JPH0471913B2 - - Google Patents

Description

[Detailed description of the invention] The present invention provides 1-carbapene useful as an antibiotic.
To the manufacturing method of mu and its pharmaceutically acceptable salts
related. The compound is generally represented by the following structural formula:
You can: In the formula, R⁶and R⁷is hydrogen, unsubstituted hydrocarbon group
and substituted with hydroxy (optionally protected)
independently selected from the group consisting of hydrocarbon groups,
and R⁸is hydrogen; substituted and unsubstituted carbon number 1-
Up to 10 alkyls, alkenyls, alkynyls
Group; the number of carbon atoms in the cycloalkyl ring is up to 3-6
Cycloar whose alkyl moiety has 1 to 6 carbon atoms
alkyl, cycloalkylalkyl, alkylcyclo
Loalkyl group; aryl group such as phenyl group;
The aryl group is phenyl and the number of carbon atoms in the aliphatic part
is up to 1 to 6 aralkyl, aralkenyl, aralkyl,
Ralkynyl group; heteroaryl, heteroaralky
heterocyclyl, heterocyclylalkyl group
[However, one or more of the above-mentioned residues
The substituents above are −X⁰ Halo (chloro, bromo, fluoro) −R¹ -OH Hydroxy −OR¹ alkoxy, aryloxy [Formula] Carbamoyloxy [Formula] Carbamoyl −NR¹R² amino −NH₂ −NHR¹ [Formula] Amidino -SO₂NR¹R² Sulfonamide [Formula] Ureido [Formula] Amide −CO₂H carboxy −CO₂R¹ carboxylate [Formula] Asil [Formula] Acyloxy −SH Mercapto [Formula] Alkyl and arylsulfinyl [Formula] Alkyl and arylsulfonyl −CN Cyano −N₃ Azide −NO₂ − N (R¹)₃ 【formula】 −SR¹; (However, the above R⁸Residue R with respect to the above substituents¹
and R²is hydrogen, alkyl having 1 to 10 carbon atoms,
alkenyl, alkynyl group; cycloalkyl ring
The number of carbon atoms is up to 3-6, and the number of carbon atoms in the alkyl part is
1-6 cycloalkyl, cycloalkyl
Alkyl, alkylcycloalkyl group; phenyl
Aryl group like group; aryl group is phenyl group
and the number of carbon atoms in the aliphatic part is from 1 to 6.
Ralkyl, aralkenyl, aralkynyl group;
loaryl, heteroaralkyl, heterocyclyl
(independently selected from
select independently from the group consisting of] select independently from the group consisting of
, provided that one or more of the above-mentioned heterocyclyl moieties
The more complex atoms are up to 1-4 oxygen, nitrogen
selected from the group consisting of sulfur, sulfur, and the heterocyclic
The number of carbon atoms in the alkyl moiety bonded to the le moiety is 1-6
up to 1. The compound produced by the method of the present invention can be further
In the formula (): [In the formula, X' is oxygen, sulfur, or NR' (R' is
Hydrogen or lower alkyl having 1-6 carbon atoms
chain); R³′ is a bicyclic β-lactam anti-
Amides, esters, and torsions known in the biological field
Realkylsilyl, acyl, pharmaceutically acceptable
Conventional protecting groups such as salts, hydrogen
But it is typically chosen ;R³The definition of ′ is detailed below.
can be induced into the compound shown in
can. 4-allyl azetidinone () with appropriate substitution
Starting from , the synthesis proceeds via intermediates and
Go to: [In the formula, R⁶and R⁷is as defined before;
X is a conventional leaving group and R²′ is hydrogen, pharmaceutically acceptable
accepted ester groups, conventional easily removable protection
[protecting group or salt cation]. In the intermediate
R²′ is as defined, but preferably R²′ in the definition of
It is an ester group. R¹′ is hydrogen or triorga
Easily removable protecting groups such as nosilyl
Ru. Details of the total synthesis are described below. The final compounds produced by the method of the present invention are as follows:
Concurrently pending commonly assigned U.S.
Patent Application No. 843375, filed October 19, 1977; U.S.
Patent Application No. 933681, filed August 17, 1978; USA
Patent application number 31694, filed on April 19, 1979 and
U.S. Patent Application No. 134604, 129851, filed at
134381 [Respectively Merck End Company
Merck & Co., Inc., Inc.
Attorney's Docket Number
Numbers) 16095IA, 16330IA, 16049IB]
Disclosed and claimed in . The aforementioned U.S. patent
Application for the final compound's utility as an antibiotic
Range and substituent R shown for⁶,R⁷,R⁸,
R', X, X', R³′ is defined above.
application is incorporated herein by reference.
Ru. The purpose of the present invention is to apply it as a therapeutic agent for animals and humans.
Advantageous new classes of antibiotics effective against non-living and non-living systems
An object of the present invention is to provide a manufacturing method. the antibiotic
is S. aureus, Strep. Pi
Strep.pyogenes, B. Zubteiri
Gram-positive bacteria and insects such as B. subtilis
-． coli (E.coli), Pseudomonas
(Pseudomona), Proteus. Morgani
(Proteus morganii), Serratia (Serratia),
Gram-negative organisms such as Klebsiella
activity of a wide range of pathogenic bacteria, typically including M.
It is gender. The method according to the invention is conveniently summarized by the following reaction diagram.
You can: To explain about the figure, starting material 1 ~ (described later)
The oxidation of 1 to methylene chloride, methanol, chloro
in solvents like form, dichloroethane, etc.
With oxidizing agents such as
temperature for 0.1 to 4 hours, then the crude product was m
- Chloroperbenzoic acid, hydrogen peroxide, peracetic acid, etc.
1 to 1 with an oxidizing agent such as and a temperature from 0 to 100℃.
After processing for 100 hours, it will be completed by giving 2 ~. Kaira
Chirality is conveniently introduced at this stage.
be done. Racemic body 2 can be resolved, for example, by brucine, N
-methylphenethylamine, N,N-dimethylphenylamine
optically active bases such as enethylamine, etc.
Fractional crystallization of the formed rubonate
This can be done by Addition reaction 2~→3~ converts 2~ to 1,1'-carbonyldi
stomach
midazole etc. and tetrahydrofuran, dimethoxy
from 0°C in solvents such as siethane, DMF, etc.
Processed at temperatures up to 50℃, followed by (R²′O₂CCH₂C.O.₂)₂Mg, from 0.5 to 3.0 equivalents
Additive treatment from 1 to 48 hours at temperatures from 0 to 50℃
This is done by managing. R²' is p-nitrobe
Easily removable substances such as benzyl, benzyl, etc.
It is a carboxyl protecting group. Also R²′ is pharmaceutical
It has also been noted that what can be done with acceptable ester groups is
Ru. The ester group is typically mentioned below.
(DMF is dimethylformamide). Protecting group R¹’ removal (3～→4～) is done by hydrolysis or
This can be done by various known methods such as hydrogenation.
I can do it. R¹′ is a triorganosilyl group (e.g.
ba[(CH₃)₃C] (CH₃)₂In the case of Si−), the removal is
methanol, ethanol, tetrahydrofuran,
Hydrochloric acid, in solvents like dioxane, DMF, etc.
0 to 100℃ in the presence of acids such as sulfuric acid, acetic acid, etc.
Acidic aqueous hydrolysis for 2 to 18 hours at temperatures up to 3~
This is typically done by Other similar deprotections occur in 1 or 2
This is noteworthy. R¹′ is H, carbon
Chain elongation can proceed directly from 2 to 4. Diazo compound 5~ is 4~ CH₃C.N., C.H.₂Cl₂,
p-carboxybenzenesulfate in a solvent such as THF
Honyl azide, toluenesulfonyl azide, meth
azides and torie such as sulfonyl azide etc.
Thylamine, pyridine, (C₂H_Five)₂Like NH etc.
Treat for 1 to 50 hours at 0-25℃ in the presence of a suitable base.
(THF is tetrahydrogen
Dorofuran). Cyclization (5~→6~) converts 5~ to benzene, toluene,
Bis(acetylacetate) in solvents such as THF etc.
nat) Cu() [Cu(acac)₂],CuSO_Four,Cu powder
End, Rh (OAc)₂, Pd(OAc)₂in the presence of a catalyst such as
to be treated at a temperature of 50-110℃ for 1-5 hours.
It is done more. Alternatively, 6~ is benzene,
CCl_Four, in a solvent such as diethyl ether, etc.
Pyrex filter for 0.5 to 2 hours at -25℃
(wavelength greater than 300nm)
Cyclization can be carried out by [“OAc” is
It is acetic acid]. Next, to activate ketoester 6,
Introduce the group X. Introduction of this leaving group X (6~→7~)
is the ketoester 6 ~ anhydrous p-toluenesulfone
Acid, p-nitrophenylsulfonic anhydride, anhydride
2,4,6-triisopropylphenyl sulfone
Acid, methanesulfonic anhydride, trifluorome anhydride
Tansulfonic acid, diphenylchlorophosphate
toluenesulfonyl chloride, p-bromov
Acylation such as enylsulfonyl chloride etc.
Agent R⁰This is done by processing X (where X
is toluenesulfonyloxy, p-nitrophenyl
rusulfonyloxy, diphenylphosphoryl and
established by conventional methods and well known in the industry.
With corresponding leaving groups such as other leaving groups
be). Typically, the above steps to establish the leaving group
Acylation can be done with methylene chloride, acetonitrile or
Diisopropylene in a solvent such as dimethylformamide
Pyrethylamine, triethylamine, 4-dime
In the presence of a base such as thylamino-pyricine etc.
The test is carried out at a temperature of -20 to 40°C for 0.1 to 5 hours.
The leaving group X of intermediate 7~ can be a halogen
Ru. The leaving group of halogen is φ~₃PCl₂,φ₃PBr₂,
(φO)₃PBr₂, such as oxalyl chloride etc.
Halogenating reagent and CH₂Cl₂,C.H.₃CN, THF etc.
diisopropylethylamine in a solvent such as
ethylamine, 4-dimethylaminopyricine
Established by processing in the presence of any base
[φ is phenyl]. Reaction 7~→8~ converts 7~ to dioxane, dimethylform
Amide, dimethyl sulfoxide, acetonitrile
Solvents such as hexamethyl phosphoramide, etc.
Medium R⁸is a mercaptan reagent as defined above
HSR⁸hydrogen carbonate in the presence of an excess of approximately equivalent to
Sodium, potassium carbonate, triethylamine,
Bases such as diisopropylethylamine etc.
Temperatures from -40 to 25℃ for 1 to 72 hours
This is done by managing. R⁸is grade 1 or 2
class amino group, e.g. -CH₂CH₂N.H.₂, by
If substituted, the mercaptan reagent is
BAHSCH₂−CH₂NHR⁰[wherein,
R⁰is p-nitrobenzyloxycarbonyl (-
C.O.₂PNB), o-nitrobenzyloxycarbonylate
Easily removable N-protecting groups such as
]. Especially indicated mercaptan reagents,
HSCH₂CH₂NHR⁰, is aminoethyl mercapta
aqueous diethyl ether, aqueous dioxane, water
Sodium bicarbonate in a solvent such as acetone etc.
