JP2620533B2 - New amino acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel amino acid derivative,
In particular, the present invention relates to a novel amino acid derivative used as a synthetic intermediate of a 1-alkylcarbapenem compound useful as an antibacterial agent.

[0002]

2. Description of the Related Art Thienamycin having useful activity as an antibacterial agent [US Pat. No. 3,950,357; J. Am. Chem.
Soc., 100, 313 (1978)] was discovered from nature, and since it was reported, methods for obtaining various carbapenem compounds in a purely synthetic manner have been reported. Recently, compounds in which the methylene group at the 1-position of the carbapenem skeleton has been substituted with an alkyl group have been synthesized, and in particular, 1-methylcarbapenem compounds [Hetero
cycles, 21, 29 (1984)] are superior to conventional 1-position unsubstituted carbapenem compounds in terms of in vivo stability and the like, and are reported to be extremely useful as antibacterial agents. Accordingly, much attention has been paid to the development of an effective method for producing a 1-alkylcarbapenem compound.

[0003]

The problem to be solved by the present invention is as follows.
As a result of various studies on an effective method for producing an alkylcarbapenem compound, they have found that a certain amino acid derivative is an important intermediate for producing a 1-alkylcarbapenem compound, and completed the present invention.

[0004]

[Means for solving the problems]

 1) Target substance The present invention has the general formula:

Embedded image [Wherein, R represents a lower alkyl group, R ₁ represents a hydrogen atom or a carboxyl group protecting group, R ₂ represents a hydrogen atom, an amino group protecting group,

Embedded image (Wherein, R ₃ and R ₄ may be the same or different from each other and represent a hydrogen atom, a lower alkyl group or an aryl group.) A substituted or unsubstituted allyl group or a hydroxyl group represented by A certain β-hydroxyethyl group, a formylmethyl group in which a formyl group is protected or unprotected, a carboxylmethyl group in which a carboxyl group is protected or a 2-furylmethyl group, and X represents a protected or unprotected carboxyl group or hydroxyl group Represents a protected or unprotected hydroxymethyl group or a substituent represented by the formula —CH ₂ SR ₅ (2), wherein R ₅ represents an aryl group or an ara (lower) alkyl group. ] The present invention provides a novel amino acid derivative represented by the formula:

In the present specification, the term "lower" used particularly in connection with the above general formula (I) generally means a group having no more than 8 carbon atoms, especially a group having no more than 6 carbon atoms, especially It shall represent no more than 4 groups. Thus, for example, "lower alkyl" includes methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, t-butyl and the like are included, and "lower alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and the like, and "lower alkanoyl" Includes acetyl, propionyl, butyryl and the like. Also, the term "halogen" is commonly used to generically mean chlorine, bromine, iodine and fluorine. In addition, the term “aryl” generally means an aromatic hydrocarbon group having no more than 20 carbon atoms, and includes phenyl, naphthyl, anthranyl and the like. When the aryl group is substituted, examples of the substituent include lower alkyl, lower alkoxy, nitro, amino, halogen and the like.

As for the method of protecting functional groups such as carboxyl group, amino group, hydroxyl group and formyl group, see "Protective Group in Organic Synthesis" 1.
981 John Willy and Sons
& Sons) New York, New Experimental Chemistry Lecture, Vol. 14, "Synthesis and Reaction of Organic Compounds [V]", page 2595, etc. (1973). The method described above may be employed in the present invention.

Examples of the carboxyl-protecting group include lower alkyl groups such as C ₁ -C ₄ alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc.); C substituted with ~ 3 halogens
₁ -C ₄ alkyl (2-ethyl iodide, 2,2,2-trichloroethyl, etc.) halo (lower) alkyl groups such as, C ₁ -C
₄ alkoxymethyl (methoxymethyl, ethoxymethyl,
Lower alkoxymethyl group such as isobutoxymethyl), C ₁ -C ₄ alkoxycarbonyloxyethyl (1-
Lower alkoxycarbonyloxyethyl groups such as methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, etc., C ₂ -C ₇ alkanoyloxymethyl
(Acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, etc.) a lower alkanoyloxymethyl group such as a substituted or unsubstituted C ₃ -C ₆ allyl (allyl, 2-methylallyl, 3-methylallyl, Substituted or unsubstituted lower alkenyl groups such as cinnamyl), substituted or unsubstituted phenylmethyl (benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl, etc. )), Substituted or unsubstituted diarylmethyl groups such as substituted or unsubstituted diphenylmethyl (diphenylmethyl, di-p-anisylmethyl, etc.), substituted or unsubstituted phenyl (phenyl, p- Nitrophenyl, p-chlorophenyl, 2,6-dimethylphenyl, etc.) Una substituted or unsubstituted aryl group, and the like.

The protecting group for the amino group includes, for example, C _1-
C ₅ alkoxycarbonyl-lower alkoxycarbonyl groups such as (t-butyloxycarbonyl, etc.), C ₁ substituted with 1-3 halogens -C ₃ alkoxycarbonyl (2
Halo (lower) alkoxycarbonyl groups such as ethoxycarbonyl iodide, 2,2,2-trichloroethoxycarbonyl and the like, substituted or unsubstituted phenylmethoxycarbonyl (benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitro Substituted or unsubstituted arylmethoxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc., substituted or unsubstituted phenylmethyl (benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, substituted or unsubstituted arylmethyl groups such as p-nitrobenzyl), substituted or unsubstituted diphenylmethyl
Substituted or unsubstituted diarylmethyl groups such as (diphenylmethyl, di-p-anisylmethyl, etc.), α-C ₁ -C ₄
Α-lower alkyl-benzyl groups such as alkyl-benzyl (α-methyl-benzyl, α-ethyl-benzyl, etc.), trityl group, substituted phenyl (p-methoxyphenyl,
2,4-dimethoxyphenyl, o-nitrophenyl, p-
Substituted aryl groups such as nitrophenyl, 2,4-dinitrophenyl, etc .; tri (lower) alkylsilyl groups such as tri (C ₁ -C ₄ ) alkylsilyl (trimethylsilyl, t-butyldimethylsilyl, etc.); Substituted lower alkyl groups such as methyl (methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, etc.), tetrahydropyranyl groups and the like can be mentioned.

Examples of the hydroxyl-protecting group include C ₁ -C ₄
Lower alkyl groups such as alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc.), substituted methyl or ethyl (methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, t-butoxymethyl, methylthiomethyl, 2,2,2
-Substituted lower alkyl groups such as -trichloroethoxymethyl, 1-methyl-1-methoxyethyl, trichloroethyl, etc., tetrahydropyranyl groups, substituted or unsubstituted monophenylmethyl, diphenylmethyl or triphenylmethyl (benzyl, p- Substituted or unsubstituted monoaryl (lower) alkyl, diaryl such as methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl, diphenylmethyl, triphenylmethyl, etc.
(Lower) alkyl or triaryl (lower) alkyl groups,
Substituted silyl groups (trimethylsilyl, triethylsilyl, t
- butyldimethylsilyl, t- butyl diphenyl silyl or the like), formyl group, C ₂ -C ₅ alkanoyl (acetyl, isobutyryl, lower alkanoyl group such as pivaloyl), C ₂ -C substituted with 1-3 halogens ₅ alkanoyl (dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.) halo (lower) alkanoyl group such as an aryl carbonyl group (benzoyl, toluoyl, naphthoyl, etc.), C ₁ -C ₅ alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, lower alkoxycarbonyl groups such as isobutoxycarbonyl, etc.), C substituted with 1-3 halogens ₁ -C ₅ alkoxycarbonyl (2
- iodide ethoxycarbonyl, 2,2,2-trichloro-halo (lower) alkoxycarbonyl groups such as ethoxycarbonyl, etc.), C ₂ -C ₆ alkenyloxycarbonyl (vinyloxycarbonyl, lower, such as allyloxycarbonyl, etc.) Alkenyloxycarbonyl group, substituted or unsubstituted phenylmethyloxycarbonyl (benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.) Such substituted or unsubstituted arylmethyloxycarbonyl groups can be exemplified.

Specific examples of protected formyl groups include
(C ₁ -C ₄₎ alkoxymethyl (dimethoxymethyl, diethoxymethyl, di -n- propyloxymethyl, etc.) di like (lower) alkoxymethyl group, a di (halo (lower) alkoxy) methyl group (di ( Trichloroethoxy) methyl), di
(Aryloxy) methyl group (such as dibenzyloxymethyl), formula:

Embedded image [In the formula, Y represents an oxygen atom or a sulfur atom, and n represents 2 or 3. And the like.

Particularly preferred among the amino acid derivatives represented by the general formula (I) are compounds in which R is a methyl group. More preferred are compounds in which R is a methyl group and R ₂ is a benzyl group, a 2-propenyl group, a 2-furylmethyl group or a 2,2-dimethoxyethyl group.

The amino acid derivative (I) has four asymmetric carbon atoms, and various optical isomers and stereoisomers are present based on these. In the present specification, these isomers are represented by a single formula for convenience, but they all belong to the technical scope of the present invention regardless of whether they are in an isolated state or in a mixture. It must be understood to be included.

2) Production of the target substance The amino acid derivative (I) which is the target substance of the present invention has, for example, the formula:

Embedded image [Wherein, R, R ₁ , R ₂ and X have the same meaning as described above. ] Can be produced by reducing the compound represented by the formula: The reduction can be performed by various methods, for example, a catalytic hydrogenation reaction using a catalyst such as platinum, palladium, or nickel, a reduction reaction using an alkali metal such as lithium or sodium in liquid ammonia or lower alkylamine, and a hydrogen reaction. Aluminum hydride, organotin hydride (triethyltin hydride, tri-n-butyltin hydride, triphenyltin hydride, etc.), hydrosilane
Reduction reactions using metal hydrides such as (trimethylsilane, triethylsilane, diethylsilane, etc.), borane (diborane, 9-borabicyclo [3,3,1] nonane, dibenzoyloxyborane, monochloroborane, dichloroborane, Reduction reaction using catechol borane, dicyclohexyl borane, etc., reduction reaction using metal hydride complex compound (lithium aluminum hydride, sodium borohydride, sodium borohydride, lithium cyanoborohydride, sodium acetoxyborohydride, etc.) You can use it. The reduction may be performed by a single method, or may be performed in two stages by combining different reduction methods. Among the preferred reduction methods, representative specific examples are as follows.

Reduction method (A): Compound (II) is dissolved in a solvent such as acetic acid, propionic acid, ethanol, methanol or the like in a mineral acid (hydrochloric acid, sulfuric acid, etc.) or a carboxylic acid.
(Acetic acid, propionic acid, tartaric acid, oxalic acid, etc.) in the presence of an acid such as sodium cyanoborohydride, sodium borohydride, by treating with a reducing agent such as sodium acetoxyborohydride, compound (I) Get. The amount of the reducing agent to be used is preferably 2 to 5 equivalents relative to compound (II). The reaction can be suppressed or promoted by cooling or heating as appropriate, but it is usually desirable to carry out the reaction at -40 ° C to 80 ° C. In the present reduction method, it is particularly preferable to act sodium borohydride or sodium cyanoborohydride in acetic acid or propionic acid.

Reduction method (B):-Compound (II) is first treated with borane in an inert solvent,
Next, after treating with a reducing agent such as a metal hydride complex compound (sodium cyanoborohydride, sodium borohydride, etc.), compound (I) is obtained by solvolysis. The borane used in the present reduction method is diborane, 9-
Borabicyclo [3,3,1] nonane, dibenzoyloxyborane, monochloroborane, dichloroborane, catecholborane and the like can be selected, and catecholborane is particularly preferred. Boranes are usually 1 to compound (II).
Use 2.5 equivalents. As the inert solvent used in the treatment with borane, ethers (tetrahydrofuran, diethyl ether, dioxane, glyme, etc.),
Halogenated hydrocarbons (such as chloroform and dichloromethane) and aromatic hydrocarbons (such as benzene and toluene) can be mentioned. The reaction is preferably performed at a temperature in the range of -100 ° C to room temperature. The following treatment with a reducing agent such as a metal hydride complex is performed in an inert solvent (acetic acid, propionic acid, ether, tetrahydrofuran, chloroform, etc.) in the presence of an acid (acetic acid, propionic acid, oxalic acid, hydrochloric acid, sulfuric acid, etc.). Can be done. The amount of reducing agent used depends on the compound (I
1 to 3 equivalents to I) are preferred. The reaction is usually -40 to 8
It is performed in the range of 0 ° C. The solvolysis can be performed in a solvent (water, methanol, etc.) in the presence of a base (sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, etc.) at a temperature of 0 to 40 ° C.

In the above-mentioned reduction methods (A) and (B), stereoisomers of R represented by the following formula and their enantiomers, ie, a total of four isomers are preferentially used. Produces:

Embedded image [Wherein, R, R ₁ , R ₂ and X have the same meaning as described above. ].

The production ratio of the isomers varies depending on the reaction conditions, the reaction substrate and the like, but by appropriately selecting them, a mixture of the stereoisomer (Ia) and its enantiomer can be obtained as the main product. When this stereoisomer (Ia) is derived into a 1-alkylcarbapenem derivative, 1β represented by the following formula is obtained.
-Industrially preferred in providing alkyl carbapenem derivatives:

Embedded image [Wherein, R and R ₁ have the same meaning as described above. R ₆ represents a hydrogen atom or a protecting group for a hydroxyl group, and Z represents an organic group. ].

