WO2008066083A1

WO2008066083A1 - Process for production of n-(n'-substituted-glycyl)- 2-cyanopyrrolidine derivative

Info

Publication number: WO2008066083A1
Application number: PCT/JP2007/072973
Authority: WO
Inventors: Toru Kuroda; Masanori Hatsuda; Shota Toshikawa
Original assignee: Mitsubishi Tanabe Pharma Corporation
Priority date: 2006-11-29
Filing date: 2007-11-28
Publication date: 2008-06-05
Also published as: JPWO2008066083A1; JP2012197291A; JP5165584B2; JP5475832B2

Abstract

Disclosed is a process for producing a high-quality N-(N'-substituted-glycyl)-2-cyanopyrrolidine derivative with a high degree of efficiency. Specifically disclosed is a process for producing a N-(N'-substituted-glycyl)-2-cyanopyrrolidine derivative represented by the general formula [I] [wherein A represents -CH2- or -S-; and R represents a lower cycloalkyl group which may be substituted, an adamantyl group which may be substituted, or the like] or a salt thereof, which comprises the steps of reacting a compound represented by the general formula [II] [wherein Z represents a reactive residue] with a compound represented by the general formula [III] [wherein Rx represents a benzyl group or the like] or a salt thereof to produce a compound represented by the general formula [IV] or a salt thereof, removing an amino-protecting group Rx from the resulting compound to produce a compound represented by the general formula [V] or a salt thereof, and converting the resulting compound into the compound represented by the general formula [I] or the salt thereof through a step involving a dehydration reaction.

Description

Specification

Preparation of N- (Ν 'monosubstituted glycyl) -1-2-cyanopyrrolidine derivatives

Technical field

[0001] The present invention relates to a novel method for producing a Ν- (Ν'-substituted dalicyl) 2 -cyanopyrrolidine derivative useful as a medicament for the treatment of diabetes.

Background art

[0002] Ν- (Ν'-substituted glycyl) -2-cyanopyrrolidine derivatives are useful as dipeptidyl peptidase IV (DPPIV) inhibitors, and are active ingredients of pharmaceuticals (diabetes therapeutics, etc.) It is known that it can be used as a production intermediate.

(The following patent documents ;! to 6).

[0003] As a method for producing N— (Ν′-substituted glycyl) -2 cyanopyrrolidine derivatives, 1

Raw materials such as loacetyl-2-cyanopyrrolidine compounds are used as amine compounds (primary amines).

) Is known to be produced by coupling (alkylation reaction) with the following (Patent Documents;! To 7 and Non-Patent Document 1)

[0004] However, when the force and the method are applied, a by-product is generated, and there is a problem that it is impossible to obtain a high-quality target object that is efficient! /, And! /.

Patent Document 1: W01998 / 19998 (Novartis)

Patent Document 2: WO2000 / 34241 (Novartis)

Patent Document 3: WO2001 / 96295 (Novartis)

Patent Document 4: WO2002 / 30890 (Tanabe Seiyaku)

Patent Document 5: WO2002 / 30891 (Tanabe Seiyaku)

Patent Document 6: WO2002 / 51836 (Kyowa Hakko Kogyo)

Patent Document 7: WO2004 / 92127 (Novartis)

Non-Patent Document l: Villhauer et al., J. Med. Chem., 2002, 45, 2362-2365

Disclosure of the invention

Problems to be solved by the invention

[0005] The present invention reduces the production of by-products and improves the quality of N— (Ν′-substituted dalicyl) 2 It is intended to provide a method for efficiently producing a conductor.

Means for solving the problem

[0006] As described above, as in a conventionally known method, 1-roacetyl-2-cyanopyrrolidine is used as a raw material, and coupling (alkylation reaction) with an amin compound (primary ammine) is carried out. When trying to produce a Ν'-substituted dalysyl) -2-cyanopyrrolidine derivative, a by-product (dialkyl compound; and amidine compound produced by the reaction of a cyano group and a free amino group, etc.) is generated, so it is efficient. Can't get the object.

[0007] Therefore, in order to prevent dialkylation from occurring, the ability to use a protected amino group (secondary amine) instead of the amine compound (primary amine) for coupling (alkylation reaction) When an amine compound protected with Boc or the like was used, the coupling reaction was greatly hindered, and it was not industrially applicable.

[0008] On the other hand, when an amine compound protected with a benzyl group or the like is used, the ability to obtain a product without the by-product of a dialkyl compound S, and removal of the amino group protecting group from the product after coupling can be achieved. As a result, only by-products were obtained, and it was impossible to obtain the target product.

(Refer to the following, Comparative Examples;! To 3) (It was considered that a side reaction occurred due to the presence of a cyano group on the pyrrolidine ring, and a ring-closed product was by-produced).

[0009] As described above, it has been considered difficult to find a production method capable of reducing the production of by-products such as dialkyl compounds and obtaining a high-quality target product. As a result of earnest research to overcome it, the present inventors have found a method of the present invention.

That is, the present invention relates to the general formula [I]

The symbols in the formula have the following meanings.

A: -CH one or — S—;

2

R: substituted! /, May! /, Lower cycloalkyl group,

Substituted, may! /, Adamantyl group or Substituted or less! /, A lower alkyl group,

A method for producing an N- (Ν′-substituted dalysyl) -2-cyanopyrrolidine derivative represented by the formula: or a salt thereof, characterized in that it comprises the following steps:

General formula [II]

^Z

In the formula, Z represents a reactive residue, and other symbols have the same meaning as described above, and a compound represented by the general formula [III]

R ^x

— NH [III] In the formula, R ^x represents an amino group protecting group selected from a benzyl group, a substituted benzyl group, an aryl group, a silyl group, and a nitrobenzenesulfonamide group, and other symbols have the same meanings as described above. Having

Is reacted with a compound represented by the general formula [IV]

R 0

R—To Ν _Kenting A Λ

[IV]

.丽 2 where the symbols have the same meaning as above,

After removing the amino-protecting group R ^x from this compound with the following! /, The general formula [V]

H O

R—N

Wherein the symbols have the same meaning as above.

After obtaining a compound represented by the formula or a salt thereof, through a process including a dehydration reaction,

This is converted into the compound represented by the above general formula [I] or a salt thereof.

[0011] In the method of the present invention,

The step of converting the compound represented by the general formula [V] or a salt thereof into the compound represented by the general formula [I] or a salt thereof is performed, for example, by any of the following methods (1) or (2): be able to.

[0012] (1) After subjecting the compound represented by the general formula [V] or a salt thereof to a dehydration reaction and further subjecting to a salt formation reaction as desired, the compound represented by the general formula [I] or a salt thereof Convert to salt

(2) —Addition of an amino group protecting group to the compound represented by the general formula [V] or a salt thereof to obtain an amino group protected body, which is then subjected to a dehydration reaction, and then the amino group protecting group is removed. If desired, it is further converted to a compound represented by the general formula [I] or a salt thereof by subjecting it to a salt formation reaction.

[0013] In the case of (2), more specifically, for example, it can be carried out as follows.

That is, an amino group-protecting group is added to the compound represented by the general formula [V] or a salt thereof, and the general formula [VI]

In formula ₂ , R ^y represents an amino-protecting group that can be removed by acid treatment, and other symbols have the same meaning as described above.

