JPH05222072A - Alpha-amino acid - Google Patents

Abstract

PURPOSE:To obtain a new alpha-amino acid useful as an NMDA antagonist having NMDA antagonist activity. CONSTITUTION:An alpha-amino acid of formula I [R<1> is COOR<6> (R<6> is H, 1-6C alkyl, etc.), CON(R<7>)2 (R<7> is H, aryl, etc.), etc.; R<2> is H, 1-6C alkyl, etc.; R<3> is H, 1-6C alkyl, etc.; R<4> and R<5> are H, 1-6C alkyl (substituted with 1-6C alkoxy, etc.), etc., or R<4> and R<5> together with C bonded may from carbonyl; Q is R<4> or 2-5C alkylene which may be substituted with 1-4 (=0), etc.; A is 1-6C alkylene, aralkyl containing 1-4C alkyl part, etc.; Y is PO(OR<9>) (OR<10>) (R<9> and R<10> are H, 1-6C alkyl, etc.;), sulfo, etc.] such as 3-amino-2-oxo-1- phosphonomethyl-3-pyrrolidinecarboxylic acid. The alpha-amino acid of formula I is obtained by reacting a compound of formula II with a compound of formula III (YE is ester of Y) to give a compound of formula IV, reacting this compound with 1, 2-dibromoethane to give a compound of formula V and adding HBr/ AcOH to the compound of formula V.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel α-amino acid and an NMDA antagonist containing this α-amino acid.

[0002]

BACKGROUND OF THE INVENTION Antagonists that selectively act on the NMDA (N-methyl-D-aspartate) receptor, which is one of the subtypes of glutamate receptors (hereinafter sometimes referred to as NMDA antagonists), are associated with various diseases. It is known to be useful as a therapeutic drug for It has been reported that NMDA antagonists are useful as, for example, anticonvulsants, antiepileptic agents, brain protectors against ischemia, digestive function improving agents, etc. (for example, JP-A-3-66628 and JP-A-3-36628). -1302
95, JP-A-3-215473).

The following formulas (A) and (B):

[0004]

[Chemical 3]

An α-amino acid having Med. C
hem. , 29 , 1988 (1986). However, it is not described that these compounds have NMDA antagonist activity.

Further, the following formula (C):

[0007]

[Chemical 4]

The α-amino acid having Med. C
hem. , 31 , 864 (1988). However, it is not described that this compound has NMDA antagonist activity.

Further, the following formula (D):

[0010]

[Chemical 5]

The α-amino acid having Med. C
hem. , 33 , 2905 (1990). However, the NMDA antagonist activity of this compound is extremely weak, and for example, NMDA having a strong activity is
It is reported to be 1/100 or less as compared with the activity of CPP [4- (3-phosphonopropyl) -2-piperazinecarboxylic acid] which is one of the DA antagonists.

[0012]

The object of the present invention is to provide an NM
Novel α-amino acid having DA antagonist activity,
And to provide an NMDA antagonist containing the same as an active ingredient.

[0013]

The present invention (first invention) is
General formula (1):

[0014]

[Chemical 6]

[Wherein R ¹ is --COOR ⁶ (provided that R 1
⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms), -CON (R ⁷ ) ₂ (provided that R is
⁷ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms), or —PO (OR ⁶ ) ₂ (provided that R ⁶ Are as described above), R is
² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms, R ³ is a hydrogen atom, 1 to 6 carbon atoms An alkyl group, an aryl group, an aralkyl group having an alkyl group having 1 to 4 carbon atoms, and 2 to 2 carbon atoms.
An alkylcarbonyl group having 7 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, or an aralkyloxycarbonyl group having an alkyl group moiety having 1 to 4 carbon atoms;
⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have an alkoxyl group having 1 to 6 carbon atoms or an aryloxy group as a substituent, and 1 carbon atom. To an aralkyl group having an alkyl group moiety of 4 to 4, an aryl group, a hydroxyl group, a carboxyl group, an alkoxyl group having 1 to 6 carbon atoms or a halogen atom, and R ⁴ and R ⁵ are carbon atoms to which they are bonded. May form a carbonyl group together with, and Q is R ⁴
A alkylene group having 2 to 5 carbon atoms, which may be substituted with 1 to 4 groups or atoms selected from the groups or atoms represented by , A is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms, an aryl group, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group, and 1 to 1 carbon atoms. 6 alkoxyl group, an aryloxy group, an aralkyloxy group having an alkyl moiety of 1 to 4 carbon atoms, -N (R ⁸⁾ ₂ (where, R ⁸ is
A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms) or a halogen atom. , An alkylene group having 1 to 5 carbon atoms or an alkenylene group, or —CO—B— (however, B
Is an alkyl group having 1 to 6 carbon atoms, or 1 to 4 carbon atoms
An aralkyl group having an alkyl group moiety, an aryl group,
A haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group,
A group represented by an amino group or an alkylene group having 1 to 5 carbon atoms or an alkenylene group which may be substituted with a halogen atom), and Y is —PO (OR ⁹ ) (O
R ¹⁰ ) (wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms).
A group represented by -COOR ¹¹ (wherein R ¹¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 carbon atom)
Is a aralkyl group having an alkyl group moiety of 4 to 4), a sulfo group or a 1H-tetrazol-5-yl group].

Another aspect of the present invention (second aspect) is an NMDA antagonist characterized by containing an α-amino acid represented by the above general formula (1) as an active ingredient.

Another aspect of the present invention (third aspect) is the general formula (2):

[0018]

[Chemical 7]

[In the formula, R ²¹ is -COOR ²⁶ (provided that R ^21
26 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group portion having 1 to 4 carbon atoms), -CON (R ²⁷ ) ₂ (provided that R is
²⁷ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group portion having 1 to 4 carbon atoms), or —PO (OR ²⁶ ) ₂ (provided that R ²⁶ Are as described above), R is
²² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group portion having 1 to 4 carbon atoms, and R ²³ is a hydrogen atom, 1 to 6 carbon atoms. An alkyl group, an aryl group, an aralkyl group having an alkyl group having 1 to 4 carbon atoms, and 2 to 2 carbon atoms.
An alkylcarbonyl group having 7 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, or an aralkyloxycarbonyl group having an alkyl group moiety having 1 to 4 carbon atoms;
²⁴ and R ²⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have an alkoxyl group having 1 to 6 carbon atoms or an aryloxy group as a substituent, and 1 carbon atom. An aralkyl group having an alkyl group moiety of 4 to 4, an aryl group, a hydroxyl group, a carboxyl group, an alkoxyl group having 1 to 6 carbon atoms or a halogen atom, and R ²⁴ and R ²⁵ are carbon atoms to which they are bonded. And a carbonyl group may be formed together, and Q ¹ is R
^One or more groups or atoms selected from the groups or atoms represented by ²⁴ , or an alkylene group having 2 to 5 carbon atoms, which may be substituted with 1 to 4 of ═O groups; And A ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having an alkyl group portion having 1 to 4 carbon atoms,
Aryl group, haloalkyl group having 1 to 6 carbon atoms, hydroxyl group, alkoxyl group having 1 to 6 carbon atoms, aryloxy group, aralkyloxy group having alkyl group portion having 1 to 4 carbon atoms, -N (R ²⁸ ) ₂ (However, R ²⁸
Is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms) or a halogen atom. Also, an alkylene group having 1 to 5 carbon atoms or an alkenylene group, or —CO—B ¹ — (wherein B ¹ is an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms). An aralkyl group having a moiety, an aryl group, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group, an amino group, or an alkylene group having 1 to 5 carbon atoms or an alkenylene group which may be substituted with a halogen atom) Wherein Y ¹ is —PO (O
R ²⁹⁾ (OR ³⁰⁾ (where, R ²⁹ and R ³⁰ are, each independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having an alkyl moiety of 1 to 4 carbon atoms A group represented by -COOR ³¹ (provided that R is
³¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms), a sulfo group or 1H-tetrazol-5-yl Which is a group].

Another aspect of the present invention (fourth aspect) is an NMDA antagonist characterized by containing an α-amino acid represented by the above general formula (2) as an active ingredient.

The preferred embodiments of the present invention are as follows. (1) In the general formula (1), R ¹ is —COOH, R ² and R ³ are hydrogen atoms, and> C (R ⁴ ) (R
⁵ ) is> CH ₂ or> C═O, Q is an ethylene group or trimethylene group, A is an alkylene group having 1 to 5 carbon atoms, or one or two alkyl groups having 1 to 2 carbon atoms. A group or an alkylene group having 1 to 5 carbon atoms substituted with an aralkyl group having an alkyl group having 1 to 2 carbon atoms, and Y is —PO ₃ H ₂ or —COOH. An α-amino acid represented by 1).

(2) In the general formula (2), R ²¹ is -C.
OOH, R ²² and R ²³ are hydrogen atoms, and> C
(R ²⁴ ) (R ²⁵ ) is> CH ₂ or> C═O, and Q ¹
Is an ethylene group or a trimethylene group, and A ¹ has an alkylene group having 1 to 5 carbon atoms, or one or two alkyl groups having 1 to 3 carbon atoms or an alkyl group portion having 1 to 2 carbon atoms. An alkylene group having 1 to 5 carbon atoms substituted with an aralkyl group, wherein Y ¹ is —PO ₃ H ₂
Or an α-amino acid represented by the above general formula (2), which is —COOH.

The α-amino acid of the present invention has the general formula (1)
As is clear from the description of the general formula (2), in addition to α-aminocarboxylic acid, α-aminocarboxylic acid ester,
α-aminocarboxylic acid amide, α-aminophosphonic acid,
Also included are so-called amino acid derivatives having an α-aminophosphonate ester and / or a substituted amino group. Accordingly, as used herein, the term "α-amino acid" refers to α-amino acid.
Aminocarboxylic acid, α-aminocarboxylic acid derivative, α-
It is meant to include all aminophosphonic acids and α-aminophosphonic acid derivatives.

