
(0,523F, 1.5 mmol) under nitrogen atmosphere
Into the cooled (Oc) solution of acetonitrile (6rn),
Diimpropylethylamine (0,314me11.8
rnrnol), then Schifeniruko. Phosphate (0,373m7!, 1.8rnmol
) and press the reaction mixture for 30 minutes, d, a-
1-(2-mercapto-2-methylethyl)pyridinium
Mumethane sulfonate (0,539, 2.1 F+
mrnol) in acetonitrile (2 m solution and di-
Propylethylamine (0,314,ml!, 1.8
rnrno1. ) was processed. The reaction mixture was heated at 0°C for 1
Question p21 Stir and lf with cold (0℃) water (24,+nl)
+i interpretation j54, Prcp BondapakC-],
8 color A (2.5X 8.5ah) top, 25~5
Water containing 0% NOA (Tonitosu A) was used as a melting agent.
Chromatographic fractionation 2, ridge drying 1.071 (97 cases)
The combination compound was obtained as a yellowish powder: 1r(K13r) Syn1aX:3700-3100(
OH), 177° (c = o of β-lactam), 1
965 (PNB:r-SternoC=0), 1.63
0 (pyridinium), 1590 (phenyl), 151
8 (N02), 1348 (NO2), 885 (NO2)
crn-',',)(mr(DMSOd6
) δ: 1.14 (d, J=6.1Hz
, 3B. CI-T, CHO),]-,33(d, , J=6.3
)1. z, 3H, CHsCH8), 4.6-5.0
Cm, CH2N'', >, 5.14 (d, two 5.
2) (Z, LH. OH), 5.37 (ABQO Center, J=12.
4.7(, z, 2H. P N P, σ) (j(2), 6.6-7.5 (
m, 10H, phenyl of phosphate), 7.69
(d, , p 8. July z, 2H, HO of PNB
), 8.0-8.4. (m, 4H, H of PNB,
rn, Hm of pyridinium), 8.4-8.8 (m,
1) Hp of L pyridinium), 9.08 (d, J=5
．． 6Hz, 2H), u, v (, H20) λmax:
263 (ε13325), 308 (ε8915.). Former
Elementary analysis 2 appearance, value (CaaH3aN30toSP・Real 3
ipii'n: C57,76, H, 4,96, N
5.36, S4.35゜(3,2,0)hept-
2-ene-2-carboxylate THF, ether, no
Kutufur (5R,6S) Valanitrobenzyl 3-(1-(R,S
) Methyl-2-(1-pyridinium]ethylthio)-6
-(1-(R)-hydroxyethyl]-7-oxo-1
-Asabicyclo(3,2,0)hept-2-ene-2-
Carboxylate diphenyl phosphate (0°60
, 0.82rnmol) of tetrahydro
Furan (33π) solution to ether (33rn, -base)
Potassium acid-sodium hydroxide buffer (17
is 12.0.15N, pH 7,22)F) on charcoal
Add 10% palladium (0,6(1) λ, the resulting mixture
The material was hydrogenated at 4 Q psi and 23°C. 2 W minutes
Then, the Arimatsu layer was extracted with water (3×7πl). (With drawing WW
) Combine with the water layer and filter with a Celite pad 1.
Prep, Bonda
pak C-18 column (2,5X 9.5m) with water
Chromatographic fractionation using 7 as eluent, 0.189<63%
)(7)') Asteres isomer mixture was obtained. two shi
The asteres isomer was determined by hplc (Prep, Bond
apak C-18), using water as the eluent.
Isomer with tension time, 0.061' (23 chi)
], Compound “′B-ir(KBr)νmax: 1
770 (β-lactam C=O), 1633 (pyridinyl
um], 1593 (carboxylate) on-”,
'Hmr(D20)δ: 1.20 (d, J=6.
3H-z. 3H, CHsCH, O), 1.42 (d, J=6.9
Hz, 3FI, CH3CHOS), 2.3-3.2
(m, 3H, H-4, H-6), 3.5-3.9(
rn, IH. 5CH), 3.9-4.2(m, 2H, H-5, CH3
CHO), 4.3-'1('', C)T2N), 7.
8-8.2 (m, 2H, Hm of pyridinium), 8
．． 4-8.7 (rn, IH, Hp of pyridium), 8
．． 7-9.0(m, 2B, T(o) of pyridium
, u v (H20) λmax ”260 (ε6727
), 300 (ε8245); [α) D-39,3° (c
, H2O), L+ =]2.6h (e constant under condition A):
0081 is an isomer with a high retention time.
f (28%), compound “A”, ir(KBr)vmaX:1755 (β-lactam
C=O), 1630 (pyridinium), 1590 (cal
boxylate]cm-','l(mr (D20
) δ: 1.18 (d, ,]”=6.3Hz. 3H, CHsCHO), ], , 40 (d, J=7.
0Hz, 3H,C)13cH3), 2.84(d,
Fire = 9.3Hz, 2 liters H-4), 3.26 (dd, Jx
2.7Hz, J=5.9Hz, IH, H-6), 3.4
-4.2 (m, 3B. 5CT (, CH3C engineering jO, H-5), 4.2-5.1
(m, CH2N+), 7.7 8.1. (m,
2 H, Hm of pyridinium), 8.3-8.65 (m
, H], pyridinium (7)HT)), 8.65-8
．． 9(m, 2H, 11O of pyridinium), u v
(H20) λrnax ” “”” (ε5694), 2
96 (ε6936), [α]. +969°(c O,
56, H20), upper = 15.6 h (measured under condition A)
[Definition] and Puhi. Example chloro(3,2,0)hept-2-ene-2-carboxy
Production of methanesulfonic acid [0.65m/! ,Q,Q1mo],
) while cooling one drop of viridine (2,42p, 0.0
3 mol). The Wei-compound is heated to zero p of nitrogen (1 under 1 atmosphere).
Finger press for 0 minutes, stop 4-cyclohexene sulfite [1,
Treated with 37'1 (85% pure bar(), 0.0102 mol)
7. Pressed at 729°C for 25 hours.
was removed under vacuum and the traces were azeotroped with water. Pickled outside
4 combination, prep, Bondapak C-18 car
Tracing the ram (5 x 13 cm), add 7.0 to 2 t of acetonite.
Chromatographic fractionation using water containing lye as an eluent, followed by sparging drying.
