JP5475832B2 - Process for producing N- (N'-substituted glycyl) -2-cyanopyrrolidine derivatives - Google Patents

Description

  The present invention relates to a novel method for producing an N- (N′-substituted glycyl) -2-cyanopyrrolidine derivative useful as a medicament for the treatment of diabetes.

N- (N′-substituted glycyl) -2-cyanopyrrolidine derivatives are useful as dipeptidyl peptidase IV (DPPIV) inhibitors, and are used as active ingredients of pharmaceuticals (diabetes therapeutics, etc.) or production intermediates thereof. It is known to get.
(The following patent documents 1-6).

  As a method for producing an N- (N′-substituted glycyl) -2-cyanopyrrolidine derivative, a 1-haloacetyl-2-cyanopyrrolidine compound or the like is used as a raw material, and coupling (alkylation) with an amine compound (primary amine) is performed. The method of manufacturing by performing reaction is known (the following patent documents 1-7 and nonpatent literature 1).

  However, when such a method is applied, there is a problem that a by-product is generated and a high-quality target cannot be obtained efficiently.

WO1998 / 19998 (Novartis) WO2000 / 34241 (Novartis) WO2001 / 96295 (Novartis) WO2002 / 30890 (Tanabe Seiyaku) WO2002 / 30891 (Tanabe Seiyaku) WO2002 / 51836 (Kyowa Hakko Kogyo) WO2004 / 92127 (Novartis)

Villhauer et al., J. Med. Chem., 2002, 45, 2362-2365

  The present invention seeks to provide a method for efficiently producing a high-quality N- (N′-substituted glycyl) -2-cyanopyrrolidine derivative with reduced production of by-products.

  As described above, as in a conventionally known method, 1-haloacetyl-2-cyanopyrrolidine or the like is used as a raw material, and coupling (alkylation reaction) with an amine compound (primary amine) is performed to obtain N- (N When trying to produce a '-substituted glycyl) -2-cyanopyrrolidine derivative, a by-product (dialkyl form; and amidine form produced by the reaction of a cyano group and a free amino group, etc.) is generated, so the target product is efficiently produced. Can't get.

  Therefore, in order to prevent dialkylation, coupling (alkylation reaction) was attempted using an amino group protector (secondary amine) instead of an amine compound (primary amine). When the amine compound protected with is used, the coupling reaction is greatly hindered, which is not applicable industrially.

On the other hand, when an amine compound protected with a benzyl group or the like was used, a product could be obtained without a by-product of a dialkyl body. However, when an attempt was made to remove the amino group protecting group from the product after coupling, Only living organisms were obtained, and the target product could not be obtained.
(Refer to the following, Comparative Examples 1 to 3) (It was considered that a secondary reaction occurred due to the presence of a cyano group on the pyrrolidine ring, and a closed ring or the like was by-produced).

  Thus, although it was 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, the present inventors diligently overcome these difficulties. As a result of the research, the method of the present invention was found.

式中の記号は、以下の意味を有する。
Ａ：−ＣＨ_２−又は−Ｓ−；
Ｒ：置換されていてもよい低級シクロアルキル基、
置換されていてもよいアダマンチル基又は
置換されていてもよい低級アルキル基、
で表されるＮ−（Ｎ’−置換グリシル）−２−シアノピロリジン誘導体又はその塩の製造方法であって、以下の如き工程からなることを特徴とする方法である：
一般式〔ＩＩ〕

式中、Ｚは反応性残基を表し、他の記号は前記と同一意味を有する、
で示される化合物と、一般式〔ＩＩＩ〕

式中、Ｒ^ｘは、ベンジル基、置換ベンジル基、アリル基、シリル基及びニトロベン
ゼンスルホンアミド基から選択されるアミノ基保護基を表し、他の記号は前記と
同一意味を有する、
で示される化合物又はその塩とを反応させて、一般式〔ＩＶ〕

式中、記号は前記と同一意味を有する、
で示される化合物を得、次いでこの化合物からアミノ基保護基Ｒ^ｘを除去して
一般式〔Ｖ〕

式中、記号は前記と同一意味を有する、
で示される化合物又はその塩を得た後、脱水反応を含む工程を経て、
これを前記一般式〔Ｉ〕で示される化合物又はその塩へ変換する。 That is, the present invention relates to the general formula [I]

The symbols in the formula have the following meanings.
A: —CH ₂ — or —S—;
R: an optionally substituted lower cycloalkyl group,
An optionally substituted adamantyl group or
An optionally substituted lower alkyl group,
A method for producing an N- (N′-substituted glycyl) -2-cyanopyrrolidine derivative represented by the formula (I) or a salt thereof, comprising the following steps:
Formula [II]

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

In the formula, R ^x represents an amino protecting group selected from a benzyl group, a substituted benzyl group, an allyl group, a silyl group, and a nitrobenzenesulfonamide group, and other symbols have the same meanings as described above.
Is reacted with a compound represented by the general formula [IV]

Wherein the symbols have the same meaning as above.
Then, the amino-protecting group R ^x is removed from this compound to remove the general formula [V]

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.

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.

(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 required to convert it to a compound represented by the general formula [I] or a salt thereof;
(2) An amino protecting group is added to the compound represented by the general formula [V] or a salt thereof,
An amino group-protected product is obtained, and then subjected to a dehydration reaction. Then, the amino group-protecting group is removed and, if desired, further subjected to a salt formation reaction to convert it into a compound represented by the general formula [I] or a salt thereof. To do.

  Further, in the case of (2) above, the details can be implemented as follows, for example.

式中、Ｒ^ｙは、酸処理にて除去可能であるアミノ基保護基を表し、他の記号は
前記と同一意味を有する、
で示されるアミノ基保護体を得、次いでこれを脱水反応に付して、一般式〔ＶＩＩ〕

式中、記号は前記と同一意味を有する、
で示される化合物を得た後、そのアミノ基保護基Ｒ^ｙを除去し、所望によりさらに造塩反応に付すことにより、一般式〔Ｉ〕で示される化合物又はその塩へ変換する。 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 the formula, R ^y represents an amino group-protecting group that can be removed by acid treatment, and other symbols have the same meaning as described above.
And then subjecting this to a dehydration reaction to give a general formula [VII]

Wherein the symbols have the same meaning as above.
After the compound represented by general formula (I) is obtained, the amino group protecting group R ^y is removed, and if desired, the compound is further subjected to a salt formation reaction to convert it to a compound represented by the general formula [I] or a salt thereof.

The present invention also relates to a method for producing a salt of an N- (N′-substituted glycyl) -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 performed simultaneously with the removal of the protecting group to convert it into a salt of the compound represented by the general formula [I].

Furthermore, this invention includes the compound shown by the said general formula [VII].
The compound represented by the general formula [VII] 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 also provides (i) protection of the first amino group by reacting an amine compound protected with a first amino group protecting group other than a benzyl group or a substituted benzyl group in the presence of a palladium catalyst. After removing the group to obtain a 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) A second amino group-protecting group selected from a benzyl group and a substituted benzyl group by subjecting the reaction system to hydrogen substitution, followed by a reduction reaction in the presence of the same palladium catalyst as in the above (i). It is related with the substitution method of amino group protection characterized by obtaining the amine compound protected by this.

