JP2000336068A - New carboxylic acid derivative and its preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new carboxylic acid derivative useful for an effective synthesis of a compound having therapeutic and preventive effects to schizophrenia, etc., which is synthesized from a specific cyclopentenone derivative and a specific sulfonium ylide compound, etc. as starting materials. SOLUTION: This compound is expressed by formula I (R1 is H, a 1-6C alkyl or the like; R2 and R3 are each a 1-6C alkyl, 3-6C cycloalkyl or the like; and Y1 and Y2 are each S, O or N), for example, (1RS, 5RS, 6RS)-ethyl 4,4- ethylenedithio-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The compound of formula I is obtained by reacting a compound of formula II (R4 is or a protecting group for hydroxyl) and a sulfonium ylide of the formula, (CH3)2S=CHCO2R5 (R5 is a 1-6C alkyl, 3-6C cycloalkyl or the like) and then obtaining a compound of formula III by protecting the carbonyl group of the product compound and changing the R4 into H in the case of the R4 of the compound of the formula III is not H and then oxidizing the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a 2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivative and a method for producing the same.

[0002]

2. Description of the Related Art Metabolotopic glutamate receptors, which are a kind of glutamate receptors, are classified pharmacologically into three groups. Group 2 (mGl
uR2 / mGluR3) binds adenyl cyclase and inhibits forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmac
ol. Sci., 14 13 (1993)), compounds that act on the group 2 metabolic topic glutamate receptor are schizophrenia, anxiety and related diseases, depression, bipolar disorder,
Psychiatric disorders such as epilepsy, such as drug addiction, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, motor disorders associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord disorders, head disorders and other neurology. It is said to have a therapeutic effect and a preventive effect on experimental diseases.

The present inventors have proposed that one of the useful compounds acting on the group 2 metabotropic glutamate receptor is 2-amino-4-oxobicyclo [3.1.0].
Hexane-2,6-dicarboxylic acid (7) was invented (Japanese Patent Application No. 10-246344). Japanese Patent Application No. Hei 10-24634
In the specification of Patent No. 4, as a production method, as shown below, benzyl alcohol is added to an enone derivative (8) to form a benzyloxy compound (9), and this is converted into a hydantoin derivative (10) by hydantoinization. Then, a synthesis method has been proposed in which the compound is converted to a thioketal-hydantoin derivative (11) by debenzylation, oxidation and thioketalization and further hydrolyzed (in the following reaction formula, R ² , R ³ and R ⁵ are the same). Or differently, carbon number 1-1
0 represents a lower alkyl group. However, R ² and R ³ together may represent-(CH ₂ ) _n- (n is 2 or 3).

Embedded image

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide schizophrenia, anxiety and related disorders, depression, bipolar disorder,
Psychiatric disorders such as epilepsy, as well as nervous disorders such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders. For efficient synthesis of 2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid acting on group 2 metabotropic glutamate receptor having therapeutic and preventive effects on biological diseases An object of the present invention is to provide a useful novel synthetic intermediate and a method for producing the same.

[0005]

The present inventors have conducted intensive studies and have found that 4-hydroxy-2-cyclopentenone or a compound in which the hydroxyl group is protected, which is easily supplied from furfuryl alcohol, is used as a starting material. Obtained as
2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivative (1) is converted to 2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (7).
The present invention was found to be useful for efficient synthesis of

[0006] That is, one embodiment of the present invention is represented by the following formula (1).

Embedded image [Wherein, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C
₆ cycloalkyl groups, C ₃ -C ₆ cycloalkyl C ₁ -C ₆
Alkyl group, aryl group, aryl C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, C ₁ -C ₆
Hydroxyalkyl group, C ₁ -C ₆ alkylthio C ₁ -C ₆
It represents an alkyl group, a C ₁ -C ₆ mercaptoalkyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group. R
² and R ³ are identical or different C ₁ -C ₆ alkyl group, C ₃ ~
C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C
_{A 6} alkyl group, an aryl group or an aryl C ₁ -C ₆ alkyl group, or together form — (CH ₂ ) _n — (n
Represents 2 or 3). Y ¹ and Y ² are the same or different and represent a sulfur atom, an oxygen atom or a nitrogen atom. 2]
-Oxobicyclo [3.1.0] hexane-6-carboxylic acid derivative.

Another aspect of the present invention is a method of formula (2)

Embedded image[Wherein, R^FourRepresents a hydrogen atom or a hydroxyl-protecting group. ]
To the cyclopentenone derivative represented by_TwoS = CHC
O_TwoR^Five[Wherein, R^FiveIs C₁~ C₆Alkyl group, C_Three~ C₆Shi
Chloroalkyl group, C_Three~ C₆Cycloalkyl C₁~ C₆Al
Kill group, aryl group, aryl C₁~ C₆Alkyl group, C
₁~ C₆Alkoxy C₁~ C₆Alkyl group, C ₁~ C₆Hydro
Xyalkyl group, C₁~ C₆Alkylthio C₁~ C₆Archi
Group, C₁~ C₆Mercaptoalkyl group, tetrahydrof
It represents a lanyl group or a tetrahydropyranyl group. ]
Or reacting the sulfonium ylide_TwoS
⁺CH_TwoCO_TwoR^Five・ X^-[Wherein, R^FiveIs the same as above.
X represents a chlorine atom, a bromine atom or an iodine atom. ]
By reacting the sulfonium salt
(3)