After that, I served 1.57r (53chi) of Hachiai syrup. ir (film) νmax: 2500 (SH),
1625 (pyridinium), 1190 (SO3-), l
Hmr (DMSOd6)δ: 1.2-2.5f:m
, 8)1. Cyclohexyl 11), 2.32 (s
, 3H,CH3SO:, -), 2.82 (d,
9.811z, SH), 3.0-3.5(m, l)
T, CIjS)I,), 4.2-4.9(m, IT
t CHN+), 8.0-8.3 (m, 2 H,,
Pyridinium Hm, l, 8.4-8.8 (m. LH, pyridinium) Tp), 8.9-9.3 (m
, 2H, 1(o) of pyridinium, uv(xo)λ
ma,”tc: 214 (ε5365.), 258
(ε3500). Elemental analysis two-word calculation value (Cl2HI9N
(as J3 S2/H20): C46,88,i(,
6,88, H4,56; Real 611! Value: C46,61,
H646, N465゜1) NEt(j,Pr)2 4) N, E:t(1Pr)z (5R,68) paranitrobene kept in nitrogen atmosphere [11
Zyl-6-[,1-(IN)-hydroxyethyl)-3,
7-thioquino 1-azabicyclo(3,2,0) to pig
ion-2-carboxylate (], , 31F, 3.93
mrnol ) of cold (OC) acetonylyl (1,5ie
) solution with diimpropylethylamine (0,822 m7
! , 4.7rnmol) and diphenylchlorophosph
ate (0,979 g, 4 mmol) was added. profit
The resulting mixture was stirred for 30 minutes and dt-(2-mercap
tho-1-cyclohegycyl pyridinium methanesulfone
Acetate (1,641i', 5,66 mmol)
Dilute with tonitrile (4.7 mL), then diisopropylene
Luetinoamine (0,822m/!, 4.7mmo)
, ). The reaction mixture was stirred with IWH for 1 hour at 0°C.
, diluted with cold (o'c) water (175 m/liter)
, l3ondapak C-18, 25-50ch
Chromatographic fractionation using water containing acetonitrile as an aging agent
and lyophilization of the appropriate fraction, 1.92 (53%
) was obtained. ir (K B r ) νrrxax: 3700
300 o (oH), 177 ° (C-
0), 17oo (PNB ester c-〇), 1628
(pyridinium), 1590 (phenyl), 1515 (
N02), 1345 (NO2), 880 (NO2)
cm −', “Hmr (D20) δ: 1.13 (
d, J=6.1. Hz, 3H. C3cHo), 1.2-2.5(m, 8H, Schifo
hexyl H), 2.7-3.5 (m, 4H, H-4
, H6, CH3), 3.5-4.4 (m. 2H, CH3C Dan0.H-5), 4.4-5.0 (rn
, LH, CHN+), 5.30 (ABq+7) center
-, J712.8Hz, PNB CH2), 6.7-
7.4 (, m, 10 H, phenyl), 7.65
(d, tongue-8,61-1,z, 2H, H of PNB,
o), 7.9S8.4(rn, 4H, Hm of PNB,
Pyridinium I], m), 8.4. −8.8 (r
n, IH, Hp of pyridinium), 9.0-9.4
(rn, 2H, pyridinium Ho), uv(H
, zO) λmax: 263 (ε9038.
), 309 (ε6394). Elemental analysis two tears first - (X', (C39H4ON3010
SP-H20 Toshite): C59,16,I]-5,35
, H5, 31; Actual 4111 value: C58, 95, H5
, 1, 5, N 5.57°C, (5R, 6 days) - 342-4 (minor or days) - (1~
pyridinium) ) -1-(tz or S)-cyclohe
xylthio] -6-(1,-(dust)-hydroxyethyl
]-7-Ogiso 1-Azabicyclo f 3.2.0
) hept-2-ene-2-carboxylate oH (5R, 6 bath) paranitrobenzyl 3-r 2-C
(R or dan)-(1-pyridinium)]-1-white also d
s)-cyclohexylthio] 6-CI-(1(
)-Hydroxyenal]-7-oxo-1-azahishik
B (3,2,0) hept-2~en-2-force/L, bogi
Sylate Cyphenyl Phosphate (1,857,2,:
Tetrahydrof containing 34 +nno l) of water
Run (96ml) FD solution was added with ether (96ml/liter, -
Basic 47'! 'ciX' Notunorium - Water... Prisoner Hina
Thorium buffer (0,15M. p117.22.50me) and 1() on charcoal
Si (1,9/) was added. The borrowed mixture was heated to 23℃
, 4 Q psi for 125 hours. organic layer
Take it out and extract it with water (3 x 20 ml). water bath liquid
Filter with Celite pad, ether (-(2X60m)
l) and 4°j, 9 to remove traces of organic solvent.
