JP2018002662A - Intermediate useful for synthesizing quinolylpyrrolopyrimidyl fused-ring compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for synthesizing or producing efficiently a quinolylpyrrolopyrimidyl fused-ring compound which has an epidermal growth factor receptor (EGFR)-inhibiting activity.SOLUTION: This invention relates to a compound expressed by formula (1), or its salt. (Ris H, nitro, amino, hydroxy, ether, alkylthio, arylthio, etc.; Ris halogen, a hydroxyl group, quinolyl, etc.; Ris H or a protective group of an amino group; Ris aldehyde or a carboxyl group when n=0, or is halogen or a hydroxyl group when n=1; Ris an amino group or a protective group when a bond part is a single bond, or is oxo, imino, or =NRwhen the bond part is a double bond; and Ris aralkyl, acyl, alkyl sulfonyl, etc.).SELECTED DRAWING: None

Description

  The present invention relates to novel intermediates useful for the preparation of quinolylpyrrolopyrimidyl fused ring compounds.

  Quinolylpyrrolopyrimidyl fused ring compounds have an epidermal growth factor receptor (EGFR) inhibitory action (Patent Document 1).

  Conventionally, methods described in Patent Documents 1 and 2 are known as methods for producing quinolylpyrrolopyrimidyl fused ring compounds.

  A method for synthesizing a pyrrolopyrimidine derivative from diaminoiodopyrimidine has been reported (Non-patent Document 1).

  In the method described in Non-Patent Document 1, it has been reported that pyrrolopyrimidine can be synthesized stepwise from diaminoiodopyrimidine and acetylene via an intermediate, but organic borane which requires expensive and excessive use Use reagents.

International Publication WO2013 / 125709 International Publication No. WO2014 / 129596

Angew. Chem. Int. Ed. , 2000, 39 (14), 2488-2490.

  An object of the present invention is to provide a method for efficiently synthesizing a quinolylpyrrolopyrimidyl fused ring compound.

  As a result of intensive studies to solve the above problems, the present inventor has found that the above problems can be solved by a production method using a novel production intermediate, and has completed the present invention.

  That is, the present invention includes the following aspects.

  [1] Formula (1)

(Where
n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an —OR _a group or a quinolyl group;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
Or a salt thereof.

  [2] Formula (1)

(Where
n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an —OR _a group or a quinolyl group;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
A step of causing an intramolecular cyclization reaction of the compound represented by
Formula (2)

(Where
R ₁ , R ₂ and R ₅ are as described above. ) Or a salt thereof.

[3] including the following steps [I], [II], [III] and [IV],
Formula (1)

(Where
n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an —OR _a group or a quinolyl group;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group when this bond is a single bond, or a hydroxyl group that may have a protecting group, and an oxo group when this bond is a double bond, Imino group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
A method for producing a compound represented by the formula:
[I] Formula (3)

(Where
R ₁ and R ₃ are as defined above;
X is a halogen atom. A process for producing a compound represented by the formula:
[II] Formula (4)
Formula (4)

(Where
n, R ₄ and R ₅ are as described above. Step [III] for producing a compound represented by formula (3) or a salt thereof: A compound represented by formula (3) or (4) or a salt thereof is reacted to form formula (5)

(Where
n, R ₁ , R ₃ , R ₄ and R ₅ are as described above. And [IV] a step of causing an intramolecular cyclization reaction of the compound represented by the formula (5) or a salt thereof.

  [4] [i] Formula (1a)

(Where
n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ ′ is a hydrogen atom;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
Or a salt thereof as a starting compound,
(A) performing an intramolecular cyclization reaction;
(B) performing the step of substituting the hydrogen atom of R ₂ ′ with a quinolyl group in any order;
Formula (6)

(Where
R ₁ and R ₅ are as described above. A step of producing a compound represented by
[Ii] A compound represented by the formula (6) or a salt thereof, an amino group optionally having a protecting group represented by R ₅ , a hydroxyl group optionally having a protecting group, a carbonyl group, an imino group, or = A step of converting the NR _b group into an amino group, and [iii] a step of amidating the compound or a salt thereof deprotected in the above step [ii].

The manufacturing method of the quinolyl pyrrolopyrimidyl condensed ring compound or its salt represented by these.

The present invention also includes the following aspects.
-The manufacturing method of the compound or its salt represented by Formula (1) including following process [III] and [IV]:
[III] Formula (3)

(Where
R ₁ and R ₃ are as defined above;
X is a halogen atom. ) And formula (4)

Is reacted with a compound represented by formula (5):

(Where
n, R ₁ , R ₃ , R ₄ and R ₅ are as described above. And [IV] a step of causing an intramolecular cyclization reaction of the compound represented by the formula (5) or a salt thereof.

  According to the production method of the present invention, a novel and useful intermediate for the production of a quinolylpyrrolopyrimidyl fused ring compound is provided. According to the present invention, a quinolylpyrrolopyrimidyl fused ring compound can be produced more efficiently than conventional methods without using an organic borane reagent that is expensive and requires an excessive amount.

  Hereinafter, embodiments of the present invention will be described. In addition, this invention is not limited to the following embodiment at all.

  The present invention provides a compound represented by the general formula (1) or a salt thereof.

  When the substituent is present, the number is typically 1 to 2.

  In the present specification, “may have a protecting group” means that a protecting group may be introduced to convert the group into a group that does not adversely affect the production method according to the present invention. The protecting group is not particularly limited as long as it can protect the group to be protected, and examples thereof include Protective Groups in Organic Synthesis, T. et al. W. As described in Greene, John Wiley & Sons (1981) and “hydroxyl group which may have a protective group”, “amino group which may have a protective group” and “protective group” which will be described later Examples of the protecting group for “good aziridine ring” may be mentioned.

  The “protecting group” in the “hydroxyl group optionally having a protecting group” and the “protecting group for hydroxyl group” is not particularly limited as long as it can protect the hydroxyl group. For example, trimethylsilyl group, triethylsilyl group, tert-butyldimethyl Tri-substituted silyl groups such as silyl group, triisopropylsilyl group, dimethyltexylsilyl group, tert-butyldiphenylsilyl group; triphenylmethyl group, 4-methoxytriphenylmethyl group, 4,4′-dimethoxyphenylmethyl group, etc. It is a triarylmethyl group which may have a substituent.

  The “protecting group” in the “amino group optionally having a protecting group” and the “protecting group for amino group” is not particularly limited as long as it can protect the amino group. For example, the alkoxy which may have a substituent Examples include a carbonyl group, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, and an arylsulfonyl group which may have a substituent, preferably a methoxycarbonyl group and an ethoxycarbonyl group N-propoxycarbonyl group, iso-propoxycarbonyl group, tert-butoxycarbonyl group.

  The “protecting group” of the “aziridine ring optionally having a protecting group” and “protecting group for the aziridine ring” is not particularly limited as long as it can protect the aziridine ring, and may have a substituent, for example. Examples include an alkoxycarbonyl group, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, and an arylsulfonyl group which may have a substituent, preferably a methoxycarbonyl group, ethoxycarbonyl Group, n-propoxycarbonyl group, iso-propoxycarbonyl group, tert-butoxycarbonyl group.

When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group. In this case, examples of the protecting group for R ₄ and R ₅ include a phenylene group and an alkylene group which may have alkoxy.

“R _a” of “—OR _a group” is not particularly limited, and for example, it may have an alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An alkylsilyl group, an alkoxymethyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent , An optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkyl phosphate group, an optionally substituted aryl phosphate group or nitro Groups, etc.
Preferably, methoxymethyl group, tetrahydropyranyl group, trimethylsilylethoxymethyl group, tert-butyldimethylsilyl group, acetyl group, mesyl group, tosyl group, triflate group,
Particularly preferred are tetrahydropyranyl group, tert-butyldimethylsilyl group, mesyl group and triflate group.

“R _b ” of “═NR _b group” is not particularly limited, and may have, for example, an aralkyl group which may have a substituent, an acyl group which may have a substituent, or a substituent. Alkoxycarbonyl group, optionally substituted alkylsilyl group, optionally substituted alkylsulfonyl group, optionally substituted arylsulfonyl group, optionally substituted sulfonamide Group, an alkylamino group which may have a substituent, and an arylamino group which may have a substituent, preferably tert-butoxycarbonyl group, benzyloxycarbonyl group, methanesulfonamide group, p-toluene A sulfonamide group, a methylamino group, a phenylamino group,
Particularly preferred are a tert-butoxycarbonyl group, a benzyloxycarbonyl group, and a p-toluenesulfonamide group.

  In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  In the present specification, examples of the “alkylthio group” include a sulfide group to which a C1-C4 alkyl group which may be either linear or branched is bonded. Examples of the C1-C4 alkylthio group include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a tert-butylthio group, and preferably a methylthio group or an ethylthio group. is there.

  In the present specification, examples of the “arylthio group” include a sulfide group to which a C6-C12 aryl group is bonded, and a phenylthio group and a naphthylthio group are preferable.

  In the present specification, examples of the “alkylsulfonyl group” include a sulfonyl group to which a linear or branched C1-C4 alkyl group is bonded. Examples include mesyl group, triflate group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, etc., preferably mesyl group, ethylsulfonyl group It is.

  In the present specification, examples of the “arylsulfonyl group” include a sulfonyl group to which a C6-C12 aryl group which may have an alkyl group is bonded. Examples of the C6-C12 arylsulfonyl group include a tosyl group, a phenylsulfonyl group, and a naphthylsulfonyl group, and a mesyl group, a tosyl group, and a triflate group are preferable.

  In the present specification, the “sulfonamido group” refers to a group formed together with the nitrogen atom to which the alkylsulfonyl group and the arylsulfonyl group are bonded.

  In the present specification, the “alkoxycarbonyl group” refers to a carbonyl group to which an alkoxy group described below is bonded, and includes a C2-C7 alkoxycarbonyl group which may be either linear or branched. Examples of the C2-C7 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, and a hexyloxycarbonyl group. Preferably, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, etc. are mentioned.

  In the present specification, examples of the “alkoxy group” include a C1-C6 alkoxy group which may be linear or branched. Examples of the C1-C6 alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group. Preferably, a methoxy group, an ethoxy group, etc. are mentioned.

  In the present specification, the “acyl group” may be either a linear or branched C1-C6 alkylcarbonyl group (acyl group to which a C1-C6 alkyl group is bonded), and a C6-C14 arylcarbonyl group. (Acyl group to which a C6-C14 aryl group is bonded). Examples of the C1-C6 alkylcarbonyl group include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a tert-butylcarbonyl group, an n-pentylcarbonyl group, An isopentylcarbonyl group, a hexylcarbonyl group, etc. are mentioned. C6-C13 arylcarbonyl group includes phenylcarbonyl group, naphthylcarbonyl group, fluorenylcarbonyl group, anthrylcarbonyl group, biphenylylcarbonyl group, tetrahydronaphthylcarbonyl group, chromanylcarbonyl group, 2,3-dihydro-1 , 4-dioxanaphthalenylcarbonyl group, indanylcarbonyl group, phenanthrylcarbonyl group and the like, preferably methylcarbonyl group, tert-butylcarbonyl group, phenylcarbonyl group and the like.

  In the present specification, examples of the “alkyl group” include a C1-C6 alkyl group which may be linear or branched. The C1-C6 alkyl group is, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n- unless otherwise defined. A pentyl group, an isopentyl group, a hexyl group, etc. are mentioned, Preferably, a methyl group, an ethyl group, a tert-butyl group etc. are mentioned.

  In the present specification, the “aryl group” is a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (“C6-C14 aromatic hydrocarbon group”), Cyclic or bicyclic. Examples of the C6-C14 aromatic hydrocarbon group include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a fluorenyl group, a tetrahydronaphthyl group, and the like, and preferably a phenyl group, a naphthyl group, and the like.

  In the present specification, the “alkylsilyl group” refers to a silyl group in which 1 to 3 identical or different alkyl groups are bonded. Preferably it is a silyl group to which 2 to 3 identical or different alkyl groups are bonded, more preferably a silyl group to which 3 identical or different alkyl groups are bonded. For example, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a tert-butyldimethylsilyl group, a di-tert-butylmethylsilyl group, and the like are preferable, and a triethylsilyl group, a triisopropylsilyl group, and a tert-butyl group are preferable. Examples thereof include a dimethylsilyl group.

  In the present specification, the “alkoxymethyl group” refers to a methyl group to which the alkoxy group is bonded, and examples thereof include a C2-C7 alkoxymethyl group which may be linear or branched. Examples of the C2-C7 alkoxymethyl group include a methoxymethyl group, a 2-methoxyethoxymethyl group, a trimethylsilylethoxymethyl group, and a benzyloxymethyl group, and preferably a methoxymethyl group and a benzyloxymethyl group.

  In the present specification, a “saturated heterocyclic group” is a 4- to 10-membered monocyclic or polycyclic ring having 1 to 4 oxygen atoms, nitrogen atoms, or sulfur atoms, unless otherwise defined. A partially saturated or saturated heterocyclic group (“4 to 10-membered saturated heterocyclic group”) of the formula is shown. Examples of the saturated heterocyclic group include a pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperazinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, and the like. Examples thereof include an oxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group, and an oxetanyl group, preferably a tetrahydrofuranyl group and a tetrahydropyranyl group. Preferably, it is monocyclic or bicyclic.

  In the present specification, examples of the “aralkyl group” include a C7-C13 aralkyl group. Examples of the C7-C13 aralkyl group include benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, phenethyl group, naphthylmethyl group, fluorenylmethyl group. Preferably, a benzyl group, p-methoxybenzyl group, etc. are mentioned.

  In the present specification, the “alkyl phosphate group” refers to a phosphate group in which 1 to 2, preferably 2 alkyl groups are bonded. For example, dimethyl phosphate group, diethyl phosphate group, di-n-propyl phosphate group, di-iso-propyl phosphate group, di-n-butyl phosphate group, di-iso-butyl phosphate group, di-tert-butyl phosphate group, etc. Preferably, a dimethyl phosphate group, a diethyl phosphate group, etc. are mentioned.

  In the present specification, the “aryl phosphate group” refers to a phosphate group in which 1 to 2, preferably 2 aryl groups are bonded. For example, a diphenyl phosphate group etc. are mentioned.

  In the present specification, “alkylamino group” refers to a group in which one or two hydrogen atoms of an amino group are substituted with the above alkyl group (“monoalkylamino group” and “dialkylamino group”, respectively). For example, a C1-C12 alkylamino group is mentioned. The C1-C12 alkylamino group refers to a group in which one or two hydrogen atoms of the amino group are substituted with the C1-C6 alkyl group.

  In the present specification, the “arylamino group” refers to a group in which one or two hydrogen atoms of the amino group are substituted with the above aryl group (“monoarylamino group” or “diarylamino group”, respectively). For example, a C6-C24 arylamino group is mentioned. The C6-C28 alkylamino group refers to a group in which one or two hydrogen atoms of the amino group are substituted with the C6-C14 aryl group.

  In the present specification, examples of the “alkylene group” include a C1-C4 alkylene group. For example, a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutylene group and the like can be mentioned.

  In the present specification, examples of the “leaving group” include a halogen atom, a sulfonic acid ester group that may have a substituent, a phosphoric acid ester group that may have a substituent, and a nitrate ester group. It is done.

  In the present specification, the “sulfonic acid ester group” refers to a group formed with an oxygen atom to which the alkylsulfonyl group or arylsulfonyl group is bonded.

  In the present specification, the “phosphate ester group” refers to a group formed with an oxygen atom to which the alkyl phosphate group is bonded.

  In the present specification, when “may have a substituent”, unless otherwise specified, the number of substituents, the position of substitution, and the type of substituent are the same as those in which the hydrogen atom of the target group is substituted. There is no particular limitation as long as it is possible. Examples thereof include a halogen atom, a hydroxyl group, a cyano group, a nitro group, and an amino group. The number of substituents is typically 1 to 2.

  Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond. Specifically, when R ₅ is an amino group that may have a protecting group, a hydroxyl group that may have a protecting group, or a carbonyl group, the bond indicated by a double line consisting of a broken line and a solid line is a single bond. It is a bond. When R ₅ is an imino group or a ═NR _b group, a bond part indicated by a double line composed of a broken line and a solid line is a double bond.

In the compound represented by the general formula (1), when n = 1 and R ₄ is a leaving group, the compound can be represented by the following general formula (1x).

(Where
R ₁ , R ₂ , R ₃ and R ₅ are as described above. L ₁ is a leaving group. )

In the compound represented by the general formula (1), n = 0, and R ₄ and R ₅ together with the carbon atom to which they are bonded form an oxirane ring or an aziridine ring which may have a protecting group When it does, it can represent with the following general formula (1y).

(Where
R ₁ , R ₂ and R ₃ are as described above. R ₇ is an oxygen atom, NH or NR ₈ . R ₈ is a protecting group for the aziridine ring. )

The case where R ₇ is an oxygen atom corresponds to the case where n = 0 in the general formula (1), and R ₄ and R ₅ form an ethylene oxide group with the carbon atom to which they are bonded. When R ₇ is NH or NR ₈ , n = 0 in the general formula (1), and R ₄ and R ₅ are each an aziridine ring which may have a carbon atom to which they are bonded and a protecting group. This corresponds to the formation.

  When the compound represented by the general formula (1) obtained by the method of the present invention has an isomer such as an optical isomer, a stereoisomer, a rotational isomer, a tautomer, etc., unless otherwise specified. Both isomers and mixtures are encompassed by the compound. For example, when an optical isomer exists in the compound represented by the general formula (1), unless otherwise specified, an optical isomer resolved from a racemate is also included in the compound of the present invention. Each of these isomers can be obtained as a single compound by synthetic methods and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).

  When an optical isomer is present in the compound represented by the general formula (1), as described above, unless otherwise specified, the compound represented by the general formula (1) includes each enantiomer and a mixture thereof. Any of these are included. The compound represented by the general formula (1) is a mixture of R-form and S-form, and the R-form is 90% or more, 95% or more, 99% or more, S-form. May be 90% or more, 95% or more, 99% or more.

  As an optical resolution method, for example, an optical resolution agent is allowed to act on the compound represented by the general formula (1) to form a salt, and one enantiomer is resolved by utilizing the solubility difference of the obtained salt. A diastereomeric method; a preferential crystallization method in which one enantiomer is added as a crystal seed to a racemic supersaturated solution; a column chromatography such as HPLC using a chiral column; Examples of the optical resolving agent that can be used in the diastereomer method include acidic resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid, and derivatives thereof; alkaloid compounds such as brucine, strychnine, and quinine , An amino acid derivative, cinchonidine, α-methylbenzylamine, and other basic resolving agents. Moreover, after obtaining the compound represented by the general formula (1) as a mixture of enantiomers, not only the method of optical resolution as described above, but also as a synthesis raw material of the compound represented by the general formula (1) Also, only one of the enantiomers of the compound represented by the general formula (1) can be obtained by using only one of the enantiomers optically resolved by the above method or the like. In addition, as a method of obtaining one of the enantiomers as the compound represented by the general formula (1) or a raw material compound thereof, one of the enantiomers is adjusted by adjusting reaction conditions such as a catalyst in a reaction step in which an asymmetric carbon is generated. A method for preferentially obtaining is also mentioned.

The compound of the present invention or a salt thereof may be in the form of a crystal, and it is included in the compound of the present invention or a salt thereof regardless of whether the crystal form is single or polymorphic. The crystal can be produced by crystallization by applying a crystallization method known per se. The compound of the present invention or a salt thereof may be a solvate (such as a hydrate) or a non-solvate, and both are included in the compound of the present invention or a salt thereof. Compounds labeled with isotopes ( ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like are also included in the compounds of the present invention or salts thereof.

  In the present specification, a salt of a compound means a conventional salt used in the field of organic chemistry. For example, when it has a carboxyl group, a base addition salt or an amino group or a basic heterocyclic group in the carboxyl group. Examples thereof include salts of acid addition salts in the amino group or basic heterocyclic group.

  Base addition salts include alkali metal salts such as sodium and potassium; for example, alkaline earth metal salts such as calcium and magnesium; for example, ammonium salts; for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, And organic amine salts such as N, N′-dibenzylethylenediamine.

  Acid addition salts include inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid; organic acids such as acetic acid, formic acid, maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid and trifluoroacetic acid Salts; for example, sulfonic acid salts such as methanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

  Next, the manufacturing method of the compound represented by the said General formula (1) based on this invention or its salt is demonstrated. The present invention also provides a method for producing the compound represented by the general formula (1) or a salt thereof. However, the method for producing the compound represented by the general formula (1) is not limited thereto.

  The manufacturing method of the compound or its salt represented by the said General formula (1) based on this invention includes process [I], [II], [III], and [IV] shown below. That is,

Process [I]
General formula (3)

(Where
R ₁ and R ₃ are as defined above;
X is a halogen atom. A process for producing a compound represented by the formula:

Process [II]
General formula (4)

(Where
n, R ₄ and R ₅ are as defined above;

Indicates that this bond is a single bond or a double bond. A process for producing a compound represented by the formula:

Step [III]
By reacting the compounds represented by the general formulas (3) and (4) or a salt thereof, the general formula (5)

(Where
n, R ₁ , R ₃ , R ₄ and R ₅ are as described above. And a step of producing a compound represented by:

Process [IV]
In this step, an intramolecular cyclization reaction of the compound represented by the general formula (5) or a salt thereof is performed.

  The process [I] is as follows, for example.

(Wherein R ₁ , R ₃ and X are as defined above.)
This step is a step for producing a compound represented by the general formula (3) or a salt thereof by allowing an acylating agent to act on the compound represented by the general formula (3a) or a salt thereof in the presence of a base. Can do.

  Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine , Collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium Hexamethyldisilazide, butyllithium, etc. can be used. As a usage-amount of a base, 2-10 mol can be used with respect to 1 mol of compounds represented by General formula (3a), Preferably 2-5 mol can be used.

  Examples of acylating agents include alkyl haloformates such as methyl chloroformate, ethyl chloroformate, and propyl chloroformate; dialkyl carbonates such as dimethyl carbonate, diethyl carbonate, and dipropyl carbonate; dibenzyl dicarbonate, di-tert-butyl dicarbonate, etc. it can. The amount of the acylating agent to be used can be 2 to 10 mol, preferably 2 to 5 mol, per 1 mol of the compound represented by the general formula (X). The reaction time is 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is −78 ° C. to the boiling temperature of the solvent, preferably −40 ° C. to 60 ° C. Examples of the solvent include single or mixed solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide and the like.

When R _{3 of the} compound represented by the general formula (3) is an amino group protected with an alkoxycarbonyl group, the alkoxy of the alkoxycarbonyl group can be exchanged with a corresponding alcohol.

  The process [II] is, for example, as follows.

(In the formula, n, R ₄ and R ₅ are as described above. R ₆ is an alkylsilyl group.)

In this step, a compound represented by the general formula (4c) is produced by adding a compound represented by the general formula (4b) obtained by allowing a base to act on the compound represented by the general formula (4a), and then a hydroxyl group. Can be converted to R ₅ to produce a compound represented by the general formula (4).

R _{6 in the} general formula (4b) is an alkylsilyl group, and as the base to be acted on, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, methyllithium, butyl Lithium or the like can be used. The compound represented by the general formula (4b) can be used in an amount of 0.1 to 10 mol, preferably 0.8 to 2 mol, with respect to 1 mol of the compound represented by the general formula (4a). Can do. As a usage-amount of a base, 1-10 mol can be used with respect to 1 mol of compounds represented by General formula (4b), Preferably 1-3 mol can be used. The reaction time is 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is -78 ° C to the boiling temperature of the solvent, preferably -78 ° C to 0 ° C. Examples of the solvent include single or mixed tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 1,2-dimethoxyethane, and the like.

R ₅ is as described above, and can be converted by a generally known method such as protection of a known hydroxyl group, oxidation, Mitsunobu reaction, or the like.

  The protection, oxidation, and elimination of the hydroxyl group can be carried out, for example, by converting the hydroxyl group into a leaving group and then reacting with a base in a solvent that does not adversely influence the reaction.

  The Mitsunobu reaction in this step can be carried out in accordance with a method described in a generally known method (for example, Synthesis, p. 1, 1981), and for example, adversely affects the reaction in the presence of an azodicarboxylic acid ester and a phosphine compound. In a solvent that does not affect

  As the azodicarboxylic acid ester, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, etc., preferably diisopropyl azodicarboxylate is used. As usage-amount of azodicarboxylic acid ester, 1-10 mol can be used with respect to 1 mol of compounds represented by the said general formula (X3), Preferably 1-5 mol can be used.

  As the phosphine compound, trialkylphosphine such as triphenylphosphine, tributylphosphine, tricyclohexylphosphine, or the like is used. As a usage-amount of a phosphine compound, 1-10 mol can be used with respect to 1 mol of compounds represented by general formula (X3), Preferably 1-5 mol can be used.

  As the solvent, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl Pyrrolidin-2-one or the like can be used alone or in combination. The reaction time is 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is -78 ° C to the boiling temperature of the solvent, preferably -20 ° C to 60 ° C.

  The compound represented by the general formula (4) thus obtained can be isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.). .

  The process [III] is, for example, as follows.

(In the formula, n, R ₁ , R ₃ , R ₄ , and R ₅ are each as described above. X is a halogen atom.)

  This step is represented by the general formula (5) by reacting the compound represented by the general formula (3) or a salt thereof with the compound represented by the general formula (4) or a salt thereof through a coupling Sonogashira reaction. It can be set as the process of manufacturing the compound. This step can be carried out according to a generally known method (for example, Chemical Reviews, Vol. 107, p. 874, 2007), for example, in a solvent that does not adversely influence the reaction in the presence of a transition metal catalyst and a base. Can be implemented.

  The compound represented by the general formula (3) or a salt thereof can be produced by the above step [I], or a commercially available product can be used. The compound represented by the general formula (4) or a salt thereof can be produced by the above step [I], or a commercially available product can be used.

  As the halogen atom represented by X, a bromine atom and an iodine atom are preferable.

  In this step, the amount of the compound represented by the general formula (4) can be used in an amount of 1 to 10 mol, preferably 1 to 3 mol relative to 1 mol of the compound represented by the general formula (3). It is.

  The transition metal catalyst that can be used in this step is, for example, a palladium catalyst, and if necessary, a ligand (ligand) is added and a copper reagent is used as a cocatalyst.

  As a palladium catalyst, a zero-valent palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), palladium carbon (0), etc .; Palladium acetate, palladium chloride, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (tri A divalent palladium catalyst such as cyclohexylphosphine) palladium (II) dichloride can be used.

  Examples of the ligand (ligand) include triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, and 6′-dimethoxy. Biphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) ) Biphenyl, 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene and the like.

  Examples of the copper catalyst include copper iodide, copper bromide, and copper acetate.

  The amount of the transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, relative to 1 mol of the compound represented by the general formula (3). is there. The amount of the ligand used is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, relative to 1 mol of the compound represented by the general formula (3). The usage-amount of a cocatalyst is 0.0001-4 mol normally with respect to 1 mol of compounds represented by General formula (3), Preferably it is 0.01-2 mol.

  Moreover, the said reaction can add a base as needed. Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine , Collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium And organic bases such as hexamethyldisilazide and butyllithium. As a usage-amount of a base, 1-100 mol can be used with respect to 1 mol of compounds represented by General formula (3), Preferably it is 1-20 mol.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 1,4-dioxane, N, N-dimethyl Formamide, dimethylacetamide, N-methylpyrrolidin-2-one, acetonitrile, tert-butanol, 1-propanol, 2-propanol, ethanol, methanol and the like can be used singly or in combination. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 60 ° C.

  The compound represented by the general formula (5) thus obtained can be isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.) or simple. It can be subjected to the next step without separation and purification.

  The step [IV] is, for example, as follows.

(In the formula, n, R ₁ , R ₃ , R ₄ , and R ₅ are each as described above. R ₂ ′ is a hydrogen atom.)

  In this step, the compound represented by the general formula (5) or a salt thereof is subjected to an intramolecular cyclization reaction to produce the compound represented by the general formula (1a) or a salt thereof. This step can be performed according to a method described in a generally known method (for example, Angew. Chem. Int. Ed., 2000, 39 (14), 2488-2490.). For example, in the presence of a base, The reaction can be carried out in a solvent that does not adversely influence the reaction. Examples of the solvent include tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tert-butanol, 1-propanol, and 2-propanol. , Ethanol, methanol, or the like.

  As the base, those described above can be used. As a usage-amount of a base, 1-100 mol can be used with respect to 1 mol of compounds represented by General formula (5), Preferably it is 1-20 mol.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and N-methylpyrrolidone or the like can be used. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is −78 ° C. to the boiling temperature of the solvent, preferably 0 to 40 ° C.

  The compound represented by the general formula (1a) thus obtained can be isolated and purified by a known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.) or simple. It can be subjected to the next step without separation and purification.

The compound represented by the general formula (1a) corresponds to a compound in which R ₂ is a hydrogen atom in the general formula (1). On the other hand, when R ₂ is a functional group R ₂ ″ other than a hydrogen atom, the compound represented by the general formula (1) can be produced in the next step [V].

  Process [V]

(In the formula, n, R ₁ , R ₂ ′, R ₃ , R ₄ , and R ₅ are each as defined above; R ₂ ″ represents a halogen atom, a hydroxyl group, an —OR _a group, and a quinolyl group.)

This step is a step of producing a compound represented by the general formula (1b) or a salt thereof by introducing R ₂ ″ into the compound represented by the general formula (1a) or a salt thereof. The compound represented by these corresponds to a compound in which R ₂ in the general formula (1) is a halogen atom, a hydroxyl group, an —OR _a group, or a quinolyl group.

This step can be performed according to a generally known method according to R ₂ ″.

For example, when R ₂ ″ is halogen, the halogenation can be produced by a generally known method (for example, a method described in International Publication WO2006 / 102079). For example, the reaction is adversely affected. For example, a halogenating agent is allowed to act on the compound represented by the general formula (1a) or a salt thereof in a non-solvent.

  As the halogenating agent, for example, bromine, iodine, N-bromosuccinimide, and N-iodosuccinimide can be used. The usage-amount of a halogenating agent can be used 0.5-2.0 mol with respect to 1 mol of compounds represented by General formula (1a), Preferably it is 0.9-1.2 mol.

  As the solvent, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, tert-butanol, methanol, ethanol or the like can be used singly or in combination. The reaction temperature is −78 ° C. to the boiling temperature of the solvent, preferably −20 to 10 ° C.

For example, when R ₂ ″ is a hydroxyl group or an OR _a group, it can be carried out in accordance with a generally known method (for example, Organic Reactions (Hoboken, NJ, United States), Vol: 35 (1988)).

For example, when R ₂ ″ is a quinolyl group, R ₂ ′ is a halogen atom (for example, bromine or iodine) or an alkylsulfonyl group which may have a substituent from the compound represented by the general formula (1a) or a salt thereof. , An arylsulfonyl group which may have a substituent, or a leaving group such as a phosphate group, and then using 3-quinolineboronic acid or 3-quinolineboronic acid ester, a generally known method (for example, Chemical Reviews, Vol. 95, p. 2457, 1995) In these cases, the reaction can be carried out in the presence of a transition metal catalyst and a base in a solvent that does not adversely influence the reaction.

  As the transition metal catalyst, for example, a palladium catalyst is used by adding a ligand (ligand) as necessary.

  Examples of palladium catalysts include zero-valent palladium such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), palladium carbon (0), etc. Catalyst; palladium acetate, palladium chloride, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis A divalent palladium catalyst such as (tricyclohexylphosphine) palladium (II) dichloride can be used.

  Examples of the ligand (ligand) include triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 6 ′. -Dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N- Dimethylamino) biphenyl, 4,5′-bis (diphenylphosphino) -9, 9′-dimethylxanthene and the like.

The amount of boronic acid or boronic acid ester corresponding to R ₂ can be used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the compound represented by the general formula (1a). . The amount of the transition metal catalyst used varies depending on the type of the catalyst, but is usually 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, relative to 1 mol of the compound represented by the general formula (1a). is there. The amount of the ligand used is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound represented by the general formula (1a).

  Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine , Collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium Examples include organic bases such as hexamethyldisilazide and butyllithium. The amount of the base used can be 1 to 100 mol, preferably 1 mol per 1 mol of the compound represented by the general formula (1a). 1 20 mol.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N- Dimethylacetamide, N-methylpyrrolidin-2-one, acetonitrile, tert-butanol, 1-propanol, 2-propanol, ethanol, methanol, water and the like can be used singly or in combination. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 25 ° C to the boiling temperature of the solvent, preferably 40 to 100 ° C.

In addition, when R ₂ ′ of the general formula (1a) is directly converted into a quinolyl group, a 3-quinoline halide is used and a generally known method (eg, ACS Catal. 2012, 2, 1033, Journal of American Chemical Society, 2008). , 130, 8172).

Also, when the R _4, R ₅ is a protective group, in a conventional known manner, it is possible to perform deprotection.

  The compound represented by the general formula (1) thus obtained can be isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.). it can. Moreover, when using the compound represented by the said General formula (1) or its salt as a manufacturing intermediate body, it can attach to the next process, without isolating and purifying.

  The compound represented by the general formula (1) or a salt thereof according to the present invention can be deprotected, further introduced with a side chain, or converted into a functional group, and can be used as a production intermediate for pharmaceuticals and the like. For example, the general formula (2), which itself is a pharmaceutical intermediate

(Wherein R ₁ , R ₂ and R ₅ are as described above.)
It can use for manufacture of the compound represented by these, or its salt. The present invention also provides a method for producing the compound represented by the general formula (2) or a salt thereof.

  That is, the production of the compound represented by the general formula (2) or a salt thereof according to the present invention includes a step of causing an intramolecular cyclization reaction of the compound represented by the general formula (1) or a salt thereof.

(In the formula, n, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above.)

  Prior to the intramolecular cyclization reaction, the general formula (1c)

(Wherein R ₁ , R ₂ and R ₅ are as described above.)
The compound represented by these corresponds to a compound in which R ₃ is a hydrogen atom and R ₄ is a hydroxyl group in the general formula (1).

Prior to the intramolecular cyclization reaction, the compound represented by the general formula (1) is a compound represented by the general formula (1x), and NR ₃ is an amino group protected by a protecting group. The deprotection reaction is carried out,

(Wherein R ₁ , R ₂ , R ₅ and L ₁ are as described above.)
Or a salt thereof can be obtained. The compound represented by the general formula (1d) corresponds to a compound in which n = 1 in the general formula (1), R ₃ is a hydrogen atom, and R ₄ is a leaving group.

Prior to the intramolecular cyclization reaction, the compound represented by the general formula (1) is a compound represented by the general formula (1y), and NR ₃ is an amino group protected by a protecting group. The deprotection reaction is carried out and the general formula (1e)

(Wherein R ₁ , R _{2 and} R ₇ are as described above.)
Or a salt thereof can be obtained. In the compound represented by the general formula (1e), n = 0 in the general formula (1), R ₃ is a hydrogen atom, and R ₄ and R ₅ have an oxirane ring together with a carbon atom to which they are bonded. It corresponds to a compound which forms or forms an aziridine ring which may have a protecting group.

  Examples of the deprotection method include generally known methods such as Protective Groups in Organic Synthesis, T. et al. W. It can be carried out by the method described in Greene, John Wiley & Sons (1981) or a method analogous thereto.

  For example, when a tert-butoxycarbonyl group is used as an amino-protecting group, examples of the deprotecting reagent include hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and the like. The amount of the reagent used is preferably 1 to 100 mol with respect to 1 mol of the compound represented by the general formula (1b).

  The solvent used for the reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water, methanol, ethanol, methylene chloride, chloroform, or a mixed solvent thereof is used. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent.

  For example, when a tert-butyldimethylsilyl group is used as a hydroxyl-protecting group, examples of the deprotecting reagent include tetrabutylammonium fluoride. The amount of the reagent used is preferably 1 to 10 mol with respect to 1 mol of the compound represented by the general formula (1).

  The solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction. For example, ethers (for example, 1,2-dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents (for example, N, N-dimethyl) Formamide, dimethyl sulfoxide, hexamethylphosphorylamide, etc.) or a mixed solvent thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. As reaction temperature, it is 0-80 degreeC, Preferably it is 0-50 degreeC.

  The deprotected compound thus obtained can be isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.) or without isolation and purification. It can be attached to the next step.

  In the intramolecular cyclization reaction, a compound represented by the general formula (1c) or a salt thereof is subjected to an intramolecular cyclization reaction by Mitsunobu reaction to produce a compound represented by the general formula (2) or a salt thereof. Can do. This step in this case can be carried out according to the method described in a generally known method (for example, Synthesis, p. 1, 1981). For example, in the presence of an azodicarboxylic acid ester and a phosphine compound, the reaction is adversely affected. In a solvent that does not affect

  As the azodicarboxylic acid ester, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, etc., preferably diisopropyl azodicarboxylate is used. As usage-amount of azodicarboxylic acid ester, 1-10 mol can be used with respect to 1 mol of compounds represented by the said General formula (1c), Preferably 1-5 mol can be used.

  As the phosphine compound, trialkylphosphine such as triphenylphosphine, tributylphosphine, tricyclohexylphosphine, or the like is used. As a usage-amount of a phosphine compound, 1-10 mol can be used with respect to 1 mol of compounds represented by General formula (1c), Preferably 1-5 mol can be used.

  As the solvent, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidine-2- ON or the like can be used singly or in combination. The reaction time is 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is -78 ° C to the boiling temperature of the solvent, preferably -20 ° C to 60 ° C.

  As another method, the intramolecular cyclization reaction is carried out by reacting the compound represented by the general formula (1d) or a salt thereof with a base in a solvent that does not adversely influence the reaction. Or a salt thereof can be produced. This step in this case can be performed according to a generally known method (for example, the method described in Tetrahedron Letters 1987, 28 (26), 2963-2966).

  Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine , Collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium Organic bases such as hexamethyldisilazide and butyllithium are raised, and the amount of the base used can be 1 to 100 mol, preferably 1 mol per 1 mol of the compound represented by the general formula (1d). 1 20 mol.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethylacetamide, N-methyl Pyrrolidin-2-one, acetonitrile, tert-butanol, 1-propanol, 2-propanol, ethanol, methanol, water and the like can be used singly or in combination. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 25 ° C to the boiling temperature of the solvent, preferably 40 to 100 ° C.

  In addition, the intramolecular cyclization reaction is carried out by subjecting the compound represented by the general formula (1e) or a salt thereof to a generally known method (for example, Journal of The American Chemical Society, 2014, 135 (30), 10890-10893, Journal). of Organic Chemistry, 54 (22), 5324-30, 1989), or a compound represented by the general formula (2) or a salt thereof can be produced.

  The compound represented by the general formula (2) thus obtained can be isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.). .

  Moreover, when using the compound or its salt represented by General formula (2) as a manufacturing intermediate body, it can attach to the next process, without isolating and purifying.

  The compound represented by the general formula (1) or a salt thereof according to the present invention can be deprotected, introduced with a further side chain, or converted into a functional group, and can be used as a production intermediate for pharmaceuticals and the like. . For example, the following general formula (1a) included in the general formula (1)

(In the formula, n, R ₁ , R ₃ , R ₄ , and R ₅ are each as described above. R ₂ ′ is a hydrogen atom. A double line consisting of a broken line and a solid line is a single bond or Indicates a double bond.)
Or a salt thereof represented by the general formula (7) having antitumor activity:

It is useful as an intermediate for producing a quinolylpyrrolopyrimidyl fused ring compound represented by the formula: The present invention also provides a method for producing a quinolylpyrrolopyrimidyl fused ring compound or a salt thereof.

  The manufacturing method of the compound or its salt represented by General formula (7) based on this invention includes process [i]-[iii] shown below.

  Process [i]

(In the formula, n, R ₁ , R ₃ , R ₄ , and R ₅ are each as described above. R ₂ ′ is a hydrogen atom. A double line consisting of a broken line and a solid line is a single bond or Indicates a double bond.)
Or a salt thereof as a starting compound,
(A) performing an intramolecular cyclization reaction;
(B) performing the step of substituting the hydrogen atom of R ₂ ′ with a quinolyl group in any order;
Formula (6)

(Wherein R ₁ and R ₅ are each as defined above),

Step [ii]
In the compound represented by the general formula (6) or a salt thereof, a protected amino group represented by R ₅ , a hydroxyl group optionally having a protecting group, a carbonyl group, an imino group or a ═NR _b group as an amino group Converting, and

Step [iii]
A step of amidating the compound or a salt thereof deprotected in the above step [ii].

Step [i] is a step of producing a compound represented by the formula (6) using the compound represented by the formula (1a) or a salt thereof as a starting compound. In particular,
(A) A step of causing an intramolecular cyclization reaction (b) A step of substituting the hydrogen atom of R ₂ ′ with a quinolyl group is performed in any order.

  Steps (a) and (b) can be performed in any order. Specific examples include a case where the steps (a) and (b) are performed, and a case where the steps (a) and (a) are performed.

  When performing in order of (a)-> (b), process (i) is as follows.

(Wherein R ₁ , R ₂ ′, R ₃ , R ₄ and R ₅ are as described above.)

  When performing in order of (b)-> (a), process (i) is as follows.

(In the formula, R ₁ , R ₂ ′, R ₃ , R ₄ and R ₅ are each as described above. L represents a leaving group.)

Step (b) may be a method performed in one step, or (b ′) a step of substituting a hydrogen atom of R ₂ ′ with a leaving group, and (b ″) a step of substituting the leaving group with a quinolyl group. It may be a method of performing.

Since the step (b ″) is a step of substituting the leaving group substituted in the step (b ″) with a quinolyl group, the step (b ″) is performed after the step (b ′).
C07D 487/14 Steps (a), (b ′), (b ″) can be performed in any order, and as a specific example, in the order of (a) → (b ′) → (b ″) , (B ′) → (a) → (b ″), and (b ′) → (b ″) → (a). Since the step (b ″) is a step of replacing the leaving group substituted in the step (b ′) with a quinolyl group, the step (b ″) is performed after the step (b ′).

  When performing in the order of (a) → (b ′) → (b ″), step (i) is as follows.

(Wherein R ₁ , R ₂ ′, R ₃ , R ₄ , R ₅ are as described above, and L represents a leaving group.)

  When performing in the order of (b ′) → (a) → (b ″), the step (i) is as follows.

(In the formula, R ₁ , R ₂ ′, R ₃ , R ₄ and R ₅ are each as described above. L represents a leaving group.)

  When performing in the order of (b ′) → (b ″) → (a), the step (i) is as follows.

(In the formula, R ₁ , R ₂ ′, R ₃ , R ₄ and R ₅ are each as described above. L represents a leaving group.)

  The step of carrying out the intramolecular cyclization reaction in the steps (a) and (a ′) comprises the step of carrying out the intramolecular cyclization reaction of the compound represented by the above formula (1) or a salt thereof. It can carry out according to the manufacturing method of the compound or its salt represented by these.

Step (b) is a step of converting R ₂ ′ directly into a quinolyl group.
Conversion of the hydrogen atom of R ₂ ′ to a quinolyl group can be carried out by a generally known method (for example, ACS Catal. 2012, 2, 1033, Journal of American Chemical Society, 2008, 130, 8172) using 3-quinoline halide. It can be done according to this.

Step (b ′) is a step of replacing the hydrogen atom of R ₂ ′ with a leaving group.

  When the leaving group is a halogen atom, it can be produced by a generally known halogenation method (for example, a method described in WO 2006/102079 pamphlet). For example, the reaction can be carried out by reacting, for example, a halogenating agent with a compound that substitutes a hydrogen atom for a leaving group in a solvent that does not adversely influence the reaction.

  As the halogenating agent, for example, bromine, iodine, N-bromosuccinimide, and N-iodosuccinimide can be used. The amount of the halogenating agent to be used can be 0.5 to 2.0 mol, preferably 0.9 to 1.2 mol, per 1 mol of the compound that substitutes a hydrogen atom for a leaving group.

  As the solvent, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, tert-butanol, methanol, ethanol or the like can be used singly or in combination. The reaction temperature is −78 ° C. to the boiling temperature of the solvent, preferably −20 to 10 ° C.

  Step (b ″) is a step of replacing the leaving group with a quinolyl group. Substitution of a leaving group to a quinolyl group can be performed using 3-quinolineboronic acid or 3-quinolineboronic acid ester according to a generally known method (for example, Chemical Reviews, Vol. 95, p. 2457, 1995). It can be carried out. In these cases, the reaction can be carried out in the presence of a transition metal catalyst and a base in a solvent that does not adversely influence the reaction.

  As the transition metal catalyst, for example, a palladium catalyst is used by adding a ligand (ligand) as necessary.

  Examples of palladium catalysts include zero-valent palladium such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), palladium carbon (0), etc. Catalyst; palladium acetate, palladium chloride, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis A divalent palladium catalyst such as (tricyclohexylphosphine) palladium (II) dichloride can be used.

  Examples of the ligand (ligand) include triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 6 ′. -Dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N- Dimethylamino) biphenyl, 4,5′-bis (diphenylphosphino) -9, 9′-dimethylxanthene and the like.

  The amount of 3-quinolineboronic acid or 3-quinolineboronic acid ester used can be 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the compound in which the leaving group is substituted with a quinolyl group. is there. The amount of transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, per 1 mol of the compound in which the leaving group is substituted with a quinolyl group. It is. The amount of the ligand used is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound in which the leaving group is substituted with a quinolyl group.

  Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine , Collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium Examples include organic bases such as hexamethyldisilazide and butyllithium. The amount of base used can be 1 to 100 moles per mole of the compound in which the leaving group is substituted with a quinolyl group. Better Is 1 to 20 mol.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N- Dimethylacetamide, N-methylpyrrolidin-2-one, acetonitrile, tert-butanol, 1-propanol, 2-propanol, ethanol, methanol, water and the like can be used singly or in combination. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 25 ° C to the boiling temperature of the solvent, preferably 40 to 100 ° C.

  The compound represented by the general formula (6) thus obtained can be isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.) or simple. The product can be subjected to the next step without separation and purification.

In the step [ii], the compound represented by the general formula (6) or a salt thereof, an amino group that may have a protecting group represented by R ₅ , a hydroxyl group that may have a protecting group, a carbonyl group, This is a step of converting an imino group or ═NR _b group into an amino group.

(Wherein R ₁ and R ₅ are as defined above.)

When R ₅ is an amino group having a protecting group, this step can be carried out according to a generally known method, for example, Protective Groups in Organic Synthesis, T.A. W. It can be carried out by the method described in Greene, John Wiley & Sons (1981) or a method analogous thereto.

  When a tert-butoxycarbonyl group is used as the protecting group, examples of the deprotecting reagent include hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and the like. The amount of the reagent used is preferably 1 to 100 mol with respect to 1 mol of the compound represented by the general formula (1a).

  The solvent used for the reaction is not particularly limited as long as it does not adversely influence the reaction, and water, methanol, ethanol, methylene chloride, chloroform and the like or a mixed solvent thereof is used. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent.

When R ₅ is a hydroxyl group, —OR _a group, carbonyl group, imino group or ═NR _b group, this step is usually a known method, for example, Mitsunobu reaction, the method described in International Publication No. WO2013 / 125709 or the like. It can be done by a method.

When R ₅ is an imino group, the reduction of the imino group in this step can be performed by a generally known method, for example, the method described in Journal of the American Chemical Society, 75, 5898-9; 1953 or a method analogous thereto. .

  The compound represented by the general formula (6a) thus obtained or a salt thereof is isolated and purified by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.). It can be subjected to the next step without isolation or purification.

  Step [iii] includes an amidation reaction between the compound represented by the general formula (6a) or a salt thereof and acrylic acid or acrylic acid chloride or bromide, or 3-hydroxypropionic acid, 3-halopropionic acid, or 3- This is a process for producing a compound represented by the general formula (7) or a salt thereof by amidation reaction with halopropionic acid chloride or bromide and β elimination.

(Wherein R ₁ is as described above.)

  When acrylic acid, 3-hydroxypropionic acid, or 3-halopropionic acid is used as an amidating reagent, carboxylic acid is reduced to 0 with respect to 1 mol of the compound represented by the general formula (6a) in the presence of an appropriate condensing agent. It is carried out using 5 to 10 mol, preferably 1 to 3 mol. In addition, the said carboxylic acid can be manufactured using a commercial item according to a well-known method. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidine 2-one, dimethyl sulfoxide, water and the like, or a mixed solvent thereof and the like are preferable. The reaction temperature is generally −78 to 200 ° C., preferably 0 to 50 ° C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.

  Examples of the condensing agent include diphenyl phosphate azide, N, N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3,5-triazine-2- Yl) -4-methylmorpholinium chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole, 2 -Chloro-1,3-dimethylimidazolinium chloride, O- (7-azabenzotriazo-1-yl) -N, N, N ', N'-tetramethylhexauronium hexafluorophosphate .

  A compound amidated with 3-hydroxypropionic acid can produce a compound represented by the general formula (7a) by a generally known method, for example, activation of a hydroxyl group or induction to a leaving group. .

  As halogen of 3-halopropionic acid, chlorine, bromine or iodine can be used. When a base is allowed to act on the amidated compound, the compound represented by the general formula (7a) can be produced. .

  Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine , Collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium Organic bases such as hexamethyldisilazide and butyllithium are raised, and the amount of the base used can be 1 to 100 mol, preferably 1 mol per 1 mol of the compound represented by the general formula (6a). 1 20 mol.

  When acrylic acid chloride or bromide, or 3-halopropionic acid chloride or bromide is used as the amidating reagent, 0.5 to 5 mol of acid halide is preferably used with respect to 1 mol of the compound represented by formula (6a). Is carried out using 0.9 to 1.1 moles. In addition, the said acid halide can use a commercial item, or can manufacture it according to a well-known method.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidine 2-one, acetonitrile, water or the like, or a mixed solvent thereof is preferable. The reaction temperature is generally −78 to 200 ° C., preferably 0 to 50 ° C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.

Moreover, the said reaction can add a base as needed. Bases include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4- (N, N-dimethylamino) pyridine, potassium-tert-butylate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyl. Organic bases such as disilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, butyllithium or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride Can be mentioned. As addition amount, it is 1-100 mol with respect to 1 mol of compounds represented by General formula (6a), Preferably it is 1-20 mol, More preferably, it is 1-10 mol. When R ₁ is a group R ₁ ′ other than an amino group, R ₁ ′ may be converted to an optionally protected amino group R ₁ ″ at any stage of steps [i] to [iii]. it can. For example, before step [i], before step [ii], before step [iii] or after step [iii]. Moreover, it can also carry out between process (a) of process [i], and (b).

  When performed before process [i], it is as follows, for example.

(Wherein R ₂ ′, R ₃ , R ₄ and R ₅ are as described above. R ₁ ′ is a hydrogen atom, a nitro group, a hydroxyl group, an —OR _a group, or an alkylthio group which may have a substituent. , An arylthio group that may have a substituent, an alkylsulfonyl group that may have a substituent, or an arylsulfonyl group that may have a substituent, and R ₁ ″ has a protecting group It is a good amino group.)

  When it is performed before step [ii], for example, it is as follows.

(In the formula, R ₅ is as described above. R ₁ ′ is a hydrogen atom, a nitro group, a hydroxyl group, an —OR _a group, an alkylthio group which may have a substituent, or an arylthio group which may have a substituent. An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent, and R ₁ ″ is an amino group which may have a protecting group.)

  When it is performed before step [iii], for example, it is as follows.

(In the formula, R ₁ ′ has a hydrogen atom, a nitro group, a hydroxyl group, an —OR _a group, an alkylthio group which may have a substituent, an arylthio group which may have a substituent, or a substituent. An alkylsulfonyl group which may be substituted or an arylsulfonyl group which may have a substituent, and R ₁ ″ is an amino group which may have a protecting group.)

  When it is performed after the step [iii], for example, it is as follows.

(In the formula, R ₁ ′ has a hydrogen atom, a nitro group, a hydroxyl group, an —OR _a group, an alkylthio group which may have a substituent, an arylthio group which may have a substituent, or a substituent. An alkylsulfonyl group which may be substituted or an arylsulfonyl group which may have a substituent, and R ₁ ″ is an amino group which may have a protecting group.)

The step of converting R ₁ ′ to an amino group which may be protected can be carried out by a generally known method, for example, Mitsunobu reaction, the method described in International Publication WO2013 / 125709, or a method analogous thereto.

The thus obtained compound in which R ₁ ′ is converted to an amino group which may be protected is simply separated by known separation and purification means (concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.). It can be separated and purified.

When R ₁ ″ is an amino group having a protecting group, deprotection can be carried out by a generally known method at a stage where the production method of the present invention is not hindered.

  The compound represented by the general formula (7) or a salt thereof thus obtained is a compound having antitumor activity.

  EXAMPLES Hereinafter, although an Example, a comparative example, etc. demonstrate this invention in detail, this invention is not limited to these.

Reference Example A: Synthesis of (S) -tert-butyl (1-hydroxyhex-5-in-2-yl) carbamate

  (Step 1) Synthesis of 2-(((R) -oxiran-2-yl) methoxy) tetrahydro-2H-pyran

  200 g of 3-chloro-1,2-propanediol was dissolved in 2000 mL of dichloromethane, 625 g of potassium carbonate was added, and the mixture was stirred at room temperature for 17.5 hours. The precipitated insoluble matter was filtered, and the filtration residue was washed with 1000 mL of dichloromethane to obtain a solution of (S) -oxiran-2-ylmethanol. To the obtained solution, 198 g of dihydropyran was added and cooled to 0 ° C., then 5.16 g of paratoluenesulfonic acid monohydrate was added at 10 ° C. or less, and the mixture was stirred at room temperature for 1.5 hours. After adding 408 g of 7.5% aqueous sodium hydrogen carbonate solution and stirring, the organic layer and the aqueous layer were separated. The obtained organic layer was concentrated and distilled to give 247.8 g of the title compound as a colorless oil.

(Step 2) Synthesis of Reference Example A Compound 11.6 g of 1- (trimethylsilyl) -1-propyne was dissolved in 136.5 mL of cyclopentyl methyl ether and cooled to -5 ° C. 60.0 mL of hexane solution (1.63 mol / L) of n-butyllithium was added and stirred for 2.5 hours, and then a solution of 9.1 g of cyclopentylmethyl ether in Step 1 compound (36.4 mL) was added and stirred for 3 hours. After adding 91.0 g of 20% aqueous ammonium chloride solution, the temperature was raised to room temperature, and the organic layer and the aqueous layer were separated. By concentrating the organic layer to 78.mL, cyclopentylmethyl of (2R) -1-((tetrahydro-2H-pyran-2-yl) oxy) -6- (trimethylsilyl) hex-5-in-2-ol An ether solution was obtained. After 26 mL of the obtained solution was diluted with 26 mL of THF, 8.6 g of triphenylphosphine and 4.2 g of phthalimide were added and cooled to 0 ° C. After adding a toluene solution (15.6 mL) of 4.9 g of diisopropyl azodicarboxylate, (2R) -1-((tetrahydro-2H-pyran-2-yl) oxy) -6 was stirred at room temperature for 7 hours. A-(trimethylsilyl) hex-5-in-2-ol solution was obtained. To the obtained solution, 22.1 mL of an ethanol solution of methylamine (about 2 mol / L) was added, stirred at 40 ° C. for 14 hours, and then stirred at 0 ° C. for 2 hours. Insoluble matter was filtered off, and the filtration residue was washed with 15.4 mL of toluene, and then the filtrate was concentrated to 46 mL, whereby (2S) -1-((tetrahydro-2H-pyran-2-yl) oxy) -6 A solution of-(trimethylsilyl) hex-5-in-2-amine was obtained. To the obtained solution, 5.8 g of a methanol solution of sodium methoxide (5.0 mol / L) was added and stirred at room temperature for 20 hours to obtain (2S) -1-((tetrahydro-2H-pyran-2-yl) A solution of (oxy) hex-5-in-2-amine was obtained.

  To this solution was added 13.8 mL of 5N hydrochloric acid, and the mixture was stirred at room temperature for 6 hours. After filtering the insoluble matter, the organic layer and the aqueous layer were separated, and the aqueous layer was washed twice with 19.0 mL of toluene to obtain an aqueous solution of (S) -2-aminohex-5-in-1-ol. To this aqueous solution was added 37.9 mL of isopropyl acetate, and then 24.0 mL of 4N aqueous sodium hydroxide solution was added. After adding 4.9 mL of di-tert-butyl dicarbonate and stirring and reacting at room temperature, the organic layer and the aqueous layer were separated.

  After adding 19.0 mL of isopropyl acetate to the aqueous layer and stirring, the organic layer and the aqueous layer were separated. The obtained two organic layers were mixed, washed with 19.0 mL of 10% brine, concentrated to 7.6 mL, added with seed crystals, and stirred for 1 hour. After adding 30.3 mL of n-heptane over 30 minutes and stirring for 4 hours, 30.3 mL of n-heptane was further added over 30 minutes and then stirring for 4 hours. The obtained crystals were filtered, washed with n-heptane / isopropyl acetate (5: 1), and dried at 40 ° C. to give 1.0 g of the title compound as white needle crystals.

¹ H-NMR (DMSO-d) δ: 1.38 (9H, s), 1.35-1.55 (1H, m), 1.63-1.76 (1H, m), 2.03-2.21 (2H, m), 2.74 (1H, t , 2.8 Hz), 3.17-3.25 (1H, m), 3.28-3.36 (1H, m), 3.37-3.48 (1H, m), 4.63 (1H, t, 5.6 hZ9, 6.53 (1H, d, 8.4 Hz) .

Reference Example B: Synthesis of di-tert-butyl (5-iodopyrimidine-4,6-diyl) dicarbamate

  After adding 40 L of tetrahydrofuran to diaminopyrimidine (2.1 kg), 1.8 kg of sodium hydride (60%) was added at 0 ° C. and stirred for 0.5 hours, followed by addition of 7.8 kg of di-tert-butyl dicarbonate for 2 hours. Stir. After adding 80.5 g of water to the reaction solution and stirring overnight at room temperature, 53.4 kg of 1N hydrochloric acid and 47.4 kg of ethyl acetate were added. The organic layer was separated, and washed with 5% aqueous sodium hydrogen carbonate solution and 24% brine. The obtained organic layer was concentrated, and heptane was added for crystallization, followed by filtration and drying to obtain 2.63 kg of the title compound as a pale yellow solid.

¹ H-NMR (DMSO-d) δ: 1.47 (18H, s), 8.56 (1 H, s), 9.57 (1H, s).

Reference Example C: Synthesis of dimethyl (5-iodopyrimidine-4,6-diyl) dicarbamate

  After adding 800 mL of methanol to 100 g of the compound of Reference Example B, the mixture was refluxed overnight. The mixture was cooled to room temperature and crystallized, followed by filtration and drying to obtain 61.5 g of the title compound as a yellow solid.

¹ H-NMR (CDCl3) δ: 3.85 (6H, s), 8.67 (1H, s).
ESI-MS m / z 353 (MH +)

Reference Example D: Synthesis of diethyl (5-iodopyrimidine-4,6-diyl) dicarbamate

  Reference Example B After adding 2.4 L of ethanol to 300 g of the compound, the mixture was refluxed overnight. The mixture was cooled to room temperature and crystallized, followed by filtration and drying to obtain 187.54 g of the title compound as a yellow solid.

¹ H-NMR (CDCl3) δ: 1.35 (6H, t, 7.2 Hz), 4.31 (4 H, q, 7.2 Hz), 8.68 (1H, s).

Reference Example E: Synthesis of dipropyl (5-iodopyrimidine-4,6-diyl) dicarbamate

  Reference Example B 40 mL of 1-propanol was added to 4.00 g of the compound, and then refluxed overnight. The mixture was cooled to room temperature and crystallized, followed by filtration and drying to obtain 3.74 g of the title compound as a yellow solid.

¹ H-NMR (CDCl3) δ: 0.98 (6H, t, J = 7.2 Hz), 1.73 (4H, qt, J = 7.2, 6.8 Hz), 4.20 (4H, t, J = 6.8 Hz), 8.67 (1H , s).
ESI-MS m / z 409.5 (MH +)

Reference Example E2: Synthesis of diisopropyl (5-iodopyrimidine-4,6-diyl) dicarbamate

  Reference Example B 40 mL of 1-isopropanol was added to 4.00 g of the compound, and then refluxed overnight. The mixture was cooled to room temperature and crystallized, and the title compound (2.43 g) was obtained as a yellow solid by filtration and drying.

¹ H-NMR (CDCl3) δ: 1.34 (12H, d, J = 6.0 Hz), 5.09 (2H, septet, J = 6.0 Hz), 8.68 (1H, s).
ESI-MS m / z 409.5 (MH +)

Example A: Synthesis of ( S) -tert-butyl (4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate (step 1) Synthesis of (S) -tert-butyl 4- (4- (4,6-diaminopyrimidin-5-yl) but-3-yn-1-yl) -2,2-dimethyloxazolidine-3-carboxylate

  4,6-diamino-5-iodopyrimidine (7.08 g) and (S) -tert-butyl 4- (but-3-yn-1-yl) -2,2-dimethyloxazolidine-3-carboxylate (5.07 g) with acetonitrile After adding 203 mL and 4.15 g potassium carbonate, the mixture is degassed under reduced pressure. Subsequently, after adding 0.38 g of copper iodide and 1.83 g of tris (dibenzylideneacetone) dipalladium, the mixture was heated to 65 ° C. and stirred for 20 hours. 200 mL of ethyl acetate was added to the residue obtained by concentrating the reaction solution to suspend it, and the mixture was filtered through celite, washed with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography to give 3.68 g of the title compound as a yellow oily component.

  ESI-MS m / z 362 (MH +)

  (Step 2) (S) -tert-butyl 4- (2- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethyl) -2,2-dimethyloxalizine-3- Carboxylate synthesis

  Step 1 To 3.68 g of the compound, 37 mL of N-methylpyrrolidone and 147 mL of tetrahydrofuran were added and dissolved, and then 3.43 g of potassium tert-butoxide was added and heated to 70 ° C. After stirring for 9 hours, the reaction solution was cooled to room temperature, and 35 mL of saturated aqueous ammonium chloride solution, 65 mL of water, and 100 mL of ethyl acetate were added. The organic layer was separated, extracted from the aqueous layer with 100 mL of ethyl acetate, and the combined organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (2.08 g) as a yellow oily component.

¹ H-NMR (CDCl3) δ: 1.37-1.62 (15H, m), 1.75-1.90 (1 H, m), 2.16-2.30 (1H, m), 2.80 (1H, t, 7 Hz), 3.68 (1H , d, 8.8 Hz), 3.94 (1H, dd, 8.8, 5.2 Hz), 4.09 (1H, ddm 11.6, 5.2 Hz), 5.10 (1H, br s), 6.09 (1H, br s), 8.28 (1H, s), 10.74 (1H, br s).

  (Step 3) Synthesis of Example A Compound

  Step 2 0.76 g of the compound was dissolved in 38 mL of ethanol, and then 1.06 g of pyridinium paratoluenesulfonate was added. The reaction was refluxed for 8 hours, then cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (0.52 g) as a white solid.

¹ H-NMR (CDCl3) δ: 1.40 (9H, s), 1.46-1.60 (1 H, m), 1.80-1.95 (1H, m), 2.55- 2.71 (2H, m), 3.25- 3.43 (3H, m), 4.63 (1H, t,), 6.44 (1H, br s), 6.57 (1H, d, 8.0 Hz), 8.01 (1H, s), 11.87 (1H, br s).
ESI-MS m / z 323 (MH +)

Example B: (S) -tert-butyl (4- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate Synthesis of

  Example A After adding 3.35 mL of DME to 335 mg of the compound, 258 mg of N-iodosuccinimide dissolved in 3.35 mL of DME after cooling to 0 ° C. was added. To the reaction solution, 13 mL of ethyl acetate and 13 mL of saturated sodium thiosulfate were added to separate the organic layer, and the aqueous layer was extracted with 13 mL of ethyl acetate, and the combined organic layer was washed with 13 mL of saturated brine. The organic layer was concentrated under reduced pressure to give 428 mg of the title compound.

¹ H-NMR (DMSO-d) δ: 1.40 (9H, s), 1.46-1.60 (1 H, m), 1.80-1.95 (1H, m), 2.55- 2.71 (2H, m), 3.25- 3.43 ( 3H, m), 4.63 (1H, t, 5.4 Hz), 6.17 (1H, br s), 6.58 (1H, d, 8.4 Hz), 6.66 (2H, br s), 7.94 (1H, s), 11.23 ( 1H, br s).
ESI-MS m / z 448.3 (MH +)

Example C: (S) -tert-butyl 4-((tert-butoxycarbonyl) amino) -6- (3-((tert-butoxycarbonyl) amino) -4-hydroxybutyl) -7H-pyrrolo [2, Synthesis of 3-d] pyrimidine-7-carboxylate

  Reference Example A Compound 4.00 g and Reference Example B Compound 8.18 g were added with 160 mL of tert-butyl alcohol and degassed, then 3.91 mL of triethylamine, 357 mg of copper iodide, tris (dibenzylideneacetone) palladium (0) 515 mg Was added. After stirring at 55 ° C. for 36 hours, the mixture was concentrated under reduced pressure to give 16.85 g of the title compound as a brown solid.

ESI-MS m / z 522 (MH +)

Example D: (S) -methyl 6- (3-((tert-butoxycarbonyl) amino) -4-hydroxybutyl) -4-((methoxycarbonyl) amino) -7H-pyrrolo [2,3-d] Synthesis of pyrimidine-7-carboxylate

  After deaeration by adding 20 mL of tert-butyl alcohol to 0.50 g of Reference Example A compound and 0.83 g of Reference Example C compound, 0.49 mL of triethylamine, 45 mg of copper iodide, and tris (dibenzylideneacetone) palladium (0) 64 mg Was added. After stirring at 55 ° C. for 14 hours, the mixture was concentrated under reduced pressure to give 1.71 g of the title compound as a brown solid.

ESI-MS m / z 438 (MH +)

Example E: (S) -Ethyl 6- (3-((tert-butoxycarbonyl) amino) -4-hydroxybutyl) -4-((ethoxycarbonyl) amino) -7H-pyrrolo [2,3-d] Synthesis of pyrimidine-7-carboxylate

  Reference Example C 0.89 g of the compound of Reference Example D was used instead of 0.83 g of the compound, and was treated in the same manner as in Example D to obtain 1.96 g of the title compound as a brown solid.

ESI-MS m / z 466 (MH +)

Example F: (S) -propyl 6- (3-((tert-butoxycarbonyl) amino) -4-hydroxybutyl) -4-((propoxycarbonyl) amino) -7H-pyrrolo [2,3-d] Synthesis of pyrimidine-7-carboxylate

  Reference Example C 0.96 g of the compound of Reference Example E was used instead of 0.83 g of the compound, and was treated in the same manner as in Example D to obtain 1.90 g of the title compound as a brown solid.

ESI-MS m / z 494 (MH +)

Example G: (S) -Iropropyl 6- (3-((tert-butoxycarbonyl) amino) -4-hydroxybutyl) -4-((isopropoxycarbonyl) amino) -7H-pyrrolo [2,3-d Synthesis of pyrimidine-7-carboxylate

  Reference Example C 0.96 g of the compound of Reference Example E2 was used instead of 0.83 g of the compound, and was treated in the same manner as in Example D to obtain 2.62 g of the title compound as a brown solid.

ESI-MS m / z 494 (MH +)

Example H: Synthesis of (S) -tert-butyl (4- (4-amino-7H-pyrrolo [2,3-D] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate

  7.78 g was added. After stirring at 80 ° C. for 24 hours, acetonitrile was removed by concentration under reduced pressure, and 500 mL of tetrahydrofuran and 20% brine were added to separate the organic layer. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.00 g) as a yellow solid.

Example I: Synthesis example of (S) -tert-butyl (4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate After adding 34 mL of acetonitrile and 17 mL of water to 1.71 g of the D compound, 1.85 g of barium hydroxide octahydrate was added. After stirring at 45 ° C. for 4 hours, 1.17 mL of 5 N hydrochloric acid was added. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to give 0.32 g of the title compound as a yellow solid.

Example J: Synthesis example of (S) -tert-butyl (4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate The same procedure as in Example I was carried out using 1.96 g of the compound of Example E instead of 1.71 g of the D compound to obtain 0.43 g of the title compound as a brown solid.

Example K: Synthesis example of (S) -tert-butyl (4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate The same procedure as in Example I was carried out using 1.90 g of the compound of Example F in place of 1.71 g of the D compound to give 0.33 g of the title compound as a brown solid.

Example L: Synthesis example of (S) -tert-butyl (4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -1-hydroxybutan-2-yl) carbamate The same procedure as in Example I was carried out using 2.62 g of the compound of Example G instead of 1.71 g of the D compound to obtain 0.49 g of the title compound as a brown solid.

Reaction Example A: Synthesis of (S) -tert-butyl (4-amino-6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) carbamate

  Example H After adding 4 mL of DME to 200 mg of the compound, 1.63 g of triphenylphosphine and 1.13 g of diisopropyl azodicarboxylate were added. After stirring for 4 hours, 2 mL of methanol was added and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (43.6 mg).

ESI-MS m / z 304 (MH +)

Reaction Example B: Synthesis of (S) -tert-butyl (4-amino-5-iodo-6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) carbamate

  Example B After adding 200 mL of THF to 10.0 g of the compound, 12.9 g of triphenylphosphine and 9.04 g of diisopropyl azodicarboxylate were added. After stirring for 4 hours, methanol (100 mL) was added and the layers were separated and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4.12 g of the title compound.

Reaction example C: Synthesis reaction example of (S) -tert-butyl (4-amino-5-iodo-6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) carbamate After adding 1.87 mL of THF to 44 mg of the A compound, 69 mg of N-iodosuccinimide dissolved in 0.37 mL of THF after cooling to 0 ° C. was added. To the reaction solution, 3 mL of ethyl acetate, 0.5 mL of 20% sodium thiosulfate and 2 mL of 20% brine were added to separate the organic layer, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 54 mg of the title compound.

¹ H-NMR (CDCl3) δ: 1.46 (9H, s), 1.94-2.04 (1 H, m), 2.09-2.19 (1H, m), 2.76-2.95 (2H, m), 3.92 (1H, dd, J = 12.8, 6.8 Hz), 4.71 (1H, br s), 4.38 (1H, dd, J = 12.4, 4.4 Hz), 6.17 (1H, br s), 6.58 (1H, d, 8.4 Hz), 6.66 ( 2H, br s), 5.55 (1H, br s), 8.23 (1H, s).
ESI-MS m / z 430.2 (MH +)

Use example A: (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) Synthesis of acrylamide

  (Step 1) (S) -tert-butyl (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl ) Synthesis of carbamate

  (S) -tert-butyl (4-amino-5-iodo-6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) carbamate 1.00 g was added with 60 mL of DME. Thereafter, 0.48 g of 3-quinolineboronic acid and 0.30 g of sodium carbonate were added. After degassing the reaction solution, 0.13 g of tetrakistriphenylphosphine palladium was added and the mixture was heated to reflux for 14 hours. After cooling the reaction solution, 60 mL of tetrahydrofuran was added, and the organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.87 g of the title compound.

  ESI-MS m / z 430 (MH +)

  (Step 2): Synthesis of (S) -5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizine-4,8-diamine

  According to the method described in the specification of WO2013 / 125709, 5N hydrochloric acid was added to an ethanol solution of the compound obtained in Step 1 at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled, basified with 5N aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol) to obtain the title compound.

  ESI-MS m / z 331 (MH +)

(Step 3) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) Synthesis of Acrylamide Step 2 A mixture of acetonitrile and water was added to 10.4 g of the compound, and then diisopropylethylamine and 3-chloropropionyl chloride were added. Subsequently, an aqueous sodium hydroxide solution was added, and a solid was precipitated by adding water to obtain 10.3 g of the title compound.

  ESI-MS m / z 385 (MH +)

Claims (4)

Formula (1)

(Wherein n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an —OR _a group or a quinolyl group;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
Or a salt thereof. Formula (1)

(Wherein n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an —OR _a group or a quinolyl group;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Alternatively, when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an aziridine ring that may have an oxirane or protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
A step of causing an intramolecular cyclization reaction of the compound represented by
Formula (2)

(Wherein R ₁ , R ₂ and R ₅ are as described above), or a method for producing a salt thereof. Including the following steps [I], [II], [III] and [IV],
Formula (1)

(Wherein n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an —OR _a group or a quinolyl group;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
A method for producing a compound represented by the formula:
[I] Formula (3)

(Wherein R ₁ and R ₃ are each as defined above;
X is a halogen atom. A process for producing a compound represented by the formula:
[II] Formula (4)
Formula (4)

(Wherein n, R ₄ and R ₅ are each as defined above) Step [III] for producing a compound represented by the formula (3) and (4) or a salt thereof Reaction is carried out to obtain the formula (5)

(Wherein n, R ₁ , R ₃ , R ₄ and R ₅ are as defined above), and [IV] a compound represented by the formula (5) or A step of causing an intramolecular cyclization reaction of the salt. [I] Formula (1a)

(Wherein n is an integer of 0 or 1;
R ₁ is a hydrogen atom, a nitro group, an amino group that may have a protecting group, a hydroxyl group, an —OR _a group, an alkylthio group that may have a substituent, an arylthio group that may have a substituent, An alkylsulfonyl group which may have a substituent or an arylsulfonyl group which may have a substituent;
R ₂ ′ is a hydrogen atom;
R ₃ is a hydrogen atom or an amino-protecting group;
R ₄ is
When n = 0, it is an aldehyde group or a carboxyl group,
when n = 1, a halogen atom or a hydroxyl group which may have a protecting group;
Double line consisting of broken line and solid line

Indicates that this bond is a single bond or a double bond;
R ₅ is an amino group that may have a protecting group or a hydroxyl group that may have a protecting group when this bond is a single bond, and an oxo group, imino when this bond is a double bond Group or = NR _b group,
When R ₄ is a hydroxyl group having a protecting group and R ₅ is an amino group having a protecting group or a hydroxyl group having a protecting group, R ₄ and R ₅ may be protected by a single protecting group;
Or when n = 0, R ₄ and R ₅ together with the carbon atom to which they are attached form an oxirane ring or an aziridine ring which may have a protecting group;
R _a is an alkyl group that may have a substituent, an aryl group that may have a substituent, an alkylsilyl group that may have a substituent, an alkoxymethyl group that may have a substituent, A saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkylsulfonyl group which may have a substituent, a substituent; An arylsulfonyl group that may have, an alkyl phosphate group that may have a substituent, an aryl phosphate group that may have a substituent, or a nitro group,
R _b is an aralkyl group which may have a substituent, an acyl group which may have a substituent, an alkoxycarbonyl group which may have a substituent, an alkylsilyl group which may have a substituent, An alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfonamide group which may have a substituent, an alkylamino group which may have a substituent, or a substituent An arylamino group which may have )
Or a salt thereof as a starting compound,
(A) performing an intramolecular cyclization reaction;
(B) performing the step of substituting the hydrogen atom of R ₂ ′ with a quinolyl group in any order;
Formula (6)

(Wherein R ₁ and R ₅ are each as defined above),
[Ii] A compound represented by the formula (6) or a salt thereof, an amino group optionally having a protecting group represented by R ₅ , a hydroxyl group optionally having a protecting group, a carbonyl group, an imino group, or = A step of converting the NR _b group into an amino group, and [iii] a step of amidating the compound or a salt thereof deprotected in the above step [ii].

The manufacturing method of the quinolyl pyrrolopyrimidyl condensed ring compound or its salt represented by these.