In the presence of a base such as sodium hydroxide, sodium hydroxide, etc.
at temperatures from 0 to 25°C in the presence of the desired acid chloride.
Produced by processing for 0.5 to 4 hours.
The aforementioned mercaptan reagent HSR⁸and its protection laws.
This is just an example. Adequate HSR⁸Reagents are below
and are typically described in the Examples. Final deprotection step 8~→ is solvolysis or hydrogen
This is done by conventional methods such as addition. typically
Dioxane-water-ethanol, tetrahydrofura
- Aqueous phosphoric acid - Dipotassium hydrogen - Isopropano
8~ is adsorbed onto activated carbon in a solvent such as alcohol.
palladium, palladium hydroxide, platinum oxide, etc.
A pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as
of hydrogen and temperatures from 0 to 50℃ for 0.25 to 4 hours.
Process and give. R²For example, o-nitro
For groups like benzyl, photolysis also
Can be used for protection. Regarding the above description of the invention, in the conversion from 7 to 8
Suitable reagents to use for HSR⁸are listed below. one
The list is thia side chain - SR⁸on the structure and functional group characteristics of
Provide a more detailed summary and annotations as necessary. To be elected
The thia side chain is the corresponding mercaptan reagent HSR⁸from
be guided. The functional group may interfere with the intended reaction pathway.
If the mercaptan contains a functional group such as
protects groups that damage it. For example, basic nitrogen
groups (e.g. -NHR or -NH₂) when you meet
Regular acylation (e.g. -CO₂PNB)
Ruboxyl group (-CO₂When H) exists, it is usually
Protected by esterification (e.g. PNB ester).
Such protection also allows the product 8 to be chromatographed.
(PNB is p
- nitrobenzyl). (1) Aliphatic (including carbocyclic) mercaptans:
R⁸is alkyl having 1-10 carbon atoms, cycloal
Kyl, alkenyl, cycloalkenyl or aryl
HSR which is ruquinyl⁸;R⁸is straight chain or branched chain
can be, example HSCH₃ HSCH₂CH₃ HSCH₂CH₂CH₃ HSCH(CH₃)₂ HS(CH₂)₃CH₃ HSCH₂CH(CH₃)₂ HS−CH₂−CH=CH₂ HS−CH₂−CH=C(CH₃)₂ HS−CH₂−C≡CH HS−CH₂-C≡C-CH₃ (2) Substituted aliphatic mercaptans: R⁸has 1 carbon
−10 straight or branched alkyl, cyclo
Alkyl, alkenyl, cycloalkenyl or
is an alkyl group with one or more halo,
OH, OR¹, [expression] [expression] [Formula] NH₂, N.H.R.¹,NR¹R², [Formula], CO₂H, CO₂R¹, CONH₂, CONHR¹,CONR¹R², C.N., S.R.¹,
[Formula] SO₂R¹, S.O.₂N.H.₂, S.O.₂NHR¹, S.O.₂NR¹R², [Formula] [Formula] [Formula] [Formula] 【formula】 [Formula] [Formula] (In the formula, R¹and R²is R⁸ (as previously defined for the substituents above)
HSRs that are more substituted⁸. Preferred substituents are
It is a basic nitrogen-containing group. example HS(CH₂)_oOR¹ n=2-4, R¹=H,
[Formula] CH₃ [Formula] n=1-3, X=0, N.H., N.R.¹,R¹=H,CH₃ HS(CH₂)_oN.H.₂ n=2-4 HS(CH₂)_oNHR¹ n=2-4, R¹＝CH₃,
CH₂CH₃,【formula】 HS(CH₂)_oNR¹R² n=2-4, R¹/R²=
CH₃,C.H.₂CH₃ HS−CH₂CH₂SCH₃ HS−CH₂CH₂NHC(CH₃)₃ [Formula] R¹=H,CH₃, 【formula】 [Formula] n=3-5 [Formula] R¹=H,CH₃;R²= H, CH₃ [Formula] R¹=H,CH₃ [Formula] n=1-3, R²=H, CH₃,R¹=H,CH₃ 5-thio-D-glucose HS−CH₂−CH=CH−CH₂N.H.₂ (3) Aryl mercaptans: R⁸is phenyl
or substituted phenyl HSR⁸. The substituent is R⁸to
independently selected from those previously defined. Special
Preferred substituents are alkyl, halo, hydroxy
cy, alkoxy, acyloxy, acyl, cal
boxy, mercapto, sulfinyl, sulfony
amino, substituted amino, aminoalkyl, substituted
Contains substituted aminoalkyls, amides, and ureidos. [Formula] n=1, 2or3, X= F, Cl, Br, OH, OR, [Formula] NH₂, NHR¹,NR¹R²,C.H.₂CH₂,C.H.₂NR¹R²,
C.O.₂H, CO₂R¹,COR¹, CONH₂,CONR¹R²,
R¹CONH, R¹NHCONH, S.R.¹,【formula】 S.O.₂R¹,C.H.₃, C.F.₃;R¹and R²is R⁸About before
As defined. example (4) Heteroaryl mercaptans: R⁸is 1-
Substituted or unsubstituted containing 4 O, N or S atoms
HSR, a substituted heteroaryl group⁸. typical
Substituents are listed in the section on aryl mercaptans.
and the groups listed above. example X=N, O Y=H X=S Y=H, Cl,
OCH₂CH₃ (5) Aryl aliphatic mercaptans: R⁸is Hue
carbon substituted by phenyl or substituted phenyl groups
Straight or branched chain alkyl with 1-6 prime numbers
cycloalkyl, alkenyl, alkynyl
The base HSR⁸. Typical phenyl substituents are
The groups described in the section of lyr mercaptans
including. example (6) Heteroarylaliphatic and heterocyclyl fats
Aliphatic mercaptans: R⁸is 1-4 O,N
or heteroaryl or heteroaryl containing an S atom
1-carbon number substituted by rosyclyl group
6 straight or branched alkyl, cycloa
Alkyl, alkenyl, alkynyl group
HSR⁸. heteroaryl or heterocyclyl
The group is defined in the section of aryl mercaptans (above, 3).
Substituted with the substituent described in section)
or unsubstituted. example (7) Alkyl-hetero atom-alkyl mercaptan
Type: R⁸ga-(CH₂)_oX(CH₂)_nR⁹[In the formula, n is 2
to 4, m is 2 to 4; X is NR⁰,
O or S (but R⁰is H, CH₃,C.H.₂CH₃,
CH₂CH₂OH or CH₂CH₂N.H.₂is) is
R, R⁹is OH, NH₂,NHCH₃,N(CH₃)₂,
[Formula] [Formula] is] HSR⁸. In the above description, methylene carbon is e.g.
Branch like [expression] [expression] etc. Note that it is possible to NextHSR⁸is a typical example of this type. Production of substituted 4-allyl azetidinones 1- Starting material 1 is 4-allyl azetyl according to the following scheme.
Conveniently produced from Zinone: figure It was noted that starting materials 1a~ are known
stomach. Furthermore, regarding this point, the concurrently pending Ordinary
Assigned U.S. Patent Application No. 59842, 7/1979
The application filed on May 23rd concerns the definition and usage of starting materials 1a~.
The references are included here. R¹′ is
Liorganosilyl, e.g. trimethylsilyl,
t-butylmethylsilyl, triphenylsilyl
What is a removable protecting group? To explain about the above reaction diagram, starting materials 1a~ are ring
can be mono- or dialkylated at the 3rd position of
can. Alkylation of 1a~ gives 1b~. typical
Specifically, 1a~ is tetrahydrofuran (THF),
Hexamethylphosphoramide, ether, dimethoxy
Lithium diisopropylene in a solvent such as siethane
Lopyramide, lithium 2,2,6,6-tetra
Methylpiperidide, potassium hydride, lithium
xamethyldisilazane, phenyllithium, etc.
The selection process is carried out with a strong base such as
Selected alkylating reagent R⁶X⁰Add (X⁰is black
bromo, iodine or bromo) or alternatively
and R the alkylating reagent.⁶- tosylate, R⁶-Me
sylate, or alkaline substances such as acetaldehyde.
It can be a dehyde or a ketone, so
Monoalkyl bodies 1b~ are obtained. If you don't aim for it
, the dialkyl body 1~ is the alkylation of 1a~ → 1b~
Obtain from 1b by repeating the method
I can do it. The 6-substituent is also N-acylimida
Direct acylation using acylating agents such as
This can be established by standardization. The N-acyl
Imidazole acylating agents are listed below. R⁶
and R⁷A detailed explanation of this second method of establishing
The following descriptions are also listed below. The following list is shown above:
1a～→1b～→R according to 1⁶and R⁷to establish
Typical alkylating agents effective for: Alkylating agent CH₃CHO φCH₂CHO φ = phenyl φCH₂CH₂CHO CH₂O CH₃I φCH₂Br CH₃COCH₃ CH₃OCH₂CHO CH₃CH₂I (CH₃)₂CHI N₃CH₂CHO Me₂NCH₂CHO R.O.₂CCH₂Br R=CH₃, benzyl, p-nit
lobenzil C.F.₃C.F.₂CHO R.O.₂CCH₂CHO R=CH₃, benzyl, p-ni
Trobenzil CH₃CH(CH₃) CHO, CH₃(CH₃)CHCH₂CHO, CH₃CH₂CHO, C.F.₃CHO [Formula] R=protecting group R is a removable carboxyl such as benzyl
It is a protecting group. As mentioned above, the 6-substituent also lends itself to acylation.
can be more established. The use of this acylating agent
Usage is preferred starting material 1 ~: (In the formula, R⁷and R¹′ is defined above.
) is proved in the following way. R⁶′ is R⁶definition
According to the definition of righteousness, in that sense it is previously identified.
Ta group R⁶is the remainder. In other words, the eyes of this definition
R at target⁶′CH(OH)−=R⁶It is. particularly preferred
Substance 1~ is R⁷If is hydrogen, then R⁶′ is methyl
It is. The preferred starting materials are described herein by reference.
The next concurrent pending case filed in
No. 59842, filed July 23, 1979
stated in the application. Basically the 1'-hydro
Kishi R⁶'Body 1~ is manufactured according to the following diagram: Alkylation 1a~→1~ (figure) was described previously.
Sea urchin 1a~ in tetrahydrofuran, dimethoxyetha
diethyl ether, hexamethyl phosphorole
Lithium isopropyl amide in a solvent like Mido
lithium hexamethyldisilazide, lithium
2,2,6,6-tetramethylpiperidide, hydrogen
-100 to -20 with a strong base such as potassium chloride etc.