To @ Prcp, Hondapak C-18 car
O-5 acetonitrile on a ram (4.5x9cm)
Dissolve water containing
0.7C15 after drying? Diastereoisomerism of (section 76)
A mixture of bodies was obtained. 1ffdhp for diastereopathic salary
tc (Prep, Bondapak C-18)
1/4% acedonitrile water was used as a separation medium,
Diastereoisomers, compounds with low retention times
“A”, (0,:297.31 article), 1r (KBr
) si1nax=1750 (C=O of β-sikucum), 1
620 (sh, viridinilla 1.), 1685 (cal
boxylate) On',' Hm r (1)20)
δ: ], 21 (d, J=6.3Hz, 3
H, Cl5CHO), 1.4. -2.5 (m, 8
ti, cyclohexyzbJ]), 2.5-3.0
5 (m, 2H, H-4), 3. (15-3, 25
(+n, l H, H-6), 3.3-3.7 (m,
]-H, Cll5), 39-43(m, 2
Hr upper knee 5. CJ (3CHO), 4.3
-4.8 (m, CHN+), 7.8-8.2 (r
n, 2H, Hm of pyridinium), 8.3 8.7
(n+. I J (, Hp of pyridinium), 8.8-9.1 (
+n, 2t1. Pyridinium Ho), uv(
H2O) λmax: 260 (ε7123), 3
00 (ε8685), [:co) tongue 3+6. z°(c
(1, ('i :3. I(20), 1+-=
　　　　　　　　　　　　　　　　　　　　　　　　　
216.6 h (side door with % note A), elemental analysis: calculation
Value: (C2Q Hz4N204S”2HzO)
: C56,59,H(5,65,N6.60.S
7.55; (P=36!'I11+'j:C56,8
3, Hti, 47. N6.59. S7.43
;1・Diastereoisomerism with small retention time 1
/to, compound" 13 'Infection035?, 38%
) 1r (KBr), n3x: 175Q (β-Rak)
C-0), 1622 (sh, pyridinium)
, 1588 (carboxy l--1·) tllJ',
'J-1Jnr (D20) June 9 (d, J=
1), 4fKz, 3N, CfL+CI(O),]
,,3-2.5(+n, 81-7゜cyclohexy/
L H, ), 2.5-3.1 (m, 2H, H-4
), 3.1-3.3 (In, LH, It-6), 3
．． 3-:S, 8 (m, 28. 11-5.C
1 (S), 41 (center of m, 11-1; C1
13CI(O), 4.25-4.7 (+n, I
H. CHN), 7.8 8.1 (m, 2Ll,
Of pyridinium! IIn), 83-3.7 (m,
l H, pyridinium H-p), 875 9o (I
rl, 2H+pyridinium 11o), 11V
(1-120)λmax” 259 (ε5992
), 23°296 (ε7646), Ice, +65.3° (c O
,43,J■20),t I=20.2 It (floor
12 itL/ζ for the measurement run at the bottom A. Fruitfulness term) Column 15 A, (51 allyl 3-[(2-pyridinioethyl)thio
]-(6S)-4(IR)-hydroxyethyl]-7~
Oxo-1-azabicyclo(3,2,0)hept-2-
En-2-carboxylate diphenyl phosphate (
5R)7') A 3,7-shioki/-(6S)-[
(IR)-hydroxyethyl]-1-azabicyclo[3
20] to] butane-2R)-carboxylate (473
Tng, 187+rrnol) (7) CH3CN (
6me) Add diiso to the m solution at about -J, 0℃, under 4 turns of air.
Propyl A ethylamine (0.42rnl, 2.4m
mol) Wow, then diphenyl chlorophosphate
(0,50m6.2.4 +nrno l) was added
. The mixture was stirred at OC for 30 min and cooled to -15 °C.
. To this, 5 drops of I) CH3CN (] scraps containing MF
N-(2-mercap'toethyl)pyridinium in l)
Chloride (527, :3.00
An oily suspension of diisopropylethylamine (
0.42ml. 2,4 +nmol) was added. Heat the mixture to -15℃
Stir for 30 min and dilute with H2O (20 me).
. This mixture was directly transferred to reverse phase silicage/L (C+s P
repPAK, 12? , WatersAss
ociates)-hi, Fh'O(200+++
(! ), 10%CH3CN/1129 (10om
e, ), 20%CH3CN/i+20 (100me)
1.30% CH3CN/! 1zO (100m1.)
f, then 4o staff c1] 3CN/H20 (100me
) was smelted and refined. Collect appropriate fractions
The organic solvent is removed using a vacuum pump, and the brown color is removed by cooling and drying.
786 m' as a solid powder? (1,26 mnol,
The title compound was obtained with a yield of 673%: 'Hm r (
DMS O-d6. CFT-20) δ: 1. ．． 16
(3H, d, Yi = 6 Hz, 1' CH3), 2.
6 3.7 (ml 3.75 4.3 (2H, m, 5
-Hand l'-H), 4.65 (2H, m, -C
O2CH2), 4.87 (2H,t, J =611z
, -C1h-N), 5-6.2 (3H,m,
Olefin rJ Nitroton, 6.6. 7.4 (
m, aromatic proton), 8.1512H, "Bi, Tsu':
:7 Hz, aromatic proton meta to nitrogen), 8.63
(I 11゜"t"t"7) (Z, 'Book element
rose aromatic protons) and9.07ppmr
211. "d", , J near) 1z, '斥;k
ortho (Dl'i'j aromatic proton); ir (film
) ν: 3400 (OH), 177° (β-lactam
), 1690 (ester), 1625'f pyridinio)
. B, (5 times)-3-[(2-pyridinioethyl)thio
]--1-7 Zabisik OC, '3.2.0) Hep)
・-2-jC>-2-carboxylate (5R) allyl 3-C(2-pyridinioethyl)thio]
-(6dan)-[(]几、)-hydroxyethyl]-7-
Oxo-1-azabicyclo[3,2,01hept-2-
En-2-carboxylate diphenylpos-7ate (
156+'lf, 0.25+nnol) CH3CN
(2ml) m solution, add potassium one after another at about 22℃.
2-ethylhexanoate (0.5M, 0.6ml
; 0.3tnno I) of EtOAci, night, avian
Hue=/L boss fin (151”!, 0.057
+rnnol) and tetrakistriphenylphosphine
Palladium (15mf, 0.013+n+nol)
〃[1. The mixture was heated to about 22°C under a nitrogen atmosphere for 2 hours.
Stirred. After addition of anhydrous Et20 (7me), the precipitate was
Separately, wash with anhydrous 1'; j 2 Q (7me).
was dried in vacuo to obtain a brownish solid with a size of 101"17. This was subjected to reverse phase column chromatography (C]8Prep
PAK, 12g, W; tiers As5o
diluted with H2O and purified.
did. appropriate fractions (fractions 7-12, each
20me) - looked up and dried 53T'? (0,
16n-+no I, aggregation:p, 64. % ) title
The compound was obtained as a yellowish powder. This Q is
f contains potash A 2-ethylhexanoate.
'Hmr(D20.CF'l''-20)δ:0.
80 (t, J=6.4Hz, ethylhexanoate
Me), 1.21 (3,F[,d, J
=6.3Hz, 1. '-^4e), 2. '13
(2H, dd. J r -5-9Hz+ J gem"" 4 Hz+
1-HS), 3.28 (II→, rld. J, :6.21TZ, J, 5:25Hz, 6-II)
, 3.42 (:2+-1,t. ,!-61]z, -C■■2S), 3.98 (Hl,
td, J5. =9Hz. Mu 〇=2.5Hz, 5-H), 4.15 (1LL,
q, two 6.2H, z. 1'-H), 4.80 (211,t, J==6.