In the general formula (1) of the first invention, R⁶ ,
R⁷ , R² , R³ , R⁸ , R⁹ , R ^TenOr R¹¹Represented by
Examples of the alkyl group having 1 to 6 carbon atoms include methyl and ether.
Chill, propyl, isopropyl, butyl, isobutyl,
Examples include pentyl and hexyl. R⁶ , R
⁷ , R² , R³ , R⁸ , R⁹ , R^TenOr R¹¹Represented by
Aralkyl having an alkyl group having 1 to 4 carbon atoms
The groups include benzyl, phenethyl and 3-phenylpro
Examples thereof include pill and 4-phenylbutyl. R
⁶ , R⁷ , R² , R³ Or R⁸ And an aryl group represented by
Phenyl group, 4-chlorophenyl group, 2-meth
A xyphenyl group etc. can be mentioned.

Examples of the alkylcarbonyl group having 2 to 6 carbon atoms represented by R ³ include acetyl and propionyl. Examples of the alkoxycarbonyl group having 2 to 6 carbon atoms represented by R ³ include methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl and the like. A benzyloxycarbonyl group etc. can be mentioned as an aralkyloxy carbonyl group which has a C1-C4 alkyl group part represented by R < ³ >.

Examples of the alkyl group having 1 to 6 carbon atoms represented by R ⁴ or R ⁵ include methyl, ethyl, propyl, isopropyl and isobutyl. 1 to 6 carbon atoms which is a substituent which the alkyl group having 1 to 6 carbon atoms represented by R ⁴ or R ⁵ may have.
Examples of the alkoxyl group include methoxy and ethoxy, and examples of the aryloxy group include a phenoxy group. Examples of the aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms represented by R ⁴ or R ⁵ include benzyl and phenethyl. Examples of the aryl group represented by R ⁴ or R ⁵ include a phenyl group, a 4-chlorophenyl group and a 2-methoxyphenyl group. The alkoxy group having 1 to 6 carbon atoms represented by R ⁴ or R ⁵ is methoxy,
Ethoxy etc. can be mentioned. Examples of the halogen atom represented by R ⁴ or R ⁵ include chlorine, bromine, fluorine and the like.

The alkylene group having 2 to 5 carbon atoms represented by Q includes ethylene group, trimethylene group,
Examples thereof include a tetramethylene group and a pentamethylene group.

Examples of the alkylene group having 1 to 5 carbon atoms represented by A or B include methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group and the like. In addition, among the substituents which the alkylene group represented by A or B may have, the number of carbon atoms is 1
To 6 alkyl groups, aralkyl groups having an alkyl group moiety having 1 to 4 carbon atoms, aryl groups, and 1 to 6 carbon atoms
Examples of the alkoxyl group, aryloxy group, and halogen atom include those described for R ⁴ . Among the substituents which the alkylene group represented by A or B may have, examples of the haloalkyl group having 1 to 6 carbon atoms include trifluoromethyl, fluoromethyl, and 2
-Chloroethyl etc. can be mentioned. Of the substituents that the alkylene group represented by A or B may have,
Examples of the aralkyloxy group having an alkyl group having 1 to 4 carbon atoms include a benzyloxy group and a phenethyloxy group.

The above-mentioned alkyl group, aralkyl group,
The aryl group may have a halogen atom as a substituent.

Among the α-amino acids represented by the general formula (1), a particularly preferred α-amino acid is, in the general formula (1), R ¹ is —COOH and R ² and R ³ are hydrogen atoms. And> C (R ⁴ ) (R ⁵ ) is> CH ₂ or> C═O
And Q is an ethylene group or a trimethylene group, A
Is substituted with an alkylene group having 1 to 5 carbon atoms, or an aralkyl group having one or two alkyl groups having 1 to 3 carbon atoms or an alkyl group portion having 1 to 2 carbon atoms, and having 1 carbon atom ~ 5 alkylene group, Y is -P
It is an α-amino acid that is O ₃ H ₂ or —COOH.

The α-amino acid represented by the general formula (1) is
It can be synthesized by combining various unit reactions. Not all α-amino acids represented by the general formula (1) can be synthesized by the same synthetic route, and it is necessary to select a synthetic raw material and a route depending on the structure, but this selection can be easily performed by those skilled in the art. You can

Of the various synthetic routes, the synthetic route 1, synthetic route 2, synthetic route 3, synthetic route 4, and synthetic route 5 are shown below as representative ones.

[0033]

[Chemical 8]

[0034]

[Chemical 9]

[0035]

[Chemical 10]

[0036]

[Chemical 11]

[0037]

[Chemical 12]

Specific examples of synthesizing the α-amino acid of the first invention by the above synthetic route will be described in detail in the following examples.

In the general formula (2) of the third invention, R ²⁶ ,
Examples of the alkyl group having 1 to 6 carbon atoms represented by R ²⁷ , R ²² , R ²³ , R ²⁸ , R ²⁹ , R ³⁰ or R ³¹ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include pentyl and hexyl. R ²⁶ , R
Examples of the aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms represented by ²⁷ , R ²² , R ²³ , R ²⁸ , R ²⁹ , R ³⁰ or R ³¹ include benzyl, phenethyl, 3-phenylpropyl, -Phenyl butyl and the like can be mentioned. R
Examples of the aryl group represented by ²⁶ , R ²⁷ , R ²² , R ^23, or R ²⁸ include a phenyl group, a 4-chlorophenyl group, a 2-methoxyphenyl group, and the like.

Examples of the alkylcarbonyl group having 2 to 6 carbon atoms represented by R ²³ include acetyl and propionyl. Examples of the alkoxycarbonyl group having 2 to 6 carbon atoms represented by R ²³ include methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl. The aralkyloxy carbonyl group having an alkyl moiety of 1 to 4 carbon atoms denoted by R ^23, may be a benzyloxycarbonyl group and the like.

Examples of the alkyl group having 1 to 6 carbon atoms represented by R ²⁴ or R ²⁵ include methyl, ethyl, propyl, isopropyl and isobutyl. 1 to 6 carbon atoms which is a substituent which the alkyl group having 1 to 6 carbon atoms represented by R ²⁴ or R ²⁵ may have.
Examples of the alkoxyl group include methoxy and ethoxy, and examples of the aryloxy group include a phenoxy group. Examples of the aralkyl group having an alkyl group having 1 to 4 carbon atoms represented by R ²⁴ or R ²⁵ include benzyl and phenethyl. Examples of the aryl group represented by R ²⁴ or R ²⁵ include a phenyl group, a 4-chlorophenyl group and a 2-methoxyphenyl group. The alkoxyl group having 1 to 6 carbon atoms represented by R ²⁴ or R ²⁵ is methoxy,
Ethoxy etc. can be mentioned. Examples of the halogen atom represented by R ²⁴ or R ²⁵ include chlorine, bromine, fluorine and the like.

Examples of the alkylene group having 2 to 5 carbon atoms represented by Q ¹ include ethylene group, trimethylene group, tetramethylene group, pentamethylene group and the like.

¹ to 5 carbon atoms represented by A ¹ or B ¹
As the individual alkylene groups, a methylene group, an ethylene group,
Examples thereof include trimethylene group, tetramethylene group, pentamethylene group and the like. Further, among the substituents which the alkylene group represented by A ¹ or B ¹ may have, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having an alkyl group portion having 1 to 4 carbon atoms, Examples of the aryl group, the alkoxyl group having 1 to 6 carbon atoms, the aryloxy group and the halogen atom include those described for R ²⁴ above. Among the substituents that the alkylene group represented by A ¹ or B ¹ may have, examples of the haloalkyl group having 1 to 6 carbon atoms include trifluoromethyl, fluoromethyl and 2-chloroethyl. it can.
Among the substituents which the alkylene group represented by A ¹ or B ¹ may have, examples of the aralkyloxy group having an alkyl group having 1 to 4 carbon atoms include a benzyloxy group and a phenethyloxy group. Can be mentioned.

The above-mentioned alkyl group, aralkyl group,
The aryl group may have a halogen atom as a substituent.

Among the α-amino acids represented by the general formula (2), a particularly preferred α-amino acid is, in the general formula (2), R ²¹ is —COOH and R ²² and R ²³ are hydrogen atoms. And> C (R ²⁴ ) (R ²⁵ ) is> CH ₂ or> C═O
And Q ¹ is an ethylene group or a trimethylene group,
A ¹ is an alkylene group having 1 to 5 carbon atoms, or a carbon atom substituted with one or two alkyl groups having 1 to 3 carbon atoms or aralkyl groups having an alkyl group moiety having 1 to 2 carbon atoms. Is an alkylene group of the number 1 to 5, Y ¹
There is a α- amino acid are -PO ₃ H ₂ or -COOH.

The α-amino acid represented by the general formula (2) is
It can be synthesized by combining various unit reactions. Not all α-amino acids represented by the general formula (2) can be synthesized by the same synthetic route, and it is necessary to select a synthetic raw material and a route depending on the structure, but this selection can be easily performed by those skilled in the art. You can

Among the various synthetic routes, the outline of synthetic route 6 is shown below as a typical one.

[0048]

[Chemical 13]

Specific examples of synthesizing the α-amino acid of the third invention by the above synthetic route are described in detail in the following examples.

Specific examples of the α-amino acid of the first invention and the third invention are shown in Tables 1 and 2 below.

[0051]

[Table 1]

[0052]

[Table 2]

[0053]

[Table 3]

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6]

[0057]

[Table 7]

The α-amino acid of the first invention and the third invention is
It is shown by the following pharmacological experiments that it has excellent NMDA antagonist activity.

[Pharmacological Experiment Method] The spinal cord was removed from newborn rats on the 1st to 7th day of birth and fixed in a perfusion tank perfused with oxygen-saturated artificial cerebrospinal fluid. From the anterior root of the 5th lumbar vertebra, extracellular changes of motor neurons were recorded using suction electrodes.
The NMDA antagonist activity is tetrodotoxin 0.
NMDA20 using 5 μM Mg ²⁺ free perfusate
It was expressed as the inhibition rate against the response induced when μM was perfused for 10 seconds. The test drug was tetrodotoxin 0.
It was dissolved in oxygen-saturated artificial cerebrospinal fluid of 5 μM, Mg ²⁺ free and applied by perfusion.

When the depolarizing activity (mV) of the control NMDA response is A and the depolarizing activity (mV) of the NMDA response during drug treatment is B, the NMDA response blocking action (inhibition rate) (%) = ( AB) /
It is represented by A × 100.

[Results] The results of the NMDA response blocking action obtained by the above-mentioned pharmacological experiment method for various α-amino acids are shown in Table 3 below.

[0062]

[Table 8]

The α-amino acids of the first and third inventions include stereoisomers such as optically active substances and diastereomers.

