JP2860379B2 - β-lactam compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] BACKGROUND OF THE INVENTION The present invention relates to a method for producing carbapenem compounds.
Novel β-lactam compound useful as an intermediate in the production
(VI-2). [Wherein, R₁And R₂Are the same or different
Each represents a hydrogen atom or a lower alkyl group.
Then R⁰ ₃Represents a lower alkyl group;₄Is Carboki
Shows a protecting group for sil group or thiol carboxyl group
X ′ represents a protected hydroxyl group, Y represents an oxygen atom or
Represents a sulfur atom, and B represents an alkali metal atom. ] The compound (VI-2) of the present invention is, for example,
Formula (I-8)⁰) Embedded image [Wherein COZ ′ is an active ester of a carboxyl group,
Or active acid anhydride, protecting group for thiol carboxyl group
Protected thiol carboxyl group, substituted aryl
Xycarbonyl group or heteroaryloxycarbo
And the other symbols have the same meanings as described above.
You. ] A compound represented by the formula
Is a compound that is efficiently obtained by treatment,
General formula liberated in the reaction solution as required Z '^- Wherein Z ′ is as defined above. Ani represented by
After trapping with an alkylating or acylating agent,
By treating with an acid group active esterifying agent, the general formula
(IX) Embedded image [Wherein, R₁, R_Two, R⁰ _Three, R "_Four, X 'and Y are as described above.
L has the same meaning, and L represents an active ester group of a hydroxyl group.
You. To produce a compound represented by the formula Further, in the presence of a base, a compound of the formula (X) R₀-SH (X) (Where R₀Represents an organic group. )
Reaction with a tan compound or the above mercaptan
By reacting a salt of compound (X) with a base,
Formula (VII) Embedded image [Wherein, R₁, R_Two, R⁰ _Three, R₀, R "_Four, X 'and Y are before
Has the same meaning as described above. Carbapenemization represented by
It is used to produce a compound. [0005] 2. Description of the Related Art Thiena having useful activity as an antibacterial agent
Mycin [US Pat. No. 3,950,357; J. Am. Che
m. Soc.,100, 313 (1978)] was found in nature,
Pure synthesis of various carbapenem compounds since was reported
It has been reported how to achieve this. Recently, the first position of the carbapenem skeleton (conventional
Numbering (see formula A below);
It corresponds to the fourth place in the numbering of the publication. ) A methylene group is
A compound substituted with an alkyl group is synthesized.
Rucarbapenem compounds, for example,
Superior to conventional 1-position unsubstituted carbapenem compounds
Has been reported to be extremely useful as an antibacterial agent.
You. Accordingly, 1-alkylcarbapenem compounds
There is also much interest in developing effective manufacturing methods. [0007] Embedded image [0008] DETAILED DESCRIPTION OF THE INVENTION The present inventors have developed a carbapenem compound.
A method for producing a 1-alkylcarbapenem compound.
As a result of the investigation, the above-mentioned compound of the present invention was found to be
In the production of 1-alkyl carbapenem compounds
The present invention was found to be a useful intermediate, and the present invention was completed. Here, the substituents in the above formula are described
I will extend it. R₁, R_TwoAs lower alkyl group in
Is the number of carbon atoms of, for example, methyl, ethyl, n-propyl group, etc.
1-4 lower alkyl groups;⁰ _ThreeLow in
Examples of the alkyl group include methyl, ethyl, n-pro
A lower alkyl group having 1 to 4 carbon atoms such as a pill group;
You. The protecting group for the hydroxyl group in X 'is usually
There is no particular limitation as long as it is a protecting group used for, for example,
having 1 to 4 carbon atoms, such as a t-butyloxycarbonyl group;
Lower alkoxycarbonyl group; for example, ethyl 2-iodide
Oxycarbonyl group, 2,2,2-trichloroethylo
A halogenated alcohol having 1 to 3 carbon atoms such as an oxycarbonyl group
Alkyloxycarbonyl group; for example, benzyloxycar
Bonyl group, o-nitrobenzyloxycarbonyl group, p
-Nitrobenzyloxycarbonyl group, p-methoxy
Aralkyloxyca such as benzyloxycarbonyl group
Rubonyl group; for example, trimethylsilyl group, t-butyldi
Tri-C 1-4 alkyl such as methylsilyl
Silyl group; for example, methoxymethyl group, 2-methoxyethoxy
Substituted methyl, such as a xymethyl or methylthiomethyl group
Groups; tetrahydropyranyl groups and the like are preferred.
Can be R "_FourCarboxyl group or thio group in
Commonly used as a protecting group for carboxylic group
But preferably, for example, methyl, ethyl,
Linear or branched such as isopropyl, tert-butyl
A branched lower alkyl group having 1 to 4 carbon atoms;
Charcoal such as ethyl iodide, 2,2,2-trichloroethyl
A halogeno lower alkyl group having a prime number of 1 to 3;
Such as methyl, ethoxymethyl, isobutoxymethyl
Lower alkoxymethyl group having 1 to 4 carbon atoms;
Xymethyl, propionyloxymethyl, butyryloxy
1 to 1 carbon atoms such as cimethyl and pivaloyloxymethyl
5 lower aliphatic acyloxymethyl groups;
Xycarbonyloxyethyl, 1-ethoxycarbonyl
C1-C4 lower alkoxyca such as oxyethyl
Rubonyloxyethyl group; for example, allyl, 2-methyla
Like ril, 3-methylallyl, 3-phenylallyl
Substituted or unsubstituted 2-lower alkenyl having 3 to 10 carbon atoms
Benzyl, p-methoxybenzyl, 2,4
-Dimethoxybenzyl, o-nitrobenzyl, p-nitro
Substitution such as robenzyl, p-chlorobenzyl or
Unsubstituted monoarylalkyl groups;
Substituted or unsubstituted such as tyl, di-p-anisylmethyl
Substituted diarylalkyl groups; for example phenyl, p-c
Lorophenyl, 2,4,5-trichlorophenyl, p-
Nitrophenyl, o-nitrophenyl, p-methoxyphenyl
Substituted or unsubstituted aryl groups such as phenyl;
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-py
Like rimidyl, 2- (4,6-dimethyl) pyrimidyl
Heteroaryl groups; and phthalidyl groups
Can be. [0012] The alkali metal atom in B
And sodium, potassium and the like. Also,
Y represents an oxygen atom or a sulfur atom. COZ 'is an active ester of a carboxyl group
Or, when it is an active acid anhydride, examples of the Z ′ group include
Halogen atoms such as, for example, chlorine, bromine, iodine;
Ethoxycarbonyloxy, isopropyloxycarbo
Nyloxy, sec-butyloxycarbonyloxy
Lower alkyloxycarbonyloxy having 1 to 5 carbon atoms
A group having 1 carbon atom such as methanesulfonyloxy
4 lower alkanesulfonyloxy groups;
Arylsulfonyloxy such as ruensulfonyloxy
A xy group; for example, dimethylphosphoryloxy, diethylpho
Di (lower alkyl having 1 to 4 carbon atoms) such as suphoryloxy
L) phosphoryloxy group; for example, di (phenyl) phospho
Diarylphosphoryloxy groups such as riloxy; examples
For example, N-succinimideoxy, N-phthalimidooxy
Cyclic imidooxy groups such as; imidazole, triazo
For example, 3- (2-thio)
Heterocycloalkyls such as xo) -thiazolidinyl
And the like. COZ 'is protected
If it is a carboxyl group or a thiol carboxyl group
Carboxyl protecting groups and thiols used in
Suitable protecting groups for the carboxyl group are the same as those described above.
Can be cited as Further substituted aryloxy
As a preferred group, p-nitrophenyloxy is preferred.
Si, o-nitrophenyloxy, 2,4,5-trichloro
And heteroaryl.
O-pyridyloxy, p-pyridyl
Oxy and the like can be mentioned. An active ester of a hydroxyl group represented by L
Is, for example, a substituted or unsubstituted arylsulfonic acid
Stele, lower alkane sulfonate, halogeno low
Grade alkane sulfonates or diaryl phosphones
Ric acid ester or halogenated water
And halides that are esters with hydrogen. Accordingly
The active esterifying agent for a hydroxyl group is a compound (VI-2)
Reacts with to form the active ester as described above
is there. Additionally, substituted or unsubstituted aryl sulfonic acids
As the ester, for example, benzenesulfonic acid ester
, P-toluenesulfonic acid ester, p-nitroben
Zensulfonic acid ester, p-bromobenzene sulfone
Acid esters, etc., with lower alkanesulfonic acid esters
For example, methanesulfonate, ethanesulfate
Halogeno lower alkane sulfone
Examples of the acid ester include trifluoromethanesulfo
Acid esters and the like, diaryl phosphoric acid
As the ester, for example, diphenylphosphoric acid
And ester, etc.
Examples include chlorine, bromine and iodide.
Preferred among such active esters of alcohols
P-toluenesulfonic acid ester, methanes
Sulfonic acid ester, diphenylphosphonic acid
Steal can be mentioned. Further, among the above-mentioned active esterifying agents for hydroxyl groups,
Are described, for example, in Examples 8, 10, 11 and 12.
Some are themselves acylating agents, such as these
Is naturally Z '^-Can also serve to capture This
In the case of an active esterifying agent such as
By obtaining, Z '^-And esterify hydroxyl groups
That act as both an acylating agent and an active esterifying agent
Can be used. In addition, with the active esterifying agent of the hydroxyl group
Prior to the reaction, a different alkylating agent or acylation
Z '^-Can also be captured. Alkylating agent
As iodomethane, iodopropane, allyl bromide,
Benzyl bromide, p-toluenesulfonic acid methyl ester
And the acylating agent is p-toluenesulfo.
Nil chloride, methanesulfonyl chloride and the like.
You. The inert solvent may be any inert solvent.
Is not particularly limited, but is preferably, for example, diethyl
Ether, tetrahydrofuran, dioxane, ethylene
Ether solvents such as glycol dimethyl ether,
Aromatic hydrocarbon solvents such as benzene and toluene, acetonitrile
Ryl, dimethylformamide, dimethylsulfoxide,
Hexamethylphosphoric triamide (HMPT), t
-Butanol and a mixed solvent thereof.
You. The general formula (I-8)⁰)
Suitable bases for the treatment include lithium diisopro
Pyramide, lithium bis (trimethylsilyl) amido
Metal salts of amines such as sodium and sodium amides, potassium
metal salts of alcohols such as t-butoxide, hydrogenated
Alkali metal hydrides such as thorium and potassium hydride
And sodium methylsulfinyl methide
Can be. In this case, the base proceeds sufficiently.
It is desirable to use an amount of 1.5 to 3 equivalents.
It can be said. The reaction may be cooled or heated as appropriate.
Can be suppressed or promoted by
The reaction temperature can be said to be -75 ° C to 50 ° C. Formula (I-8)⁰)
The compound of the present invention obtained by treating with a base in an inert solvent
Certain enolate salts (VI-2) are produced under the conditions
That is, under basic conditions, the starting compound (I-8)⁰)
The stereochemistry based on the asymmetric carbon (C5 position) of
Even after derivation to compound (IX), R⁰ _ThreeAl
A product retaining the steric nature of the kill group is obtained.
Without epimerization, carbapenem derivative (IX)
can get. Enolate (VI-2) which is the compound of the present invention
Is the following formula Embedded image It may have a chelate structure as shown in Fig. Further, a carbapenem compound is prepared from the compound of the present invention.
If it is desired to obtain the product (VII) directly,
Extraction of compound (IX) after derivation to bapenem derivative (IX)
Without further, the mercaptan compound (X) R₀-SH (X) [Wherein, R₀Has the same meaning as described above. ] And a base
The compound represented by the general formula (VII)
Carbapenem compounds. This is
It is shown in the reaction formula. [0022][Wherein, R₁, R₂, R⁰ ₃, R "₄, R₀, B, X '
And Y have the same meaning as described above. ] In this case, the treatment with the mercaptan compound (X)
In the theory, the added base is the first treatment (ring closing reaction)
May be the same or different from the one used for
Promote the reaction by adding another inert solvent
You can also. In this case, the base may be any of the compounds described above.
In addition to those used when converting to (VI-2),
Ethylamine, diisopropylethylamine, 4-dimethyl
Tylaminopyridine, 1,8-diazabicyclo [5.
4.0] -Undec-7-ene (DBU), 1,5-di
Azabicyclo [4.3.0] -non-5-ene (DB
N), 1,4-diazabicyclo [2.2.2] octane
Organic bases such as (DABCO) can be mentioned. Ma
As an inert solvent added to further promote the reaction
Is preferably acetonitrile, dimethylformamide,
Dimethyl sulfoxide and the like can be mentioned. Added together with the mercaptan compound (X)
The base is required to be in an amount sufficient for the reaction to proceed sufficiently,
Usually 1 to 1.5 equivalents to mercaptan (X)
Can do it. Mercaptan (X) reacts well
Need enough to proceed, use a large excess
Can be obtained but the compound (I-8)⁰1 to 2 equivalents
Can be done. The mercaptan compound
(X) and the base are each added separately as described above
Or alternatively, a mercaptan compound (X) and a salt
A salt with a group may be added. The carbape represented by the general formula (IX)
When the nem derivative is isolated, the derivative and mercapta
The compound (X) is reacted in the same manner as described above.
The carbapenem represented by the general formula (VII)
Compounds can be prepared. As described above, the β-lactam compound
(I-8⁰) To carbapene represented by general formula (IX)
Derivative or, if necessary, represented by the general formula (VII)
Carbapenem compounds can be produced. The carbapenem compound thus obtained
Compound (VII) is easily carbapenemized as follows
Compound (VIII) Embedded image [Wherein, R₁, R_Two, R⁰ _ThreeAnd R₀Has the same meaning as above
Have, X⁰Represents a hydrogen atom or a hydroxyl group. ]
Can be. (A) In the general formula (VII), Y is an acid
When it is an elemental atom, the compound, that is, the compound represented by the general formula (VI
I ') Embedded image [Wherein, R₁, R_Two, R⁰ _Three, R₀And X 'have the same meaning as described above.
Has a taste, R '_FourRepresents a carboxyl-protecting group. ]so
The reaction to remove the hydroxyl-protecting group from the compound represented
Removal reaction of protective group of ruboxyl group or protection of amino group
Antibacterial activity can be achieved by appropriately combining protective group removal reactions.
Carbapenem represented by general formula (VIII) having activity
A compound can be obtained. The removal of the protecting group depends on the type of the protective group.
It is removed by generally known methods. For example,
In the general formula (VII ′), a hydroxyl-protecting group and a nitrogen atom
When the protecting group of the halogen is a halogenoalkoxycarbonyl group or an aral
Compounds that are killoxycarbonyl groups, carboxyl groups
Is a halogenoalkyl group, an aralkyl group or a benzyl group.
Compounds that are hydrhydryl groups undergo an appropriate reduction reaction
By doing so, the protecting group can be removed. In such a reduction reaction, the protecting group is a halo
Genoalkoxycarbonyl groups and halogenoalkyl groups
Acetic acid, tetrahydrofuran, methanol, etc.
Reduction with an organic solvent and zinc is preferred and the protecting group is
Aralkyloxycarbonyl, aralkyl, benzhi
Platinum or palladium-carbon when drilling
A catalytic reduction reaction using a catalyst such as As a solvent used in this catalytic reduction reaction
Is a lower alcohol such as methanol or ethanol
, Ethers such as tetrahydrofuran and dioxane
Or acetic acid, or these organic solvents and water or
With buffers such as phosphoric acid and morpholinopropanesulfonic acid
Mixed solvents are preferred. The reaction temperature is in the range of 0 ° C to 100 ° C.
Although it is carried out within a range, a range of 0 ° C to 40 ° C is preferable.
Hydrogen pressure can be controlled at normal pressure or under pressure.
You. Further, when the protecting group is o-nitrobenzyloxycarbonyl,
When it is a benzyl group or an o-nitrobenzyl group,
The protecting group can also be removed by reaction. (B) In the general formula (VII), Y is sulfur
When it is a yellow atom, the compound (VII ") is as follows
To produce carbapenem compound (VIII)
Wear. Embedded image [Wherein, R₁, R_Two, R⁰ _Three, R '_Four, R₀, X 'and X⁰Is
Has the same meaning as above,⁰ _FourIs a thiol carboxyl group
Represents a protecting group. ] That is, compound (VII ") may be used as needed.