0Hz, -CHzN+), 7-7.5tm,
phenyl proton from diphenyl phosphate),
8.03 (2J-(, m, Hen of pyridinium)
, 8.56 (L H,rn, I- of pyridinium
fp) and 8.81 T)pm (2N, “d”
, ,T:6.5)iz. Pyridinium l1o). Tengun Example 16 3-C2-(N-methyl-thiomorpholinium)ethyl
ruthio)-60-C12-(dan)-hydroxyethyl]
-7-okine-1-azabicyclo[3,2,O]hept
-2-ene-2-carboxylate production A, N-methyl-N-(2-mercaptoethyl)thi
Omorpholinium methanesulfonate precooled (water bath) N-methylthiomorpholine (50%
07,42゜7+n+nol) and methanesulfone t
MA' (1,47me. 20,5 +ryno l) and ethylene suf L fi
Add (1,,30me, 21.41rlnol),
I got it. The mixture was heated to 65°C for 24 hours and water (25ml
) was diluted with Water-soluble i < da in diethyl ether (3X2
After washing at 5 m/liter and vacuuming, apply a silica gel reverse phase filter.
Pour the irradiated compound into a ram and mix it with water! #Kiseta. I
The thiol fractions are combined and evaporated to form an oil.
Obtained as a product (4,8 (1, yield: 86); ir (film), 11ax: 2550m-' (
W, SH); 'Hmr(1)MSOd6)δ:3
．． 25 2.95 (6H, m, CI (2N0), 33
2 (311, S, CHaN■), 3,20 2.6
5 (71 (, III, CH,, S. 814) and 232 p p"' (3H+ s r
CH35O3). Rice J, M, ], e11n and J, Vyla.
gner, Tetrahedron. 2(i, 4227 (1970) B, paranitrobenzyl 3-42-(N-methyl-thio
Morphonylium diphenino

[,phosphate)ethelthio]-6o-C1,'-(group)-hydroxyethyl]
-7-oxo17sahishi o [,:(,2,0]
]Hepto-2-2-2-carpogysylate)EtNr-()20-valanitrobenzyl-60-[i'-1t)-hydroxyether) -:3.7-Cioquine-1-azabicyclo[320)hebutane-2 -carboxylate (557”
fz 1.60rn+no! ) of CH3CN (g
ml) cold (water bath) solution to diisopropylethylamine (0,336me, 1.92+n+no+)
and diphenylchlorophosphate (0,400 ml,
1.92 +rwnol) was applied to the -drop. The reaction mixture was converted into N-methyl-N-(2-mercaptoethyl)thiomorpholinium methanesulfonyl 11893'f, 2
．． 29+n+nol) of CH3CN (4ml)
Solvent and diisopropylethylamine (0,336
1.92 rrwnol) and stirred for 30 minutes. The solution was diluted with water (<2 ome) and loaded onto a silica gel reverse phase column. When the desired product was produced, the proboscis was stirred with a 50% acetonitrile-water mixture. The relevant fractions were combined, pumped under vacuum for 2 hours and lyophilized to give the irradiated compound N, 01ii', yield 85%). 1rlnojol) shi,,,x: 1760(s,
β-Rakum C20) and i, 51.0cnT' (
s, NO2) : 'I(mr (DMSO-d6
) δ: 8.25 (2J1. (1, J=8.811Z
, H-aromatic), 7.70 (2H. d, , J:8.8Hz, Jl-aromatic, ah
), 7.33-t84. (1]1], m
. moon-aromatic), 5.37 (2H, AB q center, J = 1.4.21-f z. cI-r2), 5.1.4 (1, fl d,
J-4,5Hz, OH), 4. ．． 35 3.8
0(21(,m, H,-1' and H-5), 4,75
3. /1.5 (6H, m. CH2N"),'+3]]13H,S,
Cll3N+), 345-2.75 < 9
H. m, C) hs, H-6 and H-4) and 1.15
p pm (3H, d. J −=ri 21T z, C) (3). [3,2,0]-]
1-Bodo2-ene-2-kaGoxyle 1 0OP(0φ)2 1] OH 1)-nitrohenzyl 3-[2-(N~methyl-thiol erphorinium diphenylphosphate) ethylthio]-60 -[1'-113)-hydroxyethinoυ]~
7-ogine-1-azabicyclo[:32.0]hept-
2-ene-2-carboxylate (1,31#,],
]76 nnno l) Nori, 1. M pH7
,/l bosphate buffer (48.8ml), tetrahydrofuran (207ml) and diethyl ether + (20ml) dissolved in Parr4H'A
10% pd/C (], 5 F) in the chamber, 40 ps
1 ft in i! jji11 lj<originalization/ko. The reaction mixture was diluted with diethyl ether (401n/l).
The two phases were separated. Combine the organic phase with water (2X5+++g)
Extracted with. Combine the aqueous phases and count on #52 hardened p paper,
Wash with diethyl ether (2 x 20 ml) and evacuate. 71"("Pour the f4 solution into the silica gel reverse phase column", 5
The desired carbapenem was purified with acetonitrile-water. The appropriate fractions were combined and frozen.
and as an amorphous solid the title compound proboscis (2057〃'!, 3
1%); 1r(nujol)ν two 1750(s+ β−
lactam C=O)2X and] 590H' Is, C-0); 'Hm
r (D20) δ: 4.25-3.95 (21-11
, 1-1', 5), 3,70 3.4
0<6H,rn. CJT2N ), 'U35 (I H, dd, positive = 5
．． l HZ, , L=2. f'iHz, 1(-6)
,3.08 (3!(,S, (':ll3N''-),
3.25-2.75 (81-1°CH, zS, lI
-4), and 1.24 ppm (3H, d, J=6.4
．． Iiz. CH3): uv (+-f20.c O,06
2) λ+o;]x a 299 (ε10°962)t
r 17.7h (0,], M pH7 phosphate Hanwha. 37°C). Example 17 (5 ships, 6 days) -3-[211-methylmorpholino)ethylthio]-6-C(R-) -, l-hydroquinethyl J-7~oxo-1-azabicyclo[, 2o] Production of hept-2-ene-2-carboxylate A, 1-methyl-1-(2-mercaptoethyl)morpholinium trifluoromethanesulfonate □ Me C,F3SO30
N-methylmorporin (3,29rrri, 0.03
0nDl) at 10°C.