And then subjecting it to a dehydration reaction to give a general formula [VII]

Ψ 0

A [VTT] Wherein the symbols have the same meaning as above.

After obtaining the compound represented by general formula (I), the amino-protecting group R ^y is removed, and if desired, it is further subjected to a salt-forming reaction to convert it to a compound represented by the general formula [I] or a salt thereof.

[0015] The present invention also relates to a method for producing a salt of an N- (Ν'-substituted dalicyl) -2-cyanopyrrolidine derivative represented by the general formula [I], which comprises the general formula [VII]

The amino group protecting group R ^y is removed from the compound represented by the following by acid treatment:

Thus, a salt formation reaction is carried out simultaneously with the removal of the protecting group to convert it into a salt of the compound represented by the general formula [I].

Furthermore, the present invention includes a compound represented by the general formula [VII].

The compound represented by the general formula [VII] has a power that has not been known in the art so that it can be industrially produced without going through the compound [I] or a salt thereof. This compound is a novel compound that can be produced industrially for the first time by the method of the present invention. The present invention is also a first amino group protecting group other than a ω benzyl group or a substituted benzyl group. The first amino group protecting group is removed by reacting the protected amine compound in the presence of a radium catalyst to obtain a primary or secondary amine compound. Then, the primary or secondary amine compound is reacted with benzaldehyde or substituted benzaldehyde under a nitrogen atmosphere,

(After subjecting the reaction system to hydrogen substitution, a reduction reaction is carried out in the presence of the same palladium catalyst as in the above-mentioned ω to obtain a second amino group protecting group selected from a benzyl group and a substituted benzyl group. The present invention relates to a substitution method for protecting an amino group, which comprises obtaining a protected amine compound.

The invention's effect

[0017] According to the method of the present invention, compared to the conventional method, the production of by-products is reduced,

Ν— (Ν′-substituted glycyl) -2-cyanopyrrolidine derivative can be produced efficiently, and a high-quality target product can be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] The amino-protecting group represented by R ^x is a compound of compound [II] and compound [III] or a salt thereof. >'If it is a protecting group that does not interfere with the reaction, the amino group protecting group may be, for example, a-group, a substituted benzylenole group (4-methoxybenzenole group, etc.), an aryl group, a silyl group (trimethyl) , Tri-lower alkylsilyl groups such as triethylsilyl; t-group; etc.) and nitrobenzenesulfonamide groups can be suitably used.

Among them, benzyl group and 4-methoxybenzyl group are preferable.

The amino protecting group represented by R ^y may be an amino protecting group that can be removed by acid treatment (preferably by acid treatment under mild conditions). Examples of such an amino-protecting group include a t-butoxycarbonyl group and a benzyloxycarbonyl group, and among these, a t-butoxycarbonyl group is preferable.

[0020] The reactive residue represented by Z includes a halogen atom (Cl, Br, I etc.), a lower alkylsulfonyloxy group (methanesulfonyloxy etc.), a halo lower alkylsulfonyloxy group.

A conventional reactive residue such as a nyloxy group, a aryloxy group, and the like can be suitably used. A logogen atom (Cl, Br, I, etc.), a methanesulfonyloxy group, a nyloxy group, etc. are preferred. And halogen atoms (Cl, Br, I, etc.) are preferred.

[0021] The steps in the method of the present invention are shown in the figure below.

Z

In the formula, each symbol has the same meaning as described above.

[0022] Each step can be performed as follows.

Reaction of compound [II] with compound [III] or a salt thereof:

The reaction of compound [II] with compound [III] or a salt thereof can be carried out in the presence or absence of a deoxidizer, in a suitable solvent or without solvent.

[0023] Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, Alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, etc.) or organic bases (eg, triethylamine, diisopropylethylamine) N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used. Of these, potassium carbonate, in which an alkali metal carbonate such as potassium carbonate is preferred, is particularly preferred.

[0024] This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

As the solvent, any solvent that does not adversely influence the reaction may be used.

Acetonitrile, Ethanol, Isopropinoreanolol, Propinoleanole, Acetone, N, N-Dimethylacetamide, Dimethylformamide,

Dimethinolesnoreoxide, tetrahydrofuran, ether, di-dioxane,

Ethinole acetate, toluene, methylene chloride, dichloroethane, black mouth form

Or these mixed solvents can be used suitably. Of these, acetonitrile is particularly preferred, with acetonitrile, acetonitrile, toluene and ethyl acetate being preferred.

[0025] Removal of amino protecting group (R ^x ) from compound [IV] or a salt thereof:

Removal of the amino protecting group (R ^x ) from compound [IV] or a salt thereof can be carried out by a conventional method. For example, removal of a benzyl group, a substituted benzyl group and an aryl group can be carried out in a suitable solvent or without a solvent in the presence or absence of a noradium carbon catalyst, a noradium catalyst, or the like.

[0026] The removal of such a protecting group preferably proceeds at 0 to 100 ° C, particularly at room temperature to 80 ° C.

Any solvent may be used as long as it does not adversely influence the reaction. For example, ethanol, isopropyl alcohol, propyl alcohol, water, or a mixed solvent thereof can be appropriately used.

For example, the removal of the silyl group can be carried out by acid treatment or fluorine treatment. The removal of the nitrobenzenesulfonamide group can be carried out by treatment with a thiol derivative.

[0027] In the step of obtaining compound [I] or a salt thereof from compound [V] or a salt thereof!

When subjecting compound [V] or a salt thereof to a dehydration reaction:

The dehydration reaction of compound [V] or a salt thereof is carried out in a suitable solvent or insoluble in the presence of a dehydrating agent. It can be carried out with a medium.

[0028] When trifluoroacetic anhydride is used as the dehydrating agent, it is preferable to use a dehydrating agent other than acetic anhydride because the amino group in the molecule is trifluoroacetamidolated. As dehydrating agents, phosphorus oxychloride (POC1), phosphorus pentachloride (PCI), T3P (trade name; C1

3 5

ariant). Of these, phosphorus oxychloride (POC1), phosphorus pentachloride (PC1)

3 5

Particularly preferred is phosphorus oxychloride (POC1).

Three

[0029] When phosphorus oxychloride is used as a dehydrating agent, if the reaction is carried out in the presence of a base (such as triethylamine or pyridine), amidine formation (decomposition into amidine) occurs, which is undesirable. And the reaction is preferably performed in the absence of pyridine and the like.

[0030] This reaction suitably proceeds at 20 to 100 ° C, particularly 0 to 50 ° C.

The solvent may be any solvent that does not adversely affect the reaction. In addition, black mouth form or a mixed solvent thereof can be appropriately used. Of these, acetonitrile is particularly preferred, with acetonitrile and methylene chloride being preferred.

[0031] In the step of obtaining compound [I] or a salt thereof from compound [V] or a salt thereof!

When an amino group protecting group is added to compound [V] or a salt thereof, and the amino group protected body or salt thereof is subjected to a dehydration reaction:

The reaction for adding an amino group-protecting group () to compound [V] or a salt thereof can be carried out by a conventional method. For example, when adding a tert-butoxycarbonyl group as a protecting group, the reaction is carried out in a solvent (acetonitrile, ethanol, ethyl acetate, methylethylketone, methylene chloride, etc.) using a reagent such as di-tert-butyl dicarbonate. The reaction proceeds suitably at 0 to; 120 ° C, particularly from room temperature to 70 ° C.