According to the method of the present invention, compared to the conventional method, the production of by-products is reduced,
An N- (N′-substituted glycyl) -2-cyanopyrrolidine derivative can be produced efficiently, and a high-quality target product can be obtained.

The amino protecting group represented by R ^x may be any protecting group that does not interfere with the coupling reaction between the compound [II] and the compound [III] or a salt thereof. Group, substituted benzyl group (4-methoxybenzyl group and the like), allyl group, silyl group (tri-lower alkylsilyl group such as trimethylsilyl and triethylsilyl; t-butyldiphenylsilyl group; etc.) and nitrobenzenesulfonamide group are preferred. Can be used. Of these, a benzyl group and a 4-methoxybenzyl group are preferable, and a benzyl group is particularly preferable.

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

  Examples of the reactive residue represented by Z include a halogen atom (Cl, Br, I, etc.), a lower alkylsulfonyloxy group (methanesulfonyloxy etc.), a halo lower alkylsulfonyloxy group (trifluoromethanesulfonyloxy etc.), aryl Conventional reactive residues such as a sulfonyloxy group can be suitably used. Among these, a halogen atom (Cl, Br, I, etc.), a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc. are preferable, and a halogen atom (Cl, Br, I, etc.) is particularly preferable.

式中、各記号は前記と同一意味を有する。 The steps in the method of the present invention are shown in the figure below.

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

Each step can be performed as follows.
Reaction of compound [II] with compound [III] or a salt thereof:
The reaction of compound [II] and compound [III] or a salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of a deoxidizing agent.

  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, sodium hydroxide, potassium hydroxide, etc. An alkali metal hydroxide or the like) or an organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, or the like) can be preferably used. Of these, alkali metal carbonates such as potassium carbonate are preferred, and potassium carbonate is particularly preferred.

This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.
The solvent may be any solvent that does not adversely affect the reaction, such as acetonitrile, ethanol, isopropyl alcohol, propyl alcohol,
Acetone, N, N-dimethylacetamide, dimethylformamide,
Dimethyl sulfoxide, tetrahydrofuran, ether, dioxane,
Ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform or a mixed solvent thereof can be used as appropriate. Of these, acetonitrile, acetone, toluene, and ethyl acetate are preferable, and acetonitrile is particularly preferable.

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 allyl group can be carried out in the presence or absence of a palladium carbon catalyst, a palladium catalyst and the like in a suitable solvent or without a solvent.

The removal of such a protecting group suitably proceeds at 0 to 100 ° C, particularly at room temperature to 80 ° C.
The solvent may be any solvent that 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.

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 dehydration reaction:
The dehydration reaction of compound [V] or a salt thereof can be carried out in the presence of a dehydrating agent in a suitable solvent or without a solvent.

When trifluoroacetic anhydride is used as a dehydrating agent, it is preferable to use a dehydrating agent other than acetic anhydride because the amino group in the molecule is trifluoroacetamidolated. Examples of the dehydrating agent include phosphorus oxychloride (POCl ₃ ), phosphorus pentachloride (PCl ₅ ), T3P (trade name: Clariant), and the like. Of these, phosphorus oxychloride (POCl ₃ ) and phosphorus pentachloride (PCl ₅ ) are preferable, and phosphorus oxychloride (POCl ₃ ) is particularly preferable.

  When phosphorus oxychloride is used as a dehydrating agent, if the reaction is carried out in the presence of a base (such as triethylamine and pyridine), amidation (decomposition into amidine) occurs, which is undesirable. The reaction is preferably carried out under

This reaction suitably proceeds at -20 to 100 ° C, particularly 0 to 50 ° C.
The solvent may be any solvent that does not adversely influence the reaction, such as acetonitrile,
Acetone, N, N-dimethylacetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used. Of these, acetonitrile and methylene chloride are preferred, and acetonitrile is particularly preferred.

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 protected amino group or salt thereof is subjected to a dehydration reaction:
The reaction for adding an amino-protecting group (R ^y ) 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, a reagent such as di-tert-butyl dicarbonate is used, and the reaction is performed in a solvent (acetonitrile, ethanol, ethyl acetate, methyl ethyl ketone, methylene chloride, etc.). The reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 70 ° C.

The dehydration reaction of compound [VI] can be carried out in the presence of a dehydrating agent in a suitable solvent or without solvent.
As the dehydrating agent, phosphorus oxychloride (POCl ₃ ), phosphorus pentachloride (PCl ₅ ), T3P (trade name; Clariant), p-toluenesulfonyl chloride, trifluoroacetic anhydride and the like can be suitably used. Among these, phosphorus oxychloride (POCl ₃ ), p-toluenesulfonyl chloride, and trifluoroacetic anhydride are preferable, and p-toluenesulfonyl chloride is particularly preferable.

When p-toluenesulfonyl chloride or the like is used as a dehydrating agent, a base such as pyridine or triethylamine may be added to accelerate the reaction.
When phosphorus oxychloride is used as the dehydrating agent, this reaction is preferably performed under low temperature conditions (-20 ° C to room temperature). When p-toluenesulfonyl chloride is used as the dehydrating agent, heating (room temperature to 60 ° C) is performed. is necessary.

  The solvent may be any solvent that does not adversely influence the reaction. For example, acetonitrile, acetone, N, N-dimethylacetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, Chloroform or a mixed solvent thereof can be appropriately used. Of these, acetonitrile and methylene chloride are preferred, and acetonitrile is particularly preferred.

Removal of the amino-protecting group (R ^y ) from compound [VII] can be carried out by a conventional method. For example, it can be carried out by acid treatment (treatment with trifluoroacetic acid, hydrochloric acid, sulfuric acid, other inorganic acid or organic acid, etc.) in a suitable solvent or without solvent.
When removing the protecting group by acid treatment, the reaction can be suitably carried out at 0 to 100 ° C, particularly at room temperature to 60 ° C.

  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 a mixed solvent thereof is appropriately used. be able to. Of these, methanol and ethanol are preferable, and ethanol is particularly preferable.

  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, methanesulfonate, p-toluene Organic acid salts such as sulfonates can be used.

  The salt in the case of using Compound [I] as an active ingredient of a pharmaceutical product is preferably a pharmacologically acceptable salt. Such pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, Examples thereof include organic acid salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and maleate. In addition, when it has a substituent such as a carboxyl 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.

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 obtaining a salt of the compound [I] (a salt with an inorganic acid or an organic acid) as the target product, the amino group protecting group (R ^y ) is removed from the compound represented by the general formula [VII]. The compound can be converted into a salt of a compound represented by the general formula [I] (a salt with an inorganic acid or an organic acid) by carrying out an acid treatment, thereby carrying out a salt formation reaction simultaneously with the removal of the protecting group. .
The acid treatment may be performed using an acid (inorganic acid or organic acid) corresponding to the target product to be obtained.

Thus, by simultaneously carrying out deprotection and salt formation of compound [VII], the target product can be produced efficiently in a short process.
In addition, when the free form of compound [I] is unstable as compared with the salt, the deprotection and salt formation of compound [VII] are carried out at the same time, thereby causing impurities (such as decomposition of the free form of compound [I]). The excellent merit that it is possible to obtain a high-quality object free from mixed products and the like is obtained at the same time.

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

  Moreover, the raw material compound in the said method can be manufactured by the known method and / or the method as described in a postscript reference example, or those combinations.

