JPH06179643A - @(3754/24)2s,1's,2'r)-2-@(3754/24)2-carboxy-3-substituted oxymethylcyclopropyl) glycine and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound of a (2S,1'S,2'R)-2-(2-carboxy-3-substituted oximethylcyclopropyl)glycine, which an agonist having high selectivity for metabolic regulating receptors, hardly affecting an ion channel type receptor and useful as a biochemical reagent for research of L-glutamic acid receptors and a reagent for pharmacological tests, etc. CONSTITUTION:This (2S, 1'S, 2'R, 3'R)-2-(2-carboxy-3-substituted oxymethylcyclopropyl)glycine of formula I (R is 1-4C lower alkyl or 7-10C aralkyl), e.g. (2S,1'S,2'R,3'R)-2-(2-carbonyl-3-methoxymethylcyclopropyl)glycine. The compound of formula I is obtained by removing the t-butyldimethylsilyl group from a compound of formula II (Boc is t-butoxycarbonyl; TBS is t- butyldimethylsilyl), providing a compound of formula III, then alkyl or aralkyl etherifying the resultant compound of formula III, affording a compound of formula IV, passing the prepared compound of formula IV through compounds of formula V and VI, oxidizing the produced compound and subsequently removing the t-butoxycarbonyl group. This compound is useful as an anesthetic agent, its adjuvant, an antispastic paralytic agent, a muscle relaxant, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cyclopropylglycine derivative that plays a major role in the study of L-glutamic acid receptors. More specifically, it is an agonist of the metabotropic L-glutamate receptor, (2S, 1'S,
The present invention relates to 2'R) -2- (2-carboxy-3-substituted oxymethylcyclopropyl) glycine and a method for producing the same.

The present invention provides a clue to the development of L-glutamic acid receptor blockers, and is a dysfunction of the brain center resulting from ischemic nerve cell death, such as epilepsy,
It can be expected to be applied to the treatment of Huntington's disease, Parkinson's disease, etc. Further, it is expected that the provision of the compound of the present invention will provide important knowledge for elucidating the accepting mechanism from the correlation between the conformation and the activity of L-glutamic acid and its related compounds.

[0003]

2. Description of the Related Art L-Glutamic acid is used as a transmitter of excitatory nerve stimulation in the central nervous system of mammals, and as a neuroexcitotoxin that destroys nerve cells and causes various brain and nerve diseases. It is attracting attention as a substance that is deeply involved in the formation of.

The L-glutamic acid receptor is linked to such various physiological functions, and by the introduction of an exogenous agonist group, the following three subtypes, that is, (a). NMDA (N-methyl-D-aspartic acid)
Type (b). KA (kainic acid) type (c). It is classified into three sub-types: AMPA (ampa) type. Also, KA
The (kainic acid) type and the AMPA (ampa) type may be collectively referred to as a non-NMDA type. (AMP
A: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)

It has been conventionally considered that the NMDA type receptor is the center of nerve excitotoxin, and it is presumed that the nerve cells are destroyed by the excessive activation of the receptor, which eventually triggers various neurological diseases. Has been done.

Regarding the NMDA type receptor, the present inventors have established (2S, 1'R, 2'S) -2- (2-
It is disclosed that carboxycyclopropyl) glycine is a potent NMDA type agonist that surpasses NMDA, and that the folded conformation of glutamate activates the NMDA receptor (JP-A-1-09356).
3).

Further, regarding the non-NMDA type receptor, the present inventors also (2S, 1'R, 2'R, 3'R)
-2- (2-carboxy-3-methoxymethylcyclopropyl) glycine and (2S, 1'R, 2'R, 3'R)-
2- (2-Carboxy-3-benzyloxymethylcyclopropyl) glycine has been disclosed to be a non-NMDA type agonist (Tetrahedron.
Letters Volume 31 No. 28 4049-105
2 p. 1990).

In these NMDA and non-NMDA type receptors, the receptor and the ion channel regulated by the receptor are present as a receptor-channel complex, and a transmitter is bound to the receptor. It is a type that is classified as an "ion channel type receptor" in which ion channels are directly opened and closed (Metabolism 26
Vol. 6, pp. 535-542, 1989).

On the other hand, Sugiyama et al. Have a certain species in the L-glutamic acid receptor, in which the receptor and the effector regulated by the receptor exist as separate molecular species, and a transmitter binds to the receptor. , The effector is regulated via the second messenger system activated by this G protein, and the receptive reaction is triggered.
It has been found that there are types of receptors classified as “metabolite-type receptors” (Nature 325, 5
31 pages 1987). With respect to this metabotropic receptor as well, the present inventors fixed the conformation of extended type glutamate (2S, 1 ′S, 2 ′).
S) -2- (2-Carboxycyclopropyl) glycine is disclosed to be a specific agonist (Eur. J. Pharmacol., 184 Vol. 20.
Page 5, 1990, Brain Res. , Volume 537
311 1990).

[0010]

With the progress of research on such L-glutamic acid receptors, there is a demand for the development of agonists that react specifically with the respective receptors.

[0011]

[Means for Solving the Problems] The present inventors have diligently developed a cyclopropylglycine derivative using an electrophysiological assay using a neonatal rat spinal cord extract as an index, and developed the formulas (1) and (1 ′). Wherein R is a methyl group, formulas (1a) and (1′a)

[Chemical 17] (2S, 1'S, 2'R, 3'R) -2- (2-carboxy-3-methoxymethylcyclopropyl) glycine and (2S, 1'S, 2'R, 3'S) -2- (2-carboxy-3-methoxymethylcyclopropyl) glycine (hereinafter cis-MCG-I and trans-MC, respectively)
GI) may suppress monosynaptic reflex at a concentration that does not cause depolarization, and the alcohol at the 3-position of the cyclopropyl moiety may be further substituted with a lower alkoxy group having 2 to 4 carbon atoms or a carbon number having 2 to 4 carbon atoms. The compounds having 7 to 10 aralkoxy groups (hereinafter, these may be abbreviated as "the related compounds") have similar effects and have completed the present invention.