The second invention and the fourth invention each contain an α-amino acid represented by the general formula (1) or an α-amino acid represented by the general formula (2) as an active ingredient. It is a characteristic NMDA antagonist.

The above-mentioned α-amino acids can also be administered as salts thereof (salts with organic acids or inorganic acids, or salts with alkali metals or alkaline earth metals). The active ingredient of the present invention can be administered orally or parenterally (eg, intravenous or subcutaneous injection, nasal administration, rectal administration).

The dosage form may be, for example, injections, suppositories, powders, nose drops, pills, tablets, syrups, etc.,
It can be formulated with known excipients, disintegrants, binders, lubricants, coating agents, base materials and the like.

The NMDA antagonists of the second and fourth inventions are convulsions, epilepsy, cerebral ischemia, Alzheimer's disease, chorea, spinocerebellar degeneration, sequelae of stroke, cerebral palsy, senile dementia, hypoglycemic neuropathy. , Has the effect of preventing neurodegenerative disorders such as carbon monoxide poisoning, and is a brain protectant (Neuroprotec
tive), digestive function improver, etc.

[0068]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 3-amino-2-oxo-1-phosphonomethyl-3-pi
Rolidine carboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[(diethoxyphosphinyl) methylcarbamoyl] benzyl acetate

Monobenzyl 2- (benzyloxycarbonyl) aminomalonate (2.41 g, 7.02 mmol) and N-hydroxysuccinimide (0.81 g,
A solution of N, N'-dicyclohexylcarbodiimide (1.
45 g, 7.03 mmol) was added. After stirring the mixture for 30 minutes at room temperature, diethyl aminomethylphosphonate (1.30 g, 7.76 mmol) in methylene chloride (1
0 ml) solution was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, the insoluble material was filtered off, and washed with ethyl acetate. The filtrate and washings were combined, washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and then saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (ethyl acetate) to obtain 2.58 g (74.6%) of the title compound as white crystals.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.25 (6H, t, J = 7Hz), 3.65 (2
H, dd, J = 12 Hz, 6 Hz), 3.8 to 4.2
(4H, m), 4.9 to 5.3 (5H, m), 6.06
(1H, br, d, J = 7Hz), 7.0-7.5 (1
1H, m).

IR ν neat (cm ^-1 ): 324
0,3050,2970,1740,1720,168
0, 1500, 1220, 1160, 1045, 101
5,970,745,690.

(2) 3- (benzyloxycarbonyl)
Amino-1- (diethoxyphosphinyl) methyl-2-
Benzyl oxo-3-pyrrolidinecarboxylate

The compound (2.50) obtained in the above (1)
g, 5.08 mmol) and 1,2-dibromoethane (1.15 g, 6.12 mmol) in dimethylsulfoxide (DMSO) (20 ml) solution, powdered potassium hydroxide (570 mg, 10.2 mmol). Was added, and the mixture was vigorously stirred at room temperature. After 5 hours, cooled dilute hydrochloric acid was added to the reaction mixture, the mixture was extracted twice with ether, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (n-hexane / ethyl acetate = 1/10) to give 0.90 g (34.1%) of the title compound as a colorless oil. Got The oil then crystallized.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.26 (3H, t, J = 7Hz), 1.28 (3
H, t, J = 7 Hz), 2.2 to 3.0 (2H, m),
3.4-4.3 (8H, m), 4.9-5.3 (4H,
m), 6.02 (1H, br, s), 7.1-7.4.
(10H, m).

IR ν neat (cm ^-1 ): 298
0,1740,1710,1490,1450,127
0, 1230, 1050, 1020, 975, 750,
695.

MS (EI) 518 (M +)

(3) 3-Amino-2-oxo-1-phosphonomethyl-3-pyrrolidinecarboxylic acid

The compound (862m) obtained in the above (2)
g, 1.66 mmol) to 25% HBr / AcOH (1
5 ml) was added, and the mixture was left at room temperature for 3 days. Ether (100 ml) was added to the obtained reaction mixture, the mixture was stirred until the ether became clear, and the ether layer was removed by decantation. The remaining oily substance was dissolved in water, washed twice with ether, then water was distilled off under reduced pressure, water was added again, and the mixture was dried under reduced pressure to repeat twice. The colorless oily residue thus obtained was dissolved in a small amount of water, acetone was added thereto, and the mixture was allowed to stand overnight in a refrigerator. The precipitated crystals were collected by filtration, washed successively with water-acetone (1: 7), acetone, and ether, and dried under reduced pressure to give the title compound (283 mg, 71.6%) as a white powder.

NMR (400 MHz, D ₂ O-NaO
D) δppm: 1.9 to 2.1 (1H, m), 2.47
(1H, ddd, J = 12, 8, 3 Hz), 3.16
(1H, dd, J = 15, 11Hz), 3.5 to 3.7
(2H, m), 3.81 (1H, dt, J = 10, 3H
z).

IR ν KBr (cm ^-1 ): 3540,
3280, 3050, 2700, 1735, 1685,
1545, 1200, 1170, 1135, 1045
920.

MS (FAB) 239 (MH +)

Example 2 3-Amino-2-oxo-1- (2-phosphonoethyl)
-3-Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[2- (diethoxyphosphinyl) ethyl] carbamoyl] benzyl acetate

Synthesis was conducted in the same manner as in (1) of Example 1 except that diethyl 2-aminoethylphosphonate was used instead of diethyl aminomethylphosphonate, and 1.64 g of the title compound as white crystals ( 64.6%).

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.31 (6H, t, J = 7Hz), 1.6-2.
1 (2H, m), 3.2 to 3.7 (2H, m), 3.8
~ 4.3 (4H, m), 4.89 (1H, d, J = 7H
z), 5.11 (2H, s), 5.22 (2H, s),
6.00 (1H, br, d, J = 7Hz), 6.8-
7.0 (1H, m), 7.1-7.5 (10H, m).

MS (EI) 506 (M +)

(2) 3- (benzyloxycarbonyl)
Amino-1- [2- (diethoxyphosphinyl) ethyl] -2-oxo-3-pyrrolidinecarboxylate benzyl

Synthesis was performed in the same manner as in (2) of Example 1 except that the compound obtained in (1) above was used,
457 mg (47.7%) of the title compound as a colorless oil.
Got

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.32 (6H, t, J = 7Hz), 1.6-2.
2 (2H, m), 2.2-2.9 (2H, m), 3.2
-3.7 (4H, m), 4.09 (4H, dq, J =
7,7 Hz), 5.07 (2H, s), 5.18 (2
H, s), 6.05 (1H, br, s), 7.1-7.
5 (10H, m).

MS (EI) 532 (M +)

(3) 3-amino-2-oxo-1- (2
-Phosphonoethyl) -3-pyrrolidinecarboxylic acid

Synthesis was performed in the same manner as in (3) of Example 1 except that the compound obtained in (2) above was used,
The reaction crude product was subjected to cellulose column chromatography (n-
Butanol / water / acetic acid = 4/1/1 and 4/1/2) to give the title compound 9 as a pale yellow amorphous.
0 mg (54%) was obtained.

NMR (400 MHz, D ₂ O) δpp
m: 1.9 to 2.1 (2H, m), 2.29 (1H, d
t, J = 14.9 Hz), 2.66 (1H, ddd, J
= 14, 6, 3 Hz), 3.4 to 3.8 (4H, m)

IR ν KBr (cm ^-1 ): 3400,
2930, 1690, 1640, 1500, 1300,
1260, 1140, 940.

Example 3 3-Amino-2-oxo-1- (3-phosphonopropyi)
) -3-Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[3- (diethoxyphosphinyl) propyl] carbamoyl] benzyl acetate

Synthesis was performed in the same manner as in (1) of Example 1 except that diethyl 3-aminopropylphosphonate was used instead of diethyl aminomethylphosphonate,
2.01 g (96.1%) of the title compound as a colorless oil.
Got This compound then crystallized.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.29 (6H, t, J = 7Hz), 1.4-2.
0 (4H, m), 3.1 to 3.4 (2H, m), 4.0
6 (4H, dq, J = 7, 7Hz), 4.91 (1H,
d, J = 7 Hz), 5.10 (2H, s), 5.21
(2H, s), 6.04 (1H, br, d, J = 7H
z), 6.7 to 7.0 (1H, m), 7.1 to 7.5
(10H, m).

IR ν neat (cm ⁻¹ ): 326
0,2980,1745,1720,1680,150
0, 1230, 1210, 1050, 1020, 96
0,750.

MS (EI) 520 (M +)

(2) 3- (benzyloxycarbonyl)
Amino-1- [3- (diethoxyphosphinyl) propyl] -2-oxo-3-pyrrolidinecarboxylate benzyl

Synthesis was performed in the same manner as in (2) of Example 1 except that the compound obtained in (1) above was used,
212 mg (32.3%) of the title compound as a colorless oil.
Got

NMR (90 MHz, CD ₃ OD) δpp
m: 1.29 (6H, t, J = 7Hz), 1.5-2.
0 (4H, m), 2.2 to 2.8 (2H, m), 3.2
~ 3.6 (4H, m), 4.06 (4H, dq, J =
7,7 Hz), 5.06 (2H, s), 5.20 (2
H, s), 7.1-7.4 (10H, m).

IR ν neat (cm ⁻¹ ): 298
0,1740,1700,1490,1455,125
0,1050,1020,965,745,695.

MS (EI) 546 (M +)

(3) 3-amino-2-oxo-1- (3
-Phosphonopropyl) -3-pyrrolidinecarboxylic acid

Synthesis was carried out in the same manner as in (3) of Example 1 except that the compound obtained in (2) above was used,
50 mg (56) of the title compound as a pale yellow amorphous
%) Was obtained.

NMR (400 MHz, D ₂ O) δpp
m: 1.5 to 1.7 (2H, m), 1.7 to 1.9 (2
H, m), 2.2-2.4 (1H, m), 2.6-2.
7 (1H, m), 3.3 to 3.5 (2H, m), 3.6
~ 3.8 (2H, m).

IR ν KBr (cm ^-1 ): 3400,
2940, 1690, 1640, 1510, 1280,
1130, 930.

