JP2006008641A - Process for producing optically active dihydropyrrole and tetrahydropyridine derivatives - Google Patents

Abstract

［式中、Ｒ¹は水素原子あるいはアミノ基の保護基を、Ｒ²は置換されていても良い炭素数1〜6の低級アルキル基を、Ｒ³は炭素数１〜３の低級アルキル基を表す。］
で表される光学活性なアミノ酸エステルを出発物質とし、塩基の存在下これにアクリル酸エステルまたは4-ハロゲノブタン酸エステルを反応させ、閉環して得られたエノラート体(II)：

［式中、Ｒ¹とＲ²は前掲に同じ。Ｒはエステル残基を、ｍは1または2を、Ｍは一価の金属陽イオンを表す。］
を単離することなく還元して式(III)：

［式中、Ｒ¹、Ｒ²、Ｒおよびｍは前掲に同じ。］
で表されるβ-ヒドロキシエステルに変換した後、引き続いてこれを脱水反応に付することを特徴とする式(IV)：

［式中、Ｒ¹、Ｒ²、Ｒおよびｍは前掲に同じ。］
で表される光学活性なジヒドロピロールまたはテトラヒドロピリジン誘導体の製造法。
【選択図】なし
PROBLEM TO BE SOLVED: To produce an optically active dihydropyrrole and tetrahydropyridine derivative represented by the following formula (IV):
SOLUTION: Formula (I):

[In the formula, R ¹ represents a hydrogen atom or amino protecting group, R ² represents an optionally substituted lower alkyl group having 1 to 6 carbon atoms, and R ³ represents a lower alkyl group having 1 to ³ carbon atoms. To express. ]
An enolate (II) obtained by ring-closing by reacting an acrylic acid ester or 4-halogenobutanoic acid ester in the presence of a base with an optically active amino acid ester represented by the following:

[Wherein R ¹ and R ² are the same as described above. R represents an ester residue, m represents 1 or 2, and M represents a monovalent metal cation. ]
Can be reduced without isolation to formula (III):

[Wherein, R ¹ , R ² , R and m are the same as described above. ]
Formula (IV) characterized in that after being converted to a β-hydroxyester represented by the formula (IV):

[Wherein, R ¹ , R ² , R and m are the same as described above. ]
A process for producing an optically active dihydropyrrole or tetrahydropyridine derivative represented by the formula:
[Selection figure] None

Description

  The present invention relates to a method for producing optically active dihydropyrrole and tetrahydropyridine derivatives, which are important as synthetic intermediate compounds for various pharmaceuticals.

Conventionally, dihydropyrrole and tetrahydropyridine derivatives have been used as synthetic intermediates for various pharmaceuticals. For example, dihydropyrrole and tetrahydropyridine derivatives obtained by the production method provided by the present invention are used as side chain raw materials at the 2-position of carbapenem antibiotics having excellent antibacterial activity (Patent Document 1, Non-Patent Document). 1). However, for example, the Diekman ring closure conditions used in the production of tetrahydropyridine derivatives are extremely difficult to use for mass production because the reaction time is as extremely short as 1 minute. (Patent Document 1, Non-Patent Document 1) Moreover, the method of Patent Document 1 has room for further study on the optical purity of the compound obtained.
Other methods for producing dihydropyrrole and tetrahydropyridine derivatives are disclosed in, for example, Patent Documents 2, 3, 4 and Non-Patent Document 2. However, Patent Document 2 does not explicitly mention optical purity, and Non-Patent Document 2 describes only the synthesis of a racemic mixture. Furthermore, as a method for producing optically active dihydropyrrole and tetrahydropyridine derivatives, only 3-pyrroline-2-carboxylic acid derivatives (Patent Document 3) or 2-pyrroline-2-carboxylic acid derivatives (Patent Document 4) are mentioned. However, there are no reports on 3-pyrroline-2-carboxylic acid derivative products obtained by the present invention with different substitution patterns. Further, there is no report that from formula (I), formula (II) or formula (III) can be produced in one pot up to formula (IV) without isolation.
WO 02/38564 JP-A-1-233270 Special table 2000-516586 JP 2004-107288 A Journal of Antibiotics 55, 722-757 (2002) Heterocycles 43, 2131-2138 (1996)

  The problem to be solved by the present invention is to provide a method capable of efficiently and efficiently producing optically active dihydropyrrole and tetrahydropyridine derivatives with high optical purity, which are important as synthetic intermediate compounds for various pharmaceuticals. is there.