[0012] That is, according to the present invention, a selective agonist of a metabolic regulatory receptor that hardly acts on an ion channel type receptor and suppresses the accumulation of cyclic AMP (cAMP) present in presynapses. Cis-MCG-I and trans-MCG-I and their related compounds that act as the above and their production methods are provided.

The compound of the present invention, cis-MCG-I
Is (2S, 1'S, 2'S, 3'R) -N by the method described in International Publication No. WO93 / 08158, for example.
-T-Butoxycarbonyl-2- (3-t-butyldimethylsilyloxymethyl-2-methoxycarbonylcyclopropyl) glycinol t-butyldimethylsilyl ether (Tetrahedron Letters
31 Vol. 28 No. 4049-4052 (1990)) treated with dl-camphorsulfonic acid and 2,2-dimethoxypropane (1S, 5R, 6S, 4'S)
-6- [N- (t-butoxycarbonyl) -2,2-dimethyl-1,3-oxazolidin-4-yl] -3-oxabicyclo [3.1.0] hexan-2-one,

Then, after alkali hydrolysis and methyl esterification, the hydroxyl group is protected again with a t-butyldimethylsilulyl group and (4S, 1'S, 2'S, 3'R) -Nt-butoxycarbonyl. -2,2-dimethyl-4- [3- (t-butyldimethylsilyl) oxymethyl-2-methoxycarbonylcyclopropyl] -1,3-oxazolidine,

Then, the formula (2) obtained by treating with potassium bistrimethylsilylamide is obtained.

[0016]

[Chemical 18] (In the formula, Boc represents a t-butoxycarbonyl group, TB
S represents a t-butyldimethylsilyl group. (4S, 1'S, 2'R, 3'R) -Nt-butoxycarbonyl-2,2-dimethyl-4- [3- (t-butyldimethylsilyl) oxymethyl-2- Methoxycarbonylcyclopropyl] -1,3-oxazolidine (Bioor
ganic and Medicinal Chemi
story Letters Vol. 3, No. 1, pages 15-18, 19
93) can be used as a starting material and synthesized according to the following scheme.

(2S, 1'S, 2'R, 3'R) -2- (2-
Synthesis route of carboxy-3-methoxymethylcyclopropyl) glycine (cis-MCG-I)

[Chemical 19] (In the scheme 1, R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc is t
-Butoxycarbonyl group, TBS is t-butyldimethylsilyl group, nBu ₄ NF is tetrabutylammonium fluoride, THF is tetrahydrofuran, RX is carbon number 1 to
4 lower alkyl halide or aralkyl halide having 7 to 10 carbon atoms, nBu ₄ NI is tetrabutylammonium iodide, DMF is N, N-dimethylformamide, TFA is trifluoroacetic acid, and Boc ₂ O is di-t-butyl. Dicarbonate, Et ₃ N represents triethylamine, Jones Ox. Indicates Jones oxidation. )

That is, (4S, 1'S,
2'R, 3'R) -Nt-butoxycarbonyl-2,2-
Dimethyl-4- [3- (t-butyldimethylsilyl) oxymethyl-2-methoxycarbonylcyclopropyl]
-1,3-Oxazolidine is det-butyldimethylsilylated with tetrabutylammonium fluoride to give (4S, 1'S, 2'R, 3'R) -3-N represented by the formula (3).
-T-butoxycarbonyl-2,2-dimethyl-4-
(3-hydroxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine,

Then, a compound (4a) (4S, 1'S, 2'R, 3'R) -3-N in which R is a methyl group in the formula (4) is methyletherified with methyl iodide. -T-
Butoxycarbonyl-2,2-dimethyl-4- (3-methoxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine is obtained.

By replacing the methyl iodide used in this step with a desired halogenated lower alkyl or halogenated aralkyl, a desired alkyl group or aralkyl group can be introduced into R of the formula (1). .

Next, the oxazolidine ring of the obtained compound is opened with trifluoroacetic acid, and the amino group is again t-butoxycarbonylated with di-t-butyl dicarbonate, and R in the formula (5) is a methyl group. Compound (5
a) (2S, 1 ′S, 2′R, 3′R) -Nt-butoxycarbonyl-2- (2-methoxycarbonyl-3-methoxymethylcyclopropyl) glycinol,

Then, the compound is oxidized with a Jones reagent to convert the alcohol to a carboxylic acid and then methylsterified with diazomethane to give a compound (6a) (2S, 1'S, 2 'in which R is a methyl group in the formula (6). R, 3'R) -NT
-Butoxycarbonyl-2- (2-methoxycarbonyl-3-methoxymethylcyclopropyl) glycine methyl ester,

Then, after saponification by alkali treatment,
Det-butoxycarbonylation with trifluoroacetic acid can give compounds of formula (1a).

Another compound of the invention, tran
s-MCG-I can be prepared, for example, by the following synthetic scheme 2

[0025]

[Chemical 20] (In Scheme 2, R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc is t
-Butoxycarbonyl group, TBS represents t-butyldimethylsilyl group, nBu ₄ NF represents tetrabutylammonium fluoride, PDC represents pyridinium dichromate, and RX represents halogenated lower alkyl having 1 to 4 carbon atoms. Alternatively, it represents a halogenated aralkyl having 7 to 10 carbon atoms, DIABAL represents diisobutylaluminum hydride, and Jones Ox. Indicates jaws oxidation. )

In accordance with International Publication Number WO 93/081
No. 58 (4S, 1'S, 2'S, 3'R)
-Nt-butoxycarbonyl-2,2-dimethyl-4
-[3- (t-butyldimethylsilyl) oxymethyl-
Starting from 2-methoxycarbonylcyclopropyl] -1,3-oxazolidine (Compound 7), this is de-t-butyldimethylsilylated and then 3'-position is aldehydized to give the compound represented by the formula (8) (4S). , 1'S, 2'S,
3′R) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3-formyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine,

This is treated with alkali to invert the configuration at the 3'position and then reduced to give the compound represented by the formula (9) (4S,
1'S, 2'S, 3'S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3-hydroxymethyl-
2-methoxycarbonylcyclopropyl) -1,3-oxazolidine, and then methyl iodide iodide (4S, 1'S, 2'S, represented by the formula (10a)).
3 ′S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3-methoxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine.