) Wo, Tweet: L Chi'ly > Sulfite (0
,89m/! , O,O], 5 mol) was added. The resulting yellow-brown solution was heated to 50-60 °C (oil bath) under N2 for 18
heated for an hour. The volatile substances were then removed in vacuo and the remaining oil was removed to 10ml! I dissolved it in water. The aqueous solution was washed with diethyl ether (:3X5me) and residual organic solvent was removed in vacuo. The resulting aqueous solution was applied to a CI8 reverse phase column and flushed with N20, then 5% acetonitrile-water, and finally 1# of acetonitrile-water. Evaporation of the relevant fractions gives a white solid,
This was dried in vacuum (P2O3) to produce the product N, 92ii'
, 41 Section) was 1(I). 1r(KBr) ν :2560(5H)an
-';'Hnrnr (d6naX -acetone) δ: 4.25 3.6 (rn, 8H)
, 3.49 (s, 3H, N-Me), 3,35
2.7 (m, 5H). B, p-nitrobenzyl (5R,68)-3-C2
-(1-methylmorphoυ))ethylthio]-6-((R
)-1-hydroxyethyl loaf-oxo-1-azabicyclodi320] hept-2-ene-2-carboxylate diphenyl phosphate OH p-nitrobenzyl (5R,6ren)-6-C (shaku)-1
M't' in anhydrous acetonitrile (25 ml) fdgll of -hydroxyethyl,]-]3,7-thioquino-1-azabicyclo3.2.0)hebutane-2-carboxylate (0,3482,1,0+nno l) Noisobrobylethylamine (0,191ml!, ]711 to j
Opening 101) 'x, then dinoenylchlorophosphate
1-(0,228 rM, ], 1.11111101
) was added at 0°C under N2. 1 i-tl for 1 hour at 0°C
After stirring, diimbrobylethinoamine (0,226 ml, 1
．． 3+nnol), then ]-methyl-1-(2-
morpholinium trifluoromethane sulfuric acid (0,373?, 1,2111
TnOI) was added. The reaction mixture was stirred at room temperature for 15 hours, then concentrated in vacuo. The remaining material was purged with N20 and used on a CI8 reverse phase column. N20, then 20% acetonitrile-N20, and finally 30 strips of acetonitrile-H
F5 separation using zO, the product (0,3607,40
%) is good! Slaughtered. 1r (7 ()) 3300 (OH), 1.770 (
β-lactam CO),],'7(10(-COzPNB
) cnT';'Hnmr (d6-acetone) δ
:8.25.7.80 (ABq, J-=8.6H2,4
H, % aromatics), 7.4 6.8 (m, , I Of
(, nophenyl phosphate), 556.527 (ΔB
(+, J = 14.2l-IZ, 21-1.benzilic), 442 (1 of (1, J-9, 2HZ,
J-27HZl] I-1+ Il-5), 41-
2.7 (m, L 7H), (,40(s, 3
'H,N-Me), 1.22 ((+. J=62Hz, ,H(,-CIIVle). 1-azabicyclo[3,:2.
methylmorpholino)ethylthio)-6-[(R)-1-
Hydroxyenal]-7-oxo-1-azabicyclo[
320] to 7' t-2-ene-2-carboxylate diphenyl phosphate (0,360ii', 0.49
+1nol) 13m1! (7) Phosphate buffer IO, 05M p147.4) Charcoal in solution”
Two 10% palladium (0.36N), tetrahydrofuran (20m/liter) and diethyl ether (20mJ) were added. The mixture was heated with 32r) Si for 1 hour and hydrogenated (
Parr)l, ta. The mixture was filtered through Celite and the filter pad was washed with Ii20 and diethyl ether. Take out the aqueous phase and separate p
Add H7,4 phosphate buffer to pH 7.
．． I set it to 0. After removing the remaining organic beacon medium in vacuo, the aqueous solution was
8 reversed phase column. Elution with 11.20 and lyophilization of the relevant fractions gave an amorphous solid of 0.1302. This material was purified by reverse phase HPLC to give the pure product (0
,058f/,34chi) was obtained. 1r(KBr)ν ”3420(1)r,0)1)0
)1), 1750 (β-τnax @ lactam CO), 1590 (-CO2)/7n, H
nmr (D20) δ: 4.35 2.77 (m, 17H
), :3. l8(S, 31-1.N-Me), 1.23
(d, , J, 3I-Iz, 3H, CHMe)
;u v N(20)λ1naX:300(ε634
4) Old net (pH 7, 4, 36, 8℃) 18.5
h. Example 18 (5R, fi di)-3-4z-(1,4-thumenal-1
-piperazinium)ethylthio)-6-41-(R)-
hydroxyethyl]-7-okine-1~azabicyclo[
J, 2. Q) Production of hept-2-ene-2-carboxylate Δ 1-(2-acetylthioethyl)-1
, 2-furomoethelthiol aceate on 4-dimethyl f2.20? ,0,012 mol) and J,4-
Acetone (4me) solution of dimethylpiperane (1,95ml!.0.014mol)
The mixture was stirred at ℃ for 65 hours. After cooling to 25° C., the liquid phase was decanted and the gummy “material” was triturated twice in diethyl ether to give 3.2 f (9
0%); ir (Nujol)ν1113X
: i 685 (C=O of thioester) crn;
'I1mr (D20) fj: 2.37.2
．． 39 (2s, 61-T, CH, 3CO. US H, Hansen, Acta Chetn, 5ca
nd, '11, 537-40 (1957) Radinium bromide hydrochloride ■-(2-acetylthioethyl)-1,4-dimethylpiperazinium puromy 1-(llj',: 3.711T11(+ 1
A solution of 6NI (4 mt') of ) was heated to 80° C. for 1 hour under a nitrogen atmosphere. The fd liquid was concentrated under reduced pressure to obtain a white powder, 0.41f (38%); elemental analysis: total n value (CB112ON2SBrCI ・H, 20 -
): C31,03, H716, N9.05, 5103
5; Actual $1111 shift: C: 31.62. H7,46,N
9. ] 9. S], 0.19°C, (5+, 6S) p'nitro\endyl3-[2-(]-,]4-dimethyl-1-piperazinium-ethylthio)-6-C,l
-(tt)~hydroxyethyl]-7-oxo-1-
Azabicyclo(32,0)hept-2-ene-2-carboxylate diphenyl phosphate 4) (5R,6S) paranitrobenzyl 6-[1-(R) -hydroxyethyl] -3,7
-thioxo 1-azabicyclo[;u2.0]hebutane-2-(17)-carpogysilane 1- (0,4657
,]−,]33 mmol) of acetonitrile (2 m
diisopropylethylamine (0°C) in a cold (0°C) solution.