［式中、Ｒ¹は水素原子あるいはアミノ基の保護基を、Ｒ²は置換されていてもよい炭素数1〜6の低級アルキル基を、Ｒ³は炭素数1〜3の低級アルキル基を表す。］
で表される光学活性なアミノ酸エステルを出発物質とし、塩基の存在下これにアクリル酸エステルまたは4−ハロゲノブタン酸エステルを反応させ、閉環して得られたエノラート体(II)：

［式中、Ｒ¹とＲ²は前掲に同じ。Ｒはエステル残基を、ｍは1または2を、Ｍは一価の金属陽イオンを表す。］
を単離することなく還元して式(III)：

［式中、Ｒ¹、Ｒ²、Ｒおよびｍは前掲に同じ。］
で表されるβ−ヒドロキシエステルに変換した後、引き続いてこれを脱水反応に付することを特徴とする式(IV)：

［式中、Ｒ¹、Ｒ²、Ｒおよびｍは前掲に同じ。］
で表される光学活性なジヒドロピロールまたはテトラヒドロピリジン誘導体の製造法。 As a result of various studies, the present inventors have obtained an optically active amino acid ester as a starting material, which is reacted at low temperature with an acrylate ester or 4-halogenobutanoic acid ester in the presence of a base, followed by ring closure. An efficient and large amount of dihydropyrrole and tetrahydropyridine derivatives with high optical purity, characterized in that the enolate is reduced to a β-hydroxy ester without isolation and then subjected to a dehydration reaction. A production method capable of synthesis was completed.
That is, the present invention
(1) Formula (I):

[Wherein R ¹ represents a hydrogen atom or an amino-protecting group, R ² represents an optionally substituted lower alkyl group having 1 to 6 carbon atoms, and R ³ represents a lower alkyl group having 1 to ³ carbon atoms. To express. ]
An enolate (II) obtained by ring-closing by reacting an acrylate ester or 4-halogenobutanoic acid ester in the presence of a base with an optically active amino acid ester represented by the following formula:

[Wherein R ¹ and R ² are the same as described above. R represents an ester residue, m represents 1 or 2, and M represents a monovalent metal cation. ]
Can be reduced without isolation to formula (III):

[Wherein, R ¹ , R ² , R and m are the same as described above. ]
Formula (IV) characterized in that after being converted to a β-hydroxyester represented by the formula (IV):

[Wherein, R ¹ , R ² , R and m are the same as described above. ]
A process for producing an optically active dihydropyrrole or tetrahydropyridine derivative represented by the formula:

［式中、Ｒ¹、Ｒ²およびＲ³は前記１に同じ。］
で表される光学活性なアミノ酸エステルを出発物質とし、塩基の存在下これにアクリル酸エステルを反応させ、閉環して得られたエノラート体(IIa)：

［式中、Ｒ¹、Ｒ²、ＲおよびＭは前記１に同じ。］
を単離することなく還元して式(IIIa)：

［式中、Ｒ¹、Ｒ²およびＲは前記１に同じ。］
で表されるβ−ヒドロキシエステルに変換した後、引き続いてこれを脱水反応に付することを特徴とする式(IVa)：

［式中、Ｒ¹、Ｒ²、Ｒおよびｍは前記１に同じ。］
で表される光学活性なジヒドロピロール誘導体の製造法。 (2) Formula (I):

[Wherein, R ¹ , R ² and R ³ are the same as those in 1 above. ]
An enolate (IIa) obtained by ring-closing by reacting an acrylate ester in the presence of a base with an optically active amino acid ester represented by

[Wherein, R ¹ , R ² , R and M are the same as the above 1. ]
Can be reduced without isolation to formula (IIIa):

[Wherein, R ¹ , R ² and R are the same as those in 1 above. ]
Formula (IVa) characterized in that after being converted to a β-hydroxyester represented by the formula (IVa):

[Wherein, R ¹ , R ² , R and m are the same as those in 1 above. ]
The manufacturing method of the optically active dihydropyrrole derivative represented by these.

［式中、Ｒ¹、Ｒ²およびＲ³は前記１に同じ。］
で表される光学活性なアミノ酸エステルを出発物質とし、塩基の存在下これに4−ハロゲノブタン酸エステルを反応させ、閉環して得られたエノラート体(IIb)：

［式中、Ｒ¹、Ｒ²、ＲおよびＭは前記１に同じ。］
を単離することなく還元して式(IIIb)：

［式中、Ｒ¹、Ｒ²およびＲは前記１に同じ。］
で表されるβ−ヒドロキシエステルに変換した後、引き続いてこれを脱水反応に付することを特徴とする式(IVb)：

［式中、Ｒ¹、Ｒ²、Ｒおよびｍは前記１に同じ。］
で表される光学活性なテトラヒドロピリジン誘導体の製造法。 (3) Formula (I):

[Wherein, R ¹ , R ² and R ³ are the same as those in 1 above. ]
The enolate (IIb) obtained by cyclization by reacting 4-halogenobutanoic acid ester in the presence of a base with an optically active amino acid ester represented by the following formula:

[Wherein, R ¹ , R ² , R and M are the same as the above 1. ]
Can be reduced without isolation to formula (IIIb):

[Wherein, R ¹ , R ² and R are the same as those in 1 above. ]
Formula (IVb) characterized in that after being converted to a β-hydroxyester represented by the formula (IVb):

[Wherein, R ¹ , R ² , R and m are the same as those in 1 above. ]
The manufacturing method of the optically active tetrahydropyridine derivative represented by these.