By replacing the methyl iodide used in this step with the desired halogenated lower alkyl or halogenated aralkyl, it is possible to introduce the desired alkyl or aralkyl group into R of formula (1 '). it can.

Then, the ester group at the 2'position is reduced to give (4S, 1'S, 2'S, represented by the formula (11a).
3 ′S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (2-formyl-3-methoxymethylcyclopropyl) -1,3-oxazolidine.

This is treated with alkali to invert the configuration at the 2'position, and the compound represented by the formula (12a) (4S, 1'S,
2′R, 3 ′S) body, then subjected to Jones oxidation and methylesterification to give the compound represented by the formula (13a) (2S, 1 ′).
S, 2′R, 3 ′S) -Nt-butoxycarbonyl-
2- (2-methoxycarbonyl-3-methoxymethylcyclopropyl) glycine methyl ester,

Then, after saponification by alkali treatment,
De-t-butoxycarbonylation with trifluoroacetic acid to give tr
Ans-MCG-I (1'a) can be obtained.

[0032]

[Function] cis-MCG-I and trans of the present invention
As described in the measurement example described later, -MCG-I shows almost no activity in depolarizing activity even at a high concentration of 1 mM, but monosynaptic reflex is suppressed by 50% at extremely low concentrations of 4 µM and 0.5 µM, respectively. showed that. This is cis
It shows that -MCG-I and trans-MCG-I are agonists that act very little on the ion channel type receptor and have a very high selectivity for the metabotropic type receptor.

Cyclic AMP (c
There is a metabotropic receptor that suppresses the accumulation of AMP),
It is presumed that this controls the release of neurotransmitters from the presynapse. cis-MCG-I and trans-MCG-I are selective agonists of such a receptor, and are inhibitory agents from the viewpoint of suppressing nerve cell excitation. Therefore, cis-MC
G-I and trans-MCG-I are not only useful as biochemical reagents and pharmacological test reagents as agonists of L-glutamate receptors, but also because of their activity of suppressing nerve cell excitement, they are anesthetics and anesthesia adjuvants. It can be expected to be useful as an antispasmodic paralysis agent, muscle relaxant, antipyretic / analgesic agent.

[0034]

The present invention will now be described in more detail by way of examples, which should not be construed as limiting the scope of the present invention.

Example 1 Synthesis of cis-MCG-I (see Scheme 1 above) (4S, 1'S, 2'R, 3'R) -3-Nt-but
Xycarbonyl-2,2-dimethyl-4- (3-hydro
Xy-2-methoxycarbonylcyclopropyl) -1,
3-Oxazolidine (3) (4S, 1'S, 2'R, 3'R) -3-N-t-butoxycarbonyl-2,2-dimethyl-4- (3-t-butyldimethylsilyloxymethyl- 2-Carbonylcyclopropyl) -1,3-oxazolidine (2) [350
mg (0.79 mmol)] of tetrahydrofuran (5
(1 ml) solution of nBu ₄ NF in tetrahydrofuran (0.8 ml) at 0 ° C. under a nitrogen stream at 0 ° C.
For 1 hour and room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ether / hexane = 1/3, 1/1) to obtain a hydroxyl form (3). Yield 258 mg (99%). The product had the following physicochemical properties:

Properties Oily substance [α] _D + 34.6 ° (c1.4, CHCl ₃ ) ¹ H-NMR (300 MHz, CDCl ₃ ) δ (pp
m); 1.50 (s, 12H), 1.62 (brs, 3)
H), 1.70-1.92 (m, 2H), 2.05
(M, 0.7H), 2.20 (m, 0.3H), 3.6
0 (m, 2H), 3.70 (s, 3H), 3.84-
4.06 (m, 4H).

(4S, 1 ′S, 2′R, 3′R) -3-
Nt-butoxycarbonyl-2,2-dimethyl-4-
(3-methoxymethyl-2-methoxycarbonylcyclo
Propyl) -1,3-oxazolidine (4a) sodium hydride (40 mg, 1.0 mmol) in N,
A suspension of N-dimethylformamide (5 ml) was added to the hydroxyl compound (3) [191 mg (0.
58 mmol)] of N, N-dimethylformamide (7
ml) solution was added and stirred for 30 minutes. Methyl iodide (284 mg, 2.0 mmol) was added to the reaction solution, followed by tetrabutylammonium iodide (30 mg, 0.08 mmo).
1) was added and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. Water was added under ice cooling to decompose excess reagents, and the mixture was extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated to give an oily substance, which was subjected to silica gel column chromatography (ether / hexane = 1/1).
And purified to give a methyl ether compound (4a). Yield 18
3 mg (92%). The product had the following physicochemical properties:

Properties colorless crystal, melting point 109.0-10
9.5 ° C. (foaming decomposition) [α] _D + 34.2 ° (c0.12, CHCl ₃ ) ¹ H-NMR (300 MHz, CDCl ₃ ) δ (pp
m); 1.48 (s, 12H), 1.62 (brs, 3)
H), 1.80 (m, 2H), 2.0 (m, 0.7)
H), 2.2 (m, 0.3H), 3.32 (s, 3)
H), 3.32 (m, 1H), 3.55-3.90 (4
H, m) 3.92-4.01 (m, 2H).