, 278me1L59mmol) and Schiff1=/l chlorophosphe-I (0.33ml, 1.59mr
nol) was added. The reaction mixture was stirred for 30 min at 41 ml and dissolved in acetonitrile (3 m6)-1 in water (3 ml).
,4-dimethyl-1-(z-mercaptoethyl)piperazinium bromide hydrochloride (0,402,
],, ]37 mrnol) of ``i shu liquid and diisopropylethylamine (0,27Fh+Ie, 1
．． 59 mmol). After stirring for 18 hours at 5° C., L1] of cold water (15 rnfi) was added to the mixture. (4
PrepPak -500/C+s (
WatersAssociates ) column (2,5
Using water containing 25-35 m of acetonitrile (f), water containing 25-35 m of acetonitrile was chromatographed as a solvent, and after drying, a yellowish powder of 0.507 m (50 m) was obtained.
%) is good! 1r(K, Br) ν : ], 765 (C=O of β-lactam), 11]; lX 16904 C=O of PNB ester, I-5135 (
phenyl), 1512 (NO2), 875 (NO2
) cm, 'Hmr (DMSO, d6) δ:
1.16, 1.18 (2d, J=6.1Hz,
: U1.1. C13CHOH), fez, PH
10 CH2), 6.5-7.4 (m, IOH, phenyl of phosphate), 7.71. (d, J=8.8
11z, 2H, PNB Ho), 8.26 (d, J=
8.811z, Hm of PNB). D, (5dan, 6to)-34J2-H,,4-dimethyl-
1-piperazinium)ethylthio: ] -6-CI -
(R)-Hydroxyethyl]-7-ogyne-1-azabicyclo[3,20)hept-2-ene-2-carboxylate f5R,68) Valanitrobenzyl 3-C2-
(t,4-dimethyl-1-piperazinium)ethylthio)-6-[i-(It)-hydroxyethyl]-7-
Oxo-1-azabicyclo[320]hept-2-ene-2-carpogysylate diphenyl phosphate (0,
Tetrahydrofuran (25J) containing 47f, 0.623 mmol) I? 1 Solution: diethyl ether (25 Biao), -basic potassium phosphate-water sodium 11ide φ buffer (13ml 1% pH 7,22'
) and Palladium 10 on charcoal (0.47F) were added. The resulting mixed proboscis was hydrogenated at 23° C. and 40 pSi for 1 hour. Separate the two layers, add the sweetfish to the water (
Extract with 2x sifter. Combine the aqueous phases and add Cef-fl
... pass through σ-j with pat, diethyl ether f2X15
q+f) tearai/? )l, Pr(!pPak-5(10
/C+8(W;]tersΔ5sociates) column (2,5X 9.5nn) with water t fN i (
RII(,l, Totori o Madmin/J'l +,/,
71 + divination r: beg jH% f&, raw IJ again 1zo, o
97 y (4: U) is (earthed; 1r (KBr)), 2x: 3000-3700 (OH
), 1750 (β-lactam c=o), 1585f carpoxylate t·)o++. Jlmr (D20) δ: 1.24 (d, J
=6.4Hz, 31(, (J13CH-OJ(),
40-4.5 (m, Jl-5, CH3CHOH),
uv(J-120)λInaX”296(5°1476
)・['l]! 2.611(C(126・11・0
)・t±=12.411 (11 constant under condition A). Actual h'l'j Example 19 f 5R,68)-3[2(N-methyl-thiomorpholinium oxide)ethylthio]-6-C] (le)
-Hydrogyethyl]-7-Ogyso 1-'Azabinculo(3,2,0)-hept-2-ethyl-2-carboxylate (5th, 6th) 3-[2(N-methyl Naomorporinium)ethylthio]-6-Ci -
(+t)-human komagiethyl]-7-oxo-1-azabinculo(nee3.2.0)-hebdo-2-ene-
2-carboxylate (60 Bm'j. 1, 65 mmol) was mixed with 1:1 ml of acetate (9 ml) cold (-10°C) t#;
ll'i- to In-chlorohyperactivity, Kekatq2 (:<
34.81117, ], (55 m+nol) was added over 1 hour, and then the mixture was diluted with water (15 m+nol).
e), diethyl ether (: xl, 5+hl
Deko/f Toshita. The aqueous phase was pumped through a reverse phase silica gel column (120 ml) to obtain a solid consisting of a mixture of compounds. This mixture was separated by reverse-phase HPLC; fraction A was 52.4 THg (
fraction B2: 3.6”!?(
6% yield) as the diastereomer of the title compound; Fraction A: jr(nujol),,ax:
1750 (s. β-lactam C=0); lnd 1580cin (
s, C=0):'Hmr(I)20)δ: 426-
291 (20tl, m, H-4,l-1-5,j
T-6, H1, CH25, CH25O, (:113 N
'starvation CH,N) and 1.24 ppm (311,
d, J=6.1-Iz, CH3); uv(H2O. co, Q5)λn13x: 302 (C1042
5) ;L top: t2h (o, o6sM, pH 7,4 phosphate-1...buffer, 37°C). fraction 1
3:1r(nujol)shi,,1ax:1750(s
, β-Raku, :, C=0 and 1585nI+' (s
, C=0): 'Htnr (I)2o)δ:
3.862.90 (17H, m, H-4, H-5,
H-6, H-1', CH25, CIh5-Q, CH
,2N+), 3.25 (3,14,s, CH,3
N+) and 12/Ir)l)In(3H,d, J=
6.4Hz, CI(3); IIV(820,C0
,05)λ1o3x:299(C65]7):
Soil: I -]-piperazinium)ethylthio] -6-C+
+t-hydroxyethyl]-7-oxo-1-azabinclo(rs20) 1-(2-acetylthioethyl)-1,
,4-dimethylpiperaziniumpromyl' (1,4
8′? ,5. Q mmol);
) and heated to 5560°C for 30 hours. The solvate was evaporated under reduced pressure, the residue was triturated in hexane and the solid was separated from E. 1857 This solid was dissolved in hot water (8 mJ) (a
M! and 4 il with acetone until cloudy (7080rnf).