3) Utilization of Target Substance The amino acid derivative (I) of the present invention is useful as an intermediate for producing a 1-alkylcarbapenem compound having an antibacterial activity. it can:

Embedded image Wherein R, R ₂ and X have the same meaning as described above. ]. Step (i):-

The compound (I) is derivatized to a compound (IV) by subjecting it to a usual carboxyl group deprotection reaction. When X is a protected carboxyl group, that is, the compound (I
In the case of c), Tetrahedron Letters
Letters), 21, 2783-2786 (1980); 22, 913-916 (198
The compound (IV ′) can be derived as follows according to the method described in 1):

Embedded image Wherein R, R ₁ and R ₂ have the same meaning as described above.
R ′ ₁ and R ″ ₁ represent a protecting group for a carboxyl group.]

The above-mentioned conversion step (1) is a lactonization reaction, and the compound (Ic) is converted into a halogenated hydrocarbon (methylene chloride, chloroform, dichloroethane, etc.), an aromatic hydrocarbon (benzene, toluene, etc.), ether ( (Tetrahydrofuran, dioxane, etc.) or a mixed solvent thereof with hydrogen chloride or hydrogen bromide.

When a mixture of the two isomers (Ia) and (Ib) is used, the isomer (Ia) can be selectively induced into the compound (Va) as shown below. The latter is 1β-
It is possible to derive alkyl carbapenem compounds:

Embedded image [Wherein, R, R ₁ , R ₂ and R ′ ₁ have the same meaning as described above. The conversion step (2) is for converting the lactone compound (V) into the compound (IV ′) according to the method described in the above-mentioned literature. Although the lactone compound (V) contains various stereoisomers, the following description will be given using the lactone compound (Va) as an example for convenience.

[0022]

Embedded image [Wherein, R, R ₁ , R ₂ and R ″ ₁ have the same meanings as described above.] In the compound (Va), the lactone ring is selectively subjected to alkaline hydrolysis to lead to the compound (Id). To R ₁
After protecting the carboxy group in at the carboxyl protecting group R _"1, which are not affected in the removal reaction of the protecting group of the carboxyl group represented, it can lead to the compound by subjecting to removal reaction of the R ₁ (IV'a) Examples of the reagent used for the alkaline hydrolysis include an aqueous barium hydroxide solution,
Examples include an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, and an aqueous solution of tetrabutylammonium hydroxide, and an aqueous solution of barium hydroxide is particularly preferable. Any reaction solvent can be used as long as it can be used for ordinary alkali hydrolysis. Preferred examples include tetrahydrofuran, acetone, methanol, pyridine or a mixture of these with water. The reaction can be suppressed or promoted by appropriately cooling or heating, but is preferably performed at 0 to 70 ° C.
The carboxyl group protection reaction and deprotection reaction may be performed by a commonly used method.

[0023]

Embedded image [Wherein, R, R ₁ and R ″ ₁ have the same meaning as described above.
R _'2 represents a protecting group for an amino group. The compound (IV'b) in which the amino group is unprotected can be obtained from the compound (Vb) by subjecting it to a hydrolysis reaction of an ester group, a removal reaction of an amino group-protecting group, and a cleavage reaction of a lactone ring. it can. For example, the protecting group for the carboxyl group is a lower alkyl group, and the protecting group for the amino group is an arylmethyl group.
In the case of (benzyl group or the like), the ester group is selectively hydrolyzed by treating the compound (Vb) with a mineral acid (hydrochloric acid or the like) to lead to the compound (Vc). This is then subjected to a hydrogenolysis reaction in the presence of a catalyst such as palladium hydroxide-carbon to remove amino-protecting groups. Next, the compound (Vd) obtained here was subjected to an alcoholysis reaction of a lactone ring using an alcohol (such as benzyl alcohol) to give a compound (IV ′).
get b).

[0024]

Embedded image [Wherein, R, R ₁ , R ₂ and R ″ ₁ have the same meanings as described above.] The compound (IV ′) in which the steric configuration of the hydroxyl group of the compound (IV′a) is inverted.
c) leads from compound (Id) to lactone (Ve) by Mitsunobu reaction using, for example, diethylazodicarboxylate and triphenylphosphine, after which the above (a) and
The compound (IV'c) can be derived by the method described in (b). Organic base as reaction aid in Mitsunobu reaction
(Ve) by adding (e.g., triethylamine)
Can be promoted.

The compound (I) in which X is a protected carboxyl group, that is, the compound (Ic) can be selectively induced to the compound (Id) by alkaline hydrolysis. Examples of the reagent used for the selective alkaline hydrolysis include barium hydroxide aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, calcium hydroxide aqueous solution, tetrabutylammonium hydroxide aqueous solution, and the like. In particular, barium hydroxide aqueous solution The use of is preferred. Any reaction solvent can be used as long as it can be used for ordinary alkaline hydrolysis,
Preferable ones include tetrahydrofuran, acetone, methanol, pyridine or a mixture of these organic solvents and water. The reaction can be suppressed or promoted by appropriately cooling or heating,
Preferably, the reaction temperature is 0 to 70 ° C.

The above operation is performed according to the Journal of American Chemical Society (J. Am. Chem. Soc. 103, 2405-
2406 (1981) and Tetrahedron Letters
Letters), 21, 2783-2786 (1980); 22, 913-916 (198
What is necessary is just to refer to the description of 1).

Step (ii):-Compound (IV) is subjected to a dehydration ring closure reaction to give compound (V)
Get I). This dehydration and closing reaction is carried out, for example, by reacting compound (IV) in an inert solvent in the presence or absence of a base with a dehydrating agent (2,
Dipyridyl disulfide-triphenylphosphine, dicyclohexylcarbodiimide, etc.).

Step (iii):-Compound (VII) is obtained by protecting the hydroxyl group of compound (VI) as necessary and applying appropriate means depending on the type of the substituent represented by X. . The protection of the hydroxyl group of compound (VI), which is carried out as desired, may be carried out by a conventional method. When X is a protected carboxyl group, the protecting group is eliminated by applying conventional means such as hydrolysis, hydrogenation, acid treatment and the like to obtain compound (VII). When X is a protected hydroxymethyl group, the protecting group is removed by a conventional method, and a known oxidation method such as chromic acid oxidation (Journal of American Chemical Society (J .Am.Chem.
Soc.), 105, 1659-1660 (1983)).
Get. When X is a substituent of the formula (2), an alkyl halide such as methyl iodide is allowed to act thereon to form a halogenomethyl group, which is converted into a hydroxymethyl group by a known method. Compound (VII) in the same manner
[Tetrahedron Letters
s), 5787-5788 (1968)].

[0029] The (iv) Step: - the compound (VII), obtained the R compounds by applying an appropriate means according to the _two kinds of (III). Compound (VII) in which R ₂ is a hydrogen atom is a known substance.
It is used as a raw material of methyl or 1-alkylcarbapenem derivatives [Heterocycles
s), 21, 29-40 (1984); Tetrahedron Letters (Tet
rahedron Letters), 26, 587-590 (1985)].

When R ₂ is a protecting group, the protecting group is removed by a known elimination method such as hydrogenation, oxidation, acid treatment or the like, depending on the type of the protecting group.

When R ₂ is a substituent of the formula (1), the compound
(VIII) The conversion reaction was carried out as follows, for example, according to the method described in Japanese Patent Application No. 60-123117, and the compound
Get (X):

Embedded image [Wherein, R, R ₁ , R ₃ , R ₄ and R ₆ have the same meaning as described above. Ph represents a phenyl group. ]

That is, in the conversion step (a), the compound (VIII) is subjected to ozone oxidation, followed by treatment with an oxidizing agent (such as metachloroperbenzoic acid) and the presence of a phase transfer catalyst (such as a crown ether or a quaternary ammonium compound). The compound (IX) is converted by applying a known method such as oxidation with potassium permanganate in the absence or absence of the compound.

Next, in the conversion step (b), the compound (IX)
The compound (X) is obtained by applying a known method such as a carboxyl group protection reaction, a deprotection reaction, and a thiophenol acylation reaction.

A compound wherein R ₂ is a 2-furimethyl group, that is, a compound represented by the formula:

Embedded image [Wherein, R, R ₁ and R ₆ have the same meaning as described above. ] Can be led to compound (X) in the same manner as described above.

When R ₂ is a protected or unprotected β-hydroxyethyl group, if the hydroxyl group is protected, the protecting group is removed by a known method to convert it to a β-hydroxyethyl group. A compound (IX) is obtained by a method of converting a hydroxymethyl group into a carboxyl group such as acid oxidation, and this is derived into a compound (X) in the same manner as described above.

When R ₂ is a protected formylmethyl group, the protecting group is removed by a known method to form a formylmethyl group, and the formyl group is converted to a carboxyl group such as by oxidation of chromic acid. To give a compound (IX), which is derived into a compound (X) in the same manner as described above.

When R ₂ is a protected carboxylmethyl group, the carboxyl-protecting group is removed by a known method to obtain a compound (IX), and the compound (X) is derived in the same manner as described above. .

The compound (X) can be prepared, for example, by the method described in Japanese Patent Application No. 60-290.
No. 480, by the following route:
Conversion to a 1-methyl or 1-alkylcarbapenem derivative is possible.

Embedded image [Wherein, R ₁ and Ph have the same meanings as described above. R ' ₆
Represents a hydroxyl-protecting group. ]

In the conversion step (c), the compound (Xa) is treated with a base (sodium diisopropylamide, sodium diisopropylamide) in an inert solvent such as an ether (such as tetrahydrofuran), an aromatic hydrocarbon (such as toluene) or a mixture thereof. Compound (XI) is obtained by treatment with sodium hydride or the like.

In the conversion step (d), the compound (XI) is reacted with diphenylphosphoryl chloride in an inert solvent (such as acetonitrile) in the presence of a base (such as diisopropylethylamine) to obtain a compound (XII). This compound (XII) can be further derived into various 1-methylcarbapenem compounds by a known method.

As described above, the amino acid derivative (I) has optical isomers based on asymmetric carbon atoms, and these optical isomers and their mixtures (racemates) are all within the technical scope of the present invention. Included, but particularly preferred are compounds of formula (Ia), which have the formula:

Embedded image [Wherein, Z has the same meaning as described above. Which is advantageous for the synthesis of the optically active 1β-methylcarbapenem compound represented by the formula:

The optically active 1β-methylcarbapenem compound (IIIa) can be optically resolved by using the carboxyl group or amino group of the intermediate in the compound (VII) or in each intermediate derived from the amino acid derivative (I) to the compound (VII). It is also possible to obtain by doing.

For example, (3S,
A mixture of the (4S) isomer and the (3R, 4R) isomer and an optically active amine are mixed in an inert solvent to form a salt of the compound (VII) with the optically active amine, and then fractionated and crystallized as it is Alternatively, after crystallization, the crystals are collected, dissolved in an inert solvent, fractionated and crystallized, and the generated crystals are separated by filtration to obtain an optically active amine salt of the (3S, 4S) isomer.
The (3R, 4R) isomer can be separated from the optically active amine salt. (3S, 4S) isomer of compound (VII) or
When the optically active amine salt of the (3R, 4R) isomer is hydrolyzed using an acid or an alkali, the (3S, 4S) of the compound (I) is obtained.
Isomers or (3R, 4R) isomers can be obtained.

Examples of the above-mentioned optically active amine include α
-Phenethylamine, α-naphthylmethylamine, norephedrine, cinchonine, cinchonidine, quinine,
Quinidine, 1- (2-naphthyl) ethylamine, brucine, 1,1-diphenyl-2-aminopropanol, 1
-Phenyl-2-p-tolylethylamine. Particularly, cinchonine, cinchonidine, quinine, quinidine and the like are preferable.

Examples of the inert solvent for performing salt formation or fractional crystallization include hydrocarbons (pentane, hexane, cyclohexane, etc.) and aromatic hydrocarbons (benzene, benzene, etc.).
Toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.),
Ethers (diethyl ether, tetrahydrofuran,
Dioxane), alcohols (methanol, ethanol, isopropanol, etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.), ketones (acetone,
Methyl ethyl ketone), water or mixtures thereof. Suitable solvents may include isopropanol, ethyl acetate, acetone or mixtures thereof.

The salt is formed by dissolving the mixture of isomers of the compound (VII) and the optically active amine in an inert solvent under heating if necessary. Heating can be performed until the mixture of isomers and the optically active amine are dissolved within the range up to the reflux temperature of the solvent used.

The solution containing the mixture of diastereomeric salts obtained in this way is cooled, preferably gradually cooled to allow fractional crystallization, or the solution is cooled,
One diastereomer salt can be separated by fractional crystallization of the crystals obtained by filtration using an inert solvent. If necessary, further recrystallization can be performed to obtain a diastereomer salt with higher purity.

The crystallization is usually carried out in the range of 0 ° C. to room temperature, but may be carried out while heating, for example, in the range of −20 ° C. to room temperature or, for example, in the range of about 40 ° C.

The amount of the optically active amine to be used can be adjusted by the mixing ratio of the isomer mixture of the compound (VII).
For example, when the ratio of the (3S, 4S) isomer to the (3R, 4R) isomer is 1: 1, 0.5 to 1.2 mol of the optically active amine is used per 1 mol of the isomer mixture. Is used, and usually an excess amount of about 1 mol or about 1.1 mol is used.