(2S, 1'S, 2'R, 3'R) -N-
t-butoxycarbonyl-2- (2-methoxycarbonyl
Lou 3-methoxymethylcyclopropyl) glycinol
(5a) methyl ether compound (4a) [253 mg
(0.685 mmol)] in methylene chloride (4 ml) was added trifluoroacetic acid (4 ml) at 0 ° C.
The mixture was stirred for 0 minutes and room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in dioxane (2 ml) and water (2 ml), and triethylamine was added to adjust the pH to 9. Di-t-butyl dicarbonate (500 μl) was added to this solution, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure,
The oily substance obtained by extraction with chloroform and evaporation of the solvent was subjected to silica gel column chromatography (ether /
Purified with hexane = 1/1), glycinol form (5a)
Got Yield 206 mg (99%). The product had the following physicochemical properties:

Properties Oily substance [α] _D + 5.4 ° (c0.65, CHCl ₃ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ (pp
m); 1.44 (s, 9H), 1.67 (ddd, 1
H, J = 4.9, 9.3, 9.3 Hz), 1.74
(S, 1H), 1.78 (dd, 1H, J = 4.9,
4.9 Hz), 1.92 (ddt, 1H, J = 4.9,
5.7, 9.3, 9.3HZ), 2.95 (brs, 1
H), 3.34 (s, 3H), 3.34 (m, 1H),
3.48 (brs, 1H), 3.60-3.75 (m,
2H), 3.66 (s, 3H), 4.88 (d, 1H,
J = 6.5 Hz).

(2S, 1'S, 2'R, 3'R) -N-
t-butoxycarbonyl-2- (2-methoxycarbonyl
Rue 3-methoxymethylcyclopropyl) glycine
Tyl ester (6a) glycinol body (5a) [167 mg (0.55 mmo
l)] is dissolved in 5 ml of acetone and Jones is cooled under ice.
The reagents were added, and the mixture was stirred under ice cooling for 2 hours and at room temperature for 1 hour. Isopropyl alcohol was added under ice cooling to decompose excess reagents, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, the solvent was distilled off, and the resulting residue was added with an ether solution of diazomethane to effect esterification, followed by silica gel column chromatography (ether / hexane = 1/1). ) And the dimethyl ester body (6a) was obtained. Yield 132 mg (73
%). The product had the following physicochemical properties:

Properties colorless crystals, melting point 105.0-10
7.0 ° C. [α] _D + 50.0 ° (c0.2, CHCl ₃ ) ¹ H-NMR (270 MHz, CDCl ₃ ) δ (pp
m); 1.45 (s, 9H), 1.72-1.88
(M, 2H), 1.92 (dd, 1H, J = 4.9,
5.2 Hz), 3.36 (s, 3H), 3.49 (d
d, 1H, J = 5.4, 10.5 Hz), 3.67
(S, 3H), 3.68 (dd, 1H, J = 5.2, 1
0.5 Hz), 3.78 (s, 3H), 4.14 (d
d, 1H, J = 8.5, 10.0 Hz), 5.22
(D, 1H, J = 8.5 Hz).

(2S, 1'S, 2'R, 3'R) -2-
(2-carbonyl-3-methoxymethylcyclopropyl
Le) glycine (cis-MCG-I) (1a) dimethyl ester body (6a) [129 mg (0.39 m
mol)] in 1.5 ml of tetrahydrofuran,
0.93 ml of 1M sodium hydroxide aqueous solution was added, and the mixture was stirred under ice cooling for 2 hours and at room temperature for further 40 hours. The reaction solution was adjusted to pH 4 with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue is 2 ml of methylene chloride and 2 ml of trifluoroacetic acid.
And was stirred at room temperature for 30 minutes. The residue after concentration under reduced pressure was diluted with water, subjected to column chromatography with Dowex 50Wx4, washed with water, and eluted with 1N ammonia water. Ammonia water was distilled off under reduced pressure and the pH was adjusted to 2 with 1N hydrochloric acid
To cis-MCG-I (1
a) was obtained. Yield 53 mg (67%). The product had the following physicochemical properties:

Properties colorless crystal, melting point 208-212 ° C.
(Foam decomposition) [α] _D + 35.0 ° (c0.5, H ₂ O) ¹ H-NMR (270 MHz, D ₂ O) δ (ppm);
1.75-1.93 (m, 3H), 3.28 (s, 3
H), 3.33 (dd, 1H, J = 8.6, 11.0H
z), 3.44 (dd, 1H, J = 10.0 Hz),
3.81 (dd, 1H, J = 4.6, 11.0 Hz).

Example 2 (2S, 1'S, 2'R, 3 '
R) -2- (2-carboxy-3-benzyloxymethyi
Of cyclopentyl) glycine (cis-BCG-I)
Synthesis

[Chemical 21] (Each abbreviation in Scheme 3 has the same definition as in Scheme 1, and BzlBr is benzyl bromide.)

(4S, 1'S, 2'R, 3'R) -N-
t-butoxycarbonyl-2,2-dimethyl-4- (3
-Benzyloxymethyl-2-methoxycarbonyl chloride
Ropropyl) -1,3-oxazolidine (4b) sodium hydride 40 mg (1.0 mmol) of N, N
-(4S, 1'S, 2'R, 3'R) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3- in dimethylformamide (DMF) suspension (5 ml) at 0 ° C. Hydroxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine (3) 251 mg (0.
DMF solution (7 ml) of 76 mmol) was added and stirred for 30 minutes. 237 μl of benzyl bromide (2.0 m
mol) and then tetra-n-butylammonium iodide 3
0 mg (0.08 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. Excess reagent was decomposed by adding water at 0 ° C. and extracted with ether. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ether / hexane = 1/1).
The title compound (4b) (168 mg) was obtained (yield 53%). The product had the following physicochemical properties:

Properties: Oily substance [α] ²³ _D −9.8 ° (c1.12, CHCI ₃ ) IR (neat) 2988, 2944, 2384, 173
_{^{2,1700cm -1 1 HNMR (CDCI 3,}} 400MHz) δ1.45
(S, 15H), 1.62 (m, 1H), 1.83
(M, 1H), 2.0 (brs, 0.5H), 2.23
(Brs, 0.5H), 3.37 (m, 1H), 3.6
0 (m, 1H), 3.67 (s, 3H), 3.75
(M, 1H), 3.92 (dd, 1H, J = 5.0,
9.0 Hz), 3.97 (dd, 1H, J = 1.0,
9.0 Hz), 4.44 (d, 1H, J = 12.0H
z), 4.52 (d, 1H, J = 12.0 Hz), 7.
32 (m, 5H).