In the production method of the present invention, the group represented by R of the compounds [I], [III], [IV], [V], [VI] and [VII] is not particularly limited as long as it is a cyclic group. For example,
An optionally substituted lower cycloalkyl group (such as cyclohexyl optionally substituted at the 4-position and 1-position),
Examples thereof include an adamantyl group which may be substituted and a lower alkyl group which may be substituted.

The group represented by R, and more specifically, for example, the following R ^A, include groups represented by R ^B and R ^C.

Ｘ^Ａは、−Ｎ（Ｒ^Ａ３）−、−Ｏ−、又は−ＣＯ−を表す。
（Ｘ^Ａとしては、これらのうち、−ＣＯ−が好ましい。）
Ｒ^Ａ３は、水素原子又は低級アルキル基を表す。
Ｒ^Ａ１１及びＲ^Ａ１２は、各々、水素原子、低級アルキル基、
ヒドロキシ低級アルキル基又は低級アルコキシ低級アルキル基を表す。
〔Ｒ^Ａ１１及びＲ^Ａ１２としては、水素原子又は低級アルキル（メチル等）基が好ましく、
とりわけ水素原子が好ましい。〕 R ^A : a group represented by the following formula.

X ^A represents —N (R ^A3 ) —, —O—, or —CO—.
(X ^A is preferably -CO- among these.)
R ^A3 represents a hydrogen atom or a lower alkyl group.
R ^A11 and R ^A12 each represent a hydrogen atom, a lower alkyl group,
Represents a hydroxy lower alkyl group or a lower alkoxy lower alkyl group.
[As R ^A11 and R ^A12 , a hydrogen atom or a lower alkyl (such as methyl) group is preferable,
In particular, a hydrogen atom is preferable. ]

R ^A21 represents the following (1) or (2).
(1) An optionally substituted cyclic group, wherein the cyclic group moiety is
(I) a monocyclic hydrocarbon group having 3 to 7 carbon atoms; (ii) a monocyclic heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; or (iii) ) A bicyclic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein two 5 to 7 membered rings are condensed;
A group which is
(2) An amino group which may be substituted.

R ^A22 is an optionally substituted cyclic group, and the cyclic group moiety is
(I) a monocyclic hydrocarbon group having 3 to 7 carbon atoms; (ii) a monocyclic heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; or (iii) ) A bicyclic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein two 5 to 7 membered rings are condensed;
Represents a group.

Ｒ^Ｂ１、Ｒ^Ｂ２：Ｒ^Ｂ２が水素原子を表し、Ｒ^Ｂ１がヒドロキシ基、低級アルコキシ基
又は低級アルカノイルオキシ基を表すか；或は、Ｒ^Ｂ１及びＲ^Ｂ２が各々独立して
低級アルキル基を表す。 R ^B represents a group represented by the following formula.

R ^B1 , R ^B2 : R ^B2 represents a hydrogen atom and R ^B1 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 .

R ^C represents a mono-substituted amino lower alkyl group.

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,
Examples include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, indolinyl, isoindolinyl, pyrrolopyridyl, dihydropyrrolopyridyl, and groups selected from cyclic groups in which some or all of them are saturated.

Substituent group:
Halogen atom; a cyano group; a nitro group; oxo group; a carbamoyl group; a lower _{(C 1-6)} alkyl group; a lower _{(C 1-6)} alkoxy groups; lower _{(C 2-7)} alkanoyl group; a lower _{(C 1- 6} ) alkoxycarbonyl group; lower (C _1-6 ) alkoxy-substituted lower (C _1-6 ) alkyl group; lower (C _3-8 ) cycloalkyl-CO—; halogen atom, cyano group, nitro group or oxo group A phenyl group which may be substituted; a phenyl-lower (C _1-6 ) alkyl group which may be substituted with a halogen atom, a cyano group, a nitro group or an oxo group;
A monocyclic 5-6 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, cyano group, nitro group or oxo group; and may be substituted with a halogen atom, cyano group, nitro group or oxo group Good monocyclic 5-6 membered heterocyclic group -CO-.

When R ^A21 is an ^optionally substituted amino group, specifically, for example,
The amino group which may have the same or different 1 or 2 substituents selected from the following substituent groups is mentioned.

Substituent group:
A lower (C _1-6 ) alkyl group, a lower (C _3-8 ) cycloalkyl group, a lower (C _1-6 ) alkoxy-substituted lower (C _1-6 ) alkyl group, a pyrimidinyl group, a thiazolyl group, and a thiadiazolyl group.

As R ^A22 , 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,
Examples include groups selected from piperidyl, piperazinyl, morpholinyl, indolinyl, isoindolinyl, thiazolopyridyl, and cyclic groups in which some or all of them are saturated.

Substituent group:
An oxo group; a lower (C _2-7 ) alkanoyl group; a lower (C _4-9 ) cycloalkanoyl group;
A lower (C _1-6 ) alkoxycarbonyl group; and a nitrogen-containing monocyclic 5 to 6-membered aliphatic heterocyclic group —CO—.

Specific examples of the compound [I] in which R is a group represented by R ^A include the following compounds.
(2S) -2-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(2S) -2-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine; and (2S) -2-cyano-1- [trans-4- (dimethyl) Aminocarbonyl) cyclohexylamino] acetylpyrrolidine.

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

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

Specific examples of the compound [I] wherein R is a group represented by R ^C include the following compounds.
(2S) -2-cyano-1- [2- [5- (dimethylaminosulfonyl) pyridin-2-ylamino] -1,1-dimethylethylamino] acetylpyrrolidine;
(2S) -2-cyano-1- [2- [5- (methanesulfonyl) pyridin-2-ylamino] -1,1-dimethylethylamino] acetylpyrrolidine.

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 [IIIa]
In the formula, R ^X1 represents a benzyl group or a substituted benzyl group, and other symbols have the same meaning as described above.
Can be suitably produced using the following substitution method for protecting the amino group.

The following amino group protection substitution methods are also included in the present invention.
Such amino group protection substitution methods include:
(I) removing the first amino group protecting group by reacting an amine compound protected with a first amino group protecting group other than a 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) A second amino group-protecting group selected from a benzyl group and a substituted benzyl group by subjecting the reaction system to hydrogen substitution, followed by a reduction reaction in the presence of the same palladium catalyst as in the above (i). A method for substitution of amino group protection, characterized in that an amine compound protected with an amino acid is obtained.

The removal reaction of the amino-protecting group (i) can be carried out by applying conventional reaction conditions using a palladium catalyst.
The reaction conditions and reaction time of (ii) may be as usual, and are not particularly limited. For example, the reaction can be carried out by reacting at room temperature for 1 to 5 hours.
The reduction reaction (iii) is preferably performed under the conditions of room temperature and normal pressure. The reaction time is preferably 1 to 5 hours, more preferably 1 to 2 hours.
The hydrogen replacement in (iii) can be performed by performing pressure reduction / degassing and hydrogen introduction 1 to 3 times.
Said (i), (ii) and (iii) can be implemented by the same reaction system (one pot).

  As a palladium catalyst used by said (i) and (iii), a palladium carbon catalyst, a palladium hydroxide carbon catalyst, etc. are mentioned, for example, Among these, a palladium carbon catalyst is preferable.

The first amino group protecting group in (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 include benzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-phenylethoxycarbonyl group, O-piperidinyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and the like. Of these, the benzyloxycarbonyl group is particularly preferred.

