JP2006327947A - Efficient asymmetric synthesis of 4-(2-oxo-2,3-dihydro-1h-benzimidazol-1-yl)piperidine-3-carboxylic acid derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an asymmetric synthesis of an intermediate of a 2-oxoimidazole derivative useful as a medicine. <P>SOLUTION: This method of asymmetric synthesis is provided by reducing a compound expressed by formula (III) obtained by the condensation of a compound expressed by formula (II) with (R)-(+)-α-methylbenzylamine to produce a compound expressed by formula (IV), hydrogenating the above compound to form a compound expressed by formula (V), condensing the obtained compound with a compound expressed by formula (VI) to form a compound expressed by formula (VII), reducing nitro group, then reacting with carbodiimidazole to form a compound (XI) and obtaining a compound expressed by formula (I) by finally treating with a base. The compound expressed by the formula (I) is useful as an intermediate of a compound inhibiting the binding of nociseptin to a nociseptin receptor ORL1. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention is useful in the field of medicine. More specifically, the present invention relates to a method for asymmetric synthesis of intermediates of compounds useful in the field of medicine.

  International publication WO 98/54168, J. MoI. Med. Chem. 1999, 5061-5063 and Bioorg. Med. Chem. 2001, Vol. 9, 1871-1877 discloses compounds having an action of inhibiting the binding of nociceptin to the nociceptin receptor ORL1 (Opioid receptor like-1 receptor).

で表される化合物（以下、「化合物Ａ」という）は、ノシセプチン受容体へのノシセプチンの結合を選択的に阻害する作用を有するものとして特に優れている。

(Hereinafter referred to as “compound A”) is particularly excellent as having an action of selectively inhibiting the binding of nociceptin to the nociceptin receptor.

By the way, in WO98 / 54168, a racemic mixture is obtained and then racemically resolved to obtain compound A. However, in order to synthesize the compound industrially, a simpler production method is required than racemic resolution. .
International publication WO 98/54168 J. et al. Med. Chem. 1999, 5061-5063, Bioorg. Med. Chem. 2001, Vol. 9, 1871-1877

  An object of the present invention is to provide a method for asymmetric synthesis of 2-oxoimidazole derivatives represented by Compound A useful as a pharmaceutical. That is, an object of the present invention is to efficiently synthesize a compound conventionally prepared by a racemic resolution method.

That is, the present invention
1) Formula (II)

［式中、Ｒ^１は、低級アルキル基を表し、Ｐは、アミノ保護基又は式（Ｚ）

[Wherein R ¹ represents a lower alkyl group, and P represents an amino protecting group or formula (Z)

（式中、ＣＹは、炭素数６〜１２の１又は２環性脂肪族炭素環基を表す）で表される基を表す］で表される化合物と（Ｒ）−（＋）−α−メチルベンジルアミンとを縮合し、式（III）

(Wherein CY represents a group represented by 6 to 12 carbon atoms represented by a 1 or 2 cyclic aliphatic carbocyclic group) and a compound represented by (R)-(+)-α- Condensation with methylbenzylamine gives the formula (III)

［式中、Ｐｈは、フェニル基を表し、Ｒ^１及びＰは、前記に同じである］で表される化合物とする工程、
２） 式（III）で表される化合物を還元し、式(IV)

[Wherein Ph represents a phenyl group, and R ¹ and P are as defined above],
2) The compound represented by the formula (III) is reduced to give a compound of the formula (IV)

［式中、Ｐｈ、Ｒ^１及びＰは、前記に同じである］で表される化合物とする工程、
３） 式(IV)で表される化合物のベンジル基を水素化分解して式(V)

[Wherein Ph, R ¹ and P are the same as defined above],
3) Hydrogenolysis of the benzyl group of the compound represented by formula (IV) yields formula (V)

［式中、Ｒ^１及びＰは、前記に同じである］で表される化合物とする工程、
４） 式(V)で表される化合物と式(VI)

[Wherein R ¹ and P are the same as defined above],
4) Compound represented by formula (V) and formula (VI)

［式中、Ｒ^２は、水素原子、ハロゲン、低級アルキル基、水酸基及び低級アルコキシ基からなる群より選ばれる基を表し、Ｘ_１は、脱離基を表す］で表される化合物とを縮合し式(VII)

[Wherein R ² represents a group selected from the group consisting of a hydrogen atom, a halogen, a lower alkyl group, a hydroxyl group and a lower alkoxy group, and X ₁ represents a leaving group]. Formula (VII)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物とする工程、
５） 式(VII)で表される化合物のニトロ基を還元して式(IIX)

[Wherein R ¹ , R ² and P are the same as defined above],
5) Reduction of the nitro group of the compound represented by formula (VII) to formula (IIX)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物とする工程、
６） 式(IIX)で表される化合物を、溶媒中、カルボニルジイミダゾール、ホスゲン、ジホスゲン、トリホスゲン、炭酸ジエチル、クロロギ酸エチル及び尿素からなる群より選択されるカルボニル化合物と反応させ、式(IX)