(4) The process for producing an optically active dihydropyrrole or tetrahydropyridine derivative as described in 1 above, wherein R ² is optionally substituted methyl.
(5) The process for producing an optically active dihydropyrrole derivative as described in 2 above, wherein R ² is optionally substituted methyl.
(6) The process for producing an optically active tetrahydropyridine derivative as described in 3 above, wherein R ² is optionally substituted methyl.
(7) Any one of the above 1 to 6, wherein at least one selected from aprotic polar solvents such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, and hexamethylphosphoric triamide is used as a solvent for the ring-closing reaction. The production method described in 1.
(8) Lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexa Methyl disilazide, sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate The manufacturing method in any one of said 1-7 using at least 1 sort (s) chosen from.

  According to the present invention, optically active dihydropyrrole and tetrahydropyridine derivatives, which are important as synthetic intermediate compounds for various pharmaceuticals, can be produced efficiently and in large quantities with high optical purity. is there.

光学活性なアミノ酸誘導体である化合物(I)に塩基の存在下アクリル酸エステルあるいは4−ハロゲノブタン酸エステルを反応させると窒素原子上でアルキル化が起こってジエステル体が生成すると同時にディークマン閉環反応が進行し、エノラート体である化合物(II)が生成する（第一工程）。化合物(II)は単離することなく還元してβ−ヒドロキシエステルである化合物(III)へと容易に変換することが可能である（第二工程）。引き続いて化合物(III)を脱水反応に付することによって所望の光学活性なジヒドロピロールおよびテトラヒドロピリジン誘導体である化合物(IV)を高い光学純度で製造することができる（第三工程）。化合物(IV)は例えば優れた抗菌活性を有するカルバペネム系抗生物質の２位の側鎖原料として有用であり、本発明方法はこれらの中間体の製造方法として用いるのに好適である。 The present invention will be described in detail below. The reaction scheme of the method for producing optically active dihydropyrrole and tetrahydropyridine derivatives according to the present invention is as follows.

When compound (I), which is an optically active amino acid derivative, is reacted with an acrylate ester or 4-halogenobutanoate in the presence of a base, alkylation occurs on the nitrogen atom to form a diester, and at the same time, the Diekman ring closure reaction proceeds. Thus, compound (II) which is an enolate form is formed (first step). Compound (II) can be easily converted to compound (III) which is a β-hydroxy ester by reduction without isolation (second step). Subsequently, compound (IV) which is a desired optically active dihydropyrrole and tetrahydropyridine derivative can be produced with high optical purity by subjecting compound (III) to a dehydration reaction (third step). Compound (IV) is useful, for example, as a side chain raw material at the 2-position of carbapenem antibiotics having excellent antibacterial activity, and the method of the present invention is suitable for use as a method for producing these intermediates.

The substituents of the compounds represented by compounds (I), (II), (III) and (IV) will be described below.
Examples of the “amino-protecting group” in R ¹ are not particularly limited as long as they can be easily removed by a conventional method. W. Greene, P.M. G. M.M. Wuts: Protective Groups in Organic Synthesis; 3rd edition, Wiley, New York (1999) or P.W. Reference can be made to Kocienski, Protecting Groups, Thimeme, Stuttgart (1994). Suitably, for example, lower alkanoyl having 1 to 5 carbon atoms such as formyl, acetyl, propionyl, etc., halogenoalkanoyl having 2 to 5 carbon atoms such as chloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, 2-pyridylcarboxy, 3- Arylcarbonyl such as pyridylcarboxy, aralkylcarbonyl such as phenylacetyl, 3-phenylpropionyl, (lower alkyl having 1 to 5 carbon atoms) oxycarbonyl such as tert-butyloxycarbonyl, for example, 2-iodoethyloxycarbonyl, 2, (Halogenoalkyl having 1 to 5 carbon atoms) oxycarbonyl such as 2,2-trichloroethyloxycarbonyl, for example, substituted or unsubstituted (lower alkenyl having 3 to 7 carbon atoms) oxycarbonyl such as allyloxycarbonyl, such as benzyloxy Examples thereof include aralkyloxycarbonyl such as carbonyl, p-methyloxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like, for example, trialkylsilyl such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like. Furthermore, various protecting groups that can be hydrolyzed in vivo to regenerate the amino group can be used. For example, (5-methyl-1,3-dioxolen-2-one-4-yl) methyl is preferable. And oxycarbonyl.