Then, as described above, it was subjected to the removal reaction of various protecting groups,
Hydrolysis of ester groups by various known modes
Is a carbapenem compound represented by the general formula (VIII)
Silver salts such as silver trifluoroacetate
Compound (VI) by treatment with alcohols in the presence of
After conversion to I '), the same process as in (a)
The penem compound (VIII) can also be obtained. In addition,
Direct treatment with silyl compounds such as lanol
Bapenem (VIII) can be obtained. The carbapenem compounds (VII ') and (VI
3-position substituent SR in I ")₀R₀Is a carbapenem compound
Any thing can be used as long as it is used for things,
For example, the following examples can be given. Sand
A substituted or unsubstituted alkyl group having 1 to 10 carbon atoms
Or an alkenyl group; having 3-6 carbon atoms in the ring
A cycloalkyl group, an alkylcycloalkyl group,
A cycloalkyl-alkyl group; an aryl group such as phenyl,
The aryl moiety is phenyl, and the alkyl has 1 to 6 carbon atoms.
Arylalkyl groups; heteroaryl groups, heteroaryl groups
Reel alkyl group, heterocycloalkyl group;
The groups mentioned are amino, mono, di- and trialkylamido.
No group, hydroxyl group, alkoxy group, mercapto group,
Alkylthio group, arylthio group such as phenylthio,
Rufamoyl group, amidine group, guanidino group, nitro
Group, halogeno group such as chloro, bromo, fluoro, etc., cyano
Group selected from the group consisting of
It may have at least one substituent;
The heteroatom in the ring moiety is one to four oxygen, nitrogen or sulfur atoms.
Selected from the group consisting of
Has 1 to 6 carbon atoms. The present invention is not necessarily limited to the following.
However, the compound of the present invention (VI-2) is not
The following shows an example of the method for producing a tyl carbapenem compound.
You. [0037] Where R "₄, Y, B, L and R₀Is the same as above
Has taste, R '₁₀Represents a hydroxyl-protecting group. ] Formula (VI-2)^*Β-lac represented by)
Tam compounds in the following order, 1) Treat with an active esterifying agent of hydroxyl group; further required
In response to the 2) Mercaptan derivative (X) R₀-SH (X) [Wherein, R₀Has the same meaning as described above. ] And the existence of a base
Reaction in the presence or a mercaptan derivative
Reacting a salt of (X) with a base;
By reacting, the general formula (IX^*) Or (VI
I^*The carbapenem compound represented by
it can. The above reaction is not carried out in the same vessel,
Object (VI-2^*) Is subjected to a neutralization reaction with an acid, followed by post-reaction treatment
General formula (VI^*) Embedded image [Where R "_Four, R '_TenAnd Y have the same meaning as above
You. ] Under various conditions, for example, in the presence of a base.
Treatment in the presence, storage in concentrated solution, acetonitrile
The presence in a solution with a polar solvent such as ril
Epimerization of the β-methyl group at the position tends to proceed. this child
And the general formula (VI^*) Was taken out
Later, the compound (VI^*) From the general formula (IX^*Compound represented by)
If there is a problem when mass-producing objects stereoselectively
Conceivable. In contrast, the compound (VI^*)
Not the compound of the present invention (VI-2^*) To the compound (IX^*)
The method of derivation is to cause epimerization of the 1-position β-methyl group.
Carbapenem compounds (IX^*) Or (VII
^*) Is advantageous. For producing the compound (VI-2) of the present invention,
General formula (I-8) to be a raw material⁰The compound represented by) is an example
For example, it can be manufactured as follows. [A] Embedded image[Wherein, R₁, R_TwoAnd R_Four'Has the same meaning as above,
X represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group,
Y ′ represents an oxygen atom or a sulfur atom;_ThreeIs lower alk
And R represents_Five'Is carboxyl protecting group or thio
And a protecting group for the carboxyl group. M is the activity of the hydroxyl group
Represents an ester. ] The compound represented by the general formula (II) and the general formula
A salt of an acetic acid derivative represented by (III) in an inert solvent
By reacting in the presence of a group, the compound represented by the general formula (I-1)
A β-lactam compound represented by the following formula can be obtained. In the present reaction, if necessary,
Medium (Phase transfer catalyst)
You. Inert used in the present N-alkylation reaction
As the solvent, aromatic hydrocarbons such as benzene and toluene
, Tetrahydrofuran, dioxane, diethyl ether
Ethers, methylene chloride, dichloroethane,
Halogenated hydrocarbons such as loroform, acetone, methyl
Ketones such as isobutyl ketone, acetonitrile,
Methylformamide, dimethyl sulfoxide, hexame
Tyl phosphoric triamide (HMPT), t-butano
Single or mixed solvents such as water and water are preferred.
I can do it. Suitable bases include 1,8-
Diazabicyclo [5.4.0] -undec-7-ene
Organic bases such as (DBU), sodium hydride, hydrogen hydride
Alkali metal hydrides such as lithium, sodium amide,
Titanium diisopropylamide, lithium bis (trimethyl
Metal salts of amines such as lucilyl) amide, sodium hydroxide
, Potassium hydroxide, sodium carbonate, potassium carbonate
And various bases such as potassium t-butoxide.
Can be. Further, as the phase transfer catalyst, for example,
Benzyltriethylammonium chloride, tetra
-N-butylammonium bromide, tetraethyl alcohol
Nmonium bromide can be used if necessary.
Wear. When the amount of the base and the phase transfer catalyst are used
The amount of the catalyst should be sufficient to allow the reaction to proceed sufficiently.
The reaction should be cooled or heated as appropriate.
This can be suppressed or promoted. Incidentally, as M which is an active ester of a hydroxyl group,
Preferred are, for example, mesylate, tosylate, etc.
Sulfonyl ester, chlorine atom, bromine atom, iodine atom
And the like. [B-1] In the general formula (I-1)
When Y ′ is a sulfur atom, the compound is selectively hydrolyzed.
By subjecting the compound to the decomposition reaction, the compound represented by the general formula (I-2) Embedded image [Wherein, R₁, R_Two, R_Three, R '_FourAnd X are the same as above
Show the taste. To obtain a β-lactam compound represented by the formula
Can be. The selective hydrolysis reaction is performed in a usual manner, for example,
It can be carried out according to the hydrolysis method under basic conditions.
Wear. [B-2] In the above general formula (I-1)
When Y ′ is an oxygen atom, the protecting group R ′ of the compound_Four
And R '_FiveBy removing one or both of
Formula (I-3) Embedded image[Wherein, R₁, R_Two, R_ThreeAnd X have the same meaning as above
And R "_FiveAnd R_FourAre independently hydrogen or carboxyl
Shows a protecting group for a sil group. Where R "_FiveAnd R_FourFew
At least one is a hydrogen atom. And a compound represented by
And Further, (a) in the general formula (I-3)
R "_FiveAnd R_FourWhen all are hydrogen atoms,
Protecting group R '_FourOr (b) general formula
R in (I-3)_FiveIs a protecting group, and R_FourIs a hydrogen source
In the case where the compound is a child, a new protecting group R ′_FourIntroduce
Then R "_FiveSelectively removing the protecting group represented by
Thus, the β-lac represented by the general formula (I-2)
A tom compound can be obtained. Protecting group R '_FourAnd / or R '_FiveRemoval method
Varies depending on the type of protecting group, but is a known general
Techniques, such as hydrolysis, catalytic reduction, acids or bases, etc.
Can be carried out by means of processing or reduction methods, etc.
it can. R '_FourOr R '_FiveTo selectively remove one of
To make such a selective reaction possible
First R '_FourAnd R '_FiveYou just have to choose a combination. The protecting group R 'in the above method (A)_FourGuide
And the protecting group R ′ in the method (b)_FourIntroduction, protection
Group R "_FiveRemoval according to the usual general methods
can do. [C] Formula (I-2)
Of the carboxylic acid derivative by various known methods
Active ester, active acid anhydride, thiol ester, ant
Ester or heteroaryl ester
The general formula (I-4) Embedded image [Wherein, R₁, R_Two, R_Three, R '_Four, X 'and COZ' are before
Has the same meaning as Β-lactam compound represented by the formula
Things can be manufactured. This reaction is carried out, for example, as follows.
Can be. (A) For example, oxalyl chloride, thionyl chloride, etc.
Reacting the reagents as is or in the presence of a base
To produce an acid halide. (B) Chloroformate such as ethyl chloroformate
Producing mixed anhydrides using stells in the presence of a base
be able to. (C) treating with N, N'-carbonyldiimidazole
To produce an acylimidazole derivative
it can. (D) thiazolidine-2-thione is converted to dicyclohexylca
Reaction in the presence of a dehydrating agent such as rubodiimide (DCC)
To produce an acylthiazolidine-2-thione derivative.
Can be. (E) substituted or unsubstituted thiophenols, 4,6-
Dimethyl-2-mercaptopyrimidine, 2-mercapto
Condensation of pyridine and the like using a dehydrating agent such as DCC
Or the above-mentioned acid halide, mixed acid anhydride or acyl ester
Reaction with active esters such as midazole derivatives
By subjecting it to the usual acylation reaction of mercaptan,
Ester can be produced. (F) N-hydroxysuccinimide, N-hydroxyf
Talimide, substituted or unsubstituted phenols, 2-
When producing pyridones and the aforementioned thiol esters
Produce active ester by subjecting it to the same treatment as
be able to. [D] Embedded image[Wherein, R₁, R_Two, R_Three, R '_Five, X and Y 'are the same as above.
Meaning R⁰ _FourIs a protecting group for the thiol carboxyl group
Is shown. ] Compound represented by formula (I-1)
A protecting group R ′_FourOf the general formula (I-
The carboxylic acid derivative represented by 5) and a general formula HSR⁰ _Four [Wherein, R⁰ _FourHas the same meaning as described above. ]
By reacting the compound, the compound represented by the general formula (I-6) is obtained.
Β-lactam compounds can be produced.
This reaction is carried out according to a general method for acylating a mercaptan group.
Can be implemented. [E] Further, general formula (I-7) Embedded image [Wherein, R₁, R_Two, R_Three, R⁰ _Four, X and Z 'are the same as above.
Indicates the same meaning. ] -Lactam compound represented by the formula:
According to the method described in the above [B] and [C],
It can be produced from the compound represented by the general formula (I-6).
it can. [F] Embedded image [Wherein, R₁, R_Two, R_Three, R '_Four, X 'and M are as defined above.
Indicates the same meaning. ] Alcohol derivatives represented by the general formula (IV)
Inactive with the acetic acid derivative represented by the general formula (III)
By reacting in the presence of a base in a solvent, the general formula
After obtaining a β-lactam compound represented by (V),
By treating compound (V) with an oxidizing agent, the compound represented by the general formula (I)
-2⁰To obtain a β-lactam compound represented by
it can. This N-alkylation reaction is performed in the same manner as described in [A] above.
It can be carried out in the same manner as the method. More
Subsequent oxidation reactions generally involve carboxylation of primary alcohols.
Various oxidation reaction modes used to lead to acid are possible
Yes, various oxidizing agents can be used.
Chromium (VI) -sulfuric acid, chromium oxide-pyridine, etc.
be able to. As described above, the general formula (I) Embedded image [Wherein, R₁, R_Two, R_Three, R_FourAnd Y are as defined above
COZ is a carboxyl group, the activity of the carboxyl group
Esters, activated acid anhydrides of carboxyl groups, carboxyl
A carboxyl group protected by a sil-protecting group, or
Thiolka protected with all carboxyl protecting group
Represents a ruboxyl group. Β-lactam compound represented by the formula
Things can be manufactured. In the above formula (I-4) or (I-7)
In the β-lactam compound represented, X represents a hydroxyl group.
In some cases, the hydroxyl group of the compound is further converted by a usual method.
To protect the compound represented by the general formula (I-8) Embedded image [Wherein, R₁, R_Two, R_Three, R "_Four, X ', Y and Z' are before
Has the same meaning as Β-lactam compound represented by the formula
The compound represented by the general formula (I-8)⁰) In R⁰ _ThreeIs low
Compounds that are lower alkyl groups can be produced The compound represented by the general formula (VII)
The compound can also be produced by the following method. Embedded image [Wherein, R₁, R_Two, R⁰ _Three, R "_Four, X ', Y and Z' are before
Has the same meaning as ] Β-lactam compound (I-8)⁰Inactive)
By treating with a base in a solvent, the compound represented by the general formula (VI)
The obtained compound can be obtained. In this reaction, R⁰ _Three
Is a lower alkyl group, the starting compound (I-8)⁰)
Asymmetric carbon bonded to 4-position β-lactam ring of (C5 position)
Product (VI) that retains the three-dimensional structure based on
Obtainable. This reaction is carried out with compound (I-8)⁰) Closed
The same conditions as in the above-mentioned method for ring-forming compound (VI-2)
After completion of the reaction, use ordinary organic chemical means.
It can be carried out by taking out the result body. However, for example, general formula (VI-1) Embedded image The alkyl group at the 1-position of the compound represented by is treated with a base
Alternatively, epimerization may occur during post-treatment such as concentration.
Care must be taken when handling them. Next, a compound represented by the general formula (VI)
The method described in JP-A-57-123182 and the like, or
Inducing the carbapenem compound (VII) by the similar method
Can be led. The raw material compound (II) is disclosed in
Produced according to a known method described in 23182 Publication
Or a starting compound in which Y is a sulfur atom is desired
In this case, the compound is further represented by the aforementioned general formula (I-6).
In the same manner as in the production of the compound_Four
It can be produced by introducing a group. The starting compound (IV) is described in JP-A-55-89285.
It can be manufactured according to a known method described in the gazette
However, it can also be manufactured by the following method, for example.
Wear. Embedded image [Wherein, R₁, R_Two, X⁰And X ′ have the same meaning as described above.
R ′ is a protecting group for a nitrogen atom, A ′ is a halogen atom, and P is
Shows a hydroxyl-protecting group. ] [0068]Process A: General formula2The compound represented by
Usually, various known methods for obtaining an ester from a carboxylic acid
Therefore, for example, in the presence of a base, JP-A-58-96060
Carboxylic acid obtained by the method described in1The various alkyl
Reaction with halide or dehydration with lower alcohol
Can be obtained by [0069]Step B: General formula3Is a compound
Stuff2With methyl magnesium halide or methyl chloride
React with an organometallic compound such as titanium in an inert solvent,
X⁰When is a hydroxyl group, a commonly used hydroxyl group
To the protection reaction described above. [0070]C process: General formula4The compound represented by
Compound3With thionyl chloride in the presence or absence of a base
Dehydration performed by a dehydrating reagent such as
Can be obtained. [0071]D process: General formula5The compound represented by
Compound4In an inert solvent to halogenate the allylmethyl group.
Various halogenating agents used in
Reacting with N-halogenosuccinimide, etc.
Can be obtained by [0072]E process: General formula6Is a compound
Stuff5In the presence of low valent ionic salts of heavy metals such as copper and silver
It can be obtained by hydrolysis. [0073]F process: General formula7Is a compound
Stuff6By subjecting to a general hydroxyl-protecting reaction
be able to. [0074]G process: General formula8Is a compound
Stuff7To hydrogenation such as catalytic reduction
You can get more. [0075]H process: Compound represented by general formula (IVa)
Is a compound8Is a protecting group P for a hydroxyl group and a protecting group for an amino group
It can be obtained by performing the removal reaction of R 'simultaneously or sequentially.
it can. The compound of the formula (I) 3
Β-lactam ring in the 4th and 4th carbon atoms
Or a carbon atom bonded to₁= Methyl, R_Two
= Hydrogen atom, X = hydroxyl group, R₁, R_Two, X is
Each of which is different from the β-lactam ring in the 3-position substituent.
Any carbon atoms that combine are asymmetric carbons. Therefore general
The compound represented by the formula (I) has an optical difference based on an asymmetric carbon.
