JP2000191679A - Carbapenem derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new carbapenem derivative useful as, e.g., an intermediate for synthesizing a carbapenem compound having antibacterial activity. SOLUTION: This new compound is expressed by formula I or II [wherein, R1 and R2 are each H or a (substituted) lower alkyl; R3 is H or a protective group for carboxyl; Y is a (substituted) aryloxy, a lower alkoxy or the like; Q is O or S], and is e.g. bis[(4R,5R,6S)-2-(p-nitrobenzyloxycarbonyl)-4- methyl-6-((R)-1-tert-butyldimethylsilyloxyethyl)-1-aza-7-oxobicyclo[3. 2.0]hept-2-en-3- yl]phenyl phosphate. The compound of formula I or II is obtained by reacting, e.g., a compound of formula III (wherein, Z is an organothio or the like) with a base, by trapping a residue expressed by the formula Z formed in the above reaction with an alkylating agent or an acylating one and then by reacting the residue with a compound of formula IV (wherein, X is a halogen) in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a carbapenem derivative which is an important intermediate for producing a carbapenem compound having an antibacterial activity, and a method for producing the same.

[0002]

2. Description of the Related Art JP-A-60-19787, JP-A-60-104088, and JP-A-3-2645.
No. 86 reports various carbapenem compounds having excellent antibacterial activity. As a method for producing the same, Japanese Patent Application Laid-Open No. 62-103084 or Hete
Cycles, Vol. 21, 29 (1984) is known.

[0003]

However, these methods require the use of relatively expensive or commercially available active esterifying agents, such as diphenyl chlorophosphate, for example. Also, Japanese Patent Application Laid-Open No. 3-153687 discloses an equation (10).

Embedded image Wherein one of R ⁵ or R ⁶ is hydrogen and another one of R ⁵ or R ⁶ is 1-hydroxyethyl,
R ⁷ represents a chloro-substituted phenyl group. ], A method for producing carbapenems via a carbapenem compound intermediate. However, bis (chloro-substituted phenyl) chlorophosphate used in this method is not easily available industrially. Further, these methods have different reactivities depending on the type of the thiol compound represented by the following general formula (8), and the yield is sometimes low. Therefore, a more excellent method is desired from the viewpoint of an industrial production method.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, from the compound represented by the following general formula (3) or (6), the general formula (1) )

Embedded image [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ is a protecting group for a hydrogen atom or a carboxy group, and Y is an optionally substituted i) aryloxy group, b)
A lower alkoxy group, c) a dialkylamino group, d) an arylamino group, or e) a diarylamino group. Or general formula (2)

[0005]

Embedded image [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ represents a hydrogen atom or a protecting group for a carboxy group, and Q represents an oxygen atom or a sulfur atom. And the compound represented by the general formula (8) HS-R ⁴ (8) wherein R ⁴ represents an organic group. When treated with a thiol compound represented by the general formula (9):

[0006]

Embedded image [Wherein, R ¹ , R ² , R ³ , and R ⁴ have the same meaning as described above. The substituted carbapenem derivative represented by
The inventors have found that they can be obtained in good yield, and have completed the present invention.

That is, the present invention firstly provides a carbapenem derivative represented by the general formula (1) or (2), and secondly, A) a general formula (3)

Embedded image [Wherein, R ¹ , R ² and R ³ have the same meanings as described above, and Z represents an organothio group, or COZ represents an active ester or active acid anhydride of a carboxy group. The compound represented by the general formula (4) Z ⁻ (4) produced by the reaction with a base, wherein Z has the same meaning as described above. And then trapping the residue represented by the formula (5) in the presence of a base in the general formula (5) X ₂ P (= O) Y (5) wherein X is a halogen atom. , And Y may be substituted i) aryloxy group, b) lower alkoxy group, c) dialkylamino group, d) arylamino group,
Or e) a diarylamino group. Or reacting with the compound represented by

B) or the general formula (6)

Embedded image Wherein R ¹ , R ² and R ³ have the same meaning as described above. A method for producing a carbapenem derivative represented by the general formula (1), wherein the compound represented by the general formula (5) is reacted with a compound represented by the general formula (5) in the presence of a base. A) reacting the compound represented by the general formula (3) with a base, and further trapping a residue represented by the general formula (4) formed by the reaction with an alkylating agent or an acylating agent; Then, in the presence of a base, general formula (7) X ₃ P = Q (7) wherein Q represents an oxygen atom or a sulfur atom, and X represents a halogen atom. Or B) or reacting the compound represented by the general formula (6) with the compound represented by the general formula (7) in the presence of a base. A method for producing a carbapenem derivative represented by the general formula (2),

Fourth, the carbapenem derivative represented by the general formula (1) or (2) is converted into a thiol compound represented by the general formula (8) or a thiol compound thereof in the presence of a base. General formula (9) characterized by reacting a salt with a base

Embedded image [Wherein, R ¹ , R ² , R ³ , and R ⁴ have the same meaning as described above. Fifth, a carbapenem represented by the general formula (1) or (2) from the compound represented by the general formula (3) or (6) by the method described above. The present invention relates to a method for producing a compound represented by the general formula (9), which comprises producing a derivative, and subsequently isolating the derivative without isolation.

Hereinafter, the present invention will be described in detail. R ¹
Examples of the lower alkyl group represented by are lower alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Examples of the substituent of the lower alkyl group which may be substituted include a halogen atom and a hydroxyl group.
Preferred R ¹ is a lower alkyl group such as an ethyl group or an isopropyl group, a halogenated lower alkyl group such as a 1-fluoroethyl group, or a hydroxy lower alkyl group such as a 1-hydroxyethyl group in which a hydroxyl group is protected or unprotected. And more preferably a 1-hydroxyethyl group in which the absolute configuration is R and the hydroxyl group is protected or unprotected. The protecting group for the hydroxyl group is not particularly limited as long as it is a commonly used protecting group. For example, trialkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group and tert-butyldimethylsilyl group; phenyl Dialkylarylsilyl groups such as dimethylsilyl group; alkyldiarylsilyl groups such as diphenylmethylsilyl group; triarylsilyl groups such as triphenylsilyl group; benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p- Arylalkoxycarbonyl groups such as methoxybenzyloxycarbonyl group; carbon atoms such as methoxycarbonyl group, tert-butoxycarbonyl group, 2-ethoxyethoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group. Number 1
6 lower alkoxycarbonyl groups; lower alkenyloxycarbonyl groups having 8 or less carbon atoms such as allyloxycarbonyl group and crotyloxycarbonyl group; or benzyl group, p-nitrobenzyl group, p-methoxybenzyl group And arylalkyl groups such as p-chlorobenzyl group, triphenylmethyl group and bis (p-methoxyphenyl) methyl group.