[Wherein R ¹ , R ² and P are the same as defined above],
6) A compound represented by the formula (IIX) is reacted with a carbonyl compound selected from the group consisting of carbonyldiimidazole, phosgene, diphosgene, triphosgene, diethyl carbonate, ethyl chloroformate and urea in a solvent, )

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物を得る工程、及び
７） 式(IX)で表される化合物を、炭酸ナトリウム、炭酸カリウム、リチウムメトキシド及びナトリウムメトキシドからなる群より選択される塩基と反応させる工程、
を包含する、式(I)

[Wherein R ¹ , R ² and P are the same as defined above], and 7) a compound represented by formula (IX) is converted into sodium carbonate, potassium carbonate, lithium methoxy Reacting with a base selected from the group consisting of sodium methoxide and sodium methoxide;
Including formula (I)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物の製造方法、を提供する。

[Wherein, R ¹ , R ² and P are the same as defined above].

  Furthermore, the present invention uses the compound represented by formula (II) as a raw material and performs the same reaction using (S)-(−)-α-methylbenzylamine.

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである。］で表される化合物の製造方法を提供する。

[Wherein, R ¹ , R ² and P are the same as defined above. ] The manufacturing method of the compound represented by this is provided.

  Hereinafter, the present invention will be described in more detail.

  In the present specification, the term “lower” means that the group or compound to which this word is attached has 6 or less carbon atoms, preferably 4 or less.

  The “lower alkyl group” includes a straight-chain alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, and an n-propyl group. Isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-amyl group and the like.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom and iodine atom.

  The “lower alkyloxy group” includes a group in which a lower alkyl group is bonded to an oxygen atom. Specifically, as the lower alkyloxy group, a methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n- Examples include butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group and the like.

  The “1 or bicyclic aliphatic carbocyclic group” means a saturated aliphatic carbocyclic group, which means a monocyclic or bicyclic cyclic group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. Cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cycloundecyl group, cyclododecyl group, spiro [2.5] octane-4-yl group, spiro [2.5] octane-5-yl group, spiro [2.5] Octan-6-yl group, spiro [3.5] nonan-5-yl group, spiro [3.5] nonan-6-yl group, spiro [3.5] nonan-7-yl group, spiro [4.5] decane A -6-yl group, a spiro [4.5] decan-7-yl group, a spiro [4.5] decan-8-yl group and the like can be mentioned.

  The amino-protecting group is not particularly limited as long as it has the function. For example, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p Aralkyl groups such as nitrobenzyl, benzhydryl, and trityl groups; lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, and pivaloyl groups; benzoyl groups; arylalkanoyl groups such as phenylacetyl and phenoxyacetyl groups A lower alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group or a tert-butoxycarbonyl group; an aralkyloxycarbonyl such as a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group or a phenethyloxycarbonyl group; Group; lower alkylsilyl group such as trimethylsilyl group and tert-butyldimethylsilyl group; tetrahydropyranyl group; trimethylsilylethoxymethyl group; lower alkylsulfonyl group such as methylsulfonyl group and ethylsulfonyl group; benzenesulfonyl group and toluenesulfonyl group Arylsulfonyl group of the above.

  The hydroxyl-protecting group is not particularly limited as long as it has the function. For example, tert-butyl group; lower alkylsilyl group such as trimethylsilyl group, tert-butyldimethylsilyl group; methoxymethyl group; Tetrahydropyranyl group; trimethylsilylethoxymethyl group; aralkyl groups such as benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; formyl group, acetyl group And an acyl group such as a group, and a methyl group, a methoxymethyl group, a tetrahydropyranyl group, a trityl group, a trimethylsilylethoxymethyl group, a tert-butyldimethylsilyl group, an acetyl group, and the like are particularly preferable.

Hereinafter, the production method of the present invention will be described in detail with specific examples.
Step 1:
Step 1 is represented by the formula (II)

［式中、Ｒ^１は、低級アルキル基を表し、Ｐは、アミノ保護基又は式（Ｚ）

[Wherein R ¹ represents a lower alkyl group, and P represents an amino protecting group or formula (Z)

（式中、ＣＹは、炭素数６〜１２の１又は２環性脂肪族炭素環基を表す）で表される基を表す］で表される化合物と（Ｒ）−（＋）−α−メチルベンジルアミンとを縮合し、式（III）

(Wherein CY represents a group represented by 6 to 12 carbon atoms represented by a 1 or 2 cyclic aliphatic carbocyclic group) and a compound represented by (R)-(+)-α- Condensation with methylbenzylamine gives the formula (III)

［式中、Ｐｈは、フェニル基を表し、Ｒ^１及びＰは、前記に同じである］で表される化合物を得るものである。

In the formula, Ph represents a phenyl group, and R ¹ and P are the same as described above.

  The amount of (R)-(+)-α-methylbenzylamine used is, for example, 1 to 2 mol, preferably 1 to 1.3 mol per mol of the compound represented by formula (II). Is done.

  The condensation reaction is preferably performed in an organic solvent, and specific examples include methanol, ethanol, diethyl ether, tetrahydrofuran (hereinafter referred to as “THF”), acetonitrile, and the like.

  The reaction temperature is, for example, 50 to 100 ° C, and preferably 60 to 80 ° C is recommended.