MS (FAB) 267 (MH +)

Example 4 3-Amino-2-oxo-1-phosphonomethyl-3-pi
Peridinecarboxylic acid

(1) 3- (benzyloxycarbonyl)
Amino-1- (diethoxyphosphinyl) methyl-2-
Benzyl oxo-3-piperidinecarboxylate

Benzyl 2- (benzyloxycarbonyl) amino-2-[(diethoxyphosphinyl) methylcarbamoyl] acetate obtained in (1) of Example 1
Using 3-dibromopropane, (2) of Example 1
The title compound 80 mg (7%) was obtained as a colorless oily substance.

NMR (400 MHz, CDCl ₃ ) δp
pm: 1.31 (6H, t, J = 7Hz), 1.8-
2.5 (4H, m), 3.5-3.9 (4H, m),
4.12 (4H, dq, J = 7, 7Hz), 5.0-
5.3 (4H, m), 7.2-7.4 (10H, m),
8.2 (1H, br, s).

IR ν neat (cm ⁻¹ ): 335
0,2980,1720,1530,1450,141
0, 1360, 1230, 1170, 1040, 97
0,750,700.

MS (EI) 532 (M +)

(2) 3-Amino-2-oxo-1-phosphonomethyl-3-piperidinecarboxylic acid

Synthesis was performed in the same manner as in (3) of Example 1 except that the compound obtained in (1) above was used,
42 mg of the hydrobromide salt of the title compound as a slightly yellow candy.
(81%) was obtained.

NMR (400 MHz, D ₂ O) δpp
m: 1.9 to 2.2 (2H, m), 2.43 (1H, d
t, J = 14.7 Hz), 2.63 (1H, dt, J =
14,7 Hz), 3.5 to 3.7 (2H, m), 3.5
7 (1H, ddd, J = 14, 13, 1Hz), 3.6
4 (1H, ddd, J = 14, 13, 1 Hz).

IR ν KBr (cm ^-1 ): 3450,
1680, 1540, 1000, 950.

MS (FAB) 253 (MH +)

Example 5 3-Amino-2-oxo-1-carboxymethyl-3-
Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[(benzyloxycarbonyl) methylcarbamoyl] acetic acid benzyl

Monobenzyl 2- (benzyloxycarbonyl) aminomalonate (500 mg, 1.46 mmol) and N-hydroxysuccinimide (168 mg,
To a solution of 1.46 mmol) in methylene chloride (9 ml) was added N, N-dicyclohexylcarbodiimide (301
mg, 1.46 mmol) was added. After stirring for 30 minutes at room temperature, glycine benzyl ester p was added to the above mixture.
-Toluenesulfonate salt (492 mg, 1.46 mmol) was added followed by triethylamine (148 mg) and the mixture was stirred at room temperature for 15 hours. The obtained reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, the insoluble matter was filtered off, and this was washed with ethyl acetate. The filtrate and the washings were combined, washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and then saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography (chloroform / methanol = 50).
/ 1) and the title compound 500m as white crystals.
g (70.0%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 4.03 (2H, d, J = 5Hz), 4.98 (1
H, d, J = 7 Hz), 5.11 (2H, s), 5.1
6 (2H, s), 5.20 (2H, s), 6.00 (1
H, br, d, J = 7 Hz), 6.7 to 7.0 (1H,
m), 7.0-7.5 (15H, m).

IR ν KBr (cm ^-1 ): 3280,
3030, 2950, 1760, 1740, 1725,
1690, 1650, 1530, 1315, 1285,
1245, 1190, 1055, 690.

(2) 3- (benzyloxycarbonyl)
Amino-1- (benzyloxycarbonyl) methyl-2
-Benzyl-3-oxo-3-pyrrolidinecarboxylate

The compound obtained in the above (1) (246 m
g, 0.50 mmol) and 1,2-dibromoethane (1
DMSO (2 ml) with 14 mg, 0.61 mmol)
To the solution was added powdered potassium hydroxide (56 mg, 1.0 mmol). After stirring vigorously at room temperature for 3.5 hours,
Cooled dilute hydrochloric acid was added to the reaction mixture, the mixture was extracted twice with ether, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified twice by medium pressure silica gel column chromatography (first time: n-hexane / ethyl acetate = 1/1, second time: chloroform / methanol = 100/1). This gave 31 mg (12%) of the title compound as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δp
pm: 2.4 to 2.6 (2H, m), 2.7 to 2.9
(2H, m), 3.4 to 3.6 (2H, m), 3.6 to
3.8 (2H, m), 4.08 (1H, d, J = 18H
z), 4.22 (1H, d, J = 18 Hz), 4.9-
5.3 (6H, m), 6.06 (1H, s), 7.1-
7.4 (10H, m). MS (EI) 516 (M +)

(3) 3-Amino-2-oxo-1-carboxymethyl-3-pyrrolidinecarboxylic acid

The compound obtained in the above (2) (31 mg,
0.06 mmol) in methanol (1 ml),
Catalytic hydrogenation using 10% palladium on carbon (6 mg). After 1 hour, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the catalyst was filtered off. The filtrate was concentrated to dryness under reduced pressure to give 12 mg of the title compound as a white powder.
(100%) was obtained.

NMR (400 MHz, D ₂ O-NaO
D) δppm: 2.37 (1H, dt, J = 14.8H)
z), 2.68 (1H, dt, J = 14,5Hz),
3.64 (1H, d, J = 17Hz), 3.66 (2
H, dd, J = 8.5 Hz), 4.22 (1H, d, J
= 17 Hz).

IR ν KBr (cm ^-1 ): 3100,
3020, 1720, 1680, 1610, 1370,
1320, 1300, 1250, 1190.

MS (FAB) 203 (MH +)

Example 6 3-Amino-2-oxo-1- (1-phosphonoethyl)
-3-Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-hydroxyethyl) -N-
[1- (Dimethoxyphosphinyl) ethyl]] carbamoyl] ethyl acetate

Monoethyl 2- (benzyloxycarbonyl) aminomalonate (5.63 g, 20.0 mmol)
And dimethyl 1-[(2-hydroxyethyl) amino] ethylphosphonate (4.34 g, 22.0 mmol) in methylene chloride (80 ml), 1- (3-dimethylaminopropyl) -3-ethyl. Carbodiimide hydrochloride (4.22 g, 22.0 mmol) was added. After the mixture was stirred at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the ethyl acetate layer was separated. It was washed with and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (hexane / acetone = 2/3) to give the title compound (4.82 g, 5) as a colorless viscous oil.
2.3%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.27 (3H, t, J = 7Hz), 1.44 (3
H, dd, J = 16 Hz, 7 Hz), 3.2-4.5
(14H, m), 5.12 (2H, s), 5.4-5.
7 (1H, m), 5.9 to 6.2 (1H, m), 7.0
~ 7.4 (5H, m).

IR ν neat (cm ⁻¹ ): 340
0,2950,1750,1720,1650,150
0, 1445, 1420, 1320, 1220, 104
5,1025,830,750,695.

(2) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-chloroethyl) -N- [1
-(Dimethoxyphosphinyl) ethyl]] carbamoyl] ethyl acetate

The compound (4.15) obtained in the above (1)
g, 9.01 mmol) of anhydrous methylene chloride (27 m
l) Thionyl chloride (0.72 ml,
9.9 mmol) was added dropwise. After stirring at room temperature for 30 minutes, water was added to the reaction mixture to separate the methylene chloride layer,
This was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, 4.06 g (94%) of the title compound was obtained as a colorless viscous oil.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.0 to 1.7 (6H, m), 3.2 to 4.4 (1
2H, m), 4.4-5.5 (4H, m), 5.8-
6.2 (1H, m), 7.1-7.5 (5H, m).

IR ν neat (cm ⁻¹ ): 330
0,2950,1750,1715,1655,150
0, 1445, 1415, 1320, 1240, 121
0,1050,1020,825,730,695.

(3) 3- (benzyloxycarbonyl)
Amino-1- [1- (dimethoxyphosphinyl) ethyl] -2-oxo-3-pyrrolidinecarboxylate ethyl ester

The compound (4.06) obtained in the above (2) was used.
To a solution of g, 8.48 mmol) in anhydrous dimethylformamide (DMF) (16 ml) was added 60% sodium hydride (340 mg, 8.5 mmol) while stirring under ice cooling. After stirring for 30 minutes under ice cooling, cooled 0.5N hydrochloric acid was added to the reaction mixture, and the mixture was mixed with ethyl acetate to 3 times.
The extract was washed twice, washed with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (ether / acetonitrile = 5/1), and one diastereomer (diastereomer) of the title compound eluted earlier was purified. 1.23 as white crystals of A)
g (32.8%) was obtained. Since the other diastereomer (diastereomer B) of the title compound that elutes later contains impurities, it is further subjected to medium pressure silica gel column chromatography (chloroform / acetonitrile = 2/1).
Purified with 1.04 g (27.7%) as a colorless oil.
Obtained.

Diastereomer A NMR (400 MHz, CDCl ₃ ) δppm: 1.2
4 (3H, t, J = 7Hz), 1.43 (3H, dd,
J = 17 Hz, 7 Hz), 2.5 to 2.6 (1H,
m), 2.7-2.8 (1H, m), 3.5-3.6.
(1H, m), 3.78 (6H, d, J = 11Hz),
3.8-3.9 (1H, m), 4.1-4.3 (2H,
m), 4.64 (1H, dq, J = 17, 7Hz),
5.06 (1H, d, J = 12Hz), 5.14 (1
H, d, J = 12 Hz), 6.03 (1H, s), 7.
3 to 7.4 (5H, m).

IR ν KBr (cm ⁻¹ ): 3260,
2980, 1750, 1700, 1520, 1420,
1320, 1270, 1250, 1225, 1190,
1085, 1060, 1040, 1010, 985, 8
30,745.

Diastereomer B NMR (400 MHz, CDCl ₃ ) δppm: 1.2
8 (3H, t, J = 7Hz), 1.50 (3H, dd,
J = 17Hz, 7Hz), 2.4-2.5 (1H,
m), 2.7-2.8 (1H, m), 3.5-3.6.
(1H, m), 3.76 (6H, d, J = 10Hz),
3.7-3.8 (1H, m), 4.2-4.3 (2H,
m), 4.68 (1H, dq, J = 17, 7Hz),
5.06 (1H, d, J = 12Hz), 5.14 (1
H, d, J = 12 Hz), 6.11 (1H, s), 7.
3 to 7.4 (5H, m).