I interpreted it. A normal compound of 157, melting point 220-5℃ (dec, ), 68φ was obtained by crystallizing 11Jpi twice twice; 1r (KBr door: 1692cm (D==0
): '1(Inray (H20)δ: 2.40 (S, ,3I-],
CH3COO), :(,371s, N-CH3), 3
．． 39 (s, N-Cab), 3.99 (s);
u v (1120)λ1nax=226(εJ31
44). Elemental analysis: 17th? :nrj (C++Hz
<N20SBrI):C30,08,I(5,51,
N6.38; Actual value: C30,48, H5,53,
N 6.86゜1-(2-acetylthioethyl) -1
, 4,4-1-rimetherbiperazinium bromide iodite (1,84f, /1.19mmol) and 61
1:#,;+i? < 1 s m 7 ml of 7 ml was heated at 57°C under nitrogen atmosphere for 25 h. This (j4
The residue was concentrated to dryness under reduced pressure. The solid was suspended in water (10 m/m) and stirred well, and the mixture was treated with Palmchit S-1c7- until Sok I11 was obtained. The solution was poured into a column (J2 x 60/7 nm) of S-ICt-.The column was ionized with water (-, 5 ml!/gate). white powder, 0.939.1 go 1 (point 19 (+-191'C1
Obtained 85%; i r (nujol) ν+r+a
x: 246o (s n ); 'Yu nr (Dz
O) δ::U4 (s, N-C,!(3),:',4
5fS, N-CH5), 4.07(S). Elemental analysis:, τ1&? Door L (C9H22N2SC12
・0.751420): C39,3/I, H
8,62,N10.20', Sl 1.67
; Real 11 River I Nao': C: 39.48. H8,39
, Ni1), 55. S i 1.15°C, (5R,
6S) Valanitrobenzyl: 3-1:2-(1,4゜4
-trimethyl-1-piperazinium)-ethylthio]-
6-(IR-hydroxyethyl)-7-oxo-1-
Azahicyclo [I 320 ]] heptoh-2-en-2
-carboxy 1/tobischloride (5+t, 6s) balanitrobenzyl 6- [1,R-hydroxyethyl:] -:<, kept under nitrogen atmosphere
]7-thioxo-1-azabicyclo3.2.0)butane-21-carboxylate (0,941,2,7r
nmol) of acetonitrile (3me) (5°C)
Add diisopropylethylamine (0,557r) to #j solution.
rre, 3.2+nmol) and diphenylchlorophosphel. white), 663m/! , 3.2 mmol)/
The ζo reaction mixture was stirred at 5°C for 30 minutes and diisopropylethylamine (0,599me, 44
+nmol) and 1-(2-mercaptoethyl)
-1,/1.4-trimethylpiperazinium binuchloride (0907,: 44 rnmol) in water (4 m
l) Treated with MK. After 1.25 hours, diisopropylethylamine (0.1 me, 0.57 mmol)
was added and stirring continued for 2 hours. Some of the acetonitrile was removed under reduced pressure and the resulting red mixture was washed with a PrepPak
-500/C+g (Water As5ociate
s) Chromatographic fractionation on a column with water containing 25-75% acetonitrile as R4 separation 4'j* and lyophilization to give a yellowish powder (1,4y). This powder is soaked in water and applied to a column of S-ICI-.
, 2X580n) with water as the eluent. A powder of 1172 was obtained by freeze-drying the appropriate fraction, which was re-purified with a column of PrepPak-500/Cu, and a yellowish powder of 0802 (53φ) was obtained by freeze-drying of the 4S fraction. : +r(KBr)ν :3400(br,011),]
, 770 (C-0 of β11aX-lactam), 1690 (C-0 of PNB ester
20), 1605 (aromatic), 151.5 (NO2)
, 1345 (NO2)cm ;' )-1m r
(D20) δ: 1.26 (d, J=6.31
1 z, 3H, CH3CHOH), 3.39 (s
, NCH3), 4. Q 0(s), 5.37(br,
s, CH2 of PNB), 7.60 (d, J=8.6
Hz, 2H, PNB IO), 8.20 (d, J=8
．． 7Hz, 21-1. PNB Hm) ; u v
(H20) λ1r1aX: 276 (ε12094), 3
06 (ε10752). Elemental analysis: Calculated value (C25H36N406 SCI2・
:31-I20 as 7):C46,51,H6,56
, N86B, S/197. C110,98; Actual value:
C46, 31, Hfi, 18. N8.57. C5
,36゜cl 1], 37゜1), (51t, 6S) 3 [2-(1,
,4,4-trimethino-1-piperazinium)ethylthio]-6-41R-hydroxyethyl]-7-oxo-1-azabicyclo(3,2,0)hef-1-2-ene-2-carboxylate chloride (5I, 6S) Valanitrobenzyl 3-C2-(1,4,4-trimethyl-1-piperazinium)ethylthio]-6-[11t
-Hydroxyethyl]-7-oxo-1-azabicyclo(3,2,0)hept-2-ene-2-carboxylate hischloride (0,4OS', 0.68 mmol
), bosphate buffer (30ml, 0.0
5M, pH 7,0), tetrahydrofuran from
6) A mixture of ether (3 omes) and 10 palladium (o, 1 oy) on charcoal was hydrogenated at 23° C. and 35 pSi for 1 hour. The two phases were separated and the active phase was mixed with water (10 m
j). The aqueous phase was passed through a Celite pad, washed with ether (10+7 ml), concentrated to lQm6 and purified with water on a PrePak-5 (t./C18 column (2,2 x 11 cTn) for tN
After chromatographic fractionation as a +rf rs agent and freeze-drying,
70m! 17 (25%); ] r (K B r
) νo1a x : 3400 (1) r,
On), 11755 (β-lactam C-0), 15
85 (carboxylate)m;')Irnr
(H20) δ: 1.24 (3H, d,
, J=6.3)1z, CH3Cl-1011),
3.36 (s, NCH3), 398 (s) *
uV (+-I20)λ:296Y1aX (C7987); CO]o 359(c, 030
1 H20), tge<), 8h (measured with Sakae i'l''A)
. Procedural amendment harm (method) May 10, 1980 Commissioner of the Japan Patent Office Kazuo Wakasugi II Relation to the amendment case 6. Contents of amendments The specification has been rewritten as shown in the attached sheet.However, there are no amendments to the contents.

