JP2012107006A - Method for producing n-substituted cyclic amino derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a compound represented by formula (3) useful as a medicine, by which the compound is acquired more efficiently and with higher purity.SOLUTION: In the method, by making a compound represented by formula (6) (wherein each of Rand Ris independently a hydrogen atom etc., and Ris a 1C-6C alkyl group etc.) and a compound represented by formula (7) (wherein M is pyridine-2-yl-oxy etc.) react with each other, a compound represented by formula (2) is produced, and by making a compound represented by formula (1) (in formula, Ris a 1C-6C alkyl group which is optionally substituted, Ris a 1C-6C alkyl group which is optionally substituted, each of Rand Ris independently, identical to or different from each other, a 1C-6C alkyl group etc. which is optionally substituted, Ris a 1C-6C alkyl group which is optionally substituted, and G is an oxygen atom etc.) and the compound represented by formula (2) react with each other, a compound represented by formula (3) (symbols in formula are identical to those described) is produced.

Description

  The present invention relates to a method for producing N-substituted-cyclic amino derivatives. More specifically, it relates to a method for producing 1- (acyloxy) -alkyl carbamates of N-substituted moieties.

  As a cyclic amino derivative in which a nitrogen atom on a ring is substituted in a compound having a cyclic amino structure, a compound represented by the following formula is known (Patent Document 1).

[Wherein L is a single bond, S (O) ₂ , C (O), etc., Ar is aryl or heteroaryl, R ¹ is a hydrogen atom, R ² is a hydrogen atom, C _{1- 6} alkyl such as, ^{R 3} is _{C 1-6} alkyl, aryl, ^{etc., R 4, R 5, R} 6, R 7, R 8, R 9, R 10 and ^{R 11} are each independently hydrogen An atom or the like, and q is 1 or 2. ]

  Here, a compound in which a nitrogen atom such as a piperidine ring is substituted is obtained by reacting a compound in which the nitrogen atom such as a piperidine ring is unsubstituted with various acid chlorides or isocyanates, or p-nitrophenyloxycarbonyl chloride. Can be produced by reacting various amines (Schemes 1 and 2 of Patent Document 1). However, when the site substituted with a nitrogen atom such as piperidine (hereinafter sometimes referred to as a substituted site) has a complicated structure, such a production method cannot be expected to improve the yield.

  On the other hand, Patent Document 2 describes a method for producing a compound represented by the following formula.

[Wherein R ¹ is alkyl, substituted alkyl, etc., R ² and R ³ are independently a hydrogen atom, alkyl, substituted alkyl, etc., and R ⁵ and R ⁶ are independently A hydrogen atom, acylamino, acyloxy and the like. ]

  Patent Document 2 describes a method for producing the above compound and a method for producing 1- (acyloxy) -alkyl carbamate that reacts with a primary or secondary amine-containing drug using the compound. In the production method described in Patent Document 2, an achiral or chiral 1- (acyloxy) -alkyl carbamate compound group can be produced by reacting the compound with a primary or secondary amine-containing drug. The compound is produced by reacting an N-hydroxysuccinimide derivative with a corresponding thiocarbamate in the presence of peracid such as peracetic acid or m-chloroperbenzoic acid.

[式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８は、特許文献２と同義である。]

[Wherein, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are synonymous with Patent Document 2. ]

  Further, as other production examples relating to 1- (acyloxy) -alkyl carbamate compounds, for example, the production method described in Non-Patent Document 1 is known. That is, ((2,5-dioxopyrrolidin-1-yloxy) carbonyloxy) methyl acetate and 1- (2,5-dioxopyrrolidin-1-yloxy) carbonyloxy) ethyl acetate and a primary amino group This is a method for producing a 1- (methylcarbonyloxy) -alkylcarbamate by reacting a pseudomycin derivative.

  Furthermore, as a method for producing a 1- (chlorocarbonyloxy) alkyl alkanoate, for example, a production method such as Non-Patent Document 2 represented by the following formula is known.

[Wherein, R ¹ represents a C _1-13 alkyl, tert-butyl, phenyl, benzyl, 2-furyl group or the like described in Non-Patent Document 2. R ² represents a methyl, ethyl, butyl, phenyl or benzyl group. ]

It has been confirmed that this reaction affects the purity and yield by selecting R ² . In order to obtain a highly pure 1- (chlorocarbonyloxy) alkyl alkanoate, selection of an appropriate R ² is important.

  On the other hand, a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is known as a compound having excellent medicinal properties as a renin inhibitor (Patent Document 3).

[Wherein, G ¹ , G ² , G ³ , G ⁴ , R ^1a , R ^1m , R ² , R ^3a , R ^3b , R ^3c , R ^3d and n are as defined in Item 1 described in Patent Document 3. is there. ]

  In addition, the compound represented by the formula (3) or a pharmaceutically acceptable salt thereof is a compound that is extremely excellent in terms of drug efficacy and safety as a renin inhibitor that can be administered orally.

[Wherein, G ¹ , G ² , G ³ , G ⁴ , R ^1a , R ^1m , R ² , R ^3a , R ^3b , R ^3c , R ^3d and n are as defined in Patent Document 3, R ⁵ is synonymous with R ³ described in Item 1 below, R ⁶ is synonymous with R ⁴ described in Item 1 below, and R ⁷ is synonymous with R ⁵ described in Item 1 below. ]

International Publication WO2006 / 020598 Pamphlet International Publication WO2005 / 066122 Pamphlet International Publication WO2009 / 078481 Pamphlet

Bioorg. Med. Chem. Lett. 11, 1875. (2001) Synthesis 1159. (1990)

  The compound represented by the formula (3) or a pharmaceutically acceptable salt thereof has a more complex structure than the compound group described in Patent Document 1, and the high-purity formula ( It is difficult to produce the compound represented by 3) or a pharmaceutically acceptable salt thereof. Further, the compound represented by the formula (3) or a pharmaceutically acceptable salt thereof can be obtained by combining a compound represented by the formula (1) or a pharmaceutically acceptable salt with an existing method. However, there is a need for a more efficient production method that can withstand the demand as a pharmaceutical product.

  The subject of this invention is providing the manufacturing method which can acquire the renin inhibitor represented by Formula (3) which is pharmaceutically useful more efficiently and with higher purity. In the production method described in Patent Document 1, it is difficult to produce the compound group represented by the formula (3) from the complexity of the structure. Moreover, although the existing methods described in Non-Patent Documents 1 and 2 can be combined and manufactured through a plurality of steps, a more efficient manufacturing method that can withstand the demand as a pharmaceutical is needed.

  As a result of intensive studies to solve the above problems, the inventors of the present invention efficiently and highly purified the compound represented by the formula (3) from the compound represented by the formula (1) in one step. The manufacturing method which can be manufactured was discovered. Moreover, the method which can manufacture the compound represented by Formula (2) efficiently and with high purity was discovered.

  That is, the present invention is as follows.

Item 1: Compound represented by formula (6)

[式中、Ｒ^３およびＲ^４は、各々独立して、
（ａ）水素原子、
（ｂ）Ｃ_１−４アルキル基（該基は、
Ｃ_１−４アルコキシ、
Ｃ_３−６シクロアルキル（該シクロアルキルは、Ｃ_１−４アルコキシで置換されていてもよい。）、
５員もしくは６員の飽和へテロ環、または
５員もしくは６員の飽和へテロ環オキシで置換されていてもよい。）、
（ｃ）Ｃ_３−１０シクロアルキル基（該基は、１〜２個のフッ素原子、またはＣ_１−４アルコキシで置換されていてもよい。）、
（ｄ）Ｃ_６−１０アリール基（該基は、
ハロゲン原子、または
Ｃ_６−１０アリール（ハロゲン原子またはＣ_１−４アルコキシで置換されていてもよい。）で置換されていてもよい。）、
（ｅ）５員もしくは６員の飽和へテロ環基、または
（ｆ）５員〜１０員の単環式もしくは多環式のヘテロアリール基（該基は、Ｃ_１−４アルキル、またはＣ_１−４アルコキシで置換されていてもよい。）であり；
Ｒ^５は、
（ａ）Ｃ_１−６アルキル基（該基は、
１〜３個のフッ素原子、
ヒドロキシ、
Ｃ_１−４アルコキシ、
カルボキシ、
５員もしくは６員の飽和へテロ環、
Ｃ_３−６シクロアルキル、
Ｃ_１−４アルコキシカルボニル、
Ｃ_１−４アルコキシカルボニルアミノ、
アミノ、
モノ−もしくはジ−（Ｃ_１−６アルキル）アミノ、
５員〜７員の環状アミン、
１〜２個のニトロオキシ、
アミノカルボニル、または
５員〜７員の環状アミノカルボニルで置換されていてもよい。）、
（ｂ）Ｃ_３−１０シクロアルキル基（該基は、ヒドロキシで置換されていてもよい。）、
（ｃ）Ｃ_６−１０アリール基（該基は、
Ｃ_１−４アルキル、
ハロゲン、
Ｃ_１−４アルコキシ、または
Ｃ_１−４アルキルカルボニルオキシで置換されていてもよい。）、
（ｄ）Ｃ_１−４アルキルカルボニル基（該基は、ヒドロキシで置換されていてもよい。）、
（ｅ）５員〜１０員の単環式もしくは多環式ヘテロアリール基、
（ｆ）５員もしくは６員の飽和へテロ環基（該基は、Ｃ_１−４アルコキシで置換されていてもよいＣ_１−４アルキルで置換されていてもよい。）、
（ｇ）Ｃ_１−６アルコキシ基（該基は、Ｃ_３−６シクロアルキルで置換されていてもよい。）、
（ｈ）Ｃ_３−６シクロアルキルオキシ基（該基は、Ｃ_１−４アルコキシで置換されていてもよい。）、または
（ｉ）５員もしくは６員の飽和ヘテロ環オキシ基である。）である。] 、または薬学上許容される塩と、
塩化スルフリルを反応し、引き続いて、式（７）で表される化合物

Wherein R ³ and R ⁴ are each independently
(A) a hydrogen atom,
(B) a C _1-4 alkyl group (the group is
C _1-4 alkoxy,
C _3-6 cycloalkyl (which may be substituted with C _1-4 alkoxy),
It may be substituted with a 5- or 6-membered saturated heterocyclic ring, or a 5- or 6-membered saturated heterocyclic oxy. ),
(C) a C _3-10 cycloalkyl group (this group may be substituted with 1 to 2 fluorine atoms or C _1-4 alkoxy),
(D) a C _6-10 aryl group (the group is
It may be substituted with a halogen atom or C _6-10 aryl (which may be substituted with a halogen atom or C _1-4 alkoxy). ),
(E) a 5- or 6-membered saturated heterocyclic group, or (f) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group is C _1-4 alkyl, or C _{1 -4} may be substituted with alkoxy));
R ⁵ is
(A) a C _1-6 alkyl group (the group is
1 to 3 fluorine atoms,
Hydroxy,
C _1-4 alkoxy,
Carboxy,
5- or 6-membered saturated heterocycle,
C _3-6 cycloalkyl,
C _1-4 alkoxycarbonyl,
C _1-4 alkoxycarbonylamino,
amino,
Mono- or di- (C _1-6 alkyl) amino,
A 5- to 7-membered cyclic amine,
1-2 nitrooxy,
It may be substituted with aminocarbonyl or 5- to 7-membered cyclic aminocarbonyl. ),
(B) a C _3-10 cycloalkyl group (which group may be substituted with hydroxy),
(C) a C _6-10 aryl group (the group is
C _1-4 alkyl,
halogen,
It may be substituted with C _1-4 alkoxy, or C _1-4 alkylcarbonyloxy. ),
(D) a C _1-4 alkylcarbonyl group (this group may be substituted with hydroxy),
(E) a 5- to 10-membered monocyclic or polycyclic heteroaryl group,
(F) a 5- or 6-membered saturated heterocyclic group (the group may be substituted with C _1-4 alkyl which may be substituted with C _1-4 alkoxy),
(G) a C _1-6 alkoxy group (the group may be substituted with C _3-6 cycloalkyl),
(H) a C _3-6 cycloalkyloxy group (which group may be substituted with C _1-4 alkoxy), or (i) a 5- or 6-membered saturated heterocyclic oxy group. ). Or a pharmaceutically acceptable salt,
A compound represented by the formula (7) after reacting with sulfuryl chloride

［式中、Ｍは、式（４）または（５）で表される基

[Wherein, M is a group represented by the formula (4) or (5)

[Wherein, R ^6a and R ^6b each independently represent a hydrogen atom, a C _1-6 alkylcarbonyloxy group, a C _3-6 cycloalkylcarbonyloxy group, or an optionally substituted C _6-10 aryl. Carbonyloxy group, 5- to 10-membered monocyclic or polycyclic heteroarylcarbonyloxy group, saturated heterocyclic carbonyloxy group, optionally substituted C _1-6 alkyl group, optionally substituted C _{A 3-6} cycloalkyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-6 cycloalkoxy group, an optionally substituted C _6-10 aryl group, a substituted An _optionally substituted C _6-10 aryloxy group, an _optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group, C _1-6 alkylamino A carbonyloxy group, a C _3-6 cycloalkylaminocarbonyloxy group, an optionally substituted amino group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, a hydroxy group, Or a sulfonamide group, or R ^6a and R ^6b together with the atoms to which they are attached, a C _3-6 cycloalkyl ring, a saturated heterocycle, a C _5-10 cycloalkenyl ring, May form a _6-10 aryl ring, or a 5-10 membered monocyclic or polycyclic heteroaryl ring;
R ⁷ is a hydrogen atom, a halogen atom, or a C _1-6 alkyl group;
m is 1, 2, 3, or 4. ] ]
Compound represented by formula (2)

[Wherein R ³ , R ⁴ , R ⁵ and M are the same as described above. Or a method for producing a pharmaceutically acceptable salt thereof.

Item 2: Furthermore, the compound represented by the formula (1)

［式中、Ｒ^１ａは、置換されていてもよいＣ_１−６アルキル基であり；
Ｒ^１ｂは、置換されていてもよいＣ_１−６アルキル基であり；
Ｒ^１ｃおよびＲ^１ｄは、各々独立して、同一または異なって、水素原子、または置換されていてもよいＣ_１−６アルキル基であるか、あるいは
Ｒ^１ｃおよびＲ^１ｄは、一緒になって下記式

[Wherein, R ^1a represents an optionally substituted C _1-6 alkyl group;
R ^1b is an ^optionally substituted C _1-6 alkyl group;
R ^1c and R ^1d are each independently the same or different and are a hydrogen atom or an optionally substituted C _1-6 alkyl group, or R ^1c and R ^1d are taken together as follows: formula

で表される基（ｐおよびｑは、各々独立して、同一または異なって、０、１または２である。）であり；
Ｒ^２は、置換されていてもよいＣ_１−６アルキル基であり；
Ｇは、酸素原子、または硫黄原子である。]、またはその薬学上許容される塩と、
式（２）で表される化合物

A group represented by the formula (p and q are each independently the same or different and are 0, 1 or 2);
R ² is an optionally substituted C _1-6 alkyl group;
G is an oxygen atom or a sulfur atom. Or a pharmaceutically acceptable salt thereof,
Compound represented by formula (2)

[Wherein R ³ , R ⁴ , R ⁵ and M are the same as in item 1. Or a pharmaceutically acceptable salt thereof,
Compound represented by formula (3)

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ² , G, R ³ , R ⁴ and R ⁵ are the same as described above. Or a pharmaceutically acceptable salt thereof.

Item 3: The method according to Item 1 or 2, wherein G is an oxygen atom.

Item 4: The method according to Item 1 or 2, wherein G is a sulfur atom.

Item 5: The method according to any one of Items 1 to 4, wherein R ^1a is a C _1-6 alkyl group which may be substituted with 1 to 3 fluorine atoms.