[0032] The dehydration reaction of the compound [VI] is carried out in the presence of a dehydrating agent in a suitable solvent or in the absence of a solvent S.

Dehydrating agents include phosphorus oxychloride (POC1), phosphorus pentachloride (PCI), T3P (trade name; Clari

3 5

ant), p-toluenesulfuryl chloride, trifluoroacetic anhydride, and the like can be suitably used. Of these, phosphorus oxychloride (POC1), p-toluenesulfuryl chloride, Fluoroacetic anhydride is preferred. P-Toluenesulfuryl chloride is particularly preferred.

[0033] When p-toluenesulfuryl chloride is used as a dehydrating agent, bases such as pyridine and triethylamine may be added to promote the reaction! /.

When phosphorus oxychloride is used as the dehydrating agent, this reaction is preferably carried out under low temperature conditions (120 ° C to room temperature). When p-toluenesulfuryl chloride is used as the dehydrating agent, heating (room temperature To 60 ° C).

[0034] The solvent may be any solvent that does not adversely influence the reaction. For example, acetonitrile, acetonitrile, N, N-dimethylacetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, acetic acid. Ethyl, toluene, methylene chloride, dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used. Of these, acetonitrile is particularly preferred, with acetonitrile and methylene chloride being preferred.

[0035] Removal of the amino-protecting group () from the compound [VII] can be carried out by a conventional method. For example, it can be carried out by an acid treatment (treatment with trifluoroacetic acid, hydrochloric acid, sulfuric acid, other inorganic acids or organic acids) in an appropriate solvent or without a solvent.

When the protecting group is removed by acid treatment, the reaction can be suitably carried out at 0 to 100 ° C, particularly at room temperature to 60 ° C.

[0036] The solvent may be any solvent that does not adversely influence the reaction, for example, a hydrophilic solvent such as 2-butanone, acetone, methanol, ethanol, water, ethyl acetate, isopropyl acetate, diethyl ether, or the like. A mixed solvent can be used as appropriate. Of these, ethanol and ethanol are particularly preferred, with ethanol being preferred.

[0037] The salt of the compound [I], [III], [IV] or [V] is not particularly limited, and for example, a salt with an inorganic acid such as hydrochloride or sulfate, or methanesulfonate, An organic acid salt such as p-toluenesulfonate can be used.

[0038] The salt when the compound [I] is used as an active ingredient of a pharmaceutical product is preferably a pharmacologically acceptable salt. For example, as a pharmacologically acceptable salt,

Inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p — Organic acid salts such as toluene sulfonate or maleate. Also Cal When it has a substituent such as a boxyl group, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt) can be used.

[0039] These salts can be produced by a conventional salt formation reaction.

The salt formation reaction may be performed simultaneously with the removal (deprotection) of the amino group protecting group.

For example, when a salt of the compound [I] (a salt with an inorganic acid or an organic acid) is to be obtained as a target product, the amino group protecting group (R ^y ) is removed from the compound represented by the general formula [VII]. Is converted to a salt of a compound represented by the general formula [I] (a salt with an inorganic acid or an organic acid) by carrying out a salt formation reaction simultaneously with the removal of the protecting group. Can do.

The acid treatment may be performed using an acid (inorganic acid or organic acid) corresponding to the target product to be obtained.

[0040] By simultaneously carrying out deprotection and salt formation of compound [VII] in this way, the target product can be produced efficiently in a short process.

If the free form of Compound [I] is unstable compared to the salt, impurities (such as decomposition of the free form of Compound [I], etc.) can be carried out by simultaneously carrying out deprotection of Compound [VII] and salt formation. As a result, it is possible to obtain an excellent merit that it is possible to obtain a high-quality target product that does not contain a mixture of the product and the like.

[0041] The compound [I], compound [VII] or their starting compounds of the present invention is isolated as a free salt or a salt thereof and purified. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

[0042] The starting compound in the above method can be produced by a known method and / or a method described in Reference Examples below, or a combination thereof.

[0043] In the production method of the present invention, the group represented by R in compounds [I], [III], [IV], [V], [VI] and [VII] is particularly a cyclic group. For example, but not limited to

Substituted, may! /, Lower cycloalkyl group

(In the 4th and 1st positions! /, Substituted! /, May! /, Cyclohexyl, etc.),

Substituted, may! /, Adamantyl group and

Substituted, and may be! /, A lower alkyl group and the like.

[0044] The group represented by R is more specifically represented by, for example, the following R ^A , R ^B and Group.

[0045] R ^A : a group represented by the following formula:

X ^A represents N (R ^A3 ) O or one CO 2.

(X ^A is preferably CO 2 as these.)

R ^A3 represents a hydrogen atom or a lower alkyl group.

R ^AU and R ^A12 are each a hydrogen atom, a lower alkyl group,

Represents a hydroxy lower alkyl group or a lower alkoxy lower alkyl group. [ ^RAU and ^RA12 are preferably a hydrogen atom or a lower alkyl (such as methyl) group, particularly preferably a hydrogen atom. ]

R ^A21 represents the following (1) or (2).

(1) substituted! /, May! /, A cyclic group, wherein the cyclic group moiety is

(i) a monocyclic hydrocarbon group having 37 carbon atoms; (ii) selected from a nitrogen atom, an oxygen atom and a sulfur atom;! to a monocyclic heterocyclic group containing 2 heteroatoms; or (iii A nitrogen atom, an oxygen atom and a sulfur atom; a bicyclic heterocyclic group formed by condensing 2 to 5 7-membered rings containing 4 to 4 hetero atoms;

(2) Substituted, may! /, Amino groups.

[0047] R ^A22 is substituted! /, May! /, A cyclic group, and the cyclic group moiety is

(i) a monocyclic hydrocarbon group having 37 carbon atoms; (ii) selected from a nitrogen atom, an oxygen atom and a sulfur atom;! to a monocyclic heterocyclic group containing 2 heteroatoms; or (iii A nitrogen atom, an oxygen atom, and a sulfur atom;! —A bicyclic heterocyclic group containing 4 hetero atoms and 5 condensed with two 7-membered rings;

[0048] R ^B represents a group represented by the following formula.

R ^Bi , R: R represents a hydrogen atom, ¹ represents a hydroxy group, a lower alkoxy group or a lower alkanoyloxy group; or R ^B1 and R ^B2 each independently represent a lower alkyl group .

[0049] R ^G represents a mono-substituted amino lower alkyl group.

[0050] When R ^A21 is an ^optionally substituted cyclic group, specifically, for example,

The cyclic group which may have the same or different 1-3 substituents selected from the following substituent groups is mentioned. Here, as the cyclic group moiety,

Pyrrolidinyl, piperidyl, piperazil, monoreforinole, thiomorpholinyl, pyridinole, pyrimidinyl, indolinolinole, isoindolinyl, pyropyridyl, dihydropyromouth pyridinole, and some or all of them are saturated! / Group to be used.