Embedded image Wherein R ⁴ and R ⁵ are the same as above. And the step of protecting the carbonyl group of the bicyclic compound to obtain a compound of the formula (4)

Embedded image Wherein R ² and R ³ are the same or different and are a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group, an aryl group or an aryl C _1-
Represents a C ₆ alkyl group or together forms — (C
H ₂ ) _n- (n is 2 or 3). Y ¹ and Y ² are the same or different and represent a sulfur atom, an oxygen atom or a nitrogen atom. R
⁴ and R ⁵ are the same as described above. A step of a derivative represented by, otherwise R ⁴ is a hydrogen atom of the derivative R ⁴
Converting the compound to a hydrogen atom and then oxidizing the derivative. 2-oxobicyclo [3.1.0] hexane-6-
This is a method for producing the carboxylic acid derivative (1).

[0008] Still another embodiment of the present invention provides a compound of the formula (5) which can be obtained from the carboxylic acid derivative (1).

Embedded image [Wherein, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C
₆ cycloalkyl groups, C ₃ -C ₆ cycloalkyl C ₁ -C ₆
Alkyl group, aryl group, aryl C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, C ₁ -C ₆
Hydroxyalkyl group, C ₁ -C ₆ alkylthio C ₁ -C ₆
It represents an alkyl group, a C ₁ -C ₆ mercaptoalkyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group. R
² and R ³ are identical or different C ₁ -C ₆ alkyl group, C ₃ ~
C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C
_{A 6} alkyl group, an aryl group or an aryl C ₁ -C ₆ alkyl group, or together form — (CH ₂ ) _n — (n
Represents 2 or 3). Y ¹ and Y ² are the same or different and represent a sulfur atom, an oxygen atom or a nitrogen atom. And a bicyclo [3.1.0] hexane-6-carboxylic acid derivative represented by the following formula:

The terms used in the present invention are defined below. In the present invention, “C _n -C _m ” indicates that the following group has nm carbon atoms.

A C ₁ -C ₆ alkyl group has 1 to 6 carbon atoms.
Represents a linear or branched alkyl group having, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group, t-butyl group, pentyl group,
And isopentyl, hexyl, and isohexyl groups.

The C ₃ -C ₆ cycloalkyl group is a cyclic alkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclopentyl group and a cyclohexyl group.

The C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group has a complex form of a C ₃ -C ₆ cycloalkyl group and a C ₁ -C ₆ alkyl group, for example, a cyclopropylmethyl group. , Cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group and the like.

The aryl group is a phenyl group, a naphthyl group or the like, and is preferably a phenyl group. Aryl C _1-
A C ₆ alkyl group is at least one or more aryl groups;
A phenyl group, preferably substituted with 1 to 1 carbon atoms
It represents a linear or branched alkyl group having six, such as a benzyl group, a diphenylmethyl group, a 1-phenylethyl group, and a 2-phenylethyl group.

The C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group has a complex form of a C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ alkyl group. Here, the C ₁ -C ₆ alkoxy group refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group. Group, isobutoxy group, t-butoxy group, pentyloxy group, isopentyloxy group and the like. Therefore, C _{1 to} C ₆
Examples of alkoxy C ₁ -C ₆ alkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, pentyloxyethyl Group, isopentyloxyethyl group and the like.

The C ₁ -C ₆ hydroxyalkyl group represents a C ₁ -C ₆ alkyl group substituted with at least one hydroxyl group. Accordingly, examples of the C ₁ -C ₆ hydroxyalkyl group include a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and the like.

The C ₁ -C ₆ alkylthio C ₁ -C ₆ alkyl group has a complex form of a C ₁ -C ₆ alkylthio group and a C ₁ -C ₆ alkyl group. Here, the C ₁ -C ₆ alkylthio group refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, and a butylthio group. Group, isobutylthio group, t-butylthio group, pentylthio group, isopentylthio group and the like. Accordingly, examples of the C ₁ -C ₆ alkylthio C ₁ -C ₆ alkyl group include a methylthiomethyl group, a 2-methylthioethyl group, and the like.

The C ₁ -C ₆ mercaptoalkyl group represents a C ₁ -C ₆ alkyl group substituted with at least one mercapto group. Accordingly, examples of the C ₁ -C ₆ mercaptoalkyl group include a 2-mercaptoethyl group, a 3-mercaptopropyl group, a 2,3-dimercaptopropyl group, and the like.

