JPS63233950A - 3-hydroxyalkanoic acid derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is hydroxyalkyl which may be protected; R<2> is alkyl; R<3> is R<1>, H or alkyltrisubstituted silyl; R<4> is (substituted)OH or (substituted)amino or a salt thereof. EXAMPLE:5-Benzyloxy-2-[1-tertiary butyldimethylsilyloxyethyl)-3-hydroxy-N-me thoxy-4-methylpentanamide. USE:An intermediate for producing an 1-alkylcarbapenem compound having strong antibacterial action on many pathogenic bacteria. PREPARATION:For example, a compound shown by formula II is reacted with a compound shown by formula III (R<4> is substituted OH; R<5> is OH-protecting group) to give a corresponding compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 3-hydroxyalkanoic acid derivatives and salts thereof, and methods for producing the same.

More specifically, the present invention relates to novel 3-hydroxyalkanoic acid derivatives and salts thereof useful as intermediates for the production of antibacterial agents, and methods for producing the same.

That is, one of the objects of the present invention is to develop novel 3-hydroxyalkanoic acid derivatives and their salts, which are useful intermediates for the production of 1-(lower) alkylcarbapenem compounds that have strong antibacterial effects against many pathogenic bacteria. It is about providing.

Another object of the present invention is to provide a method for producing 3-hydroxyalkanoic acid derivatives and salts thereof.

The 3-hydroxyalkanoic acid derivative of this invention can be represented by the following general formula.

[wherein R1 is a protected or unprotected hydroxy (lower) alkyl group, R2 is a lower alkyl group, R
3 means hydrogen, a lower alkyl group, a protected or unprotected hydroxy (lower) alkyl group, or a trisubstituted silyl group, R4 means a hydroxy group, a substituted hydroxy group, an amino group or a protected amino group ] or its salts.

In the object compound (I) of this invention, compound (I)
One or more pairs of stereoisomers such as optically active isomers based on asymmetric carbon atoms may exist in the 2-, 3-, and 4-positions and the substituent in the 2-position, but such isomers shall also be included within the scope of this invention.

However, among the target compounds (I) of this invention, the compound represented by the following chemical formula (I') is most preferred, and in this invention, the production of compound (I') proceeded with high stereoselectivity.

. 2 (wherein R, R, R and R4 have the same meanings as before) or salts thereof.

That is, the features of the present invention mainly reside in the optically active compound of the above formula (■') and a novel method for producing the same.

Suitable salts of the target compounds (I) and (I') include inorganic base salts, such as alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. , ammonium salts, organic base salts, such as triethylamine salts, pyridine salts, pilin salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N
, organic amine salts such as N'-dibenzylethylenediamine salts, and salts with commonly used bases.

In the field of carbapenem antibiotics, it is well known that 1β-methylcarbapenem compound (A) has higher chemical and metabolic stability;
Control of positional stereochemistry is an important issue in the synthesis of carbapenem compounds using this system.

(wherein R means a group well known in the field of carbapenem antibiotics).

In recent research on the synthesis of 1β-methylcarbapenem compounds, the following azetidinone compound (B) has been considered to be one of the most important intermediates used in the synthesis of 1β-methylcarbapenem compounds.

The azetidinone compound (B) can be produced, for example, by the following reaction formula (2).

Reaction Formula I (Japanese Patent Publication No. 61-275267) However, this method has several drawbacks as described below.

b) Uses a special and dangerous reagent, namely "Bu2BOTf."

(i) expensive chiral reagents, i.e. Go.

(i) The raw material compound 4-acetoxyazetidin-2-one is produced, for example, by a process shown in the following reaction formula (2), but its production is somewhat difficult and the yield is relatively low.

- OOH C00CH3 COOCH3 [Tetrahedron, 3rd
Volume 9, No. 15, pp. 2505-2513, 1983]
Considering the above drawback (i>-(i)), it can be said that the above-mentioned methods of reaction formulas (1) and (2) are not satisfactory as industrial synthesis methods for 1β-methylcarbapenem compounds.

Although the inventors of this invention have succeeded in providing a method that is significantly superior to conventional methods, this invention can also be easily applied to the industrial synthesis of 1β-methylcarbapenem compounds.

According to this invention, the target compound (I), its salts, and azetidinone derivatives that can be used in the total synthesis of 1-(lower) alkylcarbapenem compounds can be produced by the production method shown in the reaction formula below.

Production method I (]I) or salts thereof Jutohuo 1 (Ib) or salts thereof (Ic) or salts thereof Production method 3 (Id) or reactive derivatives at the hydroxyl group or salts thereof or salts thereof [In the formula, R, R and R each have the same meaning as before, R1 is a protected hydroxyl lower alkyl group, R
is a substituted hydroxy group, Rb is a hydroxy group or a substituted hydroxy group, R.4 is an amine group or a protected amine group, Rd is a protected amine group, R is a hydroxy protecting group, R6 is an amide protecting group , R7 means a lower alkyl group, R8 means hydrogen or a trisubstituted silyl group] Compounds (V), (■) or salts thereof are known for producing carbapenem compounds by the method described in the production example below. It can also be easily converted into azetidinone compounds, which are useful and important intermediates.

In this specification, preferred examples and explanations of various definitions falling within the scope of this invention will be described in detail below.

"Lower" shall mean 1 to 6 carbon atoms unless otherwise specified.

Suitable r-unprotected hydroxy (lower) alkyl groups include hydroxymethyl, hydroxyethyl,
Mention may be made of straight or branched lower alkyl groups having a hydroxy group, such as hydroxypropyl, 1-(hydroxymethyl)ethyl, 1-hydroxy-1-methylethyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc. Among them, more preferred examples are hydroxy(01-C,)alkyl groups, most preferred are hydroxymethyl group for R1 and 1 for R3.
-hydroxyethyl group.

A suitable "protected hydroxy (lower) alkyl group" means a hydroxy group which is a conventional hydroxy protecting group such as the acyl group described below in the description of the amide protecting group;
or a(lower) alkyl group such as di- or triphenyl(lower) alkyl group; e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,
Tri(lower)alkylsilyl groups such as tertiary butyldimethylsilyl, diisopropylmethylsilyl, thexyldimethylsilyl, triarylsilyl groups such as triphenylsilyl, trial(
It means the aforementioned hydroxy(lower) alkyl group protected by a trisubstituted silyl group such as a lower) alkylsilyl group.

A more preferable example of the protected hydroxy (lower) alkyl group in this sense is (phenyl (or nitrophenyl) (01-C4) alkoxy) carbonyloxy (C-C) alkyl L (phenyl (01 -C)alkoxy)(01-C4)alkyl group and (tri(C1-C4)alkylsilyloxy)(
01-C4) alkyl groups, most preferably R and R1 benzyloxymethyl groups, R3
1-trimethylsilyloxyethyl group, 1-triethylsilyloxyethyl group and 1-tert-butyldimethylsilyloxyethyl group.

A suitable "lower alkyl group" for R7 shall mean 1 to 5 carbon atoms.

Suitable lower alkyl groups include methyl, ethyl,
Straight chain or branched chain alkyl groups such as propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, etc. are mentioned, and among them, more preferred examples include 01-C
4 alkyl groups, most preferably,
Examples include methyl groups for R2 and R7, and ethyl groups for R3.

Suitable tri-substituted silyl groups include the same groups as mentioned above for the protected hydroxy (lower) alkyl group, and more preferred among them are tri-(01-C4) alkylsilyl groups. The most preferred group is trimethylsilyl group.

Suitable "substituted hydroxy groups" include, for example, lower alkoxy groups such as methoxy, ethoxy, propoxy, impropoxy, butoxy, imbutoxy, tertiary butoxy, pentyloxy, hexyloxy, etc. It may have at least one substituent, such as acetoxymethoxy, propionyloxymethoxy, butyryloxymethoxy, valeryloxymethoxy, pivaloyloxymethoxy, hexanoyloxymethoxy, 1-(or 2-)acetoxy ethoxy, 1-
(or 2- or 3-)acetoxypropoxy, 1-
(or 2- or 3- or 4-)acetoxybutoxy, 1-(or 2-)propionyloxyethoxy,
1-(or 2-or 3-)propionyloxypropoxy, 1-(or 2>-butyryloxyethoxy,
1-(or 2-)isobutyryloxyethoxy, 1-
(or 2-)pivaloyloxyethoxy, 1-(or 2-)hexanoyloxyethoxy, isobutyryloxymethoxy, 2-ethylbutyryloxymethoxy, 3
．． Lower plucyloxy (lower) alkoxy groups such as 3-dimethylbutyryloxymethoxy, 1-(or 2-)pentanoyloxyethoxy, lower alkanesulfonyl (lower) alkoxy groups such as 2-mesylethoxy, e.g. - Mono (or di or tri) halo (lower) such as iodoethoxy, 2,2,2-trichloroethoxy, etc.
Alkoxy groups, such as lower alkoxycarbonyloxy such as methoxycarbonyloxymethoxy, ethoxycarbonyloxydimethoxy, propoxycarbonyloxymethoxy, tertiary butoxycarbonyloxymethoxy, 2-methoxycarbonyloxyethoxy, 1-ethoxycarbonyloxyethoxypropoxycarbonyloxyethoxy (lower) alkoxy group, phthalidylidene (lower) alkoxy group, or for example (5-methyl-2-oxo-1,3-dioxo-4-yl)methoxy, (5-ethyl-2-oxo-1,3- Dioxo
[5-4-yl)methoxy, (5-propyl-2-oxo-1,3-dioxo-4-yl)ethoxy, etc.
-(lower)alkyl-2-dioxo-1,3-dioxo-
-4-ylco(lower)alkoxy group; lower alkenyloxy group such as vinyloxy, allyloxy; lower alkynyloxy group such as ethynyloxy, propynyloxy; e.g. benzyloxy, 4-methquinbenzyloxy, 4-nitrobenzyloxy , phenethyloxy, trityloxy, benzhydryloxy, bis(
Al (lower) alkoxy which may have at least one suitable substituent such as methoxyphenyl)methoxy, 3,4-dimethoxybenzyloxy, 4-hydroxy-3,5-ditertiary butylbenzyloxy, etc. Groups; for example, phenoxy, 4-chlorophenoxy, tolyloxy, tert-butylphenoxy, xylyloxy, mesityloxy,
Examples thereof include an aryloxy group which may have at least one suitable substituent such as cumenyloxy; a phthalidyloxy group, and the like.

Preferred examples of the "substituted hydroxy group" include 01-C4 alkoxy groups, most preferably methoxy and ethoxy groups.

A "substituted hydroxy group" in this sense can be combined with an adjacent carbonyl (co-)J to form a so-called esterified carboxy group.

"Suitable 1-hydroxy protecting group" refers to commonly used hydroxy protecting groups such as those mentioned in the explanation of the protected hydroxy (lower) alkyl group, among which more preferred examples include tri(C1-C4 ) alkylsilyl groups, most preferably trimethylsilyl groups and triethylsilyl groups.

Suitable "protected amino groups" include lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc., such as benzyloxy, phenethyloxy, trityloxy, benzhydryloxy, etc. Examples include amine groups substituted with commonly used amino protecting groups such as Al (lower) alkoxy groups, and more preferred protecting groups include C
-C alkoxy groups and phenyl(01-C4) alkoxy groups, most preferably methoxy and benzyloxy groups.

Suitable "amide protecting groups" include, for example, lower alkoxy groups such as methoxy, ethoxy, propoxy, impropoxy, butoxy, pentyloxy, and hexyloxy; (lower) alkoxy group; substituted with carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, and aromatic or heterocyclic groups derived from carboxylic acids, hypoacids, sulfonic acids, and carbamic acids Commonly used amide protecting groups such as aliphatic acyl groups may be mentioned.

Aliphatic acyl groups include saturated or unsaturated, acyclic or cyclic acyl groups, such as lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc., e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,
Alkylsulfonyl groups such as lower alkylsulfonyl groups such as butylsulfonyl, imbutylsulfonyl, benzylsulfonyl, hexylsulfonyl, etc., N-alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Alkoxycarbonyl groups such as lower alkoxycarbonyl groups such as butoxycarbonyl, tertiary butoxycarbonyl, alkenoyl groups such as lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl, etc., such as cyclopropanecarbonyl, cyclobencunecarbonyl, Examples include cycloalkanecarbonyl groups such as cyclo(lower)alkanecarbonyl groups such as cyclohexanecarbonyl.

Examples of the aromatic acyl group include aroyl groups such as benzoyl and toluoylcarbamoyl, N-arylcarbamoyl groups such as N-phenylcarbamoyl, N-tolylcarbamoyl, and N-naphthylcarbamoyl, and arenesulfonyl groups such as benzenesulfonyl and tosyl. Examples include groups.

Examples of the heterocyclic acyl group include furoyl, thenoyl,
Examples include heterocyclic carbonyl groups such as nicotinoyl, innicinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl.

Examples of aliphatic acyl groups substituted with aromatic groups include aralkayl groups such as phenyl (lower) alkanoyl groups such as phenylacetyl, phenylpropionyl, and phenylhexanoyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, etc. Phenyl (lower)
Examples thereof include aralkyl carbonyl groups such as alkoxycarbonyl groups, and aryloxydialkanoyl groups such as phenoxy (lower) alkanoyl groups such as phenoxyacetyl and phenoxypropionyl.

Examples of the aliphatic acyl group substituted with a heterocyclic group include thhenylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolylacetyl, thenylpropionyl, thiadiazolylpropylene Examples include heterocyclic alkanoyl groups such as heterocyclic (lower) alkanoyl groups such as

These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogens such as chlorine, bromine, iodine, fluorine, methoxy, ethoxy, propoxy, impropoxy, Lower alkoxy groups such as butoxy, pentyloxy, hexyloxy, e.g. methylthio,
It may be substituted with one or more suitable substituents such as a lower alkylthio group such as ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc., a nitro group, etc. Preferred acyl groups having such substituents include is a mono(or di- or tri)haloalkanoyl group such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, mono(or di- or tri)haloalkanoyl group such as chloromethoxycarbonyl, 2,2.2-trichloroethoxycarbonyl, etc. tri)haloalkoxycarbonyl groups, such as nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl, nitro (or halo or lower alkoxy) aralkoxycarbonyl groups, such as fluoromethylsulfonyJL-, difluoromethyl Examples include mono(or di- or tri)halo-lower alkylsulfonyl groups such as sulfonyl, trifluoromethylsulfonyl, and trichloromethylsulfonyl.

Preferred examples of the "1-amide protecting group" in this sense include a C1-C4 alkoxy group and a phenyl(01-C4) alkoxy group, and most preferred examples include a methoxy group and a benzyloxy group.

The method for producing the target compound (I), the azetidinone compound derived therefrom, and the salts thereof will be explained in detail below.

(1) Production method 1 Compound (Ia) or a salt thereof can be produced by reacting compound (I[) with compound (I[I) or a salt thereof.

Suitable salts of compounds (Ia) and (I[[) include salts with bases such as those listed for compound (I).

Compound (I[[) is published, for example, in the Journal of Organic Chemistry (J, Org, Chem,
) Volume 45, p. 237, 1980 or Synthetic Communication (5ynth, Commun,
), Vol. 3, p. 67, 1973, by a slightly modified method.

In this reaction, the 3,4-anti compound of (Ia) is mainly produced, especially when R3 is a lower alkyl group, a trisubstituted silyl group or an optically active protected hydroxy (lower) alkyl group. Ru.

In order to obtain compound (Ia) with high stereoselectivity in this reaction, compound (Ia) is preferably obtained in the presence of an accurate amount of Lewis acid.
Preferably, this is carried out in the presence of an equivalent amount to II).

Suitable examples of Lewis acids include aluminum halides such as aluminum chloride and aluminum bromide, boron trihalides such as boron trichloride, boron trifluoride, and boron trifluoride ether adducts, such as zinc chloride, Zinc halides such as zinc bromide, stannic halides such as stannic chloride, titanium halides such as titanium chloride (IV), titanium (lower) alkoxides such as titanium (IV) impropoxide, etc. , or a mixture thereof.

This reaction can be carried out in conventional solvents that do not adversely affect the reaction, such as diethyl ether, toluene, benzene, chloroform, dichloromethane, dichloroethane, etc., or mixtures thereof.

The reaction temperature for this reaction is not particularly limited, but the reaction is usually carried out under cooling or heating.

When R3 is a tri-substituted silyl group, the tri-substituted silyl group can be easily eliminated, for example, by treatment with an alkali metal fluoride such as potassium fluoride as shown in the reaction formula below.

(Ie) (If) or its salts or its salts (wherein R, R and R4
each has the same meaning as before, and R3 means a trisubstituted silyl group).

Suitable salts of compounds (Ie) and (If) include:
The same salts as compound (I) can be mentioned.

This reaction involves water, alcohols such as methanol, ethanol, propatool, dioxane, acetonitrile,
in a customary solvent that does not adversely affect the reaction, such as chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, pyridine, etc., or in a mixture thereof. Can be done.

The reaction temperature for this reaction is not particularly limited, but the reaction is usually carried out under cooling or heating.

R3 is a protected or unprotected hydroxy (
(lower) alkyl group, titanium(IV) chloride
It is preferable to use titanium trichloride (■), [TiC130CH(CH3)2], prepared by mixing (mol ratio 3:1) with titanium (It/)impropoxide.

Furthermore, R3 is protected 1-hydroxy (lower)
In the case of an alkyl group, it is preferable to use an optically active (IR)-1-hydroxy (lower) alkyl group in order to obtain compound (Ia) with high stereoselectivity.

When R3 is a protected hydroxy (lower) alkyl group, the hydroxy protecting group may be eliminated in the target compound (■8), but the resulting hydroquine (lower)
Alkyl groups can be easily protected by conventional methods as shown in the Examples below.

(2) Production method 2 Compound (Ic) or a salt thereof can be produced by reacting compound (Ib) or a salt thereof with compound (IV) or a reactive derivative thereof or a salt thereof.

Suitable salts of compounds (Ib) and (Ic) include:
The same salts as those of compound (I) can be mentioned.

Suitable salts of compound (IV) include, for example, hydrochloride,
Inorganic acid addition salts such as hydrobromides, sulfates, phosphates, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonic acids Examples include organic acid addition salts such as salts.

Compound (Ib) in which Rb is a hydroxy group is a compound (
It can be produced by hydrolyzing Ia) in a conventional manner.

A preferred reactive derivative of compound (IV) is 5ynth.

It can be produced by reacting compound (II/) or a salt thereof with a tri(lower)alkylaluminum in a manner similar to that described in Common, Vol. 12, p. 989, 1982.

When R6 is a hydroxy group, the reaction of compound (Ib) with compound (IV) or a salt thereof can be performed using, for example, N
, N'-diethylcarbodiimide, N.

N'-diisopropylcarbodiimide, N,N'-cyclohexylcarbodiimide, N-cyclohexyl-N
'-morpholinoethylcarfosiimide, 8-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropylbodiimide, its hydrochloride, etc.) or Water-soluble carbodiimide compound: N,N'-
Carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole); Ketenimine compounds such as pentamethyleneketeneimine-N-cyclohexylimine, diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-alfoxy-1-chloro Ethylene; Ethyl polyphosphate; Isopropyl polyphosphate;
Combination of triphenylphosphine and carbon tetrachloride or diazendirupoxylate; 2-ethyl-7-hydroxybenziinxazolium salt; 2-ethyl-5-(
m-sulfophenyl) isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)
-6-chloro-IH-benzotriazole, N. Preferably it is carried out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like.

This reaction typically involves water, dioyasane, acetonitrile, chloroform, dichloromethane, toluene, hexamethylphosphoramide, dichloroethane, tetrahydrofuran,
hexane, ethyl acetate, dimethyl sulfoxide, N,N
- carried out in customary solvents that do not adversely affect the reaction, such as dimethylformamide, pyridine, etc., or in mixtures thereof.

The reaction temperature for this reaction is not particularly limited, but the reaction is usually carried out under cooling or heating.

(3) Compound (V) or a salt thereof can be produced by cyclizing compound (Id) or a reactive derivative thereof at a hydroxy group or a salt thereof.

Suitable salts for compounds (Id> and (V)) include the same salts as for compound (1>).

Suitable examples of reactive derivatives at the hydroxy group of compound (Id) include conventional ones such as halides such as chloride, bromide and iodite, and sulfonate compounds such as methanesulfonate, benzenesulfonate and toluenesulfonate. , preferably sulfonate compounds, particularly preferably methanesulfonate.

This reaction is carried out with a triarylphosphine such as triphenylphosphine or a triaryl phosphite such as triphenyl phosphite with an azodicarboxylic acid such as dimethyl azodicarboxylate, diethyl azodicarboxylate, etc., preferably dimethyl azodicarboxylate. This can be carried out in the presence of a suitable condensing agent, such as in combination with di(lower) alkyl.

When a reactive derivative at the hydroxy group of compound (Id) is used, this reaction can be carried out using e.g. sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, e.g. calcium hydride, etc. Alkaline earth metal hydrides, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earths such as magnesium carbonate, calcium carbonate, etc. It can be carried out in the presence of a base such as a similar metal carbonate, for example an alkali metal hydrogen carbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate.

This reaction is usually carried out using alcohols such as methanol and ethanol, dioxane, acetonitrile, chloroform, dichloromethane, benzene, toluene, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, etc.
The reaction is carried out in a conventional solvent that does not adversely affect the reaction, such as ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

In this reaction, the configuration of the carbon atom at the 3-position substituted with the hydroxy group of compound (Id) is the same as that of compound (V).
Now let's reverse it.

When R3 is a protected hydroxy (lower) alkyl group, the hydroxy protecting group may be eliminated in the target compound (v), and the generated hydroxy (lower)
Alkyl groups can be easily protected by conventional methods as shown in Examples below.

(4) The aS compound (■) or its salts can be produced by reacting the compound (Va) with the compound (Vl).

Suitable salts for compound (■) include the same salts as for compound (I).

The reaction can be carried out, for example, with a lower alkyl alkali metal such as n-butyllithium and a di(lower) alkyl amine such as diisopropylamine; For example, alkali metal di(
This can be carried out in the presence of an organic base such as a lower) alkylamide.

This reaction is usually carried out using conventional solvents that do not adversely affect the reaction, such as dioxane, chloroform, dichloromethane, hexane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, diethyl ether, benzene, toluene, N,N-dimethylformamide, pyridine, etc. or in a mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

This reaction can also be carried out in the presence of a zirconium compound, such as a bis(cyclopentadienyl)zirconium dihalide, such as bis(cyclopentadienyl)zirconium dichloride.

When R8 is a trisubstituted silyl group, the compound (■a
) or its salts can be easily rearranged to the hydroxyl group of the adjacent carbon atom with complete stereospecificity by treatment with a base such as potassium tert-butoxide, resulting in Q- A silyl ether compound (■b) is produced.

(■a) or a salt thereof (in the formula, R, R, R, and R7 each have the same meaning as before, and R8 means a trisubstituted silyl group). Suitable salts of compound (■a) include the compound The same salts as (I) can be mentioned.

The compounds obtained in the above production methods 4 to 4 can be isolated and purified by conventional methods such as extraction, precipitation, fractional chromatography, fractional crystallization, and recrystallization. It can be converted into appropriate salts by

Compounds (I) of this invention, especially optically active compounds (I)
') is a useful intermediate for the production of azetidinone compound (B), which is the known important intermediate mentioned above, and the production method of the present invention is also useful for the production of such optically active compounds. It is.

The present invention will be explained in detail below according to examples.

To a solution of large m(Ml2U)-3-benzyloxy-2-methylpropanal (1.0 g) in dichloromethane (20 m11) is added a 1.0 M solution of titanium(IV) chloride in dichloromethane (
6.2 mQ) was added dropwise at -70°C. After stirring at −70° C. for 30 minutes, trimethylsilylketene snow edeltrimethylsilyl acecool (1.57 g) was added to the solution at the same temperature. After stirring for 1 hour, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted twice with dichloromethane. The organic layers were combined and washed twice with IN hydrochloric acid, successively with a saturated aqueous solution of sodium bicarbonate, water, and brine, dried over magnesium sulfate, and the solvent was distilled off to give (3S,4S)-
5-benzyloxy-3-hydroxy-4-methyl-2
-Ethyl trimethylsilylpencunate is obtained as a crude product. 20% aqueous methanol solution (50 mQ ) of the compound obtained above and potassium fluoride (0,98 g)
The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure, and extracted with dichloromethane. Combine the extracts and wash with water,
After drying with magnesium sulfate, concentrate under reduced pressure. The residual oil was chromatographed on silica gel,
Elute with hexane/ethyl acetate (5:1-3:1),
(3R,4S)-5-Benzyloxy-3-hydroxy-4-methylpentanoate (L, 01 g) and (3R145)-5-benzyloxy-3-hydroxy-4-methylpentanoate (0,47 g) ).

NMR (CDC13,S)' 0.93 (3H1
d, J=5.8Hz), 1.23(3H,t, J=5.
8Hz>, 1.92 (1) (, ddq, J=5.
8°5.8 and 6.0Hz), 2.50 (2H,
d.

J=5.8Hz), 3.53 (2H,d, J=6
．． 0Hz), 4.00(1)1. dt, J=5.8
and 6.0) 12), 4.15 (2H.

q, J=7.2Hz), 4.48 (2H,s),
7.30 (5H,s)13CNMR(CDCl2
．． 6): 172.73.138.11゜1213
．． 41. 127.60. 125.70.73.58
゜73.41, 71.57.60.57, 39.66.
38.47°14.20. 13.71 Specific optical rotation: [α 18 + 21.8° (c 1.2L
C) IC1) IR<NEET): 3470.
1730. Titanium chloride (IV) (0.68 mA) was added to a solution of 3-benzyloxy-2-methylpropanal (1.0 g) in dichloromethane (10 mA). Add dropwise at -70°C. After stirring for 15 minutes at −70° C., (1-trimethylsilyloxyethyl)ketene-ethyltrimethylsilylacecool (<1.86 g) is added to the solution at the same temperature. 1
After stirring for an hour, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted twice with dichloromethane. The organic layers were combined and diluted twice with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution,
Wash sequentially with water and brine, dry over magnesium sulfate, and evaporate the solvent. The residue was chromatographed on silica gel to give (4S)-5-benzyloxy-3-hydroxy-2-(1-hydroxyethyl)-
Ethyl 4-methylpentanoate (294 mg) is obtained.

IR (NEET)' 3430. 1720.
1420. 1260 am″″INMR(C
DC13,8)' 0.92 (3H9t-1J=6
．． 0Hz>.

1.00-1.35 (6H, m), 1.55-1.
95 (IH, m).

2.42-2.77 (LH, m), 3.30-4.
40 (6H, m).

4.50 (2H, s), 7.30 (5H, s) (
5)-3-benzyloxy-2-methylpropanal (
A 1M solution of titanium (IV) chloride (0,42 relative) was added dropwise to a solution of 100 mg) of dichloromethane (5 relative) at -78°C. After stirring at −78°C for 30 min, this solution was added to [(I
R)-1-Trimethylsilyloxyethyl]ketene=methyltrimethylsilylacetate (177 mg) is added at the same temperature. After stirring for 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with dichloromethane.
Extract times. The combined organic layers are washed twice with IN hydrochloric acid, successively with saturated aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was chromatographed on silica gel (
2R,3S,4S>Methyl 5-benzyloxy-3-hydroxy-2-[(IR)-1-hydroxydiethyl-4-methylpentanoate (25 mg) is obtained.

IR (knee): 3400. 2100.
1960. 1880°1720 cm-1 (Mll IM solution of titanium(IV) dichloride in dichloromethane (0,
42 mm ) at room temperature with an IM solution of titanium<IV) impropoxide in dichloromethane (0.14 fllll ). After stirring for 10 minutes, the solution is cooled to -78°C.

To this suspension was added dichloromethane (1 relative) of (S)-3-benzyloxy-2-methylpropanal (100 mg).
Add the solution dropwise at the same temperature. After stirring at -78°C for 30 minutes, this solution was added to [(IR)-1-trimethylsilyloxyethylkoketen-methyltrimethylsilylacecour (17
7 mg) at the same temperature. After stirring for 1 hour, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted twice with dichloromethane.

The combined organic layers are washed twice with IN hydrochloric acid, successively with saturated aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was chromatographed on silica gel (2R,3S,
4S>5-benzyloxy-3-hydroxy-2-[(
IR)-1-hydroxyethyl-4-methylpentanoate (53 mg) is obtained.

IR (knee): 3400. 2100.
1960. 1880°1720 am-' NMR (CDC1a, S)' 1.13 (3H,
d, J=7.5Hz), 1.17 (3B, d,, C6,
3Hz), 1.70 (LH, m), 2.60 (1
)t, dd, J=9.3 and 9.3tlz), 3.
48 and 3.87 (2H, dd, J=9.3 and 3.6Hz>.

3.63 (38,s), 3.97-4.37
(4H, m>, 4.48 (2H, s), 7.3
2 (5H, s) 1 (Ml2υ (5)-3-benzyloxy-2-methylpropanal (440 mg) in dichloromethane (10 mQ) solution,
1.0 M titanium chloride (EV) solution in dichloromethane (2
, am standing) was added dropwise at -70°C. After stirring at −70° C. for 30 minutes, ethylketene-methyltrimethylsilyl acecool (st 7 mg) is added to this solution at the same temperature. After stirring for 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted twice with dichloromethane. The combined organic layers are washed twice with IN hydrochloric acid, successively with a saturated aqueous solution of sodium bicarbonate, water, and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residual oil was chromatographed on silica gel (
2R and 28,3S,4S)-5-benzyloxy-
Methyl 2-ethyl-3-hydroxy-4-methylpentanoate (603 mg) is obtained.

IR (knee): 3470. 1730.
1100 cm-1 BMR (CDCl2. l;
): 0.90 (3H, t, J=7.2Hz),
1.00 (3H, d, J=7.2Hz>, 1.47
-2.00 (3H, m), 2.47 (LH, dt,
J=7.8 and 6.0H2), 3.25-3.8
7 (3H, m), 3.37 (3H, m), 4.4
8 (2H,s), 7.30. ,.

(LH, s) Specific optical rotation: [a117-3.4G” (c L, 06
．． CI (C1) [2R: 25-86: 11 by high performance liquid chromatography (HPLC)] (4S)-5-benzyloxy-3-hydroxy obtained in Example 1-2> -2-(1-hydroxyethyl)-
Tertiary-butyldimethylsilyl chloride (99 mg) and imidazole (2
23 mH) at room temperature. After stirring for 2 hours, diethyl ether and water are added to the reaction mixture. The aqueous layer is extracted twice with diethyl ether, the combined ether layers are washed twice with IN hydrochloric acid, then with water and brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel to give ethyl (43)-5-benzyloxy-2-(1-tert-butyldimethylsilyloxyethyl)-3-hydroxy-4-methylpentanoate (463 mg). get.

IR(CDCl2): 3475.1945.190
0.1800゜1720 cm-1 NMR (CDC1s, S: 0-10 (6H1s)
, 0.90 and 0.93 (98, respectively),
0.80-L, 40 (9H, +++).

1.53-2.00 (IH, m), 1.83 (I
H, br s), 2.35-2.95 (LH, m)
, 3.30-4.47 (6H, m), 4.55 (
2H,s), 7.35 <5H,s) 'HNMR (500MHz
) analysis shows that this product is 3.4 to anti compound and 3,4
- Syn compound (75:25).

3.4-anti compound 3,4-syn compound Example 2-2) ■ (2R,33,4S)-5-benzyloxy-3-hydroxy-2-[(IR)-1-hydroxyethylco4
- To a solution of methylpentanoate (70 mg) in dimethylformamide (dimethylformamide) are added tert-butyldimethylsilyl chloride (71 mg) and imidazole (32 mg) at room temperature. After stirring for 2 hours, diethyl ether and water were added to the reaction mixture, and the ether layer was separated. The aqueous layer is extracted twice more with diethyl ether, the combined ether layers are washed twice with IN hydrochloric acid, then with water and brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel (2S, 3
S,4S)-5-benzyloxy-2-[(IR)-1
-tert-butyldimethylsilyloxyethyl]-3-hydroxy-4-methylpentanoate (61 mg) was obtained.

IR(CDCl2)' 3490.1730 cm-
'NMR (CDCl2.8): 0108 (6H
, s), 0.87 (9H, s).

1.10 (3H, d, J=7.2Hz), 1.27
(3H, d.

J=6.0)lz), 1.80 (2H,m), 2
．． 83 (11(, dd.

J=6.6 and 9.6)1z), 3.43-4.1
7 (3H, m>.

3.60 (3H, s), 4.33 (IH, dd,
J=6.6 and 6.6Hz>, 4.50 (2)1
．． s), 7.30 (5H, s) Example 3-1) 0-Methylhydroxylamine hydrochloride (1,22g)
A 291M solution of trimethylaluminum in hexane (14,61) was added to the suspension in dry toluene (20 m ) at 3°C.
Add gradually at C. After the addition is complete, the reaction mixture is allowed to warm up to room temperature and stirred for 2 hours until gas evolution has ceased.

Add (3R,4S)-5-benzyloxy-3 to this solution.
-Ethyl hydroxy-4-methylpentanoate (800m
g) Ohyohi (3R.

45) Methyl-5-benzyloxy-3-hydroxy-4-methylpentanoate (472 mg) in dry toluene (
Add 10 ml of the solution dropwise at room temperature. The solution was filtered until no chemical substances were observed by thin-pack chromatography.
Stir for 20 hours at room temperature under nitrogen atmosphere.

The reaction mixture was carefully quenched with water and then I
Add N-hydrochloric acid to this. Separate the organic layer and extract the aqueous layer twice with ethyl acetate. The combined organic extracts were washed sequentially with IN hydrochloric acid and brine, dried over magnesium sulfate, and
Concentrate under reduced pressure to obtain (3R,4S)-5-benzyloxy-
3-Hydroxy-N-methoxy-4-methylpentanamide (1,05 g) is obtained.

mp: 74-75℃ 1R (CHCla): 3400, 1680 cmNM
R (CDC1s, S ) = 0.88 (3H, d, J
=5.8Hz>, 1.63 (LH, br, s), 2
．． 00 (IH, m), 2.38 (IH, m).

3.52 (IH, d, J=4.5Hz), 3.57
(IH, d.

J=6.0Hz), 3.73 (3H,s), 3.
87 (IH, m).

4.50 (2H, s), 7.30 (5H, s),
9.10 (LH.

(4S)-5-benzyloxy-2-(1-tert-butyldimethylsilyloxyethyl)-3-hydroxy-4-methylpentane obtained in L1 Phantom Example 2-1) Ethyl acid (
300 mg) of methanol (1 mu) and water (1 m
Q) Add sodium hydroxide (141 mg) to the solution
Add with . After stirring for 2 hours at room temperature, water and diethyl ether are added to the reaction mixture. The separated aqueous layer is washed twice with diethyl ether, acidified with 6N hydrochloric acid, and extracted twice with ethyl acetate. The organic layers were combined, washed sequentially with water and brine, dried over magnesium sulfate, and the solvent was distilled off to give (4S)-5-benzyloxy-2-(1-tert-butyldimethylsilyloxyethyl). -3-hydroxy-
4-methylpentanoic acid (130 mg) is obtained.

The compound obtained above and O-benzylhydroxylamine hydrochloride (156 mg) in tetrahydrofuran (
A solution of 4111Q) and water (2) was adjusted to 4-5, and an aqueous solution of water-soluble carbodiimide (190 mg) was added to the reaction mixture, 1N hydrochloric acid was added to 4-5.
Add while keeping the temperature at 5. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are washed twice with IN citric acid, successively with 5% aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was chromatographed using silica gel,
(4S)-N,5-bis(benzyloxy)-2-(1
-tert-butyldimethylsilyloxyethyl)-3-hydroxy-4-methylpentanamide (86 mg) is obtained.

IR (NEET): 3400. 1670.
1080 am-1HMR (CDCl2.ε)
: 0.10 (6H,sun, 0.92 and 1.0
0 (9H, s each), 1.10-1.50 (
6H.

m), 1.70-2.15 (LH, m), 1.9
5 (LH, br, s).

2.37-2.62 (LH, m>, 3.38-4.
67 (4H, m).

4.50 (2H,s), 4.97 (2H,s),
7.47 (5)1. s).

7.53 (5H,s), 9.50 and 9.67
(18, br, s respectively) To a suspension of 0-methylhydroxylamine hydrochloride (81 mg) in dry toluene (41n11) was added I in hexane.
M trimethylaluminum solution (0.97d) 3
Add gradually at °C. After the addition is complete, the reaction mixture is allowed to warm up to room temperature and stirred for 2 hours until gas evolution has ceased. Add (2S, 3S, 4S)-5-benzyloxy-2-[(IR)-1-tert-butyldimethylsilyloxyethyl-3-hydroxy-4-methylpentane (61 mg) to this solution in dry toluene. (111112)
The solution is added dropwise at room temperature.

The solution is stirred for 30 hours at room temperature under nitrogen atmosphere. The reaction mixture is carefully quenched with water and a mixture of IN hydrochloric acid and ethyl acetate is added. The organic layer is separated and the aqueous layer is extracted twice with ethyl acetate.

The organic layers were combined and washed sequentially with IN hydrochloric acid and brine;
After drying with magnesium sulfate, the solvent was distilled off to obtain (2S,
3S,4S)-5-benzyloxy-2-[(IR)-
1-Tertiary butyldimethylsilyloxyethyl two 3-
Hydroxy-N-methoxy-4-methylpentanamide (aamg) is obtained.

IR (knee): 3460. 1690.
1 to 1090 cm-1 0-Methylhydroxylamine hydrochloride (446 mg)
IM trimethylaluminum solution in hexane (5,34 mQ) is slowly added to the suspension in dry toluene (10 mfL) at 3°C. After the addition is complete, the reaction mixture is allowed to warm up to room temperature and stirred for 2 hours until gas evolution has ceased. This solution was added to (2R,3S) obtained in Example 1-5).
, 43) A solution of methyl-5-benzyloxy-2-ethyl-3-hydroxy-4-methylpentanoate (456 mg) in dry toluene (2,5+119) is added dropwise at room temperature. The solution is stirred under a nitrogen atmosphere for 17 hours until no starting material is observed by thin 1 chromatography.

The reaction mixture is carefully quenched with water and a mixture of IN hydrochloric acid and ethyl acetate is added. The organic layer is separated and the aqueous layer is extracted twice with ethyl acetate. The organic layers were combined, washed sequentially with IN hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give (3!3,4S)-5-benzyloxy-2-ethyl-3-hydroxy-N- Methoxy-4
-Methylpentanamide (634 mg) is obtained.

NEET to IR): 3450. 3200.
1945. 1860. 1810°1735
, 1650.1600.1450°1080 am-1 NMR (CDC13, δ): 0.88 (3)1.
d, J=6.01 (z), 0.92 (3H, t, J4
6.0f(z), 1.70 (3H,m),
2.00-2.40 (IH, m), 3.40-3.8
3 (3)! , m>, 3.65 (3H,s).

4.50 (2H, s), 7.33 (5H, s),
9.15 (LH.

br, s) Example 4-1) (3R,4S)-5-benzyloxy-3-hydroxy-N-methoxy-4-methylpentanami)' (1,
05g) and hydriphenylphosphine (1.60g
) dimethyl azodicarboxylate (0.88 g) is added dropwise at 5° C. to a solution of tetrahedral a”y run (40 rnQ) of 100% azodicarboxylate (40 rnQ). After the addition is complete, the reaction mixture is stirred at room temperature for 1 hour.

After the reaction is completed, the solvent is distilled off under reduced pressure. Silica gel (30 fflll) was added to the residue, the solvent was distilled off, and the residual solid was subjected to chromatography using silica gel, eluting with hexane/ethyl acetate (4:1-3:1) to obtain (4S). -4-[(IR)-2-benzyloxy-
1-methylethyl]-1-methoxyazetidin-2-one (906 mg) is obtained.

IR (knee): 1770. 1450. 1
100 am-1HMR (CDCl2.δ): 1.
06 (3H, d, J=5.3Hz), 2.07<I
H, dq, J=5.3 and 6.0Hz>, 2.5
0 (LH.

dd, J=13.5 and 3.0Hz), 2.70
(IH, dd.

J=13.5 and 5.3Hz), 3.40 (2)
! , d.

J:6.0Hz), 3.70 (3H,s>, 3.
92 (LH, ddd.

J=6.0.5.3 and 3.0Hz), 4.47
(2H, s).

7.33 (5)1. s> 13CNMR (CDCl2): L64.39. L
38.16.128.41゜127.60.73.31
．． ．． 72.77, 63.01.59.17゜36.63
．． 36.25.13.00 Specific rotation; [α] ”1.525@(c 1.18.
(4S)-N,5-bis(benzyloxy)-2-(1-tert-butyldimethylsilyloxyethyl)-3-hydroxy- obtained in Example 3-2 of L1 Company Diethyl azodicarboxylate (o, o27mQ) is added dropwise to a solution of 4-methylpentanamide (86 mg) and triphenylphosphine (45 ng) in tetrahydrofuran (2 units) at 5°C. After the addition is complete, the reaction mixture is stirred at room temperature for 3 hours. After the reaction is completed, the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give 1-
Benzyloxy-4-4(IR)-2-benzyloxy-1-methylethyl]-3-(1-hydroxyethyl)
Azetidin-2-one (94 mg) is obtained.

IR (knee)>: 3420. 1755
am-1HMR (CDCl2,8)' 1.
04 (3H, dJ near, 0Hz), 1.17 (3
H,d,,C6,0Hz), 1.60(LH,br
, s), 2.00-2.27 (IH, m), 2.
80 (LH, dd, T=6.0 and 2.0Hz)
, 3.35 (2)1. d, J=6.0Hz>, 3
．． 55 (IH.

dd, J=6.0 and 2.0Hz), 3.88
(LH, m).

4.43 (2H,s), 4.95 (2H,s),
7.30 (5H, s).

7.40 (51,s)
(IR)-1-Tertiary-butyldimethylsilyloxyethyl-3-hydroxy-N-methoxy-4-methylpentanamide (44 mg) and triphenylphosphine (83 mg) in tetrahydrofuran (III) solution,
Dimethyl azodicarboxylate (45 mg) is added dropwise at 5°C. After stirring for 1 hour, the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (5:1), (3S, 4R
,)-4-[(IR)-2-penzyloxy-acetylethyl-3-[(IR)-1-tert-butyldimethylsilyloxyethyl-1-methoxyazetidine-2
-one (15 mg) is obtained.

IR(C1(C1): 1760.1255.110
0 am-1NMR (CDC13,S)'
0.08 (6H1s), 0.90 <9H9s
).

1, tO(3H, d, J=6.6Hz, 1.2
3 (3H, d.

J=6.0)1z), 2.15 (IH, m), 2
．． 73 (1M, dd.

J=2.4 and 4.8Hz), 3.45 (2H,
d.

J=6.0Hz>, 3.73 (3H,s), 4.
12 (IH, dd.

J=2.4 and 5.0Hz>, 4.15 (IH,
m), 4.52 (2H, s), 7.37 (5)
1. s) (3S, 45)-5 obtained in Example 3-4>
-benzyloxy-2-ethyl-3-hydroxy-N-
Dimethyl azodicarboxylate (476 mg) was added dropwise to a solution of methoxy-4-methylpentanamide (634 mg), hydriphenylphosphine (871 mg), and tetrahydrofuran (25 m) at 5°C. After the addition is complete, the reaction mixture is stirred at room temperature for 1 hour.

After the reaction is completed, the solvent is distilled off under reduced pressure. Silica gel is added to the residue and the solvent is distilled off until the silica gel is dry. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (4:1) to give (4R)-4-
[(IR)-2-benzyloxy-1-methylethyl-3-ethyl-1-methoxyazetidin-2-one (3
05 mg).

IR (NEET): 1765. 1450.
1100 am-1MMR (CHCl3.δ):
0.98 (38,t, J=7.2Hz>, 1.07
(3H, d, J-6,9Hz), 1.67 (2H,
m), 2.08 (1)T.

m), 2.68 (LH, dt, J=2.1 and 6
．． 9Hz).

3.42 (2H, d, J=6.0Hz), 3.60
(IH, dd, J: 2.1 and 6.0Hz), 3
．． 72 (3H, s), 4.47 (2H.

s), 7.30 (5H, s) Specific optical rotation; [α coD + 11.9° (c 1.1&, C
HCl5) 1ヱ952υ 16 in hexane? fn-butyllideum (0,75mf
i) To a solution of lithium diisopropylamide (1,20 mmol) prepared from diisopropylamine (0,221d') and tetrahydrofuran (2), (4S)-4-
[:(IR)-2-benzyloxy-1-methylethyl]-1-methoxyazetidin-.2-one (100 mg
) of tetrahydrofuran (2rnQ>) is added dropwise at -75°C. After stirring for 5 minutes, a solution of freshly distilled acetaldehyde F C0,02fflQ ) in tetrahydrofuran (
1m) Add the m solution dropwise at the same temperature. The reaction mixture is stirred for 30 minutes, then quenched with saturated aqueous ammonium chloride solution under cooling and diluted with ethyl acetate. The aqueous layer is extracted twice with ethyl acetate, the organic layers are combined, washed twice with water and then with brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (1:2) to give (33°4R)-4-[(IR)-2-benzyloxy-1-methylethyl-3- [(I S) and (I
R)-1-hydroxyethyl]-1-methoxyazetidin-2-one (IS: IR Trout 83: 17, HPL
A mixture (60 mg) of (according to C) is obtained.

IR (CHCI): 3430.1760 am-
'NMR (CDCl2.8) ' 1.07 (2H,
d, J=6.6Hz), t, t.

(LH, d, J=6.6Hz), 1.27 (3H,
d, J=6.6Hz>.

2.08 (IH, m), 2.77 (0,3H, d
d, J = 6.0 and 2.1 Hz), 2.83 (0
,7)! , dd, J: 5.1 and 2.1Hz > 3
．． 43 (1,3H, dJ=6.0Hz) 3.4
8 (0,7H, dJ=6.0Hz), 3.70-4
．． 15 (2H, m).

3.77 (3H,s), 4.47 (2H,s)
, 7.33 (5M, s)
11), diisopropylamine (0.50ml)
, (4S)- 4-[:(IR)
A solution of -2-benzyloxy-1-methylethyl]-1-methoxyazetidin-2-one (300 rng) in tetrahydrofuran (II) was added dropwise at -78°C. 1
After stirring for 0 min, tetrahydrofuran (6 m
) Add bis(cyclopentadienyl)zirconium chloride (877 mg) at the same temperature. After stirring for 15 minutes, a solution of freshly distilled acetaldehyde (o, 2 mQ) in tetrahydrofuran (2 mQ>) is added dropwise at the same temperature. The reaction mixture is stirred for 30 minutes and then quenched with saturated aqueous ammonium chloride solution under cooling. The aqueous layer is extracted twice with ethyl acetate, the organic layers are combined, washed twice with water and then with brine, dried over magnesium sulfate, and the solvent is evaporated.Residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (1:2) (3S.

4R)-4-[(IR)-2-benzyloxy-1-methylethylco-3-[(IR) and (IS)-1-hydroxyethyl]-1-methoxyazetidin-2-one (4R: I 5-56: 44, by HPLC)
(154 mg) is obtained.

IR(Ct(CI): 3430.1760 cr
n-'NMR (CDCl2.δ): 1.07 (1
, 5H, d, J=6.6Hz).

1.10 (1.5H, d, J=6.6Hz), 1.
27 (3H, d.

J=6.6Hz), 2.08 (IH, m),
2.77 (0.5H, dd.

J = 6.0 and 2.1Hz), 2.83 (0,5
H, dd.

J=5.1 and 2.1Hz), 3.43 (IH,
d.

J=6.0Hz>, 3.48 (IH, d, J=6.
0Hz), 3.70-4.23 (2H, +n),
3.77 (3H, s), 4.47 (2H, s).

7.33 (51,s) Lithium diisopropylamide (1,44 mmol) prepared from 1.55 M n-butyllithium (0,93 mm), diisopropylamine (0,25 m) and tetrahydrofuran (6111Q) in hexane at 3 °C. ) to 1 m of tetrahydrofuran (flu) was added (4S)-4-[(IR)-2-benzyloxy-1-methylethyl-1-methquinazetidin-2-one (300 mg) in tetrahydrofuran (3 relatives). Drop at -78°C.1
After stirring for 0 minutes, tetrahydrofuran (31
1111) and tertiary-butyldimethylsilylmethylketone (226 mg) was added at the same temperature. After stirring for 1 hour, IN potassium tert-butoxide in tert-butyl alcohol (1,44111 pieces) was added to the reaction mixture at the same temperature. The mixture was warmed to 0°C and stirred for 1 minute to form a saturated aqueous ammonium chloride solution. Stop the reaction, add ethyl acetate, and separate the organic layer.Extract the aqueous layer twice with ethyl acetate,
The combined organic layers are washed twice with IN hydrochloric acid, successively with a saturated aqueous solution of sodium bicarbonate, water, and brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (5:1) (3S.

4R)-7,t-[IR)-z-benzyloxy-1-
Methylethylco-3-[(IR)-1-tert-butyldimethylsilyloxyethyl]-1-methoxyazetidin-2-one (279 mg) was obtained, and further raw material 111
Collect mg.

1R (CDCIs): 1760.1255.110
0 amNMR(CDCIs, 8) = 0.08 (
6H,s), o, 90 (91(,s).

1.10 (3H, d, J=6.6Hz), 1.23
(3H, d.

J=6.0Hz), 2. i5 (IH, m), 2.
73 (IH, dd.

J=2.4 and 4.8Hz>, 3.45 (2H,
d.

J=6.0Hz), 3.73 <3H,s), 4.
12 (IH, dd.

J=2.4 and 5.0H2), 4.15 (IH,
m>, 4.52 (2H, s), 7.37 (5H,
s) Specific rotation = [α 8 + 1.607° (c 1 , 1
2. (3S,4R)-4-[(I
R)-2-benzyloxy-1-methylethyl]-3-
[(IS) and (IR)-1-hydroxyethyl]-
To a solution of 1-methoxyazetidin-2-one (55 mg) in dimethylformamide (31119) are added tert-butyldimethylsilyl chloride (100 mg) and imidazole (50 mg) at room temperature. After stirring for 1 hour, the reaction mixture is diluted with diethyl ether and water. The aqueous layer is extracted twice with diethyl ether, combined with ether 1, washed twice with water, then with salt and then with water, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel in hexane/ethyl acetate (1
(3S,4R)-4-[(IR)
-2-benzyloxy-1-methylethylco-3-[(
15) and (IR)-1-tert-butyldimethylsilyloxyethyl]-1-methoxyazedecin-2-one (70 mg) are obtained.

IR(CDCIs)' 1760.1255 am-
1HMR (CDCIs, E): 0.10 (6
H,s), 0.93 (9H,s).

1.13 (3H, d, J=6.6Hz), 1.33
(3H, d.

J=6.3Hz), 2.17 (LH, ddd, J=
6.6.6.6 and 6.6Hz), 2.77 (0
, 2H, dd, J=2.4 and 4.8Hz>, 2.
83 (0,8H, dd, J: 3.0 and 3.0Hz
>, 3.50 (2H, dJ=6.6Hz), 3.
77 (3H1s), 3.93 (0.8H, dd,
J = 3.0 and 6.6 Hz).

4, 00-4.34 <1.2H, m), 4.53
(2H,s), 7.30(5H,5) ) IPLC analysis reveals that this product is isomer A (17
%), isomer B (82%) and others (1%).

Example 7-2) 1-benzyloxy-4-[ obtained in Example 4-2)
(IR)-2-benzyloxy-1-methylethyl]-
3-(1-hydroxyethyl)azetidin-2-one (
95 mg) in dimethylformamide (2 mQ) solution,
Tert-butyldimethylsilyl chloride (77 mg) and imidazole (87 mg) are added at room temperature. After stirring for 2 hours, diethyl ether and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer is extracted twice with diethyl ether, the combined ether layers are washed twice with IN hydrochloric acid, then with water and brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel to give 1-benzyloxy-4-[(IR)-2-
benzyloxy-1-methylethyl]-3-[tert-butyldimethylsilyloxydiethylcoazetidine-2
-on (26mg).

1R(CHCL3) =1760.1455.1255
．． ttoo amNMR (CDCI3.δ): 0.
08 (6H, s), 0.88 (9H, s).

1.07 (3H, d, J=6.9Hz), 1.22
(3H, d.

J=6.3Hz), 2.100)i, m), 2.8
7 (IH, dd.

J=2.4 and 3.6Hz), 3.24 (2H,
d.

J=6.0Hz), 3.80 (IH, dd, J=2
．． 4 and 6.0Hz), 4.12 (1)1. m)
, 4.50 (2H, s), 4.95 (2H, s)
, 7.33 (5H,s), 7.40 (5H
, s) 1'' and 1 stroke (3S, 4R)-4-[(I
R)-2-benzyloxy-1-methylethyl]-3-
[To a solution of (IR) and (Is)-1-hydroxydiethyl-1-methoxyazetidin-2-one (134 mg) in dimethylformamide (5111Q) were added tert-butyldimethylsilyl chloride (138 mg) and imidazole (155 mg). Add at room temperature. After stirring for 1 hour, diethyl ether and water are added to the reaction mixture, and the organic layer is separated. The aqueous layer is extracted twice with diethyl ether, the combined ether layers are washed twice with water and then with brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (10:1) to give (3S, 4R)
-4-[:(IR)-2-benzyloxy-1-methylethyl]-3-[1-tert-butyldimethylsilyloxyethyl-1-methoxyazetidin-2-one (15
1 mg).

IR (CDCI): 1760.1255 cm-
1NMR (CDCI3.6): 0.10 (6H
,s), 0.93 (9H,s).

1, ts (3H, d, J=6.6)1z), 1.2
7 (1,5H,d.

J=6.0Hz), 1.33 (1,5H,d, J=
6.3Hz), 2.17 (LH, m, J=6.6.6
．． 6 and 6.6Hz), 2.78 (0,5H, dd
, J=2.4 and 4.8)1z), 2.85(0
, 5H, dd, J=3.0 and 3.0Hz), 3.
50 (2H.

dJ=6.6Hz: d, J=6.0Hz), 3.7
5 (1,5H,s).

3.80 (1,5H,s), 3.93 (0,5H
, dd, J=3.0 and 6.6Hz), 4.00-
4.34 (1,5H, m), 4.53 (2H, s)
, 7.40 (5H,5) HPLC analysis shows the product to be a mixture of isomer A (52%), isomer B (47%) and others (1%).

(5)-3-Benzyloxy-2-methylpropanal (1,0 g) and [(IR)-1-triethylsilyloxyethyl]ketene ■Methyltriethylsilyl acecool (2,33 g) in dichloromethane ( 201d) solution of titanium chloride (mV) in dichloromethane IM solution (
6,7211111) was added dropwise at -40±5°C. 1
After stirring for an hour, the reaction was quenched with water (1 liter), IN hydrochloric acid (201Q) and tetrahydrofuran (20ml).
), the mixture is stirred for 2 hours, and after the desilylation reaction is completed, the right layer is separated. The aqueous layer is extracted twice with ethyl acetate, and the organic layers are combined and washed twice with IN hydrochloric acid, successively with a saturated aqueous solution of sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel (2R,3
5゜4S)-5-benzyloxy-3-hydroxy-2
-Methyl-[(IR>1-hydroxyethyl]-4-methylpentanoate (934 mg) was obtained.

IR): 3400. 2100.
1960. 1880° 1720 am-1 Specific rotation = [α 25-14.6° (c 1.126.
CHCl )(2S,3S,4S>5-benzyloxy-2-[(IR)-1-tert-butyldimethylsilyloxyethyl-3-hydroxy-N-methoxy-4-
Methylpentanamide (500 mg) was dissolved in anhydrous pyridine (
2-) and cooled to 0°C. After gradual addition of methanesulfonyl chloride (0,109 mQ ), the mixture was stirred for 1 day and then added with ethyl acetate (50 mQ ) and IN! Add acid (10IIIQ). The reaction mixture is extracted three times with ethyl acetate and the organic layers are combined and washed sequentially with INm acid, water and brine. After drying with magnesium sulfate, it was concentrated under reduced pressure to give (2S, 3S, 4S)-5-benzyloxy-2.
-[(IR)-1=tertiary-butyldimethylsilyloxyethyl]-3-methanesulfonyloxy-N-methoxy-4-methylpentanamide (592 mg) is obtained. Potassium carbonate (163 mg) was added to a solution of this compound in methanol (Llmll) at room temperature, and the mixture was stirred for 1 hour. The solids are filtered off and washed with ethyl acetate (somu).

The filtrate and washings were combined and concentrated, then ethyl acetate (5
0 ml). After successively washing with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, drying over magnesium sulfate and concentration gave (3S,4R)-4-[(IR
)-2-pen, zyloxy-1-methylethylco-3-
[(IR)-1-tert-butyldimethylsilyloxyethyl-1-methoxyazetidin-2-one (375 m
g) is obtained.

IR (CHCI): 1760.1255.110
0 cm-1 specific optical rotation: [α, +1.52° (c
1.05. CHCl3) 艮1'LL Nililithium (80 mg) is dissolved in distilled ammonia (6 mQ) at -78°C. After 30 minutes, this was added with tertiary butyl alcohol (2 mf1) in tetrahydrofuran (1 mQ).
and stir the solution for 10 minutes. To this solution (3S,
4R)-4-[:(IR)-2-benzyloxy-1-
Tetrahydrofuran (1
-) Add the solution at the same temperature. After stirring for 1 hour, the mixture was carefully quenched with saturated aqueous ammonium chloride solution and warmed to room temperature to remove ammonia. The mixture is acidified and extracted twice with ethyl acetate. The combined organic layers were washed twice with IN hydrochloric acid, successively with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate, and the solvent was distilled off (3S).

4 R)-3-[(IR)-1-tert-butyldimethylsilyloxyethyl]-4-[(IR)-2-hydroxy-1-methylethyl]azetidin-2-one (12
5 mg).

mp: 62-63℃ 1R(CHCl3)' 3420,1755 amN
MR(CDC13,f; )' 0.10 (6)1
．． s), 0.90 (3H1d.

J=6.0Hz), 0.93 (9)1. s), 1
．． 30 (3H, d.

J=6.0)tz), 1.57-2.00 (LH,
m), 3.10 (IH.

d, J=8.4Hz), 3.28 (IH, dd, J
=8.4 and 2.1Hz), 3.38-3.75
(2H, d, J = 6.6Hz), 4.10 (LH, m
), 6.48 (IH, br, s) Specific rotation: [α paste 7-14.4° (ct, oo, CHCl5) Production example 1-2) Lithium (7 mg) was dissolved in distilled ammonia (3 mQ) -7
Dissolve at 8°C. After 30 minutes, tertiary Budel alcohol (1 relative) is added to this and the solution is stirred for 5 minutes. This solution was added to (35,4R)-4-[(IR>-2-benzyloxy-1-methylethyl]-3-[(IR) and (IS
)-1-Tertiary butyldimethylsilyloxyethyl]-
1-Methoxyazedecin-2-one (IR: IS Feg5
2.40,) by IPLc) (83 mg) in tetrahydrofuran (1 relative) is added at the same temperature. After stirring for 1 hour, the reaction of the mixture was quenched with a saturated aqueous ammonium chloride solution, the temperature was raised to room temperature, and ammonia was distilled off. The mixture is acidified and extracted twice with ethyl acetate. The organic layers were combined, washed sequentially with water and brine, dried over magnesium sulfate, and the solvent was distilled off to give (3S,4R)-3
-[(IR) and (IS)-1-tert-butereddimethylsilyloxyethylco-4-[(IR)-2-hydroxy-1=methylethyl]azetidin-2-one (IR
:l5-63:37, by HPLC) (33,1g
).

1R(CHCl3): 3640.3425.175
0 amNMR(CDC13,S)' 0.10
(6H9s), 0.90 (1,5H9d, J:6.0
Hz>, 0.93 (9H,s), 0.97 (1
,5H,d.

J=6.0Hz), 1.30 (1,51(,d,6.0Hz), 1.37<1.5Hz, d, J:6.
0Hz), 1.57-2.00 (LH, m>.

3.10 (LH, d, J=8.4)1z), 3.2
8 (IH, dd.

J=8.4 and 2.1Hz>, 3.38-3.75
(2)! , m).

4.00-4.37 (IH, m), 6.33 (L
Chromium oxide (IV>(104g)) made of pyridine (2-)
is added in small portions at 15° C. and the suspension mixture is stirred for 15 minutes at room temperature. To this suspension mixture (3S.

4R)-3-[(IR)-1-tert-butyldimethylsilyloxyethyl]-4-[(IR)-2-hydroxy-1-methylethylcoazetidin-2-one (100 m
Add g) dropwise and stir the mixture for 2.5 days. Add diethyl ether to the reaction mixture and filter through Celite. Wash the filter residue twice with diethyl ether. The organic layer is extracted four times with saturated aqueous sodium bicarbonate solution. The combined aqueous layers are washed twice with diethyl ether, acidified with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was washed twice with IN hydrochloric acid, then with water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (2R)-2.
-4(3S,4S)-3-((IR)-1-tert-butyldimethylsilyloxyethyl)-2-year-old xoazetedin-4-yl]propionic acid (68 mg) was obtained.

mp: 139-141℃ IR (CHCL3)' 3420.3300.173
0 cm-″1 Specific optical rotation: [α 20-18.4° (c
1.0. (2R) in MeOH>diethyl ether
-2-[(3S.

4S)-3-((IR)-1-tert-butyldimethylsilyloxyethyl)-2-oxoazedecin-4-yl]propionic acid (68 mg) was treated with a solution of diazomethane in diethyl ether to give (2R) -2-[(3S
, 4S)-3-((IR)-1-tert-butyldimethylsilyloxyethyl)-2-year-old xoazetidin-4-ylcoprobionic acid methyl (65 mg).

mp: 110 (12℃ IR (CH2C12): 3530.3410.17
65.1740°1420 cm-1 NMR (CDCl3.E) 'o, 10 (6)
1. s), o, 90 (9H1s).

1.20 (3H, d, J-6, 3Hz), 1.27
(3H, d.

J=6.3)1z), 2.75 (1)! ,qd,J
=6.6 and 5.7Hz), 3.00 (LH,d
dJ = 2.1 and 3.9Hz), 3.73 <
3H, s), 3.90 (LH, ddJ=2.1
and 5.・71 (z), 4.23 (LH, m),
6.12 (IH, br, s) Specific optical rotation: [α pasted 9-19.2° (c 0.48.CH
2Cl□) Production Example 3 Lithium (20mg) was mixed with ethylamine (311111)
Dissolve at -40°C. After 45 minutes, (3S, 4
R)-4-[(IR)-2-benzyloxy-1-methylethyl]-3-[(IR)-1-tert-butyldimethylsilyloxyether]-1-methoxyazetidine-
Tertiary butyl alcohol (I) of 2-one (100 mg)
Add IQ) and tetrahydrofuran (1 precept) solution,
Stir for 1 hour. The mixture is carefully quenched with saturated aqueous ammonium chloride solution and allowed to warm to room temperature to remove ethylamine. Add ethyl acetate to the residue,
Wash sequentially with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dry over magnesium sulfate, and concentrate.

The residue was chromatographed on silica gel to give (3S,4R)-3-[(IR)-1-tert-butyldimethylsilyloxyethyl-4-[(IR)-2-
Hydroxy-1-methylethyl coamotidin-2-one (50 mg) was obtained, and the raw material compound (32 mg) was obtained.
Collect.

Claims (1)

[Claims] 1) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a protected or unprotected hydroxy (lower) alkyl group, R^2 is a lower alkyl group , R^3 is hydrogen, a lower alkyl group, a protected or unprotected hydroxy (lower) alkyl group, or a trisubstituted silyl group, R^4 is a hydroxy group, a substituted hydroxy group, an amino group, or a protected or a salt thereof. 2) R^1 is a hydroxy (lower) alkyl group, an acyloxy (lower) alkyl group, an alkoxy (lower) alkyl group, or a trisubstituted silyloxy (lower) alkyl group, R^2 is a lower alkyl group, R^ 3 is hydrogen, lower alkyl group, hydroxy (lower) alkyl group, acyloxy (lower) alkyl group, al (lower) alkoxy (
(lower) alkyl group, trisubstituted silyloxy (lower) alkyl group or trisubstituted silyl group, R^4 is a hydroxy group, lower alkoxy group which may have at least one suitable substituent, lower alkenyloxy group, lower Alkynyloxy group, al (lower) alkoxy group which may have at least one suitable substituent, aryloxy group which may have at least one suitable substituent, phthalidyloxy group, lower alkoxy group The compound according to claim 1), which is an amino group or an alkoxyamino group. 3) R^1 is a hydroxy (lower) alkyl group or an alkoxy (lower) alkyl group, R^2 is a lower alkyl group, R^3 is hydrogen, a lower alkyl group, a hydroxy (lower) alkyl group, a tri- (lower)alkylsilyloxy(lower)alkyl group or tri(lower)alkylsilyl group, R^4 is a hydroxy group, lower alkoxy group, lower alkoxyamino group or ar(lower)alkoxyamino group The compound described in section 2). 4) R^1 is a hydroxy (C_1 to C_4) alkyl group or a phenyl (C_1 to C_4) alkoxy (C_1
~C_4) alkyl group, R^2 is C_1~C_4 alkyl group, R^3 is hydrogen, C_1~C_4 alkyl group, hydroxy (C_1~C_4) alkyl group, tri(C_1~
C_4) Alkylsilyloxy (C_1-C_4) alkyl group or tri(C_1-C_4) alkylsilyl group, R^4 is hydroxy group, C_1-C_4 alkoxy group, C_1-C_4 alkoxyamino group, phenyl (C_4)
1 to C_4) The compound according to claim 3), which is an alkoxyamino group. 5) The compound according to claim 4, wherein R^4 is a hydroxy group or a C_1 to C_4 alkoxy group. 6) R^1 is a benzyloxymethyl group, R^2 is a methyl group, R^3 is a 1-triethylsilyloxyethyl group or a 1-tertiary butyldimethylsilyloxyethyl group, R
The compound according to claim 5), wherein ^4 is a hydroxy group, a methoxy group, or an ethoxy group. 7) The compound according to claim 4, wherein R^4 is a C_1-C_4 alkoxyamino group or a phenyl(C_1-C_4) alkoxyamino group. 8) R^1 is a benzyloxymethyl group, R^2 is a methyl group, R^3 is a 1-triethylsilyloxyethyl group or a 1-tertiary butyldimethylsilyloxyethyl group, R
The compound according to claim 7), wherein ^4 is a methoxyamino group or a benzyloxyamino group. 9) The compound according to claim 8) which is N,5-bis(benzyloxy)-2-(1-tert-butyldimethylsilyloxyethyl)-3-hydroxy-4-methylpentanamide . 10) The compound according to claim 8), which is 5-benzyloxy-2-[1-tert-butyldimethylsilyloxyethyl]-3-hydroxy-N-methoxy-4-methylpentanamide. 11) Formula (a): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 means a protected or unprotected hydroxy (lower) alkyl group, and R^2 means a lower alkyl group. ] A compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^3 is hydrogen, a lower alkyl group, a protected or unprotected hydroxy (lower) alkyl group, or a Substituted silyl group, R^4_a means substituted hydroxy group, R^5 means hydroxy protecting group] By reacting with a compound represented by the formula or its salts, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R^1, R^2, R^3 and R^4_a each have the same meaning as before); and (b) formula: ▲ where the mathematical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R^2 and R^4_a each have the same meaning as before, and R^3_a means a trisubstituted silyl group.) The compound represented by or its salts is an alkali metal fluoride. A method of obtaining a compound or its salts by reacting with the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and R^4_a each have the same meaning as before); and (c) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3 and R^4_a each have the same meaning as before.) A method of obtaining a compound or its salts by hydrolysis: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and R^3 each have the same meaning as before); and (d) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and R^3 each have the same meaning as before, and R^4_b is a hydroxy group or a substituted A compound represented by the formula: R^4_c-H (wherein, R^4_c means an amino group or a protected amino group) or its reactivity. When reacted with a derivative or its salt, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3 and R^4_c each have the same meaning as before) consisting of a method for obtaining a compound or its salts;
Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and R^3 each have the same meaning as before, and R^4 is a hydroxy group, a substituted hydroxy group, an amino or a protected amino group) or a salt thereof. 12) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1_a is a protected hydroxy (lower) alkyl group, R^2 is a lower alkyl group, R^3 is hydrogen, a lower alkyl group, A protected or unprotected hydroxy (lower) alkyl group, or a trisubstituted silyl group, R^4_d means a protected amino group] or a salt thereof is characterized by cyclization. , formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1_a, R^2 and R^3 each have the same meaning as before, and R^6 means an amide protecting group)
A method for producing the compound shown or its salts. 13) R^1_a is phenyl (C_1-C_4) alkoxy (C_1-C_4) alkyl group, R^2 is C_1-
C_4 alkyl group, R^3 is tri(C_1-C_4) alkylsilyloxy(C_1-C_4) alkyl group, R
The manufacturing method according to claim 12), wherein ^4_d and R^6 are a C_1-C_4 alkoxyamino group or a phenyl(C_1-C_4) alkoxyamino group. 14) R^1_a is a benzyloxymethyl group, R^2 is a methyl group, R^3 is a 1-tertiary butyldimethylsilyloxyethyl group, R^4_d and R^6 are a methoxyamino group or a benzyloxyamino group The manufacturing method according to claim 13). 15) Formula (a): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1_a is a protected hydroxy (lower) alkyl group, R^2 is a lower alkyl group, and R^6 is an amide protecting group. ] is reacted with a compound represented by the formula: R^7COR^8 (wherein R^7 is a lower alkyl group, and R^8 is hydrogen or a trisubstituted silyl group). , formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1_a, R^2, R^6, R^7 and R
^8 each has the same meaning as before); and (b) formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1_a, R^2 and R^ (6 each has the same meaning as before) A compound represented by the formula: R^7COR^8_b (wherein R^7 has the same meaning as before and R^8_b means a trisubstituted silyl group) The formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1_a, R^2, R^6, R^7 and R
^8_b each has the same meaning as before) to obtain a compound or its salts, and then react this compound with a base to form the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1_a, R ^2, R^6, R^7 and R
^8_b each has the same meaning as before) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1_a, R^2, R^6, R^7 and R
^8 each has the same meaning as before, R^8_a means hydrogen or a trisubstituted silyl group, and when R^8_a means a trisubstituted silyl group, R^8 means hydrogen). A method for producing the indicated compound or its salts.