The amount of the solvent used for fractional crystallization may vary depending on the type of the solvent. For example, when ethyl acetate is used, the amount is about 10 to 100 times (weight ratio) the compound (VII), usually about It is about 20 to 40 times. As described above, a salt of the desired isomer of compound (VII) with an optically active amine can be obtained. Since the salt thus obtained has good filterability, it is not only excellent as an industrial production method, but also the method of the present invention can obtain an optically pure salt and is efficient.

For the salt decomposition, the optically active amine salt obtained as described above is treated with an acid or alkali in an inert solvent such as water, methyl isobutyl ketone, ethyl acetate, dichloromethane, 1,2-dichloroethane or a mixture thereof. The reaction can be carried out by hydrolysis with an aqueous solution, and then the desired product is isolated by ordinary organic chemical means. Although various acids can be used as the acid, mineral acids such as hydrochloric acid and sulfuric acid are desirable. As the alkaline aqueous solution, various alkaline aqueous solutions can be used, and an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or the like is preferable.

The above-mentioned optical resolution method can be applied equally to the compound (VII) in which R, R ₂ and R ₆ are the substituents as defined above, and particularly when R is a methyl group. , R ₆ are preferably hydrogen atoms. R ₂ represents a furylmethyl group, a substituted or unsubstituted monoarylmethyl group (benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, etc.) or a substituted or unsubstituted diarylmethyl Group (diphenylmethyl, di-p-anisylmethyl, etc.), and particularly preferably a furylmethyl group.

Next, the stereochemistry of the 1-hydroxyethyl group (8-position) which is the 6-position substituent of the compound of the formula (IIIa) will be described. When the 8-position of the compound (IIIa) is desired to have the S-configuration, the compound (Ia) can be obtained as it is, and when the R-configuration is desired, the compound (Ia) can be obtained.
It can be obtained by inverting the configuration of the hydroxyl group of each intermediate from a) to compound (VII).

As the method for inverting the hydroxyl group, various commonly used methods can be used. For example, a method by the Mitsunobu reaction using diethyl azodicarboxylate and triphenylphosphine [Tetrahedron Letters, 21] , 2783-2786 (1980) and 22, 913-916 (1981)], or a hydroxyl group is converted to a carbonyl group by an oxidation reaction and stereoselectively reduced using a reducing agent such as potassium-selectride. Method [Journal of American Chemical Society]
(J. Am. Chem. Soc.), 102, 6161 to 6163 (1980)].

4) Production of Raw Material The acetylenamine compound (II), which is the raw material of the present invention, can be produced by various methods, representative examples of which are shown below.

Production method [A]:-

Embedded image [Wherein, R ₁ , R ₂ , X and R have the same meaning as described above. The acetylenamine compound (II) is obtained by alkylating the compound (XIII).

This alkylation reaction is carried out by reacting an alkylating agent in an inert solvent in the presence of a base. Examples of the inert solvent include aromatic hydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, tetrahydrofuran, dioxane, etc.), ketones (acetone, methyl isobutyl ketone, etc.), alcohols (methanol, ethanol, t-butanol, etc.) Amides (dimethylformamide, dimethylsulfoxide, hexamethylphosphoric amide, etc.) and the like and mixtures thereof. As the base, for example, alkali metal hydride
(Sodium hydride, potassium hydride, etc.), alkali metal salts of amines (sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.),
Alkali metal salts of alcohols (sodium methylate,
Sodium ethylate, potassium methylate, potassium
t-butoxide and the like), alkali metals (such as sodium metal and lithium metal), alkali metal carbonates (such as potassium carbonate and sodium carbonate), n-butyllithium, and sodium methylsulfinyl methide. As the alkylating agent, lower alkyl halides (methyl iodide,
Examples thereof include ethyl iodide, n-butyl bromide, and the like, and lower alkyl sulfonates (methyl tosylate, ethyl tosylate, methyl methanesulfonate, ethyl methanesulfonate, methyl trifluoromethanesulfonate, and the like).

The amounts of the alkylating agent and the base are desirably used so that the reaction can proceed sufficiently. The reaction can be suppressed or promoted by appropriately cooling or heating. After completion of the reaction, the compound (I
Recovery of I) can be performed by applying ordinary organic chemical means.

Production method [B]:-

Embedded image [Wherein, R ₁ , R ₂ , R and X have the same meaning as described above. The acetylenamine compound (II) is obtained by acetylating the compound (XIV).

This acetylation reaction may be carried out by applying various means employed for acetylation of the active methylene group, and is usually carried out by reacting an acetylating agent in an inert solvent. Examples of the inert solvent include aromatic hydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ketones (acetone, etc.), etc. Or mixtures thereof. Specific examples of suitable acetylating agents include ketene, acetic anhydride, acetic halide and the like. When using acetic anhydride or acetic halide, triethylamine,
It is desirable to carry out in the presence of a base such as pyridine.

It is desirable to use the amounts of the acetylating agent and the base that are sufficient for the reaction to proceed sufficiently. The reaction can be suppressed or promoted by appropriately cooling or heating, but is preferably carried out at a temperature in the range of -10 ° C to 95 ° C. After completion of the reaction, in order to recover the compound (II), ordinary organic chemical means may be employed.

[0062]

Examples and Reference Examples 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 by these. The meanings of the abbreviations used in the following Examples and Reference Examples are as follows. PNB: p-nitrobenzyl group Bn: benzyl group Ph: phenyl group Me: methyl group Et: ethyl group tBu: t-butyl group Tr: triphenylmethyl group TBMS: t-butyldimethylsilyl group BOM: benzyloxymethyl group MOM : Methoxymethyl group MEM: 2-methoxyethoxymethyl group MTM: methylthiomethyl group

[0063]

Embodiment 1

Embedded image 2-acetyl-3-benzylamino-4-methyl-2-
4.10 g of ethyl pentenedioate benzyl ester (10 mmo
le) in 40 ml of dry tetrahydrofuran,
1.56 g (13 mmol) of catechol borane was added dropwise at ℃.
After stirring at the same temperature for 2 hours, the temperature was returned to room temperature, and the solvent was distilled off under reduced pressure. 41 ml of acetic acid was added to the residue, 757 mg (20 mmol) of sodium borohydride was gradually added at 10 to 12 ° C, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 4 hours. Thereafter, acetic acid was distilled off under reduced pressure at room temperature, chloroform was added to the residue, and the organic layer was washed six times with saturated aqueous sodium hydrogen carbonate, further washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2SR, 3RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid ethylbenzyl ester (1a) and (2RS, 3SR,
4RS) -2- [1 (RS) -Hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid ethyl benzyl ester (1b) was obtained as a mixture in a ratio of 98/2. Yield 75%. IR (neat): 3335 (broad), 1720, 1445, 11
52,730,690 (cm ^-1 ). NMR δ (CDCl ₃ ): (1a) 3.88 (ABq, 2H), 3.20 [t (J = 4.9H)
z), 1H], 2.98 (m, 1H), 2.61 [dd (J = 2.3 and 4.0 Hz), 1H]. (1b) 3.77 (ABq, 2H), 3.32 [dd (J = 4.3
6.9 Hz), 1 H], 2.86 (m, 1 H), 2.58 [dd (J
= 2.6 and 4.3 Hz), 1H].

[0064]

Embodiment 2

Embedded image 2-acetyl-3-furfurylamino-4-methyl-2
-Pentenedioic acid ethyl benzyl ester 400 mg (1 mmo
l) was dissolved in 4 ml of dry tetrahydrofuran, 156 mg (1.3 mmol) of catechol borane was added at -78 ° C, and the mixture was stirred at the same temperature for 1 hour, then returned to room temperature, and the solvent was distilled off under reduced pressure. 4.0 ml of acetic acid was added to the residue, 76 mg (2 mmol) of sodium borohydride was gradually added at 10 to 12 ° C, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 3 hours. Thereafter, acetic acid was distilled off under reduced pressure at room temperature, chloroform was added to the residue, and the organic layer was washed six times with a saturated aqueous solution of sodium hydrogencarbonate and then with a saline solution.
By drying with sodium sulfate and distilling off the solvent under reduced pressure, (2SR,
3RS, 4RS) -2- [1 (SR) -hydroxyethyl]-
3-furfurylamino-4-methylpentanedioic acid ethylbenzyl ester (2a) and (2RS, 3SR, 4RS) -2
-[1 (RS) -hydroxyethyl] -3-furfurylamino-4-methylpentanedioic acid ethyl benzyl ester
(2b) was obtained as a mixture with a ratio of 97/3. Yield 74%. IR (CHCl ₃ ): 1723,1452,1373,126
0.11160 (cm ^-1 ). NMR δ (CDCl ₃ ): (2a) 7.36 (m, 5H), 6.30 [dd (J = 2.0 and 3.
3Hz), 1H], 6.20 [d (J = 3.3Hz), 1H], 5.1
2 (ABq, 2H), 4.09 [q (J = 7.3 Hz), 2H], 4.
01 [dq (J = 2.3 and 6.6 Hz), 1H], 3.88 (ABq,
2H), 3.15 [dd (J = 4.0 and 5.6 Hz), 1H], 2.
90 (m, 1H), 2.59 [dd (J = 2.3 and 3.6 Hz), 1
H], 1.18-1.26 (9H).

[0065]

Embodiment 3

Embedded image 2-acetyl-3-benzylamino-4-methyl-5-
Benzyloxymethyloxy-2-pentenoic acid benzyl ester (23 mg, 0.047 mmole) was added to propionic acid (0.2 m).
Then, 6 mg (0.095 mmole) of sodium cyanoborohydride was gradually added at −20 to −25 ° C., and the mixture was stirred at the same temperature for 6 hours. Thereafter, the solvent was distilled off under reduced pressure at room temperature, the residue was dissolved in chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate.
After washing twice with brine and drying with sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give (2SR, 3RS, 4RS) -2- [1 (S
R) -Hydroxyethyl] -3-benzylamino-4-methyl-5-benzyloxymethyloxypentanoic acid benzyl ester (3a) and (2RS, 3SR, 4RS) -2- [1
(RS) -Hydroxyethyl] -3-benzylamino-4
A mixture of -methyl-5-benzyloxymethyloxypentanoic acid benzyl ester (3b) was obtained. The formation ratio of 3a and 3b was 57:43 based on the integral ratio of NMR. Yield 74%. IR (neat): 3340,1720,1446,1150,1
045,728,693 (cm ^-1 ). NMR δ (CDCl ₃ ): (3a) 7.32 (m, 15H), 5.12 (ABq, 2H),
4.66 (s, 2H), 4.57 (s, 2H), 4.06 [dq (J =
2.3 and 6.6 Hz), 1H], 3.85 (ABq, 2H), 3.
52 [dd (J = 6.3 and 9.6 Hz), 1H], 3.43 [dd (J
= 5.9 and 9.9Hz), 1H], 3.08 [t (J = 4.6H)
z), 1H], 2.61 [q (J = 2.3 Hz), 1H], 2.21
(m, 1H), 1.20 [d (J = 6.6 Hz), 3H], 1.01
[d (J = 6.9 Hz), 3H]. (3b) 7.31 (m, 15H), 5.13 (s, 2H), 4.7
2 (s, 2H), 4.56 (s, 2H), 4.10 [dq (J = 2.3
6.6 Hz), 3.83 (ABq, 2H), 3.54 (m, 2H),
3.17 [dd (J = 3.6 and 5.3 Hz), 1H], 2.59 (m,
1H), 2.29 (m, 1H), 1.17 [d (J = 6.6 Hz),
3H], 0.84 [d (J = 7.3 Hz), 3H].

[0066]

Embodiment 4

Embedded image 2-acetyl-3-benzylamino-4-methyl-2-
A solution of 20 g (62.6 mmoles) of pentenedioic acid dimethyl ester in 135 ml of acetic acid was treated with sodium cyanoborohydride 7.
86 g (125 mmol) of acetic acid (121 ml) at 10 to 12 ° C.
For 20 minutes and stirred at the same temperature for 2 hours. The acetic acid was distilled off under reduced pressure, and the residue was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate and once with brine, dried over sodium sulfate and evaporated under reduced pressure, and the residue was purified by silica gel chromatography. By doing, (2SR, 3RS, 4RS) -2- [1 (S
R) -Hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid dimethyl ester (4a) and (2RS, 3
SR, 4RS) -2- [1 (RS) -hydroxyethyl] -3
-Benzylamino-4-methylpentanedioic acid dimethyl ester (4b) was obtained as a mixture. The formation ratio of 4a and 4b was 3: 1 from the integration ratio of NMR. Yield 70%. IR (neat): 3340, 1730, 1160, 1023, 7
35,693 (cm ^-1 ). NMR δ (CDCl ₃ ): (4a) 3.14 [t (J = 4.6 Hz), 1H], 2.57 [dd]
(J = 2.3 and 4.0 Hz), 1 H], 1.23 [d (J = 6.6 H
z), 3H], 1.18 [d (J = 6.9 Hz), 3H].

[0067]

Embodiment 5

Embedded image 830 mg (3.08 mmol) of dimethyl 2-acetyl-3-allylamino-4-methyl-2-pentenedioate
e) and 387 mg of sodium cyanoborohydride (6.16 mm
ole) and the same operation as in Example 4 was performed.
SR, 3RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3-allylamino-4-methyl-pentanedioic acid dimethyl ester (5a) and (2RS, 3SR, 4RS) -2-
[1 (RS) -hydroxyethyl] -3-allylamino-4
-Methylpentanedioic acid dimethyl ester (5b) was obtained as a mixture. The formation ratio of 5a and 5b was 3.2: 1 from the integral ratio of NMR. Yield 69%. IR (neat): 3350, 1735, 1436, 1198, 1
164 (cm ^-1 ). NMR δ (CDCl ₃ ): (5a) 3.69 (s, 3H), 3.67 (s, 3H), 3.54
[dd (J = 5.6 and 13.5 Hz), 1H], 2.57 [dd (J =
2.0 and 3.6 Hz), 1 H], 1.23 [d (J = 7.3 Hz),
3H], 1.18 [d (J = 6.9 Hz), 3H].

