JPH0770018A - Labeled cyclopropane derivative and its production - Google Patents

Abstract

PURPOSE:To provide new (2S, 1'S, 2'S)-alpha-(2-labeled-2-carboxycylopropyl)glycine which is a selective agonist of metabolism-regulation type glutamic acid receptor and its new intermediate. CONSTITUTION:A (2S, 1'S, 2'S)-alpha-(2-labeled-2-carboxyclopropyl)glycine of formula I (R<2> is deuterium atom or tritium atom), e.g. (4S, 1'S, 2'S)-N-t- butoxycarbonyl-2,2-dimethyl-4-(2-deuterio-2-methoxycarbonylcyclopropyl )glycine. The compound of formula 1 can be provided by reducing the ester group of a compound of formula 3 (Boc is t-butoxycarbonyl; R<1> is a lower alkyl) to an alcohol, oxidizing the alcohol compound to obtain a compound of formula 4, treating with an alkali in a deuterated or tritiated solvent, oxidizing and esterifying the resultant compound of formula 5 and converting the obtained new intermediate compound of formula 2 through a compound of formula 6.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is a selective agonist of the metabotropic glutamate receptor (2S, 1 ′).
S, 2 ′S) -α- (2-carboxycyclopropyl)
Glycine (1a)

[0002]

[Chemical 7]

(A compound in which R ² is a hydrogen atom in the formula 1, hereinafter abbreviated as CCG-I) (a compound in which R ² is a deuterium atom or a tritium atom in the formula 1) and Formula (2) which is a synthetic intermediate thereof

[0004]

[Chemical 8]

(Hereinafter, in the present specification, R ¹ and R ³ each independently represent a lower alkyl group, R ² represents a deuterium atom or a tritium atom, and Boc represents t-.
(4S, 1 ′)
S, 2'S) -Nt-butoxycarbonyl-2,2-
It relates to dimethyl-4- (2-labeled-2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (2) and a method for producing the same.

[0006]

2. Description of the Related Art α- (2-Carboxycyclopropyl)
Glycine (hereinafter abbreviated as CCG) is a compound attracting attention as an agonist of glutamate receptors,
Among the eight isomers, CCG-I (1a) having the configuration of (2S, 1 ′S, 2 ′S) is an agonist that significantly activates the metabotropic glutamate receptor. It has been confirmed both physiologically and biochemically (Nakagawa et al .: European J. Pharma).
col. 84, 205, 1990. Ishida et al .: B
rain Research 537, page 311 1
990). Therefore, in order to further promote these studies, it was desired to synthesize these CCG compounds, particularly CCG-I, labeled compounds.

Of these eight CCG isomers, L
-A method for obtaining four 2S isomers corresponding to an amino acid is disclosed by the present inventors in JP-A-01-93563, and is an intermediate of CCG-I (2S, A simple synthesis method of 1'S, 2'S) -Nt-butoxycarbonyl-2- (2-lower alkoxycarbonylcyclopropyl) glycinol has also been applied for a patent by the present inventors (Japanese Patent Application No. 05- 086635).

[0008]

However, since these synthetic methods cannot be applied to the synthesis of labeled CCG-I, it has been desired to develop a new synthetic route applicable to labeling. .

[0009]

The present inventors have found that (2S, 1'S, 2'R) -Nt-butoxycarbonyl-2- (2-lower alkoxycarbonylcyclopropyl) obtained in relatively large amounts. ) Glycinol (Tetrahedro)
n Letters 29, 3803, 1989) was converted to an oxazolidine derivative by a known method (4S, 1 ′S, 2′R) -Nt-butoxycarbonyl-2,2-dimethyl-4-. Attention was paid to (2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (3), and the inventors diligently attempted to invert the 2′-position thereof and introduce a label at this position.

As a result, the ester portion of the compound (3) is reduced to an alcohol, which is then oxidized to give (4S, 1'S, 2'R) -Nt-butoxycarbonyl-2, 2-dimethyl-4- (2-formylcyclopropyl) -1,3-oxazolidine (4),
Then, this is treated with an alkali in the presence of a deuterated or tritiated solvent to obtain (4S, 1'S, 2'S)
-Nt-butoxycarbonyl-2,2-dimethyl-4
-(2-labeled-2-formylcyclopropyl)-
1,3-oxazolidine (5), which was then oxidized and then esterified to label (4S, 1'S, 2'S) -Nt-butoxycarbonyl-2 at the 2'position. , 2-Dimethyl-4- (2-labeled-2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (2) was found to be obtained, and the present invention was completed.