The lower alkyl group represented by R ^{2 includes} a lower alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Examples of the substituent of the lower alkyl group which may be substituted include a halogen atom or a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Preferred R ² is a hydrogen atom or a methyl group in β configuration.
The protecting group for the carboxy group represented by R ³ is not particularly limited as long as it is a commonly used protecting group.
Linear or branched lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, isopropyl and tert-butyl; carbons such as 2-ethyl iodide and 2,2,2-trichloroethyl A halogeno lower alkyl group having 1 to 6 atoms; a lower alkoxymethyl group having 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl, isopropoxymethyl; acetoxymethyl, propionyloxymethyl, butyryloxymethyl, C1-C6 lower aliphatic acyloxymethyl groups such as baroyloxymethyl; 1-methoxycarbonyloxyethyl,
A 1-lower alkoxycarbonyloxyethyl group having 8 or less carbon atoms such as ethoxycarbonyloxyethyl; allyl, 2-methylallyl, 3-methylallyl, 3
An optionally substituted lower alkenyl group having 1 to 6 carbon atoms such as phenylallyl; benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chloro Monoarylalkyl groups such as benzyl; diphenylmethyl, di-
diarylalkyl groups such as p-anisylmethyl; phenyl, p-chlorophenyl, 2,4,6-trichlorophenyl, p-nitrophenyl, o-nitrophenyl,
aryl groups such as p-methoxyphenyl; heteroaryl groups such as 2-pyridyl, 3-pyridyl and the like;

Examples of the aryloxy group include a phenyloxy group which is unsubstituted or substituted with a halogen atom, a nitro group, a lower alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. Specific examples include a phenyloxy group, a p-methoxyphenyloxy group, a p-chlorophenyloxy group, a p-methylphenyloxy group, and a 2,4,6-trimethylphenyloxy group. As the lower alkoxy group, one having 1 carbon atom
To 6 alkoxy groups, and more specifically, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and an n-hexyloxy group. Examples of the dialkylamino group include a dialkylamino group substituted with an alkyl group having 1 to 6 carbon atoms, and more specifically, a dimethylamino group and a diethylamino group. Examples of the arylamino group include an unsubstituted or N-phenylamino group substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Include an N-phenylamino group, an N- (p-chlorophenyl) amino group,
-(P-methoxyphenyl) amino group and N- (p-methylphenyl) amino group. Examples of the diarylamino group include an unsubstituted or halogen-substituted N, N-diphenylamino group. More specifically, an N, N-diphenylamino group, an N, N-di (p-
(Chlorophenyl) amino group and the like. Examples of the organothio group represented by Z include a phenylthio group, a p-chlorophenylthio group, a 2,4,6-trichlorophenylthio group, a p-nitrophenylthio group, an o-nitrophenylthio group, and a p-methoxyphenylthio group. Or unsubstituted or halogen atom, nitro group, or 1 carbon atom
An arylthio group substituted with up to 6 alkoxy groups; 2
Heteroarylthio groups such as -pyridylthio group, 3-pyridylthio group, 4-pyridylthio group, 2-pyrimidylthio group, 2- (4,6-dimethyl) pyrimidylthio group; methylthio group, ethylthio group, isopropylthio group, te
a lower alkylthio group having 1 to 6 carbon atoms such as an rt-butylthio group; an ethylthio iodide group, a 2,2,2
A halogeno lower alkylthio group having 1 to 6 carbon atoms optionally substituted with a halogen atom such as chlorine, bromine or iodine, such as a trichloroethylthio group; an allylthio group, a 2-methylallylthio group, A halogen atom such as chlorine or bromine, a lower alkyl group such as methyl or ethyl, or a lower alkenylthio group optionally substituted with an aryl group such as phenyl, such as a chloroallylthio group or a cinnamylthio group. .

When Z is COZ, which means an active ester or active acid anhydride of a carboxy group, Z is a halogen atom such as chlorine, bromine or iodine; ethoxycarbonyloxy, isopropoxycarbonyloxy, sec-butoxy. A lower alkoxycarbonyloxy group having 2 to 7 carbon atoms such as carbonyloxy; a lower alkanesulfonyloxy group having 1 to 6 carbon atoms such as methanesulfonyloxy; an arylsulfonyloxy group such as p-toluenesulfonyloxy Di (lower alkyl) phosphoryloxy groups such as dimethylphosphoryloxy group; diarylphosphoryloxy groups such as diphenylphosphoryloxy; cyclic imidooxy groups such as N-succinimidooxy and N-phthalimidooxy; Heterocycloalkyl groups such as 2-thioxo-3-thiazolidinyl; heteroaryl group such as azole, and the like. Examples of the halogen atom represented by X include a chlorine atom or a bromine atom, and a chlorine atom is preferable.

The organic group represented by R ⁴ is not particularly limited as long as it is stably present.
Methyl group, ethyl group, isopropyl group, n-butyl group,
N-benzoyl-2-aminoethyl group, N- (p-nitrobenzyloxycarbonyl) -2-aminoethyl group,
An optionally substituted lower alkyl group, lower alkenyl group or lower alkynyl group such as 2-propenyl group, 3-pentenyl group or 4-hexynyl group; cyclopentyl group, 6-cyclohexylhexyl group, 5-cyclopentyl- Optionally substituted cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl such as 3-pentenyl, 6-ethoxy-3-hexynyl; phenyl, p-
An optionally substituted aryl group such as a chlorophenyl group, a p-chlorobenzyl group, a cinnamyl group, a 6-phenyl-4-hexynyl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group; a 2-pyridyl group,
One to four heterocyclic moieties, such as 3- (3-pyridyl) -propyl, N-benzyloxycarbonyl-3-pyrrolidinyl, N- (p-nitrobenzyloxycarbonyl) -3-piperidinyl, A heteroaryl group, including a heteroatom selected from oxygen, nitrogen, or sulfur atom, which may be substituted, a heteroarylalkyl group, a heteroarylalkenyl group, a heteroarylalkynyl group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclylalkenyl group, And a substituent in the above-mentioned group is a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an amino group, a mono- or dialkylamino group, a trialkylammonium group, a hydroxy group, a carboxy group. Group, Merka Group, alkylthio group, arylthio group such as phenylthio group, sulfoxyl group, sulfamoyl group, amidino group, guanidino group, nitro group, halogen atom, hydroxyl group, cyano group, nitro group, alkylsulfinyl group, alkylsulfonyl group, carbamoyl group, A carbamoyl group substituted with one or two lower alkyl groups as needed, and a lower alkyl group substituted with the above substituents;

Further, the compounds represented by the general formula (8) include thiol compounds represented by the following general formulas (11a) and (11b).

