WO2006123762A1

WO2006123762A1 - Process for production of pyrrolidine compounds

Info

Publication number: WO2006123762A1
Application number: PCT/JP2006/309980
Authority: WO
Inventors: Tetsuya Ikemoto; Syoji Fukuyo; Junichi Yasuoka
Original assignee: Sumitomo Chemical Company, Limited
Priority date: 2005-05-16
Filing date: 2006-05-12
Publication date: 2006-11-23

Abstract

A process for the production of compounds represented by the general formula (3) or salts thereof: (3) which comprises reacting a compound represented by the general formula (1): (1) with a compound represented by the general formula (2) or a salt thereof: (2) in the presence of formaldehyde or a derivative thereof.

Description

Method for producing pyrrolidine compound

Technical field

The present invention relates to a method for producing a pyrrolidine compound useful as a pharmaceutical, agricultural chemical, organic electronic material or the like, or an intermediate thereof, more specifically, production of an N-trisubstituted methyl- 卜 -lance-3,4-disubstituted pyrrolidine compound. Regarding the method.

Background art

Formula (3)

(In the formula, R, R \ R ² and R ³ are each independently an aromatic group which may be substituted, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, Represents an alkenyl group which may be substituted or an alkynyl group which may be substituted, and one or two or more of one CH ₂ _ groups in each of the alkyl group, cycloalkyl group, alkenyl group and alkynyl group represent one _ Group, — S— group, one NH— group, or _ CO— group may be substituted, and one of the CH = groups may be substituted with a nitrogen atom, provided that —O The — group, —S— group and —NH— group are not adjacent to each other X is an electron-withdrawing group R and X do not represent absolute configurations, but each other with respect to the pyrrolidine ring Indicates that it is located in the trans position.

Is a compound useful as a pharmaceutical, agricultural chemical, organic electronic material or the like or an intermediate thereof. For example, tr an s— 1— t—Petitrou 4 (2, 4-difluorophenyl) monopyrrolidine—3—streptyl ethyl ester is useful as a melanocortin —4 (MC— 4) receptor agonist. It is useful as an intermediate for drugs (for example, WO04 / 092126). In addition, compound (3) has a sterically very crowded tri-substituted methyl group, and as a synthesis method thereof, for example, WO04 / 092126 discloses the method described in the following scheme 1. .

Scheme-'1

However, this method has problems such as using expensive lithium hexamethyldisilazide and requiring ultra-low temperature. Disclosure of the invention

An object of the present invention is to provide a method capable of efficiently producing a compound (3) having a sterically hindered tri-substituted methyl group without using expensive reagents or ultra-low temperature conditions.

That is, the gist of the present invention is as follows.

<1> A method for producing compound (3) or a salt thereof,

Formula (1)

(In the formula, R and X have the same meanings as described above.)

A compound represented by the formula (hereinafter sometimes referred to as compound (1)) is represented by formula (2)

(Wherein RR ² and R ³ have the same meanings as above.) A method comprising reacting a compound represented by the formula (hereinafter sometimes referred to as compound (2)) or a salt thereof in the presence of formaldehyde or a derivative thereof.

<2> The method according to 1>, wherein RR ² and R ³ are each an alkyl group.

<3> The method according to <2>, wherein RK R ² and R ³ are each a methyl group.

<4> The method according to any one of <1> to <3>, wherein R is an optionally substituted phenyl group or an optionally substituted alkyl group.

<5> The method according to <4>, wherein R is a phenyl group or a methyl group substituted with a fluorine atom.

<6> The method according to claim 5, wherein R is a 2,4-difluorophenyl group.

<7> X is a group represented by the formula (V), a group represented by the formula (VI), a formyl group, a cyano group or a two-necked group. Method.

(VI)

Wherein Rx is an optionally substituted aromatic group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group or an optionally substituted Represents an alkynyl group.)

<8> The method according to <7>, wherein X is a group represented by the formula (V).

<9> The method according to <8>, wherein X is a methoxycarbonyl group or an ethoxycarbonyl group.

<1 0> Compound (1) is 3- (2,4-difluorophenyl) ethyl acrylate, 3- (2,4-difluorophenyl) methyl acrylate, 3- (2,4-difluorophenyl) acrylic acid t-butyl, 3- (2,4-difluorophenyl) benzyl acrylate, 3- (2,4-difluorophenyl) acrylate L-menthyl or optically active 3- 3- (2, 4-difluorophenyl) acrylic acid 3 _ (4,4-Dimethyl _2 1-year-old oxo) The method according to any one of <1> to <4>, which is tetrahydrofuranyl. 1 1> Compound (2) is N—t-butylglycine, N— (1-methyl-1-phenyl) ethylglycine, N_ (1-cyclohexyl-1-ethyl) ethylglycine, From 1—, <5> to N— (1-aryl-1-methyl) ethylglycine, N— (1,1-diphenyl) ethylglycine, N_triphenylmethyldaricin or N-tricyclohexylglycine 9> The method according to any one of the above.