[0051] Substituent group:

Halogen atom; cyano group; nitro group; oxo group; force rubamoyl group; lower (C 1) alkyl group

1 -6

Lower (C) alkoxy group; lower (C) alkanoyl group; lower (C) alkoxycal;

1-6 2-7 7-6 bonyl group; lower (C) alkoxy-substituted lower (C) alkyl group; lower (C) cycloa

1 -6 1 -6 3-8 Lucinore CO—; phenyl group optionally substituted with a norogen atom, cyano group, nitro group or oxo group; substituted with norogen atom, cyano group, nitro group or oxo group May be a lower phenyl (C) alkyl group;

1 -6

A monocyclic 5- to 6-membered heterocyclic group optionally substituted by a halogen atom, a cyano group, a nitro group or an oxo group;

A monocyclic 5- to 6-membered heterocyclic group O— which may be substituted with a halogen atom, a cyano group, a nitro group or an oxo group; and

A monocyclic 5- to 6-membered heterocyclic group CO— which may be substituted with a halogen atom, a cyano group, a nitro group or an oxo group.

[0052] When R ^A21 is an ^optionally substituted amino group, specifically, for example, Examples thereof include an amino group which may have the same or different 1 or 2 substituents selected from the following substituent group.

[0053] Substituent group:

Lower (C) alkyl group, lower (C) cycloalkyl group, lower (C) alkoxy substituted

1-6 3-8 1-6 a lower (C 1) alkyl group, a pyrimidinyl group, a thiazolyl group, and a thiadiazolyl group.

1 -6

[0054] Specifically, as R ^A22 , for example,

Examples include groups selected from piperidyl, piperazil, morpholinyl, indolinyl, isoindolinyl, thiazolopyridyl, and cyclic groups in which some or all of them are saturated.

[0055] Substituent group:

An oxo group; a lower (C 1) alkanoyl group; a lower (C 2) cycloalkanoyl group;

2-7 4-9

A lower (C) alkoxycarbonyl group; and

1 -6

Nitrogen-containing monocyclic 5- to 6-membered aliphatic heterocyclic group CO—.

[0056] Specific examples of the compound [I] in which R is a group represented by R ^A include the following compounds.

(2S) -2 Cyanol 1- [trans 4- (morpholinocarbonyl) cyclohexylamino] acetinolepyrrolidine;

(2S) —2 cyano 1- [trans 4- (4 acetylbiperazine 1-ylcarbonyl) cyclohexylamino] acetyl pyrrolidine; and

(2S) -2 Siano 1- [Trans 1 4- (Dimethylolaminocanolepinole) cyclohexenorea

[0057] The group represented by R ^B, specifically, for example, include the following groups.

[0058] Specific examples of the compound [I] wherein R is a group represented by R ^D include, for example, (2S) — 1— [(3 hydroxy-1- 1-adamantyl) amino] acetyl-2-cyanopyridine.

[0059] Compound R is the group represented by R ^e as [I], specifically, for example, include the following compounds.

(2S) -2 Cyanol 1- [2- [5 (Dimethylaminosulfonyl) pyridine-2-inoreamino] 1,1-dimethylethylamino] acetyl pyrrolidine;

(2S) 2 Cyanol 1 [2— [5 (Methanesulfonyl) pyridine 2 lilamino] 1,

[0060] Among the compounds represented by the general formula [III], a compound [IIIa] wherein R ^x is a benzyl group or a substituted benzyl group (4-methoxybenzyl etc.)

R-NH-R ^X1 [Ilia]

In the formula, R ^X1 represents a benzyl group or a substituted benzyl group, and other symbols represent the same meaning as described above,

Can be suitably produced using the following substitution method for protecting the amino group.

[0061] Substitution methods for amino group protection as described below are also included in the present invention.

The substitution method for protecting the amino group is:

The first amino group protecting group is removed by reacting an amine compound protected with a first amino group protecting group other than an ω benzyl group or a substituted benzyl group in the presence of a palladium catalyst to obtain a primary or After obtaining the secondary amine compound,

(ii) Subsequently, the primary or secondary amine compound is reacted with benzaldehyde or substituted benzaldehyde in a nitrogen atmosphere in the same reaction system,

(After subjecting the reaction system to hydrogen substitution, a reduction reaction is carried out in the presence of the same palladium catalyst as in the above-mentioned ω to obtain a second amino group protecting group selected from a benzyl group and a substituted benzyl group. A method for substitution of amino group protection, characterized in that a protected amine compound is obtained.

[0062] The removal reaction of the ω-amino-protecting group can be carried out by applying conventional reaction conditions using a palladium catalyst.

The reaction conditions and reaction time of (ii) are not particularly limited as in the conventional method. For example, the reaction can be performed at room temperature for 1 to 5 hours.

The reduction reaction (iii) is preferably performed under conditions of room temperature and normal pressure. The reaction time is preferably !! to 5 hours, more preferably! To 2 hours.

The hydrogen replacement in (iii) can be performed by performing decompression, degassing and hydrogen introduction 1 to 3 times.

The above (i), (ii) and (iii) can be carried out in the same reaction system (one pot).

[0063] Examples of the palladium catalyst used in the above (i) and (iii) include a palladium carbon catalyst and a palladium hydroxide carbon catalyst, and among these, a palladium carbon catalyst is preferable.

[0064] The first amino group protecting group of (i) above may be an amino group protecting group other than a benzyl group and other than a substituted benzyl group and removable with a palladium catalyst.

Examples of the first amino group protecting group include, for example,

Examples thereof include a benzyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a 2-phenoleethoxycarbonyl group, a 0-piperidinyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group. Of these, a benzyloxycarbonyl group is particularly preferable.

[0065] The second amino group protecting group in (iii) above is a force selected from a benzyl group and a substituted benzyl group (4-methoxybenzyl etc.) Of these, a benzyl group is particularly preferred.

[0066] Examples of the amine compound protected with the first amino group-protecting group (i) above include, for example, the general formula [VIII]

R ^D -NH-R ^Z (VIII)

In the formula, ^RD represents a lower alkyl group, a lower alkoxy lower alkyl group, a hydroxy lower alkyl group, an aryl substituted lower alkyl group, an optionally substituted lower cycloalkyl group, or an optionally substituted aryl group. ,

R ^Z represents an amino group other than a benzyl group and other than a substituted benzyl group, which can be removed by a palladium catalyst.

Or a salt thereof. Aryl groups include phenyl, naphthyl and the like.

In more detail, the group represented by R ^D is, for example, an optionally substituted lower cycloalkyl group (in the 4-position and 1-position,! /, Substituted! /, May! / , Cyclohexenole, etc.), substituted! /, Mayo! /, Adamantyl group and substituted! /, Mayo! /, Lower alkyl groups, etc., more specifically R ^a, R ^B, and it includes a group represented by R ^e, without limitation.

[0067] The primary or secondary amine compound (ii) may be primary or secondary! /, But is particularly preferably a primary amine compound. Examples of suitable primary amine compounds include those represented by the general formula [IX]

R ^D -NH [IX]

2

Wherein the symbols have the same meaning as above.

Or a salt thereof.

As the amine compound protected with the second amino group-protecting group obtained in the above (iii), more specifically, for example, the general formula [X]

R ^D -NH-R ^X1 (X)

In the formula, R ^X1 represents a benzyl group or a substituted benzyl group, and other symbols have the same meaning as described above,

Or a salt thereof.

[0068] According to the amino group-protecting substitution method of the present invention, it is possible to maintain the same reaction system (one-pot), and it is extremely efficient and industrial that it is not necessary to isolate a product in the middle and to cause a side reaction. In an advantageous manner, substitution of an amino-protecting group (substitution from a benzyloxycarbonyl group or the like to a benzyl group or a substituted benzyl group)

This is the ability to produce the desired amine compound protected with a benzyl group or a substituted benzyl group.

[0069] Reference Examples 3 (2) to (3), Reference Examples 4 (2) to (3), and Reference Example 5 below describe in detail the amino group protecting substitution method of the present invention as an example thereof. However, these do not limit the invention of this application! /.

[0070] In the present invention! /, A lower alkyl group, a lower alkylthio group, a lower alkylsulfone Examples of the alkyl group, lower alkoxy group, and lower alkylamino group include straight-chain or branched-chain groups having carbon atoms of! -6, and particularly those having 1 to 4 carbon atoms.

Moreover, examples of the lower alkanoyl group and the lower alkanoylamino group include linear or branched groups having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms.

Examples of the lower cycloalkyl group and the lower cycloalkenyl group include those having 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Examples of the lower alkylene group include straight-chain or branched-chain ones having carbon numbers of! To 6 and particularly 1 to 4 carbon atoms. Examples of the lower alkenyl group and lower alkenokenylene group include those having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms. Furthermore, examples of the halogen atom include fluorine, chlorine, bromine and iodine.

In the present specification, MS′APCI (m / z) represents a mass analysis value (atmospheric pressure chemical ionization mass spectrum).

Also, abbreviations in this specification

"Me" is a methyl group,

"Et" ethyl group,

"Bu" is a butynole group,

phj is a phenyl group,

"Bn" is a benzyl group,

“: Boc” represents a tert-butoxycarbonyl group.

Example

[0072] Hereinafter, the present invention will be described in more detail by way of examples. However, these examples limit the present invention. [0073] Example 1

(1) (2S) -1- (Chloroacetyl) -2-pyrrolidinecarboxamide was obtained in the same manner as in Reference Example 1, and N-benzyl-1-trans-4- (morpholinocarbonyl) cyclohexylamine (reference Add the compound of Example 3) (159 g), anhydrous potassium carbonate fine powder (174 g), sodium iodide (7.9 g) and acetone (1.6 L), and stir at reflux for 5 hours. The insoluble material is filtered off, the crystals are washed with acetone, and the filtrate is distilled off under reduced pressure. Add ethyl acetate (1.6 L) and water (1.1 L), and adjust to pH 4-5 with 10% aqueous quenate (0.8 L). After separation, the aqueous layer is washed with ethyl acetate (1.6 U. The aqueous layer is made alkaline by adding 40% potassium carbonate aqueous solution (0.689 U), and ethyl acetate (1.6 U and isopropyl alcohol (0. Extract with 16 U. After separation, the aqueous layer is extracted with ethyl acetate (0.32 U. The organic layers are combined, dried over magnesium sulfate (159 g), filtered, and concentrated to give (2S) — 2— Forced ruber moyl 1- [N benzylenotrans-4 (morpholinocarbonino) cyclohexylamino] acetyl pyrrolidine is obtained.

MS -APCI (m / z): 457 [M + H] ⁺

[0074] (2) The compound (concentrated residue) obtained in (1) above is dissolved in ethanol (1.6 L), charged with 10% palladium carbon catalyst (50% wet product) (35.5 g), hydrogen React for 6 hours at a pressure of 0 · 8 MPa and 50 ° C. The insoluble material is filtered off and washed with ethanol (0.16 L). The solvent was distilled off and (2S) 2 strength rubermoyl-1 [trans-4 (morpholinocarbonyl) cyclohexyl

[0075] (3) The compound (50 g) obtained in (2) above was suspended in acetonitrile (500 mU), di-t-butyl dicarbonate (36 g) was added at room temperature, stirred at 25 ° C for 3 hours, and concentrated. Add acetonitrile to the residue (500mU, heat to 50 ° C, add pyridine (65g) and p-toluenesulfonyl chloride (78g). Heat to 50 ° C for 16 hours, cool to room temperature, and cool to 40% carbonic acid. Potassium water (500 mL) is added, and the mixture is further stirred for 1 hour at 40 ° C. The reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the crystals are washed with isopropyl acetate. Distribute into isopropyl, citrate, and 26% brine, and after separation, wash the organic layer with 26% saturated brine, add 26% saturated brine and a small amount of 40% aqueous potassium carbonate to the organic layer. Adjust the pH to 9 to 10; and after washing, separate the liquid twice. After stirred with dim, by concentrating the insoluble matter is filtered off. The filtrate, ( 2S) 2-Strength Rubamoyl- 1 [N-tert-Butoxycarbonyl trans- 4 (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine is obtained.

(4) The compound obtained in (3) above is dissolved in a hydrophilic solvent such as 2 butanone,

After adding water, treatment with p-toluenesulfonic acid to remove the amino protecting group removes the p Toluene sulfonate is obtained.

[0077] Example 2

(1) (2S) -1- (Chloroacetyl) -2-pyrrolidinecarboxamide was obtained in the same manner as in Reference Example 1, and this was further treated with Benzylleu Trans-4 (4-1 acetylbiperazine 1-ylcarbonyl) cyclohexylamine (compound of Reference Example 4) (180 g), anhydrous potassium carbonate fine powder (174 g), sodium iodide (7.9 g), acetone (1.8 L) were added, and the mixture was refluxed for 5 hours. Stir. The insoluble material is filtered off and washed with acetone, and then the filtrate is distilled off under reduced pressure. Ethyl acetate (1

Add 8U and water (1.33L) and adjust to 10% aqueous citrate (0 · 95U to pH 4-5. After separation, wash the aqueous layer with ethyl acetate (1.8L). Add 40% aqueous potassium carbonate (0.82 L) to make it alkaline, extract with ethyl acetate (1.8 U and isopropyl alcohol (180 mU. After separation), extract the aqueous layer with ethyl acetate (0.38 U. Organic layer) And then dried over magnesium sulfate (190 g), filtered, and concentrated to give (2S) — 2 strength ruberoyol 1 1- [N benzyl 1 trans 1 4- (4-acetylbiperazine 1-ylcarbo 2) Cyclohexylamino] acetylpyrrolidine is obtained.

MS -APCI (m / z): 498 [M + H] ⁺

(2) The compound (concentrated residue) obtained in (1) above is dissolved in ethanol (1 · 9 L), charged with 10% palladium carbon catalyst (50% wet product) (35.5 g), React for 6 hours at a pressure of 0 · 8 MPa and 50 ° C. The insoluble material is filtered off and washed with ethanol (190 mL). Evaporate the solvent To give (2S) -2-strong rubermoyl 1 [trans-4 mono (4-acetylbiperazine 1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine.