°C, followed by 1 equivalent to 10-fold excess of aldehyde.
This is done by adding . This reaction is different
gives a mixture of sex bodies, but from now on the desired trans
Su-R form 1~ by chromatography or crystallization method
can be conveniently separated. Intermediates 1a~ can be converted directly into 1~ as shown above.
However, it is possible to take a detour route via 1 to ′.
I can do it. Direct acylation to 1~' lyses 1a~
Umdiisopropylamide, lithium hexamethylene
Rudisilazide, lithium 2,2,6,6-tetra
2 or more bases such as methylpiperidide
Equivalents of above and e.g. tetrahydrofuran, diethyl
In solutions such as ether, dimethoxyethane -
N-acyl treated at temperatures from 100 to -20℃
Adding an acylating agent like midazole etc.
This is done by Acylation of a mixture of 1a~ and a base
It is preferable to add it to the agent. Representative acyl for this Figure 1a~→1~'→1~
The curing agents are listed below. [Formula] R=CH₃,ClCH₂, CH₃CH₂,C.H.₃OCH₂,【formula】 【formula】 [Formula] [Formula] RC−SCH₂CH₃;R=CF₃, C.F.₂H,CH₂=
CH, [formula] [Formula] [Formula] Furthermore, regarding the figure, the reduction 1~'→1~ reduces the ketone.
Potassium tri(sec-butyl)borohydride, lithium
Umtori (sec-butyl) borohydride, sodium
Muborohydride, sodium tris(methoxye)
Toxy) aluminum hydride, lithium aluminum
Reducing agents such as nium hydride and diethyl ethyl
ether, tetrahydrofuran, toluene, etc.
in a solvent at temperatures from -78 to 25°C.
This is done by The reaction is potassium iodide,
complex by additions like magnesium bromide etc.
Conveniently done in the presence of such salts to make. Similarly, undivided 1 ~ (cis and trans form) is shown above.
As shown in Figure 1, in order to reduce 1 to 1, oxidation to 1 to '
You can: Oxidation is dipyridine chromium () oxide,
Trifluoroacetic anhydride-dimethyl sulfoxide-
triethylamine, pyridinium dichromate,
Oxidizing agents such as acetic anhydride-dimethyl sulfoxide
and solvents such as methylene chloride, acetonitrile, etc.
5 minutes to 5 hours in medium at temperatures from -78 to 25℃
This is done by processing up to the interval. The compound produced by the method of the present invention can be further
In the formula: [In the formula, X′ is oxygen, sulfur, or NR′ (but
R' is hydrogen or lower alkyl having 1-6 carbon atoms
is a group); R³′ is hydrogen, or
Drugs known in the cyclic beta-lactam antibiotic industry
Scientifically acceptable salts, ester anhydrides (R³′ is a
syl), typically to give an amide group
Chosen; R³’ is also an easily removable protecting group.
can be induced into a compound of
Ru. −COX′R³′ group confirmation In the general representation of the above-mentioned compound (, above formula)
te, −COX′R³The group denoted by ' is especially -
COOH (X′ is oxygen and R³′ is hydrogen) and
Sphalosporins, penicillins and their core
Bicyclic β-lactam antibiotic industry like analogs
Pharmaceutically acceptable esters, anhydrides
(R³’ is acyl), which is effective as an amide group.
All known residues. Suitable protected esters (R³′, X′=O) is representative
Selected from the following list of relevant items: (i) at least R^a,R^b,R^cOne of them is an electron donor
For example, R which is p-methoxyphenyl³′＝
CR^aR^bR^c. remaining R^a,R^b,R^cThe group is hydrogen or
It is a machine substituent. A suitable ester group of this kind is
Contains p-methoxybenzyloxycarbonyl
nothing. (ii) at least R^a,R^b,R^cOne of them is an electron absorber.
Attractive groups, e.g. p-nitrophenyl, tric
Lolomethyl, o-nitrophenyl. this
A suitable ester of the species is p-nitrobenzyl oxychloride.
cycarbonyl, 2,2,2-trichloroethoxy
Contains cyclocarbonyl. (iii) at least R^a,R^b,R^cTwo of them are archi
aryl, e.g. methyl or ethyl, aryl, e.g.
For example, a hydrocarbon such as phenyl, and another
If there are one left, then there are R left.^a,R^b,R^cof
The group is hydrogen R³′=CR^aR^bR^c. suitable for this kind of
The esters are t-butyloxycarbonyl,
diphenylmethoxycarbonyl, triphenyl
Contains methoxycarbonyl. The silyl group as a protecting group in this range has the formula:
R₃ ^FourSiX′ (where X′ is like chloro or bromo)
It is a halogen and R^Fouris alkyl, e.g. methi
Halosilanes such as ethyl, ethyl, t-butyl)
It is conveniently manufactured. Furthermore, pharmaceutically acceptable carboxyl derivatives
reacts I with alcohols, acylation reagents, etc.
It is induced by for example,
Interesting esters and amides are in the 3rd position -
COX′R³Starting materials and final products as described above with ' groups
[In the formula, X' is oxygen, sulfur or NR' (R' is H
or R³) and R³' is methyl, ethyl
Direct carbon atoms with 1-6 carbon atoms, such as alcohol, t-butyl, etc.
chain or branched alkyl;
Rubonylmethyl; 2-methylaminoethyl, 2-
Aminoalkyl, including diethylaminoethyl;
Alkanoyloxy such as baloyloxymethyl
The moiety is linear or branched and has 1-6 carbon atoms.
Alkano in which the alkyl moiety has 1 to 6 carbon atoms
yloxyalkyl; halogachloro; alkyl
Straight chain or branched chain having 1-6 carbon atoms
haloalkyl which is a chain, e.g. 2,2,2-t
Lichloroethyl; 2-propenyl, 3-butenyl
1-4 carbon atoms such as
Kenyl; benzyl, benzhydryl, o-nitro
benzyl, p-methoxybenzyl, p-nitrobe
aralkyl and lower alkoxyl such as
- and nitro-substituted aralkyl; phthalidyl; ben
Zyloxymethyl, (4-nitro)benzyloxy
Benzene with 8-10 carbon atoms such as dimethyl
hydroxyalkyl]. Esters (and thioesters) listed above
In addition, amides are also encompassed by the present invention. That is, X′ is −R′ N - is a group. The amide Typical examples of this type include hydrogen, methyl, and ethyl
selected from the group consisting of lower alkyl such as
It is something. Most suitable −COX′R³′ group is (regarding the above structural formula)
) X′ is oxygen and R³' is hydrogen; carbon number 1-4
lower alkyl having; 3-methylbutenyl, 4
- lower alkenyl such as butenyl; p-ni
Benzyl and substituted benzyl such as trobenzyl
pivaloyloxymethyl, 3-phthalidyl;
It is fenacil. The aforementioned compounds () have various Gram-positive and negative
It is a valuable antibiotic active against sexually transmitted bacteria and therefore
has shown potential for use as a treatment for human and livestock diseases.
issued. Typical susceptibility to antibiotics
The pathogen is Stachylococcus aureus.
(Staphylococcus aurens), Escherichia coli
(Escherichia coli), Klebsheeler nyumo
Klebsiella pneumoniae, bacillus
Bacillus subtilis, salmonella
Hosa (Salmonella typhosa), Pseudomonas
(Pseudomonas), Bacterium Proteus
(Bacterium proteus). compound ()
The antibacterial agent contained is not limited to use as a medicine. genuine
Quality can be used in all aspects of industry, e.g.
For example, additives to animal feed, food preservatives, sterilization
agents, and other industrial aspects aimed at controlling bacterial growth.
used. For example, this substance is used in medical and dental equipment.
To destroy and prevent the growth of harmful bacteria in
Aqueous base to inhibit the growth of harmful bacteria
dyes and industrial processes such as adding them to white water in paper mills.
Concentration of antibiotics in solution as a disinfectant in applications
in aqueous compositions at concentrations ranging from 0.1 to 100 ppm.
It can be used as The products produced by the method of the present invention can be used for various pharmaceutical purposes.
Can be used anywhere in manufacturing.
This substance is available in capsules, powder form, liquid solutions and suspensions.
It can be used in the form This substance can be obtained by various methods.
Oral administration is the primary means of interest.
parenterally (intravenously), topically or by injection
or intramuscular) methods. The tablets and capsules intended for oral administration are
dosage form, for example, syrup
gum arabic, gelatin, sorbitol, tomato
such as ragacant gum, polyvinylpyrrolidone
Binders, e.g. lactose, sugar, corn lees
powder, calcium phosphate, sorbitol, glycerin
fillers such as magnesium stearate,
silium, talc, polyethylene glycol, silicon
lubricants such as mosquitoes, disintegrants such as potato starch,
Acceptable wetting such as sodium lauryl sulfate
It may contain conventional excipients such as agents.
The tablets are coated by methods known in the art. oral liquid
The formulation may be in the form of an aqueous or oily suspension or solution.
Can be taken with water or other suitable before use
Can be given as a dry formulation for reconstitution with suitable carriers.
I can do it. The liquid formulation may contain, for example, sorbitol.
Le, methylcellulose, glucose/sugar syrup
gelatin, hydroxyethylcellulose, carbonate
suspension types such as ruboxymethylcellulose
Conventional additives may be included. Suppository dot
supplements such as cocoa butter or other glycerides.
Suppository bases from the past can be included. Compositions for injection are the preferred route of administration.
Manufactured in unit dosage form in pull or multi-unit dose containers
can do. The composition may be an oily or aqueous carrier.
It can take the form of a suspension, solution, or emulsion in
and suspension, stabilizing and/or dispersing agents.
It can contain excipients such as. Alternatively,
The active ingredient may be present in a suitable carrier such as sterile water at the time of administration.
It can be in powder form for reconstitution. The composition also applies to the mucous membranes of the nose, throat or bronchial tissues.
manufactured in a suitable form for absorption through
and can conveniently be used as a liquid spray or inhaler,
It can take the form of a cream or throat liniment.
Ru. For eye or ear medicine, the preparation may be liquid or semi-
Can be given in solid form. For topical application
Ointments, creams, topical solutions, liniments, powders, etc.
Can be formulated with lipophilic or hydrophilic bases
Ru. The dose administered will depend on the route and frequency of administration as well as the treatment.
It depends largely on the condition and size of the object being placed, and
The parenteral route by injection is preferred for common infections.
be. However, this is well known to the antibiotic industry.
The physician's pattern of selection is based on established treatment principles.
Freedom of choice remains. Generally, daily dosage
once a day or more per kilogram of subject's body weight.
The composition contains from about 5 to about 600 mg of active ingredient. good
The recommended daily dose for an adult is 1 kg of active ingredient per body weight.
ranges from approximately 10 to 240 mg per day. treated
Apart from the specific characteristics of the infected individual and the nature of the infection,
Another factor influencing accurate dosing management is the
is the molecular weight of the selected compound (). Compositions for human administration per unit dose may be liquid or solid.
