JPS5899484A - Antibacterial compound, manufacture and use - 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] This invention provides novel β-lactam compounds, their production method, and
In particular, new lanom compounds (cla
vams). These compounds have antibacterial and
and β-lactamase inhibitory properties, therefore, even alone
Other β-lactams such as penicillins and cephalosporins
Treatment of bacterial infections as a synergistic composition with antibacterial agents
It is useful for Clavalanic acid has the structure of the following formula: and is described in British Patent No. 1608977.
and its many derivatives are known. Clavalanic acid and its derivatives have carboxylic acid in common.
It has a 2-ethylidene flavum core, that is, a molecule having the structure of the following formula: The inventors of this invention discovered that the #c4 carbon atom at the 2nd position of the flavum nucleus
They created a new nucleus by connecting a chain of children. Thus, this invention has a butylidene component at the second position of the flavum nucleus.
8-carboxyflavum-induced
It provides a conductor. Therefore, this invention KFi, a compound having a residue represented by the formula (■): its salts and esters
is included. Compounds of this invention include 2-(4-hydroxybutylidene)flavam-8-carbohydrates of the formula (■): ■ GO,H
This includes rubonic acid and its derivatives. Particularly relevant to this invention is 2): (wherein,
such as hydroxy or acylated hydroxy
Substituted hydroxy, mercapto, etherified mercap
Substituted mercapto or acylated mercapto
lucapto, azide, shea), nitro, inchiocyanane
, halogen atoms, amino, or alkylated amino.
or a substituted amino group such as acylated amino, or
The residue of the nucleophilic carbon may also be an activated aryl.
or a heteroaryl group), salts and esters thereof. In one embodiment, X is hydroxy, etherified
Nine hydroxy or acylated hydroxy
Substituted hydroxy, mercapto, etherified nine-mer
capto or acylated substitutions such as nine-mercapto
Mercapto, azide, cyano, nitro, inciocyana
Alto, halo, minino, or alkylated aminos are also available.
or with a substituted amino group such as a sylated 9-chomino group.
Yes, or X indicates a nucleophilic carbon residue, or
It is a modified aryl or heteroaryl group. As appropriate for compounds of formula (II), the double bond
, which has two stereochemical structures, namely:
That is, these compounds can be represented by the formula (W): ■. Suitable X is hydroxy or substituted hydroxy. -0RI for substituted hydroxy group. -00011, -0081'jl, -000,R1,
-008,R1, -0O08R1, -0080R1, -
080sH, -〇POsH, -080,Rj Oyo U-
ocowxMxj (where R'', R''k and Ha are
Independently substituted or unsubstituted carbon having 1 to 20 carbon atoms
(hydrogen group). More suitable 1kR1 is C1-1e alkyl, c, -t @
alkenyl, aryl(C1-m)alkyl, hetero
Cyclyl(0*-s)alkyl, aryl(C,-
1) Alknyl, heteroaryl (C1-.)alkyl
% am-a cycloalkyl, aryl, heteroaryl
, heterocyclyl or u C3-s cycloalkyl (
CI-.) Alkyl group, any group optionally placed
has been replaced. Suitable optional substituents of group R1 include Cl-5al
Kyl, aminos cl-/alkanoylamino, mono-
, di and tri(al-S) alkylamino, hydro
Roxy, cl-alkoxy, mercapto, C11 al
Killthio, heteroarylthio, arylthio, oxo
, sulfamoyl, carbamoyl, amidino, guanidi
nitro, bromine atom, chlorine atom, fluorine atom, carboxy
C group and its salt and ester groups, C8-・alkanois
ruoxy, ryocarbonyl and heteroarylka
Contains a rubonyl group. Preferably 1 km, X is l, 2 or 8 halogen
atom, cyano, azide, hydroxy%o, -s alkoxy
C, C1-4 furcatyloxy, C1-4 alkylthi
E, aryloxy such as phenoxy, amino, ax
-s alkanoylamino, carboxy or esterified
optionally substituted with a carboxy group
xy or benzyloxy group. Preferred X is a methoxy or ethoxy group. In another embodiment, when XFi acetoxy
4 Alkanoyloxy and methanesulfonyloxy
C1-, alkylsulfonyloxy or 1tp-toluene
Arylsulfonyloxy such as sulfonyloxy
It is. Suitable X is mercapto or substituted mercapto group
. Examples of substituted mercapto groups include -8C! OR4, -8
-14, -808R4, -Boo, R', -8O8,
R', -5CO100R4, -8080R4, -880,R
' , -8C! ONR'R', -8 (0) R4, -8 (
0), R4 and -8-8R4 (wherein R4, P and
R6 is independently a substituted or unsubstituted group having 1 to 20 carbon atoms;
hydrocarbon groups). R4, R” and
and suitable substituents for R@ include suitable substituents for R1.
Included are the groups listed above. A more suitable R4 is C1-1・alkyl, Cl-1@Ryoru
Cnyl, Rylyl (C3-6) alkyl, heterocyclyl
(Os-s)alkyl, aryl(C,-.)alke
Nyl, C3-a cycloalkyl (at -S )alkyl
heterocyclyl, heterocyclyl (C1-.)al
Kill, aryl, heteroaryl, heteroaryl (C
x-s) alkyl or 'd 0n-s cycloalkyl
and each is optionally substituted. The most suitable XFi group -8(0)nR' (where n is 0
%1 or 2; R'tl benzyl, cl-alkyls
c, -s alknyl, aryl or hetero 9-J
Ltte@di, any group R'! , 2 or 8 halo
Gen atom, azide, hydroxy, CI-・alkoxy,
C8-・alkanoyloxys'1-4furkylthio
, freeloxy such as phenoxy, amino, C1-
4 Furucatsuylamino, carboxylic acid is esterified
is optionally substituted with nine carboxy groups. Preferred X is -8(0)nR' (wherein n is 0 or
2; 1kCI-alkyl, benzyl as R'ei methyl
phenyl, phenyl or tetrazolyl group). Suitable X is amino (-mn*) or substituted amino group
It is. The substituted amino group includes -N111R1., -N
RIφR11, -11R1・R11R", -III
O][I R1・, -MHOXIZItl・, -NH8
0, R1・, −11110X”MRl・R1ν, −)i
(0!JR”)RlJ, -M(CXIR”)OZRl
M. -N (0XIRIsuzBlM, -N (axl ZR
")R" and -N(OIIZRISUCXIZR'(
In the formula, XI and Z are each an oxygen atom or a sulfur atom;
0, R11, H1 and Rlj may be independently substituted.
or an unsubstituted hydrocarbon group having 1 to 20 carbon atoms]
It will be done. Suitable substituents K for R1° to RLs are H
The nine groups listed above as being suitable as substituents for l are included.
Ru. Furthermore, the groups RM and R11 or separately the groups R11
RIJ is bonded to the carbon atom of triO and
4 atoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms
A heterocyclic ring may be formed having up to a number of heteroatoms. More appropriate R1, R11, H1! and R” Fi Germany
Standing? ,01-,・alkyl,'m-11ryukenyl,
Aryl (C1-.)alkyl, heterocyclyl (01
-s) alkyl, aryl (C, -s) alkenyl,
as-a cycloalkyl s 'j-8 cycloalkyl (
Os-g) alkyl, heterocyclyl, heterocyclyl
(01-s) alkyl, aryl, heteroaryl and
and heteroaryl('x-s)alkyl groups.
, either group is optionally substituted. The most suitable XFi, amino group, ethylamino, ethylamino
Aluminums such as amino, propylamino and butylamino
Kylamino group, G(Ct-s such as diethylamino)
) Alkylamino group, benzylamino, azetamide and
When O,-alkanoylamino, succinimide or 7
talimide, and these groups, excluding the amino group, have 1
12 or 8 halogen atoms, azide, hydroxy,
'1-alkoxy, C1, alkanoyloxy, cl-
4-furkylthio, aryloxy such as phenoxy,
Amino, C8-alkanoylamino, carboxy or
optionally substituted with an esterified carboxy group
. Preferred X is aminos C1--fulkylamino, base
ndylamino, C1, alkanoylamino or di
(01-) is a furkylamino group. Suitable Xs are adjacent via one carbon atom, e.g.
Aryl group or heteroaryl group bonded to group -OH, -
phenyl, furyl, pyrrolyl, chenyl
and fused to the benzene ring of one of these cyclic groups.
All of these groups are optionally substituted. Other heterocyclic groups of X include tetrazolyl and trioquine.
Contains midazolidinyl, C1-@alkyl or 0
, -, optionally substituted with alkoxycarbonyl. The appropriate fiX is the opening formula -Q R14R11Hll (in the formula
R14 and Hu are the same or different, at least
Stabilized carboxylic acid is a group that is attracting electrons.
Indicates a group that can generate an anion; R1' is a hydrogen atom or
is a substituted or unsubstituted hydrocarbon having 1 to 20 carbon atoms
is a nucleophilic carbon residue such as a group). Therefore, R14tHH is -CXI R1@t as mentioned above.
-OXI ZRI. similarly
R1 is defined in the same way as defined for K11.
can be done. More suitable 1kXu, -0H(OOORI')COR”
4 C< is -0H(COR1')(!OR" (RI in the formula
F and Hll are independently Cl-1@alkyl, CM-m
Cycloalkyl, furyl such as phenyl, benzyl
selected from aryl(Os-s)alkyl such as
Hlf and R18 are both 1.2 or 8 halogen
atom, azide, hydroxy, '1-@alkoxy, C
M-@alkanoyloxy, '1-4furkylthio,
Aryloxy such as phenoxy, amino C1-・al
canoylamino, carboxy or esterified
Optionally substituted by carboxy. Preferably VhX is -aH(cocms>). Also, suitable X is azide or cyano. Preferred X is hydrogen atom, iodine, bromine or chlorine
It is a child-like halogen atom. X is also azide
Compounds of halogen atoms are particularly useful chemical intermediates.
It is important to Compounds of formulas (I) to (IF), their salts and esters,
O Main use is To9 in medicine, therefore formulas (1) to (W)
The salts and esters of the compounds are preferably pharmaceutically acceptable. Pharmaceutically acceptable and non-pharmaceutical compounds of this invention
Intermediates, disinfectants or
Antibacterial agents or β for non-medical uses such as paint additives
- Can be used as a lactamase inhibitor. Suitable pharmaceutically acceptable salts of compounds of formulas (I) to (IV)
include aluminum salts, sodium salts, and potassium salts.
Eel alkali metal salts and calcium salts or mag
Alkaline earth metal O salts such as nesium salts;
monium salts and lower atom salts such as triethylamine.
rukylamine, and bicyclohexylamine, l-
Airenamine, M-ethylhyheridine and N-ben
Cycloalkylars such as di-β-phenethylamine
Examples include substituted ammonium salts such as salts of amines. Non-pharmaceutically acceptable salts used as intermediates include lithium
Contains aluminum salts and silver salts. Suitable esters of compounds of formulas (I) to (N) include enzymes
Biological methods such as hydrolysis and in vivo hydrolysis
and hydrogenolysis, hydrolysis, electrolysis or optical spectroscopy.
Contains esters that can be prepared by chemical methods such as
Ru. It is appropriate to esterify carboxylic acids with the following by-product groups.
be. That is, sub-forms (a), (1)), (C), (,
i), (8) and Vi(f): \Ml- (wherein M1 is a hydrogen atom or CI-f alkynyl
The group is optionally substituted with a C1-1 carboxylicyloxy group.
C8-alkanoyl group is Cjs-:h alkyl group
, or alkenyl or alkynyl having up to 6 carbon atoms
M1 is a hydrogen atom or a methyl group; M1 is a phenyl group
or fluorine atom, chlorine atom, JLi [child, nitro
, Cl-3 alkyl 4L<dc, substituted with -3 alkoxy group
substituted phenyl group; group 4 is a hydrogen atom or a phenyl group;
is a fluorine atom, chlorine atom, bromine atom, nitride group, or a fluorine atom, chlorine atom, bromine atom,
B, C1-1 alkyl or U 0t-s alkoxy
phenyl group substituted with a group; M is a hydrogen atom or methyl
Group; M' is 01-4 alkyl, phenyl, C1-4 alkyl
Koxy group, also linked to Muro Fi Muro, phthalidyl, di
methylphthalidyl or dimethoxyphthalidyl group
A' Fi (31-4 alkyl, phenyl
, chlorophenyl or hanitrophenyl group;
0s-a alkyl or kephenyl group; door is C1-4 alkyl
Kyl or phenyl group: M1OFi01-47
group; IQ Umuro is a Cl-4 alkyl group; or a group -O
Hm1m2 is a group represented by phenacyl or bromo7enacyl group). A preferred moiety 1 is a hydrogen atom, methyl, ethyl, vinyl or ethyl
It is a thinyl group. A preferred mu sVi hydrogen atom. suitable
Name 1 is phenyl, p-bromophenyl, p-methoxy
Phenyl or tip-nitrophenyl group. suitable mu
4 is a hydrogen atom. Preferred muro is methyl, t-butyl
Alternatively, it is linked to an ethoxy group. good
A suitable moiety is a methyl group. Preferred groups for by-products (IL) include methyl, ethyl and acetate.
Contains a tonyl group. Preferred groups include benzyl and p-nitroben.
Contains a zyl group. Preferred groups for the sub-formation (C) include acetoxymethyl,
pivaloyloxymethyl, α-ethoxycarbonyloxy
Mention may be made of dimethyl and phthalidyl groups. A preferred group of methoxymethyl groups is a methoxymethyl group. Preferred groups for sub-formation (6) include trimethylsilyl, ta
rt-butyldimethylsilyl and tart-butyldiph
Contains a phenylsilyl group. It A preferred group of formula (f) is p-methoxycarbonyl
It is a benzyl group. Particularly preferred ester groups are p-nitrobenzyl and p-nitrobenzyl.
It is a talidyl group. Pharmaceutically acceptable and in vivo hydrolyzable esters are
Essence that is hydrolyzed in the human body to produce the parent acid or its salt.
I'll call you. These esters are hydrolyzed in vivo.
The property of being able to
(I) to (N) into the animal's body fluids.
) by analyzing the presence or absence of the compound or its salt.
That's 111g. Suitable esters of this type include by-products (C) as defined above.
Contains esters. Further suitable esters include dimethylaminomethyl, dimethyl
Methylaminoethyl, diethylaminomethyl, diethyl
Di(Ol-s)alkylamino C such as aminoethyl
1-5 alkyl esters are included. Ester-like formula (T)-(IF) of by-products (a) to (f)
), the amino group is present in the group X.
If desired, they can be provided in the form of their acid addition salts.
. Is the acid used in this salt form pharmaceutically acceptable?
are most suitable, but are not pharmaceutically acceptable acid addition salts.
pharmaceutically acceptable salts, for example by ion exchange.
Vine used as an intermediate in manufacturing. appropriate pharmaceutical
Acceptable acid addition salts include addition of inorganic and organic acids.
salts, such as hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid,
Ruenesulfonic acid, queric acid, apple ill, vinegar ll,
Acid addition salts of lactic, tartaric, propionic and succinic acids
can be mentioned. Acid addition salts are most suitably provided in solid form and are
It is supplied as a solid crystalline substance. The compounds of this invention, when in crystalline form, may be
It can be made into a sea urchin solvate. This invention also provides pharmaceutical use of the compound of formula (1).
from an acceptable salt or ester and a pharmaceutically acceptable carrier.
The present invention provides an antibacterial composition. The composition of this invention can be used orally, topically or parenterally.
mammals, including humans, including forms used to
It can be used to treat bacterial infections in animals such as animals.
Wear. Suitable forms of the compositions of this invention include tablets, capsules.
agent, cream, syrup, suspension, solution, 6 compositions
including powders and sterile forms suitable for injection or infusion.
. Such compositions may contain diluents, binders, colorants, colorants,
Conventional pharmaceutical ingredients such as flavoring agents, preservatives, disintegrants, etc.
Techniques for the formulation of antibiotics containing acceptable raw materials
conventional pharmaceutical practices in a manner well known to those skilled in the art.
It can be formulated according to the requirements of the manufacturer. Injectable or injectable compositions of the compounds of this invention include
or high blood concentrations of the compounds of this invention by infusion administration.
This is particularly appropriate since it can be expected that Therefore, this
One preferred composition of the invention is sterile, particularly sterile.
It consists of the compound of this invention in a crystalline state. The injectable solution of this invention is sterile, pyrogen-free, water-based,
It can be made from liquids such as ethanol. Another method of administering the compounds of this invention is by injection.
The solution is to use a suspension. Such a suspension is
It can be made from sterile water, sterile saline, etc., and polyvinyl
Contains suspending agents such as biaridon, lecithin, etc.