Examples of the “lower alkyl group having 1 to 6 carbon atoms” in R ² include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like. Examples thereof include lower alkyl having 1 to 6 carbon atoms in the form of a chain or a branched chain. Examples of the substituent of the “optionally substituted lower alkyl group having 1 to 6 carbon atoms” include, for example, hydroxy, mercapto, (straight or branched lower alkyl having 1 to 5 carbon atoms) oxy, ( Linear or branched lower alkyl having 1 to 5 carbon atoms) thio, formyl, (linear or branched lower alkyl having 1 to 5 carbon atoms) carbonyl, formyloxy, (linear Alternatively, branched and lower alkyl having 1 to 5 carbon atoms) carbonyloxy, carboxyl, (straight or branched lower alkyl having 1 to 5 carbon atoms) oxycarbonyl, and lower cyclo having 3 to 7 carbon atoms Alkyl, halogen atom, cyano, amino, mono- or di- (linear or branched lower alkyl having 1 to 5 carbon atoms) amino, carbamoyl, mono- or di- (linear or branched) 1 carbon number 5 lower alkyl) amide, carbamoyloxy, mono- or di- (linear or branched lower alkyl having 1 to 5 carbon atoms) aminocarbonyloxy, guanidino, 4-imidazolyl, phenyl, 4-hydroxyphenyl , 3-indolyl and the like. These substituents may be protected by a suitable protecting group. The protecting group used in this case is not particularly limited as long as it can be easily removed by a conventional method. W. Greene, P.M. G. M.M. Wuts: Protective Groups in Organic Synthesis; 3rd edition, Wiley, New York (1999) or P.W. Reference can be made to Kocienski, Protecting Groups, Thimeme, Stuttgart (1994). Further, the substitution position of the substituent is not limited as long as it is chemically possible, and substitution at one place or plural places is possible.

Examples of the “lower alkyl group having 1 to 3 carbon atoms” in R ³ include linear or branched lower alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and the like. Preferred are methyl and ethyl.
Examples of the ester residue in acrylic acid ester, 4-halogenobutanoic acid ester and R include an ester residue which can be a protective group for a carboxyl group. The protecting group used in this case is not particularly limited as long as it can be easily removed by a conventional method. W. Greene, P.M. G. M.M. Wuts: Protective Groups in Organic Synthesis; 3rd edition, Wiley, New York (1999) or P.W. Reference can be made to Kocienski, Protecting Groups, Thimeme, Stuttgart (1994). Preferably, for example, linear or branched lower alkyl having 1 to 5 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, such as 2-ethyl iodide, 2,2,2-trichloroethyl, etc. Halogeno lower alkyl having 1 to 5 carbon atoms, for example, lower alkyloxymethyl having 1 to 5 carbon atoms such as methyloxymethyl, ethyloxymethyl, isobutyloxymethyl, such as acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, C1-C5 lower aliphatic acyloxymethyl such as valoyloxymethyl, 1- (C1-5) lower alkyloxycarbonyloxyethyl such as 1-ethyloxycarbonyloxyethyl, such as benzyl, p- Aralkyl groups such as methyloxybenzyl, o-nitrobenzyl, p-nitrobenzyl Examples thereof include lower alkenyl having 3 to 7 carbon atoms such as allyl and 3-methylallyl, benzhydryl, phthalidyl and the like.
The “halogeno” in the 4-halogenobutanoic acid ester preferably includes, for example, chloro, bromo and iodo.

Examples of the base used in the first step of the present invention include those composed of a monovalent metal cation represented by M, and suitable metal cations include lithium, sodium, and potassium. More specifically, lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide , Sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate Can do. These bases can be used alone or in combination. The amount to be used can be 0.1 to 5.0 mol, preferably 0.5 to 3.0 mol, per 1 mol of compound (I). On the other hand, the amount of acrylic acid ester or 4-halogenobutanoic acid ester used can be 0.1 to 20 mol, preferably 0.5 to 10 mol, per 1 mol of compound (I). The reaction in the first step can be carried out under cooling to room temperature, but is preferably carried out preferably under cooling, for example at −40 ° C. to + 10 ° C. Further, this reaction can be carried out in a solvent, and there are no particular restrictions on the solvent as long as it does not adversely affect the reaction, but preferred are dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide. And aprotic polar solvents such as hexamethylphosphoric triamide. These solvents can be used alone or in combination.
As the reducing agent used in the second step of the present invention, metal hydride compounds such as sodium borohydride and sodium cyanoborohydride are used. The amount used can be 0.1 to 5.0 equivalents relative to compound (II), but preferably 0.5 to 3.0 equivalents. The reaction in the second step can be carried out under cooling to room temperature, but is preferably carried out under cooling, for example, at −15 ° C. to + 10 ° C. This reaction can be carried out in a solvent, and the solvent is not particularly limited as long as it does not adversely affect the reaction, and preferred examples include protic polar solvents such as water, methanol, ethanol and the like. These solvents can be used alone or in combination.