Claims (1)

[Claims] 1. Formula, where R8 is hydrogen, and R1 is hydrogen; having a substituent or having no substituent: alkyl,
Alkenyl and alkyl moieties have 1-10 carbon atoms; cycloalkyl has 3-6 carbon atoms and alkyl moieties have 1-6 carbon atoms; phenyl; aryl moieties have 1-10 carbon atoms; The aliphatic moiety is aralkyl, aralkenyl and aralkynyl having 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, one molecule for hetero in the above hetero apical moiety is 1
- selected from the group consisting of 4 oxygens, nitrogens or mints; Substituted substances directly related to the above-mentioned groups are: Cs Ce alkyl-〇R3 1 -OCNR3R4 1 -CNR3R'-NR3R' which may be slightly substituted with amine, halo, hydroxy or carboxyl; 302 NR3R' 0 -NH convex NR"R' R3 and NR4- C02R" 100-0 (5R' SR3 ○SR9 SR9 CN N3 10503R3 -O802R3 NR,3802R'-NR39=NR" 3 NR" C02R 'NO2; in relation to the substituents mentioned above, radicals R3 and R4 are independently hydrogen; alkyl, alkenyl and alkynyl, having 1-10 carbon atoms; cycloalkyl; , cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety; phenyl;
The alkyl portion is phenyl and the aliphatic portion is 1-
aralkyl, aralkenyl and aralkenyl having 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and hheterocyclylalkyl, the heteroatoms in the above heteromoieties being] -4 oxygen, nitrogen or yellow atoms; The alkyl moiety selected from the group consisting of and attached to the heterocyclic moiety has 1-6 carbon atoms; or R3 and R4 are at least one of the nitrogens with which it is associated (which together with the atoms may form a 5- or 6-membered nitrogen-containing heterocycle; or R1 and R8 together represent C2CIO alkyritene or C2Cl0 hydroxy-substituted alkylidene;
A is cyclobenzene, cyclohexylene or 11iCz
C6 alkylene (one or more ct -C4
(optionally substituted with an alkyl group); R2 is hydrogen, an anionic charge, or a conventional easily removable carbonyl protecting group (if R2 is hydrogen or a protective group, a counteranion is also present); ); R14 is a quaternized nitrogen-containing aromatic or non-aromatic heterocycle bonded to A via its ring nitrogen, thereby forming a quaternary ammonium group; or a carbapenem derivative thereof; In a pharmaceutically acceptable manufacturing method, the formula (wherein R1 and R8 are the same as in the definition of Kita,
is a common easily removable carboxyl anchoring group,
L is the usual Sugamaei) intermediate of the formula % formula % (where 1, A and R14 are as defined above, Xo
is a counter anion) with a C thiol compound in an inert solvent in the presence of a base, and the formula (where R1, R8, R", A, R14 and producing a carbapenem product of
and carbapenem derivatives or pharmaceutically acceptable compounds thereof, characterized in that the carboxyl retaining group is removed as desired to obtain a compound of formula (1) from which the corresponding retaining group is removed, or a pharmaceutically acceptable derivative thereof. A method of manufacturing a pot. 2. The base is a non-nucleophilic tertiary amine or
C<) The method described in Section 1 of the Eclipse 4 of the city report, which is an alkylamine. 3. The method according to claim 2, wherein the base is a non-nucleophilic tertiary amine. 4. The method according to claim 1.2 or 3, wherein the reaction is carried out at a temperature from -15°C to room temperature. 5. Process Q6 according to claim 4m, in which the reaction is carried out at a temperature of about -15°C to +15°C and ambient humidity; the inert solvent is acetonitrile, a mixture of acetonitrile;
A method according to any of claims 1.2.3.4 or 5, wherein the method is selected from the group consisting of dimethylformamide, tetrahydrofuran, a mixture of tetrahydrofuran and water, acetonitrile and a mixture of water and acetone. . 7. Formula % Formula % However, A is cyclopentylene, cyclohexylene or R
"R12 1 C-C- 1 R"R"' (wherein R101R11, R12 and R13 are independently hydrogen or C1-C4 alkyl), is an xQ anion, and R'4 is It has at least one nitrogen atom in the ring and has a substituent which is bonded to A via ring penetration and in this case forms a quaternary ammonium group or has a member-converting substituent. In the method for producing a quaternary amine thiol compound of the formula (however, R101R11%
R12 and Iya13 are each independently hydrogen or CI
sulfide of C4 alkyl) with a strong acid and the following (
Either a) or (b); however, it contains at least one nitrogen in the ring that can be combined, has a substituent, or has a substituent). , B or a polycyclic aromatic heterocyclic group],
mono-, di- or poly-substituents containing at least one nitrogen atom in the ring and bonded to the carbon atom of substituent A, with or without substituents. Represents a cyclic non-aromatic heterocyclic group, and R'' is (a) aliphatic, cyphroariphatic, cycloaliphatic, aryl, ararifatic, hetero which may have a substituent. aryl, heteroararifatic, heterocyclyl or heterocyclyl aliphatic group, or divalent phenylene or Cs C4 alkylene group; Manufacturing method. 8. The method according to claim 7, wherein the reaction is carried out at a temperature in the range of about -20°C to about 100°C. methanesulfonic acid, p
-) The method according to item 7 or 8 of the conventional method, which is luenesulfonic acid or trifluoromethanesulfonic acid. 10 non-polar organic solvent, preferably methylene chloride,
The method according to item 7 of the scope of Zhaoqiu, wherein the reaction is carried out in the presence of benzene, xylene or toluene. 11. When the amine and sulfide reagent are liquid, or when the amine reagent is solid and the sulfide reagent is liquid, and the solid amine is soluble in the liquid sulfide reagent, addition of the sulfide
The method according to Isuwaka of claim 7.8.9 or 10, wherein the reaction is carried out without. Formula 12, where A is cyclobenzene, cyclohexylene or bar C-C-I R''R13 [wherein Rlo, R'', R12 and R13 are each independently hydrogen or CI C4 alkyl]; , X(E) is a counter anion, containing at least one nitrogen (atom) in the ring R
mono-, bi-, polycyclic aromatic or non-aromatic heterocyclic radicals, with or without substituents, which form a quaternary ammonium ring with A quaternary amine thiol compound representing;