Isomers and stereoisomers, and all of these isomers
Are represented by a single equation,
The range of the publication is not limited. However, good
Suitably, the carbon atom at position 4 is coordinating with thienamycin.
Compounds of the following formula can be mentioned. [0077] Embedded image [0078] EXAMPLES The present invention will be further described with reference to Examples and Reference Examples.
Although described specifically, the present invention is of course
It is not limited at all. The meaning of the abbreviations is as follows
It is as follows. TBDMS: t-butyldimethylsilyl group Me: methyl group Ph: phenyl group Z: benzyloxycarbonyl group t-Bu: t-butyl group PNB: p-nitrobenzyl group PMB: p-methoxybenzyl group Im: 1-imidazolyl group Bt: 1-benzotriazolyl group Ac: acetyl group PNZ: p-nitrobenzyloxycarbonyl group DAM: di- (p-anisyl) methyl group Embodiment 1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidi
Non (60 mg) was treated with heavy benzene-heavy tetrahydrofuran.
Dissolve in (4: 1) mixed solvent (0.6 ml) and add hydrogen
Add 11 mg of sodium chloride (50% oil) and stir for 1 hour
After stirring, the reaction mixture was directly subjected to NMR measurement. NMRδ [C₆D₆-THFd₈(4: 1)]: 3.08 (1H, d, J = 6.3Hz, 5-
H), 3.93 (1H, d, J = 8.9 Hz, 6-H). The NMR spectrum of the reaction solution left at room temperature for 5 hours is β
-Methyl form. The compound is a 4-α-methyl compound (4S, 5
R, 6S, 8R) -4-methyl-6- [1-t-butyl
Dimethylsilyloxyethyl] -1-azabicyclo
[3.2.0] Hept-3,7-dione-2-carboxylic
The acid p-nitrobenzyl ester was used as in Example 1 above.
When the treatment was performed, the reaction solution was different from the NMR in Example 1.
The spectrum is shown. NMRδ [C₆D₆-THFd₈(4: 1)]: 2.93 (1H, d, J = 6Hz, 5-H),
3.52 (1H, d, J = 9Hz, 6-H). Embodiment 2 The reaction described in Example 1 was carried out
The reaction was carried out in a mixed solvent of rufoxide (9: 1),
NMR measurement was performed as it was. NMRδ [C₆D₆-DMSOd₆(9: 1)]: 3.16 (1H, d, J = 7.3Hz, 5-
H), 4.00 (1H, d, J = 7.6Hz, 6-H). Embodiment 3 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidi
Non (70mg) dissolved in dry toluene (0.6ml)
Then, under ice cooling, sodium hydride (50% oily) (12.5m
g) in dry tetrahydrofuran (0.1 ml) suspension
The mixture was added dropwise and stirred for 30 minutes. p-Toluenesulfonic acid 1
57 mg of hydrate was added, and the mixture was further stirred for 10 minutes and then cooled.
Dilute with 20 ml of ethyl acetate, wash with saturated saline,
After drying over magnesium acid, the solvent was distilled off (4R, 5R, 6
(S, 8R) -4-Methyl-6- (1-t-butyldimethylene)
Lucylyloxyethyl) -1-azabicyclo [3.2.
0] Hept-3,7-dione-2-carboxylic acid p-nit
The robenzyl ester was obtained. IR^neat(cm^-1): 1760, 1605, 1520, 146
0, 1350, 1250, 1220, 1110, 1045, 835, 780, 738; NMR δ (CDCl_Three): 1.21 (3H, d, J = 7.6Hz), 1.29 (3H, d, J =
6.3Hz), 2.80 (1H, m), 3.22 (1H, dd, J = 2.3 and 6.3Hz), 4.18
(1H, dd, J = 2.3 and 1.9Hz), 4.29 (1H, m), 4.72 (1H, s), 5.30
(2H, ABq, J = 13.2Hz), 7.54 (2H, d, J = 8.9Hz), 8.24 (2H, d, J
= 8.9Hz). The (4R, 5R, 6S, 8
R) -4-methyl-6- (1-t-butyldimethylsilyl)
Ruoxyethyl) -1-azabicyclo [3.2.0]
Pt-3,7-dione-2-carboxylic acid p-nitroben
The reaction liquid was subjected to the same treatment as in Example 1 by treating the gill ester.
According to NMR measurement, β-methyl form and α-methyl form were almost
1: 1. Embodiment 4 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidi
Non (117 mg, 0.2 mM) in dry tetrahydrofura
Dissolved in a mixture of toluene and toluene (1: 1) (1.2 ml).
And sodium hydride (50% oily) (22 mg, 0.46
mM) and dry tetrahydrofuran-toluene (1: 1)
Was added dropwise at −20 ° C. to a suspension with a mixture (0.2 ml) of
After stirring for 1 hour, 2M iodomethane in tetrahydrofuran
The solution (0.1 ml) was added and stirred for another 30 minutes. Next
To diphenylchlorophosphate 56mg (0.21mM)
Was dissolved in 0.1 ml of dry toluene and added dropwise, and stirred for 1.5 hours.
Stirred. The reaction mixture was diluted with 20 ml of ethyl acetate,
After washing several times with brine, magnesium sulfate-potassium carbonate
It dried with the mixed drying agent of (10: 1), and the solvent was distilled off.
The residue was purified by silica gel thin-layer chromatography.
(4R, 5R, 6S, 8R) -3-diphenyl phosphoryl
Luoxy-4-methyl-6- (1-t-butyldimethyl
Silyloxyethyl) -1-azabicyclo [3.2.
0] Hept-2-en-7-one-2-carboxylic acid p-
The nitrobenzyl ester (115 mg) was obtained. IR^neat(cm^-1): 1775, 1725, 1630, 158
5,1518,1482,1340,1285,1185,1160,938,825,7
70; NMR δ (CDCl_Three): 0.06 (3H, s), 0.07 (3H, s), 0.86 (9H,
s), 1.20 (3H, d, J = 7.9 Hz), 1.23 (3H, d, J = 6.3 Hz), 3.29 (1
H, dd, J = 3.0 and 6.0Hz), 3.43 (1H, m), 4.22 (2H, m), 5.28 (2
H, ABq, J = 13.5Hz), 7.56 (2H, d, J = 8.9Hz), 8.14 (2H, d, J =
8.9Hz). Embodiment 5 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidi
Non (415 mg, 0.708 mM) in dry toluene-tet
Dissolved in a mixture (4 ml) of lahydrofuran (4: 1)
And sodium hydride (50% oily) (75 mg, 1.56
mM) and dry toluene-tetrahydrofuran (4: 1)
Was added dropwise at −20 ° C. to a suspension with a mixture (0.75 ml) of
After stirring for 1 hour, 0.5M tetrahydrofuran of iodomethane
Solution (1.49 ml, 0.745 mM) was added dropwise for another 30 minutes.
While stirring. Then, at the same temperature, diphenylchlorophosphate
(218.5 mg, 0.814 mM) in dry toluene (2.2 m
l) The solution was added dropwise and stirred for 2 hours. Then, [2S,
4S] -1-p-nitrobenzyloxycarbonyl-2
-Dimethylaminocarbonyl-4-mercaptopyrrolidi
(237.5 mg, 0.67 mM), then sodium hydride
(50% oily) (32.3 mg, 0.67 mM) and stir for 2 hours
Stirred. The reaction mixture was diluted with 50 ml of ethyl acetate and cooled.
Wash several times with saline, dry over magnesium sulfate, then dissolve
The medium was distilled off. Residue on silica gel chromatography
And purified (4R, 5S, 6S, 8R, 2'S, 4'S)
-3- [4- (1-p-nitrobenzyloxycarbonyl)
2-dimethylaminocarbonylpyrrolidinyl) thio
E] -4-methyl-6- (1-t-butyldimethylsilyl)
Ruoxyethyl) -1-azabicyclo [3.2.0]
P-Nitro-2-en-7-one-2-carboxylate
The benzyl ester (3.29 mg) was obtained. IR^neat(cm^-1): 1775, 1715, 1660, 161
0, 1525, 1400, 1345, 1210, 1140, 1110, 835, 755. Embodiment 6 Embedded image (3S, 4S) -3-[(1R) -1-to
Limethylsilyloxyethyl] -4-[(1R) -1-
Phenylthiocarbonylethyl] -1-p-nitroben
Ziroxycarbonylmethyl-2-azetidinone (10
9 mg, 0.2 mM) in the same manner as in Example 5 (4
R, 5S, 6S, 8R, 2'S, 4'S) -3- [4-
(1-p-nitrobenzyloxycarbonyl-2-dime
Tylaminocarbonylpyrrolidinyl) thio] -4-methyl
Ru-6- (1-trimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-o
2-carboxylic acid p-nitrobenzyl ester
Was. IR^neat(cm^-1): 1765, 1705, 1650, 160
0, 1512, 1395, 1335, 1200, 1130, 1100, 840, 740. Embodiment 7 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-fe
Nylthiocarbonylmethyl-2-azetidinone 20 mg
Water in 0.2 ml of dry N, N-dimethylformamide
Add 2.6 mg of sodium iodide and stir at room temperature for 20 minutes.
Was. After diluting the reaction solution with diethyl ether, pH 6.86 phosphoric acid
A buffer was added and the layers were separated. Add more aqueous layer to diethyl ether
After extracting twice with water, the organic layers are combined, and water (three times) and brine are added.
Washing was performed in the order of (twice). After drying the organic layer with sodium sulfate, the solvent is removed.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography.
Purification and (4R, 5R, 6S, 8R) -4-methyl-6
-(1-t-butyldimethylsilyloxyethyl) -1
-Azabicyclo [3.2.0] hept-3,7-dione
-2-Carboxylic acid phenylthioester was obtained. IR^neat(cm^-1): 1780 (sh), 1760, 1750 (s
h), 1710, 1250, 1140, 1062, 830, 775, 742. Embodiment 8 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-fe
Nylthiocarbonylmethyl-2-azetidinone (60 m
g, 0.107 mM) in dry acetonitrile (1 ml).
After cooling with ice, sodium hydride (50% oil) (13m
g, 0.27 mM) and stirred for 15 minutes. Next
Drying of nilchlorophosphate (57.5 mg, 0.21 mM)
A dry acetonitrile (0.3 ml) solution was added dropwise and stirred for 1.5 hours.
Stirred. Dilute with 10 ml of ethyl acetate and wash several times with saline
After cleaning, magnesium sulfate-potassium carbonate (10:
It dried with the mixed desiccant of 1), and the solvent was distilled off. Residue
Purify by Kagel thin layer chromatography (4R, 5
R, 6S, 8R) -3-diphenylphosphoryloxy-
4-methyl-6- (1-t-butyldimethylsilyloxy)
Ciethyl) -1-azabicyclo [3.2.0] hept-
2-ene-7-one-2-carboxylic acid phenylthioes
Tell (55 mg) was obtained. IR and IR of the compound obtained here
And NMR were the same as those of the compound obtained in Reference Example 3-1. Embodiment 9 Embedded image(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-phenylthiocarbonylethyl] -1- (1
-T-butyloxycarbonylmethyl) -2-azetidi
Dissolve 65 mg of nonone in 1.0 ml of dry tetrahydrofuran
And lithium bis (trimethylsilyl) amido at -70 ° C.
3.84 ml of a 0.1 M tetrahydrofuran solution of
Was. After raising the temperature to 0-5 ° C, pH 8.0 phosphate buffer was added.
The reaction was stopped and extracted twice with diethyl ether.
Was. The organic layer was washed with a pH 8.0 phosphate buffer (twice).
It was then dried over sodium sulfate. The solvent is distilled off (4R, 5R, 6S,
8R) -4-Methyl-6- (1-t-butyldimethyloxy)
Ryloxyethyl) -1-azabicyclo [3.2.0]
Hept-3,7-dione-2-carboxylate
Got a steal. NMR δ (CDCl_Three): 0.10 (6H, s), 0.89 (9H,
s), 1.18 (3H, d, J = 7.9 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.46 (9
H, s), 2.76 (1H, m), 3.18 (1H, dd, J = 2.5 and 5.8Hz), 4.22 (1H
H, dd, J = 2.5 and 8.1Hz), 4.58 (1H, s). Embodiment 10 Embedded image (3S, 4S) -4-[(1R) -1-F
Enylthiocarbonylethyl] -3-[(1R) -1-
t-butyldimethylsilyloxyethyl] -1-tert-butyl
Toxicarbonylmethyl-2-azetidinone 101 mg
Dissolved in dry tetrahydrofuran (2 ml) under a stream of nitrogen
Cooled to -50 ° C. Lithium diisopropyl alcohol
5 ml of a tetrahydrofuran solution of amide (0.1 M) was added dropwise.
Then, the temperature was raised to 0 ° C. in 2 hours. Then diphenyl chloride
Lophosphate 120mg in dry acetonitrile 7ml
, And added dropwise under ice-cooling. After stirring for 2 hours,
20 ml of cooled diethyl ether and phosphoric acid of pH 6.86
The reaction solution was injected into a mixed solution of 20 ml of the buffer solution, and separated.
Wash the organic layer with saturated saline and dry over magnesium sulfate
Then, the solvent was distilled off, and the obtained oily residue was dried with a silica gel thin layer.
Purify by chromatography (4R, 5R, 6S, 8
R) -3-Diphenylphosphoryloxy-4-methyl-
6- (1-t-butyldimethylsilyloxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-On-2-carboxylic acid t-butyl ester (83.5m
g) was obtained. IR^neat(cm^-1): 1780, 1718, 1635, 158
5,1482,1360,1285,1185,1158,960,940,830,76
Five; NMR δ (CDCl_Three): 1.17 (3H, d, J = 7.6Hz), 1.21 (3H, d, J =
6.3Hz), 3.22 (1H, dd, J = 3.0 and 6.0Hz), 3.42 (1H, m), 4.12
(1H, dd, J = 3.0 and 10.0Hz), 4.21 (1H, m). Embodiment 11 Embedded image(3S, 4R) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1- (1-Imidazolylcarbonyl) ethyl]-
1-p-nitrobenzyloxycarbonylmethyl-2-
Azetidinone (52 mg, 0.096 mM) in dry toluene
A mixture of tetrahydrofuran (4: 1) (0.5 ml)
Sodium hydride (50% oil) under ice-cooling
After adding 0 mg, dry N, N-dimethylformamide
0.05 ml was added. Then diphenyl chlorophosphate
(60 mg, 0.22 mM) and stirred for 2 hours.
S, 4S] -1-p-nitrobenzyloxycarbonyl
-2-dimethylaminocarbonyl-4-mercaptopyro
Lysine (35.3 mg, 0.1 mM) was added.
Thorium (50% oily) (5 mg) is added and 1.5 hours
Stir, dilute with 10 ml of ethyl acetate and several times with cold saline
The extract was washed, dried over magnesium sulfate, and the solvent was distilled off.
The obtained residue was subjected to silica gel thin layer chromatography.
Purified, (4R, 5S, 6S, 8R, 2'S, 4'S)-
3- [4- (1-p-nitrobenzyloxycarbonyl)
-2-dimethylaminocarbonylpyrrolidinyl) thio]
-4-methyl-6- (1-t-butyldimethylsilylthio)
Xylethyl) -1-azabicyclo [3.2.0] hept
P-Nitroben-2-ene-7-one-2-carboxylic acid
A gill ester was obtained. IR and N of the compound obtained here
The MR was the same as the compound obtained in Example 5. Embodiment 12 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidi
Non (69 mg, 0.12 mM) dry toluene (0.6 m
l) Transfer the solution to sodium hydride (50% oily) (12.5m
g, 0.26 mM) and dry tetrahydrofuran (0.1 ml)
Was added dropwise to the suspension under ice-cooling, and stirred for 30 minutes.
Add chlorophosphate (67mg, 0.25mM) and add 1 hour
While stirring. Dilute the reaction mixture with 10 ml of ethyl acetate
After washing several times with saline, magnesium sulfate-potassium carbonate
(10: 1) mixed solvent, and the solvent is distilled off.
Was. The residue is purified by silica gel thin-layer chromatography.