<1 2> The compound (3) is trans-1- 1-tert-butyl-4-41 (2,4-difluoro-orcenyl) pyrrolidine-3-streptyl ethyl sulfonate, trans-1- 1-tert-butyl-4 1 (2 , 4-Difluorophenyl) Pyrrolidine mono 3 _methyl carboxylate, trans mono l _ t-Butyl 4-1 (2,4-Difluorophenyl) Pyrrolidine mono 3-Strength isopropyl sulfonate, trans- 1- t-Butyl 4-one (2 , 4-difluorophenyl) pyrrolidine mono-3-t-butyl sulfonate, trans- 1- t-butyl -4- (2,4-difluorophenyl) pyrrolidine- 3-carboxylate, optically active tr an s— 1 _ t-Butyl— 4— (2, 4-Difluorophenyl) pyrrolidine — 3— Menthyl carboxylate or optically active trans _ 1— t-butyl — 4— (2, 4-Difluorophenyl) pyrrolidine Rubonic acid 3— (4 , 4-Dimethyl-2-oxo) The method according to <1>, which is tetrahydrofuranyl.

<1 3> The method according to any one of <1> to <1 2>, wherein the formaldehyde or a derivative thereof is paraformaldehyde, trioxane, a formalin aqueous solution, methoxymethane, or dimethoxymethane.

<14> The method according to <1 3>, wherein the formaldehyde or a derivative thereof is paraformaldehyde. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be specifically described.

Explanation of R in Equation (3) and Equation (1)

Examples of “alkyl group” in “optionally substituted alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec_butyl group, t-butyl group, pentyl group. A straight chain or branched chain having 1 to 12 carbon atoms such as a group, isopentyl group, neopentyl group, hexyl group, 2-ethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, etc. An alkyl group is mentioned. Examples of the “cycloalkyl group” in the “optionally substituted cycloalkyl group” include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. Cycloalkyl groups.

Examples of “alkenyl group” in “optionally substituted alkenyl group” include ethenyl group, 1-propenyl group, allyl group, 1-methyl-2-propenyl group, 1-butenyl group, 2- Butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 1-hexenyl group, 2-hexenyl group, 1-heptenyl group, 2-heptenyl group, 1-octenyl group, 2-octenyl group, Examples thereof include linear or branched alkenyl groups having 2 to 12 carbon atoms such as 1-nonenyl group, 2-nonenyl group, 1-decenyl group, 2-decenyl group, 1-undecenyl group, 1-dodecenyl group.

Examples of “alkynyl group” in “optionally substituted alkynyl group” include ethynyl, 1-propynyl, 2_propynyl, 1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 —Pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 1-heptynyl, 2-heptynyl, 1-octynyl, 2-octynyl, 1-nonynyl, 2-nonynyl, 1-decynyl, Examples thereof include straight-chain or branched alkynyl groups having 2 to 12 carbon atoms such as 2-decynyl, 1-undecynyl, and 1-dodecyl.

In each of the “alkyl group”, “cycloalkyl group”, “alkenyl group” and “alkynyl group”, one or more of —CH ₂ — groups are —O— groups, —S— groups, one NH It may be substituted with a — group or —C〇— group, and one of the —CH═ groups may be substituted with a —N == group. However, the —O— group, _S— group, and —NH— group are not adjacent to each other. Examples thereof include methoxymethyl group, methoxy group, t-butoxymethyl group, methoxyethoxymethyl group, methylthiomethyl group, 2-dimethylaminoethyl group, dimethylamino group, 2-jetylaminoethoxymethyl group, 4-methyl group. Toxicyclohexyl group, 4-dimethylaminocyclohexyl group, tetrahydro-2-/-pyran-2-yloxymethyl group, 3-acetylpropyl group, 2-acetyloxychetyl group, bivalyloxymethyl group, 4-a Riloxybutyl group and the like are included. Examples of the substituent that the “alkyl group”, “cycloalkyl group”, “alkenyl group” and “alkynyl group” may have include a phenyl group, a naphthyl group, a furanyl group, a chenyl group, a pyridyl group, Benzofuranyl group, indoyl group, benzophenyl group, pyrimidyl group, birazinyl group, quinolinyl group, isoquinolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, halogen atom, nitro group, cyano group, etc. . The number of substituents is not particularly limited, but 1 to 3 is preferable. When two or more substituents are present, they may be the same or different.

Examples of the “aromatic group” in the “optionally substituted aromatic group” include an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, phenyl group, naphthyl group, etc.); nitrogen other than carbon atom 5- to 7-membered aromatic heterocyclic groups having 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms (for example, furanyl group, chenyl group, pyridyl group, pyrimidyl group, birazinyl group) A condensed ring group composed of the same or different aromatic heterocycles (for example, naphthyridinyl group, imidazopyrimidinyl group, pyridopyrazinyl group, pyrimidovirazinyl group, pyro-oral pyrimidinyl group, etc.); A condensed ring group consisting of a telo ring and the above aromatic hydrocarbon (eg, benzofuranyl group, indolyl group, benzochelyl group, quinolinyl group, isoquino group) Group, full evening piperazinyl group, Kinazori two group, quinoxalinyl group, include cinnolinyl group and the like) and the like.