Embedded image [Wherein, R ⁸ represents a tert-butyloxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group,
Methoxybenzyloxycarbonyl group, benzyl group, p
And R ⁹ and R ¹⁰ independently represent (a) a hydrogen atom; (b) a methyl group, an ethyl group, a 2-methoxyethyl group,
-(N, N-dimethylaminocarbonyl) -propyl group, allyl group, lower alkyl group having 1 to 6 carbon atoms which may be substituted, such as 3-pentynyl group, lower alkenyl group, lower alkynyl group; c) an optionally substituted cycloalkyl group such as a cyclopentyl group, a 6-cyclohexylhexyl group, a 6-cyclohexyl-3-methoxyhexyl group, a cycloalkylalkyl group, a cycloalkylalkenyl group, a cycloalkylalkynyl group; optionally substituted aryl groups such as p-chlorophenyl group and p-methoxyphenylpropyl group, or arylalkyl groups, arylalkenyl groups, arylalkynyl groups; (e) 2-pyridyl group, 3- (3-pyridyl) propyl Group, such as a 3- (4-methyl-3-pyridyl) propyl group Are also heteroaryl groups or heteroarylalkyl group, the heteroaryl alkenyl group, heteroarylalkynyl group; one or shown, or, in R ⁹ and R ¹⁰ 1
-Azetidino group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2-methoxyethyl) -1-piperazinyl group, 4-methyl-
An alkylene chain bonded to each other, such as a 1,4-diaza-1-cycloheptyl group and a 5- (2-methoxyethyl) -1,5-diazacyclooctyl group, or an oxygen atom, a sulfur atom, or a substituted nitrogen A 4- to 8-membered ring with an adjacent nitrogen atom representing an alkylene chain through the atom,
It means a cyclic amino group which may be substituted.

W ¹ is an oxygen atom, a sulfur atom, or NH
In it, ^{W 2} is a nitrogen atom or a carbon atom,, ^{W 2}
Is n = 0 when n is a nitrogen atom, n = 1 when W ² is a carbon atom
It is. R ¹¹ and R ¹² each independently represent: (a) a hydrogen atom; (b) a methyl group, an ethyl group, a 2-methoxyethyl group,
-(N, N-dimethylaminocarbonol) -propyl group, allyl group, lower alkyl group having 1 to 6 carbon atoms which may be substituted such as 3-butynyl group, lower alkenyl group, lower alkynyl group; c) cyclohexyl group, cyclohex-1-cene-1-
An optionally substituted cycloalkyl group or cycloalkenyl group such as an yl group; (d) an optionally substituted cycloalkyl group such as a phenyl group, a phenylmethyl group, a 2-phenylvinyl group or a 4-phenyl-2-butynyl group; Aryl group, arylalkyl group, arylalkenyl group, arylalkynyl group; (e) 2-pyridyl group, 2-pyrazinylmethyl group, 2-
(3-pyridyl) -vinyl group, 5- (4-pyridyl)-
Heteroaryl group such as 3-pentynyl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group; (f) dimethylamino group, 1-allyloxycarbonyl-4-piperazinyl group, 1-allyloxycarbonyl-
An optionally substituted amino group such as a 1,2,5,6-tetrahydropyridin-4-yl group, a cyclic amino group having a 3- to 8-membered ring; (g) a 2-oxotetrahydrofuran-3-yl group, 3
An optionally substituted 3- to 8-membered cyclic lactone group or cyclic lactam group such as an aza-2-oxocyclopentyl group; (h) a hydroxyl group; (i) a methoxy group, an allyloxy group, a 2-butynyloxy group, or a phenoxy group A lower alkyloxy group having 1 to 6 carbon atoms, a lower alkenyloxy group, a lower alkynyloxy group, an aryloxy group, a heteroaryloxy group, which may be substituted, such as a 2-pyridyloxy group; An optionally substituted alkylthio group, an arylthio group, a heteroarylthio group such as a phenylthio group or a 2-pyridylthio group;

(K) an optionally substituted carbamoyl group such as an N, N-dimethylcarbamoyl group; (1) a carboxyl group; (m) an ethyloxycarbonyl group, an allyloxycarbonyl group, a 2-propynyloxycarbonyl group, A phenyloxycarbonyl group, an optionally substituted lower alkoxycarbonyl group such as a 4-pyridyloxycarbonyl group, a lower alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, an aryloxycarbonyl group,
Heteroaryloxycarbonyl group; (n) ethyloxycarbonyloxy group, allyloxycarbonyloxy basis, 2-propynyloxycarbonyloxy group, phenyloxycarbonyloxy group, 4-
A lower alkoxycarbonyloxy group which may be substituted, such as a pyridyloxycarbonyloxy group, a lower alkenyloxycarbonyloxy group, a lower alkynyloxycarbonyloxy group, an aryloxycarbonyloxy group, a heteroaryloxycarbonyloxy group; (o) halogen (P) nitro group; (q) cyano group; (r) alkylsulfonyl group such as methanesulfonyl group and phenylsulfonyl group, arylsulfonyl group; (s) alkylsulfinyl group such as ethanesulfinyl group and phenylsulfinyl group group, an arylsulfinyl group, one or shown, or, a cyclohexene ring in R ¹¹ and R ^12, a benzene ring, dihydropyridine ring, an imidazole ring, an oxazole ring, a furan ring, a thiazole ring, Isoo A methylene chain, a methine chain, a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, or a 4- to 8-membered optionally substituted cycloalkenyl group, cycloaryl group, hetero atom It means a cycloalkenyl group or a heterocycloaryl group.

The substituents in the above-mentioned groups include a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
Amino group, mono- and dialkylamino group, trialkylammonium group, hydroxyl group, carboxyl group,
Alkylthio group, arylthio group such as phenylthio group, sulfamoyl group, amidino group, guanidino group, nitro group, halogen atom, hydroxyl group, cyano group, nitro group,
An alkylsulfinyl group, an alkylsulfonyl group, a carbamoyl group, a carbamoyl group optionally substituted with one or two lower alkyl groups, and a lower alkyl group substituted with the above substituents; . When the thiol compound represented by the general formula (8) forms a salt with a base, examples of the salt with the base include alkali metal salts such as a lithium salt, a sodium salt, and a potassium salt.

The carbapenem derivative represented by the general formula (1) or (2) and the substituted carbapenem derivative represented by the general formula (9) include a carbapenem moiety at the 4-position, 5-position,
And stereoisomers based on the asymmetric carbon at the 6-position, all of which are conveniently represented by a single formula,
Of course, the present invention includes all of these isomers. However, as a suitable intermediate for the carbapenem compound, a lower alkyl group which may be substituted at the 4-position is β-coordinate, a hydrogen atom at the 5-position is α-coordination, and Is a compound in which a hydrogen atom is β-coordinate.

Hereinafter, the compounds (1) and (2) of the present invention
And the method for producing the substituted carbapenem derivative represented by the general formula (9) from the compound (1) or (2) will be described in detail. (1) Step 1

Embedded image

[Wherein R ¹ , R ² , R ³ , Z, Y and Q have the same meanings as above, B represents an alkali metal atom, and RA represents an alkylating agent or an acylating agent. Show. The compound (1) or the compound (2) is obtained in Step 1- (i)
In step 1), the compound (3) is reacted with a base, and if necessary, the residue represented by the general formula (4) in the reaction solution is captured. Then, in step 1- (ii), the compound is reacted in the presence of a base. (5) or in step 1- (ii)
In i), it can be produced by reacting with compound (7) in the presence of a base. Step 1- (i), 1
-(Ii) or step 1- (iii) can be performed in a similar manner, and will be described together. Step 1-
The reaction (i), (ii) or (iii) includes, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, acetonitrile, Conventional solvents that do not adversely affect the reaction, such as aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, and sulfolane, or a mixed solvent thereof And so on. The reaction temperature is not particularly limited, but is usually performed under cooling or at room temperature. Preferably -78
It is carried out between 10 ° C and 10 ° C.