  The reaction time is typically 3 to 6 hours.

  As the compound represented by the formula (II), those described in WO98 / 54168 can be used. Here, the amino protecting group for P needs to be stable in the steps described below, particularly in step 3, and for example, a tert-butyloxycarbonyl group is recommended.

  P is the formula (Z)

（式中、ＣＹは、炭素数６〜１２の１又は２環性脂肪族炭素環基を表す）である場合のＣＹとしては、例えば、シクロヘキシル基、シクロヘプチル基、シクロオクチル基、シクロノニル基、シクロデシル基、シクロウンデシル基、シクロドデシル基、スピロ［2.5］オクタン−４−イル基、スピロ［2.5］オクタン−5−イル基、スピロ［2.5］オクタン−６−イル基、スピロ［3.5］ノナン−5−イル基、スピロ［3.5］ノナン−６−イル基、スピロ［3.5］ノナン−７−イル基、スピロ［４.5］デカン−６−イル基、スピロ［４.5］デカン−７−イル基、スピロ［４.5］デカン−８−イル基等が挙げられ、中でもシクロヘキシル基、シクロヘプチル基、シクロオクチル基、スピロ［2.5］オクタン−４−イル基、スピロ［3.5］ノナン−5−イル基、スピロ［４.5］デカン−６−イル基等が推奨される。

(In the formula, CY represents a monocyclic or bicyclic aliphatic carbocyclic group having 6 to 12 carbon atoms) As CY, for example, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, Cyclodecyl group, cycloundecyl group, cyclododecyl group, spiro [2.5] octane-4-yl group, spiro [2.5] octane-5-yl group, spiro [2.5] octane-6-yl group, spiro [3.5] nonane -5-yl group, spiro [3.5] nonan-6-yl group, spiro [3.5] nonane-7-yl group, spiro [4.5] decan-6-yl group, spiro [4.5] decane-7 -Yl group, spiro [4.5] decan-8-yl group, etc. Among them, cyclohexyl group, cycloheptyl group, cyclooctyl group, spiro [2.5] octane-4-yl group, spiro [3.5] nonane- 5-yl group, spiro [4. 5] A decan-6-yl group or the like is recommended.

R ¹ is preferably a methyl group, an ethyl group or the like.

Step 2:
Step 2 reduces the compound represented by formula (III) to form formula (IV)

［式中、Ｐｈ、Ｒ^１及びＰは、前記に同じである］で表される化合物を得るものである。

[Wherein, Ph, R ¹ and P are the same as defined above].

  This reaction is preferably performed in an organic solvent, and examples thereof include methanol, ethanol, diethyl ether, THF, acetonitrile and the like.

As a reduction method,
1) Reduction with sodium triacetoxyborohydride,
2) reduction using sodium borohydride in the presence of carboxylic acid, or 3) hydrogenation reaction in the presence of a metal catalyst.

1) Reduction with sodium triacetoxyborohydride (Tetrahedron: Asymmetry 1455, 1994)
In this reaction, the compound represented by the formula (III) is reduced with sodium triacetoxyborohydride in an organic solvent.

  As usage-amount of a reducing agent, 1-4 mol is mentioned with respect to 1 mol of compounds represented by Formula (III), Preferably 2-3 mol is recommended.

  The reaction temperature is -10 to 50 ° C, preferably 0 to 30 ° C is recommended, and the reaction time is usually 2 to 24 hours.

  This reaction is preferably performed in the presence of an inert gas such as nitrogen gas or argon.

2) Reduction with sodium borohydride in the presence of carboxylic acid In this reaction, the compound represented by formula (III) is reduced with sodium borohydride in the presence of carboxylic acid in an organic solvent.

  Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, pivalic acid, trifluoroacetic acid and the like, and preferably trifluoroacetic acid is recommended.

  As usage-amount of sodium borohydride, 1-3 mol is mentioned with respect to 1 mol of compounds represented by Formula (III), Preferably 1.5-2.5 mol is recommended.

  Examples of the amount of carboxylic acid used include 1 to 5 mol, preferably 1.5 to 3 mol per mol of sodium borohydride.

  As the reaction temperature, -100 to 0 ° C is exemplified, preferably -80 to -20 ° C is recommended, and the reaction time is usually 2 to 4 hours.

  This reaction is preferably performed in the presence of an inert gas such as nitrogen gas or argon.

3) Hydrogenation reaction in the presence of a metal catalyst The compound represented by formula (III) is subjected to a hydrogenation reaction in an organic solvent in the presence of a metal catalyst in a hydrogen atmosphere, and represented by formula (IV). A compound is obtained.

  An example of the metal catalyst is palladium on carbon.

  The amount of the metal catalyst used is 10 to 100 parts by weight, preferably 10 to 20 parts by weight, based on 100 parts by weight of the compound represented by the formula (III).

  The reaction temperature is exemplified by 0 to 50 ° C., preferably 20 to 30 ° C. is recommended, and the reaction time is usually 2 to 24 hours.