(2S, 1 ′S, 2′R, 3′R) -N-
t-butoxycarbonyl-2,2- (2-methoxycal
Bonyl-3-benzyloxymethylcyclopropyl) g
Ricinol (5b) Compound (4b) 220 mg (0.52 mmol) in methylene chloride solution (4 ml) was added to trifluoroacetic acid 4 m at 0 ° C.
1 was added, and the mixture was stirred at 0 ° C for 30 minutes and at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dioxane (2 ml) and water (2 ml), triethylamine was added, and the pH was adjusted to 9
Adjusted to. Di-t-butyl carbonate (500 μl) was added to this solution, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the residue was extracted with chloroform and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ether / hexane = 1/1) to give the title compound (5b) 1
86 mg was obtained (yield 94%). The product had the following physicochemical properties:

Properties: Oily substance [α] ²³ _D −9.7 ° (c1.90, CHCI ₃ ) IR (neat) 3384, 2984, 2888, 17
_{^{16cm -1 1 HNMR (CDCI 3,}} 400MHz) δ1.45
(S, 9H), 1.69 (ddd, 1H, J = 4.7,
9.2, 10.5 Hz), 1.79 (dd, 1H, J =
4.7, 4.7 Hz), 1.95 (dddd, 1H, J
= 4.7, 5.5, 9.2, 10.5 Hz), 2.74
(Brs, 1H), 3.41 (dd, 1H, J = 10.
5,10.5Hz), 3.48 (m, 1H), 3.67
(M, 1H), 3.67 (s, 3H), 3.74 (m,
1H), 3.81 (dd, 1H, J = 5.5, 10.5)
Hz), 4.51 (s, 2H), 4.85 (brs, 1
H), 7.35 (m, 5H).

(2S, 1 ′S, 2′R, 3′R) -2-
(3-benzyloxymethyl-2-carboxycyclop
186 mg (0.49 mmol) of ropyl ) glycine (cis-BCG-I) compound (5b) was dissolved in 5 ml of acetone, the Jones reagent was added under ice cooling, and the mixture was stirred under ice cooling for 20 hours. 2-Propanol was added under ice cooling to decompose excess reagents, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue obtained was added with an ether solution of diazomethane for esterification and purified by silica gel column chromatography (ether / hexane = 1/1) to give 160 m of methyl ester.
g was obtained. This was dissolved in tetrahydrofuran (1.5 ml), 1M aqueous sodium hydroxide solution (0.93 ml) was added, and the mixture was stirred under ice-cooling for 2 hr and at room temperature for 40 hr. 1 reaction mixture
After adjusting the pH to 4 with M hydrochloric acid, the solvent was evaporated, the residue was dissolved in 2 ml of methylene chloride and 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The residue after concentration under reduced pressure is diluted with water, and D
It was subjected to column chromatography of owex 50Wx4, washed with water, and eluted with 1M aqueous ammonia. After distilling off the aqueous ammonia under reduced pressure, the pH was adjusted to 2 with 1M hydrochloric acid and recrystallized from water to give the title compound (cis-BCG-I) 59m.
g was obtained (yield 43%). The product had the following physicochemical properties:

Properties: colorless crystals mp 187-189 ° C. (foaming decomposition) [α] ²³ _D + 32.8 ° (c0.40, 1M HCl) ¹ HNMR (D ₂ O, 400 MHz) δ 1.71 (dd,
1H, J = 4.9, 4.9 Hz), 1.76 (ddd,
1H, J = 4.9, 10.5, 10.7 Hz), 1.8
5 (dddd, 1H, J = 4.9, 4.9, 9.3, 1
0.5Hz), 3.35 (d, 1H, J = 10.7H
z), 3.40 (dd, 1H, J = 9.3, 11.2H
z), 3.92 (dd, 1H, J = 4.9, 11.2H
z), 4.50 (s, 2H), 7.30 (m, 5H).

Example 3 trans-MCG-I (see Scheme 2 above) (4S, 1'S, 2'S, 3'R) -Nt-butoxy
Carbonyl-2,2-dimethyl-4- (3-formyl-
2-methoxycarbonylcyclopropyl) -1,3-o
Xazolidine (8) described in International Publication No. WO93 / 08158 ((4)
S, 1 ′S, 2 ′S, 3′R) -Nt-butoxycarbonyl-2,2-dimethyl-4- [3- (t-butyldimethylsilyl) oxymethyl-2-methoxycarbonylcyclopropyl] In a tetrahydrofuran (THF) solution (3 ml) of 240 mg (0.54 mmol) of -1,3-oxazolidine (compound 7), 1M tetra-n fluoride.
-Butyl ammonium in THF solution (810 μl)
The mixture was added at 0 ° C and stirred for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (ether) to dissolve the lactone product in 2 ml of methanol, and
1 ml of an aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 3 with citric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the residue obtained was added with an ether solution of diazomethane to effect esterification and purified by silica gel column chromatography (ether). Obtained (4
S, 1'S, 2'S, 3'R) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3-hydroxymethyl-2-methoxycarbonylcyclopropyl) -1,3
-Pyridinium dichromate (PDC) (558 mg, 1.48 mmol) was added to a methylene chloride solution (2 ml) of oxazolidine (163 mg, 0.49 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ether and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (ether / hexane =
The title compound (8) 119 after purification by 1/3 to 1/1)
mg was obtained (74% yield). The product had the following physicochemical properties:

Properties: colorless solid mp84.0-86.6
C [α] ²³ _D -62.5 ° (c0.60, CHCI ₃ ) IR (neat) 3488, 2988, 2884, 17
_{^{32,1694cm -1 1 HNMR (CDCI 3,}} 400M
Hz) δ1.44 (s, 9H), 1.58 (s, 3)
H), 1.61 (s, 3H), 2.00 (ddd, 1
H, J = 9.0, 9.0, 9.0 Hz), 2.06
(M, 1H), 2.48 (dd, 1H, J = 9.0,
9.0 Hz), 3.79 (s, 3H), 3.86 (d,
1H, J = 9.0 Hz), 4.08 (dd, 1H, J =
6.0, 9.0 Hz), 4.68 (m, 1H), 9.8
9 (brs, 1H).