The base used in step 1- (i) includes, for example, metal salts of amines such as lithium isopropylamide, lithium bis (trimethylsilyl) amide and sodium amide; and hydrogenation such as sodium hydride and potassium hydride. Examples thereof include metal salts of amines such as alkali metals, sodium methylsulfinyl methide, and sodium amide. These bases are desirably used in an amount sufficient for the reaction to proceed sufficiently, and an appropriate amount can be said to be 1.5 to 3 equivalents to compound (3).

As the scavenger (RA) for the residue represented by the general formula (4) in the reaction solution, which is added in step 1- (i),
Examples include alkylating agents such as iodomethane, iodopropane, allyl bromide, benzyl bromide, and methyl ester of p-toluenesulfonic acid, and acylating agents such as p-toluenesulfonyl chloride and methanesulfonyl chloride. These scavengers are desirably used in such an amount that the reaction proceeds sufficiently.
It can be said to be 8 to 1.5 equivalents. Although the reaction can be carried out without adding these scavengers, it is usually preferable to add them. These scavengers may be added to the reaction solution before the base is added, or may be added after the base is added. The compound (5) added in the step 1- (ii) is desirably used in such an amount that the reaction proceeds sufficiently.
It can be said to be 8 equivalents. The compound (7) to be added in the step 1- (iii) is desirably used in such an amount that the reaction proceeds sufficiently.
It can be said that it is 2 to 0.6 equivalent. The compound (1) or (2) obtained in the step 1 can be isolated and purified by a usual organic chemical technique, but usually the compound (1) or (2) needs to be isolated. And it is preferable to use it as is without separation or purification.

(2) Step 2 and Step 3

Embedded image [Wherein, R ¹ , R ² , R ³ , Y and Q have the same meaning as described above. Compound (1) or compound (2) can be produced by reacting compound (6) with compound (5) or compound (7) in the presence of a base. Step 2 or step 3 can be performed in a similar manner, and will be described together. Examples of the solvent used in the step 2 or the step 3 include ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether; methylene chloride; chloroform;
Halogenated hydrocarbons such as dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric trioxide The reaction can be carried out using a non-protonic polar solvent such as amide and sulfolane, a common solvent that does not adversely affect the reaction such as an acetate ester such as ethyl acetate, or a mixed solvent thereof. The reaction temperature is not particularly limited, but is usually performed under cooling or at room temperature. It is preferably carried out between -78 ° C and 10 ° C.

The base used in step 2 or 3 includes trialkylamines such as triethylamine and diisopropylethylamine, pyridine compounds such as pyridine, lutidine, picoline and 4-dimethylaminopyridine, quinoline, imidazole and N-methylpyrrolidine. , 1,5-diazabicyclo [4.3.0] non-5-
Ene (DBN), 1,4-diazabicyclo [2.2.
2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the like. These bases are desirably used in an amount sufficient for the reaction to proceed sufficiently, and an appropriate amount can be said to be 0.8 to 2 equivalents to compound (6).
The compound (5) or the compound (7) added in the step 2 or the step 3 is desirably used in such an amount that the reaction proceeds sufficiently, and an appropriate amount of the compound (5) or the compound (7) is 0.4) to 0.8
Equivalent, that is, 0.2 to 0.6 equivalent. Step 2
Alternatively, compound (1) or (2) obtained in step 3
Can be isolated and purified by ordinary organic chemistry techniques, but usually it is not necessary to isolate compound (1) or (2), and the compound can be used as is without separation or purification. preferable.

(3) Step 4 and Step 5

Embedded image [Wherein, R ¹ , R ² , R ³ , R ⁴ , Y, and Q have the same meaning as described above. Compound (9) can be produced by reacting compound (1) or compound (2) with compound (8) in the presence of a base. Step 4 or step 5 can be performed in a similar manner, and will be described together. Examples of the solvent used in step 4 or 5 include ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, benzene, Aromatic hydrocarbons such as toluene, xylene and chlorobenzene, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, and sulfolane; The reaction can be carried out using a common solvent that does not adversely affect the reaction, such as an acetate ester such as ethyl acetate, or a mixed solvent thereof. The reaction temperature is not particularly limited, but is usually performed under cooling or at room temperature. Preferably, it is carried out at a temperature between -50 ° C and 20 ° C. Step 4 or Step 5 can be performed subsequently to Step 1, Step 2 or Step 3, in which case Step 1 or Step 2
Alternatively, the reaction can be carried out in the solvent used in step 3, or if necessary, any of the above-mentioned solvents may be added.

The base used in step 4 or 5 includes trialkylamines such as triethylamine and diisopropylethylamine, pyridine compounds such as pyridine, lutidine, picoline and 4-dimethylaminopyridine, quinoline, imidazole and N-methylpyrrolidine. , 1,5-diazabicyclo [4.3.0] non-5-
Ene (DBN), 1,4-diazabicyclo [2.2.
2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the like. When Step 4 or Step 5 is performed subsequently to Step 2 or Step 3, the base used at that time may be the same as or different from the base used in Step 2 or Step 3. The base added in Step 4 or Step 5 is desirably used in such an amount that the reaction sufficiently proceeds. In Step 4 or Step 5, respectively, an appropriate amount is determined based on Compound (1) or Compound (2), respectively. 1.8-4 equivalents, 2.7-6
Equivalents are preferred.

Compound added in step 4 or step 5
For (8), use an amount that allows the reaction to proceed sufficiently.
Desirably, an appropriate amount is used in step 4 or step 5, respectively.
Where, for compound (1) or compound (2),
1.6 to 3 equivalents, 2.4 to 4.5 equivalents are preferred, respectively.
No. Compound (9) obtained in Step 4 or Step 5 is
Can be isolated and purified by ordinary organic chemical techniques
Or the next reaction without separation or purification
It is also possible to use it. The above steps 1, 2, 3,
In general formula (3) or general formula (4) or (5)
R in (6)² May be substituted with lower alkyl
If it is a group ² Of the asymmetric carbon to which
Carbapenem derivative (1) or
(2) or a substituted carbapenem derivative (9) is obtained.
It is.