In the various groups described above, at least one hydrogen atom on the group is, for example, a fluorine atom, a chlorine atom,
A halogen atom such as a bromine atom or an iodine atom, a nitro group, an amino group, a hydroxyl group, a thiol group, a formyl group, a carboxyl group, a cyano group, a carbamoyl group, a methyl group,
Alkyl groups such as ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group; phenyl group, naphthyl group, biphenyl Groups, anthranyl groups, pyrrolyl groups, pyridyl groups, thienyl groups and other aryl groups and heterocyclic groups; methoxycarbonyl groups, ethoxycarbonyl groups and other alkoxycarbonyl groups; acetyl groups, benzoyl groups and other acyl groups; methoxy groups and ethoxy groups , An alkoxythio group such as a propoxy group; an alkylthio group such as a methylthio group, an ethylthio group or a propylthio group; or a non-hydrogen atom or a group. Therefore, for example, R ¹ and R ² also include a 2,2,2-trichloroethyl group, a phenacyl group, a 2,6-dimethylcyclohexyl group, a 4-methoxybenzyl group, and the like. The number of carbon atoms in these substituents is not included in n or m described above.

In the present invention, the hydroxyl-protecting group is
C written₁~ C₆Alkyl group, C_Three~ C₆Cycloalkyl
Group, C_Three~ C₆Cycloalkyl C₁~ C₆Alkyl group, ant
Group, aryl C₁~ C₆Alkyl group, C₁~ C₆Arco
Kishi C₁~ C₆Alkyl group, C ₁~ C₆Hydroxyalkyl
Group, C₁~ C₆Alkylthio C₁~ C₆Alkyl group, C₁~
C₆Mercaptoalkyl group, tetrahydrofuranyl group and
And tetrahydropyranyl groups, acyl groups or trisubstituted groups
Includes commonly used protecting groups such as silyl groups. here,
An acyl group is a straight or branched chain having 1 to 6 carbon atoms.
An aliphatic or aromatic acyl group, such as an acetyl group,
And pivaloyl and benzoyl groups. In addition, trisubstitution
Ryl is an alkyl or phenyl group having 1 to 6 carbon atoms.
A silyl group having three optional substituents
For example, trimethylsilyl group, triethylsilyl group,
tert-butyldimethylsilyl group, tert-butyldiphenyl
And a lusilyl group.

In the compound represented by the formula (1), R ²
-Y ¹ -and R ³ -Y ^2- represent the same group, or
Y ¹ and Y ² are the same and R ² and R ³ together
(CH ₂ ) n- (n is 2 or 3) represents 1,5
And three asymmetric carbon atoms at position 6. Also, Y ¹
Or when Y ² or R ² or R ³ is different, 1,4
There are four asymmetric carbon atoms at positions 5 and 6. Therefore, the compound of the present invention can exist as an enantiomer mixture such as an optically active substance, a racemate or a diastereomer mixture. That is, the compound of the present invention includes all of the optically active and racemic forms of the compound represented by the formula (1), including enantiomeric mixtures and diastereomeric mixtures.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula (1) according to the present invention can be produced by the following reaction. (In the following reaction formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Y ² are the same as described above.)

Embedded image

Step 1: One step from furfuryl alcohol
(When R ⁴ is a hydrogen atom) or in two steps (when R ⁴ is other than a hydrogen atom) (2) (JP-A-57-62).
No. 236), the previously prepared Me ₂ S = CHCO ₂
Sulfonium ylide wherein represented by R ^5, R ⁵ are as defined above. Is reacted in an inert solvent, or M
e ₂ S ⁺ CH ₂ CO ₂ R ⁵ .X ⁻ [wherein, R ⁵ is the same as defined above. X represents a chlorine atom, a bromine atom and an iodine atom. And the reaction is carried out in an inert solvent in the presence of a base to obtain a bicyclic compound (3).

Examples of the inert solvent include hydrocarbon solvents such as benzene, toluene and hexane; halogen solvents such as dichloromethane and chloroform; ether solvents such as tetrahydrofuran and diethyl ether; acetonitrile; Etc. can be used. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine and 1,8-diazabicyclo [5.4.0] -7-undecene, and inorganic bases such as potassium carbonate and sodium hydroxide. Can be used. This reaction is preferably performed at a temperature of 0 to 30 ° C. When a sulfonium ylide represented by Me ₂ S = CHCO ₂ R ⁵ is used, the reaction is preferably performed for 12 hours to 3 days.

Step 2: The carbonyl group site of the bicyclic compound (3) is protected by Protecting Groups in Organic Synthesis (The
The derivative (4) is protected by a general method as described in odora W. Greene, John Wilely & Sons Inc.). Examples of the form of protection of the carbonyl group include, for example, dimethyl ketal, diethyl ketal, 1,3-
Dioxane, 1,3-dioxolan, S, S'-dimethylketal, 1,3-dithiane, 1,3-dithiolan, 1,
Protected forms in the general cyclic or acyclic form, such as 3-oxathiolane, oxazolidine, N-methyloxazolidine, can be employed.

For example, when R ⁴ is a silyl protecting group or the like,
In the case of a protecting group that can be easily replaced with a hydrogen atom in the presence of a Lewis acid, for example, by protecting the carbonyl group site in the presence of a Lewis acid such as boron trifluoride diethyl ether complex, the hydroxyl group side The protecting group may be removed and R ⁴ ＨH.