And (4R, 5S, 6S, 8R) -3-phenylthio-
4-methyl-6- [1-t-butyldimethylsilyloxy
Ciethyl] -1-azabicyclo [3.2.0] hept-
2-en-7-one-2-carboxylic acid p-nitrobenzyl
Luster (37mg) and (4R, 5R, 6S, 8R)
-3-Diphenylphosphoryloxy-4-methyl-6-
(1-t-butyldimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-o
2-carboxylic acid p-nitrobenzyl ester (34
mg). (4R, 5R, 6S, 8R) -3-dife
Nylphosphoryloxy-4-methyl-6- (1-t-bu
Tyldimethylsilyloxyethyl) -1-azabicyclo
[3.2.0] Hept-2-en-7-one-2-cal
IR and NMR of p-nitrobenzyl borate
Was identical to that obtained in Example 4. (4R, 5S, 6S, 8R) -3-phenyl
Luthio-4-methyl-6- (1-t-butyldimethylsi
Ryloxyethyl) -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylic acid p-nit
Robenzyl ester IR^neat(cm^-1): 1765, 1707, 1522, 1378, 1350, 134
0, 1140; NMR δ (CDCl_Three): 0.06 (6H, s), 0.84 (9H, s), 0.95 (3H,
d, J = 7.3Hz), 1.17 (3H, d, J = 6.3Hz), 3.06 (1H, m), 3.19 (1
H, dd, J = 2.9 and 5.0Hz), 4.22 (2H, m), 5.40 (2H, ABq, J = 13.9
Hz), 7.3 to 7.6 (5H, m), 7.69 (2H, d, J = 8.9Hz), 8.23 (2H,
d, J = 8.9Hz). Reference Example 1-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone 30
1 mg, N, N'-carbonyldiimidazole 194 m
of 8.6 ml of dry acetonitrile at room temperature for 1 hour.
Stirred. Add 132 mg of thiophenol to dry acetone
2.3 ml of nitrile solution followed by triethylamine 121
mg of dry acetonitrile in 2 ml was added at room temperature.
Stirred for minutes. Dilute the reaction with ethyl acetate and add brine
Washed. The aqueous layer was extracted twice more with ethyl acetate,
The layers were combined, washed with saline, and dried over sodium sulfate. Reduce solvent
The residue obtained by distillation under reduced pressure is purified by silica gel chromatography.
(3S, 4S) -3-[(1R) -1-t-butyl)
Dimethylsilyloxyethyl] -4-[(1R) -1
-Phenylthiocarbonylethyl] -2-azetidinone
I got IR^neat(cm^-1): 3200 (br), 1760, 1700,
1370, 1250, 1140, 955, 830, 773, 740, 680. Reference Example 1-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone 40
0 mg, N, N'-carbonyldiimidazole 259 m
g of 11 ml of dry acetonitrile was stirred at room temperature for 1 hour.
Stirred. To this, 281 mg of p-chlorothiophenol was added.
3.2 ml of dry acetonitrile solution, then triethyl alcohol
A solution of 162 mg of min in 2.3 ml of dry acetonitrile was added.
And stirred at room temperature for 30 minutes. The reaction mixture is
The mixture was diluted with water and saline and separated. The aqueous layer is diethyl ether
Extract two more times with tel, combine the previous organic layers and dilute salt
After washing with acid and saline solution (3 times),
Was. Solvent is distilled off and the residue is subjected to silica gel chromatography.
And purified to give (3S, 4S) -3-[(1R) -1-t-
Butyldimethylsilyloxyethyl] -4-[(1R)
-1-p-chlorophenylthiocarbonylethyl] -2
-Azetidinone was obtained. IR^neat(cm^-1): 3250 (br), 1770, 1750,
1700, 1478, 1247, 1140, 1090, 820, 770; NMR δ (CDCl_Three): 0.07 (6H, s), 0.88 (9H, s), 1.18 (3H,
d, J = 6.3Hz), 1.33 (3H, d, J = 6.9Hz), 2.97 (1H, m), 3.02 (1
H, m), 3.93 (1H, dd, J = 2.0 and 5.3Hz), 4.22 (1H, m), 5.86 (1
H, br.s), 7.36 (4H, m). Reference Example 1-3 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone 1.00
g, triethylamine 369 mg, p-methoxybenzyl
779 mg of luchloride in dry N, N-dimethylforma
The 1 ml solution of the mid was stirred at 70 ° C. for 2 hours and 40 minutes. Anti
The reaction mixture was poured into ice-water and adjusted to pH 2-3 with dilute hydrochloric acid.
Extracted three times with ethyl ether. Combine the organic layers and cool 1
With N-NaOH (3 times), water (3 times), brine (3 times)
After washing, it was dried with sodium sulfate. The solvent is distilled off and the residue is silica
Purify by gel chromatography (3S, 4S)-
3-[(1R) -1-t-butyldimethylsilyloxy
Ethyl] -4-[(1R) -1-p-methoxybenzyl
Oxycarbonylethyl] -2-azetidinone was obtained. IR^neat(cm^-1): 3225 (br), 1760, 1740,
1605, 1505, 1458, 1240, 1160, 1030, 950, 825, 76
7; NMR δ (CDCl_Three): 0.05 (6H, s), 0.86 (9H, s), 1.13 (3H,
d, J = 6.0Hz), 1.21 (3H, d, J = 7.0Hz), 2.70 (1H, m), 2.95 (1
H, dd, J = 2.0 and 4.0Hz), 3.81 (3H, s), 3.89 (1H, dd, J = 2.0
And 5.0Hz), 4.16 (1H, m), 5.05 (2H, s), 5.96 (1H, br.s),
6.87 (2H, d, J = 9.0Hz), 7.27 (2H, d, J = 9.0Hz). Reference Example 2-1 Embedded image 4-Carboxy-3- (1-hydroxyd
Tyl) -1-di- (p-anisyl) methyl-2-azeti
Dissolve 34 g of dinone in 310 ml of methanol and then concentrate
After adding 2.9 g of sulfuric acid and stirring at 65 ° C for 3 hours,
Cool to 15% with 8% aqueous sodium hydroxide solution
Summed up. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 1,2-dichloromethane.
Dissolve in 105 ml of roethane, wash with water, and reconstitute the aqueous layer with 1,
Extract with 105 ml of 2-dichloroethane and combine the organic layers.
And washed with water. After drying the sodium sulfate, the solvent is distilled off and 4-methoxycal
Bonyl-3- (1-hydroxyethyl) -1-di- (p
-Anisyl) methyl-2-azetidinone was obtained. Reference Example 2-2 Embedded image 4-methoxycarbonyl-3- (1-hydrido)
Roxyethyl) -1-di- (p-anisyl) methyl-2
32.5 g of azetidinone in dry tetrahydrofuran 310
The mixture was dissolved in ml and cooled on ice. 1M-methyl mag under nitrogen stream
370 g of nesium bromide-tetrahydrofuran solution
The mixture was added dropwise at 5 ° C. or lower, stirred for 1 hour, and then stirred at 350% for 20% aqueous hydrochloric acid.
ml at 20 to 25 ° C. and stirred for 1 hour.
Was. Next, 110 ml of ethyl acetate was added for extraction. Water layer
Was re-extracted with 110 ml of ethyl acetate, and the organic layers were combined.
Wash with saturated saline, saturated aqueous sodium bicarbonate and water in that order, and dry with sodium sulfate.
Was. The solvent was distilled off, and 4- (1-hydroxy-1-methyl) was removed.
Ethyl) -3- (1-hydroxyethyl) -1-di-
(P-Anisyl) methyl-2-azetidinone was obtained. Melting point: 154-156 [deg.] C. Reference Example 2-3 Embedded image 4- (1-hydroxy-1-methylethyl)
) -3- (1-hydroxyethyl) -1-di- (p-
Anisyl) methyl-2-azetidinone 26 g dry chloride
Dissolve in 200 ml of methylene, then add N-dimethylamino
16 g of pyridine was added and the mixture was ice-cooled. Benzy under nitrogen flow
20 g of ruchloroformate is dropped in 1 hour, and
Stir for 2 hours, then at room temperature for 10 hours, then cool on ice
Then, 100 ml of 5% hydrochloric acid aqueous solution is added, and the mixture is stirred for 30 minutes and separated.
did. Wash the organic layer with water, saturated aqueous sodium bicarbonate, and saturated saline in this order.
And then dried over sodium sulfate and evaporated to remove the solvent.
1-methylethyl) -3- (1-benzyloxycarbo
Nyloxyethyl) -1-di- (p-anisyl) methyl
-2-Azetidinone was obtained. IR^neat(cm^-1): 3450, 1750, 1615, 151
5, 1250, 1180, 1030; NMR δ (CDCl_Three): 1.13 (6H, s), 1.38 (3H, d, J = 6.0Hz),
3.70 (3H, s), 3.75 (3H, s), 5.10 (2H, s), 5.55 (1H, br.
s), 7.29 (5H, s). Reference Example 2-4 Embedded image4- (1-hydroxy-1-methylethyl)
) -3- (1-benzyloxycarbonyloxyethyl)
Ru) -1-di- (p-anisyl) methyl-2-azetidi
Dissolve 30 g of nonone in 350 ml of toluene and add pyridine 1
0 ml, and then add 9.0 g of thionyl chloride at 20-30 ° C.
Then, the mixture was stirred as it was for 5 hours. Add 100 ml of water
The organic layer is washed with water, dried over sodium sulfate, and the solvent is distilled off.
The residue was crystallized from cyclohexane-ethyl acetate to give 4-
(1-methylethenyl) -3- (1-benzyloxyca
Rubonyloxyethyl) -1-di- (p-anisyl) meth
Cyl-2-azetidinone was obtained. Melting point: 117-118 [deg.] C. Reference Example 2-5 Embedded image 4- (1-methylethenyl) -3- (1-
Benzyloxycarbonyloxyethyl) -1-di-
(P-anisyl) methyl-2-azetidinone (200
g, 0.388M) in 3 liters of ethyl acetate,
15 minutes chlorine-carbon tetrachloride solution (3.85%, 870g)
Then, the mixture was stirred for 1 hour. Then 1 liter of water,
Add 50 ml of 10% sodium thiosulfate aqueous solution and stir
Thereafter, the organic layer was separated and washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline.
After purification, the solution was dried over sodium sulfate and the solvent was distilled off to give 4- (1-chloromethyi).
Ruethenyl) -3- (1-benzyloxycarbonylo
(Xyethyl) -1-di- (p-anisyl) methyl-2-
Azetidinone was obtained. Melting point: 84-85 [deg.] C. Reference Example 2-6 Embedded image 4- (1-chloromethylethenyl) -3-
(1-benzyloxycarbonyloxyethyl) -1-
Di- (p-anisyl) methyl-2-azetidinone 20 g
Was dissolved in 160 ml of dimethyl sulfoxide, and stirred.
40 ml of water is added, and then 6.76 g of cuprous oxide, p-
Add 7.6 g of toluenesulfonic acid monohydrate, and add 50 to 55 ° C.
For 2 hours. Cool to room temperature and 1% phosphoric acid aqueous solution
Add 90 ml, dilute with 200 ml of ethyl acetate, insoluble
The thing was filtered off on Celite. Insoluble matter is ethyl acetate 20m
After washing three times with 1 l, the filtrate was separated. The aqueous layer is ethyl acetate
Extract with 200 ml, combine the previous organic layers, and add saturated saline
After washing, it was dried over sodium sulfate and concentrated under reduced pressure.
-Recrystallized from n-hexane (1: 1) to give 4- (1-hydr
Roxymethylethenyl) -3- (1-benzyloxyca
Rubonyloxyethyl) -1-di- (p-anisyl) meth
Cyl-2-azetidinone was obtained. Melting point: 118-120C. Reference Example 2-7 Embedded image 4- (1-hydroxymethylethenyl)-
3- (1-benzyloxycarbonyloxyethyl)-
1-di- (p-anisyl) methyl-2-azetidinone 2
0 g is dissolved in 45 ml of N, N-dimethylformamide
5.6 g of imidazole and then t-butyldimethyl chloride
After adding 6.77 g of silane at room temperature, the mixture was stirred for 2 hours.
Was. Add 200 ml of cold water and then 150 ml of ethyl acetate
And separated. The aqueous layer was extracted with 150 ml of ethyl acetate.
2 times with 5 ml of 5% aqueous hydrochloric acid, then
After washing three times with 80 ml each of sodium chloride solution, it was dried over sodium sulfate.
Was. The solvent is distilled off, and the residue is re-
After crystallization, 4- (1-t-butyldimethylsilyloxyme
Cylethenyl) -3- (1-benzyloxycarbonyl
Oxyethyl) -1-di- (p-anisyl) methyl-2
-Azetidinone was obtained. Melting point: 90-92C. Reference Example 2-8 Embedded image 4- (1-t-butyldimethylsilyloxy)
Cimethylethenyl) -3- (1-benzyloxycarbo
Nyloxyethyl) -1-di- (p-anisyl) methyl
20 g of 2-azetidinone in 200 ml of acetonitrile
In a nitrogen stream, 4.0 g of 5% platinum carbon catalyst and water
Add 4 ml, replace with hydrogen at room temperature, and add hydrogen at 10 ° C.
Done. After filtering off the catalyst and washing the filtrate with ethyl acetate,
The filtrate was concentrated to give 4- (1-t-butyldimethylsilyl).
Ruoxymethylethyl) -3- (1-benzyloxyca
Rubonyloxyethyl) -1-di- (p-anisyl) meth
Cyl-2-azetidinone was obtained. This product is liquid chromatography
Raffy [Lichrosorb (registered trademark) RP-18, aceto
Nitrile-water (85:15), flow rate 1 ml / min] and
From NMR measurement, 4- (1- (R) -t-butyl dimethyl
(Silyloxymethylethyl) form and the corresponding (S) form
It was a mixture and the ratio was R / S = 7.7. This mix
For the compound, ethyl acetate-n-hexane (1:10)
From a mixed solvent of 4- (1- (R) -t-butyl)
Dimethylsilyloxymethylethyl) -3- (1-b
Benzyloxycarbonyloxyethyl) -1-di- (p
-Anisyl) methyl-2-azetidinone only
Can be. Melting point: 78-81 ° C .; NMR δ (CDCl_Three): 0.01 (6H, s), 0.87 (9H, s), 1.40 (3H,
d, J = 6.0Hz), 3.31 (1H, dd, J = 2.2 and 7.0Hz), 3.44 (2H, d, J =
5.3Hz), 3.73 (3H, s), 3.76 (3H, s), 5.07 (1H, m), 5.17 (2
H, s), 7.38 (5H, s). Reference Example 2-9 Embedded image 4- (1- (R) -t-butyldimethyloxy
Ryloxymethylethyl) -3- (1-benzyloxy
Carbonyloxyethyl) -1-di- (p-anisyl)
20 g of methyl-2-azetidinone was dissolved in 200 ml of methylene chloride.
and add 7.8 g of 1,3-dimethoxybenzene.
And then boron trifluoride etherate at 10-20 ° C
After dropping 23g, stir at room temperature for 3 hours and heat to 45 ° C
And refluxed for 3-5 hours. After cooling to 10-15 ° C, 5
Wash twice with 200 ml of 2.5% sodium chloride solution, and then add 2.5%
00 ml and again with 200 ml of 5% saline,
After drying and distilling off the solvent, the residue was chromatographed on silica gel.
And purified by 4- (1- (R) -hydroxymethylethyl).
) -3- (1-benzyloxycarbonyloxyethyl)
1) -2-azetidinone was obtained. IR^neat(cm^-1): 3350, 1750, 1740, 145
5, 1382, 1260, 1030; NMR δ (CDCl_Three): 0.95 (3H, d, J = 7.0Hz), 1.48 (3H, d, J =
6.5Hz), 3.14 (1H, dd, J = 2.0 and 9.0Hz), 3.55 (1H, d, J = 2.0H
z), 5.15 (2H, s), 6.05 (1H, br.s), 7.37 (5H, s). Reference Example 2-10 Embedded image 2.78 g of chromium trioxide, 4.4 g of 98% sulfuric acid
And Jones reagent prepared from 8.1 ml of water and 4- (1
-(R) -hydroxymethylethyl) -3- (1-ben
(Zyloxycarbonyloxyethyl) -2-azetidino
6.1 g acetone (60 ml) solution at 10-20 ° C
The mixture was added dropwise and stirred for 1 hour. Next, isopropyl alcohol
After adding 0.5 ml of alcohol and stirring for 15 minutes, 135 m of water was added.
l, 122 ml of ethyl acetate was added, and the mixture was separated.
Re-extract with 61 ml of chill, combine the oil layers, and add 5% saline 10
Washed twice with 0 ml. Next, 61 ml of 5% aqueous sodium bicarbonate was added.
The mixture was separated and the oil layer was extracted again with 5% aqueous sodium bicarbonate. Water layer
Was washed with 60 ml of methylene chloride, and 10% hydrochloric acid aqueous solution was added under ice-cooling.
Add 20 ml to make it acidic and add 2 ml with 60 ml of methylene chloride.
It was extracted once, washed with 10% saline, and then dried over sodium sulfate. Solvent
Distilled off, 4- (1- (R) -carboxyethyl) -3-
(1-benzyloxycarbonyloxyethyl) -2-
Azetidinone was obtained. IR^neat(cm^-1): 3270, 1740, 1460, 138
5, 1270, 750; NMR δ (CDCl_Three): 1.19 (3H, d, J = 7.0Hz), 1.40 (3H, d, J =
6.2Hz), 2.67 (1H, m), 3.22 (1H, br.d, J = 7.5Hz), 3.84 (1H
H, br.d, J = 5.5Hz), 5.14 (2H, s), 6.57 (1H, br.s), 7.35 (5
H, s), 7.63 (1H, br.s). Reference Example 2-11 Embedded image 4- (1- (R) -carboxyethyl)-
3- (1-benzyloxycarbonyloxyethyl)-
2-azetidinone (51.69 g) in 510 ml of acetone
Melted, anhydrous potassium carbonate (89 g), benzyl bromide 3
0.3 g was added, and the mixture was stirred at 60 ° C. for 1.5 hours. Reaction solution at room temperature
Cool to remove insolubles, combine filtrate and washings,
The solvent is distilled off, and the oily residue is subjected to silica gel chromatography.
And (3S, 4S) -3-[(1R) -1-ben
Diloxycarbonyloxyethyl] -4-[(1R)
-1-benzyloxycarbonylethyl] -2-azeti
I got ginone. IR^neat(cm^-1): 1760 (sh), 1735, 1450,
1380, 1260, 1155; NMR δ (CDCl_Three): 1.22 (3H, d, J = 6.9Hz), 1.39 (3H, d, J =
6.3Hz), 2.71 (1H, quintet, J = 6.9Hz), 3.19 (1H, dd, J = 2.0
7.9Hz), 3.83 (1H, dd, J = 2.0 and 6.3Hz), 5.92 (1H, s). Reference Example 3-1 Embedded image (4R, 5R, 6S, 8R) -4-methyl
-6- (1-t-butyldimethylsilyloxyethyl)
-1-Azabicyclo [3.2.0] hept-3,7-di
Crude product of on-2-carboxylic acid phenylthioester
Approximately 0.22mmole (including thiophenol)
Dissolve in 0.8 ml of tonitrile and distill under ice
59 mg of isopropylethylamine in dry acetonitrile
0.5 ml solution, then diphenylchlorophosphate
124 mg of a dry acetonitrile 0.5 ml solution was added,
The mixture was stirred at the same temperature for 1 hour. Reaction solution with diethyl ether
After dilution, a pH 6.86 phosphate buffer was added to carry out liquid separation. Water layer
After extracting twice with diethyl ether and combining the organic layers,
1M potassium dihydrogen phosphate aqueous solution (3 times), water (2
Times) and saline. Dissolve the organic layer after drying with sodium sulfate
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography.
And purified by (4R, 5R, 6S, 8R) -3- (diff
Enylphosphoryloxy) -4-methyl-6- [1-t
-Butyldimethylsilyloxyethyl] -1-azabizi
Black [3.2.0] hept-2-en-7-one-2-
Carboxylic acid phenylthioester and (4R, 5S, 6
(S, 8R) -3-phenylthio-4-methyl-6- (1
-T-butyldimethylsilyloxyethyl) -1-aza
Bicyclo [3.2.0] hept-2-en-7-one-
2-Carboxylic acid phenylthioester was obtained. (4R, 5R, 6S, 8R) -3- (Ziff
Enylphosphoryloxy) -4-methyl-6- (1-t
-Butyldimethylsilyloxyethyl) -1-azabizi
Black [3.2.0] hept-2-en-7-one-2-
Carboxylic acid phenylthioester IR^neat(cm^-1): 1778, 1673, 1607, 1582, 1487, 119
8, 1182, 1002, 962, 935, 767, 740, 680; NMR δ (CDCl_Three): 0.09 (3H, s), 0.11 (3H, s), 0.91 (9H,
s), 1.21 (3H, d, J = 7.3 Hz), 1.22 (3H, d, J = 6.0 Hz), 3.29 (1
H, dd, J = 3.0 and 5.0Hz), 3.52 (1H, m), 4.28 (2H, m). (4R, 5S, 6S, 8R) -3-phenyl
Luthio-4-methyl-6- [1-t-butyldimethylsi
Ryloxyethyl] -1-azabicyclo [3,2,0]
-Hept-2-en-7-one-2-carboxylic acid phenyl
Luthioester IR^CHCl3 (cm^-1): 1780, 1660 (sh), 1647, 1520, 147
8, 1285, 1260, 1115, 1018, 945, 837; NMR δ (CDCl_Three): 0.09 (3H, s), 0.13 (3H, s), 0.92 (9H, s)
s), 0.95 (3H, d, J = 7.6 Hz), 1.17 (3H, d, J = 6.3 Hz), 3.07 (1
H, m), 3.20 (1H, dd, J = 2.6 and 4.3Hz), 4.31 (1H, dd, J = 2.8 and
9.8Hz). Reference Example 3-2- (1) Embedded image (4R, 5R, 6S, 8R) -3- (Ziff
Enylphosphoryloxy) -4-methyl-6- (1-t
-Butyldimethylsilyloxyethyl) -1-azabizi
Black [3.2.0] hept-2-en-7-one-2-
Carboxylic acid phenylthioester 10 mg
Dissolve it in 0.1 ml of nitrile and dilute at -30 ° C in a nitrogen stream.
5.2 mg of isopropylethylamine in dry acetonitrile
0.2 ml solution, then 4.8 m N-acetylcysteamine
g of dry acetonitrile in a 0.2 ml solution.
The temperature rose. After confirming the disappearance of raw materials, the reaction mixture was
After dilution with a buffer, a phosphate buffer (pH 6.86) was added to separate the solution. Water layer
Was further extracted twice with diethyl ether, and the organic layers were combined.
PH 6.86 phosphate buffer, 0.1 M potassium hydrogen phosphate
And an aqueous solution of sodium chloride. Dry the organic layer with Glauber's salt
After that, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography.
(4R, 5S, 6S, 8R) -3-
(2-acetaminoethylthio) -4-methyl-6-
(1-t-butyldimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-o
2-carboxylic acid phenylthioester was obtained. IR^CHCl3 (cm^-1): 3460, 1765, 1665, 125
0,1102,830; NMR δ (CDCl_Three): 0.11 (3H, s), 0.14 (3H, s), 0.94 (9H,
s), 1.25 (3H, d, J = 7.3 Hz), 1.25 (3H, d, J = 6.3 Hz), 1.97 (3
H, s), 5.90 (1H, br.s), 7.3 to 7.6 (5H, m). Reference Example 3-2- (2) Embedded image (4R, 5R, 6S, 8R) -3-dife
Nylphosphoryloxy-4-methyl-6- (1-t-bu
Tyldimethylsilyloxyethyl) -1-azabicyclo
[3.2.0] Hept-2-en-7-one-2-cal
Bonic acid phenylthioester 6mg, diisopropyl
1.4 mg of tylamine, (2S, 4S) -1-p-nitro
Benzyloxycarbonyl-2-dimethylaminocarbo
Reference Example 3 using 4 mg of nyl-4-mercaptopyrrolidine
-2- (1) (4R, 5S, 6S, 8
R, 2'S, 4'S) -3- [4- (1-p-nitroben
Diloxycarbonyl-2-dimethylaminocarbonyl
Pyrrolidinyl) thio] -4-methyl-6- (1-t-bu
Tyldimethylsilyloxyethyl) -1-azabicyclo
[3.2.0] Hept-2-en-7-one-2-cal
The phenyl thionate was obtained. IR^CHCl3 (cm^-1): 1767, 1700, 1650, 151
8, 1340, 1100. Reference Example 3-2- (3) Embedded image (4R, 5R, 6S, 8R) -3-dife
Nylphosphoryloxy-4-methyl-6- (1-t-bu
Tyldimethylsilyloxyethyl) -1-azabicyclo
[3.2.0] Hept-2-en-7-one-2-cal
Bonic acid phenylthioester 20mg, diisopropyl
5.2 mg of ethylamine and 5 mg of benzyl mercaptan
In the same manner as in Reference Example 3-2- (1), (4R, 5
S, 6S, 8R) -3-Benzylthio-4-methyl-6
-(1-t-butyldimethylsilyloxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylic acid phenylthioester was obtained. [0161] IR^CHCl3 (cm^-1): 1770, 1660 (sh), 164
0, 1298, 1266, 1250, 1142, 1102, 835; NMR δ (CDCl_Three): 0.10 (3H, s), 0.13 (3H, s), 0.92 (9H,
s), 3.24 (1H, dd, J = 2.6 and 5.3Hz), 3.37 (1H, m), 4.09 (2H,
m), 4.2 to 4.4 (2H, m), 7.30 (5H, s), 7.3 to 7.6 (5H, m). Reference Example 4 Embedded image (4R, 5S, 6S, 8R, 2'S, 4 '
S) -3- [4- (1-p-nitrobenzyloxycal
Bonyl-2-dimethylaminocarbonylpyrrolidinyl)
Thio] -4-methyl-6- (1-trimethylsilyloxy
Ciethyl) -1-azabicyclo [3.2.0] hept-
2-en-7-one-2-carboxylic acid p-nitrobenzyl
Ester (1 g, 1.3 mM) in tetrahydrofuran 1
0 ml and add phosphate buffer (8 ml) of pH3.
And stirred vigorously at room temperature for 2.5 hours.
, Washed with saline and dried over magnesium sulfate.
The solvent was distilled off and (4R, 5S, 6S, 8R, 2'S,
4 ′S) -3- [4- (1-p-nitrobenzyloxy)
Carbonyl-2-dimethylaminocarbonylpyrrolidini
Ru) thio] -4-methyl-6- (1-hydroxydiethyl
L) -1-Azabicyclo [3.2.0] hept-2-e
N-7-one-2-carboxylic acid p-nitrobenzyles
Got a tell. IR^neat(cm^-1): 1760, 1705, 1645, 152
0, 1402, 1342, 1135, 1110; NMR δ (CDCl_Three): 1.30 (3H, d, J = 7.0Hz), 1.35 (3H, d, J =
6.5Hz), 2.99 (3H, s), 3.02 (3H, d, J = 15.0Hz), 5.21 (2H,
s), 5.20 and 5.43 (2H, ABq, J = 14Hz), 7.51 (2H, d, J = 8.5H
z), 7.64 (2H, d, J = 8.5Hz), 8.20 (4H, d, J = 8.5Hz). Reference Example 5-1 Embedded image (4R, 5S, 6S, 8R) -3-phenyl
Luthio-4-methyl-6-[(1R) -1-t-butyl
Dimethylsilyloxyethyl] -1-azabicyclo
[3.2.0] Hept-2-en-7-one-2-cal
Bonic acid phenylthioester 17mg and p-nitroben
24 mg of Zyl alcohol to 0.6 mg of dry methylene chloride
Dissolve, 7mg silver trifluoroacetate protected from light in a nitrogen stream
Was added. Then, 1,8-diazabicyclo [5.4.
0] -7-undecene 5mg dry methylene chloride 0.3m
g solution was added at room temperature and stirred for 4.3 hours. reaction
To the solution was added 3 ml of pH 7, 0.1 M phosphate buffer, and then
Diluted with methylene chloride. Filtration of insolubles and methyl chloride
After washing with water and water, the filtrate and washing solution are combined, and washed with methylene chloride.
Extracted times. The organic layer is 2.5% aqueous sodium dihydrogen phosphate
Wash the solution and saline solution in that order, and remove sodium sulfate and magnesium sulfate.
And dried. The residue obtained by evaporating the solvent under reduced pressure was silica gel
(4R, 5S, 6)
(S, 8R) -3-phenylthio-4-methyl-6- (1
-T-butyldimethylsilyloxyethyl) -1-aza
Bicyclo [3.2.0] hept-2-en-7-one-
2-carboxylic acid p-nitrobenzyl ester was obtained. This
IR and NMR of the compound obtained here were obtained in Example 12.
Identical to compound. Reference Example 5-2- (1) Embedded image(4R, 5S, 6S, 8R) -3-phenyl
Luthio-4-methyl-6-[(1R) -1-t-butyl
Dimethylsilyloxyethyl] -1-azabicyclo
[3.2.0] Hept-2-en-7-one-2-cal
20 mg of phenyl thionate borate
Dissolve in 0.3 ml of lofuran and fluorinate in a nitrogen stream under ice cooling
0.27M tetrahydrofuran of tetra-n-butylammonium
0.14 ml of a run solution was added dropwise and stirred for 1 hour. pH 7,
After dilution with 0.1 M phosphate buffer, use methylene chloride three times
Extracted. The organic layer was washed with brine, dried over sodium sulfate, and distilled off under reduced pressure.
The residue was purified by silica gel chromatography.
And (4R, 5S, 6S, 8R) -3-phenylthio-
4-methyl-6-[(1R) -1-hydroxyethyl]
-1-azabicyclo [3.2.0] hept-2-ene-
7-one-2-carboxylic acid phenylthioester was obtained.
Was. IR^CHCl3 (cm^-1): 3600 (br), 1775, 1660
(sh), 1645, 1300, 1273; NMR δ (CDCl_Three): 0.98 (3H, d, J = 7.3Hz), 1.35 (3H, d, J =
6.3Hz), 3.11 (1H, m), 3.23 (1H, dd, J = 2.3 and 6.9Hz), 4.27
(1H, dd, J = 2.6 and 9.2Hz), 4.27 to 4.3 (1H, m), 7.3 to 7.6 (1
0H, m). Reference Example 5-2- (2) Embedded image (4R, 5S, 6S, 8R) -3-phenyl
Luthio-4-methyl-6-[(1R) -1-hydroxy
Ethyl] -1-azabicyclo [3.2.0] hept-2
-En-7-one-2-carboxylic acid phenylthioester
3 mg and trimethylsilanol 14 mg in dry toluene
Dissolved in 0.1 ml of trifluoromethyl
1.6 mg of silver acetate was added. Then, 1,8-diazavik
B [5.4.0] -7-undecene 1.1 mg dry torr
Add 0.1 ml of ene solution at room temperature, and further at 80 ° C for 15 minutes
The mixture was stirred while heating. The reaction was cooled to room temperature, pH 7, 0.
Add 1 ml of 1M phosphate buffer, then add methylene chloride
Diluted. Filter off insolubles and wash with methylene chloride and water
Thereafter, the filtrate and the washing solution are combined, and extracted twice with methylene chloride.
Was. The aqueous layer was stirred at room temperature under reduced pressure to remove the organic solvent.
Was. High-performance liquid chromatography (Lichrosorb (registered trademark)
Mark) RP-18; methanol-pH 7.0 to 7.2, 0.005M
Phosphate buffer (3: 7); 0.8 ml / min) and thin layer chromatography
Matography (silica gel; chloroform-methanol)
Acetic acid (200: 50: 1)) to obtain in Reference Example 6-2.