The compound represented by the general formula (1), specifically, for example, bis [(4R, 5R, 6) is obtained by the method of Step 1- (i), 1- (ii) or the method of Step 2.
S) -2-Allyloxycarbonyl-4-methyl-6
((R) -1-trimethylsilyloxyethyl) -1-
Aza-7-oxobicyclo [3.2.0] hept-2-
En-3-yl] phenyl phosphate; bis [(5R, 6S) -2-allyloxycarbonyl-6-
((R) -1-trimethylsilyloxyethyl) -1-
Aza-7-oxobicyclo [3.2.0] hept-2-
En-3-yl] phenyl phosphate; bis [(4R, 5R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-aza-7 -Oxobicyclo [3.
2.0] Hept-2-en-3-yl] p-methoxyphenyl phosphate; bis [(4R, 5R, 6S)
-2-allyloxycarbonyl-4-methyl-6-
((R) -1-trimethylsilyloxyethyl) -1-
Aza-7-oxobicyclo [3.2.0] hept-2-
[En-3-yl] N, N-dimethyl phosphoramidate;

Bis [(4R, 5R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2. 0] Hept-2-en-3-yl]
N-phenyl phosphoramidate; bis [(4R, 5
(R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-trimethylsilyloxyethyl)
-1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] N- (p-chlorophenyl)
Phosphoramidate; bis [(4R, 5R, 6S) -2
-(P-nitrobenzyloxycarbonyl) -4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2 -En-3-yl] phenyl phosphate; bis [(5R, 6S) -2- (p-
Nitrobenzyloxycarbonyl) -6-((R) -1
-Tert-butyldimethylsilyloxyethyl) -1
-Aza-7-oxobicyclo [3.2.0] hept-2
-En-3-yl] phenyl phosphate; bis [(4R, 5R, 6S) -2- (p-nitrobenzyloxycarbonyl) -4-methyl-6-((R) -1-t
tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] p-methoxyphenylphosphe-
G; bis [(4R, 5R, 6S) -2- (p-nitrobenzyloxycarbonyl) -4-methyl-6-((R)
-1-trimethylsilyloxyethyl) -1-aza-7
-Oxobicyclo [3.2.0] hept-2-ene-3
-Yl] phenyl phosphate; bis [(4R, 5
(R, 6S) -2-benzyloxycarbonyl-4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept- 2-en-3-yl] phenyl phosphate; bis [(4R, 5R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1
-Tert-butyldimethylsilyloxyethyl) -1
-Aza-7-oxobicyclo [3.2.0] hept-2
-En-3-yl] phenyl phosphate; bis [(4R, 5R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-hydroxyethyl)
-1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] phenyl phosphate; bis [(4R, 5R, 6S) -2- (p-nitrobenzyloxycarbonyl)- 4-methyl-6-((R) -1-
Hydroxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] phenyl phosphate; bis [(4R, 5R, 6S) -2-
Allyloxycarbonyl-4-methyl-6-((R)-
1-trimethylsilyloxyethyl) -1-aza-7-
Oxobicyclo [3.2.0] hept-2-en-3-
Yl] methyl phosphate; bis [(4R, 5R,
6S) -2- (p-nitrobenzyloxycarbonyl)
-4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.
2.0] Hept-2-en-3-yl] methyl phosphate; bis [(4R, 5R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-hydroxyethyl)- 1-aza-7-oxobicyclo [3.
2.0] Hept-2-en-3-yl] methyl phosphate; bis [(4R, 5R, 6S) -2- (p-nitrobenzyloxycarbonyl) -4-methyl-6-
((R) -1-hydroxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] methyl phosphate;

The compound represented by formula (2), specifically, for example, tris [(4R, 5R,
6S) -2-Allyloxycarbonyl-4-methyl-6
-((R) -1-trimethylsilyloxyethyl) -1
-Aza-7-oxobicyclo [3.2.0] hept-2
-En-3-yl] phosphate; tris [(5R,
6S) -2-allyloxycarbonyl-6-((R)-
1-trimethylsilyloxyethyl) -1-aza-7-
Oxobicyclo [3.2.0] hept-2-en-3-
Yl] phosphate; tris [(4R, 5R, 6S)
-3- [2- (p-nitrobenzyloxycarbonyl)
-4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl]
Phosphate; Tris [(5R, 6S) -2- (p-nitrobenzyloxycarbonyl) -6-((R) -1-
tert-butyldimethylsilyloxyethyl) -1-
Aza-7-oxobicyclo [3.2.0] hept-2-
En-3-yl] phosphate; tris [(4R, 5
(R, 6S) -2-benzyloxycarbonyl-4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept- 2-en-3-yl] phosphate; tris [(4R, 5R, 6S) -2- (p-nitrobenzyloxycarbonyl) -4-methyl-6-
((R) -1-trimethylsilyloxyethyl) -1-
Aza-7-oxobicyclo [3.2.0] hept-2-
[En-3-yl] phosphate;

Tris [(4R, 5R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-
tert-butyldimethylsilyloxyethyl) -1-
Aza-7-oxobicyclo [3.2.0] hept-2-
En-3-yl] phosphate; tris [(4R, 5
(R, 6S) -2-allyloxycarbonyl-4-methyl-6-((R) -1-trimethylsilyloxyethyl)
-1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] thiophosphate; tris [(5R, 6S) -2- (p-nitrobenzyloxycarbonyl) -6 -((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] thiophosphate; tris [(4R , 5R, 6S) -2-
Allyloxycarbonyl-4-methyl-6-((R)-
1-hydroxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] phosphate; tris [(4R, 5R, 6S) -2- (p-
Nitrobenzyloxycarbonyl) -4-methyl-6-
((R) -1-hydroxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] phosphate; tris [(4R, 5R, 6S)-
2-allyloxycarbonyl-4-methyl-6-
((R) -1-hydroxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] thiophosphate; tris [(4R, 5R, 6
S) -2- (p-Nitrobenzyloxycarbonyl)-
4-methyl-6-((R) -1-hydroxyethyl)-
1-aza-7-oxobicyclo [3.2.0] hept-
2-en-3-yl] thiophosphate;

According to the method of the above step 4 or step 5,
The compound represented by the general formula (9), specifically, for example, allyl (4R, 5S, 6S) -3-[(2S, 4S)-
1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyridinylthio] -4-methyl-6
((R) -1-trimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate; benzyl (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyridinylthio] -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.
0] hept-2-en-7-one-2-carboxylate; allyl (4R, 5S, 6S) -3-[(2S, 4
S) -1- (p-Nitrobenzyloxycarbonyl)-
2-dimethylaminocarbonyl-4-pyridinylthio]
-4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate; allyl (4R, 5S, 6S) -3-[(2S, 4S) -1-
Benzyloxycarbonyl-2-dimethylaminocarbonyl-4-pyridinylthio] -4-methyl-6
((R) -1-trimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate; allyl (4R, 5S, 6
S) -3-[(2S, 4S) -1-allyloxycarbonyl) -2- (1-pyrrolidinylcarbonyl) -4-pyridinylthio] -4-methyl-6-((R) -1-trimethylsilyloxy Ethyl) -1-azabicyclo [3.
2.0] hept-2-en-7-one-2-carboxylate; allyl (4R, 5S, 6S) -3-[(2
(S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (1-pyrrolidinylcarbonyl) -4-pyridinylthio] -4-methyl-6-((R) -1-trimethylsilyloxyl)- 1-azabicyclo [3.2.
0] hept-2-en-7-one-2-carboxylate;