You can. Alternatively, such compositions may be mixed with peanut oil or
Equivalents may also be made with acceptable oil suspensions, such as
can. To use the compounds of this invention as such suspensions:
, must be in the form of a fine powder. Oral unit dosage preparations comprising compounds of this invention
is another suitable composition of the compositions of this invention
. Unit dosage compositions for topical administration comprising compounds of this invention also include
Included in this invention. “Local administration 1 means, for example, mammary gland
During mastitis treatment with internal administration, topical application to the inner surface of the cow's mammary gland
This also includes cases where it is given. The compound of the invention with is present as the sole therapeutic agent in the composition.
However, drugs such as penicillins and cephalosporins
It may also be present in conjunction with other therapeutic agents. β-lactamer
Contains penicillins and cephalosporins that are unstable to
When present, the efficacy of the composition is enhanced (synergistic effect).
This is very advantageous. This synergistic composition contains
Suitable penicillins, cephalosporins to have
or other β-lactam antibiotics, including β-lactamer
Antibiotics known to be highly sensitive to antibiotics
Not only that, but there is also a certain degree of uniqueness to β-lactamases.
Also includes antibiotics to which resistance exists. Suitable penicillin to be included in the composition of this invention
These include benzylpenicillin and phenoxymethylpenicillin.
Silin, carbenicillin, azidocillin, propicillin
, ampicillin, amoxicillin, evicillin, tical
Syrin, Cyclacillin, Viapenicillin, Azidosiri
mezlocillin, sulpenicillin, piperagiline, etc.
Known nohenicillins and precursors of these penicillins
Medicines [-Ampicillin, benzylpenicillin, etc.]
Amoxicillin, with a 6-alpha-di-onoacetamide side chain
The aldehyde of penicillin (e.g.
For example hetacillin, metaampicillin and amoxicillin
(similar derivatives of
such as phenyl esters and indanyl α-esters.
acetoxymethyl ester of α-esters, pivalo
yloxymethyl ester, α-ethoxycarbonyl ester
Raw materials such as xyethyl esters or phthalidyl esters
Contains esters that can be hydrolyzed in the body. Further, as penicillin to be included in the composition of this invention,
Suitable ones include benzylpenicillin, phenoxymethylin
Lupenicillin, carbenicillin, azidocillin, propylene
Sirin, ampicillin, amoxicillin, evicillin,
Decalcillin, Cyclacillin, Viapenicillin, Azi
Docilin, mezlocillin, sulpenicillin, piperajiri
and other known penicillins and these penicillins.
Precursor drugs [e.g. benzylpenicillin or amoxicillin]
cilin, and carbenicillin and decalcillin phenylene
α-esters such as esters and indanyl α-esters
Acetoxymethyl ester of esters, hivaloyloxy
Methyl ester, α-ethoxycarbonyloxyethyl
Esthetics that can be hydrolyzed in vivo due to ester
] is included. Cephalosporin contained in the composition of the present invention
Suitable examples include cefatridine, cephaloridine,
Cephalothin, Cefazolin, Cephalexin, Cefa
Cedryl, Cefamant-Lunaphate, Cefavirin
, cefradine, 4-hydroxycephalexin, cefa
Valol, cephaloglycin, cefoperazone, other known
cephalosporins and their precursor drugs. Such compounds may be used in the form of salts, hydrates, etc.
There are many. Penicillin or cephalosporin used in the composition of this invention
If phosphorus is not suitable for oral administration, it is of course available for parenteral administration.
Used as a composition. The preferred penicillin used in the composition of this invention is
, ampicillin, amoxicillin, carbenicillin and
Contains Calcirin. This type of penicillin is
Can be used as a pharmaceutically acceptable salt such as the sodium salt
can. On the other hand, ampicillin and amoxicillin, e.g.
For example, if the compounds of this invention were previously described, then note 9.
When used as a topical composition, the zwitterionic form (generally amphibious)
Such as picillin octahydrate or amoxicillin octahydrate
) can be used in the form of fine powder. Preferred as penicillin for use as a synergistic composition
is amoxicillin, for example its sodium salt
Matake octahydrate is used. Particularly suitable cephalosporins for use in the compositions of this invention
Porins include cephaloridine and cefazolin.
, these include pharmaceutically acceptable substances such as sodium salts.
It may also be in the form of salt. When coexisting with cephalosporins or penicillins, this
of a compound of the invention and a penicillin or a cephalosporin.
The ratio can range from 10:1 to 1:10.
It may be varied, for example about 8:1, 2:1, 1:1%.
l:2, l:8, l:4, l:6 or l:6 (pure free anti-
weight/weight ratio based on biomass equivalents). This issue
Compositions for oral administration containing the compounds of
Contains a relatively higher amount of synergist than other injectable compositions. The total amount of compounds of this invention in a unit dosage form is
Usually 26-100 ell, usually 5O-50
For example, about 62h5.100, 126.160.
200 or 26911II. The compositions of this invention are suitable for use in the human respiratory system, secretion, inter alia.
in the urinary system, soft tissues, and mammary glands of livestock including cows.
It can be used to treat infectious diseases. The compounds of this invention usually contain 60 to 800 doses per treatment day.
For example, this is administered 1 to 6 times per day.
, more commonly administered in 14 doses of Fiz, a or V. death
However, more severe systemic infections or particularly persistent
High doses according to clinical practice for treatment of biological infections
amount may be used. Penicillin or Ceph in the synergistic composition of this invention
Allosporin is used in approximately the same amount as they are usually used.
amount is present, which amount is about 62.6 to 62.6 per dose.
s o o o lv, more commonly about 126.260.
It may be 500 or 1000 TIv. A particularly desirable composition of this invention is amoxicillin (8
(as hydrate or sodium salt) 150-1000 II
I and the compound of this invention from 25 to 500 Da.
. Other particularly desirable compositions of this invention include ampicillin or
is a compound of the present invention with its precursor 15GN1000MfI.
It contains 26 to 500 Da. Compositions in this form include ampicillin octahydrate, ampicillin octahydrate,
Ampicillin Anhydrous, Ampicillin Sodium Salt, Hetashi
phosphorus, bibambicillin mu salt, bacambicillin hydrochloride,
those containing tarambicillin hydrochloride are most suitable
. In this form of composition, the compound of the present invention may be combined.
It is most appropriate to contain it in crystalline form. This form of composition contains penicillin at 200-TO
The one containing G ~ is the most suitable, and the embodiment of this invention
Contains 50 to 250 μ of the compound (preferably crystal form II)
Preferably. Such compositions include arepicillin or amoxicillin.
Contains esters that can be hydrolyzed in the body, but it is non-transparent.
For oral or parenteral use, except when not used orally.
Can be used. Other particularly desirable compositions of this invention include carbenicillin
, decalcillin or their precursors tooNzooo
and 50 to 600 # of the compound of this invention. This form of the composition includes carbenicillin disodium
Contain salt or decalcillin disodium salt
is appropriate. More suitable in this form of composition are compounds of the invention
preferably containing 75 to 250 capes in crystalline form.
It is. Also, carbenicillin di-salt and tycarcillin
These compositions containing di-salts are used parenterally. This invention also provides for administering compositions of this invention.
provides a method for treating bacterial infections in humans or livestock;
It is something to do. The infection to be treated is usually Staphylococcus aureus.
us, Klebscilla erogenes, Escherichia coli,
Bacteria such as Proteus species and Bacteroides fragilis
There is something to be said for it. Among these, Staphylococcus au
Reus is the most tolerated by antimicrobially effective doses of the compounds of this invention.
It is a microorganism that is believed to be easily treated. mentioned above
Infections caused by other microorganisms can be treated with the compounds of this invention and with penicillin.
using a synergistically effective amount of phosphorus or cephalosporin.
Can be easily treated. Administration of these two components separately
Although synergistic agents (i.e.
compound of the invention) and a penicillin or a cephalosporin.
It is preferable to use a composition containing
This includes mastitis in livestock, including cattle. This invention also provides the formula (V): (wherein Ha is a hydrogen atom or a carboxy group)
; Y is oxygen or sulfur atom), and then, if necessary, 1)
Formula (Ill) (wherein X is hydroxy or mercap
The compound of formula (■) (in the formula, x is hydroxy or mer
I) Carboxy
Removal of the membrane-retaining group R1L and
a compound of formula (III) consisting of converting it into a
, provides a method for producing its salts and esters.
. In the compound of formula σ), the YFi oxygen atom is
preferable. The compound of formula σ) is new and can be used as an intermediate.
Useful. In addition, it is itself an active antimicrobial agent. A compound of formula (V) (when used as an intermediate, Y is sulfur)
atoms) are usually produced and reacted as they are without isolation.
let Compounds of formula (ma) can be prepared by reduction using conventional methods.
, X is a hydroxy or mercapto formula (l [l)
It can be converted into the compound of Appropriate reduction method
, complex hydrides such as boron hydride, e.g. lithium boron hydride.
um, sodium borohydride, potassium borohydride, water
Sodium cyano boron
boron hydrie), di-isobutyl aluminum
Nimium hydride, etc.; Moshike aluminum tree
Reagents such as isopropoxide are utilized. Kayo
Such reactions can be carried out with hydrocarbons, chlorinated hydrocarbons or ethers.
such as toluene, cyclohexane, diethyl ether
111 Heptane, hexane, dichloromethane or tetrahydrogen
It can be carried out in an inert organic solvent such as Dorofuran.
Ru. In addition, the reaction of the kernels takes place at temperatures that are not extreme, e.g. -80 to +
60℃, more appropriately 0 to +80℃, but usually
It can be carried out at room temperature. Formula (Ill) where X is hydroxy or mercapto
The compounds can be prepared by conventional methods using methods appropriate for the formation of each functional group.
On the other hand, for compounds of formula ([11) where X is not OH or EIH]
can be converted. For example, compounds where X is a halogen atom are nonmetal halides.
For example, produced by reaction with halogen 4j such as phosphorus trichloride, phosphorus tribromide, thionidyl chloride, and thionyl bromide.
can. This halogenating agent also contains halogen ions.
Hydrocarbonsulfonyl halide commonly used in
It may be a ride. Oka, ttf methanesulfonyl
Alkanesulfonyl halides such as chloride or
p-)Arylsulfur such as luenesulfonyl chloride
Honyl halide may also be used. Also, halogen io
The source may be a lithium halide or an amine salt.
stomach. The presence of a base such as pyridine is preferred for the hydrogenation reaction.
Delicious. This reaction can be observed at lower temperatures or at room temperature, e.g.
For example, it is preferable to carry out at -60 to +20°C. X is iodine
Compounds of the atomic formula (IIN) may contain the corresponding chloride or
reacts bromide with an iodide ion source such as lithium iodide
most commonly produced by a halogen exchange reaction
Ru. X is monosubstituted hydroxy or substituted mercapto (Il
The compound of l) can also be prepared by conventional methods, e.g. etherification reaction.
Alternatively, it can be produced by an acylation reaction. -OR or Vi-
For the etherification reaction of 8H, a Lewis acid catalyst such as boron trifluoride
in the presence of an inert solvent at reduced or room temperature.
The reaction of diazoalkanes can be carried out in the same manner. -O
The acylation reaction of H or -8i1 is performed using an acylating agent.
For example, RCY-te or REIO,-te (where T is nucleophilic
This can be done by reaction with a leaving group (which can be substituted with a neutral group).
. A suitable material is a halogen such as a chlorine or bromine atom.
or more mesylate or tosylate atoms;
C1-furkyl- or aryl-sulfonyloxy
a sulfonyloxy molecule such as a group, or 1 to 8 hydrogen atoms
C3-/cholkanoyloxy group optionally substituted with an atom
carboxylate molecules, especially acetoxy groups;
is an arylcarbonyl such as benzoyloxy
It's oxy. This reaction can be carried out using alkali metal salts or
Alkaline earth metal salts, especially lithium carbonate and sodium carbonate
a base, such as aluminum or potassium carbonate; or an amine
For example, pyridine or Vi 8th amine especially triethyl
It is carried out in the presence of an organic base such as an amine. appropriate
Solvents include chloroform, dichloromethane, and tetrahydride.
Lofuran, dimethylformamide, dimethylsulfoxy
Includes do and a seven tons. Generally anti-acylation with
For example, at non-extreme temperatures such as -20 to +20°C.
It is carried out at room temperature or slightly lower temperature. On the other hand
is a hydroxy group or a human n carbonyloxy group
For example, C1-, alkoxy, or phenoxy.
It may also be lyloxy. When Te is a hydroxy group
In this case, Y is an oxygen atom of dicyclohexylcarbodiimide.
It is preferable to carry out the reaction in the presence of a dehydrating agent. Compounds where X is an azide), X is a halogen atom (salt)
bromine atom) or sulfonyloxy group
Compounds of formula ([) with easily convertible groups such as
It can be produced by reacting with This conclusion
Alkali metal azide such as sodium azide
or tetramethylguanidinium acid or tet
No organic azides such as butylammonium azide
It is something. This reaction uses acetonitrile, dimethylene
Rusulfoxide, ethyl acetate, dichloromethane, acetate
Inert polar solvents such as
Preferably, it is carried out in a medium at non-extreme temperatures. A compound of formula (ill) in which X is a 7-mino group is, for example,
Catalytic hydrogenation reactions such as on dium-charcoal or e.g.
The above method was carried out by the dissolved metal reduction method using zinc and aqueous hydrochloric acid solution.
It can be produced by reducing the azide group.
The compound of 2〇) in which X is a substituted amino group, X is an amine
For example, alkylation and/or
Or by acylation! 3! Can be built. The alkylation reaction of primary amine (-NH,)
RX 輔 (in the formula xI'IFi secondary 7 non (-HHR)
can be carried out by reaction with a leaving group (forming a leaving group). This secondary amine is then combined with another compound RX'' (initially
(which may be the same or different from the compound)
can be used to form an 8th-class amine (-NR,).
Ru. Then, if desired @ quaternary amine (-NH2O)
[The substituents may be the same or different] can be produced. appropriate
What a base! Trout contains halogens such as iodine and bromine atoms.
ion atom, or cl-. Alkyl-or-Rusulfonate N, ttf
Methanesulfonate or p-)luenesulfonate
Includes sulfonate groups such as. Kayouna Archi
The reaction is usually carried out using dimethylformamide, acetonitrile,
in an inert organic solvent such as dichloromethane,
-go~+, preferably in the presence of a strong non-nucleophilic organic base
50'C, preferably -10~+20°C, but not extreme.
The most common temperature is 0°C to room temperature. appropriate
Examples of organic bases include 1,5-diazabicyclo(4,8,0
) non-6-ene and 1,8-diazabicyclo[6゜
4.0] Contains undecene. In addition, primary, secondary and 8th class amines are
Formation of formula (III) with an excellent leaving group such as a hydroxyl group
The compound and the secondary amine (RNHR') are reacted to form the eighth
amine and then one of the groups R and Ro
or both, for example, by hydrogenation reaction to obtain primary
Alternatively, it can be produced by providing a secondary amine.
Ru. Primary amine (-MHL) (D acylation reaction is acylation
It can be carried out by reaction with an agent. A suitable acylating agent
is 6-aminopenicillanic acid, 7-aminosephalosbo
To carry out similar reactions with lanic acid, its salts or esters
suitable acylating agents such as acids and enzymes or dicyclo
formed by reaction with a condensation accelerator such as xylcarbodiimide.
Acid halides, acid anhydrides or mixed acid anhydrides such as
or other reactive derivatives. Thus the general
The acylating agent is replaced with 2RX''(X''-1 in the formula).
Hydrogen groups such as halogen atoms, sulfonate groups, carboxylic groups, etc.
sylate group). Also, the acylating agent is
Ketenes, incyanates, isothiocyanates or
It may also be a sexualized imide. This acylation reaction
For example, alkali metal salts or alkaline earth metal salts
Lithium carbonate, sodium chloride or potassium carbonate
an inorganic base such as; or an atom such as triethylamine;
Preferably, the reaction is carried out in the presence of an organic base such as amine. This reaction consists of dimethylformamide, acetonitrile,
Aprotons such as ethyl acetate and dimethyl sulfoxide
Suitably, this is carried out in a neutral solvent. Water may be added as necessary to aid dissolution. This reaction can be carried out at less than extreme temperatures, e.g. -20 to +40°C.
Preferably, it is appropriate to carry out the reaction at room temperature. The acylation reaction is 1 for the primary amine (-nut) sc.
It is carried out once or twice, and monoacyl or diacyl-induced
A conductor is formed. In the case of diacyl derivatives, the acyl
The groups may be the same or different. Separately, the acylation reaction is performed on secondary amines (-NHR).
to form the entire N-alkyl-y-acyl derivative.
You can also do that. The two acyl groups form a heterocyclyl ring.