MS -APCI (m / z): 408 [M + H] ⁺

[0079] (3) The compound (50 g) obtained in (1) above was suspended in acetonitrile (500 mU), di-t-butyl dicarbonate (32 g) was added at room temperature, and the mixture was stirred at 25 ° C for 3 hours and concentrated. Add acetonitrile to the residue (500mU, heat to 50 ° C, then add pyridine (58 · 2g) and p-toluenesulfoninochloride (70.2g). Heat to 50 ° C for 16 hours, then warm to room temperature. Cool, add 40% aqueous potassium carbonate (500 mL), and further stir for 1 hour at 40 ° C. Cool the reaction mixture with ice, filter the precipitated crystals, and wash the crystals with isopropyl acetate. Concentrate and partition into isopropyl acetate, citrate aqueous solution and 26% brine.After separation, wash organic layer with 26% saturated Japanese brine.26% saturated saline solution and a small amount of 40% potassium carbonate aqueous solution in organic layer The pH is adjusted to 9 to 10; and after washing, the liquid is separated twice. Um, after it stirred with silica gel, and insoluble materials are removed by filtration.

By concentrating the filtrate, (2S) 2-force rubamoyl-l [N- tert butoxyca norboninole trans 4-1 (4 acetyl piperazine 1 alkylcarbonyl) cyclohexane

MS -APCI (m / z): 490 [M + H] ⁺

After adding water, treatment with hydrochloric acid to remove the protecting group of the amino group, (2S) 2-cyanone 1- [trans 4- (4-acetylbiperazine 1-ylcarbonyl] Nore) cyclohexylamino] acetyl pyrrolidine hydrochloride is obtained.

[0081] Example 3

(1) Same as reference example (2S) 2- Trans-4-monobenzylamino-N, N dimethylcyclohexanecarboxamide (compound of Reference Example 5) (208 g), anhydrous potassium carbonate fine powder (265 g), sodium iodide (12 g), acetone ( 2. Add 1 U and stir for 5 hours under reflux, filter the insoluble material, wash the crystals with acetone, and evaporate the filtrate under reduced pressure.Ethyl acetate (2.1 L), water (1. 5 L), and adjust the pH to 4 to 5 with 10% aqueous citrate (1.25 L) After separation, wash the aqueous layer with ethyl acetate (2.1 U. Add 40% aqueous potassium carbonate ( Add 89 U to make it alkaline, and extract with ethyl acetate (2.1 U and isopropyl alcohol (0.21 U. After separation), extract the aqueous layer with ethyl acetate (0.42 U. Combine the organic layers. Dry with magnesium (208g), filter, and concentrate to give (2S) — 2-force rubermoyl— 1— [N-benzyl- Lance 4 to (dimethyl § amino carbonylation Honoré) cycloalkyl Kishiruamino] get Asechinore pyrrolidine.

[0082] (2) The compound obtained in the above (1) is dissolved in ethanol (2.1 L), charged with 10% palladium carbon catalyst (50% wet product) (55 g), hydrogen pressure 0 · 8 MPa, React at 50 ° C for 6 hours. The insoluble material is filtered off and washed with ethanol (400 mU. The solvent is distilled off (2S) — 2—force no valamoyl 1 [trans 4— (dimethylaminocarbonylamino) cyclohexylamino] acetylpyrrolidine. Get.

[0083] (3) The compound (50 g) obtained in (1) above was suspended in acetonitrile (500 mL), di-t-butyl dicarbonate (32 g) was added at room temperature, and the mixture was stirred at 25 ° C for 3 hours. Concentrate. Add acetonitrile to the residue (500mU, heat to 50 ° C, add pyridine (69g) and p-toluenesulfuryl chloride (83.5g). Heat to 50 ° C for 16 hours, cool to room temperature, and cool to 40% carbonic acid. Potassium water (500 mL) is added, and the mixture is further stirred for 1 hour at 40 ° C. The reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the crystals are washed with isopropyl acetate. After separation, wash the organic layer with 26% saturated saline, add 26% saturated saline and a small amount of 40% aqueous potassium carbonate to pH 9 After washing, adjusting to 10 and separating the liquid twice, add anhydrous magnesium sulfate and silica gel to the organic layer, stir, and filter off insoluble matter.

By concentrating the filtrate, (2S) 2-cyanol [N- tert butoxycarbonyl-trans 4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine Get. Melting point: 85-87 ° C

After adding water and treating with hydrochloric acid to remove the amino protecting group, (2S) 2-cyanol 1- [trans 1- (dimethylaminocarbonyl) cyclohexylamino] acetyl pyrrolidine The hydrochloride is obtained.

[0085] Example 4

((22SS)) —— 22 Powerful Rurubaba Momoy Loo 11 (1100gg) is suspended in acetotonitryl trillyl (220000mmUU, then dropped into oxyoxy chloride chlorinated phosphorus (77.66mmUU under ice-ice cooling). Stir and stir at room temperature for 4488 hours at room temperature, and then concentrate and reduce.Concentrate with chlorinated methylethylenelenen ((llOOOOmmUU) to dissolve and dissolve. Then, add 4400 %% potassium potassium carbonate ((6600mmUU can be added under ice-cold cooling). Raise the temperature at 2200 ° CC and keep the water ((5500mmUU In addition, the aqueous layer is separated from the chlorinated methylethylenelene. ((Re-extract with llOOOOmmUU. Combine the organic layers) Wash and clean with 2266 %% NNaaCCll ((3300mmLL). Organic) Depending on the concentration of the layer, ((22SS)) —— 22 Shisyanano 11 [[Torarans Sue 44 ((Momoluluholino-no-Carbo-Boboninorele) ) Cyclochlorohexyl chloride

[0086] Example 5

(2S) — 2—Strengthen rubermoyl 1 [Trans 4 -— (4 acetylbiperazine 1-yl carbolinole) cyclohexylamino] acetylpyrrolidine (10 g) is suspended in acetonitrinole (200 mL) and oxychlorinated. Phosphorus (5.8 mU is added dropwise under ice cooling. Stir at room temperature for 60 hours, then concentrate. Dissolve by adding methylene chloride (lOOmL), and add 40% potassium carbonate (6 OmU under ice cooling. 20 ° The temperature is raised to C, and water (50 mU is added for liquid separation. The aqueous layer is re-extracted with methyl chloride (lOOmU. The organic layers are combined and washed with 26% NaCl (30 mU. Concentrate the organic layer). (2 S) — 2—Cyanol 1 [Trans 4 1 (4 Acetylbi [0087] Example 6

(2S) 2 strength ruber moile 1 [trans-4 (dimethylamino

Xyllamino] acetylpyrrolidine (10 g) was suspended in acetonitrile (200 mU, phosphorus oxychloride (8.6 mU was added dropwise under ice-cooling), stirred for 62 hours at room temperature, and concentrated. Methylene chloride (lOOmU was added. Dissolve and add 40% potassium carbonate (60mU under ice-cooling. Heat to 20 ° C and separate with water (50mU. Re-extract the aqueous layer with methylene chloride (lOOmU. Combine the organic layers). Wash with 26% NaCl (30 mL) by concentrating the organic layer to give (2S) -2 cyanone 1 [trans 4 (dimethylaminocarbonyl) cyclohexyl.

Reference example 1

7g), add cereals linole (233mL) to refrigerate and cool to 10 ° C or below. Separately, L prolinamide (77.5 g, diisopropylethylamine (87.8 g) is suspended in acetonitrile (1550 mL) and added dropwise to the acetonitrile solution of chloroacetyl chloride at 20 ° C or lower. Stir at ° C for 30 minutes, transfer to 3L—4 cervical Kolben and evaporate under reduced pressure at 35 ± 5 ° C in the outer bath to leave a residue of (2S) -1- (chloroacetyl) -2 p-lysine carboxamide. Get.

[0089] Reference Example 2

〇 CN

L-prolinamide (50 g) in methylene chloride (500 mU solution)

(55.5 g). This solution was added to the salt of chloroacetyl chloride (49.5 g) Add dropwise to OmU solution over 1 hour while maintaining at 20 ° C. After dripping, stir at 20 ° C for 30 minutes. Add trifluoroacetic anhydride (119.6 g) to this, add pyridine (45 g), and stir at 20 ° C for about 1 hour. The reaction solution is washed with water (400 mL), saturated aqueous sodium hydrogen carbonate (400 mL), 1 N hydrochloric acid (400 mU, water (400 mU, respectively). After separation, the solution is concentrated, and isopropanol (165 mU, methylene chloride (33 mU) is added to the residue. Dissolve by heating at 45 ° C. Add methyl-tert-butyl ether (300mU, cool to 25 ° C over 1 hour, stir at the same temperature for 30 minutes. Cool to 0 ° C over 1 hour and keep at the same temperature. The crystals are filtered and dried to obtain (2S) -1- (chloroacetyl) -2-cyanopyrrolidine.

[0090] Reference Example 3 Bn

H

H, ...

(1) Dimethoxyethane (4 g) of trans 4 (benzyloxycarbonylamino) cyclohexane carboxylic acid (l lmU solution with thionyl chloride (1.37 mL) and dimethylformamide (28 υ added at 40 ° C) The reaction mixture was concentrated, dimethoxyethane (11 m U was added, and this solution was added dropwise to morpholine (7.5 g) in water (10 mU solution under ice-cooling. After stirring for 2 hours, water ( Add 16mU, cool with ice, and separate the precipitated crystals by filtration to give N-benzyloxycarbonyl trans-4 (morpholinocarbonyl) cyclohexylamine, melting point: 161-162 ° C

[0091] (2) The compound (4.4 g) obtained in (1) above is dissolved in ethanol (80 mU), and 10% palladium carbon catalyst (50% wet product) (0.8 g) is added. Introduce hydrogen three times and stir at room temperature and normal pressure for 3 hours.

Thereby, trans-4- (morpholinocarbonyl) cyclohexylamine is obtained as a reaction product.

(3) Benzaldehyde (1.62 g) is added to the reaction solution of (2) containing 10% palladium carbon catalyst (50% Wet product) in a nitrogen atmosphere and stirred at room temperature for 1 hour. Hydrogen was replaced by degassing under reduced pressure and introducing hydrogen three times, and this was stirred at room temperature and normal pressure for 1 hour and 20 minutes. Touch The medium is removed by filtration and concentrated. The residue is crystallized from a heptane / tert butyl methyl ether (3: 1) mixture and then separated by filtration to give N benzylditrans 4 (morpholinocarbonyl) cyclohexylamine.

Melting point: 63—65 ° C

[0092] Reference Example 4

(1) Dimethoxyethane (4 g) of trans 4 (benzyloxycarbonylamino) cyclohexanecarboxylic acid (l lmU solution with thionyl chloride (1.37 mL) and dimethylformamide (28 υ added at 40 ° C) The reaction mixture is concentrated, dimethoxyethane (11 mL) is added, and this solution is added dropwise to a solution of 1-acetylbiperazine (l lg) in water (10 mL) under ice-cooling. After stirring, add water (32 mU, cool with ice, separate the precipitated crystals by filtration, and add N-benzyloxycarbonyl-trans-4 (4-acetylbiperazine 1-ylcarbonyl) cyclohexylamine. Get.

Melting point: 180—181 ° C

[0093] (2) The compound (4.4 g) obtained in (1) above is dissolved in ethanol (80 mU, and 10% palladium carbon catalyst (50% wet product) (0.8 g) is added. Introduce hydrogen three times and stir at room temperature and normal pressure for 3 hours.

Thus, trans-4- (4-acetylbiperazine-1-ylcarbonyl) cyclohexylamine is obtained as a reaction product.

(3) Benzaldehyde (1.45 g) is added to the reaction solution of (2) containing 10% palladium carbon catalyst (50% wet product) in a nitrogen atmosphere and stirred at room temperature for 1 hour. Hydrogen was replaced by degassing under reduced pressure and introducing hydrogen three times, and this was stirred at room temperature and normal pressure for 1 hour and 20 minutes. The catalyst is removed by filtration and concentrated. The residue is crystallized from isopropyl ether, and then separated by filtration to give N benzylthiotrans-4-one (4-1acetylbiperazine 1-1ylcarbonyl) cyclohexylamine. Melting point: 127—128 ° C

[0094] Reference Example 5 Trans-4 monobenzylamino-N, N dimethylcyclohexanecarbox Samid

Trans 4 Benzyloxycarbonylamino-N, N dimethylcyclohexane force Lupoxamide (4.4 g) is dissolved in ethanol (80 mU, and 10% palladium carbon catalyst (50% Wet product) (0.8 g) is added. Degas and introduce hydrogen three times, and stir at room temperature and normal pressure for 3 hours.

This gives trans-4-amino-N N-dimethylcyclohexanecarboxamide as a reaction product.

Benzaldehyde (1.45 g) is added to the reaction solution (2) containing 10% palladium carbon catalyst (50% Wet product) under a nitrogen atmosphere and stirred at room temperature for 1 hour. Degassed under reduced pressure and introduced with hydrogen three times to replace the hydrogen. Stir at room temperature and normal pressure for 1 hour and 20 minutes. The catalyst is removed by filtration and concentrated. The residue is crystallized from a heptane / tert butyl methyl ether (3: 1) mixture and then separated by filtration to give trans-4-benzylamino-1-N, N-dimethylcyclohexanecarboxamide. Melting point: 69 ° C

Comparative Example 1

⁰

(1) ベンジル -Benzyl-trans 4- (morpholinocarboninole) cyclohexylamine (1.0 g) and (2S) — 1- (chloroacetyl) -2 cyanopyrrolidine (0.74 g) were converted to acetonitol (12 mU). Into the solution, anhydrous potassium carbonate fine powder (1. lg) and sodium iodide (50 mg) were added and allowed to react for 3.5 hours at 60 ° C. The mixture was cooled to room temperature and insolubles were removed by filtration. The solution was concentrated, partitioned between ethyl acetate (20 mL), water (15 mU and 10% aqueous citrate (10 mL), and separated. The aqueous layer was washed with ethyl acetate (20 mL) and separated. % Potassium carbonate (5mU was added to neutralize, and ethyl acetate (extracted 3 times with 20mU). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give (2S) 2-sia No 1— [N benzyl trans 4— (morpholinocarboninole) cyclohexylamino]

[0096] (2) (2S) -2 Siano 1 [N Benjirou Transformer obtained in the same manner as (1) above

4 (morpholinocarboninole) cyclohexylamino] acetylpyrrolidine (800 mg) was dissolved in ethanol (5 mU, and 10% palladium on carbon catalyst (50% wet product) (124 mg) was added. This was repeated 10 times and stirred for 10 hours at 60 ° C. After purging with nitrogen, the catalyst was removed by filtration and then concentrated to obtain the product.

However, the target compound, that is, (2S) -2-cyanol 1 [trans 4 (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine could not be obtained.

[0097] Comparative Example 2

(1) N-Benzinoretrans 4 4 Acetenorebiperazine 1 Inorecanole poninole) Cyclohexylamine (1. Og) and (2S) 1- (Chloroacetyl) -2-cyclonopyrrolidine (0 · 65 g) (12 mL), potassium carbonate anhydrous fine powder (962 mg) and sodium iodide (44 mg) were added, and the mixture was reacted at 60 ° C for 3.5 hours. The mixture was cooled to room temperature, and insoluble materials were removed by filtration. The filtrate was concentrated, partitioned between ethyl acetate (20 mL) and water (15 mU and 10% aqueous quenate (10 mL), and separated. The aqueous layer was washed with ethyl acetate (20 mL) and separated. The aqueous layer was neutralized with 40% aqueous potassium carbonate (5 mL) and extracted three times with ethyl acetate (20 mU. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give (2S) — 2-Cyanol 1 [N benzylthio 4- (4-acetylpiperazine 1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine was obtained.

[0098] (2) (2S) —2 Cyanol 1 [N Benzylutrans 1 (4 acetylbiperazine 1 ylcarbonino) cyclohexylamino] acetylpyrrolidine (800 mg) obtained in the same manner as (1) above ) Was dissolved in ethanol (5 mU, and 10% palladium carbon catalyst (50% wet product) (114 mg) was added. Nitrogen introduction and hydrogen introduction were repeated 3 times. Stir for hours. After purging with nitrogen, the catalyst was removed by filtration and then concentrated to obtain the product. However, the desired compound, that is, (2S) -2-cyanol 11- [trans-41- (41-acetylbiperazine 1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine could not be obtained.

[0099] Comparative Example 3

_ClCl

(1) trans 4 benzylamino 1 N, N -dimethylcyclohexanecarboxamide (0.17 g), (2S) -1- (chloroacetyl) 1 2 cyanopyridine (0.25 g), sodium iodide (14 · 4 mg) and potassium carbonate (0.16 g) were suspended in acetone (2.5 mU) and stirred at 60 ° C overnight to obtain (2S) —2 Cyanol 1 [N Penzinoretrans 4- (Dimethyl Aminocarbonyl) cyclohexylamino] acetylpyrrolidine was obtained.

[0100] (2) Obtained in the same manner as (1) above (2S) —2—Channo 1 [N Benjirou Transformer

4 (Dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine (200 mg) was dissolved in ethanol (1.6 mU), 10% palladium carbon catalyst (50% wet product) (200 mg) was added, and hydrogen was introduced. Stir for 2 hours at ° C to give the product.

However, the desired compound, ie, (2S) -2-cyanol 1 [trans 4 (dimethylaminocarbonyl) cyclohexylamino] acetyl pyrrolidine could not be obtained.

Industrial applicability

[0101] The present invention is an industrially advantageous method for producing an N- (Ν'-substituted dalysyl) -2-cyanopyrrolidine derivative.

Claims

Claims General Formula [I] HOR-Hachi NC The symbols in the formula have the following meanings: A: -CH 1 or — S—; 2 R: substituted! /, May! / Lower cycloalkyl group, substituted les, may! /, Adamantyl group, or substituted les, may! /, Lower alkyl groups, N— (Ν′-substituted dalysyl) -2- A method for producing a cyanopyrrolidine derivative or a salt thereof, characterized by comprising the following steps: General formula [II] Z ACA] NH2 wherein Z represents a reactive residue, The symbol has the same meaning as described above, and a compound represented by the general formula [III] Rx R—NH [III] wherein Rx is a benzyl group, a substituted benzyl group, an aryl group, a silyl group, or a nitrobenzenesulfone. An amino group-protecting group selected from amide groups, and the other symbols have the same meaning as described above, or a compound thereof To obtain a compound represented by the general formula [IV], wherein the symbols have the same meaning as described above, or a salt thereof, and then removing the amino-protecting group Rx from this compound with! / General formula [V] HO [V] In the formula, the symbol has the same meaning as described above, and after obtaining a compound represented by the formula: Convert to the indicated compound or salt thereof. [2] The step of converting the compound represented by the general formula [V] or a salt thereof into the compound represented by the general formula [I] or a salt thereof is either of the following (1) or (2)! / The manufacturing method according to claim 1, wherein the method is carried out by a method:

(1) The compound represented by the general formula [V] or a salt thereof is subjected to a dehydration reaction, and then further subjected to a salt-forming reaction as desired to convert it to a compound represented by the general formula [I] or a salt thereof. Do

[3] The process according to claim 1, wherein the step of converting the compound represented by the general formula [V] or a salt thereof into the compound represented by the general formula [I] or a salt thereof is performed as follows. Production method An amino group-protecting group is added to the compound represented by the general formula [V] or a salt thereof, and the general formula [VI

]

R ^y

/ 0

R-N Hei A [VI]

0:

In the thigh ₂ formula, R ^y represents an amino protecting group that can be removed by acid treatment, and the other symbols have the same meaning as defined in claim 1.

[VII]

Wherein the symbols have the same meaning as above.

[4] The amino group protecting group R ^y is removed from the compound represented by the general formula [VII] by acid treatment, whereby a salt-forming reaction is performed simultaneously with the removal of the protecting group, and the general formula [I 4. The production method according to claim 3, wherein the compound is converted to a salt of a compound represented by the formula:

[5] General formula [I]

In which the symbols have the same meaning as defined in claim l,

A method for producing a salt of an N— (ダ ′ -substituted dalysyl) -2-cyanopyrrolidine derivative represented by the general formula [VII] [VTT]

In the formula, R ^y represents an amino-protecting group that can be removed by acid treatment, and other symbols have the same meaning as described above.

The amino group-protecting group R ^y is removed from the compound represented by formula (1) by acid treatment, whereby a salt-forming reaction is carried out simultaneously with the removal of the protecting group to convert it into a salt of the compound represented by the general formula [I]. The method characterized by changing.

[6] The production method according to any one of claims 3 to 5, wherein ^Ry is a t-butoxycarbonyl group or a benzyloxycarbonyl group.

[7] The production method according to any one of claims 3 to 5, wherein ^Ry is a t-butoxycarbonyl group.

[8] The production method according to any one of claims 1 to 7, wherein R ^x is a benzyl group, a 4-methoxybenzyl group or an aryl group.

[9] The production method according to any one of claims 1 to 7, wherein the ^Rx force is a benzyl group.

[10] The production method according to any one of claims 1 to 9, wherein R is optionally substituted lower cycloalkyl.

[11] General formula [VII]

In the formula, R ^y represents an amino-protecting group that can be removed by acid treatment, and other symbols have the same meaning as defined in claim 1.

A compound represented by

[12] The first amino group protecting group is removed by reacting an amine compound protected with a first amino group protecting group other than an ω benzyl group or a substituted benzyl group in the presence of a palladium catalyst. After obtaining the primary or secondary amine compound, (ii) Subsequently, the primary or secondary amine compound is reacted with benzaldehyde or substituted benzaldehyde in a nitrogen atmosphere in the same reaction system,

(iii) After subjecting the reaction system to hydrogen substitution, a second amino group selected from a benzyl group and a substituted benzyl group is protected by carrying out a reduction reaction in the presence of the same palladium catalyst as that of ω. A method for substitution of amino group protection, characterized in that a amine compound protected with a group is obtained.