(4) 3- (benzyloxycarbonyl)
Amino-1- [1- (dimethoxyphosphinyl) ethyl] -2-oxo-3-pyrrolidinecarboxylic acid

Diastereomer A obtained in (3) above
(443 mg, 1.00 mmol) ethanol (2.
(4 ml), a 1N aqueous sodium hydroxide solution (1.2 ml) was added to the solution with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To this, 0.5N hydrochloric acid was added under ice cooling to acidify the reaction mixture, which was diluted with water, extracted with ethyl acetate three times, and the extract was washed with water (twice) and saturated saline, It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 400 mg (97%) of diastereomer A of the title compound as white crystals.

NMR (400 MHz, CDCl ₃ ) δp
pm: 1.42 (3H, dd, J = 17Hz, 7H
z), 2.5 to 2.7 (2H, m), 3.5 to 3.9.
(6H, m), 4.63 (1H, dq, J = 17, 7H
z), 5.0 to 5.2 (2H, m), 6.17 (1H,
br, s), 7.2-7.4 (5H, m).

IR ν KBr (cm ^-1 ): 3400,
2910, 1720, 1700, 1480, 1445,
1270, 1220, 1200, 1055, 1040,
1020.

Diastereomer B obtained in the above (3)
(890 mg, 2.01 mmol) was reacted and treated in the same manner as the siastereomer A, and the product was recrystallized from ethyl acetate to obtain 503 mg (60%) of the title compound, diastereomer B as white crystals. It was

NMR (400 MHz, CD ₃ OD) δp
pm: 1.48 (3H, dd, J = 17Hz, 7H
z), 2.3-2.5 (1H, m), 2.6-2.7.
(1H, m), 3.5 to 3.8 (2H, m), 3.76
(6H, d, J = 11 Hz), 4.64 (1H, dq,
J = 17,7 Hz), 5.06 (1H, d, J = 13H
z), 5.10 (1H, d, J = 13 Hz), 7.2-
7.4 (5H, m).

IR ν KBr (cm ⁻¹ ): 3410,
3340, 2950, 1715, 1700, 1445,
1270, 1180, 1040.

(5) 3-amino-2-oxo-1- (1
-Phosphonoethyl) -3-pyrrolidinecarboxylic acid

Diastereomer A obtained in (4) above
To (350 mg, 0.846 mmol) was added 25% hydrogen bromide / acetic acid (6 ml). After leaving it at room temperature for 4 days,
The reaction mixture was poured into ether (40 ml) and stirred, and the clear ether layer was removed by decantation. The residual oil was washed with ether, then dissolved in water and washed twice with ether, and the water was distilled off under reduced pressure (at a bath temperature of 35 ° C or lower). Add water again and reduce the pressure to dryness. 2
After repeating times, the residue was crystallized from water-acetone to obtain 142 mg (67%) of diastereomer A of the title compound as white crystals.

NMR (400 MHz, D ₂ O-NaO
D) δppm: 1.30 (3H, dd, J = 13,7H
z), 1.98 (1H, dt, J = 13, 7Hz),
2.43 (1H, ddd, J = 13, 8, 2Hz),
3.5-3.6 (1H, m), 3.79 (1H, dt,
J = 10, 2 Hz), 4.03 (1H, dq, J = 1
6, 7 Hz).

Diastereomer B obtained in (4) above
(415 mg, 1.00 mmol) was reacted and treated in the same manner as diastereomer A and the product was crystallized from water-acetone to give 177 mg (70%) of diastereomer B of the title compound as white crystals. It was

NMR (400 MHz, D ₂ O) δpp
m: 1.41 (3H, dd, J = 15, 7Hz), 2.
29 (1H, ddd, J = 14, 9, 8 Hz), 2.7
4 (1H, ddd, J = 14, 8, 2Hz), 3.71
(1H, dt, J = 10, 2Hz), 3.83 (1H,
dt, J = 10, 8 Hz), 4.24 (1H, dq, J
= 17,7 Hz).

IR ν KBr (cm ^-1 ): 3540,
3460, 3270, 2710, 1720, 1680,
1615, 1550, 1440, 1290, 1270,
1140, 1065, 1050, 1025, 880.

Reference Example 1 Synthesis of dimethyl 1-[(2-hydroxyethyl) amino] ethylphosphonate used in (1) of Example 6.

Dimethyl phosphite (5.50 g, 50.0
Mmol) and ethanolamine (3.05 g, 49.9).
Anhydrous sodium sulfate (15 g) was added to a methanol (50 ml) solution with (mmol) and then 90% acetaldehyde (2.45 g, 49.9 mmol) in methanol (12 ml) was added dropwise. After stirring the reaction mixture at room temperature overnight, the insoluble material was filtered and washed with methanol. The filtrate and the washing solution were combined, the solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (chloroform / methanol = 20/1).
6.30 g (63.9%) of the title compound as a colorless oil.
Got

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.34 (3H, dd, J = 18Hz, 7Hz),
2.52 (2H, br), 2.7 to 3.3 (3H,
m), 3.64 (2H, t, J = 5Hz), 3.79.
(6H, d, J = 10 Hz).

Example 7 3-Amino-2-oxo-1- (1-phosphonopropyne
) -3-Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-hydroxyethyl) -N-
[1- (Dimethoxyphosphinyl) propyl]] carbamoyl] benzyl acetate

A reaction was conducted from monobenzyl 2- (benzyloxycarbonyl) aminomalonate and dimethyl 1-[(2-hydroxyethyl) amino] propylphosphonate in the same manner as in (6) of Example 6. , The title compound was obtained as a colorless oil (yield 57.0%).

NMR (90 MHz, CDCl ₃ ) δpp
m: 0.6 to 1.0 (3H, m), 1.5 to 2.1 (2
H, m), 3.3 to 3.9 (10H, m), 3.9 to
4.6 (1H, m), 5.09 (2H, s), 5.18
(2H, s), 5.4 to 5.7 (1H, m), 6.0
6.4 (1H, m), 7.0-7.5 (5H, m).

IR ν neat (cm ⁻¹ ): 340
0,2950,1750,1720,1650,150
0, 1450, 1425, 1330, 1215, 105
0,1025,750,700.

(2) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-chloroethyl) -N- [1
-(Dimethoxyphosphinyl) propyl]] carbamoyl] benzyl acetate

Using the compound obtained in (1) above, the reaction was carried out in the same manner as in (2) of Example 6 to obtain the title compound as a colorless oil (yield 98%).

NMR (90 MHz, CDCl ₃ ) δpp
m: 0.6 to 1.0 (3H, m), 1.5 to 2.0 (2
H, m), 3.2-4.0 (11H, m), 5.0-
5.2 (4H, m), 5.9-6.2 (1H, m),
7.0-7.4 (5H, m).

IR ν neat (cm ⁻¹ ): 295
0,1750,1710,1650,1495,142
5,1415,1240,1030,740,695.

(3) 3- (benzyloxycarbonyl)
Amino-1- [1- (dimethoxyphosphinyl) propyl] -2-oxo-3-pyrrolidinecarboxylate benzyl

The compound obtained in (2) above was used and reacted in the same manner as in (3) of Example 6 to obtain the title compound as a colorless oil (yield 34%, diastereo). Diastereomeric mixture with mer ratio = 3/2).

NMR (90 MHz, CDCl ₃ ) δpp
m: 0.71 (1.8H, t, J = 7Hz), 0.96
(1.2H, t, J = 7Hz), 1.4 to 2.1 (2
H, m), 2.1-3.0 (2H, m), 3.2-3.
9 (8H, m), 4.0-4.6 (1H, m), 4.8
~ 5.4 (4H, m), 5.98 (1H, br), 7.
1-7.5 (10H, m).

(4) 3-amino-2-oxo-1- (1
-Phosphonopropyl) -3-pyrrolidinecarboxylic acid

Using the diastereomer mixture obtained in (3) above, the reaction was carried out in the same manner as in (3) of Example 1 to give the hydrobromide salt of the title compound as a pale yellow amorphous substance. Obtained (yield 73%, diastereomer ratio =
3/2).

NMR (400 MHz, D ₂ O) δpp
m: 0.8 to 1.0 (3H, m), 1.7 to 2.0 (2
H, m), 2.3-2.5 (1H, m), 2.7-2.
8 (1H, m), 3.6 to 3.9 (2H, m), 4.0
~ 4.1 (1H, m).

MS (FAB) 267 (MH +)

[Reference Example 2] Synthesis of dimethyl 1-[(2-hydroxyethyl) amino] propylphosphonate used in (1) of Example 7.

The reaction was performed in the same manner as in Reference Example 1 except that propionaldehyde was used instead of acetaldehyde, and 3.61 g of the title compound was obtained as a colorless oil.
(57.0%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.05 (3H, t, J = 7Hz), 1.4-2.
0 (2H, m), 2.6 to 3.0 (3H, m), 3.6
2 (2H, t, J = 5Hz), 3.78 (6H, d, J
= 10 Hz).

IR ν neat (cm ⁻¹ ): 335
0, 2960, 1460, 1220, 1025.

Example 8 3-Amino-2-oxo-1- (α-phosphonopheneti
) -3-Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-hydroxyethyl) -N-
[Α- (Dimethoxyphosphinyl) phenethyl]] carbamoyl] benzyl acetate

A reaction was conducted from monobenzyl 2- (benzyloxycarbonyl) aminomalonate and dimethyl α-[(2-hydroxyethyl) amino] phenethylphosphonate in the same manner as in (6) of Example 6. The title compound was obtained as a colorless viscous oil (yield 68.7%).

NMR (90 MHz, CDCl ₃ ) δpp
m: 2.0 to 4.0 (13H, m), 4.0 to 5.5
(6H, m), 5.8 to 6.3 (1H, m), 6.8 to
7.5 (15H, m).

(2) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-chloroethyl) -N- [α
-(Dimethoxyphosphinyl) phenethyl]] carbamoyl] benzyl acetate

Using the compound obtained in (1) above, the reaction was carried out in the same manner as in (2) of Example 6 to obtain the title compound as a colorless viscous oil (yield 100%). ..

NMR (90 MHz, CDCl ₃ ) δpp
m: 2.6-4.0 (12H, m), 4.4-5.5
(6H, m), 5.5-6.1 (1H, m), 6.8-
7.5 (15H, m).