Diacyl derivatives linked as
Compound and formula: HNRARB (where RA and RB are
forming a terocyclyl ring system) and a compound of the formula (W
): Azo of R”°O(!0-N=N-00OR”)
dicarboxylate compound (in the formula, R1- and RlO are independent)
and O,-alkyl, arylC1-@alkyl or
) and formula (■): (in the formula, %l and m are
independently 0 or ril; Hjl, BMM and RIJ
are independently C1-・alkyl, arylcl-alkyl
or aryl)
It can be easily manufactured by this
The reaction is carried out using inert substances such as tetrahydrofuran and benzene.
in a non-extreme organic solvent at a temperature of 1-20 to +Zo. ℃, usually -60 to 60℃ It is usually appropriate to carry out at room temperature.
Ru. In addition, the above reaction is a dialysis reaction in which two acyl groups are not linked.
It can also be used to produce chemical derivatives. One or both of the two acyl groups can be removed
For example, if the vine is hydrogenolyzed, the monoacyl derivative
It is possible to form a primary amine (-NH□).
Wear. The compound of formula (III) in which X is a hydrogen atom,
From a compound of the formula (Ill) of a gene atom such as iodine, reduction
Can be produced by reaction. tri-n-butyltin hydride, vinegar
Zinc, Sodium Boron Hydride and Cyano Hydride in Acid
Examples include sodium boron. A compound of formula (01) where X is cyano is a compound of formula (01) where X is OH0
The compound of formula (vl) is combined with the compound of formula (vl) and hydrogen cyanide.
and a compound of formula (W), a reaction similar to that of the above-mentioned mourning
It can be produced by reacting under specific conditions. X is activated aryl or heteroaryl group
The compound of formula (Ill) is a compound in which X is OH and a suitable aromatic compound.
Manufactured by reaction with aromatic heteroaromatic compounds
can. ■Activated aryl or heteroaryl
The term radical refers to
aromatic or
means a group derived from a heteroaromatic compound
. Suitable such compounds include phenol;
xy, halogen Tl, C*-a alkoxy, C1-・
Alkyl also selected from C1-, cycloalkyl group
1% 2 or 8 atoms or groups substituted
Phenol; phenol optionally substituted with C1-alkyl
Lyle group, C1-alkyl optionally substituted chenyl group
, a pyrrolyl group optionally substituted with #jl by C11 alkyl,
or condensed to optionally substituted benzene 11
Examples include phenols substituted with each of the following functional groups.
As a catalyst, it is known as the Friedel-Crauflo reaction.
A known catalytic reaction can be used. Suitable catalysts include octa-aluminum chloride, zinc chloride, and zinc bromide.
Lead, antimony tetrachloride, ferric chloride, tin chloride, trichloride
boron triflu-orid
etherate) and its chemical equivalents.
It will be done. Among these catalysts, boron trifluoride ether is preferred.
Delicious. This reaction is generally carried out in an inert solvent, preferably
Non-polar solvents such as halogenated hydrocarbons, e.g. chloro
in the presence of form, carbon tetrachloride or dichloromethane
It will be done. This reaction takes place at low or moderate temperatures, i.e.
In other words, it is carried out at +60 to -70°C, preferably FiO to -80°C.
is appropriate. This reaction is also carried out in an inert atmosphere.
It is preferable to do so. Compounds of formula (m) in which X is a residue of a nucleophilic carbon,
Compounds of formula ■ which are vine groups substituted by reaction with nucleophilic carbon
It can be manufactured from This substitutable group is a chlorine atom, a bromine atom,
Atom or iodine atom such as halo 721M child or fi
p-h luenesulfonyloxy or methanesulfony
A further substitution of sulfonyloxy or sulfonyloxy or C
It may also be 1-furkylsulfonyloxy. this
The reaction is carried out in an aprotic organic solvent at reduced temperature or room temperature.
For example, the temperature is preferably -20-0°C.
is appropriate. Suitable solvents include tetrahydrofurane.
dimethylformamide or dimethylsulfoxy
Contains de. The nucleophilic carbon is
The compound R-H or may exist as a salt
. The cations of such salts are metal ions or anhydrides.
Monium ions such as sodium, potassium, thallium
Mu's cation model Tetra 01-s alkyl ammonium
The um cation is suitable. Thallium salts are particularly preferred.
Yes. Group in formula (ma) -〇! Proper carboxy protection of O,Ra
Derivatives include carboxylic acid salts, esters and anhydride derivatives.
Conductor can be impregnated. This derivative is readily available at later stages of the reaction.
It can be cleaved into two. Suitable ester-forming carboxyl protecting groups are:
To9 is a group that can be removed under normal conditions, and the by-product (IL) is a group that can be removed under normal conditions.
) to (f) are included. Such R'F) group
Examples include benzyl group, p-methoxybenzyl group, 2.4.
6-) Limethylpenzyl group, 8.5-di-t-butyl-
4-hydroxybenzyl group, benzoylmethyl group, p-
Nitrobenzyl group, 4-pyridylmethyl group, 2,2.2
-trichloroethyl group, 2,2.2-)ribromoethyl
group, acetonyl, 2-methylallyl group, t-butyl group,
t-amyl group, diphenylmethyl group, triphenylmethyl group
group, methyl group, ethyl group, allyl group, adamantyl group
, O-nitrobenzyl group, 2-benzyloxyphenyl
group, tetrahydrofuryl 2-yl group, tetrahydrofila
-2-yl group, methoxymethyl group, silyl group, stane
Nyl group or phosphorus-containing group, or an ester that can be hydrolyzed in vivo
Includes tell. Suitable salts include pharmaceutically acceptable and non-pharmaceutically acceptable salts.
Includes introspection with inorganic salts, such as complex salts or water complexes.
Metal salts such as salts, lithium salts or sodium salts
a, alkali metal salts, and 8th class amine salts. Carboxyl groups can be added in the usual manner appropriate to the particular group Ha.
It can be regenerated from the above ester salts. for example
Acid-base catalyzed hydrolysis method, enzyme catalyzed hydrolysis method, photolysis method
Alternatively, a hydrogenation method may be mentioned.゛ This hydrolysis method is
Of course, this must be done under conditions where other groups in the molecule are stable.
Must be. Furthermore, the present invention provides the formula ([): [in the formula Ha and! is expressed by the same definition as in equation (ma)
subjecting a compound or its precursor to a rearrangement reaction
The present invention provides a method for producing a compound of formula (ma) consisting of
Ru. It is a preferred Ha11 ester group. Y in the compound of formula (m) is preferably an oxygen atom. Also expression
The compound in (■) has a red structure adjacent to the vinyl group! elementary atom
two epimeric forms formed in or these
It is understood that scales exist as a mixture of epimers of
Will. The compound of formula (1m) is novel and itself
The body of this invention is Kt housing. Compounds of formula (-) are usually not isolated, but are formed as such.
Let's react. This rearrangement reaction generally involves the high boiling point of the compound of formula (1m).
Solutions of active solvents are kept at moderately high temperatures, typically around 70°C.
Significant thermal decomposition occurs at high temperatures. Add to the temperature f not exceeding
It is done by heating. A suitable Il& is 70-150'C, more appropriately
ll1so-1110'C1 preferably at about 110'C
be. Convenient solvents for this method include benzene; and toluene.
Seven substances such as xylene, xylene, and cumene,
is an aromatic carbon such as Tory 01-4 alkylbenzenes.
Contains hydrogen chloride. Toluene has a boiling point of approximately 110'C
Therefore, it is a particularly suitable solvent, and the reaction is oxidative in this solvent.
If you do it conveniently while flowing, you can do seven. As mentioned above, compounds of formula (Vl) are usually prepared by
It is isolated intact. Formula (ma) of the compound of formula (1m)
It is necessary to use high temperatures for the rearrangement reaction to
It's not even necessary. However, the compound of formula (II)
Since it is formed at high temperatures, it is more convenient to use high temperatures. The time to continue the reaction depends on the specific starting materials chosen.
for a suitable time, e.g. using ethyl acetate as a developing agent.
: Silica high performance liquid chromatography using cyclohexane
Monitor the reaction process using chromatography or thin layer chromatography.
can be easily determined by monitoring
. The compound of formula (■) is a compound of formula (n): (wherein Y and Ra are the same as defined above;
(Group that accepts β-e'11m1nation “))
By removing the 'H-Q element from the represented compound,
It can be manufactured as follows. For example, Q, sulfoxy
Do-8(0)R, selenoxide-Be(0)R or
may be xanthate-oc(s)su. This elimination reaction is generally carried out at elevated temperatures, e.g.
in an aromatic hydrocarbon at 150°C, preferably about 110°C.
It will be done. A suitable Q includes its phenyl field.
is converted to inert one, -〇(1!(8)8Ph,
-8e(0)Ph, -8(0)Ph and these
Contains deformed items. Suitable Q-138 (0)
Ph or -s e(0)(3H,
convert the compound into the compound of formula (ma) without isolating it.
can do. The compound of formula (IK) is a compound of formula (I): (wherein Ha and Y are the same as defined above; trFi substituted
Uru groups, such as tosylate and mesylate, are bromine atoms.
or a halogen atom such as a chlorine atom)
For example, a halogen atom such as a bromine atom in a compound is replaced by a group Q.
It can be produced by substitution. For example, CAL Vi-8e(0)P h and its
The substituent is the corresponding selenide (5elen1de)
-8ePh etc. with sodium metaperiodide, permanate
Like potassium ganate or tin-chloroperbenzoic acid
It can be produced by oxidizing with a suitable oxidizing agent. selenium
The compound is a compound of formula (I) and a suitable selenol (arl
enol) and selenide anion (θ
・React in the presence of 1enle anion)
It can be manufactured by Q is -5(o)Ph and its substitution
Compounds having the following properties can be prepared in a similar manner. The compound of formula (1) has the formula: (wherein Ha is the same as defined above; R2 & is a hydrogen atom or
Hydrocarbon group having 1 to 20 longitudinal atoms; HM@ and R37 are
A compound independently represented by 01-alkyl group) and 2cm> : U-CH-OH-Yll (31)2
rich (in the formula, U is a halogen such as a bromine atom or a chlorine atom)
Atom; Y is oxygen or sulfur atom)
It can be produced by reacting. child
The reaction of polar non-nucleophilic substances such as dimethylformamide
It can be easily carried out in a neutral solvent at room temperature to 60℃ under reduced pressure.
can. The compound of formula (1) is a compound of formula (■): ■ 00, Ra and a compound of formula (■): and RMT are the same as defined above.
;OR1@ is, for example, the 01-alkoxy group of methoxy.
(leaving group) by reacting the compound with a suitable orthoester.
Therefore, it can be manufactured. This reaction is an equilibrium reaction
I can believe it. Therefore, BRaO is R””O
Selecting H to be removed or consumed during the reaction
is preferred, and if R3” OH is volatile, such
Removal can be conveniently carried out, for example, by evaporation or under reduced pressure.
Wear. The compound of formula (x) has the formula (IV): Co, Ra (wherein Haij carboxyl protecting group; R is alkyl,
alknyl, alkynyl, aryl, alkoxy, aryl
2, aralkoxy, and aralkyl groups.
Reacting a compound represented by (active group) with a compound of formula (■)
It can be manufactured by This reaction takes place at room temperature.
or at an elevated temperature of 20-80°C, for example 60°C.
, performed in an inert organic solvent such as dimethylformamide.
I like Uno. The compound of formula (IT) is patented in European Patent Publication No. 000.
No. 2820. The present invention also provides the formula (II): ■ (wherein Ha is a hydrogen atom or a carboxyl protective group;
Ys is an oxygen atom or a yellow atom; RJ is an ester group
) is reduced, and then, if necessary, 1)
A compound of formula ([0) where X is hydroxy,
i) carbo
Removal of t[IRa and -) product with salt or ether
a compound of formula (III) consisting of converting it into a stellate,
A method for producing the salts and esters thereof is provided. The compound of formula (nu) can be reduced in the usual manner.
Therefore, ■ is converted to a compound of formula (1) where hydroxy is
be able to. Appropriate reduction methods optionally sulfurize
Complex hydrides such as boron hydride, e.g. lithium boron hydride
um, boron hydride) IJ um, potassium boron hydride,
Sodium cyanoborohydride or diisobutyl a
Luminium/1 hydride is used. Such a reaction also produces hydrocarbons, chlorinated hydrogen, and hydrogen.
-thyl, such as toluene, cyclohexane, diethyl ethyl
ether, heptane, hexane, dichloromethane or
This can be done in an inert organic solvent such as tetrahydrofuran.
I can do that. This reduction reaction takes place at non-extreme temperatures, e.g.
If Fio ~ +80℃ is more suitable than -sO ~ +60℃
It can also be easily carried out at room temperature. The above reaction smell
It is a preferred hydrogen atom. Suitable R1.substituted or unsubstituted 1 to 20 carbon atoms.
It is a substituted hydrocarbon group. A more suitable R1@ is a,
-1@alkyl, C3-1・alkenyl, C2-1-a
ruquinyl, ryol ((3t-s) alkyl, aryl
(OB-s) alkenyl, heteroaryl (Ot-
・) alkyl s ax-s cycloalkyl, aryl,
Heteroaryl, CM-8 cycloalkyl (C1-6)
Alkyl, heterocyclyl or heterocyclyl (0
,−・)alkyl, and any of these groups can be optionally
Replaced. Preferred R1 is methyl, ethyl or benzyl.
, a suitable Yl is oxygen. The compound of formula (Ivl) is novel and can be used as a chemical intermediate.
It is useful. Furthermore, these compounds themselves have anti-inflammatory properties.
fungicides or β-lactamers (useful as inhibitors)
. In addition, if RRO is sodium or potassium
substituted with a pharmaceutically acceptable salt-forming cation such as
Formula (X■) and compounds are active and useful antimicrobial agents. This invention also provides the formula (1m): (wherein, Ha is a hydrogen atom or a carboxy protecting group; Y
s and R10 (same as defined above), and then if necessary 1) force hf
+9 protecting group R& is removed and the product is salted or
Formula (IN) consisting of converting into tel: (in the formula, Y1, Ra and R”Fi are the same as defined above)
provides methods for producing compounds, their salts and esters.
be. Preferred ym is an oxygen atom. This reduction reaction involves triaryl silver hydride, dialkyl water
Silver hydride such as silver hydride or trialkyl silver hydride
Suitably, this is carried out using a reducing agent. appropriate aryl
Groups include phenyl groups and optionally modified phenyl groups.
It will be done. Suitable alkyl groups include C7, especially alkyl groups.
An n-butyl group may be mentioned. The preferred reducing agent is truffles.
phenyl silver hydride and tri-n-butyl silver hydride. This reaction can be performed using di-t-butyl peroxide or azobisulfur.
carried out in the presence of a radical initiator such as sobutyronitrile.
You can. This reaction generally involves benzene, toluene and saturated carbonization.
It is carried out in an inert solvent such as hydrogen. Solvents of halogenated hydrocarbons and ether iIg are
Active solvents are not suitable. This reaction starts
However, the reaction mixture usually has sufficient
Heating to about 80°C is required for the reaction to occur. low
At high temperatures, reactions can be carried out using radical initiators or photochemically.
It can be started automatically. The compound of formula (■) has formula (X'ml) or (m):
■ A compound of (wherein Ha is the same as the above definition; B is a leaving group) and
By reacting a compound of formula (■): No, -OH,-CY'' RJ・(■)1 in the presence of a base.
can be manufactured. Suitable bases are inorganic bases and
It is a compound that forms a carbanion of the compound of formula (■).
For example, a suitable base is sodium hydride. If appropriate, Q is an organic carboxylate molecule (-0
00Q). A more suitable cL is cl-, furkyl
, Benzyl also works with dichloromethyl. Formula (1v111) (m) Compound U, British patent compilation
1 Company No. 9484, 15114508 and 16
It can be made by the method described in each specification of No. 70496.
Ru. After making it emit, tor the chroma dog 2 of the silikage μ.
ene/ethyl acetate A/10:l), title of crystalline solid
from promide (diete μate A/or ethanol)
Crystallization) 0.498t was obtained (yield 26%), and benzene
0.28t'ft (yield
2C%). What are the physical properties of the obtained product? It's 6
O ■, R, (KBr) 1780 and 1751aM-N
, M, R, (CDCI,) J, 3.0'/(IH, d
d,,r 16 and 1.5Hz. 6β-CH), 3.36(3H,m, 6a-CH and
and 0CHsCHaBr), 3.74(2H,m,O
CH, CHtBr), 4. -15 (IH, S. 3-CH), 5. on(gH,s,CH鵞Ph),
5.22 (IH, q, JlO and 4 Hz, C
Character CH 龜5.64 (3H,!11.5-CH and O:
CH-tomi) and 7.32 (5H, 8, aromatic). Example 2 people (improved method) Benji Cluba 2) (30?, 0.104 mo
1) containing traces of 1)-) luens μphonic acid.