[0068]

Embodiment 6

Embedded image 2-acetyl-3-benzylamino-4-methyl-2-
Pentenedioic acid dimethyl ester (32 mg, 0.1 mmol) was dissolved in dry tetrahydrofuran (0.1 ml), 0.55 N catecholborane-tetrahydrofuran solution (0.2 ml) was added dropwise at -70 ° C, and the mixture was stirred at the same temperature for 2 hours and then cooled to room temperature. It was returned and the solvent was distilled off under reduced pressure. The residue was dissolved in 0.1 ml of acetic acid, 13 mg (0.2 mmole) of sodium cyanoborohydride was added at 10 to 12 ° C, and the mixture was heated at the same temperature for 1 hour.
The mixture was further stirred at room temperature for 1.5 hours. Thereafter, acetic acid was distilled off under reduced pressure at room temperature, the residue was dissolved in chloroform, and the organic layer was washed six times with a saturated aqueous solution of sodium bicarbonate, and further washed with a saline solution.
After drying over sodium sulfate and distilling off the solvent under reduced pressure, (2SR, 3
RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3
-Benzylamino-4-methylpentanedioic acid dimethyl ester (4a) and (2RS, 3SR, 4RS) -2- [1 (RS)
-Hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid dimethyl ester (4b) was obtained as a mixture. The formation ratio of 4a and 4b was 94: 6 from the integral ratio of NMR.
Met. Yield 78%. I of 4a and 4b obtained by this reaction
R and NMR were consistent with those obtained in Example 4.

[0069]

Embodiment 7

Embedded image 2-acetyl-3-benzylamino-4-methyl-5-
101 mg (0.2 mmole) of phenylthio-2-pentenoic acid p-nitrobenzyl ester was dissolved in 0.2 ml of acetic acid, and 15 mg (0.24 mmole) of sodium cyanoborohydride was dissolved in 8 ml.
The mixture was gradually added while being kept at 〜１０10 ° C., and stirred at the same temperature for 2 hours. After acetic acid was distilled off under reduced pressure, the residue was diluted with ethyl acetate, and the organic layer was washed three times with saturated aqueous sodium hydrogen carbonate and once with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. And (2SR, 3RS, 4RS) -2
-[1 (SR) -hydroxyethyl] -3-benzylamino-4-methyl-5-phenylthiopentanoic acid p-nitrobenzyl ester (7a) and (2RS, 3SR, 4RS) -2
-[1 (RS) -Hydroxyethyl] -3-benzylamino-4-methyl-5-phenylthiopentanoic acid p-nitrobenzyl ester (7b) was obtained in an isolation ratio of 2: 1. Yield 7
5%. IR (neat): 3340, 1722, 1512, 1338, 1
142,728 (cm ^-1 ). NMR δ (CDCl ₃ ): (7a) 5.20 (s, 2H), 4.03 [dq (J = 2.8 and 6.
4Hz), 1H], 3.76 (ABq, 2H), 3.11 [t (J =
4.3Hz), 1H], 3.05 [dd (J = 8.5 and 12.8H
z), 1H], 2.61 [dd (J = 2.8 and 4.4 Hz), 1
H], 2.53 [dd (J = 8.6 and 12.8 Hz), 1H], 2.
17 (m, 1H), 1.19 [d (J = 6.3 Hz), 3H], 1.
11 [d (J = 6.9 Hz), 1H]. (7b) 5.20 (s, 2H), 4.02 [dq (J = 2.6 and 6.
6Hz), 1H], 3.74 (ABq, 2H), 3.17 [dd (J
= 3.3 and 4.6 Hz), 1 H], 2.90 [d (J = 6.9 H)
z), 2H], 2.53 [t (J = 2.6 Hz), 1H], 2.26
(m, 1H), 1.15 [d (J = 6.3 Hz), 3H], 0.91
[d (J = 7.3 Hz), 3H].

[0070]

Embodiment 8

Embedded image The same operation as in Example 8 was carried out using 92 mg (0.2 mmole) of p-nitrobenzyl 2-acetyl-3-allylamino-4-methyl-5-phenylthio-2-pentenoate to obtain (2SR, 3RS, 4RS) -2- [1 (SR)-
Hydroxyethyl] -3-allylamino-4-methyl-
5-phenylthiopentanoic acid p-nitrobenzyl ester (8a) and (2RS, 3SR, 4RS) -2- [1 (RS) -hydroxyethyl] -3-allylamino-4-methyl-5
-Phenylthiopentanoic acid p-nitrobenzyl ester
(8b) was obtained with an isolation ratio of 2: 1. IR (neat): 3360,1730,1521,1342,1
152,738 (cm ^-1 ). NMR δ (CDCl ₃ ): (8a) 5.81 (m, 1H), 5.22 (s, 2H), 5.08
(m, 2H), 4.04 [dq (J = 2.6 and 6.6 Hz), 1H],
2.61 [dd (J = 2.6 and 4.3 Hz), 1H], 2.54 [dd
(J = 8.6 and 12.5 Hz), 1H], 2.08 (m, 1H),
1.20 [d (J = 6.3 Hz), 3H], 1.08 [d (J = 6.
8 Hz), 3H]. (8b) 5.83 (m, 1H), 5.21 (s, 2H), 5.13
(m, 2H), 4.09 [dq (J = 2.6 and 6.6 Hz), 1H],
3.36 [dd (J = 5.6 and 13.9 Hz), 1H], 3.14 [d
d (J = 3.3 and 5.3 Hz), 1H], 3.08 [dd (J = 6.
6 and 13.9 Hz), 1 H], 2.90 [dd (J = 3.3 and 7.3)
Hz), 2H], 2.55 [t (J = 3.3 Hz), 1H], 2.1
6 (m, 1H), 1.18 [d (J = 6.3 Hz), 3H], 0.8
8 [d (J = 7.3 Hz), 3H].

[0071]

Embodiment 9

Embedded image 350 mg of 2-acetyl-3-allylamino-4-methyl-5-benzyloxy-2-pentenoic acid methyl ester
(1.06 mmole) was dissolved in 3.5 ml of acetic acid, and 138 mg (2.2 mmole) of sodium cyanoborohydride was added thereto.
Stirred at １２12 ° C. for 1 hour. After acetic acid was distilled off under reduced pressure, the residue was diluted with ethyl acetate, and washed three times with saturated aqueous sodium hydrogen carbonate and once with brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography.
3RS, 4RS) -2- [1- (SR) -hydroxyethyl]
-3-allylamino-4-methyl-5-benzyloxypentanoic acid methyl ester (9a) and (2RS, 3SR, 4R
A mixture of methyl (S) -2- [1 (RS) -hydroxyethyl] -3-allylamino-4methyl-5-benzyloxypentanoate (9b) was obtained. The formation ratio of 9a and 9b was 1.5: 1 from the integral ratio of NMR. IR (neat): 3349, 1725, 1450, 1158, 1
086,910,732 (cm ^-1 ). NMR δ (CDCl ₃ ): (9a) 3.64 (s, 3H), 2.54 [dd (J = 2.3 and 4.
0 Hz), 1 H], 1.20 [d (J = 6.3 Hz), 3 H], 1.
00 [d (J = 6.9 Hz), 3H]. (9b) 3.68 (s, 3H), 2.46 (m, 1H), 1.18
[d (J = 6.6 Hz), 3H], 0.85 [d (J = 6.9 Hz),
3H].

[0072]

Examples 10 to 21 In the same manner as in the method described in Example 1, 3, 4 or 6, an amino acid derivative was converted from the corresponding acetylenamine derivative into (1′SR, 2SR, 3RS,
4RS) body (a) and (1'RS, 2RS, 3SR, 4RS) body (b)
As a mixture. The reaction conditions, yields and mixture formation ratios (a) :( b) are as shown in the table below.

[0073]

[Table 1]

[0074]

[Table 2]

[0075]

[Table 3]

[0076]

[Table 4]

[0077]

[Table 5]

[0078]

[Table 6]

Reference Example 1-1

Embedded image 6.88 g (80 mmole) of methacrylic acid was dissolved in 40 ml of dry tetrahydrofuran, and 8.0 g of triethylamine was added at room temperature.
(80 mmol) and 8.81 g (80 mmol) of thiophenol were sequentially added, and the mixture was stirred for 24 hours. The solvent was distilled off under reduced pressure to obtain 2-methyl-3-phenylthiopropionic acid. IR (neat): 1705, 1572, 1475, 1390, 1
212,1160 (cm ^-1 ).

Reference Example 1-2

Embedded image 4.60 g of 2-methyl-3-phenylthiopropionic acid
(23.44 mmol) was dissolved in 20 ml of dry acetonitrile, and 4.56 of 1,1-carbonyldiimidazole was added under ice cooling.
g (28.13 mmole) was added and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was gradually added dropwise at 50 ° C to a solution of 17.53 g (35 mmole) of magnesium malonate mono-p-nitrobenzyl ester in 70 ml of dry acetonitrile.
Stirred for 0 minutes. After the reaction is completed, return to room temperature, dilute with ethyl acetate, wash the organic layer with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine in that order, dry over sodium sulfate, distill off the solvent under reduced pressure, and silica gel the residue. Purification by chromatography gave p-nitrobenzyl 3-oxo-4-methyl-5-phenylthiopentanoate. IR (neat): 1738,1704,1415,1347,7
32 (cm ^-1 ).

Reference Example 1-3

Embedded image 3-oxo-4-methyl-5-phenylthiopentanoic acid
1.12 g (3 mmol) of p-nitrobenzyl ester was dissolved in a mixed solvent of 1 ml of methylene chloride and 4 ml of methanol, and 1.61 g (15 mmol) of benzylamine and 2 g of molecular sieves 3A were added. To the reaction mixture was added a solution prepared by adding 785 mg (10 mmoles) of acetyl chloride to 2 ml of dry methanol under ice-cooling, followed by stirring for 1 minute, and left at room temperature for 2 days. After filtering the molecular sieves and diluting with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate,
The extract was washed with water and brine in that order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 3-benzylamino-4-methyl-5.
-Phenylthio-2-pentenoic acid p-nitrobenzyl ester was obtained. IR (neat): 1652,1600,1344,1171,7
33 (cm ^-1 ).

Reference Example 1-4 (1)

Embedded image 3-benzylamino-4-methyl-5-phenylthio-
2-pentenoic acid p-nitrobenzyl ester 505mg
(1 mmol) was dissolved in 5 ml of toluene, ketene gas was passed through at room temperature, the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give 2-acetyl-3-benzylamino-4-methyl-methyl. 5-phenylthio-2-pentenoic acid p-nitrobenzyl ester was obtained. IR (neat): 1705,1583,1519,1341,1
270,1092,737 (cm ^-1 ).

Reference Example 1-4 (2)

Embedded image 3-benzylamino-4-methyl-5-phenylthio-
1.58 g of 2-pentenoic acid p-nitrobenzyl ester
(3.51 mmole) in 5 ml of toluene,
Then, 1.06 g (10.5 mmole) of triethylamine was added.
Further, 630 mg (8.0 mmole) of acetyl chloride was added at once, and the mixture was stirred for 10 minutes. To the reaction mixture was added 50 ml of benzene, washed successively with saturated aqueous sodium hydrogen carbonate, water, dilute hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2-acetyl. -3-benzylamino-4-methyl-5-phenylthio-2-pentenoic acid p-nitrobenzyl ester was obtained.

Reference Example 1-5

Embedded image Reference Example 1 using 842 mg (15 mmole) of allylamine
The same operation as in -3 was performed to obtain p-nitrobenzyl 3-allylamino-4-methyl-5-phenylthio-2-pentenoate. IR (neat): 1650, 1596, 1342, 1163, 7
36 (cm ^-1 ).

Reference Example 1-6

Embedded image 3-allylamino-4-methyl-5-phenylthio-2
-454 mg of pentenoic acid p-nitrobenzyl ester (1 m
mole)) and the same operation as in Reference Example 1-4- (1) was carried out to give 2-acetyl-3-allylamino-4-methyl-.
5-phenylthio-2-pentenoic acid p-nitrobenzyl ester was obtained. IR (neat): 1700,1581,1517,1341,1
266,733 (cm ^-1 ).

Reference Example 2-1

Embedded image Under a stream of N ₂ , 5.28 g (0.1%) of sodium hydride (50%)
(1 mol) was added to 50 ml of dry tetrahydrofuran, and a solution of 7.2 g (0.1 mol) of methallyl alcohol in 20 ml of dry tetrahydrofuran was gradually added dropwise thereto under ice-cooling. 3
After stirring for 0 minutes, 17.1 g (0.1 mol) of benzyl bromide
le) in 20 ml of dry tetrahydrofuran to stop the reaction, dilute with ethyl acetate, wash the organic layer successively with 1N hydrochloric acid, water and brine, dry over sodium sulfate and distill off the solvent under reduced pressure to give 1-. Benzyloxy-2-methyl-2
-Propene was obtained. IR (neat): 1650, 1490, 1442, 1090, 8
92 (cm ^-1 ).