Examples of the substituent that the “aromatic group” may have include: a halogen atom; a nitro group; a cyan group; an “optionally substituted alkyl group” as defined above; and a “substituted” as defined above. An alkenyl group which may be substituted ”; an“ optionally substituted alkynyl group ”as defined above (wherein one or more of the CH ₂ — groups in the alkyl group, alkenyl group and alkynyl group are — O— group, — S— group, —NH— group, or —CO— group may be substituted, and one —CH = group may be substituted with one N = group. 1—O—, —S— and 1—NH— groups are not adjacent to each other.); Halogen atom, nitro group, cyan group, “optionally substituted alkyl group” as defined above, “Optionally substituted alkenyl group” as defined above and above "Optionally substituted alkynyl" from optionally substituted aromatic group with a substituent selected synonymous with (For example, phenyl group, naphthyl group, furanyl group, chenyl group, pyridyl group, etc.) and the like.

R is preferably an optionally substituted phenyl group or an optionally substituted alkyl group, more preferably a phenyl group substituted with a fluorine atom or a methyl group, and particularly preferably a 2,4-difluorophenyl group. Explanation of X in Equation (3) and Equation (1)

Examples of the electron withdrawing group include a group represented by the following formula (V), a group represented by the formula (VI), a formyl group, a nitrile group, and a nitro group.

(VI)

(In the formula, R x represents an optionally substituted aromatic group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted group; Good alkynyl group.)

Here, “optionally substituted aromatic group”, “optionally substituted alkyl group”, “optionally substituted cycloalkyl group”, “optionally substituted” represented by R x The “alkenyl group” and the “optionally substituted alkynyl group” have the same meanings as defined for R, respectively, and each of the “alkyl group”, “cycloalkyl group”, “alkenyl group” and “ One or more of the —CH ₂ — groups in the “alkynyl group” may be substituted with ten-, one S-, one NH— or —C0_ groups. One of the two groups may be substituted with one N == group. However, the —O — group, — S— group and _ NH _ group are not adjacent to each other.

R x is preferably an alkyl group which may be substituted, and more preferably a methyl group or an ethyl group.

X is preferably a group represented by the formula (V), more preferably a methoxycarbonyl group or an ethoxycarbonyl group. In addition, by using an optically active substituent having an asymmetric center in Rx, an asymmetry is induced at positions 3 and 4 of the pyrrolidine ring of the obtained compound (3) to obtain an optically active compound (3). Can do. Then, by removing the Rx group by hydrolysis or oxidation treatment, it can be led to a photoactive pyrrolidine compound. Therefore, the use of an optically active substituent having an asymmetric center in Rx is advantageous for obtaining an optically active pyrrolidine compound. Explanation of R ¹ , R ² and R ³ in formula (3) and formula (2)

“Aromatic group which may be substituted” represented by RR ² and R ³ , “alkyl group which may be substituted”, “cycloalkyl group which may be substituted”, “which may be substituted” The “alkenyl group” and the “optionally substituted alkynyl group” have the same meanings as defined for R, and each of the “alkyl group”, “cycloalkyl group”, “alkenyl group” ”And“ Alkynyl group ”, one or more of —CH ₂ _ groups may be substituted with one group, one S— group, —NH— group or —CO— group. One of the CH = groups may be substituted with an —N = group. However, the —O— group, —S— group and —NH— group are not adjacent to each other.

An alkyl group which may have a substituent is preferable, and a methyl group is more preferable. Examples of Compound (1), Compound (2) and Compound (3)

Examples of compound (1) are: 3_ (2,4-difluorophenyl) ethyl acrylate, 3_ (2,4-difluorophenyl) methyl acrylate, 3- (2,4-difluorophenyl) acrylic Isopropyl acid, 3- (2,4-difluorophenyl) t-butyl acrylate, 3- (2,4-difluorophenyl) benzyl acrylate, optically active 1- (2,4-difluorophenyl) menthyl acrylate, Optically active 3- (2,4-difluorophenyl) acrylic acid 3— (4,4-dimethyl_2-oxo) tetrahydrofuranyl, 3— (2,4-difluorophenyl) acrylonitrile, 3— (2, 5-Difluorophenyl) Ethyl acrylate, 3 _ (2-Fluorophenyl) Methyl acrylate, 3— (4 monofluorophenyl) Ethyl acrylate, 3 _ (2, 4-Dichlorophenyl) Ethyl acrylate, 3-— (4-phenyl) Ethyl acrylate, 3 _ (4-Methoxyphenyl) benzyl acrylate, 3-— ((N, N-dimethylamino) phenyl) Acrylic Ethyl acrylate, 3— (4-12 tropenyl) Ethyl acrylate, 3 _ (4-Chanophenyl) Ethyl acrylate, 3 _ (4-Methylthiophenyl) Ethyl acrylate, 3 _ (4-acetyl phenyl) Ethyl acrylate, Ethyl cinnamate, Ethyl crotonate, 3- (3-Pyridinyl) Ethyl acrylate, 4-Benzyloxy-2-methyl butenoate, 4- (methoxy) Methoxy-2-methyl butenoate, 4- (N, N— Dimethylamino) — includes 2-methyl butenoate, 4-monophenyl, 3-butene — 2-one, 2-nitrovinylbenzene, and preferably 3- (2, 4-difluoro Enyl) ethyl acrylate, 3- (2,4-difluorophenyl) methyl acrylate, 3- (2,4-difluorophenyl) tert-butyl acrylate, 3- (2,4-difluorophenyl) benzyl acrylate, 3 _ (2, 4-Difluorophenyl) L-menthyl acrylate and optical activity — 3 _ (2, 4-difluorophenyl) acrylate 3— (4,4-dimethyl-2-hydroxy) tetrahydrofuranyl, More preferred are 3- (2,4-difluorophenyl) ethyl acrylate and 3- (2,4-difluorophenyl) methyl acrylate.