(5od) K was dissolved. reaction
Place the container under vacuum (14 fl Hf) and occasionally
Heated to 0°C. The reaction time can be changed (about 6 hours)
, after TLC showed yellowing of the starting material, the reaction mixture evaporated.
let The remaining oil was dissolved in 2-bromoethanol-μ (25 m
1) and placed under reduced pressure (10 at). After 6-10 hours, the reaction mixture was diluted with diethyl ether μ.
and washed with saturated sodium hydrogen oxide solution (5 times). The ether layer was dried with magnesium oxide and passed through Celite.
It was filtered and evaporated. Residue silica gel chroma
For tography, μene-acetate ethene A/7: l
), the crystalline homologue of the title product'i from ethanol
11.5f was obtained (yield 28%)0 Example 3
Moi μ Kurabarane) (17-681F, 37mi
Dry limo Ja/) with DMF (511j) and 2-lio
'a:t, evening/-A' (20-1149 mm
The mixture was dissolved and heated at 55°C for 6 hours. When heating
At the end of the interval, the reaction mixture was diluted with ethyl acetate and diluted with brine (3
(times), saturated sodium hydrogen oxide solution and water (three times).
Washed. The organic layer was dried with magnesium sulfate and evaporated.
An oily substance was obtained which was subjected to chromatography on silicage gel.
(eluted with toluene-acetate ethyl A/8:l), the crystalline congener
The title Esthe μ2.138jF was obtained (yield 16.4%)
). The physical properties of the obtained Esthe μ were as follows. Engineering, R8 (Nugeot A/) 1786 and 1755
tx. N, M, R, (CDC14) J 2 to 9O-3-8
8 (6H, nl, 6-0Hz $P and OCR, OH
, C1), 1vy(:tH,8,3-CH), 5.
05 (2H. s, CH, Ph), 5.23 (IH, q,, T 9
and <Hz, CH:C! H,), 5.5-5.8(
3H,m,5-CH>YohiCH:OH,). '7.35 (5H, 8, aromatic). Example 4 Pensilk 2 Ba 2 in dichloromethane (loo+wj)
Ne) (11,5:V, 39.9 mm A/)
and tric on acetate p incyanate (5-68iaj
, 47.88 mmol) or Lahenji A/9-(N-tri
Chloroacetyl) force~generates bamoyl kuppa 2 net~
, concentrate and. -t after tllDMF (1 oiu). child
2-10 Moetano~A' (8,6m, 119
．． 7 mmol) and heated the reactant i to 50C.
. After a reaction time of 6-8 hours, the mixture was diluted with ethyl acetate.
and washed with seed water and saturated sodium hydrogen oxide solution.
. The organic layer was dried with 9 ml of sulfuric acid magnesium and evaporated to an oil.
I got it. Crystallize this (from ethanol) or
Chromatography on silica gel (toluene-vinegar
4. Isolate the ester of zelkova (eluted with ethyl acid). ．． 38f
t was obtained (yield 28%). BendiA' 2- (Q-bromoethoxy)-2,- and
-rooflavum-3-carboxyle) (3,”l'
1? . 9.5mm-vw) f DMF' (15m)
and cooled to 0°C. benzene selenol) V (
1,2 tons (11-36 mm), followed by Torie
Thylamine (1,46117, IQ, 49 mmA/)
DMF (211j) solution was added dropwise over t-5 minutes.
. After 1 hour, the reaction was diluted with ethyl acetate, brine and
# Washed with hydrochloric acid. The organic layer was dried with magnesium talate.
, evaporated and then subjected to silica gel chromatography.
Toluene-acetate ethene A/? : eluted with 1), the title esthetician
A/3. A 826 ft. (yield: 1%) was obtained. obtained
The physical properties of the ester were as follows. ■, R1 (Fi A/A) 180o and 1750
m. N, M, R, (CDC13) a, 3. ol(4H,
m, 6-CH2 and o2CHsSe), L64(2
H, m, OCH, CH2O), k-/(LH. 8.3-0H), 5.04 (2H, S, CHBPh)
, 5.22 (IH, q. J9 and +Hz, CH:OH,), 55g (3H,
m, 5-OH and C: CH,), and
32 (IOH, m, aromatic). Example 5a Bendi1v2-(2-benzylselenoethoxy)-2-
Vinyl clavam-3 ~ Under the flow of carboxylate nitrogen
BendiA/2-(2-prosoethoxy)-2-vinyl
Klapamu 3-KaN Boxile-) (0,3969%
Dissolve 1 mmA/) in dry DMFKII and cool to =20°C.
Rejected. For another 5 minutes, di7-diselenide (0
, 1'72F, 0.55mm tv) DiLF
RI fluid and water bulked sodium boron (o, o416P
% 1.1 millimoA') was added dropwise. Finished this addition
Post-cooling was discontinued, and the temperature was raised to room temperature while the reaction was waiting. always
After 15 minutes of warming, the reaction mixture was diluted with ethyl acetate and
Brine (twice), 111 hydrochloric acid and saturated sodium hydride
Washed with worm solution. Separate the organic layer and add it to magnesium sulfate.
After drying with silica gel and evaporating with
- ethyl acetate A/7: eluted with 1) divided into 7 lactations
, the title ester/I/l″0.33 was obtained (yield 70
%). Example 6 Bendi#2-(2-benzeneselenoethoxy)-2-bi
Nilukrapamu S-Carboxylate Penge A/2
- (2-chloroethoxy)-2-vinyl-flavum-
3-ka~boxyre) (4,281442,12,2
A dry toluene solution (zaaj) of Milimo A') is diluted with benzene.
Nsereno-A/ (1.54m, 14.64mm~)
Processed with. Next, Trieter Anne (1, 85 II
j. 1λ81 mmol) was added dropwise. After 6-8 hours, the reactant
diluted with ethyl acetate, mixed with brine (3 times) and saturated carbonated water.
Cleaned with +7um solution. Separate the organic layer and sulfur
Clotgraph on silica gel dried with magnesium acid
(dissolved in toluene-acetic acid ethyl pv1z:x'')
away). The title A/f was obtained in the form of a colorless syrup (yield
88%). Example 7 -2-Vinyl Clapham 3-Power Boxylate Pencil
A/2-(2-benzeneselenoethoxy)-2-vinyl
-Flavam-3-force~boxylate (3,0446r,
6.45 mm*) 1 acetone (2011j) K+l
I understand and next. This solution was thoroughly ground in water (5-).
Li sodium periodate! A cloudy suspension was added. After 15 minutes, the reaction mixture was diluted with ethyl acetate and diluted with brine (2
), washed with saturated sodium bicarbonate solution. Yes511
Dry with magnesium sulfate and evaporate to form a foam 2.g.
99f was obtained (yield 95%). The physical properties of the obtained foam are
It was as follows. 1, R, (film) 1799 and 1748 cm
-N, M, R, (CDCI,) J L2 (4H, m
, 6-0HI and OCH, CHISe), 3. -1
6 (2H, I!L, 0CH2C%Sθ), 4.61 and
and 4.67 (6 II (, 8, 3-0H), 5.05
(2H, 8, C4h). 5.22 (IH, m, CH:CH,), 5.56 (3H
, m, 5-CH and 0: CH,) and f, 4'
7 (IOH, IL aromatic). Example 7A Bendi, a/2-(2-benzeneselenoethoxy)-2
-vinyl-flavam-3-force μboxylate (10f
, 21.2 mm/I/) of acetone (1ooMJ)
The solution was diluted with sodium periodate (lof, 46
．． It was treated with water (25 m) containing 7 mmA/). T.L.
C showed that the starting material was consumed (approximately 30 minutes).
The post-reaction mixture was filtered and concentrated to half its volume. Add this vinegar
Dilute with acid ethyp, add sodium hydrogen chloride solution (3 times) and
and brine (twice). Magnesium sulfate organic layer
dried, evaporated to extract, and crystallized from toluene.
9.9'Fft- was obtained (yield 96%). Example 8 Mu3-force~boxylatebenziA/2-(2-benzeneleninylethoxy'/
)-2-vinyl-flavam-3-carboxylate) (
2,991F, drying 6.13 mmA/) Hz
7 (5011117)K was dissolved and heated to reflux. return
After 20 minutes of beginning flowing heating, the reaction was cooled and evaporated. A quick look at the chromatography of oil-based #Iit silicage
(eluted with toluene/ethyl acetate 9:1), the title ester ~
1.9: V was obtained (yield 60%). the resulting ester
The physical properties of were as follows. ■, R3 (film) 1800.1748, 1728
and 1698 countries. N, M, R, (CDCII) J, 22-33 (4H1
, CHtCHl), &94 and 98 (each + 1H
, d, J 16H2,6β-0H), 3.41 and
and 3.45 (respectively IH, dd, , T 16 and binary,
6α-CH), 4.54 O and 4.94 (4 each
LH, m, 8-CH), 4.99 and H5.23 (
Each + IH, m, 3-CH), 5.15 (2H,
8, CH. Ph), 5.63 (IH, m, 5-0H), '
/, 32 (5H, 8, aromatic), 9.5 and 9.6
6 (IH, 8, aldehyde, respectively). Example 9 Benjilkl! ! -(4-oxobutylidene)-ri
2bam-3-carboxylene) (0.5f%1.58
Fumilimo fi/) was dissolved in dry toluene (LOIU).
, cooled for a while (-20CK) under dry nitrogen gas.
diisobutylaluminum hydride (AL from D) (2
A 5% toluene solution (!10411j) was added dropwise. After 2 hours, the viscous reaction mixture was taken up in ethyl acetate and diluted.
Washed with hydrochloric acid. Filter the emulsion through 1
After fractionation, dry with magnesium sulfate and evaporate.
I let it happen. Regarding silica gel chromatography
(eluted with toluene-acetate ethane/L'2:1), 41110
Z-isomer t-yield'F 13.55+, g-mm form
0.034F and 0.03 respectively at t-a half 12%
I got 0f. The physical properties of each isomer were as follows. E-isomer ■, R, (film) 3430.1800.1747
and 1697QII-N, M, E, (CDC!l,
) J 1.53 (2H, m, CH, 0H2CH,)
, 1. '74 (IH, br s, OH), &01
(2u, m, C: CHCHri. 5.99CIH, d, J 17Hz, 6β-CH)
, s, 49 (3a, m. 6α-4 and beaten mushroom OH), 5. og(lH, dt,
J a and IHz, 8-CH), 5.2 (!H,
8, OH, pH), 5.26 (IH, br s, 3
-CH), 5.66 (lad, J 3Hz, 5-CH
), 7.39 (aH,s, aromatic), (DzO
The addition of brs in 11 and 4 disappeared] Z-isomer engineering, R, (film) 3420, 1801.1745
and 1700QII. N, M, R, (CDCI,) J, 1.65 (2H, II
I, CHIC'H, CH,), 1. 'F8(IH,
br s, OH), 2.2 (2H, m, C: CHCH
I), 3.05 (IH, d, J 18Hz, 6α
-CH), 3.54(3H,m, 6β-CH and
CH, OH), 461 (IH, dt, J 8 and I
Hz. g-OH), 5. o7(IH,'br s, 3-0
H), 5.23 (2H, 8°OH?h), 5.6
9(LH, (1,J 2H1,5-CH) and 7.4
1 (5H, 8, aromatic) [by addition of KarasuO J1. 〒8
br s disappeared] Example 1O Bendi-2-(4-oxobutylidene)-flavam-3
-force y boxylate (29, 6, 35 mmol: Z and
and E-isomer 50:50O mixture) cooled to 1-20°C.
Then, add Jethiate A/l'', which had been cooled to -20C in advance.
I got it. The mixture was stirred until it became a solution. E - isomerism
Crystals precipitated as a white solid. This solution -20
Leave for 4 hours at 'C, filter to obtain a white solid, cool diethyl
and washed with ether. 75% yield of E-isomer crystals
So 0. 5 was obtained, and the remaining oil contained Z and E-isomers.
A mixture of bodies (8:2) remained. repeat this method
E-isomer #0.91F i obtained with 90% Ft content, remaining
A 9:10 mixture of Z and E isomers was added to the oil.
. The physical properties of E-isomer are as follows. E-isomer ■, R0 (Nujol) 1789.1743.171
5 and 1694 Confucianism. N, M, R, (CDC13) J L2'y (4H, m
, CH*0Hz), L94 (IH. d, J 17H2, a-βCH), 3.45 (IH,
(ld,, T 17 and 3H2,6-a Ci),
5.02(4H,m, 3CT(, 8岨and CHS
Ph), 5.61 (IH, d, J 2Hz, 5CH)
, 7.33 (5H,8, aromatic) and 9.5F (I
H, 8, CO, g). Example 11 2-bamu 3-carboxylate benzyl 2-(4-oxobutylidene)-kusibamu
5-carboxylate (0.5f% 1.58〒Z 9+
A/) Dissolved in t-dry toluene (gom). This melt
Add aluminum dielectric resin to the liquid (AT Engineering P) (
0,324f%1.581mmSo14/)1-Little by little
added. Heat the homogeneous solution to 60°C to evaporate acetone
After 20 minutes, the reaction mixture was cooled and diluted with ethyl acetate.
After that, wash with dilute tacic acid and saturated sodium chloride solution.
Purified. Dry with 9 ml of organic 1ita acid magnesium and evaporate.
Then, toluene was added to the silica gel matrix.
(eluted with ethyl acetate/l'2:1), the title Z and E-different
0.03 t with yields of 12% and 11%, respectively.
and 0.0275 f t-obtained. Example 12 1 CO□co, ph BendiA' 2-(4-oxobutylidene)-klapa
Mu-3-carboxylate (0,8583f%λ125
Dry 7μ; 8:2 mixture of Z and E isomers)
Dimethoxyethane (DME) (1ojIj) Kjll solution
and cooled to -20°C. Sodium borohydride (0
, 1249, 3,278 mm 7μ) for 5 minutes.
Add the reaction mixture in portions and leave it open for an additional 15 minutes at 1-20°C.
did. At this reaction time rlJK starting material is consumed. This was thwarted by tracking with TLO. reaction mixture
Dilute with #ethyl acid, brine (twice), #hydrochloric acid and
Finally, wash with Kle sodium hydrogen oxide solution and remove the organic layer with sulfuric acid.
Dry with magnesium acid. This organic layer is evaporated in the tube and the remaining
Distillate T silicage μ fraction and L()#ene/acetic acid
Ethi/L'2:l). E-isomer of the title ester μ (0,1123f, yield 6
5%) and 2-isomer (0,53?2f, yield 78%
) was obtained. *1 Example 13 Benzitv w-z=(4-hydroxybutylidene)
-'aOcK Cooled Veggie 7 A/E-2- (4-1 Ki
sobutylidene)-flavum-3-carboxylene) (
0.4 St, 1.365 mmopv) dimethoxye
Sodium borohydride (0,062f%1
．． 64 mm A/) f: Added little by little. After 2'O minutes,
The reaction mixture was diluted with ethyl acetate, brine (twice), diluted salt
Washed with acid and saturated sodium chloride solution. Dry the organic layer over magnesium sulfate and evaporate to an oil.
chromatography on silica gel.
-Eluted with ethyl acetate A'2:1], titled Ester I@10
．． 2814f t- was obtained (yield 65%). Example 14 Lapam-3-carboxylate benzyA/2-(Z)-(4-hydroxybutylidene)
-flavum-3-carboxyle) (0,028f,
Tetrahydro 7″ containing 0.0883 mmol &/)
) (abbreviated as THF) (2 m) was added to
Contains 0.00327f, 0.0442 mmol')
Pre-hydrogenated palladium-based compound (10%, 12
D) was added to a water-containing (1+aj) THF (3 m) solution. The reaction mixture was incubated for 20 minutes until the reaction was determined to be complete by TLC.
1A of water was added per minute. The catalyst tF was removed and washed with water. F
The liquid and the eIC purified liquid were combined and evaporated to give 9 dabs of solid (yield
43.7%). The physical properties of the obtained isomer are as follows.
It was Oshi. , IJ (, (nuji door) 3400,1770.17
00 and 1623 countries. N, M, R, δ (D, O) 1.62 (2H, Quinte
6Hz, oca, cn, ), 2.
14 (2n, ddt, JaHz, 8Hz h and o
, vHz, C:CHCH,), 3.075(la,
d, J18aZ. 6-βCH), 3.535(IH, (ld, J2 and
and 18H2,6-αCH), a, aas(gH,t,
4. F1 (IH, dt, J8 and
and IHz, C:CH), csvs (IH. br, B, 5-CH), 5.665 (IH, d, J
2H2,5-CH,) Example 15 BendiA/Z-2-(4-hydroxybutylidene)-ri
5ha A -3-force 14/ykl + sylate (0,531
29Q 1.695 mmopy) f-containing ethanol
(10aj)l, palladium-legged catalyst (0,2f%10
%) and ester A (0,0626F, 0.8
4F milli% A/) in water (5-). reaction
The U&M was hydrogenated until the starting material was consumed. To the touch
Remove 'kP, wash with ethanol, combine with F solution and concentrate under reduced pressure.