  Examples of the dehydration reaction used in the second step of the present invention include a method using an acid catalyst such as sulfuric acid, phosphoric acid and succinic acid, a method using a solid catalyst such as alumina, silica gel and montmorinolite, iron (II) sulfate, sulfuric acid Methods using metal catalysts such as copper (II) and nickel (II) sulfate are known (for example, New Experimental Chemistry Course, Vol. 14, p. 119). In the case where a β-hydroxy ester such as compound (III) is a substrate, it is known that the elimination reaction proceeds even when a strong base catalyst such as potassium hydroxide or sodium methoxide is used (for example, Journal of the American Chemical Society, 70, 1895-1898 (1948) or Journal of the American Chemical Society, 81, 2822-2826 (1959). In addition, after converting the hydroxy group to a suitable leaving group using a halogenating agent such as phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, sulfonylating agent, etc., it is removed under mild conditions. A method of releasing reaction is also known (for example, New Experimental Chemistry Course, Volume 14, p. 122). Furthermore, the dehydration reaction can be carried out with a combination of an appropriate Lewis acid and Lewis base (for example, JP-A-2004-107288). Preferable examples include a method in which a hydroxy group is converted into an appropriate leaving group using a sulfonylating agent such as methanesulfonyl chloride or p-toluenesulfonyl chloride and then treated with a base. Examples of the base used in this case include organic amine compounds. Preferably, tri (amine having 1 to 4 carbon atoms) such as triethylamine, tributylamine, diisopropylethylamine, or 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] Bicyclic amidine compounds such as non-5-ene can be mentioned. This reaction can be carried out in a solvent, and the solvent is not particularly limited as long as it does not adversely affect the reaction. Preferred examples include aliphatic hydrocarbons such as hexane, heptane, and octane, chloride Halogenated aliphatic hydrocarbons such as methylene, chloroform, carbon tetrachloride and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated aromatic hydrocarbons such as monochlorobenzene and dichlorobenzene . These solvents can be used alone or in combination.

EXAMPLES Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
The meanings of the abbreviations used in the following examples are as follows.
ALOC: Allyloxycarbonyl
DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene
DMF: Dimethylformamide
Me: methyl
THF: tetrahydrofuran

氷冷・窒素雰囲気下に60％水素化ナトリウム（1.01ｇ、25.3mmol）を乾燥DMF（25ml）に懸濁し、アクリル酸メチル（11.5ｇ、134mmol）を注加した。内温を−5〜0℃に保ちながらN−（アリルオキシカルボニル）−L−アラニンメチルエステル（純分5.00ｇ、26.7mmol）の乾燥DMF（25ml）溶液を1時間で滴下した。０℃で1.5時間攪拌を継続した後、光学純度検定用に反応液（1 ml）をサンプリングした。内温を0〜+5℃に保ちながら予め冷却したイオン交換水（150ml）を20分間で滴下した。リン酸を加えて反応液のpHを7.24に調整した。メタノール（6ml）を加えた後、内温を−6〜−3℃に保ちながら水素化ホウ素ナトリウム（0.30ｇ、7.9mmol）のイオン交換水（6ml）溶液を15分間で滴下した。この際同時に6N塩酸を滴下してpHを6.5〜7.5に保った。０℃で1時間攪拌を継続した後、予め冷却したヘプタン（100ml）を加えて抽出・分液した。一部析出物を含む水層に酢酸エチル（200ml）を加えて抽出・分液した。水層を酢酸エチル（100ml）で再抽出後、酢酸エチル層を合わせて飽和食塩水（100ml）洗浄・無水硫酸マグネシウム乾燥・減圧濃縮してアルコール体の粗製品（9.25g、プロトンNMR純度＝73.0%）を得た。このものをトルエン（65ml）に溶解し、氷冷した。内温4〜5℃でトリエチルアミン（5.4ｇ、53.4mmol）を滴下し、引き続いて内温を1〜6℃に保ちながら塩化メタンスルホニル（4.59ｇ、40.1mmol）を12分間で滴下した。内温3〜5℃で1.5時間攪拌した後、DBU（12.2ｇ、80.1mmol）を内温5〜13℃で滴下した。内温を30℃に加熱した後、同温度で140分間攪拌を継続した後、内温を4℃まで冷却した。内温4〜6℃で氷水（65ml）を12分間で滴下し、抽出・分液した。トルエン層を冷1N塩酸（39ml）・冷飽和重曹水（39ml）・冷飽和食塩水（39ml）の順に用いて洗浄後、無水硫酸マグネシウム乾燥・減圧濃縮して標題化合物の粗製品（7.30g、残存トルエンを除いた見かけ収率は88％）を得た。
（光学純度検定）
最初の反応（ディークマン反応）でサンプリングした反応液（1 ml）にジメチル硫酸（3滴）を加え、室温で10分間攪拌した。酢酸エチル（5 ml）と水（5 ml）で希釈し、抽出・分液した。有機層を無水硫酸ナトリウム乾燥・減圧濃縮して得られた下記構造のエノールエーテルをシリカゲル薄層クロマトグラフィーで精製した。

このものを以下に示す光学活性カラムを用いた高速液体クロマトグラフィーで分析したところ光学純度は99％e.e.以上であった。
カラム：ダイセル CHIRALCEL OJ−R (4.6mmφ×15cm)
移動相：水 / メタノール = 3 / 7
測定波長：254 nm
流量：0.5ml/分
保持時間：13.3分 Example 1
1-allyl 3-methyl (5S) -5-methyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate

Under ice-cooling and nitrogen atmosphere, 60% sodium hydride (1.01 g, 25.3 mmol) was suspended in dry DMF (25 ml), and methyl acrylate (11.5 g, 134 mmol) was added thereto. While maintaining the internal temperature at −5 to 0 ° C., a dry DMF (25 ml) solution of N- (allyloxycarbonyl) -L-alanine methyl ester (pure content 5.00 g, 26.7 mmol) was added dropwise over 1 hour. After stirring for 1.5 hours at 0 ° C., the reaction solution (1 ml) was sampled for optical purity test. While maintaining the internal temperature at 0 to + 5 ° C., ion-cooled water (150 ml) cooled in advance was added dropwise over 20 minutes. Phosphoric acid was added to adjust the pH of the reaction solution to 7.24. After adding methanol (6 ml), a solution of sodium borohydride (0.30 g, 7.9 mmol) in ion-exchanged water (6 ml) was added dropwise over 15 minutes while maintaining the internal temperature at −6 to −3 ° C. At the same time, 6N hydrochloric acid was added dropwise to maintain the pH at 6.5 to 7.5. After stirring at 0 ° C. for 1 hour, heptane (100 ml) cooled in advance was added to perform extraction and liquid separation. Ethyl acetate (200 ml) was added to the aqueous layer containing a part of the precipitate, followed by extraction and liquid separation. The aqueous layer was re-extracted with ethyl acetate (100 ml), and the ethyl acetate layers were combined, washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude alcohol product (9.25 g, proton NMR purity = 73.0 %). This was dissolved in toluene (65 ml) and cooled on ice. Triethylamine (5.4 g, 53.4 mmol) was added dropwise at an internal temperature of 4-5 ° C., and methanesulfonyl chloride (4.59 g, 40.1 mmol) was subsequently added dropwise over 12 minutes while maintaining the internal temperature at 1-6 ° C. After stirring at an internal temperature of 3 to 5 ° C. for 1.5 hours, DBU (12.2 g, 80.1 mmol) was added dropwise at an internal temperature of 5 to 13 ° C. After the internal temperature was heated to 30 ° C, stirring was continued at the same temperature for 140 minutes, and then the internal temperature was cooled to 4 ° C. Ice water (65 ml) was added dropwise over 12 minutes at an internal temperature of 4 to 6 ° C., followed by extraction and liquid separation. The toluene layer was washed with cold 1N hydrochloric acid (39 ml), cold saturated aqueous sodium bicarbonate (39 ml), and cold saturated brine (39 ml) in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title compound (7.30 g, The apparent yield excluding residual toluene was 88%).
(Optical purity test)
Dimethyl sulfate (3 drops) was added to the reaction solution (1 ml) sampled in the first reaction (Diekmann reaction), and the mixture was stirred at room temperature for 10 minutes. Diluted with ethyl acetate (5 ml) and water (5 ml), extracted and separated. The enol ether having the following structure obtained by drying the organic layer over anhydrous sodium sulfate and concentrating under reduced pressure was purified by silica gel thin layer chromatography.

When this product was analyzed by high performance liquid chromatography using the optically active column shown below, the optical purity was 99% ee or higher.
Column: Daicel CHIRALCEL OJ-R (4.6mmφ × 15cm)
Mobile phase: water / methanol = 3/7
Measurement wavelength: 254 nm
Flow rate: 0.5ml / min Retention time: 13.3 minutes

Example 2
1-allyl 3-methyl (5S) -5-methyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate N- (allyloxycarbonyl) -L-alanine methyl as in Example 1 The crude alcohol product (185 g, proton NMR purity = 87.0%) was obtained from the ester (pure content 125 g, 667.5 mmol). A crude product of the title compound was obtained using 4.60 g of this, and then purified by silica gel column chromatography to obtain a purified product of the title compound (2.63 g, yield 71%). When the optical purity after the Diekman reaction was tested in the same manner as in Example 1, the optical purity was 99% ee or higher.

Example 3
1-allyl 3-methyl (5S) -5-methyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate N- (allyloxycarbonyl) -L-alanine methyl as in Example 1 The alcohol obtained from the ester (500 mg, proton NMR purity = 80.1%) was dissolved in dichloromethane (10 ml), and methanesulfonyl chloride (353 mg, 3.1 mmol) was added at an internal temperature of 0 to 5 ° C., followed by triethylamine (520 mg, 5.1 mmol). ) Was added dropwise and stirred at the same temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (5 ml), triethylamine (1.04 g, 10.3 mmol) was added dropwise, and the mixture was stirred at 90 ° C. for 5 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a purified product of the title compound (282 mg, yield 76%).