Contains from 0.1 to 99% of active substances regardless of the body.
The preferred range is approximately 10-60%.
be. The compositions generally contain from about 15 mg of active ingredient to about
Can contain up to 1500mg, but typically around 250mg
It is preferred to use doses ranging from mg to 1000 mg.
Delicious. For parenteral administration, the unit dose is usually pure
Soluble intended for sterile aqueous solutions or solutions of compounds
It is in the form of a powder. Bisexual as shown in the structure
Because it is an ionic compound, the pH of the solution is typically isoelectric.
depending on the individual characteristics of solubility and stability.
Considering that the aqueous solution has a PH different from the isoelectric point PH,
For example, it is necessary to range from 5.5 to 8.2.
Ru. Total synthesis of defined carbapenem antibiotics
In the explanation of the reaction diagram above, please refer to the exact reaction parameters.
It is understood that there is considerable range in the choice of
Ru. This range and its breadth implications are generally
The presence of media, temperature range, protecting groups, and reagents used
Indicated by enumeration of degrees. Furthermore, given the reaction
in a reaction diagram as separate steps in a chain of
What is shown is more of a convenience of description than a necessary request.
It is the one above; the mechanically cut figure is the composite
It is a unified diagram, and in practice certain stages are merged and identical.
materially modifying the process or process of synthesis
Things that can be done in reverse order without
It can be understood. The examples below list an exact picture of the total synthesis.
The purpose of this detailed explanation is to further explain total synthesis.
and shall not be subject to any limitations whatsoever.
should be understood. Temperatures are given in °C. Example 1 1-(t-butyldimethylsilyl)-4-(pro-
Production of (p-2-ene)-azetidin-2-one t-Butyldimethylchlorosilane (7.51g,
49.8 mmol) to 4-(prop-2-ene)-aze
Tidin-2-one (5.26 g, 47.4 mmol) and
Dehydration of ethylamine (5.04 g, 49.8 mmol)
dimethylformamide (100ml) ice-cooled with stirring
Add to the liquid at once. There is a lot of white precipitate.
occur at the same time. The reaction mixture was kept at 0-5° for 1 hour.
Stir and warm to room temperature. Vacuum most of the solvent
The residue obtained by removing the following was dissolved in diethyl ether (250 ml).
and water. The ether layer was diluted with 2.5N hydrochloric acid (50
ml), water (3 x 50 ml), saturated saline, and sulfuric acid solution.
After dehydrating with magnesium, filtering, and concentrating under vacuum,
Obtain an oil that can be distilled under vacuum or on silica gel.
chromatograph (petroleum ether containing 20% ether)
1-(t-butyldimethane)
tylsilyl)-4-(prop-2-ene)-azethi
Zin-2-one is obtained. NMR (CDCl)₃) δ4.8−6.0 (3H, m, olefin
), δ3.5 (1H, m, H4), δ3.03 (1H, dd, J=
15, 5.2, H3x), δ2.56 (1H, dd, J=15, 2.8,
H2β), δ1.8−2.8 (2H, m, allylic), δ0.9 (9H
,
s), δ0.2(6H, s). Example 2 1-(t-butyldimethylsilyl)-3-(1-
hydroxyethyl)-4-(prop-2-ene)
-Production of azetidin-2-one A hexane solution of n-butyllithium (26.25 ml)
diisopropylamine at -78℃
(26.25 mmol) of dehydrated tetrahydrofuran
(100 ml) solution was slowly added using a syringe. obtained
The solution was stirred for 15 minutes and 1-(t-butyldimethyl
silyl)-4-(prop-2-ene)-azetidine
-2-one (25.0 mmol) dehydrated tetrahydro
Add furan (25ml) solution. Stir at -78℃ for 15 minutes.
After stirring, inject acetaldehyde (75 mmol).
Add with a sprayer and stir the resulting solution at -78℃ for 5 minutes.
do. Saturated aqueous ammonium chloride solution (15ml)
added via syringe and allowed the reaction mixture to warm to room temperature.
Dilute with ether (250 ml) and add 2.5N hydrochloric acid solution (2
×50ml), water (100ml), washed with saturated saline, sulfuric acid
Dehydrate with magnesium. Remove the solvent under reduced pressure and
Chromatograph the solid residue on silica gel
(1:1, ether:petroleum ether). melt
The first product is cisR^*Compound (688mg),
NMR (CDCl)₃+D₂O) δ4.8−6.2 (3H, m, Olef
(in character), δ4.2 (1H, dq, J = 6.5, 3.7, H-8),
δ3.75 (1H, ddd, J=5.5, 5, 4.8, H-5),
δ3.28 (1H, dd, J=5.5, 3.7, H-6), δ2.2-
3.0 (2H, m, allylic), δ1.35 (3H, d, J=
6.5,CH ₃-CHOH), δ1.0 (9H, s, ±Si-),
δ0.3(6H, s, (CH ₃)₂Si). second minute
The image part is trans R^*and S^*product mixture
(5.56g). This substance from petroleum ether
Pure trans-R when recrystallized^*substance, melting point 81−
Obtain 82℃. IR (CHCl₃) 3400, 2920, 2850, 1723cm^-1;
NMR (CDCl)₃+D₂O) δ4.9−6.2 (3H, m, Olef
in), δ4.1 (1H, dq, J = 7.0, 6.8, H8),
δ3.66 (1H, ddd, J=11, 4.5, 3.0, H5), δ2.9
(1H, dd, J=6.8, 3.0, H6), δ1.8−2.8 (2H,
m, allylic), δ1.26 (3H, d, J=7.0, CH ₃
-), δ1.0 (9H, s, ±Si), δ0.28 (6H, 2s, (C
H
₃)₂Si). Example 3 (3S^*,4R^*)-1-(t-butyldimethylsilicate
)-3-(1-oxoethyl)-4-(prop-
2-ene)-azetidin-2-one A Trifluoroacetic anhydride (7.5 mmol) is diluted with
Dehydrated methyl sulfoxide (10 mmol)
Syringe in methylene chloride solution (15 ml) at −78 °C.
Drip more. The resulting mixture was incubated at −78°C for 20 min.
A white precipitate forms during stirring. 1-t-
(butyldimethylsilyl)-3-(1-hydroxy
ethyl)-4-(prop-2-ene)-azethi
Zin-2-one (5.0 mmol) in methylene chloride
Add the solution (15 ml) using a syringe and add the resulting solution.
Stir at -78°C for 30 minutes. Triethylamine (14
mmol) with a syringe and remove the cooling bath. Sara
After 1 hour, the reaction mixture was diluted with methylene chloride (100
ml) and washed with water (50 ml) and saturated saline.
and dehydrate with magnesium sulfate. Dissolve under reduced pressure.
When the medium is removed, an oily substance is obtained, which is mixed with silica gel.
Chromatograph (2:1, petroleum ether: ether)
(tell), (3S ^*, 4R ^*)-1-(t-
butyldimethylsilyl)-3-(1-oxoethyl)
)-4-(prop-2-ene)-azetidine-
Get 2-on. IR (CHCl₃) 2925, 2855,
1734, 1705cm^-1;NMR (CDCl₃) δ4.8−6.1
(3H, m, olefinic), δ3.8−4.2 (2H, heavy
m, H5, H6), δ2.0−2.9 (2H,
m, allylicity), δ2.3 (3H, s, [formula]), δ0.96 (9H, s, ±Si), δ0.25 (6H, 2s, (CH ₃)
₂Si). Mass spectrum m/e267 (m⁺), 252, 226,
210. B Hexane solution of n-butyllithium (4.10 ml)
diisopropylamine (4.10 mmol)
in dehydrated tetrahydrofuran solution (16 ml) of
Add via syringe at −78°C. The resulting solution
Stir at -78°C for 15 minutes and 1-(t-(butyldimethyl)
silyl)-4-(prop-2-ene)-azetidi
Dehydrated tetrahedron-2-one (2.0 mmol)
Add Dorofuran solution (2 ml). 15 at −78℃
After a few minutes, the reaction mixture was passed through a Teflon tube and
Dehydration of cetyl imidazole (4.1 mmol)
Add trahydrofuran mixture (16 ml) at -78°C.
I can do it. The resulting yellow reaction mixture was incubated at −78 °C for 15
Stir for 10 min and stir for saturated aqueous ammonium chloride solution (10
ml) to stop the reaction. reaction mixture
Dilute the compound with ether (100ml) and add 2.5N hydrochloric acid.
Wash with solution (25 ml), water (25 ml), and saturated saline.
Ru. The organic layer was dehydrated with magnesium sulfate and dried under reduced pressure.
When concentrated to give an oil. Siri this substance
Chromatograph by Kagel (2:1, petroleum
-ether: ether) and (3S ^*, 4R ^*)
-1-(t-butyldimethylsilyl)-3-(1
-oxoethyl)-4-(prop-2-ene)-
Azetidin-2-one is obtained. Example 4 (3S ^*, 4R ^*)-1-(t-butyldimethylsiloxane)
Lil)-3-[(R ^*)-1-hydroxyethyl]-
4-(Prop-2-ene)-azetidine-2-o
hmm K-selectride (potassium tri-sec-butyl
borohydride) of tetrahydrofuran (4.8 milliliters)
) with potassium iodide (2.0 mmol) and (3
S ^* , 4R ^* )-1-(t-butyldimethylsilyl)
-3-(1-oxoethyl)-4-(prop-2-
ene)-azetidin-2-one (2.0 mmol) in dry ether (20 ml) at room temperature. The resulting mixture was stirred at room temperature for 2.5 h and glacial acetic acid (9.6
The reaction is stopped by adding (mmol).
The resulting mixture is diluted with ethyl acetate (100ml) and filtered through Celite. Removal of the solvent under reduced pressure gave an oil which was chromatographed on silica gel (1:1, ether:petroleum ether) to yield 1.90 g (95%) of ( 3S ^* , 4R ^* )-1-
(t-Butyldimethylsilyl)-3-(1-hydroxyethyl)-4-(prop-2-ene)-azetidin-2-one is obtained as a white solid. NMR measurements of this substance show R ^* /at the hydroxy center.