(4S, 1'S, 2'S, 3'S) -N-
t-butoxycarbonyl-2,2-dimethyl-4- (3
-Hydroxymethyl-2-methoxycarbonylcyclop
Ropyr) -1,3-oxazolidine (9) Compound (8) 112 mg (0.34 mmol) 0.1
It was dissolved in 10 ml of MCH ₃ ONa / CH ₃ OH and stirred at 70 ° C. for 6 hours. The reaction solution was neutralized with acetic acid, 60 mg (1.6 mmol) of sodium borohydride was added at 0 ° C., the mixture was stirred for 15 minutes, and then extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ether) to give 75 mg of the title compound (9) (yield 67%). The product had the following physicochemical properties:

Properties: Oily substance ¹ HNMR (CDCI ₃ , 400 MHz) δ1.44
(S, 9H), 1.54-1.64 (m, 7H), 1.
66 (m, 1H), 1.85 (dd, 1H, J = 5.
0, 9.0 Hz), 3.58 (m, 2H), 3.74
(S, 3H), 3.91 (d, 1H, J = 7.5H
z), 4.02 (m, 2H).

(4S, 1'S, 2'S, 3'S) -N-
t-butoxycarbonyl-2,2-dimethyl-4- (3
-Methoxymethyl-2-methoxycarbonyl cyclopro
Pill) -1,3-oxazolidine (10a) Compound (9) 75 mg (0.23 mmol) in DMF solution (2 ml) 18 mg sodium hydride (0.46 m)
mol) and tetra-n-butylammonium iodide 8 mg
(0.02 mmol) was added, and the mixture was stirred at 0 ° C for 20 minutes. 42 mg (0.69 mmol) of methyl iodide
Was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The excess reagent was decomposed by adding 5% citric acid aqueous solution at 0 ° C., and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried,
The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ether / hexane = 1/3) to obtain 52 mg of the title compound (10a) (yield 66%). The product had the following physicochemical properties:

Properties: Oily substance [α] ²³ _D −24.8 ° (c1.12, CHCI ₃ ) IR (neat) 2988, 2948, 1732, 17
_{^{02cm -1 1 HNMR (CDCI 3,}} 400MHz) δ1.44
(S, 12H), 1.58-1.68 (m, 5H),
1.83 (dd, 1H, J = 5.0, 9.0 Hz),
3.25-3.36 (m, 2H), 3.31 (s, 3)
H), 3.73 (s, 3H), 3.92 (d, 1H, J
= 7.0 Hz), 4.01 (m, 2H).

(4S, 1'S, 2'S, 3'S) -N-
t-Butoxycarbonyl-2,2-dimethyl-4- (2
-Formyl-3-methoxycarbonylcyclopropyl)
-1,3-Oxazolidine (11a) Compound (10a) 69 mg (0.20 mmol) in methylene chloride solution (2 ml) was added to diisobutylaluminum hydride 1.5M toluene solution 402 μl (0.60 mm).
was added at −78 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Ether was added to the reaction solution to dilute it, and excess reagents were decomposed with ice pieces. After washing with 1 M chlorine and saturated saline, the organic layer was dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ether) to obtain 54 mg of alcohol (yield 94%). This alcohol body 34
mg (0.12 mmol) methylene chloride solution (2 m
170 mg of pyridinium dichromate (PDC) in l)
(0.45 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ether and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ether) to give the title compound (11
a) 26 mg was obtained (yield 76%). The product had the following physicochemical properties:

Properties: Oily substance [α] ²³ _D + 6.9 ° (c0.65, CHCI ₃ ) IR (neat) 2992, 2944, 1708, 16
_{^{96cm -1 1 HNMR (CDCI 3,}} 400MHz) δ1.42
(S, 12H), 1.60 (s, 3H), 1.78 (d
dd, 1H, J = 5.0, 5.5, 11.5 Hz),
2.07 (ddd, 1H, J = 4.0, 5.0, 9.0
Hz), 3.28 (m, 1H), 3.31 (s, 3)
H), 3.37 (dd, 1H, J = 6.0, 10.0H
z), 3.77 (brs, 1H), 3.92 (dd, 1)
H, J = 1.5, 9.0 Hz), 4.03 (dd, 1)
H, J = 5.5, 9.0 Hz), 9.59 (d, 1H,
J = 4.0 Hz).