実施例2で得られた1−アリル 3−メチル (5S)−5−メチル−2,5−ジヒドロ−1H−ピロール−1,3−ジカルボキシレートはWO02/38564に開示されている方法（上記のスキーム）に従って、標題化合物へ誘導することができた。物性データはWO02/38564の参考例1で開示されているものに一致した。 Reference example 1
Allyl (2S) -2-methyl-4- (2-mercapto-1,3-thiazol-4-yl) -2,5-dihydro-1H-pyrrole-1-carboxylate

1-allyl 3-methyl (5S) -5-methyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate obtained in Example 2 was prepared according to the method disclosed in WO02 / 38564 (above To the title compound. The physical property data agreed with that disclosed in Reference Example 1 of WO02 / 38564.

a) 実施例2と同様にして得られた1−アリル 3−メチル (5S)−5−メチル−2,5−ジヒドロ−1H−ピロール−1,3−ジカルボキシレート（45g、200mmol）のTHF（450ml）溶液を氷冷した。1N水酸化ナトリウム（220ml、220mmol）を滴下した。内温を3〜5℃に保ちながら2時間攪拌を続けた。減圧濃縮して大部分のTHFを留去し、クロロホルム（90ml）を用いて抽出・分液した。水層に6N塩酸を加えてpHを2に調整した後、クロロホルム（113ml）を用いて抽出・分液した。水層をさらにクロロホルム（113ml）を用いて抽出・分液し、有機層を合わせて、無水硫酸マグネシウム乾燥・減圧濃縮してカルボン酸の粗製品（43.8g、見かけ収率は定量的）を得た。 Reference example 2
Allyl (2S) -2-methyl-4- (2-mercapto-1,3-thiazol-4-yl) -2,5-dihydro-1H-pyrrole-1-carboxylate

a) THF of 1-allyl 3-methyl (5S) -5-methyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (45 g, 200 mmol) obtained as in Example 2 (450 ml) The solution was ice-cooled. 1N sodium hydroxide (220 ml, 220 mmol) was added dropwise. Stirring was continued for 2 hours while maintaining the internal temperature at 3 to 5 ° C. Concentrated under reduced pressure to remove most of the THF, and extracted and separated using chloroform (90 ml). 6N Hydrochloric acid was added to the aqueous layer to adjust the pH to 2, followed by extraction and liquid separation using chloroform (113 ml). The aqueous layer was further extracted and separated using chloroform (113 ml), and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of carboxylic acid (43.8 g, apparent yield is quantitative). It was.

b) A solution of the carboxylic acid (43.8 g) obtained in step a) in THF (1050 ml) was cooled to -20 ° C. Triethylamine (52.4 g, 518 mmol) and ethyl chloroformate (27 g, 248 mmol) were added dropwise in this order, and stirring was continued at −20 ° C. for 45 minutes. N, O-dimethylhydroxylamine hydrochloride (60.6 g, 622 mmol) and triethylamine (63 g, 622 mmol) were suspended in dry DMF (394 ml) and added to the previously prepared mixed anhydride solution. Stirring was continued for 0.5 hours at −15 ° C. and 1.5 hours at room temperature, and then the precipitated salt was filtered off and washed twice with THF (200 ml). Combine the filtrate and washings, add 6N hydrochloric acid to adjust the pH to 2, add saturated brine (1200 ml), then evaporate most of the THF and extract with ethyl acetate (400 ml). Liquid separation was performed. The aqueous layer was further extracted and separated using ethyl acetate (400 ml), and the organic layers were combined and washed twice with 1N hydrochloric acid (200 ml) and once with saturated aqueous sodium hydrogen carbonate (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of Weinreb amide (46.4 g).

c) A solution of Weinreb amide (46.4 g) obtained in step b) in THF (464 ml) was ice-cooled. A 1M methylmagnesium bromide / THF solution (274 ml, 274 mmol) was added dropwise, and stirring was continued for 1.5 hours while maintaining the internal temperature at 2 to 4 ° C. Saturated aqueous ammonium chloride solution (90 ml) was added dropwise to stop the reaction, water (767 ml) and ethyl acetate (1534 ml) were added, and the mixture was extracted and separated. The aqueous layer was further extracted and separated using ethyl acetate (384 ml), and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of methyl ketone (39.4 g).
d) A solution of methyl ketone (39.4 g) obtained in step c) in acetonitrile (788 ml) was ice-cooled. Triethylamine (28.6 g, 283 mmol) and trifluoromethanesulfonic acid trimethylsilyl ester (50.2 g, 226 mmol) were added dropwise in this order, and stirring was continued for 1.5 hours while maintaining the internal temperature at 2 to 4 ° C. After adding trifluoromethanesulfonic acid trimethylsilyl ester (4.18 g, 18.8 mmol), stirring was further continued at the same temperature for 1 hour. After pyridinium bromide perbromide (60.9 g, 190 mmol) was added, stirring was continued at the same temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate (900 ml) and ethyl acetate (800 ml) were added, and the mixture was extracted and separated. The aqueous layer was further extracted and separated using ethyl acetate (200 ml), and the organic layers were combined and washed with 2N hydrochloric acid (400 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue (98 g) was dissolved in ethyl acetate (400 ml) and washed once with 1N hydrochloric acid (200 ml) and three times with water (200 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue (48.6 g) was dissolved in ethyl acetate (400 ml), saturated aqueous sodium hydrogen carbonate (200 ml), 2N hydrochloric acid (200 ml), saturated aqueous sodium hydrogen carbonate (200 ml), 2N hydrochloric acid. (200 ml) followed by water (200 ml) for washing. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of bromomethyl ketone (42.3 g).