It shows that the S ^* ratio is >5/1. The R ^* isomer is isolated by recrystallization from petroleum ether. Example 5 ( 3S ^* , 4R ^* )-1-(t-butyldimethylsilyl)-3-[( R ^* )-1-hydroxyethyl]-
4-(carboxymethyl)-azetidin-2-one ( 3S ^* , 4R ^* )-1-(t-butyldimethylsilyl)-3-[( R ^* )-1-hydroxyethyl]-4
-(Prop-2-ene)-azetidin-2-one (3.0 mmol) in dehydrated methylene chloride solution (30 ml)
cooled to -78℃ (dry ice-acetone),
Bubble ozone gas into the reaction mixture until it turns blue. The ozone flow is stopped and the reaction is purged by bubbling nitrogen until the blue color disappears. solid m-
Add chloroperbenzoic acid (3.0 mmol) and remove the cooling bath. Once the reaction mixture reaches room temperature, the flask is fitted with a reflux condenser and the mixture is heated to reflux for 3 days. Removal of the solvent under reduced pressure gave a white solid which was chromatographed on silica gel (methylene chloride containing 2% glacial acetic acid) to yield 663 mg (77%) of ( 3S ^* , 4R ^* )-1-( t-butyldimethylsilyl)-3-[( R ^* )-1-hydroxyethyl]-4-
(Carboxymethyl)-azetidin-2-one is obtained. NMR (CDCl ₃ + D ₂ O) δ3.6−4.3 (2H, m),
δ2.98 (1H, dd, J = 7, 2.1), δ2.7 (2H, d of AB type q, -CH ₂ CO ₂ H), δ1.29 (3H, d, J =
6), δ0.95 (9H, s), δ0.25 (6H, s). Example 6 ( 3S ^* , 4R ^* )-1-(t-butyldimethylsilyl)-3-[( R ^* )-1-hydroxyethyl]-
4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidine-2-
on 1,1'-Carbonyldiimidazole (1.10 mmol) was converted into ( 3S ^* , 4R ^* )-1-(t-butyldimethylsilyl)-3-[( R ^* )-1-hydroxyethyl]-4-carboxy Methyl-azetidine-2-
(1.0 mmol) in dry tetrahydrofuran (5 ml) at room temperature in one portion. The resulting solution is stirred at room temperature for 6 hours. In a second flask, magnesium ethoxide (5 mmol) was mixed with mono-p-nitrobenzyl ester of malonic acid (10
mmol) in dehydrated tetrahydrofuran solution (25
ml) at once. The resulting mixture is 1 at room temperature.
After stirring for an hour, the tetrahydrofuran is pumped off and the resinous residue is triturated with ether to give the magnesium salt as a white solid. 1.1 mmol of this magnesium salt is added to the first reaction flask and the resulting mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into 50 ml of ether, washed with 0.5N hydrochloric acid solution (20 ml), water (20 ml), saturated aqueous sodium bicarbonate solution (20 ml), saturated brine, and dried over magnesium sulfate. Removal of the solvent under reduced pressure yielded an oil, which was chromatographed on silica gel (ether) to yield ( 3S ^* , 4R ^* )-1-
(t-butyldimethylsilyl)-3-[( R ^* )-1-
Hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one is obtained. NMR ( _CDCl3 − _D2O ) δ8.24, 8.10, 7.52, 7.38
(2H, AB type, aromatic), δ5.26 (2H, s, -CH ₂ -
Ar), δ3.5-4.2 (2H, m, H-5, H-8), δ2.6
-3.3 (3H, m, H-6, [formula]), δ1.3 (3H, d, J=6.6, C H ₃ -), δ0.98 (9H, s, ±
Si−), δ0.25 (6H, s, (C H ₃ ) ₂ Si). Example 7 ( 3S ^* , 4R ^* )-3-[( R ^* )-1-hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidine-2- on manufacturing ( 3S ^* , 4R ^* )-1-(t-butyldimethylsilyl)-3-[( R ^* )-1-hydroxyethyl]-4
-(3-p-nitrobenzyloxycarbonyl-
2-oxopropyl)-azetidin-2-one (1.0 mmol) in 9:1 (V/V) methanol-
Cool the 20 ml solution of water to 0°C. Concentrated hydrochloric acid (0.34
ml) and the resulting solution was stirred at 0°C for 15 minutes and warmed to room temperature. After 2.5 hours, the reaction mixture was diluted with ethyl acetate (20 ml) and water (10 ml) at room temperature.
and saturated saline, dehydrated with magnesium sulfate,
When concentrated under reduced pressure, ( 3S ^* , 4R ^* )-3-[( R ^* )-
1-hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)
-Azetidin-2-one is obtained. Example 8 ( 3S ^* , 4R ^* )-3-[( R ^* )-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)
Production of oxycarbonyl-2-oxo-3-diazopropyl]-azetidin-2-one Triethylamine (263 mg, 2.6 mmol) was converted into ( 3S ^* , 4R ^* )-3-[( R ^* )-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl] Add via syringe to a mixture of azetidin-2-one (253 mg, 0.72 mol) and p-carboxybenzenesulfonyl azide (196 mg, 0.84 mmol) in dry acetonitrile (6 ml) at 0°C. After the addition is complete, the cooling bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (50ml) and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on a short silica gel column (ethyl acetate) to yield 222 mg.
( 3S ^* , 4R ^* )-1-(t-butyldimethylsilyl)-3-[( R ^* )-1(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl) )oxycarbonyl-2-oxopropyl]-
In total, 81%] of ( 3S ^* , 4R ^* )-3-[( R ^* )-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxy] from azetidin-2-one carbonyl-2-oxo-3-diazopropyl]
-Azetidin-2-one is obtained as a white solid. IR ( _CHCl3 , cm ^-1 ) 3410, 2132, 1756, 1718,
1650, 1350, 1280, 1120; NMR ( _CDCl3 ) δ7.9 (2d-aromatic, 4H), δ5.4
(s, 2H), δ6.2 (brs 1H), δ4.1 (m, 2H), δ2.
6
−3.6 (m, 4H), δ1.32 (d, 3H, J=6.2). Example 9 ( 5R ^* , 6S ^* ) p-nitrobenzyl 6-[( R
^* )-1-hydroxyethyl]-1-azabicyclo[3.2.0]heptane-3,7-dione-2-
Production of carboxylates ( 3S ^* , 4R ^* )-3-[( R ^* )-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]-azetidine- A suspension of 2-one (56.4 mg, 0.15 mmol) and rhodium acetate (0.1 mg) in dehydrated benzene (3 ml) is deoxygenated by bubbling nitrogen for 10 minutes. Heat the mixture at 78°C for 1 hour. During heating the solid starting material gradually dissolves. The mixture was cooled, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give (5 R ^* , 6 S ^* ) p-
Nitrobenzyl 6-[( R ^* )-1-hydroxyethyl]-1-azabicyclo[3.2.0]heptane-3,
7-dione-2-carboxylate is obtained. Physical properties: PNB=p-nitrobenzyl group NMR: (300MHz) δ8.26, 7.54 (aromatic, 4H),
5.29 (AB type, 2H), 4.77 (s, 1H), 4.32 (dq,
1H, J=6.6, 7) 4.16 (ddd, 1H, J=7, 7.5,
2.2), 3.21 (dd, 1H, J=7, 2.2), 2.94 (dd,
1H, J=19.5, 7), 2.50 (dd, 1H, J=19.5,
7.5), 2.2 (brs, 1H), 1.37 (d, 3H, J=6.6). IR: ( _CHCl3 , cm ^-1 ) 1770, 1758, 1610, 1522,
1353. Example 10 Production of p-nitrobenzyloxycarbonylaminoethanethiol Diethyl ether ( _Et2O ) stirring in an ice bath
Add 3.2 g of cysteamine hydrochloride (molecular weight = 114; 28.1 mmol) to 600 ml - 75 ml of _H2O . _H2O75
7.14 g of NaHCO ₃ (molecular weight = 84; 85
mmol) solution. At room temperature, excluding the ice bath
A solution of 6.75 g of p-nitrobenzyl chloroformate (molecular weight = 216; 31.3 mmol) in 270 ml of Et ₂ O is added dropwise over the course of 1 hour. After 10 minutes, separate the two layers. Extract the ether layer with 150 ml of 0.25NHCl and 200 ml of saturated saline. each water layer
Backwash continuously with 100ml of _Et2O . Collected Et ₂ O
The layers are dried over anhydrous MgSO ₄ , filtered, and concentrated under a stream of N ₂ . The crystalline residue is suspended in a small amount of ether, filtered, and the resulting pale yellow crystals are dried under vacuum to obtain 4.7 g of p-nitrobenzyloxycarbonylaminoethanethiol (65% yield). NMR (CDCl ₃ ): 8.18 (d, J = 8 Hz, aromatic proton ortho to the nitro group), 7.47 (d, J = 8 Hz, aromatic proton meta to the nitro group) in ppm from TMS to the down magnetic field side. group proton), 5.27( -NH
-), 5.20 (s, -CH ₂ -NH-), 2.67 (m, -CH
₂ -SH), 1.35 (t, J = 8.5Hz, -SH ) IR ( _CHCl3 solution): Carbonyl -1725cm ^-1 Mass spectrum: Molecular ion -256, 209 (M-47), 120
(M-136), 136( ⁺ _{CH2φpNO2 )} . Example 11 ( 5R ^* , 6S ^* )p-nitrobenzyl 3-[2
-(p-nitrobenzyloxycarbonyl)aminoethylthio]6-[( R ^* )-1-hydroxyethyl]-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate Manufacturing of (5 R ^* , 6 S ^* ) p-nitrobenzyl 6-[( R
^* )-1-Hydroxyethyl]-1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (51 mg, 0.147 mmol) in acetonitrile (3 ml) and cooled the resulting solution to 0°C. do. Diisopropylamine (22 mg, 0.17 mmol) is added via syringe and the resulting solution is stirred for 1 minute at 0°C before a solution of freshly recrystallized anhydrous p-toluenesulfonic acid (51 mg, 0.156 mmol) in dehydrated acetonitrile (1 ml) is added. The resulting solution was stirred at 0° C. for 1 hour, resulting in (5 R ^* , 6 S ^* ) p-nitrobenzyl 3-(p-toluenesulfonyloxy)-
6-[( R ^* )-1-Hydroxyethyl]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is provided and cooled to -25<0>C. Diisopropylethylamine (80.5mg,
0.624 mmol) is added via syringe followed immediately by a solution of N-p-nitrobenzyloxycarbonylcysteamine (40 mg, 0.156 mmol) in dehydrated acetonitrile (1 ml). Store the reaction mixture in the refrigerator for 70 hours. The mixture is diluted with 25 ml of ethyl acetate, washed with saturated brine, and then dried over magnesium sulfate. The yellow oil obtained by removing the solvent by vacuum concentration was transferred to a silica gel plate (ethyl acetate,
When chromatography is performed using R _f =0.4), (5 R
^* ． 6S ^* ) p-nitrobenzyl 3-[2-(p-nitrobenzyloxycarbonyl)aminoethylthio]-6-[( R )-1-hydroxyethyl]-1-
Azabicyclo[3.2.0]hept-2-ene-7-
One-2-carboxylate is obtained as a yellow solid. IR (Kneaded with Nujiyor) 1773 and 1690cm
^-1 . NMR (CDCl ₃ ) δ7.54−8.26 (overlapping
AB type q, 4H), δ5.40 (AB type q, 2H), δ5.22 (s,
2H), δ4.27(m, 2H), δ3.47(m), δ3.23(dd,
1H), δ3.14 (dd, 1H), δ3.40 (dd, 1H), δ3.04
(m, 2H), δ1.37 (d, 3H). Example 12 Production of thienamycin N-p-nitrobenzyloxycarbonylthienamycin p-nitrobenzyl ester (10 mg,
0.017 mmol) and 10% pd/c-Boihofer tetrahydrofuran (2
ml), 0.1 M dipotassium hydrogen phosphate (1.4 ml), and 2-propanol (0.2 ml) is hydrogenated on a Parr shaker at 40 psi for 30 minutes.