IR ν neat (cm ⁻¹ ): 303
0,2960,1755,1720,1660,149
5,1450,1245,1210,1070,103
0,750,695.

(3) 3- (benzyloxycarbonyl)
Amino-1- [α- (dimethoxyphosphinyl) phenethyl] -2-oxo-3-pyrrolidinecarboxylate benzyl

Using the compound obtained in (2) above, the reaction was carried out in the same manner as in (3) of Example 6, and the two diastereomer A / diastereomer B ratios were 10 /.
1 fraction (yield 10.1%), 1/1 fraction (yield 25.3%), and 1/3 fraction (yield 1
9.5%) respectively as a pale yellow oil.

Diastereomer A NMR (90 MHz, CDCl ₃ ) δppm: 1.8-
2.3 (1H, m), 2.6-3.9 (5H, m),
3.58 (3H, d, J = 11Hz), 3.60 (3
H, d, J = 11 Hz), 4.6 to 5.3 (5H,
m), 5.66 (1H, br s), 6.8 to 7.5.
(15H, m).

IR ν CHCl ₃ (cm ⁻¹ ): 360
0,2960,1700,1480,1280,124
0,1210,1040.

MS (FAB) 581 (MH +)

Diastereomer B NMR (90 MHz, CDCl ₃ ) δppm: 2.0-
3.9 (6H, m), 3.72 (3H, d, J = 11H
z), 3.79 (3H, d, J = 11 Hz), 4.4-
5.3 (5H, m), 5.88 (1H, br s),
6.8-7.5 (15H, m).

IR ν CHCl ₃ (cm ⁻¹ ): 340
0,2990,2950,1705,1490,145
0, 1270, 1250, 1050, 1025.

MS (FAB) 581 (MH +)

(4) 3-amino-2-oxo-1- (α
-Phosphonophenethyl) -3-pyrrolidinecarboxylic acid

Diastereomer A obtained in (3) above
Using the mixture having a ratio of / 1 / diastereomer B of 10/1 and the mixture having a ratio of 1/3, the reaction was conducted in the same manner as in (3) of Example 1 to give the hydrobromic acid of the title compound. Each salt was obtained as a pale yellow amorphous substance (former: yield 75%, diastereomer ratio = 10/1, latter: yield 7).
3%, diastereomeric ratio = 1/3).

Diastereomer A NMR (400 MHz, D ₂ O) δ ppm: 2.14
(1H, dt, J = 14,9Hz), 2.69 (1H,
dd, J = 14.6 Hz), 3.1 to 3.4 (2H,
m), 3.6 to 3.8 (2H, m), 4.4 to 4.6.
(1H, m), 7.2-7.5 (5H, m).

MS (FAB) 329 (MH +)

Diastereomer B NMR (400 MHz, D ₂ O) δ ppm: 2.35
(1H, dt, J = 14,9Hz), 2.69 (1H,
dd, J = 14.7 Hz), 3.0 to 3.4 (2H,
m), 3.6-4.0 (2H, m), 4.5-4.7.
(1H, m), 7.2-7.5 (5H, m).

MS (FAB) 329 (MH +)

[Reference Example 3] Synthesis of dimethyl α-[(2-hydroxyethyl) amino] phenethylphosphonate used in (1) of Example 8.

The title compound 5.50 was obtained as a colorless oil by reacting in the same manner as in Reference Example 1 except that phenylacetaldehyde was used instead of acetaldehyde.
g (40.3%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.9 (2H, br), 2.4 to 3.5 (7H,
m), 3.78 (3H, d, J = 10Hz), 3.80.
(3H, d, J = 10Hz), 7.0-7.4 (5H,
m).

Example 9 3-Amino-2-oxo-1- (1-methyl-1-phos)
Honoethyl) -3-pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-hydroxyethyl) -N-
[[1- (Dimethoxyphosphinyl) -1-methyl] ethyl]] carbamoyl] ethyl acetate

Monoethyl 2- (benzyloxycarbonyl) aminomalonate (5.63 g, 20.0 mmol)
And anhydrous triethylamine (2.03 g, 20.1 mmol) in anhydrous tetrahydrofuran (40 ml) was cooled to −10 ° C. with ice-salt, and isobutyl chlorocarbonate (2.74 g, 20.0 mmol) was added dropwise thereto. did. After stirring the mixture at the same temperature for 15 minutes, a solution of dimethyl [1- (2-hydroxyethyl) amino-1-methyl)] ethylphosphonate (4.25 g, 20.1 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise. , -10 ℃ ~ 0
The mixture was stirred at 0 ° C for 30 minutes. The mixture was further stirred at room temperature for 5 hr, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The oil obtained by distilling off the solvent under reduced pressure was purified by medium pressure silica gel column chromatography (ethyl acetate / methanol = 100/1) to give 1.66 of the title compound as a colorless viscous oil.
g (17.5%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.24 (3H, t, J = 7Hz), 1.55 (3
H, d, J = 15Hz), 1.58 (3H, d, J = 1
5 Hz), 3.71 (3H, d, J = 11 Hz), 3.
83 (3H, d, J = 11 Hz), 3.2 to 4.4 (6
H, m), 4.6 to 4.9 (1H, br), 5.12
(2H, s), 5.59 (1H, d, J = 8Hz),
6.12 (1H, br d, J = 8Hz), 7.1-
7.4 (5H, m).

IR νCHCl ₃ (cm ⁻¹ ): 361
0,3410,2970,1720,1660,140
5,1220,1060,1040.

(2) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-chloroethyl) -N-
[[1- (Dimethoxyphosphinyl) -1-methyl] ethyl]] carbamoyl] ethyl acetate

The compound obtained in (1) above was used and reacted in the same manner as in (2) of Example 6 to obtain the title compound as a pale yellow amorphous substance (yield: 68.5).
%).

(3) 3- (benzyloxycarbonyl)
Amino-1-[[1- (dimethoxyphosphinyl) -1
-Methyl] ethyl] -2-oxo-3-pyrrolidinecarboxylate ethyl ester

The compound obtained in (2) above was used and reacted in the same manner as in (3) of Example 6 to obtain the title compound as a colorless oil (yield 16.6%). ..

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.23 (3H, t, J = 7Hz), 1.70 (6
H, d, J = 16 Hz, 2.0 to 3.0 (2H,
m), 3.4 to 3.9 (2H, m), 3.78 (6H,
d, J = 11 Hz), 4.20 (2H, q, J = 7H
z), 5.10 (2H, s), 5.90 (1H, b
r), 7.1-7.4 (5H, m).

IR ν neat (cm ⁻¹ ): 340
0,2980,2950,1740,1700,149
0, 1290, 1260, 1030.

(4) 3- (benzyloxycarbonyl)
Amino-1-[[1- (dimethoxyphosphinyl) -1
-Methyl] ethyl] -2-oxo-3-pyrrolidinecarboxylic acid

The compound obtained in (3) above was used and reacted in the same manner as in (4) of Example 6 to obtain the title compound as white crystals (yield 84.7%).

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.58 (3H, br d, J = 16Hz), 1.
80 (3H, br d, J = 16 Hz), 2.2-2.
7 (2H, m), 3.73 (3H, d, J = 11H
z), 3.79 (3H, d, J = 11 Hz), 3.3-.
4.0 (2H, m), 4.8-5.2 (2H, m),
6.19 (1H, br s), 7.1 to 7.4 (5H,
m).

IR ν KBr (cm ⁻¹ ): 3410,
2950, 2850, 2550, 1710, 1690,
1485, 1440, 1410, 1285, 1260,
1205, 1170, 1045, 1020.

(5) 3-amino-2-oxo-1- (1
-Methyl-1-phosphonoethyl) -3-pyrrolidinecarboxylic acid

The compound obtained in (4) above was used and reacted in the same manner as in (5) of Example 6 to obtain the title compound as white crystals (yield 33%).

NMR (400 MHz, D ₂ O) δpp
m: 1.57 (3H, d, J = 14Hz), 1.66
(3H, d, J = 14Hz), 2.28 (1H, dt,
J = 14.9 Hz, 2.63 (1H, dt, J = 1)
4,4Hz), 3.87 (2H, dd, J = 9, 4H
z).

IR ν KBr (cm ⁻¹ ): 3410,
3180, 2990, 1700, 1520, 1305,
1205, 1140, 1110, 1040, 935. M
S (FAB) 267 (MH +)

Example 10 3-Amino-2-oxo-1- (α-phosphonobendi
) -3-Pyrrolidinecarboxylic acid

(1) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-hydroxyethyl) -N-
[Α- (Dimethoxyphosphinyl) benzyl]] carbamoyl] ethyl acetate

1-[(2-hydroxyethyl) amino]
The reaction was carried out in the same manner as in (1) of Example 6 except that dimethyl α-[(2-hydroxyethyl) amino] benzylphosphonate was used in place of dimethyl ethylphosphonate to give white amorphous. Compound 1.2
0 g (yield 45.8%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.0 to 1.5 (3H, m), 3.0 to 4.4 (1
3H, m), 4.9 to 5.3 (2H, m), 5.5
6.3 (3H, m), 7.1-7.6 (10H, m).

(2) 2- (benzyloxycarbonyl)
Amino-2-[[N- (2-chloroethyl) -N- [α
-(Dimethoxyphosphinyl) benzyl]] carbamoyl] ethyl acetate

Using the compound obtained in (1) above, the reaction was carried out in the same manner as in (2) of Example 6 to give 1.19 g of the title compound as a white amorphous substance (yield: 100).
%) Was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.0 to 1.5 (3H, m), 3.0 to 4.4 (1
2H, m), 4.9-6.4 (5H, m), 7.1-
7.8 (10H, m).

(3) 3- (benzyloxycarbonyl)
Amino-1- [α- (dimethoxyphosphinyl) benzyl] -2-oxo-3-pyrrolidinecarboxylate ethyl ester

Using the compound obtained in (2) above, the reaction was carried out in the same manner as in (3) of Example 6 to give one diastereomer (diastereomer A) of the title compound as white crystals. Was obtained as a colorless oil, and 266 mg (24.4%) of the other diastereomer of the title compound (diastereomer B) was obtained.

Diastereomer A NMR (90 MHz, CDCl ₃ ) δppm: 0.90
(3H, t, J = 7Hz), 2.3 to 2.7 (2H,
m), 3.1 to 4.2 (10H, m), 5.11 (2
H, s), 5.73 (1H, d, J = 21 Hz), 6.
06 (1H, br s), 7.1 to 7.7 (10H,
m).

IR ν KBr (cm ⁻¹ ): 323
0,2960,1740,1715,1700,151
0, 1310, 1265, 1250, 1230, 122
0, 1080, 1065, 1050, 1035, 70
0,550.

Diastereomer B NMR (90 MHz, CDCl ₃ ) δppm: 1.29
(3H, t, J = 7Hz), 2.0 to 2.5 (1H,
m), 2.5-2.9 (1H, m), 3.1-4.1
(8H, m), 4.25 (2H, q, J = 7Hz),
4.9-5.2 (2H, m), 5.74 (1H, d, J
= 21 Hz), 6.00 (1H, br s), 7.1-
7.8 (10H, m).

(4) 3- (benzyloxycarbonyl)
Amino-1- [α- (dimethoxyphosphinyl) benzyl] -2-oxo-3-pyrrolidinecarboxylic acid Other than using the diastereomer mixture (1: 1) of the compound obtained in (3) above, The reaction is performed in the same manner as in (4) of Example 6, the reaction crude is purified by medium pressure silica gel column chromatography (chloroform / methanol / acetic acid = 200/10/1), and is eluted first. 84 mg (39%) of one diastereomer (diastereomer A) of the title compound as white crystals, and 103 mg of the other diastereomer (diastereomer B) of the title compound that eluted later as white amorphous.
(47%) obtained.

Diastereomer A NMR (90 MHz, CDCl ₃ ) δppm: 2.2
2.7 (2H, m), 3.1-4.0 (8H, m),
5.05 (2H, s), 5.57 (1H, d, J = 22
Hz), 6.34 (1H, brs), 7.0-7.6.
(10H, m).

Diastereomer B NMR (90 MHz, CDCl ₃ ) δ ppm: 2.1-
2.7 (2H, m), 3.1-4.0 (8H, m),
5.03 (2H, s), 5.87 (1H, d, J = 22
Hz), 6.47 (1H, br s), 6.9 to 7.7.
(10H, m).

(5) 3-amino-2-oxo-1- (α
-Phosphonobenzyl) -3-pyrrolidinecarboxylic acid

Diastereomer A obtained in (4) above
And diastereomer B were used respectively, and the reaction was performed in the same manner as in (5) of Example 6 to obtain 42 mg (37 mg) of diastereomer A of the title compound as a white powder.
%), And 147 mg (91%) of diastereomer B of the title compound as a pale yellow amorphous substance was obtained.

Diastereomer A NMR (400 MHz, D ₂ O-NaOD) δ ppm:
2.03 (1H, ddd, J = 13, 9, 8Hz),
2.45 (1H, ddd, J = 13,8,3Hz),
3.57 (1H, dt, J = 10, 8Hz), 4.09
(1H, dt, J = 10, 3Hz), 5.14 (1H,
d, J = 20 Hz), 7.3 to 7.7 (5H, m).

IR ν KBr (cm ^-1 ): 340
0,3080,3020,2940,1670,160
0,1510,1380,1330,1310,128
5,1255,1215,1165,980,920,
910, 580, 550.

Diastereomer B NMR (400 MHz, D ₂ O-NaOD) δ ppm:
1.9 to 2.0 (1H, m), 2.5 to 2.7 (1H,
m), 3.7 to 3.9 (1H, m), 4.0 to 4.2
(1H, m), 5.05 (1H, d, J = 20Hz),
7.3-7.6 (5H, m).

Reference Example 4 Synthesis of dimethyl α-[(2-hydroxyethyl) amino] benzylphosphonate used in (1) of Example 10.

The reaction was carried out in the same manner as in Reference Example 1 except that benzaldehyde was used instead of acetaldehyde, and 4.54 g (3%) of the title compound was obtained as a colorless oil.
5.0%) was obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 2.2 to 3.0 (4H, m), 3.53 (3H,
d, J = 11 Hz), 3.74 (3H, d, J = 11H)
z), 3.4 to 3.8 (2H, m), 4.07 (1H,
d, J = 20 Hz), 7.2-7.5 (5H, m).

Example 11 1-Amino-3-phosphonomethyl-1-cyclopentane
carboxylic acid

(1) Diethyl (3-oxocyclopentyl) methylphosphonate 3-bromomethyl-1-cyclopentanone (980 m
g, 5.54 mmol) and triethyl phosphite (15
The mixture was heated to reflux at 180 ° C. for 8 hours. After distilling off excess triethyl phosphite under reduced pressure, the residue was subjected to vacuum distillation to give the title compound (400 mg, 30.8%)
Was obtained as a colorless oil.

Boiling point: 150 ° C./2 mmHg

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.33 (6H, t, J = 7Hz), 1.3-2.
7 (9H, m), 4.07 (2H, q, J = 7Hz),
4.11 (2H, q, J = 7Hz).

IR ν neat (cm ⁻¹ ): 345
0,2975,1730,1400,1230,115
5,960,820,750.

(2) Diethyl (3-amino-3-cyanocyclopentyl) methylphosphonate The compound (369 mg, 1.58 mmol) obtained in (1) above, sodium cyanide (155 mg, 3.15).
Mmol), ammonium chloride (169 mg, 3.15)
(Mmol) and concentrated aqueous ammonia (2.6 ml) were stirred at room temperature for 20 hours while protected from light. The reaction solution was extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (374 mg, 91.2 mg).
%) As a colorless oil.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.32 (6H, t, J = 7Hz), 1.4-2.
7 (9H, m), 4.05 (2H, q, J = 7Hz),
4.14 (2H, q, J = 7Hz).

IR ν neat (cm ⁻¹ ): 335
0,2975,2200,1440,1390,138
0, 1230, 1155, 1090, 1020, 96
0,820.

(3) 1-amino-3-phosphonomethyl-
1-Cyclopentanecarboxylic acid A mixture of the compound (100 mg, 0.38 mmol) obtained in (2) above and 6N hydrochloric acid (6 ml) was stirred with heating for 15 hours. After cooling, the reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was dried under reduced pressure. This operation was repeated 3 times to give the title compound (100 mg, 100%) as an orange amorphous substance.

NMR (400 MHz, D ₂ O) δpp
m: 1.5 to 2.7 (9H, m).

IR ν KBr (cm ⁻¹ ): 1720,
1620, 1510, 1440, 1400, 980, 9
40,520.

Example 12 3-Amino-1-phosphonomethyl-3-piperidine calc
Boric acid dihydrochloride

(1) 3-Amino-1-benzyl-3-piperidinecarbonitrile 1-benzyl-3-piperidone (5 g, 22.2 mmol), sodium cyanide (2.41 g, 44.4 mmol), chloride A mixture of ammonium (2.41 g, 44.4 mmol) and concentrated aqueous ammonia (32 ml) was stirred at room temperature in the dark for 17 hours. The reaction mixture was extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.64 g) as an orange oil.

(2) 3-Acetylamino-1-benzyl-3-piperidinecarbonitrile A solution of the compound (3.82 g, 17.9 mmol) obtained in (1) above in pyridine (38 ml) was cooled with ice. Acetic anhydride (3.29 g, 32.3 mmol) was added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, the mixture was extracted with chloroform, washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained crude product was subjected to medium pressure silica gel column chromatography, and the title compound (3.40 g, 65.8%) was eluted from the eluate of chloroform / methanol = 40/1. Was obtained as an oil.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.5 to 2.9 (8H, m), 1.99 (3H,
s), 3.46 (1H, d, J = 16Hz), 3.60
(1H, d, J = 16Hz), 5.90 (1H, br
s), 7.1-7.4 (5H, m).

IR ν KBr (cm ^-1 ): 3250,
3050, 2950, 2800, 2230, 1650,
1540, 1450, 1370, 1290, 1140,
1020, 940, 890, 740, 690, 600.

(3) Ethyl 3-amino-1-benzyl-3-piperidinecarboxylate dihydrochloride A mixture of the compound (3.00 g, 11.8 mmol) obtained in (2) above and 6N hydrochloric acid (50 ml). Was heated to reflux for 14 hours. The solvent was distilled off from the reaction mixture under reduced pressure,
Ethanol and toluene were added to this and the mixture was concentrated to dryness to obtain a crude product (3.5 g). A 10N hydrogen chloride-ethanol solution (100 ml) was added to this crude product, and the mixture was heated with stirring at 90 ° C. for 5 hours. After the solvent was distilled off from the reaction mixture under reduced pressure, the operation of adding ethanol and toluene to the residue and concentrating to dryness was repeated, ethanol was added to the residue, and the insoluble material was filtered off. The solvent was distilled off from the filtrate under reduced pressure to give the title compound (4.3 g) as a pale brown amorphous substance.

(4) Ethyl 3- (tertiarybutyloxycarbonyl) amino-1-benzyl-3-piperidinecarboxylate The crude product (4.3 g) obtained in the above (3), triethylamine (7.57 g, 75) Mmol) and water (40 ml)
A solution of ditertiary butyl dicarbonate (3.36 g, 15.4 mmol) in tetrahydrofuran (40 ml) was added to the mixture of under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. Tetrahydrofuran was distilled off from the reaction mixture at 40 ° C. under reduced pressure, water was added, the mixture was extracted with ethyl acetate, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained crude product was subjected to medium pressure silica gel column chromatography, and the title compound (4.0 g, above (2) was eluted from the eluate of chloroform / methanol = 100/1). Yield 94% from the obtained compound) was obtained as an oil.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.24 (3H, t, J = 8Hz), 1.44 (9
H, s), 1.1 to 2.3 (6H, m), 2.6 to 2.
8 (2H, m), 3.46 (2H, s), 3.9-4.
3 (2H, m), 5.36 (1H, br s), 7.1
~ 7.4 (5H, m).

MS (EI) 362 (M +)

(5) Ethyl 3- (tert-butyloxycarbonyl) amino-3-piperidinecarboxylate The compound (4.0 g, 11 mmol) obtained in the above (4), 10% palladium-carbon (600 mg) and A mixture of ethanol (120 ml) was stirred at room temperature under hydrogen atmosphere (1 atmosphere) for 12 hours. The insoluble material was filtered off from the reaction mixture, and the solvent was distilled off under reduced pressure to obtain a solid.
-Wash with hexane and air dry to give the title compound (2.4 g,
80%) as a white solid.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.24 (3H, t, J = 8Hz), 1.44 (9
H, s), 1.3 to 2.1 (6H, m), 2.6 to 3.
2 (4H, m), 4.6 (2H, q, J = 8Hz),
5.12 (1H, br s).

MS (EI) 237 (M +)

(6) 3- (tert-Butyloxycarbonyl) amino-1- (diethoxyphosphinyl) methyl-
Ethyl 3-piperidinecarboxylate To a solution of the compound (500 mg, 83 mmol) obtained in (5) above and diethyl phosphite (300 mg, 2.17 mmol) in benzene (25 ml) was added 35% formalin (0.2 ml). In addition, the mixture was heated and stirred at 80 ° C. for 20 hours. The solvent and excess diethyl phosphite were distilled off from the reaction mixture under reduced pressure, chloroform was added to the residue, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained crude product was subjected to medium-pressure silica gel column chromatography to give the title compound (540 mg, 70%) as an oily substance from the eluate of chloroform / methanol = 60/1. Obtained.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.24 (3H, t, J = 8Hz), 1.34 (6
H, t, J = 8 Hz), 1.40 (9H, s), 1.4
-2.5 (6H, m), 2.74 (2H, d, J = 12)
Hz), 2.9 to 3.1 (2H, m), 3.9 to 4.3
(6H, m), 5.40 (1H, br s).

(7) 3-Amino-1-phosphonomethyl-
3-piperidinecarboxylic acid dihydrochloride A mixture of the compound (250 mg, 0.59 mmol) obtained in (6) above and 6N hydrochloric acid (10 ml) was added at 100 ° C.
The mixture was heated and stirred for 20 hours. After distilling off the solvent under reduced pressure and concentrating and drying with water several times, methanol was added and the mixture was allowed to stand in a cool place. The precipitated crystals were collected by filtration and dried at 50 ° C. under reduced pressure to give the title compound (120 mg, 65.2%) as a white solid.

NMR (400 MHz, D ₂ O) δpp
m: 1.8 to 2.0 (1H, m), 2.0 to 2.2 (2
H, m), 2.1-2.3 (1H, m), 3.1-3.
5 (4H, m), 3.76 (1H, d, J = 12H
z), 4.07 (1H, d, J = 12 Hz).

IR ν KBr (cm ⁻¹ ): 3350,
1705, 1630, 1550, 1420, 1370,
1340, 1180, 1120, 1100, 970, 9
10, 810, 770, 750, 620, 550.

Example 13 3-Amino-1- (3-phosphonopropyl) -3-pipet
Lysine carboxylic acid dihydrochloride

(1) Ethyl 3- (tert-butyloxycarbonyl) amino-1- [3- (diethoxyphosphinyl) propyl] -3-piperidinecarboxylate 3 Obtained in Example 12 (5). Ethyl-(tertiary butyloxycarbonyl) amino-3-piperidinecarboxylate (137 mg, 0.50 mmol) (4 m
l) To the solution were added anhydrous sodium carbonate (106 mg, 1.0 mmol) and diethyl 3-bromopropylphosphonate (130 mg, 0.50 mmol), and the mixture was heated under reflux for 6 hours with stirring. After cooling, the insoluble matter was filtered from the reaction mixture, the filtered solid was washed with ethanol, the filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to medium pressure silica gel column chromatography, and the title compound (210 mg, 93%) was obtained as a colorless oil from a fraction eluted with chloroform / methanol = 50/1.

NMR (90 MHz, CDCl ₃ ) δpp
m: 1.0 to 1.4 (9H, m), 1.43 (9H, m
s), 1.5 to 2.5 (12H, m), 2.6 to 2.9.
(2H, m), 3.9 to 4.3 (6H, m), 5.40
(1H, br s).

IR ν neat (cm ^-1 ): 340
0,3260,2970,1740,1705,148
0, 1365, 1280, 1240, 1160, 106
0,1020,960.

(2) 3-Amino-1- (3-phosphonopropyl) -3-piperidinecarboxylic acid dihydrochloride The compound (167 mg, 0.37 mmol) obtained in the above (1) and 6N hydrochloric acid (2 ml). ) Was heated to reflux for 13 hours. After cooling, hydrochloric acid was distilled off from the reaction mixture under reduced pressure, water was added to the residue and the mixture was concentrated to dryness, and the title compound (126 mg, 100%) was obtained as a pale yellow amorphous substance.

NMR (400 MHz, D ₂ O) δpp
m: 1.7 to 2.3 (8H, m), 3.0 to 3.2 (2
H, m), 3.3 to 3.4 (2H, m), 3.5 to 3.
6 (1H, m), 3.8 to 3.9 (1H, m).

MS (FAB) 267 (M + 1)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/40 AAY 7252-4C 31/41 ACJ 7252-4C 31/66 AAF 8314-4C C07C 229 / 24 8930-4H 271/24 6917-4H 309/19 9160-4H 309/23 9160-4H C07D 207/16 7019-4C 257/04 7433-4C 403/06 8829-4C C07F 9/40 D 7106-4H 9 / 572 7106-4H 9/59 7106-4H

Claims (4)

[Claims] 1. General formula (1): [Wherein R ¹ is —COOR ⁶ (wherein R ⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms). ), -CON (R ⁷ ) ₂ (wherein R ⁷ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms), Or —PO (OR ⁶ ) ₂ (wherein R ⁶ is as described above), R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or carbon. An aralkyl group having an alkyl group moiety having 1 to 4 atoms, R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms. , An alkylcarbonyl group having 2 to 7 carbon atoms, a carbon atom 2-6 alkoxycarbonyl group, or an aralkyloxycarbonyl group having an alkyl moiety of 1 to 4 carbon atoms, R ⁴ and R ⁵
Are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms, which may have an alkoxyl group having 1 to 6 carbon atoms or an aryloxy group as a substituent, and an alkyl group having 1 to 4 carbon atoms. An aralkyl group having a base moiety,
An aryl group, a hydroxyl group, a carboxyl group, an alkoxyl group having 1 to 6 carbon atoms or a halogen atom,
R ⁴ and R ⁵ may form a carbonyl group together with the carbon atom to which they are bonded, and Q is one or more groups or atoms selected from the groups or atoms represented by R ^4. Or an alkylene group having 2 to 5 carbon atoms, which may be substituted with 1 to 4 of ═O groups, and A
Is an alkyl group having 1 to 6 carbon atoms, or 1 to 4 carbon atoms
An aralkyl group having an alkyl group moiety, an aryl group,
A haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group,
An alkoxyl group having 1 to 6 carbon atoms, an aryloxy group, an aralkyloxy group having an alkyl group moiety having 1 to 4 carbon atoms, -N (R ⁸ ) ₂ (wherein R ⁸ is a hydrogen atom or the number of carbon atoms). A group represented by an alkyl group having 1 to 6 or an aryl group or an aralkyl group having an alkyl group having 1 to 4 carbon atoms), or 1 to 6 carbon atoms which may be substituted with a halogen atom. 5 alkylene group or alkenylene group, or -CO-B- (wherein B is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms, an aryl group, carbon A haloalkyl group having 1 to 6 atoms, a hydroxyl group, an amino group, or an alkylene group having 1 to 5 carbon atoms or an alkenylene group, which may be substituted with a halogen atom). ^{, -PO (OR 9) (OR} 10)
(However, R ⁹ and R ¹⁰ are each independently a hydrogen atom,
An alkyl group having 1 to 6 carbon atoms, or 1 to 4 carbon atoms
Is an aralkyl group having an alkyl group moiety of --COOR ¹¹ (wherein R ¹¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 4 carbon atoms). An aralkyl group having a moiety), a sulfo group or a 1H-tetrazol-5-yl group]. 2. An NMDA antagonist comprising the α-amino acid according to claim 1 as an active ingredient. 3. General formula (2): [In the formula, R ²¹ represents -COOR ²⁶ (wherein R ²⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms). ), —CON (R ²⁷ ) ₂ (wherein R ²⁷ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms), Or —PO (OR ²⁶ ) ₂ (provided that R ²⁶ is as described above), R ²² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or carbon. An aralkyl group having an alkyl group moiety having 1 to 4 atoms, wherein R ²³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms. , An alkylcarbonyl group having 2 to 7 carbon atoms, charcoal Atoms 2-6 alkoxycarbonyl group, or an aralkyloxycarbonyl group having an alkyl moiety of 1 to 4 carbon atoms, R ²⁴ and R
²⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have an alkoxyl group having 1 to 6 carbon atoms or an aryloxy group as a substituent, and an alkyl group having 1 to 4 carbon atoms. An aralkyl group having an alkyl group moiety, an aryl group, a hydroxyl group, a carboxyl group, an alkoxyl group having 1 to 6 carbon atoms or a halogen atom, wherein R ²⁴ and R ²⁵ are a carbonyl group together with the carbon atom to which they are bonded. And Q ¹ may be substituted with 1 to 4 groups or atoms selected from the groups or atoms represented by R ²⁴ , or 1 to 4 of ═O groups. Is an alkylene group having 2 to 5 carbon atoms, A ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms, an aryl group, and 1 carbon atom ~ Haloalkyl group, a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, an aryloxy group, an aralkyloxy group having an alkyl moiety of 1 to 4 carbon atoms, -N (R ²⁸⁾ ₂ (where, R ²⁸ is ,
A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms) or a halogen atom. , An alkylene group having 1 to 5 carbon atoms or an alkenylene group, or —CO—B ¹ — (however,
B ¹ is an alkyl group having 1 to 6 carbon atoms, 1 carbon atom
An aralkyl group having an alkyl group moiety of 4 to 4, an aryl group, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group, an amino group, or an alkylene group having 1 to 5 carbon atoms which may be substituted with a halogen atom, or An alkenylene group), Y ¹ is —PO (OR
²⁹ ) (OR ³⁰ ) (wherein R ²⁹ and R ³⁰ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms). Group represented by), —COOR ³¹ (wherein R ³¹ is
A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having an alkyl group moiety having 1 to 4 carbon atoms), a sulfo group or 1H-tetrazole-
It is a 5-yl group]. 4. An NMDA antagonist comprising the α-amino acid according to claim 3 as an active ingredient.