JP2778122B2 - Phosphinic acid derivatives - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to phosphinic acid derivatives, and more particularly, the present invention relates to a novel phosphinic acid having a dipeptidase inhibitory activity for use with carbapenem or penem antibiotics. The present invention relates to derivatives, synthetic intermediates thereof, and uses thereof.

2. Prior Art Carbapenem or penem antibiotics have a broad antibacterial spectrum and strong bactericidal activity against Gram-positive and Gram-negative bacteria, which are not found in existing antibiotics. Stable for lactamases. Therefore, carbapenems and penems are characterized in that they do not show cross-resistance with existing β-lactams. In addition, its mechanism of action is specific inhibition of bacterial cell wall peptidoglycan biosynthesis, so it is similar to conventional β-lactam antibiotics such as penicillin compounds and cellopharosporin compounds, and its safety is extremely high. .

However, as described above, it is generally stable to bacterial β-lactamase, but on the other hand, mammalian dipeptidase, ie, dehydropeptidase-I (hereinafter referred to as DHP).
-I).

The first solution to this problem was the selective DHP-I with imipenem, one of the carbapenem antibiotics.
It was brought about by the combined use of the inhibitor cilastatin. This combination has been shown to significantly improve urine recovery of imipenem and prevent its potential nephrotoxicity [J. Antimicrob. Chemother. Volume 12 (Supp
ID), pp.1-35 (1983), chemotherapy (Chemother
apy) 33 (S-4) 217-226 (1985)]. Further, some proposals have been made on DHP-I inhibitors and carbapenem and penem antibiotic nephrotoxicity reducing agents (Japanese Patent Application Laid-Open Nos. 55-40669 and 56-8-8).
Nos. 1518, 57-98256, 58-77885, 60-248612
No. 63-2964 and U.S. Pat. No. 4,715,994].

Problems to be solved by the invention
-I-inhibiting compounds have the problem that the duration of action is not always satisfactory, and that no activity is exhibited by oral administration.

Means for Solving the Problems The present inventors have conducted intensive studies to solve the problems of the compounds described in the known literature including cilastatin, and as a result, the compound represented by the following general formula [I] has been found to be persistent in the body. The present invention has been found to be excellent in sex and to show a DHP-I inhibitory effect even by oral administration.

Thus, according to the present invention, the general formula In the formula, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aralkyl group; R ² and R ⁵ may be the same or different , Each represents a hydrogen atom or an ester residue capable of forming a nontoxic ester hydrolysable in vivo; Wherein R ³ is an alkyl group; (Wherein, R ³⁰ is a halogen atom, a carboxyl group, a hydroxyl group,
An optionally substituted cycloalkyl group, an optionally substituted aryl group, an arylthio group, an optionally substituted heteroarylthio group, an optionally substituted alkylthio group, an optionally substituted amino group Or a lower alkoxycarbonyl group; R ³¹ represents a hydrogen atom or a lower alkyl group; n represents an integer of 0 to 6), an optionally substituted cycloalkyl group or a substituted And the configuration of the double bond in A indicates the Z configuration.] Or a group represented by the formula: Wherein R ⁴ represents a cycloalkyl group which may be substituted, and a phosphinic acid derivative represented by｝ and a non-toxic salt thereof are provided. Further, according to the present invention, there is provided a compound represented by the general formula [I]: And general formula Wherein R ¹ , R ³ , A have the above-mentioned meanings; R ²⁰ and R ⁵⁰ may be the same or different, each represent a hydrogen atom or a lower alkyl group; and R ²⁴ and R ⁵⁵ are the same Or may be different and each represents a hydrogen atom or a lower alkyl group. However, R ²⁴
And R ⁵⁵ are not simultaneously hydrogen atoms. Or a salt thereof. The present invention further provides a use of the phosphinic acid derivative of the general formula [I] or a non-toxic salt thereof.

Next, definitions and specific examples of various terms included in the scope of the present invention referred to in the description of this specification will be described.

The term lower is used to mean that the compound or group modified by the term has no more than 6 carbon atoms. An optionally substituted alkyl group is, for example, a chlorine atom, a fluorine atom or a A halogen atom such as a bromine atom; a lower cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; a methoxymethyloxy group, an ethoxymethyloxy group, a 2-methoxyethyloxy group, a 1-methoxyethyloxy group A lower alkoxy lower alkyloxy group such as a 1,1-ethoxyethyloxy group or a 2-ethoxyethyloxy group; which may be substituted with one or two substituents selected from the group consisting of a hydroxyl group, for example, a methyl group, ethyl Group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t ert-butyl group, pentyl group,
A linear or branched alkyl group having 1 to 10, preferably 3 to 10 carbon atoms such as isopentyl group, neopentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group or decyl group. Be included. Specific examples of such optionally substituted alkyl groups include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, hexyl group, isohexyl Group, heptyl group, octyl group, nonyl group, decyl group, cyclopropylmethyl group, 3-cyclopropylpropyl group, 4-cyclopropylbutyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 3-chloropropyl Group, 3-
Bromopropyl group, 3-fluoropropyl group, 4-chlorobutyl group, 4-bromobutyl group, 4-fluorobutyl group, 5-chloropentyl group, 5-bromopentyl group, 5-fluoropentyl group, 6-chlorohexyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 5-hydroxypentyl group, 3
A -methoxymethyloxypropyl group, a 4-methoxymethyloxybutyl group, a 5-methoxymethyloxypentyl group or a 6-methoxymethyloxyhexyl group.

Examples of the optionally substituted cycloalkyl group include a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; A halogen atom such as a bromine atom or a fluorine atom; a carboxyl group; which may be substituted with 1 to 4, preferably 1 to 2 substituents selected from the group consisting of a hydroxyl group;
For example, a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group is included. Specific examples of such optionally substituted cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, 2,2
-Dimethylcyclopropyl group, 2,3-dimethylcyclopropyl group, 2-methylcyclopentyl group, 3-methylcyclopentyl group, 2,2-dimethylcyclopentyl group, 2,5-dimethylcyclopentyl group, 2,2,5,5 -Tetramethylcyclopentyl group, 3-tert-butylcyclopentyl group, 2-hydroxycyclopentyl group, 3-hydroxycyclopentyl group, 2
-Chlorocyclopentyl group, 3-chlorocyclopentyl group, 2-fluorocyclopentyl group, 3-fluorocyclopentyl group, 2-methylcyclohexyl group, 2,2-dimethylcyclohexyl group, 2,2,6,6-tetramethylcyclohexyl group, 3,3-dimethylcyclohexyl group, 4,4-dimethylcyclohexyl group, 4-tert-butylcyclohexyl group, 2-chlorocyclohexyl group, 3-chlorocyclohexyl group, 4-
Chlorocyclohexyl group, 2-bromocyclohexyl group, 3
-Bromocyclohexyl group, 4-bromocyclohexyl group, 2-fluorocyclohexyl group, 3-fluorocyclohexyl group, 4-fluorocyclohexyl group, 2-hydroxycyclohexyl group, 3-hydroxycyclohexyl group, 4-
Hydroxycyclohexyl group, 2-carboxycyclopropyl group, 2-carboxycyclobutyl group, 3-carboxycyclobutyl group, 2-carboxycyclopentyl group, 3-carboxycyclopentyl group, 2-carboxycyclohexyl group, 3-carboxycyclohexyl group or 4 -Carboxycyclohexyl group and the like.

The lower alkyl group can be straight-chain or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl.
-Alkyl groups having 1 to 6 carbon atoms such as -butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group and isohexyl group.

The aralkyl group which may be substituted is, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; Or a halogen atom such as a fluorine atom; which may be substituted by one or two, preferably one substituent selected from the group consisting of a hydroxyl group, for example, a benzyl group, a phenethyl group, a 3-phenylpropyl group or a 4-phenyl group. It includes aralkyl groups having 7 to 11 carbon atoms such as phenylbutyl group. Specific examples of the aralkyl group which may be substituted include, for example, 2-methylbenzyl group, 2,6-dimethylbenzyl group, 4
-Methylbenzyl group, 3,4-dimethylbenzyl group, 2,4-dimethylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-butylbenzyl group, 4-tert-butylbenzyl group, 4-butyl Phenethyl group, 4-tert-butylphenethyl group, 3- (4-butylphenyl) propyl group, 3- (4-
tert-butylphenyl) propyl group, 4- (4-butylphenyl) butyl group, 4- (4-tert-butylphenyl) butyl group, 4-hydroxybenzyl group, 3-hydroxybenzyl group, 4-hydroxyphenethyl group, 3- (4-hydroxyphenyl) propyl group, 4- (4-hydroxyphenyl)
Butyl group, 4-chlorobenzyl group, 4-fluorobenzyl group, 4-bromobenzyl group, 4-chlorophenethyl group, 4-fluorophenethyl group, 3- (4-chlorophenyl) propyl group or 4- (4-chlorophenyl) Butyl group and the like.

Examples of the ester residue capable of forming a nontoxic ester that can be hydrolyzed in vivo include a 1- (methoxycarbonyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group, a methoxycarbonyloxymethyl group, and an ethoxycarbonyloxy group. Methyl group, acetoxymethyl group, 1-acetoxyethyl group, pivaloyloxymethyl group, 1-pivaloyloxyethyl group, phthalidyl group, (5-methyl-2
-Oxo-1,3-dioxol-4-yl) methyl group, 1
-(5-methyl-2-oxo-1,3-dioxole-4
-Yl) ethyl group or (5-phenyl-2-oxo-1,
An ester residue capable of forming a normal non-toxic ester which can be hydrolyzed in vivo, such as a 3-dioxol-4-yl) methyl group, is included.

Halogen atoms include, for example, fluorine, chlorine and bromine atoms.

The arylthio group includes, for example, an arylthio group having 6 to 10 carbon atoms, such as a phenylthio group, a 1-naphthylthio group, and a 2-naphthylthio group.

Examples of the optionally substituted heteroarylthio group include a 2-pyridylthio group, a 3-pyridylthio group, a 4-pyridylthio group, a 3-hydroxy-2-pyridylthio group, a 2-imidazolylthio group, and a 1-methyl-2-imidazolyl group. Thio group, 1,
3,4-thiadiazol-2-ylthio group, 5-methyl-1,
3,4-thiadiazol-2-ylthio group, 1,2,3-triazol-4-ylthio group, tetrazol-5-ylthio group, 1-methyltetrazol-5-ylthio group, thiazol-2-ylthio group, 2- Group consisting of nitrogen atom, oxygen atom and sulfur atom such as aminothiazol-4-ylthio group, 2-aminothiazol-5-ylthio group, 2-aminooxazol-4-ylthio group and 2-aminooxazol-5-ylthio group A heteroarylthio group containing from 1 to 4 heteroatoms selected from as a ring atom and optionally substituted by 1 to 2 substituents selected from the group consisting of a lower alkyl group, a hydroxyl group and an amino group; included.

Examples of the alkylthio group which may be substituted include, for example, an amino group; a hydroxyl group; a carboxyl group; May be substituted with a group,
For example, methylthio, ethylthio, propylthio,
Lower alkylthio groups such as isopropylthio and butylthio are included.

The amino group which may be substituted is, for example, a methyl group,
Lower alkyl groups such as ethyl group, propyl group, isopropyl group and butyl group; carboxy lower alkyl groups such as carboxymethyl group; aralkyloxycarbonyl lower alkyl groups such as benzyloxycarbonylmethyl group; lower alkoxycarbonyl groups such as ethoxycarbonylmethyl group It includes an amino group which may be substituted with one or two substituents selected from the group consisting of lower alkyl groups.

The lower alkoxycarbonyl group includes, for example, a lower alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group or a tert-butoxycarbonyl group.

Examples of the optionally substituted aryl group include a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a tert-butyl group; a halogen atom such as a chlorine atom, a fluorine atom and a bromine atom. Atom selected from the group consisting of: a hydroxyl group; a mercapto group; a carboxy group; a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group; And mono- or polynuclear aryl groups having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group, which may be substituted with 3 to 3, preferably 1 or 2 substituents. Specific examples of such a substituted or unsubstituted aryl group include, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 2-methylphenyl group. Methyl-1-naphthyl group, 4-methyl-1-naphthyl group, 6-methyl-2-naphthyl group, 4-ethylphenyl group, 6-ethyl-2-naphthyl group, 4-propylphenyl group, 6-propyl- 2-naphthyl group, 6-isopropyl-2-naphthyl group, 4-isopropylphenyl group, 4-butylphenyl group, 6-butyl-2-naphthyl group, 4-hydroxyphenyl group, 3-hydroxyphenyl group, 2-hydroxy Phenyl group, 4-mercaptophenyl group, 4-hydroxy-1-naphthyl group, 6-hydroxy-2
-Naphthyl group, 4-mercapto-1-naphthyl group, 6-mercapto-2-naphthyl group, 4-methoxyphenyl group, 4-methoxy-1-naphthyl group, 6-methoxy-2-naphthyl group, 4-chlorophenyl group , 3-chlorophenyl group, 2-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 6-chloro-2-naphthyl group, 6-fluoro-2-naphthyl group, 4-bromo-1-naphthyl group, 6-bromo-2-
Naphthyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dibromophenyl group, 3,5-dibromophenyl group, etc. Is mentioned.

Thus, among the compounds of the formula [I] of the present invention, a preferred group of compounds is that wherein R ¹ has 1 to 10 carbon atoms which may be substituted by a hydroxyl group, a lower alkoxy lower alkyloxy group or a halogen atom. A linear or branched alkyl group, a cycloalkyl group having 3 to 6 ring carbon atoms which may be substituted by 1 to 4 same or different lower alkyl groups, cycloalkyl having 4 to 10 carbon atoms An alkyl lower alkyl group or an aralkyl group having 7 to 11 carbon atoms; R ² is a hydrogen atom; R ⁵ is a hydrogen atom, a 1- (lower alkylcarbonyloxy) lower alkyl group, a phthalidyl group, a lower alkoxycarbonylmethyl A group or a 1- (5-lower alkyl or phenyl-2-oxo-1,3-dioxol-4-yl) lower alkyl group; (Wherein R ^3a is a phenyl group, an aralkyl group having 7 to 11 carbon atoms, a cycloalkyl lower alkyl group having 4 to 10 carbon atoms,
Or substituted by a halogen atom, a carboxyl group, a di-lower alkyl-substituted amino group, an N-methyl-N-carboxymethylamino group, a phenylthio group, a triazolylthio group, a carboxy lower alkylthio group, a lower alkoxycarbonyl lower alkylthio group, or a hydroxyl group. A pyridylthio group, an imidazolylthio group optionally substituted with a lower alkyl group, a hydroxy lower alkylthio group, an amino lower alkylthio group or a 2-amino-2-carboxyethylthio group, which may be substituted with 1 to 1 carbon atoms. Ten
Linear or branched alkyl groups or 3 ring carbon atoms
Represents 6 cycloalkyl groups; the configuration of the double bond in A is the Z configuration) or a group represented by the formula: (Wherein, R ^4a represents a cycloalkyl group having 3 to 6 carbon atoms).

A further preferred group of compounds of the invention are those wherein R ¹ has 3 to ¹ carbon atoms.
0 linear or branched alkyl groups, 1 to 4 same or different lower alkyl groups, which may be substituted with 3 to 6 ring carbon cycloalkyl groups or 4 carbon atoms.
Represents 2 to 10 cycloalkyl lower alkyl groups; R ² is a hydrogen atom; R ⁵ is a hydrogen atom, a 1- (lower alkylcarbonyloxy) lower alkyl group, a phthalidyl group, a lower alkoxycarbonylmethyl group or 1- ( 5-lower alkyl or phenyl-2-oxo-1,3-dioxole-
4-yl) represents a lower alkyl group; A has the formula: (Wherein R ^3b is a phenyl group, an aralkyl group having 7 to 11 carbon atoms, a cycloalkylmethyl group having 4 to 7 carbon atoms, or a halogen atom, a carboxyl group, a phenylthio group, 1,2,3-
Triazol-4-ylthio group, carboxy lower alkylthio group, lower alkoxycarbonyl lower alkylthio group, 3-hydroxy-2-pyridylthio group, 1-methyl-2
A linear or branched alkyl group having 1 to 10 carbon atoms or a ring carbon atom having 3 to 10 carbon atoms which may be substituted with an imidazolylthio group, a hydroxy lower alkylthio group or a 2-amino-2-carboxyethylthio group; Represents 6 to 6 cycloalkyl groups; the configuration of the double bond in A is the Z configuration), or a group represented by the formula: (Wherein, R ^4a represents a cycloalkyl group having 3 to 6 carbon atoms).

Particularly preferred compounds of the present invention are those wherein R ¹ is a straight-chain or branched alkyl group having 3 to 10 carbon atoms, and 3 to 3 ring carbon atoms which may be substituted with 1 to 2 lower alkyl groups. shows six cycloalkyl group or the number 4-7 cycloalkyl methyl group carbons; R ² is hydrogen atom; R ⁵ is a hydrogen atom, a lower alkylcarbonyloxymethyl group, a phthalidyl group or (5-methyl - 2-oxo-1,3-dioxol-4-
Yl) represents a methyl group; A is of the formula: (Wherein, R ^3c represents a linear or branched alkyl group having 3 to 10 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms; the configuration of the double bond in A is a Z configuration. The compound of the above formula [I] is represented by the formula:

Specific examples of the compound of the formula [I] of the present invention are as follows.

(Z) -2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid, (Z) -3-cyclohexyl- 2- (hydroxyisopropylphosphinoyl) methylpropenoic acid, (Z) -3-cyclohexyl-2- (decylhydroxyphosphinoyl) methylpropenoic acid,
(Z) -3-cyclohexyl-2- (2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid, (Z) -2- (Hydroxyisobutylphosphinoyl) methyl-2-dodeceneic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-4-methyl-2-pentenoic acid, (Z) -2
-(Hydroxyisobutylphosphinoyl) methyl-5
-Methyl-2-hexenoic acid, (Z) -3-cyclopropyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid, (Z) -3-cyclopentyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid , (Z) -2- (Hydroxyisobutylphosphinoyl) methyl-5-phenyl-2-pentenoic acid, (Z)-
6-chloro-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid, (Z) -8-chloro-2
-(Hydroxyisobutylphosphinoyl) methyl-2
-Octenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-2-heptenedioic acid, (Z) -3
-Cyclopropyl-2- (2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoic acid,
(Z) -2- (cyclohexylmethylhydroxyphosphinoyl) methyl-3-cyclopropylpropenoic acid,
(Z) -3-cyclohexyl-2- (cyclopentylmethylhydroxyphosphinoyl) methylpropenoic acid,
(Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-6-phenylthio-2-hexenoic acid, (Z)-
2- (hydroxyisobutylphosphinoyl) methyl-
6- (1,2,3-triazol-4-yl) thio-2-hexenoic acid, (Z) -8-carboxymethylthio-2-
(Hydroxyisobutylphosphinoyl) methyl-2-
Octenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-8-methoxycarbonylmethylthio-2-octenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (3-hydroxy −
2-pyridyl) thio-2-hexenoic acid, (Z) -6-
[(L) -2-amino-2-carboxyethyl] thio-
2- (hydroxyisobutylphosphinoyl) methyl-
2-hexenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (1-methylimidazol-2-yl) thio-2-hexenoic acid, (Z) -2-
(Hydroxyisobutylphosphinoyl) methyl-8-
(3-hydroxy-2-pyridyl) thio-2-octenoic acid, 2- (butylhydroxyphosphinoyl) methyl-3
-Cyclohexylpropionic acid, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl)
Methylpropenoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (Z) -3-
Cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid phthalidyl ester, (Z)
Pivaloyloxymethyl 3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate, (1-acetoxyethyl) (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate Ester, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-3-phenylpropenoic acid, (Z) -3-cyclohexyl-2-
(Ethyl hydroxyphosphinoyl) methylpropenoic acid, (Z) -3-cyclohexyl-2- [hydroxy (4-methoxymethoxybutyl) phosphinoyl] methylpropenoic acid, (Z) -3-cyclohexyl-2- [hydroxy (4 -Hydroxybutyl) phosphinoyl] methylpropenoic acid, (Z) -2- (4-chlorobutylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid, (Z) -3-cyclohexyl-2- (hexylhydroxyphosphinoyl ) Methylpropenoic acid,
(Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-4,4-dimethyl-2-pentenoic acid, (Z) -2
-(Benzylhydroxyphosphinoyl) methyl-3-
Cyclohexylpropenoic acid, (Z) -3-cyclohexyl-2- (cyclohexylmethylhydroxyphosphinoyl) methylpropenoic acid, (Z) -6-dimethylamino-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid , (Z) -6-carboxymethyl (methyl) amino-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid, (Z) -8-dibutylamino-2- (hydroxyisobutylphosphinoyl)
Methyl-2-octenoic acid, (Z) -6- (2-aminoethyl) thio-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid, (Z) -6- (2-hydroxyethyl) thio -2- (Hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid, 3-cyclohexyl-2- (hexylhydroxyphosphinoyl) methylpropionic acid, 3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropionic acid 3-cyclohexyl-2- (hydroxyisopropylphosphinoyl) methylpropionate, 3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropionate, 3-cyclohexyl-2- (decylhydroxyphosphinoyl) methylpropionate Acid, 3-cyclohexyl-2
-(2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropionic acid, (Z) -3-cyclohexyl-2- (hydroxyisopentylphosphinoyl)
Methylpropenoic acid, (Z) -3-cyclopentyl-2-
(Cyclopentylhydroxyphosphinoyl) methylpropenoic acid, (Z) -2- (2-cyclohexylethylhydroxyphosphinoyl) methyl-3-cyclopropylpropenoic acid, (Z) -3-cyclopropyl-2- (hydroxyphenethyl Phosphinoyl) methylpropenoic acid,
(Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-8-phenyl-2-octenoic acid, (Z) -4-
Cyclopropyl-2- (hydroxyisobutylphosphinoyl) methyl-2-butenoic acid, (Z) -4-cyclopentyl-2- (hydroxyisobutylphosphinoyl)
Methyl-2-butenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl) methyl-2-decenedioic acid,
(Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-4-methyl-2-heptenedioic acid, (Z) -3-
(4-carboxycyclohexyl) -2- (hydroxyisobutylphosphinoyl) methylpropenoic acid, (Z)
-5-cyclopropyl-2- (hydroxyisobutylphosphinoyl) methyl-2-pentenoic acid, (Z) -3-
Cyclohexyl-2- (2,2-dimethylcyclopentylhydroxyphosphinoyl) methylpropenoic acid.

Further, the compounds of the formula [I] of the present invention can also exist in the form of pharmaceutically acceptable salts, and examples of such salts include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid. And salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium, and more specifically, for example, (Z) -3-cyclohexyl-2-
Disodium (hydroxyisobutylphosphinoyl) methylpropenoate, (Z) -3-cyclohexyl-2-
Calcium (hydroxyisobutylphosphinoyl) methylpropenoate, (Z) -3-cyclohexyl-2-
Disodium (2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoate and (Z) -8-dibutylamino-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid hydrochloride may be mentioned. it can.

In the above formula [I], A is a formula: The stereochemical relationship due to the double bond of the group when the group is represented by the following formula is defined in IUPAC Organic Chemistry Nomenclature Part E, Stereochemistry (Recommended 1974) (Pure and Applied Chemistry) 45, pp. 11-30 (1976)]. That is, two atoms bonded to a carbon atom of one bonded with a double bond (Dan), R ³ and the R ³ is a predominance of the hydrogen atom, the two atoms bonded to other carbon atoms Group, Are compared, the prefix Z is used when both are on the same side of the reference plane, and the prefix E is used when both are on the opposite side.

The compound of the present invention is preferably a Z isomer.

Next, the method for producing the compound of the present invention will be described below.

The compound of the present invention can be produced by any of the following production routes 1 to 9.

(Where R¹And R^ThreeHas the meaning given above; R^{twenty two}, R⁵²And R⁶Is
May be the same or different and represent a lower alkyl group; M
Is, for example, lithium ion, sodium ion, potassium
Base such as umium ion or triethylammonium ion
The cations derived from each are shown. ](Where R¹, R^Three, R²⁰And R⁵⁰Has the meaning given above; R⁵³Is water
Represents an element atom or a lower alkyl group. ](Where R¹, R²⁰, R^ThreeAnd R⁵⁰Has the above-mentioned meaning. ](Where R¹, R^{twenty two}, R^ThreeAnd R⁵²Has the above-mentioned meaning. ](Where R¹, R²⁰And R⁵⁰Has the meaning given above; R³²Is alley
Ruthio group, optionally substituted heteroarylthio
Group, an optionally substituted alkylthio group,
A reel group, an optionally substituted heteroaryl group, or
X represents an optionally substituted alkyl group; X represents a general formula:(Where R³¹And n has the meaning described above)
Or a cycloalkylene group; L is, for example, a chlorine atom,
Bromine atom, methanesulfonyloxy group and toluenes
Each represents a leaving group such as a rufonyloxy group. Compound
By double bond in [XVI] and compound [XVIII]
The steric relationship is a Z, E, or ZE mixture. ](Where R¹, R²⁰, R⁵⁰, X and L have the meanings given above; R³³Passing
And R³⁴May be the same or different;
The substituents on the amino group which may be
Show. Double in compound [XVI] and compound [XX]
The steric relationship by bonding is a Z, E or ZE mixture. ](Where R¹, R²⁰, R^FourAnd R⁵⁰Has the above-mentioned meaning. Compound
Due to the double bond in the product [XXI], the steric relationship is Z, E, or
Or ZE mixture. ](Where R¹, R²⁰, R⁵⁰And A have the meaning given above; R^{twenty three}Is water
Represents a hydrogen atom or a lower alkyl group; R⁵²Is a lower alkyl group
Are respectively shown. ](Where R¹, R²⁰, A and L have the meanings given above and R⁵⁴Is a living body
Which can form non-toxic esters hydrolysable in water
Indicates a residue. Production Route 1 Compound [III] is reacted with Compound [II] to give Compound [I
V] can be produced by, for example, triethylamine, 1,8-
Diazabicyclo [5,4,0] -7-undecene, sodium
Mumethoxide, sodium ethoxide, potassium tert-
Butoxide, sodium hydride, butyllithium or
Example in the presence of a base such as lithium diisopropylamide
For example, methanol, ethanol, isopropanol
Is an alcohol such as tert-butyl alcohol; diethyl
Ether, tetrahydrofuran, dioxane or 1,
Ethers such as 2-dimethoxyethane; benzene, toluene
Aromatic hydrocarbons such as ene or xylene; acetonitrile
Tolyl, dimethylformamide or dimethylsulfo
Aprotic dipolar solvent such as oxide; or a mixture thereof
-78 ° C in a solvent that does not adversely affect the reaction, such as a mixed solvent.
To the boiling point of the solvent, preferably at 0 ° C to room temperature for 10 minutes to 2 minutes.
4 hours, preferably 30 minutes to 2 hours
Can be done. The amount of compound [III] used
Is from 0.5 mol to 10 mol per 1 mol of the compound [II],
Preferably, it is 0.8 mol to 1.2 mol.

The compound [IV] thus produced can be directly reacted with the compound [V] without isolation and purification, but if necessary, isolated and purified as a protonated [IV ']. After that, the compound can be reacted again with the compound [V] in the presence of the aforementioned base.

The step of reacting compound [IV] with compound [V] to produce compound [VI] and compound [VII], each of which is a Z and E isomer of an olefin, comprises isolating compound [IV],
When the reaction is carried out without purification, the compound [I] is added to the reaction mixture after the reaction of the compound [II] with the compound [III].
I] 0.5 mol to 10 mol, preferably 0.8 mol, per 1 mol
Add from 3 to 3 moles of compound [V] and add the solvent from -78 ° C to the boiling point of the solvent, preferably from -50 ° C to room temperature, from 1 hour to 7 hours.
The reaction can be carried out for a day, preferably for 3 to 24 hours. On the other hand, when the reaction is performed after isolating and purifying the compound [IV], an acid is added to the reaction mixture to extract the compound [IV '], extract it by crystallization, column chromatography such as silica gel, thin-layer chromatography or the like. After isolation and purification by a combination or the like, compound [IV '] is converted to an alcohol such as methanol, ethanol, isopropanol or tert-butyl alcohol; ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Aromatic hydrocarbons such as benzene, toluene or xylene; aprotic dipolar solvents such as acetonitrile, dimethylformamide or dimethylsulfoxide; or solvents which do not adversely affect the reaction such as a mixed solvent thereof, for example, triethylamine , 1,8− After adding a base such as azabicyclo [5,4,0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, butyllithium or lithium diisopropylamide, the compound [IV '] 1 0.5 to 10 moles, preferably 0.8 to 3 moles of the compound [V] is added per mole, and the mixture is added at -78 ° C.
To the boiling point of the solvent, preferably from -50 ° C to room temperature, for 1 hour to 7 days, preferably 3 hours to 24 hours. Separation of the compound [VI] and the compound [VII], which are Z and E isomers of the olefin, can be performed by means of column chromatography such as silica gel or thin layer chromatography.

The step of producing the compound [VIII] by simultaneously carrying out the deesterification reaction of the carboxylic acid ester and the phosphinic acid ester from the compound [VI] comprises the step of preparing at least two equivalents of the compound [VI], for example, lithium hydroxide. Water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide or a mixture thereof in the presence of an alkali such as sodium hydroxide, potassium hydroxide, calcium hydroxide or tetramethylammonium hydroxide. Reaction in a solvent that does not adversely affect the reaction, such as a solvent, from room temperature to the boiling point of the solvent for 1 to 48 hours, or, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid. In the presence of water with acid, for example, water, methanol , Isopropanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, or a mixture of these solvents, which has no adverse effect on the reaction, at room temperature to the boiling point of the solvent for 1 to 48 hours.

The step of producing a compound [IX] by subjecting the carboxylic acid ester to a deesterification reaction from the compound [VI] is performed in an amount of 0.5 to 2 equivalents, preferably 0.1 equivalent to the compound [VI].
In the presence of 9 to 1.1 equivalents of an alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, In a solvent that does not adversely affect the reaction, such as dimethyl sulfoxide or a mixed solvent thereof, the temperature should be from 0 ° C to the boiling point of the solvent, preferably 0 ° C.
The reaction can be carried out at 30 ° C to room temperature for 30 minutes to 24 hours.

The step of producing the compound [VIII] by subjecting the phosphinic ester to the deesterification reaction from the compound [IX] is performed in the same manner as the step of producing the compound [VIII] in one step from the compound [VI]. Can be.

The step of producing a compound [X] by subjecting the phosphinic ester to a deesterification reaction from the compound [VI] is carried out in an amount of at least one equivalent to the compound [VI], for example, hydrogen chloride or hydrogen bromide. In the presence of hydrogen halide,
For example, methanol, ethanol, isopropanol, ethyl acetate, butyl acetate, diethyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform,
The reaction can be performed in a solvent that does not adversely affect the reaction, such as acetonitrile, dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof, at room temperature to the boiling point of the solvent for 1 to 48 hours. As another method, 1 to 10 moles per 1 mole of compound [VI] is used in a solvent that does not adversely affect the reaction, such as methylene chloride, chloroform, acetonitrile, dimethylformamide, or a mixed solvent thereof. For example, a halosilane such as bromotrimethylsilane is reacted at a reaction temperature of 0 ° C.
The reaction can be carried out by reacting the mixture at 0 to room temperature for 10 minutes to 1 hour.

The step of producing the compound [VIII] by subjecting the carboxylic acid ester to hydrolysis from the compound [X] can be carried out in the same manner as the step of producing the compound [VIII] in one step from the compound [VI]. it can.

The compound [VIII] produced in this way is usually used in this field such as solvent extraction, crystallization, column chromatography such as silica gel, alumina or ion exchange resin, thin layer chromatography or a combination thereof. It can be purified by a purification means. Compound [VIII] is, for example, water, methanol,
Ethanol, isopropanol, tetrahydrofuran,
Dioxane, acetonitrile, dimethylformamide,
In a solvent that does not adversely affect the reaction, such as dimethyl sulfoxide or a mixed solvent thereof, for example, lithium hydroxide,
A salt can be produced by the action of an alkali such as sodium hydroxide, potassium hydroxide or calcium hydroxide. Further, when the deesterification reaction of the compound [VI], the compound [IX] or the compound [X] is performed using an alkali, the salt of the compound [VIII] can be prepared by selecting a suitable reaction solvent. It can also be isolated and purified by crystallization directly from the reaction solvent.

Further, after the compound [VI] and the compound [VII] are treated by the isomerization method for EZ of olefin shown in Production Route 2 and Production Route 3 described below without separation, deesterification operation or deesterification is performed. The compound [VIII] can also be produced by treating the compound by an olefin isomerization method after carrying out the operation for isomerization.

The compound [II] as a starting material in the production route 1 can be obtained by a known method, for example, MI Kabchnik et al. [Doklady Akad. Nauk SSSR12
5, 1260 (1959); Chemical Abstracts (Ch
em.Abst.), Vol. 53, 21754f (1959)], M. Sander. [Chemis Berichte (Chem. Be
r.), Vol. 93, p. 1220 (1960)] and the like.

Production Route 2 The step of producing a compound [XII] by performing an isomerization reaction of the olefin of the olefin from the compound [XI] includes, for example,
In the presence of hydrogen halide such as hydrogen chloride or hydrogen bromide,
For example, water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, butyl acetate, diethyl ether, tetrahydrofuran, dioxane, methylene chloride,
The reaction can be carried out in a solvent that does not adversely affect the reaction, such as chloroform, acetonitrile, dimethyl sulfoxide or a mixed solvent thereof, at room temperature to 200 ° C. for 30 minutes to 72 hours. At this time, when a water-containing solvent is used as the solvent, hydrolysis of the carboxylic acid ester can be performed. When an alcohol-based or ester-based solvent is used, esterification of the carboxylic acid or transesterification of the carboxylic acid ester can be performed simultaneously. In the compound (XII), R ⁵³
Is a lower alkyl group, the compound [VIII] can be produced by deesterifying the carboxylic acid ester described in Production Route 1.

Production Route 3 The step of producing a compound [XIII] from the compound [XI] by subjecting the olefin to EZ isomerization is carried out, for example, in the presence of a hydrogenation catalyst such as palladium-carbon, platinum oxide or Raney nickel. By reacting in a solvent that does not adversely affect the reaction, such as methanol, ethanol, acetic acid, ethyl acetate, or a mixed solvent thereof, under a hydrogen pressure of 1 to 4 atm at 0 to 50 ° C for 30 minutes to 8 hours Can do it. In compound (XIII), R ²⁰ ,
When one or both of R ⁵⁰ is a lower alkyl group,
The compound [VIII] can be produced by deesterifying the carboxylic acid ester and / or phosphinic ester described in Production Route 1.

Production Route 4 Compound [V] is reacted with compound [XIV] to give compound [X], each of which is an isomer of olefins Z and E.
And the compound [XV] are prepared, for example, in the presence of a strong base such as sodium ethoxide, potassium tert-butoxide or sodium hydride, for example, ethanol or te.
alcohols such as rt-butyl alcohol; ethers such as diethyl ether or tetrahydrofuran; aromatic hydrocarbons such as benzene or toluene; or -20 in a solvent which does not adversely affect the reaction such as a mixed solvent thereof.
The reaction can be carried out at a temperature of from 0 ° C. to the boiling point of the solvent for 30 minutes to 7 days. The amount of compound [V] used is 0.5 to 10 moles per mole of compound [XIV].
Preferably, it is 0.8 mol to 1.2 mol.

Compound [X] and compound [XV] thus produced
Can be isolated and purified by extraction, crystallization, column chromatography such as silica gel, thin-layer chromatography, or a combination thereof.
Compound [X] can be treated under the conditions of carboxylic ester deesterification described in Production Route 1 to give
Compound [VIII] is obtained. Compound [XV] is treated with the olefin EZ isomerization method described in Production Route 2 or Production Route 3 and then deesterified to give Compound [VIII]. can get. The compound [X] and the compound [XV] were treated without any isolation and purification by the isomerization method of the EZ isomer of an olefin described in Production Route 2 or Production Route 3. Thereafter, the compound [VIII] can also be obtained by performing deesterification or performing an operation of deesterification, followed by treatment with an olefin isomerization method.

The starting compound [XIV] in Production Route 4 can be prepared by a known method, for example, ANPudovik et al. [Izv.
ad.Nauk SSSR, Otd. Khim. Nauk 902 (1952); Chemical Abstracts (Chem. Abst.), Vol. 47, 10469.
c (1953)], JKThottathil et al. [Tetrahedron Letters, Vol. 25, p. 4737 (1984)
Year)].

Production Route 5 The step of producing compound [XVIII] by reacting compound [XVII] with compound [XVI] includes, for example, triethylamine,
1,8-diazabicyclo [5,4,0] -7-undecene, tetramethylammonium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-
In the presence of a base such as butoxide, sodium hydride or butyllithium, for example, water, methanol, ethanol,
Reaction in a solvent that does not adversely affect the reaction, such as isopropanol, tert-butyl alcohol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, or a mixture thereof, from -20 ° C to the boiling point of the solvent for 1 to 48 hours Can be performed. The amount of compound [XVII] used was
The amount is 0.5 to 10 mol, preferably 0.8 to 1.5 mol, per 1 mol of compound [XVI]. In the compound [XVIII], when the olefin is a mixture of E or ZE, a compound having the olefin of Z can be produced by the method shown in Production Route 2 or Production Route 3. When both or one of R ²⁰ and R ⁵⁰ is a lower alkyl group, it can be deesterified by the method shown in Production Route 1.

Production Route 6 The step of producing compound [XX] by reacting compound [XIX] with compound [XVI] includes, for example, water, methanol, ethanol, isopropanol, tert-butyl alcohol,
In a solvent that does not adversely influence the reaction, such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, or a mixture thereof, or without a solvent at 0 ° C to 200 ° C, if necessary, for example, iodine The reaction can be carried out for 1 hour to 7 days in the presence of a catalyst such as sodium iodide or potassium iodide. The amount of compound [XIX] to be used is 0.5 to 100 mol, preferably 1 to 20 mol, per 1 mol of compound [XVI]. Compound (XX)
In the above, when the olefin is a mixture of E or ZE, a product having the olefin of Z can be produced by the method shown in Production Route 2 or Production Route 3. When both or one of R ²⁰ and R ⁵⁰ is a lower alkyl group, the ester can be deesterified by the method shown in Production Route 1.

Production Route 7 The step of producing compound [XXII] by catalytically reducing the double bond of compound [XXI] includes, for example, palladium-
In the presence of a hydrogenation catalyst such as carbon, platinum oxide or Raney nickel, for example, methanol, ethanol, acetic acid,
In a solvent that does not adversely affect the reaction, such as ethyl acetate or a mixture thereof, under a hydrogen pressure of 1 to 4 atm.
The reaction can be carried out at 50 ° C for 1 to 72 hours. When both or either of R ²⁰ and R ^{50 in} the compound [XXII] is a lower alkyl group, it can be deesterified by the method shown in Production Route 1.

Production Route 8 The step of producing compound [XXV] by reacting compound [XXIII] with an alcohol of formula [XXIV] includes, for example, hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, or p-toluenesulfonic acid. In the presence of an acid, such as dichloromethane, dichloroethane, benzene, toluene, or a solvent that does not adversely affect the reaction, or the alcohol itself of compound [XXIV] as a solvent without using these solvents. The reaction can be carried out at room temperature to the boiling point of the solvent for 1 to 24 hours. When R ²³ is a lower alkyl group in the compound [XXV], it can be deesterified by the method shown in Production Route 1.

Production Route 9 The step of producing compound [XXVIII] by reacting compound [XXVII] with compound [XXVI] includes, for example, triethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
In the presence of a base such as potassium carbonate or sodium hydride, in a solvent that does not adversely affect the reaction, for example, water, methanol, ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or a mixed solvent thereof, From 0 ° C to the boiling point of the solvent, 1
The reaction can be carried out for 48 hours to 48 hours. Further, the compound [XXVI] can be reacted with the above-mentioned base to form a salt, the salt can be isolated and dissolved in the above-mentioned solvent, and then the compound [XXVII] can be reacted. Compound (X
XVIII], when R ²⁰ is a lower alkyl group,
Deesterification can be performed by the method shown in Production Route 1.

The compound of the formula [I], which can be produced as described above, can be converted into a pharmaceutically acceptable salt, if necessary.

For example, the disodium salt of the compound of formula [I] is precipitated by adding an aqueous solution of 2 equivalents of sodium hydroxide to a lower alcohol solution of the compound of formula [I], for example, methanol, ethanol or isopropanol. It can be obtained by filtering the crystals. Further, the calcium salt can be obtained by adding an aqueous solution of calcium chloride to the aqueous solution of the disodium salt and collecting the precipitated crystals by filtration. The compound of the formula [I] provided by the present invention shows a DHP-I inhibitory effect even by oral administration and has excellent persistence in the body.

Such pharmacological properties of the compounds of the present invention are demonstrated by the following pharmacological tests.

Pharmacological Test Example Test Compound (1) (Z) -2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid [Example 3 (b)] (2) (Z) -3-cyclohexyl-2- ( (Hydroxyisobutylphosphinoyl) methylpropenoic acid [Example 5 (b)] (3) (Z) -3-cyclohexyl-2- (hydroxyisopropylphosphinoyl) methylpropenoic acid [Example 11 (c)] (4 ) (Z) -3-Cyclohexyl-2- (decylhydroxyphosphinoyl) methylpropenoic acid [Example 13
(C)] (5) (Z) -3-cyclohexyl-2- (2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoic acid [Example 14 (c)] (6) (Z) -2- (Hydroxyisobutylphosphinoyl) methyl-2-octenoic acid [Example 16 (c)] (7) (Z) -2- (Hydroxyisobutylphosphinoyl) methyl-2-dodeceneic acid [Example 17 (c) (8) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-4-methyl-2-pentenoic acid [Example
19 (c)] (9) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-5-methyl-2-hexenoic acid [Example
20 (c)] (10) (Z) -3-cyclopropyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid [Example 21 (c)] (11) (Z) -2- (hydroxyisobutylphospho) (Finoyl) methyl-5-phenyl-2-pentenoic acid [Example 22 (c)] (12) (Z) -6-chloro-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid [Example
23 (c)] (13) (Z) -8-chloro-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid [Example
24 (c)] (14) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-2-heptenedioic acid [Example 25
(C)] (15) (Z) -3-cyclopropyl-2- (2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoic acid [Example 26 (c)] (16) (Z) -2 -(Cyclohexylmethylhydroxyphosphinoyl) methyl-3-cyclopropylpropenoic acid [Example 27 (b)] (17) (Z) -3-cyclohexyl-2- (cyclopentylmethylhydroxyphosphinoyl) methylpropenoic acid [ Example 29 (b)] (18) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6-phenylthio-2-hexenoic acid
[Example 42 (b)] (19) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (1,2,3-triazol-4-yl) thio-2-hexenoic acid [Example 43 (b)] (20) (Z) -8-carboxymethylthio-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid [Example 44 (a)] (21) (Z) -2- ( (Hydroxyisobutylphosphinoyl) methyl-8-methoxycarbonylmethylthio-2
-Octenoic acid [Example 44 (b)] (22) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (3-hydroxy-2-pyridyl)
Thio-2-hexenoic acid [Example 45 (b)] (23) (Z) -6-[(L) -2-amino-2-carboxyethyl] thio-2- (hydroxyisobutylphosphinoyl) methyl- 2-hexenoic acid [Example 46
(B)] (24) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (1-methylimidazol-2-yl) thio-2-hexenoic acid [Example 49 (b)] (25 ) (Z) -2- (Hydroxyisobutylphosphinoyl) methyl-8- (3-hydroxy-2-pyridyl)
Thio-2-octenoic acid [Example 50 (b)] (26) 2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropionic acid [Example 35] (27) (Z) -3-cyclohexyl-2 -(Hydroxyisobutylphosphinoyl) methylpropenoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester [Example 57] (28) (Z) -3-cyclohexyl-2- (Cyclohexylmethylhydroxyphosphinoyl) methylpropenoic acid [Example 4 (b)] (29) (Z) -2- (Hydroxyisobutylphosphinoyl) methyl-3-phenylpropenoic acid [Example 1
(B)] (30) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-2-butenoic acid [Example 15 (b)] (31) (Z) -6- (2-hydroxyethyl) thio -2
-(Hydroxyisobutylphosphinoyl) methyl-2
-Hexenoic acid [Example 38] Test method (1) Pig kidney dehydropeptidase-I inhibitory activity (i) Purification of pig kidney dehydropeptidase-I After homogenizing pig renal cortex, it is cooled in a dry ice-acetone bath beforehand. 1/4 volume of butanol was added.
Stirring was performed at 4 ° C. for 43 hours. After dialysis all day and night, 3,000g
The supernatant was obtained by centrifugation for 30 minutes, and the crude enzyme was obtained by 50-75% ammonium sulfate precipitation. This was further dissolved in a 50 mM MOPS buffer containing 0.5 M NaCl, adsorbed on a cilastatin affinity column, and eluted with 50 mM MOPS-0.5 M NaCN to obtain a purified enzyme.

(Ii) Measurement of inhibitory activity 3 mU of the enzyme obtained above [1 U is 50 mM MOPS buffer (pH 7.
4) The amount of the enzyme which shows an enzymatic activity to hydrolyze 1 μmol of the substrate per minute at a substrate (glycyldehydrophenylalanine) concentration of 0.05 mM at 37 ° C. ] And inhibitor at 37 ° C in 2.7 ml of 50 mM MOPS buffer (pH 7.4).
After pre-incubation for 2 hours, 2.475 ml was transferred into a cuvette, and 25 μm of 5 mM glycyldehydrophenylalanine 50 mM MOPS buffer (pH 7.4) was added as a substrate to start the reaction. The reaction was performed at 37 ° C in a spectrophotometer equipped with a thermostat, and the decrease in absorbance at 275 nm in 5 minutes was measured. The percent inhibition at each inhibitor concentration was determined by comparison with the value of a control containing no inhibitor, from which the IC ₅₀
Values were calculated. Table 1 shows the results.

From the above test results, the compound of the present invention has a strong DHP-I inhibitory activity.
It is considered useful for use in combination with the antibiotic.

(2) Effect of carbapenem on urinary recovery rate Three 8-week-old male SD rats were grouped into groups, and the first group was intravenously administered with 10 mg / kg of imihenem alone.
For the group, imipenem 10 mg / kg, Compound No. 2 10 mg / kg
Is administered intravenously in combination with Compound N.
o.2 Imipenem 10 mg / kg 30 minutes after oral administration of 10 mg / kg
Was administered intravenously. For comparison, group 4 was intravenously administered with imipenem 10 mg / kg and cilastatin 10 mg / kg in combination. The urine of rats was collected up to 8 hours after imipenem administration, and the concentration of imipenem in the collected whole urine was determined using Bacillus subtilis ATCC12432 as a test bacterium.
The urinary recovery was determined by the c-plate method. Table 2 shows the results.

As is clear from the above test results, the compound of the present invention significantly increased the urinary recovery of imipenem in rats, whether administered intravenously or orally, and was found to be effective in combination with carbapenem or penem antibiotics. It is considered useful to use.

(3) Inhibitory effect on nephrotoxicity induced by carbapenem antibiotics Twelve 18-week-old male Japanese white rabbits (body weight 3.19 to 3.45)
kg) were divided into three groups each consisting of four animals. For the first group, imipenem 150 mg / kg alone, and for the second group, imipenem 150 mg / kg and Compound No. 2 150 mg / kg. In combination with 0.9% as a control for group 3
Was administered intravenously via the marginal vein of the auricle. Forty-eight hours later, blood samples were collected, BUN and creatinine were measured, and rabbit kidneys were collected for histopathological examination. Table 3 shows the results.

As is evident from the above test results, the compound of the present invention markedly suppresses nephrotoxicity induced by high doses of imipenem in rabbits, and is useful for use in combination with carbapenem or penem antibiotics. It is believed that there is.

(4) Pharmacokinetic evaluation (4-a) Test in rats 9-week-old male SD rats were grouped in groups of three, compound No. 2 for the first group, and compound No. 2 for the second group. No. 5, Compound No. 10 for the third group, Compound No. 14 for the fourth group, Compound No. 17 for the fifth group, and Compound No. 17 for the sixth group Was administered intravenously at a dose of 10 mg / kg each for compound No. 23 and for group 7 compound 28. On the other hand, Compound No. 2 was used for Group 8, Compound No. 5 was used for Group 9, Compound No. 10 was used for Group 10, and Compound No. 11 was used for Group 10.
Compound No. 17 for the group and Compound N for the twelfth group
o.28, and Compound No.27 for Group 13
0 mg / kg dose (However, in the case of compound No. 27, 10 mg in terms of the corresponding free acid compound, compound No. 2)
/ kg) orally. In addition, group 14 received 10 mg / kg of cilastatin intravenously as a control group.

After administration, 1/12, 1/4, 1/2, 1, 2, 4, 6, 8, and 24 hours later, blood was collected over time from a cannula inserted into the carotid artery, and the plasma concentration of each compound was determined by porcine DHP- It was measured by an enzyme assay using I. The results are shown in Table 4-a. However, the plasma concentration after administration of Compound No. 27 indicates the concentration as a free acid compound (Compound No. 2), and the area under the blood concentration curve (AUC) was determined by the trapezoidal method.

As is evident from the above test results, the compound of the present invention shows much superior persistence in blood concentration as compared with cilastatin. Unlike cilastatin, which is not orally absorbed,
It shows good oral absorption by itself. On the other hand, it is also possible to further improve the oral absorbability by making a prodrug. For example, Compound No. 27, which is a prodrug of Compound No. 2, shows better oral absorption than Compound No. 2, which is the parent compound.

(4-b) Test in dogs Three groups of 14-month-old male beagle dogs were administered as a group. Compound 1 was administered intravenously at 10 mg / kg to Group 1, and Compound No. 2 was administered to Group 2 2 10 mg / kg was orally administered. After administration, 1/1
After 2,1 / 4,1 / 2,1,2,4,6,8,24 hours, blood was collected over time from the cephalic vein, and the plasma concentration was measured by an enzyme assay using porcine DHP-I. . The results are shown in Table 4-b. However, the area under the blood concentration curve (AUC) was determined by the trapezoidal method.

As is clear from the above test results, the compound of the present invention shows excellent persistence and good oral absorption in dogs as well as rats.

(5) Acute toxicity test in mice Four-week-old male ddY mice (body weight: 24-26 g) were grouped in groups of five, and Compound 1 (2000 mg / kg) was intravenously administered to the first group. To the two groups, Compound No. 2 was orally administered at 4000 mg / kg. After drug administration, the occurrence of death was observed for 7 days. Table 5 shows the results.

As is clear from the above test results, the compounds of the present invention have very low toxicity.

The compound [I] of the present invention can be used as a therapeutic agent for bacterial infections in mammals including humans by using it in combination with a carbapenem or penem antibiotic. Compound [I] of the present invention
The carbapenem or penem antibiotics are used separately or in combination, but in any case, they can be prepared into oral or parenteral preparations as needed.

Examples of the oral preparation include tablets, granules, capsules, syrups, suspensions, and solutions for internal use.
In preparing these oral preparations, additives suitable for each dosage form can be used. For example, excipients such as lactose, sucrose, glucose, starch, crystalline cellulose, etc., such as methylcellulose, Binders such as hydroxypropylcellulose, gum arabic, gelatin and the like, disintegrants such as calcium carboxymethylcellulose, starch and the like, such as magnesium stearate, talc,
Lubricants such as silicic anhydride, for example, emulsifiers such as gum arabic, carboxymethylcellulose, glycerin fatty acid ester, sodium lauryl sulfate, and other suitable suspending agents, dispersants, solubilizing agents, flavoring agents, pH adjusters, and stability Agent,
Preservatives, coloring agents and the like can be exemplified.

Examples of the parenteral administration agent include an injection for intravenous administration and an injection for intramuscular administration.

The injections can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles.

In preparing these injections, appropriate additives can be used as necessary. Examples of such additives include isotonic agents such as sodium chloride, glycerin, and glucose, tartaric acid, and the like. Buffering agents such as sodium acetate, sodium hydrogen phosphate, sodium carbonate, sodium hydrogen carbonate, etc., suspending agents such as gum arabic, sodium alginate, carboxymethylcellulose, methylcellulose, paraoxybenzoate (methyl, ethyl, propyl), benzyl alcohol And other suitable soothing agents, solubilizing agents, and the like. Also,
As the solvent, physiological saline, distilled water for injection, sterilized purified water, propylene glycol, vegetable oil, and the like can be used. Also, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, for injection, or the like, immediately before use.

The compound of the present invention is administered in an amount of 1 to 500 mg / kg, preferably 1 to 100 mg / kg per day in the case of oral administration in one or several doses, and 1 to 200 mg / kg in the case of parenteral administration.
kg, preferably 1 to 100 mg / kg, in one or several divided doses. However, this dosage can be varied depending on the nature of the carbapenem or penem antibiotic used in combination. In addition, this dose may be increased or decreased depending on the condition, weight, age, etc. of the patient.

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 Preparation of (Z) and (E) -2- (hydroxyisobutylphosphinoyl) methyl-3-phenylpropenoic acid (a) (Z) and (E) -2- (ethoxyisobutylphosphinoyl) methyl Preparation of -3-phenylpropenoic acid ethyl ester Under a nitrogen atmosphere, 7.3 ml (11 mmol) of 1.5 M butyllithium-hexane was added dropwise to a solution of 1.5 ml (11 mmol) of diisopropylamine in 20 ml of dry tetrahydrofuran. The mixture was cooled to -78 ° C (dry ice-methanol bath), and ethyl isobutylphosphinate was added.
1.50 g (10 mmol) and then 2.46 g (10.4 mmol) of ethyl 2-diethoxyphosphinoylpropenoate are added, followed by stirring at 0 ° C. for 30 minutes. The mixture is cooled to −30 ° C., 1.1 ml (11 mmol) of benzaldehyde are added and stirred at −30 ° C. for 3 hours and at room temperature overnight. To the reaction mixture was added 50 ml of saturated aqueous ammonium chloride, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 20 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by medium-pressure liquid chromatography (Merck Rover column size C recroprep SI60, ethyl acetate), and the first fraction was concentrated to give (Z) -2- (ethoxyisobutyl) 1.00 g (30% yield) of ethyl phosphinoyl) methyl-3-phenylpropenoate was obtained as a colorless oil.

^{IR (neat, cm -1):} 2962,1713,1266,1203,1161,1035,957 FAB-MS (m / e): 339 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.01 (6H , dd, J = 3.6Hz, 6.4H
z), 1.21 (3H, t, J = 7.1 Hz), 1.36 (3H, t, J = 7.0 Hz), 1.
59-1.67 (2H, m), 2.02-2.10 (1H, m), 3.10-3.27 (2
H, m), 3.84-4.14 (2H, m), 4.29 (2H, q, J = 7.2Hz), 7.3
3-7.43 (3H, m), 7.61 (2H, d, J = 6.8Hz), 7.83 (1H, d, J
= 4.9 Hz) The second fraction is concentrated to give 0.74 g (yield 22%) of (E) -2- (ethoxyisobutylphosphinoyl) methyl-3-phenylpropenoic acid ethyl ester as a colorless oil.

^{IR (neat, cm -1):} 2962,1719,1230,1161,1035,954 FAB-MS (m / e): 339 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.05-1.10 (9H , m), 1.30 (3
H, t, J = 7.1Hz), 1.63-1.77 (2H, m), 2.04-2.21 (1H,
m), 2.94-3.11 (2H, m), 3.98-4.18 (4H, m), 6.92 (1
(H, d, J = 4.9Hz), 7.26-7.44 (5H, m) ¹ H-NM
This was done by measuring the nuclear Overhauser effect (NOE) in R. That is, in the (E) the body (A), H α ^{(δ2.94-3.11ppm,} m) and H β ^(δ6.92ppm, d) is + 19.5% of NOE between observed. On the other hand, in the (Z) -form [B], H ^{α '} (δ 3.10-3.27 ppm, m) and H
NOE was not observed during ^{β ′} (δ7.83 ppm, d).

(B) (Z) -2- (hydroxyisobutylphosphinoyl)
Production of methyl-3-phenylpropenoic acid (Z) -2- (ethoxyisobutylphosphinoyl)
Methyl-3-phenylpropenoic acid ethyl ester 330mg
To a solution of (1.0 mmol) in 6 ml of ethanol was added 3 ml of a 6N aqueous sodium hydroxide solution, and the mixture was heated under reflux for 8 hours. After cooling, the reaction mixture was concentrated under reduced pressure, 10 ml of water was added to the residue, and the mixture was acidified with hydrochloric acid, and then extracted three times with 10 ml of ethyl acetate. The organic layer is washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was reconstituted from ethyl acetate-hexane (2: 1) to give 130 mg (yield 47%) of the title compound as colorless crystals.

mp: 114-115 ℃ IR (KBr, cm -1): 2962,1704,1215,1131,966,945 FAB-MS (m / e): 283 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.01 (6H, d, J = 6.6Hz), 1.74
(2H, dd, J = 6.7Hz, 13.2Hz), 2.00−2.12 (1H, m), 3.15
(2H, d, J = 17.3Hz), 7.33-7.45 (3H, m), 7.63 (2H, d, J
= 7.4Hz), 7.87 (1H, d, as J = 4.9 Hz) Elemental analysis _{(C 14 H 13 O 4 P} ): Calculated: C59.57%, H6.79% Found: C59.42%, H6 .82% (c) (E) -2- (hydroxyisobutylphosphinoyl)
Production of methyl-3-phenylpropenoic acid (E) -2- (ethoxyisobutylphosphinoyl)
330 mg of methyl-3-phenylpropenoic acid ethyl ester
(1.0 mmol) is hydrolyzed in the same manner as in Example 1 (b), and recrystallized from ethyl acetate to obtain 130 mg (yield 47%) of the title compound.

mp: 130.5-131.5 ℃ IR (KBr, cm -1): 2956,1698,1245,1122,966,948 FAB-MS (m / e): 283 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.07 (6H, d, J = 6.6Hz), 1.74
(2H, dd, J = 6.7Hz, 13.5Hz), 2.01-2.20 (1H, m), 2.97
(2H, d, J = 17.1Hz), 6.89 (1H, d, J = 5.2Hz), 7.23-7.3
6 (5H, m) (as C ₁₄ H ₁₃ O ₄ P) Calcd: C59.57%, H6.79% Found: C59.53%, H6.84% Example 2 (Z) and Production of (E) -3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropenoic acid (a) Ethyl (Z) and (E) -3-cyclohexyl-2- [ethoxy (ethyl) phosphinoyl] methylpropenoate Manufacture of ester Under a nitrogen atmosphere, metallic sodium 0.23 g (10 mmol)
Is dissolved in 20 ml of dry ethanol. The solution was cooled to 0 ° C., and 1.22 g (10 mmol) of ethyl phosphinic acid ethyl ester and 2.40 g (10 mmol) of 2-diethoxyphosphinoylpropenoic acid ethyl ester were added thereto.
And stir for 1 hour. To this, 1.20 ml (9.9 mmol) of cyclohexane carbaldehyde is added and reacted at room temperature for 3 days. To the reaction mixture, add saturated aqueous ammonium chloride
Add ml and extract three times with 50 ml of ethyl acetate. The organic layer is washed with saturated saline (30 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was separated by medium pressure liquid chromatography (Merck Rover column size C recroprep SI60, ethyl acetate), and the first fraction was concentrated to give (Z) -3-cyclohexyl-2.
-0.33 g of [ethoxy (ethyl) phosphinoyl] methylpropenoic acid ethyl ester as a colorless oil (yield 10
%)obtain.

^{IR (neat, cm -1):} 2932,1713,1278,1227,1170,1044,954 FAB-MS (m / e): 317 (M + H) + 1 H-NMR (CDCl 3, δppm): 0.82-2.00 (21H, m), 2.10−
2.60 (1H, m), 2.88 (2H, d, J = 20Hz), 3.76-4.35 (4H,
m), 6.66 (1H, dd, J = 6 Hz, 14 Hz) The second fraction was concentrated and concentrated to (E) -3-cyclohexyl-2-
0.70 g of [ethoxy (ethyl) phosphinoyl] methylpropenoate ethyl ester as a colorless oil (yield: 22
%)obtain.

^{IR (neat, cm -1):} 2932,1719,1248,1218,1179,1044,954 FAB-MS (m / e): 317 (M + H) + 1 H-NMR (CDCl 3, δppm): 0.82-2.00 (21H, m), 2.55−
3.20 (1H, m), 2.78 (2H, d, J = 18Hz), 3.77-4.37 (4H,
m), 5.86 (1H, dd, J = 6 Hz, 14 Hz) (b) Production of dilithium (Z) -3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropenoate (Z) -3-cyclohexyl- 2- [ethoxy (ethyl) phosphinoyl] methylpropenoic acid ethyl ester
To a solution of 205 mg (0.65 mmol) of ethanol in 7 ml of water was added 1.0 ml of a 1.5 N aqueous solution of lithium hydroxide, and the mixture was refluxed for 4 hours.
After allowing to cool, the precipitated crystals are collected by filtration and dried to give the title compound as colorless crystals (78 mg, yield 44%). mp:> 300 ℃ IR (KBr , cm -1): 2926,1578,1404,1158,1071,1044 FAB-MS (m / e): 273 (M + H) + 1 H-NMR (CD 3 OD-D 2 O, δppm): 0.80-1.82 (15H, m), 2.
41−2.55 (1H, m), 2.71 (2H, d, J = 18.3Hz), 6.28 (1H, d
d, as J = 4.7Hz, 10.5Hz) Elemental analysis _{C 12 H 19 Li 2 O 4} P): Calculated: C52.96%, H7.04% Found: C52.57%, H6.99% (c ) Preparation of dilithium (E) -3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropenoate Ethyl (E) -3-cyclohexyl-2- [ethoxy (ethyl) phosphinoyl] methylpropenoate
161 mg (0.51 mmol) was treated in the same manner as in Example 2 (b) to give the title compound as colorless crystals, 89 mg (64% yield).
obtain.

mp:> 300 ℃ IR (KBr , cm -1): 2932,1557,1452,1143,1128,1047 FAB-MS (m / e): 273 (M + H) + 1 H-NMR (CDOD 3, δppm): 0.95-1.80 (15H, m), 2.45 (2
H, d, J = 15Hz), 2.55-2.75 (1H, m), 5.18 (1H, dd, J = 4.
7 Hz, 9.5 Hz) Elemental analysis (as _{C 12 H 19 Li 2 O 4} P · 0.5H 2 O): Calculated: C51.27%, H7.17% Found: C51.22%, H7.19% ( d) Production of (Z) -3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropenoic acid (Z) -3-cyclohexyl-2- [ethoxy (ethyl) phosphinoyl] methylpropenoic acid ethyl ester
To a solution of 100 mg (0.32 mmol) in 3 ml of ethanol is added 0.70 ml of a 1.5 N lithium hydroxide aqueous solution, and the mixture is refluxed for 6 hours.
After cooling, add 20 ml of water to dissolve insolubles, and add 20 ml of ether.
Extract with. After adding 3N hydrochloric acid to the aqueous layer to make it strongly acidic,
Extract three times with 20 ml of ether. The ether layers extracted under acidity are combined, washed with 20 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was reconstituted from ethyl acetate-hexane (1: 5).
55 mg (66% yield) of the title compound are obtained as colorless crystals.

mp: 160-162 ℃ IR (KBr, cm -1): 2932,1677,1281,1236,1170,960 FAB-MS (m / e): 261 (M + H) + 1 H-NMR (CD 3 OD, δppm ): 1.10-1.82 (15H, m), 2.42-
2.55 (1H, m), 2.92 (2H, d, J = 17.1Hz), 6.76 (1H, dd, J
= 5.1 Hz, 10.5 Hz) as the element analysis _{(C 12 H 21 O 4 P} ): Calculated: C55.38%, H8.13% Found: C55.63%, H8.21% (e ) (E) Production of -3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropenoic acid (E) -3-Cyclohexyl-2- [ethoxy (ethyl) phosphinoyl] methylpropenoic acid ethyl ester
120 mg (0.38 mmol) was treated in the same manner as in Example 2 (d) and recrystallized from ethyl acetate-hexane (1: 5) to obtain 59 mg (61%) of the title compound as colorless crystals.

mp: 132-133 ℃ IR (KBr, cm -1): 2926,1683,1278,1170,1101,1008,948 FAB-MS (m / e): 261 (M + H) + 1 H-NMR (CD 3 OD , δppm): 1.08-1.80 (15H, m), 2.81 (2
H, d, J = 17.1 Hz), 2.95-3.15 (1H, m), 5.96 (1H, dd, J =
4.8 Hz, 9.6 Hz) Elemental analysis (as C ₁₂ H ₂₁ O ₄ P): Calculated: C 55.38%, H 8.13% Actual: C 55.59%, H 8.22% Example 3 (Z) and Preparation of (E) -2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid (a) (Z) and (E) ethyl 2- [butyl (ethoxy) phosphinoyl] methyl-3-cyclohexylpropenoate Manufacture of ester Under nitrogen atmosphere, 1.55M butyllithium-hexane 3.30ml
(5.1 mmol) in 5 ml of dry tetrahydrofuran,
At -70 ° C, butylphosphinic acid ethyl ester 0.75 g
(5.0 mmol) in 5 ml of dry tetrahydrofuran
Add dropwise over minutes. After stirring at the same temperature for 10 minutes, the mixture was heated to −50 ° C., and a solution of 1.18 g (5.0 mmol) of 2-diethoxyphosphinoylpropenoic acid ethyl ester in 5 ml of dry tetrahydrofuran was added dropwise over 10 minutes. ,
Stir at 0 ° C. for 1 hour. The mixture is cooled to -25 DEG C., a solution of 0.56 g (5.0 mmol) of cyclohexanecarbaldehyde in 5 ml of dry tetrahydrofuran is added and stirred at the same temperature for 2 hours and at room temperature for 1 hour. To the reaction mixture is added 100 ml of a saturated aqueous solution of ammonium chloride, extracted twice with 80 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by medium-pressure liquid chromatography (Merck Rover column size C recroprep SI60, ethyl acetate). The first fraction was concentrated to give (Z) -2- [butyl 0.38 g (yield 22%) of (ethoxy) phosphinoyl] methyl-3-cyclohexylpropenoic acid ethyl ester was obtained as a colorless oil.

^{IR (neat, cm -1):} 2930,1714,1223,1170,1035,953 1 H-NMR (CDCl 3, δppm): 0.90 (3H, t, J = 6Hz), 1.09-
2.00 (22H, m), 2.10−2.58 (1H, m), 2.94 (2H, d, J = 17H
z), 3.80-4.40 (4H, m), 6.72 (1H, dd, J = 5 Hz, 10 Hz) The second fraction was concentrated, and (E) -2- [butyl (ethoxy) phosphinoyl] methyl-3-cyclohexyl 0.14 g (yield 8%) of ethyl propenoate was obtained as a colorless oil.

^{IR (neat, cm -1):} 2937,1724,1220,1177,1038,953 1 H-NMR (CDCl 3, δppm): 0.90 (3H, t, J = 6Hz), 1.08-
2.01 (22H, m), 2.83 (2H, d, J = 16Hz), 2.78-3.20 (1H,
m), 3.79-4.41 (4H, m), 5.90 (1H, dd, J = 4 Hz, 9 Hz) (b) Production of (Z) -2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid ( Z) -2- [Butyl (ethoxy) phosphinoyl]
Methyl-3-cyclohexylpropenoic acid ethyl ester
360 mg (1.05 mmol) was treated in the same manner as in Example 2 (d) and recrystallized from methanol-ethyl acetate-hexane to obtain 215 mg (yield 71%) of the title compound as colorless crystals.

mp: 146-147 ° C IR (KBr, cm ^-1 ): 2930,1690,1235,1164,963 ¹ H-NMR (CD ₃ OD, δ ppm): 0.95 (3H, t, J = 6Hz), 1.07-
2.00 (16H, m), 2.19-2.64 (1H, m), 2.90 (2H, d, J = 17H
z), 6.75 (1H, dd , J = 5Hz, 10Hz) FAB-MS (m / e): 289 (M + H) + Elemental Analysis (as _{C 14 H 25 O 4 P)} : Calculated: C58.32%, H8.74% Found: C58.04%, H8.83% (c) Production of (E) -2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid (E) -2- [butyl ( Ethoxy) phosphinoyl]
Methyl-3-cyclohexylpropenoic acid ethyl ester
To a solution of 470 mg (1.36 mmol) in 24 ml of acetone is added 24 ml of a 1N aqueous solution of lithium hydroxide, and the mixture is refluxed for 24 hours. After allowing to cool, acetone is distilled off under reduced pressure, the mixture is made strongly acidic with 1N sulfuric acid, and then extracted twice with 60 ml of ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Preparative thin-layer chromatography of the residue (silica gel 60F254, chloroform-methanol (3: 1) manufactured by Merck)
After recrystallization from methanol-ethyl acetate-hexane, 52 mg of the title compound were obtained as colorless crystals (13% yield).

mp: 130-132 ℃ IR (KBr, cm -1): 2930,1687,1225,1150,1030 FAB-MS (m / e): 289 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.92 (3H, t, J = 6Hz), 1.00-
1.89 (16H, m), 2.48 (2H, d, J = 15Hz), 2.60-2.80 (1H,
m), 5.60 (1H, dd , as J = 5Hz, 10Hz) Elemental analysis _{(C 14 H 25 O 4 P} ): Calculated: C58.32%, H8.74% Found: C57.74%, H8. 98% Example 4 Preparation of (Z) -3-cyclohexyl-2- (cyclohexylmethylhydroxyphosphinoyl) methylpropenoic acid (a) (Z) and (E) -3-Cyclohexyl-2- (cyclohexylmethylhydroxyphos Production of Ethyl Finoyl) methylpropenoate 30 mg of oily sodium hydride 30 mg (0.69%) under nitrogen atmosphere
Mmol) in 1.0 ml of dry hexane, 200 mg (0.69 mmol) of ethyl 3- [cyclohexylmethyl (ethoxy) phosphinoyl] propanoate, 70 mg (0.69 mmol) of cyclohexanecarbaldehyde, and
A solution of one drop of dry ethanol in 0.70 ml of dry benzene is added and stirred at room temperature for 18 hours. 3 ml of water and 0.70 ml of acetic acid are added to the reaction mixture, and the mixture is extracted three times with 10 ml of ether. The organic layers are combined and extracted four times with 10 ml of 5% aqueous sodium bicarbonate. The aqueous layer was acidified with concentrated hydrochloric acid, and then chloroform
Extract three times with 10 ml. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
get g. According to ¹ H-NMR, it was determined that (E) -3-cyclohexyl-2- (cyclohexylmethylhydroxyphosphinoyl) methylpropenoic acid ethyl ester and (Z) -3-cyclohexyl-2- (cyclohexylmethylhydroxyphosphinoethyl) were obtained. Il) It was found to be a 1: 3 mixture of methyl propenoic acid ethyl ester. Yield 53
% (Value of the sum of both (E) and (Z) isomers).

(B) Production of (Z) -3-cyclohexyl-2- (cyclohexylmethylhydroxyphosphinoyl) methylpropenoic acid (Z) and (E) -3-Cyclohexyl-2- (cyclohexylmethylhydroxyphosphinoyl) methylpropene 90 mg (0.25 mmol) of a mixture of acid ethyl ester (3: 1) is dissolved in 1 ml of 4.7N hydrogen chloride-butyl acetate,
After heating in a sealed tube at 24 ° C for 24 hours, the solvent is distilled off under reduced pressure. The residue is dissolved in 0.32 ml of ethanol and 0.16 ml of 6N sodium hydroxide and heated under reflux for 3 hours. After cooling, the reaction mixture was diluted with 3 ml of water, acidified with hydrochloric acid, and extracted three times with 10 ml of ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-hexane (1: 4) to give the title compound as colorless crystals (29 mg, yield 35%).

mp: 170-171.5 ℃ IR (KBr, cm -1): 2932,2854,1692,1239,1146,954 FAB-MS (m / e): 329 (M + H) + 1 H-NMR (CD 3 OD, δppm ): 1.01-1.39 (10H, m), 1.60-
1.92 (13H, m), 2.46-2.50 (1H, m), 2.90 (2H, d, J = 17.
1Hz), 6.74 (1H, dd , as J = 5.2Hz, 10.5Hz) Elemental analysis _{(C 17 H 29 O 4 P} ): Calculated: C62.18%, H8.90% Found: C61.43%, H8.84% Example 5 Production of (Z) and (E) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid (a) (Z) and (E) -3-cyclohexyl-2- Production of (ethoxyisobutylphosphinoyl) methylpropenoic acid ethyl ester All the title compounds are obtained as colorless oils using cyclohexanecarbaldehyde in place of benzaldehyde in Example 1 (a).

(Z)-3-cyclohexyl-2- (ethoxyisobutyl phosphinoyl) methyl propenoate ester ^{IR (neat, cm -1: 2992,1710,1260,1167,1029,969} 1 H-NMR (CDCl 3, δppm ): 1.04 (6H, dd, J = 3.9Hz, 6.6H)
z), 1.08-1.36 (11H, m), 1.60-1.76 (7H, m), 2.09-
2.16 (1H, m), 2.39−2.42 (1H, m), 2.93 (2H, d, J = 16.8
Hz), 3.96−4.13 (2H, m), 4.20 (2H, q, J = 7.0Hz), 6.71
(1H, dd, J = 4.9Hz, 10.5Hz) (E) -3-Cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoic acid ethyl ester IR (neat, cm ^-1 ): 2986,1716,1251, 1179,1038,960 ¹ H-NMR (CDCl ₃ , δ ppm): 1.03 (6H, d, J = 7 Hz), 1.10 −
1.92 (18H, m), 1.90-2.25 (1H, m), 2.60-3.00 (1H,
m), 2.78 (2H, d, J = 16 Hz), 3.86-4.44 (4H, m), 5.88
(1H, dd, J = 5Hz, 9Hz) (b) Production of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid (Z) -3-cyclohexyl-2- (ethoxyisobutylphospho) Finoyl) methylpropenoic acid ethyl ester is treated as in Example 2 (d) and reconstituted from ether-hexane to give the title compound as colorless crystals.

mp: 155-156 ° C IR (KBr, cm ^-1 ): 2932,1692,1638,1314,1242,1170,1152,
957 FAB-MS (m / e ): 289 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.05 (6H, d, J = 6.6Hz), 1.07
-1.45 (5H, m), 1.64 (2H, dd, J = 6.6Hz, 12.9Hz), 1.69
−1.79 (5H, m), 2.01−2.19 (1H, m), 2.41−2.54 (1H,
m), 2.90 (2H, d, J = 17.1 Hz), 6.75 (1H, dd, J = 5.1 Hz, 1
0.5 Hz) Elemental analysis (as _{C 14 H 25 O 4 P)} : Calculated: C58.32%, H8.74%, P10.74 % Found: C58.32%, H8.63%, P10.9 % Also, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) obtained as described above
When methylpropenoic acid is reconstituted from methanol-water,
Colorless crystals with different crystal forms are obtained.

mp: 167-169 ° C IR (KBr, cm ^-1 ): 2932,1716,1644,1263,1248,1125,1053,
972 ( ¹ H-NMR, FAB-MS completely matched the spectrum of the crystal obtained above.) (C) (E) -3-Cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid Preparation of (E) -3-cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoic acid ethyl ester was treated in the same manner as in Example 2 (d) and reconstituted from ether-hexane to give the title compound. Obtained as colorless crystals.

mp: 162-163 ℃ IR (KRr, cm -1): 2926,1719,1230,1119,954 High Resolution FAB-MS (m / e, as ^{_{+ (C 14 H 25 O 4}} P + H)): Calculated: 289.1569 actual value: 289.1598 ¹ H-NMR (CD ₃ OD, δ ppm): 1.04 (6H, d, J = 6.6 Hz), 1.07
−1.42 (6H, m), 1.62 (2H, dd, J = 6.6Hz, 13.2Hz), 1.68
-1.76 (4H, m), 1.97-2.16 (1H, m), 2.79 (2H, d, J = 1
6.8Hz), 2.94-3.10 (1H, m), 5.94 (1H, dd, J = 4.8Hz, 9.
Example 6 Preparation of disodium (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate 18.5 (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate g (64.2
24 mmol (144 mmol) of 6N sodium hydroxide is added dropwise to a solution of the same in 370 ml of methanol with stirring under ice-cooling. The precipitated crystals are collected by filtration and dried to give the title compound as colorless crystals.
19.1 g (90% yield) are obtained.

mp:> 300 ° C IR (KBr, cm ^-1 ): 3292,2926,1551,1401,1140,1038 ¹ H-NMR (D ₂ O, δ ppm): 0.79 (6H, d, J = 6.6 Hz), 0.85 −
1.17 (6H, m), 1.22 (2H, dd, J = 6.7Hz, 11.9Hz), 1.44-
1.52 (4H, m), 1.72-1.85 (1H, m), 2.18-2.25 (1H,
m), 2.52 (2H, d, J = 18.3Hz), 6.00 (1H, dd, J = 4.9Hz, 1
0.1 Hz) Elemental analysis (as _{C 14 H 23 Na 2 O 4} P · 0.85H 2 O): Calculated: C48.38%, H7.16% Found: C48.54%, H7.38% moisture determination (Karl Fischer method): Calculated value: 4.41% Actual value: 4.4% Na content measurement (flame light method): Calculated value: 13.23% Actual value: 14.5% Example 7 (Z) -3-cyclohexyl-2- (hydroxy) Preparation of Calcium Isobutylphosphinoyl) methylpropenoate Disodium (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate
0.24 ml (0.72 mmol) of a 3M aqueous solution of calcium chloride was added to 200 mg (0.58 mmol) of a 2.0 ml solution of water while stirring under ice-cooling.
Is dropped. The precipitated crystals are collected by filtration and dried to give the title compound (200 mg, yield 99%) as a white powder.

mp:> 300 ℃ IR (KRr , cm -1): 3448,2932,1542,1434,1413,1158,1032 Elemental analysis (as _{C 14 H 23 CaO 4 P ·} 1.2H 2 O): Calculated: C48. 32%, H7.36% Actual value: C48.25%, H7.19% Water content measurement (Karl Fischer method): Calculated value: 6.21% Actual value: 5.6% Ca content measurement (flame light method): Calculated value: 11.52% Found: 12.0%. Example 8 (E) -3- of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid
Preparation from ethyl cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoate (E) -3-Ethylcyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoate
11.1 g (32.2 mmol) of 4.3N hydrogen chloride-butyl acetate 100
Dissolve in ml and heat in a sealed tube at 100 ° C for 48 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate and (E) -3-cyclohexyl-2- (hydroxyisobutylphosphino) were added. Il) A mixture of methyl propenoic acid ethyl ester is obtained as a pale yellow oil. ^When this mixing ratio was measured by ¹ H-NMR, it was (Z) :( E) = 90.10. This mixture is dissolved in 32 ml of ethanol and 16 ml of 6N sodium hydroxide and heated under reflux for 3 hours. After heat release, the solvent is distilled off under reduced pressure, and the residue is
Dissolve in 0 ml and make it acidic with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and recrystallized from methanol-water (2: 1) to obtain 4.6 g of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid (yield 49%). . Melting point, IR, and ¹ H-NMR were measured in Example 5 (b).
Was consistent with that obtained in.

Example 9 (E) -3- of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid
Preparation from cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate 13 mg (0.045) of (E) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate
(Mmol) is dissolved in 0.13 ml of 4.3N hydrogen chloride-butyl acetate and heated in a sealed tube at 100 ° C. for 24 hours. After allowing to cool, the solvent is distilled off under reduced pressure, the residue is dissolved in 0.2 ml of ethanol, 0.1 ml of 6N sodium hydroxide is added, and the mixture is refluxed for 1.5 hours.
After cooling, 5 ml of water was added, and hydrochloric acid was added to make it acidic.
Extract three times with 5 ml of ethyl acetate. The ethyl acetate extract is washed with 5 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
Recombined from hexane to give (Z) -3-cyclohexyl-2
7 mg (54% yield) of-(hydroxyisobutylphosphinoyl) methylpropenoic acid were obtained as colorless crystals. Melting point, I
R, ¹ H-NMR was consistent with that obtained in Example 5 (b).

Example 10 (a) (Z) and (E) -3-cyclohexyl-2- [ethoxy (4-methoxymethoxybutyl) phosphinoyl]
Preparation of methyl propenoic acid ethyl ester 3.20 g (15.2 mmol) of 4-methoxymethoxybutylphosphinic acid ethyl ester was treated in the same manner as in Example 2 (a) to obtain a crude product of a mixture of (E) and (Z). This crude product was separated by medium pressure liquid chromatography (Merck's Rover column size C recroprep SI60, ethyl acetate), and the first fraction was concentrated to (Z) -3-
1.60 g (26% yield) of cyclohexyl-2- [ethoxy (4-methoxymethoxybutyl) phosphinoyl] methylpropenoic acid ethyl ester was obtained as a colorless oil.

^{IR (neat, cm -1):} 2932,1713,1227,1149,1110,1041,957 FAB-MS (m / e): 405 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.14-1.36 (11H, m), 1.65−
1.78 (11H, m), 2.40-2.43 (1H, m), 2.95 (2H, d, J = 17.
1Hz), 3.34 (3H, s), 3.51-3.55 (2H, m), 4.00-4.12.
(2H, m), 4.21 (2H, q, J = 7.0Hz), 4.61 (2H, s), 6.73
(1H, dd, J = 4.9Hz, 10.5Hz) The second fraction was concentrated and concentrated to (E) -3-cyclohexyl-2-
1.90 g (yield 31%) of ethyl [ethoxy (4-methoxymethoxybutyl) phosphinoyl] methylpropenoate was obtained as a colorless oil.

^{IR (neat, cm -1):} 2932,1719,1218,1164,1110,1038,960 FAB-MS (m / e): 405 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.06-1.35 (11H, m), 1.65−
1.74 (11H, m), 2.78-2.94 (3H, m), 3.35 (3H, s), 3.50
−3.55 (2H, m), 3.98−4.12 (2H, m), 4.22 (2H, q, J = 7.
0 Hz), 4.60 (2H, s), 5.91 (1H, dd, J = 4.8 Hz, 9.6 Hz) (b) (Z) -3-cyclohexyl-2- (4-methoxymethoxybutylhydroxyphosphinoyl) methylpropene Production of acid (Z) -3-cyclohexyl-2- [ethoxy (4-
(Methoxymethoxybutyl) phosphinoyl] methylpropenoic acid ethyl ester 200 mg (0.50 mmol) in ethanol 0.8 ml solution, 6N sodium hydroxide aqueous solution 0.4 ml (2.4
Mmol) and heat to reflux for 6 hours. After cooling, the reaction mixture is concentrated under reduced pressure, 10 ml of water is added to the residue, acidified by adding hydrochloric acid, and extracted three times with 15 ml of ethyl acetate.
The organic layer is washed with a saturated saline solution (15 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was reconstituted from ethyl acetate-hexane (1: 1) to give 140 mg (91% yield) of the title compound as unoccupied crystals.

mp: 112.5-113.5 ° C IR (KBr, cm ^-1 ): 2932,1686,1287,1167,1152,1110,1053,
960 FAB-MS (m / e ): 349 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.14-1.40 (5H, m), 1.65-1.
75 (11H, m), 2.46-2.50 (1H, m), 2.92 (2H, d, J = 17.6H
z), 3.33 (3H, s), 3.54 (2H, d, J = 5.8Hz), 4.59 (2H,
s), 6.76 (1H, dd , as J = 5.0Hz, 10.5Hz) Elemental analysis _{(C 16 H 29 O 6 P} ): Calculated: C55.16%, H8.31% Found: C55.02%, H8.31% (c) (Z) -3-cyclohexyl-2- [hydroxy (4-
Preparation of (hydroxybutyl) phosphinoyl] methylpropenoic acid (Z) -3-cyclohexyl-2- [hydroxy (4
-Methoxymethoxybutyl) phosphinoyl] methylpropenoic acid (300 mg) in methanol (3 ml) is added with concentrated hydrochloric acid (0.2 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to medium-pressure liquid chromatography (Merck Rover column size B recroprep RP-18,2).
After purification with 5% aqueous methanol), the residue was reconstituted with isopropyl ether-hexane (1: 1) to give 87 mg (33% yield) of the title compound as colorless crystals.

mp: 110-111 ° C IR (KBr, cm ^-1 ): 3454,2932,1689,1278,1245,1149,1029,
963 FAB-MS (m / e ): 305 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.11-1.40 (5H, m), 1.59-1.
77 (11H, m), 2.46-2.50 (1H, m), 2.92 (2H, d, J = 17.3H
z), 3.56 (2H, t, J = 6.1 Hz), 6.76 (1H, dd, J = 5.2 Hz, 10.
5 Hz) Elemental analysis (as _{C 14 H 25 O 5 P)} : Calculated: C55.25%, H8.28% Found: C55.10%, H8.22% (d ) (Z) -2- (4 -Chlorobutylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid (Z) -3-cyclohexyl-2- [ethoxy (4-
(Methoxymethoxybutyl) phosphinoyl] methylpropenoic acid ethyl ester (300 mg) was dissolved in a mixture of dioxane (3 ml) and concentrated hydrochloric acid (3 ml), and the mixture was refluxed for 20 hours. After cooling, the reaction mixture is concentrated under reduced pressure, 10 ml of water is added to the residue, and the mixture is extracted three times with 15 ml of ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is reconstituted from ethyl acetate-hexane (1: 1) to obtain 72 mg (30% yield) of the title compound as colorless crystals. .

mp: 149.5-151 ℃ IR (KBr, cm -1): 2932,1716,1275,1230,1119,972 FAB-MS (m / e): 323 (M + H) + 1 H-NMR (CD 3 OD, δppm ): 1.14-1.40 (5H, m), 1.67-1.
83 (11H, m), 2.45-2.50 (1H, m), 2.93 (2H, d, J = 17.6H
z), 3.58 (2H, t, J = 6.2Hz), 6.77 (1H, dd, J = 5.2Hz, 10.
7 Hz) Elemental analysis (as _{C 14 H 24 ClO 4 P)} : Calculated: C52.10%, H7.49% Found: C51.87%, according to H7.44% Example 11-30 Example 1 The following compounds of Examples 11 to 30 were obtained.

Example 11 (a) (Z) -3-cyclohexyl-2- (ethoxyi
Sopropylphosphinoyl) methyl ethyl propenoate
Stele oil IR (neat, cm^-1): 2932,1713,1278,1227,1167,1044,954 FAB-MS (m / e): 331 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.06-1.40 (18H, m), 1.65-
1.80 (4H, m), 1.84-2.03 (1H, m), 2.35-2.50 (1H,
m), 2.90 (1H, dd, J = 14.7Hz, 14.7Hz), 2.97 (1H, dd, J =
14.7Hz, 14.7Hz), 3.94−4.11 (2H, m), 4.21 (2H, q, J =
(7.2Hz), 6.74 (1H, dd, J = 5.1Hz, 10.5Hz) (b) (E) -3-cyclohexyl-2- (ethoxyi
Sopropylphosphinoyl) methyl ethyl propenoate
Stele oil IR (neat, cm^-1): 2932,1722,1218,1032,954 FAB-MS (m / e): 331 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.01-1.40 (18H, m), 1.55-
1.75 (4H, m), 1.83-1.95 (1H, m), 2.75-2.95 (1H,
m), 2.83 (2H, d, J = 14.4 Hz), 3.91-4.13 (2H, m), 4.23
(2H, q, J = 7.2Hz), 5.93 (1H, dd, J = 4.5Hz, 9.6Hz) (c) (Z) -3-cyclohexyl-2- (hydroxy
Isopropylphosphinoyl) methylpropenoic acid m.p .: 139.5-141.5 ° C IR (KBr, cm^-1): 3412,2926,1713,1149,1119,966 FAB-MS (m / e): 275 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 1.10-1.43 (6H, m), 1.19 (6
H, dd, J = 7.2Hz, 17.1Hz), 1.65-1.80 (4H, m), 1.83-1.
96 (1H, m), 2.42−2.55 (1H, m), 2.92 (2H, d, J = 15.9H
z), 6.76 (1H, dd, J = 4.8Hz, 10.5Hz) Elemental analysis (C₁₃H_{twenty three}O_FourP): Calculated: C 56.92%, H 8.45% Actual: C 56.89%, H 8.57% (d) (E) -3-cyclohexyl-2- (hydroxy
Isopropylphosphinoyl) methylpropenoic acid m.p .: 144.5-146.5 ° C IR (KBr, cm^-1): 3040,2920,1725,1197,1176,1122,954 FAB-MS (m / e): 275 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 1.05-1.40 (6H, m), 1.16 (6
H, dd, J = 6.9Hz, 16.8Hz), 1.64-1.80 (4H, m), 1.83-1.
97 (1H, m), 2.82 (2H, d, J = 16.2Hz), 2.96-3.10 (1H,
m), 5.96 (1H, d, J = 4.2Hz, 9.9Hz) Elemental analysis (C₁₃H_{twenty three}O_FourP): Calculated: C 56.92%, H 8.45% Actual: C 56.84%, H 8.98% Example 12 (a) (Z) -3-cyclohexyl-2- [ethoxy
(Hexyl) phosphinoyl] ethyl methyl propenoate
Ester Oil IR (neat, cm^-1): 2926,1713,1260,1227,1173,1038,954 FAB-MS (m / e): 373 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.88 (3H, t, J = 6.6Hz), 1.05
-1.78 (26H, m), 2.34-2.47 (1H, m), 2.95 (2H, d, J = 1
7.1Hz), 3.98-4.10 (2H, m), 4.21 (2H, q, J = 7.2Hz),
6.73 (1H, dd, J = 4.8Hz, 10.5Hz) (b) (E) -3-cyclohexyl-2- [ethoxy
(Hexyl) phosphinoyl] ethyl methyl propenoate
Ester Oil IR (neat, cm^-1): 2926,1719,1248,1215,1179,1038,954 FAB-MS (m / e): 373 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.88 (3H, t, J = 6.6Hz), 1.00
-1.76 (20H, m), 1.28 (3H, t, J = 6.9Hz), 1.33 (3H, t, J
= 6.9Hz), 2.71−2.95 (3H, m), 3.95−4.10 (2H, m), 4.
22 (2H, q, J = 6.9Hz), 5.90 (1H, dd, J = 4.5Hz, 9.9Hz) (c) (Z) -3-cyclohexyl-2- (hexylhi)
Droxyphosphinoyl) methylpropenoic acid m.p .: 152.5-155 ° C IR (KBr, cm^-1): 2926,1689,1287,1167,1149,960 FAB-MS (m / e): 317 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.91 (3H, t, J = 6.9Hz), 1.12
−1.80 (20H, m), 2.40−2.56 (1H, m), 2.91 (2H, d, J = 1
7.7Hz), 6.75 (1H, dd, J = 5.4Hz, 10.8Hz) Elemental analysis (C₁₆H₂₉O_Four(Calculated as P): Calculated value: C60.74%, H9.24% Actual value: C60.57%, H9.63%
Droxyphosphinoyl) methylpropenoic acid m.p .: 121-123 ° C IR (KBr, cm^-1): 2926,1716,1230,1182,1146,1116,972 FAB-MS (m / e): 317 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.91 (3H, t, J = 6.9Hz), 1.06
-1.80 (20H, m), 2.80 (2H, d, J = 17.4Hz), 2.95-3.10
(1H, m), 5.95 (1H, dd, J = 5.1Hz, 9.9Hz) Elemental analysis (C₁₆H₂₉O_FourP): Calculated value: C60.74%, H9.24% Actual value: C60.68%, H9.43% Example 13 (a) (Z) -3-cyclohexyl-2- [decyl (d)
Toxy) phosphinoyl] methylpropenoate ethyls
Tell oil IR (neat, cm^-1): 2930,1716,1305,1230,1176,1043,958 FAB-MS (m / e): 429 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.86 (3H, t, J = 7.2Hz), 1.02
-1.78 (34H, m), 2.32-2.46 (1H, m), 2.92 (2H, d, J = 1
7.1Hz), 3.93−4.08 (2H, m), 4.18 (2H, q, J = 7.0Hz),
6.70 (1H, dd, J = 4.6Hz, 9.4Hz) (b) (E) -3-cyclohexyl-2- [decyl (d
Toxy) phosphinoyl] methylpropenoate ethyls
Tell oil IR (neat, cm^-1): 2925,1722,1213,1036,955 FAB-MS (m / e): 429 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.86 (3H, t, J = 7.2Hz), 0.99
-1.78 (34H, m), 2.71-2.97 (3H, m), 3.91-4.11 (2H,
m), 4.20 (2H, q, J = 7.1 Hz), 5.88 (1H, dd, J = 4.6 Hz, 9.6
Hz) (c) (Z) -3-cyclohexyl-2- (decylhydride
Roxyphosphinoyl) methylpropenoic acid m.p .: 132.5-133.5 ° C IR (KBr, cm^-1): 2920,1689,1162,1144,960 FAB-MS (m / e): 373 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.90 (3H, t, J = 6.8Hz), 1.05
−1.87 (28H, m), 2.40−2.56 (1H, m), 2.91 (2H, d, J = 1
7.6Hz), 6.75 (1H, dd, J = 4.8Hz, 10.6Hz) Elemental analysis (C₂₀H₃₇O_Four(Calculated as P): Calculated value: C64.49%, H10.01% Actual value: C64.01%, H10.23% (d) (E) -3-cyclohexyl-2- (decylhydroxide)
Roxyphosphinoyl) methylpropenoic acid m.p .: 111.0-112.0 ° C IR (KBr, cm^-1): 2930,1690,1235,1100,989 FAB-MS (m / e): 373 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.89 (3H, t, J = 6.7Hz), 1.02
−1.81 (28H, m), 2.80 (2H, d, J = 17.6Hz), 2.96−3.11
(1H, m), 5.95 (1H, dd, J = 4.9Hz, 9.8Hz) Elemental analysis (C₂₀H₃₇O_FourP): Calculated: C 64.49%, H10.01% Actual: C64.31%, H10.01% Example 14 (a) (Z) -3-cyclohexyl-2-[(2,2- The
Methylcyclopropyl) ethoxyphosphinoyl] methyl
Lupropenoic acid ethyl ester Oil IR (neat, cm^-1): 2932,2854,1713,1647,1227,1164,948 FAB-MS (m / e): 357 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.49-1.08 (3H, m), 1.10-1.
80 (22H, m), 2.40-2.60 (1H, m), 2.94-3.12 (2H, m),
4.00-4.17 (4H, m), 6.69-6.80 (1H, m) (b) (E) -3-cyclohexyl-2-[(2,2-di
Methylcyclopropyl) ethoxyphosphinoyl] methyl
Lupropenoic acid ethyl ester Oil IR (neat, cm^-1): 2926,2854,1719,1215,1167,972 FAB-MS (m / e): 357 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.45-1.05 (3H, m), 1.10-1.
80 (22H, m), 2.75-3.05 (3H, m), 4.00-4.30 (4H, m),
5.94 (1H, dd, J = 4.8Hz, 9.6Hz) (c) (Z) -3-cyclohexyl-2-[(2,2-di
Methylcyclopropyl) hydroxyphosphinoyl] me
Tilpropenoic acid m.p .: 169-174 ° C IR (KBr, cm^-1): 2932,1692,1245,1161,951 FAB-MS (m / e): 301 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 0.60-1.00 (3H, m), 1.10-1.
48 (5H, m), 1.11 (3H, d, J = 2.4Hz), 1.30 (3H, s), 1.64
−1.81 (5H, m), 2.45−2.60 (1H, m), 2.94 (2H, d, J = 1
8.9Hz), 6.72 (1H, dd, J = 5.1Hz, 10.5Hz) Elemental analysis (C_FifteenH_{twenty five}O_FourP): Calculated: C59.99%, H8.39% Actual: C59.62%, H8.31% (d) (Z) -3-cyclohexyl-2-[(2,2-di)
Methylcyclopropyl) hydroxyphosphinoyl] me
Disodium tilpropenoate m.p.:>300℃ IR (KBr, cm^-1): 3382,2926,1560,1452,1416,1140,1068 FAB-MS (m / e): 345 (M + H)^{+ 1} H-NMR (D_TwoO, δppm): 0.37-0.50 (3H, m), 1.00-1.40
(5H, m), 1.04 (3H, s), 1.21 (3H, s), 1.50-1.80 (5H,
m), 2.35-2.50 (1H, m), 2.74 (2H, d, J = 18.9Hz), 6.16
(1H, dd, J = 5.1Hz, 9.6Hz) Elemental analysis (C_FifteenH_{twenty three}Na_TwoO_FourP 1 / 3H_TwoO): Calculated: C 51.43%, H 6.81% Found: C 51.47%, H 7.19% (e) (E) -3-Cyclohexyl-2-[(2,2-di)
Methylcyclopropyl) hydroxyphosphinoyl] me
Disodium tilpropenoate m.p.:>300℃ IR (KBr, cm^-1): 3418,2926,1551,1428,1335,1146,1035 FAB-MS (m / e): 345 (M + H)^{+ 1} H-NMR (D_TwoO, δppm): 0.55-0.75 (3H, m), 1.00-1.35
(5H, m), 1.07 (3H, d, J = 2.1Hz), 1.22 (3H, s), 1.50-
1.70 (5H, m), 2.35-2.50 (1H, m), 2.50 (2H, d, J = 16.5
Hz), 5.37 (1H, dd, J = 4.4Hz, 12.8Hz) Elemental analysis (C_FifteenH_{twenty three}Na_TwoO_FourP ・ 3 / 4H_TwoO): Calculated: C50.35%, H6.90% Actual: C50.20%, H7.14% Example 15 (a) (Z) -2- (ethoxyisobutylphosphinoy
E) Methyl-2-butenoic acid ethyl ester Oil IR (neat, cm^-1): 2962,1713,1278,1176,1038,954 FAB-MS (m / e): 277 (M + H)^{+ 1} H-NMR (CDCl_Threeδppm): 1.04 (6H, dd, J = 2.9Hz, 6.6H)
z), 1.24-1.31 (6H, m), 1.62 (2H, dd, J = 6.9Hz, 12.4H
z), 1.91 (3H, dd, J = 4.6Hz, 7.1Hz), 2.04--2.20 (1H,
m), 2.93 (2H, d, J = 16.6 Hz), 3.95-4.15 (2H, m), 4.20
(2H, q, J = 7.1Hz), 7.06 (1H, dq, J = 5.4Hz, 7.1Hz) (b) (Z) -2- (hydroxyisobutylphosphino
Yl) methyl-2-butenoic acid m.p .: 156-159 ° C IR (KBr, cm^-1): 2962,1701,1251,1167,1119,957 FAB-MS (m / e): 221 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 1.04 (6H, d, J = 6.1 Hz), 1.63
(2H, dd, J = 6.7Hz, 12.8Hz), 1.90 (3H, dd, J = 4.5Hz, 7.1
Hz), 2.09 (1H, m), 2.92 (2H, d, J = 17.0Hz), 7.09 (1H,
dq, J = 5.5Hz, 7.1Hz) Elemental analysis (C₉H₁₇O_FourP): Calculated: C 49.04%, H 7.78% Found: C 48.73%, H 8.02% Example 16 (a) (Z) -2- (ethoxyisobutylphosphinoy)
E) Methyl-2-octenoic acid ethyl ester Oil IR (neat, cm^-1): 2960,1718,1265,1170,1039,952 FAB-MS (m / e): 333 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.90 (3H, t, J = 7.0Hz), 1.05
(6H, dd, J = 3.9Hz, 6.5Hz), 1.25-1.34 (10H, m), 1.48
(2H, m), 1.63 (2H, dd, J = 6.9Hz, 12.5Hz), 2.12 (1H,
m), 2.27 (2H, m), 2.93 (2H, d, J = 16.6Hz), 4.03 (2H,
m), 4.22 (2H, q, J = 7.0Hz), 6.94 (1H, dt, J = 5.2Hz, 7.3)
Hz) (b) (E) -2- (ethoxyisobutylphosphinoy
E) Methyl-2-octenoic acid ethyl ester Oil IR (neat, cm^-1): 2955,1722,1242,1161,1038,952 FAB-MS (m / e): 333 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.89 (3H, t, J = 7.0Hz), 1.05
(6H, d, J = 7.0Hz), 1.25-1.36 (10H, m), 1.44 (2H,
m), 1.62 (2H, m), 2.11 (1H, m), 2.49 (2H, m), 2.85 (2
H, m), 4.04 (2H, m), 4.23 (2H, q, J = 7.0Hz), 6.12 (1H,
dt, J = 4.6 Hz, 7.6 Hz) (c) (Z) -2- (hydroxyisobutylphosphino)
Yl) methyl-2-octenoic acid m.p .: 104-105 ° C IR (KBr, cm^-1): 2956,1692,1242,1173,1062,987 FAB-MS (m / e): 277 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.92 (3H, t, J = 6.8Hz), 1.04
(6H, d, J = 6.6Hz), 1.35 (4H, m), 1.49 (2H, m), 1.63
(2H, dd, J = 6.6Hz, 13.0Hz), 2.09 (1H, m), 2.30 (2H,
m), 2.91 (2H, d, J = 17.4Hz), 6.97 (1H, dt, J = 5.1Hz, 7.
6Hz) Elemental analysis (C₁₃H_{twenty five}O_FourAs P): Calculated: C 56.51%, H9.12% Actual: C 55.29%, H 8.86% (d) (E) -2- (Hydroxyisobutylphosphino)
Yl) methyl-2-octenoic acid m.p .: 76.5-77.5 ° C IR (KBr, cm^-1): 2962,2932,1692,1275,1161,981 FAB-MS (m / e): 277 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.90 (3H, t, J = 6.7Hz), 1.04
(6H, d, J = 6.6Hz), 1.34 (4H, m), 1.46 (2H, m), 1.63
(2H, dd, J = 6.9Hz, 13.2Hz), 2.09 (1H, m), 2.53 (2H,
m), 2.81 (2H, d, J = 16.9 Hz), 6.17 (1H, dt, J = 4.8 Hz, 7.
6Hz) Elemental analysis (C₁₃H_{twenty five}O_FourAs P): Calculated: C 56.51%, H9.12% Actual: C 56.36%, H9.01% Example 17 (a) (Z) -2- (ethoxyisobutylphosphinoy)
F) Methyl-2-dodeceneic acid ethyl ester Oil FAB-MS (m / e): 389 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.88 (3H, t, J = 6.3Hz), 1.00
−1.50 (26H, m), 1.63 (2H, dd, J = 6.6Hz, 12.6Hz), 2.05
−2.20 (1H, m), 2.20−2.35 (2H, m), 2.93 (2H, d, J = 1
6.5Hz), 3.95-4.15 (2H, m), 4.22 (4H, q, J = 6.9Hz),
6.94 (1H, dt, J = 5.1Hz, 7.5Hz) (b) (E) -2- (ethoxyisobutylphosphinoy
F) Methyl-2-dodeceneic acid ethyl ester Oil FAB-MS (m / e): 389 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.88 (3H, t, J = 6.9Hz), 1.04
(6H, d, J = 6.6Hz), 1.15-1.50 (20H, m), 1.59-1.66
(2H, m), 2.00-2.20 (1H, m), 2.45-2.55 (2H, m), 2.7
0−3.00 (2H, m), 3.95−4.15 (2H, m), 4.19−4.26 (2H, m
m), 6.12 (1H, dt, J = 4.8 Hz, 7.2 Hz) (c) (Z) -2- (hydroxyisobutylphosphino
Yl) methyl-2-dodecenoic acid m.p .: 103-105 ° C IR (KBr, cm^-1): 2926,1689,1242,1170,984 FAB-MS (m / e): 333 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.90 (3H, t, J = 6.6Hz), 1.05
(6H, d, J = 6.6Hz), 1.20-1.55 (14H, m), 1.64 (2H, dd,
J = 6.6Hz, 12.9Hz), 2.00-2.20 (1H, m), 2.20-2.40 (2
H, m), 2.91 (2H, d, J = 17.4Hz), 6.97 (1H, dt, J = 5.1Hz,
7.2Hz) Elemental analysis (C₁₇H₃₃O_FourP): Calculated: C 61.42%, H10.01% Actual: C60.89%, H 9.92% (d) (E) -2- (Hydroxyisobutylphosphino)
Yl) methyl-2-dodecenoic acid m.p .: 50-52.5 ° C IR (KBr, cm^-1): 2920,2854,1692,1155,954 FAB-MS (m / e): 333 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.89 (3H, t, J = 6.6Hz), 1.04
(6H, d, J = 6.6Hz), 1.20-1.50 (14H, m), 1.63 (2H, dd,
J = 6.9Hz, 13.2Hz), 2.00-2.20 (1H, m), 2.45-2.60 (2
H, m), 2.82 (2H, d, J = 16.8Hz), 6.16 (1H, dt, J = 4.8Hz,
7.5Hz) Elemental analysis (C₁₇H₃₃O_FourAs P): Calculated: C 61.42%, H10.01% Actual: C61.29%, H 9.85% Example 18 (a) (Z) -2- (ethoxyisobutylphosphinoy)
E) Methyl-4,4-dimethyl-2-pentenoate
Stele oil IR (neat, cm^-1): 2962,1713,1260,1200,1155,1038,954 FAB-MS (m / e): 319 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.05 (6H, dd, J = 3.5Hz, 6.6H
z), 1.24-1.33 (15H, m), 1.68 (2H, dd, J = 6.9Hz, 12.9H
z), 2.04-2.19 (1H, m), 3.12 (2H, d, J = 16.4Hz), 3.96
−4.11 (2H, m), 4.21 (2H, q, J = 7.1Hz), 6.86 (1H, d, J
= 4.6 Hz) (b) (E) -2- (ethoxyisobutylphosphinoy
E) Methyl-4,4-dimethyl-2-pentenoate
Stele oil IR (neat, cm^-1): 2962,1731,1239,1197,1052,957 FAB-MS (m / e): 319 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.05 (6H, dd, J = 2.3Hz, 6.6H
z), 1.12 (9H, s), 1.27-1.36 (6H, m), 1.62-1.69 (2
H, m), 2.00−2.14 (1H, m), 2.63−2.89 (2H, m), 3.94−
4.27 (4H, m), 5.71 (1H, d, J = 4.4Hz) (c) (Z) -2- (hydroxyisobutylphosphino
Yl) methyl-4,4-dimethyl-2-pentenoic acid m.p .: 141-143 ° C. IR (KBr, cm^-1): 2962,1686,1248,1185,1104,972 FAB-MS (m / e): 263 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.05 (6H, d, J = 6.6Hz), 1.24
(9H, s), 1.70 (2H, dd, J = 6.5Hz, 13.2Hz), 2.07-2.15
(1H, m), 3.10 (2H, d, J = 16.9Hz), 6.93 (1H, d, J = 4.9H
z) Elemental analysis (C₁₂H_{twenty three}O_FourP): Calculated: C 54.95%, H 8.84% Actual: C 54.71%, H 8.95% (d) (E) -2- (Hydroxyisobutylphosphino)
Yl) methyl-4,4-dimethyl-2-pentenoic acid m.p .: 157-158.5 ° C IR (KBr, cm^-1): 2962,1713,1257,1191,1119,972 FAB-MS (m / e): 263 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.05 (6H, d, J = 6.6Hz), 1.16
(9H, s), 1.69 (2H, dd, J = 6.9Hz, 13.4Hz), 2.02-2.14
(1H, m), 2.72 (2H, d, J = 17.1Hz), 5.76 (1H, d, J = 4.9H
z) Elemental analysis (C₁₂H_{twenty three}O_FourAs P): Calculated: C 54.95%, H 8.84% Actual: C 54.78%, H 8.90% Example 19 (a) (Z) -2- (ethoxyisobutylphosphinoy)
E) Ethyl methyl-4-methyl-2-pentenoate
Le oil IR (neat, cm^-1): 2962,1713,1269,1170,1038,960 FAB-MS (m / e): 305 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.03 (6H, d, J = 6.4Hz), 1.05
(6H, d, J = 6.3Hz), 1.28 (3H, t, J = 7.1Hz), 1.32 (3H,
t, J = 7.0Hz), 1.61 (2H, dd, J = 6.5Hz, 12.7Hz), 2.13 (1
H, m), 2.75 (1H, m), 2.95 (2H, d, J = 6.6Hz), 4.02 (2H,
m), 4.22 (2H, q, J = 7.1 Hz), 6.69 (1H, dd, J = 4.9 Hz, 10.
(5Hz) (b) (E) -2- (ethoxyisobutylphosphinoy
E) Ethyl methyl-4-methyl-2-pentenoate
Le oil IR (neat, cm^-1): 2962,1722,1236,1185,1038,963 FAB-MS (m / e): 305 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.01 (6H, d, J = 6.6Hz), 1.04
(6H, d, J = 6.6Hz), 1.28 (3H, t, J = 7.1Hz), 1.32 (3H,
t, J = 7.1Hz), 1.55-1.65 (2H, m), 2.13 (1H, m), 2.81
(2H, m), 3.15-3.30 (1H, m), 4.04 (2H, m), 4.22 (2H, m
m), 5.86 (1H, dd, J = 4.7 Hz, 7.2 Hz) (c) (Z) -2- (hydroxyisobutylphosphino
Yl) methyl-4-methyl-2-pentenoic acid m.p .: 114.2-114.7 ° C IR (KBr, cm^-1): 2962,1692,1284,1179,1065,969 FAB-MS (m / e): 249 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.038 (6H, d, J = 7.0Hz), 1.04
3 (6H, d, J = 6.6Hz), 1.65 (2H, dd, J = 6.5Hz, 12.9Hz),
2.10 (1H, m), 2.79 (1H, m), 2.88 (2H, d, J = 17.1Hz),
6.73 (1H, dd, J = 5.2Hz, 10.5Hz) Elemental analysis (C₁₁H_{twenty one}O_FourAs P): Calculated value: C53.22%, H8.53% Actual value: C53.26%, H8.91% Example 20 (a) (Z) -2- (ethoxyisobutylphosphinoy)
E) Ethyl methyl-5-methyl-2-hexenoate
Le oil IR (neat, cm^-1): 2962,1713,1290,1260,1173,1038,954 FAB-MS (m / e): 319 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.94 (6H, d, J = 7.1Hz), 1.04
(6H, dd, J = 3.9Hz, 6.8Hz), 1.27 (3H, t, J = 7.0Hz), 1.3
1 (3H, t, J = 7.0Hz), 1.63 (2H, dd, J = 6.7Hz, 12.6Hz),
1.78 (1H, m), 2.04-2.22 (3H, m), 2.93 (2H, d, J = 16.6
Hz), 4.04 (2H, m), 4.21 (2H, q, J = 7.0Hz), 6.96 (1H, d
(t, J = 4.9 Hz, 7.3 Hz) (b) (E) -2- (ethoxyisobutylphosphinoy
E) Ethyl methyl-5-methyl-2-hexenoate
Le oil IR (neat, cm^-1): 2962,1719,1224,1173,1038,954 FAB-MS (m / e): 319 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.95 (6H, d, J = 6.5Hz), 1.06
(6H, d, J = 7.0Hz), 1.29 (3H, t, J = 6.5Hz), 1.34 (3H,
t, J = 7.0Hz), 1.63 (2H, m), 1.74 (1H, m), 2.13 (1H, m
m), 2.35-2.45 (1H, m), 2.79-2.96 (2H, m), 3.95-4.
15 (2H, m), 4.2-4.3 (2H, m), 6.15 (1H, dt, J = 4.6Hz,
7.4 Hz) (c) (Z) -2- (hydroxyisobutylphosphino)
Yl) methyl-5-methyl-2-hexenoic acid m.p .: 127.5-129.0 ° C IR (KBr, cm^-1): 2962,1683,1302,1272,1074,969 FAB-MS (m / e): 263 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.95 (6H, d, J = 7.0Hz), 1.03
(6H, d, J = 6.5Hz), 1.62 (2H, dd, J = 6.5Hz, 13.0Hz), 1.
76 (1H, m), 2.11 (1H, m), 2.15-2.25 (2H, m), 2.89 (2
H, d, J = 17.4Hz), 7.00 (1H, dt, J = 5.1Hz, 7.3Hz) Elemental analysis (C₁₂H_{twenty three}O_FourP): Calculated: C 54.95%, H 8.84% Actual: C 54.93%, H 8.90% Example 21 (a) (Z) -3-cyclopropyl-2- (ethoxyi)
Sobutylphosphinoyl) methylpropenoic acid ethyl ester
Tell oil IR (neat, cm^-1): 2962,1710,1272,1182,1038,966 FAB-MS (m / e): 303 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.68 (2H, m), 1.01 (2H, m),
1.04 (6H, m), 1.23-1.32 (6H, m), 1.65 (2H, m), 1.76
(1H, m), 2.14 (1H, m), 3.01 and 3.07 (2H, AB type dd, J = 1
4.8Hz, 16.5Hz), 4.09 (2H, m), 4.19 (2H, q, J = 7.0Hz),
6.29 (1H, dd, J = 4.9Hz, 10.7Hz) (b) (E) -3-cyclopropyl-2- (ethoxyi
Sobutylphosphinoyl) methylpropenoic acid ethyl ester
Tell oil IR (neat, cm^-1): 2962,1713,1251,1188,1098,966 FAB-MS (m / e): 303 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.53 (2H, m), 0.95 (2H, m),
1.03 (6H, d, J = 6.5Hz), 1.26 (3H, t, J = 7.1Hz), 1.32
(3H, t, J = 7.1Hz), 1.62 (2H, m), 2.10 (1H, m), 2.60
(1H, m), 2.76 and 2.84 (2H, AB type dd, J = 15.2Hz, 15.5H
z), 4.08 (2H, m), 4.26 (2H, m), 5.40 (1H, dd, J = 4.4H)
z, 10.8 Hz) (c) (Z) -3-cyclopropyl-2- (hydroxy
Isobutylphosphinoyl) methylpropenoic acid m.p .: 153-14.5 ° C IR (KBr, cm^-1): 2962,1695,1248,1173,1119,957 FAB-MS (m / e): 247 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.66 (2H, m), 1.01 (2H, m),
1.05 (6H, d, J = 6.1Hz), 1.66 (2H, dd, J = 6.7Hz, 12.9H
z), 1.77 (1H, m), 2.13 (1H, m), 3.01 (2H, d, J = 17.3H
z), 6.35 (1H, dd, J = 5.0Hz, 10.8Hz) Elemental analysis (C₁₁H₁₉O_FourP): Calculated: C53.66%, H7.78% Actual: C53.30%, H7.74% Example 22 (a) (Z) -2- (ethoxyisobutylphosphinoy)
E) Methyl-5-phenyl-2-pentenoate ethyles
Tell oil IR (neat, cm^-1): 2962,1713,1272,1248,1179,1038,954 FAB-MS (m / e): 367 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.03 (6H, dd, J = 2.6Hz, 6.6H
z), 1.25 (3H, t, J = 6.8 Hz), 1.30 (3H, t, J = 7.1 Hz), 1.
62 (2H, dd, J = 6.7Hz, 12.5Hz), 2.12 (2H, m), 2.65 (2H,
m), 2.78 (2H, m), 2.85 (2H, d, J = 16.5Hz), 4.03 (2H,
m), 4.22 (2H, q, J = 7.1 Hz), 6.99 (1H, dt, J = 5.1 Hz, 7.2
Hz), 7.16 (5H, m) (b) (E) -2- (ethoxyisobutylphosphinoy
E) Methyl-5-phenyl-2-pentenoate ethyles
Tell oil IR (neat, cm^-1): 2962,1716,1236,1188,1035,954 FAB-MS (m / e): 367 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.03 (6H, d, J = 6.3Hz), 1.26
(3H, t, J = 7.1Hz), 1.31 (3H, t, J = 7.2Hz), 1.59 (2H,
m), 2.10 (2H, m), 2.73-2.90 (6H, m), 4.04 (2H, m),
4.23 (2H, m), 6.16 (1H, dt, J = 4.6Hz, 7.4Hz), 7.27 (5
H, m) (c) (Z) -2- (hydroxyisobutylphosphino)
Yl) methyl-5-phenyl-2-pentenoic acid m.p .: 127.0-127.5 ° C IR (KBr, cm^-1): 2962,1650,1308,1236,1110,1014,939 FAB-MS (m / e): 311 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.04 (6H, dd, J = 6.6Hz), 1.62
(2H, dd, J = 6.3Hz, 12.9Hz), 2.10 (1H, m), 2.62 (2H,
m), 2.76-2.86 (4H, m), 7.02 (1H, dt, J = 5.0Hz, 7.3H
z), 7.25 (5H, m) Elemental analysis (C₁₆H_{twenty three}O_FourAs P): Calculated: C 61.93%, H 7.47% Found: C 62.05%, H 7.77% Example 23 (a) (Z) -6-chloro-2- (ethoxyisobutyl)
Ethyl phosphinoyl) methyl-2-hexenoate
Le oil FAB-MS (m / e): 339 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.05 (6H, dd, J = 2.7Hz, 6.6H
z), 1.28 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.
64 (2H, dd, J = 6.6Hz, 12.9Hz), 1.93−2.02 (2H, m), 2.0
5-2.20 (1H, m), 2.50 (2H, ddt, J = 3.9Hz, 7.5Hz, 7.5H
z), 2.95 (2H, d, J = 16.5Hz), 3.57 (2H, t, J = 6.3Hz),
3.95−4.15 (2H, m), 4.22 (2H, q, J = 7.2Hz), 6.90 (1H, m
dt, J = 5.4 Hz, 7.5 Hz) (b) (E) -6-chloro-2- (ethoxyisobutyl
Ethyl phosphinoyl) methyl-2-hexenoate
Le oil FAB-MS (m / e): 339 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.05 (6H, d, J = 6.9Hz), 1.28
(3H, t, J = 7.2Hz), 1.33 (3H, t, J = 7.2Hz), 1.60 (2H, d
d, J = 6.6Hz, 12.6Hz), 1.85-2.00 (2H, m), 2.00-2.20
(1H, m), 2.60-2.70 (2H, m), 2.80-2.90 (2H, m), 3.5
6 (2H, t, J = 6.6Hz), 3.95−4.20 (2H, m), 4.24 (2H, q, J
= 7.2 Hz), 6.12 (1H, dt, J = 5.1 Hz, 7.5 Hz) (c) (Z) -6-chloro-2- (hydroxyisobutyi)
Ruphosphinoyl) methyl-2-hexenoic acid m.p .: 129.5-130.5 ° C IR (KBr, cm^-1): 2962,1692,1278,1245,1167,969 FAB-MS (m / e): 283 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.05 (6H, d, J = 6.6Hz), 1.65
(2H, dd, J = 6.6Hz, 12.9Hz), 1.90-2.00 (2H, m), 2.00
−2.20 (1H, m), 2.48 (2H, ddt, J = 3.9Hz, 7.2Hz, 7.2H
z), 2.95 (2H, d, J = 17.1 Hz), 3.60 (2H, t, J = 6.6 Hz),
6.95 (1H, dt, J = 5.1Hz, 7.5Hz) Elemental analysis (C₁₁H₂₀ClO_FourAs P): Calculated: C 46.74%, H 7.13% Actual: C 46.72%, H 7.61% Example 24 (a) (Z) -8-chloro-2- (ethoxyisobutyl)
Phosphinoyl) methyl-2-octenoate
Le oil IR (neat, cm^-1): 2962,1713,1275,1173,1104,1038,954 FAB-MS (m / e): 367 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.04 (6H, dd, J = 2.6Hz, 7.0H
z), 1.28 (3H, t, J = 7.1 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.
48-1.53 (4H, m), 1.60-1.67 (2H, m), 1.77-1.82 (2
H, m), 2.08-2.16 (1H, m), 2.31-2.35 (2H, m), 2.93
(2H, d, J = 16.4Hz), 3.54 (2H, t, J = 6.5Hz), 3.96-4.1
3 (2H, m), 4.22 (2H, q, J = 7.1Hz), 6.93 (1H, dt, J = 5.1
Hz, 7.3 Hz) (b) (E) -8-chloro-2- (ethoxyisobutyl
Phosphinoyl) methyl-2-octenoate
Le oil IR (neat, cm^-1): 2962,1716,1233,1176,1104,1038,954 FAB-MS (m / e): 367 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.04 (6H, d, J = 7.0Hz), 1.28
(3H, t, J = 7.0Hz), 1.32 (3H, t, J = 7.0Hz), 1.45-1.51
(4H, m), 1.56-1.65 (2H, m), 1.75-181 (2H, m), 2.04
−2.14 (1H, m), 2.50−2.54 (2H, m), 2.84 (2H, m), 3.5
3 (2H, t, J = 6.8Hz), 4.01-4.12 (2H, m), 4.13-4.27
(2H, m), 6.11 (1H, dt, J = 4.6Hz, 7.6Hz) (c) (Z) -8-chloro-2- (hydroxyisobutyi)
Ruphosphinoyl) methyl-2-octenoic acid m.p .: 97.2-98.5 ° C IR (KBr, cm^-1): 2956,1692,1284,1170,1059,966 FAB-MS (m / e): 311 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.05 (6H, d, J = 6.5Hz), 1.49
-1.54 (4H, m), 1.64 (2H, dd, J = 6.9Hz, 12.9Hz), 1.76
−1.82 (2H, m), 2.06−2.12 (1H, m), 2.30−2.35 (2H, m
m), 2.90 (2H, d, J = 17.0Hz), 3.57 (2H, t, J = 6.8Hz),
6.97 (1H, dt, J = 5.5Hz, 7.3Hz) Elemental analysis (C₁₃H_{twenty four}ClO_FourAs P): Calculated value: C50.25%, H7.78% Actual value: C49.24%, H7.68% Example 25 (a) (Z) -2- (ethoxyisobutylphosphinoy)
R) Methyl-6-methoxycarbonyl-2-hexenoic acid
Ethyl ester oil FAB-MS (m / e): 363 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.05 (6H, dd, J = 2.7Hz, 6.6H
z), 1.27 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.
63 (2H, dd, J = 6.9Hz, 12.6Hz), 1.75-1.90 (2H, m), 2.0
0−2.20 (1H, m), 2.30−2.45 (2H, m), 2.37 (2H, t, J =
7.5Hz), 2.92 (2H, d, J = 16.8Hz), 3.67 (3H, s), 3.95-
4.15 (2H, m), 4.22 (2H, q, J = 7.2Hz), 6.91 (1H, dt, J =
(5.1Hz, 7.2Hz) (b) (E) -2- (ethoxyisobutylphosphinoy
R) Methyl-6-methoxycarbonyl-2-hexenoic acid
Ethyl ester oil FAB-MS (m / e): 363 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.04 (6H, d, J = 6.0Hz), 1.28
(3H, t, J = 6.9Hz), 1.32 (3H, t, J = 6.9Hz), 1.62 (2H, d
d, J = 6.3Hz, 12.6Hz), 1.70-1.90 (2H, m), 2.00-2.20
(1H, m), 2.35 (2H, t, J = 7.8Hz), 2.50-2.60 (2H, m),
2.70−3.00 (2H, m), 3.67 (3H, s), 3.90−4.15 (2H,
m), 4.23 (2H, m), 6.09 (1H, dt, J = 4.5 Hz, 7.5 Hz) (c) (Z) -2- (hydroxyisobutylphosphino
Yl) methyl-2-heptenedioic acid m.p .: 144-146 ° C IR (KBr, cm^-1): 2962,1707,1248,966 FAB-MS (m / e): 293 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.05 (6H, d, J = 6.6Hz), 1.64
(2H, dd, J = 6.9Hz, 12.9Hz), 1.78 (2H, tt, J = 7.2Hz, 7.2
Hz), 2.00-2.10 (1H, m), 2.30-2.40 (2H, m), 2.35 (2
H, t, J = 7.2Hz), 2.93 (2H, d, J = 17.1Hz), 6.96 (1H, dt,
J = 5.4Hz, 7.5Hz) Elemental analysis (C₁₂H_{twenty one}O₆P): Calculated: C 49.31%, H 7.24% Actual: C 49.53%, H 7.68% Example 26 (a) (Z) -3-cyclopropyl-2-[(2,2 −
Methylcyclopropyl) ethoxyphosphinoyl] methyl
Lupropenoic acid ethyl ester Oil IR (neat, cm^-1): 2986,1707,1332,1272,1179,1050,966 FAB-MS (m / e): 315 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.54 (1H, m), 0.65 (2H, m),
0.78 (1H, m), 1.01 (2H, m), 1.07 (6H, d, J = 2.4Hz), 1.
08 (1H, m), 1.30 (6H, m), 1.84 (1H, m), 3.00−3.21 (2
H, m), 4.05 (2H, m), 4.19 (2H, q = J = 7.0Hz), 6.32 (1
(H, dd, J = 11.1 Hz, 5.1 Hz) (b) (E) -3-cyclopropyl-2-[(2,2-di
Methylcyclopropyl) ethoxyphosphinoyl] methyl
Lupropenoic acid ethyl ester Oil IR (neat, cm^-1): 2986,1710,1248,1188,1038,966 FAB-MS (m / e): 315 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.55 (3H, m), 0.81 (1H, m),
0.96 (2H, m), 1.12 (6H, s), 1.10 (1H, m), 1.30 (6H,
m), 2.66 (1H, m), 2.88 (2H, m), 4.17 (2H, m), 4.23 (2
H, m), 5.42 (1H, dd, J = 4.6 Hz, 10.0 Hz) (c) (Z) -3-cyclopropyl-2-[(2,2-di
Methylcyclopropyl) hydroxyphosphinoyl] me
Tilpropenoic acid m.p .: 158.0-159.0 ° C IR (KBr, cm^-1): 2956,2878,1683,1239,1179,1155,975 FAB-MS (m / e): 259 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 0.64 (2H, m), 0.68-0.78 (2
H, m), 0.93 (1H, ddd, J = 16.8Hz, 6.3Hz, 3.9Hz), 1.02 (2
H, m), 1.11 (3H, d, J = 2.2Hz), 1.30 (3H, s), 1.82 (1H,
m), 3.06 (2H, m), 6.35 (1H, dd, J = 5.1Hz, 11.1Hz) Elemental analysis (C₁₂H₁₉O_FourAs P): Calculated value: C 55.81%, H 7.42% Actual value: C 55.41%, H 7.39% Example 27 (a) (Z) -2- (cyclohexylmethylethoxyphospho)
(Sphinoyl) methyl-3-cyclopropylpropenoic acid
Ethyl ester Oil IR (neat, cm^-1): 2926,1710,1272,1158,1035,966 FAB-MS (m / e): 343 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.65-0.70 (2H, m), 0.98-1.
29 (13H, m), 1.59-1.91 (9H, m), 2.95-3.13 (2H, m),
3.98-4.15 (2H, m), 4.19 (2H, q, J = 7.1Hz), 6.29 (1H, m
(dd, J = 4.9 Hz, 10.7 Hz) (b) (Z) -2- (cyclohexylmethylhydroxy)
Phosphinoyl) methyl-3-cyclopropylpropene
Acid m.p .: 173.5-175.0 ° C IR (KBr, cm^-1): 2926,1686,1284,1167,969 FAB-MS (m / e): 287 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 0.63-0.68 (2H, m), 0.97-1.
37 (7H, m), 1.62-1.93 (9H, m), 3.01 (2H, d, J = 17.3H
z), 6.35 (1H, dd, J = 5.0Hz, 10.9Hz) Elemental analysis (C₁₄H_{twenty three}O_FourAs P): Calculated: C 58.73%, H 8.10% Found: C 58.23%, H 8.13% Example 28 (a) (Z) -2- (benzylethoxyphosphinoy)
E) Methyl-3-cyclohexylpropenoate ethyles
Tell oil IR (neat, cm^-1): 2926,1713,1278,1227,1173,1038,957 FAB-MS (m / e): 379 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.13 (3H, t, J = 7.1Hz), 1.10
-1.40 (5H, m), 1.30 (3H, t, J = 7.1Hz), 1.67 (5H, m),
2.34 (1H, m), 2.93 (2H, d, J = 16.7Hz), 3.12 and 3.19
(2H, AB type dd, J = 15.0Hz, 15.0Hz), 3.90 (2H, m), 4.21
(2H, q, J = 7.0Hz), 6.80 (1H, dd, J = 5.0Hz, 10.4Hz), 7.
30 (5H, m) (b) (E) -2- (benzylethoxyphosphinoy
E) Methyl-3-cyclohexylpropenoate ethyles
Tell oil IR (neat, cm^-1): 2926,1719,1251,1218,1179,1038,957 FAB-MS (m / e): 379 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.18 (3H, t, J = 7.0Hz), 1.00
−1.50 (5H, m), 1.31 (3H, t, J = 7.3Hz), 1.70 (5H, m),
2.78 (2H, m), 3.13 (2H, d, J = 16.1Hz), 3.93 (2H, m),
4.21 (2H, q, J = 7.0Hz), 5.88 (1H, dd, J = 4.4Hz, 9.6H
z), 7.29 (5H, m) (c) (Z) -2- (benzylhydroxyphosphinoy
M) p .: 196.0-197.0 ° C IR (KBr, cm^-1): 2926,1686,1170,1149,978 FAB-MS (m / e): 323 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 1.05-1.40 (5H, m), 1.70 (5
H, m), 2.34 (1H, m), 2.89 (2H, d, J = 16.6Hz), 3.17 (2
H, d, J = 16.6Hz), 6.75 (1H, dd, J = 5.0Hz, 10.3Hz), 7.32
(5H, m) Elemental analysis (C₁₇H_{twenty three}O_FourAs P): Calculated: C 63.35%, H 7.19% Actual: C 63.34%, H 7.18% Example 29 (a) (Z) -3-cyclohexyl-2- (cyclopen)
Tylmethylethoxyphosphinoyl) methylpropenoic acid
Ethyl ester oil FAB-MS (m / e): 371 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 1.10-2.00 (26H, m), 2.05-
2.25 (1H, m), 2.40 (1H, m), 2.94 (2H, d, J = 16.5Hz),
4.05 (2H, m), 4.21 (2H, q, J = 7.2Hz), 6.72 (1H, dd, J =
(5.1 Hz, 10.8 Hz) (b) (Z) -3-cyclohexyl-2- (cyclopen
Tylmethylhydroxyphosphinoyl) methylpropene
Acid m.p .: 178-180 ° C IR (KBr, cm^-1): 2932,2854,1692,1638,1317,1290,1152,
960 FAB-MS (m / e): 315 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δ ppm): 1.10-2.00 (20H, m), 2.18 (1
H, m), 2.48 (1H, m), 2.91 (2H, d, J = 17.1Hz), 6.75 (1
H, dd, J = 5.1Hz, 10.5Hz) Elemental analysis (C₁₆H₂₇O_FourP): Calculated: C 61.13%, H 8.66% Actual: C 60.90%, H 8.57% Example 30 (a) (Z) -3-cyclohexyl-2- (cyclohexyl)
Silmethylethoxyphosphinoyl) methylpropenoic acid
Ethyl ester Oil IR (neat, cm^-1): 2932,1713,1278,1227,1173,1038,954 FAB-MS (m / e): 385 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.97-1.39 (16H, m), 1.59-
1.90 (13H, m), 2.39−2.43 (1H, m), 2.93 (2H, d, J = 16.
9Hz), 3.95−4.12 (2H, m), 4.20 (2H, q, J = 7.0Hz), 6.7
1 (1H, dd, J = 4.9Hz, 10.6Hz) (b) (Z) -3-cyclohexyl-2- (cyclohexyl)
Silmethylethoxyphosphinoyl) methylpropenoic acid
Ethyl ester Oil IR (neat, cm^-1): 2926,1719,1218,1035,954 FAB-MS (m / e): 385 (M + H)^{+ 1} H-NMR (CDCl_Three, δppm): 0.99-1.35 (16H, m), 1.56-
1.87 (13H, m), 2.77−2.93 (3H, m), 3.93−4.12 (2H,
m), 4.22 (2H, q, J = 7.2 Hz), 5.89 (1H, dd, J = 4.7 Hz, 9.8
Hz) (c) (Z) -3-cyclohexyl-2- (cyclohexyl)
Silmethylhydroxyphosphinoyl) methylpropene
Acid m.p .: 170.0-171.5 ° C IR (KBr, cm^-1): 2932,2854,1692,1239,1146,954 FAB-MS (m / e): 329 (M + H)^{+ 1} H-NMR (CD_ThreeOD, δppm): 1.01-1.39 (1OH, m), 1.60-
1.92 (13H, m), 2.46-2.50 (1H, m), 2.90 (2H, d, J = 17.
1 Hz), 6.74 (1H, dd, J = 5.2Hz, 10.5Hz) Elemental analysis (C₁₇H₂₉O_FourAs P): Calculated value: C62.18%, H8.90% Actual value: C61.69%, H8.86% Example 31 (Z) -3-cyclohexyl-2- (ethoxyhexyl)
Phosphinoyl) methyl propenoic acid ethyl ester
(E) -3-cyclohexyl-2- (ethoxyhexyl
From phosphinoyl) methylpropenoic acid ethyl ester
Production of (E) -3-cyclohexyl-2- (ethoxyhexyl)
Ruphosphinoyl) methyl propenoic acid ethyl ester 10
To a 10 mg solution of 0 mg (0.27 mmol) in 10 ml of ethanol
Add 10mg of di-carbon, room temperature under hydrogen atmosphere at normal pressure
And stir for 3 hours. Filter the palladium-carbon and reduce
Evaporation of the solvent under pressure gives a pale yellow oil. this
Is (Z) -3-cyclohexyl-2- (ethoxy)
Hexylphosphinoyl) methylpropenoate ethyls
Ter, (E) -3-cyclohexyl-2- (ethoxy
Xylphosphinoyl) methyl ethyl propenoate
And 3-cyclohexyl-2- (ethoxyhexyl
Ruphosphinoyl) methyl propionic acid ethyl ester
A mixture of¹H-NMR signal corresponding to each
When the mixture ratio is determined by measuring the integral ratio, it is 74: 12: 1
Was 4.

Example 32 Production of 3-cyclohexyl-2- (hexylhydroxyphosphinoyl) methylpropionic acid (a) Production of ethyl 3-cyclohexyl-2- (ethoxyhexylphosphinoyl) methylpropionate (E) -3- Cyclohexyl-2- (ethoxyhexylphosphinoyl) methylpropenoic acid ethyl ester 0.
To a solution of 37 g (1.0 mmol) in 30 ml of ethanol was added 50 mg of 10% palladium-carbon, and 3 kg / cm ² in a Parr apparatus.
For 8 hours. After filtering off the palladium-carbon, the solvent is distilled off under reduced pressure to obtain 0.37 g (yield: 99%) of the title compound as a pale yellow oil.

^{IR (neat, cm -1):} 2926,1737,1218,1194,1038,954 FAB-MS (m / e): 375 (M + H) + 1 H-NMR (CDCl 3, δppm): 0.75-0.95 (5H , m), 1.06-1.
85 (25H, m), 2.17 (1H, m), 2.83 (1H, m), 3.95-4.25
(4H, m) (b) Production of 3-cyclohexyl-2- (hexylhydroxyphosphinoyl) methylpropionic acid Ethyl 3-cyclohexyl-2- (ethoxyhexylphosphinoyl) methylpropionate was prepared according to Example 2 ( d) Treatment in the same manner as in d), methanol-ethyl acetate-
Recrystallization from hexane (1: 4: 40) gives the title compound as colorless crystals.

mp: 121.5-123.0 ℃ IR (KBr, cm -1): 2926,1722,1218,1116,960 FAB-MS (m / e): 319 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.83-1.90 (27H, m), 2.15 (1
H, m), 2.81 (1H , m) as the element analysis _{(C 16 H 31 O 4 P} ): Calculated: C60.36%, H9.81% Found: C60.10%, H9.99% Example 33 to 38 The following compounds of Examples 32 to 38 were obtained according to Example 32.

Example 33 (a) 3-cyclohexyl-2- (ethoxyethylphosphinoyl) methylpropionic acid ethyl ester Oil IR (neat, cm ^-1 ): 2926,1737,1212,1044,954 FAB-MS (m / m e): 319 (M + H ) + 1 H-NMR (CDCl 3, δppm): 0.83-2.10 (26H, m), 2.80 (1
H, m), 3.78-4.30 (4H, m) (b) 3-cyclohexyl-2- (ethylhydroxyphosphinoyl) methylpropionic acid mp: 116-118.5 ° C IR (KBr, cm ^-1 ): 2926,1728 , 1227,1176,1154,1119,951 FAB-MS (m / e): 263 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.85-1.90 (19H, m), 2.15 (1
H, m), 2.82 (1H , m) as the element analysis _{(C 12 H 23 O 4 P} ): Calculated: C54.95%, H8.84% Found: C55.75%, H9.02% Example 34 (a) Ethyl 3-cyclohexyl-2- (ethoxyisopropylphosphinoyl) methylpropionate Oil IR (neat, cm ^-1 ): 2926,1737,1212,1032,954 FAB-MS (m / e) ^{: 333 (M + H) +} 1 H-NMR (CDCl 3, δppm): 0.80-2.25 (31H, m), 2.90 (1
H, m), 4.00-4.25 (4H, m) (b) 3-cyclohexyl-2- (hydroxyisopropylphosphinoyl) methylpropionic acid mp: 129.5-130.5 ° C IR (KBr, cm ^-1 ): 2926,1722 , 1230,1176,1131,951 FAB-MS (m / e): 277 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.85-1.90 (21H, m), 2.16 (1
H, m), 2.83 (1H , m) as the element analysis _{(C 13 H 25 O 4 P} ): Calculated: C56.51%, H9.12% Found: C56.59%, H9.70% Example 35 2- (butylhydroxyphosphinoyl) methyl-3-
Cyclohexyl propionic acid mp: 118-121 ℃ IR (KBr, cm -1): 3440,2940,1686,1138,1030 FAB-MS (m / e): 291 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.93 (3H, t, J = 6Hz), 1.16−
1.97 (21H, m), 2.71-2.87 (1H, m) ( as C ₁₄ H ₂₇ O ₄ P) Calcd: C57.92%, H9.37% Found: C57.48%, H9. 02% Example 36 (a) Ethyl 3-cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropionate Oil IR (neat, cm ^-1 ): 2932,1740,1260,1227,1170,1035,966 ¹ H-NMR (CDCl ₃ , δ ppm): 0.80-2.30 (3OH, m), 2.60-
3.10 (1H, m), 3.90-4,40 (4H, m) (b) 3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropionic acid mp: 154-155 ° C IR (KBr, cm ^-1 ) : 2926,1719,1227,1173,1122,969 high resolution FAB-MS (m / e, as ^{_{+ (C 14 H 27 O 4}} P + H)): calculated: 291.1725 ^{Found: 291.1717 1 H-NMR (CD} 3 OD, δ ppm): 0.85-0.96 (2H, m), 1.05 (6
H, d, J = 6.6Hz), 1.18-1.89 (14H, m), 2.02-2.18 (2H,
m), 2.79-2.83 (1H, m) Example 37 (a) Ethyl 3-cyclohexyl-2- (decylethoxyphosphinoyl) methylpropionate Oil IR (neat, cm ^-1 ): 2930,1740, 1455,1381,1197,1041,956 FAB-MS (m / e ): 431 (M + H) + 1 H-NMR (CDCl 3, δppm): 0.88 (3H, t, J = 7Hz), 1.05-
1.89 (38H, m), 2.09-2.27 (1H, m), 2.74-2.94 (1H,
m), 3.92-4.28 (4H, m) (b) 3-cyclohexyl-2- (decylhydroxyphosphinoyl) methylpropionic acid mp: 124-125.5 ° C IR (KBr, cm ^-1 ): 2920,1720,1450 , 1230,1175,958 FAB-MS (m / e): 375 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.90 (3H, t, J = 7.2Hz), 1.11
−1.93 (32H, m), 2.07−2.21 (1H, m), 2.72−2.88 (1H,
m) Elemental analysis (as _{C 20 H 39 O 4 P)} : Calculated: C64.14%, H10.50% Found: C64.15%, H10.48% Example 38 (a) 3--cyclohexyl-2 -[(2,2-dimethylcyclopropyl) ethoxyphosphinoyl] methylpropionic acid ethyl ester (mixture of diastereomers) Oil IR (neat, cm ^-1 ): 2926,1737,1452,1194,1170,1035 , 948 FAB-MS (m / e): 359 (M + H) + 1 H-NMR (CDCl 3, δppm): 0.42-2.40 (3OH, m), 2.90 (1
H, m), 3.96-4.26 (4H, m) (b) 3-cyclohexyl-2-[(2,2-dimethylcyclopropyl) hydroxyphosphinoyl] methylpropionic acid (one of the diastereomers) mp: 160.5 ^{-161 ℃ IR (KBr, cm -1} ): 3424,2926,1707,1452,1236,1182,978 FAB-MS (m / e): 303 (M + H) + 1 H-NMR (CD 3 OD, δppm) : 0.62-1.90 (18H, m), 1.14 (3
H, d, J = 1.5Hz, 1.23 (3H, s), 2.15 (1H, ddd, J = 9.2Hz,
11.2Hz, 15.3Hz), 2.75-2.95 (1H , m) as the element analysis _{(C 15 H 27 O 4 P} ): Calculated: C59.59%, H9.00% Found: C59.48%, H8. 91% (c) 3-cyclohexyl-2-[(2,2-dimethylcyclopropyl) hydroxyphosphinoyl] methylpropionic acid (the other diastereomer) mp: 128-130 ° C IR (KBr, cm ^-1) ): 3424,1725,1452,1173,1137,1122,966 FAB-MS (m / e): 303 (M + H) + 1 H-NMR (CD 3 OD, δppm): 0.67-1.90 (18H, m), 1.16 (3
H, d, J = 2.1Hz), 1.31 (3H, s), 2.17 (1H, ddd, J = 9.1Hz,
15.3Hz, 15.3Hz), 2.75-2.90 (1H , m) as the element analysis _{(C 15 H 27 O 4 P} ): Calculated: C59.59%, H9.00% Found: C59.33%, H8. 98% Example 39 Preparation of (Z) -6-dimethylamino-2- (hydroxyisobutylphosphinoyl) methyl-2-hexanoic acid (a) (Z) -6-dimethylamino-2- (ethoxyisobutylphosphino) Preparation of yl) methyl-2-hexanoic acid ethyl ester (Z) -6-chloro-2- (ethoxyisobutylphosphinoyl) methyl-2-hexenoic acid ethyl ester 30
0 mg (0.89 mmol) is dissolved in 12 ml of a 12.9% dimethylamine-tetrahydrofuran solution and reacted at room temperature for 4 days. The solvent is distilled off under reduced pressure, the residue is dissolved in 30 ml of ethyl acetate, and the desired product is extracted with 30 ml of 3N hydrochloric acid. Sodium bicarbonate was added to the aqueous layer to pH 8, and ethyl acetate 20m
Extract three times with l. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 160 mg (yield: 52%) of the title compound as a pale yellow oil.

FAB-MS (m / e) : 348 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.06 (6H, d, J = 6.6Hz), 1.28
(3H, t, J = 7.2Hz), 1.30 (3H, t, J = 7.2Hz), 1.68-1.75
(4H, m), 2.02-2.17 (1H, m), 2.26 (6H, s), 2.31-2.4
0 (4H, m), 2.98-3.06 (2H, m), 3.95-4.11 (2H, m), 4.
21 (2H, q, J = 7.2 Hz), 6.95 (1H, dt, J = 5.1 Hz, 7.2 Hz) (b) (Z) -6-dimethylamino-2- (hydroxyisobutylphosphinoyl) methyl-2 Preparation of hexenoic acid 125 mg (0.36 mmol) of (Z) -6-dimethylamino-2- (ethoxyisobutylphosphinoyl) methyl-2-hexenoic acid ethyl ester was dissolved in 10 ml of 3N hydrochloric acid, and
Heat to reflux for hours. After cooling, the solvent was distilled off under reduced pressure, the residue was dissolved in water, and the solution was poured onto a Dowex 50W-X4 (50-100 mesh, H ⁺ ) ion exchange resin column (2.5 x 16 cm). Elute with water until no more (200 ml). Next, the column is eluted with 2N aqueous ammonia, and the fractions containing the target compound are collected and concentrated under reduced pressure to obtain a pale yellow hygroscopic foam. Dissolve this substance in water and add Dowex 1X-8
(200-400 mesh, AcO ^-) ion exchange resin column (2.5
And elute with 150 ml of water, then elute with 0.6 M acetic acid. Fractions containing the desired compound were collected and concentrated under reduced pressure to give a pale yellow oil, which was triturated with ether to give 44 mg of the title compound as a pale yellow amorphous powder (yield 42%).
%)obtain.

IR (KBr, cm ^-1 ): 3418,2956,1698,1116,1026 High-resolution FAB-MS (m / e, as (C ₁₃ H ₂₆ NO ₄ P + H) ⁺ ): Calculated: 292.1678 Actual: 292.1706 ¹ H-NMR (CD ₃ OD, δ ppm): 1.07 (6H, d, J = 6.6 Hz), 1.58
(2H, dd, J = 6.6Hz, 6.6Hz), 1.99−2.14 (3H, m), 2.48−
2.56 (2H, m), 2.79 (6H, s), 2.8-2.9 (2H, m), 3.09 (2
H, t, J = 6.6 Hz), 6.76 (2H, dt, J = 5.1 Hz, 7.2 Hz) Example 40 (Z) -6-carboxymethylmethylamino-2- (hydroxyisobutylphosphinoyl) methyl-2 Preparation of -hexenoic acid (a) Preparation of (Z) -6-benzyloxycarbonylmethylmethylamino-2- (ethoxyisobutylphosphinoyl) methyl-2-hexenoic acid ethyl ester (Z) -6-chloro-2- (Ethoxyisobutylphosphinoyl) methyl-2-hexenoic acid ethyl ester 36
0 mg (1.06 mmol), benzyl ester of sarcosine 5
30 mg (2.97 mmol) and 180 mg sodium iodide
(1.20 mmol) is dissolved in 5 mg of dimethylformamide and stirred at room temperature for 29 hours and at 60 ° C. for 3 hours. 25 ml of water is added to the reaction mixture, extracted twice with 35 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to medium pressure liquid chromatography (Merck's Rover column size B recroprep).
Purification with SI60, dichloromethane-methanol (40: 1) yields 90 mg (18% yield) of the title compound as a pale yellow oil.

FAB-MS (m / e) : 482 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.05 (6H, dd, J = 3.0Hz, 6.9H
z), 1.27 (3H, t, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz), 1.
60-1.71 (4H, m), 2.09-2.16 (1H, m), 2.29-2.36 (2
H, m), 2.38 (3H, s), 2.54 (2H, t, J = 7.5Hz), 2.94 (2H,
d, J = 16.5Hz), 3.31 (2H, s), 3.96-4.13 (2H, m), 4.22
(2H, q, J = 6.9Hz), 5.16 (2H, s), 6.93 (1H, dt, J = 5.4H)
(z, 7.5 Hz), 7.32-7.37 (5H, m) (b) Production of (Z) -6-carboxymethylmethylamino-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid (Z) -6 89 mg (0.19 mmol) of benzyloxycarbonylmethylmethylamino-2- (ethoxyisobutylphosphinoyl) methyl-2-hexenoic acid ethyl ester are dissolved in 1.3 ml of concentrated hydrochloric acid, and the mixture is heated under reflux for 12 hours. After allowing to cool, concentrate under reduced pressure, dissolve the residue in water
Pour into a 50W-X4 (50-100 mesh, H ⁺ ) ion exchange resin column (2.5 x 9 cm) until the eluate is no longer acidic (10
0ml) elute with water. Next, the column was eluted with 2N aqueous ammonia, and the fractions containing the target compound were collected and concentrated under reduced pressure to give the title compound as a pale yellow amorphous powder (60 mg, yield 94%).
%)obtain.

^{IR (KBr, cm -1):} 3418,3190,2962,1635,1404,1128,1029 High Resolution FAB-MS (m / e, as ^{_{+ (C 14 H 26 NO 6}} P + H)): Calculated: 336.1576 Found Value: 336.1567 ¹ H-NMR (CD ₃ OD, δ ppm): 1.04 (6H, d, J = 6.9 Hz), 1.50
(2H, dd, J = 6.9Hz, 13.2Hz), 1.93 (2H, tt, J = 7.5Hz, 7.5
Hz), 2.03-2.15 (1H, m), 2.39 (2H, ddt, J = 3.3Hz, 7.5H
z, 7.5Hz), 2.69 (2H, d, J = 15.9Hz), 2.89 (3H, s), 3.20
(2H, t, J = 7.5Hz), 3.62 (2H, s), 6.64 (1H, dt, J = 5.1H)
Example 41 Production of (Z) -8-dibutylamino-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid hydrochloride (a) (Z) -8-dibutylamino-2 Preparation of-(ethoxyisobutylphosphinoyl) methyl-2-octenoic acid ethyl ester (Z) -8-chloro-2- (ethoxyisobutylphosphinoyl) methyl-2-octenoic acid ethyl ester 36
7 mg (1.0 mmol) and 150 mg sodium iodide
(1.0 mmol) to 1.7 ml of dibutylamine (10 mmol)
And stirred at 60 ° C for 28 hours. 10m water in the reaction mixture
and diluted with 6N hydrochloric acid and adjusted to pH 1 with ethyl acetate.
Extract with 0 ml to remove unreacted raw materials. The aqueous layer was adjusted to pH 9 by adding sodium bicarbonate, and added with 20 ml of ethyl acetate.
Extract twice. The organic layer is washed twice with 10 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 316 mg (yield: 69%) of the title compound as a pale yellow oil.

^{IR (neat, cm -1):} 2956,1713,1251,1176,1095,954 FAB-MS (m / e): 460 (M + H) + 1 H-NMR (CDCl 3, δppm): 0.90 (6H, t , J = 7.0Hz), 1.04
(6H, dd, J = 3.5Hz, 6.5Hz), 1.27 (3H, t, J = 6.9Hz), 1.3
0 (3H, t, J = 7.0Hz), 1.23-1.53 (14H, m), 1.62 (2H, d
d, J = 6.7Hz, 12.5Hz), 2.05-2.18 (1H, m), 2.25-2.42
(8H, m), 2.92 (2H, d, J = 16.6Hz), 3.95-4.15 (2H, m
m), 4.21 (2H, q, J = 7.0 Hz), 6.92 (1H, dt, J = 5.2 Hz, 7.7
Hz) (b) Production of (Z) -8-dibutylamino-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid hydrochloride (Z) -8-dibutylamino-2- (ethoxyisobutylphosphino) Yl) Methyl-2-octenoic acid ethyl ester (200 mg, 0.43 mmol) was dissolved in concentrated hydrochloric acid (5 ml).
Stir at 5.5 ° C for 5.5 hours. After allowing to cool, the mixture is concentrated under reduced pressure, and the residue is purified by medium pressure liquid chromatography (Merck's Rover column size B Licroprep RP-18, methanol-water (7: 3)) to give the title compound as a pale yellow oil. 178 mg (94% yield) are obtained.

^{IR (neat, cm -1):} 3412,2962,1704,1236,1161,945 High Resolution FAB-MS (m / e, (C 21 H 42 NO 4 P + H) as a ^+): Calculated: 404.2930 Found: 404.2953 ¹ H-NMR (CD ₃ OD, δ ppm): 1.01 (6H, t, J = 7.0 Hz), 1.04
(6H, d, J = 6.6Hz), 1.38-1.80 (16H, m), 2.04-2.18
(1H, m), 2.32−2.41 (2H, m), 2.93 (2H, d, J = 17.1H
z), 3.10-3.16 (6H, m), 6.98 (1H, dt, J = 4.8Hz, 7.2H
z) Example 42 (Z) -2- (hydroxyisobutylphosphinoyl)
Production of methyl-6-phenylthio-2-hexenoic acid (a) Production of (Z) -2- (ethoxyisobutylphosphinoyl) methyl-6-phenylthio-2-hexenoic acid ethyl ester (Z)- To a solution of 169 mg (0.50 mmol) of ethyl 6-chloro-2- (ethoxyisobutylphosphinoyl) methyl-2-hexenoate in 1.0 ml of dimethylformamide was added 62 μl (0.60 mmol) of thiophenol.
Mmol) and potassium carbonate 83mg (0.60mmol)
And stirred for 2 hours at room temperature. Water 20 in the reaction mixture
Then, the mixture was extracted three times with 15 ml of ethyl acetate, and the organic layer was washed with 10 ml of a saturated aqueous sodium hydrogen carbonate solution and 10 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to dry column flash chromatography (silica gel 60 15 g, Merck, hexane-ethyl acetate (0 → 10
(0%) gradient elution) to give 202 mg (98% yield) of the title compound as a pale yellow oil.

FAB-MS (m / e) : 413 (M + H) + 1 H-NMR (CDCl 3, δppm: 1.04 (6H, dd, J = 2.7Hz, 6.3Hz),
1.27 (3H, t, J = 7.2Hz), 1.30 (3H, t, J = 7.2Hz), 1.63
(2H, dd, J = 6.9Hz, 12.6Hz), 1.83 (2H, tt, J = 7.5Hz, 7.5
Hz), 2.10 (1H, m), 2.47 (2H, ddt, J = 4.2Hz, 7.5Hz, 7.5H
z), 2.93 (2H, d, J = 16.2Hz), 2.95 (2H, t, J = 7.5Hz),
4.02 (2H, m), 4.21 (2H, q, J = 7.2Hz), 6.90 (1H, dt, J =
(5.1Hz, 7.5Hz), 7.14-7.38 (5H, m) (b) (Z) -2- (hydroxyisobutylphosphinoyl)
Preparation of methyl-6-phenylthio-2-hexenoic acid (Z) -2- (ethoxyisobutylphosphinoyl)
To a solution of 155 mg (0.376 mmol) of methyl-6-phenylthio-2-hexenoic acid ethyl ester in 5 ml of dioxane is added 5 ml of concentrated hydrochloric acid, and the mixture is stirred under reflux with heating for 3 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica gel 60F254, Merck, chloroform-methanol-acetic acid (9: 1: 1)).
Recrystallization from ethyl acetate-hexane (1: 3) gave the title compound as colorless crystals (74 mg, 55% yield).

mp: 115.2-117 ℃ IR (KBr, cm -1): 2962,1689,1245,1170,966 FAB-MS (m / e): 357 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.05 (6H, d, J = 6.3Hz), 1.64
(2H, dd, J = 6.6Hz, 12.9Hz), 1.79 (2H, tt, J = 7.5Hz, 7.5
Hz), 2.10 (1H, m), 2.46 (2H, ddt, J = 3.9Hz, 7.5Hz, 7.5H
z), 2.92 (2H, d, J = 17.4Hz), 2.98 (2H, t, J = 7.5Hz),
6.93 (1H, dt, J = 5.1Hz, 7.5Hz), ( as _{C 17 H 25 O 4 PS)} 7.13-7.35 (5H, m) Elemental analysis: Calculated: C57.29%, H7.07% Found : C57.18%, H7.37% Example 43 (Z) -2- (Hydroxyisobutylphosphinoyl)
Preparation of methyl-6- (1,2,3-triazol-4-yl) thio-2-hexenoic acid (a) (Z) -2- (ethoxyisobutylphosphinoyl) methyl-6- (1,2, 3-triazol-4-yl) thio-
Preparation of 2-hexenoic acid ethyl ester (Z) -6-chloro-2- (ethoxyisobutylphosphinoyl) methyl-2-hexenoic acid ethyl ester 33
To a solution of 9 mg (1.0 mmol) in 2 ml of dimethylformamide,
Add 265 mg (1.2 mmol) of disodium salt of 4-mercapto-1,2,3-triazole hexahydrate and add 2.
Stir for 5 hours. Add 20 ml of water to the reaction mixture, and add 6N hydrochloric acid.
After adjusting the pH to 7, extract three times with 10 ml of ethyl acetate.
The organic layer is washed with 5 ml of a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to dry column flash chromatography (silica gel 60 15 g, Merck, hexane-ethyl acetate (50 → 100%)).
Purification by gradient elution) to give the title compound as a colorless oil
341 mg (85% yield) are obtained.

FAB-MS (m / e) : 404 (M + H) + 1 H-NMR (DMSO-d 6, δppm): 0.97 (6H, dd, J = 2.1Hz, 6.6
Hz), 1.16 (3H, t, J = 7.2Hz), 1.22 (3H, t, J = 7.2Hz),
1.57 (2H, dd, J = 6.6Hz, 13.2Hz), 1.69 (2H, tt, J = 7.5H
z, 7.5Hz), 1.85-2.05 (1H, m), 2.36 (2H, ddt, J = 3.6H
(z, 7.5Hz, 7.5Hz), 2.80-2.97 (4H, m), 3.90 (2H, m), 4.
13 (2H, q, J = 7.2Hz), 6.76 (1H, dt, J = 4.8Hz, 7.5Hz),
7.95 (1H, bs) (b) (Z) -2- (hydroxyisobutylphosphinoyl)
Preparation of methyl-6- (1,2,3-triazol-4-yl) thio-2-hexenoic acid (Z) -2- (ethoxyisobutylphosphinoyl)
To a solution of 243 mg (0.60 mmol) of methyl-6- (1,2,3-triazol-4-yl) thio-2-hexenoic acid ethyl ester in 5 ml of methanol was added 1.5N aqueous solution of lithium hydroxide.
Add 0 ml and heat to reflux for 8 hours. After cooling, methanol was distilled off under reduced pressure. The residue was adjusted to pH 2 by adding a 10% aqueous citric acid solution, saturated with sodium chloride, and extracted three times with 30 ml of ethyl acetate. The organic layer is washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to medium pressure liquid chromatography (Merck's Rover column, size B, recroprep).
Purification with RP-18, 0.1 M acetic acid-methanol (50:50)) gave the title compound as a colorless glassy substance (140 mg, yield 6%).
7%).

^{IR (KBr, cm -1):} 3142,2962,1698,1239,1146,1059,969 High Resolution FAB-MS (as _{m / e, (C 13 H} 22 N 3 O 4 PS + H) +): Calculated: 348.1147 Found: 348.1191 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.6 Hz), 1.65
(2H, dd, J = 6.6Hz, 12.9Hz), 1.78 (2H, tt, J = 7.5Hz, 7.5
Hz), 2.10 (1H, m), 2.46 (2H, ddt, J = 4.2Hz, 7.5Hz, 7.5H
z), 2.94 (2H, d, J = 17.1 Hz), 2.95 (2H, t, J = 7.5 Hz),
6.94 (1H, dt, J = 5.1 Hz, 7.5 Hz), 7.86 (1H, s) Example 44 (a) (Z) -8-carboxymethylthio-2- (hydroxyisobutylphosphinoyl) methyl-2-octene Production of acid 100 mg (0.32 mmol) of (Z) -8-chloro-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid was dissolved in 1.5 ml of 1N aqueous sodium hydroxide solution.
To this is added 42 μm (0.38 mmol) of thioglycolic acid ethyl ester, and the mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with 10 ml of water, diluted with 3.5N hydrochloric acid to make it strongly acidic, and extracted three times with 20 ml of ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to give the title compound as a colorless oil.
115 mg (98% yield) are obtained.

^{IR (neat, cm -1):} 2932,1713,1281,1242,1218,1143,948 High Resolution FAB-MS (m / e, as ^{_{+ (C 15 H 27 O 6}} PS + H)): Calculated: 367.1344 Found Value: 367.1371 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.6 Hz), 1.45
-1.53 (4H, m), 1.64 (2H, dd, J = 6.6Hz, 12.9Hz), 2.06
−2.14 (1H, m), 2.29−2.36 (2H, m), 2.65 (2H, t, J = 7.
5Hz), 2.91 (2H, d, J = 17.1Hz), 3.21 (2H, s), 6.96 (1
(H, dt, J = 5.4Hz, 7.2Hz) (b) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-8-methoxycarbonylmethylthio-2
-Production of octenoic acid (Z) -8-carboxymethylthio-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid
366 mg (1 mmol) was dissolved in 10 ml of dry methanol,
Concentrate under reduced pressure at ℃. This operation was repeated twice, and the pale yellow oily residue thus obtained was subjected to medium pressure liquid chromatography (Merck's Rover Column Size B Recroprep RP-18, 0.1 M acetic acid-methanol (70: 3
0)) and the title compound as a colorless oil (80 mg)
(21% yield).

^{IR (neat, cm -1):} 2932,1740,1700,1281,1143,951 High Resolution FAB-MS (m / e, (C 16 H 29 O 6 PS + H) as a ^+): Calculated: 381.1501 Found: 381.1537 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.6 Hz), 1.43
-1.58 (4H, m), 1.63 (2H, dd, J = 6.6Hz, 13.2Hz), 2.04
−2.14 (1H, m), 2.28−2.37 (2H, m), 2.63 (2H, t, J = 7.
2Hz), 2.91 (2H, d, J = 17.1Hz), 3.25 (2H, s), 3.70 (3
H, s), 6.97 (1H, dt, J = 5.4 Hz, 7.5 Hz) Examples 45 to 50 The following compounds of Examples 45 to 50 were obtained according to Example 42.

Example 45 (a) (Z) -2- (Ethoxyisobutylphosphinoyl) methyl-6- (3-hydroxy-2-pyridyl) thio-2-hexenoic acid ethyl ester Oil FAB-MS (m / e) ^{: 430 (M + H) +} 1 H-NMR (CDCl 3, δppm): 1.04 (6H, dd, J = 1.0Hz, 6.3H
z), 1.26 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.
66 (2H, dd, J = 6.9Hz, 12.9Hz), 1.84 (2H, tt, J = 7.2Hz,
7.2Hz), 2.00−2.20 (1H, m), 2.47 (2H, ddt, J = 3.9Hz,
7.2Hz, 7.2Hz), 2.93 (2H, d, J = 16.5Hz), 3.17 (2H, t, J
= 7.2Hz), 3.90-4.15 (2H, m), 4.21 (2H, q, J = 7.2H
z), 6.93 (1H, dt, J = 5.1 Hz, 7.2 Hz), 6.96 (1H, dd, J = 4.
5Hz, 8.1Hz), 7.12 (1H, dd, J = 1.2Hz, 8.1Hz), 8.05 (1H,
(dd, J = 1.2 Hz, 4.5 Hz) (b) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (3-hydroxy-2-pyridyl)
Thio-2-hexenoic acid mp: 164-16.5 ° C IR (KBr, cm ^-1 ): 3412,2956,1701,1455,1305,1269,1257,
1011 FAB-MS (m / e ): 374 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.03 (6H, d, J = 6.6Hz), 1.62
(2H, dd, J = 6.6Hz, 12.9Hz), 1.84 (2H, tt, J = 7.2Hz, 7.2
Hz), 2.00-2.20 (1H, m), 2.46 (2H, ddt, J = 3.9Hz, 7.2H
z, 7.5Hz), 2.90 (2H, d, J = 17.1Hz), 3.16 (2H, t, J = 7.2
Hz), 6.97 (1H, dt, J = 5.4 Hz, 7.2 Hz), 6.93 (1H, dd, J =
4.5Hz, 7.8Hz), 6.99 (1H, dd, J = 1.8Hz, 7.8Hz), 7.92 (1
H, dd, the J = 1.8Hz, 4.5Hz) Elemental analysis _{(C 14 H 24 NO 5 PS} ): Calculated: C51.47%, H6.48%, N3.75 % Found: C51.79%, H6.65%, N3.93% Example 46 (a) (Z) -6-[(L) -2-amino-2-methoxycarbonylethyl] thio-2- (ethoxyisobutylphosphinoyl) methyl-2 - hexenoic acid ethyl ester oil FAB-MS (m / e) : 438 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.05 (6H, dd, J = 3.0Hz, 6.6H
z), 1.28 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.
63 (2H, dd, J = 6.6Hz, 12.6Hz), 1.78 (2H, tt, J = 7.2Hz,
7.2Hz), 2.00−2.20 (1H, m), 2.43 (2H, ddt, J = 3.9Hz,
7.2Hz, 7.2Hz), 2.58 (2H, t, J = 7.2Hz), 2.77 (1H, dd, J
= 7.2Hz, 13.5Hz), 2.92 (1H, dd, J = 4.8Hz, 13.5Hz), 2.9
3 (2H, d, J = 16.2Hz), 3.65 (1H, dd, J = 4.8Hz, 7.2Hz),
3.75 (3H, s), 3.90-4.15 (2H, m), 4.22 (2H, q, J = 7.2H
z), 6.90 (1H, dt, J = 5.1 Hz, 7.2 Hz) (b) (Z) -6-[(L) -2-amino-2-carboxyethyl] thio-2- (hydroxyisobutylphosphinoyl ) Methyl-2-hexenoic acid amorphous white powder IR (KBr, cm ^-1 ): 3456,2962,1698,1641,1251,1143,1059,
966 High Resolution FAB-MS (m / e, as ^{_{+ (C 14 H 26 NO 6}} PS + H)): Calculated: 368.1297 Found: 368.1341 ▲ [α] _{^{20 D ▼: -9.01 (C1.08,}} CH 3 OH ) ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.6 Hz), 1.62
(2H, dd, J = 6.9Hz, 12.9Hz), 1.81 (2H, tt, J = 7.5Hz, 7.5
Hz), 2.00-2.20 (1H, m), 2.43 (2H, ddt, J = 3.6Hz, 7.5H
z, 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 2.89 (2H, d, J = 16.8
Hz), 2.97 (1H, dd, J = 8.1 Hz, 14.7 Hz), 3.17 (1H, dd, J =
3.9Hz, 14.7Hz), 3.94 (1H, dd, J = 3.9Hz, 8.1Hz), 6.91
(1H, dt, J = 5.1 Hz, 7.5 Hz) Example 47 (a) (Z) -6- (2-aminoethyl) thio-2-
(Ethoxyisobutyl phosphinoyl) methyl-2-hexenoic acid ethyl ester oil FAB-MS (m / e) : 380 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.00-1.10 (6H, m) , 1.25-1.
35 (6H, m), 1.58-1.90 (4H, m), 2.00-2.20 (1H, m),
2.40-2.70 (6H, m), 2.70-3.00 (4H, m), 3.90-4.30
(4H, m), 6.91 (1H, m) (b) (Z) -6- (2-aminoethyl) thio-2-
(Hydroxyisobutylphosphinoyl) methyl-2-
Hexenoic acid white foam ^{IR (KBr, cm -1):} 3412,2956,1695,1641,1122,1020,954 High Resolution FAB-MS (m / e, as ^{_{+ (C 13 H 26 NO 6}} PS + H)) : calculated: 324.1398 ^{Found: 324.1379 1 H-NMR (CD} 3 OD, δppm): 1.04 (6H, d, J = 6.6Hz), 1.52
(2H, dd, J = 6.9Hz, 12.9Hz), 1.81 (2H, tt, J = 7.5Hz, 7.5
Hz), 2.00-2.20 (1H, m), 2.40 (2H, ddt, J = 3.6Hz, 7.5H
z, 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 2.70 (2H, d, J = 16.2)
Hz), 2.80 (2H, t, 6.9Hz), 3.10 (2H, t, J = 6.9Hz), 6.72
Example 48 (a) (Z) -2- (ethoxyisobutylphosphinoyl) methyl-6- (2-hydroxyethyl) thio-2- (1H, dt, J = 4.8Hz, 7.5Hz)
Hexenoic acid ethyl ester Oil IR (neat, cm ^-1 ): 3388,2962,1713,1290,1257,1176,103
8,954 FAB-MS (m / e ): 381 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.04 (6H, dd, J = 2.4Hz, 6.6H
z), 1.28 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.
65 (2H, dd, J = 6.6Hz, 12.9Hz), 1.81 (2H, tt, J = 7.2Hz,
7.2Hz), 2.04-2.15 (1H, m), 2.40-2.49 (2H, m), 2.60
(2H, tt, J = 7.2Hz, 7.2Hz), 2.73 (2H, t, J = 6.3Hz), 2.9
4 (2H, d, J = 15.6Hz), 3.73 (2H, t, J = 6.3Hz), 3.97-4.
12 (2H, m), 4.22 (2H, q, J = 7.2Hz), 6.94 (1H, dt, J = 5.
(B) (Z) -6- (2-hydroxyethyl) thio-2
-(Hydroxyisobutylphosphinoyl) methyl-2
- hexenoic acid oil ^{IR (neat, cm -1):} 3200,2926,1704,1257,1143,1059,948 High Resolution FAB-MS (m / e, as ^{_{+ (C 13 H 25 NO 5}} PS + H)): Calculated: 325.1239 Observed: 325.1284 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.3 Hz), 1.63
(2H, dd, J = 6.6Hz, 12.9Hz), 1.77 (2H, tt, J = 7.8Hz7.8H
z), 2.07-2.15 (1H, m), 2.38-2.47 (2H, m), 2.60 (2
H, t, J = 7.5Hz), 2.65 (2H, t, J = 6.9Hz), 2.91 (2H, d, J
= 16.8Hz), 3.67 (2H, t, J = 6.9Hz), 6.92 (1H, dt, J = 5.
Example 49 (a) (Z) (Z) -2- (ethoxyisobutylphosphinoyl) methyl-6- (1-methylimidazol-2-yl) thio-2-hexenoic acid ethyl ester Oil IR ( ^{neat, cm -1): 2962,1713,1281,1257,1176,1038,957 FAB} -MS (m / e): 471 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.04 (6H, dd , J = 3.0Hz, 6.3H
z), 1.27 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.
63 (2H, dd, J = 6.9Hz, 12.6Hz), 1.87 (2H, tt, J = 7.5Hz,
7.5Hz), 2.05-2.15 (1H, m), 2.41-2.50 (2H, m), 2.92
(2H, d, J = 16.5Hz), 3.08 (2H, t, J = 7.2Hz), 3.62 (3H,
s), 3.95−4.12 (2H, m), 4.21 (2H, q, J = 7.2Hz), 6.90
(1H, dt, J = 5.1Hz, 7.5Hz), 6.92 (1H, d, J = 1.2Hz), 7.0
5 (1H, d, J = 1.2Hz) (b) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-6- (1-methylimidazol-2-yl) thio-2-hexenoic acid Oil IR (neat, cm ^-1): 2962,1695,1278,1131 high resolution FAB-MS (m / e, as ^{_{+ (C 15 H 25 N 2}} O 4 PS + H)): calculated: 361.1351 Found: 361.1390 ¹ H -NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 7.5 Hz), 1.58
(2H, dd, J = 6.6Hz, 13.2Hz), 1.81 (2H, tt, J = 7.2Hz, 7.2
Hz), 2.08-2.16 (1H, m), 2.46-2.52 (2H, m), 2.81 (2
H, d, J = 16.5Hz), 3.11 (2H, t, J = 7.2Hz), 3.83 (3H,
s), 6.77 (1H, dt, J = 4.8 Hz, 7.5 Hz), 7.34 (1H, d, J = 1.8
Hz), 7.45 (1H, d, J = 1.8 Hz) Example 50 (a) (Z) -2- (ethoxyisobutylphosphinoyl) methyl-8- (3-hydroxy-2-pyridyl) thio-2- octene acid ethyl ester oil ^{IR (neat, cm -1):} 2932,1713,1452,1275,1185,1038,960 FAB-MS (m / e): 458 (M + H) + 1 H-NMR (CDCl 3, δppm): 1.04 (6H, dd, J = 2.5Hz, 7.0H
z), 1.28 (3H, t, J = 7.0 Hz), 1.31 (3H, t, J = 7.0 Hz), 1.
48 (4H, m), 1.50-1.65 (4H, m), 2.10 (1H, m), 2.29 (2
H, m), 2.93 (2H, d, J = 16.7Hz), 3.12 (2H, t, J = 7.3H)
z), 4.09 (2H, m), 4.20 (2H, m), 6.91 (1H, dt, J = 4.9H)
z, 7.5Hz), 7.00 (1H, dd, J = 4.6Hz, 8.1Hz), 7.15 (1H, d
d, J = 1.9 Hz, 8.1 Hz), 8.09 (1 H, dd, J = 1.9 Hz, 4.6 Hz) (b) (Z) -2- (hydroxyisobutylphosphinoyl) methyl-8- (3-hydroxy- 2-pyridyl)
Thio-2-octene acid oil ^{IR (neat, cm -1):} 2932,1695,1458,1308,1143,954 High Resolution FAB-MS (m / e, as ^{_{+ (C 18 H 28 O 5}} NPS + H)) : Calculated value: 402.1504 Actual value: 402.1519 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.6 Hz), 1.54
(4H, m), 1.65 (2H, dd, J = 6.5Hz, 12.9Hz), 1.74 (2H,
m), 2.12 (1H, m), 2.33 (2H, m), 2.92 (2H, d, J = 17.1H
z), 3.23 (2H, t, J = 6.5Hz), 6.97 (1H, dt, J = 5.5Hz, 7.3
Hz), 7.34 (1H, dd, J = 4.7Hz, 8.3Hz), 7.42 (1H, d, J = 8.
Example 5 Preparation of ethyl (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate (Z) -3-cyclohexyl-2 (3 Hz), 8.05 (1H, d, J = 4.7 Hz) -(Ethoxyisobutylphosphinoyl) methylpropenoic acid ethyl ester
107 mg (0.31 mmol) of 4N hydrogen chloride-butyl acetate 1.0 ml
And heat in a sealed tube at 100 ° C for 2 hours. After cooling down
The solvent was distilled off under reduced pressure, and the residue was purified by dry column flash chromatography (silica gel 60 15 g, Merck, chloroform-methanol-acetic acid (50: 1: 1)) to give the title compound as a colorless oil (91 mg). (94% yield).

^{IR (neat, cm -1):} 2932,1710,1227,1155,1059,972 High Resolution FAB-MS (m / e, (C 16 H 29 O 4 P + H) as a ^+): Calculated: 317.1882 Found: 317.1919 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.9 Hz), 1.09
−1.79 (10H, m), 1.29 (3H, t, J = 7.5Hz), 1.63 (2H, dd,
J = 6.9Hz, 12.9Hz), 2.04-2.14 (1H, m), 2.43-2.52 (1
H, m), 2.91 (2H, d, J = 16.8Hz), 4.19 (2H, q, J = 6.9H
z), 6.71 (1H, dd, J = 5.1 Hz, 10.8 Hz) Example 52 Production of ethyl (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate (Z) -3- Cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid 150 mg (0.52
Was dissolved in 10 ml of 8N hydrogen chloride-ethanol and heated under reflux for 2 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by dry column flash chromatography (silica gel 60 15 g, Merck, chloroform-methanol-acetic acid (50: 1: 1)) to give the title compound as a colorless oil. 130 mg (79% yield) are obtained as material. IR and ¹ H-NMR were measured in Example 5
Consistent with that of the product obtained in 1.

Example 53 Preparation of ethyl (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate Ethyl (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate was prepared. Example 52
The same procedure was followed as in Example 52 except that hydrogen chloride-methanol was used instead of hydrogen chloride-ethanol in to give the title compound as a colorless oil.

^{IR (neat, cm -1):} 2932,1716,1281,1227,1155,1062,975 High Resolution FAB-MS (m / e, as ^{_{+ (C 15 H 27 O 4}} P + H)): Calculated: 303.1725 Found Value: 303.1714 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.9 Hz), 1.10
-1.45 (6H, m), 1.63 (2H, dd, J = 6.5Hz, 12.8Hz), 1.70
−1.80 (4H, m), 2.10 (1H, m), 2.48 (1H, m), 2.92 (2H,
d, J = 16.5Hz), 3.73 (3H, s), 6.72 (1H, dd, J = 5.3Hz, 1
Example 54 Preparation of (Z) -3-cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoic acid Ethyl (Z) -3-cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoate
To a solution of 176 mg (0.51 mmol) in 2 ml of ethanol is added 0.51 ml of 1N sodium hydroxide, stirred at room temperature for 3 hours and refluxed for another 30 minutes. After cooling, the reaction mixture is diluted with 30 ml of water and extracted with 20 ml of ether. The aqueous layer is acidified by adding 4N hydrochloric acid, and extracted three times with 20 ml of ether. The organic layer is washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 143 mg (89% yield) of the title compound as a colorless oil.

^{IR (neat, cm -1):} 2932,2854,1701,1236,1149,1035,966 FAB-MS (m / e): 317 (M + H) + 1 H-NMR (CD 3 OD, δppm): 1.05 ( 6H, d, J = 6.6Hz), 1.10
-1.45 (6H, m), 1.29 (3H, t, J = 6.9Hz), 1.65-1.71 (6
H, m), 2.10 (1H, m), 2.35−2.51 (1H, m), 2.98 (2H, d, J
= 16.8Hz), 3.95-4.15 (2H, m), 6.74 (1H, dd, J = 5.1H)
Example 55 Production of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid pivaloyloxymethyl ester (Z) -3-cyclohexyl-2- (hydroxyisobutylphospho) Finoyl) methylpropenoic acid 100mg (0.347
Mmol) in 1.0 ml of dimethylformamide and 1.8
-Diazabicyclo [5,4.0] -7-undecene 130μ
(0.87 mmol) and chloromethyl pivalate 75μ
(0.52 mmol) and stir at room temperature for 21 hours.
To the reaction mixture is added 50 ml of a saturated aqueous ammonium chloride solution, and the mixture is extracted three times with 30 ml of ethyl acetate. Organic layer is saturated with saline 10
Wash with ml and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica gel 60F254, manufactured by Merck, dichloromethane-methanol-acetic acid (30: 1: 1)) to give 90 mg of the title compound as a colorless oil (yield: 90%). 64%).

^{IR (neat, cm -1):} 2932,1755,1731,1158,1119,1029,978 High Resolution FAB-MS (m / e, as ^{_{+ (C 20 H 35 O 6}} P + H)): Calculated: 403.2249 Found Value: 403.2201 ¹ H-NMR (CD ₃ OD, δ ppm): 1.10-1.46 (6H, m), 1.19 (9
H, s), 1.60-1.80 (6H, m), 2.10 (1H, m), 2.53 (1H,
m), 2.92 (2H, d, J = 16.5 Hz), 5.81 (2H, s), 6.80 (1H, d
d, J = 4.7 Hz, 10.7 Hz) Example 56 Production of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid phthalidyl ester (a) (Z) -3-cyclohexyl-2 Preparation of-(ethoxyisobutylphosphinoyl) methylpropenoic acid phthalidyl ester 80 mg (0.25 mmol) of (Z) -3-cyclohexyl-2- (ethoxyisobutylphosphinoyl) methylpropenoic acid was dissolved in 0.80 ml of dimethylformamide. 1,8-diazabicyclo [5,4,0] -7-undecene 112μ (0.75
Mmol) and 107 mg (0.50 mmol) of 3-bromophthalide are added and stirred at room temperature for 28 hours. 15 ml of water is added to the reaction mixture, and the mixture is extracted three times with 15 ml of ethyl acetate. The organic layer is washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by preparative thin-layer chromatography (Merck silica gel 60F2).
Purification with 54, dichloromethane-methanol (30: 1) yields 50 mg (45% yield) of the title compound as a colorless oil.

(B) Production of (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid phthalidyl ester (Z) -3-cyclohexyl-2 under an argon atmosphere
Dissolve 48 mg (0.11 mmol) of-(ethoxyisobutylphosphinoyl) methylpropenoic acid phthalidyl ester in 0.50 ml of dry dichloromethane and add bromotrimethylsilane.
Add 29μ (0.22 mmol) and stir at room temperature for 18 hours. To the reaction mixture are added 2.0 ml of ethyl acetate and 3.0 ml of saturated ammonium chloride in water, and the mixture is stirred at room temperature for 30 minutes. 3 ml of saturated ammonium chloride is added to this mixture, and the mixture is extracted three times with 8 ml of ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (silica gel 60F254, manufactured by Merck, dichloromethane-methanol-acetic acid (30: 1:
1)), and the title compound was converted to a colorless oil (16 mg).
Yield 35%). It solidifies on standing.

mp: 64.5-67.5 ℃ IR (neat, cm -1): 2932,1794,1734,1218,1146,1053,975 High Resolution FAB-MS (m / e, as ^{_{+ (C 22 H 29 O 6}} P + H)) : calculated: 421.1780 ^{Found: 421.1816 1 H-NMR (CD} 3 OD, δppm): 1.04 (6H, dd, J = 1.2Hz, 6.6H
z), 1.06-1.77 (10H, m), 1.63 (2H, dd, J = 6.9Hz, 12.9H
z), 2.00-2.20 (1H, m), 2.45-2.60 (1H, m), 2.94 (2
H, d, J = 15.9Hz), 6.79 (1H, dd, J = 4.8Hz, 10.2Hz), 7.53
(1H, s), 7.70-7.94 (4H, m) Example 57 (Z) -3-Cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate (5-methyl-
Preparation of 2-oxo-1,3-dioxol-4-yl) methyl ester (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid was prepared according to Example 55.
The title compound is obtained as colorless crystals by treating in the same manner as in Example 55 except that 4-chloromethyl-5-methyl-1,3-dioxol-2-one is used instead of chloromethyl = pivalate in the above.

mp: 129.5-131.5 ° C IR (KBr, cm ^-1 ): 2932,1824,1722,1221,1146,1047,1014,
981 High-resolution FAB-MS (as m / e, (C ₁₉ H ₂₉ O ₇ P + H) ⁺ ): Calculated: 401.1729 Actual: 401.1737 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 (6H, d, J = 6.6Hz), 1.14
−1.78 (10H, m), 1.62 (2H, dd, J = 6.6Hz, 13.2Hz), 2.02
−2.16 (1H, m), 2.19 (3H, s), 2.43−2.57 (1H, m), 2.9
2 (2H, d, J = 16.2 Hz), 4.99 (2H, s), 6.76 (1H, dd, J = 5.
Example 58 (Z) -3-Cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate 2-ethoxy-
Preparation of 2-oxoethyl ester (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid was prepared according to Example 55.
The title compound is obtained as colorless crystals by treating in the same manner as in Example 55 except that ethyl bromoacetate is used in place of chloromethyl pivalate in the above.

mp: 77.5-78 ℃ IR (KBr, cm -1): 2938,1764,1731,1212,1149,1086,951 High Resolution FAB-MS (m / e, (C 18 H 31 O 6 P + H) + calc : 375.1937 actual value: 375.1962 ¹ H-NMR (CD ₃ OD, δ ppm): 1.05 ((6H, d, J = 6.6 Hz), 1.2
7 (3H, t, J = 7.2Hz), 1.15-1.76 (12H, m), 2.06-2.16
(1H, m), 2.45-2.60 (1H, m), 2.94 (2H, d, J = 17.1H
z), 4.21 (2H, q, J = 7.2Hz), 4.70 (2H, s), 6.86 (1H, d
d, J = 4.8 Hz, 10.5 Hz) Example 59 Tablet 250 mg / 320 mg Tablet Compound No. 2 250 parts Lactose 34 Maize Starch 15 Carboxymethyl Cellulose Calcium 13 Methyl Cellulose 6 Magnesium Stearate 2 320 Parts Compound No. 2 250 parts, lactose 34 parts, corn starch
15 parts and 13 parts of carboxymethylcellulose calcium are uniformly mixed, and a paste made from 6 parts of methylcellulose and purified water is added and kneaded. After granulation, 2 parts of magnesium stearate is added and mixed. Tablets were prepared according to the method described above to give tablets containing 250 mg of compound No. 2 in one tablet.

Example 60 Granules 350 mg / 1 g Compound No. 27 350 parts Lactose 490 〃 Corn starch 150 〃 Hydroxypropylcellulose 10 〃 1000 parts Compound No. 27 350 parts, lactose 490 parts, corn starch 150 parts uniformly mixed Then, glue made from 10 parts of hydroxypropylcellulose and purified water is added and kneaded.
After granulating by the usual method, sieving and compound No.27 in 1g 350m
g was obtained.

Example 61 Injection Intravenous drip infusion 250 mg / 100 ml Compound No. 2 250 mg Sodium bicarbonate 150 mg Make the total amount 100 ml with physiological saline Compound No. 2 was added to a solution prepared by adding 20 ml of physiological saline to 150 mg of sodium hydrogen carbonate. 2 After adding and dissolving 250mg,
Physiological saline was added to make up to 100 ml, sterile filtered and filled into vials to make injections.

Example 62 Injection 250 mg / 100 ml for intravenous drip Infusion 2Na salt of Compound No. 2 288 mg The total amount was made up to 100 ml with physiological saline, and 288 mg of 2Na salt of Compound No. 2 was added with physiological saline and dissolved.
The volume was adjusted to 100 ml, sterilized, filtered, and filled in a vial to give an injection.

Example 63 Injection 250 mg / 2 ml 2Na salt of compound No. 2 288 mg Make the total amount to 2 ml with distilled water for injection Distilled water for injection was added to 288 mg of 2Na salt of compound No. 2 and dissolved to make 2 ml. After filling, fill the ampoule and
And sterilized by heating for 20 minutes.

Effect of the Invention Since the compound of the present invention has excellent properties that it has a long-lasting blood concentration and is effective even when administered orally, it can be used in humans in combination with carbapenems or penem antibiotics. It contributes to improving the therapeutic effect of bacterial infections in mammals.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ identification symbol FI // C12N 9/99 C12N 9/99 (58) Field surveyed (Int. Cl. ⁶ , DB name) CA (STN)

Claims (8)

(57) [Claims] (1) General formula In the formula, R ¹ is a linear or branched C 1-10 carbon atom which may be substituted with one substituent selected from the group consisting of a hydroxyl group, a lower alkoxy lower alkyloxy group and a halogen atom. An alkyl group; a cycloalkyl group having 3 to 6 ring carbon atoms which may be substituted with 1 to 4 same or different lower alkyl groups; a cycloalkyl lower alkyl group having 4 to 10 carbon atoms; Represents 7 to 11 aralkyl groups, R ² is a hydrogen atom, R ⁵ is a hydrogen atom, 1- (lower alkylcarbonyloxy)
A lower alkyl group, a phthalidyl group, a lower alkoxycarbonylmethyl group or a 1- (5-lower alkyl or phenyl-2-oxo-1,3-dioxol-4-yl) lower alkyl group; Wherein R ^3a is a phenyl group; an aralkyl group having 7 to 11 carbon atoms; a cycloalkyl lower alkyl group having 4 to 10 carbon atoms; or a halogen atom, a carboxyl group, a di-lower alkyl-substituted amino group. Group, N-methyl-N-carboxymethylamino group,
Phenylthio group, triazolylthio group, carboxy lower alkylthio group, lower alkoxycarbonyl lower alkylthio group, pyridylthio group optionally substituted with hydroxyl group, imidazolylthio group optionally substituted with lower alkyl group, hydroxy lower alkylthio group, amino lower A linear or branched alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 6 ring carbon atoms, which may be substituted with an alkylthio group or a 2-amino-2-carboxyethylthio group. Wherein the steric configuration of the double bond in A is a Z configuration, and R ^4a is a cycloalkyl group having 3 to 6 carbon atoms. 2. R ¹ is a linear or branched alkyl group having 3 to 10 carbon atoms; and 3 to 3 ring carbon atoms which may be substituted by 1 to 4 same or different lower alkyl groups. 6 cycloalkyl groups; or a cycloalkyl lower alkyl group having 4 to 10 carbon atoms, R ² is a hydrogen atom, R ⁵ is a hydrogen atom, 1- (lower alkylcarbonyloxy)
A lower alkyl group, a phthalidyl group, a lower alkoxycarbonylmethyl group or a 1- (5-lower alkyl or phenyl-2-oxo-1,3-dioxol-4-yl) lower alkyl group; Wherein R ^3b is a phenyl group; an aralkyl group having 7 to 11 carbon atoms; a cycloalkylmethyl group having 4 to 7 carbon atoms; or a halogen atom, a carboxyl group, a phenylthio group, , 3-Triazol-4-ylthio group, carboxy lower alkylthio group, lower alkoxycarbonyl lower alkylthio group, 3-hydroxy-2-pyridylthio group, 1-methyl-2-imidazolylthio group, hydroxy lower alkylthio group or 2-amino- A linear or branched alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 6 ring carbon atoms which may be substituted with a 2-carboxyethylthio group, configuration of a Z configuration, R ^4a represents a 3-6 cycloalkyl group having a carbon number, phosphine acid derivatives and thereof of claim 1 Toxic salts. Wherein R ¹ is the number 3 to 10 straight or branched alkyl group having a carbon; 1-2 lower alkyl 3-6 good number ring atoms optionally substituted with a group of cyclo An alkyl group; or a cycloalkylmethyl group having 4 to 7 carbon atoms, wherein R ² is a hydrogen atom, R ⁵ is a hydrogen atom, a lower alkylcarbonylmethyl group, a phthalidyl group, or (5-methyl-2-oxo- 1,3-dioxol-4-yl) methyl group, Wherein R ^3c represents a linear or branched alkyl group having 3 to 10 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms;
The phosphinic acid derivative and the non-toxic salt thereof according to claim 1 or 2, wherein the configuration of the double bond in is a Z configuration. 4. (Z) -2- (butylhydroxyphosphinoyl) methyl-3-cyclohexylpropenoic acid, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid, (Z) -3-cyclohexyl-2- (hydroxyisopropylphosphinoyl) methylpropenoic acid, (Z) -3-cyclohexyl-2- (decylhydroxyphosphinoyl) methylpropenoic acid, (Z) -3-cyclohexyl-2- ( 2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-2-octenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-2-dodecenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-4-methyl-2-pentenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-5-methyl-2-hexenoic acid, (Z) -3-cyclopropyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid, (Z) -3-cyclopentyl-2- (hydroxyisobutylphosphinoyl) Methylpropenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-5-phenyl-2-pentenoic acid, (Z) -6-chloro-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid, (Z) -8-chloro-2- (hydroxyisobutylphosphino) Yl) methyl-2-octenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-2-heptenedioic acid, (Z) -3-cyclopropyl-2- (2,2-dimethylcyclopropylhydroxyphosphinoyl) methylpropenoic acid, (Z) -2- (cyclohexylmethylhydroxyphosphinoyl) Methyl-3-cyclopropylpropenoic acid, (Z) -3-cyclohexyl-2- (cyclopentylmethylhydroxyphosphinoyl) methylpropenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-6-phenylthio-2-hexenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-6- (1,2,3-triazol-4-yl) thio-2-hexenoic acid, (Z) -8-carboxymethylthio-2- (hydroxyisobutylphosphinoyl) methyl-2-octenoic acid, Z) -2- (Hydroxyisobutylphosphinoyl)
Methyl-8-methoxycarbonylmethylthio-2-octenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-6- (3-hydroxy-2-pyridyl) thio-
2-hexenoic acid, (Z) -6-[(L) -2-amino-2-carboxyethyl] thio-2- (hydroxyisobutylphosphinoyl) methyl-2-hexenoic acid, (Z) -2- ( Hydroxyisobutylphosphinoyl)
Methyl-6- (1-methylimidazol-2-yl) thio-2-hexenoic acid, (Z) -2- (hydroxyisobutylphosphinoyl)
Methyl-8- (3-hydroxy-2-pyridyl) thio-
2-octenoic acid, 2- (butylhydroxyphosphinoyl) methyl-3-
Cyclohexylpropionic acid, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate (5-methyl-
2-oxo-1,3-dioxol-4-yl) methyl ester, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoic acid phthalidyl ester, (Z) -3-cyclohexyl-2 -(Hydroxyisobutylphosphinoyl) methyl pivaloyloxymethyl ester, (Z) -3-cyclohexyl-2- (hydroxyisobutylphosphinoyl) methylpropenoate (1-acetoxyethyl) ester and non-toxic substances The compound according to any one of claims 1 to 3, which is a salt. 5. The general formula In the formula, R ¹ and R ^3a have the meaning described in claim 1, R ²⁰ and R ⁵⁰ may be the same or different, each represents a hydrogen atom or a lower alkyl group, The compound represented by the formula: and a salt thereof, wherein the bond is in an E configuration. 6. The general formula Wherein R ¹ and A have the meanings according to claim ¹ and R ²⁴ and R ⁵⁵ may be the same or different and each represent a hydrogen atom or a lower alkyl group, provided that R ²⁴ and R ⁵⁵ Is not a hydrogen atom at the same time; 7. A method for reducing nephrotoxicity caused by a carbapenem or penem antibiotic, which comprises the phosphinic acid derivative of the general formula [I] or a non-toxic salt thereof as an active ingredient. Agent. 8. A dipeptidase inhibitor comprising the phosphinic acid derivative of the general formula [I] according to claim 1 or a non-toxic salt thereof as an active ingredient.