  The second amino group protecting group in (iii) is selected from a benzyl group and a substituted benzyl group (4-methoxybenzyl etc.), and among these, a benzyl group is particularly preferred.

The amine compound protected with the first amino group-protecting group (i) above is more specifically described, for example, by 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.
Examples of the aryl group include phenyl and naphthyl.
More specifically, the group represented by ^RD may be, for example, an optionally substituted lower cycloalkyl group (such as cyclohexyl optionally substituted at the 4-position and 1-position), or an optionally substituted group. Examples thereof include an adamantyl group and a lower alkyl group which may be substituted, and more specifically, groups represented by R ^A , R ^B , and R ^C are exemplified, but not limited thereto.

The amine compound that is primary or secondary (ii) may be either primary or secondary, but primary amine compounds are particularly preferred. Examples of such suitable primary amine compounds include those represented by the general formula [IX]
R ^D —NH ₂ [IX]
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 (iii) above, 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.

According to the amino group-protecting substitution method of the present invention, the product remains in the same reaction system (one pot), and there is no need to isolate the intermediate product and no side reaction occurs. To the amino group protecting group (from benzyloxycarbonyl group or the like to benzyl group or substituted benzyl group),
A target amine compound protected with an amino group by a benzyl group or a substituted benzyl group can be produced.

  Reference Examples 3 (2) to (3), Reference Examples 4 (2) to (3), and Reference Example 5 described later explain the amino group protection substitution method of the present invention in detail as examples. However, these do not limit the present invention.

In the present invention, the lower alkyl group, the lower alkylthio group, the lower alkylsulfonyl group, the lower alkoxy group, and the lower alkylamino group include linear or branched ones having 1 to 6 carbon atoms. 1-4 are mentioned.
Moreover, as a lower alkanoyl group and a lower alkanoylamino group, a C2-C7, especially C2-C5 linear or branched thing is mentioned.
Examples of the lower cycloalkyl group and the lower cycloalkenyl group include those having 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms. Examples of the lower alkylene group include straight chain or branched chain groups having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms. Examples of the lower alkenyl group and the lower alkenylene 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).
Further, the abbreviation “Me” in this specification is a methyl group,
“Et” ethyl group,
“Bu” is a butyl group,
“Ph” is a phenyl group,
“Bn” is a benzyl group,
“Boc” represents a tert-butoxycarbonyl group.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, these Examples do not restrict | limit this invention.

（１）参考例１と同様にして（２Ｓ）−１−（クロロアセチル）−２−ピロリジンカルボキサミドを得、これに、Ｎ−ベンジル−トランス−４−（モルホリノカルボニル）シクロヘキシルアミン（参考例３の化合物）（１５９ｇ）、炭酸カリウム無水微粉（１７４ｇ）、ヨウ化ナトリウム（７．９ｇ）、アセトン（１．６Ｌ）を加え、５時間、還流下で撹拌する。不溶物をろ別し、結晶をアセトンで洗浄した後、ろ液を減圧留去する。酢酸エチル（１．６Ｌ）、水（１．１Ｌ）を加え、１０％クエン酸水（０．８Ｌ）でｐＨ４〜５に調整する。分液後、水層を酢酸エチル（１．６Ｌ）で洗浄する。水層に４０％炭酸カリウム水（０．６８９Ｌ）を加えてアルカリ性とし、酢酸エチル（１．６Ｌ）及びイソプロピルアルコール（０．１６Ｌ）で抽出する。分液後、水層を酢酸エチル（０．３２Ｌ）で抽出する。有機層を合せて硫酸マグネシウム（１５９ｇ）で乾燥し、ろ過後、濃縮することにより、（２Ｓ）−２−カルバモイル−１−［Ｎ−ベンジル−トランス−４−（モルホリノカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得る。
MS・APCI(m/z): 457 [M+H]⁺ Example 1

(1) (2S) -1- (Chloroacetyl) -2-pyrrolidinecarboxamide was obtained in the same manner as in Reference Example 1, and N-benzyl-trans-4- (morpholinocarbonyl) cyclohexylamine (of Reference Example 3) was obtained. Compound) (159 g), anhydrous potassium carbonate fine powder (174 g), sodium iodide (7.9 g) and acetone (1.6 L) are added, and the mixture is stirred for 5 hours under reflux. Insolubles are filtered off, and the crystals are washed with acetone, and then 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 citric acid (0.8 L). After separation, the aqueous layer is washed with ethyl acetate (1.6 L). The aqueous layer is made alkaline by adding 40% aqueous potassium carbonate (0.689 L), and extracted with ethyl acetate (1.6 L) and isopropyl alcohol (0.16 L). After separation, the aqueous layer is extracted with ethyl acetate (0.32 L). The organic layers were combined, dried over magnesium sulfate (159 g), filtered and concentrated to give (2S) -2-carbamoyl-1- [N-benzyl-trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine. Get.
MS ・ APCI (m / z): 457 [M + H] ⁺

  (2) The compound (concentrated residue) obtained in (1) above is dissolved in ethanol (1.6 L), 10% palladium carbon catalyst (50% Wet product) (33.5 g) is charged, and the hydrogen pressure is adjusted to 0. It reacts at 8 MPa and 50 ° C. for 6 hours. Insoluble material is filtered off and washed with ethanol (0.16 L). The solvent is distilled off to obtain (2S) -2-carbamoyl-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine.

  (3) The compound (50 g) obtained in (2) above is suspended in acetonitrile (500 mL), di-t-butyl dicarbonate (36 g) is added at room temperature, and the mixture is stirred at 25 ° C. for 3 hours and concentrated. Acetonitrile (500 mL) is added to the residue, and after heating to 50 ° C., pyridine (65 g) and p-toluenesulfonyl chloride (78 g) are added. After heating at 50 ° C. for 16 hours, the mixture is cooled to room temperature, 40% aqueous potassium carbonate (500 mL) is added, and the mixture is further stirred at 40 ° C. for 1 hour. The reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the crystals are washed with isopropyl acetate. The filtrate is concentrated and partitioned between isopropyl acetate, aqueous citric acid and 26% brine. After separation, the organic layer is washed with 26% saturated saline. 26% saturated saline and a small amount of 40% potassium carbonate water are added to the organic layer to adjust to pH 9 to 10, and after washing, liquid separation is performed twice. Anhydrous magnesium sulfate and silica gel are added to the organic layer and the mixture is stirred, and the insoluble material is filtered off. The filtrate is concentrated to give (2S) -2-carbamoyl-1- [N-tert-butoxycarbonyl-trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine.

(4) The compound obtained in (3) is dissolved in a hydrophilic solvent such as 2-butanone,
(2S) -2-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine by adding water followed by treatment with p-toluenesulfonic acid to remove the amino protecting group Of p-toluenesulfonate is obtained.