That is, according to the present invention, the following reaction process formula

[0012]

[Chemical 9]

(4S, 1'S, 2'R) -N according to
-T-butoxycarbonyl-2,2-dimethyl-4-
(2-lower alkoxycarbonylcyclopropyl)-
Using 1,3-oxazolidine (3) as a raw material (4S,
1'S, 2'S) -Nt-butoxycarbonyl-2,
2-Dimethyl-4- (2-labeled-2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (2) can be obtained.

Next, each step in the process will be described. First, the ester moiety of the compound (3) is reduced to an alcohol compound, which is further oxidized to (4S, 1 ′).
S, 2′R) -Nt-butoxycarbonyl-2,2-
Dimethyl-4- (2-formylcyclopropyl) -1,
3-Oxazolidine (4) can be obtained.

As the reducing agent used here, various known reducing agents can be used, but it is preferable to use diisobutylaluminum hydride from the viewpoint of reactivity. Also,
As the oxidizing agent, various known oxidizing agents can be used, but it is preferable to use a sulfur trioxide / pyridine complex.

The resulting compound (4) is treated with an alkali in the presence of a deuterated or tritiated solvent to invert the 2'position and introduce a label at this position. 4S, 1'S, 2'S) -N-t
-Butoxycarbonyl-2,2-dimethyl-4- (2-
Labeled 2-formylcyclopropyl) -1,3-oxazolidine (5) can be obtained.

Here, the deuterated or tritiated solvent means a solvent in which hydrogen that can be exchanged when the 2'-position is inverted is deuterated or tritiated, and is deuterated methanol (CD ₃ OD). ), Deuterated methanol- (C
Examples include deuterated or tritiated alcohols such as H ₃ OD) and tritiated methanol (CH ₃ OT). Examples of the alkali used for the alkali treatment include alkali metal alcoholates such as sodium methylate. Here, when introducing a tritium label, a tritium label compound having a desired radioactivity can be obtained by selecting a solvent having various degrees of tritiation in accordance with the required radioactivity.

The obtained compound (5) is oxidized to a carboxylic acid with an oxidizing agent such as potassium permanganate and then esterified to obtain the desired (4S, 1'S, 2'S) -N-.
t-Butoxycarbonyl-2,2-dimethyl-4- (2
-Labeled-2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (2) can be obtained.

Here, the lower alkyl group represented by R ¹ and R ³ means a linear or branched alkyl group having 1 to 4 carbon atoms, and a 2′-position carboxyl group in the CCG synthesis step. Protect. Examples of such an alkyl group include a methyl group, an ethyl group, a linear or branched propyl group, a linear or branched butyl group, and the like.
Methyl and ethyl groups are preferred.

This cyclopropane derivative (2) is disclosed in JP-A-01-093563 and Japanese Patent Application No. 05-086.
No. 635, the following reaction process formula is described.

[0021]

[Chemical 10]

According to the method, after opening the oxazolidine ring,
Obtained by reprotecting the amino group (2S, 1'S, 2 '
S) -Nt-butoxycarbonyl-2- (2-labeled-2-loweralkoxycarbonylcyclopropyl) glycinol via Jones oxidation of the hydroxymethyl group at the 1-position and methyl esterification, saponification and amino group The labeled CCG-I (1) can be obtained through the deprotection step of.

[0023]

EXAMPLES Next, the present invention will be described in more detail by way of examples with respect to the case of deuterium labeling, but the scope of the present invention is not limited to these. Also in the case of a tritium label, in step 2 of this example, CH ₃ ON was used instead of the CD ₃ ONa / CD ₃ OD solution.
It goes without saying that the synthesis can be performed by using an a / CH ₃ OT solution.