The mixture is filtered and the catalyst is washed with water (3 x 3 ml).
The combined filtrate and washings were extracted with ethyl acetate-ethyl ether, concentrated to ~3 ml, and lyophilized. Example 13 Preparation of 6-methylthienamycin 1-(t-butyldimethylsilyl)-3-(1-
hydroxyethyl)-3α,β-methyl-4-
(prop-2-ene)azetidin-2-one 342μ diisopropylamine stirred under _N2
(2.44 mmol) of 2.54 M n-butyllithium in 5 ml of dehydrated tetrahydrofuran (THF).
Add ml (2.45 mmol). After stirring for 10 minutes, 1-
(t-butyldimethylsilyl)-4-(prop-2
-ene)-azetidin-2-one 500 mg anhydrous
Add 2ml THF solution. After stirring for 10 minutes, add 153μ of methyl iodide (2.46 mmol). The cooling bath is removed and the reaction mixture is stirred for 25 minutes. Recool to −78° C. and add 1 ml (2.45 mmol) of 2.45 Mn-butyllithium. After 5 minutes, 250μ of distilled acetaldehyde (4.49 mmol) is added and the cooling bath is removed. After 30 minutes, convert the reaction mixture to 10 ml of 1M
Add to KH ₂ PO ₄ - saturated saline solution - Et ₂ O. Separate into two layers and wash the organic layer with 10 ml of 1M KH ₂ PO ₄ -15 ml of saturated brine and then with saturated brine. After dehydration with magnesium sulfate, filtration, and concentration under reduced pressure, 626 mg of crude reaction product is obtained. Chromatography on silica gel (0-20% ether: petroleum ether) yields a mixture of 125 mg of 3α-methyl compound and 234 mg of a slightly more polar 3β-methyl compound ( R ^* and S ^* ). NMR of 3α methyl component (300MHz, CDCl ₃ ) δ0.24
and 0.26(2s, Si( _CH3 ) ₂ ), 0.97(s, Si-C
( _CH3 ) ₃ ), 1.22 (d, J=6Hz _, CH3CHOH- ),
1.30 (s, CH ₃ ), 2.34 (d, OH), 2.42−2.81 (m,
CH2CH = _CH2 ), 3.44( _dd , J=4 and 10Hz,
H4), 4.09−4.19 (m, CH ₃ C H OH−), 5.09−
6.02 (m, -CH= _CH2 ). NMR of 3β methyl component (300MHz, CDCl ₃ ) δ0.23
-0.25 (s, Si(CH ₃ ) ₂ ), 0.95 and 0.96 (2s, Si-C
(CH ₃ ) ₃ ), 1.14-1.22 (continuation of α peaks of CH 3 and CH ₃ CHOH, 2.29-2.62 (m, CH ₂ CH=CH _{2 )} ,
3.40 (dd, J=3.5 and 11Hz, S ^* H4), 3.70 (dd,
J = 3.5 and 11Hz, R ^* H4) 3.86−4.00 (m, CH ₃ C
HOH-), 5.08-5.96 (m _, -CH = CH2 ). 1-(t-butyldimethylsilyl)-3-(1-
oxoethyl)-3β-methyl-4-(prop-
2-ene)azetidin-2-one Trifluoroacetic anhydride (180 μ, 1.28 mmol) is added dropwise via syringe to a solution of dimethyl sulfoxide (120 μ, 1.69 mmol) in dehydrated methylene chloride (2.5 ml) at −78° C. under N ₂ . The resulting mixture is stirred at -78°C for 15 minutes. 1-(t-butyldimethylsilyl)-3-(1-hydroxyethyl)-3β
-Methyl-4-(prop-2-ene)-azetidin-2-one (234 mg, 0.83 mmol) in methylene chloride (2 ml) was added and the resulting solution was heated at -78°C.
Stir for 1 hour. Triethylamine (382μ,
Add 2.76 mmol) with a syringe and remove the cooling bath. 1
After an hour, the reaction mixture was diluted with methylene chloride, water,
Wash with saturated saline, dehydrate with magnesium sulfate, and filter. The solvent was removed by concentration under reduced pressure to obtain a partially crystalline oil. Chromatography on silica gel (0-10% ether: petroleum ether) yields 191 mg of the title compound. IR (CHCl ₃ ) μ5.76, 5.87 Mass spectrum m/e 266, 240, 224 NMR (60MHz, CDCl ₃ ) 0.25 (2s, Si(CH ₃ ) ₂ ),
0.97 (s, Si-C( _CH3 ) ₃ ), 1.45 (s, _CH3 ), 2.28
(s, CH ₃ −C=O), 2.33−2.62 (m, CH 2 _CH =
_CH2 ), 4.15 (dd, J=5 and 10Hz, H4), 4.88−
6.10 (m, C H =C H ₂ ). 1-(t-butyldimethylsilyl)-3-(1-
Hydroxyethyl)-3β-methyl-4-(prop-2-ene)-azetidin-2-one 4.26 g of 1-(t-butyldimethylsilyl)-3
To a stirred solution of -(1-oxoethyl)-3β-methyl-4-(prop-2-ene)-azetidin-2-one (15.2 mmol) in 90 ml isopropanol was added 807 mg of sodium borohydride (21.2 mmol). Add. After stirring vigorously for 45 min under N ₂ , the reaction mixture was mixed with ~100 ml 1M KH ₂ PO ₄ −400 ml H ₂ O−
Pour (carefully) into _500mlEt2O . After separation into two layers, the aqueous layer is washed twice with _Et2O . The combined organic layer was washed twice with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 4.1 g of an oil. When chromatographed with 300g of silica gel (0-10% acetone:hexane), mainly S ^*
3.84 g of diastereomer-containing substance and 1.58 g of R ^* diastereomer are obtained. Measured values of R ^* diastereomer: IR (CHCl ₃ ) μ5.80 Mass spectrum m/e284 (M ⁺ +1), 268, 226 NMR (300MHz, CDCl ₃ ) δ0.24 (2s, Si
(CH ₃ ) ₂ ), 0.96 (s, Si(CH ₃ ) ₃ ), 1.17 (d, 1.18
partially obscured by satellite peaks of
CH ₂ CHOH−), 1.18 (s, CH ₃ ), 1.70 (d,
OH) _, 2.32-2.60 (m, CH2CH = _CH2 ), 3.71
(dd, J=4 and 11Hz, H4), 3.89−3.98 (m,
CH ₂ C H OH), 5.12-5.90 (m, CH = CH ₂ ) 1-(t-butyldimethylsilyl)-3-(1-
t-butyldimethylsilyloxyethyl)-3β
-Methyl-4-(prop-2-ene)-azetidin-2-one While stirring under _N2 , 582 mg of 1-(t-butyldimethylsilyl)-3-(1-hydroxyethyl)
-3β-Methyl-4-(prop-2-ene)-azetidin-2-one (2.06 mmol) in 6 ml of dehydrated N,N-dimethylformamide was added to 320μ
of triethylamine (2.31 mmol) followed by 356 mg of t-butyldimethylsilyl chloride (2.37 mmol). After stirring overnight, the reaction mixture was diluted with 1.3 ml of 1M KH ₂ PO ₄ −50 ml of saturated saline −
Pour into 50ml methylene chloride. After dividing into two layers,
The aqueous layer is extracted again with methylene chloride. The combined organic layer was washed twice with saturated brine, dried over magnesium sulfate, filtered, and concentrated to obtain 699 mg of crude material.
Chromatography on silica gel (0-50% ethyl acetate:hexane) yielded 473 mg of the title compound.