（１）参考例１と同様にして（２Ｓ）−１−（クロロアセチル）−２−ピロリジンカルボキサミドを得、これに、Ｎ−ベンジル−トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミン（参考例４の化合物）（１８０ｇ）、炭酸カリウム無水微粉（１７４ｇ）、ヨウ化ナトリウム（７．９ｇ）、アセトン（１．８Ｌ）を加え、５時間、還流下で撹拌する。不溶物をろ別し、アセトンで洗浄した後、ろ液を減圧留去する。酢酸エチル（１．８Ｌ）、水（１．３３Ｌ）を加え、１０％クエン酸水（０．９５Ｌ）でｐＨ４〜５に調整する。分液後、水層を酢酸エチル（１．８Ｌ）で洗浄する。水層に４０％炭酸カリウム水（０．８２Ｌ）を加えてアルカリ性とし、酢酸エチル（１．８Ｌ）及びイソプロピルアルコール（１８０ｍＬ）で抽出する。分液後、水層を酢酸エチル（０．３８Ｌ）で抽出する。有機層を合せて硫酸マグネシウム（１９０ｇ）で乾燥し、ろ過後、濃縮することにより、（２Ｓ）−２−カルバモイル−１−［Ｎ−ベンジル−トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得る。
MS・APCI(m/z): 498 [M+H]⁺ Example 2

(1) In the same manner as in Reference Example 1, (2S) -1- (chloroacetyl) -2-pyrrolidinecarboxamide was obtained, and N-benzyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) was added thereto. Add cyclohexylamine (compound of Reference Example 4) (180 g), anhydrous potassium carbonate fine powder (174 g), sodium iodide (7.9 g) and acetone (1.8 L), and stir for 5 hours under reflux. The insoluble material is filtered off and washed with acetone, and then the filtrate is distilled off under reduced pressure. Ethyl acetate (1.8 L) and water (1.33 L) are added, and the pH is adjusted to 4 to 5 with 10% aqueous citric acid (0.95 L). After separation, the aqueous layer is washed with ethyl acetate (1.8 L). The aqueous layer is made alkaline with 40% aqueous potassium carbonate (0.82 L), and extracted with ethyl acetate (1.8 L) and isopropyl alcohol (180 mL). After separation, the aqueous layer is extracted with ethyl acetate (0.38 L). The organic layers were combined, dried over magnesium sulfate (190 g), filtered and concentrated to give (2S) -2-carbamoyl-1- [N-benzyl-trans-4- (4-acetylpiperazin-1-yl). Carbonyl) 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) (33.5 g), and hydrogen pressure of 0. It reacts at 8 MPa and 50 ° C. for 6 hours. Insoluble material is filtered off and washed with ethanol (190 mL). The solvent is distilled off to obtain (2S) -2-carbamoyl-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine.
MS ・ APCI (m / z): 408 [M + H] ⁺

(3) The compound (50 g) obtained in (1) above is suspended in acetonitrile (500 mL), di-t-butyl dicarbonate (32 g) is added at room temperature, and the mixture is stirred at 25 ° C. for 3 hours and concentrated. Acetonitrile (500 mL) is added to the residue, and after heating to 50 ° C., pyridine (58.2 g) and p-toluenesulfonyl chloride (70.2 g) are added. After heating at 50 ° C. for 16 hours, the mixture is cooled to room temperature, 40% aqueous potassium carbonate (500 mL) is added, and the mixture is further stirred at 40 ° C. for 1 hour. The reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the crystals are washed with isopropyl acetate. The filtrate is concentrated and partitioned between isopropyl acetate, aqueous citric acid and 26% brine. After separation, the organic layer is washed with 26% saturated saline. 26% saturated saline and a small amount of 40% potassium carbonate water are added to the organic layer to adjust to pH 9 to 10, and after washing, liquid separation is performed twice. Anhydrous magnesium sulfate and silica gel are added to the organic layer and the mixture is stirred, and the insoluble material is filtered off.
The filtrate is concentrated to give (2S) -2-carbamoyl-1- [N-tert-butoxycarbonyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine.
MS ・ APCI (m / z): 490 [M + H] ⁺

(4) The compound obtained in (3) is dissolved in a hydrophilic solvent such as 2-butanone,
(2S) -2-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino was removed by treating with hydrochloric acid after adding water to remove the amino protecting group. Acetylpyrrolidine hydrochloride is obtained.

（１）参考例１と同様にして（２Ｓ）−１−（クロロアセチル）−２−ピロリジンカルボキサミドを得、これに、トランス−４−ベンジルアミノ−Ｎ，Ｎ−ジメチルシクロヘキサンカルボキサミド（参考例５の化合物）（２０８ｇ）、炭酸カリウム無水微粉（２６５ｇ）、ヨウ化ナトリウム（１２ｇ）、アセトン（２．１Ｌ）を加え、５時間、還流下で撹拌する。不溶物をろ別し、結晶をアセトンで洗浄した後、ろ液を減圧留去する。酢酸エチル（２．１Ｌ）、水（１．５Ｌ）を加え、１０％クエン酸水（１．２５Ｌ）でｐＨ４〜５に調整する。分液後、水層を酢酸エチル（２．１Ｌ）で洗浄する。水層に４０％炭酸カリウム水（０．８９Ｌ）を加えてアルカリ性とし、酢酸エチル（２．１Ｌ）及びイソプロピルアルコール（０．２１Ｌ）で抽出する。分液後、水層を酢酸エチル（０．４２Ｌ）で抽出する。有機層を合せて無水硫酸マグネシウム（２０８ｇ）で乾燥し、ろ過後、濃縮することにより、（２Ｓ）−２−カルバモイル−１−［Ｎ−ベンジル−トランス−４−（ジメチルアミノカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得る。 Example 3

(1) (2S) -1- (Chloroacetyl) -2-pyrrolidinecarboxamide was obtained in the same manner as in Reference Example 1, and trans-4-benzylamino-N, N-dimethylcyclohexanecarboxamide (of Reference Example 5) was obtained. Compound) (208 g), anhydrous potassium carbonate fine powder (265 g), sodium iodide (12 g) and acetone (2.1 L) are added and stirred for 5 hours under reflux. Insolubles are filtered off, and the crystals are washed with acetone, and then the filtrate is distilled off under reduced pressure. Add ethyl acetate (2.1 L) and water (1.5 L), and adjust to pH 4-5 with 10% aqueous citric acid (1.25 L). After separation, the aqueous layer is washed with ethyl acetate (2.1 L). The aqueous layer is made alkaline by adding 40% aqueous potassium carbonate (0.89 L), and extracted with ethyl acetate (2.1 L) and isopropyl alcohol (0.21 L). After separation, the aqueous layer is extracted with ethyl acetate (0.42 L). The organic layers were combined, dried over anhydrous magnesium sulfate (208 g), filtered, and concentrated to give (2S) -2-carbamoyl-1- [N-benzyl-trans-4- (dimethylaminocarbonyl) cyclohexylamino]. Acetylpyrrolidine is obtained.

  (2) The compound obtained in (1) above is dissolved in ethanol (2.1 L) and charged with 10% palladium carbon catalyst (50% Wet product) (55 g) at a hydrogen pressure of 0.8 MPa and 50 ° C. React for 6 hours. The insoluble material is filtered off and washed with ethanol (400 mL). The solvent is distilled off to obtain (2S) -2-carbamoyl-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine.

(3) The compound (50 g) obtained in (1) above is suspended in acetonitrile (500 mL), di-t-butyl dicarbonate (32 g) is added at room temperature, and the mixture is stirred at 25 ° C. for 3 hours and concentrated. Acetonitrile (500 mL) is added to the residue, and after heating to 50 ° C., pyridine (69 g) and p-toluenesulfonyl chloride (83.5 g) are added. After heating at 50 ° C. for 16 hours, the mixture is cooled to room temperature, 40% aqueous potassium carbonate (500 mL) is added, and the mixture is further stirred at 40 ° C. for 1 hour. The reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the crystals are washed with isopropyl acetate. The filtrate is concentrated and partitioned between isopropyl acetate, aqueous citric acid and 26% brine. After separation, the organic layer is washed with 26% saturated saline. 26% saturated saline and a small amount of 40% potassium carbonate water are added to the organic layer to adjust to pH 9 to 10, and after washing, liquid separation is performed twice. Anhydrous magnesium sulfate and silica gel are added to the organic layer and the mixture is stirred, and the insoluble material is filtered off.
The filtrate is concentrated to give (2S) -2-cyano-1- [N-tert-butoxycarbonyl-trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine. Melting point: 85-87 ° C

(4) The compound obtained in (3) is dissolved in a hydrophilic solvent such as 2-butanone,
(2S) -2-cyano-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine hydrochloride is obtained by treating with hydrochloric acid after adding water to remove the amino protecting group. obtain.

（２Ｓ）−２−カルバモイル−１−［トランス−４−（モルホリノカルボニル）シクロヘキシルアミノ］アセチルピロリジン（１０ｇ）をアセトニトリル（２００ｍＬ）に懸濁し、オキシ塩化リン（７．６ｍＬ）を氷冷下滴下する。室温にて４８時間攪拌した後、濃縮する。塩化メチレン（１００ｍＬ）を加えて溶解し、氷冷下４０％炭酸カリウム（６０ｍＬ）を加える。２０℃まで昇温して水（５０ｍＬ）を加えて分液する。水層を塩化メチレン（１００ｍＬ）で再抽出する。有機層を合わせて２６％ＮａＣｌ（３０ｍＬ）で洗浄する。有機層を濃縮することにより、（２Ｓ）−２−シアノ−１−［トランス−４−（モルホリノカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得る。 Example 4

(2S) -2-carbamoyl-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine (10 g) is suspended in acetonitrile (200 mL), and phosphorus oxychloride (7.6 mL) is added dropwise under ice cooling. . Stir at room temperature for 48 hours, then concentrate. Add methylene chloride (100 mL) to dissolve, and add 40% potassium carbonate (60 mL) under ice cooling. The temperature is raised to 20 ° C., and water (50 mL) is added for liquid separation. Re-extract the aqueous layer with methylene chloride (100 mL). Combine the organic layers and wash with 26% NaCl (30 mL). The organic layer is concentrated to give (2S) -2-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine.

（２Ｓ）−２−カルバモイル−１−［トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミノ］アセチルピロリジン（１０ｇ）をアセトニトリル（２００ｍＬ）に懸濁し、オキシ塩化リン（５．８ｍＬ）を氷冷下滴下する。室温にて６０時間攪拌した後、濃縮する。塩化メチレン（１００ｍＬ）を加えて溶解し、氷冷下４０％炭酸カリウム（６０ｍＬ）を加える。２０℃まで昇温して水（５０ｍＬ）を加えて分液する。水層を塩化メチレン（１００ｍＬ）で再抽出する。有機層を合わせて２６％ＮａＣｌ（３０ｍＬ）で洗浄する。有機層を濃縮することにより、（２Ｓ）−２−シアノ−１−［トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得る。 Example 5

(2S) -2-carbamoyl-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine (10 g) was suspended in acetonitrile (200 mL), and phosphorus oxychloride (5.8 mL) was suspended. ) Is added dropwise under ice cooling. Stir at room temperature for 60 hours, then concentrate. Add methylene chloride (100 mL) to dissolve, and add 40% potassium carbonate (60 mL) under ice cooling. The temperature is raised to 20 ° C., and water (50 mL) is added for liquid separation. Re-extract the aqueous layer with methylene chloride (100 mL). Combine the organic layers and wash with 26% NaCl (30 mL). The organic layer is concentrated to give (2S) -2-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine.

（２Ｓ）−２−カルバモイル−１−［トランス−４−（ジメチルアミノカルボニル）シクロヘキシルアミノ］アセチルピロリジン（１０ｇ）をアセトニトリル（２００ｍＬ）に懸濁し、オキシ塩化リン（８．６ｍＬ）を氷冷下滴下する。室温にて６２時間攪拌した後、濃縮する。塩化メチレン（１００ｍＬ）を加えて溶解し、氷冷下４０％炭酸カリウム（６０ｍＬ）を加える。２０℃まで昇温して水（５０ｍＬ）を加えて分液する。水層を塩化メチレン（１００ｍＬ）で再抽出する。有機層を合わせて２６％ＮａＣｌ（３０ｍＬ）で洗浄する。有機層を濃縮することにより、（２Ｓ）−２−シアノ−１−［トランス−４−（ジメチルアミノカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得る。 Example 6

(2S) -2-carbamoyl-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine (10 g) was suspended in acetonitrile (200 mL), and phosphorus oxychloride (8.6 mL) was added dropwise under ice cooling. To do. Stir at room temperature for 62 hours, then concentrate. Add methylene chloride (100 mL) to dissolve, and add 40% potassium carbonate (60 mL) under ice cooling. The temperature is raised to 20 ° C., and water (50 mL) is added for liquid separation. Re-extract the aqueous layer with methylene chloride (100 mL). Combine the organic layers and wash with 26% NaCl (30 mL). The organic layer is concentrated to give (2S) -2-cyano-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine.

クロロアセチルクロリド（７６．７ｇ）、アセトニトリル（２３３ｍＬ）をコルベンに仕込み、１０℃以下に冷却する。別途、Ｌ−プロリンアミド（７７．５ｇ、ジイソプロピルエチルアミン（８７．８ｇ）をアセトニトリル（１５５０ｍＬ）に懸濁し、２０℃以下でクロロアセチルクロリドのアセトニトリル液に滴下する。滴下後、２０℃で３０分撹拌し、３Ｌ−４頚コルベンに移し替えて外浴３５±５℃で減圧留去することにより、（２Ｓ）−１−（クロロアセチル）−２−ピロリジンカルボキサミドの残渣を得る。 Reference example 1

Chloroacetyl chloride (76.7 g) and acetonitrile (233 mL) are charged into a Kolben and cooled to 10 ° C. or lower. 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, followed by stirring at 20 ° C. for 30 minutes. Then, the residue is transferred to 3L-4 cervical colben and distilled under reduced pressure at an outer bath of 35 ± 5 ° C. to obtain a residue of (2S) -1- (chloroacetyl) -2-pyrrolidinecarboxamide.

Ｌ−プロリンアミド（５０ｇ）の塩化メチレン（５００ｍＬ）溶液にジイソプロピルエチルアミン（５５．５ｇ）を加える。この溶液をクロロアセチルクロリド（４９．５ｇ）の塩化メチレン（１３０ｍＬ）溶液に２０℃に保ちながら１時間かけて滴下する。滴下後、２０℃で３０分間撹拌する。これにトリフルオロ酢酸無水物（１１９．６ｇ）を加え、続けてピリジン（４５ｇ）を加えて、２０℃で約１時間撹拌する。反応液を水（４００ｍＬ）、飽和重曹水（４００ｍＬ）、１Ｎ塩酸（４００ｍＬ）、水（４００ｍＬ）でそれぞれ洗浄する。分液後、濃縮し、残渣にイソプロパノール（１６５ｍＬ）、塩化メチレン（３３ｍＬ）を加え、４５℃加熱して溶解する。メチル−ｔｅｒｔ−ブチルエーテル（３００ｍＬ）を加え、１時間かけて２５℃まで冷却し、同温で３０分撹拌する。さらに１時間かけて０℃まで冷却し同温で２時間撹拌する。結晶をろ過、乾燥することにより、（２Ｓ）−１−（クロロアセチル）−２−シアノピロリジンを得る。 Reference example 2

To a solution of L-prolinamide (50 g) in methylene chloride (500 mL) is added diisopropylethylamine (55.5 g). This solution is added dropwise to a solution of chloroacetyl chloride (49.5 g) in methylene chloride (130 mL) over 1 hour while maintaining at 20 ° C. After dropping, the mixture is stirred at 20 ° C. for 30 minutes. To this is added trifluoroacetic anhydride (119.6 g) followed by pyridine (45 g) and stirred at 20 ° C. for about 1 hour. The reaction solution is washed with water (400 mL), saturated aqueous sodium hydrogen carbonate (400 mL), 1N hydrochloric acid (400 mL), and water (400 mL). After separation, the solution is concentrated, and isopropanol (165 mL) and methylene chloride (33 mL) are added to the residue and dissolved by heating at 45 ° C. Add methyl-tert-butyl ether (300 mL), cool to 25 ° C. over 1 hour, and stir at the same temperature for 30 minutes. The mixture is further cooled to 0 ° C. over 1 hour and stirred at the same temperature for 2 hours. The crystals are filtered and dried to obtain (2S) -1- (chloroacetyl) -2-cyanopyrrolidine.

（１）トランス−４−（ベンジルオキシカルボニルアミノ）シクロヘキサンカルボン酸（４ｇ）のジメトキシエタン（１１ｍＬ）溶液に塩化チオニル（１．３７ｍＬ）、ジメチルホルムアミド（２８μＬ）を加えて４０℃で１時間攪拌する。反応液を濃縮し、ジメトキシエタン（１１ｍＬ）を加え、この溶液をモルホリン（７．５ｇ）の水（１０ｍＬ）溶液中に氷冷下滴下する。２時間攪拌の後、水（１６ｍＬ）を加えて氷冷し、析出結晶をろ過により分離して、Ｎ−ベンジルオキシカルボニル−トランス−４−（モルホリノカルボニル）シクロヘキシルアミンを得る。融点：１６１−１６２℃ Reference example 3

(1) Thionyl chloride (1.37 mL) and dimethylformamide (28 μL) are added to a solution of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid (4 g) in dimethoxyethane (11 mL), and the mixture is stirred at 40 ° C. for 1 hour. . The reaction mixture is concentrated, dimethoxyethane (11 mL) is added, and this solution is added dropwise to a solution of morpholine (7.5 g) in water (10 mL) under ice cooling. After stirring for 2 hours, water (16 mL) is added and ice-cooled, and the precipitated crystals are separated by filtration to give N-benzyloxycarbonyl-trans-4- (morpholinocarbonyl) cyclohexylamine. Melting point: 161-162 ° C

(2) The compound (4.4 g) obtained in (1) above is dissolved in ethanol (80 mL), and 10% palladium carbon catalyst (50% Wet product) (0.8 g) is added. Vacuum degassing and hydrogen introduction are performed three times, and the mixture is stirred 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 replacement was performed by performing 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 a heptane / tert-butyl methyl ether (3: 1) mixture and then separated by filtration to give N-benzyl-trans-4- (morpholinocarbonyl) cyclohexylamine.
Melting point: 63-65 ° C

（１）トランス−４−（ベンジルオキシカルボニルアミノ）シクロヘキサンカルボン酸（４ｇ）のジメトキシエタン（１１ｍＬ）溶液に塩化チオニル（１．３７ｍＬ）、ジメチルホルムアミド（２８μＬ）を加えて４０℃で１時間攪拌する。反応液を濃縮し、ジメトキシエタン（１１ｍＬ）を加え、この溶液を１−アセチルピペラジン（１１ｇ）の水（１０ｍＬ）溶液中に氷冷下滴下する。２時間攪拌の後、水（３２ｍＬ）を加えて氷冷し、析出結晶をろ過により分離し、Ｎ−ベンジルオキシカルボニル−トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミンを得る。
融点：１８０−１８１℃ Reference example 4

(1) Thionyl chloride (1.37 mL) and dimethylformamide (28 μL) are added to a solution of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid (4 g) in dimethoxyethane (11 mL), and the mixture is stirred at 40 ° C. for 1 hour. . The reaction mixture is concentrated, dimethoxyethane (11 mL) is added, and this solution is added dropwise to a solution of 1-acetylpiperazine (11 g) in water (10 mL) under ice cooling. After stirring for 2 hours, water (32 mL) is added and ice-cooled, and the precipitated crystals are separated by filtration to obtain N-benzyloxycarbonyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamine. .
Melting point: 180-181 ° C

(2) The compound (4.4 g) obtained in (1) above is dissolved in ethanol (80 mL), and 10% palladium carbon catalyst (50% Wet product) (0.8 g) is added. Vacuum degassing and hydrogen introduction are performed three times, and the mixture is stirred at room temperature and normal pressure for 3 hours.
Thereby, trans-4- (4-acetylpiperazin-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 replacement was performed by performing 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-benzyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamine. Melting point: 127-128 ° C

トランス−４−ベンジルオキシカルボニルアミノ−Ｎ，Ｎ−ジメチルシクロヘキサンカルボキサミド（４．４ｇ）をエタノール（８０ｍＬ）に溶解し、１０％パラジウム炭素触媒（５０％Ｗｅｔ品）（０．８ｇ）を加える。減圧脱気、水素導入を３回行い、室温、常圧で３時間攪拌する。
これにより、反応生成物として、トランス-4-アミノ-N,N-ジメチルシクロヘキサンカルボキサミドを得る。
10％パラジウム炭素触媒（50％Wet品）を含む前記（２）の反応液に、窒素雰囲気下、ベンズアルデヒド（１．４５ｇ）を加えて室温下、１時間攪拌する。減圧脱気、水素導入を３回行うことにより水素置換し、これを、室温、常圧で１時間２０分攪拌する。触媒をろ過により除去し、濃縮する。残渣を、ヘプタン／ｔｅｒｔ−ブチルメチルエーテル（３：１）混合物にて結晶化後、ろ過により分離して、トランス−４−ベンジルアミノ−Ｎ，Ｎ−ジメチルシクロヘキサンカルボキシアミドを得る。融点：６９℃ Reference Example 5 trans-4-benzylamino-N, N-dimethylcyclohexanecarboxamide

Trans-4-benzyloxycarbonylamino-N, N-dimethylcyclohexanecarboxamide (4.4 g) is dissolved in ethanol (80 mL) and 10% palladium on carbon catalyst (50% Wet product) (0.8 g) is added. Vacuum degassing and hydrogen introduction are performed three times, and the mixture is stirred at room temperature and normal pressure for 3 hours.
Thereby, trans-4-amino-N, N-dimethylcyclohexanecarboxamide is obtained as a reaction product.
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 replacement was performed by performing 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 a heptane / tert-butyl methyl ether (3: 1) mixture and then separated by filtration to give trans-4-benzylamino-N, N-dimethylcyclohexanecarboxamide. Melting point: 69 ° C