  Step 2 is preferably exemplified by 1) reduction with sodium triacetoxyborohydride, or 2) reduction with sodium borohydride in the presence of carboxylic acid, especially hydrogenation in the presence of trifluoroacetic acid. Reduction with sodium boron is recommended.

  For example, when using sodium borohydride / trifluoroacetic acid as a reducing agent, trifluoroacetic acid is added to a tetrahydrofuran suspension of sodium tetrahydroborate at 5-10 ° C. over about 20 minutes, and this is added at 0 ° C. After stirring for about 25 minutes, trifluoroacetic acid is further added at once to prepare a reducing agent. Then, a compound represented by the formula (III) is added to the suspension and subjected to a reduction reaction at a temperature from −78 to −20 ° C., and then 25% aqueous ammonia is added to the reaction solution over 1 hour. In addition, excess reducing agent can be decomposed by an operation such as stirring at -20 ° C for 1 hour.

Step 3:
In step 3, the benzyl group of the compound represented by the formula (IV) is hydrogenolyzed to give the formula (V)

［式中、Ｒ^１及びＰは、前記に同じである］で表される化合物を得るものである。

[Wherein R ¹ and P are the same as defined above].

  That is, compound (V) can be obtained by hydrogenating a compound represented by formula (IV) in an organic solvent using a metal catalyst in a hydrogen atmosphere.

  An example of the metal catalyst is palladium-carbon.

  The amount of the metal catalyst used is, for example, 1 to 100 parts by weight, preferably 5 to 15 parts by weight per 100 parts by weight of the compound represented by formula (IV).

  Examples of the organic solvent include methanol, ethanol, THF and the like.

  As a hydrogen pressure, 1-5 atmospheres etc. are illustrated, Preferably 2-4 atmospheres etc. are recommended.

  The reaction temperature is exemplified by 0 to 5 ° C, preferably 20 to 30 ° C being recommended.

  The reaction time is typically 2 to 6 hours.

Step 4;
Step 4 is a compound represented by the formula (V) and the formula (VI).

［式中、Ｘ_１及びＲ^２は、前記に同じである］で表される化合物とを、好ましくは塩基の存在下で縮合し式(VII)

[Wherein X ₁ and R ² are the same as defined above], preferably in the presence of a base, to give a compound of formula (VII)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物を得るものである。

[Wherein R ¹ , R ² and P are the same as described above].

  This reaction is preferably performed in an organic solvent, and examples thereof include N, N-dimethylformamide (hereinafter referred to as “DMF”), dimethyl sulfoxide (hereinafter referred to as “DMSO”), THF, and the like.

  Examples of the amount of the compound represented by the formula (VI) include 1 to 1.5 mol, preferably 1 to 1.1 mol per mol of the compound represented by the formula (V).

  Examples of the base include sodium carbonate and potassium carbonate, and sodium carbonate is recommended.

  The amount of the base used is, for example, 1 to 1.5 mol, preferably 1 to 1.2 mol per mol of the compound represented by the formula (V).

  An example of the reaction temperature is 50 to 100 ° C., preferably 70 to 90 ° C. is recommended.

  The reaction time is typically 10 to 24 hours.

In the formula (VI), R ² is preferably a hydrogen atom, a fluorine atom, a methyl group, an ethyl group or the like.

X ₁ is exemplified by halogen such as fluorine atom, chlorine atom, bromine atom, etc., preferably fluorine atom is recommended.

  And as a compound represented by Formula (VI), the thing as described in WO98 / 54168 is illustrated.

Step 5:
In step 5, the nitro group of the compound represented by formula (VII) is hydrogenated to form formula (IIX)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物を得るものである。

[Wherein R ¹ , R ² and P are the same as described above].

  Hydrogenation is performed in the presence of a metal catalyst in an organic solvent, for example, palladium-carbon.

  The amount of the metal catalyst used is 1 to 100 parts by weight, preferably 5 to 15 parts by weight per 100 parts by weight of the compound represented by the formula (VII).

  Examples of the organic solvent include methanol, ethanol, THF and the like.

  Examples of the hydrogen pressure include 1 to 5 atm, preferably 2 to 4 atm.

  As reaction temperature, 0-50 degreeC is illustrated, Preferably 20-30 degreeC is recommended.

  The reaction time is typically 2 to 6 hours.

Step 6:
Step 6 is a reaction of a compound represented by the formula (IIX) with a carbonyl compound selected from the group consisting of carbonyldiimidazole, phosgene, diphosgene, triphosgene, diethyl carbonate, ethyl chloroformate, and urea in an organic solvent. To formula (IX)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物を得るものである。

[Wherein R ¹ , R ² and P are the same as described above].

  Examples of the carbonyl compound include carbonyl imidazole, phosgene, diphosgene, triphosgene, diethyl carbonate, ethyl chloroformate, urea and the like, and preferably carbonyl imidazole, diethyl carbonate and the like are recommended.

  The amount of the carbonyl compound used is, for example, 1 to 2 mol, preferably 1 to 1.3 mol per mol of the compound represented by the formula (IIX).

  Examples of the organic solvent include DMF, DMSO, THF, acetonitrile and the like, preferably THF is recommended.

  Examples of the reaction temperature include 0 to 50 ° C., preferably 0 to 20 ° C. is recommended.