Shrunk. Add acetone to the concentrated aqueous solution to make the title woodcutter.
Crystallized. After removing P and drying -p#, pure lithium is obtained.
Z-g-(4-hydroxybutylidene)-klapamu
3-ka4hoxyL/-) (0,26'751F,
Yield 67-'l')6) t'obtained*. StmELX 3 with the obtained homogeneous engineering R#i Nujol
570°3320.1784. l'100 and 16
It was 23 ts. Yi-Example 16 Benzitv E-2-(4-hydroxybutylidene)
-ri2bamu3-force pboxylate (0,2814F. 0.888 mm/L/) containing noetano A/(8 m
) t-palladium-paricum sulfate (0,15f, 5%
) and isthmus lithium (o, o3gsy%0.444
Mi! J moiv) was added to the containing O water (3-). reaction
Hydrogenate the mixture for 20 minutes until starting material is consumed.
did. Remove the touch*tp, wash with ethanol, and combine with F solution.
The mixture was concentrated under reduced pressure. Add acetone to this concentrated aqueous solution to crystallize the title salt.
I let it happen. This solid #F is removed and dried to produce pure lithium.
E-2-(4-hydroxybutylidene)-flavum-
3-KaN boxylate ((110121, yield 49%)
I got it. The physical properties of the obtained product were as follows. ■, R9 (Nujo A/) 3490.1759.16
90 and 162061m. N, M, R, (D30) J 1.55 (2H, m,
CH, C town OH,), LOI (2H. m, C:CHCHz), a, 96 (la, d, J1
7a2.6-βCH). 3-49 (3H,m, 6-excH and CH,O
H), 4.98 (2H. m, 3 strokes and 5cH), 5.5 holes IH, d, J
2H2,5CH). Example 17 Oil containing sodium hydride (480 mg, 50% in oil)
Dispersion, lO Milimo A'1. 2) 0 ethyl acetate/l/ (2
, □t, 15 millimofi/) containing dried re-evaporated DMF
Stir the resulting 1Iil suspension for 20 minutes.
did. benzyldichloroacetate~) (4f, lo milli7
Add a dry DMF' solution of A/) to the reaction mixture for 2 oc.
The mixture was stirred for 0 minutes and then at room temperature for 4 hours. A red solution is obtained
, pour this into Methiacetate TV (300d) and add water.
(100-×2 times) and saturated brine (looIIjX1
and dried over anhydrous magnesium sulfate. Melting lol
& was evaporated to obtain an oil, which was chromatographed on silica gel.
eluted with cyclohexane and methyl acetate 2:l.
did. Rf = 0.37 (silica/cyclohexane
- Methyl acetate #2: developed with potassium permanganate
Detection) 7 lacquer containing the epimer compound shown in 1.
I collected a lot of information. The yield was 40%, and the physical properties of the obtained compound were as follows.
It was as follows. H< νmaX, (Fi A/A) 1795.1740
．． 1695 ts'. NMRJ (CDCIs) 1.29 (3H, t, J7
H2, CH, CH, ), +9fu (2H, m, 9ci
-i, ), ao9(la, bd, +17H2,a
β-0H). 3.5(IH, d(1, Jl'/ and 3H2,6α-
CH), 4.57 (2H, 2 Cultits overlap +
J'yHz Pesci C). 4.6(IH,1)d, J7Hz, 8-0H),
5.04 (IH, bs, 3-(J), 5-09,
5.13 (IH, 2X d(i, +6 and 3 Xiang. CH(No,) CO, CH, CH3) 5.1
5. 5.21(2H, AE(1,, T12Hz, C
H゛), 5-69.5-72 (lH* 2 X d,
+3. 5-CH) 7.38 (5H, m, Ar-H). Example 18 Benzyl nitroacetate) (5, s5f, 30 mm
Dry redistilled DMF (35jIj) containing Mo#) at 0℃
Sodium hydride (960 Da, 5096 dispersed in oil,
Treat with 20 mmol I4/) and stir the suspension for 10 min.
Ta. Bendi-dichloroacete mu clavatsunate (8f,
20 mmol) of dry redistilled DMF (15 m+4)
Add the solution and incubate the mixture at tO °C for 30 min then at room temperature for 4 h.
Stir for a while. The reaction mixture was diluted with acetic acid ethene pv (300@t
) IIC pouring, water (looIljXZ times) and
Wash with saturated salt water (loose x 2) and place in an anhydrous sulfuric acid mug.
Drying with nesium and evaporation gave an oil. silica gel
Preparative elution with cyclohexane and ethyl acetate (3:1)
, Rf = 0.26 (silica/cyclohexane, vinegar
Developed with acid engineering ff112;1, potassium permanganate aqueous solution
7'C (yield: 35
%). The physical properties of the obtained product were as follows. Engineering Rν (CuCl2) 1803.1752.1698
Country NMRJ (CDCIs) 2.99 (2H, m,
9-CH,) 3-05(IH, d, +17.5H2
+6β-CH), 3. +6 (LH, dd, J 17
．． 5 and 3H2,aα-CH) 4.56, 4.58
(LH, 2x dt, J +7 and 1.5H2,a
-aH), 5.02.5.04(IH,z x d
, Jx, aHz, 3-CH), a, 15 (IH, m,
OH(NO,)CO,Bz. Partially obscured by J 5.15 no. 8), 5.
16(2H.s, (m-I), 5.22,5.24(2H,2
X [3, CH, Ar). 5.63, 5.66 (LH, 2X d, J 3Hz,
5-CH) '7.35 (1oH, m, Ar-H)
. Example 19 The product of Example 17 (480 Da, 1.2 mmol) was added to 1
7 Zabisisobuteronitri/I/(3919,0,24
Milimo A/) is present and toluene (50 m) is refluxed under nitrogen.
, the reaction'i hydrogenated tributyl &
/tin (379-, 1-4 mm7A/). Fishing 4
After a period of time, the solution was evaporated under reduced pressure to obtain an oily product.
Toluene-ethyl acetate μ? :
It was eluted with l. The product was obtained as a colorless oil (42% yield).
, its physical properties are as follows. IR & X, (Fi A/A) 1795.1740(b)
, 1695 ts. NMRJ (CDCI,) 1.25 (3H,t, J
'y, o-shin, OH, et al), 龜35 (4H, m, OH,
CH,,Co,CH,CH,), 3.05(LH,
dd,, r1 and x, sHz, 6β-0H),
3.4'y (:iE, aa, Jl'y and 3H2,6
m-(J(), 4.12(2H,q, J'F,OH
2,OH@CH,), 4.62(IH, bt, Hz
, a-CH), 5.03 (LH. bs, 3-an), 5.15, 5.21 (2!H,
ABq, Ju, 5EfZ, OH. Ar) a, aa(IH, d,, T:iHz, s-(
1m), 7.3'y (5H, m. Ar-H). Example 20 2) L1υh Contains the product of Example 19 (12 o drops, 0.33 mSO β)
Add dry redistilled THF (25114) to 10% palladium
The suspension was added for 40 minutes in the presence of 60q. catalyst
Remove kW, add #'ff1K water (loiaj), and add
Add LK0.1M lithium hydroxide and titrate to pHqs
did. The aqueous solution was evaporated to dryness and the product was crystallized from acetone.
Obtained with a yield of 51%. The physical properties of the obtained product are as follows.
Met. IRνmaX, (KBr) 1760-1790(1
)), x72o(b). 1618 x”. NMRa (D!0)l-22(3H1t-J7.5
H2, CH, CHs), L42 (4H-In-C
H*CHzC01CH Snow CHa)-3-07(IH, d
, JllHz, 6β-0H), 3.53(IH, dd
, Jl〒 and 3 songs. 6a-OH), 4-12 (2H, q, J), aHz
, CHmCHs), '-68 (IH, bt, J7
．． 5Hz, a-CH), 4. aa(IH,'bs
, 3-(m). a, s 6 (IH, d, J3Hz, a-OH). Example 21 - BendiIW 2- (4-hydroxy) cooled to 30°C
(sibutylidene)-flavam-3-carboxylene) (
408 drops, 1.29 mmol) containing dry dichlorothane
(611J) 1 equivalent of t-pyridine, then methanesulfonate
One equivalent of nil chloride was used as requested. After raising the temperature of the reactant to Wi temperature, further pyridine i
0. g- and 1 equivalent of methane μhoni ~ chloride t0
．． 1- Added. Starting materials disappear with thin layer chromatography
The mixture was stirred for 72 hours until indicated. The reaction mixture was diluted with dichloromethane (5 am) and saturated
Wash with seed water, dry with anhydrous magnesium sulfate, and then evaporate.
An oil was obtained. This oily silica chromatograph
eluted with toluene-ethyl acetate 1L/3:1
and Rf=Q, a (silica/toluene-ethyl acetate 3
: Developed with 1 and diluted with potassium perganate aqueous solution t*ll.
72 sections containing the desired product (detection) were collected.
. 7 lactations were combined and evaporated to an oily mass of 0.4'lt.
F was obtained (yield 9296), and its physical properties were as follows.
Ta. Engineering RJ/(5%OC)IC1, solution) 1800.17
50.1700°1358, 1335.1305.11
? 2.1120.1000.970°955, 932
Country NMRJ (CDCIs) 1.68-1.83 (!H
,m, OH,OH,(1,0). 2.20 (21(, broad dt, , r7 and ?
H2,2'CH,). 2.98(3H18,5(J(3), 3.0'F(
IH, broad d, J1'7H2, 6βC! 3.4
7 (IH, d (1, J17 and L5Hz, 6αCH)
, 4. o7421 (2H, m, CH2CH2CH1
0). 4.53 (LH, dt, J? and IH2, l'OH
), 5.04 (IH, (1, J IHz, 3C Dan)
+”ia and 5.25 (2H. ABq, J 12aZ, colca,), a, 5
6 (IH, broad d. J 2-5shi, 5αq ¥), Fufu 31-fu, ■ (5
H,I! 1. c-ri). Example 22 Benzyl 2-[No.-(1)-toens μhoniμole]
Benzi*ja-(4-human a) cooled to 30°C
cypteriden) - klapamu 3 - force ivy medium sire)
Dry cyclization method containing (0,81C%L66millimofi/)
1 equivalent of tyrene (laad)t pyridine (P-) #e
Bulk methylene containing 1.1 equivalents of sulfonyl chloride (
5-). Stir the mixture and increase the mixture temperature to aOC in 30 minutes.
Once warmed, El equivalent of pyridine was added. After 24 hours 1) -) j%' engineering phoniμri ν lid I
one equivalent of pyridine was added. After stirring for another 244 hours, no results were detected by thin layer chromatography.
The presence of starting material for the reaction was indicated. Furthermore, Toshikuroli
Add i equivalent of hydrogen and hold the reaction mixture at 5C for 48 hours.
However, TLC showed the disappearance of starting material. reaction mixture
Dilute with diluted methylene and wash with saturated salt water.51
1JX5 times), dried with anhydrous magnesium sulfate and then evaporated.
An oil was obtained. The crude oil was applied to a silica chromatograph, and
Eluted with toluene-acetate ethyl A/4:1, Rf=0.66
(Developed with silica/toene-acetic acid ethyl A'4:l,
(detected by ejecting potassium permanganate aqueous solution)
Fractions containing product were collected. Fractions [combined and evaporated to obtain 0.90f of oil.
(yield: 76 yen), and its physical properties were as follows. IRJ/ (Film) 1805.1752.1700
cm” U (5% CHCl5 solution) 1800.1
750.1700.1360.130? . 11?5,1000.968,935exa. NMRJ (CD(31,) 1.44-1.80(2
H,m, C%CH,OSO,), 2kll(flH
, at, J q and ? H2, CHICHHIGHIO
8OI). &41 (3H, B, CH,), &98 (IH,
d, J 16.5H! i1.6#CH). 3.41(lH, (1(1, J la, 5 and &5H
z, 6 g C @ a, 9 g (gH, t, J eHz
,OH,080,), &*3(IL Broadt, J
PIHz, 1'cH), a, 9'y (in, bro
Code 8゜Example 23
c) Butylidene]-Kutupamu 3-force N boxylene) (
175q) containing DMF (,4m) l azide)
The mixture was treated with 2 equivalents of 9 um and stirred for 6 hours. Mixture with ethyl acetate
* Dilute with (10011j) and wash with saturated salt water!
SOmx 5 times), dried over anhydrous magnesium sulfate, and evaporated.
Oily substance 1-*Good. The obtained oil was applied to a silica paste and acetic acid was added.
Elution was carried out with ethyl root ρene l:6. Rf=+=0.5
(Silica/#acid ether μ-toluene l:6 exhibit II)
The fractions containing the oil are collected, combined and evaporated to form an oil.
(30 Da) was obtained. The physical properties of the obtained oil are as follows:
Met. Sho ν (film) 2090.1802.1750.16
9? , 740°98 am NMRJ (CDC1g)x, al-x, av(ji
H, m, CH, CH1CH1N3). 2hx6(gH, dclt, J't, l and qH
z, OH, OH, CLNs), 3.05 (IH,
Broad c1. J 16Hz, aβC dan). 3.18 (2H=t-J?H2e CHJs)-
L4'F(ILd(1-J166 and f4-5HL6a
CH)-4,53(IH-6t*J'y and xHs
, x'cH), ho4(IH, bd, , r IH
2,s(m). 5.16 and 5.25 (2H, ABq, , T IJ
HJ, Co, CH,). a, av (lH, broad d, J LaB5.5aC
H), "2.30-1.45 (aH,m, CH,C
J4). Example 24 0 room temperature f benzene 4/2-(4-p-toluenesulfonyl
xybutylidene)-flavum-3-force A/lΦsylate
(0,)5f, 1.6 mmA/) DMF @liquid (
10m) was treated with 2 equivalents of sodium azide for 4 hours.
After stirring for 5 minutes, the mixture was diluted with acetic acid ethypoly(150ia
Pour into 50 g of water and wash with saturated ring water.
), dried over anhydrous magnesium sulfate and evaporated to an oil.
And so. This oil was subjected to chromatography on silica.
Elution was performed with μene-ethene acetate A/8:l. 0.6 (silica/toluene-acetic acid ethyl acetate A/6:1
Collect the 7 lactations containing the title compound (Tenma) and combine them.
and evaporated to obtain 250 da of oil (yield 45%);
The positive value is J/(film) 2090.1803.175
0°1695, ? It was 40.698 yen. Example 25 Bendi p.2-(4-7 didoptylidene)-Clapamu
3-force μ poxyre) (34,0IIiF, 0.1
'rHF (311j) 'i 1 containing Milimo A/)
U hours at normal pressure in the presence of 0% palladium on charcoal (goiy)
Hydrogenated. Touch llX1! :P left, 1F (1011
4) Then washed with water (zoiaj) in step i. water-containing cleaning solution
The white crystalline solid #F (l
olflk was obtained, and its physical properties were as follows. Positive ν (Nujo IM) 179? , 1690.16
38.1585 msNMR# (DIO; HOD 3
t J 4.80) 1.6-7-1.81 (2H, m
, C! H. CHICH, N), 2.12-2.28 (2H, In
, 2'CH,), 2.9B(2H,t,J?Hz
, CJH3), 3.07(LH,d, J 16H
2゜6#CH), 3.53(IH, d(1, J 16
and s Hz, aa CH), 4 = 68 (IH, block
load t, J) H2, l'cH). 4J39 (LH, Broad S, 3CH), 5.68 (
IH,d,,T3H2,6C! H). Example 26 Benzyl 2-(4-hydroxybutylidene) at 0°C
-Klapamu 3-Power Boxilet) (0,5252%
dichloromethane (5-) containing 1.7 mmopy),
Diazomethane diet A'* solution (7osd; approx. 0.4mol)
lI/fII liquid) and boron trifluoride ether complex compound
A catalytic amount of the product was added. The reaction mixture was left at 1o℃ for 8 hours.
Ta. Pass the solution with nitrogen until it becomes colorless, then
4/(Rod)l of ethyl acetate was added. Leg acid water in the organic layer′
Bulk sodium solution (aodxg times) and double water (50a
c# x 2 times) and finally with anhydrous magnesium sulfate.
Dry. The solvent was removed in vacuo to give a pale yellow oil, which was silicaed.
The acetate ethyl alcohol was subjected to Kagel column chromatography.
Eluted with clohequinane 2::s, Rf = 0.44 (vinegar
Extracted with acidic acid and μm cyclohexane 2:3 (R) (D title)
A compound (α36F% yield 92%) was obtained, Rf: 0.16
(acetate ethyl p-cyclohexynane 2:S i!If)
Starting material (α15F) was recovered. Both are oily substances, and the physical properties of the obtained compounds are as follows.
It was Oshi. IRarma! , (caclm) 1790.174
0 and 1690, ts. NMRJH (CDCl5) l-59 (2H, In,
: CHCH2cH2CH2OCH45. LIJ and a, 16 (2H, dt, J t Hz,
:CHCH, C%CHeg0cHs), 3.02(LH,
Broad d, J 16 Hz. 6β-CH), 3.32 (3H,S,0CHs),
L32(IH,t,,r7H2,:CHCHICH40
H, OCH, ), 3.45 (IH, dd, J16
>yo (j 2.6 Hz, 6a-CB), 4.5'F (
IL(lt, J] and l Hz, :CHCH1CH
Tomi CH snow O), 6.03 (1 island d, J I H
! ili, 3-C! H), ts, 24 and 5
．． 16 (JiiH, ABq. J 1z Hz, CHlPh), 5.65 (RB,
Broad d, JL5H2,5-CH), 1.23-
1.45 (5H, 11, Ar:). Example 27 Benji A' j! -(4-methoxybutylidene)-ri
2Pam-3-Power~Bochu Shire) (0.35t%1.0
6% hydrated THF (15wl) containing 5millimo J4/)
) f: 10% palladium-vertical (0,1JP) at room temperature
Hydrogenation was carried out for 20 minutes. Thin layer chromatography begins
This indicated that all of the substance had been consumed. Filter the reaction mixture
It was concentrated to a small volume (approximately 1 m), and then diluted with ethyl acetate μ (1 m).
5m) and water (lamt). sodium hydroxide
Adjust the pH to 2.0 m with a solution of
The desired material in the form of pale yellow glue was obtained by fractionation and evaporation.
-te l@/ was added to make the 1iiit form (o, gsf)
(Yield 93%). The physical properties of the obtained solid were as follows. IRaaaq, (103r) 17B5.1695 s
p and 1610 as. NMRaH(DIO) 1.63(S!H,H,:CH
CH, CH, (30CH,) all (gH, m, =
(mcH, CH, OH, OCH,) 5LOa (I
H, d, J 16H2,6β-CH), 3.31(
3H,8,0CH3), 3.4j6(IH.t,,Ty,:CHC,cH,cH,ocH,),x
sz (xa, ad. J 16 and 2.) H2, aa-CH), 4.69
(IH, dt, Jl and IH2,:CHCH,C%
CH, 0CH3), 4.86 (IH. d, J I Hz, 3-CH), 5.65 (I
H, d, J & 5 Hz, 5-CH). Example 28 Bendi μ 2-(4-hydroxybutylidene) Clapham
-3-carpoxylate (α31〒f%lmilimoμ),
acid, chemical @ (o, ast), sulfuric acid p-sium (α32f
) and methi iodide J' (0.65 m, 0.4 mm
#) in dichloromethane (5-) in a flask with one stopper.
Add LO, stir continuously for 48 hours in a dark place, and perform a single-layer chromatograph.
Fi)K analysis revealed that approximately 50% of the starting material remained.
Rukoto has been shown. Filter the reaction mixture and add fresh reagent (
Methiodide A/0.65 m, silver oxide 0.23t, sulfur
Acid force μsium o, saf) is added and the mixture is further
Stirred for 15 hours. This was t-filtered and the solvent was removed under reduced pressure.
Yellow oil 't*, silica gel column chromatography
and eluted with acetic acid ethyl μ-toluene l:10.
. i'tr=o, 46 (acetic acid ethyl-toluene 1 nia
The fractions containing the components (developed) were combined and evaporated under reduced pressure.
The desired etherpy (80ap, Q rate z5%) was obtained as a colorless oil.
) t-1 again. The truth behind this ether is yma! (5%C
HCIm) 1790.1740 and 1690 ts
Same as the product data in FiNMR#iJ Example 26.
◎ Example 29a O′ Bendi A/ 2-(2-chloroethoxy)-2-vinyl
-Klapamu 3-Ka-Boxile) (1,2834f
, &02tlimo)v) containing dry DMF (10
1117) as thiopheno-jll/ (0,6JP)
and trietheramine (0,6m) continuously
did. After 6 hours at room temperature, the reaction mixture was diluted with ethyl acetate and
Salt water (3 times), water (3 times), dilute hydrochloric acid (2 times) and finally
It was then washed with a saturated sodium hydroxide solution. After drying and evaporation
, the residue was applied to a silica gel column and treated with toene-acetic acid ethyl chloride.
A'9:1) to obtain the title EST IVT yield T6
．． A 6% yield of 1-191F was obtained. The resulting beauty salon
The physical properties were as follows. IRn car (film) 1800 and 1749 (+
11. NMRJ (CDCIs) L two o-3, ao (aH, m
, 0-CH, (H, -13 and β-lactam C mountain),
L6fu (IH, 8, C3-H), 4.98 (gH, 8,
OH, Ph), 5.13 (IH, q, J 8 and
4H2゜CH:CH,), a, +x-a, vo(sH
, m, 01-H and CH:q), 6.96-F
, 1o (1oH, m, aromatic). *Example 291)
Viny~-Clapamu 3-carbo-medium sylate (0,804
Hydrous acetone (gO
- A mixture of acetone and 5-water) is thoroughly ground and
Treated with sodium iodine (iF). The reaction product was analyzed by thin layer chromatography until the reaction was completed.
The mixture was stirred at room temperature for 2 days until it was determined that it was. The reaction product was washed with ethyl acetate, diluted with double water (3 times) and saturated.
The silica is washed with leg acid aqueous sodium chloride solution and evaporated.
It was subjected to gel chromatography. Elution with μene-acetic acid ethane A/31:l gave the title S
Teru α61Jf was obtained with a yield of 3.3%, and
The physical properties were as follows. 1 1Rymax (x di"I-A') 1793.17
4m (@. NIJRa (CDCII) a, 62-&1O (aa
, m, o, ca,, OH,, S k5.04(2)
1,8. CH4), L134.43 (lH, m, cH
:CHI). 5.50-5. Bl(3H, m, CH:CHik and C
20-B), '/Jl-7, 〒6 (log, m
, aromatic). Example 290 Benzi #2-(2-pensense 14/F42~Etho
xy)-3-vinyl-flavam-3-carboxylate
(0,431f%0.9'79 mm)v) containing dry
Drying'/V7 (2011114) was flowed at 36 o'clock opening.
. At this time, all starting materials are consumed and K is added to the reaction mixture.
was evaporated and the residue was chromatographed on silica.
(Toluene-ethyl acetate 7:1"t"t" apart)
] The title compound was obtained in a yield of 5%. Example 30 Benzi/L' 2-(ban-acytobutylidene) flava
(180 da, 0.63 mm
U) Containing pure ethyl-cyanoformin) (aaLl)
) Pressed at t86℃ for 21 hours, and then 1.5-ethyl
Cyanophoμmate was added. This reactant tso c 2
The mixture was stirred for 3 hours at 70° C. for 65 hours. thin layer chromatography
The graph showed that starting material was still present. difference
Furthermore, l-ethyl cyanoformate was added to form reaction product 18.
It was pressed at 0° C. for 61 hours (170 hours in total). Ete μ
The cyanoformate was evaporated under reduced pressure and the residue was evaporated on silica.
Subjected to chromatography, acetic acid ethene, 4'-) to ene 1:
6 and eluted. Rf = 0.30 (silica/vinegar
Tet μ-ene l゛: 6-1 potassium permanganate
7 lactis containing the title compound (detected by erupting an aqueous solution)
The components were collected, combined and evaporated to give an oil xx7* (
yield 50%). The physical properties of the obtained oil are as follows.
It was.゛ IRy (Fim) 1803.1743.1
? 00esNMR(C!DCIs, 250MH2F
T"H) 1.49 (3H, t, J mai. CH, cHa), x, 9o-a, o5 (gH, m, C
H, OH, OH, N), 2h1n (2T1. (it
, J'/and qHz, (Jl, CH, CH, N),
3-at(IH, d, J 1'77, 6βC, 3
．． 4mas (IH, ad, , T1tsu and lrei 6aCH)
, 4.521 (2EI, q, J'yHz, CH
. CH, ), 4.55 (IH, dt, , T l and 7
H2,=(HC-). 4.64 (2!H, tt J 76, (:% et OH,
N), 5.04 (iH, eL,, r17, 3CH)
, 6.11 (IH) and 翫25 (IH) super q, 51
2Hz, 0CRIG crystal), 5.65 (IH, d,
, 73Hz, s a CH). ? , 34 (5H,8,C crystal). Example 31a ^-3-carboxylate Benzi-hydroxypteriden-Klapa at 20°C
Mu 3-Ka-Bo Medium Shire) (0.5f, 11.58mm
Dried 'ff1Fl tetrazo containing IIM(
221 drops, 3.16 mm7A/) and triphenylpho
Treated with Sphin (497qF, 1.9-ken Limo A/)
, cooled to 0°C, add diethyl azodicarboxylene to this
-) (3304, 1.9 mm 7) was added under stirring. After 20 minutes, add 0.2 equivalents of triphenylphosphine.
and 50μ of diet azodicarboxylate were added. After stirring for 45 minutes, the temperature of the reaction mixture was raised to 5°C. Molten g
Evaporate and dissolve the residue in acetic acid ether-citalohexane 1:2.
Dissolve and collect the obtained crystal t-F, PftLt-silica
After chromatography, #acid ethyl hexa
l:2~l:1. eluted with a gradient solution of
. m = o, 5(silica/11 acid ethene p-cyclohe
Extracted with chiten l:l ■, potassium permanganate aqueous solution 1*
7: Collect the iF action and combine it.
and evaporate it to make Nato2C A/-2-I#1IJll#
2'761 fft* of colorless curved material (yield 47%)
). The physical properties of the obtained curved object were as follows: ◎ IRy (I #A) 1800.1750.1700,
1305, 1230° 1180, 1lio, 1040
．． 1025.1015.1005.895゜−鳳740.900 (IIl, ν(5% CHCl5JI
Liquid) 1800°1750.1700.130? , 12
i20.1180, 1118.1040゜〜γ汀IH,
d, J 16.5H2i, 6βCH), 3.47
(IH, dd, J16.5H2 and 3Hz, 6a
CTj), 4. a5-4.65 (3H, m. 5cu)-('1a (IH-dAI3qf J x1
5.25 (IH. d,..., 711Hz), 0CH=C crystal), 5.6
5 (IH, diluted with prohexane 1:1) (D fraction)
The mixture was combined and evaporated to leave a curved material containing intracrystalline bodies. child
The mixture was rechromatographed on silica with ethyl acetate.
Elute with μ and develop with = 0.8 (silica/acetate)
, detected by erupting potassium permanganate aqueous solution).
Collected Kushiyon. Combine these fractions and evaporate
The colorless curved product of Nat2C A/-1-I μ derivative is
Obtained with a yield of 15%. The physical properties of the obtained derivative are determined by the following formula.
Met. IRJ/ (FIMU) 1800.1?47,1695
,1305.1330°1170,1115.1040
．． 1015.1000.960.890°? 44700
m', J/ (5% CHCl5 solution) 18
00°1?45.1695,1305,1220,11
65,1115,1040°1010.1000 countries. NMRJ (CDOI,) 1.83-2.14 (4H, Bu
Load m, CHICHIβC1(), 3,475(I
H, d(i, J 1? and 3 aiiS, 6aCH
). (IH, dt, JI7 and decimal, aCdan) 15.0
5 (IH, (1°J1, 3CH), (5,1?,
(IH, d super q-J l 1 movement). &2F (IH, d JlxHz), OCH, C
, H, ), a, av (ABq" IH, broad d, J3 Hz, 5aCH), 7.35
(5H, Example 31'b BendiA/4-tetrazo-A/-1'-ypteridene
-Kuppamoo 3~Power pbokikure-1-(211519,
-2 (20@l) containing 0,61
Hydrogenation at normal pressure for 70 minutes in the presence of radium sowg.
did. Touch KkP is lost, P liquid t'JIjk distilled water (Bowl
) was diluted with This solution to, 2 molar lithium hydroxide solution
The pH was adjusted to 1.2Kf14'M. * Steam g'
Emit cream-colored 1iti + body 120 from acetone
(yield 7.96). This body is the gray of chestnut power
with a mixture of 4:2:l of ethyl acetate-ethanol-water.
jll! L. Testing by erupting potassium permanganate aqueous solution.
When obtained, it shows Rf = 0.43'i, and its physical properties
was the following and 5i-b. Stop ν (Nujo-A/ ) 17B5.1685.161
0.1302.11?0°1110, 1040.101
5.995.8QB, 735 tax; #(K
Br) 17BL L692.1610.1408.1
305.1170°1115, 104g, 10!0.
998.89'7. '737 ag. 3.09 (IH, d, J 17H2,6βO!(),
3.55 (:ta, aa,,yl? and 3chi, 6
αC tan), 4.54 (aH, broad t. (&CHm), 4.86 (IH, 8, 3CH), 5.
6'F (IH, d, J 3' Example 32!! Bendijll/4-tetrazol-21-ylptelide
Nklapam 3-carboxylate (540Mg, 1
Tff (Roal) containing 4 mmA/) was added at 10%
Decompose with open book for 70 minutes in the presence of radium-containing @2oOq
Ta. Touch WXtP lost, P liquid t-'I'HF 2511111
Diluted 4"t" and added distilled water to give 5011j. In this solution, use 0.2 mol of hydroxide Lytecum solution.
Titration with H7.20 and evaporation gave the crystalline homologue. Koya same
Precipitate the body with acetone and dry it to 330? g (yield 80
%)tl14Diisl[)Rf jet O,4? hand
There was (silica/6al ether ρ-ethanol-water a:
a: 2, by ejecting potassium permanganate aqueous solution
detection). The physical properties of this painting body were as follows. IRy (p, diEl-A/) 3160. (Tet
Lazo-w C-H5tr). 1787, 1690.1620 (?id band),
1603゜1580←Nide band), 1308
．． 1295.1185°119θ, lit! 5.11
03.1070.105! , 1038.1030゜1
015, 1ooji, 991.897.740 am
. w (KBr disk) 3170.1785.1690
．． 1606.1410°1306, 1295.1a8L
118? , 130S, 1070.105! S. 1037.101? , 1015. Yu002,996,8
98,740°1 700 as. NMRa(r)Bo, 250161'H)SLIJ(4
H, Broad 8°L12(LH, (1(1, Jl tsu and
and 3 H2, 6αCH), 4.58 (IH, t, J
-F dynamic, CEIC115CH,)4J55-4.77
(aH2m. Implementation @ 33 & 0C4DF-Nitrobendiμcla A5: i# -) (
Department. dichloromethane (1
00111) Solution KP-) Luens A/Eiji N Isocia
dichloride containing nate (14.89% 14.8 mm 7μ)
Lomethan (3081) f full application. The reaction mixture was kept at 0°C for 1 hour.
Stir for a while. Then the title compound was removed as a yellow foam under reduced pressure.
39.5! I got f. The physical properties of the obtained compound are as follows.
It was a long time ago. IRyrmx (CHCIm) 1810.1750
and 1700 ts. NMRJH (CDCIs) L41 (3H, 8, C familiar)
s-). 3.05 (IH, d, J 1.'/EIZ, 6β-C
H), xal(lH, da. J 17 and sHz, am, -CH), 4.50-*
as (3H, II. 9-CH5k Yohi a-an), 5.09 (IH
,8,3-OH) *a,26(2H,8saG No,
), 5.68 (IH, d, JaH2,6-CH),
7.30-'7.4B (5H, m, NH. Example 33m) p-nitrobendiA' 9-(I)-) luenesulfonate
Claparanate (12?,
22. ．． 6 mm A/) l 2-pu C1 moz tano
III (20-1280 built 7μ) and DMP (z d
) was dissolved in a mixture of The reaction mixture was heated at 40°C for 16 hours.
Leave for a while, then add ethyl acetate A/(15011j).
I got it. Organic i* was washed with water 1 (aooIljXS times) and saturated brine, then -
It was dried with anhydrous magnesium sulfate. Melt removed, yellow
The image was obtained and subjected to two-person chromatography on silica gel.
Elution was carried out with ethyl acetate-toluene. Rf = 0
．． 52 (ethyl acetate-toluene l:)
Combine the 7 lactations containing the ingredients and evaporate under reduced pressure to form a white solid.
The title compound was obtained. Crystallized from ethanol, colorless
It was made into needle-like crystals (yield 24%). The physical properties of this crystal are as follows.
It was Tooshi. IR#maX (KBr) 1780 OyoU 175
0 ex'. NMRJH (CDCIs) 3.09 (IH, dd, J
l'7 and IH2. 6b-CH), 3.2t2-3.55(3H, m, 6
a-OH and. -〇HaCB, Br), 3.60-
3.90 (2H, m, OOH, CH, B1-). 4, Tsu 9 (IH, 8, 3-circle) t 5.12 (2H, 8
゜3H2, (H:CHI), 5.55-5.78 (3H
, m, 5-OH and CH:CH, 7.46 and
8-2o (4H, ABq,, r9Hz. Phantom 1). Example 330 Sodium silate borohydride (0.26t, 6.9 mmol)
diphenyldiselenide (lJ36) under nitrogen at room temperature.