Allyl (4R, 5S, 6S) -3-
[(2S, 4S) -1-allyloxycarbonyl-2-
(4-Methyl-1-piperazinylcarbonyl) -4-pyrrolidinylthio] -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept- 2-en-7-one-2-carboxylate; p-nitrobenzyl (4R, 5S, 6
S) -3- (N-Benzyloxycarbonyl-2-aminoethylthio) -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] hept-2-en-7-one-2-carboxylate; allyl (4R, 5S, 6S) -3- [N-
(P-nitrobenzyloxycarbonyl) -2-aminoethylthio] -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] hept-2-en-7-one-2-carboxylate; allyl (5S, 6S) -3-[(2S, 4
S) -1-Allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyridinylthio] -6-((R)-
1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate; allyl (5S, 6S) -3- [N-
(P-Nitrobenzyloxycarbonyl) -2-aminoethylthio] -methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.
0] Hept-2-en-7-one-2-carboxylate; p-nitrobenzyl (4R, 5S, 6S) -3-
[(2S, 4S) -1- [2-hydroxy-3- (te
rt-butyldimethylsilyloxy) benzoyl] -2
-(N, N-dimethylaminocarbonyl) -4-pyrrolidinylthio] -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] hept-2-en-7-one-2-carboxylate; allyl (4R, 5S, 6S) -3-[(2
S, 4S) -1- [4,5-bis (allyloxy) -2
-Pyridylmethyl] -2- (N, N-dimethylaminocarbonyl) -4-pyrrolidinylthio] -4-methyl-6
-((R) -1-trimethylsilyloxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylate; p-nitrobenzyl
(4R, 5S, 6S) -3-[(2S, 4S) -1-
(P-nitrobenzyloxycarbonyl) -2- [4,
5-bis (allyloxy) -2-pyridylcarbonylaminomethyl] -4-pyrrolidinylthio] -4-methyl-
6-((R) -1-trimethylsilyloxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-One-2-carboxylate; allyl (4R, 5
S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyridinylthio] -4-methyl-6-((R) -1-hydroxyethyl) -1- Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate p-nitrobenzyl (4R, 5S, 6S) -3-
[(2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2-dimethylaminocarbonyl-4-pyridinylthio] -4-methyl-6-((R) -1-hydroxyethyl) -1-azabicyclo [ 3.2.0] Hept-2-en-7-one-2-carboxylate p-nitrobenzyl (4R, 5S, 6S) -3- (4-methylthiazol-2-ylthio) -4-methyl-6-
((R) -1-trimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate p-nitrobenzyl (4R, 5S, 6S) -3- (4
-Phenyloxazol-2-ylthio) -4-methyl-6-((R) -1-trimethylsilyloxyethyl)
-1-Azabicyclo [3.2.0] hept-2-ene-
7-one-2-carboxylate allyl (4R, 5S, 6S) -3- (benzothiazol-2-ylthio) -4-methyl-6-((R) -1-
Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate allyl (4R, 5S, 6S) -3- (benzoxazol-2-ylthio) -4- Methyl-6-((R) -1
-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate is obtained.

[0035]

Industrial Applicability According to the present invention, it has become possible to industrially produce a carbapenem derivative which is an important intermediate in producing a substituted carbapenem derivative known to have excellent antibacterial activity.

[0036]

Next, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is of course not limited to these examples. Abbreviations in the formulas indicate the following. Example 1 TBS tert-butyldimethylsilyl group PNB p-nitrobenzyl group TMS trimethylsilyl group PMB p-methoxybenzyl group

Embedded image

(I) (3S, 4S) -3-[(R)-
1-tert-butyldimethylsilyloxyethyl]-
A mixed solvent of 4-[(R) -1- (p-chlorophenylthiocarbonyl) ethyl] -1- (p-nitrobenzyloxycarbonylmethyl) -2-azetidinone (311 mg) in toluene-tetrahydrofuran (4: 1) ( 2m
l) and dissolved in 60% sodium hydride (oil-based) (54
mg), benzyl bromide (111 mg), trimethylsilanol (2 mg), and a mixed solvent (2 ml) of toluene-tetrahydrofuran (4: 1).
At -10 ° C to phenyldichlorophosphate (6 ° C).
3 mg) was added. After stirring for further 4 hours, a 0.1 M aqueous solution of potassium dihydrogen phosphate (10 ml) was added to the reaction mixture.
And extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with a 0.1 M phosphate buffer (pH 7.0), dried over magnesium sulfate-potassium carbonate (1: 1), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, and bis [(4R, 5R, 6
S) -2- (p-Nitrobenzyloxycarbonyl)-
4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] phenylphospho- I got it. IR (KBr): 1786, 1731, 1525, 14
37,1216,1190 cm ^-1 . NMR (CDCl ₃ ) δ: 0.06 (6H × 1/2,
s), 0.07 (6H × 1/2, s), 0.08
(6H × 1/2, s), 0.09 (6H × 1/2,
s), 0.85 (18H x 1/2, s), 0.86
(18H × 1/2, s), 1.16 (6H × 1/2,
d, J = 7.3 Hz), 1.22 (6H × 1/2,
d, J = 5.9 Hz), 1.23 (6H × 1/2,
d, J = 6.3 Hz), 1.28 (6H × 1/2, d,
J = 7.3 Hz), 3.31 (2H, m), 3.4
8 (2H, m), 4.25 (4H, m), 5.19
(1H, d, J = 14.0 Hz), 5.33 (2H × 1
/ 2, d, J = 14.0 Hz), 5.37 (2H × 1 /
2, d, J = 14.0 Hz), 7.21-7.26
(3H, m), 7.31-7.37 (2H, m),
7.58 (4H × 1/2, d, J = 8.9 Hz),
7.59 (4H × 1/2, d, J = 8.9 Hz),
8.16 (4H × 1/2, d, J = 8.9 Hz),
8.17 (4H × 1/2, d, J = 8.9 Hz).

(Ii) Bis [(4R, 5R, 6S)-
2- (p-nitrobenzyloxycarbonyl) -4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept- 2-en-3-yl] phenyl phosphate (109 mg) was treated with acetonitrile (1
ml), and N-benzoyl-2-aminoethanethiol (36 mg) was added at -15 ° C to -10 ° C.
Then, diisopropylethylamine (39 mg) was added, and the mixture was stirred at -15 ° C to -10 ° C overnight. A 0.1 M aqueous solution of potassium dihydrogen phosphate (5 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (5 ml). The organic layers were combined, washed with a 0.1 M phosphate buffer of pH 7.0, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, and p-nitrobenzyl (4R, 5S, 6S) -3-
(N-benzoyl-2-aminoethylthio 1-4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-ene- 7-one-2-carboxylate IR (KBr): 1773, 1654, 1524 cm
^-1 . NMR (CDCl ₃ ) δ: 0.05 (3H, s),
0.06 (3H, s), 0.85 (9H, s),
1.22 (3H, d, J = 6.7 Hz), 1.23
(3H, d, J = 7.3 Hz), 4.16 (1H, d
d, J = 2.6, 9.6 Hz), 4.24 (1H,
m), 5.24 (1H, d, J = 13.9 Hz),
5.45 (1H, d, J = 13.9 Hz), 6.61
(1H, br, s), 7.40-7.55 (3H,
m), 7.65 (2H, d, J = 8.9 Hz), 7.
73-7.76 (2H, m), 8.20 (2H, d,
J = 8.9 Hz).