Item 6: The method according to Item 5, wherein R ^1a is a trifluoromethyl group.

Item 7: R ^1b is a C _1-6 alkyl group _optionally substituted with C _1-4 alkylcarbonylamino optionally substituted with 1 to 3 fluorine atoms, Item 1 to Item 6 The method as described in any one of.

Item 8: The method according to Item 7, wherein R ^1b is a 2- (ethylcarbonylamino) ethyl group.

Item 9: Any one of Items 1 to 8, wherein R ^1c and R ^1d are each independently a hydrogen atom, a halogen atom, or a C _1-6 alkyl group optionally substituted with C _1-4 alkoxy. The method according to claim 1.

Item 10: The method according to Item 9, wherein R ^1c is a C _1-6 alkyl group.

Item 11: The method according to Item 10, wherein R ^1c is a methyl group.

Item 12: The method according to any one of Items 9 to 11, wherein R ^1d is a C _1-6 alkyl group which may be substituted with C _1-4 alkoxy.

Item 13: The method according to Item 12, wherein R ^1d is a methyl group.

Item 14: The method according to Item 12, wherein R ^1d is a methoxymethyl group.

Item 15: R ^1c and R ^1d together are represented by the following formula:

で表される基である、項１〜項８のいずれか一項に記載の方法。

Item 9. The method according to any one of Items 1 to 8, which is a group represented by:

Item 16: p and q are any of the following (i) to (iii) (where,
(I) p and q are the same and are 2, or one of p and q is 2 and the other is 1, or (ii) p and q are the same and 1 Or (iii) one of p and q is 1 and the other is 0).

Item 17: R ^1c and R ^1d together represent the following formula

で表される基である、項１６に記載の方法。

Item 17. The method according to Item 16, which is a group represented by:

Item 18: R ² is
_{(1) C 3-6 C 1-6} alkyl group (said _{C 1-6} alkyl optionally substituted with a cycloalkyl may be substituted with 1 to 3 halogen atoms, the _{C 3-6} cycloalkyl Alkyl may be substituted with a halogen atom, C _1-4 alkyl or C _1-4 alkoxy);
(2) a C _3-6 cycloalkyl group optionally substituted with a halogen atom or C _1-4 alkyl;
Any one of Items 1 to 17, which is one group selected from the group consisting of (3) a C _2-6 alkenyl group; and (4) a C _7-10 aralkyl group optionally substituted with a halogen atom. The method according to claim 1.

Item 19: The method according to Item 18, wherein R ² is a C _1-6 alkyl group.

Item 20: The method according to Item 19, wherein R ² is an isopropyl group.

Item 21: R ³ and R ⁴ are each independently the same or different and each represents a hydrogen atom or a C _1-4 alkyl group,
R ⁵ is
(1) C _1-6 alkyl group (the group is
(A) 1 to 3 fluorine atoms,
(B) amino,
(C) hydroxy,
(D) C _1-4 alkoxy,
(E) carboxy,
(F) C _1-4 alkoxycarbonyl,
(G) C _1-4 alkoxycarbonylamino,
(H) 1-2 nitrooxy,
(I) 5- or 6-membered saturated heterocyclic ring, or (j) optionally substituted with C _3-6 cycloalkyl. ),
(2) a C _3-10 cycloalkyl group,
(3) C _1-4 alkylcarbonyl group (this group may be substituted with hydroxy),
(4) C _6-10 aryl group (the group is
(A) C _1-4 alkyl,
(B) C _1-4 alkoxy, or (c) C _1-4 alkylcarbonyloxy may be substituted. ),
(5) 5- to 10-membered monocyclic or polycyclic heteroaryl group,
(6) a 5- or 6-membered saturated heterocyclic group,
(7) C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
(8) a C _3-6 cycloalkyloxy group, or (9) a 5- or 6-membered saturated heterocyclic oxy group. )
The method according to any one of Items 1 to 20, wherein

Item 22: The method according to Item 21, wherein R ³ is a hydrogen atom, and R ⁴ is a C _1-4 alkyl group.

Item 23: The method according to Item 22, wherein R ⁴ is a methyl group.

Item 24: R ⁵ is
(1) C _1-6 alkyl group (the group is
(A) 1 to 3 fluorine atoms,
(B) amino,
(C) hydroxy,
(D) C _1-4 alkoxy,
(E) carboxy,
(F) C _1-4 alkoxycarbonyl,
(G) C _1-4 alkoxycarbonylamino,
(H) 1-2 nitrooxy,
(I) 5- or 6-membered saturated heterocyclic ring, or (j) optionally substituted with C _3-6 cycloalkyl. ),
(2) a C _3-10 cycloalkyl group,
(3) C _1-4 alkylcarbonyl group (this group may be substituted with hydroxy),
(4) C _6-10 aryl group (the group is
(A) C _1-4 alkyl,
(B) substituted with C _1-4 alkoxy, or (c) C _1-4 alkylcarbonyloxy. ),
Item 24. The structure according to any one of Items 21 to 23, which is a 5-membered to 10-membered monocyclic or polycyclic heteroaryl group, or (6) a 5-membered or 6-membered saturated heterocyclic group. the method of.

Item 25: R ⁵ is
(1) C _1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C _1-4 alkoxy,
(C) 5 or 6 membered saturated heterocycle, or (d) optionally substituted with C _3-6 cycloalkyl. ),
(2) a C _3-6 cycloalkyl group,
(3) C _6-10 aryl group (the group is
(A) C _1-4 alkyl, or (b) C _1-4 alkoxy may be substituted. ), Or (4) The method according to Item 24, which is a 5- or 6-membered saturated heterocyclic group.

Item 26: The method according to Item 25, wherein R ⁵ is a C _1-4 alkyl group.

Item 27: The method according to Item 26, wherein R ⁵ is an isopropyl group.

Item 28: The method according to any one of Items 1 to 27, wherein R ^6a and R ^6b are each independently a C _6-10 arylcarbonyloxy group.

Item 29: The method according to Item 28, wherein R ^6a and R ^6b are each independently a phenylcarbonyloxy group.

Item 30: The method according to any one of Items 1 to 27, wherein R ^6a and R ^6b together with the atoms to which they are attached form a C _6-10 aryl ring.

Item 31: The method according to any one of Items 1 to 30, wherein R ⁷ is a hydrogen atom.

Item 32: A compound represented by formula (4-1) or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^３１は、水素原子であり、Ｒ^４１は、Ｃ_１−４アルキル基であり、Ｒ^５１は、Ｃ_１−４アルキル基であり、Ｒ^６ａ１およびＲ^６ｂ１は、共にフェニルカルボニルオキシ基、もしくはＲ^６ａ１およびＲ^６ｂ１が一緒になってベンゼン環、またはノルボルネン環である。］

[Wherein R ³¹ is a hydrogen atom, R ⁴¹ is a C _1-4 alkyl group, R ⁵¹ is a C _1-4 alkyl group, and both R ^6a1 and R ^6b1 are phenylcarbonyloxy A group, or R ^6a1 and R ^6b1 together are a benzene ring or a norbornene ring. ]

Item 33: A compound represented by the formula (5-1), or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^３１は、水素原子であり、Ｒ^４１は、Ｃ_１−４アルキル基であり、Ｒ^５１は、Ｃ_１−４アルキル基、Ｒ^７は、水素原子、ハロゲン原子、またはＣ_１−６アルキル基であり、
ｍは、１、２、３、または４である。］

[Wherein R ³¹ is a hydrogen atom, R ⁴¹ is a C _1-4 alkyl group, R ⁵¹ is a C _1-4 alkyl group, R ⁷ is a hydrogen atom, a halogen atom, or C _{1. A -6} alkyl group,
m is 1, 2, 3, or 4. ]

Item 34: The compound represented by formula (5-1) is

で表される化合物である、項３３に記載の化合物、またはその薬学上許容される塩。

Item 34. The compound of Item 33, or a pharmaceutically acceptable salt thereof.

Item 35: The compound according to Item 33 or Item 34, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a hydrogen atom.

Item 36: A compound represented by formula (6-1) or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^３１は、水素原子であり、Ｒ^４１は、Ｃ_１−４アルキル基であり、Ｒ^５１は、Ｃ_１−４アルキル基である。］

[Wherein, R ³¹ is a hydrogen atom, R ⁴¹ is a C _1-4 alkyl group, and R ⁵¹ is a C _1-4 alkyl group. ]

Item 37: The compound according to any one of Items 32 to 36, or a pharmaceutically acceptable salt thereof, wherein R ⁴¹ is a methyl group and R ⁵¹ is an isopropyl group.

  According to the present invention, a compound represented by formula (2), a compound represented by formula (3), or a pharmaceutically acceptable salt thereof can be produced with high yield and high purity.

The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-4 ”, for example. Specifically, the expression “C _1-4 alkyl” is synonymous with an alkyl group having 1 to 4 carbon atoms. In the present specification, a group that does not clearly indicate the term “optionally substituted” means an “unsubstituted” group. For example, “C _1-4 alkyl” means “unsubstituted”.

  In this specification, the term “group” means a monovalent group unless otherwise specified. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of each group in this specification, the term “group” may be omitted. The number of substituents in the group defined as “optionally substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. Further, unless otherwise specified, the description of each group includes the case where the group is a part of another group.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“C _1-6 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, " _C1-4 alkyl group" etc. are mentioned. Specific examples of “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

The “C _2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one double bond. Specific examples include vinyl, propenyl, methylpropenyl, butenyl and methylbutenyl.

“C _3-10 cycloalkyl group” means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms. Preferably, it is “C _3-6 cycloalkyl group”. Specific examples of “C _3-10 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“C _3-6 cycloalkyl C _1-4 alkyl” refers to a group in which “C _3-6 cycloalkyl” is bonded to “C _1-4 alkyl”. Specific examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.

“C _6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferably, and the like "C ₆ aryl group" (phenyl). Specific examples of “C _6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

The “C _7-14 aralkyl group” means a “C _6-10 aryl C _1-4 alkyl group”, and means a group in which the “aryl group” is substituted on the “alkyl group”. Preferably, _{"C 7-10} aralkyl group" _{(C 6} aryl _{C 1-4} alkyl group). Specific examples of “C _7-14 aralkyl group” include, for example, benzyl, 2-phenylethyl, 1-phenylpropyl, 1-naphthylmethyl and the like.

  Examples of the “heteroaryl group” include a 5-membered to 10-membered monocyclic or polycyclic group, and the group includes the same or different heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. It is different and includes one or more (for example, 1 to 4). Preferable examples include a 5-membered or 6-membered monocyclic group, and the like includes one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Specific examples of the “heteroaryl group” include, for example, pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzthiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridadyl, quinolyl , Isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo [1,2-a] pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl or isoquinolinolyl.

_{"C 1-6} alkoxy group" is synonymous with _{"C 1-6} alkyl group", _{"C 1-6} alkyl" moiety is the same as defined in the _{"C 1-6} alkyl". Preferably, " _C1-4 alkoxy group" etc. are mentioned. Specific examples of “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

_{"C 1-6} alkyl" moiety of the _{"C 1-6} alkylsulfonyl" is the same as defined in the _{"C 1-6} alkyl". Preferably, " _C1-4 alkylsulfonyl group" etc. are mentioned. Specific examples of the “C _1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

The “C _3-6 cycloalkoxy group” has the same meaning as the “C _3-6 cycloalkyloxy group”, and the “C _3-10 cycloalkyl” moiety has the same meaning as the above “C _3-10 cycloalkyl”. . Preferably, " _C3-6 cycloalkoxy group" etc. are mentioned. Specific examples of “C _3-10 cycloalkoxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy, norbornyloxy and the like.

The “C _6-10 aryl” part of the “C _6-10 aryloxy group” has the same _{meaning as} the above “C _6-10 aryl”. “C ₆ aryloxy” (phenyloxy) is preferred. Specific examples of the “C _6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

The “C _7-14 aralkyl” portion of the “C _7-14 aralkyloxy group” has the same meaning as the “C _7-14 aralkyl”. Preferred is “C _7-10 aralkyloxy”. Specific examples of the “C _7-14 aralkyloxy group” include benzyloxy and the like.

  The “heteroaryloxy group” means a group in which the “aralkyl” part of the “aralkyloxy group” is replaced with “heteroaryl”. For example, “5- to 10-membered monocyclic or polycyclic heteroaryloxy group” and the like can be mentioned.

_{"C 1-4} alkoxy" moiety of the _{"C 1-4} alkoxy sulfonyl group" is the same as defined in the _{"C 1-4} alkoxy group". For example, methoxysulfonyl and the like can be mentioned.

_{"C 3-6} cycloalkoxy" portion of the _{"C 3-6} cycloalkoxy sulfonyl group" is the same as defined in the _{"C 3-6} cycloalkoxy group". For example, cyclopropyloxysulfonyl and the like can be mentioned.

_{"C 6-10} aryl" moiety of the _{"C 6-10} aryloxy sulfonyl group" is the same as defined in the _{"C 6-10} aryl group". For example, phenoxysulfonyl and the like can be mentioned.

_{"C 7-14} aralkyloxy" portion of the _{"C 7-14} aralkyloxy sulfonyl group" is the same as defined in the _{"C 7-14} aralkyloxy group". For example, benzyloxysulfonyl and the like can be mentioned.

“C _1-4 alkoxycarbonyl group” means a group in which the “C _1-4 alkoxy group” is bonded to a carbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, and the like.

The “C _3-6 cycloalkoxycarbonyl group” means a group in which the “C _3-6 cycloalkoxy group” is bonded to a carbonyl group. Specifically, as the C _3-6 cycloalkoxy moiety, those exemplified as the aforementioned cycloalkoxy group can be mentioned.

The “C _1-6 alkylcarbonyl group” means a group in which the “C _1-6 alkyl group” is bonded to a carbonyl group. Preferably, it is “C _1-4 alkylcarbonyl group”. Specific examples include acetyl, propionyl, butyryl and the like.

_{"C 1-4} alkyl" moiety of the _{"C 1-4} alkyl-thio group" is the same as the _{"C 1-4} alkyl".

The “C _3-6 cycloalkylcarbonyl group” means a group in which the “C _3-6 cycloalkyl group” is bonded to a carbonyl group. Specific examples of the “C _3-6 cycloalkylcarbonyl group” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, norbornylcarbonyl and the like.

The “C _3-6 cycloalkyl C _1-4 alkylcarbonyl group” means a group in which the “C _3-6 cycloalkyl C _1-4 alkyl group” is bonded to a carbonyl group. Specific examples include cyclopropylmethylcarbonyl and the like.

The “C _6-10 arylcarbonyl group” means a group in which the “C _6-10 aryl group” is bonded to a carbonyl group. The “C _6-10 aryl” moiety has the same _{meaning as the} “C _6-10 aryl group”. Preferably, “C ₆ arylcarbonyl group” (phenylcarbonyl group) is used. Specific examples of “C _6-10 arylcarbonyl group” include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

_{"C 7-14} aralkyl" moiety of the _{"C 7-14} aralkylcarbonyl group" is the same as defined in the _{"C 7-14} aralkyl group". Preferably, it is “C _7-10 aralkylcarbonyl group”. Specific examples of “C _7-14 aralkylcarbonyl group” include, for example, benzylcarbonyl and the like.

_{"C 1-4} alkyl" moiety of the _{"C 1-4} alkylcarbonyloxy group" is the same as defined in the _{"C 1-4} alkyl group". Specific examples include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy and the like.

_{"C 3-6} cycloalkyl" moiety of the _{"C 3-6} cycloalkyl carbonyl group" is the same as defined in the _{"C 3-6} cycloalkyl group". Specific examples include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy and the like.

_{"C 6-10} aryl-carbonyl" moiety of the _{"C 6-10} aryl-carbonyl group" is the same as defined in the _{"C 6-10} arylcarbonyl group". Specific examples include phenylcarbonyloxy and the like.

  The “heteroarylcarbonyl” part of the “heteroarylcarbonyloxy group” has the same meaning as the “heteroarylcarbonyl group”. Specific examples include pyridylcarbonyloxy and the like.

“C _3-6 cycloalkyl C _1-4 alkoxy” means a group obtained by substituting the “C _3-6 cycloalkyl group” with a “C _1-4 alkoxy group”. Specific examples include cyclopropylmethoxy and the like.

_{"C 3-6} cycloalkyl _{C 1-4} alkoxy" moiety of the _{"C 3-6} cycloalkyl _{C 1-4} alkoxycarbonyl group" is the same as defined in the _{"C 3-6} cycloalkyl _{C 1-4} alkoxy" . Specific examples include cyclopropylmethoxycarbonyl and the like.

The “C _1-4 alkylcarbonylamino” means a group in which the “C _1-4 alkylcarbonyl group” is substituted with one amino group. Specific examples include methylcarbonylamino and the like. In addition, “C _1-4 alkyl” may be substituted with 1 to 3 fluorine atoms.

“C _1-4 alkylsulfonylamino” means a group in which the above “C _1-4 alkylsulfonyl group” is substituted with one amino group. Specific examples include methylsulfonylamino, ethylsulfonylamino and the like.

  Examples of the “saturated heterocyclic group” include a 5-membered or 6-membered saturated heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. Specifically, pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxo Examples include oxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl and the like. In the group, the nitrogen atom constituting the ring is not a bond of the “group”. That is, the group does not include concepts such as a pyrrolidino group.

  The “saturated heterocyclic group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. For example, a bicyclic 11- or 12-membered “saturated heterocycle” in which the 5-membered or 6-membered “saturated heterocyclic group” and the 6-membered aromatic hydrocarbon or 6-membered unsaturated heterocycle are condensed. Is mentioned. Examples of the 6-membered aromatic hydrocarbon include benzene. Examples of the 6-membered unsaturated heterocycle include pyridine, pyrimidine, pyridazine and the like. Specifically, dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrololidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl , Decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.

  The “saturated hetero ring” part of the “saturated hetero ring oxy group” has the same meaning as the “saturated hetero ring group”. Specific examples include 4-pyranyloxy and the like.

  “Saturated heterocyclic carbonyl” means a group in which the “saturated heterocyclic group” is bonded to a carbonyl group. Specific examples include 4-pyranylcarbonyl and the like.

The “saturated heterocyclic C _1-4 alkyl” means a group in which the “saturated heterocyclic group” is bonded to a “C _1-4 alkyl group”. Specific examples include 4-pyranylmethyl and the like.

  The “saturated heterocyclic oxy” part of “saturated heterocyclic oxycarbonyl” has the same meaning as the above “saturated heterocyclic oxy”. Specific examples include 4-pyranyloxycarbonyl and the like.

Partial "heterocycle C _1-4 alkyl into saturation" of the "heterocyclic C _1-4 alkylcarbonyl to saturation" is synonymous with the "heterocycle C _1-4 alkyl to saturation." Specific examples include 4-pyranylmethylcarbonyl and the like.

“4- to 7-membered cyclic amino group” means a 4- to 7-membered cyclic amino group. A group in which the nitrogen atom of the ring is a direct bond of the “group” is meant. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thiomorpholino oxide, piperazino, 2-pyrrolidone-1-yl and the like. The ring may be substituted with, for example, a halogen atom, C _1-4 alkyl, or C ₆ aryl optionally substituted with C _1-4 alkoxy.

  The “4- to 7-membered cyclic amino group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. Specific examples include “groups” shown below.

  The cyclic amino moiety of the “4- to 7-membered cyclic aminocarbonyl group” is the same as the “4- to 7-membered cyclic amino”.

“Optionally substituted C _1-6 alkyl group”, “optionally substituted C _1-6 alkoxy group”, “optionally substituted C _3-6 cycloalkyl group” and “substituted As the substituent in the “optionally C _3-6 cycloalkyloxy group”, for example,
(1) 1 to 3 halogen atoms,
(2) a cyano group,
(3) C _3-6 cycloalkyl group (the group is
(A) 1-2 halogen atoms,
(B) hydroxy,
_{(C) C 1-4} alkoxy optionally substituted _{C 1-4} alkyl, or _{(d) C 1-4} optionally substituted alkoxy. ),
(4) hydroxyl group,
(5) C _1-4 alkoxy group (the group is
(A) a halogen atom,
(B) cyano,
(C) C _3-6 cycloalkyl optionally substituted with C _1-4 alkyl,
(D) C _3-6 cycloalkoxy optionally substituted with mono- or di- (C _1-6 alkyl) aminocarbonyl,
(E) mono- or di- (C _1-6 alkyl) aminosulfonyl,
(F) C _1-6 alkylsulfonyl,
(G) aminocarbonyl optionally substituted by mono- or di- (C _1-6 alkyl);
(H) C _1-4 alkylcarbonyl,
(I) a 4- to 7-membered cyclic aminocarbonyl,
(J) hydroxy,
(K) C _1-4 alkoxy,
(L) a 5-membered or 6-membered saturated heterocyclic ring (which may be substituted with C _1-4 alkyl),
(M) C _1-4 alkoxycarbonyl, and (n) the same or different 1-3 selected from the group consisting of C _6-10 aryloxy (wherein the aryl may be substituted with a halogen atom) It may be substituted with groups. ),
(6) C _3-6 cycloalkyloxy group (the group may be substituted with C _1-4 alkyl which may be substituted with C _1-4 alkoxy),
(7) C _6-10 aryloxy group (the aryl is
(A) a halogen atom,
(B) cyano, and (c) optionally substituted with the same or different groups selected from the group consisting of C _1-4 alkoxy. ),
(8) C _7-14 aralkyloxy group,
(9) formyl group,
(10) C _1-6 alkylcarbonyl group (this group may be substituted with C _1-4 alkoxy),
(11) a C _3-6 cycloalkylcarbonyl group,
(12) a C _6-10 arylcarbonyl group,
(13) C _7-14 aralkylcarbonyl group,
(14) formylcarbonyloxy group,
(15) a C _1-4 alkylcarbonyloxy group,
(16) a C _3-6 cycloalkylcarbonyloxy group,
(17) a carboxyl group,
(18) C _1-4 alkoxycarbonyl group,
(19) C _3-6 cycloalkoxycarbonyl group,
(20) Amino group (the group is
(A) C _1-6 alkyl (the alkyl may be substituted with 1 to 3 fluorine atoms),
(B) C _3-6 cycloalkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl _optionally substituted with aminocarbonyl,
(D) C _7-14 aralkyl,
(E) C _3-6 cycloalkyl C _1-4 alkoxycarbonyl,
(F) formyl,
(G) C _1-4 alkylcarbonyl (the alkyl may be substituted with 1 to 3 fluorine atoms),
(H) C _3-6 cycloalkylcarbonyl optionally substituted with C _1-4 alkylsulfonylamino;
(I) C _1-4 alkoxycarbonyl (this alkoxy may be substituted with 1 to 3 fluorine atoms),
_{(J) C 1-4} heterocyclic _{C 1-4} alkyl alkyl to are optionally the 5-membered or 6-membered saturated substituted,
(K) a 5- or 6-membered saturated heterocyclic carbonyl,
(L) a 5- or 6-membered saturated heterocyclic oxycarbonyl,
(M) a 5- or 6-membered saturated heterocyclic C _1-4 alkylcarbonyl,
(O) C _1-6 alkylsulfonyl,
(P) C _1-4 alkylthiocarbonyl,
(Q) C _1-6 alkylaminocarbonyl,
(R) C _1-6 alkylaminothiocarbonyl,
(S) C _6-10 aryloxycarbonyl (the aryl may be substituted with a halogen atom),
(T) 5 or 6 membered monocyclic heteroaryloxycarbonyl,
(U) C _1-6 alkoxycarbonyl,
(V) C _1-6 alkylsulfonyl, and (w) C _6-10 arylsulfonyl (wherein the aryl is the same or different 1-2 groups selected from the group consisting of a halogen atom and C _1-4 alkyl) And may be substituted with one or two groups of the same or different types selected from the group consisting of: ),
(21) a 4- to 7-membered cyclic amino group (the group is
(A) C _1-4 alkyl,
(B) C _6-10 aryl,
(B) C _7-14 aralkyl, and (c) optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of oxo. ),
(22) an aminocarbonyl group (the amino is
(A) C _1-6 alkyl (which may be substituted with 1 to 3 fluorine atoms), and (b) the same or different selected from the group consisting of C _3-6 cycloalkyl May be substituted with 1 to 2 groups. ),
(23) a 4- to 7-membered cyclic aminocarbonyl group (the cyclic amino may be substituted with C _1-4 alkyl),
(24) Aminocarbonyloxy group (the amino is
(A) C _1-6 alkyl _optionally substituted with a 5-membered or 6-membered saturated heterocyclic ring,
(B) C _3-6 cycloalkyl optionally substituted with hydroxy, and (c) the same or different 1-2 groups selected from the group consisting of 5-membered or 6-membered saturated heterocycles Replaced. ),
(25) a 4- to 7-membered cyclic aminocarbonyloxy group (the cyclic amino may be substituted with 1 to 2 fluorine atoms), or (26) a saturated heterocyclic group (the ring is ,
_{(A) C 1-4} optionally substituted alkoxy _{C 1-4} alkyl,
(B) C _1-4 alkoxy,
(C) C _1-4 alkylcarbonylamino, or (d) optionally substituted with oxo. ),
(27) a 5- or 6-membered saturated heterocyclic oxy group (the ring is
(A) C _1-4 alkyl,
(B) C _6-10 aryl _optionally substituted with a halogen atom,
(C) Saturated heterocyclic carbonyl, and (d) optionally substituted with 1 or 2 groups of the same or different types selected from the group consisting of oxo. ),
(28) a nitro group,
(29) a C _6-10 aryl group (the group is
(A) a halogen atom,
(B) C _1-4 alkyl _optionally substituted by carboxy,
(C) It may be substituted with a C _1-4 alkoxy which may be substituted with a fluorine atom, a hydroxyl group, or carboxy. ),
(30) a C _1-6 alkylsulfonyl group,
(31) a sulfonyl group,
(32) C _1-4 alkoxysulfonyl group,
(33) C _3-6 cycloalkoxysulfonyl group,
(34) C _6-10 aryloxysulfonyl group (the phenyl is
(A) a halogen atom,
(B) cyano, and (c) optionally substituted with the same or different groups selected from the group consisting of C _1-4 alkoxy. ),
(35) C _7-14 aralkyloxysulfonyl group,
(36) an aminosulfonyl group, and (37) a 5- to 10-membered monocyclic or polycyclic heteroaryloxy group (the group may be substituted with C _1-4 alkyl). Can be mentioned.

“Optionally substituted C _6-10 aryl group”, “ _optionally substituted C _6-10 aryloxy group”, “optionally substituted C _6-10 arylcarbonyloxy group”, “substituted” In "optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group" and "optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group" Examples of the substituent include the groups (1) to (37) and a C _1-4 alkyl group (which may be substituted with, for example, a halogen atom, a hydroxyl group, or amino). It may be substituted with the same or different group selected from

  The “optionally substituted amino group” means an amino group, a mono- or di-substituted amino group, and a 4- to 7-membered cyclic amino group.

  The “mono- or di-substituted amino group” is substituted with the same or different 1-2 groups selected from the group consisting of the above (20) (a) to (20) (w). An amino group is meant.

Specific examples of the “mono- or di-substituted amino group” include, for example,
“Amino group substituted with mono- or di- (C _1-6 alkyl)” (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.),
“Amino group substituted with mono- or di- (C _3-6 cycloalkyl)” (for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, dicyclopropylamino, dicyclobutylamino, cyclodipentylamino, etc.) ,
“Amino group substituted with mono- (C _3-6 cycloalkylC _1-4 alkyl)” (for example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, etc.),
“Amino group substituted with (C _1-4 alkyl) (benzyl)” (eg, N-methyl-N-benzylamino, N-ethyl-N-benzylamino, etc.),
“Amino group substituted with (C _3-6 cycloalkyl) (benzyl)” (for example, N-cyclopropyl-N-benzylamino, N-cyclopentyl-N-benzylamino, N-cyclohexyl-N-benzylamino, etc. ),
“C _3-6 cycloalkyl C _1-4 alkoxycarbonylamino” (eg, cyclopropylmethoxycarbonylamino, etc.),
“5-membered or 6-membered saturated heterocyclic amino group” (eg, 3-pyrrolidinylamino),
“Saturated heterocyclic C _1-4 alkylcarbonylamino group” (for example, (4-pyranylmethylcarbonyl) amino and the like),
“N- (C _1-6 alkyl) -N- (saturated heterocyclic C _1-4 alkylcarbonyl) -amino group” (eg, N-methyl-N- (4-pyranylmethylcarbonyl) amino, etc.),
“Saturated heterocyclic carbonylamino group” (eg 4-pyranylcarbonylamino etc.),
“N- (C _1-6 alkyl) -N- (saturated heterocyclic carbonyl) -amino group” (eg, N-methyl-N- (4-pyranylcarbonyl) amino, etc.),
“N- (C _1-4 alkylcarbonyl) -N- (C _1-6 alkyl) -amino group” (eg, N-methyl-N-methylcarbonylamino, etc.),
“(Saturated heterocyclic oxycarbonyl) amino group” (for example, 3-tetrahydrofuryloxycarbonylamino, etc.),
“N- (saturated heterocyclic C _1-4 alkyl) -N— (C _1-6 alkyl) -amino group” (eg, N-methyl-N- (4-pyranylmethyl) amino, etc.),
“N- (saturated heterocyclic carbonyl) -N— (C _1-6 alkyl) -amino group” (eg, N-methyl-N- (4-pyranylcarbonyl) amino, etc.),
“N- (saturated heterocyclic C _1-4 alkylcarbonyl) -N— (C _1-6 alkyl) -amino group” (eg, N-methyl-N- (4-pyranylmethylcarbonyl) amino, etc.),
“N- (saturated heterocyclic oxycarbonyl) -N— (C _3-6 cycloalkyl) -amino group” (for example, N-cyclopropyl-N- (4-pyranyloxycarbonyl) amino, etc.),
“N- (saturated heterocyclic C _1-4 alkylcarbonyl) -N— (C _3-6 cycloalkyl) -amino group” (eg, N-cyclopropyl-N- (4-pyranylmethylcarbonyl) amino and the like ) And the like.

“C _1-6 alkylaminocarbonyl” means an “aminocarbonyl group substituted with mono- (C _1-6 alkyl)”.

“C _1-6 alkylaminothiocarbonyl” means a group in which the carbonyl of the “C _1-6 alkylaminocarbonyl group” is replaced with thiocarbonyl. Specific examples include methylaminothiocarbonyl and the like.

  The amino moiety in “aminocarbonyloxy” and “aminosulfonyl” is the same as the above “optionally substituted amino”.

“R ^6a and R ^6b , together with the atoms to which they are attached, are a C _3-6 cycloalkyl ring, a saturated heterocycle, a C _5-10 cycloalkenyl ring, a C _6-10 aryl ring, or a heterocycle An aryl ring may be formed "means that the compound represented by the formula (4) is a C _3-6 cycloalkyl ring (saturated cyclic alkyl ring having 3 to 6 carbon atoms), a saturated heterocycle (nitrogen atom, oxygen A 5- or 6-membered saturated heterocyclic ring having 1 to 3 of the same or different atoms selected from an atom and a sulfur atom, a C _5-10 cycloalkenyl ring (having 5 to 10 carbon atoms, A cyclic alkenyl ring containing an unsaturated bond), a C _6-10 aryl ring (aromatic ring having 6 to 10 carbon atoms), or a heteroaryl ring (5 to 10 membered monocyclic or polycyclic), Nitrogen atom, sulfur atom, oxygen atom Containing one heteroatom selected et.) 2 means that it is tricyclic compounds (wherein the carbon atom in each ring, formula (4) containing and R ^6a in the compound represented by Also included are carbon atoms to which R ^6b is attached.). For example,

で表される群から選択される化合物が挙げられる（式中、Ｒ^８は、各々独立して、水素原子、ハロゲン原子、Ｃ_１−４アルキル基、またはＣ_１−４アルコキシ基であり、ｎは、１〜４の整数である。）。

A compound selected from the group represented by the formula: wherein R ⁸ is each independently a hydrogen atom, a halogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxy group; Is an integer from 1 to 4.)

  Following formula

で表される基としては、例えば、下記群

Examples of the group represented by

で表される化合物が挙げられる。

The compound represented by these is mentioned.

  Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate, inorganic salts such as sodium, potassium and calcium, or acetate, propionic acid Salt, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbine Organic acid salts such as acid salts, or organic salts such as ethanolamine, meglumine, and triethanolamine.

The present invention is a method for producing a compound represented by the formula (3) including the following (1) to (3), or a pharmaceutically acceptable salt thereof.
(1): Step 2 of reacting a compound represented by formula (6) or a pharmaceutically acceptable salt thereof with sulfuryl chloride,
(2): Step 3 of reacting the compound represented by formula (7) following (1) above, and (3): the compound represented by formula (2) obtained by (2), or A step 1 of reacting a pharmaceutically acceptable salt with a compound represented by the formula (1) to produce a compound represented by the formula (3) or a pharmaceutically acceptable salt thereof.

  The present invention may be a method for producing a compound represented by the formula (2) including the above (1) and (2), or a pharmaceutically acceptable salt thereof.

Hereinafter, the manufacturing method in the present invention will be further described.
Production method 1 : Method for producing a compound represented by formula (3) or a pharmaceutically acceptable salt thereof

［式中、式中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、Ｇ、Ｒ^２、Ｍ、Ｒ^３、Ｒ^４およびＲ^５は、項１、または項２と同じである。］

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , G, R ² , M, R ³ , R ⁴ and R ⁵ are the same as in item 1 or item 2. ]

  In step 1, a compound represented by formula (3) (hereinafter sometimes referred to as compound (3)) is converted into a compound represented by compound (1) and formula (2) (hereinafter referred to as compound (2)). Can be prepared by reacting in a suitable inert solvent, if necessary, in the presence of a suitable base. The reaction temperature ranges from about -78 ° C to the boiling point of the solvent used, and is preferably -10 ° C to 40 ° C. The reaction time is 10 minutes to 5 days.

  Specific examples of the base used when used in Step 1 include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium hydroxide, sodium hydroxide. Inorganic bases such as sodium hydride, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide And organometallic reagents such as sodium bis (trimethylsilyl) amide, lithium amide, and n-butyllithium. Preferably 4-dimethylpyridine is mentioned. The amount of the base used is 0.1 to 100 equivalents, preferably 0.2 to 2 equivalents, relative to the equivalent of compound (7).

  Specific examples of the inert solvent in Step 1 include acetone, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane. And an aprotic polar solvent such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof, such as dimethoxyethane, tert-butyl methyl ether and cyclopentyl methyl ether. Preferably, tetrahydrofuran is used.

Production method 2 : Method for producing a compound represented by formula (2) or a pharmaceutically acceptable salt thereof

[式中、Ｒ^３、Ｒ^４、Ｒ^５およびＭは、項１、または項２と同じである。]

[Wherein R ³ , R ⁴ , R ⁵ and M are the same as in item 1 or item 2. ]

  The compound represented by the formula (6) (hereinafter sometimes referred to as the compound (6)) can be produced by using a known production method (for example, Synthesis 1990, 12, 1159.). I can do it. As the compound represented by the formula (7) (hereinafter sometimes referred to as the compound (7)), a commercially available one is used, or a known production method (for example, Tetrahydron Letters 1981, 22, 1109). Etc.) can be used.

  In step 2, the compound represented by formula (6a) (hereinafter sometimes referred to as compound (6a)) is produced by reacting compound (6) with sulfuryl chloride in a suitable inert solvent. I can do it. The reaction temperature ranges from about −78 ° C. to the boiling point of the solvent used, and is preferably −10 ° C. to 25 ° C. The reaction time is 10 minutes to 5 days. The amount of sulfuryl chloride used is 0.1 to 100 equivalents, preferably 0.8 to 2 equivalents, relative to the equivalent of compound (6).

  Specific examples of the inert solvent in Step 2 include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, Examples thereof include ether solvents such as tert-butyl methyl ether and cyclopentyl methyl ether, or a mixed solvent thereof. Preferably, toluene, tetrahydrofuran, chloroform, or dichloromethane is used.

  Compound (6a) produced in Step 2 is used in the next Step 3 with or without isolation.

  In step 3, compound (2) can be produced by reacting compound (6a) with compound (7) in a suitable inert solvent, if necessary, in the presence of a suitable base. The reaction temperature ranges from about -78 ° C to the boiling point of the solvent used, and is preferably -20 ° C to 40 ° C. The reaction time is 10 minutes to 5 days. The amount of the base used is 0 to 100 equivalents, preferably 0.8 to 5 equivalents, relative to the equivalent of compound (6) or compound (6a).

  The base used in Step 3 is, for example, an organic base such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, cesium carbonate, Inorganic bases such as sodium carbonate and sodium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, And organometallic reagents such as lithium amide and n-butyllithium. Preferred is pyridine or N-methylmorpholine. The amount of the base used is 0.1 to 100 equivalents, preferably 1 to 3 equivalents, relative to the equivalent of compound (7).

  Specific examples of the inert solvent in Step 3 include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, Examples thereof include ether solvents such as tert-butyl methyl ether and cyclopentyl methyl ether, or a mixed solvent thereof. Preferably, toluene, tetrahydrofuran, chloroform, or dichloromethane is used.

  Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

Note that in this specification, the following abbreviations may be used for simplification of description for simplification of description.
Boc: tert-butoxycarbonyl group Cbz: benzyloxycarbonyl group Ac: acetyl group Me: methyl group Et: ethyl group Pr: propyl group i-Pr: isopropyl group Bu: butyl group i-Bu: isobutyl group t-Bu: tert -Butyl group Ph: phenyl group Bn: benzyl group Bz: benzoyl group TFA: trifluoroacetic acid NMM: N-methylmorpholine DMAP: 4-dimethylaminopyridine

Reference Example 1: O- (1-chloroethyl) S-cyclohexyl carbonothioate

1-クロロエチル クロロホルメート (20g, 140 mmol)とシクロヘキサンチオール (12.2g, 105 mmol)のトルエン (100g)溶液に氷冷下、N-メチルモルホリン (14.9g)を10分間かけて滴下した。同温下、1時間半攪拌した後、室温に昇温させ、さらに3時間攪拌した。反応液に水 100ml)を加え、抽出した。有機層を5% 重曹水 (100ml)、水 (100ml)にて洗浄後、減圧濃縮し、参考例１の化合物 (36.5g, 93%)を得た。
¹H NMR (300 MHz, CDCl₃) δ:6.60 (q, J = 6.0 Hz, 1H), 3.48-3.36 (m, 1H), 2.11-1.95(m, 2H), 1.82 (d, J = 6.0 Hz, 3H), 1.85-1.22 (m, 8H).

N-methylmorpholine (14.9 g) was added dropwise over 10 minutes to a solution of 1-chloroethyl chloroformate (20 g, 140 mmol) and cyclohexanethiol (12.2 g, 105 mmol) in toluene (100 g) under ice cooling. After stirring at the same temperature for 1 hour and a half, the mixture was warmed to room temperature and further stirred for 3 hours. The reaction solution was extracted with 100 ml of water. The organic layer was washed with 5% aqueous sodium bicarbonate (100 ml) and water (100 ml) and then concentrated under reduced pressure to obtain the compound of Reference Example 1 (36.5 g, 93%).
¹ H NMR (300 MHz, CDCl ₃ ) δ: 6.60 (q, J = 6.0 Hz, 1H), 3.48-3.36 (m, 1H), 2.11-1.95 (m, 2H), 1.82 (d, J = 6.0 Hz , 3H), 1.85-1.22 (m, 8H).

Reference Example 2: 1-{[(cyclohexylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate

参考例１の化合物 (28g, 107 mmol)とイソ酪酸 (14.19g, 161 mmol)のトルエン (28g)溶液に氷冷下、N,N-ジイソプロピルエチルアミン (20.8g, 161 mmol)の混合液を10分間かけて滴下した。75℃下に加温し、10時間、加熱攪拌した。反応液にトルエン (50ml)と水 (72ml)を加えて抽出した。有機層を5% NaHCO₃水溶液 (72ml×2)、水 (72ml×2)で洗浄した。有機層を減圧濃縮し、参考例２の化合物 (26g, 88%)を得た。
¹H NMR (300 MHz, CDCl₃) δ:6.92 (q, J = 6.0 Hz, 1H), 3.43-3.22 (m, 1H), 2.62-2.49 (m, 1H), 2.09-1.92 (m, 2H), 1.82-1.68 (m, 2H), 1.65-1.07 (m, 15H).

A mixture of N, N-diisopropylethylamine (20.8 g, 161 mmol) in a toluene (28 g) solution of the compound of Reference Example 1 (28 g, 107 mmol) and isobutyric acid (14.19 g, 161 mmol) was cooled with ice. Added dropwise over a period of minutes. The mixture was heated at 75 ° C. and stirred for 10 hours. To the reaction solution, toluene (50 ml) and water (72 ml) were added for extraction. The organic layer was washed with 5% aqueous NaHCO ₃ solution (72 ml × 2) and water (72 ml × 2). The organic layer was concentrated under reduced pressure to obtain the compound of Reference Example 2 (26 g, 88%).
¹ H NMR (300 MHz, CDCl ₃ ) δ: 6.92 (q, J = 6.0 Hz, 1H), 3.43-3.22 (m, 1H), 2.62-2.49 (m, 1H), 2.09-1.92 (m, 2H) , 1.82-1.68 (m, 2H), 1.65-1.07 (m, 15H).

Reference Example 3: (3S, 4S) -1-hydroxy-2,5-dioxopyrrolidine-3,4-diyl dibenzoate

ジベンゾイル−Ｌ−酒石酸(50g, 140 mmol)に無水酢酸 (100g, 980 mmol)を室温下、加えた後、80℃下で2時間攪拌した。攪拌しながら室温に放冷し、さらに氷冷下で攪拌した。析出固体を濾過し、(3S,4S)-2,5-ジオキソテトラヒドロフラン-3,4-ジイル ジベンゾエート(44.1g, 93%)を得た。
得られた(3S,4S)-2,5-ジオキソテトラヒドロフラン-3,4-ジイル ジベンゾエート (44g, 129 mmol)のテトラヒドロフラン (220g)溶液に氷冷下、50% ヒドロキシアミン水溶液 (10.3g, 155 mmol)を10分間かけて滴下した。その後、室温に昇温させ、3時間攪拌した。反応液に0.5N 塩酸水 (220ml)と酢酸エチル (440ml)を加え、抽出した。有機層を飽和食塩水 (300ml)で洗浄後、硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別後、ろ液を減圧濃縮した。得られた残渣にトルエン (132ml)を加え、80℃下に4時間攪拌した。その後、攪拌しながら氷冷下に冷却し、2時間攪拌した。析出した固体を濾取し、参考例３の化合物 (42.8g, 93%)を得た。
¹H NMR (400 MHz, CDCl₃) δ:8.09-8.06 (m, 4H), 7.67-7.62 (m, 2H), 7.62-7.46 (m, 4H), 5.86 (s, 2H).

Acetic anhydride (100 g, 980 mmol) was added to dibenzoyl-L-tartaric acid (50 g, 140 mmol) at room temperature, and then stirred at 80 ° C. for 2 hours. The mixture was allowed to cool to room temperature with stirring, and further stirred under ice cooling. The precipitated solid was filtered to obtain (3S, 4S) -2,5-dioxotetrahydrofuran-3,4-diyl dibenzoate (44.1 g, 93%).
The obtained (3S, 4S) -2,5-dioxotetrahydrofuran-3,4-diyldibenzoate (44 g, 129 mmol) in tetrahydrofuran (220 g) solution under ice-cooling, 50% hydroxyamine aqueous solution (10.3 g, 155 mmol) was added dropwise over 10 minutes. Thereafter, the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was extracted with 0.5N aqueous hydrochloric acid (220 ml) and ethyl acetate (440 ml). The organic layer was washed with saturated brine (300 ml) and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated under reduced pressure. Toluene (132 ml) was added to the obtained residue, and the mixture was stirred at 80 ° C. for 4 hours. Thereafter, the mixture was cooled with ice cooling while stirring and stirred for 2 hours. The precipitated solid was collected by filtration to obtain the compound of Reference Example 3 (42.8 g, 93%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.09-8.06 (m, 4H), 7.67-7.62 (m, 2H), 7.62-7.46 (m, 4H), 5.86 (s, 2H).

Reference Example 4: (3R, 4R) -1-hydroxy-2,5-dioxopyrrolidine-3,4-diyl dibenzoate

参考例３に記載の同様の方法にて、ジベンゾイル−Ｄ−酒石酸(10.3g, 28.7 mmol)より参考例４の化合物 (5.5g, 73%)を得た。
1H NMR (400 MHz, CDCl₃) δ:8.11-8.03 (m, 4H), 7.67-7.59 (m, 2H), 7.51-7.41 (m, 4H), 5.89 (s, 2H).

In the same manner as described in Reference Example 3, the compound of Reference Example 4 (5.5 g, 73%) was obtained from dibenzoyl-D-tartaric acid (10.3 g, 28.7 mmol).
1H NMR (400 MHz, CDCl ₃ ) δ: 8.11-8.03 (m, 4H), 7.67-7.59 (m, 2H), 7.51-7.41 (m, 4H), 5.89 (s, 2H).

Reference Example 5: N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R) -piperidin-3-yl] -4- [2- (propionylamino) ethyl] -7- (trifluoromethyl ) -3,4-Dihydro-2H-1,4-benzoxazine-6-carboxamide

特許文献３に記載と同様の方法を用いて、参考例５の化合物を合成した。
¹H NMR (300 MHz, CDCl₃) δ:7.28-7.08 (m, 3H), 5.91 (brs, 1H), 4.26-2.60 (m, 11H), 2.41-2.10 (m, 2H), 1.69-1.38 (m, 10H), 1.22-1.00 (m, 8H).

Using the same method as described in Patent Document 3, the compound of Reference Example 5 was synthesized.
¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.28-7.08 (m, 3H), 5.91 (brs, 1H), 4.26-2.60 (m, 11H), 2.41-2.10 (m, 2H), 1.69-1.38 ( m, 10H), 1.22-1.00 (m, 8H).

Reference Example 6: N-isopropyl-2,2,7-trimethyl-3-oxo-N-[(3R) -piperidin-3-yl] -4- [2- (propionylamino) ethyl] -3,4- Dihydro-2H-1,4-benzoxazine-6-carboxamide

特許文献３に記載と同様の方法にて、参考例６の化合物を合成した。
¹H NMR (300 MHz,DMSO-d₆) δ:9.00-8.61 (m, 1H), 7.37-7.31 (m, 2H), 3.95-3.86 (m, 2H), 3.62-3.17 (m, 7H), 1.91-1.63 (m, 3H), 1.63-1.42 (m, 8H), 1.23-1.03 (m, 7H).

The compound of Reference Example 6 was synthesized by the same method as described in Patent Document 3.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.00-8.61 (m, 1H), 7.37-7.31 (m, 2H), 3.95-3.86 (m, 2H), 3.62-3.17 (m, 7H), 1.91-1.63 (m, 3H), 1.63-1.42 (m, 8H), 1.23-1.03 (m, 7H).

Reference Example 7: N-isopropyl-7-methyl-3-oxo-N-[(3R) -piperidin-3-yl] -4- [2- (propionylamino) ethyl] -3,4-dihydrospiro [1 , 4-Benzoxazine-2,1'-cyclobutane] -6-carboxamide

特許文献３に記載と同様の方法にて、参考例７の化合物を合成した。
1H NMR (300 MHz, CDCl₃) δ:7.28-7.10 (m, 2H), 6.86-6.75 (m, 2H), 6.14 (brs,1H), 4.30-3.32 (m, 4H), 3.26-2.57 (m, 4H), 2.49-2.10 (m, 8H), 2.08-1.41 (m, 11H), 1.22-1.01 (m, 6H).

The compound of Reference Example 7 was synthesized by the same method as described in Patent Document 3.
1H NMR (300 MHz, CDCl ₃ ) δ: 7.28-7.10 (m, 2H), 6.86-6.75 (m, 2H), 6.14 (brs, 1H), 4.30-3.32 (m, 4H), 3.26-2.57 (m , 4H), 2.49-2.10 (m, 8H), 2.08-1.41 (m, 11H), 1.22-1.01 (m, 6H).

Reference Example 8: (2S) -2- (methoxymethyl) -2,7-dimethyl-3-oxo-N-[(3R) -3-piperidinyl] -4- [2- (propanoylamino) ethyl]- N- (2-propanyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

N-isopropyl-2- (methoxymethyl) -2,7-dimethyl-3-oxo-N-[(3R) -piperidin-3-yl] -4-synthesized by the same method as described in Patent Document 3 [2- (propionylamino) ethyl] -3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride was subjected to HPLC fractionation under the following conditions to obtain the title compound.
CHIRALCEL® OD-H (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / 2-propanol / diethylamine (50/50 / 0.1), flow rate: 1.0 ml / min, temperature: 40 ° C. , Wavelength: 294nm
RT 4.252 min

¹ H NMR (400 MHz, CDCl ₃ ) δ6.92-6.72 (m, 2H), 6.30-6.03 (m, 1H), 4.14-3.66 (m, 4H), 3.65-2.61 (m, 10H), 2.30- 2.04 (m, 5H), 1.97-1.68 (m, 3H), 1.62-1.43 (m, 3H), 1.31-0.98 (m, 9H). MS (ESI +) 489 (M ⁺ +1, 100%).

Example 1: (3S, 4S) -1-[({(1R) -1-[(2-methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4- Diyl dibenzoate

窒素雰囲気下、参考例２の化合物 (10g, 36.5 mmol)のテトラヒドロフラン (20g)溶液に-5℃下、塩化スルフリル (7.4g, 54.7 mmol)を15分間かけて滴下した後、1時間攪拌した。同温下、参考例３の化合物 (10.4g, 29.2 mmol)のテトラヒドロフラン (17ml)溶液を加えた後、N-メチルモルホリン (7.4g, 72.9 mmol)を30分間かけてゆっくりと滴下した。同温下で2時間攪拌した後、反応液をセライト濾過し、ろ液に酢酸エチル (100ml)と水 (100ml)を加え、抽出した。有機層を水 (100ml)、飽和食塩水 (100ml)で洗浄した後、硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別し、ろ液を減圧濃縮した。得られた残渣にヘプタン (100ml)を加え、攪拌した後、濾取し、ジアステレオマー混合物として(3S,4S)-1-[({1-[(2-メチルプロパノイル)オキシ]エトキシ}カルボニル)オキシ]-2,5-ジオキソピロリジン-3,4-ジイル ジベンゾエート (14.4g)を得た。
得られたジアステレオマー混合物 (14.4g)に酢酸エチル (49ml)を加え、50℃下に加熱し、溶解させた後、ヘプタン (24.5ml)を加え、同温下で1時間攪拌した。室温に戻し、3時間攪拌した後、析出した個体 (3.6g)を濾取した。得た個体 (3.6g)に酢酸エチル (25ml)を加えて50℃下で溶解させた後、ヘプタン (16.5ml)を加え、同温下で1時間攪拌した。室温に戻した後、2時間攪拌し、析出した個体を濾取することで、実施例１の化合物 (2.6g, 98.9% d.e.)を得た。
1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエート
1H NMR (300 MHz, CDCl₃) δ:6.88-6.78 (m, 1H), 2.68-2.53 (m, 1H), 1.58 (d, J =5.5 Hz, 3H), 1.23-1.12 (m, 6H).
(3S,4S)-1-[({(1R)-1-[(2-メチルプロパノイル)オキシ]エトキシ}カルボニル)オキシ]-2,5-ジオキソピロリジン-3,4-ジイル ジベンゾエート
¹H NMR (400 MHz, CDCl₃) δ:8.12-8.07 (m, 4H), 7.68-7.60 (m, 2H), 7.52-7.45 (m, 4H), 6.89 (q, J = 5.4 Hz, 1H), 6.01 (brs, 2H), 2.61 (qq, J = 7.0, 7.0 Hz, 1H), 1.65 (d, J = 5.4 Hz, 3H), 1.20 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK（登録商標） IC (0.46 cmI.D. x 25 cmL)、移動層： n-ヘキサン/塩化メチレン=60/40、流速：1.0 mL/min、温度：40℃、波長：254nm
RT 17.855 min.

Under a nitrogen atmosphere, sulfuryl chloride (7.4 g, 54.7 mmol) was added dropwise to a tetrahydrofuran (20 g) solution of the compound of Reference Example 2 (10 g, 36.5 mmol) at −5 ° C. over 15 minutes, followed by stirring for 1 hour. Under the same temperature, a solution of the compound of Reference Example 3 (10.4 g, 29.2 mmol) in tetrahydrofuran (17 ml) was added, and N-methylmorpholine (7.4 g, 72.9 mmol) was slowly added dropwise over 30 minutes. After stirring at the same temperature for 2 hours, the reaction mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with water (100 ml) and saturated brine (100 ml) and then dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. Heptane (100 ml) was added to the resulting residue, stirred, and then collected by filtration to obtain (3S, 4S) -1-[({1-[(2-methylpropanoyl) oxy] ethoxy} as a diastereomeric mixture. Carbonyl) oxy] -2,5-dioxopyrrolidine-3,4-diyl dibenzoate (14.4 g) was obtained.
Ethyl acetate (49 ml) was added to the obtained diastereomer mixture (14.4 g), heated at 50 ° C. to dissolve, heptane (24.5 ml) was added, and the mixture was stirred at the same temperature for 1 hour. After returning to room temperature and stirring for 3 hours, the precipitated solid (3.6 g) was collected by filtration. Ethyl acetate (25 ml) was added to the obtained solid (3.6 g) and dissolved at 50 ° C., heptane (16.5 ml) was added, and the mixture was stirred at the same temperature for 1 hr. After returning to room temperature, the mixture was stirred for 2 hours, and the precipitated solid was collected by filtration to obtain the compound of Example 1 (2.6 g, 98.9% de).
1-{(Chlorocarbonyl) oxy} ethyl 2-methylpropanoate
1H NMR (300 MHz, CDCl ₃ ) δ: 6.88-6.78 (m, 1H), 2.68-2.53 (m, 1H), 1.58 (d, J = 5.5 Hz, 3H), 1.23-1.12 (m, 6H).
(3S, 4S) -1-[({(1R) -1-[(2-Methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4-diyl dibenzoate
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.12-8.07 (m, 4H), 7.68-7.60 (m, 2H), 7.52-7.45 (m, 4H), 6.89 (q, J = 5.4 Hz, 1H) , 6.01 (brs, 2H), 2.61 (qq, J = 7.0, 7.0 Hz, 1H), 1.65 (d, J = 5.4 Hz, 3H), 1.20 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / methylene chloride = 60/40, flow rate: 1.0 mL / min, temperature: 40 ° C., wavelength: 254 nm
RT 17.855 min.

Example 2: (3R, 4R) -1-[({(1S) -1-[(2-methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4- Diyl dibenzoate

実施例１に記載と同様の方法にて、参考例２の化合物と参考例４の化合物より実施例２の化合物 (97.5% d.e.)を得た。
¹H NMR (400 MHz, CDCl₃) δ:8.12-8.06 (m, 4H), 7.68-7.61 (m, 2H), 7.53-7.45 (m, 4H), 6.89 (q, J = 5.4 Hz, 1H), 6.01 (brs, 2H), 2.61 (qq, J = 7.0, 7.0 Hz, 1H), 1.65 (d, J = 5.4 Hz, 3H), 1.20 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK（登録商標） IC (0.46 cmI.D. x 25 cmL)、移動層： n-ヘキサン/塩化メチレン=60/40、流速：1.0 mL/min、温度：40℃、波長：254nm
RT 10.018 min.

In the same manner as described in Example 1, the compound of Example 2 (97.5% de) was obtained from the compound of Reference Example 2 and the compound of Reference Example 4.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.12-8.06 (m, 4H), 7.68-7.61 (m, 2H), 7.53-7.45 (m, 4H), 6.89 (q, J = 5.4 Hz, 1H) , 6.01 (brs, 2H), 2.61 (qq, J = 7.0, 7.0 Hz, 1H), 1.65 (d, J = 5.4 Hz, 3H), 1.20 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / methylene chloride = 60/40, flow rate: 1.0 mL / min, temperature: 40 ° C., wavelength: 254 nm
RT 10.018 min.

Example 3: 1-({[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) oxy] carbonyl} oxy) ethyl 2-methylpropanate

窒素雰囲気下、参考例２の化合物 (1g, 3.64 mmol)のテトラヒドロフラン (18.2 ml)溶液に0℃下、塩化スルフリル (0.59ml, 7.29 mmol)をゆっくりと滴下した後、30分間攪拌した。さらに同温下でヒドロキシフタルイミド (535mg, 3.28 mmol)のテトラヒドロフラン (18.2 ml)溶液をゆっくりと滴下した後、さらにN-メチルモルホリン (1.2 ml)をゆっくりと滴下した。同温下で2時間攪拌後、反応液をセライト濾過した。ろ液に酢酸エチル (20ml)と水 (20ml)を加え、抽出した。有機層を飽和食塩水 (30ml)で洗浄した後、硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別後、ろ液を減圧濃縮した。得られた残渣にイソプロピルアルコール (1.05g)を加え、40℃下で加温し、溶解させた。そこにヘキサン (16.8ml)を加え、30分間攪拌した。自然と室温まで放冷させた後、氷冷下で30分間攪拌した。析出した白色個体を濾取し、白色個体として実施例３の化合物 (660mg, 56%)を得た。
¹H NMR (400 MHz, CDCl₃) δ:8.00-7.71 (m, 4H), 6.87 (q, J = 5.5 Hz, 1H), 2.61 (qq, J = 6.9, 6.9 Hz, 1H), 1.20 (dd, J = 3.1, 3.1 Hz, 3H), 1.31-1.08 (m, 6H).

Under a nitrogen atmosphere, sulfuryl chloride (0.59 ml, 7.29 mmol) was slowly added dropwise to a solution of the compound of Reference Example 2 (1 g, 3.64 mmol) in tetrahydrofuran (18.2 ml) at 0 ° C., followed by stirring for 30 minutes. Further, a solution of hydroxyphthalimide (535 mg, 3.28 mmol) in tetrahydrofuran (18.2 ml) was slowly added dropwise at the same temperature, and further N-methylmorpholine (1.2 ml) was added dropwise slowly. After stirring at the same temperature for 2 hours, the reaction solution was filtered through Celite. Ethyl acetate (20 ml) and water (20 ml) were added to the filtrate for extraction. The organic layer was washed with saturated brine (30 ml) and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated under reduced pressure. Isopropyl alcohol (1.05 g) was added to the resulting residue and heated at 40 ° C. to dissolve. Hexane (16.8 ml) was added thereto and stirred for 30 minutes. The mixture was naturally allowed to cool to room temperature, and then stirred for 30 minutes under ice cooling. The precipitated white solid was collected by filtration to obtain the compound of Example 3 (660 mg, 56%) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.00-7.71 (m, 4H), 6.87 (q, J = 5.5 Hz, 1H), 2.61 (qq, J = 6.9, 6.9 Hz, 1H), 1.20 (dd , J = 3.1, 3.1 Hz, 3H), 1.31-1.08 (m, 6H).

Example 4: (1S) -1-({[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) oxy] carbonyl} oxy) ethyl 2-methylpropanoate

参考例２の化合物を下記に示したＨＰＬＣ条件にて分取し、(1S)-1-{[(シクロヘキシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート(>98% e.e.)を得た。
実施例３に記載と同様の方法にて、得られた(1S)-1-{[(シクロヘキシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (1g, 3.64 mmol)より実施例４の化合物 (736mg, 63%)を得た。
¹H NMR (300 MHz, CDCl₃) δ:7.91-7.78 (m, 4H), 6.84 (q, J = 5.5 Hz, 1H), 2.58 (qq, J = 7.0, 7.0 Hz, 1H), 1.62 (d, J = 5.5 Hz, 3H), 1.18 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK（登録商標） AD-H (0.46 cmI.D. x 25 cmL)、移動層： n-ヘキサン/エタノール=98/2、流速：0.5 mL/min、温度：40℃、波長：254nm
RT 7.810 min.

The compound of Reference Example 2 was fractionated under the HPLC conditions shown below to obtain (1S) -1-{[(cyclohexylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (> 98% ee). .
In the same manner as described in Example 3, the compound of Example 4 was obtained from (1S) -1-{[(cyclohexylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (1 g, 3.64 mmol). (736 mg, 63%) was obtained.
¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.91-7.78 (m, 4H), 6.84 (q, J = 5.5 Hz, 1H), 2.58 (qq, J = 7.0, 7.0 Hz, 1H), 1.62 (d , J = 5.5 Hz, 3H), 1.18 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK (registered trademark) AD-H (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / ethanol = 98/2, flow rate: 0.5 mL / min, temperature: 40 ° C., wavelength: 254 nm
RT 7.810 min.

Example 5: (1R) -1-({[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) oxy] carbonyl} oxy) ethyl 2-methylpropanoate

参考例２の化合物を下記に示したＨＰＬＣ条件にて分取し、(1R)-1-{[(シクロヘキシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (>98% e.e.)を得た。
実施例３に記載と同様の方法にて、得られた(1R)-1-{[(シクロヘキシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (1g, 3.64 mmol)より実施例５の化合物 (720mg, 62%)を得た。
¹H NMR (300 MHz, CDCl₃) δ:7.92-7.79 (m, 4H), 6.86 (q, J = 5.3 Hz, 1H), 2.63 (qq, J = 7.0, 7.0 Hz, 1H), 1.63 (d, J = 5.3 Hz, 3H), 1.19 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK（登録商標） AD-H (0.46 cmI.D. x 25 cmL)、移動層： n-ヘキサン/エタノール=98/2、流速：0.5 mL/min、温度：40℃、波長：254nm
RT 9.336 min.

The compound of Reference Example 2 was fractionated under the HPLC conditions shown below to obtain (1R) -1-{[(cyclohexylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (> 98% ee). .
In a similar manner as described in Example 3, the compound of Example 5 was obtained from (1R) -1-{[(cyclohexylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (1 g, 3.64 mmol). (720 mg, 62%) was obtained.
¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.92-7.79 (m, 4H), 6.86 (q, J = 5.3 Hz, 1H), 2.63 (qq, J = 7.0, 7.0 Hz, 1H), 1.63 (d , J = 5.3 Hz, 3H), 1.19 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK (registered trademark) AD-H (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / ethanol = 98/2, flow rate: 0.5 mL / min, temperature: 40 ° C., wavelength: 254 nm
RT 9.336 min.

Example 6: 1-[({[1,3-Dioxo-1,3,3a, 4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl] oxy} carbonyl) oxy] Ethyl 2-methylpropanoate

実施例３に記載と同様の方法にて、参考例２の化合物 (581mg, 2.12 mmol)から実施例６の化合物(900mg)を得た。
¹H NMR (300 MHz, CDCl₃) δ:6.79 (q, J = 5.3 Hz, 1H), 6.18 (s, 2H), 3.54-3.22 (m, 4H), 2.58 (qq, J = 7.0, 7.0 Hz, 1H), 1.84-1.49 (m, 5H), 1.20-1.16 (m, 6H).

In the same manner as described in Example 3, the compound of Example 6 (900 mg) was obtained from the compound of Reference Example 2 (581 mg, 2.12 mmol).
¹ H NMR (300 MHz, CDCl ₃ ) δ: 6.79 (q, J = 5.3 Hz, 1H), 6.18 (s, 2H), 3.54-3.22 (m, 4H), 2.58 (qq, J = 7.0, 7.0 Hz , 1H), 1.84-1.49 (m, 5H), 1.20-1.16 (m, 6H).

Example 7: 1-{[(Pyridin-2-yloxy) carbonyl] oxy} ethyl 2-methylpropanoate

実施例３に記載と同様の方法にて、参考例２の化合物 (1g, 3.64 mmol)から実施例７の化合物 (242mg)を得た。
¹H NMR (300 MHz, CDCl₃) δ:8.44-8.38 (m, 1H), 7.83-7.78 (m, 1H), 7.30-7.13 (m, 2H), 6.85 (q, J = 5.5 Hz, 1H), 2.59 (qq, J = 7.0, 7.0 Hz, 1H), 1.60 (d, J = 5.5 Hz, 3H), 1.16 (dd, J = 7.0, 7.0 Hz, 6H).

In the same manner as described in Example 3, the compound of Example 7 (242 mg) was obtained from the compound of Reference Example 2 (1 g, 3.64 mmol).
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.44-8.38 (m, 1H), 7.83-7.78 (m, 1H), 7.30-7.13 (m, 2H), 6.85 (q, J = 5.5 Hz, 1H) , 2.59 (qq, J = 7.0, 7.0 Hz, 1H), 1.60 (d, J = 5.5 Hz, 3H), 1.16 (dd, J = 7.0, 7.0 Hz, 6H).

Example 8: (1R) -1-[(2-methylpropanoyl) oxy] ethyl (3R) -3-[({2,2-dimethyl-3-oxo-4- [2- (propanoylamino) Ethyl] -7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazin-6-yl} carbonyl) (propan-2-yl) amino] piperidine-1-carboxylate

参考例５の化合物 (1.87g, 3.64 mmol)のテトラヒドロフラン (18.2ml)溶液に室温下、実施例１の化合物 (1.87g, 3.64 mmol)を加え、2時間攪拌した。反応液を減圧濃縮後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、実施例８の化合物(2.19g, 90%)を得た。
¹H NMR (300 MHz, CDCl₃) δ:7.28-7.21 (m, 2H), 6.90-6.80 (m, 1H), 5.90 (brs, 1H),4.25-3.81 (m, 5H), 3.72-3.30 (m, 3H), 3.28-2.71 (m. 2H), 2.60-2.42 (m, 1H), 2.25-2.11 (m, 2H), 1.86-1.33 (m, 13H), 1.25-1.07 (m, 15H).
MS (ESI+) 671 (M+1, 100%)．

The compound of Example 1 (1.87 g, 3.64 mmol) was added to a solution of the compound of Reference Example 5 (1.87 g, 3.64 mmol) in tetrahydrofuran (18.2 ml) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain the compound of Example 8 (2.19 g, 90%).
¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.28-7.21 (m, 2H), 6.90-6.80 (m, 1H), 5.90 (brs, 1H), 4.25-3.81 (m, 5H), 3.72-3.30 ( m, 3H), 3.28-2.71 (m. 2H), 2.60-2.42 (m, 1H), 2.25-2.11 (m, 2H), 1.86-1.33 (m, 13H), 1.25-1.07 (m, 15H).
MS (ESI +) 671 (M + 1, 100%).

Example 9: 1-[(2-Methylpropanoyl) oxy] ethyl (3R) -3- [propan-2-yl ({2,2,7-trimethyl-3-oxo-4- [2- (prop Noylamino) ethyl] -3,4-dihydro-2H-1,4-benzoxazin-6-yl} carbonyl) amino] piperazine-1-carboxylate

実施例８に記載と同様の方法にて、参考例６の化合物 (97.4mg, 0.21 mmol)と実施例７の化合物 (53.8mg, 0.21 mmol)から実施例９の化合物 (97.8mg, 75%)を得た。
¹H NMR (300 MHz, d₆-DMSO) δ:8.01-7.94 (m, 1H), 7.33-7.10 (m, 1H), 6.86-6.84 (m, 1H), 6.67-6.65 (m, 1H), 3.85-3.62 (m, 3H), 3.34-3.01 (m, 3H), 2.78-2.70 (m, 2H), 2.16-2.14 (m, 3H), 2.04-1.98 (m, 2H), 1.50-1.35 (m, 13H), 1.13-0.81 (m, 18H)．
MS (ESI+) 617 (M+1, 37%)．

In the same manner as in Example 8, the compound of Reference Example 6 (97.4 mg, 0.21 mmol) and the compound of Example 7 (53.8 mg, 0.21 mmol) to the compound of Example 9 (97.8 mg, 75%) Got.
¹ H NMR (300 MHz, d ₆ -DMSO) δ: 8.01-7.94 (m, 1H), 7.33-7.10 (m, 1H), 6.86-6.84 (m, 1H), 6.67-6.65 (m, 1H), 3.85-3.62 (m, 3H), 3.34-3.01 (m, 3H), 2.78-2.70 (m, 2H), 2.16-2.14 (m, 3H), 2.04-1.98 (m, 2H), 1.50-1.35 (m , 13H), 1.13-0.81 (m, 18H).
MS (ESI +) 617 (M + 1, 37%).

Example 10: (1R) -1-[(2-methylpropanoyl) oxy] ethyl (3R) -3- [propan-2-yl ({2,2,7-trimethyl-3-oxo-4- [ 2- (propanoylamino) ethyl] -3,4-dihydro-2H-1,4-benzoxazin-6-yl} carbonyl) amino] piperazine-1-carboxylate

窒素雰囲気下、参考例６の化合物 (1.01g, 2.2 mmol)のテトラヒドロフラン (4.5 ml)溶液に室温下、実施例１の化合物 (1.1g, 2.20 mmol)を加え、1時間半攪拌した。反応液に酢酸エチル (5ml)と水 (10ml)を加え、抽出した。有機層を飽和食塩水 (10ml)にて洗浄した後、硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別後、ろ液を減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィーにて精製し、実施例１０の化合物 (1.17g, 88%)を得た。
¹H NMR (400 MHz, CDCl₃) δ:6.93-6.77 (m, 3H), 6.03-5.88 (m, 1H), 4.17-3.86 (m, 6H), 3.80-3.69 (m, 1H), 3.63-3.49 (m, 2H), 3.13-2.72 (m, 3H), 2.58-2.47 (m, 1H), 2.22 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1.89-1.70 (m, 2H), 1.54-1.41 (m, 9H), 1.17-1.09 (m, 15H)．
MS (ESI+) 617 (M+1, 7%)．
CHIRALPAK（登録商標） IC (0.46 cmI.D. x 25 cmL)、移動層：ヘキサン/エタノール=50/50 (v/v)、流速：1.0 mL/min、温度：25℃、波長：254nm、RT 13.706 min.

Under a nitrogen atmosphere, the compound of Example 1 (1.1 g, 2.20 mmol) was added to a solution of the compound of Reference Example 6 (1.01 g, 2.2 mmol) in tetrahydrofuran (4.5 ml) at room temperature, and the mixture was stirred for 1.5 hours. Ethyl acetate (5 ml) and water (10 ml) were added to the reaction solution and extracted. The organic layer was washed with saturated brine (10 ml) and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain the compound of Example 10 (1.17 g, 88%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.93-6.77 (m, 3H), 6.03-5.88 (m, 1H), 4.17-3.86 (m, 6H), 3.80-3.69 (m, 1H), 3.63- 3.49 (m, 2H), 3.13-2.72 (m, 3H), 2.58-2.47 (m, 1H), 2.22 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1.89-1.70 (m, 2H), 1.54-1.41 (m, 9H), 1.17-1.09 (m, 15H).
MS (ESI +) 617 (M + 1, 7%).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: hexane / ethanol = 50/50 (v / v), flow rate: 1.0 mL / min, temperature: 25 ° C., wavelength: 254 nm, RT 13.706 min.

Example 11: (1R) -1-[(2-methylpropanoyl) oxy] ethyl (3R) -3-[({7-methyl-3-oxo-4- [2- (propanoylamino) ethyl] -3,4-Dihydrospiro [1,4-benzoxazine-2,1'-cyclobutane] -6-yl} carbonyl) (propan-2-yl) amino] piperidine-1-carboxylate

実施例１０に記載と同様の方法にて、参考例７の化合物 (1.11g, 2.35 mmol)から実施例１１の化合物 (1.23g, 83%)を得た。
¹H NMR (400 MHz, CDCl₃) δ:6.92-6.78 (m, 3H), 6.06-5.96 (m, 1H), 4.21-3.87 (m, 6H), 3.81-3.42 (m, 3H), 3.12-2.15 (m, 13H), 2.04-1.80 (m, 4H), 1.54-1.45 (m, 3H), 1.25-1.09 (m, 15H)．
MS (ESI+) 629 (M+1, 100%)．
CHIRALPAK（登録商標) IC (0.46 cmI.D. x 25 cmL)、移動層：ヘキサン/エタノール=50/50 (v/v)、流速：1.0 mL/min、温度：25℃、波長：254nm、RT 15.809 min

In the same manner as described in Example 10, the compound of Example 11 (1.23 g, 83%) was obtained from the compound of Reference Example 7 (1.11 g, 2.35 mmol).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.92-6.78 (m, 3H), 6.06-5.96 (m, 1H), 4.21-3.87 (m, 6H), 3.81-3.42 (m, 3H), 3.12- 2.15 (m, 13H), 2.04-1.80 (m, 4H), 1.54-1.45 (m, 3H), 1.25-1.09 (m, 15H).
MS (ESI +) 629 (M + 1, 100%).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: hexane / ethanol = 50/50 (v / v), flow rate: 1.0 mL / min, temperature: 25 ° C., wavelength: 254 nm, RT 15.809 min

Example 12: (1S) -1-[(2-methylpropanoyl) oxy] ethyl (3R) -3-[({7-methyl-3-oxo-4- [2- (propanoylamino) ethyl] -3,4-Dihydrospiro [1,4-benzoxazine-2,1'-cyclobutane] -6-yl} carbonyl) (propan-2-yl) amino] piperidine-1-carboxylate

参考例７の塩酸塩 (34.1mg, 0.067 mmol)のテトラヒドロフラン (1ml)溶液に室温下、実施例２の化合物 (34.5mg, 0.067 mmol)と4-ジメチルアミノピリジン (3.3mg, 0.027 mmol)を加えた後、3時間攪拌した。反応液に酢酸エチル (10ml)と水 (10ml)を加え、抽出した。有機層を飽和食塩水 (5ml)で洗浄後、硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別後、ろ液を減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィーにて精製し、実施例１２の化合物 (35.7mg, 85%)を得た。
¹H NMR (400 MHz, CDCl₃) δ:6.91-6.78 (m, 3H), 6.14-6.00 (m, 1H), 4.21-3.88 (m, 6H), 3.82-3.68 (m, 1H), 3.62-49 (m, 2H), 3.14-2.98 (m, 1H), 2.97-2.74 (m, 2H), 2.73-2.64 (m, 1H), 2.62-2.49 (m, 1H), 2.48-2.38 (m, 1H), 2.47-2.13 (m, 5H), 2.05-1.71 (m, 4H), 1.62-1.38 (m, 3H), 1.77-1.08 (m, 15H)．
MS (ESI+) 629 (M+1, 100%)．
CHIRALPAK（登録商標） IC (0.46 cmI.D. x 25 cmL)、移動層：ヘキサン/エタノール=50/50 (v/v)、流速：1.0 mL/min、温度：25℃、波長：254nm、 RT 9.675 min.

To a solution of the hydrochloride salt of Reference Example 7 (34.1 mg, 0.067 mmol) in tetrahydrofuran (1 ml) at room temperature was added the compound of Example 2 (34.5 mg, 0.067 mmol) and 4-dimethylaminopyridine (3.3 mg, 0.027 mmol). Then, the mixture was stirred for 3 hours. Ethyl acetate (10 ml) and water (10 ml) were added to the reaction solution and extracted. The organic layer was washed with saturated brine (5 ml) and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain the compound of Example 12 (35.7 mg, 85%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.91-6.78 (m, 3H), 6.14-6.00 (m, 1H), 4.21-3.88 (m, 6H), 3.82-3.68 (m, 1H), 3.62- 49 (m, 2H), 3.14-2.98 (m, 1H), 2.97-2.74 (m, 2H), 2.73-2.64 (m, 1H), 2.62-2.49 (m, 1H), 2.48-2.38 (m, 1H ), 2.47-2.13 (m, 5H), 2.05-1.71 (m, 4H), 1.62-1.38 (m, 3H), 1.77-1.08 (m, 15H).
MS (ESI +) 629 (M + 1, 100%).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: hexane / ethanol = 50/50 (v / v), flow rate: 1.0 mL / min, temperature: 25 ° C., wavelength: 254 nm, RT 9.675 min.

Example 13: 1-[(2-Methylpropanoyl) oxy] ethyl (3R) -3-[({7-methyl-3-oxo-4- [2- (propanoylamino) ethyl] -3,4 -Dihydrospiro [1,4-benzoxazine-2,1'-cyclobutane] -6-yl} carbonyl) (propan-2-yl) amino] piperidine-1-carboxylate
a)

実施例１０に記載と同様の方法にて、参考例７の化合物 (94.9mg, 0.20 mol)と実施例３の化合物 (68mg, 0.21 mmol)から実施例１３の化合物 (102mg, 80%)を得た。
b)

In the same manner as described in Example 10, the compound of Example 13 (102 mg, 80%) was obtained from the compound of Reference Example 7 (94.9 mg, 0.20 mol) and the compound of Example 3 (68 mg, 0.21 mmol). It was.
b)

実施例１０に記載と同様の方法にて、参考例７の化合物 (13.8mg, 0.029 mol)と実施例６の化合物 (9.9mg, 0.029 mmol)から実施例１３の化合物 (15.2mg, 83%)を得た。

In the same manner as described in Example 10, the compound of Reference Example 7 (13.8 mg, 0.029 mol) and the compound of Example 6 (9.9 mg, 0.029 mmol) to the compound of Example 13 (15.2 mg, 83%) Got.

Example 14: (R)-((R) -1- (isobutyryloxy) ethyl) 3-((S) -N-isopropyl-2- (methoxymethyl) -2,7-dimethyl-3-oxo -4- (2-propionamidoethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-6-carboxamide) piperidine-1-carboxylate

実施例１０に記載と同様の方法にて、参考例８の化合物 (1.67g, 3.42 mmol)から実施例１４の化合物 (1.13g, 51%)を得た。
¹H NMR (400 MHz, d6-DMSO) δ:8.02-7.89 (m, 1H), 7.38-7.04 (m, 1H), 6.88-6.79 (m, 1H), 6.70-6.62 (m, 1H), 4.09-3.72 (m, 5H), 3.67-3.41 (m, 3H), 3.32 (s, 3H), 3.27-3.05 (m, 6H), 2.84-2.62 (m, 2H), 2.21-1.95 (m, 4H), 1.54-1.23 (m, 9H), 1.14-0.89 (m, 12H).
MS (ESI+) 647 (M+1, 91%)．
CHIRALPAK（登録商標） IC (0.46 cmI.D. x 25 cmL)、移動層：n-ヘキサン/エタノール=50/50、流速：1.0 mL/min、温度：40℃、波長：254nm、RT 10.753 min

In the same manner as in Example 10, the compound of Example 14 (1.13 g, 51%) was obtained from the compound of Reference Example 8 (1.67 g, 3.42 mmol).
¹ H NMR (400 MHz, d6-DMSO) δ: 8.02-7.89 (m, 1H), 7.38-7.04 (m, 1H), 6.88-6.79 (m, 1H), 6.70-6.62 (m, 1H), 4.09 -3.72 (m, 5H), 3.67-3.41 (m, 3H), 3.32 (s, 3H), 3.27-3.05 (m, 6H), 2.84-2.62 (m, 2H), 2.21-1.95 (m, 4H) , 1.54-1.23 (m, 9H), 1.14-0.89 (m, 12H).
MS (ESI +) 647 (M + 1, 91%).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / ethanol = 50/50, flow rate: 1.0 mL / min, temperature: 40 ° C., wavelength: 254 nm, RT 10.753 min

In addition to the compound represented by Formula (3) described above, for example, Compound Nos. 1 to 78 described in the following table can be similarly produced by the production method of the present application.

Comparative Example 1: 1-chloro-2-methylpropyl (3R) -3- [isopropyl ({2,2,7-trimethyl-3-oxo-4- [2- (propionylamino) ethyl] -3,4- Dihydro-2H-1,4-benzoxazin-6-yl} carbonyl) amino] piperidine-1-carboxylate

窒素雰囲気下、参考例６ (4g, 8.1 mmol)のクロロホルム (40ml)溶液に氷冷下、トリエチルアミン (2.3ml, 16.2 mmol)、1-クロロエチル クロロホルメート (0.9ml, 8.1 mmol)を順次加えた後、室温に昇温させ、3時間攪拌した。反応液に水 (20ml)と飽和食塩水 (20ml)を加え、クロロホルムで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィーにて精製し、1-クロロ-2-メチルプロピル(3R)-3-[イソプロピル({2,2,7-トリメチル-3-オキソ-4-[2-(プロピオニルアミノ)エチル]-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル}カルボニル)アミノ]ピペリジン-1-カルボキシレート (3.8g, 84%)を得た。
MS (ESI+) 565 (M+1, 10%)

Under a nitrogen atmosphere, triethylamine (2.3 ml, 16.2 mmol) and 1-chloroethyl chloroformate (0.9 ml, 8.1 mmol) were sequentially added to a chloroform (40 ml) solution of Reference Example 6 (4 g, 8.1 mmol) under ice cooling. Thereafter, the mixture was warmed to room temperature and stirred for 3 hours. Water (20 ml) and saturated brine (20 ml) were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography, and 1-chloro-2-methylpropyl (3R) -3- [isopropyl ({2,2,7-trimethyl-3-oxo- 4- [2- (propionylamino) ethyl] -3,4-dihydro-2H-1,4-benzoxazin-6-yl} carbonyl) amino] piperidine-1-carboxylate (3.8 g, 84%) was obtained. It was.
MS (ESI +) 565 (M + 1, 10%)

Comparative Example 2:

  Propionic acid (2 mL) and silver carbonate (2.93 g) were added to a chloroform (35 ml) solution of the compound of Comparative Example 1 (4 g), and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/80) to give the compound of Example 9 (2.5 g, 56%).

Comparative Example 3:

比較例１、および比較例２に記載と同様の方法にて、参考例５の化合物からアキラルな実施例８の化合物（51%, 2steps）を得た。
¹H NMR (300 MHz, d₆-DMSO) δ:8.15-7.97 (m, 1H), 7.75-7.27 (m, 2H), 6.69-6.46 (m, 1H), 3.92-3.61 (m, 3H), 3.34-2.98 (m, 3H), 2.75-2.69 (m, 2H), 2.08-2.00 (m, 2H), 1.77-1.33 (m, 13H), 1.18-0.81 (m, 18H) ．
MS (ESI+) 671 (M+1, 32%)．

The achiral compound of Example 8 (51%, 2steps) was obtained from the compound of Reference Example 5 in the same manner as described in Comparative Example 1 and Comparative Example 2.
¹ H NMR (300 MHz, d ₆ -DMSO) δ: 8.15-7.97 (m, 1H), 7.75-7.27 (m, 2H), 6.69-6.46 (m, 1H), 3.92-3.61 (m, 3H), 3.34-2.98 (m, 3H), 2.75-2.69 (m, 2H), 2.08-2.00 (m, 2H), 1.77-1.33 (m, 13H), 1.18-0.81 (m, 18H).
MS (ESI +) 671 (M + 1, 32%).

Comparative Example 4:

比較例１、および比較例２に記載と同様の方法にて、参考例７の化合物 (300mg)から実施例１３の化合物（187mg, 56%）を得た。

In the same manner as described in Comparative Example 1 and Comparative Example 2, the compound of Example 13 (187 mg, 56%) was obtained from the compound of Reference Example 7 (300 mg).

  The yields when Example 9, Chiral Example 8, and Example 13b) were produced by the production method described in the present invention were 75%, 90%, and 83%, respectively. Significant improvements over the yields described in 4 (47%, 51%, and 56%) were observed. That is, the present invention is an excellent method for producing the compound represented by the formula (3).

Comparative Example 5:

実施例１に記載と同様の方法にて、参考例２の化合物 (1.0g, 3.64 mmol)に塩化スルフリルを氷冷下で反応させ、1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートを得た。反応液に参考例３の化合物よりも先にN-メチルモルホリン (0.18ml)を加えたところ、1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートの分解が認められた。

In the same manner as described in Example 1, the compound of Reference Example 2 (1.0 g, 3.64 mmol) was reacted with sulfuryl chloride under ice-cooling to give 1-{(chlorocarbonyl) oxy} ethyl 2-methylpropano. Got ate. When N-methylmorpholine (0.18 ml) was added to the reaction solution prior to the compound of Reference Example 3, decomposition of 1-{(chlorocarbonyl) oxy} ethyl 2-methylpropanoate was observed.

  In order to efficiently obtain the compound of Example 1 having high purity, the order of adding the reagents is necessary. That is, it is important to react the compound (2) with sulfuryl chloride, confirm the formation of the chlorocarbonyloxy form, add the compound (7), and finally add N-methylmorpholine dropwise.

Comparative Example 6:

窒素雰囲気下、参考例２の化合物 (258mg, 0.94 mmol)のテトラヒドロフラン (1ml)溶液に0℃下、塩化スルフリル (0.15ml, 1.88 mmol)を加え、1時間攪拌し、1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートが生成していることを確認した。同温下、反応液に参考例７の化合物 (431mg, 0.94 mmol)とN-メチルモルホリン (0.31ml, 2.82 mmol)のテトラヒドロフラン (1ml)溶液をゆっくりと滴下した後、1時間攪拌したが、目的物の生成は確認出来なかった。

Under a nitrogen atmosphere, sulfuryl chloride (0.15 ml, 1.88 mmol) was added to a solution of the compound of Reference Example 2 (258 mg, 0.94 mmol) in tetrahydrofuran (1 ml) at 0 ° C. and stirred for 1 hour, and 1-{(chlorocarbonyl) It was confirmed that oxy} ethyl 2-methylpropanoate was produced. At the same temperature, a solution of the compound of Reference Example 7 (431 mg, 0.94 mmol) and N-methylmorpholine (0.31 ml, 2.82 mmol) in tetrahydrofuran (1 ml) was slowly added dropwise to the reaction solution, followed by stirring for 1 hour. The production of objects could not be confirmed.

It is difficult to obtain a highly pure compound (3) efficiently by directly reacting the compound (1) with a chlorocarbonyloxy form.

Comparative Example 7:

参考例１、および２に記載と同様の方法にて、1-クロロエチル クロロホルメート(2.2g, 15.7 mmol)から1-{[(ドデシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (6.8g)を得た。
実施例１に記載と同様の方法にて、1-{[(ドデシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (151mg, 0.42 mmol))から1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートの合成を試みたが、0℃下では反応が完結せず、室温に昇温させた。しかし、室温下でクロロ体の一部の分解が認められた。さらに実施例１に記載と同様の方法にて参考例３の化合物 (149mg, 0.42 mmol)との反応を試みたが、目的の(3S,4S)-1-[({1-[(2-メチルプロパノイル)オキシ]エトキシ}カルボニル)オキシ]-2,5-ジオキソピロリジン-3,4-ジイル ジベンゾエートはほとんど得られなかった。
1-{[(ドデシルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート
¹H NMR (400 MHz, CDCl₃) δ:6.93 (q, J = 8.0 Hz, 1H), 2.92-2.79 (m, 2H), 2.59-2.49(m, 1H), 1.70-1.46 (m, 5H), 1.43-1.06 (m, 24H), 0.92-0.81 (m, 3H)．

In the same manner as described in Reference Examples 1 and 2, 1-chloroethyl chloroformate (2.2 g, 15.7 mmol) to 1-{[(dodecylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (6.8 g) was obtained.
In a manner similar to that described in Example 1, 1-{[(dodecylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (151 mg, 0.42 mmol)) to 1-{(chlorocarbonyl) oxy} ethyl 2 -An attempt was made to synthesize methylpropanoate, but the reaction was not completed at 0 ° C, and the temperature was raised to room temperature. However, partial decomposition of the chloro compound was observed at room temperature. Further, a reaction with the compound of Reference Example 3 (149 mg, 0.42 mmol) was attempted in the same manner as described in Example 1, but the desired (3S, 4S) -1-[({1-[(2- Methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4-diyl dibenzoate was hardly obtained.
1-{[((dodecylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.93 (q, J = 8.0 Hz, 1H), 2.92-2.79 (m, 2H), 2.59-2.49 (m, 1H), 1.70-1.46 (m, 5H) , 1.43-1.06 (m, 24H), 0.92-0.81 (m, 3H).

Comparative Example 8:

参考例１、および２に記載と同様の方法にて、1-クロロエチル クロロホルメート (7.0g, 49.1 mmol)から1-{[(シクロペンチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (14g)を得た。
実施例１に記載と同様の方法にて、1-{[(シクロペンチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (350mg, 1.34 mmol))から1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートの合成を試みたが、2.5当量の塩化スルフリルを用いても0℃下では反応が完結せず、室温に昇温させた。室温下で一晩攪拌したが、1-{[(シクロペンチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエートは完全に消失することなく、また1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートもほとんど分解してしまった。
1-{[(シクロペンチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート
¹H NMR (400 MHz, CDCl₃) δ:6.93 (q, J = 8.0 Hz, 1H), 3.69-3.58 (m, 1H), 2.62-2.52(m, 1H), 2.19-2.05 (m, 2H), 1.80-1.45 (m, 9H), 1.25-1.10 (m, 6H)．

In the same manner as described in Reference Examples 1 and 2, 1-chloroethyl chloroformate (7.0 g, 49.1 mmol) to 1-{[(cyclopentylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (14 g )
In a manner similar to that described in Example 1, 1-{[(cyclopentylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (350 mg, 1.34 mmol)) to 1-{(chlorocarbonyl) oxy} ethyl 2 Attempts were made to synthesize -methylpropanoate, but even with 2.5 equivalents of sulfuryl chloride, the reaction was not completed at 0 ° C, and the temperature was raised to room temperature. After stirring overnight at room temperature, 1-{[(cyclopentylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate did not disappear completely and 1-{(chlorocarbonyl) oxy} ethyl 2-methyl Propanoate has also almost decomposed.
1-{[(Cyclopentylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.93 (q, J = 8.0 Hz, 1H), 3.69-3.58 (m, 1H), 2.62-2.52 (m, 1H), 2.19-2.05 (m, 2H) , 1.80-1.45 (m, 9H), 1.25-1.10 (m, 6H).

Comparative Example 9:

参考例１、および２に記載と同様の方法にて、1-クロロエチル クロロホルメート (9.9g, 69.2 mmol)から1-{[(エチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (13.7g, 90%: 2 steps)を得た。
窒素雰囲気下、1-{[(エチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (1g, 4.5 mmol)のテトラヒドロフラン (22.7ml)溶液に0℃下、塩化スルフリル (0.74ml, 9.1 mmol)を加え、同温下で1時間攪拌することで、目的の1-{(クロロカルボニル)オキシ}エチル 2-メチルプロパノエートを得た。反応液に、同温下で参考例３の化合物 (1.3g, 3.6 mmol)のテトラヒドロフラン (22.7 ml)溶液とN-メチルモルホリン (1ml, 9.1 mmol)を順次、ゆっくりと滴下し、同温下で2時間攪拌した。反応液をサンプリングし、反応確認したところ、目的物はほとんど認められなかった。
1-{[(エチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート
¹H NMR (400 MHz, CDCl₃) δ:6.94 (q, J = 7.3 Hz, 1H),2.29-2.82 (m, 2H), 2.61-2.50(m, 1H), 1.50 (d, J = 7.3 Hz, 3H), 1.32 (t, J = 10.0 Hz, 3H), 1.19-1.15 (m, 6H)．

In the same manner as described in Reference Examples 1 and 2, 1-chloroethyl chloroformate (9.9 g, 69.2 mmol) to 1-{[(ethylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (13.7 g, 90%: 2 steps).
In a nitrogen atmosphere, 1-{[(ethylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (1 g, 4.5 mmol) in tetrahydrofuran (22.7 ml) at 0 ° C. under sulfuryl chloride (0.74 ml, 9.1 mmol) Was added and stirred at the same temperature for 1 hour to obtain the desired 1-{(chlorocarbonyl) oxy} ethyl 2-methylpropanoate. To the reaction solution, a solution of the compound of Reference Example 3 (1.3 g, 3.6 mmol) in tetrahydrofuran (22.7 ml) and N-methylmorpholine (1 ml, 9.1 mmol) were added slowly and slowly dropwise at the same temperature. Stir for 2 hours. When the reaction solution was sampled and the reaction was confirmed, the target product was hardly observed.
1-{[(Ethylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.94 (q, J = 7.3 Hz, 1H), 2.29-2.82 (m, 2H), 2.61-2.50 (m, 1H), 1.50 (d, J = 7.3 Hz , 3H), 1.32 (t, J = 10.0 Hz, 3H), 1.19-1.15 (m, 6H).

Comparative Example 10:

参考例１、および２に記載と同様の方法にて、1-クロロエチル クロロホルメートから1-{[(tert-ブチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (82%: 2 steps)を得た。
実施例１に記載の方法と同様の方法にて、窒素雰囲気下、1-{[(tert-ブチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート (1.19g, 3.64 mmol)のテトラヒドロフラン (10g)溶液に氷冷下、塩化スルフリル (0.98g, 7.29 mmol)を加え、3時間反応させた。1-{[(tert-ブチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエートの残存が認められたため、塩化スルフリル (0.49g)を追加し、さらに1時間攪拌した後、室温に昇温させ、さらに2時間攪拌した。1-{[(tert-ブチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエートの残存が認められたため、さらに塩化スルフリル (0.49g)を追加し、30分間攪拌した。反応液を氷冷下に冷却し、参考例３の化合物 (1.29g, 3.64 mmol)のテトラヒドロフラン (10g)溶液を滴下した後、N-メチルモルホリン (2.58g, 25.5 mmol)を加え、一晩攪拌した。反応液に酢酸エチル (20g)と0.1N 塩酸水 (20g)を加え、抽出した。有機層を減圧濃縮し、油状物を得た。精製を試みたが、純度の高い(3S,4S)-1-[({1-[(2-メチルプロパノイル)オキシ]エトキシ}カルボニル)オキシ]-2,5-ジオキソピロリジン-3,4-ジイル ジベンゾエートは得られなかった。
1-{[(tert-ブチルスルファニル)カルボニル]オキシ}エチル 2-メチルプロパノエート
¹H NMR (400 MHz, CDCl₃) δ:6.95-6.89 (m, 1H), 2.60-2.51 (m, 1H), 1.50-1.46 (m, 12H), 1.19-1.15 (m, 6H)．
以上の比較例７、８、９、および１０の結果から、高純度のクロロカルボニルオキシ誘導体を得るためには適切なスルファニルカルボニルオキシ基の選択が必要である。すなわち、式（６）で表されるシクロヘキシルカルボニルオキシ体と塩化スルフリルの組み合わせが最も反応性よく、効率的に高純度なクロロカルボニルオキシ体を製造することが出来る。また、効率的に高純度な化合物（２）を製造するためには、高純度な化合物（６ａ）を得ることが重要である。

In the same manner as described in Reference Examples 1 and 2, 1-chloroethyl chloroformate to 1-{[(tert-butylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (82%: 2 steps) Got.
In a manner similar to that described in Example 1, in a nitrogen atmosphere, 1-{[(tert-butylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate (1.19 g, 3.64 mmol) in tetrahydrofuran (10 g ) Sulfuryl chloride (0.98 g, 7.29 mmol) was added to the solution under ice cooling, and the mixture was reacted for 3 hours. 1-{[(tert-Butylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate remained, so added sulfuryl chloride (0.49 g), stirred for 1 hour, then warmed to room temperature. The mixture was further stirred for 2 hours. 1-{[(tert-butylsulfanyl) carbonyl] oxy} ethyl Since 2-methylpropanoate remained, sulfuryl chloride (0.49 g) was further added and stirred for 30 minutes. The reaction solution was cooled under ice-cooling, a solution of the compound of Reference Example 3 (1.29 g, 3.64 mmol) in tetrahydrofuran (10 g) was added dropwise, N-methylmorpholine (2.58 g, 25.5 mmol) was added, and the mixture was stirred overnight. did. Ethyl acetate (20 g) and 0.1N aqueous hydrochloric acid (20 g) were added to the reaction mixture, and the mixture was extracted. The organic layer was concentrated under reduced pressure to obtain an oil. Attempted purification but high purity (3S, 4S) -1-[({1-[(2-methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4 -Diyl dibenzoate was not obtained.
1-{[(tert-Butylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.95-6.89 (m, 1H), 2.60-2.51 (m, 1H), 1.50-1.46 (m, 12H), 1.19-1.15 (m, 6H).
From the results of Comparative Examples 7, 8, 9, and 10 above, it is necessary to select an appropriate sulfanylcarbonyloxy group in order to obtain a highly pure chlorocarbonyloxy derivative. That is, the combination of the cyclohexylcarbonyloxy compound represented by the formula (6) and sulfuryl chloride is most reactive, and a highly pure chlorocarbonyloxy compound can be produced efficiently. Moreover, in order to produce a highly pure compound (2) efficiently, it is important to obtain a highly pure compound (6a).

According to the present invention, a compound represented by formula (2), a compound represented by formula (3), or a pharmaceutically acceptable salt thereof can be produced with high yield and high purity. Therefore, it is a highly productive manufacturing method that can cope with scale-up.

Claims (37)

Compound represented by formula (6)

Wherein R ³ and R ⁴ are each independently
(A) a hydrogen atom,
(B) a C _1-4 alkyl group (the group is
C _1-4 alkoxy,
C _3-6 cycloalkyl (which may be substituted with C _1-4 alkoxy),
It may be substituted with a 5- or 6-membered saturated heterocyclic ring, or a 5- or 6-membered saturated heterocyclic oxy. ),
(C) a C _3-10 cycloalkyl group (this group may be substituted with 1 to 2 fluorine atoms or C _1-4 alkoxy),
(D) a C _6-10 aryl group (the group is
It may be substituted with a halogen atom or C _6-10 aryl (which may be substituted with a halogen atom or C _1-4 alkoxy). ),
(E) a 5- or 6-membered saturated heterocyclic group, or (f) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group is C _1-4 alkyl, or C _{1 -4} may be substituted with alkoxy));
R ⁵ is
(A) a C _1-6 alkyl group (the group is
1 to 3 fluorine atoms,
Hydroxy,
C _1-4 alkoxy,
Carboxy,
5- or 6-membered saturated heterocycle,
C _3-6 cycloalkyl,
C _1-4 alkoxycarbonyl,
C _1-4 alkoxycarbonylamino,
amino,
Mono- or di- (C _1-6 alkyl) amino,
A 5- to 7-membered cyclic amine,
1-2 nitrooxy,
It may be substituted with aminocarbonyl or 5- to 7-membered cyclic aminocarbonyl. ),
(B) a C _3-10 cycloalkyl group (which group may be substituted with hydroxy),
(C) a C _6-10 aryl group (the group is
C _1-4 alkyl,
halogen,
It may be substituted with C _1-4 alkoxy, or C _1-4 alkylcarbonyloxy. ),
(D) a C _1-4 alkylcarbonyl group (this group may be substituted with hydroxy),
(E) a 5- to 10-membered monocyclic or polycyclic heteroaryl group,
(F) a 5- or 6-membered saturated heterocyclic group (the group may be substituted with C _1-4 alkyl which may be substituted with C _1-4 alkoxy),
(G) a C _1-6 alkoxy group (the group may be substituted with C _3-6 cycloalkyl),
(H) a C _3-6 cycloalkyloxy group (which group may be substituted with C _1-4 alkoxy), or (i) a 5- or 6-membered saturated heterocyclic oxy group. ). Or a pharmaceutically acceptable salt thereof,
A compound represented by the formula (7) after reacting with sulfuryl chloride

[Wherein, M is a group represented by the formula (4) or (5)

[Wherein, R ^6a and R ^6b each independently represent a hydrogen atom, a C _1-6 alkylcarbonyloxy group, a C _3-6 cycloalkylcarbonyloxy group, or an optionally substituted C _6-10 aryl. Carbonyloxy group, 5- to 10-membered monocyclic or polycyclic heteroarylcarbonyloxy group, saturated heterocyclic carbonyloxy group, optionally substituted C _1-6 alkyl group, optionally substituted C _{A 3-6} cycloalkyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-6 cycloalkoxy group, an optionally substituted C _6-10 aryl group, a substituted An _optionally substituted C _6-10 aryloxy group, an _optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group, C _1-6 alkylamino A carbonyloxy group, a C _3-6 cycloalkylaminocarbonyloxy group, an optionally substituted amino group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, a hydroxy group, Or a sulfonamide group, or R ^6a and R ^6b together with the atoms to which they are attached, a C _3-6 cycloalkyl ring, a saturated heterocycle, a C _5-10 cycloalkenyl ring, May form a _6-10 aryl ring, or a 5-10 membered monocyclic or polycyclic heteroaryl ring;
R ⁷ is a hydrogen atom, a halogen atom, or a C _1-6 alkyl group;
m is 1, 2, 3, or 4. ] ]
Compound represented by formula (2)

[Wherein R ³ , R ⁴ , R ⁵ and M are the same as described above. Or a method for producing a pharmaceutically acceptable salt thereof. Furthermore, the compound represented by Formula (1)

[Wherein, R ^1a represents an optionally substituted C _1-6 alkyl group;
R ^1b is an ^optionally substituted C _1-6 alkyl group;
R ^1c and R ^1d are each independently the same or different and are a hydrogen atom or an optionally substituted C _1-6 alkyl group, or R ^1c and R ^1d are taken together as follows: formula

A group represented by the formula (p and q are each independently the same or different and are 0, 1 or 2);
R ² is an optionally substituted C _1-6 alkyl group;
G is an oxygen atom or a sulfur atom. Or a pharmaceutically acceptable salt thereof,
Compound represented by formula (2)

[Wherein R ³ , R ⁴ , R ⁵ and M are the same as in claim 1. Or a pharmaceutically acceptable salt thereof,
Compound represented by formula (3)

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ² , G, R ³ , R ⁴ and R ⁵ are the same as described above. Or a pharmaceutically acceptable salt thereof. The method according to claim 1 or 2, wherein G is an oxygen atom. The method according to claim 1 or 2, wherein G is a sulfur atom. The method according to any one of claims 1 to 4, wherein R ^1a is a C _1-6 alkyl group which may be substituted with 1 to 3 fluorine atoms. The method according to claim 5, wherein R ^1a is a trifluoromethyl group. R ^1b is a C _1-6 alkyl group which may be substituted with C _1-4 alkylcarbonylamino which may be substituted with 1 to 3 fluorine atoms. The method according to one item. The method according to claim 7, wherein R ^1b is a 2- (ethylcarbonylamino) ethyl group. R ^1c and R ^1d are each independently a hydrogen atom, a halogen atom, or a C _1-6 alkyl group which may be substituted with C _1-4 alkoxy. The method described in 1. The method according to claim 9, wherein R ^1c is a C _1-6 alkyl group. The method according to claim 10, wherein R ^1c is a methyl group. The method according to any one of claims 9 to 11, wherein R ^1d is a C _1-6 alkyl group which may be substituted with C _1-4 alkoxy. The method according to claim 12, wherein R ^1d is a methyl group. The method according to claim 12, wherein R ^1d is a methoxymethyl group. R ^1c and R ^1d together are represented by the following formula:

The method as described in any one of Claims 1-8 which is group represented by these. p and q are any of the following (i) to (iii) (where,
(I) p and q are the same and are 2, or one of p and q is 2 and the other is 1, or (ii) p and q are the same and 1 Or (iii) one of p and q is 1 and the other is 0). R ^1c and R ^1d together form the following formula

The method of Claim 16 which is group represented by these. R ² is
_{(1) C 3-6 C 1-6} alkyl group (said _{C 1-6} alkyl optionally substituted with a cycloalkyl may be substituted with 1 to 3 halogen atoms, the _{C 3-6} cycloalkyl Alkyl may be substituted with a halogen atom, C _1-4 alkyl or C _1-4 alkoxy);
(2) a C _3-6 cycloalkyl group optionally substituted with a halogen atom or C _1-4 alkyl;
The group according to any one of claims 1 to 17, which is one group selected from the group consisting of (3) a _C2-6 alkenyl group; and (4) a _C7-10 aralkyl group optionally substituted with a halogen atom. The method according to claim 1. The method according to claim 18, wherein R ² is a C _1-6 alkyl group. The method according to claim 19, wherein R ² is an isopropyl group. R ³ and R ⁴ are each independently the same or different and each represents a hydrogen atom or a C _1-4 alkyl group;
R ⁵ is
(1) C _1-6 alkyl group (the group is
(A) 1 to 3 fluorine atoms,
(B) amino,
(C) hydroxy,
(D) C _1-4 alkoxy,
(E) carboxy,
(F) C _1-4 alkoxycarbonyl,
(G) C _1-4 alkoxycarbonylamino,
(H) 1-2 nitrooxy,
(I) 5- or 6-membered saturated heterocyclic ring, or (j) optionally substituted with C _3-6 cycloalkyl. ),
(2) a C _3-10 cycloalkyl group,
(3) C _1-4 alkylcarbonyl group (this group may be substituted with hydroxy),
(4) C _6-10 aryl group (the group is
(A) C _1-4 alkyl,
(B) C _1-4 alkoxy, or (c) C _1-4 alkylcarbonyloxy may be substituted. ),
(5) 5- to 10-membered monocyclic or polycyclic heteroaryl group,
(6) a 5- or 6-membered saturated heterocyclic group,
(7) C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
(8) a C _3-6 cycloalkyloxy group, or (9) a 5- or 6-membered saturated heterocyclic oxy group. )
21. The method according to any one of claims 1 to 20, wherein The method according to claim 21, wherein R ³ is a hydrogen atom and R ⁴ is a C _1-4 alkyl group. The method according to claim 22, wherein R ⁴ is a methyl group. R ⁵ is
(1) C _1-6 alkyl group (the group is
(A) 1 to 3 fluorine atoms,
(B) amino,
(C) hydroxy,
(D) C _1-4 alkoxy,
(E) carboxy,
(F) C _1-4 alkoxycarbonyl,
(G) C _1-4 alkoxycarbonylamino,
(H) 1-2 nitrooxy,
(I) 5- or 6-membered saturated heterocyclic ring, or (j) optionally substituted with C _3-6 cycloalkyl. ),
(2) a C _3-10 cycloalkyl group,
(3) C _1-4 alkylcarbonyl group (this group may be substituted with hydroxy),
(4) C _6-10 aryl group (the group is
(A) C _1-4 alkyl,
(B) substituted with C _1-4 alkoxy, or (c) C _1-4 alkylcarbonyloxy. ),
24. (5) A 5-membered to 10-membered monocyclic or polycyclic heteroaryl group, or (6) a 5-membered or 6-membered saturated heterocyclic group. the method of. R ⁵ is
(1) C _1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C _1-4 alkoxy,
(C) 5 or 6 membered saturated heterocycle, or (d) optionally substituted with C _3-6 cycloalkyl. ),
(2) a C _3-6 cycloalkyl group,
(3) C _6-10 aryl group (the group is
(A) C _1-4 alkyl, or (b) C _1-4 alkoxy may be substituted. Or (4) a 5- or 6-membered saturated heterocyclic group. R ⁵ _{is C 1-4} alkyl group, The method of claim 25. R ⁵ is an isopropyl group, The method of claim 26. R ^6a and ^{R 6b} are each _{independently} a _{C 6-10} arylcarbonyloxy group, the process according to any one of claims 1 to 27. ^30. The method of claim 28, wherein ^R6a and ^R6b are each independently a phenylcarbonyloxy group. R ^6a and ^{R 6b,} taken together with the atom to which they are attached _form a _{C 6-10} aryl ring, Process according to any one of claims 1 to 27. The method according to any one of claims 1 to 30, wherein R ⁷ is a hydrogen atom. A compound represented by formula (4-1) or a pharmaceutically acceptable salt thereof.

[Wherein R ³¹ is a hydrogen atom, R ⁴¹ is a C _1-4 alkyl group, R ⁵¹ is a C _1-4 alkyl group, and both R ^6a1 and R ^6b1 are phenylcarbonyloxy A group, or R ^6a1 and R ^6b1 together are a benzene ring or a norbornene ring. ] A compound represented by formula (5-1) or a pharmaceutically acceptable salt thereof.

[Wherein R ³¹ is a hydrogen atom, R ⁴¹ is a C _1-4 alkyl group, R ⁵¹ is a C _1-4 alkyl group, R ⁷ is a hydrogen atom, a halogen atom, or C _{1. A -6} alkyl group,
m is 1, 2, 3, or 4. ] The compound represented by formula (5-1) is

The compound of Claim 33 which is a compound represented by these, or its pharmaceutically acceptable salt. The compound according to claim 33 or claim 34, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a hydrogen atom. A compound represented by formula (6-1) or a pharmaceutically acceptable salt thereof.

[Wherein, R ³¹ is a hydrogen atom, R ⁴¹ is a C _1-4 alkyl group, and R ⁵¹ is a C _1-4 alkyl group. ] Salts R ⁴¹ is a methyl group, the R ⁵¹ is isopropyl group, a compound according to any one of claims 31 to 35, or are allowed a pharmaceutically.