Reference Example 2-2

Embedded image 8.1 g of 1-benzyloxy-2-methyl-2-propene
(50 mmole) was dissolved in 50 ml of dry tetrahydrofuran, and 1M borane-tetrahydrofuran solution 25 was added under ice cooling.
ml (25 mmole) was added dropwise, followed by stirring at room temperature for 1 hour. 4 ml of water, 8.5 ml of a 3M aqueous sodium hydroxide solution (2
After addition of 5.5 mmol), the mixture was stirred at 40 ° C. for 5 minutes, 5.1 ml (53 mmol) of 35% aqueous hydrogen peroxide was further added, and the mixture was stirred at the same temperature for 1.5 hours. Return to room temperature, saturated saline 10
0 ml, ether extraction (150 ml × 3), all organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
8.5 g of crude product of -benzyloxy-2-methylpropanol were obtained. Among them, 5.41 g (30 mmole) was dissolved in 22 ml of acetone, and Jones reagent was prepared by a known method.
(1.8 mmol / ml) 16.7 ml (30 mmol) was added dropwise under ice cooling, and the mixture was stirred for 3 hours. The insoluble material is filtered off, and the filtrate is iced water 25.
After adding 0 ml and 400 ml of ethyl acetate and extracting, the whole organic layer was washed with saturated aqueous sodium hydrogen carbonate, separated into an aqueous layer and an organic layer, and the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 3-benzyloxy-2-methylpropionic acid. IR (Nujol): 1695,1455,1070,932,7
06 (cm ^-1 ).

Incidentally, (S)-(+)-3-hydroxy-2-
When benzyl bromide is allowed to act on methyl methyl propionate in the presence of silver oxide, the hydroxyl group can be protected with a benzyl group.

Embedded image IR (neat): 1735, 1450, 1360, 1195, 1
090,735 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.32 (m, 5H), 4.52 (s, 2)
H), 3.70 (s, 3H), 3.66 [dd (J = 2.7 Hz and 9.
2Hz), 1H], 3.49 [dd (J = 5.9Hz and 9.2Hz),
1H], 2.79 (m, 1H), 1.18 [d (J = 7.3 Hz),
3H].

Reference Example 2-3

Embedded image 3.0 g of 3-benzyloxy-2-methylpropionic acid
(15.4 mmoles) dissolved in 20 ml of dry acetonitrile,
2.92 g of 1,1′-carbonyldiimidazole under ice-cooling
(18 mmol) was added and stirred for 30 minutes. This solution was gradually added dropwise to a solution of 9.01 g (18 mmole) of magnesium salt of malonic acid mono-p-nitrobenzyl ester in 40 ml of dry acetonitrile at 50 ° C, and the mixture was heated under reflux for 3 hours. After returning to room temperature, the mixture was diluted with ethyl acetate, and the organic layer was washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine in that order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. , 3-oxo-5-benzyloxy-4-methylpentanoic acid p-nitrobenzyl ester was obtained. IR (neat): 1720,1683,1576,1490,1
316,1065,705 (cm ^-1 ).

Reference Example 2-4

Embedded image 1.89 g (50 mmole) of sodium borohydride was added to 20 ml of methanol, heated under reflux for 10 minutes, returned to room temperature, and 3.7 g of p-nitrobenzyl 3-oxo-5-benzyloxy-4-methylpentanoate (3.7 g). 10mmole)
Was added dropwise without a solvent, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid and brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 3-oxo-5-benzyloxy-. 4-methylpentanoic acid methyl ester was obtained. IR (neat): 1742, 1713, 1622, 1448, 1
305, 1090, 735 (cm ^-1 ).

Reference Example 2-5

Embedded image 1.11 g (4.43 mmol) of methyl 3-oxo-4-methyl-5-benzyloxypentanoate was added to 5 ml of dry methanol.
And 1.26 g of allylamine and 0.6 g of molecular sieve 3A were added. Further, under ice-cooling, a solution prepared by adding 1.04 g (13.3 mmole) of acetyl chloride to 2 ml of dry methanol and then stirring for 1 minute was added.
The reaction was performed at 40 ° C. for 12 hours. The molecular sieves were filtered, the filtrate was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of toluene, and after completion of the reaction through ketene gas at room temperature, the solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to give 2-acetyl-3-allylamino-4-methyl-5-benzyloxy. -2-Pentenoic acid methyl ester was obtained. IR (neat): 1702,1577,1445,1438,1
264, 1080, 736 (cm ^-1 ).

Reference Example 3-1 (1)

Embedded image 2.0 g (16.9 mmoles) of methyl (S)-(+)-2-methyl-3-hydroxypropionate and 2.2 g (17.1 mmoles) of diisopropylethylamine were dissolved in 2 ml of anhydrous dichloromethane, and benzyloxymethyl chloride 2 .7g (17.3
mmole) was added dropwise and stirred for 1 hour. 10 ml of 1N hydrochloric acid and 20 ml of ethyl acetate were added to carry out liquid separation, and the aqueous layer was further extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue is purified by silica gel chromatography to give (S)
Methyl -3-benzyloxymethyloxy-2-methylpropionate was obtained. IR (neat): 1730, 1445, 1370, 1195,
1030 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.34 (s, 5H), 4.75 (s, 2)
H), 4.59 (s, 2H), 3.70 (s, 3H), 2.81 (m,
1H), 1.20 [d (J = 7.0 Hz), 3H].

The following methyl ester derivatives were obtained by the same procedure as described in Reference Example 3-1 (1) using methoxymethyl chloride or 2-methoxyethyl chloride instead of benzyloxymethyl chloride. Was.

Embedded image IR (neat): 1725, 1450, 1430, 1193, 1
030,910 (cm ^-1 ). NMR δ (CDCl ₃ ): 4.61 (s, 2H), 3.70 (s, 2)
H), 3.65 (m, 2H), 3.34 (s, 3H), 2.79 (m, 1
H), 1.19 [d (J = 7.0 Hz), 3H].

Embedded image IR (neat): 1735, 1450, 1200, 1110, 1
040 (cm ^-1 ). NMR δ (CDCl ₃ ): 4.72 (s, 2H), 3.71 (s, 3)
H), 3.41 (s, 3H), 2.80 (m, 1H), 1.19 [d (J
= 7.3 Hz), 3H].

Reference Example 3-1- (2)

Embedded image 2.36 g (20 mmol) of methyl (S)-(+)-2-methyl-3-hydroxypropionate was dissolved in 40 ml of acetic anhydride, 40 ml of dry dimethylsulfoxide was added, and the mixture was added at room temperature.
Stirred for days. The reaction solution was diluted with 500 ml of water and extracted with n-hexane-ethyl acetate (1: 1). The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and water, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to obtain methyl (S) -3-methylthiomethoxy-2-methylpropionate. IR (neat): 1730, 1450, 1432, 1160, 1
042 (cm ^-1 ). NMR δ (CDCl ₃ ): 1.20 [d (J = 7.3 Hz), 3
H], 2.13 (s, 3H), 2.76 (m, 1H), 3.5-3.3.
8 (m, 2H), 3.71 (s, 3H), 4.63 (s, 2H).

Reference Example 3-1 (3)

Embedded image 2.36 g (20 mmole) of methyl (S)-(+)-2-methyl-3-hydroxypropionate were dried in 30 ml of dichloromethane.
After adding 0.2 ml of concentrated sulfuric acid, -60 to -70
After cooling to ℃, 23.5 g of isobutene was blown, and the mixture was stirred at room temperature for 3 hours. The reaction solution was sealed and stirred overnight, after which unreacted isobutene was distilled off, washed successively with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and the solvent was distilled off, to give (S) -3-t-butoxy-2. -Methyl methyl propionate was obtained. IR (neat): 1735, 1710, (sh), 1450, 13
60, 1195, 1080, 1050 (cm ^-1 ). NMR δ (CDCl ₃ ): 3.69 (s, 3H), 3.58 [dd (J
= 7.25 and 8.6 Hz), 1 H], 3.35 [dd (J = 6.2 and 8.6 Hz), 1 H], 2.66 (m, 1 H), 1.17 (s, 9)
H), 1.16 [d (J = 7.0 Hz), 3H].

Reference Example 3-1- (4)

Embedded image 1.18 g (10 mmoles) of methyl (S)-(+)-2-methyl-3-hydroxypropionate, 3.1 g of trityl chloride
(11.13 mmol) and 1.34 g (11 mmol) of N, N-dimethylaminopyridine were added to dry dimethylformamide 1
Dissolve in 0 ml and stir at room temperature overnight. To eliminate unreacted trityl chloride, 5 ml of methanol was added and 3
After stirring for 20 hours, 20 ml of water was added to the reaction solution, and toluene 2
The mixture was extracted three times with 0 ml, the extract was washed with water, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography to give methyl (S) -3-trityloxy-2-methylpropionate. Obtained. IR (neat): 1725, 1450, 1370, 1195, 1
080,705 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.43 to 7.22 (m, 15H),
3.70 (s, 3H), 3.28 [dd (J = 7.1 and 8.75H
z), 1H], 3.17 [dd (J = 5.8 and 8.75 Hz), 1
H], 2.73 (m, 1H), 1.15 [d (J = 7.3 Hz), 3
H].

Reference Example 3-1 (5)

Embedded image 1.0 g (8.47 mmole) of methyl (S)-(+)-2-methyl-3-hydroxypropionate, 1.15 g of imidazole
(16.9 mmole) was dissolved in 10 ml of dry dimethylformamide, and 1.30 g (8.6) of t-butyldimethylchlorosilane was dissolved.
2 mmol) and stirred at room temperature overnight. The reaction solution was diluted with 60 ml of ethyl acetate and washed three times with 50 ml of a saline solution.
After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography to give (S) -3-t-butyldimethylsilyloxy-2-
Methyl methyl propionate was obtained. IR (neat): 1740, 1460, 1250, 1195, 1
090,830,770 (cm ^-1 ). NMR δ (CDCl ₃ ): 3.78 [dd (J = 6.9 and 9.6H)
z), 1H], 3.68 (s, 3H), 2.65 (m, 1H), 1.1
4 [d (J = 6.9 Hz), 3H], 0.87 (s, 9H), 0.04
(s, 3H), 0.01 (s, 3H).

Reference Example 3-2- (1)

Embedded image 1.20 g (5 mmole) of methyl (S) -3-benzyloxymethyloxy-2-methylpropionate was added to 12 ml of methanol.
1N sodium hydroxide solution 5.5 under ice-cooling.
ml was added and the mixture was stirred at room temperature overnight. The reaction was diluted with 30 ml of water and washed twice with 20 ml of ether. The aqueous layer was acidified with 6N hydrochloric acid under ice cooling, and extracted three times with 30 ml of ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (S) -3-benzyloxymethyloxy-2-methylpropionic acid. IR (neat): 1705, 1445, 1370, 1100, 1
035 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.34 (s, 5H), 4.76 (s, 2)
H), 4.59 (s, 2H), 3.78 [dd (J = 7.6 and 9.6
Hz), 1H], 3.68 [dd (J = 5.3 and 9.6 Hz), 1
H], 2.80 (m, 1H), 1.23 [d (J = 7.25 Hz),
3H].

Reference Examples 3-2- (2) to 3-2- (8) For the carboxylic acids shown in the following tables, the corresponding methyl esters were treated in the same manner as in the method described in Reference Example 3-2- (1). And obtained.

Embedded image

[0100]

[Table 7]

Reference Example 3-3- (1)

Embedded image 0.69 g (3.075 mmol) of (S) -3-benzyloxymethyloxy-2-methylpropionic acid, 0.60 g (3.675 mmole) of 1,1'-carbonyldiimidazole and magnesium salt of malonic acid monobenzyl ester 1 .50g
The same operation as in Reference Example 1-2 was carried out using (3.675 mmole) to obtain benzyl (S) -3-oxo-4-methyl-5-benzyloxymethoxypentanoate. IR (neat): 1735, 1710, 1445, 1035, 7
35,690 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.35 (s, 5H), 7.32 (s, 5)
H), 5.17 (s, 2H), 4.68 (s, 2H), 4.54 (s, 2H)
2H), 3.72 [dd (J = 7.9 and 9.6 Hz), 1H], 3.
61 (s, 2H), 2.96 (m, 1H), 1.10 [d (J = 6.9
Hz), 3H].

Reference Examples 3-3- (2) to 3-3- (8) The β-keto ester derivatives shown in the following tables were prepared by converting the corresponding carboxylic acids in the same manner as in the method described in Reference Example 3-3- (1). And obtained by the following treatment.

Embedded image

[0103]

[Table 8]

Reference Example 3-4- (1)

Embedded image 140 mg (0.39 mm) of benzyl (S) -3-oxo-4-methyl-5-benzyloxymethoxypentanoate
ole) was dissolved in 0.9 ml of benzyl alcohol, 0.2 g of molecular sieve 3A, 50 mg of benzylamine (0.47 mm).
ole) and triethylamine hydrochloride (54 mg, 0.39 mmole) were added, and the mixture was reacted at 80 ° C. for 10 hours. The reaction solution was diluted with chloroform (10 ml), insolubles such as molecular sieves were removed by filtration, and the filtrate was washed with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and then benzyl alcohol was distilled off under reduced pressure. The residue was dissolved in dry toluene, ketene gas was passed at room temperature to confirm the completion of the reaction, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give (R) -2-acetyl-3-benzylamino-4
-Methyl-5-benzyloxymethoxy-2-pentenoic acid benzyl ester was obtained. IR (neat): 1700,1580,1448,1352,1
270 (br), 1097, 1033 (cm ^-1 ).