Examples of compounds (2) include N—t _ butylglycine, N— (1 methyl-1-phenyl) ethylglycine, N— (1-cyclohexyl-1-methyl) ethylglycine, N- (1-aryl) 1-methyl) ethylglycine, N- (1,1-diphenyl) ethylglycine, N-triphenylmethylglycine, N-tricyclohexylmethyldaricin, N- (1-methoxy-1-methyl) ethylglycine, N- ( 1— (1— (N, N-dimethylamino) — 1—methyl) ethyl glycine, N_ (1—methylthio— 1—methyl) ethyl glycine, N— (1-acetyl- 1-methyl) ethyl glycine, N— (1-acetylyloxy— 1 -Methyl) ethylglycine, etc., preferably N—t-butylglycine, N_ (1-methyl-1-monophenyl) ethylglycine, N— (1-cyclohexyl) — 1-methyl) ethyl glycine, N_ (1-aryl) 1-methyl) ethyl glycine, N— (1; 1-diphenyl) ethyl glycine, N_triphenylmethy Luglycine and N-tricyclohexylmethylglycine, more preferably N 1 tert-butylglycine.

Examples of compound (3) are trans-1 _ t-butyl-4_ (2, 4-difluorophenyl) pyrrolidine 1-3 carboxylate ethyl, trans _1-t butyl-4- (2, 4-difluoro Phenyl) Pyrrolidine—3—Strength methyl sulfonate, trans _ 1— t-Petilu 4_ (2,4-Difluorophenyl) Pyrrolidine—3—Isopropyl carbonate, trans— 1 _ t-butyl—4— (2, 4 —Difluorophenyl) Pyrrolidine 1-3-t-butyl sulfonate, trans-1 1-t-butyl- 4— (2,4-difluorophenyl) pyrrolidine 1-carboxylate, optically active trans _ 1- t-butyl- 4_ (2, 4-difluorophenyl) pyrrolidine _ 3 _ Menthyl carboxylate, optically active trans— 1— t-Petilu 4 (2,4-Difluorophenyl) pyrrolidine— 3-carboxylic acid 3— (4, 4-dimethyl-2-oxo) tetrahydrofuranyl, trans _ 1— t-butyl _ 3—cyanol 4-— (2, 4 difluorophenyl) pyrrolidine, trans— 1 _ t-butyl- 4 ((2,5-difluorophenyl) pyrrolidine — Ethyl 3-carboxylate, trans- l _ tert-butyl 4- (2-fluorophenyl) pyrrolidine— Ethyl 3-carboxylate, trans — 1-tert-butyl-4- (4-fluorophenyl) pyrrolidine— 3-Carpon Acid, trans— 1— t-butyl — 4— (2, 4-dichlorophenyl) pyrrolidine—

3-ethyl ethylate, trans _ 1 _ t-butyl-4- (4-cyclophenyl) pyrrolidine-3- ethyl carboxylate, trans _ 1- t-butyl- 4-1 (4-methoxyphenyl) pyrrolidine-3 3-power lpong Acidyl, trans-1-t-butyl

4-(4- (N, N-dimethylamino) phenyl) pyrrolidine-3-ethyl carboxylic acid, trans-1- 1 _butyl _4 (4-nitrophenyl) pyrrolidine 3-methyl ether sulfonate _ t-Butyl _4 (4-Cianophenyl) Pyrrolidine 1 3-Strength rubonate, trans _ 1 _ t-Butyl— 4_ (4-Methylthiophenyl) Pyrrolidine—3-Carboxylate, trans— 1— t— Butyl—4- (4-acetyl-phenyl) pyrrolidine—3—streptylethyl ethyl benzoate, trans—1—tert-butyl-4-monophenylpyrrolidine—3—strength yl sulfonate, trans _ 1— t _ Butyl-4 Monomethylpyrrolidine 1 3-Strong ethyl ether, trans 1-tert-butyl 4- (3-pyridinyl) Pyrrolidine 1 3-Strong ethyl ether, trans- l _t-Butyl-4- (benzylo Xymethyl) pyrrolidine mono 3-carboxylate, trans 1- t-butyl _4 mono (methoxymethoxymethyl) pyrrolidine mono 3-carboxylate, trans 1- t-petite 4- (N, N-dimethylamino) Methyl) Pyrrolidine-3-methyl carboxylate, trans-1-tert-butyl-3-acetyl-1-4-phenylpyrrolidine, trans-1-tert-butyl-1-3-tallow 4-phenylpyrrolidine, trans-l— (1-Methyl-1 monophenyl) -4 (2,4-difluorophenyl) Pyrrolidine-3 _Strong ethyl sulfonate, trans- l- (1-Cyclohexyl 1-methylethyl) _4 1 (2,4-Difluorophenyl ) Pyrrolidine 1 _Strong ethyl sulfonate, trans- 1 _ (1-aryl-1-methylethyl) _4 _ (2,4-difluorophenyl) pyrrolidine-3 _ethyl carboxylic acid, trans 1-(1, 1 —Diphenylethyl) —4-— (2,4-Difluorophenyl) pyrrolidine monoethyl 3-carboxylate, trans- l- (triphenylmethyl) -4- (2,4-difluorophenyl) pyrrolidine-3-ethyl carboxylate , Trans-1-(tricyclohexylmethyl) 4-1 (2, 4-difluorophenyl) pi-lysine — 3 _ ethyl ruponate, trans— l _ (triphenylmethyl) —4— (2, 4-difluoro Phenyl) pyrrolidine-3-ethyl ethyl, trans-1-(1-methoxy-1-methyl ethyl) 4- (2,4-difluorophenyl) pyridine lysine 3-ethyl ethyl, trans- l- (1— (N, N—Dimethyl Amino) 1 1-methylethyl) _4— (2,4-difluorophenyl) pyrrolidine 1 3— strong ethyl sulfonate, tr an s— l— (1-methylthio-1-methylethyl) -4 (2, 4— Difluorophenyl) pyrrolidine- 3-ethyl ethylate, trans- 1-(1 _acetyl- 1-methylethyl) —4— (2, 4-difluorophenyl) pyridine lysine— 3—power ethyl ethyl sulfonate, trans— 1— ( 1-acetyloxy 1-methylethyl) _4 mono (2, 4-difluorophenyl) pyrrolidine mono 3-ethyl rubonate, etc., preferably trans-1-tert-butyl 4- (2,4-difluorophenyl) Pyrrolidine 1-streptyl ethyl sulfonate, trans-1-t-butyl- 4- (2,4-difluorophenyl) pyrrolidine _3_methyl carboxylate, tr an s— l _ t-butyl _4_ (2, 4-difluorophenyl) pyrrolidine mono 3-isopropyl carbonate, tr an s— 1— t-Pitreux 4_ (2, 4-Difluorophenyl) Pyrrolidine mono 3-power luponate t-Putyl, trans- 1- t-Butyl 4-_ (2, 4-Difluorophenyl) Pyrrolidine mono 3-carboxylate, optical Active trans _ 1— t-Butyl-4- (2,4-difluorophenyl) pyrrolidine 1- 3-Menthyl ruponate and optically active trans 1-tert-butylene 4 _ (2, 4-difluorophenyl) pyrrolidine 1 3-force Rubonic acid 3 _ (4,4-dimethyl-2-oxo) tetrahydrofuranyl, more preferably tr an s— 1 _ t-butyl-4 mono (2,4-difluorophenyl) pyrrolidine-3-carboxylic Acid ethyl and tr an s— 1 _ t _ butyl— 4 (2,4-difluorophenyl) pyrrolidine-3-methyl carbonate. In the formula (3), R and X do not indicate absolute configuration, but indicate that they are arranged in trans position with respect to the pyrrolidine ring. For example, in formula (3), trans is 1-tert-butyl-4 where R is a 2,4-difluorophenyl group, X is an ethoxycarbonyl group, and R ¹ , R ² and R ³ are all methyl groups. — In the case of (2,4-difluorophenyl) -pyrrolidine mono-3-carboxylic acid ethyl ester, it represents either the (3R, 4S) or (3 S, 4 R) isomer or a mixture thereof. Description of formaldehyde or its derivatives

Formaldehyde or its derivatives are formaldehyde, formaldehyde polymer, formaldehyde cyclic, formaldehyde hydrate, formaldehyde and alcohol hemiacetal, formaldehyde and alcohol diacetal, formaldehyde and alkylene diol cyclic alcohol Refers to 1 liter etc. Specific examples include formaldehyde, paraformaldehyde, trioxane, formalin aqueous solution, methoxymethanol, ethoxymethanol, propoxymethanol, isopropoxymethanol, butoxymethanol, isobutoxymethanol, t-butoxymethanol, dimethylmethane, diethoxymethane, and dimethoxymethane. Propoxymethane, diisopropoxymethane, dibutoxymethane, diisobutoxymethane, di-t-butoxymethane, 1, 3-Dioxolan, 1,3-dioxane and the like can be mentioned. Any of these derivatives can be suitably used, but paraformaldehyde, trioxane, formalin aqueous solution, methoxymethane and dimethoxymethane are preferable, and paraformaldehyde is more preferable because of easy handling and availability. Description of salt of compound (2) and: ^ of compound (3)

Compound (2) has an amine and a carboxylic acid, and may form an acid addition salt or a salt with a base. Compound (3) has a pyrrolidine ring and may form an acid addition salt.

When a salt of compound (2) is used, an acid or base may be added as appropriate during the reaction to neutralize it.

Examples of acid addition salts include inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (eg, acetate, propionate, methanesulfonate, 4_toluenesulfonate, Examples of salts with bases include alkali metal salts (for example, sodium salts and potassium salts); alkaline earth metal salts (for example, calcium salts and magnesium salts); organic And basic salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.). Method for producing compound (1) and compound (2)

Compound (1) is an aldol reaction between a compound represented by CH ₃ X (where X is as defined above) and a compound represented by R—CH 0 (where R is as defined above) ₂ XCOO H (where X is as defined above) and RCH 0 (where R is as defined above) Nevena-gel reaction, or B rCH ₂ X (where X is A compound represented by the following formula: a Wittig reagent or Horner-Emmons reagent prepared from triphenylphosphine or dialkoxyphosphine and a compound represented by RCH 2 O (R is as defined above) It is prepared by a general reaction such as the Wützig reaction or the Horner-Emmons reaction. On the other hand, the compound (2) It is prepared by a condensation reaction between a haloacetic acid and a compound represented by RiRSRSNH (RR ² and R ³ are as defined above). Detailed production method of compound (3)

Compound (3) can be obtained by reacting compound (1) with compound (2) in the presence of formaldehyde or a derivative thereof. For example, the methods described in [1] to [6] below can be given, and a method in which they are partially combined can also be mentioned.

[1] A method in which formaldehyde or a derivative thereof is first dispersed or dissolved in a solvent, and compound (1) and compound (2) are sequentially added.

[2] A method in which formaldehyde or a derivative thereof is first dispersed or dissolved in a solvent, and compound (2) and compound (1) are sequentially added.

[3] A method in which compound (1) is first dispersed or dissolved in a solvent, and compound (2) and formaldehyde or a derivative thereof are sequentially added.

[4] Method in which compound (1) is first dispersed or dissolved in a solvent, and formaldehyde or a derivative thereof and compound (2) are sequentially added

[5] A method in which compound (2) is first dispersed or dissolved in a solvent, and compound (1) and formaldehyde or a derivative thereof are sequentially added

[6] Method in which compound (2) is first dispersed or dissolved in a solvent, and formaldehyde or a derivative thereof and compound (1) are sequentially added

In the methods [2] and [6], the compound (2) and formaldehyde or a derivative solution thereof may be sufficiently reacted in advance before adding the compound (1). Further, as a modification of [2] and [6], the compound (2) and formaldehyde or its derivative are mixed and then sufficiently reacted in advance, and the reaction solution is dispersed or dissolved in the compound (1). Examples of the method include adding them to the inside, and a method of combining them partially.

The amount of compound (2) is usually 1 to 10 mol, preferably 1 to 4 mol, more preferably 2 to 4 mol, per 1 mol of compound (1). Formaldehyde or its invitation The amount of the conductor is usually 1 to 20 moles, preferably 1 to 10 moles, and more preferably 2 to 6 moles relative to 1 mole of the compound (1).

The solvent is not particularly limited as long as it does not inhibit the reaction. For example, an aliphatic hydrocarbon solvent, an aromatic solvent, an ether solvent, an alcohol solvent, a chlorinated hydrocarbon, and the like can be suitably used. And ether solvents are more preferred. Examples of aliphatic hydrocarbon solvents include n-pentane, n-hexane, isohexane, n-heptane, isoheptane, n-octane, isooctane, n-nonane, isononane, n-decane, isodecane, n- Examples include undecane, n-dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, and petroleum ether. Examples of aromatic solvents include benzene, toluene, ethylbenzene, isopropyl benzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, H, H, α-trifluoromethylbenzene, 1, 2— Examples include dichroic benzene, 1,3-dichloro benzene, 1,2,3-trichloro benzene, 1,2,4-trichlorobenzene, and the like. Examples of ether solvents include tetrahydrofuran, methyltetrahydrofuran, jetyl ether, di-eta-propyl ether, diisopropyl pill ether, di-eta-butyl ether, di-eta-pentyl ether, di-eta-hexyl ether, di-eta-heptyl ether. 1 ter, di η-octyl ether, t-butyl methyl ether, cyclopentyl methyl ether, 1,2_dimethyl shetan, diethylene glycol dimethyl ether, anisole, diphenyl ether and the like. Examples of alcohol solvents include methanol, ethanol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol, n-pentanol, 2-pentanol, isopentyl alcohol, n-hexanol, 2 _Hexanol, isohexyl alcohol, n-heptanol, 2-heptanol, 3-heptanol, isoheptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol mono n-propyl ether, ethylene glycol monoisopropyl ether, ethylene dallicol mono n_butyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol monomethyl Ether, diethylene glycol Examples thereof include rumonoethyl ether, diethylene glycol mono n-propyl ether, diethylene glycol monoisopropyl ether, diethylene glycol mono n-butyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono t-butyl ether and the like. Examples of chlorinated hydrocarbons include dichloromethane, black mouth form, and 1,2-dichloroethane. Of these, xylene and ethylene glycol dimethyl ether (diglyme) are particularly preferred.

The amount of the solvent is usually 1 to: L 00 L, preferably 5 to 50 L with respect to 1 kg of compound (1) from the viewpoints of stirrability and reaction time.

The reaction time is usually 1 to 48 hours, and the reaction temperature is usually 50 to 200 ° C., preferably 100 to L: 50 ° C.

An appropriate catalyst may be added to the reaction solution to promote the reaction. As the catalyst, those having the effect of lowering the LUMO (lowest orbital orbital) of the compound (1) are preferable, and for example, Lewis acid, amino acid, secondary amine and the like are preferable. In addition, this catalyst is an optically active substance, or compound (3) can be obtained as an optically active substance by adding an optically active ligand.

Isolation of compound (3) can be carried out by subjecting the reaction solution to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, salt formation, crystallization, etc.). In addition, the purification

(3) or its salt can be obtained by recrystallization, extraction purification, distillation, silica gel column chromatography, etc. Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Production example 1

3-— (2,4-Difluorophenyl) Synthesis of Ethyl Acrylate

Under a nitrogen atmosphere, 60 wt% sodium hydride (4.0 g, 0.1 Omo 1) was added to THF (200 ml) and cooled to 0 ° C. A solution of jetylphosphonoacetic acid ethyl ester (22.0 g, 0.09 8mo 1) in THF (20.0 ml) was added dropwise, and the reaction mixture was stirred at 0 ° C for 30 minutes. Next, a solution of 2,4-difluorobenzaldehyde (13.5 g, 0.095 mol) in THF (100 ml) was added dropwise at 0 ° C, and the reaction mixture was allowed to warm to room temperature and stirred overnight. Ethyl acetate (300 ml) and water (200 ml) were added to the reaction mixture, and the mixture was stirred and separated. The resulting organic phase was further washed twice with water (100 ml). The washed organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (19.0 g, 0.090 mol). (Yield 94%)

1H-NMR (CDC1 ₃ , 400MHz) d 1.34 (3H, t, J = 7Hz), 4.27 (2H, q, J = 7 Hz), 6.47 (1H, d, J =

16 Hz), 6.83-6.93 (2H, m), 7.49-7.55 (lH, m), 7.74 (1H, d, J = 16Hz) ppm.

1 ³ C-NMR (CDC1 ₃ , lOOMHz) d 14.29, 60.59, 104.5, 111.8, 118.9, 120.4, 130.0, 136.0, 166.4 ppm. Production Example 2

Synthesis of N-t-butyldaricin hydrochloride

Add t_ptyramine (35. 0 g, 0. 479 mol 1) in toluene (12 Om 1) under a nitrogen atmosphere, and add a solution of bromoethyl acetate (40.1 g, 0.240 mol) in toluene (40 ml). Was added dropwise at 25-40 ° C and the reaction mixture was stirred at room temperature overnight. The solid precipitated from the reaction solution was removed by filtration, the filtrate was concentrated under reduced pressure, 6M aqueous sodium hydroxide solution (4 Om 1, 0.240 mol) was added, and the mixture was heated to reflux at 100 ° C for 20 minutes. After returning to room temperature and adjusting the pH to 1-2 with concentrated hydrochloric acid, the mixture was concentrated under reduced pressure. Concentrated hydrochloric acid (50 ml) was added to the obtained white solid, heated to 80 ° C., and the aqueous phase obtained by decantation was concentrated. The generated crystals were washed with acetone to obtain the title compound (24.9 g, 0.149 mo 1). (Yield 62%)

1H-NMR (CD ₃ 0D, 400MHz) d 1.39 (9H, s), 3.89 (2H, s) ppm.

1 ³ C-NMR (CD ₃ OD, lOOMHz) d 25.77, 42.95, 58.33, 168.9 ppm. Example 1

tr an s— 1— t-butyl— 4— (2, 4-difluorophenyl) —pyrrolidine mono 3-carboxylic acid ethyl ester After adding methanol (10 ml) to N_t-butylglycine hydrochloride (1. lg, 6.6 mmo 1) and neutralizing with 28 wt% sodium methoxide methanol solution (1.3 g, 6.7 mmo 1) And concentrated under reduced pressure. Xylene (25m 1), paraformaldehyde (0.45 g, 15 mmo 1), 3- (2,4-difluorophenyl) ethyl acrylate (0.53 g, 2.5 mmo 1) were mixed with the concentrated residue. The mixture was heated to reflux at 135-141 ° C for 24 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and 1M hydrochloric acid (10 ml) was added. The hydrochloric acid solution was washed with heptane (10 ml), separated, and extracted three times with ethyl acetate (20 ml). The obtained organic phases were combined and washed with 1 M sodium hydroxide (10 m 1) and water, and the washed organic phase was concentrated under reduced pressure to obtain the title compound (0.42 g, 1.4 mmo 1). It was. (Yield 54%)

_{1H-NMR (CDC1 3, 400MHz} ) d 1.10 (9H, s), 1.19 (3H, t, J = 7Hz), 2.77 (1H, t, J = 8Hz), 2.98 (1H, t, J = 8Hz), 3.06 (1H, q, J = 8Hz), 3.14 (1H, t, J = 8Hz), 3.19 (1H, t, J = 8Hz), 3.79 (1H, q, J = 8Hz), 4.05- 4.18 (2H, m), 6.72-6.78 (lH, m), 6.80-6.86 (lH, m), 7.36-7.41 (lH, m) ppm.

^{_{1 3 C-NMR (CDC1 3}} , 100MHz) d 14.16, 25.98, 39.95, 49.74, 49.86, 52.47, 53.09, 60.65, 103.6, 111.1, 126.1, 129.5, according to the 173.6 ppm. The present invention, or expensive reagents, This is an industrially advantageous method because it can produce a compound (3) having a trisubstituted methyl group which is very sterically crowded efficiently in a short process without using an ultra-low temperature reaction.

Claims

The scope of the claims

1. Formula (3)

(In the formula, R, RR ² and R ³ are each independently an aromatic group which may be substituted, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, Represents an alkenyl group which may be substituted or an alkynyl group which may be substituted, and one or more of one CH ₂ — groups in each of the alkyl group, cycloalkyl group, alkenyl group and alkynyl group are _〇— groups , 1 S— group, —NH— group, or —C〇 group may be substituted, and one —CH═ group may be substituted with a nitrogen atom, provided that Group, —S _ group and —NH— group are not adjacent to each other X represents an electron-withdrawing group R and X do not indicate absolute configuration, but each represents a trans to the pyrrolidine ring It is placed in the place.)

A method for producing a compound represented by the formula:

Formula (1)

(In the formula, R and X have the same meanings as described above.)

A compound represented by the formula (2)

(Wherein R ¹ R ² and R ³ have the same meanings as described above.)

And a salt thereof in the presence of formaldehyde or a derivative thereof.

2. The method according to claim 1, wherein RR ² and R ³ are each an alkyl group.

3. The method according to claim ^{2, wherein} R \ R ² and R ³ are each a methyl group.

4. The method according to claim 1, wherein R is an optionally substituted phenyl group or an optionally substituted alkyl group.

5. The method according to claim 4, wherein R is a phenyl group or a methyl group substituted with a fluorine atom.

6. The method according to claim 5, wherein R is a 2,4-difluorophenyl group.

7. The method according to claim 1, wherein X is a group represented by the formula (V), a group represented by the formula (VI), a formyl group, a cyano group, or a nitrite group.

尸 O

,, R

(V) (VI)

8. The method according to claim 7, wherein X is a group represented by the formula (V).

9. The method according to claim 8, wherein X is a methoxycarbonyl group or ethoxycarbonyl group.

10. The compound represented by the formula (1) is 3- (2,4-difluorophenyl) ethyl acrylate, 3_ (2,4-difluorophenyl) methyl acrylate, 3- (2,4-difluorophenyl ) T-butyl acrylate, 3- (2,4-difluorophenyl) benzyl acrylate, 3- (2,4-difluorophenyl) L-methyl acrylate or optically active— 3— (2, 4-difluoro) The process according to claim 1, which is phenyl) acrylic acid 3- (4,4-dimethyl-2-oxo) tetrahydrofuranyl.

1 1. The compound represented by the formula (2) is N—t-butylglycine, N— (1-methyl-1- 1-phenyl) ethylglycine, N— (1-cyclohexyl-1-ethyl) ethylglycine, N The method according to claim 1, which is — (1-aryluyl 1-methyl) ethylglycine, N— (1,1-diphenyl) ethylglycine, N-triphenylmethyldaricin or N_tricyclohexyldaricin.

1 2. The compound represented by the formula (3) is trans-1_t-butyl-4_ (2,4-difluorophenyl) pyrrolidine-1-3-ethyl sulfonate, trans-l_t-butyl-4 (2, 4-Difluorophenyl) pyrrolidine 1_methyl sulfonate, trans-1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3 isopropyl rubonic acid trans-1, 1-t Butyl 4- (2,4-difluoro-phenyl) pyrrolidine-3-carboxylic acid t-butyl, trans-1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-branyl rubonate, optical Active trans _ 1— t-Butyl _4_ (2, 4-difluorophenyl) pyrrolidine — 3—Strength of menthol rubonate or optically active trans _ 1— t-Butyl _ 4— (2, 4-difluorophenyl) pyrrolidine— 3— Carboxylic acid 3— (4, The process according to claim 1, which is 4-dimethyl-2-oxo) tetrahydrofuranyl.

1 3. The method according to claim 1, wherein the formaldehyde or a derivative thereof is paraformaldehyde, trioxane, an aqueous formalin solution, methoxymethane or dimethoxymethane.

14. The method according to claim 13, wherein the formaldehyde or a derivative thereof is paraformaldehyde.