Example 1. (4S, 1'S, 2'S) -N
-T, butoxycarbonyl-2,2-dimethyl-4-
(2-deuterio-2-methoxycarbonylcyclop
Ropil) 1,3-oxazolidine (2a, odor of formula 2
And R ³ is a methyl group and R ² is a deuterium atom.
Compound) :

Step 1. (4S, 1'S, 2'R)-
Nt-butoxycarbonyl-2,2-dimethyl-4-
(2-formylcyclopropyl) -1,3-oxazoli
Synthesis of gin (4): (4S, 1'S, 2'R) -NT
-Butoxycarbonyl-2,2-dimethyl-4- (2-
Methoxycarbonylcyclopropyl) -1,3-oxazolidine (3a, a compound in which R ¹ is a methyl group in Formula 3) 576 mg (1.92 mmol) in methylene chloride solution (5 ml) was added to diisobutylaluminum hydride 1.5M toluene. 4.2 ml (6.3 mmol) of the solution was added at -78 ° C, and the mixture was stirred at 0 ° C for 30 minutes. The reaction solution was diluted with ether, and ice pieces were added to decompose excess reagents. The organic layer was dried after washing with 1M hydrochloric acid and saturated brine, and the resulting residue was purified by silica gel column chromatography (ether).

To 10 ml of a dimethylsulfoxide (DMSO) solution of the obtained oily compound, 917 mg (5.76 mmol) of sulfur trioxide / pyridine complex and 810 μl (5.76 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 1 hour.
Stir for 5 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate, and the organic layer was washed with a 5% aqueous citric acid solution and saturated saline. After drying, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography (ether),
357 mg of the title compound (4) was obtained (yield 62%).

The physical properties of the obtained compound (4) are shown below. Properties: Amorphous solid [α] ²³ _D : -49.5 ° (c0.95, CHC
l ₃ ) IR (neat) (cm ⁻¹ ): 2992,294
4,2892,1696,1386 ¹ H-NMR (δ ppm) (CDCl ₃ , 400 MH)
z): 1.10 (m, 2H), 1.45 (s, 9H),
1.58 (s, 6H), 2.11 (m, 1H), 3.7
2 (brs, 1H), 3.92 (d, 1H, J = 8.5
Hz), 4.03 (dd, 1H, J = 5.5, 8.5H
z), 9.57 (d, 1H, J = 4.0 Hz)

Step 2. (4S, 1'S, 2'S)-
Nt-butoxycarbonyl-2,2-dimethyl-4-
(2-Duterio-2-formylcyclopropyl)-
1,3-oxazolidine (5a, in Formula 5, R ² is
Synthesis of deuterium atom): (4S, 1 ′S, 2′R) -Nt-butoxycarbonyl-2,2-dimethyl-4- (2-formylcyclopropyl) obtained in Step 1 -1,3-oxazolidine (4) 20 mg
(0.074 mmol) of 0.1 MCD ₃ ONa / CD
₃ OD 1 ml solution was stirred at 65 ° C. for 2 days. The reaction solution was neutralized with acetic acid and extracted with ethyl acetate. The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel cam chromatography to obtain 17 mg of the title compound (5a).

The physical properties of the obtained compound (5a) are shown below. Properties: colorless crystals Melting point: 74.5-76.0 ° C. [α] ²³ _D : + 74.9 ° (c0.67, CHC
l ₃ ) IR (neat) (cm ⁻¹ ): 2988,294
8, 2876, 1700, 1384 ¹ H-NMR (δ ppm) (CDCl ₃ , 400 MH
z): 0.98 (dd, 1H, J = 5.5, 5.5H
z), 1.24 (dd, 1H, J = 5.5, 9.0H
z), 1.44 (s, 9H), 1.60 (m, 6H),
1.80 (dd, 1H, J = 5.5, 9.0 Hz),
3.50 (m, 0.5H), 3.78 (m, 1.5
H), 3.98 (m, 1H), 9.02 (brs, 0.
5H), 9.25 (brs, 0.5H) MS (FAB) m / z: 271 (M + H) ⁺

Step 3. (4S, 1'S, 2'S)-
Nt-butoxycarbonyl-2,2-dimethyl-4-
(2-deuterio-2-methoxycarbonylcyclop
Ropil) 1,3-oxazolidine (2a, odor of formula 2
And R ³ is a methyl group and R ² is a deuterium atom.
Compound) : (4S, 1 ′S, obtained in Step 2 )
2'S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (2-du-terio-2-formylcyclopropyl) -1,3-oxazolidine (5a) 6.8 mg
(0.025 mmol) t-butanol solution (0.2
100 ml of 1M sodium hydroxide and 0.25M
An aqueous potassium permanganate solution (500 μl) was added, and the mixture was stirred at room temperature for 3 hours. The excess reagent was decomposed with a 5% aqueous Na ₂ S ₂ O ₃ solution, diluted with ether, washed with 1M hydrochloric acid and saturated saline, and the organic layer was dried and concentrated under reduced pressure. To the residue ether solution (1 ml) was added a diazomethane ether solution to form a methyl ester, which was purified by silica gel column chromatography (ether) to give the title compound (2a).
4.2 mg was obtained (60% yield).

The physical properties of the obtained compound (2a) are shown below. Properties: Oily substance [α] ²³ _D : + 67.0 ° (c0.77, CHC
l ₃ ) IR (neat) (cm ⁻¹ ): 2988,173
4,1700,1390 ¹ H-NMR (δppm) (CDCl ₃ , 400 MH)
z): 0.75 (m, 0.5H), 0.80 (m, 0.
5H), 1.12 (dd, 1H, J = 4.5, 9H
z), 1.45 (s, 9H), 1.40 to 1.65
(M, 6H), 1.70 (ddd, 1H, J = 4.5,
8.0, 8.0 Hz), 3.37 (m, 0.5H),
3.67 (s, 3H), 3.79 (m, 1.5H),
3.94 (m, 1H)

[0032]

According to the present invention, (4S, 1'S, 2'S) -Nt-butoxycarbonyl-2,2-dimethyl-4- (2-label) having a label introduced at the 2'position is introduced. Conversion-2-
Methoxycarbonylcyclopropyl) -1,3-oxazolidine (2) can be prepared. This cyclopropane derivative (2) was labeled with CC by a known method.
According to the present invention, the labeled CCG-I, which is important as a research reagent for biochemistry, pharmacology, and physiology, can be synthesized because it can lead to GI (1).

Therefore, the present invention not only contributes to the study of glutamate receptors via labeled CCG-I, but also contributes to the development of pharmaceuticals through the development of glutamate receptor agonists.

Claims (3)

[Claims] 1. A formula (1): (In the formula, R ² represents a deuterium atom or a tritium atom.) (2S, 1 ′S, 2 ′S) -α- (2
Labeled-2-carboxycyclopropyl) glycine (1). 2. Formula (2): (In the formula, R ² represents a deuterium atom or a tritium atom, R ³ represents a lower alkyl group, and Boc represents a t-butoxycarbonyl group.) (4S, 1 ′S,
2'S) -N-t-butoxycarbonyl-2,2-dimethyl-4- (2-labeled-2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (2). 3. Formula (3): (In the formula, Boc represents a t-butoxycarbonyl group, and R
¹ is a lower alkyl group) (4S, 1 ')
S, 2′R) -Nt-butoxycarbonyl-2,2-
The ester moiety of dimethyl-4- (2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (3) is reduced to an alcohol, which is then oxidized to give a compound of formula (4): (Where Boc is the same as above) (4S, 1 ′
S, 2′R) -Nt-butoxycarbonyl-2,2-
Dimethyl-4- (2-formylcyclopropyl) -1,
3-oxazolidine (4) is treated with an alkali in the presence of a deuterated or tritiated solvent to give the compound of formula (5) (In the formula, R ² represents a deuterium atom or a tritium atom, and Boc represents the same as the above) (4
S, 1'S, 2'S) -Nt-butoxycarbonyl-
2,2-Dimethyl-4- (2-labeled-2-formylcyclopropyl) -1,3-oxazolidine (5), which was then oxidized and esterified to give the compound of formula (2) (In the formula, R ² and Boc represent the same as above, and R ^2
3 represents a lower alkyl group) (4S, 1 ′)
S, 2'S) -Nt-butoxycarbonyl-2,2-
A method for producing dimethyl-4- (2-labeled-2-lower alkoxycarbonylcyclopropyl) -1,3-oxazolidine (2).