Reference Examples 3-4- (2) to 3-4- (8) The acetylenamine derivatives shown in the following tables correspond to the corresponding β-
The ketoester derivative was obtained in the same manner as in the method described in Reference Example 3-4- (1).

Embedded image

[0106]

[Table 9]

[Table 10]

Reference Example 3-5

Embedded image Except that glycine benzyl ester was used instead of benzylamine, treatment was conducted in the same manner as described in Reference Example 3-4- (1) to give 2-acetyl-3-benzyloxycarbonylmethylamino-4-methyl-5- There was obtained benzyl t-butoxypentenoate. IR (neat): 1747, 1702, 1588, 1450, 1
358,1190 (cm ^-1 ).

Reference Example 4-1 (1)

Embedded image Acetone dicarboxylic acid dimethyl ester 50 g (0.29 m
mole) in 150 ml of toluene, and benzylamine 3
2.2 g (0.3 mmol) was added, and the mixture was heated to reflux while being dehydrated for 30 minutes. After returning to room temperature, ketene gas was passed through the reaction solution, and the resulting crystals were collected by filtration and recrystallized from ethanol to give dimethyl 2-acetyl-3-benzylamino-2-pentenedioic acid. m. p. 123.5-124.0 ° C. IR (Nujol): 1718, 1685, 1585, 1365,
1092 (cm ^-1 ).

Reference Example 4-1 (2)

Embedded image Acetone dicarboxylic acid dimethyl ester 10 g (57.4 m
mole) and 11.5 g (0.2 mmole) of allylamine,
The same operation as in Reference Example 4-1 (1) was performed to obtain 2-acetyl-3-allylamino-2-pentenedioic acid dimethyl ester. mp 91.5-92.0 ° C. IR (Nujol): 1720, 1690, 1592, 1371,
1100 (cm ^-1 ).

Reference Example 4-2 (1)

Embedded image Under a stream of N ₂ , 1.68 g (42 mmol) of sodium hydride (60%) was added to 10 ml of dry tetrahydrofuran, and 6.2 g of dimethyl 2-acetyl-3-benzylamino-2-pentenedioate under ice cooling. (20 mmole) in 40 ml of dry tetrahydrofuran was added slowly, and
Stirred for minutes. Then, at room temperature, 5.68 g of methyl iodide (4
(0 mmol) and stirred at room temperature for 1 hour and at 40 ° C. for 1 hour. The reaction was stopped by adding water, and the reaction solution was diluted with ethyl acetate. The organic layer was washed successively with water, diluted hydrochloric acid and brine, then dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give 2-acetyl-3-benzylamino-4-methyl-. Dimethyl 2-pentenedioate was obtained. IR (neat): 1735,1698,1582,1427,1
256 (cm ^-1 ).

Reference Example 4-2 (2)

Embedded image 0.8 g (20 mmole) of sodium hydride (60%), 2.55 g (10 mmole) of dimethyl 2-acetyl-3-allylamino-2-pentenedioate, 2.84 g of methyl iodide
(20 mmol) and the same operation as in Reference Example 4-2 (1) was performed to obtain dimethyl 2-acetyl-3-allylamino-4-methyl-2-pentenedioate. IR (neat): 1739,1700,1583,1431,1
262 (cm ^-1 ).

Reference Example 5-1

Embedded image 10.11 g of acetone dicarboxylic acid diethyl ester (5
0 mmol) and 5.57 g (52 mmol) of benzylamine were used, and the same operation as in Reference Example 4-1 (1) was carried out to obtain 2-acetyl-3-benzylamino-2-pentenedioic acid diethyl ester. mp 85-86 ° C.

Reference Example 5-2

Embedded image Sodium hydride (60%) 88 mg (2.2 mmol), 2-acetyl-3-benzylamino-2-pentenedioic acid diethyl ester 333 mg (1 mmol), methyl iodide 156 mg
The same operation as in Reference Example 4-2 (1) was carried out using (1.1 mmole) to obtain diethyl 2-acetyl-3-benzylamino-4-methyl-2-pentenedioic acid diethyl ester. IR (neat): 1730,1696,1580,1438,1
257 (cm ^-1 ).

Reference Example 6-1

Embedded image 1.24 g (9 mmol) of methyl acetoacetate sodium salt prepared from methyl acetoacetate and sodium methylate are suspended in 10 ml of dry toluene, and a solution of 1.12 g (6.8 mmole) of ethyl 2-chloroformylpropanoate in 5 ml of dry toluene is added. It was added dropwise at room temperature. After stirring at the same temperature for 1 hour, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure at 40 ° C. The residue was purified by silica gel chromatography to obtain ethyl 3,5-dioxo-4-methoxycarbonyl-2-methylhexanoate. IR (neat): 1750 (shoulder), 1730 (shoulder),
1720, 1570 (broad), 1435 (cm ^-1 ).

Reference Example 6-2

Embedded image 176 mg (0.72 mmol) of ethyl 3,5-dioxo-4-methoxycarbonyl-2-methylhexanoate was dissolved in 1.3 ml of tetrahydrofuran, and 0.85 ml of a 1.7N aqueous ammonia solution was added at room temperature. After standing at the same temperature overnight, tetrahydrofuran was distilled off under reduced pressure, 0.7 ml of 1N hydrochloric acid and brine were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain methyl 4-ethoxycarbonyl-3-oxopentanoate. IR (neat): 1735, 1720 (shoulder), 1438,
1322, 1240, 1193 (cm ^-1 ). NMR δ (CDCl ₃ ): 1.28 (3H, t, J = 7.1 Hz),
1.37 (3H, d, J = 7.3 Hz), 3.63 (2H, m),
3.74 (3H, s), 4.20 (2H, q, J = 7.1 Hz).

Reference Example 6-3

Embedded image 200 ml (1.06 mmol) of 4-ethoxycarbonyl-3-oxopentanoic acid methyl ester were dried in methanol.
The resulting solution was dissolved in 5 ml, 386 mg (3.6 mmol) of benzylamine and 0.3 g of molecular sieve 3A were added, and under ice cooling, 170 mg (2.17 mmol) of acetyl chloride was added to 0.9 ml of dry methanol, and the solution was adjusted at room temperature. In addition, 16
Left for hours. The molecular sieves were filtered off, the filtrate was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 2.5 ml of toluene, ketene gas was passed through at room temperature, the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give 2-acetyl-3-benzylamino-4-methyl-methyl. 2-Pentenedioic acid methyl ethyl ester was obtained. IR (neat): 1727,1692,1575,1428,1
252 (cm ^-1 ). NMR δ (CDCl ₃ ): 4.52 (m, 3H), 3.71 (s, 3)
H), 2.31 (s, 3H), 1.42 [d (J = 7.3 Hz), 3
H].

Reference Example 7-1

Embedded image 3.65 g of ethyl 2-carboxy-propionate (25 mmo
le) 4.455 g of 1,1'-carbonyldiimidazole (2
7.5 mmole) and 11.275 g (27.5 mmole) of magnesium salt of malonic acid monobenzyl ester were subjected to the same operation as in Reference Example 1-2 to obtain benzyl 4-ethoxycarbonyl-3-oxopentanoate. IR (neat): 1730, 1445, 1370, 1315, 1
230,740,690 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.35 (s, 5H), 5, 17 (s, 2)
H), 4.16 [q (J = 7.0 Hz), 2H], 3.70 [q (J
= 7.0 Hz), 1H], 3.67 (s, 2H), 1.35 [d (J
= 7.0 Hz), 3H], 1.24 [t (J = 7.0 Hz), 3
H].

Reference Example 7-2- (1)

Embedded image 695 mg (2.5 mmol) of benzyl 4-ethoxycarbonyl-3-oxopentanoate, 535 mg (5.
Was dissolved in 1.4 ml of isopropanol, and 260 mg (1.875 mmol) of triethylamine hydrochloride and 0.7 g of molecular sieve 3A in powder form were added thereto.
For 3 to 4 hours. The reaction solution was cooled to room temperature, the insolubles were removed by filtration, the solution after washing with ethyl acetate was combined with the washing solution, diluted with 15 ml of ethyl acetate, washed twice with water, and the organic layer was dried over magnesium sulfate. The solvent was distilled off.
After the residue was sufficiently dried under reduced pressure, dry methylene chloride 20
The reaction solution was washed with aqueous sodium bicarbonate and then with brine, dried over magnesium sulfate, and then the solvent was distilled off. The oily residue was purified by silica gel chromatography to obtain ethyl benzyl 2-acetyl-3-benzylamino-4-methyl-2-pentenedioate. IR (neat): 1733,1692,1578,1450,1
255, 1120, 1085 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.36 (m, 10H), 5.19 (AB
q, 2H), 4.48 (m, 2H), 3.94 (m, 1H), 2.26
(s, 3H), 1.42 [d (J = 7.3 Hz), 3H], 1.15
[t (J = 7.3 Hz), 3H].

Reference Example 7-2- (2)

Embedded image 2-acetyl-3-furfurylamino-4-methyl-2-pentenedioic acid ethyl benzyl ester was prepared in the same manner as described in Reference Example 7-2- (1), except that benzylamine was changed to furfurylamine. I got IR (neat): 1730, 1690, 1580, 1435, 1
248, 1115, 1075 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.36 (m, 5H), 6.32 [dd (J
= 2.0 and 3.3 Hz), 1H], 6.26 [dd (J = 0.7 and 3.3 Hz), 1H], 5.19 (ABq, 2H), 4.43 (m,
2H), 2.24 (s, 3H), 1.46 [d (J = 6.9 Hz),
3H], 1.20 [t (J = 7.3 Hz), 3H].

Reference Example 7-2- (3)

Embedded image Except that benzylamine was replaced with 2-aminoacetaldehyde dimethyl acetal, 2-acetyl-3-dimethoxymethylamino-4-methyl-2-pentenoic acid ethylbenzyl ester was prepared in the same manner as described in Reference Example 3-4. Obtained. IR (neat): 1731,1692,1580,1440,1
358,1243,1125,1070 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.36 (m, 5H), 5.18 (AB
q, 2H), 4.45 [t (J = 5.3 Hz), 1H], 3.42
(S, 6H), 2.24 (s, 3H), 1.22 [t (J = 7.3H)
z), 3H].

Reference Example 7-2- (4)

Embedded image (A) 278 mg (1.0 mmole) of benzyl 4-ethoxycarbonyl-3-oxopentanoate was dissolved in a mixed solvent of 0.4 ml of isopropanol and 0.8 ml of benzyl alcohol, and 605 mg (3.0 mm) of glycine benzyl ester hydrochloride was dissolved.
ole) and 303 mg (3.0 mmole) of triethylamine.
Further, 0.3 g of molecular sieve 3A was added, and the mixture was left at room temperature for 2 days. After removing the impurities by filtration and washing with chloroform,
The solvent was distilled off. The oily residue was subjected to silica gel chromatography to obtain an acetylenamine derivative. (b) The acetylenamine derivative obtained in the above (a) was dissolved in 1 ml of dry methylene chloride, and after completion of the reaction through ketene gas at room temperature, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. 2-acetyl-3-
Benzyloxycarbonylmethylamino-4-methyl-
Ethyl benzyl 2-pentenedioate was obtained. IR (neat): 1750, 1730, 1682, 1580 (b
r), 1452, 1230 (br), 1115, 1042 (cm ^-1 ).

Reference Example 8

Embedded image (a) 509 mg of (2SR, 3RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid ethylbenzyl ester in methanol 5
dissolved in 3 ml, and in the presence of 102 mg of palladium hydroxide carbon powder 3
The mixture was stirred at room temperature under a hydrogen atmosphere of ４4 kg / cm ² . After the disappearance of the raw materials, the catalyst was filtered off, the filtrate and the washings were combined, and concentrated under reduced pressure to give (2SR, 3RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3-amino-4-ethoxy. Carbonylpentanoic acid was obtained. IR (neat): 3350 (br), 1720, 1620 (sh), 1
590 (br), 1205 (cm ^-1 ). (b) (2SR, 3RS, 4RS) -2- [1 (SR) obtained in (a)
-Hydroxyethyl] -3-amino-4-ethoxycarbonylpentanoic acid was suspended in 5 ml of dry acetonitrile, and N, N'-dicyclohexylcarbodiimide 266 was added.
mg was added and the mixture was stirred at room temperature for 10 minutes and then at 60 ° C. for 2 hours. After evaporating the solvent under reduced pressure, 5 ml of ethyl acetate was added to the residue, and the mixture was stirred at room temperature. After allowing the suspension to stand at about 5 ° C. for 5 hours, insolubles were filtered off and washed with cold ethyl acetate. The filtrate and the washings were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography to give (3SR, 4SR) -3- [1 (SR) -hydroxyethyl] -4- [1 (RS) -ethoxy. Carbonylethyl] -2-azetidinone was obtained. IR (neat): 3400 (sh), 3300 (br), 1760 (s
h), 1730 (br), 1455, 1370, 1180 (c
m ^-1 ). NMR δ (CDCl ₃ ): 2.65 (m, 1H), 3.06 [dd (J
= 2.3 and 5.6 Hz), 1H], 3.71 [dd (J = 2.3 and 7.3)
Hz), 1H].