e) Thioisonicotinamide (203 mg, 1.47 mmol) was added to a solution of the bromomethyl ketone (42.3 g) obtained in step d) in methanol (1692 ml), and the mixture was ice-cooled. Ammonium dithiocarbamate (24.2 g, 220 mmol) was added while maintaining the internal temperature at 3 to 6 ° C., and stirring was further continued at the same temperature for 0.5 hour. The mixture was heated to reflux for 2 hours and then concentrated under reduced pressure. Chloroform (787 ml) and 1N sodium hydroxide (787 ml) were added to the residue, and the mixture was extracted and separated. The alkaline aqueous layer was washed again with chloroform (393 ml), 6N hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted and separated with chloroform (590 ml). The aqueous layer was further extracted and separated using chloroform (295 ml), and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of the title compound (22.0 g, apparent yield excluding residual chloroform was 36 %). The physical property data of this product coincided with that disclosed in Reference Example 1 of WO02 / 38564.

The problem to be solved by the present invention is to provide a method capable of efficiently and efficiently producing optically active dihydropyrrole and tetrahydropyridine derivatives with high optical purity, which are important as synthetic intermediate compounds for various pharmaceuticals. is there.

Claims (8)

Formula (I):

[In the formula, R ¹ represents a hydrogen atom or amino protecting group, R ² represents an optionally substituted lower alkyl group having 1 to 6 carbon atoms, and R ³ represents a lower alkyl group having 1 to ³ carbon atoms. To express. ]
An enolate (II) obtained by ring-closing by reacting an acrylic acid ester or 4-halogenobutanoic acid ester in the presence of a base with an optically active amino acid ester represented by the following:

[Wherein R ¹ and R ² are the same as described above. R represents an ester residue, m represents 1 or 2, and M represents a monovalent metal cation. ]
Can be reduced without isolation to formula (III):

[Wherein, R ¹ , R ² , R and m are the same as described above. ]
Formula (IV) characterized in that after being converted to a β-hydroxyester represented by the formula (IV):

[Wherein, R ¹ , R ² , R and m are the same as described above. ]
A process for producing an optically active dihydropyrrole or tetrahydropyridine derivative represented by the formula: Formula (I):

[Wherein R ¹ , R ² and R ³ are the same as in claim 1. ]
An enolate (IIa) obtained by ring-closing by reacting an acrylate ester in the presence of a base with an optically active amino acid ester represented by

[Wherein R ¹ , R ² , R and M are the same as in claim 1. ]
Can be reduced without isolation to formula (IIIa):

[Wherein R ¹ , R ² and R are the same as in claim 1. ]
Formula (IVa), characterized in that it is converted to a β-hydroxyester represented by the following formula and subsequently subjected to a dehydration reaction:

[Wherein R ¹ , R ² , R and m are the same as in claim 1. ]
The manufacturing method of the optically active dihydropyrrole derivative represented by these. Formula (I):

[Wherein R ¹ , R ² and R ³ are the same as in claim 1. ]
An enolate compound (IIb) obtained by cyclization by reacting 4-halogenobutanoic acid ester in the presence of a base with an optically active amino acid ester represented by the formula:

[Wherein R ¹ , R ² , R and M are the same as in claim 1. ]
Can be reduced without isolation to formula (IIIb):

[Wherein R ¹ , R ² and R are the same as in claim 1. ]
Formula (IVb), characterized in that it is converted to a β-hydroxyester represented by the following formula and subsequently subjected to a dehydration reaction:

[Wherein R ¹ , R ² , R and m are the same as in claim 1. ]
The manufacturing method of the optically active tetrahydropyridine derivative represented by these. ^{2. The} process for producing an optically active dihydropyrrole or tetrahydropyridine derivative according to claim 1, wherein R ² is optionally substituted methyl. ^{3. The} process for producing an optically active dihydropyrrole derivative according to claim 2, wherein R ² is optionally substituted methyl. 4. The process for producing an optically active tetrahydropyridine derivative according to claim 3, wherein R ² is optionally substituted methyl. 7. The solvent according to any one of claims 1 to 6, wherein at least one selected from aprotic polar solvents such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, and hexamethylphosphoric triamide is used as the solvent for the ring-closing reaction. Manufacturing method. Lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisila Selected from zido, sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate The production method according to claim 1, wherein at least one kind is used.