Step 3: When R ⁴ is other than a hydrogen atom in the derivative (4), the protecting group R ⁴ for the hydroxyl group is deprotected to R ⁴ ＨH, followed by oxidation to obtain the compound of the present invention. It can be derived to a certain (±) -2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivative (1). Here, the deprotection of the hydroxyl-protecting group R ⁴ is performed, for example, when R ⁴ is an acyl-type protecting group, for example, an alcohol-based solvent such as methanol or ethanol, for example, a ketone such as acetone or methyl ethyl ketone, or an ether such as tetrahydrofuran. The reaction can be carried out in a system solvent, water or a mixed solvent thereof with an organic solvent, for example, in the presence of an inorganic base such as potassium carbonate or sodium hydroxide.
Further, when R ⁴ is a benzyl group, for example, deprotection can be performed by hydrogenation or Birch reduction using palladium as a catalyst. Further, for example, when R ⁴ is a silyl-based protecting group, deprotection can be performed using a desilylating agent such as tetra-n-butylammonium fluoride (Protecting Groups in Organic Synthesis).
(See Theodora W. Greene, John Wilely & Sons Inc.)).

Here, the oxidation means, for example, Jones oxidation, Collins oxidation, or pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC).
Chromium-based oxidizing agents represented by, for example, potassium permanganate, manganese-based oxidizing agents such as manganese dioxide, for example, oxalyl chloride, acetic anhydride, diphosphorus pentoxide, sulfur trioxide-pyridine and the like as an activator Dimethyl sulfoxide-based oxidizing agent used, for example, palladium, oxygen oxidation using platinum or the like as a catalyst, for example, cerium-based oxidizing agent such as diammonium cerium, cerium sulfate, tetrapropylammonium perruthenate, ruthenium-based oxidizing agent such as ruthenium oxide, For example, Dess
-Martin reagents, etc. (OXIDATIONS IN ORGANIC CHEMIST
RY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, 1990, MI
Oxidizing agents such as ethers such as tetrahydrofuran and diethyl ether; hydrocarbons such as toluene and benzene; halogenated solvents such as dichloromethane and chloroform; and ketones such as acetone and ethyl methyl ketone. , Acetonitrile, N, N-dimethylformamide, acetic acid, pyridine, water, or an inert solvent such as a mixed solvent thereof.

Here, when R ¹ is a lower alkyl group or a benzyl group, R ¹ can be converted to a hydrogen atom by hydrolysis of the ester under acidic or basic conditions. Also, if R ¹ is a benzyl group, it can also be converted to R ¹ a hydrogen atom by hydrogenation.

The (±) -form carboxylic acid derivative (1) can be obtained by (+) HPLC method using a chiral carrier such as a cellulose carbamate derivative or an amylose carbamate derivative.
It can be optically divided into a body and a (-) body. Further, a carboxylic acid derivative of the (±) form wherein R ¹ is a hydrogen atom
(1) is, for example, (+) or (−)-1-phenylethylamine, (+) or (−)-phenylglycinol, (+) or
Using salts with optically active amines such as (−)-2-amino-1-butanol, (+) or (−)-alaninol, brucine, cinchonidine, cinchonine, quinine, quinidine, dehydroabiethylamine, or Even when an amide derivative with an optically active primary or secondary amine is introduced, it can be optically resolved into (+)-form and (-)-form.

By the way, 2-oxobicyclo [3.1.
0] The hexane-6-carboxylic acid derivative (1) has a carbonyl group site protected by a pair of R ² —Y ¹ and R ³ —Y ² and an unprotected carbonyl group site as shown in the following formula. The compound (12) which is equivalent to the (+)-form (1) is obtained by converting the (-)-form carboxylic acid derivative (1) into each other.
And the (+)-form carboxylic acid derivative (1) can be converted to the compound (12) equivalent to the (-)-form (1). (In the following formula, R ¹ , R ² , R ³ , Y ¹ and Y ² are the same as above, R ⁶ and R ⁷ are the groups defined by R ² and R ³ , and Y ³ and Y ⁴ are It is the same as defined for Y ¹ and Y ^2. )

Embedded image

That is, (+) divided from the (±) field
Each of the optically active forms (-) and (-) can be used without waste in the synthesis of the optically active form of 2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (7). it can. Thus, the carboxylic acid derivative (1) of the present invention is extremely useful for the synthesis of optically active 2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (7). is there.

Such conversion is performed, for example, as follows.
I can. That is, for example, one carbonyl group
R to protect^Two-Y¹-And R^Three-Y^Two-Together-S
CH _TwoCH_TwoWhen it represents an S-group, it is unprotected
The other carbonyl group is, for example, -OCH_TwoCH_TwoO-group
While protecting -SCH_TwoCH_TwoSelect only S-group
Protecting Groups in Organic Synth
esis (Theodora W. Greene, John Wilely & Sons In
c.)). Thereby, initially, -SCH_TwoCH_TwoIn the S-group
The protected carbonyl group becomes unprotected and
On the other hand, the unprotected carbonyl group is -OCH_TwoCH_Two
Protected by O-group. In this way the optically active
Change the protection position of the carbonyl group of the carboxylic acid derivative (1)
In this way, the carboxylic acid derivative (1) can be used without waste.
Can be used.