Reference Example 9

Embedded image (a) Dissolve 40 mg (0.1 mmole) of (2SR, 3RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3-furfurylamino-4-pentanedioic acid ethylbenzyl ester in 1 ml of ethanol, 8 mg of 10% palladium-carbon was added, and hydrogenation was performed at normal temperature and normal pressure. After completion of the reaction, the catalyst was filtered off, and the solvent was distilled off under reduced pressure to obtain (2SR, 3RS, 4RS)-
2- [1 (SR) -Hydroxyethyl] -3-furfurylamino-4-ethoxycarbonylpentanoic acid was obtained. IR (neat): 1730, 1705 (sh), 1590, 138
0,1195,1010,750 (cm ^-1 ). (b) (2SR, 3RS, 4RS) -2- [1 obtained in (a)
(SR) -Hydroxyethyl] -3-furfurylamino-
29 mg (0.1 mmole) of 4-ethoxycarbonylpentanoic acid
Was dissolved in 2 ml of dry acetonitrile, 25 mg (0.12 mmole) of dicyclohexylcarbodiimide was added at room temperature, and 6
The temperature was raised to 0 to 65 ° C, and the mixture was stirred for 2.5 hours. After returning to room temperature, dicyclohexylurea was separated by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography.
(3SR, 4SR) -3- [1 (SR) -hydroxyethyl]
4- [1 (RS) -Ethoxycarbonyl] ethyl-1-furfuryl-2-azetidinone was obtained. IR (CHCl ₃ ): 3450 (br), 1740, 1375, 1
178, 1050, 1012 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.37 (m, 1H), 6.33 [dd (J
= 2.0 and 3.3 Hz), 1H], 6.27 [dd (J = 0.7 and 3.3 Hz), 1H], 4.42 (ABq, 2H), 4.02 (m,
1H), 3.61 [dd (J = 2.3 and 5.3 Hz), 1H], 3.
09 (m, 1H), 2.81 (m, 1H), 2.23 [d (J = 5.0
Hz), 1H], 1.19 to 1.29 (9H).

Reference Example 10

Embedded image (2SR, 3RS, 4RS) -2- [1 (RS) -hydroxyethyl] -3-benzylamino-4-methyl-5-phenylthiopentanoic acid p-nitrobenzyl ester 30 mg
2 ml of concentrated hydrochloric acid was added to (0.059 mmole), and the mixture was heated under reflux for 17 hours. The hydrochloric acid was distilled off under reduced pressure, acetonitrile was added to the residue, and excess triethylamine was added dropwise to neutralize. After the solvent and excess triethylamine were distilled off under reduced pressure, acetonitrile 1 ml, 2,2′-dipyridyl disulfide 26 mg
(0.12 mmole) and 31 mg of triphenylphosphine (0.1
(2 mmol) at room temperature and heated to reflux for 5.5 hours. After returning to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give (3SR, 4S
R) -3- [1 (SR) -hydroxyethyl] -4- [1 (R
(S) -Methyl-2-phenylthio] ethyl-1-benzyl-2-azetidinone was obtained. IR (neat): 3430, 1738, 1578, 1437, 1
395, 1375, 1012 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.23 (m, 10H), 4.68 [d
(J = 15.2 Hz), 1H], 3.93 (m, 1H), 3.78
[d (J = 15.2 Hz), 1 H], 3.30 [dd (J = 2.3 and 5.0 Hz), 1 H], 2.50 [dd (J = 9.2 and 12.7 H)
z), 1H], 1.87 (m, 1H), 1.20 [d (J = 6.3H)
z), 3H], 0.97 [d (J = 6.6 Hz), 3H].

Reference Example 11

Embedded image (2SR, 3RS, 4RS) -2- [1 (SR) -hydroxyethyl] -3-allylamino-4-methyl-5-phenylthiopentanoic acid p-nitrobenzyl ester 27 mg
(3SR, 4SR) -3- [1 (SR) -hydroxyethyl] -4- [1 (RS) -methyl-2-phenylthio] by performing the same operation as in Reference Example 10 using (0.06 mmole). Ethyl-1-benzyl-2-azetidinone was obtained. IR (neat): 3425, 1740, 1639, 1439, 1
398,1376,1275,927 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.34 (m, 5H), 5.70 (m, 1)
H), 5.21 (m, 2H), 3.55 [dd (J = 2.3 and 5.0
Hz), 1H], 3.43 [dd (J = 7.3 and 16.8 Hz), 1
H], 3.04 [dd (J = 4.3 and 12.9 Hz), 1H], 2.
87 [dd (J = 1.7 and 6.6 Hz), 1H], 2.65 [dd (J
= 8.9 and 12.9 Hz), 1H], 2.00 (m, 1H), 1.3
1 [d (J = 6.3 Hz), 3H], 1.13 [d (J = 6.9 H
z), 3H].

Reference Example 12-1

Embedded image (3SR, 4SR) -3- [1 (SR) -hydroxyethyl]
30 mg (0.1 mmole) of 4- [1 (RS) -ethoxycarbonyl] ethyl-1-furfuryl-2-azetidinone is dissolved in 0.3 ml of methanol, and 0.2N-NaOH 0.5 is added under ice cooling.
After dropwise addition of ml (0.1 mmol), the mixture was stirred at the same temperature for 10 hours. Ethyl acetate was added to the reaction mixture to dilute it, followed by extraction and separation of an organic layer and an aqueous layer.
Methyl isobutyl ketone was added for extraction. The organic layer was washed with water and brine in that order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give (3SR, 4SR) -3- [1 (SR) -hydroxyethyl] -4- [1 (RS)-. [Carboxy] ethyl-1-furfuryl-2-azetidinone was obtained. mp 125-127 ° C IR (KBr): 3450, 3370, 1723, 1692 (s
h), 1437, 1210 (cm ^-1 ). NMR δ (CD ₃ OD): 4.42 (ABq, 2H), 4.02
(m, 1H), 3.78 (dd (J = 2.3 and 4.6 Hz), 1H),
3.78 (m, 1H) 2.83 (m, 1H), 1.25 (d (J =
6.3 Hz, 3H), 1.16 (d (J = 7.3 Hz), 3H).

Reference Example 12-2

Embedded image In a mixed solvent of 1 ml of ethyl acetate and 0.1 ml of isopropyl alcohol, 20 mg (0.068 mmol) of cinchonidine and 3-
(1'-hydroxyethyl) -4- (1'-carboxyethyl) -1-furfuryl-2-azetidinone [(3S, 4
S, 1'S, 1 "R) :( 3R, 4R, 1'R, 1" S) :( 3S, 4
S, 1'S, 1 "S) :( 3R, 4R, 1'R, 1" R) = 45: 4
5: 5: 5] (20 mg, 0.075 mmole) and dissolved by heating. After allowing to cool and standing at room temperature for 12 hours, the precipitated crystals were separated by filtration and filtered (3S, 4S) -3- [1 (S) -hydroxyethyl] -4- [1 (R) -carboxyethyl] -1. 18.5 mg of furfuryl-2-azetidinone cinchonidine salt were obtained. mp 177.5-178.5 ° C.

The salt was dissolved by adding 1N hydrochloric acid and extracted with methyl isobutyl ketone. The extract was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give (3S, 4S) -3- [1.
9 mg of (S) -hydroxyethyl] -4- [1 (R) -carboxyethyl] -1-furfuryl-2-azetidinone was obtained. This was dissolved in a mixture of 0.4 ml of benzene and 1 ml of methanol, and 40 ml (0.035 mmol) of trimethylsilyldiazomethane (10% hexane solution) was added.
After stirring for minutes, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give (3S, 4S) -3- [1 (S)-
A mixture containing hydroxyethyl] -4- [1 (R) -methoxycarbonyl] ethyl-1-furfuryl-2-azetidinone as a main product was obtained. HPLC analysis (column: OA-3000, developing solution: ED
C-hexane-ethanol = 35-65-4)
(3S, 4S, 1'S, 1 "R): (3S, 4S, 1'S, 1" S):
(3R, 4R, 1'R, 1 "S) = 88: 10: 3 [α] ²⁵ _D = + 24.0 ° (CHCl ₃ ) IR (neat); 3420 (broad) , 1745,1715,13
65, 1193, 1050, 1000 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.37 (m, 1H), 6.33 (m, 1
H), 6.27 (m, 1H), 4.41 (ABq, 2H), 4.02
(m, 1H), 3.69 (s, 3H), 3.61 (dd (J = 2.3 and 5.3 Hz), 1H), 3.09 (m, 1H), 2.82 (m, 1H) 1.
27 (d (J = 6.3 Hz), 3H), 1.21 (d (J = 7.3 H)
z), 3H).

In the above reaction, the use of cinchonidine in place of quinine also allows the use of optically active (3S,
4S) -3- [1 (S) -hydroxyethyl] -4- [1 (R)
-Methoxycarbonyl] ethyl-1-furfuryl-2-
Azetidinone can be obtained.

Reference Example 12-3

Embedded image 8.0 mg of (3S, 4S) -3- [1 (S) -hydroxyethyl] -4- [1 (R) -methoxycarbonyl] ethyl-1-furfuryl-2-azetidinone obtained in Reference Example 12-2 ( 0.
028 mmol) in 0.6 ml of dichloromethane and 0.6 ml of methanol.
After dissolving in 3 ml of the mixture and cooling to -78 ° C, ozone gas was blown. After 30 minutes, the temperature was returned to room temperature, 8 mg (0.03 mmol) of triphenylphosphine was added, and the mixture was stirred for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure.
A mixture of 75 ml and 0.25 ml of methanol was added, and at room temperature, 100 mg (0.088 mmol) of trimethylsilyldiazomethane (10% hexane solution) was added. After stirring at the same temperature for 1 hour, the solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give (3S, 4S) -3.
-[1 (S) -Hydroxyethyl] -4- [1 (R) -methoxycarbonyl] ethyl-1-methoxycarbonylmethyl-2-azetidinone was obtained. IR (CHCl ₃ ); 3470 (br), 1750 (sh), 173
2,1358,1170,1118 (cm ^-1 ). NMR δ (CDCl ₃ ); 4.16 (m, 1H), 4.06 (AB
q, 2H), 3.99 (dd (J = 2.6 and 4.6 Hz), 1H), 3.
76 (s, 3H), 3.70 (s, 3H), 3.10 (dd (J = 2.
6 and 6.6 Hz) 1 H), 2.84 (m, 1 H), 1.33 (d (J =
6.3 Hz), 3H) 1.25 (a (J = 6.9 Hz), 3H).

Reference Example 13-1

Embedded image In a mixture of 1 ml of ethyl acetate and 0.1 ml of isopropyl alcohol, 20 mg (0.065 mmol) of cinchonine and 3- (1-
(Hydroxyethyl) -4- (1-carboxyethyl) -1
-Furfuryl-2-azetidinone [(3S, 4S, 1'S,
1 "R) :( 3R, 4R, 1'R, 1" S) :( 3S, 4S, 1'S,
1 "S) :( 3R, 4R, 1'R, 1" R) = 45: 45: 5:
5] 20 mg (0.075 mmole) was added and dissolved by heating. After allowing to cool and standing at room temperature for 24 hours, the precipitated crystals were separated by filtration and filtered (3R, 4R,)-3- [1 (R) -hydroxyethyl]-.
4- [1 (S) -carboxyethyl] -1-furfuryl-2
-17 mg of azetidinone cinchonine salt were obtained. mp 170-172 ° C. The above-mentioned cinchonine salt was post-treated in the same manner as in Reference Example 12-2.
(3S, 4S, 1'S, 1 "R): (3R, 4R, 1'R, 1" S):
(3R, 4R, 1′R, 1 ″ R) = 6.5: 93: 0.5 was obtained. [Α] ²⁵ _D = + 26.4 ° (CHCl ₃ ) NMR and IR are reference This was consistent with that obtained in Example 12-2.

Reference Example 13-2

Embedded image 8.0 mg of (3R, 4R) -3- [1 (R) -hydroxyethyl] -4- [1 (S) -methoxycarbonyl] ethyl-1-furfuryl-2-azetidinone obtained in Reference Example 13-1 And (3R, 4R) -3-as in Reference Example 12- (3).
[1 (S) -hydroxyethyl] -4- [1 (R) -methoxycarbonyl] ethyl-1-methoxycarbonylmethyl-
2-azetidinone was obtained. [α] ²⁵ _D = -11.3 ° (CHCl ₃ ) NMR and IR were the same as those obtained in Reference Example 12-3.

Reference Example 14

Embedded image (a) (3SR, 4SR) -3- [1 (SR) -hydroxyethyl] -4- [1 (RS) -ethoxycarbonyl] ethyl-1
-Furfuryl-2-azetidinone (30 mg, 0.1 mmole) was dissolved in dry tetrahydrofuran (0.3 ml) under a stream of N ₂ , and triphenylphosphine (31 mg, 0.12 mmol) was added under ice cooling.
e) 7 mg (0.15 mmole) of formic acid (98-100%) was added in order, and the mixture was stirred at the same temperature for 5 minutes. After addition of 23 mg (0.13 mmole) of diethyl azodicarboxylate, the mixture was heated and stirred at room temperature for 21 hours. After evaporating the solvent under reduced pressure, the residue is purified by silica gel chromatography to give (3SR, 4SR) -3- [1 (RS) -formyloxyethyl] -4- [1 (RS) -ethoxycarbonyl] ethyl-1. -Furfuryl-2-azetidinone was obtained. IR (CHCl ₃ ): 3325,1738 (sh), 1720,1
395, 1205 (br), 1170 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.97 (s, 1H), 7.38 (m, 1
H), 6.34 [dd (J = 2.0 and 3.3 Hz), 1H], 6.2
6 [d (J = 3.3 Hz), 1H], 5.28 (m, 1H), 4.4
2 (ABq, 2H), 4.16 [q (J = 7.3 Hz), 2H],
3.63 [dd (J = 2.0 and 4.6 Hz), 1H], 3.28 [dd
(J = 2.0 and 7.3 Hz), 1H], 2.85 (m, 1H), 1.
38 [d (J = 6.3 Hz), 3H], 1.26 [t (J = 7.3 H)
z), 3H], 1.18 [d (J = 7.3 Hz), 3H].