Obtain 211 mg of recovered starting material. IR (CHCl ₃ ) μ5.78 Mass spectrum m/e 397 (M ⁺ ), 382, 340 NMR (300MHz, CDCl ₃ ) δ 0.05, 0.08, 0.21
0.26 (4s, Si( _CH3 ) ₂ ), 0.90 and 0.96 (2s, Si-C
( _CH3 ) ₃ ), 1.11 (d, J=6Hz _{, CH3CHOSi-} ) ,
1.14 (s, CH ₃ ), 2.30−2.56 (m, CH 2 _CH =
CH ₂ ), 3.66 (dd, J=4 and 10Hz, H4), 3.91 (q,
J=6Hz, CH ₃ C H OSi−), 5.08−5.94 (m, C H
= CH2 ) _. 1-(t-butyldimethylsilyl)-3-(1-
t-butyldimethylsilyloxyethyl)-3β
-Methyl-4-(2-oxoethyl)-azetidin-2-one 1.05g of 1-(t-butyldimethylsilyl)-3
-(1-t-butyldimethylsilyloxyethyl)
A dehydrated methylene chloride solution (30 ml) of -3β-methyl-4-(prop-2-ene)-azetidin-2-one (2.6 mmol) was cooled to -78°C, and a gas stream containing dry ozone in oxygen was heated until a blue color appeared. Blow in until it disappears. The cooling bath is removed and the reaction mixture is then concentrated in vacuo under a stream of _N2 . Dissolve the crude ozonide in 5 ml of methylene chloride and add 580μ of dimethyl sulfide (7.9
mmol) and replaced with _N2 . 6 hours later,
Add another 580μ of dimethyl sulfide and allow the reaction to stir under _N2 overnight. The reaction is concentrated under high vacuum and chromatographed on silica gel (methylene chloride). The yield can be increased by re-treating the previous fraction containing unreacted ozonide as well as the target aldehyde with dimethyl sulfide. The latter fraction contains 531 mg of the desired aldehyde. IR (CHCl ₃ ) μ5.75, 5.80 (sh) Mass spectrum m/e400 (M ⁺ +1), 384, 342. NMR (300MHz, _CDCl3 ) δ0.06, 0.09, 0.19
0.24 (4s, Si( _CH3 ) ₂ ), 0.88 and 0.95 (2s, SiC
(CH ₃ ) ₃ ), 1.09 (s, CH ₃ ), 1.15 (d, J=6Hz,
CH3CHOSi- ), 2.75-2.80 ( _m , _CH2CHO ),
3.98 (q, J=6Hz, CH ₃ CHOSi−), 4.16 (dd,
J = 5.5 and 7.5Hz, H4), 9.84 (t, CHO). 1-(t-butyldimethylsilyl)-3-(1-
t-butyldimethylsilyloxyethyl)-3β
-Methyl-4-(carboxymethyl)-azetidin-2-one 620 mg of 1-(t-butyldimethylsilyl)-3
-(t-butyldimethylsilyloxyethyl)-
3β-Methyl-4-(2-oxoethyl)-azetidin-2-one (1.55 mmol) in distilled acetone
The 22 ml solution is cooled in an ice bath and treated with 447μ Johns reagent (2.6M CrO ₃ , 1.16 mmol). After stirring for 15 minutes, add 409μ of absolute ethanol and continue stirring for 5 minutes. The cooling bath is removed and the reaction mixture is quickly concentrated to a small volume under a stream of _N2 . Add ethyl acetate and water to the concentrate. Divide into two layers, wash the organic layer three times with saturated saline, dehydrate with magnesium sulfate,
Filter and concentrate to obtain 629 mg of crude product. Chromatography on silica gel (0-1% acetic acid:methylene chloride) yields 498 mg of the desired product. IR (CHCl ₃ ) μ5.76br Mass spectrum m/e (silylated product) 487, 472,
430 (487-t-butyl) NMR (300MHz, CDCl ₃ ) δ0.04, 0.07, 0.20
0.24 (4s, Si( _CH3 ) ₂ ), 0.86 and 0.93 (2s, Si-C
( _CH3 ) ₃ ), 1.09 (d, J=6Hz _, CH3CHOSi ),
1.11 (s, CH ₃ ), 2.63−2.72 (2dd, respectively J=
9 and 16Hz and J = 5 and 16Hz, C H ₂ CO ₂ H), 3.96
(q, J=6Hz, CH ₃ C H OSi−), 4.11 (dd, J=
5 and 9Hz, H4). 1-(t-butyldimethylsilyl)-3-(1-
t-butyldimethylsilyloxyethyl)-3β
-Methyl-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)azetidin-2-one 1,1'-carbonyldiimidazole was added to 251 mg of 1-(t-butyldimethylsilyl)-3-(1-t
-butyldimethylsilyloxyethyl)-3β-methyl-4-(carboxymethyl)-azetidine-2
-one (0.60 mmol) in dry tetrahydrofuran (3 ml) in one portion at room temperature under _N2 . The resulting solution is stirred at room temperature for 3.5 hours. In a second flask, magnesium ethoxide (5 mmol) is added once to a solution of mono-p-nitrobenzyl ester of malonic acid (10 mmol) in anhydrous tetrahydrofuran (25 ml). The resulting mixture is stirred at room temperature for 1 hour, the tetrahydrofuran is pumped off and the resinous residue is triturated with ether to give the magnesium as a white solid. The magnesium salt (339 mg, 0.678 mmol) is added to the first reaction flask and the resulting mixture is stirred at room temperature overnight. The reaction mixture is poured into 50 mg of ether, washed with 0.5N hydrochloric acid solution (12.3 ml), water (12.3 ml), saturated aqueous sodium bicarbonate solution (12.3 ml), saturated brine and dried over magnesium sulfate. The solvent was removed by concentration under reduced pressure to obtain 356 mg of oil, which was added to 6-
1000μ silica gel GF plate (25% acetone/
Perform chromatography using hexane). Objective
Immediately scrape off the UV absorption band and extract with 70% acetone/hexane. Concentration under reduced pressure yields 235 mg of the title compound. IR (CHCl ₃ ) μ5.75 Mass spectrum m/e 592, 577 (M ⁺ -t-butyl) NMR (300MHz, CDCl ₃ ) δ 0.04, 0.08, 0.15
0.20 (4s, Si( CH3 ) ₂ ), 0.86 and _0.92 (2s, Si-C
(CH ₃ ) ₃ ), 1.02 (s, CH ₃ ), 1.12 (d, J=6Hz,
CH3CHOSi− ), 2.87(brd, J ₌ 6Hz,
[Formula], )3.58 (s, [Formula]), 3.95 (q, J=6Hz, CH ₃ C H OSi−), 4.17 (brt, J=6Hz, H4),
5.29 (s, CO ₂ CH ₂ φpNO ₂ ), 7.56 and 8.27 (2d, aromatic proton). 3-(1-hydroxyethyl)-3β-methyl-
4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)azetidin-2-one Dilute concentrated hydrochloric acid (0.68ml) with 9:1 methanol:water at 40%
22 ml (4.5 mmol) of that solution with a volume of ml
319 mg of 1-(t-butyldimethylsilyl)-3-
(1-t-butyldimethylsilyloxyethyl)-
Add to 3β-methyl-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (0.54 mmol) with good stirring under N ₂ . After 8 hours, add 8 ml of the reaction product to 1M
Add to KH ₂ PO ₄ −150 ml H ₂ O −150 ml ethyl acetate. Separate into two layers, and wash the organic layer with saturated saline containing 8 ml of 1M K ₂ HPO ₄ and then with saturated saline alone (×2). After dehydration with magnesium sulfate, filtration, and concentration under reduced pressure, 241 mg of oil was obtained. Chromatograph on 6-1000μ silica gel GF plates (50% acetone/hexane). Next, 129 mg of the title compound is obtained by extracting the desired UV absorption band with 70% acetone/hexane. The less polar UV absorption band still contains 57 mg of material with the o-silyl group intact. Compound measurements: IR (CHCl ₃ ) μ5.70 (br), 5.81 (sh) Mass spectrum m/e NMR (300MHz, CDCl ₃ ) δ1.14 (s, CH ₃ ),
1.23 (d, J=6Hz, CH3CHOH ) _, 2.81−2.98
(m, [formula]), 3.62 (s, C H ₂ CO ₂ CH ₂ φpNO ₂ ), 4.05 (center of m, H4 and
CH ₃ CHOH), 5.30 (s, CO ₂ C H ₂ φpNO ₂ ), 6.01
(br, s, NH), 7.57 and 8.30 (2d, aromatic). 3-(1-hydroxyethyl)-3β-methyl-
4-(3-Diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one Triethylamine (55 μ, 0.397 mmol) was dissolved in 3-(1-hydroxyethyl)-3β-methyl-4
-[3-(p-Nitrobenzyl)oxycarbonyl-2-oxopropyl]-azetidin-2-one (40 mg, 0.11 mmol) and p-carboxybenzenesulfonyl azide (30 mg, 0.13 mmol) in dehydrated acetonitrile (1 ml) mixture by syringe at 0°C. After the addition is complete, the cooling bath is removed and the reaction mixture is stirred at room temperature for 1.5 hours. The mixture is diluted with ethyl acetate (10ml) and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methylene chloride, filtered, and concentrated under reduced pressure to obtain 53 mg of a white foam. Quick filtration through a short silica gel column (ethyl acetate) yields the title compound as a slightly cloudy white solid.
Get 41 mg. On a large scale, the product crystallizes from the reaction mixture together with the by-products of the reaction. The product is obtained in this case by extracting the actual insoluble material with methylene chloride and then chromatographing the contents of the filtrate. Melting point 162-170℃ decomposition IR (CHCl ₃ ) μ4.70, 5.70, 5.81 NMR (300MHz, d ₆ -DMSO) δ0.95 (s,
CH ₃ ), 1.03 (d, J=6Hz, CH 3 CHOH ₎ , 3.05
(d, J=6Hz, [formula]), 3.68-3.76 (m, CH ₃ C H OH), 3.90 (t, J=6Hz,
H4), 4.85 (d, OH), 5.46 (s, CH ₂ −φ−p−
_NO2 ), 7.76 and 8.31 (2d, aromatic proton), 7.93
(s, NH). p-Nitrobenzyl 6-(1-hydroxyethyl)-6β-methyl-3-[2-p-nitrobenzyloxycarbonyl)amino]ethylthio-
1-Azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate 3-(1-hydroxyethyl)-3β-methyl-
4-[3-Diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl]-azetidin-2-one (35 mg, 0.09 mmol) and rhodium acetate (0.1 mg) suspended in anhydrous toluene (3.2 ml). The suspension is deoxygenated by alternately (3x) vacuum and _N2 treatments. The mixture is heated at about 100° C. for 1 hour with stirring under N ₂ . During heating the solid starting material gradually dissolves. The mixture is cooled, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to yield the bicyclic ketone as a white foam.
The crude bicyclic ketone (32.5 mg, 0.09 mmol) is dissolved in dry acetonitrile (1.8 ml) and the resulting solution is cooled to 0° C. under N ₂ . Diisopropylethylamine (18.9μ, 0.11 mmol) was added followed by diphenylchlorophosphate (19.9μ,
0.10 mmol) and the resulting solution was incubated at 0 °C.
Stir for 1 minute. Diisopropylethylamine (17.7 μ, 0.10 mmol) was added via syringe followed by p-nitrobenzyloxycarbonylaminoethanethiol (26.6 mg, 0.104 mmol);
The reaction is stirred for 2.5 hours. Add the reaction to 20ml ethyl acetate - 10ml water. Divide into two layers and remove 8ml of organic layer.
Extract with 0.1M KH ₂ PO ₄ , 8 ml 0.1M K ₂ HPO ₄ , 2× saturated brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to give 65 mg of a yellow foam. 3
- Perform chromatography on a 1000μ silica gel GF plate (ethyl acetate), extract the desired UV absorption band (ethyl acetate), concentrate to obtain an oil, add methylene chloride (dehydrate with magnesium sulfate),
Filtration and reconcentration under reduced pressure afford 31 mg of the title compound as a pale yellow foam. IR (CHCl ₃ ) μ5.64, 5.81 (br) Mass spectrum m/e600 (M ⁺ ), 556, 301 NMR (300MHz, CDCl ₃ ) δ1.24 (s, CH ₃ ),
1.27 (d, J = 6 Hz, CH ₃ CHOH), 3.15 (2.94-
J = 9 Hz d over m of 3.2, -SC H ₂ CH ₂ NH
−), 3.39−3.52 (m, −SCH ₂ C H ₂ NH−), 4.15
(center of m, CH ₃ C H OH), 4.31 (brt, J=9Hz,
H5), 5.20 (s, _{NHCO2CH2 -} aromatic), 5.38 (broadly spaced center of d, non-equivalent methylene proton of ester), 7.50-8.27 (continuity of peaks, aromatic). (±)-6-methylthienamycin 5.3 mg of p-nitrobenzyl 6-(1-hydroxyethyl)-6β-methyl-3-[2-p-nitrobenzyloxycarbonyl)amino]ethylthio-1-azabicyclo[3.2.0]hept-2-ene- 7-one-2-carboxylate with 500μ distilled THF, 500μ anhydrous EtOH, 330μ DI−
water, 33 μ MOPS buffer, 6.9 mg platinum oxide, 2
Add the glass beads. The reaction mixture is placed on a Parr shaker and subjected to alternating vacuum and application of N ₂ (3x), followed by vacuum and application of 50 psi H ₂ . Cool in an ice bath, centrifuge the reaction mixture, and filter the supernatant through a small cotton plug into a cold centrifuge tube. The residual catalyst is washed with 15 drops of DI- _H2O and centrifuged (3x); the supernatant is added to the first filtrate and finally extracted with ethyl acetate (3x1 ml). The aqueous layer was briefly aspirated to remove the remaining organic solvent, and the XAD- ₂ resin (~7 ml
(volume) and elute with DI-H ₂ O.