Embodiment 2

Embedded image

(I) (3S, 4S) -3-((R)-
1-tert-butyldimethylsilyloxyethyl)-
A mixed solvent of 4-[(R) -1- (p-chlorophenylthiocarbonyl) ethyl] -1- (p-nitrobenzyloxycarbonylmethyl) -2-azetidinone (311 mg) in toluene-tetrahydrofuran (4: 1) ( 2m
l) and dissolved in 60% sodium hydride (oil-based) (54
mg), benzyl bromide (111 mg), trimethylsilanol (2 mg), and a mixed solvent (2 ml) of toluene-tetrahydrofuran (4: 1).
C. to -10.degree. C., methyl dichlorophosphate (3
5 mg) was added. After stirring for further 4 hours, a 0.1 M aqueous solution of potassium dihydrogen phosphate (10 ml) was added to the reaction mixture.
And extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with a 0.1 M phosphate buffer (pH 7.0), dried over magnesium sulfate-potassium carbonate (1: 1), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, and bis [(4R, 5R, 6
S) -2- (p-Nitrobenzyloxycarbonyl)-
4-methyl-6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept-2-en-3-yl] methylphospho- I got it. IR (neat): 1772, 1734, 1521, 1
347 cm ^-1 . NMR (CDCl ₃ ) δ: 0.08 (12H, s),
0.85 (18H, s), 1.25 (12H,
m), 3.31 (2H, m), 3.50 (2H,
m), 4.00 (3H, d, J = 11.9 Hz),
4.25 (4H, m), 5.22 (2H, d, J = 1
3.7Hz), 5.43 (2H, d, J = 13.7H)
z), 7.62 (4H, d, J = 8.9 Hz),
8.20 (4H, d, J = 8.9 Hz).

(Ii) Screw [(4R, 5R, 6S)-
2- (p-nitrobenzyloxycarbonyl) -4-methyl-6-((1R) -1-tert-butyldimethylsilyloxyethyl) -1-aza-7-oxobicyclo [3.2.0] hept- 2-en-3-yl] methyl phosphate (103 mg) was added to acetonitrile (1 m
l), and at -15 ° C to -10 ° C, N-benzoyl-2-aminoethanethiol (36 mg) was added, followed by diisopropylethylamine (39 mg).
The mixture was stirred at -15 ° C to -10 ° C overnight. A 0.1 M aqueous solution of potassium dihydrogen phosphate (5 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (5 ml). The organic layers were combined, washed with a 0.1 M phosphate buffer of pH 7.0, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography,
Nitrobenzyl (4R, 5S, 6S) -3- (N-benzoyl-2-aminoethylthio) -4-methyl-6
((R) -1-tert-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2
-En-7-one-2-carboxylate was obtained.

Embodiment 3

Embedded image

(3S, 4S) -3-((R) -1-trimethylsilyloxyethyl) -4-[(R) -1- (p
-Chlorophenylthiocarbonyl) ethyl] -1- (p
-Nitrobenzyloxycarbonylmethyl) -2-azetidinone (579 mg) was dissolved in a mixed solvent (3 ml) of toluene-tetrahydrofuran (4: 1), and 60% sodium hydride (oil-based) (108 mg), benzyl bromide (222 mg) were dissolved. , Trimethylsilanol (3 mg) and a mixed solvent of toluene-tetrahydrofuran (4: 1) (3
ml) at −15 ° C. to −10 ° C.
After stirring for an hour, p-chlorophenyl dichlorophosphate (147 mg) was added at the same temperature. After stirring for another 4 hours, N-benzoyl-2-aminoethanethiol (181 mg) in acetonitrile (6 ml)
Solution and then diisopropylethylamine (19
4 mg), and the mixture was stirred at -15 ° C to -10 ° C overnight. A 0.1 M aqueous solution of potassium dihydrogen phosphate (10 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with a 0.1 M phosphate buffer of pH 7.0, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain p-nitrobenzyl (4R, 5S,
6S) -3- (N-benzoyl-2-aminoethylthio) -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-ene -7-one-2-carboxylate was obtained. IR (KBr): 1773, 1524, 1344 cm
^-1 . NMR (CDCl ₃ ) δ: 0.11 (9H, s),
1.23 (3H, d, J = 7.3 Hz), 1.24
(3H, d, J = 5.9 Hz), 4.11 (1H, d
d, J = 2.6, 9.6 Hz), 4.21 (1H,
m), 5.24 (1H, d, J = 13.9 Hz),
5.47 (1H, d, J = 13.9 Hz), 7, 40
−7.55 (3H, m), 7.65 (2H, d, J =
8.7 Hz), 7.73-7.77 (2H, m),
8.20 (2H, d, J = 8.7 Hz).

Embodiment 4

Embedded image In Example 3, p-nitrobenzyl (4R, 5S, 6S) -3 was obtained by using p-chloroanilide phosphoryl dichloride (126 mg) instead of p-chlorophenyl dichlorophosphate (147 mg).
-(N-benzoyl-2-aminoethylthio) -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one -2-carboxylate was obtained.

Embodiment 5

Embedded image In Example 3, phosphorous oxychloride (6 mg) was used instead of p-chlorophenyl dichlorophosphate (147 mg).
1 mg) to give p-nitrobenzyl
(4R, 5S, 6S) -3- (N-benzoyl-2-aminoethylthio) -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] Hept-2-en-7-one-2-carboxylate was obtained.

Embodiment 6

Embedded image In Example 3, p-nitrobenzyl (4R, 5S, 6S) -3- (N-benzoyl-2-aminoethyl) was obtained by using thiophosphoryl chloride (68 mg) instead of p-chlorophenyl dichlorophosphate (147 mg). Thio) -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate was obtained.

Embodiment 7

Embedded image (3S, 4S) -3-((R) -1-trimethylsilyloxyethyl) -4-[(R) -1- (p-chlorophenylthiocarbonyl) ethyl] -1- (allyloxycarbonylmethyl) -2- Azetidinone (484 mg) was dissolved in a mixed solvent (3 ml) of toluene-tetrahydrofuran (4: 1), and 60% sodium hydride (oil-based) was dissolved.
(108 mg), benzyl bromide (222 mg), trimethylsilanol (3 mg), and a suspension in a mixed solvent (3 ml) of toluene-tetrahydrofuran (4: 1).
After dropwise addition at 5 ° C to -10 ° C and stirring for 2 hours, phenyl dichlorophosphate (127 m
g) was added. After stirring for another 4 hours, (2S, 4
S) -1-Allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (258 m
g) in tetrahydrofuran (2 ml) was added, followed by 1,8-diazabicyclo [5.4.0] undec-7.
-Ene (228 mg) was added, and the mixture was stirred at -15 ° C to -10 ° C overnight. A 0.1 M aqueous solution of potassium dihydrogen phosphate (10 ml) was added to the reaction mixture, and ethyl acetate (10 m
Extracted twice in l). Combine the organic layers, 0.1M, pH
After washing with a phosphate buffer of 7.0 and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, and allyl (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyrrolidinylthio] -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1 -Azabicyclo [3.2.
0] Hept-2-en-7-one-2-carboxylate was obtained. IR (neat): 1770, 1705, 1655, 1
405, 1320, 1210, 1135, 980, 84
0 cm ^-1 .

Embodiment 8

Embedded image (3S, 4S) -3-((R) -1-trimethylsilyloxyethyl) -4-[(R) -1- (p-chlorophenylthiocarbonyl) ethyl] -1- (allyloxycarbonylmethyl) -2- Azetidinone (484 mg) was dissolved in a mixed solvent (3 ml) of toluene-tetrahydrofuran (4: 1), and 60% sodium hydride (oil-based) was dissolved.
(108 mg), benzyl bromide (222 mg), trimethylsilanol (3 mg), and a suspension in a mixed solvent (3 ml) of toluene-tetrahydrofuran (4: 1).
After dropwise addition at 5 ° C to -10 ° C and stirring for 2 hours, phenyl dichlorophosphate (127 m
g) was added. After stirring for another 4 hours, (2S, 4
S) -1-Allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (258 m
g) in acetonitrile (6 ml) was added, followed by diisopropylethylamine (194 mg).
Stirred at 5 ° C to -10 ° C overnight. Allyl (4R, 5S, 6S) -3-[(2
[S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyrrolidinylthio] -4-methyl-6-((R) -1-trimethylsilyloxyethyl) -1-azabicyclo [3.2. 0] Hept-2-en-7-one-2-carboxylate was obtained.

Example 9 In Example 8, N, N- was used instead of acetonitrile.
By using dimethylformamide, allyl
(4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-pyrrolidinylthio] -4-methyl-6-((R)
-1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
The carboxylate was obtained. Example 10

Embedded image

P-methoxybenzyl (5R, 6S)-
6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] -hept-3,7-dione-2-carboxylate (448m
g) was dissolved in acetonitrile (5 ml), diisopropylethylamine (194 mg) was added at −15 ° C. to −10 ° C. under a nitrogen stream, phenyldichlorophosphate (127 mg) was added, and the mixture was stirred at the same temperature for 2 hours, and then stirred. , N-benzoyl-2-aminoethanethiol (163 mg) and then diisopropylethylamine (194 mg) were added.
Stirred at night. A 0.1 M aqueous solution of potassium dihydrogen phosphate (10 ml) was added to the reaction mixture, and ethyl acetate (10 m
Extracted twice in l). Combine the organic layers, 0.1M, pH
After washing with a phosphate buffer of 7.0 and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give p-methoxybenzyl.
(5S, 6S) -3- (N-benzoyl-2-aminoethylthio) -6-((R) -1-tert-butyldimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate was obtained. IR (KBr): 3376, 1778, 1697 cm
^-1 . NMR (CDCl ₃ ) δ: 0.04 (3H, s),
0.05 (3H, s), 0.85 (9H, s),
1.20 (3H, d, J = 6.3 Hz), 3.78
(3H, s), 4.10 (1H, dd, J = 2.8,
9.7 Hz), 4.17 (1 H, m), 5.20 (2
H, s), 6.67 (1H, br s), 6.85
(2H, d, J = 8.6 Hz), 7.35-7.52
(5H, m), 7.75 (2H, d, J = 8.6H)
z).

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Takashi Bando 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. F-term (reference) 4C050 KA08 KA11 KB02 KB03 KB05 KB13 KB16 KC03 KC07 4H050 AA01 AA02 AB84 AC20 BA92 BD70 BE54 WA15 WA23

Claims (8)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ is a protecting group for a hydrogen atom or a carboxy group, and Y is an optionally substituted i) aryloxy group, b)
A lower alkoxy group, c) a dialkylamino group, d) an arylamino group, or e) a diarylamino group. And a carbapenem derivative represented by the formula: 2. A compound of the general formula (2) [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ represents a hydrogen atom or a protecting group for a carboxy group, and Q represents an oxygen atom or a sulfur atom. And a carbapenem derivative represented by the formula: 3. A) General formula (3) [Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group which may be substituted,
³ represents a hydrogen atom or a protecting group for a carboxy group, and Z represents an organothio group, or COZ means an active ester or an active acid anhydride of a carboxy group. The compound represented by the general formula (4) Z ⁻ (4) produced by the reaction with a base, wherein Z has the same meaning as described above. Is trapped with an alkylating agent or an acylating agent, and then, in the presence of a base, a compound represented by the general formula (5): Wherein X is a halogen atom, and Y is an optionally substituted a) aryloxy group, b) lower alkoxy group, c) dialkylamino group, d) arylamino group,
Or e) a diarylamino group. Or B) a compound represented by the following general formula (6): Wherein R ¹ , R ² and R ³ have the same meaning as described above. Wherein the compound represented by the general formula (1) is reacted with the compound represented by the general formula (5) in the presence of a base. Wherein R ¹ , R ² , R ³ and Y have the same meaning as described above. ] The method for producing a carbapenem derivative represented by the formula: 4. A) General formula (3) [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ represents a hydrogen atom or a protecting group for a carboxy group, and Z represents an organothio group, or COZ means an active ester or an active acid anhydride of a carboxy group. The compound represented by the general formula (4) Z ⁻ (4) produced by the reaction with a base, wherein Z has the same meaning as described above. And then trapping with an alkylating agent or an acylating agent, and then in the presence of a base, X ₃ P = Q (7) wherein Q represents an oxygen atom or a sulfur atom. , X represents a halogen atom. Or reacting with the compound represented by
Or B) General formula (6) Wherein R ¹ , R ² and R ³ have the same meaning as described above. Wherein the compound represented by the general formula (7) is reacted with a compound represented by the general formula (7) in the presence of a base. Wherein R ¹ , R ² , R ³ and Q have the same meaning as described above. ] The method for producing a carbapenem derivative represented by the formula: 5. A compound of the general formula (1) [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ is a protecting group for a hydrogen atom or a carboxy group, and Y is an optionally substituted i) aryloxy group, b)
A lower alkoxy group, c) a dialkylamino group, d) an arylamino group, or e) a diarylamino group. A carbapenem derivative represented by the general formula (8) HS-R ⁴ (8) wherein R ⁴ represents an organic group. Or a salt of the thiol compound represented by the general formula (9) with a base. [Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. ] The method for producing a substituted carbapenem derivative represented by the formula: 6. A compound of the general formula (2) [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ represents a hydrogen atom or a protecting group for a carboxy group, and Q represents an oxygen atom or a sulfur atom. A carbapenem derivative represented by the general formula (8) HS-R ⁴ (8) wherein R ⁴ represents an organic group. Wherein the thiol compound represented by the general formula (9) is reacted with a salt of the thiol compound and a base. [Wherein, R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted lower alkyl group,
³ a hydrogen atom or a protecting group for a carboxy group, R ⁴
Represents an organic group. ] The method for producing a substituted carbapenem derivative represented by the formula: 7. The compound represented by the general formula (1) produced by the method according to claim 3 without isolation.
6. The method according to claim 5, wherein the subsequent step is performed in the same reaction vessel. 8. The compound represented by the general formula (2) produced by the method according to claim 4, without isolation.
7. The method according to claim 6, wherein the subsequent step is performed in the same reaction vessel.