(B) 9.0 mg of (3SR, 4SR) -3- [1 (RS) -formyloxyethyl] 4- [1 (RS) -ethoxycarbonyl] ethyl-1-furfuryl-2-azetidinone
(0.029 mmole) was dissolved in methanol (0.2 ml), anhydrous sodium acetate (12 mg, 0.15 mmole) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, the organic layer was washed with water and brine in that order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (3SR, 4S
R) -3- [1 (RS) -hydroxyethyl] -4- [1 (R
S) -Ethoxycarbonyl] ethyl-1-furfuryl-2
-Azetidinone was obtained. IR (CHCl ₃ ): 3450,1732,1370,117
8,1050,1005 (cm ^-1 ). NMR δ (CDCl ₃ ): 7.37 (m, 1H), 6.33 [dd (J
= 2.0 and 3.3 Hz), 1H], 6.26 [d (J = 3.3H)
z), 1H], 4.43 (ABq, 2H), 4.15 [q (J = 7.
3Hz), 2H], 3.72 [dd (J = 2.0 and 5.6Hz), 1
H], 3.05 [dd (J = 1.3 and 6.3 Hz), 1H], 2.8
2 (m, 1H), 2.32 (broad s, 1H), 1.21-1.3
0 (9H).

Reference Example 15

Embedded image 105 mg of a mixture of 2- [1-hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid diethyl ester (10a) and (10b) obtained in Example 14 was dissolved in 0.9 ml of dry dichloromethane, and the mixture was dissolved at room temperature in 1 ml. After hydrogen chloride gas was blown in for an hour, the mixture was further stirred for 1.5 hours. The reaction solution was diluted with 10 ml of diethyl ether and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted again with diethyl ether, the diethyl ether layers were combined, washed repeatedly with a saturated saline solution, dried over magnesium sulfate, distilled off with a solvent, and the oily residue was purified by thin-layer chromatography. (2S
Ethyl (R, 3SR, 4RS, 5RS) -tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyran-3-carboxylate was obtained. IR (Nujol): 1730, 1715, 1282, 1198,
1175, 1102 (cm ^-1 ). NMR δ (CDCl ₃ ): 1.26 [t (J = 6.9 Hz), 3
H], 1.33 [d (J = 6.6 Hz), 3H], 1.45 [d (J
= 6.6 Hz), 3H], 2.36 [dq (J = 8.25 and 6.6
Hz), 1H], 2.77 [dd (J = 2.0 and 3.0 Hz), 1
H], 3.02 [dd (J = 2.0 and 8.25 Hz), 1H], 3.0.
71 [d (J = 13.2 Hz), 1H], 3.88 [d (J = 13.2 Hz)
2Hz), 1H], 4.18 [dq (J = 1.3 and 6.9Hz), 1
H], 4.74 [dq) J = 3.0 and 6.6 Hz), 2H].

Reference Example 16

Embedded image 2- [1-hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid dimethyl ester obtained in Example 4
Dissolve 2.15 g of the mixture of (4a) and (4b) in 18 ml of dry dichloromethane, blow in hydrogen chloride gas at room temperature for 1 hour, stir as it is for 1 hour, and concentrate the reaction solution under reduced pressure at 30 to 40 ° C. Diethyl ether was added to the concentrated solution with stirring, and (2SR, 3SR, 4RS, 5RS) -tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyran-3-carboxylic acid methyl hydrochloride was added. Obtained as crystals. mp 159.5-161 ° C (dec.).

Reference Example 17

Embedded image 140 mg (10a: 10b = 5: 2) of 2- [1-hydroxyethyl] -3-benzylamino-4-methylpentanedioic acid diethyl ester obtained in Example 14 was dissolved in 4 ml of tetrahydrofuran, and 250 mg of barium hydroxide was added. After
2 ml of water was added and stirred vigorously at room temperature for 45 minutes. After filtering off the insoluble matter and washing with ethanol, the filtrate was concentrated under reduced pressure. The residue was checked by silica gel thin layer chromatography. A new spot was found, and spots were also found in the raw material portion and the origin portion. The residue was subjected to silica gel thin layer chromatography, and the newly formed spot was fractionated and purified (2RS, 3
70 mg of (RS, 4SR, 5SR) -2-methyl-3-benzylamino-4-ethoxycarbonyl-5-hydroxy-hexanoic acid were obtained. IR (neat): 1730,1600,1455,1380,1
180, 1105, 1020, 745 (cm ^-1 ). NMR δ (CDCl ₃ ): 1.23 [d (J = 6.6 Hz), 3
H], 1.27 [d (J = 6.9 Hz), 3H], 1.29 [t (J =
7.3Hz), 3H], 2.61 [dd (J = 2.6 and 2.9H
z), 1H], 2.82 (m, 1H), 3.17 [dd (J = 3.0 and 5.6 Hz), 1H], 3.74 [d (J = 13.2 Hz), 1
H], 3.83 [dq (J = 3.0 and 6.6 Hz), 1H].

Reference Example 18

Embedded image (2SR, 3SR, 4RS, 5RS) -tetrahydro-2,5
-Dimethyl-6-oxo-4-benzylamino-2H-
Ethyl pyran-3-carboxylate 3mg and barium hydroxide 7
mg was vigorously stirred at room temperature for 1 hour in a mixture of tetrahydrofuran-water (2: 1). The reaction solution was treated in the same manner as in Reference Example 17, and (2RS, 3RS, 4SR, 5SR) -2
-Methyl-3-benzylamino-4-ethoxycarbonyl-5-hydroxy-hexanoic acid was obtained. This product had the same IR and NMR spectra as those obtained in Reference Example 17.

Reference Example 19

Embedded image (2SR, 3SR, 4RS, 5RS) -tetrahydro-2,5
-Dimethyl-6-oxo-4-benzylamino-2H-
62 mg of pyran-3-carboxylic acid methyl hydrochloride was dissolved in 4 ml of tetrahydrofuran, 166 mg of barium hydroxide and 2 ml of water were added, and the mixture was vigorously stirred at room temperature for 1 hour. The reaction solution was treated in the same manner as in Reference Example 17, and (2RS, 3RS, 4
SR, 5SR) -2-methyl-3-benzylamino-4-
Methoxycarbonyl-5-hydroxy-hexanoic acid was obtained. IR (Nujol): 3300, 1715, 1450, 1400,
1370 (cm ^-1 ).

Reference Example 20

Embedded image (2SR, 3SR, 4RS, 5RS) -tetrahydro-2,5
-Dimethyl-6-oxo-4-benzylamino-2H-
110 mg of methyl pyran-3-carboxylate hydrochloride was dissolved in 0.9 ml of concentrated hydrochloric acid and refluxed for 2 hours. After cooling, the reaction solution was diluted with ethanol and evaporated under reduced pressure. The residue was purified by thin layer chromatography, and (2SR, 3SR, 4RS, 5R
S) -tetrahydro-2,5-dimethyl-6-oxo-4
-Benzylamino-2H-pyran-3-carboxylic acid was obtained. IR (neat): 1722,1450,1385,1205,1
050 (cm ^-1 ).

Reference Example 21

Embedded image (2SR, 3SR, 4RS, 5RS) -tetrahydro-2,5
-Dimethyl-6-oxo-4-benzylamino-2H-
100 ml of pyran-3-carboxylic acid was dissolved in 20 ml of acetic acid, and palladium hydroxide-carbon powder [J. Am. Chem. Soc., 8
3, 4798 (1961). ] And stirred at room temperature under a hydrogen atmosphere of ³ to 4 kg / cm ² .
After the disappearance of the raw materials, the catalyst was filtered off, the catalyst was washed with water, the filtrate and the washing were combined, and concentrated under reduced pressure at 40 ° C. (2SR, 3SR, 4
(RS, 5RS) -tetrahydro-2,5-dimethyl-6-
Oxo-4-amino-2H-pyran-3-carboxylic acid was obtained. IR (neat): 3400 (broad), 1720, 1385, 12
15,1107 (cm ^-1 ). NMR δ (CD ₃ OD): 1.41 [d (J = 5.9 Hz), 3
H], 1.49 [d (J = 6.3 Hz), 3H], 2.95 (m, 1
H), 3.69 [dd (J = 3.0 and 9.4 Hz), 1H], 5.0
0 (m, 1H).

Reference Example 22

Embedded image 340 mg (1.1 mmole) of (2RS, 3RS, 4SR, 5SR) -2-methyl-3-benzylamino-4-methoxycarbonyl-5-hydroxyhexanoic acid and 393 mg (1.5 mmole) of triphenylphosphine in 6 ml of dry toluene. Then, 151.5 mg (1.5 mmole) of triethylamine was added, the mixture was cooled to -15 ° C, 261 mg (1.5 mmole) of diethyl azodicarboxylate was added, and the mixture was stirred at -10 to -5 ° for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (2RS, 3SR, 4RS,
5RS) -tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyran-3-carboxylic acid methyl ester 190 mg and (2SR, 3SR, 4RS, 5RS)-
Methyl tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyran-3-carboxylate
55 mg were obtained.

(2RS, 3SR, 4RS, 5RS) spectral data IR (neat): 3300,1715,1220,1058
(cm ^-1 ). NMR δ (CDCl ₃ ): 1.37 [d (J = 6.3 Hz), 3H],
1.42 [d (J = 7.3 Hz, 3H), 2.55 (m, 1H), 2.
67 [t (J = 10.6 Hz), 1 H], 3.15 [dd (J = 9.6
And 10.6 Hz], 1H], 3.78 [s, 3H], 4.51 [dq
(J = 10.6 and 7.3 Hz), 1H].

(2SR, 3SR, 4RS, 5RS) spectral data IR (neat): 1740,1450,1390,128
0, 1200, 1172, 1105, 740 (cm ^-1 ). NMR δ (CDCl ₃ ): 1.34 [d (J = 6.6 Hz), 3
H], 1.43 [d (J = 6.6 Hz, 3H), 2.38 [dq (J =
8.25 and 6.6 Hz)], 1H], 2.80 [dd (J = 2.0 and 2.6 Hz), 1H], 3.02 [dd (J = 2.0 and 8.25H)
z], 1H], 3.71 [d (J = 12.9 Hz), 1H], 3.71
[s, 3H], 3.88 [d (J = 12.9 Hz), 1H], 4.74
[dq (J = 2.6 and 6.6 Hz), 1H].

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location C07D 307/52 C07D 307/52 405/06 205 405/06 205 // C07D 205/08 309/30 D 309 / 30 9159-4C 205/08 K (72) Inventor Haruki Matsumura 3-1-198 Kasuganaka, Konohana-ku, Osaka-shi, Osaka Sumitomo Pharmaceutical Co., Ltd. (56) References JP-A-62-116550 (JP, A)

Claims (6)

(57) [Claims] 1. The formula: embedded image [Wherein, R represents a lower alkyl group, R ₁ represents a hydrogen atom or a protecting group for a carboxyl group, R ₂ represents a hydrogen atom, a protecting group for an amino group, and a compound represented by the formula: (Wherein, R ₃ and R ₄ may be the same or different and each represent a hydrogen atom, a lower alkyl group or an aryl group.)
A hydroxyl group is a protected or unprotected β-hydroxyethyl group, a formyl group is a protected or unprotected formylmethyl group, a carboxyl group is a protected carboxylmethyl group or a 2-furylmethyl group, and X is protected or unprotected. carboxyl group or the formula is a protected: (wherein, R ₅ is an aryl group or Ala (lower) alkyl group.) -CH ₂ SR ₅ represents a substituent represented by. ] An amino acid derivative represented by 2. The method according to claim 1, wherein R represents a methyl group.
The amino acid derivative according to the above item. 3. The amino acid derivative according to claim 1, wherein X represents a protected or unprotected carboxyl group. 4. The amino acid derivative according to claim 1, wherein X represents a substituent represented by the formula: —CH ₂ SR ₅ . Wherein R ₂ is a benzyl group, 2-propenyl group,
The amino acid derivative according to any one of claims 1 to 4, which represents a 2,2-dimethoxyethyl group or a 2-furylmethyl group. 6. The formula: embedded image [Wherein, R represents a lower alkyl group, R ₁ represents a hydrogen atom or a protecting group for a carboxyl group, R ₂ represents a hydrogen atom, a protecting group for an amino group, and a compound represented by the formula: (Wherein, R ₃ and R ₄ may be the same or different and each represent a hydrogen atom, a lower alkyl group or an aryl group.) A substituted or unsubstituted allyl group represented by the formula: Represents a β-hydroxyethyl group, a formylmethyl group in which a formyl group is protected or unprotected, a carboxylmethyl group or a 2-furylmethyl group in which a carboxyl group is protected, X represents a protected or unprotected carboxyl group or formula: (wherein, R ₅ is an aryl group or Ala (lower) alkyl group.) -CH ₂ SR ₅ represents a substituent represented by. A compound represented by the formula: [Wherein, R, R ₁ , R ₂ and X have the same meaning as described above. A method for producing an amino acid derivative represented by the formula: