JP2012254945A - Method for producing 6-disubstituted amino-7-deazaxanthine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 6-disubstituted amino-7-deazaxanthine compound useful as an intermediate of therapeutic agents for diabetes mellitus, etc.; its intermediate; and a method for producing 6-disubstituted amino-5-benzyl-7-deazaxanthine using the compound.SOLUTION: This method for producing the compound expressed by formula (4) comprises: reacting a compound expressed by formula (1) (in formula, Rand Rare the same or different and each represents a 1-6C alkyl or the like) with secondary amines and ortho-formate to obtain a compound expressed by formula (3) (where Rrepresents a 1-6C alkyl or the like, and Rrepresents a 1-6C alkyl or the like); and reducing the compound expressed by formula (3) using sodium dithionite, etc. There is disclosed also a method for producing a compound expressed by formula (6) by reacting the compound expressed by formula (4), protected if needed, with benzyl alcohols in the presence of a phosphine compound, etc., and performing deprotection reaction, if needed.

Description

  The present invention relates to a method for producing a 6-disubstituted amino-7-deazaxanthin compound useful as an intermediate for therapeutic agents such as diabetes, and an intermediate thereof, and 6-disubstituted amino-5-benzyl using the compound. The present invention relates to a method for producing a -7-deazaxanthine derivative.

A 6-disubstituted amino-5-benzyl-7-deazaxanthine derivative is known as one of dipeptidyl peptidase-IV (hereinafter referred to as “DPP-IV”) inhibitors that are expected as therapeutic agents for diabetes and the like. (For example, see Patent Document 1 and Patent Document 2). In this document, as a method for producing the compound, for example, the production methods shown in the following [Chemical Formula 1] and [Chemical Formula 2] are disclosed.
However, these production methods have many steps and the overall yield is low, and in the production of compound A, compounds (1-5), (1-7), (1-8) and (1-9) ) Is not a crystal and is difficult to purify in large-scale production, which is not satisfactory from the viewpoint of industrial production.

  Non-Patent Documents 1 and 2 disclose that a 6-dimethylamino-7-deazaxanthine compound is produced by catalytic reduction of a 6- (2-dimethylaminovinyl) -5-nitrouracil derivative in the presence of palladium carbon. (See [Chemical Formula 3] and [Chemical Formula 4] below). However, in the production method disclosed in Non-Patent Document 1, a 7-deazaxanthine compound from which a dimethylamino group is eliminated is obtained as a main product (yield 31% to 84%). The 7-deazaxanthine compound having a group is only obtained as a by-product (yield 0% to 16%). Non-Patent Document 2 also discloses the same results, and 3 out of 4 cases produced only 7-deazaxanthine compound from which dimethylamino group was eliminated (yield 14% to 36%), only 1 case. Produced a 6-dimethylamino-7-deazaxanthine compound (22% yield) together with a 7-deazaxanthine compound (yield 16%) from which a dimethylamino group was eliminated. Furthermore, there is no description or suggestion on a method for selectively and efficiently producing these compounds in any literature.

(Wherein, R ¹ and R ² represent the following groups: R ¹ = R ² = methyl group; R ¹ = methyl group, R ² = cyclohexyl group; R ¹ = hydrogen atom, R ² = butyl group; R ¹ = hydrogen atom, R ² = methyl group; R ¹ = hydrogen atom, R ² = propyl group; or R ¹ = R ² = propyl group.)

International Publication No. 2006/068163 Pamphlet International Publication No. 2009/113423 Pamphlet

Chem. Pharm. Bull., 1974, 22, 2593 J. Med. Chem., 1994, 37, 1526

  An object of the present invention is to provide a novel process for producing a 6-disubstituted amino-5-benzyl-7-deazaxanthine derivative which is short and simple and suitable for industrial production.

  As a result of intensive studies, the inventors used a compound represented by the following formula (1) as a starting material, and after reacting an amine represented by the following formula (2) with an orthoformate, It has been found that a 6-disubstituted amino-7-deazaxanthine compound represented by the following formula (4) can be efficiently obtained by reducing the product with a specific reducing agent. Further, in the presence of a phosphine compound and an azo compound, a compound represented by the following formula (4a) and a benzyl alcohol represented by the formula (5) are reacted to produce a 6-di compound that is expected as a therapeutic agent for diabetes and the like. The inventors have found that the substituted amino-5-benzyl-7-deazaxanthine derivative (6) can be efficiently produced, and have completed the present invention.

That is, according to the present invention, a method for producing a 6-disubstituted amino-7-deazaxanthine compound and a novel 6-disubstituted amino-5-benzyl-7-deazaxanthine derivative using the compound produced by the production method. Manufacturing methods are provided.
[1] Formula (4) including the following step (1) and step (2):

(Wherein R ¹ and R ² are the same or different and are each a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, Represents an optionally substituted aryl group, or an optionally substituted heteroaryl group, and R ³ represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, or Represents an optionally substituted heterocyclic group, R ⁴ represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, an _optionally substituted heterocycle; Represents a cyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, or R ³ and R ⁴ are substituted together with the nitrogen atom to which they are attached; May form a 4- to 7-membered cyclic amino group Method of manufacturing and may be) a compound represented by.:
(1) Formula (1):

(Wherein R ¹ and R ² have the same meanings as described above), and the formula (2):

(Wherein R ³ and R ⁴ have the same meanings as described above) and an orthoformate ester are reacted to give the formula (3):

(Wherein R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above),
(2) The compound represented by the formula (3) is reduced using a reducing metal, a reducing metal salt, a mixture of a reducing metal and a reducing metal salt, sodium dithionite, or sodium sulfide, and the formula ( 4) a process for producing the compound represented by
[2] The production method according to [1], wherein R ¹ and R ² are the same or different and are a hydrogen atom or a C _1-6 alkyl group.
[3] R ³ is one to three halogen atoms or C _1-6 alkoxy group optionally substituted by a C _1-6 alkyl group, R ⁴ is C _1-6 alkyl (in which the group May be substituted with 1 to 3 halogen atoms, a C _1-6 alkoxy group, an optionally protected amino group, or an optionally protected hydroxyl group), C _3-7 cycloalkyl A group (the group may be substituted with a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an optionally protected amino group, or an optionally protected hydroxyl group), Or a heterocyclic group (the group may be a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, an optionally protected amino group, or an optionally protected group) The production according to [1] or [2], which may be substituted with a hydroxyl group. Law.
[4] R ³ and R ⁴ together with the nitrogen atom to which they are bonded, a 4- to 7-membered cyclic amino group [the group is substituted with a halogen atom or 1 to 3 halogen atoms A C _1-6 alkyl group which may be substituted, a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C _1-6 alkyl group which may be substituted with 1 or 2 C _1-6 alkyl which may be the same or different A good amino group, an aryl group (the group is a halogen atom, C _1-4 alkoxy optionally substituted with 1 to 3 halogen atoms, or C optionally substituted with 1 to 3 halogen atoms) _1-4 may be substituted with _1-4 alkyl.), C _1-6 alkoxycarbonyl group, C _1-6 alkylsulfonyl group, may be substituted with the same or different 1-2 C _1-6 alkyl aminocarbonyl group, the same or different one or two C _1-6 alkyl Optionally substituted aminosulfonyl group, an optionally protected amino group or may be substituted by optionally protected hydroxyl group,. The production method according to [1] or [2].
[5] R ³ and R ⁴ are taken together with the nitrogen atom to which they are attached to form a piperidino group (the group is a halogen atom, a C _1-6 alkyl group, an optionally protected amino group, or a protected group) And may be substituted with a hydroxyl group which may be substituted.), The production method according to [4].
[6] The production method according to any one of [1] to [5], wherein the ortho formate is tri (C _1-6 alkyl) orthoformate.
[7] The production method according to any one of [1] to [6], wherein in the step of producing the compound represented by the formula (3) of [1], the reaction is further performed by adding an acid.
[8] Formula (6):

(Wherein R ¹¹ and R ²¹ are the same or different and may be substituted C _1-6 alkyl group, optionally substituted C _3-7 cycloalkyl group, optionally substituted) Represents an aryl group or an optionally substituted heteroaryl group, and R ³¹ represents a C _1-6 alkyl group (the group may be substituted with a halogen atom or a C _1-6 alkoxy group), A C _3-7 cycloalkyl group (the group may be substituted with a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group), or a heterocyclic group (the group is a halogen atom; , A C _1-6 alkyl group, a C _1-6 alkoxy group, or a C _1-6 alkoxycarbonyl group, which may be substituted, and R ⁴¹ represents a C _1-6 alkyl group (the group is halogen atom, C _1-6 alkoxy group, protected amino group or protected is, Hydroxyl group in optionally substituted.), C _3-7 cycloalkyl (in which the group, halogen atom, C _1-6 alkyl, C _1-6 alkoxy group, protected amino group or protected, A heterocyclic group (which may be a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a protected amino group). Or optionally substituted with a protected hydroxyl group), an aryl group (this group is a halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-6 alkoxycarbonyl group, protected Or a heteroaryl group (the group is a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-6 alkoxy group). Carbonyl group, protected amino group, or protected R ³¹ and R ⁴¹ may be a 4- to 7-membered cyclic amino group together with the nitrogen atom to which they are bonded [the group is a halogen atom , A C _1-6 alkyl group optionally substituted with a halogen atom, a C _1-6 alkoxy group optionally substituted with a halogen atom, a di-C _1-6 alkylamino group, an aryl group (the group is C _1-4 alkoxy which may be substituted with a halogen atom, or C _1-4 alkyl which may be substituted with a halogen atom.), C _1-6 alkoxycarbonyl group, C _{1 -6} alkylsulfonyl group, a di -C _1-6 alkylamino group, di -C _1-6 alkylaminosulfonyl group, protected amino group or may be substituted with a protected hydroxyl group. R ⁵ may be one or more, and each R ⁵ may be independently substituted with a hydrogen atom, a halogen atom, a nitro group, a cyano group, or a halogen atom. A good C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted with a halogen atom, a di-C _1-6 alkylamino group, an aryl group (the group is substituted with a halogen atom or a halogen atom) which may be substituted with a which may C _1-4 alkyl which may be substituted C _1-4 alkoxy or a halogen atom,.), C _1-6 alkoxycarbonyl group, C _1-6 alkylsulfonyl group, It represents a di-C _1-6 alkylaminocarbonyl group, a di-C _1-6 alkylaminosulfonyl group, a protected amino group, or a protected hydroxyl group. In the presence of a phosphine compound and an azo compound, or in the presence of a phosphorane compound,
Formula (4a):

(Wherein R ¹¹ , R ²¹ , R ³¹ , and R ⁴¹ have the same meanings as described above), and the formula (5):

(Wherein R ⁵ has the same meaning as described above).
[9] The production method according to [8], wherein R ¹¹ and R ²¹ are the same or different and are a C _1-6 alkyl group.
[10] ^{R 31} is a 1 to 3 halogen atoms or C _1-6 C _1-6 alkyl group optionally substituted by an alkoxy ^{group, R 41} is C _1-6 alkyl (in which the group Is optionally substituted with 1 to 3 halogen atoms, a C _1-6 alkoxy group, a protected amino group, or a protected hydroxyl group), a C _3-7 cycloalkyl group (the group is A halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a protected amino group, or a protected hydroxyl group, or a heterocyclic group (the group is a halogen atom, And may be substituted with a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a protected amino group, or a protected hydroxyl group. ] The manufacturing method of description.
[11] R ³¹ and R ⁴¹ are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered cyclic amino group [the group is substituted with a halogen atom or 1 to 3 halogen atoms; be a C _1-6 alkyl group, 1-3 a C _1-6 alkoxy group optionally substituted by a halogen atom, di -C _1-6 alkylamino group, an aryl group (said group, a halogen atom , optionally substituted with 1 to 3 halogen atoms which may be substituted C _1-4 alkoxy or 1-3 optionally C _1-4 alkyl optionally substituted by halogen atom.) , A C _1-6 alkoxycarbonyl group, a protected amino group, or a protected hydroxyl group. The production method according to [8] or [9].
[12] R ³¹ and R ⁴¹ , together with the nitrogen atom to which they are bonded, form a piperidino group (the group is a halogen atom, a C _1-6 alkyl group, a protected amino group, or a protected hydroxyl group) The production method according to [10], in which the compound may be substituted with a hydrogen atom.
[13] R ⁵ is one or more present, is independently in the presence of two or more, a hydrogen atom, a halogen atom, a cyano group, optionally substituted with 1 to 3 halogen atoms C _1- [8] to [12] The production method according to any one of [8] to [12], which is a ₆ alkyl group or a C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.
[14] Formula (9):

(Wherein R ⁶ and R ⁷ are the same or different and each represents a C _1-6 alkyl group, and ring A may form a condensed ring with phenyl or a 5-membered or 6-membered heterocycle 4 Represents a membered to 7-membered cyclic amino group, R ⁸ represents an amino group or a hydroxyl group, and R ⁹ represents a hydrogen atom, a halogen atom, or a C _1-6 optionally substituted with 1 to 3 halogen atoms. Represents an alkyl group or a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and R ¹⁰ is one or more, and when there are a plurality of them, each independently represents a halogen atom A cyano group, a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms. Wherein the phosphine compound and In the presence of azo compounds or in the presence of phosphorane compounds,
Formula (7):

(Wherein R ⁶ , R ⁷ and R ⁹ are as defined above, and R ¹¹ represents a protected amino group or a protected hydroxyl group), and a compound represented by formula (8 ):

(Wherein R ¹⁰ has the same meaning as described above); and a production method comprising a step of deprotecting a protected amino group or a protected hydroxyl group.
[15] 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine -2,4 (3H, 5H) -dione in the presence of a phosphine compound and an azo compound or in the presence of a phosphorane compound, 6-[(3R) -3- (tert-butoxycarbonyl) amino Reaction of piperidin-1-yl] -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione with (2-chloro-5-fluorophenyl) methanol And a production method comprising a step of treating the compound obtained in the step with an acid.
Furthermore, according to the present invention, a novel intermediate represented by the following formula (10) is provided.
[16] Formula (10):

(Wherein R ⁶ and R ⁷ are the same or different and each represents a C _1-6 alkyl group, and ring A may form a condensed ring with phenyl or a 5-membered or 6-membered heterocycle 4 Represents a 7-membered cyclic amino group, and R ⁹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or 1 to 3 halogen atoms. in an optionally substituted C _1-6 alkoxy group, R ¹¹ is a compound represented by the representative.) the protected amino group or a protected hydroxyl group.

  Commercially available and readily available 6-methyl-5-nitropyrimidine-2,4 (1H, 3H) -diones (1), secondary amines (2) and orthoformate reaction product [enamine ( 3)] using a specific reducing agent, the elimination reaction of the disubstituted amino group is suppressed, and the cyclization reaction proceeds efficiently, and 6-disubstituted amino-5-benzyl-7-deazaxanthin The derivative intermediate (4) can be obtained efficiently in a short process. Further, benzylation of the 5-position of the compound has many by-products when a conventional method (for example, a reaction using benzyl halide and a base) is used, and the yield is low, so that a phosphine compound and an azo compound coexist. Then, the intermediate (4a) and benzyl alcohol (5) are reacted and subjected to a deprotection reaction as necessary, whereby the 6-disubstituted amino-5-benzyl-7-deazaxanthin derivative (6) is recovered. Can be manufactured efficiently. That is, by using the production method of the present invention, a 6-disubstituted amino-7-deazaxanthine derivative useful as a drug substance for a therapeutic agent such as diabetes can be efficiently produced in a shorter process than a known method. Can do.

The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the expression “C _1-6 alkyl” is synonymous with an alkyl group having 1 to 6 carbon atoms. In the present specification, a substituent that does not clearly indicate the term “optionally substituted” means an “unsubstituted” substituent. For example, “C _1-6 alkyl” means “unsubstituted”.

In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted.
In addition, the substituent in the group defined by “optionally substituted” can be substituted at a substitutable position within the range of the substitutable number unless otherwise specified in quantity. For example, when the optionally substituted C _1-6 alkyl group is a methyl group, the range of the number of substitutable substituents in the methyl group is 1 to 3. When the aryl group which may be substituted is a phenyl group, the range of the number of substitutable substituents in the phenyl group is 1-5. When the number of substituents is 2 or more, the substituents may be the same or different. Further, unless otherwise indicated, the description of each group also applies if the group is part of another group or a substituent.

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

The “C _1-6 alkyl group” means a straight chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is a “C _1-4 alkyl group”. Specific examples of the “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

“C _3-7 cycloalkyl group” means a cyclic saturated or unsaturated hydrocarbon group having 3 to 7 carbon atoms. Preferred is a “C _3-6 cycloalkyl group”. Specific examples of “C _3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexynyl and the like.

In the “C _3-7 cycloalkyl group”, “C _3-7 cycloalkyl” and one hetero atom selected from phenyl or a 5- or 6-membered nitrogen atom, sulfur atom and oxygen atom are the same or different. A group condensed with a ring containing the above (for example, 1 to 4) is also included. Specific examples of the group include groups represented by the following formulas. These phenyls or substituents optionally substituted by a ring containing one or more (for example 1 to 4) heteroatoms selected from the group consisting of a 5- or 6-membered nitrogen atom, sulfur atom or oxygen atom. Includes a substituent in the “optionally substituted aryl group” and the “optionally substituted heteroaryl group”.

“Aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is a “C ₆ aryl group” (phenyl). Specific examples of the “aryl group” include phenyl, 1-naphthyl, 2-naphthyl and the like.

  The “aryl group” is a ring containing one or more (for example, 1 to 4) of the same or different heteroatoms selected from phenyl and 5- to 7-membered nitrogen, sulfur or oxygen atoms, or 5 Also included are groups fused to membered to 7-membered cycloalkyl rings (cyclopentane or cyclohexane). Specific examples of the group include groups represented by the following formulas.

However, in the case of an aryl group that is condensed, only the aromatic ring has a “group” bond. For example, the following formula

In the case of the “aryl group” represented by the formula, it means that the “group” is bonded at the 4-, 5-, 6-, or 7-position.

  Examples of the “heteroaryl group” include a 5- to 12-membered monocyclic or polycyclic aromatic group, and the group includes a heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. It contains the same or different one or more (for example, 1 to 4). As the “polycyclic heteroaryl group”, a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable. The polycyclic heteroaryl group includes a condensed ring of the monocyclic heteroaryl group and an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, etc.). Specific examples of the “heteroaryl group” include a group represented by the following formula.

  The bond across the ring in the above formula means that the “group” is bonded at a substitutable position in the ring. For example, the following formula

In the case of the heteroaryl group, it means a 2-furyl group or a 3-furyl group.
Further, when the “heteroaryl group” is a polycyclic group, for example, the following formula

In addition to 2-benzofuryl or 3-benzofuryl, 4-, 5-, 6-, or 7-benzofuryl may be used.

  However, in the case of a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (such as piperidine) are condensed, only the aromatic ring has a “group” bond. For example, the following formula

In the case of the “polycyclic heteroaryl group” represented by the formula, it means that the “group” is bonded at the 2-, 3-, or 4-position. The “heteroaryl group” is preferably a 5- to 10-membered monocyclic or polycyclic aromatic group, more preferably a 5- or 6-membered monocyclic aromatic group.

  The “heterocyclic group” has, for example, 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may form a condensed ring with phenyl or 6-membered heteroaryl. Examples include 3- to 7-membered heterocyclic groups. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. The monocyclic heterocyclic group may be either saturated or partially unsaturated. A saturated heterocyclic group is preferable, and a 5-membered or 6-membered saturated heterocyclic group is more preferable. Specific examples include pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like. In the group, the nitrogen atom constituting the ring is not a bond of the “group”. That is, the group does not include concepts such as a 1-pyrrolidino group.

Examples of the 3-membered to 7-membered heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom forming a condensed ring include, for example, the 5-membered or 6-membered compounds described above. Bicyclic 9-membered or 10-membered “heterocycle” in which a monocyclic heterocyclic group having a member and phenyl or 6-membered heteroaryl are condensed. Examples of the 6-membered aromatic hydrocarbon include benzene. Examples of 6-membered heteroaryl include pyridine, pyrimidine or pyridazine. Specifically, dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrololidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl , Decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like. Examples of the substituent which may be substituted by these phenyl or 6-membered heteroaryl include the substituents in “optionally substituted ₀ aryl group” and “optionally substituted heteroaryl group”. It is.

The “C _1-6 alkyl” part of the “C _1-6 alkoxy group” has the same _{meaning as} the above “C _1-6 alkyl”. Preferably, it is a “C _1-4 alkoxy group”. Specific examples of “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The “C _1-6 alkyl” part of the “C _1-6 alkylsulfonyl group” has the same meaning as the above “C _1-6 alkyl”. Preferably, it is “C _1-4 alkylsulfonyl group”. Specific examples of “C _1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

  The “aryl” part of the “aryloxy group” has the same meaning as the above “aryl”. Specific examples of the “aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

  The “heteroaryl” part of the “heteroaryloxy group” has the same meaning as the above “heteroaryl”. Preferable examples include “5- to 6-membered monocyclic heteroaryloxy group”. Specific examples of the “heteroaryloxy group” include, for example, pyridyloxy, imidazolyloxy, thiazolyloxy and the like.

The “C _1-6 alkoxy” part of the “C _1-6 alkoxycarbonyl group” has the same _{meaning as} the above “C _1-6 alkoxy”. Preferably, “C _1-4 alkoxycarbonyl group” and the like can be mentioned. Specific examples of “C _1-4 alkoxycarbonyl group” include, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.

  The “4- to 7-membered cyclic amino group” means a 4- to 7-membered cyclic amino group which may form a condensed ring with phenyl or a 5- or 6-membered heterocyclic ring. A group in which the nitrogen atom of the ring is a direct bond of the “group” is meant. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples of the monocyclic amino group include azetidino, pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholinooxide, thiomorpholinodioxide, piperazino and the like. In addition, the cyclic amino group which is a ring containing partial unsaturation is also contained in this group.

Specific examples of the cyclic amino group forming a condensed ring with phenyl or a 5-membered or 6-membered heterocyclic ring include “groups” shown below. Examples of the substituent which may be substituted on the phenyl or 5-membered or 6-membered heterocyclic ring include “optionally substituted C _6-10 aryl group” and “optionally substituted heteroaryl group” In the above formula.

Examples of the substituent in the “optionally substituted C _1-6 alkyl group” include:
(A) a halogen atom,
(B) a C _1-4 alkoxy group (this group may be substituted with 1 to 3 halogen atoms),
(C) a C _3-7 cycloalkyl group,
(D) a di-C _1-6 alkylamino group,
(E) an aryl group (the group is
(E1) a halogen atom,
(E2) C _1-4 alkyl (the group may be substituted with 1 to 3 halogen atoms), or (e3) C _1-4 alkoxy (the group is substituted with 1 to 3 halogen atoms). It may be substituted with an atom). ),
(F) an aryloxy group (this group may be substituted with a group selected from the group consisting of the above (e1) to (e3)),
(G) a heteroaryl group (this group may be substituted with a group selected from the group consisting of the above (e1) to (e3)),
(H) a heteroaryloxy group (this group may be substituted with a group selected from the group consisting of the above (e1) to (e3)),
(I) an amino group which may be protected, or (j) a hydroxyl group which may be protected.
Preferably, a halogen atom, a C _1-4 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), an aryl group (the group is a halogen atom, C _1-4 alkyl (the group The group may be substituted with 1 to 3 halogen atoms), or C _1-4 alkoxy (the group may be substituted with 1 to 3 halogen atoms). An amino group which may be protected, or a hydroxyl group which may be protected.

“Optionally substituted C _3-7 cycloalkyl group”, “optionally substituted 4- to 7-membered cyclic amino group”, “optionally substituted aryl group”, “substituted” Examples of the substituent in “may be a heteroaryl group” and “optionally substituted heterocyclic group” include:
(A2) a halogen atom,
(B2) C _1-4 alkyl group (this group may be substituted with 1 to 3 halogen atoms),
(C2) C _1-4 alkoxy group (this group may be substituted with 1 to 3 halogen atoms),
(D2) di-C _1-6 alkylamino group (e2) aryl group (the ring is
(E21) a halogen atom,
(E22) C _1-4 alkoxy (said group may be substituted with 1 to 3 halogen atoms.), Or (e23) C _1-4 alkyl (said groups, 1-3 halogens It may be substituted with an atom). ),
(F2) C _1-4 alkoxycarbonyl group,
(G2) an aminocarbonyl group optionally substituted by the same or different 1-2 C _1-4 alkyl,
(H2) a C _1-4 alkylsulfonyl group,
(I2) an aminosulfonyl group which may be substituted with the same or different 1-2 C _1-4 alkyl,
(J2) an amino group which may be protected, or (k2) a hydroxyl group which may be protected.
Preferably, a halogen atom, a C _1-4 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), a C _1-4 alkyl group (the group is represented by 1 to 3 halogen atoms). An optionally substituted amino group), an optionally protected amino group, or an optionally protected hydroxyl group.
In the definition of the compound of the formula (2), examples of the substituent in the “optionally substituted 4- to 7-membered cyclic amino group” include the above (a2), (b2), (c2), (d2), The group mentioned in (e2), (f2), (g2), (h2) or (i2), a protected amino group, a protected hydroxyl group, or the like is preferable.

  Specific examples of the “protected hydroxyl group” include a trialkylsilyl group (for example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, etc.), an acetal type protecting group (for example, tetrahydropyran-2-yl, methoxymethyl, methoxy Ethoxymethyl, etc.), alkoxycarbonyl groups (eg, tert-butoxycarbonyl, etc.), aralkyl groups (eg, benzyl, 4-methoxybenzyl, 2,4-dimethoxy) optionally substituted with one or two methoxy groups And a hydroxyl group substituted with benzyl, etc.).

Specific examples of the “protected amino group” include an alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, etc.), an alkenyloxycarbonyl group (eg, vinyl Oxycarbonyl etc.), aralkyloxycarbonyl groups (eg benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl etc.), aralkyl groups (eg benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl etc.), acyl groups ( For example, formyl, acetyl, trifluoroacetyl, benzoyl, etc.), arylsulfonyl group (eg, p-toluenesulfonyl, benzenesulfonyl, etc.), alkylsulfonyl group (eg, methanesulfonyl, etc.), etc. Substituted amino group. Preferably, (C _1-6 alkoxy) carbonyl group, allyl (C _1-4 alkyl) oxycarbonyl group, allyl (C _1-4 alkyl) carbonyl group and arylsulfonyl optionally substituted with C _1-4 alkyl An amino group substituted with a group, more preferably an amino group substituted with tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-toluenesulfonyl, or benzenesulfonyl.

  The production method of the present invention will be described.

Production Method The compound represented by formula (4) can be produced in the following two steps using the compound represented by formula (1) as a starting material.

(In the formula, R ¹ , R ² , R ³ , and R ⁴ are as defined above.)

Step (A-1)
A compound represented by the formula (3) can be produced by performing a reaction using the compound represented by the formula (1), the amine represented by the formula (2), and an orthoformate ester.
Specific examples of the orthoformate ester include, for example, trialkyl orthoformate, diethylphenyl orthoformate and the like, and triformate (C _1-6 alkyl) orthoformate (for example, trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate). And tributyl orthoformate) are preferred.

The usage-amount of amine (2) is 1.0-5.0 mol times normally with respect to the compound represented by Formula (1), Preferably it is 1.5-2.5 mol times.
The amount of orthoformate used is usually 1.0 mole or more, and there is no particular upper limit. For example, a large excess amount may be used also as a solvent.

  The reaction is carried out without solvent or using a solvent. Specific examples of the solvent include ether solvents such as diethyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane and chloroform; aromatic hydrocarbons such as toluene and benzene. System solvents; aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide and the like can be mentioned, and these solvents are used alone or in combination of two or more.

  The reaction temperature is usually 0 ° C to 300 ° C, preferably 70 ° C to 150 ° C. The reaction time is not particularly limited, but is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 5 hours.

  In this step, an acid can be added to accelerate the reaction. The amount of the acid used is, for example, in the range of 0.5 to 2 mole times, preferably 0.5 to 1 mole times the amount of the compound represented by the formula (1). Specific examples of the acid include lower carboxylic acids having 1 to 6 carbon atoms such as acetic acid and propionic acid; sulfonic acids such as camphorsulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid; inorganic acids such as hydrochloric acid and sulfuric acid Is mentioned. Preferably, lower carboxylic acids having 1 to 6 carbon atoms (such as acetic acid) and sulfonic acids (such as camphorsulfonic acid) can be used.

Step (A-2)
The compound represented by the formula (4) can be synthesized by reducing the compound represented by the formula (3) under specific reaction conditions. Specifically, a reduction method using a reducing metal such as iron, zinc, tin, magnesium, or indium, or a reducing metal salt such as tin dichloride or titanium trichloride; using sodium dithionite or sodium sulfide And a reduction method.

In the case of reducing using a reducing metal or a reducing metal salt, the reducing metal and the reducing metal salt can be used alone or in combination. With respect to the amount of the reducing metal and reducing metal salt used, the range of 0.5 to 5 mol times, preferably 1 to 3 mol times of the compound represented by the formula (3) can be mentioned. is there.
Usually, hydrochloric acid, sulfuric acid, acetic acid, sodium hydroxide, sodium hydrogen sulfite, ammonium chloride, ammonium sulfide, aqueous ammonia and the like are used as additives. With respect to the use amount of the additive, the range of 0.5 to 20 mole times the amount is mentioned with respect to the compound represented by the formula (3), preferably 1.0 to 10 mole times the range.
The reaction is carried out without solvent or using a solvent. Specific examples of the solvent include water; ether solvents such as diethyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane and chloroform; aromatics such as toluene and benzene. Hydrocarbon solvents; ester solvents such as ethyl acetate and isopropyl acetate; aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide; alcohol solvents such as methanol and isopropanol; Used in a mixture of more than one species.
The reaction temperature is usually -78 ° C to 300 ° C, preferably -20 ° C to 150 ° C. The reaction time is not particularly limited, but is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 10 hours.

When reducing using sodium dithionite or sodium sulfide, the amount used is usually 1.0 to 5.0 moles per mole of compound (3). The amount is preferably 1.0 to 2.5 mole times.
The reaction is carried out without solvent or using a solvent. Specific examples of the solvent include water; ether solvents such as diethyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane and chloroform; aromatics such as toluene and benzene. Hydrocarbon solvents; ester solvents such as ethyl acetate and isopropyl acetate; aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide; alcohol solvents such as methanol and isopropanol; Used in a mixture of more than one species.
The reaction temperature is usually -78 ° C to 300 ° C, preferably -20 ° C to 150 ° C. The reaction time is not particularly limited, but is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 10 hours.

The compound represented by the formula (3) can also be produced by a catalytic reduction method using a hydrogenation catalyst.
Specific examples of the hydrogenation catalyst used in the catalytic reduction method include a palladium catalyst, a platinum catalyst, a nickel catalyst, a rhodium catalyst, a ruthenium catalyst, and an osmium catalyst. Specifically, for example, palladium-carbon, palladium-black, palladium-carbon-ethylenediamine complex, palladium-fibroin, palladium hydroxide-carbon, palladium hydroxide, palladium oxide, platinum oxide, platinum-carbon, platinum-black,
Examples include Raney nickel, rhodium-carbon, rhodium-alumina, ruthenium-carbon, osmium-carbon, and Lindlar catalyst. The amount of the hydrogenation catalyst used is usually 0.01% by weight to 20% by weight based on the metal based on the compound (3). The amount is preferably 0.5 to 10% by weight When carrying out this method, a poisoning agent such as dimethyl sulfoxide or ethylenediamine can be added in order to suppress the catalytic ability. With respect to the use amount of the poisoning agent, a range of 1.0 to 5.0 mol times, preferably 2.0 to 3.0 mol times of the compound represented by the formula (3) can be mentioned.
The reaction is carried out without solvent or using a solvent. Specific examples of the solvent include water; ether solvents such as diethyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane and chloroform; aromatics such as toluene and benzene. Hydrocarbon solvents; ester solvents such as ethyl acetate and isopropyl acetate; aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide; alcohol solvents such as methanol and isopropanol; Used in a mixture of more than one species.
The reaction temperature is usually -78 ° C to 300 ° C, preferably -20 ° C to 150 ° C. The reaction time is not particularly limited, but is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 5 hours.

  The compound represented by the formula (6) can be produced in one step as follows using the compound represented by the formula (4a) as a starting material.

(Wherein R ¹¹ , R ²¹ , R ³¹ , and R ⁴¹ and R ⁵ have the same meanings as described above.)

Step (A-3)
A compound represented by formula (6) can be synthesized by reacting a compound represented by formula (4a) with benzyl alcohol represented by formula (5) in the presence of a phosphine compound and an azo compound. it can.

  The usage-amount of benzyl alcohol (5) is 1.0-5.0 mol times normally with respect to the compound represented by Formula (4a), Preferably it is 1.0-2.0 mol times.

  Specific examples of the phosphine compound include trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, triphenylphosphine, hexamethylphosphorustriamide, hexaethylphosphorustriamide, and the like. The usage-amount of a phosphine compound is 1.0-20.0 mol times normally with respect to a compound (4a), Preferably it is 1.0-3.0 mol times.

  Specific examples of the azo compound include azo compounds usually used in Mitsunobu reaction, for example, alkyl azocarboxylate compounds such as diethyl azodicarboxylate and diisopropylpyro azodicarboxylate, or N, N, N ′. Azodicarboxamide compounds such as N, N'-tetramethylazodicarboxamide, N, N, N ', N'-tetraisopropylazodicarboxamide, 1,1'-(azodicarbonyl) dipiperidine. N, N, N ′, N′-tetramethylazodicarboxamide or 1,1 ′-(azodicarbonyl) dipiperidine is preferable. The usage-amount of an azo compound is 1.0-20.0 mol times normally with respect to a compound (4a), Preferably it is 1.0-3.0 mol times.

  Further, as an alternative to the coexistence of phosphine compounds and azo compounds, phosphorane compounds commonly used in Mitsunobu reaction, for example, (cyanomethylene) phosphorane compounds such as (cyanomethylene) trimethylphosphorane, (cyanomethylene) tributylphosphorane, etc. Can be used. The usage-amount of a phosphorane compound is 1.0-20.0 mol times normally with respect to a compound (4a), Preferably it is 1.0-3.0 mol times.

  The reaction is carried out using a solvent. Specific examples of the solvent include ether solvents such as diethyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane and chloroform; aromatic hydrocarbon solvents such as toluene and benzene; Amide solvents such as dimethylformamide and N-methyl-2-pyrrolinone; nitrile solvents such as acetonitrile and propionitrile, and the like are used alone or in combination of two or more.

  The reaction temperature is usually -78 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time is not particularly limited, but is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 5 hours.

When a protected hydroxyl group and / or a protected amino group are present in the reaction product of the compound represented by the formula (4a) and the compound represented by the formula (5), conventional methods or literature (for example, Green, TW and Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (2007), etc.) can be used to remove hydroxyl and / or amino protecting groups. Therefore, for example, a 6-disubstituted amino-5-benzyl-7-deazaxanthine derivative having an amino group includes a compound represented by the formula (4a) having an amino group protected with an alkoxycarbonyl group and the formula (5). ) Can be produced by treating the reaction product with a compound represented by (1) with an acid (for example, sulfuric acid, hydrochloric acid, etc.). Preferably, concentrated sulfuric acid can be used.
To the mixture after the reaction, either “adjust the pH to 12 to 14 by adding a base” or “add a poor solvent with low solubility to the reaction product” or both operations Thus, the reaction product can be obtained as a crystal without performing an extraction operation.
As the base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are used. As the poor solvent, when obtaining the reaction product as an acid addition salt, a hydrocarbon solvent such as hexane, heptane, toluene, or an ether solvent such as diethyl ether, t-butyl methyl ether, cyclopentyl methyl ether, Water is used when the reaction product is obtained as a free form.

  The compound represented by the formula (1) which is the raw material compound in the step (A-1) is a known compound or a known method from a known compound (for example, C. Esteve et al., Bioorg. Med. Chem. Lett. 16 (2006) 3642).

  The compound represented by the formula (4a) is produced by the production method of the compound (4) or is a compound produced by introducing a protective group into the compound (4) according to a conventional method.

  The compound obtained by each reaction described above can be isolated and purified by a fractional recrystallization method which is a conventional separation means, a purification method using chromatography, a solvent extraction method, reprecipitation or the like.

  When the compound of the present invention or the raw material compound obtained by each reaction is a racemate or a mixture of diastereomers, each stereoisomer is prepared according to a conventional method, for example, the method described in EP 455006. Can be separated.

  In addition, optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. An optically active substance can also be used as a starting material.

  In the case where the compound obtained by the production method of the present invention has optical isomers, stereoisomers, tautomers such as keto enols, and / or geometric isomers, the present invention includes all possible It includes isomers and mixtures thereof.

  The product obtained in any reaction takes the form of an acid addition salt or free base, depending on the reaction conditions. These products can be converted into the desired acid addition salt or free base form by conventional methods.

  The compound obtained by the production method of the present invention and a salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Furthermore, the present invention also includes all tautomers, all stereoisomers present, and all forms of crystalline forms of the compounds involved in the production method of the present invention.

  The production method and production intermediate of the present invention will be described in more detail with reference to the following examples and reference examples, but the present invention is not limited to these specific examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

The following abbreviations may be used in the examples, reference examples and specification.
Boc: tert-butoxycarbonyl group
Me: Methyl group
Et: Ethyl group
DMSO: Dimethyl sulfoxide

The measurement conditions described in the HPLC measurement conditions represent the following contents.
Column: Ascentis C18, 2.7μm 4.6mmφ × 100mm (SUPELCO)
Moving layer:
A liquid: 10mM ammonium acetate water
Liquid B: acetonitrile gradient conditions:

Flow rate: 1.0mL / min
Detector: UV (254nm)
Column temperature: 40 ° C
In this condition, tert-butyl (3R) -1- (1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo [3,2-d] pyrimidine-6 The retention time of -yl) piperidin-3-ylcarbamate was 11.9 minutes.

Reference example 1
Preparation of tert-butyl 3-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -2-cyano-3- (methylthio) acrylate

tert-Butyl 2-cyano-3,3-bis (methylthio) acrylate (140.0 kg) in toluene (129.3 L) solution, (3R) -3- (tert-butoxycarbonyl) aminopiperidine (114.6 kg) in toluene solution (242.5 L) was added and stirred at 40-50 ° C. Seven hours later, heptane (458.5 L) was added and stirred at 40-50 ° C., and then seed crystals were added. After crystal precipitation, heptane (458.5 L) was added. Then, after stirring in an ice bath for 2 hours, a cooled mixed solvent of toluene / heptane (1: 2) (189 kg) was added and filtered to obtain the title compound (217.5 kg, yield 95.9%). Obtained.
¹ H-NMR (DMSO-d6) δ: 1.38 (9H, s), 1.41 (9H, s), 1.49-1.57 (2H, m), 1.80-1.87 (2H, m), 2.54 (3H, s), 3.15 (1H, dd, J = 12.2, 9.6 Hz), 3.20-3.25 (1H, m), 3.47 (1H, m), 3.61-3.71 (2H, m), 7.04 (1H, d, J = 7.0 Hz) .

Reference example 2
tert-butyl 3-[(2-chloro-5-fluorobenzyl) amino] -3-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -2-cyanoacrylate Manufacturing

The compound of Reference Example 1 (218.0 kg) was dissolved in acetonitrile (178.5 L), and a solution of DBU (167.2 kg) and 2-chloro-5-fluorobenzylamine (105.4 kg) in acetonitrile (27.8 L) was added. Stir at ~ 60 ° C. After 6 hours, the mixture was diluted with toluene (637.6 L) and washed with water. The obtained organic layer was washed with 8.5% aqueous potassium hydrogen sulfate solution, 10% aqueous sodium hydroxide solution and water, and concentrated under reduced pressure to give the title compound (194.3 kg, yield 69.6%).
¹ H-NMR (DMSO-d6) δ: 1.42 (9H, s), 1.42-1.45 (1H, m), 1.49 (9H, s), 1.61-1.71 (1H, m), 1.81-1.85 (1H, m ), 1.96-2.00 (1H, m), 3.00 (1H, dd, J = 13.2, 9.6 Hz), 3.18 (1H, ddd, J = 10.4, 10.4, 2.8 Hz), 3.39 (1H, d, J = 13.2 Hz), 3.65-3.67 (2H, m), 4.42 (1H, dd, J = 17.6, 5.6 Hz), 4.46 (1H, dd, J = 17.6, 6.4 Hz), 4.53 (1H, br s), 6.97 ( 1H, ddd, J = 8.8, 8.0, 2.8 Hz), 7.18 (1H, dd, J = 8.8, 2.8 Hz), 7.34 (1H, dd, J = 8.8, 5.2 Hz), 8.52 (1H, br s).

Reference example 3
tert-butyl 3-[(2-chloro-5-fluorobenzyl) (2-ethoxy-2-oxoethyl) amino] -3-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidine-1 Of 2-yl} -2-cyanoacrylate

The compound of Reference Example 2 (194.0 kg) was dissolved in N, N-dimethylformamide (346.4 L), potassium carbonate (184.4 kg) was added, and the mixture was stirred at room temperature. After dropwise addition of ethyl bromoacetate (89.1 kg), the mixture was stirred at 30 to 40 ° C. for 2 hours. Further, ethyl bromoacetate (12.7 kg) was added, and the mixture was stirred at 30 to 40 ° C. for 2 hours. Toluene was added, washed with water, and concentrated under reduced pressure to give the title compound (224.1 kg, yield 98.8%).
MS (ESI +) 595 (M ⁺ + 1,40%)
IR (attenuated total reflection) cm ^-1 : 3315, 2958, 2933, 2867, 2193, 1741, 1681, 1675, 1587, 1508, 1475, 1448, 1099.

Reference example 4
4-tert-butyl 2-ethyl 3-amino-1- (2-chloro-5-fluorobenzyl) -5-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} Production of -1H-pyrrole-2,4-dicarboxylate

To a solution of lithium tert-butoxide (45.2 kg) in tert-butyl alcohol (621.4 L) and acetonitrile (857.2 L), add a toluene (112.0 L) solution of the compound of Reference Example 3 (224.1 kg) to 20-30 ° C. And stirred for 2 hours. After adding toluene (776.3 L), the reaction mixture was washed with 20% aqueous acetic acid and concentrated under reduced pressure to give the title compound (203.5 kg, yield 90.8%).
¹ H-NMR (DMSO-d6) δ: 1.05 (3H, t, J = 6.8 Hz), 1.14-1.17 (2H, m), 1.34 (9H, s), 1.52-1.57 (1H, m), 1.57 ( 9H, s), 1.73 (2H, m), 2.74 (1H, m), 2.92-2.96 (1H, m), 3.07-3.17 (2H, m), 4.05 (2H, q, J = 6.8 Hz), 5.40 (2H, s), 6.02 (2H, s), 6.12 (1H, d, J = 7.6 Hz), 6.86 (1H, br s), 7.14 (1H, ddd, J = 8.8, 8.0, 2.8 Hz), 7.54 (1H, dd, J = 8.8, 5.2 Hz).

Reference Example 5
4-tert-butyl 2-ethyl 3-[(aminocarbonyl) amino] -1- (2-chloro-5-fluorobenzyl) -5-{(3R) -3-[(tert-butoxycarbonyl) amino]- Preparation of piperidin-1-yl} -1H-pyrrole-2,4-dicarboxylate

To a mixture of the compound of Reference Example 4 (204.0 kg) dissolved in acetic acid (1283.5 L) and toluene (414.0 L), a solution of potassium cyanate (64.1 kg) dissolved in water (93.8 kg) was added dropwise at 40 ° C. And stirred. After 2 hours, the temperature was returned to room temperature, diluted with toluene (1123.4 L), and washed 3 times with water. The pH was adjusted to 7-10 with an aqueous sodium hydroxide solution, washed with brine, and concentrated under reduced pressure to give the title compound (212.4 kg, yield 97.1%).
¹ H-NMR (DMSO-d6) δ: 1.08 (3H, t, J = 7.2 Hz), 1.13-1.23 (2H, m), 1.33 (9H, s), 1.49-1.52 (1H, m), 1.52 ( 9H, s), 1.73 (1H, m), 2.77-2.86 (2H, m), 2.96 (1H, m), 4.06 (2H, q, J = 7.2 Hz), 5.40 (2H, s), 6.10 (1H , d, J = 6.8 Hz), 6.27 (2H, s), 6.82 (1H, d, H = 5.2 Hz), 7.15 (1H, ddd, J = 8.8, 8.0, 2.8 Hz), 7.55 (1H, dd, J = 8.8, 5.2 Hz).

Reference Example 6
tert-butyl 5- (2-chloro-5-fluorobenzyl) -6-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -1,3-dimethyl-2, Preparation of 4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo [3,2-d] pyrimidine-7-carboxylate

After adding N, N-dimethylformamide (877.6 L) to a toluene solution of the compound of Reference Example 5 (212.0 kg), potassium carbonate (114.8 kg) and water (8.5 kg) were added and stirred at 45-50 ° C. . After 5 hours, the mixture was cooled to 30 ° C. and potassium carbonate (68.8 kg) was added. Methyl iodide (141.5 kg) was added dropwise and stirred. After 3 hours, the mixture was diluted with toluene, washed with water, and concentrated under reduced pressure. The obtained solid was heated to 70 ° C. in isopropanol (1620 L) and returned to room temperature. After stirring at 5 ° C. for 5 hours, the solid was collected by filtration and dried under reduced pressure to obtain the title compound (172.1 kg, yield 88.3%).
¹ H-NMR (DMSO-d6) δ: 1.18-1.26 (2H, m), 1.33 (9H, s), 1.52-1.59 (1H, m), 1.68-1.72 (1H, m), 2.66-2.74 (2H , m), 2.81 (1H, t, J = 10 Hz), 2.94-2.96 (1H, m), 3.18 (3H, s), 3.18-3.20 (1H, m), 3.43 (3H, s), 5.49 ( 1H, d, J = 17.2 Hz), 5.56 (1H, d, J = 17.2 Hz), 6.28 (1H, d, J = 7.6 Hz), 6.80 (1H, d, J = 6.8 Hz), 7.16 (1H, ddd, J = 8.4, 8.4, 3.2 Hz), 7.56 (1H, dd, J = 9.2, 5.2 Hz).

Reference Example 7
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2, Production of 4 (3H, 5H) -dione

Concentrated sulfuric acid (60.9 kg) was added dropwise to tetrahydrofuran (204.7 L). To the mixture was added dropwise a solution of the compound of Reference Example 6 (181.4 kg) in tetrahydrofuran (819.0 L) at 55-60 ° C. and stirred. After 2 hours, the temperature was returned to room temperature, and toluene (460.8 L) and water (634.9 L) were added for liquid separation. To the aqueous layer were added NaOH (46.8 kg), water (187.2 L) and tetrahydrofuran (450.4 L), and the mixture was separated, 2-propanol was added to the organic layer, the mixture was concentrated, washed with water, and further concentrated under reduced pressure. 2-Propanol (1620.3L) was added to the residue and the temperature was raised to 70 ° C. The title compound (172.1 kg, yield 88.9%) was obtained by cooling to 0 ° C., washing with 2-propanol, and drying under reduced pressure.
¹ H-NMR (DMSO-d6) δ: 1.02-1.04 (1H, m), 1.38-1.48 (3H, m), 1.60-1.65 (1H, m), 1.73-1.77 (1H, m), 2.39 (1H , dd, J = 11.2,9.2Hz), 2.59 (1H, dd, J = 11.2,2.4Hz), 2.62-2.68 (1H, m), 2.86-2.89 (1H, m), 3.01 (1H, dd, J = 11.2, 3.6Hz), 3.15 (3H, s), 3.39 (3H, s), 5.43 (2H, s), 5.98 (1H, s), 6.19 (1H, dd, J = 9.5, 3.0Hz), 7.16 (1H, ddd, J = 8.6,8.4,3.0Hz), 7.54 (1H, dd, J = 8.8,5.1Hz).

Example 1-1
Preparation of 6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-ylvinyl] -1,3-dimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione

N, N of 1,3,6-trimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione (20.0 g) and (3R) -3- (tert-butoxycarbonyl) aminopiperidine (30.17 g) -Acetic acid (3.02 g) was added to a dimethylacetamide (94.20 g) solution, and then triethyl orthoformate (89.30 g) was added dropwise at 98 ± 5 ° C over 1 hour. After stirring for 2.5 hours, the temperature was returned to room temperature, and toluene (433 g) and water (200 g) were added for partition extraction. The organic layer is washed with water (200 g), the solvent is distilled off under reduced pressure, and the resulting crude product is separated by silica gel column chromatography. The resulting crude product is recrystallized from toluene (50 g). This gave the title compound (30.5 g, yield 74.2%).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.60-1.67 (1H, m), 1.76-1.82 (1H, m), 1.94-1.98 (1h, M), 3.04 (1H, dd, J = 11.5, 8.0Hz), 3.14-3.19 (1H, m), 3.28-3.32 (1H, m), 3.37 (3H, s), 3.46 (3H, s), 3.61 (1H, dd, J = 13.0, 3.5 Hz), 3.68 (1H, m), 4.57 (1H, m), 4.79 (1H, d, J = 13.1Hz), 6.84 (1H, d, J = 13.1Hz).

Example 1-2
Preparation of 6- [2- (dimethylamino) vinyl] -1,3-dimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione

1,3,6-Trimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione (2.99 g) was suspended in toluene (20 mL), and N, N-dimethylformamide diethyl acetal (5.15 mL) was added. And heated to reflux for 4.5 hours. The reaction mixture was ice-cooled and n-heptane (20 mL) was added dropwise. After stirring for 1 hour, the precipitated crystals were collected by filtration and washed with n-heptane-toluene (1: 1, 6 mL) to obtain the title compound (3.65 g, yield 96%).
¹ H-NMR (DMSO-d6) δ: 2.99 (6H, s), 3.37 (3H, s), 3.47 (3H, s), 4.51 (1H, d, J = 12.8Hz), 6.95 (1H, d, J = 12.8 Hz).

Example 1-3
Preparation of 6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-ylvinyl] -1,3-dimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione (3a)
1,3,6-trimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione (99.6 mg) and (3R) -3- (tert-butoxycarbonyl) aminopiperidine (300.4 mg) with triethyl orthoformate (444.6 mg) in N, N-dimethylacetamide (0.5 mL) was added nothing to Entry1, 10-camphorsulfonic acid (58.1 mg) was added to Entry2, and the mixture was stirred at 100 ° C. Sampling was performed over time, analysis was performed by HPLC, and the reaction was followed.
The results of plotting the reaction yield of the compound (3a) are shown in [Table 1].

Example 2-1
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H)- Production of dione

N, N of 1,3,6-trimethyl-5-nitropyrimidine-2,4 (1H, 3H) -dione (4.50kg) and (3R) -3- (tert-butoxycarbonyl) aminopiperidine (6.79kg) -Acetic acid (0.68 kg) was added to a dimethylacetamide (21.20 kg) solution, and then triethyl orthoformate (20.09 kg) was added dropwise at 98 ± 5 ° C over 1 hour. After 2 hours, the reaction was cooled to -15 ° C. Sodium dithionite (14.05 kg) was added, water (84.30 kg) was added dropwise over 2 hours, and the mixture was further stirred at 0 to 0 ° C. for 1 hour. Concentrated hydrochloric acid (2.93 kg) was added to the reaction solution to adjust the pH to 3.0 or lower. After adding methanol (4.46 kg), the mixture was stirred at 50 to 60 ° C. for 2 hours. Water (28.10 kg) was added dropwise to the reaction solution over 30 minutes. After stirring for 1 hour, the precipitated crystals were collected by filtration, washed twice with water (23 kg), twice with methanol (18 kg), and dried under reduced pressure to give the title compound (5.54 kg, yield 65.0 %).
¹ H-NMR (DMSO-d6) δ: 1.24-1.37 (1H, m), 1.40 (9H, s), 1.47-1.56 (1H, m), 1.69-1.72 (1H, m), 1.77-1.80 (1H , m), 2.59 (1H, dd, J = 12.0,10.0Hz), 2.69-2.75 (1H, m), 3.19 (3H, s), 3.30 (3H, s), 3.42-3.45 (1H, m), 3.59-3.62 (1H, m), 3.66 (1H, dd, J = 12.0,4.0Hz), 5.44 (1H, d, J = 1.6Hz), 6.89 (1H, d, J = 8.0Hz), 11.06 (1H , br.s).

Example 2-2
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H)- Production of dione

To a solution of the compound obtained in Example 1-1 (200 mg) in N, N-dimethylformamide (2.0 g), tin (II) chloride (231 mg) and sodium bisulfite (127 mg) were added and stirred at room temperature for 23 hours. did. The reaction solution was diluted with dimethyl sulfoxide, the content of the title compound was analyzed by HPLC, and the yield was calculated to be 79.9%.

Example 2-3
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H)- Production of dione

Reduced iron (81.8 mg) and acetic acid (176 mg) were added to a methanol-toluene (1: 1, 2.0 g) solution of the compound obtained in Example 1-1 (200 mg), and the mixture was stirred at 40 ° C. for 7 hours. Chloroform-methanol solution (1: 1, 10 mL) was added to the reaction solution, and unnecessary substances were filtered off. The content of the title compound in the filtrate was analyzed by HPLC, and the yield was calculated to be 75.7%.

Example 2-4
Preparation of 6- (dimethylamino) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione

Sodium dithionite (1.20 g) was added to a solution of the compound obtained in Example 1-2 (501 mg) in N, N-dimethylacetamide (4.67 mL), and water (7.20 g) was added dropwise at 0 ° C. over 1 hour. The mixture was further stirred at 0 to 10 ° C. for 1.5 hours. Concentrated hydrochloric acid (0.3 g) was added to the reaction solution to adjust the pH to 3.0 or lower, and the mixture was stirred at 60 ° C. for 2 hours. The mixture was further stirred at 40 ° C. for 1 hour, and the precipitated crystals were collected by filtration. The crystals were washed twice with water (1 mL), twice with methanol (1 mL), and dried under reduced pressure to give the title compound (313.3 mg, yield 71.6%).
¹ H-NMR (DMSO-d6) δ: 2.89 (6H, s), 3.19 (3H, s), 3.31 (3H, s), 5.29 (1H, d, J = 2.5 Hz), 10.86 (1H, brs) .

Comparative Example 1
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H)- Production of dione

5% Palladium carbon (20 mg) and dimethyl sulfoxide (0.9 mL) were added to a solution of the compound obtained in Example 1-1 (200 mg) in methanol (1.27 mL), and the mixture was stirred at room temperature for 24 hours under a hydrogen stream. Dimethyl sulfoxide (6 mL) was added to the reaction solution, and the catalyst was filtered off. The content of the title compound in the filtrate was analyzed by HPLC, and the yield was calculated to be 24.9%. At the same time, a content analysis of 1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione was conducted and the yield was calculated to be 9.2%.

Example 3-1
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -5- (2-cyanobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine- Production of 2,4 (3H, 5H) -dione

To a suspension of the compound obtained in Example 2-1 (25 mg), (2-cyanophenyl) methanol (35 mg) and 1,1 ′-(azodicarbonyl) dipiperidine (66 mg) in tetrahydrofuran (3 mL) at room temperature. Tri n-butylphosphine (65 μL) was added and stirred for 4 hours. After completion of the reaction, ethyl acetate and water were added for partition extraction. The crude product obtained by distilling off the solvent of the organic layer under reduced pressure was separated and purified by silica gel column chromatography to obtain the title compound (28.5 mg, yield 87%).
¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 1.42-1.50 (1H, m), 1.55-1.74 (3H, m), 2.65 (1H, dd, J = 10.3
, 7.0Hz), 2.77 (2H, m), 3.19 (1H, dd, J = 11.0, 2.5Hz), 3.33 (3H, s), 3.44 (3H, s), 3.74 (1H, m), 4.62 (1H , d, J = 7.6Hz), 5.59 (1H, s), 5.66 (1H, d, J = 16.5Hz), 5.77 (1H, d, J = 16.5Hz), 6.77 (1H, d, J = 7.8Hz) ), 7.32 (1H, dd, J = 7.8, 7.8Hz), 7.45 (1H, ddd, J = 7.8, 7.8, 1.0Hz), 7.65 (1H, dd, J = 7.8, 1.0Hz).

Example 3-2
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2- d] Preparation of pyrimidine-2,4 (3H, 5H) -dione

The compound obtained in Example 2-1 (5.00 kg), (2-chloro-5-fluorophenyl) methanol (2.55 kg) and N, N, N ′, N′-tetramethylazodicarboxamide (3.42 kg) Of n-butylphosphine (4.30 kg) was added dropwise at 20 to 30 ° C. over 1 hour. After stirring for 3 hours, the precipitate was filtered off, and the filtered product was washed with tetrahydrofuran (25.1 kg). The filtrate was concentrated under reduced pressure, 2-propanol (75 kg) was added, and the mixture was further concentrated. 2-Propanol (18.7 kg) was added and the temperature was raised to 45-55 ° C. Water (84.35 kg) was added and stirred for an additional hour. The reaction was cooled to 0-10 ° C. After 10 hours, the precipitated crystals were collected by filtration, and the crystals were cooled to 0 to 10 ° C in a 2-propanol / water (1: 1.5) mixture (10.0 kg) and 2-propanol cooled to 0 to 10 ° C. The title compound (6.05 kg, yield 87.4%) was obtained by washing / n-heptane (1: 3) mixture (10.0 kg) and drying under reduced pressure.
¹ H-NMR (DMSO-d6) δ: 1.25-1.28 (1H, m), 1.33 (9H, s), 1.43-1.49 (1H, m), 1.66-1.74 (2H, m), 2.45 (1H, dd , J = 10.5, 10.0Hz), 2.58-2.63 (1H, m), 2.87-2.90 (1H, m), 3.02-3.06 (1H, m), 3.14 (3H, s), 3.39 (3H, s), 3.41 (1H, m), 5.37 (1H, d, J = 17.3Hz), 5.43 (1H, d, J = 17.3Hz), 6.01 (1H, s), 6.22 (1H, dd, J = 9.2,3.0Hz ), 6.78 (1H, d, J = 8.0Hz), 7.14 (1H, ddd, J = 8.8,8.4,3.0Hz), 7.53 (1H, dd, J = 8.8,5.1Hz).

Comparative Example 2
6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl] -5- (2-chlorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine- Production of 2,4 (3H, 5H) -dione

To a suspension of the compound obtained in Example 2-1 (100 mg) in N, N-dimethylaminoformamide (3 mL), potassium carbonate (73.2 mg) was added and stirred at 50 ° C. for 30 minutes. Thereafter, 2-chlorobenzyl chloride (50 μL) was added, and the mixture was stirred at 50 ° C. for 8 hours. After returning to room temperature, ethyl acetate and water were added to the reaction solution for partition extraction, and the aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, the solvent was distilled off under reduced pressure, and the resulting composition product was separated and purified by silica gel column chromatography to obtain the title compound (47.6 mg, yield 35.8%).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.52-1.58 (2H, m), 1.66-1.68 (2H, m), 2.70-2.81 (3H, m), 3.06-3.09 (1H, m), 3.35 (3H, s), 3.47 (3H, s), 3.78 (1H, s), 5.56 (1H, d, J = 16.8Hz), 5.59 (1H, s), 5.67 (1H, d, J = 16.8Hz), 6.48 (1H, d, J = 7.2Hz), 7.11 (1H, ddd, 7.5, 7.2, 1.4Hz), 7.17 (1H, ddd, J = 7.8, 7.5, 1.7Hz), 7.38 (1H , dd, J = 7.8,1.4Hz).

Example 4
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2, Production of 4 (3H, 5H) -dione

To a suspension of the compound (5.00 kg) obtained in Example 3-2 in 2-propanol (10.0 kg), water (5.0 kg) was added, and concentrated sulfuric acid (1.92 kg) was added dropwise at 60 to 70 ° C. over 1 hour. did. After 5 hours, 20% aqueous sodium hydroxide solution was added to adjust the pH to 13.0. The reaction solution was inoculated at 45 to 55 ° C., and water (20.0 kg) was added. After incubating for 1 hour, water (25.0 kg) was further added, and the mixture was cooled to 5 to 10 ° C. After 1 hour, the precipitated crystals were collected by filtration, and the crystals were cooled to 0 to 0 ° C. in a 2-propanol / water (1: 5) mixture (7.5 kg), water (15.0 kg) and 2-propanol / The mixture was washed with n-heptane (1: 3) (7.5 kg) and dried under reduced pressure to give the title compound (3.79 kg, yield 93.9%).
¹ H-NMR (DMSO-d6) δ: 1.02-1.04 (1H, m), 1.38-1.48 (3H, m), 1.60-1.65 (1H, m), 1.73-1.77 (1H, m), 2.39 (1H , dd, J = 11.2,9.2Hz), 2.59 (1H, dd, J = 11.2,2.4Hz), 2.62-2.68 (1H, m), 2.86-2.89 (1H, m), 3.01 (1H, dd, J = 11.2, 3.6Hz), 3.15 (3H, s), 3.39 (3H, s), 5.43 (2H, s), 5.98 (1H, s), 6.19 (1H, dd, J = 9.5, 3.0Hz), 7.16 (1H, ddd, J = 8.6,8.4,3.0Hz), 7.54 (1H, dd, J = 8.8,5.1Hz).

  By using the production method and intermediate of the present invention, a 6-disubstituted amino-5-benzyl-7-deazaxanthine derivative useful as a drug substance for a therapeutic agent such as diabetes can be efficiently produced in a short process. Can do.

Claims (16)

Formula (4) including the following step (1) and step (2):

(Wherein R ¹ and R ² are the same or different and are each a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, Represents an optionally substituted aryl group, or an optionally substituted heteroaryl group, and R ³ represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, or Represents an optionally substituted heterocyclic group, R ⁴ represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, an _optionally substituted heterocycle; Represents a cyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, or R ³ and R ⁴ are substituted together with the nitrogen atom to which they are attached; May form a 4- to 7-membered cyclic amino group Method of manufacturing and may be) a compound represented by.:
(1) Formula (1):

(Wherein R ¹ and R ² have the same meanings as described above), and the formula (2):

(Wherein R ³ and R ⁴ have the same meanings as described above) and an orthoformate ester are reacted to give the formula (3):

(Wherein R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above),
(2) The compound represented by the formula (3) is reduced using a reducing metal, a reducing metal salt, a mixture of a reducing metal and a reducing metal salt, sodium dithionite, or sodium sulfide, and the formula ( 4) a process for producing the compound represented by The production method according to claim 1, wherein R ¹ and R ² are the same or different and are a hydrogen atom or a C _1-6 alkyl group. R ³ is one to three halogen atoms or C _1-6 alkoxy C _1-6 alkyl group optionally substituted with a group, ^{R 4} is C _1-6 alkyl group (said group, 1 To 3 halogen atoms, a C _1-6 alkyl group, an optionally protected amino group, or an optionally protected hydroxyl group), a C _3-7 cycloalkyl group (including The group may be a halogen atom, a C _1-6 alkyl group, an amino group that may be protected, or an optionally protected hydroxyl group, or a heterocyclic group (the group may be a halogen atom) And optionally substituted with an atom, a C _1-6 alkyl group, a C _1-6 alkoxycarbonyl group, an optionally protected amino group, or an optionally protected hydroxyl group. The manufacturing method as described in. R ³ and R ⁴ together with the nitrogen atom to which they are attached, a 4- to 7-membered cyclic amino group [the group may be substituted with a halogen atom or 1 to 3 halogen atoms A C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, an amino group optionally substituted by 1 or 2 C _1-6 alkyls which are the same or different , an aryl group (said group, halogen atom, 1 to 3 halogen atoms in the optionally substituted C _1-4 alkoxy or 1-3 optionally C _1-4 optionally substituted by halogen atom, Optionally substituted with alkyl.), C _1-6 alkoxycarbonyl group, C _1-6 alkylsulfonyl group, aminocarbonyl group optionally substituted with 1 or 2 identical or different C _1-6 alkyl , replaced with the same or different one or two C _1-6 alkyl Which do may be aminosulfonyl group, protected Also an amino group or may be substituted with may be a hydroxyl group be protected. The manufacturing method of Claim 1 or 2 which forms. R ³ and R ⁴ together with the nitrogen atom to which they are attached are piperidino groups (the group being a halogen atom, a C _1-6 alkyl group, an optionally protected amino group, or a protected The production method according to claim 4, which may be substituted with a good hydroxyl group. Orthoformate is a orthoformate tri (C _1-6 alkyl), A process according to any one of claims 1 to 5.   The production method according to any one of claims 1 to 6, wherein in the step of producing the compound represented by the formula (3) of claim 1, an acid is further added to carry out the reaction. Formula (6):

(Wherein R ¹¹ and R ²¹ are the same or different and may be substituted C _1-6 alkyl group, optionally substituted C _3-7 cycloalkyl group, optionally substituted) Represents an aryl group or an optionally substituted heteroaryl group, and R ³¹ represents a C _1-6 alkyl group (the group may be substituted with a halogen atom or a C _1-6 alkoxy group), A C _3-7 cycloalkyl group (the group may be substituted with a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group), or a heterocyclic group (the group is a halogen atom; , A C _1-6 alkyl group, a C _1-6 alkoxy group, or a C _1-6 alkoxycarbonyl group, which may be substituted, and R ⁴¹ represents a C _1-6 alkyl group (the group is halogen atom, C _1-6 alkoxy group, protected amino group or protected is, Hydroxyl group in optionally substituted.), C _3-7 cycloalkyl (in which the group, halogen atom, C _1-6 alkyl, C _1-6 alkoxy group, protected amino group or protected, A heterocyclic group (which may be a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a protected amino group). Or optionally substituted with a protected hydroxyl group), an aryl group (this group is a halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-6 alkoxycarbonyl group, protected Or a heteroaryl group (the group is a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-6 alkoxy group). Carbonyl group, protected amino group, or protected R ³¹ and R ⁴¹ may be a 4- to 7-membered cyclic amino group together with the nitrogen atom to which they are bonded [the group is a halogen atom , A C _1-6 alkyl group optionally substituted with a halogen atom, a C _1-6 alkoxy group optionally substituted with a halogen atom, a di-C _1-6 alkylamino group, an aryl group (the group is C _1-4 alkoxy which may be substituted with a halogen atom, or C _1-4 alkyl which may be substituted with a halogen atom.), C _1-6 alkoxycarbonyl group, C _{1 -6} alkylsulfonyl group, a di -C _1-6 alkylamino group, di -C _1-6 alkylaminosulfonyl group, protected amino group or may be substituted with a protected hydroxyl group. R ⁵ may be one or more, and each R ⁵ may be independently substituted with a hydrogen atom, a halogen atom, a nitro group, a cyano group, or a halogen atom. A good C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted with a halogen atom, a di-C _1-6 alkylamino group, an aryl group (the group is substituted with a halogen atom or a halogen atom) which may be substituted with a which may C _1-4 alkyl which may be substituted C _1-4 alkoxy or a halogen atom,.), C _1-6 alkoxycarbonyl group, C _1-6 alkylsulfonyl group, It represents a di-C _1-6 alkylaminocarbonyl group, a di-C _1-6 alkylaminosulfonyl group, a protected amino group, or a protected hydroxyl group. In the presence of a phosphine compound and an azo compound, or in the presence of a phosphorane compound,
Formula (4a):

(Wherein R ¹¹ , R ²¹ , R ³¹ , and R ⁴¹ have the same meanings as described above), and the formula (5):

(Wherein R ⁵ has the same meaning as described above). The production method according to claim 8, wherein R ¹¹ and R ²¹ are the same or different and are a C _1-6 alkyl group. R ³¹ is a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms or a C _1-6 alkoxy group, and R ⁴¹ is a C _1-6 alkyl group (the group is 1 -3 halogen atoms, a C _1-6 alkoxy group, a protected amino group, or a protected hydroxyl group, which may be substituted, a C _3-7 cycloalkyl group (the group is a halogen atom, A C _1-6 alkyl group, a C _1-6 alkoxy group, a protected amino group, or a protected hydroxyl group, or a heterocyclic group (the group is a halogen atom, C _{1- The} alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a protected amino group, or a protected hydroxyl group, which may be substituted). Method. R ³¹ and R ⁴¹ , together with the nitrogen atom to which they are attached, are a 4- to 7-membered cyclic amino group [the group may be substituted with a halogen atom or 1 to 3 halogen atoms. A C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, a di-C _1-6 alkylamino group, an aryl group (the group is a halogen atom, 1 to 3 may be optionally substituted C _1-4 alkoxy optionally substituted by halogen atoms or by one to three optionally C _1-4 alkyl optionally substituted by halogen atom,.), C _{1 It} may be substituted with a _-6 alkoxycarbonyl group, a protected amino group, or a protected hydroxyl group. The manufacturing method of Claim 8 or 9 which forms. R ³¹ and R ⁴¹ , together with the nitrogen atom to which they are attached, are substituted with a piperidino group (the group is substituted with a halogen atom, a C _1-6 alkyl group, a protected amino group, or a protected hydroxyl group). 12. The manufacturing method according to claim 11, wherein: R ⁵ is present in one or a plurality, and when there are a plurality of R ^{5 s} , each independently represents a hydrogen atom, a halogen atom, a cyano group, or a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms. Or a production method according to any one of claims 8 to 12, which is a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms. Formula (9):

(Wherein R ⁶ and R ⁷ are the same or different and each represents a C _1-6 alkyl group, and ring A may form a condensed ring with phenyl or a 5-membered or 6-membered heterocycle 4 Represents a membered to 7-membered cyclic amino group, R ⁸ represents an amino group or a hydroxyl group, and R ⁹ represents a hydrogen atom, a halogen atom, or a C _1-6 optionally substituted with 1 to 3 halogen atoms. Represents an alkyl group or a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and R ¹⁰ is one or more, and when there are a plurality of them, each independently represents a halogen atom A cyano group, a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms. Wherein the phosphine compound and In the presence of azo compounds or in the presence of phosphorane compounds,
Formula (7):

(Wherein R ⁶ , R ⁷ and R ⁹ are as defined above, and R ¹¹ represents a protected amino group or a protected hydroxyl group), and a compound represented by formula (8 ):

(Wherein R ¹⁰ has the same meaning as described above); and a production method comprising a step of deprotecting a protected amino group or a protected hydroxyl group.   6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2, A process for producing 4 (3H, 5H) -dione, comprising 6-[(3R) -3- (tert-butoxycarbonyl) aminopiperidine-1 in the presence of a phosphine compound and an azo compound or in the presence of a phosphorane compound. Reacting -yl] -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione with (2-chloro-5-fluorophenyl) methanol; and The manufacturing method including the process of processing the compound obtained by this process with an acid. Formula (10):

(Wherein R ⁶ and R ⁷ are the same or different and each represents a C _1-6 alkyl group, and ring A may form a condensed ring with phenyl or a 5-membered or 6-membered heterocycle 4 Represents a 7-membered cyclic amino group, and R ⁹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or 1 to 3 halogen atoms. in an optionally substituted C _1-6 alkoxy group, R ¹¹ is a compound represented by the representative.) the protected amino group or a protected hydroxyl group.