（１）Ｎ−ベンジル−トランス−４−（モルホリノカルボニル）シクロヘキシルアミン（１．０ｇ）および（２Ｓ）−１−（クロロアセチル）−２−シアノピロリジン（０．７４ｇ）をアセトニトリル（１２ｍＬ）に溶解し、炭酸カリウム無水微粉（１．１ｇ）およびヨウ化ナトリウム（５０ｍｇ）を加え、６０℃で３．５時間反応させた。室温まで冷却し、不溶物をろ過により除去した。ろ液を濃縮し、酢酸エチル（２０ｍＬ）、水（１５ｍＬ）および１０％クエン酸水（１０ｍＬ）に分配後、分液した。水層を酢酸エチル（２０ｍＬ）で洗浄、分液した。水層に４０％炭酸カリウム水（５ｍＬ）を加えて中和し、酢酸エチル（２０ｍＬ）で３回抽出した。有機層を合わせて無水硫酸マグネシウムで乾燥後、濃縮することにより、（２Ｓ）−２−シアノ−１−［Ｎ−ベンジル−トランス−４−（モルホリノカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得た。 Comparative Example 1

(1) N-benzyl-trans-4- (morpholinocarbonyl) cyclohexylamine (1.0 g) and (2S) -1- (chloroacetyl) -2-cyanopyrrolidine (0.74 g) dissolved in acetonitrile (12 mL) Then, anhydrous potassium carbonate fine powder (1.1 g) and sodium iodide (50 mg) were added and 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), water (15 mL) and 10% aqueous citric acid (10 mL), and then 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 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give (2S) -2-cyano-1- [N-benzyl-trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine.

(2) (2S) -2-cyano-1- [N-benzyl-trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine (800 mg) obtained in the same manner as in (1) above is added to ethanol (5 mL). After dissolution, 10% palladium on carbon catalyst (50% Wet product) (124 mg) was added. Nitrogen introduction and hydrogen introduction were repeated three times, and the mixture was stirred at 60 ° C. for 10 hours. 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-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine could not be obtained.

（１）Ｎ−ベンジル−トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミン（１．０ｇ）および（２Ｓ）−１−（クロロアセチル）−２−シアノピロリジン（０．６５ｇ）をアセトニトリル（１２ｍＬ）に溶解し、炭酸カリウム無水微粉（９６２ｍｇ）およびヨウ化ナトリウム（４４ｍｇ）を加え、６０℃で３．５時間反応させた。室温まで冷却し、不溶物をろ過により除去した。ろ液を濃縮し、酢酸エチル（２０ｍＬ）、水（１５ｍＬ）および１０％クエン酸水（１０ｍＬ）に分配後、分液した。水層を酢酸エチル（２０ｍＬ）で洗浄、分液した。水層に４０％炭酸カリウム水（５ｍＬ）を加えて中和し、酢酸エチル（２０ｍＬ）で３回抽出した。有機層を合わせて無水硫酸マグネシウムで乾燥後、濃縮することにより、（２Ｓ）−２−シアノ−１−［Ｎ−ベンジル−トランス−４−（４−アセチルピペラジン−１−イルカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得た。 Comparative Example 2

(1) N-benzyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamine (1.0 g) and (2S) -1- (chloroacetyl) -2-cyanopyrrolidine (0.65 g) Was dissolved in acetonitrile (12 mL), anhydrous potassium carbonate 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), water (15 mL) and 10% aqueous citric acid (10 mL), and then 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 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give (2S) -2-cyano-1- [N-benzyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino]. Acetylpyrrolidine was obtained.

(2) (2S) -2-cyano-1- [N-benzyl-trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine (800 mg) obtained in the same manner as (1) above ) Was dissolved in ethanol (5 mL), and 10% palladium carbon catalyst (50% Wet product) (114 mg) was added. Nitrogen introduction and hydrogen introduction were repeated three times, and the mixture was stirred at 60 ° C. for 10 hours. 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-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine could not be obtained.

（１）トランス−４−ベンジルアミノ−Ｎ，Ｎ−ジメチルシクロヘキサンカルボキサミド（０．１７ｇ）、（２Ｓ）−１−（クロロアセチル）−２−シアノピロリジン（０．２５ｇ）、ヨウ化ナトリウム（１４．４ｍｇ）および炭酸カリウム（０．１６ｇ）をアセトン（２．５ｍＬ）に懸濁し、６０℃で終夜攪拌することにより、（２Ｓ）−２−シアノ−１−［Ｎ−ベンジル−トランス−４−（ジメチルアミノカルボニル）シクロヘキシルアミノ］アセチルピロリジンを得た。 Comparative Example 3

(1) trans-4-benzylamino-N, N-dimethylcyclohexanecarboxamide (0.17 g), (2S) -1- (chloroacetyl) -2-cyanopyrrolidine (0.25 g), sodium iodide (14. 4 mg) and potassium carbonate (0.16 g) were suspended in acetone (2.5 mL) and stirred at 60 ° C. overnight to give (2S) -2-cyano-1- [N-benzyl-trans-4- ( Dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine was obtained.

(2) (2S) -2-cyano-1- [N-benzyl-trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine (200 mg) obtained in the same manner as in (1) above was added to ethanol (1. 6 mL), 10% palladium carbon catalyst (50% Wet product) (200 mg) was added, and the mixture was stirred at 25 ° C. for 2 hours under introduction of hydrogen to obtain a product.
However, the target compound, that is, (2S) -2-cyano-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine could not be obtained.

  The present invention is an industrially advantageous method for producing an N- (N′-substituted glycyl) -2-cyanopyrrolidine derivative.

Claims (3)

(I) removing the first amino group protecting group by reacting an amine compound protected with a first amino group protecting group other than a benzyl group or a substituted benzyl group in the presence of a palladium catalyst; After obtaining the primary or secondary amine compound,
(Ii) Subsequently, in the same reaction system, the primary or secondary amine compound is reacted with benzaldehyde or substituted benzaldehyde under a nitrogen atmosphere,
(Iii) A second amino group-protecting group selected from a benzyl group and a substituted benzyl group by subjecting the reaction system to hydrogen substitution followed by a reduction reaction in the presence of the same palladium catalyst as in the above (i). A method for substitution of amino group protection, characterized in that an amine compound protected with an amino acid is obtained. The amine compound protected with the second amino group protecting group obtained in (iii) is represented by the following formula [IIIa]
R-NH-R ^X1 [IIIa]
(In the formula, R represents an optionally substituted lower cycloalkyl group, an optionally substituted adamantyl group or an optionally substituted lower alkyl group, and R ^X1 represents a benzyl group or a substituted benzyl group) The method of Claim 1 which is an amine compound shown by these. The amine compound protected with the first amino-protecting group of (i) is represented by the following 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 and represents an amino group that can be removed by a palladium catalyst),
(Ii) a primary or secondary amine compound represented by the following formula [IX]
R ^D —NH ₂ [IX]
(Wherein the symbols have the same meaning as described above),
The amine compound protected with the second amino group-protecting group obtained in (iii) is represented by the following formula [X]
R ^D —NH—R ^X1 [X]
The method according to claim 1 or 2, wherein R ^X1 represents a benzyl group or a substituted benzyl group, and other symbols have the same meaning as described above.