  The reaction time is typically 10 to 24 hours.

Step 7:
Step 7 comprises reacting the compound represented by the formula (IX) with a base selected from the group consisting of sodium carbonate, potassium carbonate, lithium methoxide, sodium methoxide,

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物を得るものである。

[Wherein R ¹ , R ² and P are the same as described above].

  Examples of the base include sodium carbonate, potassium carbonate, lithium methoxide, sodium methoxide and the like, preferably sodium carbonate is recommended.

  The amount of the base used is, for example, 0.3 to 2 mol per mol of the compound represented by the formula (XI), preferably 0.5 to 1.0 mol.

  The reaction is carried out in an organic solvent, and examples thereof include methanol and THF.

  An example of the reaction temperature is 50 to 100 ° C., preferably 50 to 80 ° C. is recommended.

  The reaction time is typically 10 to 24 hours.

  In the above reaction, when an amino group, a hydroxyl group, a carboxyl group, an oxo group, a carbonyl group, etc. that are not involved in the reaction are present in the reactant, the amino group, hydroxyl group, carboxyl group, oxo group, carbonyl group is appropriately After protecting with a protecting group for a group, a protecting group for a hydroxyl group, a protecting group for a carboxyl group, a protecting group for an oxo group or a carbonyl group, each reaction of Steps 1 to 7 is performed, and the protecting group can be removed after the reaction.

  The method for removing the protecting group varies depending on the kind of the protecting group and the stability of the compound represented by the formula (I). For example, the method described in the literature [Protective Groups in Organic Synthesis] Synthesis), T .; W. According to Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto, for example, solvolysis using, for example, an acid or base, ie, from 0.01 mole to a large excess of acid, Preferably, trifluoroacetic acid, formic acid, hydrochloric acid or the like, or a method in which an equimolar to large excess base, preferably potassium hydroxide, calcium hydroxide or the like is allowed to act; chemical reduction using a metal hydride complex or palladium-carbon catalyst , Catalytic reduction using Raney nickel catalyst or the like.

  In the above reaction, the same reaction was carried out using (S)-(−)-α-methylbenzylamine instead of (R)-(+)-α-methylbenzylamine, and the compound of formula (Ib)

［式中、Ｒ^１、Ｒ^２及びＰは、前記に同じである］で表される化合物を得ることも可能である。

[Wherein R ¹ , R ² and P are as defined above] can be obtained.

  The compound represented by the formula (I) obtained by the above method (when P is an amino protecting group) can be led to the compound A by the following method.

Reference pharmacological test example 1 (nociceptin receptor binding inhibition experiment)
CDNA encoding the human nociceptin receptor gene was incorporated into an expression vector pCR3 (manufactured by Invitrogen) to prepare pCR3 / ORL1. Next, pCR3 / ORL1 was introduced into CHO cells using a transfectam (manufactured by Nippongene) to obtain a stable expression strain (CHO / ORL1 cells) resistant to 1 mg / ml G418. A membrane fraction was prepared from this stable expression strain, and a receptor binding experiment was conducted. Membrane fraction 11 μg, 50 pM [ ¹²⁵ I] Tyr ¹⁴ -Nociceptin (Amersham Pharmacia), 1 mg Wheatgermagglutinin SPA beads (PVT-based; 10 Amersham Pharmacia NC) After suspending in sodium, 1 mM magnesium chloride, 2.5 mM calcium chloride, 0.1% BSA, 0.025% bacitracin, pH 7.4) and incubating at 37 ° C. for 60 minutes, the radioactivity was measured. The binding activity to the nociceptin receptor is expressed as a 50% inhibitory concentration (IC ₅₀ value) of [ ¹²⁵ I] Tyr ₁₄ -Nociceptin binding by Compound A. As a result, Compound A was 1.8 nM.

Reference pharmacology test example 2 (antagonism against nociceptin-induced G protein activation)
Using CHO cells stably expressing the nociceptin receptor ORL1, the effect of the test compound on nociceptin-induced G protein activation was examined. Membrane fraction prepared from CHO / ORL1 cells, 50 nM nociceptin, 200 pM GTPγ [ ³⁵ S] (manufactured by NEN), 1.5 mg of Wheatgerm agglutinin SPA beads (manufactured by Amersham Pharmacia) and test compound (GDP buffer, 20 mM) Radioactivity was measured after mixing in 100 mM sodium chloride, 10 mM magnesium chloride, 1 mM EDTA, 5 μM GDP, pH 7.4) and incubating at 25 ° C. for 150 minutes. Antagonism against nociceptin-induced G protein activation is expressed as a 50% inhibitory concentration (IC ₅₀ value) of GTPγ [ ³⁵ S] binding by Compound A. As a result, Compound A was 18 nM.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to the examples. The various reagents used in the examples were commercially available unless otherwise specified. 1H-NMR was measured using AL-400-2 (400 MHz) manufactured by JEOL and using tetramethylsilane as a standard substance. The mass spectrum was measured by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) using a Micromass ZQ manufactured by Waters.