The carboxylic acid derivative (1) of the present invention can be obtained, for example, through the following steps by subjecting it to 2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (7).
Is converted to

Step 4: The (±), (+) or (−)-carboxylic acid derivative (1) is synthesized from Strecker Amino Acid
ino Acid Synthesis) (Ann., 75 , 27 (1850); 91 , 349 (185
0)), Bucherer-Bergs React
ion) (J. Prakt. Chem., 140 , 69 (1934)) or a modification thereof leads to a hydantoin derivative (5) or an aminocyanide derivative (6).

Step 5: The hydantoin derivative (5) or the aminocyanide derivative (6) is obtained by deprotection of a carbonyl group site protected by a pair of R ² —Y ¹ — and R ³ —Y ² — and hydrolysis. (±), (+) or (−)-2-amino-4-oxobicyclo [3.1.0] hexane-2,6
-To the dicarboxylic acid (7).

Here, the hydrolysis is carried out by, for example, hydrochloric acid, odor, etc.
Under acidic conditions using acids such as hydrofluoric acid, sulfuric acid, or
Sodium hydroxide, potassium hydroxide, barium hydroxide
And the like, under basic conditions using a base such as Ma
For deprotection of the protecting group at the carbonyl group,
General deprotection conditions can be used as appropriate (Protectin
g Groups in Organic Synthesis (Theodora W. Greene
Author, John Wilely & Sons Inc.)). Further, for example, R
^Two-Y¹-And R^Three-Y^Two-Together-SCH_TwoCH_TwoS
-When indicating a group, for example, acid hydrolysis conditions using sulfuric acid
Hydantoin or amino acid
-SCH simultaneously with hydrolysis of the anide moiety _TwoCH_TwoS-group
Can be removed.

2-amino-4-oxobicyclo [3.
1.0] Hexane-2,6-dicarboxylic acid (7)
Since there are four asymmetric carbon atoms at positions 2, 5, and 6,
It can exist as a mixture of two enantiomers, optically active, racemic, and a mixture of diastereomers. Here, the diastereomers can be separated by a general technique such as column chromatography using silica gel or the like or recrystallization. Then, each separated diastereomer can be separated into the corresponding enantiomers by a common resolving method such as a resolution using a basic chiral resolving agent. Here, the basic chiral resolving agent is, for example, (+) or (−)-1-phenylethylamine, (+) or (−)-2-amino-1-butanol,
Optically active amines such as (+) or (−)-alaninol, brucine, cinchonidine, cinchonine, quinine, quinidine, dehydroabiethylamine and the like.

The thus obtained 2-amino-4-
Oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (7) is in the form of a pharmaceutically acceptable salt or hydrate, for example, in combination with a carrier, diluent or excipient. Can be used as a pharmaceutical composition. here,
Pharmaceutically acceptable salts include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, and organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and benzenesulfonic acid. And salts with amines such as trimethylamine and methylamine, and salts with metal ions such as sodium ion, potassium ion and calcium ion.

[0039]

The present invention will be described in more detail with reference to the following Examples, which by no means limit the present invention.

Embodiment 1: (1SR, 4RS, 5RS, 6S
R) -ethyl 4-tert-butyldimethylsilyloxy-2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 4SR, 5RS, 6S
Synthesis of R) -ethyl 4-tert-butyldimethylsilyloxy-2-oxobicyclo [3.1.0] hexane-6-carboxylate

To a solution of 13.6 g of ethyl (dimethylsulfanylidene) acetate in 120 mL of toluene was added 4-t
A solution of 18 g of ert-butyldimethylsilyloxy-2-cyclopentenone in 60 mL of toluene was added under ice cooling. The reaction was stirred at room temperature for 6 hours. The reaction mixture was further added with 24.0 g of ethyl (dimethylsulfanilidene) acetate.
Was added at 0 ° C., and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into 1N hydrochloric acid and separated.
After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako gel C200 (Wako Pure Chemical Industries, Ltd., developing solvent; hexane-ethyl acetate = 15: 1).
(1SR, 4RS, 5RS, 6SR) -ethyl 4-tert-
Butyldimethylsilyloxy-2-oxobicyclo [3.1.0] hexane-6-carboxylate and
(1SR, 4SR, 5RS, 6SR) -ethyl 4-tert-
19.0 g of a mixture of butyldimethylsilyloxy-2-oxobicyclo [3.1.0] hexane-6-carboxylate were obtained.