? . DMF (10d) lc containing 5.96ξ
I prayed for drop man. This solution was allowed to stand until it became colorless, and then heated with nitrogen at -20°C.
Underneath, p-nitrobendi A/2-(2-bromoeth)
xy)-2-vinyμm flavum-3-carboxylate
(4,05?, 9.2 mmol) containing DMF (
2511j) over 10 minutes. Finished adding the drops
The mixture was then heated to 1mM and stirred for an additional 45 minutes.
◎Then, this solution was passed through ethyl acetate A/(room)K.
Including 1 liter of organic saturated brine (1501JX twice), diluted
Hydrochloric acid (xaosd) and saturated sodium chloride9. Muyu
(160111) and anhydrous magnesium sulfate.
Dry. Evaporation under reduced pressure yielded a yellow oil, which was evaporated from silica gel.
Column chromatography of ethyl acetate
: Eluted with Rf = 0.44 (ethyl acetate)
Combine 72 combs containing toluene (1:50 ml) of toluene.
The solvent was removed under pressure to obtain selenide as a colorless oil.
97%), and its physical properties were discussed in the following evening with JO. IRymaX (CHCII) 1800 and 175
0 as'. NMRJH(ODO]J) 2.83-3.1! (3f
(, JO-OH, CH, SO & and 6β-0H), 3
．． 3'6 (IH, d (1, J16 and 3 Hz. 6a-CH), xaO-3-80 (2H, m,
oca! ca, se), 4.705.19 (IH
,dd,J9 &jhi3H2,CH:1Cf(,),5
．． 51-&'F6(3H,m,5-CH and CH:C
H,), 7.10-7.60shi and a, go (9
B, rn, ArH). Example 33 (1 p-nitrobendi pv2-(2-benzeneselenoethoxy)
C)-2-vinyroof 2-pamu-3-carboxylate (
4,3f, &3milimo f&/) f o t:
Toy (35m) Kllll dissolved, sodium metaperiodate
Water (lad) containing Licum (rare t% 162 mm μ)
Added turbulence. The reaction mixture was allowed to warm up to room temperature.
, stirred for 1 hour and a half, then added acetic acid ethane*(room)K stream.
It sunk in. Organic 11 saturated brine (15011JXg times)
and saturated sodium bicarbonate (16011jXa times)
It was washed and dried over anhydrous magnesium sulfate. remove solvent
The title compound (4.6f, yield 97%) was obtained as a colorless oil.
T-Toku, its IRId atm&X (CHOII)
1800°1750 and 1610. Met. Example 3 3θ p-nitombenzi #2-(2-benzene 722μ
ethoxy)-2-viny--clapham 3-carboxylene
-) (4,5F, 8.4 mmol)t)j'Men
(50aj) heated under Q reflux for 30 minutes, then cooled,
Evaporated under reduced pressure. Obtained oil t column chromatograph
The mixture was eluted with 7 liters of ethyl acetate and toluene. ni=
Components of αaO (MII in ethyl acetate-toluene)
The fractions containing
of aldehyde was obtained. Yield was 44% with E and 2-isomers
The physical properties of the 1:1 mixture were as follows. IRJ/maX (Cf(C1s) 1810.176
0.1730 and 1700 cmNMRJH (CDC
II) Lll-&58(4H,m, CH1CH4HO
). 3.06 and 3.19 (IH,!
and IH2゜679-CH), 3.49 > and 3
．． 53 (IH, 2X dd, J4 and 16Hz,
6α-0H), 4.63 and 5.10 (IH-x
at, Ja > and 2Hz, C Dan CH, CH, CHO)
, 5.07 and a, 33 (1 kl, 2 X d, J2
H2,3-C! H), 5.25-a, vo(IH, m
, 5-CB), 1.45-1.60 and a,
18-8.53 (4H, m, ArH), 9. 'y-
9, a (la, m, aH (cn4). CB0). Example 33f p-Nitro with a mixing ratio of 2 and E-isomers of 6:3
Pendi# 5t-(4-oxobutyritene)cutepam
-3-Carbo Medium Shire) (1,2F%!3 Mi17Mo
#) dissolved in t-dry dimethoxyethane (jiom),
Cooled to -20°C. Sodium borohydride (0,1
5F, 3.96ζ remote μ)' gradually over 5 minutes.
I got it. The reaction was stirred at -20°C for 15 minutes and then poured into a thin layer.
)/? All of the aldehyde starting material has been consumed.
After showing 1 reaction product was diluted with ethyl acetate μ(100-).
Ta. Organic mt saturated brine (roomXi group), dilute hydrochloric acid solution
and magnesium sulfate.
It was dried. Evaporate and column with silica gel.
and eluted with acetic acid ethyl μ:toluene 1:1.
2-Is it an isomer? Sae was obtained (yield 6%), and its physical properties were
The following was]. IRum&X (CHCII) 1800.1750
and 1700 ex. Nklm aH (ODClm) 1.35 (IH, blow
dos, OH), 1.60 (2H, tt, J'yHz
, : CHCHIC spider0ff), 2kjilO(
S! H, (It. J'FH2, CHOHI (CHI)!OH) t '0
8 (IHe'l *"6H!'a e6β-岨)e
3.50 (IH, dd, J16 and ternary, 6β-0H
), 3.55-3.65 (2H, m, CH (CHI)
, (3HOEI). 4, a3 (IH, at, Jy and mountain, :岨(C horse) S
OU). 6.09 (IH, (1, JIHz, 3-CH), 5.2
5 and 5.33 (IH, (1,, r3H5,6-CH
), 7.51 and L2B (4E1゜ABq, J 8
H2, ArH). Example 34a Benji #S! -(4-phenoxybutylidene) Clapa-5
-3-Force μ boxylate At 0°C, triphenylphosphine (0,15f.
Contains t&benziIs/2-(4-hydroxy
Butylidene)-cutupamu 3-kaμ is xylate (0,
THII' (3sl) of 16f, 0.51mm 7p)
into solution. Diete p Azoshika μ po life sylate (α09-1αb Tsumi
Rimo J&-) was added. Reactant tot: Lower 1. s share
Stir and heat up with subsequent batch stirring. thin layer chromatograph
indicates that all the starting material has been consumed and the reaction mixture
[-(Concentrated to 1 m) and added aoml of toene. Yes
The machine layer was diluted with dilute sodium hydroxide solution (goMJx l l1
il) Wash with saturated salt water until the washing solution becomes neutral.
, dried over anhydrous magnesium sulfate. Molten gt depressurization, removal
A yellow oil was obtained, which was analyzed by column chromatography on silicage μ.
and eluted with acetic acid ether-cyclohexane 2:3.
Ta. Rf=0. L54 (Ethyl acetate-citalohex
The fractions containing the components (developed with Sun 2:3) were combined,
Evaporation gave the title compound in 46% yield. obtained
The physical properties of the compound were as follows. IR#/111&1 [(CHCIm) 1800.17
50 and 1700 ts-NMRJH' (CDCI
s) 1. M8 (2H, tt, 5'/, 5H2, C
HCH, OH. C old-0Ph), Lit6 (2H, dt, J?, 5
fL! i, OHOHm(CHs)zOph), 2h
oz (IFl, dd, :flq and IH2,6β-C
H)=L40(IH, (id, Jltsu and 3 songs, 6α
-岨), 3.8B (2H, t, J), 5H2, CH ((
4)! OH,0Ph), 4.60 (IEI. it, J?,s and 2H2,Cg((&)sOPh
), 5.03 (IH. d, JgHz, 5-CH), 5β, 5. zz(2H
,AT3q ,,T12! JSH2゜9νul'),
5.58 (LH, (1, J3 base, 5-tomo) t 6.81
-6.98 sodium substitute 12-(4-phenoxybutylene)
Den) - Benji*j! -(4-phenoxybutylidene)
(0,21j,
0.53 mmopv) 0THF (xod) @
Parajik A-J (0,0'/l) was added to the liquid. Hydrogen 1
Addition of this mixture for 30 minutes at temperature at atmospheric pressure,
Filtered. Reduce the P solution to a small volume (l-), then add acetic acid ethyl chloride.
Partitioned between chill and water. pH 1.5 with sodium hydroxide
KIII has been adjusted. Separate the aqueous layer and evaporate it to produce a pale yellow gas.
Obtain a lath-like substance and tritulate it with acetonitrile.
The title compound is an off-white isomer in 81% yield.
I got something. The physical properties of this compound were as follows. IR#max (ICI3r) 1780e 1700 death
and 1610511”. NMRaH(Dlo) x, Pla-x, 95(2H,
m, CHCH1CH1C%0Ph). jl-13-jL43(2H-m@OHOHm(Ck
ls), oph) L73 (1111#d, J 1
7Hz, aβ-CH), 3.40 (IH, dd, Jl?
and 3Hz, 6a-CH), 4.06(2H,t,
J'FH2,:CH((H,).OH,0Ph), 4.72(tH,t,J'FE[
2+, :CH(CH,), 0Ph). 4.85 (IH, d, Jl, 5H2,3-CH), 5.
51 (IH, (1, J3H2° Benge° #2-(4-H)
Droxybutylidene) (2pam-5-carboxylene)
(041% IJ 66 mmol) 1) Rifeni μphos
Fin (0,3651P, 1.39 mm I&/) and
(N-Benji〃OmishikaNboniμ)-p-toμenseμ
Honnamido (0.6F, 1.9 Tsumilimo 711<)
The dry redistilled THF containing (1) Km was dissolved. this
Place the mixture in a cooling bath of dry ice/four-year-old
While stirring vigorously, mix Azocica ~ Poxylate (
THF (dried
Redistilled, immediately treated with 5yd) II# solution:
. After 6 minutes, the reaction mixture was heated to room temperature, and after another 16 minutes, the reaction mixture was heated to room temperature.
Dilute with acid ether, wash with brine, and sulfuric acid! Gnesicum
Dry and evaporate. Chromatograph the residue on silica gel
The title Q compound was obtained by eluting with toluene-ethyl acetate.
0.5105f of compound was obtained (yield 67%), a good compound obtained.
The physical properties of objects are as follows. IRvm&X (74Wm) 1802.1740 m,
1731 and 1701 (1ml”. NIJRJ ((,!DCIs) 1.64J5 (4H
,m,q蜘e'jjsN)e 31-33 yo rJf8
6 (3H, 8 each
), L94 (IH, d, J17m, 6β-Cg)
, 3.46 (II(.d, Jx? and 3H2,6α-Cg)t 3.63-
3.96 (IH. m, 0:C, CH@), 4.5a (IH, brt, J
'yHz C:CH). 1LOil (IH, br8, 3-0H),! S,O'F
& JL15 (4H @ 48,00H each), L
12 (IH, (1, J3Hz, 5-CH) and 7.0
0-1.80 (14H, m, aromatic)・Example 35b Leg acid hydrogen sodium chloride A (Q, O?lF, 0.845
Mi941h/) and touch [(10% Balajikumu tO, 1
2-(4-(N-bendiμ) containing lP)
Oxycarbon y Boni 14')
Mythos μ Honga Z de] Petit Ridden-Clapham-3-Cal
Hoxiley) (0.5105F, 0.845 mm
A/), water (l-) TI (F (1jifj)
i Hydrogenated for 1 hour. After this reaction, filter the reaction mixture
The P solution was evaporated. Filter the residue (in dry acetone)
filtration and concentrate the solvent to obtain 0.01 of the white isotropic compound.
55f'i was obtained, the yield was 4.6%. worshiped
The physical properties of the compound and O were as follows. IRvrrmx (Nuji:1-A/) 3270.1
789.1701 and 1600 countries. NMRJ(M)l-38-IJ-/(2H, m, CH,
,0%,CH,), 1.9l-L13(2E[,m,C
HJ), ju2(3H,8,CHI), &79-f
L92 (2H, m, C:C,C spider), 2.98 (IH
, d, J17Hz6β-CHri, s, 5a (IH, d
a,, r17 and mHz 6a-CH), 4 to 63
(IH,brt,,T8a2S (3:CH), 44
SO (2H. s, C-Ph), phrase a (IHa a * s-CH),
a, go (xa, a. J ghHz, a-OH) and tsu, 45. 〒3(4)
H, Crystal I■; J13Hz, ArH). Example 36a °bendi*2-(4-hydroxybutylidene)darapam
-3-carboxylate (0.19F, 0.6 mmol)
U) in dichloromethane (2-) solution under tOc
06m+j, O, fumirimopy) and aceteμ chloride
(α05TIL1.0.7mm above 1m/) for 5 minutes at 0℃
After that, thin layer chromatography is performed to identify the starting material.
It was shown that all the alcohol-N was consumed. this
The solution was diluted with dichloromethane to make 25- and the organic layer was separated.
Water (S!511Llx 2 times), dilute hydrochloric acid (2511X 1 time)
), saturated sodium hydrogen oxide solution (25MJ x 1 time) and
and saturated salt water (g5@lXg yen), and sulfuric acid! Gune
Dry friends with Shikum. IJ11 rope was removed under reduced pressure and colorless Q marker
The title compound was obtained (yield 88%), and its physical properties are as follows.
Met. ,. IRym&x (s%CHCl3) 1800.173
5 and 1700 ts. NMRJH (CDCl2) 1.64 (2H, tt, J
7 Hz, CH, OH, (EH. C horse 0-) Lo4 (3H, s, q horse Co) &14 (
2H, dt, J7 Hz, CHOH*(OHa)sO-
L 3.05 (LH, d, J 1vHz. 6β-CH), 3.46 (If!, dd, J l'F
and 3 H2, 6a-CH), 4. oo(2H,t
, J Tsushi, CH(CH,), CH,0-)4.5a(L
H, at, J q and I H2,0H(CHs)so
) 5.03 (LH, d, Jl base, 3-Yin), 5.1
5 and 6.24 (gH, ABq, J 12Hs, O
H, Ph), 5.65 (IH, 11, 73Hz,
5-CB), 7.30-7.45 (5H, m, Ar
H). Example 36b Bajik penta-parisulfate (0.08p) for 5 minutes at room temperature
Add bulk water in THF beforehand, then add Benzi A/2-(
4-Aryutoxypteriden)-Furano(Mu3-Carbo
THF containing xylate (0, lf, α68 mm〃)
(10d) was added. Open the reaction mixture for 5 minutes.
and then in thin layer chromatography, the starting material
All of the energy is consumed 7X L,
Mv&t-P' left L7t. Touch v&tTHF (goII
Wash with j) and combine with solution F to make a small volume (approx. 1111).
The mixture was reduced and partitioned between ethyl acetate and water. Hydroxide Lytecum p
Disperse the aqueous layer and add water under reduced pressure.
After removal, 1!1 off-white bodies were obtained. This is TH
Washed with F, removed P, and dried under reduced pressure to obtain the title compound.
(Yield 61%). The physical properties of the obtained compound are as follows.
there were. IR#maX (KBr) 1780.1700 (8h
) and 1615 ts t. NMRJH (crow 0) 1. -14 (aH, tt, J6.
JH2, CHCH mountain range 0), 2LOtsu<3a, s, ca
, o), 2. ．． 1O-2,2B(2H,m,CH庰,(
CH Tomi) snow 0), 3.05 (IH, d, J hexadecimal,
6β-constant). 3.54 (1, H, dd, , r 18 and L'FH2
, 6a-CH) cog(2H,t, J 6-8H!
2s, CH('C&)*CHsO) *4-'FO(
IH. dt, J aJ3 s? 1Hz=CH(CHxhO
), 4.8'F (IH. d, J I E2i, 3-CHH), &65 (IH,
(i, J L'FH2,6-4) Example 37a BendiA/2-(4-hydroxypudeli
・Den)-Tatsuvamu 3-Force:p poxylate (α2
t, 0.63 mmA/) of dichloromethane (2114
) Add pyridine (0.06m, 0.7mm7μ) to the solution.
Bendi μ chloride (0,0811j, 0.7 mm J &
/) 1 added. After stirring this reaction mixture for b minutes at t-O℃
In thin layer chromatography, the starting material alcohol μ is all
was shown to be consumed. Dichloromethane
Diluted with water (20 m) and the organic layer was diluted with water (25 m x a time).
, dilute hydrochloric acid (aamx IIMI), saturated sodium hydroxide
solution (25d×1 time) and saturated salt water (2511
JXj (once) and dried with anhydrous magnesium sulfate.
Ta. Removal of the solvent gave a yellow oil, which was washed with silicage μO color.
Attach to Muchromadog 2F and add acetic acid to μm cyclohexane.