Example
1-t-butyl 3-methyl (3R, 4R) -4- (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylate 1) methyl 4- Preparation of hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate Methyl 1-benzyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate 762.7 g of methanol To the 5 L solution, 157.4 g of 10% palladium-carbon catalyst (containing water) was added, and the mixture was stirred at room temperature and 3 atm for 4 hours under a hydrogen atmosphere. The reaction system was replaced with nitrogen, and the catalyst was removed by filtration through glass fiber filter paper. The residue was washed with methanol-water (300 mL-200 mL). The filtrate was evaporated under reduced pressure to give 520 g of the title compound as a pale amber solid.
1HNMR (400 MHz, CD3OD) δ: 2.67 (2H, t, J = 6.6 Hz), 3.41 (2H, t, J = 6.6 Hz), 3.81 (3H, s), 3.84 (2H, brs)
ESI-MS Found: m / z 158.3 [M + H] +

2) Preparation of 1-t-butyl 3-methyl 4-hydroxy-5,6-dihydropyridine-1,3 (2H) -dicarboxylate 1100 g of the compound obtained in 1 above and di-t-butyl dicarboxylate under a nitrogen atmosphere To a solution of 1274 mL of carbonate in 6.6 L of water-dioxane (1: 1), 983 g of anhydrous sodium bicarbonate was carefully added over 10 minutes. After stirring at room temperature for 3 hours, the reaction mixture was diluted with 6.0 L of water and extracted twice with 4.5 L of ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1480 g of the title compound as a pale reddish brown oil.
1HNMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 2.38 (2H, t, J = 5.9 Hz), 3.57 (2H, t, J = 5.9 Hz), 3.78 (3H, s), 4.06 (2H, brs), 11.98 (1H, brs)
ESI-MS Found: m / z 258.3 [M + H] +, 202.3 [M-Bu + H] +

3) Preparation of 1-t-butyl 3-methyl 4-{[(1R) -1-phenylethyl] amino} -5,6-dihydropyridine-1,3 (2H) -dicarboxylate (R)-(+)-α-methylbenzylamine (826 mL) and acetic acid (396 mL) were added to a methanol-tetrahydrofuran (1: 1) 6.0 L solution of the compound obtained in 1480 g and stirred at 65 ° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with 12.0 L of ethyl acetate, and the organic layer was washed with 9.0 L of water, 9.0 L of 0.5N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1940 g of the title compound as a yellow oil.
1HNMR (400 MHz, CDCl3) δ: 1.43 (9H, s), 1.50 (3H, d, J = 6.8 Hz), 2.05 (1H, m), 2.38 (1H, m), 3.30 (1H, m), 3.42 (1H, m), 3.72 (3H, s), 4.06 (2H, brs), 4.61 (1H, quintet, J = 7.1 Hz) 7.22-7.35 (5H, m), 9.25 (1H, brd, J = 6.8 Hz)
ESI-MS Found: m / z 361.3 [M + H] +

4) Preparation of 1-t-butyl 3-methyl (3S, 4R) -4-{[(1R) -1-phenylethyl] amino} piperidine-1,3-dicarboxylate Sodium tetrahydroborate under nitrogen atmosphere To a suspension of 295 g of tetrahydrofuran (5.7 L), 1224 mL of trifluoroacetic acid was added at 5-10 ° C. over 20 minutes. After stirring this at 0 ° C. for 25 minutes, 546 mL of trifluoroacetic acid was further added at once and cooled to −78 ° C. A solution of 1420 g of the compound obtained in 3 above in 1.8 L of acetonitrile was added dropwise to this reaction solution over 1 hour, stirred at −78 ° C. for 1.5 hours, heated to −20 ° C., and 25% Aqueous ammonia solution was added over 1 hour. The mixture was further stirred at −20 ° C. for 1 hour, gradually returned to room temperature, stirred for 30 minutes at room temperature, and then poured into 11.0 L of water. This solution was extracted with 11.0 L and 4.3 L of ethyl acetate, and the ethyl acetate layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1660 g of the title compound as a light brown solid.
1H NMR (400 MHz, CDCl3) δ: 1.28 (3H, d, J = 6.3 Hz), 1.43 (9H, s), 1.72-1.81 (3H, m), 2.77-2 .86 (2H, m), 2.98 (1H, ddd, J = 13.2, 9.5, 3.7 Hz), 3.15 (1H, dd, J = 13.7, 3.4 Hz), 3.72 (4H, s), 3.87 (1H, q, J = 6.3 Hz), 4.01 (1H, brd, J = 9.5 Hz), 7.22-7.33 (5H, m )
ESI-MS Found: m / z 363.2 [M + H] +