The data of ¹ H-NMR spectrum of the obtained compound is shown below. ¹ H-NMR (CDCl ₃ ) δ (ppm); 0.08 (3H × 5/8,
s), 0.11 (3H x 3/8, s), 0.90 (9H x 5/8, s), 0.92 (9H x 3/8,
s), 1.27 (3H, t, J = 7.3Hz), 1.85 (1H x 5/8, dd, J = 3.5, 2.6H
z), 1.92-2.70 (4H + 1H × 3/8, m), 4.17 (2H × 5/8, q, J = 7.3H
z), 4.20 (2H x 3/8, q, J = 7.3Hz), 4.52 (1H x 5/8, d, J = 4.8H
z), 4.73 (1H × 3/8, m)

Embodiment 2: (1RS, 4RS, 5RS, 6R
S) -ethyl 2,2-ethylenedithio-4-hydroxybicyclo [3.1.0] hexane-6-carboxylate and (1RS, 4SR, 5RS, 6RS) -ethyl 2,2-ethylenedithio-4 Of -Hydroxybicyclo [3.1.0] hexane-6-carboxylate

The following reactions were performed in a nitrogen atmosphere. (1S
R, 4RS, 5RS, 6SR) -ethyl 4-tert-butyldimethylsilyloxy-2-oxobicyclo [3.1.
0] hexane-6-carboxylate and (1SR, 4
SR, 5RS, 6SR) -Ethyl 4-tert-butyldimethylsilyloxy-2-oxobicyclo [3.1.0]
16.8 g of a mixture of hexane-6-carboxylate and 5.7 mL of ethanedithiol 168 mL of methylene chloride
In the solution, boron trifluoride diethyl ether complex 2.1m
L was added at room temperature and stirred for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was separated with a saturated aqueous solution of sodium bicarbonate and chloroform. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wako gel C200 (Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-ethyl acetate = 4:
(1RS, 4RS, 5RS, 6R)
S) -Ethyl 2,2-ethylenedithio-4-hydroxybicyclo [3.1.0] hexane-6-carboxylate and (1RS, 4SR, 5RS, 6RS) -ethyl 2,2
-Ethylenedithio-4-hydroxybicyclo [3.1.
0] 13.7 g of a mixture of hexane-6-carboxylate
I got

The data of ¹ H-NMR spectrum of the obtained compound is shown below. _{^{1 H-NMR (CDCl 3)}} δ (ppm); 1.26 (3H × 5/8, t,
J = 7.1Hz), 1.28 (3H × 3/8, t, J = 7.1Hz), 1.53 (1H × 5/8, t, J =
3.1Hz), 1.70-2.54 (5H + 1H × 3/8, m), 3.28-3.50 (4H, m), 4.1
3 (2H × 3/8, q, J = 7.1Hz), 4.14 (2H × 5/8, q, J = 7.1Hz), 4.36
(1H × 5/8, dd, J = 7.5,4.8Hz), 4.64 (1H × 3/8, m)

Example 3 Synthesis of (1RS, 5RS, 6RS) -ethyl 4,4-ethylenedithio-2-oxobicyclo [3.1.0] hexane-6-carboxylate

(1RS, 4RS, 5RS, 6RS) -ethyl 2,2-ethylenedithio-4-hydroxybicyclo [3.1.0] hexane-6-carboxylate and
To a solution of 13.1 g of a mixture of (1RS, 4SR, 5RS, 6RS) -ethyl 2,2-ethylenedithio-4-hydroxybicyclo [3.1.0] hexane-6-carboxylate in 520 mL of dimethyl sulfoxide was added 40.5 g. Of dicyclohexylcarbodiimide, 5.0 mL of pyridine and 2.8 mL of trifluoroacetic acid were sequentially added at 15 ° C. After stirring the reaction solution at room temperature for 24 hours, the precipitated solid was separated by filtration and washed with ethyl acetate. The combined filtrate and washings were poured into water and extracted with chloroform. The organic layer was washed three times with water and dried over anhydrous sodium sulfate. After the desiccant was separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Wako gel C200 (Wako Pure Chemical Industries, Ltd., developing solvent; hexane-ethyl acetate = 5: 1)) to give (1RS, 5RS, 6RS) -Ethyl 4,4-
10.5 g of ethylenedithio-2-oxobicyclo [3.1.0] hexane-6-carboxylate were obtained.

The following shows ¹ H-NMR and MS spectrum data of the obtained compound. _{^{1 H-NMR (CDCl 3)}} δ (ppm); 1.29 (3H, t, J = 7.1H
z), 2.25 (1H, dd, J = 3.3,2.8Hz), 2.53 (1H, dd, J = 5.5,2.8H
z), 2.75 (2H, s), 3.01 (1H, dd, J = 5.5,3.3Hz), 3.37-3.53 (4
H, m), 4.18 (2H, dq, J = 2.2, 7.1 Hz) MS (FAB) (Pos.) M / e; 259 (M ⁺⁺ 1)

(1RS, 5RS, 6RS) -ethyl
4,4-ethylenedithio-2-oxobicyclo [3.
1.0] Hexane-6-carboxylate was prepared by HPLC (C
HIRALPAK AD 0.46 * 25cm (Daicel Chemical Industries), Elue
nt: n-hexane / 2-propanol = 3: 1, Fl
ow rate: 1.0 mL / min, Temp .: r
t., Detect: UV210nm) (1R ^* _, 5R ^*)
_, 6R ^*) - Ethyl 4,4-ethylenedithio-2-oxobicyclo [3.1.0] hexane-6-carboxylate (t _R:. 7.65min) and (1R _^*, 5R _^*, 6
R ^* )-Ethyl 4,4-ethylenedithio-2-oxobicyclo [3.1.0] hexane-6-carboxylate
(t _R : 9.17 min.).