Next, elute with gas. Bi-OJ56 (acetic acid ether-Schiff)
7 lactyone containing the component
The mixture was combined and evaporated under reduced pressure to give the title compound as a colorless oil (yield
rate 81%). The physical properties of the obtained compound are as follows.
Ta. IRMTmX (5%0HCIs) 1800.174
5 and 1710ffiNMRIH (CDOI,)
1.1a (za, tt,, r tsu H2, CHCH,
Oh. OH, O-), Si4 (gH, dt, J?ka, Co
Cl1s)tO-)*3. o2(IHeddtJ
1) and IH2,6β-0H). s-4m (llll, dd, J 17 and 3Hz, e
a-CA), t, jla (2H, t, J t Hz, 0
H(OHa)*CHJ-), 4.60(IH. dt,, Ty and l Hz, CH(CHt)sO
-), 5.04 (IH. (1,, T lachi, 3-tomo), 5.16 and 42B (
岨, super q. J laJ Hz, 9yl), 5.62 (IH, (1
, J3H2,5-CH),'p,so-'1.3
s(sH,m,CH,Ph), 7.39-7.5o
(*Example 37b pudge 9 mu sulfate balik' (o, O'lf) t'i
ii. pre-hydrogenated for 6 min in warm THF (6-).
, then benzyfi/2-(4-benzyμoxybuty
lyden), rubber 5-3-force μ poxylate (α20
? , α4 mmol) in THF (10117) solution
added. IIILjI was added in bulk to the reaction mixture for t1 hour.
In I-layer chromatography, the starting material Esthe μ is
To show that it is being consumed, touch KtP and Lft. touch
l Wash with THF (go 114) and combine with %P solution.
The mixture was reduced to a small volume and partitioned between ethyl acetate and water. hydroxide
Adjust the pH to 1.2 with Retekumu, separate the aqueous layer,
Water is removed under pressure to obtain an off-white lliil body.
Ta. This was washed with tTf (F), filtered, and dried under reduced pressure.
The title compound was obtained (68% yield). Compound obtained
The gender was as follows. IRUm&X ([Br)1785.1715.17
00 (811) Th and 1610 tm - NMRJH (D, 0) 1.83-2.01 (2H, m
, CHCH, (J, (H, O-). 16-L44 (2B, Ml, CH0Hs (CH snow) g
o-), IL84 (LH, d, J hexadecimal, 6β-
3.43a (IH, d(1,, T 16 and 3
Hz, 6a-OH) 4.34 (2H, t, J 6.
'F fiz. CH(CHshCHlo-), &-/6(IH,t
,,T6. '/H2,OH(CHt)@O-,H
peaks partially obscured at OD). 6.58(lfl, (1, J 3 m, a-CH),
'7.65 (2H, dd, J Example 38a -1aC with benzyA/2-(4-hydroxybutyritene)
)/j bamu 3-carboxylene) (227Ill,
Dichloromethane (5
-) tl)-toluenesulfonyl isocyanate $-) 1 equivalent
The mixture was treated with water and agitated for 30 minutes to increase l0cK. The solvent was evaporated and the residue was chromatographed on silica.
and ethyl acetate-cyclohexane l;l'''c was eluted.
. Rf = 0.43 (Silica/Ediacetate~-Cyclo
Hequinane 1:1, by ejecting potassium permanganate aqueous solution.
A 7-lactone containing the title compound (detected by a method) was collected. Combine 7 lactations and evaporate to form an oily substance sso*tll
Ta. The process R of the obtained oily substance is (74#A) 180
NM at 0.1750.1700 (shi5jllz goo)
R was the same as that of the desired product. Dormitory Example 38b Midoka~Bonyy Oxybutylidene] Clapham-3 Benji
A/ 2-(4-(p-)μence! Honamidoka A/
g 2 μ oxybutylidene Clapham-3-calhoki
(200 Misaki, 0.389ξ Rimo W) containing T
HF (lom) lO% palladium vertical at normal pressure (
70 Da), 30 portions were hydrogenolyzed. This touch 11
F, PftLt THF (25m) and water (25m)
m) and diluted. Adjust pH to 1.2 with dilute sodium hydroxide
K adjusted. THF was evaporated under reduced pressure and the water-containing residue was diluted with water.
Diluted and washed several times with ethyl acetate. Evaporate the water layer
Tritulate with 'I'HF/acetonitrile
110 qt of a pale yellow solid was obtained. The engineering R of this li body is ν′
(Nugeot A/) 1785.1700.1620.
1280. x14d. 1120, 10?2.895.860.810.790
ts), the association is the same as that of the desired compound.
there were. Example 39a Triphenylphosphine (α3639,11.346O
rimole) and N-methyA/-4, 5-trioxoimida
Contains zolidine (0,236f, L836 mmA/)
Bendi A/g-(4-hydroxybutylidene)
Rubber 5-3-force μ boxyre) (0 Jasf, x,
Dry redistilled THF (51wJ) solution 1 of a2a mm7μ)
It was left under dry nitrogen flow at oc. Next is pure Jiechi.
μazoshika μboxy V −) (0,234t, 1.
Add 346 mmol, 4/) and evaporate the reaction mixture for 20 minutes with acetic acid.
It was diluted with Tep and washed twice with seed water. organic layer tact,
, evaporated and applied to Silikageμ Chromadog 2F (
Elution with toluene-ethyl acetate μ7:1]. Esther of the title
0.488f was obtained with a yield of 93%, and its physical properties are as follows.
There was. IRMWJ&X (Fi A/A) 1801.1779.
1732 and 1703 sh txs NMRJ (CDCI,) 1.604J3 (4H, m
, :C,CH,,CHI). 2-1a (lE[, d, J 16 H2,6β-Cdan)
, 3J3 (3H, 8°OR3), 3.26-3.
'F6 (3H, m, 6a-CH and C Yang, N). 4h55 (IB, br, t, J 6 Hz, 8-CH)
, a, o3 (IH, br. 8.3-C!1), 5.19 (2H, 8, OCH Tomi C
j(t), 5.63 (IH. d, J: sHz, a-CH) and ? -36 (5H, 8
, ArH). Example 39b Benjipy a-(number-(3-methyl-electronic number+a-)
rioxoimidazolidi=py)butylidene]clapa
Mu3-Force~Pochusylate (0.1F, α23 mmol
) THF (asIj) solution KIO% palladium-legged
(0,02f) was added. This mixture t - 16 minutes at room temperature
Addition of the starting material and thin layer chromatography
It was shown that all Ste μ was consumed. Touch 11tF left
Wash with THF (1all), combine with P solution and add a small amount.
Reduce to spring product, ethyl acetate* (1011+1) and water (15
m). Adjust pH with sodium hydroxide skin fluid
The aqueous layer was separated. Remove water and colorless glass
A white substance was obtained, which was tritulated with acetone to give a white wA substance.
The title compound was obtained in 75% yield. The positive value of this compound is #m
aX (X di*-1v) 1790.1740°17
There were 00 countries and 1610 countries. Example 40 Sylate Bendi A/g-(4-hydroxybutylidene) Klapa
Mu-3-carboxylate (044B9% 1.4132
Dry toluene (8seJ) 1 dry nitrogen containing 2μ)
The mixture was left under an air flow and cooled to -20°C. Next - Triete
Ruamine (α197-, 1.413 mm7~), followed by
Trif 1 &/olomethane μphonic anhydride (α23
Dry toluene containing 15-11.413 mmj%/)
(3-) was added. The reaction was complete after 1 hour (by TLC).
diluted with ethyl acetate, brine =, (tffi
) and saturated sodium bicarbonate solution. organic
Dry with a layer of magnesium chloride and evaporate to give the title compound.
0.51 Bat of ST was obtained with a yield of 91% (further purification
used without). The physical properties of the obtained esthetics are
It was as follows. IR&ma! (Fi #A) 1803.1754 and
170sims. NyRJ(CDCl2) 1.4o-2J5o(+H,
m,:c,(J(,,(4,).3°o2(zH,d,J 18H2,6β-0H),3
．． 50 (IH, dd., T 18shi and 3H2,6α-03), 4.2<-
4,66 (3H, m. s-c dan > x OEj,, 0.8), 5. oq(l
H, br, a, 3-C! , 5.2i0(aH,8,C
o, OH,), 5.6-/(IJ(1,, T 3H2,
5-cp)t and 7.3a (5H, 8, OA). Example 41? 17m no jlL/ (0,04114) DMF (
4m) Dissolve the solution in a wooden stove and add water volumized sodium (S
t1611F) dispersed in mineral oil was added. solution
Shun Benji #ji-(a-(p-toluene) became transparent
Sulfonyloxy)butylidene] Clavamo 3-kabo
xylene) (139q) in DMF (2i1111j)
liquid was added. The mixture was stirred for 11 hours and brought to room temperature. roar
I set it. Next, acetic acid (α1aj) was added and the solution was dissolved in ethyl acetate.
diluted with Acetic acid ethyl μ solution t-sodium hydrogen sulfate solution
The solution was washed three times with water and brine successively. sulfur solution
Dry with magnesium acid, evaporate and remove the residue by column chromatography.
Attachment to kiese pge p1 petroleum ether vinegar
53 drops of the product (eluting with acid ethyl A/4:1) were obtained. profit
The physical properties of the obtained product were as follows. IRymaX (CHCII) 1803.1750
and 1698 ts t. NMRa (CDCl2) 1.55 (2f(,/(
:/ft), J'7H2). Li2 (2H, q, J '7H2) SL'y (2H
, t, J aH2). 2h9o (IH, d, J hexadecimal) t 3.38 (
IH, dd, J 3 and x'yaz), 4.4'/
(IH, Broadt, J 7H2). 4h93 (IH, 8), 5.08 (2H, 8), 5
．． 53 (IH, d, J 3Hz)? , 1-7.5(x
oH, m). Example 42 Xylate Bendi A/E-2-(+-Hydroxybutylidene)
Rapamoo 3-carboxylate (2401p, 0.76
A, a methane (3m) containing
l)-)Luenesulfonychloride (2899, IJs
tlimoμ) and dry pyridine (183sj, &2?mm)
mol). 2 hours at reaction mixture tl temperature
Stir for a while. After that, TLC (acetic acid step μm cyclo)
The reaction was completed when the Rf value was 0.67.
I showed that I did it. Remove the dissolved V& under reduced pressure and transfer the reading to acetic acid
Wash with 20% citric acid solution, water and seed water
The organic layer was separated, dried over magnesium sulfate, and then evaporated.
I let it emanate. Add ethyl acetate μm to residual oily silica μm.
Fractionation by elution with 1:2 lohexane yields the desired tosylate.
was obtained in a yield of 65%. The physical properties of the obtained tosylate were as follows. Engineering RIIm! (Fi A/A) 1800.1?50.1
700 as. NMRI (CDOIB) 1.53 (zH, m,
CH, CH, CH, O20,). 1.9'/(aH,m,C%CH,C%O8O,),2
．． 45 (3H, 8°C), 3.0 (IH, (1,,
rl? Tortoise, 6β-CH) 1B (IH. dd, Jl and 3 out 16α-CH), 3.9 (j
tH, t, Ja, 5Hz, CH, CH, QH, 08OI
), 4.91 (IH, dt,, r? and h2aiS
, 1B-Cq), 5.1$! (LH,1)8,3-C
H), a, l'F (aH, s, co, c spider), 5-
63 (IH, (1, J 3Hz, 5a-Example 43 BendiyE-a-(4-hydroxybutylidene) Taraba
Mu 3-capoxylate (50 Da) in dry benzene (
10084) Quartz spring solution under nitrogen atmosphere! IK insertion 5!
A Hanobia low pressure lamp (Ha
novia low pressure lamp)
The NMR of the mixture after irradiation for 6 hours revealed the 2 and E-isomers.
It was a 60:40 mixture. Example 44 Bendifi/Z-2-(4-hydroxybutylidene)
Clapham 3-carboxylene) (134 da, 04
Dry DMF (8m) containing 3imilimo)i nitrogen at room temperature
Triphenylphosphite methioside (229
Drops, 0.51 mm ~) were treated. Cool the reactants at room temperature.
Stir at night and remove under Sat vacuum to obtain an oily substance.
Dissolve the oil in ethyl acetate and wash with water and brine.
After that, it was dried with magnesium sulfate. solvent t - evaporate
A yellow oil was obtained which was fractionated on silica gel (chromatography).
NMR#i of the crude material before being subjected to
). Example 45 Triphenylphosphine (0.35f, 1.33 mm
#) and N-bendi~oxycarbony~acetamide
Benzyl containing (0.35f% 1.82 mmol)
2-(Number-Hydroxybutylidene) Clapham 3-Ka~
boxyley) (o, 3aay, 1.22 mmol)
TaF(am)# solution at 0℃
(OJlm, 1.33 μm) was added. The reaction mixture was stirred open for 30 min at Ioc and then allowed to warm to room temperature.
The temperature was raised. In this thin layer chromatography, the starting material
Indicates that all has been consumed, and the reaction mixture is converted to Shoshun (
111111)'! and add toluene (30-)
Ta. Wash the organic layer with saturated brine (3011x2 times),
It was dried with anhydrous magnesium sulfate. Remove solvent and turn yellow
An oil was obtained and subjected to column chromatography on silica gel.
The mixture was eluted with ethyl acetate-cyclohexane (2:3). Rf: 0.50 (ethyl acetate-cyclohexane 2:3
The fractions containing the components of
The title compound as a colored oil was obtained in 28% yield. obtained value
The physical properties of the compound were as follows. NMRJH (CDCII) l-00-5LS! 6(
4H,m, CHCHI(CHm)sN and CHCH@
trout CHJ), L45 (3 turtles, NO et al.). L92! (IH,d,,T P2H4,6β-Cf(
), 3.42 (IH, da. J1 ma and binary, 6α part, J3.68 t partially
(indistinct), 3.68 (2He broad t, J7Hz. CH (C mountain), CH, N, J part with dd of 3.42
(partially unclear), 4.50 (IH, Broad, J.
Friend (CHm voice). 4.94 (IH, broad 8.3-CH), L16 and
and 6.20 (4H, 2x s, NCO, ρp, ph *
and C, CO, CHf1). ri, 66(IH, (1, J 2H2, 5-0H), '
7.25 and 1.30 (loH, 1x s, ArH)
.

Claims (1)

[Scope of Claims] 1. An 8-carboxyclapam derivative characterized by having a butylidene molecule at the 2-position of the 3-carboxyclapam nucleus. 12 Qll): (wherein, X is a hydrogen atom, hydroxy, substituted hydroxy,
mercapto, substituted mercapto, cyano, nitro, isothiocyanate, halogen atom, amino, or substituted acetate group; 2. The compound according to claim 1, which is a compound represented by the following formula (representing an aryl group or a heteroaryl group), salts and esters thereof. 8. The compound according to claim 2, which has a two-stereochemical structure at the double bond. Claim 11! t in the form of the free acid or its pharmaceutically acceptable salt or ester! L1 term maku is the 8th
Compounds described in Section. 5. Is X human? /, C3-1, full: l'/
, at-t. Alkanoyloxy, benzoyloxys '1-1゜alkylthio, benzoylthio, azide, halogen atom, dicyro, amino, '1-1゜alkylamino, '1-
1゜Alkanoylamino, ok-rusulfonylamino or hete? 5. The compound according to any one of claims 2 to 4, which is cyclyl. 6. A compound according to any one of claims 2 to 5, wherein aX is hydroxy. 7. Formula (Ma): ■ (In the formula, Ha is a hydrogen atom or a protecting group for a carboxy group; Y is an oxygen or sulfur atom) is reduced, and 1) formula (I): A compound of the formula (wherein X is neither hydroxy nor mercapto)
-) removing the carboxy protecting group R1, and -) converting the product into a salt or ester CUt): ■ (wherein X is a hydrogen atom, hydroxy, substituted hydroxy,
mercapto, substituted mercapto, azide, cyano, nitro, isothiocyanate, halogen atom, amino or substituted amino group, or X represents the residue of a nucleophilic carbon or an activated aryl or heteroaryl group)
A method for producing the compound represented by, its salt and ester. 8. An antibacterial composition comprising an 8-carboxyflavam derivative characterized by having a butylidene molecule at the 2-position of the 8-carboxyflavam nucleus and a pharmaceutically acceptable carrier. 9.8-Carboxyflavam derivative has the formula (1) :(
In the formula, X is a hydrogen atom, hydroxy, substituted hydroxy, mercapto, substituted mercapto, azide, cyano, nitro,
compounds represented by inthiocyanates, halogen atoms, amino or substituted amino groups, or where X represents a nucleophilic carbon residue or an activated aryl or heteroaryl group, their salts and esters; An antibacterial composition according to certain claims. 1G, an additional antimicrobially active β-lactam compound. 11. The antibacterial composition according to claim 10'gIK, wherein the β-lactam compound is a penicillin or a cephalosporin.