(2S, 1'S, 2'R, 3'S) -N-
t-butoxycarbonyl-2- (2-methoxycarbonyl
L-3-methoxymethylcyclopropyl) glycine
Chyl ester (13a) Compound (11a) 41 mg (0.13 mmol)
Dissolve in 10 ml of 1 MCH ₃ ONa / CH ₃ OH, 70 ℃
And stirred for 22 hours. The reaction solution is neutralized with acetic acid and purified by silica gel column chromatography (ether),
A 2.5: 1 mixture of the 2'R form (12a) and the raw material (11a) was obtained. This mixture was dissolved in acetone (2 ml), Jones reagent was added at 0 ° C., and the mixture was stirred at room temperature for 5 hr. 2-Propanol was added to decompose excess reagent, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the obtained residue was esterified by adding an ether solution of diazomethane. Purification by silica gel column chromatography (ether / hexane = 1/1) gave 15 mg of the title compound (13a) (yield 35
%). The product had the following physicochemical properties:

Properties: oily substance [α] ²³ _D + 42.6 ° (c1.00, CHCI ₃ ) IR (neat) 3384, 2984, 1730, 17
_{^{24cm -1 1 HNMR (CDCI 3,}} 400MHz) δ1.41
(S, 9H), 1.75 (m, 2H), 1.93 (d
d, 1H, J = 5.5, 9.0 Hz), 3.28 (s,
3H), 3.42 (dd, 1H, J = 8.0, 10.5)
Hz), 3.66 (dd, 1H, J = 5.0, 10.5)
Hz), 3.68 (s, 3H), 3.77 (s, 3)
H), 4.08 (m, 1H), 5.08 (brs, 1
H).

(2S, 1 ′S, 2′R, 3 ′S) -2-
(2-carboxy-3-methoxymethylcyclopropyl
G) Glycine (trans-MCG-1) (1'a) Compound (13a) 20 mg (0.06 mmol) TH
A 1 M aqueous sodium hydroxide solution was added to the F solution (1.5 ml), and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 5 hours. The reaction solution was adjusted to pH 1 with 1M hydrochloric acid and stirred at room temperature for 20 hours.
The residue obtained by concentration under reduced pressure was subjected to Dowex 50Wx4 column chromatography, washed with water, and eluted with 1M aqueous ammonia. Lyophilization was repeated to remove ammonia and to give the title compound (trans-MCG-I) (1 ′
a) 9.5 mg was obtained (yield 79%). The product had the following physicochemical properties:

Properties: colorless crystals mp164-168 ° C. [α] ²³ _D + 19.9 ° (c0.95, H ₂ O) ¹ HNMR (D ₂ O, 400 MHz) δ 1.68 (dd
d, 1H, J = 4.5, 5.0, 10.0 Hz), 1.
83 (dddd, 1H, J = 5.0, 5.5, 8.5,
9.5 Hz), 1.92 (dd, 1H, J = 4.5,
9.5Hz), 3.28 (d, 1H, J = 10.0H
z), 3.35 (s, 3H), 3.53 (dd, 1H,
J = 8.5, 11.0 Hz, 3.79 (dd, 1H,
J = 5.5, 11.0 Hz).

Test Example 1. Measurement of depolarizing activity The depolarizing activity of cis-MCG-I and trans-MCG-I in newborn rat spinal cord isolated specimens was measured by Shinoza.
ki et al. (Br. J. Pharmacol. 98).
Vol. 1213-1224, 1989). That is, using a newborn rat spinal cord extirpated sample, under artificial physiological fluid (spinal fluid) perfusion containing 0.5 μM of tetrodotoxin,
Extracellular recordings of depolarizing activity from the motor neuron anterior roots were measured for L-glutamic acid and the compounds of the invention at concentrations of 10 ⁻³ M to 10 ⁻⁷ M to determine the minimum effective concentration (ME).
C) was determined. As shown in Table 1, while the MEC of L-glutamic acid was measured to be 0.1 mM, ci
s-MCG-I and trans-MCG-I are 1 mM
However, it was revealed that it showed no depolarizing activity and almost no depolarizing activity.

Table 1 Compound minimum effective concentration (MEC) L-glutamic acid 1 × 10 ⁻⁴ M cis-MCG-I> 1 × 10 ⁻³ M trans-MCG-I> 1 × 10 ⁻³ M

Test Example 2. Measurement of monosynaptic reflex inhibitory activity The measurement of single synaptic reflex in a newborn rat spinal cord isolated specimen was performed by Otsuka (Masatoku Otsuka, Biological Science, Vol. 36, No. 4, 325).
~ 327 page) was used. That is,
The spinal cord of a newborn Wistar rat was removed under ether anesthesia while surrounded by the spinal column, and immersed in artificial spinal fluid saturated with 95% oxygen and 5% carbon dioxide, and anterior root and posterior from L3 to L5 under a stereoscopic microscope. Prepare a semi-sectioned spinal cord with the root attached. The obtained semi-sectioned spinal cord removed specimen is transferred to a perfusion tank and perfused with artificial spinal fluid saturated with 95% oxygen and 5% carbon dioxide.

A single stimulus is applied to the dorsal root via the suction electrode,
When recording the anterior root reflex potential from the same anterior root, an early time-course spike is observed, followed by a slow depolarization and an asynchronous potential change. This early spike corresponds to the monosynaptic reflex (Koni
shi, S.N. Advances in Pharma
cology and Therapeutics I
I, Pergamon, Oxford Vol. 2 p
255-260, 1982). Various concentrations of cis-MCG-I and tra were added to the perfusate.
ns-MCG-I was added and the monosynaptic reflex was measured, and its 50% inhibitory concentration (IC ₅₀ ) was determined.

The results are shown in Table 2 as cis-MCG.
-I and trans-MCG-I are each 4.0 μM,
The concentration of 0.5 μM suppressed the monosynaptic reflex by 50%.

Table 2 50% inhibitory concentration (IC ₅₀ ) of monosynaptic reflex inhibitory active compound cis-MCG-I 4.0 × 10 ⁻⁶ M trans-MCG-I 5.0 × 10 ⁻⁷ M

On the other hand, the IC ₅₀ of baclofen, a GABA (Gamma AminoButyric Acid) derivative, which is a therapeutic agent for spastic paralysis due to brain injury or the like, is 5 × 10 ⁻⁷ M.
Since it is measured to be about (0.5 μM), trans
IC ₅₀ of -MCG-I is equal to baclofen, cis
IC ₅₀ of -MCG-I corresponds to about 10 times the baclofen. Thus, cis-MCG-I and trans
It was found that -MCG-I exhibits monosynaptic reflex inhibitory activity at a low concentration with an IC ₅₀ of 0.1 μM order to μM order.

[0071]

INDUSTRIAL APPLICABILITY According to the present invention, cis-MC that selectively suppresses monosynaptic reflex with almost no depolarizing activity.
GI and trans-MCG-I and related compounds and methods for their preparation are provided. Cis of the present invention
-MCG-I and trans-MCG-I are agonists that act very little on the ion channel type receptor and have a very high selectivity for the metabotropic type receptor, and are of the L-glutamate receptor study. Not only useful as a biochemical reagent and pharmacological test reagent, but also expected to be applied as an anesthetic, anesthesia auxiliary, antispasmodic paralysis agent, muscle relaxant, antipyretic / analgesic agent due to its activity of suppressing nerve cell excitement it can. In addition, the related compound is useful as a biochemical reagent / pharmacological test reagent, including analysis of receptor binding ability and chemical structure.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Atsuko Shinozaki 477-17-15-507 Imaha-cho, Omiya City, Saitama Prefecture (72) Inventor Michiko Ishida 3-9-1-312 Naka-Aoki, Kawaguchi City, Saitama Prefecture

Claims (4)

[Claims] 1. A method (2S, 1 ′S, 2 ′) represented by the formula (1).
R, 3'R) -2- (2-carboxy-3-substituted oxymethylcyclopropyl) glycine. [Chemical 1] (In the formula, R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms.) 2. (2S, 1 ′S, 2 ′) represented by the formula (1)
R, 3′R) -2- (2-carboxy-3-substituted oxymethylcyclopropyl) glycine embedded image (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms),
(A) Formula (2): (In the formula, Boc represents a t-butoxycarbonyl group, TB
S represents a t-butyldimethylsilyl group. (4S, 1 ′S, 2′R, 3′R) -3-Nt-butoxycarbonyl-2,2-dimethyl-4- (3-t-butyldimethylsilyloxymethyl-2) -Methoxycarbonylcyclopropyl) -1,3-oxazolidine is removed
-Butyldimethylsilylated to give formula (3): (In the formula, Boc represents a t-butoxycarbonyl group.) (4S, 1'S, 2'R, 3'R) -3-Nt-butoxycarbonyl-2,2-dimethyl-4-. (3-Hydroxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine, (b) and then alkyl or aralkyl etherification to give a compound of formula (4) (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (4S, 1 ′S, 2 ′).
R, 3'R) -3-Nt-butoxycarbonyl-2,2
-Dimethyl-4- (3-substituted oxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine, (c) Next, the oxazolidine ring was opened, and the amino group was protected again with t-butoxycarbonyl group. Then, the formula (5): (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (2S, 1 ′S, 2 ′).
R, 3′R) -Nt-butoxycarbonyl-2- (2-
Methoxycarbonyl-3-substituted oxymethylcyclopropyl) glycinol, and (d) the alcohol was converted to a carboxylic acid by an oxidation reaction and then methyl esterified to give a compound of the formula (6): (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (2S, 1 ′S, 2 ′).
R, 3′R) -Nt-butoxycarbonyl-2- (2-
Methoxycarbonyl-3-substituted oxymethylcyclopropyl) glycine methyl ester, (e) then saponified and then det-butoxycarbonylated to give the compound of formula (1). 3. (2S, 1 ′S, 2 ′) represented by the formula (1 ′)
R, 3'S) -2- (2-Carboxy-3-substituted oxymethylcyclopropyl) glycine. [Chemical 8] (In the formula, R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms.) 4. (2S, 1 ′S, 2 ′) represented by the formula (1 ′)
R, 3 ′S) -2- (2-carboxy-3-substituted oxymethylcyclopropyl) glycine embedded image (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms),
(A) Formula (7): (In the formula, Boc represents a t-butoxycarbonyl group, TB
S represents a t-butyldimethylsilyl group. (4S, 1 ′S, 2 ′S, 3 ′S) -Nt-butoxycarbonyl-2,2-dimethyl-4- [3- (t-butyldimethylsilyl) oxymethyl-2 -Methoxycarbonylcyclopropyl] -1,3-oxazolidine is removed
-Butyldimethylsilylation followed by oxidation to give formula (8) (In the formula, Boc represents a t-butoxycarbonyl group.) (4S, 1'S, 2'S, 3'S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3 -Formyl-2-methoxycarbonylcyclopropyl) -1,3-
Oxazolidine is prepared, and (b) this is treated with an alkali to invert the configuration at the 3'position and then reduced to give the compound of the formula (9): (In the formula, Boc represents a t-butoxycarbonyl group.) (4S, 1'S, 2'S, 3'S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3 -Hydroxymethyl-2-methoxycarbonylcyclopropyl)-
1,3-oxazolidine, (c) and then alkyl or aralkyl etherification to give a compound of formula (10) (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (4S, 1 ′S, 2 ′).
S, 3 ′S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (3-substituted oxymethyl-2-methoxycarbonylcyclopropyl) -1,3-oxazolidine, (d) then this To reduce the formula (11) (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (4S, 1 ′S, 2 ′).
S, 3 ′S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (2-formyl-3-substituted oxymethylcyclopropyl) -1,3-oxazolidine, (e)
Then, this is subjected to an alkali treatment to invert the configuration at the 2'position to give a compound of the formula (12): (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (4S,
1 ′S, 2′R, 3 ′S) form, (f) Next, the alcohol form is converted into a carboxylic acid form by an oxidation reaction, and then methyl esterified to give a compound of the formula (13) (Wherein R represents a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Boc represents a t-butoxycarbonyl group) (2S, 1 ′S, 2 ′).
R, 3 ′S) -Nt-butoxycarbonyl-2- (2-
Methoxycarbonyl-3-substituted oxymethylcyclopropyl) glycine methyl ester, (g) followed by saponification and det-butoxycarbonylation to give the compound of formula (1 ′).