(4R, 5S, 6)
S, 8R) -3-Phenylthio-4-methyl-6
[(1R) -1-hydroxyethyl] -1-azabisic
B [3.2.0] hept-2-en-7-one-2-ca
It was confirmed that rubonic acid was obtained. Reference Example 6-1 Embedded image (4R, 5R, 6S, 8R) -4-methyl
-6 [(1R) -1-hydroxyethyl] -1-azabi
Cyclo [3.2.0] hept-3,7-dione-2-ca
100 mg of p-nitrobenzyl rubonic acid is dried
Dissolve in 1 ml of acetonitrile, and in a nitrogen stream under ice-cooling
67 mg of diphenylchlorophosphate in dry acetonitrile
Add 0.5 ml of tril solution, then diisopropylethyl
A solution of 32 mg of amine in 0.5 ml of dry acetonitrile was added.
Then, the mixture was stirred at the same temperature for 30 minutes. Cool the reaction to -30 ° C
Thiophenol 37 mg dry acetonitrile 0.
2 ml solution, then diisopropylethylamine 44 mg
0.2 ml of dry acetonitrile solution of
The mixture was stirred for 5 minutes and further under ice-cooling for 15 minutes. Vinegar
Diluted with ethyl acid, washed with brine, aqueous solution of potassium phosphate
After washing, washing with brine and drying over magnesium sulfate-potassium carbonate
The solvent is distilled off and the residue is chromatographed on silica gel.
(4R, 5S, 6S, 8R) -3-f
Enylthio-4-methyl-6-[(1R) -1-hydro
Xylethyl] -1-azabicyclo [3.2.0] hept
P-Nitroben-2-ene-7-one-2-carboxylic acid
A gill ester was obtained. IR^neat(cm^-1): 3480 (br), 1764, 1707,
1520, 1342, 1215, 1140; NMR δ (CDCl_Three): 0.97 (3H, d, J = 7.3Hz), 1.31 (3H, d, J =
6.3Hz), 3.10 (1H, m), 3.21 (1H, dd, J = 2.8 and 6.8Hz), 4.18
(1H, dd, J = 2.8 and 9.4Hz), 4.23 (1H, m), 5.42 (2H, m), 7.3
~ 7.6 (5H, m), 7.69 (2H, d, J = 8.9Hz), 8.24 (2H, d, J = 8.9H
z). Reference Example 6-2 Embedded image (4R, 5S, 6S, 8R) -3-phenyl
Luthio-4-methyl-6-[(1R) -1-hydroxy
Ethyl] -1-azabicyclo [3.2.0] hept-2
-En-7-one-2-carboxylate p-nitrobenzyl
Dissolve 37mg of ester in 2ml of tetrahydrofuran
PH 7.0 morpholinopropane sulfonic acid buffer 2m
1 and 56 mg of 10% palladium-carbon,
Under normal hydrogen pressure, hydrogenation was performed at room temperature for 4.5 hours. Catalyst
After filtration, tetrahydrofuran is distilled off under reduced pressure.
After washing with methylene chloride, the aqueous layer is again distilled under reduced pressure to remove the organic solvent.
The residue is removed by polymer chromatography (CHP-2).
2P and 5% aqueous tetrahydrofuran
(4R, 5S, 6S, 8R)-
3-phenylthio-4-methyl-6-[(1R) -1-
Hydroxyethyl] -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylic acid was obtained. UV^HTwo^O(nm): 306; IR^KBr(cm^-1): 3425 (br), 1745, 1595, 1400; NMRδ (D_TwoO): 0.90 (3H, d, J = 7.3Hz), 1.18 (3H, d, J = 6.3
Hz), 3.00 (1H, m), 3.32 (1H, dd, J = 2.6 and 5.9 Hz), 4.09 (1
H, dd, J = 2.6 and 9.2Hz), 4.16 (1H, m), 7.3-7.6 (5H, m). Reference Example 7-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -2-a
Dissolve 755 mg of zetidinone in 10 ml of methylene chloride
And 1.88 g of t-butyl α-bromoacetate,
620 mg of thorium aqueous solution, triethylbenzyl alcohol chloride
221 mg of ammonium and then stirred at room temperature for 2 hours.
Was. Water and diethyl ether are added and the mixture is separated.
Extract twice more with chill ether and combine with the previous organic layer
And washed twice with water and then three times with saline, and then dried over sodium sulfate.
Was. The solvent was distilled off, and the residue was subjected to silica gel chromatography.
And purify the raw materials together with (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl
] -4-[(1R) -1-benzyloxycarbonyl
Ethyl] -1-t-butoxycarbonylmethyl-2-a
Zetidinone was obtained. IR^neat(cm^-1): 1755, 1730, 1450, 140
0, 1380, 1360, 1242, 1220, 1150, 830, 765, 740, 68
Five; NMR δ (CDCl_Three): 0.04 (3H, s), 0.07 (3H, s), 0.85 (9H,
s), 1.23 (3H, d, J = 6.3 Hz), 1.24 (3H, d, J = 6.9 Hz), 1.44 (9
H, s), 2.90 (1H, qd, J = 3.6 and 6.9Hz), 2.99 (1H, dd, J = 2.0 and
6.6Hz), 3.83 (2H, m), 5.10 (2H, s), 7.35 (5H, s). Reference Example 7-2 Embedded image(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -1-t
-Butoxycarbonylmethyl-2-azetidinone 0.45 g
Is dissolved in 6 ml of 99.5% ethanol and 10% palladium
-90 mg of carbon was added and hydrogenated at normal temperature and normal pressure.
After filtering off the catalyst, the filtrate and washings are combined, and the solvent is distilled off.
(3S, 4S) -3-[(1R) -1-t-butyldi
Methylsilyloxyethyl] -4-[(1R) -1-ca
Ruvoxyethyl] -1-tert-butoxycarbonylmethyl
-2-Azetidinone was obtained. IR^neat(cm^-1): 1760, 1740, 1730, 145
5, 1360, 1245, 1224, 1150, 830, 770, 745; NMR δ (CDCl_Three): 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H,
s), 1.24 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.3 Hz), 1.48 (9
H, s), 2.94 (1H, qd, J = 7.0 and 3.0Hz), 3.04 (1H, dd, J = 2.8 and
5.5Hz), 3.98 (2H, m), 4.00 (1H, m), 4.21 (1H, m). Reference Example 7-3- (1) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycal
1.29 g of bonylmethyl-2-azetidinone, N, N'-ca
Dry acetonitrile of 604 mg of rubonyl diimidazole
The 25 ml solution was stirred at room temperature for 1 hour. This is Chioff
A solution of 410 mg of enol in 6 ml of dry acetonitrile,
Then 377 mg of triethylamine in dry acetonitrile
6 ml of a solution was added, and the mixture was stirred at room temperature for 30 minutes. Reaction liquid
Was diluted with ethyl acetate and washed with diluted hydrochloric acid. Water layer
The mixture was extracted twice with ethyl acetate, and the organic layers were combined.
After washing twice, it was dried over sodium sulfate. The solvent was distilled off under reduced pressure.
The residue is purified by silica gel chromatography (3
S, 4S) -3-[(1R) -1-t-butyldimethyl
Silyloxyethyl] -4-[(1R) -1-phenyl
Thiocarbonylethyl] -1-t-butoxycarbonyl
Methyl-2-azetidinone was obtained. IR^neat(cm^-1): 1760, 1740, 1705, 1367, 1250, 122
7,835,770,740. Reference Example 7-3- (2) Embedded image The thiophenol is converted to p-chlorothiopheno
According to the same method as in Reference Example 7-3- (1).
(3S, 4S) -3-[(1R) -1-t-butyldimene
Tylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -1-t-but
Xycarbonylmethyl-2-azetidinone was obtained. IR^neat(cm^-1): 1760, 1740, 1705, 148
0, 1365, 1260, 1230, 1155, 1095, 838, 775; NMR δ (CDCl_Three): 0.10 (6H, s), 0.89 (9H, s), 1.26 (3H,
d, J = 6.3Hz), 1.31 (3H, d, J = 6.9Hz), 1.43 (9H, s), 3.02 (1
H, dd, J = 2.3 and 6.9Hz), 3.14 (1H, qd, J = 3.3 and 6.9Hz), 3.92
(2H, m), 7.34 (4H, m). Reference Example 7-3- (3) Embedded image(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycal
Bonylmethyl-2-azetidinone 100 mg and 2,4
33 mg of 5-trichlorophenol in dry tetrahydro
Dissolve it in 4 ml of furan and cool under ice-cooling 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride 96m
g was added and stirred overnight. The reaction solution was treated with diethyl ether and water
And extracted. Wash the organic layer with saline and dry it with sodium sulfate
And concentrated under reduced pressure to give (3S, 4S) -3-[(1R) -1
-T-butyldimethylsilyloxyethyl] -4-
[(1R) -1- (2,4,5-trichlorophenylo)
Xy) carbonylethyl] -1-tert-butoxycarboni
Obtained is methyl-2-azetidinone. IR^neat(cm^-1): 1760, 1740 (sh), 1455, 1362, 1250,
1225. Reference Example 7-3- (4) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycal
98 mg of bonylmethyl-2-azetidinone was dried
Dissolve in 1 ml of styrene and add 34 mg of thionyl chloride at room temperature.
Add 0.5 ml of dry methylene chloride solution and leave at the same temperature for 1 hour
The mixture was further stirred for 3 hours while heating under reflux. After distilling off the solvent
The residue was redissolved in dry toluene, evaporated under reduced pressure, and dried in vacuo.
Dry and dry (3S, 4S) -3-[(1R) -1-t-butyl.
Dimethylsilyloxyethyl] -4-[(1R) -1
-Chlorocarbonylethyl] -1-t-butoxycarbo
Nylmethyl-2-azetidinone was obtained. IR^neat(cm^-1): 1800 (sh), 1740, 1450,
1360, 1244, 1220, 930, 825, 770. Reference Example 7-3- (5) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycal
Bonylmethyl-2-azetidinone 104 mg, 1-oxo
53 mg of cibenzotriazole, 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride 93
mg (3S, 3S) in the same manner as in Reference Example 7-3- (3).
4S) -3-[(1R) -1-t-butyldimethylsilyl
Roxyethyl] -4-[(1R) -1- (1-benzo
Triazolyloxy) carbonylethyl] -1-t-bu
Toxicarbonylcarbonyl-2-azetidinone was obtained. IR^neat(cm^-1): 1740 (sh), 1730, 1450,
1360, 1240, 1220, 822. Reference Example 7-3- (6) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycal
Bonylmethyl-2-azetidinone 100 mg, 2-mer
35 mg of captopyridine, 1-ethyl-3- (3-dimethyl
Tylaminopropyl) carbodiimide hydrochloride 100mg
(3S, 4) in the same manner as in Reference Example 7-3- (3).
S) -3-[(1R) -1-t-butyldimethylsilyl
Oxyethyl] -4-[(1R) -1- (2-pyridyl
Thio) carbonylethyl] -1-t-butoxycarboni
Obtained is methyl-2-azetidinone. IR^neat(cm^-1): 1755, 1690, 1360, 124
7, 1220, 1142, 830, 770. Reference Example 7-4 Embedded image Dry N, N- of 31 mg of sodium hydride
Α-Bromoacetic acid in 4.3 ml of dimethylformamide suspension
835 mg of t-butyl, then (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl
] -4-[(1R) -1-phenylthiocarbonyl
Chill] -2-azetidinone 0.42 g and room temperature in a nitrogen stream
For 1 hour. Then with diethyl ether under ice cooling
A pH 6.86 phosphate buffer was added for extraction. Add more water layers
After extracting twice with ethyl ether, the organic layers are combined,
And dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure
The residue is purified by silica gel chromatography (3
S, 4S) -3-[(1R) -1-t-butyldimethyl
Silyloxyethyl] -4-[(1R) -1-phenyl
Thiocarbonylethyl] -1-t-butoxycarbonyl
Methyl-2-azetidinone was obtained. Of the compound obtained here
The IR spectrum was the same as that obtained in Reference Example 7-3- (1).
Was one. Reference Example 7-5 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-chlorophenylthiocarbonylethyl]
-2-azetidinone in the same manner as in Reference Example 7-1.
(3S, 4S) -3-[(1R) -1-t-butyldimene
Tylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -1-t-but
Xycarbonylmethyl-2-azetidinone was obtained. here
IR and NMR of the compound obtained in Reference Example 7-3-
It was identical to that obtained in (2). Reference Example 8-1 Embedded image (3S, 4S) -3-[(1R) -1-B
Ndyloxycarbonyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -2-a
Zetidinone (71.94 g) was dried in N, N-dimethylform
Dissolve in 700 ml of amide and add tert-butyl bromoacetate under ice-cooling.
Luster (68.25 g) and sodium hydride
(50% oil) (9.24 g) and stir for 1 hour
Was. 500 ml of 10% aqueous ammonium chloride solution
, And stirred for 30 minutes, and then with toluene (2 liters).
After extraction, the organic layer was washed with saline and dried over sodium sulfate,
Evaporation gave an oily residue. This is silica gel chromatog
Raffy, (3S, 4S) -3-[(1R) -1
-Benzyloxycarbonyloxyethyl] -4-
[(1R) -1-benzyloxycarbonylethyl]-
1-t-butoxycarbonylmethyl-2-azetidinone
I got [0206] IR^neat(cm^-1): 1765 (sh), 1740, 1455,
1370, 1268, 1160; NMR δ (CDCl_Three): 1.18 (3H, d, J = 6.9Hz), 1.45 (3H, d, J =
6.3Hz), 1.45 (9H, s), 2.86 (1H, m), 3.26 (1H, dd, J = 2.0
9.0Hz), 3.55 (1H, d, J = 18.0Hz), 4.04 (1H, dd, J = 2.0 and 4.6
Hz), 4.10 (1H, d, J = 18.0Hz). Reference Example 8-2 Embedded image (3S, 4S) -3-[(1R) -1-B
Ndyloxycarbonyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -1-t
-Butoxycarbonylmethyl-2-azetidinone (81.5
0g) in 800 ml of ethanol and 10%
Um-carbon (8.15g) and hydrogenation at normal temperature and pressure
did. After removing the catalyst by filtration, the filtrate and washing solution are combined, and the solvent is distilled off.
Leave to remove (3S, 4S) -3-[(1R) -1-hydroxy
Ciethyl] -4-[(1R) -1-carboxyethyl]
-1-t-butoxycarbonylmethyl-2-azetidino
I got it. [0209] IR^Nujol(cm^-1): 1740, 1720, 1440, 136
0; NMR δ (CDCl_Three): 1.28 (3H, d, J = 6.9Hz), 1.33 (3H, d, J =
6.6Hz), 2.84 (1H, m), 3.09 (1H, dd, J = 2.0 and 6.6Hz), 3.76
(1H, d, J = 18.0Hz), 4.03 (1H, dd, J = 2.0 and 5.3Hz). Reference Example 8-3 Embedded image (3S, 4S) -3-[(1R) -1-H
Droxyethyl] -4-[(1R) -1-carboxye
Tyl] -1-tert-butoxycarbonylmethyl-2-aze
The same treatment as in Reference Example 7-3- (1) using thidinone
And (3S, 4S) -3-[(1R) -1-hydro
Xyethyl] -4-[(1R) -1-phenylthiocar
Bonylethyl] -1-tert-butoxycarbonylmethyl-
2-azetidinone was obtained. [0212] IR^Nujol(cm^-1): 1745, 1725, 1290, 123
0, 1140, 950, 750. Reference Example 9-1 Embedded image (A) 4-[(1R) -1-hydroxyme
Tylethyl] -3-[(1R) -1-benzyloxyca
Rubonyloxyethyl] -2-azetidinone 30.7 g, charcoal
Acetic acid 27.6 g and tert-butyl bromoacetate 33.0 g
300 ml of ton was added, and the mixture was stirred under reflux with heating for 17 hours. Anti
The reaction solution was returned to room temperature, and insolubles were removed by filtration. (B) After adding 15 ml of water to the filtrate, the mixture was cooled on ice.
49.2 g of water, 16.92 g of chromium trioxide, 26.52 of concentrated sulfuric acid
g, the Jones reagent prepared using
It was dropped. After stirring under ice-cooling for 60 minutes, ethyl acetate 1
One liter and 300 ml of water were added to carry out liquid separation. Ethyl acetate layer
Was washed four times with 300 ml of saline, and then magnesium sulfate was added.
50 g was added and dried, and the solvent was distilled off. Silica residue
Purified by gel chromatography, (3S, 4S)-
3-[(1R) -1-benzyloxycarbonyloxy
Ethyl] -4-[(1R) -1-carboxyethyl]-
1-t-butoxycarbonylmethyl-2-azetidinone
23.73 g (54.5% yield) was obtained. [0216] IR^neat(cm^-1): 1735, 1450, 1365, 125
0, 1150, 1040; NMR δ (CDCl_Three): 1.19 (3H, d, J = 6.9Hz), 1.46 (9H, s),
3.26 (1H, dd, J = 2.3 and 8.6Hz), 4.06 (1H, dd, J = 2.3 and 4.0H
z), 7.36 (5H, s). (3S, 4S) -3-[(1R) -1-B
Ndyloxycarbonyloxyethyl] -4-[(1
R) -1-Hydroxymethylethyl] -1-t-butoki
Cycarbonylmethyl-2-azetidinone IR^neat(cm^-1): 1735, 1360, 1250, 1150, 1030, 95
Five. Reference Example 9-2 Embedded image (3S, 4S) -3-[(1R) -1-B
Ndyloxycarbonyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycal
23.75 g of bonylmethyl-2-azetidinone was acetonitrile
Dissolve in 237 ml of N, N'-carbonyldiene under ice-cooling.
10.55 g of imidazole were added. Stir for 30 minutes under ice-cooling
After adding 7.21 g of thiophenol, triethyl alcohol was added.
6.62 g of min was added. After stirring for 2.5 hours under ice cooling,
500 ml of chill and 200 ml of 1N hydrochloric acid were added to carry out liquid separation.
The aqueous layer was separated twice with 200 ml of ethyl acetate and then ethyl acetate.
The layers were combined and separated three times with 300 ml of saline. Organic
After the layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure.
Was. The residue was purified by silica gel chromatography,
(3S, 4S) -3-[(1R) -1-benzyloxy
Carbonyloxyethyl] -4-[(1R) -1-fe
Nylthiocarbonylethyl] -1-tert-butoxycarbo
19.46 g of nilmethyl-2-azetidinone (67.64% yield)
I got [0220] IR^neat(cm^-1): 1760, 1735, 1700, 144
0, 1365, 1255, 1150, 1045, 950, 740; NMR δ (CDCl_Three): 1.25 (3H, d, J = 6.9Hz) 、 1.44 (9H, s) 、
1.47 (3H, d, J = 6.2Hz), 4.12 (1H, m), 4.13 (1H, dd, J = 2.6
4.5Hz), 7.36 (10H, m). Reference Example 10-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -2-a
Of 3.50 g of zetidinone and 8.73 g of t-butyl α-bromoacetate
50% aqueous sodium hydroxide in 45 ml of methylene chloride solution
2.86 g of the solution and 1.02 g of triethylbenzylammonium chloride
g in the same manner as in Reference Example 14-1 except that g was added.
S, 4S) -3-[(1R) -1-t-butyldimethyl
Silyloxyethyl] -4-[(1S) -1-benzyl
Oxycarbonylethyl] -1-tert-butoxycarboni
Obtained is methyl-2-azetidinone. IR^neat(cm^-1): 1760 (sh), 1735, 1455, 1362, 1245,
1222, 835, 773. Reference Example 10-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -1-t
-Butoxycarbonylmethyl-2-azetidinone 2.9 g
Was hydrogenated exactly as in Reference Example 7-2 (3S, 4
S) -3-[(1R) -1-t-butyldimethylsilyl
Oxyethyl] -4-[(1S) -1-carboxyethyl
1] -tert-butoxycarbonylmethyl-2-azeti
I got ginone. [0225] IR^Nujol(cm^-1): 3300 (br), 1760 (sh), 1
742, 1690, 990, 940, 825, 767. Reference Example 10-3- (1) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycal
Reference Example 7-3 using bonylmethyl-2-azetidinone
-By the same method as (1), (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl
] -4-[(1S) -1-phenylthiocarbonyl
Tyl] -1-tert-butoxycarbonylmethyl-2-aze
Thidinone was obtained. [0228] IR^neat(cm^-1): 1760, 1740 (sh), 1700,
1365, 1250, 1225, 950, 830, 773, 740, 680. Reference Example 10-3- (2) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycal
Dry chloride of 100 mg of bonylmethyl-2-azetidinone
Dissolve in methylene and add catalytic amount of N, N-dimethylforma
At room temperature with 37 mg of oxalyl chloride in the presence of amide.
After stirring for an hour, the corresponding acid chloride was obtained. This is 4,6
-Dimethyl-2-mercaptopyrimidine 50 mg and 4-
44 mg of dimethylaminopyridine was added and stirred. reaction
Dilute the solution with methylene chloride, dilute sulfuric acid, water, sodium hydrogen carbonate
It was washed sequentially with an aqueous solution of lithium and brine, and dried over sodium sulfate.
After evaporation of the solvent, the residue was purified by silica gel chromatography.
(3S, 4S) -3-[(1R) -1-t-butyl)
Dimethylsilyloxyethyl] -4-[(1S) -1
-(4,6-dimethylpyrimidin-2-ylthiocarbo
Nyl) ethyl] -1-tert-butoxycarbonylmethyl-
2-azetidinone was obtained. [0231] IR^neat(cm^-1): 1760, 1740 (sh), 1580,
1362, 1247, 830, 770. Reference Example 10-3- (3) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycal
Bonylmethyl-2-azetidinone 100mg and N-hydrid
33 mg of roxysuccinimide in dry N, N-dimethyl
Dry N, N'-dicyclohexene in 0.3 ml formamide solution
Add 74mg of silcarbodiimide and react at 0-5 ° C overnight
did. After diluting the reaction solution with ethyl acetate, dilute sulfuric acid was added to separate the solution.
Was. The aqueous layer was extracted twice more with ethyl acetate, and the organic layers were combined.
And washed successively with water (4 times) and brine. Glauber's organic layer
After drying with, the solvent is distilled off and the residue is purified by silica gel chromatography.
Purify with a feed (3S, 4S) -3-[(1R)-
1-t-butyldimethylsilyloxyethyl] -4-
[(1S) -1-succinimidooxycarbonylethyl
1] -tert-butoxycarbonylmethyl-2-azeti
I got ginone. [0234] IR^neat(cm^-1): 1805, 1760 (sh), 1740,
1455, 1360, 1200, 1145, 1055, 830, 762, 745. Reference Example 10-3- (4) Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycal
Bonylmethyl-2-azetidinone 42 mg and N, N'-
19 mg of carbonyldiimidazole in dry acetonitrile
After stirring 0.9 ml of the solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography.
(3S, 4R) -3-[(1R) -1-t-butyldimension
Tylsilyloxyethyl] -4-[(1S) -1- (1
-Imidazolyl) carbonylethyl] -1-t-butoki
Cycarbonylmethyl-2-azetidinone was obtained. [0237] IR^neat(cm^-1): 1760 (sh), 1735, 1382,
1360, 1225, 1145, 935, 827, 745. Reference Example 11-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -2-a
Dissolve 1.56 g of zetidinone in 20 ml of methylene chloride and add α
-916 mg of methyl bromoacetate, 50% sodium hydroxide
Aqueous solution 1.28 g, triethylbenzylammonium chloride
455 mg were sequentially added and the mixture was stirred at room temperature for 2 hours. To the reaction solution
After water and diethyl ether were added and the layers were separated, the aqueous layer was
Extract two more times with ether, combine the organic layers and add water
After washing twice and then with a saline solution three times, the solution was dried over sodium sulfate. solvent
And the residue is purified by silica gel chromatography.
And recover some of the raw materials (3S, 4S)
3-[(1R) -1-t-butyldimethylsilyloxy
Ethyl] -4-[(1S) -1-benzyloxycarbo
Nylethyl] -1-methoxycarbonylmethyl-2-a
Zetidinone was obtained. [0240] IR^neat(cm^-1): 1760, 1740, 1460, 140
7, 1360, 1250, 1215, 1180, 1140, 835, 770, 745; NMR δ (CDCl_Three): 0.07 (3H, s), 0.08 (3H, s), 0.87 (9H, s
s), 1.24 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.2 Hz), 2.77 (1
H, m), 3.63 (3H, s), 3.93 (2H, s), 3.96 (1H, dd, J = 2.0 and 9.
6Hz), 4.19 (1H, m), 5.09 (2H, s), 7.36 (5H, s). Reference Example 11-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -1-me
400 mg of toxiccarbonylmethyl-2-azetidinone
Was dissolved in 6 ml of 99.5% ethanol and 10% palladium-
80 mg of carbon was added and hydrogenated at normal temperature and normal pressure. Touch
The solvent is removed by filtration, the back solution and the washing solution are combined, and the solvent is distilled off (3.
S, 4S) -3-[(1R) -1-t-butyldimethyl
Silyloxyethyl] -4-[(1S) -1-carboxy
Siethyl] -1-methoxycarbonylmethyl-2-aze
Thidinone was obtained. [0243] IR^neat(cm^-1): 1740, 1705, 1435, 124
0, 1215, 1135, 830, 770. Reference Example 11-3 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-methoxycarbonyl
Reference Example 7-3- using methyl 2-azetidinone
By the same method as (1), (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
4-[(1S) -1-phenylthiocarbonylethyl]
-1-methoxycarbonylmethyl-2-azetidinone
Obtained. IR^neat(cm^-1): 1750, 1695, 1437, 140
5, 1247, 1202, 950, 830, 770, 740; NMR δ (CDC
l_Three): 0.07 (3H, s), 0.09 (3H, s), 0.87 (9H, s), 2.88 (1H, d
d, J = 2.3 and 6.6 Hz), 3.03 (1H, m), 3.70 (3H, s), 4.02 (1H, d
d, J = 2.0 and 9.2 Hz), 4.19 (1H, m), 7.41 (5H, m). Reference Example 12-1 Embedded image (A) (3S, 4S) -3-[(1R)-
1-t-butyldimethylsilyloxyethyl] -4-
[(1R) -1-phenylthiocarbonylethyl] -1
-T-butoxycarbonylmethyl-2-azetidinone 1
1.5 ml of 6N hydrochloric acid was added to a solution of 90 mg of methanol in 4.5 ml.
The mixture was stirred at room temperature for 15 minutes. After confirming the disappearance of raw materials, react
Chloroform and saline were added to the liquid for extraction. Water layer
After extracting twice with chloroform, the organic layers are combined,
Dried. After evaporating the solvent under reduced pressure, trifluoro
A mixture of acetic acid (1 ml) and anisole (0.1 ml) was added, and the mixture was added at room temperature for 25 minutes.
Stirred for minutes. After the trifluoroacetic acid is distilled off under reduced pressure, the residue is dried.
The mixture was azeotroped twice with dry toluene to give (3S, 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-
Phenylthiocarbonylethyl] -1-carboxymethyl
Ru-2-azetidinone was obtained as a crude product. (B) The crude product obtained in (a), t-butyldi
246 mg of methylsilyl chloride, imidazole 151
mg of a dry N, N-dimethylformamide solution in 2 ml.
Reacted overnight. Pour the reaction solution into water and use ethyl acetate
And extracted three times. Combine the organic layers and dilute sulfuric acid, water (5
Wash) and saline (twice) in that order, and dried over sodium sulfate.
The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel chromatography.
(3S, 4S) -3-[(1R) -1-
t-butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-cal
Boxymethyl-2-azetidinone was obtained. IR^neat(cm^-1): 3350 (br), 1760 (sh), 17
37, 1700, 1245, 1140, 830, 767, 742. Reference Example 12-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-cal
Boxymethyl-2-azetidinone 154mg, N, N '
66 mg of carbonyldiimidazole in dry acetonitrile
The 2.9 ml Lil solution was stirred at room temperature for 1 hour. Reaction liquid
Dissolve 56 mg of Ophenol in 1 ml of dry acetonitrile
Liquid, then 52 mg of triethylamine in dry acetonitrile
Lil 0.5 ml solution was added and stirred for 30 minutes. Vinegar
Diluted with ethyl acid and poured into cold dilute sulfuric acid. Ethyl acetate
After extracting three times with water, the organic layers are combined, and diluted with sulfuric acid and saline.
Washing was performed in the order of (twice). The organic layer is dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography.
(3S, 4S) -3-[(1R) -1-t-butyldi
Methylsilyloxyethyl] -4-[(1R) -1-F
Enylthiocarbonylethyl] -1-phenylthiocar
Bonylmethyl-2-azetidinone was obtained. IR^neat(cm^-1): 1760, 1700, 1478, 144
0, 1250, 1140, 835, 773, 740, 682; NMR δ (CDCl_Three): 0.08 (3H, s), 0.10 (3H, s), 0.89 (9H,
s), 1.27 (3H, d, J = 6.3 Hz), 1.32 (3H, d, J = 7.3 Hz), 3.11 (1
H, dd, J = 2.0 and 6.9Hz), 3.20 (1H, m), 4.24 (1H, m), 4.30 (2
H, m), 7.41 (10H, s). Reference Example 13-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Phenylthiocarbonylethyl] -1-t-
Butoxycarbonylmethyl-2-azetidinone 243m
g was purified after the reaction in exactly the same manner as in Reference Example 12-1.
(3S, 4S) -3-[(1R) -1-t-butyldimene
Tylsilyloxyethyl] -4-[(1S) -1-fe
Nylthiocarbonylethyl] -1-carboxymethyl-
2-azetidinone was obtained. IR^neat(cm^-1): 3350 (br), 1760 (sh), 17
40, 1250, 950, 825, 770, 740, 680. Reference Example 13-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Phenylthiocarbonylethyl] -1-cal
87 mg of boxymethyl-2-azetidinone, N, N'-
Carbonyldiimidazole 37mg, thiophenol 2
Reference except that 5 mg and 23 mg of triethylamine were used.
Exactly as in Example 12-2, (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl
] -4-[(1S) -1-phenylthiocarbonyl
Tyl] -1-phenylthiocarbonylmethyl-2-aze
Thidinone was obtained. IR^neat(cm^-1): 1760, 1705, 1480, 144
2,1250,955,835,742,682. Reference Example 14-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-methoxybenzyloxycarbonylethyl
1. 2-g of 2-azetidinone in 14 ml of methylene chloride
Was dissolved in 1.09 g of p-nitrobenzyl α-bromoacetate,
0.85 g of 50% aqueous sodium hydroxide solution, triethyl chloride
303 mg of benzylammonium were added sequentially, and the mixture was
Stirred for 0 minutes. Water and diethyl ether-methylene chloride
(3: 1) was added and the mixture was separated.
Extract 2 more times with methylene chloride (3: 1)
Combine the layers and wash twice with water and then three times with saline,
The glass was dried. The solvent is distilled off, and the residue is chromatographed on silica gel.
Purify by luffy and collect raw materials (3S, 4S)
-3-[(1R) -1-t-butyldimethylsilyloxy
Ciethyl] -4-[(1R) -1-p-methoxybenzyl
Ruoxycarbonylethyl] -1-p-nitrobenzyl
Oxycarbonylmethyl-2-azetidinone was obtained. IR^neat(cm^-1): 1760, 1742, 1607, 151
5, 1458, 1342, 1241, 1170, 830, 747; NMR δ (CDCl_Three): 0.01 (3H, s), 0.05 (3H, s), 0.83 (9H, s
s), 2.86 (1H, qd, J = 7.2 and 3.0 Hz), 3.00 (1H, dd, J = 2.3 and 6.
6Hz), 3.80 (3H, s), 5.01 (2H, m), 5.20 (2H, s), 6.88 (2H,
d, J = 8.6Hz), 7.49 (2H, d, J = 8.9Hz), 8.22 (2H, d, J = 8.6H)
z). Reference Example 14-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-methoxybenzyloxycarbonylethyl
L] -1-p-nitrobenzyloxycarbonylmethyl
-142 mg of azetidinone dry methylene chloride 1.4
Boron trifluoride diethyl ether complex
163 mg was added, and the temperature was raised to room temperature. Reaction after disappearance of raw materials
The liquid was poured into a cold aqueous sodium hydrogen carbonate solution. Use diluted hydrochloric acid
The mixture was made acidic and extracted with ethyl acetate. Aqueous layer with ethyl acetate
Extract twice more, combine with the previous organic layer, dilute hydrochloric acid, salt
After washing in the order of water, it was dried with sodium sulfate. Evaporate the solvent and remove the residue.
Purify by silica gel chromatography, (3S, 4
S) -3-[(1R) -1-t-butyldimethylsilyl
Oxyethyl] -4-[(1R) -1-carboxyethyl
L] -1-p-nitrobenzyloxycarbonylmethyl
-2-azetidinone and (3S, 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-
Carboxyethyl] -1-p-nitrobenzyloxyca
Rubonylmethyl-2-azetidinone was obtained. (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-p-nitrobenzyl
Luoxycarbonylmethyl-2-azetidinone IR^neat(cm^-1): 3100 (br), 1760, 1730, 1520, 1342,
1245, 1180, 830, 770; NMR δ (CDCl_Three): 0.03 (3H, s), 0.07 (3H, s), 0.85 (9H,
s), 1.25 (2H, d, J = 6.3 Hz), 1.26 (2H, d, J = 7.3 Hz), 2.91 (1
H, qd, J = 7.3 and 3.0Hz), 3.05 (1H, dd, J = 2.3 and 5.9Hz), 4.13
(2H, m), 5.26 (2H, s), 7.52 (2H, d, J = 8.9Hz), 8.23 (2H, d,
J = 8.9Hz). (3S, 4S) -3-[(1R) -1-H
Droxyethyl] -4-[(1R) -1-carboxye
Tyl] -1-p-nitrobenzyloxycarbonylmethyl
Ru-2-azetidinone IR^neat(cm^-1): 3430 (br), 1760, 1735, 1705, 1520,
1345, 1180, 745. Reference Example 15-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-chlorophenylthiocarbonylethyl]
-1-t-butoxycarbonylmethyl-2-azetidino
200 mg in 1.5 ml of dry methylene chloride
Add 263 mg of boron fluoride diethyl ether complex and add room
Stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was treated with methanol 0.
Redissolve in 5 ml, add 1 ml of 1N hydrochloric acid, and eliminate raw materials
Thereafter, ethyl acetate and brine were added to the reaction mixture, and the mixture was separated.
The aqueous layer was extracted twice more with ethyl acetate and combined with the previous organic layer.
The mixture was washed with saline and dried over sodium sulfate. Evaporate the solvent,
(3S, 4S) -3-[(1R) -1-hydroxyethyl
] -4-[(1R) -1-p-chlorophenylthioca
Rubonylethyl] -1-carboxymethyl-2-azeti
I got ginone. This is dried N, N-dimethylformamide
Dissolved in 2.5 ml of t-butyldimethylsilyl chloride
246 mg and imidazole 151 mg were added at room temperature.
Reacted overnight. Pour the reaction solution into cold saline and add 1M hydrogen sulfate
Neutralized with an aqueous solution of lithium. Add diethyl ether and add
The aqueous layer was adjusted to pH 2 using a 1M aqueous solution of potassium hydrogen sulfate.
It was extracted after adjusting to. Wash the aqueous layer with diethyl ether
Extracted twice, combined with the previous organic layer and washed twice with saline.
After that, it was dried with sodium sulfate. The solvent is distilled off, and the residue is
Purified by chromatography, (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl
] -4-[(1R) -1-p-chlorophenylthioca
Rubonylethyl] -1-carboxymethyl-2-azeti
I got ginone. IR^neat(cm^-1): 3300 (br), 1760, 1740,
1700, 1480, 1382, 1250, 1140, 1087, 830, 775. Reference Example 15-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-chlorophenylthiocarbonylethyl]
-1-carboxymethyl-2-azetidinone 70 mg,
24 mg of p-nitrobenzyl alcohol in dry ethyl acetate
N, N'-dicyclohexylcal in 0.3 ml solution under ice-cooling
A solution of 30 mg of bodiimide in 0.2 ml of dry ethyl acetate was added.
The reaction was carried out overnight at 5 to 10 ° C. N, N'-dishes that precipitate
After filtering and washing clohexyl urea, filtrate and washing solution
And washed with water. The organic layer is further washed with saline and awn
The glass was dried. The solvent is distilled off, and the residue is chromatographed on silica gel.
Purified by luffy, (3S, 4S) -3-[(1R)
-1-tert-butyldimethylsilyloxyethyl] -4-
[(1R) -1-p-chlorophenylthiocarbonyle
Tyl] -1-p-nitrobenzyloxycarbonylmethyl
Thus, ru-2-azetidinone was obtained. IR^neat(cm^-1): 1760, 1750, 1700, 160
2,1520,1478,1343,1250,1180,1090,835,775,7
42; NMR δ (CDCl_Three): 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H,
s), 1.27 (3H, d, J = 6.3 Hz), 1.31 (3H, d, J = 7.3 Hz), 3.01 (1
H, dd, J = 2.6 and 7.1Hz), 3.14 (1H, qd, J = 2.6 and 7.3Hz), 4.12
(2H, m), 4.17 (2H, m), 5.20 (2H, m), 7.34 (4H, m), 7.44 (2
H, d, J = 8.6Hz), 8.17 (2H, d, J = 8.9Hz). Reference Example 16-1 Embedded image (A) (3S, 4S) -3-[(1R)-
1-hydroxyethyl] -4-[(1R) -1-phenyi
Ruthiocarbonylethyl] -1-t-butoxycarboni
Trimethyl vinegar in methyl 2-azetidinone (72.0 g)
500 g of acid was added, and the mixture was stirred for 2 hours under ice cooling. Reaction solution 5
The solution was concentrated under reduced pressure at 0 ° C. or less, and the oily residue was dissolved in 250 ml of toluene
And the solvent was again distilled off. (B) The obtained residue (72.1 g) was
Dissolve in 720 ml of tonitrile and add 43.2 of triethylamine.
5 g are added, followed by 92.33 g of p-nitrobenzyl bromide.
The mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with 1.5 l of ethyl acetate.
Dilute with turtle, wash several times with 20% saline and dry with sodium sulfate
Thereafter, the solvent was distilled off. Silica gel chromatography of oily residue
And (3S, 4S) -3-[(1R)-
1-hydroxyethyl] -4-[(1R) -1-phenyi
Ruthiocarbonylethyl] -1-p-nitrobenzylo
Xycarbonylmethyl-2-azetidinone was obtained. IR^CHCl3 (cm^-1): 1740, 1680, 1600, 151
5, 1360, 1205, 1180, 950, 740. Reference Example 16-2 Embedded image(3S, 4S) -3-[(1R) -1-B
Ndyloxycarbonyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-t-
8.5 g of butoxycarbonylmethyl-2-azetidinone
Dissolve in 185 ml of ethylene dichloride and cool to -10 ° C
Rejected. While stirring, 26.4 g of ethylenedibromide
A 100 ml solution of chloride was added dropwise over 20 minutes. Anti
The reaction solution was stirred for 1 hour while keeping it at -10 ° C.
Dissolve 40 g of sodium bicarbonate and 600 g of ice water in the reaction solution.
The solution was added and washed with 200 ml of ethyl acetate. 2N for water layer
After adding 200 ml of hydrochloric acid, 300 ml of ethyl acetate was added.
Extracted. The aqueous layer is further extracted with 300 ml of ethyl acetate
After that, the ethyl acetate layers were combined, and added with 200 ml of a saline solution.
Washed twice. After drying the organic layer with magnesium sulfate
Separately, the solvent was distilled off under reduced pressure to obtain (3S, 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-
Phenylthiocarbonylethyl] -1-carboxymethyl
Thus, 10.4 g of ru-2-azetidinone (87.9% yield) was obtained. [0279] IR^Nujol(cm^-1): 1740, 1710, 1690, 121
0, 1130, 1070, 940, 740. Reference Example 16-3 Embedded image (3S, 4S) -3-[(1R) -1-H
Droxyethyl] -4-[(1R) -1-phenylthio
Carbonylethyl] -1-p-nitrobenzyloxyca
Drying of rubonylmethyl-2-azetidinone (52.36g)
Dissolve in 262 ml of N, N-dimethylformamide and add
Midazole (16.6 g), t-butyldimethylsilyl chloride
Lido (23.28 g) was added and the mixture was stirred at room temperature for 5 hours. Reaction liquid
Diluted with 1 liter of ethyl acetate and washed with 20% saline,
The aqueous layer was extracted with 500 ml of ethyl acetate, and the organic layers were combined.
And washed twice with 20% saline. After drying the sodium sulfate, distill off the solvent
The oily residue was subjected to silica gel chromatography.
And (3S, 4S) -3-[(1R) -1-t-butyl
Dimethylsilyloxyethyl] -4-[(1R) -1-
Phenylthiocarbonylethyl] -1-p-nitroben
To obtain dizyloxycarbonylmethyl-2-azetidinone
Was. IR^neat(cm^-1): 1755, 1690, 1600, 151
5, 1340, 1250, 1180, 835; NMR δ (CDCl_Three): 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H,
s), 1.28 (3H, d, J = 6.0 Hz), 1.32 (3H, d, J = 7.3 Hz), 3.01 (1
H, dd, J = 2.3 and 7.3Hz), 3.16 (1H, dd, J = 2.3 and 7.3Hz), 3.96
(1H, d, J = 17.8Hz), 4.17 (2H, m), 4.31 (1H, d, J = 17.8Hz),
5.20 (2H, ABq, J = 13.5Hz), 7.25 ~ 7.45 (5H), 8.12 (2H, d, J
= 8.9Hz). Reference Example 16-4 Embedded image (3S, 4S) -3-[(1R) -1-H
Droxyethyl] -4-[(1R) -1-phenylthio
Carbonylethyl] -1-p-nitrobenzyloxyca
T-butyldimension from rubonylmethyl-2-azetidinone
Replace tylsilyl chloride with trimethylsilyl chloride
By performing the same processing as in Reference Example 16-3,
S, 4S) -3-[(1R) -1-trimethylsilylthio
Xyethyl] -4-[(1R) -1-phenylthiocar
Bonylethyl] -1-p-nitrobenzyloxycarbo
Nylmethyl-2-azetidinone was obtained. [0285] IR^neat(cm^-1): 1760, 1695, 1600, 152
0, 1440, 1340, 1250, 1180, 950, 840, 740; NMR δ (CDCl_Three): 0.13 (9H, s), 3.04 (1H, dd, J = 2.3 and 7.6
Hz), 3.15 (1H, qd, J = 2.3 and 7.0Hz), 3.92 (1H, d, J = 18.0H
z), 4.38 (1H, d, J = 18.0Hz), 5.21 (2H, ABq, J = 13.5Hz), 8.
12 (2H, d, J = 8.9Hz). Reference Example 17-1 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethyloxyethyl] -4-[(1S) -1
-Phenylthiocarbonylethyl] -1-methoxycal
50 mg of bonylmethyl-2-azetidinone in dry hexa
Methyl phosphoric triamide-tetrahydrofuran
(1: 100) Dissolve in 0.6 ml of mixed solvent, and
Lithium bis (trimethylsilyl) amide 1M tetra
0.44 ml of a hydrofuran solution was added dropwise. Bring the reaction to room temperature
After the disappearance of the raw materials, the reaction solution was cooled with ice. To the reaction mixture
After adding a pH 6.86 phosphate buffer, diethyl ether is used.
Diluted. After liquid separation, the aqueous layer is further extracted twice with diethyl ether.
After extracting and combining with the organic layer of the destination, washing with saline 5 times,
Glauber's salt was dried. The solvent is distilled off, and the residue is chromatographed on silica gel.
Purified by chromatography (4S, 5R, 6S, 8R)-
4-methyl-6- (1-t-butyldimethylsilyloxy)
Ciethyl) -1-azabicyclo [3.2.0] hept-
3,7-dione-2-carboxylic acid methyl ester
Was. [0288] IR^CHCl3 (cm^-1): 1770, 1760, 1740, 143
5, 1245, 1120, 825; NMR δ (CDCl_Three): 0.10 (6H, s), 0.90 (9H, s), 1.27 (8H, s
d, J = 7.0Hz), 1.30 (3H, d, J = 6.2Hz), 2.29 (1H, m), 3.14 (1
H, dd, J = 1.5 and 5.7Hz), 3.77 (3H, s), 4.31 (1H, m), 4.71 (1
H, s). Reference Example 17-2 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethyloxyethyl] -4-[(1S) -1
-Phenylthiocarbonylethyl] -1- (1-methoxy
Dry 15 mg of (cycarbonylmethyl) -2-azetidinone
Dry hexamethylphosphoric triamide-tetrahydro
Dissolve in 0.2 ml of a mixed solvent of furan (1: 100) and add hydrogen
2.6 prepared from sodium iodide and dimethyl sulfoxide
M sodium methylsulfinyl methide / dimethyl sulf
0.05 ml of a hydroxide solution is added dropwise at −20 ° C. to −25 ° C.
Was. After stirring for 5 minutes, the temperature is raised to 0 to 5 ° C, and the temperature is raised to room temperature for 30 minutes.
For 20 minutes. Cool to 0-5 ° C again and add
After adding a pH 6.86 phosphate buffer, diethyl ether is used.
Diluted. After separation, the aqueous layer was further extracted once with diethyl ether.
Extract, combine with previous organic layer, 3 times with water, then brine
After drying with sodium sulfate, drying was performed. The solvent is distilled off and the residue is silica
Purify by gel chromatography (4S, 5R, 6
(S, 8R) -4-Methyl-6- (1-t-butyldimethylene)
Lucylyloxyethyl) -1-azabicyclo [3.2.
0] hept-3,7-dione-2-carboxylate
Got a steal. The IR and NMR of the compound obtained here are
It was the same as the compound obtained in Reference Example 17-1. Reference Example 17-3 Embedded image (3S, 4S) -3-[(1R) -1-t
-Butyldimethyloxyethyl] -4-[(1S) -1
-Phenylthiocarbonylethyl] -1-methoxycal
15 mg of bonylmethyl-2-azetidinone in dry hexa
Methyl phosphoric triamide-tetrahydrofuran
(1: 100) Dissolve in 0.2 ml of mixed solvent,
Add 15 mg of potassium t-butoxide and warm to room temperature
And stirred for 30 minutes. Re-cool the reaction to 0-5 ° C.
After adding a pH 6.86 phosphate buffer, diethyl ether is used.
Diluted. After separation, the aqueous layer was further extracted once with diethyl ether.
Extract, combine with the previous organic layer, twice with water, then brine
After drying with sodium sulfate, drying was performed. The solvent is distilled off and the residue is
Purified by Kagel chromatography (4S, 5R,
6S, 8R) -4-methyl-6- (1-tert-butyldim
Tylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-3,7-dione-2-carboxylic acid methyl
The ester was obtained. IR and NM of the compound obtained here
R was the same as the compound obtained in Reference Example 17-1.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-62-103084 (JP, A) West German Patent Application Publication 2949269 (DE, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 487/04 134 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] General formula (VI-2) Wherein, R ₁ and R ₂ may be the or different in the same, each represents a hydrogen atom or a lower alkyl group, R ⁰ ₃ is a lower alkyl group, R _"4 represents a carboxyl group or a thiol carboxyl group X 'represents a protected hydroxyl group, Y represents an oxygen atom or a sulfur atom, and B represents an alkali metal atom.] 2. R ₁ is a hydrogen atom R ₂ is a methyl group;
⁰ ₃ is a methyl group, R ″ ₄ is a carboxyl protecting group, X ′ is a protected hydroxyl group, Y is an oxygen atom, and B is a sodium, lithium or potassium atom. the compound according to claim 1. 3. formula ^(I-8 0) Wherein COZ ′ represents an active ester of a carboxyl group or an active acid anhydride, a thiol carboxyl group protected by a thiol carboxyl protecting group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; The symbols have the same meaning as in claim 1. By treating a compound represented by the formula (VI-) with a base containing an alkali metal atom.
2) ^{_{Wherein, R 1, R 2, R}} 0 3, R "4, X ', Y and B show. The description of the same tooth meaning of the claims 1] method for producing a β- lactam compound represented by the.