After the first 2.5 ml, the next 30 ml eluate contains the product. Repeat the above procedure with additional 5.4 mg and 5.0 mg of starting material. The combined aqueous solution is concentrated under reduced pressure without heating to a volume of 3 ml. Divide the solution in half (9.5 ml bond volume) μ-Bondapak
-C ₁₈ high performance liquid chromatography column (3% THF/DI
-H ₂ O, flow rate 2 ml/min, 254 mμ filter) and collect the large peaks. When concentrated as above, hydroxylamine-disappeared UV at 297 mμ
A solution of 2.1 mg of the title compound is obtained with a clean HPLC pattern (retention time ˜6.5 min) with a maximum and no electrophoretic mobility (1500 V - 30 min) in phosphate buffer at PH 7. Example 14 Following the method of Example 2 and modifying the basic method of Example 2 according to the notes included in the table, the azetidinones in the table are obtained. [Table] [Table] [Table] Can be treated with chloroformates.
Example 15 According to the above examples and text, especially Example 9,
If the substitution shown in Example 14 is carried out as shown in the diagram of Example 9, a representative intermediate of the present invention can be obtained. R=PNB (p-nitrobenzyl group) EXAMPLE 16 In accordance with the foregoing examples and text, the following compounds are prepared as representative demonstrations of the process of the invention. In the table below, the compounds obtained are selected from the starting materials available according to the text and the table of Examples, in particular Example 15 above. The column labeled "Precautions and Reagents" annotates established methods necessary to obtain the indicated compounds. In most cases, compounds are deprotected by the method described in Example 12. However, if the ^SR8 side chain does not contain a basic functional group, the final product can be easily obtained as a sodium salt (M=Na) by deprotection with a slight excess of _NaHCO3 . isolated.
In any case, if R ⁶ or R ⁷ has a basic group, the final product is most easily isolated as the free salt (M=H) rather than the sodium salt. Note that compounds actually shown as "free acids" are isolated as internal salts as a result of their zwitterionic nature. M=H, Na [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] Incorporation by reference Final antibiotic compound of the invention, structural formula: [wherein R ⁶ , R ⁷ and R ⁸ are as defined above] is fully disclosed in co-pending, commonly assigned U.S. Patent Application No. 129851, filed March 27, 1980. and claimed; the extent to which this co-pending U.S. patent application defines compounds of structural formula, their synthesis, and utility as antibiotics is incorporated herein by reference. The compounds of the present invention are also prepared by the methods disclosed and claimed in three co-pending commonly assigned U.S. patent applications of Christensen, Ratcliff and Salzmann: can do. These patent applications have structural formulas R ⁶ , R ⁷
and the ranges defining R ⁸ and the ranges they indicate for the synthesis of intermediates (defined above) are incorporated herein by reference. [wherein R ⁶ , R ⁷ and X are as defined above]. (1) Process for producing 1-carbapenems and their intermediates via 4-allyl azetidinone; U.S. Patent Application No. 134408, filed March 27, 1980 [Merck & Co., Inc., Attorney's List] Table No. 16479] (2) Process for producing 1-carbapenems and their intermediates via trithioorthoacetate; U.S. Patent Application No. 134396, filed March 27, 1980 [Merck & Co., Inc., Atony list number 16485〕 (3) 1 via silyl-substituted dithioacetal
- Process for producing carbapenems and their intermediates; U.S. Patent Application No. 134397, filed March 27, 1980 [Merck & Co., Inc., Attorney's Listing No. 16478] Also, those listed by reference are published European patent application 0007614 (application number 79102615.6, July 24, 1976)
). This application discloses certain dipeptidase inhibitors that increase the efficacy of certain 1-carbadithiapenem antibiotics when co-administered to mammals. The cited applications are incorporated by reference to the extent that they disclose (1) a definition of how susceptible carbadetiapenem substrates of the invention may be identified and (2) suitable inhibitors, compositions, and methods of treatment. It is being A particularly preferred inhibitor is 6-(L-2-amino-2-carboxyethylthio)-2-(2,2-DCC)-2-hexenoic acid.

Claims (1)

[Claims] 1 Formula: [wherein R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, unsubstituted hydrocarbon groups, and hydroxy (optionally protected) substituted hydrocarbon groups, and R ⁸ is hydrogen; Substituted and unsubstituted: alkyl, alkenyl, alkynyl groups having 1 to 10 carbon atoms; cycloalkyl, cyclo having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety; Alkylalkyl, alkylcycloalkyl groups; phenyl, aralkyl, aralkenyl, aralkynyl groups in which the aryl group is phenyl and the aliphatic moiety has up to 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl groups [however, One or more substituents for the above residues may be chloro, bromo, fluoro, R ¹ , -OH -OR ¹ [Formula] [Formula] [Formula] -NR ¹ R ² -NH ₂ -NHR ¹ [Formula] -SO ₂ NR ¹ R ² [Formula] −CO ₂ H −CO ₂ R ¹ −SH −CN −N ₃ −NO ₂ − N (R ¹ ) ₃ -SR ¹ ; (However, regarding the substituent on R ⁸ above, residue R ¹
and R ² is hydrogen, alkyl having 1 to 10 carbon atoms,
Alkenyl, alkynyl group; cycloalkyl, cycloalkylalkyl, alkylcycloalkyl group in which the cycloalkyl ring has up to 3 to 6 carbon atoms and the alkyl moiety has up to 1 to 6 carbon atoms; phenyl group; the aryl part is a phenyl group selected from the group consisting of aralkyl, aralkenyl, aralkynyl groups with an aliphatic moiety having 1 to 6 carbon atoms; independently selected from heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl groups]
independently selected from the group consisting of, with the proviso that one or more heteroatoms of the heterocyclyl moiety are selected from the group consisting of up to 1-4 oxygen, nitrogen, sulfur, and the carbon atoms of the alkyl moiety attached to the heterocyclyl moiety are The number is up to 1 to 6. In the method for producing a compound represented by the formula and a pharmaceutically acceptable salt, the formula The compound represented by is treated with 1,1'-carbonyldiimidazole and reacted with (R ² 'O ₂ CCH ₂ CO ₂ ) ₂ Mg to form the formula The protecting group R ¹ ′ of this compound is removed to form a compound of formula This compound is diazotized and cyclized to form a compound of formula form a compound and activate this compound to form the formula and reacting this compound with HSR ⁸ [wherein R ¹ ' is an N-protecting group and R ² ' is a protecting group or a pharmaceutically and X is a leaving group]. 2 R ⁸ is: 1) alkyl, cycloalkyl, alkenyl,
aliphatic (including carbocyclic) groups having 1 to 10 carbon atoms selected from cycloalkenyl and alkynyl groups; 2) alkyl, cycloalkyl, alkenyl;
Substituent groups selected from cycloalkenyl and alkynyl having 1 to 10 carbon atoms are chloro, bromo, fluoro, R ¹ , -OH -OR ¹ [Formula] [Formula] -NR ¹ R ² -NH ₂ - NHR ¹ [Formula] −SO ₂ NR ¹ R ² [Formula] −CO ₂ H −CO ₂ R ¹ −SH −CN −N ₃ −NO ₂ − N (R ¹ ) ₃ -Substituted aliphatic group selected from ¹ ; 3) Aryl and substituted aryl groups in which the aryl group is a phenyl group and the substituents are as defined in 2) above; 4) 1-4 O, N or Heteroaryl and substituted heteroaryl groups having an S atom and whose substituents are as defined in 2) above; 5) The aryl group is a phenyl group, and the aliphatic residue is phenyl or substituted phenyl (provided that the phenyl group 6) The aliphatic moiety is as defined in 1) above, wherein the substituent is as defined in 2) above; 6) the aliphatic moiety is as defined in 1) Yes; substituted or unsubstituted heteroaryl and heterocyclyl moieties have 1-4 O, N or S atoms, and the substituents are as defined in 2) above; heteroarylaliphatic and heterocyclylaliphatic groups; and 7) the heteroatom is selected from O, S, NR ⁰ (wherein R ⁰ is H, a substituted or unsubstituted alkyl group), and the substituent has 4 carbon atoms as defined in 2) above. - up to 12 substituted or unsubstituted alkyl-heteroatoms-alkyl groups. 3 ^R8 is: −CH ₃ −CH ₂ CH ₃ −CH ₂ CH ₂ CH ₃ −CH(CH ₃ ) ₂ −(CH ₂ ) ₃ CH ₃ −CH ₂ CH(CH ₃ ) ₂ -CH ₂ -CH=CH ₂ -CH ₂ -CH=C(CH ₃ ) ₂ -CH ₂ -C≡CH -CH ₂ -C≡C-CH ₃ 2
The method described in section. 4 R ⁸ is: −(CH ₂ ) _o OR ¹ ; n=2-6; R ¹ =H,
[Formula] CH ₃ [Formula] n = 1-6; X = O, NH, NR ¹ , R ¹ = H, CH ₃ - (CH ₂ ) _{o NH 2 ;} ^NHR1 ; n=2-6; ^R1 = _CH3 ,
CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , [Formula] −(CH ₂ ) _o NR ¹ R ² ; n=2-6; R ¹ /R ² =
_CH3 , _CH2CH3 ; _CH3 , _{CH3 ; CH2CH3 ,}
CH ₂ CH ₃ −CH ₂ CH ₂ SCH ₃ −CH ₂ CH ₂ NHC(CH ₃ ) ₃ [Formula] CH ₃ , [Formula] n=3-5 [Formula] R ¹ and R ² are independently selected from H and CH ₃ [Formula] R ¹ = H, CH ₃ [Formula] n=1, R ² /R ¹ = H, H; CH ₃ , H −CH ₂ −CH=CH−CH ₂ NH ₂ The method according to claim 2, wherein the substituted aliphatic group is a substituted aliphatic group selected from. 5 R ⁸ is: The method according to claim 2, wherein the aryl or substituted aryl group is selected from the following. 6 R ⁸ is: The method according to claim 2, wherein the heteroaryl or substituted heteroaryl group is selected from the following. 7 R ⁸ is: The method according to claim 2, wherein the arylaliphatic group is selected from the following. 8 R ⁸ is: 3. The method according to claim 2, wherein the heteroarylaliphatic or heterocyclylaliphatic group is selected from: 9 R ⁸ is: The method according to claim 2, wherein the substituted or unsubstituted alkyl-hetero atom-alkyl group is selected from the following. 10th formula: (R=phenyl, m-aminomethylphenyl,
o-, p-, m-hydroxyphenyl group A method according to claim 1 for the production of a compound of