Embodiment 4: (1RS, 2SR, 5RS, 6R
S) -Ethyl 2-spiro-5'-hydantoin-4,4
-Ethylenedithiobicyclo [3.1.0] hexane-6
-Synthesis of carboxylate

(1RS, 5RS, 6RS) -ethyl 4,4
-Ethylenedithio-2-oxobicyclo [3.1.0]
A mixture of 73.2 g of hexane-6-carboxylate, 68.1 g of ammonium carbonate and 20.8 g of potassium cyanide was stirred in a mixed solvent of 460 mL of ethanol-307 mL of water at 35 ° C. for 3 days. The reaction mixture was stirred at 0 ° C. for 2 hours, and the precipitated solid was collected by filtration. The obtained solid was mixed with chloroform-methanol (9: 1) mixed solvent 1.1.
After stirring at 65 ° C. for 1.5 hours in L, the mixture was cooled to room temperature and the crystals were collected by filtration. The crystals are chloroform-methanol
The same operation was performed with 100 mL of the mixed solvent (9: 1),
(1RS, 2SR, 5RS, 6RS) -ethyl 2-spiro-
5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylate 35.
2 g were obtained.

The following shows ¹ H-NMR and MS spectrum data of the obtained compound. ¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.20 (3H, t, J = 7.0 Hz), 2.
00 (1H, t, J = 3.1Hz), 2.21 (1H, d, J = 16Hz), 2.25-2.29 (1H, m,
J = 3.1Hz), 2.46 (1H, dd, J = 6.2Hz, 3.1Hz), 2.60 (1H, d, J = 16H
z), 3.20-3.42 (4H, m), 4.07 (2H, q, J = 7.0Hz), 7.91 (1H, s), 1
0.70 (1H, s) .MS (Ion Spray) (Nega) m /
e; 327 (M ⁺ -1)

Example 5: (+)-(1S, 2S, 5R, 6R)
Synthesis of -2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid

(1) (1RS, 2SR, 5RS, 6RS)-
A mixture of 2.10 g of ethyl 2-spiro-5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylate and 13 ml of 2N aqueous sodium hydroxide solution was stirred at room temperature for 1 hour. , Concentrated hydrochloric acid was added to adjust the pH to 1.0. The generated crystals are filtered off,
Wash with 70 ml of water, dry (1RS, 2SR, 5RS,
1.87 g of 6RS) -2-spiro-5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylic acid was obtained. (2) (1RS, 2SR, 5RS, 6RS) -2-spiro-5
1.87 g of '-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylic acid
0.91 g of (R)-(+)-1-phenylethylamine was added to N,
The residue was dissolved in 50 ml of N-dimethylformamide, and 1.05 g of 1-hydroxybenzotriazole monohydrate and 1.43 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added under ice-cooling. Stirred for hours. The reaction solution was added to 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (silica gel: MSG40-60A (Dokai Chemical Industry), developing solvent: chloroform-methanol = 40: 1).
２５25: 1) and (1S, 2R, 5S, 6S) -2-spiro-5′-hydantoin-4,4-ethylenedithio-N
-((R) -1-phenylethyl) -bicyclo [3.1.
0] hexane-6-carboxamide (Rf value 0.54
(TLC: silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform - methanol = 9: 1)) 1.17 g and
(1R, 2S, 5R, 6R) -2-spiro-5'-hydantoin-4,4-ethylenedithio-N-((R) -1-phenylethyl) -bicyclo [3.1.0] hexane-6 -Carboxamide (Rf 0.51 (TLC: silica gel 6
0F ₂₅₄ (manufactured by Merck), developing solvent: chloroform-methanol = 9: 1)). (3) (1R, 2S, 5R, 6R) -2-spiro-5'-hydantoin-4,4-ethylenedithio- obtained in (2) above.
1.10 g of N-((R) -1-phenylethyl) [3.1.0] hexane-6-carboxamide was added to 60% (w / v).
%) Aqueous sulfuric acid solution (20 mL) and stirred at 145 ° C. for 4 days. The reaction solution was cooled to room temperature, adjusted to pH 7 with a 5N aqueous sodium hydroxide solution, and then subjected to ion exchange chromatography (AG1-X8 anion exchange resin (Bio-R).
ad), OH ^- type, eluting solvent: water to 50% tetrahydrofuran-water to water to 30% acetic acid aqueous solution) to give 0.37 crystals.
g was obtained. 10 ml of acetone was added to the crystals, and
After stirring for an hour, the crystals were separated by filtration, washed with 5 ml of acetone, 5 ml of tetrahydrofuran and 5 ml of acetone, dried and dried to give (+)-(1S, 2S, 5R, 6R) -2-amino-4-.
0.30 g of oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.