5) Preparation of 1-t-butyl 3-methyl (3S, 4R) -4-aminopiperidine-1,3-dicarboxylate 10% palladium in a 2.5 L solution of 1160 g of the compound obtained in 4 above and 238 mL of acetic acid -293 g of carbon catalyst (containing water) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature and 3 atm for 4 hours. The reaction system was replaced with nitrogen, and the catalyst was filtered off with glass fiber filter paper. The residue was washed with 100 mL of methanol. The filtrate was distilled off under reduced pressure, the residue was dissolved in 4.6 L of water, and this solution was washed with 3.5 L of methyl-t-butyl ether. After the methyl-t-butyl ether layer was extracted again with 2.3 L of water, the aqueous layers were combined and neutralized with 1N aqueous sodium hydroxide solution, and the aqueous layer was then added with methyl-t-butyl ether-tetrahydrofuran (2: 1). Extracted with 0 L and ethyl acetate (3.5 L + 1.7 L). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 580 g of the title compound as a colorless transparent oil.
1HNMR (400 MHz, CDCl3) δ: 1.45 (9H, s), 1.76 (3H, m), 2.66 (1H, m), 3.37 (1H, m), 3.45 (2H, m) 3.69 (1H, m), 3.71 (3H, s)
ESI-MS Found: m / z 259.3 [M + H] +, 203.3 [M-Bu + H] +

6) Preparation of 1-t-butyl 3-methyl (3S, 4R) -4-[(2-nitrophenyl) amino] piperidine-1,3-dicarboxylate 580 g of the compound obtained in 5 above was obtained under a nitrogen atmosphere. To a 2.9 L solution of dimethylformamide, 260 mL of ortho-fluoronitroaniline and 286 g of sodium carbonate were sequentially added, followed by stirring at 80 ° C. for 15 hours. The reaction mixture was cooled to 10 ° C., 5.0 L of water was added, and the mixture was extracted with ethyl acetate (4.5 L + 3.5 L). The organic layers were combined, washed with 3.5 L of water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 860 g of the title compound as a yellow oil.
1HNMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 1.84 (1H, m), 2.05 (1H, m) 2.94 (1H, m), 3.43 (1H, m ) 3.65 (2H, m), 3.69 (3H, s), 3.99 (1H, dd, J = 14.1, 7.3 Hz), 4.16 (1H, septet, J = 4. 1 Hz), 6.68 (1 H, m), 6.90 (1 H, d, J = 8.8 Hz), 7.44 (1 H, m), 8.19 (1 H, dd, J = 8.8, 1.5Hz), 8.62 (1H, brs)
ESI-MS Found: m / z 380.2 [M + H] +, 324.2 [M-Bu + H] +

7) Preparation of 1-tert-butyl 3-methyl (3S, 4R) -4-[(2-aminophenyl) amino] piperidine-1,3-dicarboxylate 780 g of the compound obtained in 6 above, 3.0 L of tetrahydrofuran To the solution, 156 g of 10% palladium-carbon catalyst (containing water) was added, and the mixture was stirred for 1.5 hours at room temperature and 3 atm under a hydrogen atmosphere. The reaction system was replaced with nitrogen, and the catalyst was filtered off with glass fiber filter paper. The residue was washed with 300 mL of methanol. The filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in 8.0 L of ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After adding 400 g of silica gel to this solution and stirring, the solid was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 640 g of the title compound as a black oil.
1HNMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.66 (1H, m), 1.77 (1H, m), 2.91 (1H, m) 3.23 (1H, ddd , J = 13.2, 9.0, 4.1 Hz), 3.45 (2H, brdd, J = 13.2, 3.2 Hz) 3.68 (3H, s), 3.76 (1H, m ), 4.08 (1H, dd, J = 14.9, 5.6 Hz), 6.66-6.79 (4H, m)
ESI-MS Found: m / z 350.2 [M + H] +, 294.2 [M-Bu + H] +

8) Preparation of 1-t-butyl 3-methyl (3S, 4R) -4- (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylate Nitrogen Under an atmosphere, a suspension of 640 g of the compound obtained in 7 above in 4.0 L of tetrahydrofuran was added with a suspension of 500 mL of N, N-carbonyldiimidazole in 356 g of tetrahydrofuran under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with 6.0 L of ethyl acetate, and the organic layer was washed with 4.4 L of 0.5N aqueous hydrochloric acid and saturated brine. The solvent was distilled off under reduced pressure to obtain 720 g of the title compound as a brown foam.
1HNMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.88 (1H, m), 2.94 (1H, m), 3.06-3.30 (3H, m) 3.44 (3H, s), 4.33-4.68 (3H, m) 7.01-7.09 (3H, m), 7.30 (1H, m), 9.17 (1H, brs)
ESI-MS Found: m / z 376.3 [M + H] +, 320.2 [M-Bu + H] +

9) Preparation of 1-tert-butyl 3-methyl (3R, 4R) -4- (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylate Nitrogen Under an atmosphere, 256 g of sodium carbonate was added to 6.8 L of a methanol-tetrahydrofuran (1: 1) solution of 1680 g of the compound obtained in 8 above and stirred at 70 ° C. for 16 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in 7.5 L of ethyl methyl ketone and 3.4 L of tetrahydrofuran. This solution was washed with 5.0 L of 1N hydrochloric acid aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in 5.0 L of methanol, stirred at 50 ° C. for 1 hour, and further stirred at room temperature for 20 hours. The suspension was filtered, and the resulting white solid was washed three times with 700 mL of methyl-t-butyl ether and dried in an oven under vacuum to give 509 g of the title compound (purity 99.9%, optical purity 99.9%). ) Was obtained as a white solid. The filtrate was collected, concentrated under reduced pressure, and then subjected to the same operation, whereby 45.0 g of second crystal (purity 99.6%, optical purity 99.8%) and third crystal (purity 99.3%, optical purity 98.98). 6%).

Purity and optical purity were determined by the following column conditions.
Purity column: YDS ODS AQ-303, 250 × 4.6 mm
Column temperature: 40 ° C
Elution rate: 1.0 ml / min
Eluent: 0.1% phosphoric acid aqueous solution: acetonitrile = 80: 20- (gradient, 10 min) -40: 60- (gradient, 10 min)
Detection: UV 210 nm

Optical purity column: ChiralPAK AD, 250X4.6 mm, manufactured by Daicel
Column temperature: 25 ° C
Elution rate: 1.0 ml / min
Eluent: hexane / 2-propanol / diethylamine = 900/100/1
Detection: UV 280 nm
1HNMR (400 MHz, CDCl3) δ: 1.52 (9H, s), 1.85 (1H, brd, J = 12.7 Hz), 2.51 (1H, m), 2.82-3.05 (2H , M) 3.46 (3H, s), 3.57 (1H, m) 4.22-4.62 (3H, m), 7.03-7.12 (4H, m) 9.59 (1H , Brs)
ESI-MS Found: m / z 376.3 [M + H] +, 320.2 [M-Bu + H] +

The compound (A) is useful as a medicine, and the present invention provides an industrially advantageous asymmetric synthesis method for the compound represented by the formula (I), which is an intermediate of the compound (A).

Claims (2)

1) Formula (II)

[Wherein R ¹ represents a lower alkyl group, and P represents an amino protecting group or formula (Z)

(Wherein CY represents a group represented by 6 to 12 carbon atoms represented by a 1 or 2 cyclic aliphatic carbocyclic group) and a compound represented by (R)-(+)-α- Condensation with methylbenzylamine gives the formula (III)

[Wherein Ph represents a phenyl group, and R ¹ and P are as defined above],
2) The compound represented by the formula (III) is reduced to give a compound of the formula (IV)

[Wherein Ph, R ¹ and P are the same as defined above],
3) Hydrogenolysis of the benzyl group of the compound represented by formula (IV) yields formula (V)

[Wherein R ¹ and P are the same as defined above],
4) Compound represented by formula (V) and formula (VI)

[Wherein R ² represents a group selected from the group consisting of a hydrogen atom, a halogen, a lower alkyl group, a hydroxyl group and a lower alkoxy group, and X ₁ represents a leaving group]. Formula (VII)

[Wherein R ¹ , R ² and P are the same as defined above],
5) Reduction of the nitro group of the compound represented by formula (VII) to formula (IIX)

[Wherein R ¹ , R ² and P are the same as defined above],
6) A compound represented by the formula (IIX) is reacted with a carbonyl compound selected from the group consisting of carbonyldiimidazole, phosgene, diphosgene, triphosgene, diethyl carbonate, ethyl chloroformate and urea in a solvent, )

[Wherein R ¹ , R ² and P are as defined above], and 7) a compound represented by formula (IX) is converted to sodium carbonate, potassium carbonate, lithium methoxy Reacting with a base selected from the group consisting of sodium methoxide and sodium methoxide;
Including formula (I)

[Wherein R ¹ , R ² and P are the same as defined above]. 1) Formula (II)

[Wherein R ¹ represents a lower alkyl group, and P represents an amino protecting group or formula (Z)

(Wherein CY represents a group represented by 1 or 2 cyclic aliphatic carbocyclic group having 6 to 12 carbon atoms) and (S)-(-)-α- Condensation with methylbenzylamine gives the formula (IIIb)

[Wherein Ph represents a phenyl group, and R ¹ and P are as defined above],
2) The compound represented by the formula (IIIb) is reduced to give the formula (IVb)

[Wherein Ph, R ¹ and P are the same as defined above],
3) Hydrogenolysis of the benzyl group of the compound represented by formula (IVb)

[Wherein R ¹ and P are the same as defined above],
4) Compound represented by formula (Vb) and formula (VI)

[Wherein R ² represents a group selected from the group consisting of a hydrogen atom, a halogen, a lower alkyl group, a hydroxyl group and a lower alkoxy group, and X ₁ represents a leaving group]. Formula (VIIb)

[Wherein R ¹ , R ² and P are the same as defined above],
5) Reduction of the nitro group of the compound represented by formula (VIIb) to formula (IIXb)

[Wherein R ¹ , R ² and P are the same as defined above],
6) A compound represented by the formula (IIXb) is reacted in a solvent with a carbonyl compound selected from the group consisting of carbonyldiimidazole, phosgene, diphosgene, triphosgene, diethyl carbonate, ethyl chloroformate and urea, )

[Wherein R ¹ , R ² and P are the same as defined above], and 7) a compound represented by the formula (IXb), sodium carbonate, potassium carbonate, lithium methoxy Reacting with a base selected from the group consisting of sodium methoxide and sodium methoxide;
Including formula (Ib)

[Wherein R ¹ , R ² and P are the same as defined above].