Hereinafter, ¹ H-NMR of the obtained compound,
The data of MS spectrum and specific light intensity are shown. ¹ H-NMR (pyridine-d ₅ / D ₂ O = 1/1) δ (ppm); 2.86
(1H, dd, J = 3.5Hz, 2.7Hz), 2.93 (1H, d, J = 18Hz), 3.00 (1H, d
d, J = 5.7Hz, 2.7Hz), 3.05 (1H, d, J = 18Hz), 3.30 (1H, dd, J = 5.
7 Hz, 3.5 Hz) MS (FAB) (Nega.) M / e; 198 (M + -1) [α] _D ³² = +43.06 (c = 0.20, H ₂ O)

[0056]

The compound of the present invention, bicyclo [3.
1.0] Hexane-6-carboxylic acid derivatives are useful for schizophrenia, anxiety and related diseases, depression, bipolar disorder, psychiatric disorders such as epilepsy, drug dependence, cognitive disorders, Alzheimer's disease, Acts on group 2 metabotropic glutamate receptors with therapeutic and preventive effects on neurological diseases such as Huntington's chorea, Parkinson's disease, motor dysfunction associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord injury, head injury 4-substituted-2-aminobicyclo [3.
1.0] It is useful as an intermediate material for the synthesis of hexane-2,6-dicarboxylic acid.

Then, 2-oxobicyclo [3.1.
When 0] hexane-6-carboxylic acid derivative is used as a starting material, 2-amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid can be efficiently produced. This makes it possible to synthesize an optically active substance with a high yield.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Kazunari Sakagami 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazuki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo Taisho Within a pharmaceutical company

Claims (3)

[Claims] (1) Formula (1) [Wherein, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C
₆ cycloalkyl groups, C ₃ -C ₆ cycloalkyl C ₁ -C ₆
Alkyl group, aryl group, aryl C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, C ₁ -C ₆
Hydroxyalkyl group, C ₁ -C ₆ alkylthio C ₁ -C ₆
It represents an alkyl group, a C ₁ -C ₆ mercaptoalkyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group. R
² and R ³ are identical or different C ₁ -C ₆ alkyl group, C ₃ ~
C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C
_{A 6} alkyl group, an aryl group or an aryl C ₁ -C ₆ alkyl group, or together form — (CH ₂ ) _n — (n
Represents 2 or 3). Y ¹ and Y ² are the same or different and represent a sulfur atom, an oxygen atom or a nitrogen atom. 2]
-Oxobicyclo [3.1.0] hexane-6-carboxylic acid derivative. (2) Formula (2)[Wherein, R^FourRepresents a hydrogen atom or a hydroxyl-protecting group. ]
To the cyclopentenone derivative represented by_TwoS = CHC
O_TwoR^Five[Wherein, R^FiveIs C₁~ C₆Alkyl group, C_Three~ C₆Shi
Chloroalkyl group, C_Three~ C₆Cycloalkyl C₁~ C₆Al
Kill group, aryl group, aryl C₁~ C₆Alkyl group, C
₁~ C₆Alkoxy C₁~ C₆Alkyl group, C ₁~ C₆Hydro
Xyalkyl group, C₁~ C₆Alkylthio C₁~ C₆Archi
Group, C₁~ C₆Mercaptoalkyl group, tetrahydrof
It represents a lanyl group or a tetrahydropyranyl group. ]
Or reacting the sulfonium ylide_TwoS
⁺CH_TwoCO_TwoR^Five・ X^-[Wherein, R^FiveIs the same as above.
X represents a chlorine atom, a bromine atom or an iodine atom. ]
By reacting the sulfonium salt
(3)[Wherein, R^Four, R^FiveIs the same as above. ]
Forming a cyclic compound, and protecting the carbonyl group of the bicyclic compound.
And formula (4)[Wherein, R^TwoAnd R^ThreeAre the same or different C₁~ C₆Alkyl
Group, aryl group or aryl C₁~ C₆Indicates an alkyl group
Together or-(CH_Two)_n-(N is 2 or
3) is shown. Y¹And Y^TwoAre the same or different sulfur atoms,
Indicates an oxygen atom or a nitrogen atom. R^FourAnd R^FiveIs the same as above
It is. A process represented by the formula:^FourIs other than a hydrogen atom, R^FourIs the hydrogen atom
Oxidizing the derivative after conversion to
2. A method for producing the carboxylic acid derivative according to 1. (3) Formula (5) [Wherein, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C
₆ cycloalkyl groups, C ₃ -C ₆ cycloalkyl C ₁ -C ₆
Alkyl group, aryl group, aryl C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, C ₁ -C ₆
Hydroxyalkyl group, C ₁ -C ₆ alkylthio C ₁ -C ₆
It represents an alkyl group, a C ₁ -C ₆ mercaptoalkyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group. R
² and R ³ are identical or different C ₁ -C ₆ alkyl group, C ₃ ~
C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C
_{A 6} alkyl group, an aryl group or an aryl C ₁ -C ₆ alkyl group, or together form — (CH ₂ ) _n — (n
Represents 2 or 3). Y ¹ and Y ² are the same or different and represent a sulfur atom, an oxygen atom or a nitrogen atom. And a bicyclo [3.1.0] hexane-6-carboxylic acid derivative represented by the formula: