TW200835692A - Process for preparing 1-substituted-2-pyridone-3-carboxylic acid derivatives - Google Patents

Abstract

The present invention provides a convenient process for preparing 1-substituted-2-pyridone-3-carboxylic acid derivatives, which is the important intermediate of 2-pyridone-3-carbamoyl derivative having cannabinoid receptor agonist activity and also provides a convenient process for preparing 2-pyridone-3-carbamoyl derivatives. The present invention provides a process for preparing the compound of of the following formula (II), which consists of following steps: Step A: hydrolyzing a compound of the following formula (I) (wherein, R1 represents an alkyl group that may be substituted by noe-reactiveness substituents etc.; R2 and R3 independently represents an alkyl group etc.; or R2 and R3 may be combined with the adjacent carbon atom to form a cycloalkene), and Step B: adding an alcohol to the hydrolyzate of the compound produced by the Step A to form a crystal of a compound of the following formula (II) (wherein, R1, R2, R3, and R4 are the same meanings as the above-mentioned).

Description

200835692, IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a process for producing a 2-pyridinone-3-aminecarboxamido derivative having excellent cannabinoid receptor agonist activity and an important intermediate thereof. [Prior Art] The 2-pyridone-3-aminocarbazinyl derivatives described in Patent Documents 1 and 2 have excellent cannabinoid receptor agonist activity and are useful for allergic diseases. Patent Document 3 discloses that a 2-pyridone-3-aminecarboxamido derivative has 5-HT4 receptor agonist activity. Patent Document 1 to 3 describes a process for producing a 1-substituted-2-pyridinone-3-carboxylic acid derivative which is an important intermediate in the production of a 2-pyridone-3-amine methyl hydrazino derivative, and is produced from the intermediate. The method of 2-pyridone-3-aminemethanyl derivative is to improve the compound in high reaction yield and/or high purity, and the like. [Patent Document 1] International Publication No. 02/53543 Booklet [Patent Document 2] International Publication No. 2006/046778 Booklet [Patent Document 3] International Publication No. 2005/073222 Booklet [Invention Content] (Invention Problem to be solved) The convenience of providing a 2-pyridone-3-amine carbaryl derivative having a cannabinoid receptor agonist activity and an important intermediate thereof, a 1-substituted-2-pyridone-3-carboxylic acid derivative System of law. (Means for Solving the Problem) In view of the above, the present inventors have found that 2-pyridone-3-aminecarbomethoxy-6-200835692 derivative having excellent cannabinoid receptor agonist activity has been repeatedly evaluated as a result of repeated review. Its important intermediate 1-substituted-2-pyridone-3-carboxylic acid derivative is obtained in a simple, high yield and high purity. That is, the present invention relates to: 1) a process for the preparation of a compound comprising the following works: Engineering A: Hydrolysis of a compound of the following formula (I):

R3 N^OI R1 (wherein R1 is an alkyl group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent; R2 and R3 Each independently is a hospital base, a courtyard oxygen base, or a hospital oxygen; or R2 and R3 may form a cycloolefin together with an adjacent carbon atom; R4 is a hydrogen atom or a hydroxyl group; R5 is a hospital base)' and Engineering B: in engineering A hydrolyzate of the compound of formula (I) produced by A is added with an alcohol, and a compound of the following formula (Π) is obtained:

(wherein R1, R2, R3, and R4 have the same meanings as defined above). Engineering A can be carried out in the presence of an acid or in the presence of a base. When the work A is carried out in the presence of a base, the acid may be added after the treatment with the alkali. Acid can also be added to Project B. Further includes the following 2) ~ 18): 200835692 2) The method described in 1), in which the engineering A and the engineering b are continuously implemented. 3) The preparation method as described in 1) or 2), including: Engineering C: A compound of the following formula (III): R1-NH2 (III) (wherein R1 and 1) have the same meaning, and reacts with a compound of the following formula (IV) : R2"^rR3 αν) 〇 (where R2 and R3 are the same as 1), and Engineering D: a compound to be produced in Engineering C, reacting with Compound # of the following formula (V): R6O^R4 X (V) R5OOC Eight COOR5 (wherein R4 and R5 are the same as in R); R6 is alkyl), and the compound of formula (1) is as follows: R4

R1 (wherein R1, R2, R3, R4, and R5 have the same meaning as 1). 4) The process according to 3), wherein R6 is a C1-C2 alkyl group. 5) The process according to any one of 1) to 4, wherein R5 is a C1-C2 alkyl group 6), comprising: engineering C: a compound of the following formula (III): r1-nh2 (III) (wherein R1 and 1) have the same meaning) and react with a compound of the following formula (IV): r2, R3 (iv) 〇 (wherein R2 and R3 are the same as 1), 200835692 Engineering D: a compound produced by Engineering C, Reacts with a compound of the following formula (V): r6o^r4 X (V) F^OOC^^OOR5 (wherein R4 and R5 have the same meaning as in R); R6 has the same meaning as 3), and a compound of the following formula (I) is formed :

R1 (wherein R1, R2, R3, R4, and R5 have the same meaning as 1), Engineering A: Hydrolysis of the compound of formula (I), Engineering B: Addition of alcohol to the hydrolyzate of the compound of formula (1) produced in Engineering A And obtained the following compound (II):

(wherein R1, R2, R3, and R4 have the same meanings as 1). X Path E: The obtained compound of the formula (π) is reacted with a halogenated reagent to form a compound of the following formula (VI): R4 Ο

R1

Hal (VI) (wherein R1, R2, R3, and R4 have the same meaning as in 1); Hal is a halogen atom), and Engineering F: The resulting compound of the formula (VI) is reacted with a compound of the following formula (VII): 200835692 /X , ^COOR7 (VII) H2N〆, Y〆 (wherein R7 is a hydrogen atom or a hospital base;

X is an alkylene group which may have a hetero atom and may be substituted with a non-reactive substituent, an alkenyl group which may have a hetero atom and may have a non-reactive substituent, may have a hetero atom, and may have a non-reaction a substituted alkynyl group substituted with a substituent, a cycloalkanediyl group which may be substituted with a non-reactive substituent, a cycloalkenyldiyl group which may be substituted with a non-reactive substituent, an aryldiyl group which may be substituted with a non-reactive substituent, a heteroaryldiyl group which may have a non-reactive substituent, or a non-aromatic heterocyclic diyl group which may have a non-reactive substituent; and an alkyl group which may be a single bond and may have a non-reactive substituent An alkenyl group which may be substituted with a non-reactive substituent or an alkynyl group which may be substituted with a non-reactive substituent, and if necessary, is hydrolyzed to give a compound of the following formula (VIII): R4〇

/X, v, COOR7 Y (VIII) R1 (wherein R1, R2, R3, and R4 have the same meaning as 1); R7, X, and Y have the same meanings as above. 7) The method described in 6), characterized in that the works E and F are continuously performed. 8) The method according to 6) or 7), wherein Hal is a chlorine atom. 9) The process according to any one of 6), wherein R7 is a C1-C2 alkyl group. 10) The process according to any one of 6), wherein X is an alkylene group, a cycloalkanediyl group, an aryldiyl group, a heteroaryldiyl group or a non-aromatic heterocyclic diyl group. 11) The method according to any one of the preceding claims, wherein γ is a single bond or an alkylene group. -10- 200835692 12) The method of any one of 3) to 11), wherein the works c, .D, A, and B are continuously performed. 13) The process according to any one of 1) to 12) wherein the compound of the formula (11) is obtained by crystallization. 14) The method according to any one of 1) to 13) wherein the hydrogen atom is a hydrogen atom. The process of any one of 1) to 14) wherein f is a C1-C3 alkyl group or a C1-C3 alkoxy group. The process according to any one of 1), wherein R3 is a C3 alkyl group or a C1-C3 alkoxy group C1-C3 alkyl group. (17) The process according to any one of 1) to 15, wherein & 2 is a cyclooctene together with an adjacent carbon atom; The process of any one of 1) to 1 7 wherein r 1 is an alkyl group which may be substituted with a non-reactive substituent. The process of any one of 1) to 1 6), wherein r 1 is an alkyl group which may be substituted with a non-reactive substituent, R 2 is a C 1 -C 3 alkyl group, and R 3 is a C 1 -1 C3 alkyl, R4 is a hydrogen atom, and R5 is a C1-C2 alkyl group. The process of any one of 1) to 14), wherein R1 is an alkyl group which may be substituted with a non-reactive substituent, and R2 and R3 are a ring together with an adjacent carbon atom; Xinhua, R4 is a hydrogen atom, and R5 is a C1-C2 yard. The method according to any one of 1 to 20, wherein the alcohol added to the hydrolyzate is isopropanol. 22) A process for the crystallization of a compound of the following formula (II), characterized in that an alcohol is added to a solution containing a compound of the following formula (II): -11 - (II) 200835692 R4

I R1 (wherein R1, R2, R3, and R4 are 1) have the same meaning). The solvent in the above solution may be an aromatic hydrocarbon (for example, toluene, xylene), an aliphatic carboxylic acid ester (for example, ethyl acetate, methyl acetate, butyl acetate), an ether (for example, diethyl ether, tetrahydrofuran), and a ketone. Classes (eg acetone, methyl ethyl ketone), hydrazine, hydrazine-dimethyl acetamide, N-methyl pyrrolidone, and water-selective solvents,

Used alone or in combination. 23) The process alcohol as described in 22) is isopropanol. Further, the present invention also includes the following (1) to (19): (1) A process for producing a compound of the formula (X), comprising the process Aa: hydrolyzing a compound of the following formula (IX):

(wherein Rla is an alkyl group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent, R2a and R3a are each independently an alkyl group, An alkoxyalkyl group, or an alkoxy group; or R2a and R3a may form a cycloolefin together with an adjacent carbon atom; R4a is a hydrogen atom or a hydroxyl group; R5a is an alkyl group), and engineering Ba: a formula formed in the engineering Aa ( IX) The hydrolyzate of the compound is added with an alcohol to form a crystal of the compound of the following formula (X): -12- 200835692

(wherein Rla, R2a, R3a, and R4a have the same meanings as described above). Engineering Aa can be carried out in the presence of an acid or in the presence of a base. When the work Aa is carried out in the presence of a base, an acid is added after the treatment with a base. (2) The manufacturing method described in (1), in which the engineering Aa and the engineering Ba are continuously applied. (3) The method described in (1) or (2), including: Engineering Ca: a compound of the following formula (XI): R1a-NH2 (XI) (wherein Rla and (1) have the same meaning), and the following formula (χπ) Compound Reaction: R2a^YR 0QI) (wherein 1^ and 1^ have the same meaning as (1)), and Engineering Da: a compound produced by engineering Ca, which reacts with a compound of the following formula (XIII):

(XIII) (wherein R4a and R5a have the same meaning as (1); R6 is an alkyl group), and a compound of the following formula (IX) is produced:

(wherein Rla, R2a, R R4a, and 11 have the same meaning as (1)).

Ca, Da, Aa, and Ba (4) The method of (3) g, which is carried out continuously in engineering order. -13- 200835692 (5) The method of (3) or (4)g, wherein the ruler is "C1_C2 alkyl. (6) The method described in any one of (1) to (5), wherein R5a The method for preparing a compound of C2 alkyl hydrazine (7), comprising: engineering Ca: a compound of the following formula (XI): R1a-NH2 (XI) (wherein Ria has the same meaning as (1)), and the following formula (ΧΠ) compound reaction: R2a^YR3a (4) (wherein R2a and R3a have the same meaning as (1)), and a compound of the following formula (ΧΠΙ) is formed

(XIII) (Formula 11" and R5a have the same meaning as (1); ruler "with (a))), Project Da: a compound obtained by engineering Ca, which reacts with a compound of the following formula (IX):

(wherein Rla 'R?a, R3a, R", and (1) have the same meaning), Π: Process Aa: Hydrolysis of the obtained compound (Ιχ), Engineering Ba: Compound of formula (IX) produced in Engineering Aa The hydrolyzate is added with an alcohol' to obtain a compound of the following formula (X): R4a

F^A^COOH -14- 200835692 (wherein Rla, R2a, R3a, and R4a have the same meaning as (1)), and Engineering Ea: the obtained compound of the formula (X) is reacted with a halogenated reagent to form a compound of the following formula (XIV):

(wherein Rla, R2a, R3a, and & "the same meaning as (1); Hala is a halogen atom), and Process Fa: a compound of the formula (XIV) obtained, which is reacted with a compound of the following formula (XV)

(wherein R7a is a hydrogen atom or an alkyl group;

Xa is an alkylene group which may have a hetero atom-substituted and may have a non-reactive substituent, an alkenyl group which may have a hetero atom and may have a non-reactive substituent, may have a hetero atom, and may have a non-reaction a substituted alkynyl group substituted with a substituent, a cycloalkanediyl group which may be substituted with a non-reactive substituent, a cycloalkenyldiyl group which may be substituted with a non-reactive substituent, an aryldiyl group which may be substituted with a non-reactive substituent, a heteroaryldiyl group which may have a non-reactive substituent or a non-aromatic heterocyclic diyl group which may have a non-reactive substituent;

Ya is a single bond, an alkyl group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent), and if necessary, hydrolyzed Reaction to produce a compound of the following formula (XVI): -15- (XVI) 200835692 R4a〇

Xa, Ya, C00R7 have the same meaning as above). (8) The method according to (7), wherein the works Ca, Da, Aa, and Ba are continuously performed. (9) As in (7), the production method 'where Ea and F a are continuously applied.

(10) The process according to any one of (7) to (9) wherein Hala is a chlorine atom. (11) The process according to any one of (7) to (10) wherein it is a C1-C2 alkyl group. (12) The process according to any one of (7) to (11) wherein Xa is an alkylene group, a cycloalkanediyl group, an aryldiyl group, a heteroaryldiyl group or a non-aromatic heterocyclic diyl group. The process of any one of (7) to (1), wherein γa is a single bond or an alkylene group. (14) The method according to any one of (1) to (13) wherein ya is a hydrogen atom. (15) The process according to any one of (1) to (14) wherein it is a C1-C2 alkyl group or a C1-C2 alkoxy group. (16) The process according to any one of (1) to (15) wherein R3a is a cn-C3 alkyl group or a C1-C2 alkoxy C1-C2 alkyl group. (17) The process according to any one of (1) to (14) wherein R3a is cyclooctene together with an adjacent carbon atom. The process of any one of (1) to (17), wherein r 1 a is an alkyl group which may be substituted with a non-reactive substituent. (1) The process according to any one of (1) to (18) wherein the alcohol added to the hydrolyzate is -16-200835692 and the alcohol is isopropanol. The meaning of each term is explained below. The terms used in this specification in a uniform sense are used in the same sense when used alone or in combination with other terms. In the present specification, the "hetero atom" is an oxygen atom, a sulfur atom or a nitrogen atom. In the present specification, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In the present specification, the "alkyl group" includes a linear or branched 1-chain hydrocarbon group having 1 to 8 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl , n-heptyl, n-octyl and so on. It is preferably a C1-C6 alkyl group. When a specific carbon number is specified, it is preferred that the "alkyl group j R1 and η "alkyl group" having a carbon number in the range thereof are preferably a C1-C6 alkyl group. The "alkyl group" of R2 and R2a is preferably a C1-C4 alkyl group, more preferably a C1-C3 alkyl group, a C1-C2 alkyl group is preferably 〇R3, and an "alkyl group" of R3a is a C1-C4 alkyl group. good. The "alkyl group" of R5 and R5a is preferably a C1-C4 alkyl group, more preferably a C1-C3 alkyl group, and the "alkyl group" of R6 and R6a is preferably a C1-C4 group, more preferably a C1-C2 alkane. Preferably, in the present specification, the "household oxygen base" is one or two substituents of the following "household oxygen" in the different carbon atoms of the above alkyl group. For example, methoxymethylethoxymethyl, n-propoxymethyl, isopropoxymethyl [, n-butoxymethyl-17-.200835692 2-methoxyethyl, 2-ethoxyethyl, 2-positive Propoxyethyl ' 1-isopropoxyethyl, 丨-n-butoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-n-propoxypropyl, 2-isopropyloxypropyl , 2-n-butoxypropyl and the like. It is preferably a C1-C4 alkoxy group C1-C4 alkyl group. More preferably, it is a C1-C2 alkoxy C1-C2 alkyl group. When a specific carbon number is specified, it means an "alkoxyalkyl group" having a carbon number in the range of the number. The "alkoxyalkyl group" of R2 and R2a is preferably a C1-C4 alkoxy C1-C4 alkyl group, more preferably a C1-C2 alkoxy C1-C2 alkyl group. The "alkoxyalkyl group" of R3 and R3a is preferably a C1-C4 alkoxy C1-C4 alkyl group, more preferably a C1-C2 alkoxy C1-C2 alkyl group. In the present specification, the "alkyl group" is a monovalent hydrocarbon group containing a linear or branched chain having 2 to 8 carbon atoms and having one or two or more double bonds. For example, vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl and the like. It is preferably a C2-C6 alkenyl group. When a specific carbon number is specified, it means an "alkenyl group" having a carbon number in its range. R1 and Rla2 "alkenyl" are preferably C2-C6 alkenyl. In the present specification, the "alkynyl group" is a monovalent hydrocarbon group containing a linear or branched chain having 2 to 8 carbon atoms and having two or more triple bonds. For example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, 2-octynyl and the like. It is preferably a C2-C6 alkynyl group. When a specific carbon number is specified, 'the number refers to an "alkenyl group" having a carbon number in the range of the number. The "alkynyl group" of R1 and Rla is preferably a C2-C6 alkynyl group. In the present specification, "cycloalkyl group" includes a cycloalkyl group having 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclohetero. It should be a C 3 - C 6 ring yard base. When a specific carbon number is specified, it means a "cycloalkyl group" having a carbon number of -18-200835692. In the present specification, "cycloalkenyl group" includes a cycloalkyl group having 3 to 8 carbon atoms. For example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl. It is preferably a C 3-C6 cycloalkenyl group. When a specific carbon number is specified, it means a "cycloalkenyl group" having a carbon number in the range of the number. In the present specification, the "cycloolefin" in which "R2 and R3 may form a cyclic olefin together with an adjacent carbon atom" is a 5- to 10-member ring having a double bond between a carbon atom adjacent to R2 and a carbon atom adjacent to R3. Cycloolefin. For example, cyclopentene, cyclohexene, #cycloheptene, cyclooctene, cycloolefin, and cyclodecene. It is preferably a C5-C8 cyclic olefin. More preferably cyclooctene. When a specific carbon number is specified, it means a "cycloalkenyl group" having a carbon number in the range of the number. In the present specification, the "cycloolefin" in which "1122 and R3a may form a cyclic olefin together with an adjacent carbon atom" is a single bond having a double bond between a carbon atom adjacent to the & 23 and a carbon atom adjacent to R3a. 10 ring ring of cycloolefin. For example, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cycloolefin, and cyclodecene. It is preferably a C5-C8 cycloolefin. More preferably cyclooctene. When a specific carbon number is specified, it means a "cycloalkenyl group" having a carbon number in the range of ® . In the present specification, the "alkoxy group" is a group having one substituent of the above-mentioned "alkyl group" in the oxygen atom. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, tert-butoxy, n-pentyloxy, isopentyloxy 2-pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy and the like. It is preferably a C1-C6 alkoxy group. More preferably, it is a C1-C4 alkoxy group. When a specific carbon number is specified, it means an "alkoxy group" having a carbon number in the range of the number. -19- 200835692 The "alkoxy group" of R2 and R2a is preferably (M-C4 alkoxy group, more preferably CL. C2 alkoxy group. "Alkoxy group" of R3 and R3a is CM-C4 alkoxy group. In the present specification, the "alkenyloxy group" is a group having one substituent of the above "alkenyl group" in the oxygen atom. For example, a vinyloxy group, an allyloxy group, a propyleneoxy group, a 2-butenyloxy group. 2 -pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octeneoxy, etc. Preferably, it is a C2_C6 alkenyloxy group, more preferably a C2-C4 alkenyloxy group. In the present specification, the "alkenyloxy group" has a carbon number in the range of the number. In the present specification, the "alkynyloxy group" is a group having one substituent of the above-mentioned "alkenyl group" in the oxygen atom. For example, acetyleneoxy group, 1 - propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy, etc. It is preferably a C2-C6 alkynyloxy group. More preferably, it is a C2-C4 alkynyloxy group. When a carbon number is specified, it means an "alkynyloxy group" having a carbon number in the range of the number. In the present specification, "cycloalkoxy" is The oxygen atom has one substituent of the above "cycloalkyl group", for example, a cyclopropoxy group or a cyclobutoxy group. , cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy. It is preferably a C3-C6 cycloalkoxy. When a specific carbon number is specified, it refers to a "cycloalkane" having a carbon number in its range. In the present specification, the "alkylthio group" is a group having one substituent of the above "alkyl group" in the sulfur atom. For example, a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butyl group. Sulfur, isobutylthio, second butylthio, tert-butylthio, n-pentylthio, isopentylthio, 2-pentylthio, 3-pentylthio, n-hexylthio, isohexylthio, 2-hexylthio, 3-hexylthio, n-heptylthio, n-octylthio, etc., preferably a C1-C6 alkylthio group, more preferably a C1-C4 alkylthio group. The "alkylthio group" of the carbon number in the range of -20-200835692 In the present specification, the "alkenylthio group" is a group having one substituent of the above "alkenyl group" in the sulfur atom. For example, an ethylenethio group or an allyl sulfide. Base, 1-propenylthio, 2-butenylthio, 2-pentenylthio, 2-hexenylthio, 2-heptenethio, 2-octenethio, etc., preferably C2-C6 olefin Sulfur-based. More preferably C2-C4 alkylthio. When the carbon number is specified, it has a range The "alkenylthio group" of the carbon number. In the present specification, the "alkynylthio group" is a group having one substituent of the above "alkynyl group" in the sulfur atom. For example, acetylenethio group, 1-propynylthio group, 2-propene group An alkynylthio group, a 2-butynylthio group, a 2-pentynylthio group, a 2-hexynylthio group, a 2-heptynylthio group, a 2-octyl-alkynylthio group, etc., preferably a C2-C6 alkynylthio group. More preferably, it is a C2-C4 alkynylthio group. When the carbon number is specified, it means an "alkynylthio group" having a carbon number in the range of the number. In the present specification, the "cycloalkylthio group" has the above-mentioned "cycloalkane" in the sulfur atom. A substituted group such as a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group or a cyclooctylthio group. It is preferably a C3-C6 cycloalkylthio group. When a specific carbon number is specified, it means a "cycloalkylthio group" having a carbon number in the range of the number. In the present specification, "alkylene group" is a linear or branched alkyl group having 1 to 10 carbon atoms. For example, methylene, 1-methylmethylene, 1, dimethyldimethylmethylene, ethyl, 1-methylethyl, ethylidene, 1, dimethyl 1,1,2-dimethylexylethyl, 1,diethylethylidene, 1,2-diethylexylethyl, 1-ethyl-2-methylethylidene, trimethylene, anthracene -methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, I,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, Buethyl Sanya Methyl, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2 -methyltrimethylene, tetramethylene, ^methyltetramethylene, 2-methyltetramethylene, M-dimethyltetramethylene, • 21 - 200835692 1,2-dimethyl Tetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene, 1-isobutylexeneethyl, 1-(2,2-dimethylpropyl Methylene, 1-tert-butylethyl, 1-isobutyltrimethylene, and the like. When a specific carbon number is specified, it means an "alkyl group" having a carbon number in the range of the number. In the present specification, the "alkylene group which may have a hetero atom and may have a non-reactive substituent substituted" is a methylene moiety of an alkylene group which may have a non-reactive substituent substituted alkyl group. There may be a group in which the above "hetero atom" is substituted at one or two positions adjacent to each other. The "alkyl group may have a hetero atom" may be, for example, a methylene group, a 1-methylmethylene group, a 1,1-dimethylmethylene group, a fluorenyl group, a 1-methyl-ethyl group, and 1 -ethylethyl, 1,1 - _'methylethyl, 1,2-dimethylethyl, 1,1-diethylethyl, 1,2-diethylethyl, 1 -ethyl-2-methylethyl, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyl Trimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltriazine Methyl, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene, 1 -isobutylexeneethyl, 1-(2,2-dimethylpropyl)methylene, 1-tert-butylethyl, 1-isobutyltrimethylene, methyleneoxymethylene, sub Methylthiomethylene, methylene (N-methylamino) methylene Ethylene oxide, ethylene thiomethylene, ethyl (N-methylamino) methylene, methylene oxide ethyl, methylene sulfide ethyl, methylene (N-methylamine) Base) Ethyl, Trimethylene, Trimethylene, Trimethylene, 1-isobutylmethyleneoxy-22-200835692 Methylene, 1-(2,2- Dimethyl propyl) methyleneoxymethylene, 1-tert-butylmethyleneoxymethylene, 1-isobutyl ethoxymethylene, acetonyl methoxymethylene and the like. When the carbon number is specified, it means that there is a carbon number in the range of the number of carbon atoms. In the present specification, "alkenyl group" is a linear or branched alkenyl group having 2 to 10 carbon atoms. For example, vinyl, 1-methylvinyl, 1-ethylvinyl, 1,2-dimethylvinyl, 1,2-diethylvinyl, 丨-ethyl-2-methyl Ethylene, propyl, methyl-2-propanyl, 2-methylamino-2-propenyl, ι, κ-dimethyl-2-propenyl, 1,2-di Methyl-2-extended propylene, 1-ethyl-2-propanyl, 2-ethyl-2-propenyl, 1,1,diethyl-2-exetylene, l,2 -diethyl-2-extended propylene, 1-butenyl, 2-butenyl' 1-methyl-2-exenbutyl, 2-methyl-2-exenbutyl, 1 , 1-dimethyl-2-butenyl, i,2-dimethyl-2-butenyl, 1-isobutylvinyl, 1-(2,2-dimethylpropyl) -2-Extended propylene group, 1-tert-butyl-2-propenyl group, 1-isobutyl propylene group, and the like. When a carbon number is specified, ^ means an "alkenyl group" having a carbon number in the range of its number. "Extend alkenyl group which may be substituted with a hetero atom and may have a non-reactive substituent" is a methylene moiety of an alkylene group which may be substituted with an alkene group which may be substituted with a non-reactive substituent. A hetero atom is substituted at one or two of the adjacent positions. "Alkenyl groups may be present in the presence of a hetero atom", such as vinyl, 1-methylvinyl, 丨-ethyl, vinyl, i, 2, dimethyl, vinyl, 1,2, 2 Base vinyl, ethyl-2-methylmethyl, propylene, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1, dimethyl-2- Propylene, i,2-dimethyl-2-exetylene, 1-ethyl-2-Exetylene-23-200835692, 2-ethyl-2-extended propylene, 1, diethyl -2-Extended propylene, 1,2-diethyl-2-exetylene, 1-exenbutenyl, 2-extenylbutene, 1-methyl-2-exetylene, 2-methyl Base-2-exenbutyl, 1,1-dimethyl-2-butenyl, 1,2-dimethyl-2-butenyl, 1-isobutylvinyl, l-( 2,2-Dimethylpropyl)-2-propenyl, 1-tert-butyl-2-propenyl, 1-isobutyl-2-propenyl, 1-methyl-2-stretch Butenoxymethylene, 1-isobutyl-2-cyclobutoxymethyl, 1-(2,2-dimethylpropyl)-2-butenoxymethyl, 1- Tributyl-2-butenyloxymethylene and the like. When the carbon number is specified, it means that there is a carbon number in the range of #, "the hetero atom may be present in the alkenyl group." In the present specification, the "alkenyl group" is a linear or branched alkynyl group having a carbon number of 2 to 10. For example, ethynyl, propynyl, 1-methyl-2-propynyl, 1-ethyl-2-propankynyl, butynyl, 1-methyl-2-butenyl , 2-methyl-3-butenyl, 1,1-dimethyl-2-butynyl, 1,2-dimethyl-3-butenyl, 2,2-dimethyl 3--3-butynyl, 1-isobutyl ethynyl, 1-(2,2-dimethylpropyl)-propargynyl, 1-tert-butyl-propenyl, 1-isobutyl Base-extended propynyl and the like. When a specific carbon number is specified, it means an "alkenyl group" having a carbon number in its range. In the present specification, the "extended alkynyl group which may be substituted with a hetero atom and may have a non-reactive substituent" is a methylene moiety of an alkyl group which may be substituted with an alkynyl group which may be substituted with a non-reactive substituent. There may be a group in which the above "hetero atom" is substituted at one or two positions adjacent to each other. "A heteroacetylene-containing alkynyl group" may be, for example, an ethynyl group, a propynyl group, a 1-methyl-2-propankyne group, a 1-ethyl-2-propankyne group, a butyne group. 1, 1-methyl-2-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-butenyl, 1,2-dimethyl-3 - extended butynyl group 24 - 200835692, 2,2-dimethyl-3-butenyl, 1-isobutyl ethynyl, fluorenyl-dimethyl propyl)-propargynyl, 1-tert-butyl-proparginyl, 1-isobutyl-propenyl, b-methyl-2-butenoxymethyl, 1-isobutyl-2-butenoxyoxymethylene , 1-(2,2·dimethylpropyl)-2-butenyloxymethylene, 1-tert-butyl-2-butenyloxymethylene, and the like. When a specific carbon number is specified, it means that "the number of carbon atoms in the range of the number may be a hetero atom." In the present specification, "aryl" includes a monocyclic or fused cyclic aromatic hydrocarbon. This may be fused to the above-mentioned "cycloalkyl group", the above-mentioned "cycloalkenyl group", and the "non-aromatic heterocyclic group" described later at all possible positions. Any of the aryl groups are monocyclic and fused, and may be combined at all possible positions. For example, phenyl, naphthyl, 2-naphthyl, anthracenyl, tetrahydronaphthyl, iota, 3-benzodioxanyl, 1,4-benzodioxanyl, and the like. It is preferably a phenyl group, an i-naphthyl group or a 2-naphthyl group. More preferably phenyl. In the present specification, the "heteroaryl group" is a 5- to 6-membered aromatic ring containing at least one atom selected from the group consisting of oxygen, sulfur or nitrogen. This may be fused to the above-mentioned "cycloalkyl group", the above-mentioned "aryl group", the "non-aromatic heterocyclic group" described later, or other heteroaryl groups based on all possible positions. Any of the heteroaryl groups are monocyclic and fused, and may be combined at all possible positions. For example, pyrrolyl (eg, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl) , imidazolyl (eg 2-amidino, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3 ·pyrazolyl), isothiazolyl (eg 3-isothiazolyl), isoxazole (eg, 3-isoxazolyl), oxazolyl (eg 2-oxazolyl), thiazolyl (eg 2-thiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridine) Base), pyridinyl (Example-25-200835692 such as 2-pyridyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl), hydrazine (eg 3-mercapto), tetrazolyl (eg 1H-tetrazolyl), oxadiazolyl (eg 1,3,4-oxadiazolyl), thiadiazolyl (eg 1,3,4-thiadiazolyl), oxime-based (eg eg 2-吲-till, 6-fluorene-based, iso-decyl (eg 2-isodecyl), fluorenyl (eg 1-mercapto, 2-mercapto, 3-mercapto) , carbazolyl (eg 3-oxazolyl), fluorenyl (eg 8-decyl), quinacyl (eg 2-quinolyl), isoquinolinyl (eg 3-isoquinolinyl), quinolinyl (eg 2-quinolinyl, 5-quinolinyl), sulfhydryl (eg 1-indole) a naphthyridinyl group (e.g., 2-naphthyridinyl), a quinoxalyl group (e.g., 2-quinoxalyl), a quinazolinyl group (e.g., 2-quinazolinyl), a porphyrin group (e.g., 3- Carbolinyl), acridinyl (eg 2-oxaridinyl), oxazolyl (eg. 2-oxazolyl, 4-oxazolyl), morphinyl (eg 2-cylindinyl, 3-morphine) Pyridyl), acridinyl (eg 1-oxaridinyl, 2-acridinyl), dibenzofuranyl (eg 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg 2-benzimidazolyl), benzisoxazolyl (eg 3-benzoisoxazolyl), benzoxazolyl (eg 2-benzoxazolyl), benzoxadiazole (eg 4-benzoxadioxazolyl), benzisothiazolyl (eg 3-benzoisothiazolyl), benzothiazolyl (eg 2-benzothiazolyl), benzofuranyl (eg 3- Benzofuranyl), benzothienyl (eg 2-benzothienyl), dibenzothiophenyl (eg 2-diphenyl) And thienyl), benzodioxyl (for example, 1,3-benzodioxyl) and the like. In the present specification, the "non-aromatic heterocyclic group" is a 3 to 12 member non-aromatic heterocyclic group containing one or more nitrogen atoms in the ring and more preferably an oxygen atom and/or a sulfur atom. For example, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, piperidinyl, dihydropyridyl, tetrahydropyridyl, -26 - 200835692 piperazine, two Hydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, perhydropyrimidinyl and the like. In the present specification, the "aryloxy group" is a group in which an oxygen atom has one substituent of the above "aryl group". For example, phenoxy, naphthyloxy and the like. In the present specification, the "arylthio group" is a group having one substituent of the above-mentioned "aryl group" in the sulfur atom. For example, phenylthio, naphthylthio, and the like. In the present specification, the "heteroaryloxy group" is a group having one substituent of the above-mentioned "heteroaryl group" in the oxygen atom. For example, pyrroloxy, furanoxy, thienyloxy, ® imidazolyloxy, pyrazolyloxy, isothiazolyloxy, isoxazolyloxy, oxazolyloxy, thiazolyloxy, pyridyloxy, pyridyloxy , pyrimidinyloxy, oxonyloxy, tetrazolyloxy, oxadiazolyloxy, thiadiazolyloxy, oximeoxy, isodecyloxy, decyloxy, oxazolyloxy, hydrazine Oxy, quinoline, isoquinolinyloxy, quinolinyloxy, oxime oxy, naphthyridinyloxy, quinoxalyloxy, quinazolinyloxy, porphyrinoxy, acridineoxy , oxazolyloxy, phenanthryloxy, acridineoxy, dibenzofuranyloxy, benzimidazolyloxy, benzoiso Dfn, benzooxy, benzoxazolyloxy Base, benzisothiazolyloxy, benzothiazolyloxy, benzofuranyloxy, benzothienyloxy, dibenzothiophenoxy, benzodioxyloxy, and the like. Suitable as furanoxy, thienyloxy, imidazolyloxy, pyrazolyloxy, isothiazolyloxy, isoxazolyloxy, oxazolyloxy, thiazolyloxy, pyridyloxy, pyrenyloxy, pyrimidineoxy Base, argon, etc. In the present specification, the "heteroarylthio group" is a group in which one of the above-mentioned "heteroaryl groups" is substituted with a sulfur atom. For example, pyrrolylthio, furanthio, thiophenothionyl, imidazolyl, pyrazolyl, isothiazolthio, isoxazolylthio, Dfsulfuryl-27-200835692, thiazolylthio, pyridylthio, Pyridylthio, pyrimidinylthio, sulfonium thio, tetrazolylthio, oxadiazolethio, thiadiazolethio, sulfonium thio, isodecylthio, sulfonylthio, oxazolidine Base, sulfhydryl, quinacinyl, isoquinolinylthio, quinolinethio, hydrazine, naphthyridinyl, quinoxalyl, quinazolinethio, porphyrinthio, anthracene Alkylthio, oxazolidine, phenothiathio, acridinethio, dibenzofuranthio, benzimidazolylthio, benzisoxazolethio, benzoxazolethio, benzopyrene A oxazolylthio group, a benzisothiazolylthio group, a benzothiazolethio group, a benzofuranthio group, a benzothiophenethio group, a dibenzothiophenethio group, a benzodi Df thiol group, or the like. It is preferably furanthio, thiophenethio, imidazolyl, pyrazolyl, isothiazolthio, isoxazolethio, oxazolidine, thiazolidine, pyridylthio, pyridylthio, pyrimidine sulfur Base, sulfhydryl thiol and the like. In the present specification, "cycloalkanediyl" is a group having one more bond to the above "cycloalkyl group". For example, a cyclopentanediyl group, a cyclohexanediyl group, a cyclooctanediyl group, etc. In the present specification, the "cycloalkenyldiyl group" is a group having one of the above-mentioned "cycloalkenyl groups". For example, 1-cyclopentenediyl, 1-cyclohexenediyl, 1-cyclooctenediyl, and the like. In the present specification, the "aryldiyl group" is a group having one more bond to the above "aryl group". For example, benzene, naphthalene diyl, and the like. In the present specification, the "heteroaryldiyl group" has one bond group of the above "heteroaryl group". For example, pyrrole diyl, furandiyl, thiophenediyl, pyrazolediyl, imidazolyl, isothiazolidine, isoxazolediyl, carbazolediyl, thiazolidine, pyridyldiyl, pyrimidinediyl, Sorghum diyl, oxadiazole diyl, -28-

200835692 Thiadiazole diyl, hydrazine diyl, isoindole diyl, fluorenyl, fluorenyl, quinolon diyl, isoquinolinyl, g diyl, naphthalene π-diyl, quinine Eryl, quinolinyldiyl acridinediyl, carbazolediyl, phenanthryldiyl, 吖η定二三基基,本卩卩卩Π付一^基基,苯苯曙D卩嗣3-yl, benzoisoxazolediyl benzoxazole diyl, benzobenzoisoxazole diyl, benzothiazolediyl, benzofuranyl, dibenzothiophenediyl, In the basic specification of benzodioxane II, the "non-aromatic heterocyclic diradical" is a heterocyclic group and has one more bonded group. For example, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidine, piperidinyl, dihydropyridinediyl, tetrahydropyridinedihydropyridinyl, tetrahydropyridinediyl, dihydropyrimidine Dibasic, perhydropyrimidinyl, tetrahydrofuranyl, tetramethylpyrrolidinyl, tetrahydropyranyl, N-methyl, "In the specification," may have a non-reactive substituent. a trihalomethyl group, a cycloalkyl group which may have 1 to 2 substituents substituted by a substituent group, a cycloalkenyl group which may have 1 to 2 substituent groups substituted by a substituent group, may have a group of substituents 1 to 2 a substituted alkoxy group, which may have a cycloalkoxy group substituted by a substituent group a 1 to 2, an alkylthio group which may have 1 to 2 substituent groups substituted by a substituent group, may have a substituent group a 1 ~2 substituted cycloalkylthio groups, may have a group of substituents (diyl, carbazolyldiyl, anthracene, rosindiyl, dibenzofuran, benzimidazole dioxadiazolediyl) , dibasic, benzothiazide, etc.. "Non-aromatic: phenyl, pyrroline II: 卩 嗤 嗤 一 ;;; piperidine diyl, ., tetrahydropyrimidine, thiophenediyl, N-: hydrogen Alkyl group of pyridinediyl group is selected from the group A. The substitution of A is selected. The substituent selected is the substituent selected. The substituent selected is the substituent selected: the substituent -29-200835692 1~3 a substituted aryl group, which may have a substituent selected from the substituent group C, 1 to 3 substituted heteroaryl groups, a substituent group selected from the substituent group C, 3 to 3 substituted aryloxy groups, and may have 1 to 3 substituted heteroaryloxy groups selected from the substituent group C, 1 to 3 substituted arylthio groups which may be selected from the substituent group C, may be selected from the substituent group C The substituent has 1 to 3 substituted heteroarylthio groups, N-pyrrolidinyl group, N-piperidinyl group, N-morpholinyl group and the like, and may have 1 to 2 substituents. Substituent group A: C1-C4 alkane a group, a trihalomethyl group, a ChC4 alkoxy group, a C1-C4 alkylthio group, a phenyl group which may be substituted with a substituent selected from the substituent group C, and a substituent which may be selected from the substituent group C. 1 to 3 substituted phenoxy groups, heteroaryl groups. Substituent group B: trihalomethyl group, C1-C4 alkoxy group, C1-C4 alkylthio group, may have substituent 1 selected from substituent group C ~3 replacements a phenyl group which may have a substituent selected from the substituent group C, 1 to 3 substituted phenoxy groups, a heteroaryl fluorene substituent group C ··a halogen atom, a C1-C4 alkyl group, a trihalomethyl group, C1- a C4 alkoxy group, a C1-C4 alkylthio group, a phenyl group which may have 1 to 3 substituents selected from the substituent group C, and 1 to 3 substituents which may be selected by the substituent group C Phenoxy group, heteroaryl group. In the present specification, "alkenyl group which may be substituted with a non-reactive substituent", "alkynyl group which may be substituted with a non-reactive substituent", "may be substituted with a non-reactive substituent" The non-reactive substituent in the alkyl group, the "alkenyl group which may be substituted with a non-reactive substituent", and the "alkynyl group which may have a non-reactive substituent may be a trihalomethyl group, may have The substituent selected in the above substituent group A is a substituted cycloalkyl group having 1 to 2 substituents selected from the substituent group a, and may be substituted by the above. The group 1 to 3 substituted aryl groups selected by the group C may have 1 to 3 substituted heteroaryl groups selected from the substituent group C, and may have 1 to 2 substitutions. In the present specification, the non-reactive substituent in the "cycloalkanediyl group which may have a non-reactive substituent may be substituted" or "the cycloalkenyl diyl group which may have a non-reactive substituent may be" may have a substituent group B selected substituents 1 to 2 substituted alkyl groups, trihalomethyl groups, may have a substituent selected from the above substituent group A, 1 to 2 substituted cycloalkyl groups, may be selected from the above substituent group A The substituent 1 to 2 substituted cycloalkenyl groups may have 1 to 3 substituted aryl groups selected from the substituent group C, and may have 1 to 3 substituents selected from the above substituent group C Instead of a heteroaryl group or the like, there may be 1 to 2 substitutions. In the present specification, "an aryldiyl group which may have a non-reactive substituent substituted", "a heteroaryldiyl group which may have a non-reactive substituent substituted", and "a non-aromatic miscellaneous which may be substituted with a non-reactive substituent" The substituent in the cyclodiyl group may be a halogen atom, an alkyl group which may have 1 to 2 substituents selected from the substituent group B, a trihalomethyl group, and a substituent which may be selected from the above substituent group A 1 to 2 substituted cycloalkyl groups, 1 to 2 substituted alkoxy groups which may be selected from the above substituent group B, and 1 to 2 substituents which may be selected from the above substituent group A The cycloalkoxy group may have 1 to 2 substituted alkylthio groups selected from the substituent group B, and 1 to 2 substituted cycloalkylthio groups which may be selected from the substituent group A, There may be a substituent of 1 to 3 substituents selected from the above substituent group C, a heteroaryl group which may have 1 to 3 substituents selected from the substituent group C, and may have a substituent group -31 - 200835692 C selected substituents 1 to 3 substituted aryloxy groups, may have substituents 1 to 3 selected from the above substituent group C a substituted heteroaryloxy group, an arylthio group substituted with 1 to 3 substituents selected from the above substituent group C, and 1 to 3 substituted heteroaromatic sulfurs which may be selected from the above substituent group C Base, etc., and can have 1 to 2 substitutions. In the present specification, the "non-reactive substituent" is a substituent which does not react in the reaction of any of the above-mentioned items A to F. For example, the above substituents. In the present specification, the "hydrolyzate of the compound of the formula (I)" is a compound of the formula (II) or a metal salt of a carboxylic acid thereof (the metal is sodium, potassium or lithium). In the present specification, the "hydrolyzate of the compound of the formula (IX)" is a compound of the formula (X) or a metal salt thereof (the metal is sodium, potassium or lithium). In the present specification, "hydrolysis" includes acidic conditions. Hydrolysis and hydrolysis under alkaline conditions. When hydrolyzed under alkaline conditions, an acid may also be added. In the present specification, the "addition of alcohol to the hydrolyzate" includes: 1) after the hydrolysis, the reaction solution is extracted with an organic solvent, and when an alcohol is added to the organic layer, 2) after hydrolysis, an organic solvent is added to the reaction solution to separate the solution. In the case where alcohol is added to the water layer, 3) after hydrolysis, acid is added to the reaction solution, and extraction is carried out with an organic solvent, and when an alcohol is added to the organic layer, 4) after hydrolysis, an acid is added to the reaction solution, and an organic solvent is added thereto. When liquid is added to the water layer, 5) after hydrolysis, the reaction solution is extracted with an organic solvent, and when an alcohol and an acid are added to the organic layer, 6) after hydrolysis, an organic solvent is added to the reaction solution to separate the liquid. Where alcohol and acid are added to the water layer. The solution may also be concentrated and/or diluted if necessary. In the present specification, "the process A and B are continuously reacted" is a compound which is produced after the reaction of the work a, and is not used for the next work B. -32 - 200835692 In this manual, "Complete and React" of Engineers & and 3& Continuously reacts to the compound produced after the reaction of Project Aa, and the second project is used. In this manual, "Engineering c, D, A, and B are continuously reacted. The compounds formed after the reaction of Engineering C, D, and A are not separated and are used in the next projects D, A, and B. In the present specification, "the process of continuously reacting Ca, Da, Aa, and Ba" is a compound which is produced after the reaction of each of Ca, Da, and Aa, and is used for the next projects Da, Aa, and Ba. In the present specification, "the process E and F are continuously reacted" is a compound which is produced after the reaction of the process E, and is not used for the next project F. "Continuously reacting Ea and Fa in the project" is a compound produced after the reaction of Project Ea and is not used separately for the next project Fa. Suitable for R1 to R7, X, Y, and Hal of the compounds of the formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) The substituent group is represented by (la) to (lib). Compounds which are possible combinations of these are preferred. R1 is preferably (la) an alkyl group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent. The alkyl group substituted with a non-reactive substituent is preferred, and the alkyl group substituted with 1 to 2 substituents selected from the group of substituents d (Ic) is most preferred. Substituent group D: trifluoromethyl, C1-C4 alkoxy, C5-C6 cycloalkyl, phenyl substituted with 1 to 2 halogen atoms, and N-morpholinyl. R2 is preferably an alkyl group of (Id), an alkoxyalkyl group or an alkoxy group, more preferably an alkyl group of (Ie)-33-200835692 or an alkoxy group, and more preferably an (If) CM-C3 alkyl group. good. R3 is preferably an (Ig) alkyl group, an alkoxyalkyl group or an alkoxy group, more preferably an (Ih) alkyl group or an alkoxy group, and more preferably an (Ii) Cl-C3 group. Or R2 and R3 may form (Ij) a cycloolefin having 5 to 10 member rings of one double bond together with an adjacent carbon atom, and more preferably (Ik) cyclooctene. R4 is preferably a (II) hydrogen atom or a hydroxyl group, more preferably an (Im) hydrogen atom. R5 is preferably an (In) alkyl group, more preferably a (l) Cl-C2 alkyl group. R6 is preferably (Ip) alkyl, more preferably (Iq) Cl-C2 alkyl.

R7 is preferably an (Ir) hydrogen atom or an alkyl group, more preferably an (IS) C1-C2 alkyl group. X may have an alkyl group which may have a hetero atom or may have a non-reactive substituent, an alkenyl group which may have a hetero atom and may have a non-reactive substituent, and may have a hetero atom. An alkynyl group substituted with a non-reactive substituent, a cycloalkanediyl group which may be substituted with a non-reactive substituent, a cycloalkenyldiyl group which may be substituted with a non-reactive substituent, and a aryl group which may be substituted with a non-reactive substituent a diradical, a heteroaryldiyl group which may be substituted with a non-reactive substituent, or a non-aromatic heterocyclic diradical which may be substituted with a non-reactive substituent, and may have a hetero atom (IU) a non-reactive substituent-substituted alkylene group, a cycloalkanediyl group which may be substituted with a non-reactive substituent, an aryldiyl group which may be substituted with a non-reactive substituent, or a heteroaromatic group which may be substituted with a non-reactive substituent a non-aromatic heterocyclic diyl group which may be substituted with a non-reactive substituent, preferably a (Iv) cycloalkanediyl group, an aryldiyl group, a heteroaryldiyl group which may have a halogen atom, or a tetrahydro group The pyranyl group is optimal. Y is an (Iw) single bond, an alkylene group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkyne which may have a non-reactive substituent-34-200835692 Preferably, the group is preferably a (lx) single bond or an alkylene group, and more preferably an (Iy) single bond or an (Iz)Cl-C2 alkylene group.

Hal is preferably a (Ila) halogen atom, and more preferably a (lib) chlorine atom. Further suitable for Rla~R7a, Xa, Ya, and Hala of the compounds of formula (XI), (X), (XI), (XII), (XIII), (XIV), (XV), and (XVI) The substituent group is represented by (Iaa) to (Ilba). Compounds which are possible combinations of these are preferred.

Rla is preferably an alkyl group which may have a non-reactive substituent substituted with (Iaa), an alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent, and more preferably (Iba) The alkyl group substituted with a non-reactive substituent is preferred, and the alkyl group which may be substituted with 1 to 2 substituents selected from the substituent group D is most preferred. The substituent group Da is a trifluoromethyl group, a C1-C4 alkoxy group, a C5-C6 cycloalkyl group, a phenyl group substituted with 1 to 2 halogen atoms, and an N-morpholinyl group. R2a is preferably (Ida)alkyl, alkoxyalkyl or alkoxy, more preferably (lea)alkyl or alkoxy, more preferably (Ifa)Cl-C2 alkyl. R3a is preferably (Iga)alkyl, alkoxyalkyl or alkoxy, more preferably (Iha)alkyl or alkoxyalkyl, more preferably (Iia)Cl-C3 alkyl. Alternatively, 1123 and R3a may form (I" a) a cycloolefin having 5 to 10 membered rings having one double bond, and more preferably (Ika) cyclooctene. Preferably, the "Ila" hydrogen atom or the hydroxyl group is more preferably an (Ima) hydrogen atom. The R5aW(Ina) alkyl group is preferably a further (Ioa)Cl-C2 alkyl group. R6aU(Ipa) alkane Preferably, the (Iqa)Cl-C2 alkyl group is preferred. The R7a U(Ira) hydrogen atom or the hospital base is preferred, and the (Isa)Cl-C2 hospital base is preferred -35- 200835692

Xa may have an alkylene group which may have a hetero atom or may have a non-reactive substituent, and may have a hetero atom, may have a non-reactive substituent, and may have a hetero atom. An alkynyl group substituted with a non-reactive substituent, a cycloalkanediyl group which may be substituted with a non-reactive substituent, a cycloalkenyldiyl group which may be substituted with a non-reactive substituent, and a aryl group which may be substituted with a non-reactive substituent a diaryl group, a heteroaryldiyl group which may be substituted with a non-reactive substituent, or a non-fragrance heterocyclic diyl group which may be substituted with a non-reactive substituent, and may have a hetero atom (Iua) An alkyl group substituted with a non-reactive substituent, a cycloalkanediyl group which may be substituted with a non-reactive substituent, an aryldiyl group which may be substituted with a non-reactive substituent, or a heteroaryl group which may be substituted with a non-reactive substituent The diradical or non-aromatic heterocyclic diradical which may be substituted with a non-reactive substituent is preferably an (Iva) cycloalkanediyl group, an aryldiyl group, a heteroaryldiyl group which may have a halogen atom, or Hydropyrandiyl is most preferred.

Ya is preferably a (Iwa) single bond, an alkylene group which may be substituted with a non-reactive substituent, an extended alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent. Further, it is preferably an (Ixa) single bond or an alkylene group, and more preferably an (Iya) single bond or an (Iza)Cl-C2 alkylene group.

Hala is preferably a (Ilaa) halogen atom, more preferably an (Ilba) chlorine atom. (Effects of the Invention) The 2-pyridone-3-aminocarbamoyl derivative having an excellent action as a cannabinoid receptor agonist and an important intermediate thereof are useful in a simple, high-yield, high-purity preparation method. [Embodiment] -36-200835692 (Best Mode for Carrying Out the Invention) The compound of the present invention can be synthesized by any of the following methods: Formula (1), (Π), (III), (IV), (V), In the compounds represented by VI), (VII), and (VIII), when they have an asymmetric center, they include a racemate and/or an optically active body. Further, formula (I), (II), (III), (IV) The compounds shown in (V), (VI), (VII), and VIII) may also be suitable for salt or solvate in each project.

Form exists. R2^YR3 0 (IV) r1-nh2 (III) Engineering c

R4 (Ο R4

(VI) (II)

(wherein R1, R2, R3, R4, and R5 are the same as 1); R6 is the same as 3); R7, X, Y, and Hal are the same as 6). Engineering C is a compound of formula (IV) Dehydration condensation of a compound of the formula (ΠΙ) -37· 200835692 This work can be carried out in the absence of a solvent or a solvent. The compound of the formula (III) may be used in an amount of 0.1 to 1 mol equivalent, preferably 0.35 to 0.85 mol equivalent, to the compound of the formula (IV). When R2 and R3 are not together with adjacent carbon atoms, it is more preferred to use 0.35 to 0.55 molar equivalents. Further, when R2 and R3 form a cycloolefin together with an adjacent carbon atom, it is more preferably used in an amount of 0.65 to 0.85 mol equivalent. The reaction solvent may be toluene, xylene, chlorobenzene, or a mixed solvent of these, and is preferably toluene. The reaction time is from 30 minutes to 48 hours, preferably from 30 minutes to 10 hours. • The reaction temperature is from 50 ° C to the reflux temperature of the reaction solvent, preferably from 10 ° C to the reflux temperature of the reaction solvent. If necessary, the compound of the formula (IV) can be used in the reaction of the reaction C with acetic acid of 0.05 to 0.10 molar equivalent. After the reaction of the reaction C, the reaction liquid can be used for this purpose or concentrated for use in the work D. The target compound for dehydration condensation can also be used in the engineering D for general separation. Engineering D is a process in which a compound of the formula C is closed with a compound of the formula (V) to form a compound of the formula (I). This work is carried out in the absence of solvent or solvent. The compound of the formula (V) is used in an amount of from 0.3 to 1.2 mol equivalents to the compound of the formula (IV), preferably from 0.5 to 1.0 mol equivalent. When R2 and R3 are not together with adjacent carbon atoms, it is preferred to use 0.55 to 0.75 mole equivalents. Further, when R2 and R3 form a cycloolefin together with an adjacent carbon atom, it is more preferably used in an amount of from 0.85 to 1.05 mol. The reaction solvent is toluene, xylene, chlorobenzene, or a mixed solvent of these, and toluene is preferably used. 38· 200835692 The reaction time is 30 minutes to 4 8 hours, preferably 3 minutes ~ i 6 hours. The reaction temperature is from 50 ° C to the reflux temperature of the reaction solvent, preferably from 1 Torr to the reflux temperature of the solvent. After the end of the reaction of the work D, the reaction liquid is used for the work a, or if necessary, it can be concentrated for use in the work A. The compound of the formula (I) can also be used in the engineering A by extraction according to a general method and by single purification. Process A is a process for hydrolyzing a compound of the formula (1) obtained in Process D to form a hydrolyzate of the compound of the formula (1). When hydrolyzed under acidic conditions, after hydrolysis, the alcohol was added to the reaction mixture to extract with an organic solvent. Alternatively, the reaction liquid may be extracted with an organic solvent, and then an alcohol may be added to the organic layer. When the hydrolysis is carried out under alkaline conditions, after the hydrolysis, an acid may be added to the reaction solution to form an acidity, and then the alcohol is added to the reaction solution, followed by extraction with an organic solvent. Further, after adding an acid to the reaction liquid to make it acidic, it is extracted with an organic solvent, and then an alcohol is added to the organic layer. Further, when the hydrolyzate is dissolved in the organic layer, the reaction solution may be extracted with an organic solvent, and then an alcohol and an acid may be added to the organic layer. After hydrolysis, the reaction solution can be used for the next project or, if necessary, concentrated for the next project. The organic solvent is preferably ethyl acetate or toluene. A) When hydrolyzed under acidic conditions, the acid is preferably used in an amount of from 0.25 to 1 (1 mol) to the compound of the formula (1), preferably from 1 to 3 mol equivalents. The acid can be hydrochloric acid or sulfuric acid. The reaction solvent, the reaction time, the reaction temperature, the precipitation time of the crystal, the precipitation temperature of the crystal, and the like can be used in the same manner as in the case of the hydrolysis described below under alkaline conditions. -39- 200835692 B) In the hydrolysis under alkaline conditions, the base may be used in the compound of the formula (I) in an amount of from 0. 25 to 3 mol equivalents, preferably from 0.8 to 2.5 mol equivalents, more preferably from 1.2 to 2 mol equivalents. The test may be sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide. The base can be used as a solid or as an aqueous solution. The reaction solvent may be a mixed solvent of an alcohol (methanol, ethanol, n-propanol, or isopropanol) / water or a mixed solvent of toluene / alcohol (methanol, ethanol, n-propanol, or isopropanol) / water, preferably Toluene/methanol/water or methanol/water. The reaction time is 0.25 to 8 hours, preferably 0.5 to 2 hours. Φ The reaction temperature is from 10 ° C to 70 ° C, preferably from 20 ° C to 60 ° C. . . After the completion of the hydrolysis, if necessary, the reaction liquid may be washed with toluene to obtain a layer (aqueous layer or organic layer) in which the hydrolyzate of the compound of the formula (I) is dissolved. The acid to be added to the layer in which the reaction liquid or the hydrolyzate of the compound of the formula (I) is dissolved may be hydrochloric acid or sulfuric acid, preferably sulfuric acid. Engineering B is an engineering in which an alcohol is added to the hydrolyzate of the compound of the formula (I) produced in Engineering A to form a crystal of the compound of the formula (II). The added alcohol may be methanol, ethanol, n-propanol, isopropanol, or a mixed solvent of these, preferably isopropanol. The crystallization can be 0.25 to 12 hours, preferably 0.25 to 2 hours. The crystals may be precipitated at -10 ° C to 25 ° C, preferably at -5 ° C to 5 ° C. Works C, D, and A can be continuously implemented without leaving. Engineering E is a process in which a compound of the formula (II) is reacted with a halogenating agent to form a compound of the formula (VI). The halogenating agent may be used in the compound of the formula (II) in an amount of from 0.5 to 2 mol equivalents, preferably from 0.8 to 1.5 mol equivalents. -40- 200835692 The reaction solvent may be toluene, tetrahydrofuran, N, N_: methylformamide, N-methylpyrrolidone, or a mixed solvent thereof, and is preferably toluene/N-methylpyrrolidone or tetrahydrofuran/N. , a mixed solvent of N-dimethylformamide. The reaction time is 0 · 2 5~1 2 hours, preferably 〇 · 2 5~2 hours. The reaction temperature is 10 ° C ~ 5 0 X:, preferably 20 ° C ~ 3 0. After the end of the reaction of the work 4, the reaction liquid can be concentrated or concentrated as necessary for use in Engineering F. Engineering F is the engineering of a compound of formula (VIII) and a compound of formula (VII) or an acid salt thereof in the presence of a base of the base to form a compound of formula (VIII). The compound of the formula (vii) or its acid salt may be used in the compound of the formula (VI) in an amount of from 5 to 2 moles, preferably from 0.8 to 1.5 moles. The acid salt can be a hydrochloride, a hydrobromide or a sulfate, preferably a hydrochloride. The compound of the formula (VI) can be used in an amount of 〜 5 to 2 molar equivalents, preferably 〇 8 to 15 moles. The reaction solvent may be toluene, tetrahydrofuran, hydrazine, hydrazine-dimethylmethylamide, νmethylpyrrolidone, or a mixed solvent thereof, and is preferably toluene/hydrazine-methyl hydrazide® pyridine or tetrahydrofuran/oxime. , a mixed solvent of hydrazine-dimethylformamide. The reaction time is 0.2 5 to 1 2 hours, preferably 〇 · 2 5 to 2 hours. The reaction temperature is from 10 ° C to 50 ° C, preferably from 20 ° C to 30 ° C. When R7 is a hydrogen atom, the $p crystal can be analyzed after the end of the reaction of the engineering F. If necessary, alcohol is added to precipitate crystals, and methanol, ethanol, 1 ^ y-n-propanol, isopropanol, or a mixed solvent of these may be used, and it is preferably isopropyl alcohol. The crystallization can be from 0 to 25 to 12 hours, preferably from 0.25 to 2 hours. The crystallization may be -1 ° C to 25 ° C, preferably -5 ° C to 5 ° C. -41 - •200835692 When R7 is an alkyl group, it can be hydrolyzed under acidic conditions or in the presence of a base in the same manner as in Engineering A to obtain a compound of the formula (VIII) wherein R7 is a hydrogen atom. If necessary, in the same manner as in Engineering B, alcohol may be added to precipitate crystals, and methanol, ethanol, n-propanol, isopropanol, or a mixed solvent of these may be used, and it is preferred to use isopropyl alcohol crystallization to be 0 · 2 5 to 1 2 hours. It should be precipitated by 〇. 2 5~2 hours. The crystal may be -1 (TC~25 ° C, preferably -5 ° C to 5 ° C. In the present specification, the "solvate" includes, for example, a solvate with an organic solvent, a hydrate, etc., and an organic solvent. In the case of a solvate, it can be coordinated with any number of organic solvent molecules. When a hydrate is formed, it can be coordinated with any number of water molecules. It is preferred to use a hydrate. In the present specification, "Formula (I), (II) And (III), (IV), (V), (VI), (VII), and (VIII) a salt of a compound may be, for example, the formula (I), (11), (111), (IV), (V), (VI), (VII), and (VIII) compounds and alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases and amino acids, Or salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). It is usually formed by the method of the above. The crystal of the compound of the formula (II) and the formula (VIII) produced by the above-mentioned production method can be obtained by X-ray analysis of the powder to obtain an X-ray diffraction pattern. It is easy to handle the manufacture of a pharmaceutical composition having the compound of the formula (VIII) as an active ingredient, and is useful for the production of a pharmaceutical composition due to high purity. As for the compound of the formula (II) and the formula (VIII) Crystallization is shown by the X-ray diffraction pattern in Examples 1 to 20 -42 to 200835692 described later (X-ray diffraction measurement conditions: tube ball CuKa line, tube voltage 40 Kv, tube current 40 mA or 50 mA, dsin θ = η λ ( η is an integer, d is a plane spacing (unit: A), and 0 is a diffraction angle (unit: degree)). These crystals are characterized by the respective diffraction angles or surface intervals. The following examples and test examples are further described. The present invention will be described in detail, but the present invention is not limited thereto. In the examples, the following abbreviations are used.

Me: methyl Et: ethyl DMF: N,N-dimethylformamide THF: tetrahydrofuran-furan DMSO: dimethyl hydrazine TMS: tetramethyl decane (Example) The compound of Example 1 (ΙΙ- a) synthesis

(IV-a) Project 1

Ο (IH-a)

Process 1 A solution of the compound (III-a, 39.1 2, 0.454 mol) and the compound (IV-a, 20.3 - 43 - 200835692 g, 0.189 mol) in toluene (142 mL) was refluxed for 1.5 hours. The reaction solution was concentrated under reduced pressure to give a concentrate. This concentrate is used in the next reaction. In the concentrate obtained in the first step, the compound (Va, 61.3 g '0.283 m〇O, was stirred at 120 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing compound (Ia). In the next reaction, the concentrate obtained in Engineering 2 was added with methanol (60 mL), 24% sodium hydroxide water solution (38 mL), and stirred at 25 ° C for 0.5 hour. The reaction solution was concentrated under reduced pressure toluene. (213 mL) was washed. Add 61% sulfuric acid (3.3 g) and 31% sulfuric acid (26 g) to the aqueous layer for acidification, and extract with ethyl acetate (144 mL). Propanol (24 mL) was crystallized at 0 ° C for 0.5 h. The crystals were crystallized and dried to give compound (II-a, 36.6 g, 71.4%).

Melting point: 114 ° C NMR (CDCh ^ TMS): 1.18 (t, 3H, J = 7.7), 2.24 (s, 3H), 2.73 (q, 2H, J = 7.5), 5.49 (br s, 2H), 7.09 (m, 2H), 7.29-7.3 8 (m, ® 3H), 8.38 (s, 1H), 14.53 (br s, 1H) The results of powder X-ray diffraction are shown in Table 1 and Figure 1. Main. The diffraction angle of the peak: 20 = 10.5, 15.1, 19.5, 21.7, 25.2 degrees [Table 1] -44- 200835692

27.860 0.188 28.460 0.188 28. 960 0.165 29.520 0.188 30· 260 0.141

7 6 6 4 2 9 3 0 3 1 9 3>8>25 110 0 9 ci 3· 3· 3· CsJ 30. 500 0.165 2. 9285 7170 30.940 0.212 2. 8878 7727 33.180 0.188 2. 6978 5917 33.480 0.141 2 6743 3375 33. 580 0. t18 2. 6666 3507 35.120 36.540 37. 840 38. 800 6 5 1215 7 3 8 8 3 Λ/* 1— fi»~<– 1* 1— 0·0·0· 5 9 2 03⁄4 3 5 8 2 22 23 3 f 1. 6 o 3 7 5 9 !55I5J7J1 »4 3 3 Cv} 2· 2· 2· 8 7 0 3 6 7 3 7 6 15 2 3 4 5 5 - 2 . 1J · 2 捜 Peak set width d値 intensity relative intensity 10. 240 0.118 8.6314 8850 19 10. 540 0-165 8. 3864 4S120 100 11.540 0.188 7. 6618 21325 45 13. 600 0.165 6. 5055 13748 29 14 080 0.165 6. 2848 4192 9 14.340 0.165 6.1714 5617 Ϊ2 15.100 0.188 5.8625 33417 70 16.380 0.188 5. 4071 3875 9 17. 280 0.212 5.1275 25265 53 m mi 18. 620 0.165 4. 7614 16650 35 19.160 0.118 4, 6284 5147 11 19. 460 0.188 4.5577 29203 61 20· 200 0.165 4.3924 4033 9 21.480 0.141 4.1335 16787 35 21,740 0,165 4.0846 27045 57 22.040 0.118 4.0297 19158 40 22· 220 0.165 3. 9974 22852 48 22.800 0. 21 2 3.8971 6607 14 23· 220 0.188 3· 8275 9S07 21 23.580 0. t41 3.7699 4500 10 25. 220 0.188 3.5283 42992 90 26.160 0.188 3.4036 62Q8 13 26.500 0.188 3.3607 6187 13 27.420 0.188 3· 2500 4648 10 17108 11918 4882 5660 5187 Implementation Synthesis of the compound of Example 2 (Π-b) -45 - 200835692

Project 1

A solution of the compound (ΙΠ-a, 39.1 g, 0.454 mol) and the compound (IV-b, 23.7 g, 0.189 mol) in toluene (142 mL) was refluxed for 5 hr. The reaction solution was concentrated under reduced pressure to give a concentrate. This concentrate is used in the next reaction. Engineering 2 The concentrate obtained in Engineering 1 was added with a compound (V-a, 61.3 g, 0.283 mol), and stirred at 1 17 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing compound (I-b). This concentrate is used in the next reaction. Engineering 3 The concentrate obtained in Engineering 2 was added with methanol (60 mL) and 26% aqueous sodium hydroxide solution (4 3.7 g), and stirred at 25 ° C for 0.5 hour. The reaction solution was concentrated under reduced pressure and washed with toluene (213 mL). In the aqueous layer, 61% sulfuric acid (3.3 g) and 31% sulfuric acid (26 g) were acidified and extracted with ethyl acetate (144 mL). After washing with water (95 mL), the extract was concentrated under reduced pressure, and then 2-propanol (24 <RTIgt; The crystals were precipitated by filtration and dried to give compound (II-b, 35.9 g, 65.6%).

Melting point: 1 10~11 1°C -46· 200835692 NMR (DMS〇-(h, TMS): 1.05 (t, 3H, J = 7.5), 2.24 (s, 3H), 2.75 (q, 2H, J = 7.5), 5.48 (s, 2H), 7.15-7.25 (m, 4H), 8.32 (s, 1H), 14.68 (s, 1H) The results of powder X-ray diffraction are shown in Table 2 and Figure 2. Main peak winding Shooting angle: 20=13.7,19.〇,24·2,26·4,27·8 degrees [Table 2]

ο ο ο ο ο 2 0 4 2 8 »2275 Ιο2.3.3.4. 1—1» 1—1 1 8 16 5 -88406 t—1— 1. 00 i— ιο· ο· ο· ο· ο· d値Strength 8.1700 13027 7. 24S7 3957 6.6816 17142 6. 4489 77085 6.0704 3063

15.060 0.212 5. 8780 5818 8 15. 780 0.165 5.6114 10943 15 17.160 0.165 5.1631 7473 10 18. 040 0.188 4. 9132 27957 37 18. 960 0.188 4. 6768 48507 63 20. 440 21.740 22. 700 22-900 23. 320 24.180 25.140 25. 700 26. 420 27. 760 6 8 4 1 &amp; if 1— it it 1. 0·0·0·0· ο· 0Γ2ΪΙ 0.141 0.235 0.188 0.188 4. 3414 15035 4. 0846 9210 3. 9140 6683 3. 8803 5162 3.8113 7670 3. 6777 3. 5394 3.4635 3.3707 3. 2110 34875 3605 18045 34753 39982 20129 710465244652 28.240 0.188 3.1575 3567 5 29. 360 0.188 3.0395 3997 6 29. 820 0.235 2. 9937 17890 24 30. 380 0.165 2.9398 4750 7 31.900 0.118 2.8031 3463 5 32.160 0.188 2.7810 5760 8 32.880 0.2ί2 2.7217 5135 7 33.900 0. 212 2.6421 3972 6 36. 380 0.212 2.4675 3473 5 37.320 0.235 2.4075 4157 6 Synthesis of the compound of Example 3 (II-c) - 47- 200835692

A solution of the compound (ΙΠ-a, 39.1 g, 0.454 mol) and the compound (IV-c, 21.4 g, 0.189 mol) in toluene (142 mL) was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a concentrated liquid. This concentrate is used in the next reaction. Engineering 2 The concentrate obtained in Engineering 1 was added with a compound (V-a, 61.3 g, 0.283 mol), and stirred at 1 1 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing compound (I-c). This concentrate is used in the next reaction. Engineering 3 The concentrate obtained in Engineering 2 was added with methanol (60 mL) and 24% aqueous sodium hydroxide solution (3 8.4 mL), and stirred at 25 ° C for 0.5 hour. The reaction solution was concentrated under reduced pressure and washed with toluene (213 mL). The aqueous layer was sequentially acidified with 61% sulfuric acid (3.3 g) and 31% sulfuric acid (26 g), and extracted with ethyl acetate (144 mL). After washing with water (95 mL), the extract was concentrated under reduced pressure, and then 2-propanol (24 <RTIgt; The crystals were precipitated by filtration and dried to give compound (II-c, 37.5 g, 71.5%).

Melting point: 1 3 1 ° C -48 - 200835692 NMR (DMSO-d6, TMS): 1.00 - 1.30 (m, 5H), 1.22 (t, 3H, J = 7.5), 1.55 - 1.90 (m, 6H), 2.24 (s, 3H), 2.82 (q, 2H, J = 7.2), 3.90-4.20 (m, 2H), 8.29 (s, 1H) The results of powder X-ray diffraction are shown in Table 3 and Figure 3. The diffraction angle of the main peak: 20=9·8, 14·5, 2〇.4, 21·9, 25.6 degrees [Table 3] 2 Θ Peak setting amplitude Strength relative intensity

9.160 9. 780 11.380 12.700 14. 520 15:26〇17. 860 18. 420 19· 240 19. 800 5 15 8 9 6 4 6 8 5 1» t» 1» 1» rt/~ ο· d ο· ο· 5 5 5 5 8 6 6 6 3 1» 1— i— 1 Λ/- ci 0·0·0· o· 9, 6465 26548 9. 0363 60607 7.7692 15588 6. 9645 9470 6.0953 37578 5. 8241 10905 4.9623 9370 4.8126 10147 4. 6093 8260 4. 4802 15892 4 0 6 6 2 φ ο 2 1 6 8 6 7 if it 1427 20.440 0.165 21. 940 0.188 22. 520 0,188 22. 940 0.165 24. 000 0.188 4. 3414 28042 4. 0478 27668 3. 9449 22020 3. 8736 8088 3. 7048 4438 47463714δ 24. 320 24. 980 25.580 27.020 28. 060 29:160...' 30.140 30· 900 32. 080 3 8 8 2 5·1 2 β 55 5 5 8 8 1 6;1 8 India 6 ^01121 „.2 111 0·0*0· 0· 010· ο· ο· ο. 3.6568 6000 to 3.5617 19927 33 3.4795 29438 49 3. 2972 10233 17 3J773 44S0 8 3: lion f 12447'...... ......·21 2. 9626 3910 7 2.8915 6073 11 2. 7878 6487 11 Synthesis of the compound of Example 4 (Π-d) -49- , 200835692 Project 1

Me Me—( NH2 (IV-d)

〇 (lll-a)

The solution of the compound (ΙΠ-a, 39·1 g, 0.454 mol) and the compound (IV-d, 16.5 g, 0.189 mol) in toluene (142 mL) was refluxed for 8 hours. The reaction solution was concentrated under reduced pressure to give a concentrate. This concentrate is used in the next reaction. Engineering 2 The concentrate obtained in Engineering 1 was added with a compound (V-a, 61.3 g, 0.28 3 mol), and stirred at 120 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing compound (I-d). This concentrate is used in the next reaction.

Engineering 3 The concentrate obtained in Engineering 2 was added with methanol (60 mL) and 24% aqueous sodium hydroxide solution (3 8.4 mL), and stirred at 25 ° C for 0.5 hour. The reaction solution was concentrated under reduced pressure and washed with toluene (213 mL). The aqueous layer was sequentially acidified with 61% sulfuric acid (3.3 g) and 31% sulfuric acid (26 g), and extracted with ethyl acetate (144 mL). After washing with water (95 mL), the extract was concentrated under reduced pressure, and then 2-propanol (24 <RTIgt; The crystals were precipitated by filtration and dried to give compound (Il-d, 28.2 g, 59.3%).

Melting point: 1 0 6 ° C -50- .200835692 NMR (DMS〇-d6, TMS) : l.〇2(d, 6H, J = 6.6), 1.28(t, 3H, J = 7.5), 1.56- 1.66 (m, 2H), 1.78(m, 1H), 2.23(s, 3H)? 2.79(q? 2H, J = 7.5), 4.10-4.21(m, 2H), 8.28(s, 1H) powder X-ray winding The results of the shooting are shown in Table 4 and Figure 4. The diffraction angle of the main peak: 20=1〇.1,1〇·8,21·3,26·〇 [Table 4] 2 Θ Peak setting width d値 Intensity Relative strength

Oooo Q 4 6 2 2 4 17 9 17 ο· ο· 2·4.5. i— li 1— 1» 1— 8 5 5 5 1 18 6 6 6 4 1— 1» 1 t» 1» 8. 7163 65433 100 8. 2154 32057 49 6· 8464 7662 12 6· 2671 13083 20 5.6255 3253 5 16.060 0.165 5.5142 10022 16 18. 000 0.188 4. 9240 15025 23 18. 680 0.165 4. 7462 11157 18 19.740 0.165 4.4937 10558 17 20. 380 0.188 4. 3540 4202 7 20. 900 0.188 4.2468 14033 22 21. 260 0.188 4.1757 38532 59 21. 660 0.188 4. 0995 16912 26 21.860 0.118 4.0625 8093 13 22.440 0.188 3. 9588 11630 18 22.960 0.188 3/8703 6895 11 23. 320 0.188 3.8113 9763 15 24. 500 0.165 3. 6304 3357 6 25.120 0.188 3.5421 16370 26 25.360 0.118 3.5092 8232 13 §§gQSIII§ 2628293131:32333 ___Β 1» S Γ______, 8 8 4 25 ρ:6 6 π i— i— It .tf Λύ ^11 i· 0.ο· 0.0.010.ο· ο· 6 ο 7 1 6【6 ο 8 1 φ 5 8^7 t 2 2 8 4 7 τ«5 ο 7 4 1 ο 8 8Τ 7 6 3· 3· 3* m2* 2· C\i 6512931822703-0705 9 8 7 Building 43⁄4 rr 7 7 3 3 2 4 00 436 620716 714 Synthesis of the compound of Example 5 (Π-e) -1l - . 200835692

Me〆 〇 (lll-a)

Project 1

(l-e)

Project 1

A solution of the compound (III-a, 58.6 g, 0.681 mol), compound (IV-e, 27.1 g, 0.189 mol) in toluene (142 mL) was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure to give a concentrate. This concentrate is used in the next reaction. Engineering 2 The concentrate obtained in Engineering 1 was added with a compound (V-a, 61.3 g, 0.283 mol), and stirred at 117 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing compound (I-e). This concentrate is used in the next reaction. Engineering 3 The concentrate obtained in Engineering 2 was added with methanol (59 mL) and 24% aqueous sodium hydroxide solution (3 8.6 mL), and stirred at 25 ° C for 0.5 hour. The reaction solution was concentrated under reduced pressure and washed with toluene (212 mL). The aqueous layer was sequentially added with 61% sulfuric acid (3.3 g), followed by 31% sulfuric acid (26 g), and extracted with ethyl acetate (144 mL). After washing with water (95 mL), the extract was concentrated under reduced pressure, and then 2-propanol (24 <RTIgt; The crystals were precipitated by filtration and dried to give compound (π_e, 39.6 g, 68.1%).

Melting point: 1 3 1~1 3 2 °C -52- 200835692 H-NMR (CDCh, TMS): 1.21 (t, 3H, J = 7.7), 2.25 (s, 2, 73 (q, 2H, J = 7.4) ), 5.42 (br s, 2H), 6.86 (m, 1H), 6·9ι 1H, J = 10.8, 7.4 and 2.3), 7.15 (dt, 1H, J = 9.9 and 8.39 (s, 1H), 14.31 ( Br s, 1H) The results of powder X-ray diffraction are shown in Tables 5 and 5. The diffraction angle of the main peaks: 20=13.4, 13.8, 19·〇, 24·3, 27.9 degrees [Table 5] ~2 Θ 捜Peak set width d値—~ intensity relative intensity 3H), (ddd, 8.3),

Owoo Q 04(0 ο 4 8 0 4 8 0 ο· 2· 3· 3* 5· 1— ii 1— 1— 1 0.188 0.188 0.188 0.188 0.165 0 7 2 7 7 5 4 2 15 8 4 0 18 13 6 4 8 5 5 〇9 8 8 6 6558 8 1 t— 1 1— 1. cri ο· ο· ο· ο· 5 4 t &gt;-420 :0592t ”90260 5 2 9 6 4 19250 40 5348 12 27512 57 48528 100 4795 10 8180 17 a 3640 8 18187 38 22233 46 5250 11 15. 840 11020 17.980 19.020 20.160 21.820 0.306 4.0698 4742 10 22. m 0.165 3. 9518 3413 8 22.820 0.188 3· 8937 5980 13 23.400 0.188 3· 7985 5430 12 24. 260 0.212 3. 6657 22273 46 25. 620 26.460 26. 900 27.880 28,480 a 29:*800^.... 30.240 31.620 32.840 33.340 2 8 5 85^8 3 2 8 2 18 6 86^8 5 1-8^ 2 t 1 11* 3 A/wf 2 0·0·0♦0.0·*0:0·0·0· ο. 3· 4741 12558 26 3· 3657 21558 45 3.3117 4582 to 3.1974 30877 64 3.1314 3447 8 ...2 :尔厂—Portuguese 7...............—39* 2.9531 61S5 13 2,8273 4927 11 2.7250 3157 7 2.6852 3182 7 2.2630 3738 8 39.800 0.212 Synthesis of the compound of Example 6 (ΙΙ-f) -53- 200835692

A solution of the compound (III-b, 10.0 g, 0.079 mol) and the compound (IV-C, 8.97 g, 0.07 mol) in toluene (100 mL) was refluxed for 7 hr. In the reaction liquid obtained in the above, the compound (V-b, 20.56 g, 0.095 mol) was added and heated under reflux for 16 hours. The reaction solution was concentrated under reduced pressure to give a concentrated liquid containing compound (I-f). This concentrate is used in the next reaction. Engineering 3 The concentrate obtained in Engineering 2 was added with methanol (150 mL), 2N aqueous sodium hydroxide solution (7 9 mL, 0.158 mol), and stirred at 25 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, toluene and water were added, and the aqueous layer was separated. 5N Hydrochloric acid (34 mL) was added to aq. The extract was concentrated under reduced pressure and EtOAc (EtOAc) The crystals were precipitated by filtration and dried to give compound (?-f, 15.5 g, 61.6%). NMR (CDCh, TMS): 1.05-1.71 (m, 19H), 2.70-2.74 (m, 2H), 2.98-3.01 (m, 2H), 4.06 (bs, 2H), 8. 21 (s, 1H), 14.96 (s, 1H) The results of powder X-ray diffraction are shown in Tables 6 and 6. Diffraction angle of the main peak: 20 = 11.2, 11.4, 15.0, 18.2, 20.6, 21.5 degrees -54- 200835692

2 Θ d値 intensity relative intensity 10.225 8.64424 75.6 68.3 11.368 7.777 72.3 65.4 14.963 5.91599 70.3 63.5 15.34 5.7713 32.9 29.7 15.857 5.58444 21.2 19.2 17.052 5.19562 34.5 31.2 18.15 4.88349 72.3 65.4 18.713 4.73784 15 13.6 19.73 4.49593 26.2 23.7 20.074 4.41965 42.2 38.1 20.565 4.31529 111 100 21.196 4.18823 ^ 43.8 39.6 21.466 4.13617 83.3 75.3 21.975 4.04138 27.9 25.2 22.823 3.89325 62.6 56.6 23.408 3.79726 50.8 45.9 23.748 3.74359 49.8 45,1 24.105 3.68889 26.5 24 26.736 3.33161 14.3 13 28.598 3.11872 12.4 ^ 11.2 28.892 3.08773 11.8 10.7 29.557 3.01971 13.5 12.2 29.82 2.99372 13 11.7 31.52 2.83599 16.1 14.6 33.017 2.71078 11.3 10.2 33.454 2.67632 9.61 8.7 34.817 2.57465 8.55 7.7 35.301 2.54042 8.78 7.9 35.937 2.49694 8.51 7.7 36.337 2.47034 6.89 6.2 37.262 2.4111 6.34 5.7 38,3 2.34809 7.61 6.9 Synthesis of the compound of Example 7 (II_g) Et〇, 0

Me- (IV-f)

NH 2 (lll-b) Project 1

EtOOC COOEt (V-b) -^ Project 2

(i-g) Project 3

(ii-g) -55- 200835692. Project 1 A solution of the compound (ΙΠ-b, 30.0 g, 0.238 mol), compound (iv-f, 20.9 g, 0.286 mol) in toluene (80 mL) was refluxed for 5.5 hours. Engineering 2 The compound obtained in Engineering 1 was added with a compound (V-b, 5 1.5 g, 0.238 mol), and heated under reflux for 2 hours. The reaction liquid was concentrated under reduced pressure to give a concentrated liquid containing compound (I-g). This concentrate is used in the next reaction. Engineering 3 The concentrated liquid obtained in Engineering 2 was added with methanol (200 mL), tetrahydrofuran (200 mL), and 2N aqueous sodium hydroxide solution (149 mL). After the reaction was completed, the operation of Example 1 was carried out, and methanol was added to the obtained crystalline residue. (200 mL), recrystallization was performed. The crystals were separated by filtration and dried to give compound (II- g, 47.9 g, 72.5%) NMR (DMSO-d6, TMS): 1.00 (t, · 3H, J = 7.5), 1.3 5 - 1.5 5 (m, 6H), 1.60- 1.86 (m, 6H), 2.63-2.71 (m, 2H), 2.90-2.99 (m, 2H), 3.99-4.21 (m, 2H), 8.27 (s, 1H), 14.78 (br s , 1H) The results of powder X-ray diffraction are shown in Table 7 and Figure 7. The diffraction angle of the main peak: 20 = 9.2, 9.7, 1 〇. 〇, 15.5, 19.7 degrees -56- 200835692

2 「 "d値 intensity relative strength 9.157 9.64983 515 100 9.74 ί 9.0733 82.4 16 9.998 8.83963 165 32 10.701 8.26016 16.5 Bu 3.2 14.051 6.29757 24.7 4.8~ 15.129 5.8512 37.9 7.4 15.504 5.71047 77.8 "15.1 16.271 5.44302 20.2 3.9~ 17.419 5.08702 8.46 1.6 18.146 4.88461 43.7 8.5 18.432 4.80948 32.7 6.4 18.749 ^4.7289 25.2 4.9 19.4 4.57168 41.5 8 19.66 4.51179 80.8 15.7 20.188 4.39506 33.8 Γ 6.6 20.53 4.32258 47.7 9.3 21.466 4.13612 77.1 15 22.073 4.02376 22.6 4.4 22.349 3.97472 20.2 3.9 22.882 3.88329 10.6 2.1 23.449 3.79069 23.4 4.5 24.491 3.63169 29 5.6 24.807 3.5861 27.9 5.4 25.1 3.54492 16.3 3.2 26.069 3.41533 18 3.5 26.504 3,3602 12.2 2.4 27.549 3.23514 8,93 1.7 28.49 3.13036 11.8 2.3 28.914 3.08543 17.5 3,4 29.707 3.00485 13,6 2.6 30.226 2.95439 13.9 2.7 30.66 2.91355 14.9 2.9 30.92 2,88962 35,6 6.9 31.382 2.84813 8.82 1.7 31.978 2.79642 18.2 3.5 32.236 2.77461 14.7 2.9 32.916 2.71881 7.92 1.5 34.088 2.62797 7.28 1.4 34.783 2.57704 9.52 1.8 35 .37 2.53563 10.3 2 36.075 2.48769 6.57 1.3 38.451 2.33925 8.15 1.6 38.959 2.30987 6.79 L3 Synthesis of the compound of Example 8 (ΙΙ-h) -57- .200835692 〇

(lll-b)

(ll-h) Hydrolysis Engineering 3 Project 1

A solution of the compound (III-b, 10.0 g, 0.079 mol) and the compound (IV-b, 11.9 g, 0.095 mol) in toluene (100 mL) was refluxed for 7 hr. Engineering 2 The reaction liquid obtained in Engineering 1 was added (V-b, 2 3.99 g, 0.111 mol), and heated under reflux for 15 hours. The reaction solution was concentrated under reduced pressure to give a concentrated liquid containing compound (I-h). This concentrate is used in the next reaction. Engineering 3 The concentrate obtained in Engineering 2 was stirred with methanol (150 mL), 2N aqueous sodium hydroxide (7 9 mL, O, 15 8 mol) and stirred at 25 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, toluened water and water, and the aqueous layer was separated. 2-propanol (35 mL) and 5N hydrochloric acid (34 mL) were added to the aqueous layer, and the mixture was stirred at 25 ° C for 1 hour to crystallize. The crystals were precipitated by filtration and dried to give a compound (y-h, 19.8 g, 76.0%). NMR (DMSO-d6, TMS): 1.20- 1.45 (m, 4H), 1.5 5 - 1.63 (m, 4H), 2.70-2.80 (m, 2H), 2.85-2.95 (m, 2H), 5.47 (s, 2H), 7.18 (d, 4H, J = 8.1), 8.29 (s, 1H), 14.7 (s, 1H) The results of powder X-ray diffraction are shown in Table 8 and Figure 8. The diffraction angle of the main peak: 2Θ=13.2, 18.7, 19.5, 20.0, 22.7 degrees -58 - 200835692

2 Θ d値 intensity relative strength 7.566 11.67471 15 9.6 10.77 8.20772 15.4 Γ 9.9 12.192 7.25359 41.7 26.7 13.203 6.70005 ^ 84.9 54.4 14.048 6.29902 25.7 16.4 14.683 6.02792 7.87 5 15.147 5.8443 48.2 30.8 17.193 5.15322 39 24.9 17.799 4.97912 11.3 7.2 18.657 4.75212 136 86.8 19.469 4.55556 101 64.7 20.022 4.43099 156 100 21.775 4.0781 "33.4 21.4 22.332 3.97759 18.2 11.6 22.707 Bu 3.91287 96.4 61.7 23.972 3.70907 37.4 23.9 24.275 3.66343 [45.2 28.9 25.153 3.5375 34.9 22.3 25.995 3.42484 32.8 21 26.297 3.38625 14.7 9.4 26.62 3.34582 11.4 7.3 27.171 3.27922 14.4 9.2 28.373 3,14302 9.63 6.2 28.98 3.07852 10.4 6.7 29.205 3.05527 13.4 8.6 30.55 2.92382 8.97 5.7 30.839 2.89702 14.1 9 31.677 2.82234 14.7 9.4 32.168 2.78033 9.8 6.3 32.465 2.75559 15.4 9.8 32.75 2.7322 8.08 5.2 33.771 2.6519 8.76 5.6 34.306 2.6118 13.7 8.8 34.966 2.56396 13, 7 8.8 36.025 2.49102 17 10.9 39.509 2.27902 16.6 10.6 Synthesis of the compound of Example 9 (Π-i) -59- 200835692

A solution of the compound (ΙΠ-b, 10.1 g, 0.0800 mol) and the compound (IV-d, 6·98 g, 0.0800 mol) in toluene (100 mL) was refluxed for 6 hours. Process 2 The compound (V-b, 20.8 g, 0.0960 mol) was added to the reaction solution obtained in Engineering 1, and heated under reflux for 15 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing compound (I-i). This concentrate is used in the next reaction. Project 3

The concentrate obtained in the work 2 was stirred with methanol (86 mL) and tetrahydrofuran (86 mL), 2N aqueous sodium hydroxide (80.0 mL), and stirred at 25 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, toluene and water were added, and the aqueous layer was separated. The resulting aqueous layer was combined with EtOAc (EtOAc) The extract was concentrated under reduced pressure, and 2-propanol (8 mL) was added and stirred at 25 ° C for 15 hours to crystallize. The crystals were precipitated by filtration and dried to give a compound (?-i, 12.1 g, 52.0%). NMR (DMS 〇-d6): 0.95 (d, 6H, 1 = 6.6), 1.33 (brs, 2H), 1.43 (brs, 2H), 1.50-1.60 (m, 4H), 1.71-1.78 (m, 3H) , 2.70 (m, -60- .200835692 2H), 2.97 (m, 2H), 4.14 (m, 2H)? 8.19(s, 1 H), 1 4.9 (s, 1 H) powder X-ray diffraction results See Table 9 and Figure 9. The diffraction angle of the main peak·· 20 = 8.4, 9.8, 14.3, 20.3, 21.8 degrees [Table 9]

2 Θ d値 Intensity relative strength 8.353 10.57689 232 100 9.833 8.98789 211 90.9 13.02 6.79412 6.61 2.9 13.585 6.51263 9.94 4.3 14.328 6.17642 96.4 41.6 15.338 5.77198 25.4 11 15.666 5.65203 51.9 22.4 16.078 5.50794 12.6 5.4 16.586 5.34029 35.5 15.3 17.345 5.10841 29.8 12.9 19.34 4.58573 63.5 27.4 19.572 4.532 114 49.4 20.319 4.36688 71.5 30.9 20.668 4.29392 20.5 8.8 21.371 4.15431 24.4 10.5 21.771 4.0789 71.3 30.8 22.525 3.94392 15.7 6.8 23.241 3.82401 19 8.2 24.12 3.68663 67.3 29.1 24.791 3.58837 38.5 16.6 25.156 3.53711 10.5 4.6 25.8 3.45029 8.02 3.5 27.238 3.2713 8.36 3.6 28.016 3.18219 10.3 4.5 29.022 3.07416 42.1 18.2 29.417 3.03379 10.4 4.5 29.859 2.98982 19.3 8.4 30.463 2.93195 15 6.5 30.925 2,88921 9.75 4.2 31.742 2.81665 9.82 4.2 32.534 2.74985 10.1 4.4 32.892 2.72077 13.8 5.9 33.51 2.67202 7.83 3.4 34.2 2.61964 9.04 3.9 34.484 2.59868 8.55 3.7 35 , 75 2.50956 8.67 3.7 36.751 2.44343 8.08 3.5 37.722 2.38277 11.8 5.1 39.205 2.29599 9.1 3.9 39.7 65 2.26492 7.78 3.4 -61 - .200835692

Synthesis of the compound of Example 10 (Il-j)

A solution of the compound (III-b, 10.6 g, 0.084 mol), compound (IV-e, 10.0 g, 0.07 mol) in toluene (80 mL) was refluxed for 7 hr. Engineering 2 The compound obtained in Engineering 1 was added with a compound (V-b, 15.9 g, 0.074 mol), and heated under reflux for 7 hours. The reaction solution was concentrated under reduced pressure to give a concentrate containing Compound (Ij). This concentrate is used in the next reaction. Project 3

The concentrate obtained in the work 2 was added with a solution of methanol (70 ml) and sodium hydroxide (8.38 g) in water (40 mL) and stirred at room temperature for 1 hour. After the completion of the reaction, the procedure of Example 1 was carried out, and methanol (1 〇〇 mL) was added to the obtained crystalline concentrated residue, and the mixture was concentrated to 50 g and stood at 0 ° C. The crystals were precipitated by filtration, washed with a small amount of cold methanol and dried to give compound (?-j, 12.5 g, 51.7%). NMR (DMS〇-d6, TMS): 1.37 - 1.5 5 (m, 4H), 1·65-1·80 (ιη, 4H), 2.64-2.72 (m, 2Η), 2.82-2.91 (m, 2H) , 5.42(s, 2H), 6.85(m, 1H), 6.95(m, 1H), 7.15(m, 1H), 8.38(s, 1H), 14.34(br s, 1H) Results of powder X-ray diffraction See Table 10 and Figure 10. -62- , 200835692 , 27.7 degrees Diffraction angle of main peaks: 20 = 14.6, 15.7, 1 7.9, 23.5, 26.8 [Table 1 0]

2 Θ d値 strength relative strength 8.874 9.95659 8.86 1.2 9.756 9.05824 32.6 4.3 10.305 8.57703 47.9 6.4 11.144 7.93334 51.1 6.8 12.553 7.04558 28.5 3.8 12.919 6.84683 9.64 1.3 13.851 6.38822 13.2 1.8 14.621 6.05345 134 17.8 15.313 5,78145 41.5 5.5 15.731 5.62873 148 19.7 17.352 5.10646 90.8 12.1 17.9 4.95135 751 100 19.655 4.51293 27.7 3.7 20.749 4.27748 58.3 7.8 21.418 4.14532 13.1 1.7 21.857 4.06297 87.7 11.7 22.607 3.92993 14.1 1.9 23.513 3.78048 216 28.8 24.278 3.66308 116 15.4 25.212 3.52939 8.67 1.2 25.957 3.42984 14 1.9 26.267 3.39 20 2.7 26.794 3.32453 128 17.1 27.652 3.22326 160 21.3 27.965 3.18785 57.8 7.7 28.673 3.11081 15 2 29.929 2.98303 29.2 3.9 30.87 2.89423 9.3 1.2 31.709 2.81953 47.4 6.3 32.895 2.72054 10.5 1.4 34.761 2.57864 21.3 2.8 35.43 2.53147 21.3 2.8 35.996 2.49297 9.23 1.2 37.007 2.42715 10.1 1.3 37.632 2.38823 7.93 1.1 38.335 2.34608 9.16 1.2 39.15 2.29909 8.46 1.1 Synthesis of the compound of Example 11 (VIII-a) -63- 200835692

•CI+H3N^COOMe (Vll-a) Project 2

(ll-b) (Vl-a)

Engineering 1 A solution of the compound obtained in Example 2 (Π-b, 7.35 g, 25·4 mmol), toluene (8.7 mL), and N-methylpyridone (8.7 mL), and sulfinium chloride (3.32) g, 27.9 mmol), and stirred at 25 ° C for 0.5 hour to obtain a reaction liquid containing the compound (VI-a). This reaction solution was used for the next reaction. Project 2

A solution of the compound (VII-a, 5.90 g, 30.5 mmol) and triethylamine (3.1 g, 30.5 mmol) in toluene (18.5 mL) and N-methylpyridone (18.5 mL) was added. After triethylamine (5.66 g, 55.9 mmol) was added thereto, the mixture was stirred at 25 ° C for 0.5 hour to obtain a reaction mixture containing Compound (IX-a). It was washed with 6% sulfuric acid (34.6 g), 4% sodium hydroxide (32.2 g), purified water (14.5 mL), and concentrated. This concentrate is used in the next reaction. The concentrate obtained in Engineering 2 was added with methanol (25.9 mL) and a 36% aqueous sodium hydroxide solution (7.06 g), and stirred at 50 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and then -64-2008356922-propanol (54.6 g) and 10% sulfuric acid (68.5 g) were acidified and crystallized at 25 ° C for 3 hours. The crystals were precipitated by filtration and dried to give compound (vill-a, 9.78 g, 9. 2.9%). Melting point: 237~23 8°C NMR (DMS〇-d6, TMS): 1.05 (t, 3H, J = 7.8 Hz), 1.15-2.10 (m, 10H), 2.19 (s, 3H), 2.67 (dd, 2H, J = 7.2 and 15 Hz), 5.42 (s, 2H), 7.13-7.22 (m, 4H), 8.19 (s, 1H), 10.14 (s, IH), 12.17 (br, 1H) Φ powder X-ray The results of the diffraction are shown in Tables 1 1 and 11. The diffraction angle of the main peak: 20=9.4,17·8,18·5,2Ο·9,38·4 degrees [Table 1 1] 2 搜 Search peak setting ___I 値 虔: Relatively strong ίί 8 8 2 6 8 QV 7* 1» βν Λ» 2 3 8 6 8 4 3 1» 8 8 0 9 0 4 3 J-1 1—

9.440 9. 840 12. 840 13.220 14.860 0. 212 0.212 0.212 0.235 0.212 9.3610 8.9813 6. 8888 6.6917 5. 9566 15.720 0,235 5. 6326 2123 24 17.820 0.235 4.9733 6841 76 18. 540 0. 235 4.7818 3695 42 19.520 0. 282 4. 5439 1781 20 20. 880 0. 235 4.2509 3834 43 21. 700 22. 340 22. 840 23.140 23. 740 24.320 24. 640 25. 800 26. 540 28. 500 '29.000 29. 340 29. 780 30. 280 32. 920 35.300 36.140 38. 400 39.160 9 5 5 2 8 5 3 3 18 2 2 2 2 1 00.0.0·0· 82699..5 2592 8 1055:3 1358 1 2 3 2 2:2 2 2 2 2 00.0·00.:0.0.0·0.0· 8 9 6 6 8 5 0 0 12 3 3 0·.00.0. 4. 0920 3. 9762 3. 8903 3.8406 3. 7448 0568 3.6100 3. 4503 3.3558 3.1293 3: 0764 3.0416 2. 9976 2. 9493 2.7185 2: 5405 2. 4833 2. 3422 2. 2985 3 0 3 9 7 3 3 4 8 5 3 2 6 4 5 12 11 6 9 3 9-^ : 98492 3 2619:3 6716 6!106 :o 7583 3 1 1:1 7 6 12 8 7 0 0 4 3 0 6 9 5 5 9 7 _ 12 11 8 9 6 2 9i2 9 7 ο 0〇1— 1— -1— 1— 5 6 5 00 Synthesis of the compound of Example 12 (VIII-b) -65- 200835692

(ll-b) (Vl-a)

(IX-b) ... 丨丨丨 7) Project 1 The compound obtained in Example 2 (Π-b, 7.36 g ' 25.4 mmol), DMF (1.0 mL), THF (73.6 mL) was added with sulfinium chloride (3.3) g, 27.9 mm ο 1), stirred at 25 ° C for 5 hours to obtain a reaction solution containing the compound (VI - a). This reaction solution was used for the next reaction. Project 2

To the reaction mixture obtained in the procedure 1, the compound (VII-b, 5.85 g, 27.9 mmol), pyridine (20.1 g, 254 mmol), dimethylaminopyridine (620 mg '5.1 mmol) was stirred at 25 ° C for 20 hours. , □ 14% hydrochloric acid (134.6 g), extracted with ethyl acetate (217 mL). The extract was washed with water (74 mL) and 5% aqueous sodium hydrogen carbonate (74 mL). The extract was concentrated under reduced pressure to give a concentrate containing Compound (IX-b). This concentrate is used in the next reaction. Project 3

The concentrate obtained in Engineering 2 was added with THF (35.7 mL), methanol (25.5 mL), and IN aqueous sodium hydroxide (45.9 mL), and stirred at 0 ° C for 2 hours. Add 2N-66 - .200835692 hydrochloric acid (25.2 mL) to make acidity, add water (40 mL), and crystallize at 〇 °C for 0.5 hours. The crystals were precipitated by filtration, and dried to give Compound (VIII-b, 9.04 g, 91.7%).

Melting point: 202~203 °C NMR (DMS 〇-d6, TMS): 1.06 (t, 3H, J = 7.5 Hz), 2.24 (s, 3H), 2.75 (q, 2H, J = 7.5 Hz), 3.79 ( s, 2H), 5.49(br-s, 2H), 7.13-7.28(m, 4H), 8.42(s, 1H), 13.65(s, 1H) The results of powder X-ray diffraction are shown in Table 1 2 and 1 2 picture. Diffraction angle of the main peak: 20 = 8.5, 18.4, 23.9, 25.2 degrees [Table 12 2 θ 8.000 8.540 10. 720 11.140 11.880 Ϊ 5:400 16.160 16.340 16.940 17.740 Ϊ8.380 19. 440 20.120 20.680 21.000

I |値i Id i5 8888i8 5882ί2 2288 6 00 8 8 8:8 6 8 8 1:1 1 1 8 8 1— 11 1 1—1i '1—i—1· 1—1—1—0·00.00. 0.0.0·0*0·00.0*0·0 ί4 4 9 ο 3:0 3 3 6 6io 4 7 5 8 2 5 5 β 3:9 ο ο 3 5:cc{ 2 玢Π SR 4 4 4 3 4.4 8 2 2 9-2 6 0 9 2 ο 3 2 9 φ_7 4 4 2 9:8 5 4 2 2 1*0*8* L 7Ί5· 5* 5 54.4.4.4.4· 4. 7 9 6 7 5-8 17 5 4 8 7 7 2 9 7 7 1 1 3:5 7 o 5 4:6 9 1 6 &amp; 5 5 0 4 2 0 8 3 9 41 0 5 7 8 2 1 :1 1 ..3 1 once | ii I-to-85464 5 2836 00 5711 no 1» '1· 1– 1 1– 4 1 11 21.960 22. 840 23.080 23.480 23. 880 25.160 25.920 27. 240 28. 380 29. 260 30.960 34. 700 38. 360 0.188 4. 0442- 0.188 3. 8903 0.188 3. 8504 0.188 3. 7857 0. 212 3. 7232 0: 212 3. 5366 0. 259 3, 4346 0.235 3. 2711 0. 259 3.1422 0 259 3. 0497 0.447 18860 0. 235 2. 5830 0. 235 2. 3446 9 5 3 9 0 8 3 7 7 4 2 4 4 6 4 3 4 6 i 5 6 7 6 15 73 557&amp;8054 34477434 CvJ 1 —1— 7. o 7-2 7 0 4 ^—6 5 o 143 221 o Synthesis of the compound of Example 13 (VIII-c) -67- .200835692

(VHI-c) Engineering 1 The compound obtained in Example 4 (Π-d, 6.38 g, 25.4 mmol), toluene (10.7 1111), 1 methylpyridone (1〇.7 1111〇 solution plus sulfinium chloride (3.32 g, 27.9 mmol), stirred at 25 ° C for 0.5 hours to obtain a reaction solution containing the compound (VI-d). This reaction solution was used for the next reaction.

A solution of the compound (VII-a, 5.41 g, 27.9 mmol) and triethylamine (2.83 g, 27.9 mmol) in toluene (15.9 mL) and N-methylpyridinone (15.9 mL) was added. After triethylamine (5.66 g, 55 -9 mmol) was added thereto, the mixture was stirred at 25 ° C for 1 hour to obtain a reaction mixture containing the compound (IX-c). After washing with 6% sulfuric acid (30.3 g), 4% sodium hydroxide (28.3 g), and water (12.6 mL), it was concentrated under reduced pressure. This concentrate is used in the next reaction. The concentrate obtained in Engineering 2 was added with methanol (22.7 mL) and a 36% aqueous sodium hydroxide solution (7.06 g), and stirred at 50 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and then -68 - &lt;RTI ID=0.0&gt;&gt; 〇 Crystallization 1 · 5 hours. The crystals were precipitated by filtration, and dried to give a compound (vd-d, 7.77 g, 81.3%).

Melting point: 1 7 0 to 1 7 1 ° C NMR (DMS 〇-d6, TMS): 0.97 (d, 6H, J = 6.6), 1.18 (s, 3H, J = 7.5), 1.26- 1.78 (m, 8H) ), 2· 16(s, 3H), 2.75 (Q, 2H, J = 7.5), 4.09 (m, 2H), 8.09 (s, 1H), 10.24 (s, 3H) The result of powder X-ray diffraction Table 1 3 and Figure 13.

Diffraction angle of the main peak: 20 = 1 〇.9, 13.3, 2 〇 _4, 22.7 degrees [Table 13] 2 θ peak set width d 値 intensity rent versus intensity 8.200 0.188 10.7735 1992 18 9.320 0.141 9.4812 570 5 9.600 0.165 9.2053 1527 14 ! 10. 900 0·188 8J102 9876 86 | 13.300 0.188 6. 6516 5380 47 ! 14.940 0.165 5.9249 604 6 15.660 0.235 5.6541 646 6 16.440 0.212 5.3875 2045 18 17.080 0.306 5.1871 2255 20 17.580 0.212 5.0407 2161 19 : 0.235 4.7513 864 8 0.212 4.5952 2117 19 0.212 4.4624 1848 17 0.212 4.3498 2649 24 0.188 4.0920 2470 22 : 0.188 4.0369 2234 20 0.165 3. 9762 1512 14 0. 259 3.9106 2561 23 0. 212 3.6539 780 7 0.212 3.4216 2090 19 26. 620 0. 235 3.3459 1382 13 27.040 0.212 3. 2948 658 6 28. 760 0. 165 3.1016 671 6 30.440 0.165 2.9341 569 5 30.620 0.165 2. 9173 546 5 32.360 0. 188 2. 7643 544 5 33.500 0; 259 2. 6728 734 7 37.640 0.165 2.3878 693 7 38.420 0J88 2.3411 11499 100 ο ο ο ο ο . 6:630884070 8.9.οί ο* L — 112 2 ο ο ο ο ο J0J4?2J4)2 J 3 7 3 ο 2.2.2.4.6. 2 2 2 22 Real Synthesis Example 14 Compound (VIII-d) of -69- .200835692

(H-e) (Vl-c)

a solution of the compound (li-e, 7.81 g, 25.4 mmol), toluene (18 mL), N-methylpyridinone (18 mL), and sulfinium chloride (3.33 g, 28.0 mmol), After stirring at 25 ° C for 0.5 hour, a reaction liquid containing the compound (VI-c) was obtained. This reaction solution was used for the next reaction. Project 2

To the reaction solution obtained in Engineering 1, compound (VII-c, 6.20 g, 28.0 mmol), toluene (10.8 mL), N-methylpyridinone (10.8 mL), triethylamine (8.49 g, 83.9 mmol) were added. The mixture was stirred at 25 ° C for 0.5 hour to obtain a reaction liquid containing the compound (IX-e). After washing with 6% sulfuric acid (37·3 g), 4% sodium hydroxide (33.7 g), and water (15.6 mL), it was concentrated under reduced pressure. This concentrate is used in the next reaction. The concentrate obtained in Engineering 2 was added with THF (42 mL), methanol (30 mL), and 1N aqueous sodium hydroxide (50·8 mL), and stirred at 50 ° C for 3 hours. The 2N hydrochloric acid (25.4 mL) was made acidic, and after adding water (24 mL), it was crystallized at 0 °C for 0.3 small -70- ‘200835692. The crystals were precipitated by filtration and dried to give a compound (νπΐ-d, 10.6 g, 90.7%).

Melting point: 1 9 4 to 1 9 5 ° C NMR (DMS 〇-d6, TMS): 1.04 (t, 3H, J = 7.5), 1.22 - 1.58 (m, 1 〇Η)? 2.17 (s, 2H), 2.18 (s, 3H), 2.65 (q, 2H, J = 7.5), 3.40 (d, 2H, J = 6.3), 5.43 (brs, 2H), 7.11-7.21 (m, 4H), 8.25 (s, 1H ), 9.94 (t, 1H, J = 5.7), 12.15 (brs, 1H) The results of powder X-ray diffraction are shown in Tables 14 and 14. 10 Diffraction angle of the main peak: 2 Θ = 4.7, 12.8, 15.8, 17·5, 24.3, 25·7 degrees [Table 14] _________ 验 验 验 验 . . 8.86 8.380 9.680 12.800 14. 200 15: 760 17.460 17. 860 18. 520 19.740 20.940 21.140 22.220 24. 280 25.220

Strong I 2 0·0·0·0· οΓ·.ο· 0·0·0·0*0.0·0.0· ο* 88 25.720 26.460 28.180 28. 660 29.260 29:540 29. 900 30.340 31.480 32.000 33.700 37.560 38.420 39. 320 ιζ cvi CVI CVJ 1:3 1 3 2 2:2 2 3 0·00.00.:0·0·0*0'0·0.0♦0* ο. 2 2 2 2-5 5 2 5 5.5 8 9 5 6^5 5 2 5 5-9 5 3 9 9 2 2 6 8 1 1 1 1:3 3 1 3 3:6 8 5 3 7 3 3 8 3 6:2 6 5 5 5:8 1 ο 8 2 2 2 2&quot;CSJ 2 2 2 2·1 1 2 2 3 2 2 2 2 1:3 1 3 2 2:2 2 3 1 18.1675 10.5425 9.1294 6 . 9103 6. 2320 5.6184 5.0750 4. 9623 4. 7869 4.4937 4.2388 4.1992 3. 9974 3. 6628 3. 5283TUM 3. 3657 3.1641 3.1122 3.0497 3; 0214 2.9859 2. 9436 2. 8395 2.7945 2. 6574 2.3927 2.3411 2. 2895 degrees i76 6 8 9 9 6 7 4 3 9 0 19 6 8 5 3 2 9 6 7 5 2 7 3 0 8 23⁄4 4 0 8 2 3 4 2 5 9 9 2 8 15 7159592311 2 1 12 3 1 5 0596:9 1281 2 0 12 2 1 06408.5 9805 7 227 42979: 6 854 3:8 2 2 2 87273733303323 2 18 37414440 4 343 11 7 Synthesis of the compound of Example 15 (VIII-e) -7l - .200835692

A solution of the compound obtained in Example 6 (Π-f, 800 mg, 2.52 mmol) and tetrahydrofuran (8 mL) was added with chlorobenzene (35 2 mg, 2.77 mmol) and dimethylformamide (2 drops) at 25 After stirring at ° C for 1 hour, a reaction liquid containing the compound (VI-d) was obtained. This reaction solution was used for the next reaction. Project 2

To the reaction mixture obtained in Engineering 1, compound (VII-d, 516 mg, 2.77 mmol) and triethylamine (0.798 g, 7.89 mmol) were added. After stirring at 25 ° C for 2 hours, a reaction liquid containing the compound (IX-e) was obtained. Diluted with hydrochloric acid, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and purified water (14.5 mL) and concentrated. Residues were recrystallized from acetone-hexane to give IX-e (577 mg, 47%). </ RTI> </ RTI> IX-e (350 mg, 0.72 mmol) from Engineering 2 with methanol (3 m) and THF (3 mL) IN aqueous sodium hydroxide (2.2-72-, 200835692 mL, 2.2 mmol) was stirred at room temperature for 2 h. Dilute hydrochloric acid was added for extraction with ethyl acetate and washed with water. The organic layer was concentrated, and the residue was recrystallized from P. The crystals were collected by filtration and dried to give compound (VIII-e, 80.9%). NMR (CDCh ' TMS) : 1.00-1.90 (m, 19H), 2.62-2.73 2.90-3.00 (m, 2H), 3.90-4.20 (br, 2H), 5.68 (br, (br, 1H), 8.35 (s , 1H), 8.91 (s, 1H), 13.64 (s, 1H) The results of powder X-ray diffraction are shown in Tables 1 5 and 15. Figure ♦ Diffraction angle of main peaks: 20 = 6.9, 14.0, 19.4, 21.6 Acidic, ketone-hexane, 370 mg (m, 2H), 1H), 7.46

-73- .200835692 [Table 15]

2 Θ d値 intensity relative intensity 6.949 12.71033 ~~ 69.4 1 100 9.383 9.4175 19.8 28,6 9.976 8,85919 6.77 Γ 9.8 10.494 "8.42308 6.46 9.3 10.842 8.15343 13.2 19 11.195 7.89695 7.49 10.8 11.687 7.56596 13 18.8 12.927 6.84278 10.8 15.6 13.652 6.48101 7.87 11.3 13.984 6.32766 51.8 74.6 15.096 5.86399 23.7 34.1 15.575 Γ 5.68475 Γ 10.9 15.8 16.531 5.35819 19 27.4 16.903 5.24084 7.62 11 17.856 4.96333 24.1 34.7 18.43 4.81014 30.6 44.1 19.354 4.58237 64.3 92.7 19.995 4.43699 9.79 14.1 20.529 4.32276 32.5 46.9 21.057 4.21553 ^ 16.5 23.8 21.594 4.11181 48.7 70.2 21.78 4.07719 35.5 51.2 22.495 3.94922 23.1 33.2 23.35 3.80645 ^ 11.1 16.1 25.334 3.51274 12.3 17.7 26.345 3.38018 15.9 22.9 27.262 3.26852 7.63 11 27.908 3.19429 10.3 14.9 28.811 3.09624 11.6 16.8 29.656 3.00984 8.7 12.5 31.556 2.8328 11.9 17.1 32.193 2.77826 6.21 8.9 32.632 2.74186 6.26 9 33.814 2.64866 7.25 10.4 34.344 2.60901 8.31 12 35.005 2.56119 6.12 8.8 36.622 2.45176 7.11 10.2 37.24 2.41248 6.2 8.9 38.748 2.32197 10.3 14.8 Synthesis of the compound of Example 16 (Vlll-f) -74- 200835692

Engineering 1 A suspension of the compound obtained in Example 6 (Π-f, 0.73 g, 2 3〇mm〇1) in THF (3.5 mL), sulfinium chloride (300 mg, 2.53 mmol) and DMF (2 drops) After stirring at 25 ° C for 0.5 hour, a reaction liquid containing the compound (vi-d) was obtained. This reaction solution was used for the next reaction. The reaction solution obtained in the work 1 was slowly dropped under ice cooling in a solution of the compound (VII-e, 529 mg, 2.53 mmol), triethylamine (815 mg, 8.05 mmol) and tetrahydrofuran (4 mL), and stirred at 25 ° C. 1.5 hours. Dilute hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water and 5% sodium hydrogencarbonate. The extract was concentrated under reduced pressure, and the residue was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methanol (1.5 mL), 1 N aqueous sodium hydroxide solution (2.5 mL) was stirred at room temperature for 3 hours. Toluene and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was separated from the -75- 褽200835692 aqueous layer. The crystals were precipitated by filtration, and dried to give the title compound ( VIII-f, 838 mg, quantitative). NMR (DMS 〇-d6, TMS): 1.04- 1.88 (m, 19H), 2.60 (t, 2H, J = 7.5 ), 2.71(t-like, 2H), 2.84(t, 2H, J-7.5), 3.00(t-like, 2H), 4.07(brd, 2H), 6.86(s, 1H), 8.28(s, 1H) ), 12,15(br, 1H), 13.43(s, 1H) The results of powder X-ray diffraction are shown in Table 16 and Figure 16. The diffraction angle of the main peaks: 20 = 12.9, 19.9, 20.4, 21.2 degrees

-76- , 200835692 [Table 1 6]

2 Θ d値 intensity relative strength 8.852 9.98183 17.6 16.8 10.352 8.53796 10.8 10.3 11.18 7.90788 12.8 12.2 11.557 7.65022 24 23 12,378 7.14502 17.7 16.9 12.896 6.8589 54.7 52.3 13.529 6.53961 28,1 26.8 14.554 6.08113 26.1 24.9 14.937 5.92591 8.7 8.3 16.278 5.44072 19.6 18.7 17.059 5.19342 48.5 46.3 17.7 5.00682 21.4 20.4 18.735 4.73242 15.1 14.4 19.018 4.66255 21.2 20.2 19.937 4.44975 68.6 65.5 20.441 4,34118 105 100 20.764 4.27442 40.4 38.6 21.224 4.18275 54.3 51.8 21.855 4.06333 37.1 35.4 22.324 3.97903 12 11.4 23.186 3.833 31.8 30.4 24.18 3.6776 21.4 20.4 24.815 3.58502 17.9 17 26.771 3.32733 9.96 9.5 27.751 3.21199 9.41 9 28.115 3.17129 7.64 7.3 28.69 3.109 9.85 9.4 29.415 3.03399 11.2 10.7 31.776 2.81376 8.94 8.5 32.046 2.79062 8.99 8.6 32.698 2.73647 7.7 7.4 34.257 2.61544 6.36 6.1 36.77 2.44222 6.31 6 37.503 2.39615 6.75 6.4 38.905 2.31298 7.03 6.7 39.776 2.26429 8.36 8 Synthesis of the compound of Example 17 (Vlll-g) -77- , 200835692

Engineering 1 A suspension of the compound obtained in Example 6 (π-f, i.oo g, 3.15 mmol) in THF (5 mL) with sulfinium chloride (410 mg, 3.45 mmol) and DMF (2 drops). After stirring at 25 ° C for 0.5 hour, a reaction liquid containing the compound (vi-d) was obtained. This reaction solution was used for the next reaction. Project 2

The reaction solution obtained in the work 1 was slowly dropped on a solution of the compound (νπ-f, 786 mg, 4.76 mmol), triethylamine (958 mg, 9.47 mmol) and tetrahydrofuran (5 mL) at 25 ΐ: after stirring for 1.5 hours, Dilute hydrochloric acid was extracted with ethyl acetate. The extract was washed with water and 5% sodium bicarbonate water. The extract was concentrated under reduced pressure to give a residue (1·57 g) of Compound (IX-g). This residue was used in the next reverse engineering. 3 Residues from Engineering 2 (1·57 g) plus THF (7.8 mL), methanol (7.8 mL), 2N aqueous sodium hydroxide (4·73 mL). ·5 hours. Toluene and water were added to the reaction mixture, and the aqueous layer was separated. The separated aqueous layer was diluted with hydrochloric acid as -78-, 200835692 to acid and extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated to give a residue. After the residue was crystallized by ether, it was recrystallized from acetone-hexane to give Compound ( VIII g, 917 mg, 65%). NMR (DMSO-d6, TMS): 1.04- 1.84 (m, 1 9H), 2.6 3 - 2.7 5 (m, 2H), 2 · 90-3.0 5 (m, 2H), 3.67 (s, 2H), 3.95 -4.20(m, 2H), 7.09(m, 1H), 7.23-7.32(m, 2H), 8.06(d, 1H, J = 8.1), 8.24(s, 1H), 12.08(s, 1H), 12.37 (br s, 1H) The results of powder X-ray diffraction are shown in Tables 17 and 17. # diffraction angle of the main peak: 2 Θ =6.6,9.8,13.2,16.1,20.1,20.9,24.1 degrees

-79- .200835692 [Table 17]

2 Θ d値 strength relative strength 6.558 13.4674 67.4 59.6 7.285 12.12488 21.1 18.7 9.765 9.05037 76.6 67.8 10.226 wide 8.64285 53.2 47.1 10.548 8.37979 11.8 10.4 13.197 Γ 6.70345 67.4 59.6 14.067 6.29065 33.8 29.9 14.915 5.93493 21.4 18.9 16.05 5.51758 59.1 52.3 16.888 5.24575 9.95 8.8 18.351 4.83054 38.7 34.3 19.031 4.6595 32.1 28.4 19.37 4.57858 32.2 28.5 19.708 4.50103 37.4 33.1 20.09 4.41622 91.7 81.2 20.855 4.25595 104 92.2 22.339 3.97649 30.2 26.7 22.87 3.88526 24.4 21.6 24.09 3.69114 113 100 25.31 3.51598 30.5 27 25.778 3.45322 12.3 10.9 26.5 3.36071 9.03 8 27.674 3.22072 8 7.1 28.341 3.14647 10 8.8 28.75 3.10262 12.9 11.4 29.803 2.99537 10.3 9.1 30.402 2.93767 13.3 11.8 30.97 2.88513 11.9 10.5 32.176 2.77966 8.35 7,4 32.92 2.71848 7.08 6.3 34.161 2.62251 14.1 12.5 34.764 2.5784 7.62 6.7 35.746 2.50978 6.53 5.8 36.454 2.4627 7.46 6.6 37.348 2.40576 8.57 7.6 38.582 2.3316 5.86 5.2 Synthesis of the compound of Example 18 (VIII-h), 200835692

Engineering 1 A solution of the compound obtained in Example 10 (500 mg 'i.44 mmol) and tetrahydrofuran (5 mL) was added with hydrazine chloride (201 mS, i.58 mmol) and dimethylformamide (1 drop). The mixture was stirred at 25 ° C for 1 hour to obtain a reaction liquid containing the compound (VI-e). This reaction solution was used for the next reaction. Engineering 2 The reaction solution obtained in Engineering 1 was slowly added to a solution of the compound (VII-d, 320 mg, 1.72 mmol) and triethylamine (〇·435 g, 4.30 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at 25 ° C for 2 hours to obtain a reaction liquid containing the compound (IX-h). Diluted with hydrochloric acid, extracted with ethyl acetate and washed with saturated aqueous sodium bicarbonate water, and concentrated under reduced pressure. The residue was recrystallized from acetone-hexane to give IX-h (600 mg, 81%). Engineering 3 IX-h (5 80 mg, 1.12 mmol) obtained in Engineering 2, methanol (3.4 mL), tetrahydrofuran (3.4 mL) and 1N aqueous sodium hydroxide (3. 4 mL, 3.4 mmol). hour. Dilute hydrochloric acid was used as acid-81-200835692, extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was recrystallized from acetone-hexane, and crystals were collected by filtration to give compound (VIII-h, 520 Mg, 95.2%). NMR (DMS〇-d6, TMS): 1.27-1.49 (m, 4H), 1·55-1·72 (ιη, 4H), 2.67-2.80 (m, 2H), 2.85-2.97 (m, 2H), 3.60(s, 2H), 5.48(br s, 2H), 6.96-7.04(m, 1H), 7.03(s, 1H), 7.30-7.46(m, 2H), 8.38(s, 1H), 12.39(br s, 1H), 13.26 (s? 1H) The results of powder X-ray diffraction are shown in Tables 18 and 18. Diffraction angle of the main peak: 20 = 1 〇. 〇, 17.9, 18.7, 20.6, 21.5, 21.9 degrees

-82- 200835692 [Table 18]

2 Θ d値 intensity relative intensity 6.93 12.74467 14.9 17.7 9.22 9.58399 4.7 5.6 9.965 8.86909 48.7 57.7 10.694 8.26601 8.06 9.6 11.435 7.73216 10.8 12.8 11.783 7.50413 6.36 7.5 12.246 7.22174 14.4 17.1 12,897 6,85834 23.2 27.5 13.897 6.36718 14.9 17.6 14.948 5.92164 35.4 42 16.764 5.28428 8.47 10 17.855 4.96368 45.9 54.3 18.48 4.79715 26.4 31.3 18.728 4.7343 75.2 89.2 19.652 4.51364 14.5 17.2 20.595 4.30904 53.8 63.7 21.536 4.12277 75.5 89.5 21.871 4.06047 84.4 100 22.893 3.88147 18.4 21.8 24.118 3.687 8.55 10.1 24.732 3.59682 11.6 13.7 25.731 3.45937 7.53 8.9 26,261 3.39075 30.9 36.6 27.083 3.28971 8.25 9.8 27.799 3.20653 9.91 11.7 28.488 3.13054 25.4 30 30.135 2.96313 11.6 13.7 30.827 2.89811 12.7 15.1 31.354 2.85067 ^ 9v67 11.5 32.333 2.76655 5.56 6.6 32.827 2.72603 11.9 14.1 33.707 2.6568 5 5.9 36.292 2.47327 9.49 11.2 36.823 2.43882 7.03 8.3 37.19 2.41562 7.76 9.2 37.769 2.37988 8.61 10.2 39.238 2.29409 6.65 7.9 39.846 2.26049 5.73 6.8 -83- 2008356 92

Process 1 A solution of the compound obtained in Example 9 (Π-i' 300 mg, 1.03 mmol), tetrahydrofuran (3 mL) was added with chlorobenzene (143 mg, 1.13 mmol) and dimethylformamide (1 drop). After stirring at 25 ° C for 0.5 hour, a reaction liquid containing the compound (vi-f) was obtained. This reaction solution was used for the next reaction. Project 2

The reaction solution obtained in Engineering 1 was slowly added to a solution of the compound (VII-g, 260 mg, 1.24 mmol) and pyridine (3 mL). After stirring at 25 ° C for 14 hours, a reaction liquid containing the compound (IX-i) was obtained. Dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and purified water, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate (1: 2)) to give IX-i pale-yellow solid (350 mg, 76.1%) 〇 Engineering 3 IX - i (3 4 0 mg, 0 · 7 6 mm ο 1) Add methanol (2.3 m L), tetrahydrofuran (2.3 mL) and 1N aqueous sodium hydroxide (2.3 mL '2.3 mmol) and stir at room temperature for 1 hour. Adding dilute hydrochloric acid to make acid' is extracted with ethyl acetate -84-^200835692, and the organic layer is washed with water. The organic layer was dried, concentrated, and the residue was recrystallized from acetone-hexane, and crystals were collected by filtration to afford compound (VIII-i, 250 mg 5 76.1%). NMR (DMS 〇-d6, TMS): 0.98 (d, 6H, J = 6.6), 1.26- 1.86 (m, 11H), 2.65-2.80 (m, 2H), 2.90-3.05 (m, 2H), 3.81 ( s, 2H)? 4.10-4.25(m, 2H), 8.32(s? 1H), 12.65(br s, 1H), 13.84(s, 1H) The results of powder X-ray diffraction are shown in Table 1 9 and No. 9 Figure. Diffraction angle of the main peak: 20 = 10.4, 18.0, 20.7, 21.0 degrees • [Table 19] 2 Θ d値 Strength relative strength 7.156 12.34303 7.55 1 10.477 8.43668 789 100 11.78 7.50651 6.6 0.8 13.103 6.75132 24.8 3.1 14.007 6.31735 16.9 2Λ 14.36 6.16303 8.91 1.1 15.704 5.63842 17.8 2.3 17.15 5.16619 29.1 3.7 18.016 4.91976 63.8 8.1 18.596 4.76749 28.4 3.6 20.691 4.28929 60.7 7.7 20.988 4.22917 52.9 6.7 21.547 4.12084 17.2 2.2 22.62 3.92757 13 1,7 23.018 3.86056 9.8 1.2 23.629 3.76217 10.8 1.4 24.281 3.66264 8.27 1 24.867 3.5776 29.2 3.7 26.363 3.37783 16.3 2.1 27.151 3,28156 17.2 2.2 28.762 3.10138 7.19 0.9 29.739 3.00163 11.5 1.5 30.329 2.94461 13.5 1.7 31.724 2.81822 15.7 2 33.979 2.63617 10 1.3 38.848 2.31625 5 0.6 -85- 200835692

Work 1 A solution of the compound (II-i, 300 mg, 1. 〇3 mmο 1) and tetrahydrofuran (3 mL) obtained in Example 4 was added with hydrazine chloride (143 mg, 1.13 mmol) and dimethylformamide ( One drop) was stirred at 25 ° C for 0.5 hour to obtain a reaction liquid containing the compound (VI-f). This reaction solution was used for the next reaction. Engineering 2 The reaction solution obtained in Engineering 1 was slowly added to a solution of the compound (VII-h, 310 mg, 1.22 mmol) and triethylamine (415 mg, 4.1 mmol) and tetrahydrofuran (3 mL). After stirring at 25 ° C for 14 hours, a reaction liquid containing the compound (IX-j) was obtained. Diluted with hydrochloric acid, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and purified water. The residue was purified by silica gel chromatography (hexane-ethyl acetate (2:1)) to yield IX-j (3 50 mg, 76.3%). Engineering 3 IX-j (340 mg, 0.76 mmol) from Engineering 2 was added methanol (2.3 mL), tetrahydrofuran (2.3 mL) and 1N aqueous sodium hydroxide (2·3 mL, 2.3 mmol). . Force [] dilute hydrochloric acid is made acidic, extracted with ethyl acetate -86-.200835692 ethyl ester, the organic layer is washed with water, dried and concentrated, and the residue is recrystallized from acetone-hexane to decompose and precipitate crystals, which are dried to obtain compound (VIII-j). , 230 mg, 70.1%). NMR (DMS〇-d6, TMS): 0.98 (d, 6H, J = 6.6), 1.26- 1.84 (m, 11H), 2.65-2.77 (m, 2H), 2.90-3.03 (m, 2H)? s, 2H), 4.1〇.4.25(m, 2H), 7.31(s, 1H), 8.24(s, 1H), 12.63(br s, 1H), 13.39(s, 1H) Results of powder X-ray diffraction See Table 20 and Figure 20. Φ The diffraction angle of the main peak: 20=9.1, 12.1, 18.0, 18.3, 19.7 degrees -87- 200835692 [Table 20]

2 Θ d値 strength relative strength 8.59 10.2848 6.48 2.1 9.103 9.70638 94.3 30 11.69 7.56398 15.7 5 12.143 7.28278 314 100 12.676 6.9775 13.1 4.2 14.963 5.91566 19.1 6.1 16.459 5.38127 12.2 ~ 3.9 17.536 5.05318 119 38 18.007 4.9222 93.9 29.9 18.255 4.85589 87.4 27.8 18.522 4.78638 44.1 14.1 18.935 4.68288 44.2 14.1 19.503 4.54787 53.1 16.9 19.704 4.50176 60.6 19.3 19.96 4.44466 33.2 10.6 20.349 4.36048 29.4 9.4 20.579 4.31244 35 11.2 21.386 4.15142 14.6 4.7 22.764 3.90315 28.2 9 23.736 3.7455 18.3 5.8 23.954 3.71186 23.3 7.4 24.316 3.65734 13.7 4.4 24.783 3.58953 13.5 4.3 25.843 3.4447 8.89 2.8 26.668 3.33999 47.2 15 27.399 3.25242 10.2 r 3.2 28.948 3.08184 11.7 3.7 29,136 3.0624 9.3 3 30.006 2.97557 9.05 2.9 30.971 2.88499 24.8 7.9 31.478 2.83971 6.16 2 32.29 2.77007 9.95 3.2 34.289 2.61305 15.6 5 34.762 2.57857 12.3 3.9 35.325 2.53873 6.28 2 35.734 2.5106 7.04 2.2 37.371 2.40432 6.61 2.1 39.096 2.30212 7.75 2.5 In the same way as in Examples 1 to 20, To compound (VIII-k) ~ (VIII-nn). The structural formula is as shown in Table 21 to Table 26. [Table 2 1] -88- 200835692

[Table 22] -89- 200835692

[Table 23] -90- 200835692

[Table 24] -91 - 200835692 Compound No. Structural NMR (DMS 〇-d 6, TMS) 5 VIII - Z ocC^ 1.04-1.88 (m, 19H), 2.7 〇 (brt, 2H), 2.99 (brt, 2H) ), 3.49(s, 2H), 4.05(br, 2H), 6.78*6.7 9(m, 2H), 8.23(s, 1H), 12.8 8(s, 1H) VIII -aa 0, 0 SN Voh OCC〆 1.0-1.8 (m, 19H), 2.72 (br-s, 2H), 3.0 l (br-s, 2H), 3.8 l (s, 2H), 4.07 (br-s, 2H), 8.33 (s, 1H) ), 12.6(br-s, 1H), 13.8(b rs, 1H) VIII -bb Me 〇T^N々. H Nk 〇 CDC13: 0.94 (t, 3H, J = 7.2), 1.05-1.88 (m, 25H), 2.60-2.8 2 (m, 4H), 2.93 (t, 2H, J = 6.0), 4.00 (bs, 1H), 4.3l(bs, 1H), 8.33(s, 1H), 10.4(s, 1H) VIII -cc Me 〇rx^ to H CDC13: 0.90(t, 3H, J=6.9), 1.00-1.90 ( m, 27H), 2.60-2.8 0(m, 4H), 2.93(t, 2H, J=6.0), 4.00(bs, 1H), 4.25-4.37(m ,1H), 8.33(s, 1H), 10.4 (s, 1 H) VIII -dd ccC^B? 1.00-L90(m, 19Ή), 2.65-2.7 7(m, 2H), 2.93-3.07(m, 2H), 3.6l(s, 2H), 3.95 -4.15(br, 2H), 8.29(s, 1H), 12.20Ί3.0 0(br, 1H), 13.64(s, 1H) [Table 25 -92- 蜒200835692 蜒

Compound No. Construction NMR (DMS 〇-d 6, TMS) δ VIII -ee 〇cci0H &quot;o 1.02*1.86(m, 19H), 2.62-2. 75(m, 2H), 2.92-3.05(m, 2 H), 3.85-4.15(br, 2H), 5.43 (m, 1H), 8.18(s, 1H), 10.8 3(d, 1H, J=9.0), 14.22(brs, 1H) VIII —ff 〇cC^ OH &quot;cc; 1.26-1.68(m, 18H), 2.17(s, 2H), 2.67(br s, 2H), 2.81 (br s, 2H), 3.40 (d, 2H, J 6.3), 5.41 ( Br s,2H), 6.86( m,1H), 7.25(ddd,1H,J=1 1.9,7.7 and 2.3), 7,39(dt, 1H, J=10.8 and 8.4), 8.2 3(s, 1H ), 9.89(t,1H,J=6. 0),12.06(br s,1H) VIII -gg 〇CC^0H 1.25-1.50(m, 4H), 1.57Ί.7 0(m, 4H), 2.67 -2.77(m, 2H ), 2·85·2·95(ιη, 2H), 3.60(s, 2H), 5.48(s, 2H), 7.12-7. 26(m, 4H), 7.72 (dd, 1H, J = 2.4, 8.4), 8.19 (d, 1H, J = 2.1), 8.23 (d, 1H, J = 8.4), 8 • 38 (s, 1H), 12.47 (s, 1H) VIII - hh ocx &gt ;, n 〇&quot;a; 1.26-1.50(m,4H), 1.55-1.7 3(m, 4H), 2.66*2.78(m, 2H ), 2.83-2.95(m, 2H), 3,6〇 ( s , 2H), 5.46(s, 2H), 6.96(m ,1H), 7.26-7.48(m, 2H), 7 • 72(dd,1H, J=2.4, 8.4), 8. 19(d, 1H , J = 2.4), 8.23(d, 1H, J=8.4), 8.37(s, 1H), 1 2.43(s, lH), 12.44(br s, 1H) VIII —i i 0[〇]0 OCC Bu. H &quot;cc 1.20*2.20(m, 12H), 2.60-2. 95(m, 4H), 2,86(s, 2H), 3 •48(t' 2H, J=10.5), 3·60· 3. 75(m,2H),5,30-5.55(m, 2 H), 6.82-7.48(m, 2H), 8.2 0(s, 1H), 9.98(s, 1H) -93- .200835692 ( Industrial Applicability) It has been found that a method for producing an important intermediate of 2-pyridone-3-amine-methyl hydrazino derivative having excellent cannabinoid receptor agonist activity in a simple, high-yield and high-purity manner is further found. A process for producing a 2-pyridone-3-aminecarbamyl derivative in high yield and high purity using this important intermediate. BRIEF DESCRIPTION OF THE DRAWINGS [Fig. 1] A powder X-ray diffraction pattern of a compound (Π-a) obtained in Example 1 and its peak enthalpy. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2 0, unit: degree). [Fig. 2] A powder X-ray diffraction pattern of the compound (ΙΙ-b) obtained in Example 2 and its peak enthalpy. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2 0, unit: degree). [Fig. 3] A powder X-ray diffraction pattern of the compound (11-c) obtained in Example 3 and its peak enthalpy. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2 (9, unit: degree). [Fig. 4] The powder of the compound (Π-d) obtained in Example 4 is X-ray® diffraction pattern. And its peak value. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2 Θ, unit: degree). [Fig. 5] Powder X-ray of the compound (Π-e) obtained in Example 5 Diffraction pattern and its peak 値. The vertical axis is the intensity (unit: cps) 'The horizontal axis is the diffraction angle (20, unit: degree). [Fig. 6] The compound obtained in Example 6 (Π-0 crystal powder) X-ray diffraction pattern and its peak 値. The vertical axis is the intensity 'horizontal axis is the diffraction angle (2 Θ, unit: degree). -94- 200835692 [Fig. 7] The compound (π-g) crystal obtained in Example 7 The powder enthalpy diffraction pattern and its peak 値. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (20, unit: degree). ' [Fig. 8] The powder of the compound (nh) obtained in Example 8 is X. The line diffraction pattern and its peak 値. The vertical axis is the intensity 'the horizontal axis is the diffraction angle (20, unit: degree). [Fig. 9] The compound obtained in Example 9 (Π-i) is crystallized. The powder X-ray diffraction pattern and its peak 値. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (20, single β position: degree). [Fig. 10] The compound (ΙΙ-j) obtained in Example 10 is crystallized. Powder X-ray diffraction pattern and its peak 値. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (20, unit: degree). [Fig. 11] The powder of the compound (VIII-a) obtained in Example 11 is X. The line diffraction pattern and its peak 値. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (20, unit: degree). [Fig. 12] Crystallization of the compound (VIII-b) obtained in Example 12 The powder X ® line diffraction pattern and its peak 値. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2 Θ, unit: degree). [Fig. 13] The compound obtained in Example 13 (VIII) -c) crystallization of the powder X-ray diffraction pattern and its peak 値. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (20, unit: degree). [Fig. 14] The compound obtained in Example 14 (VIII-d) Crystalline powder X-ray diffraction pattern and its peak 値. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2 (9, unit: degree) -95-200835692 [Fig. 15] The powder χ diffraction pattern of the compound (Vlll-e) obtained in Example 15 and its peak 値. The vertical axis is the intensity (unit: cps), and the horizontal axis is the diffraction angle (2). 0, unit: degree) [Fig. 16] The powder of the compound (VIII-f) obtained in Example 16 is a ruthenium diffraction pattern and its peak 値. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (20). Unit: degree) [Fig. 17] The powder of the compound (VIII-g) obtained in Example 17 was a ruthenium diffraction pattern and its peak. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (2 θ, unit: degree). [Fig. 18] A powder entangled pattern of the compound (VIII_h) obtained in Example 18 and its peak enthalpy. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (2|9, unit: degree). [Fig. 19] The powder of the compound (vill-i) obtained in Example 19 was a ruthenium diffraction pattern and its peak. The vertical axis is the intensity, and the horizontal axis is the diffraction angle (20, unit: degree). [Fig. 20] Example 2 χ The obtained compound (νηΜ) crystal powder χ line diffraction pattern and its peak 値. The vertical axis is the intensity and the horizontal axis is the diffraction angle (2 Θ in degrees). -96-

Claims (1)

200835692 X. Patent application scope: 1. A method for preparing a compound, including the following works: Engineering A: Hydrolysis of a compound of the following formula (I): R4 R1 (wherein R1 is an alkyl group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkynyl group which may be substituted with a non-reactive substituent; R2 and R3 are each independently an alkyl group Or alkoxy, or alkoxy; or R2 and R3 may form a cycloolefin together with an adjacent carbon atom; R4 is a hydrogen atom or a hydroxyl group; R5 is a hospital base), and Engineering B: a formula generated in Engineering A ( I) The hydrolyzate of the compound is added with an alcohol' to obtain a compound of the following formula (II): R4 I R1 (wherein R1, R2, R3, and R4 have the same meanings as defined above). 2. For the application of the first paragraph of the patent scope, Project A and Project B are continuously implemented. 3. For the preparation of the patent scope 1 or 2, including: Engineering C: a compound of the following formula (III): r1-nh2 (III) (wherein R1 is as defined in claim 1), and For example, the following formula (IV) -97- 200835692 Compound reaction: R2^YR3 (iv) ο (wherein R2 and R3 are as defined in claim 1 of the patent application &gt; and Engineering D: a compound to be produced in Engineering C, Run the reaction of the compound of the following formula (V): R60, /R4 T (V) R5OOC^COOR5 (wherein R4 and R5 are as defined in the first item of the patent application; ^ is too complete), and the following formula is obtained ( I) Compound: R4 XOOR5 (I) (where R1, V, V, R, and V are as defined in the scope of the patent application). 4. A process for the preparation of a compound comprising: Engineering C: a compound of the formula (III): R1-NH2 (III) (wherein R1 is as defined in claim 1) and reacted with a compound of the formula (IV): R2) R3 (iv) (wherein R2 and R3 are as defined in claim 1), and engineering D: reacting a compound produced by engineering C with a compound of the following formula (v): R〇X (V) r5o〇c&quot; ^c〇or5 (wherein R4 and R5 are as defined in claim 1; R6 is as defined in claim 3 of the scope of the patent-98-200835692), and a compound of the following formula (I) is formed: (wherein R1, R2, R3, R4, and R5 are as defined in claim 1 of the patent application) Engineering A: Hydrolysis of a compound of formula (I), Engineering B · Hydrolysis of a compound of formula (I) produced in Engineering A Adding alcohol, and getting The following compound (II): (wherein R1, R2, R3, and R4 are as defined in claim 1 of the patent application), Process E: reacting the obtained compound of the formula (II) with a halogenated reagent to form a compound of the formula (VI): R4 Ο R1 Hal (VI) (wherein R1, R2, R3, and R4 are as defined in claim 1; Hal is a halogen atom), and Engineering F: reacting the obtained compound of the formula (VI) with a compound of the following formula (VII) : h2n-xy-coor7(vii) (wherein R7 is a hydrogen atom or a deutero group; X is an alkylene group which may have a hetero atom and may have a non-reactive substituent, may have a hetero atom or may be a reactive substituent substituted alkenyl group, may be -99-200835692 having an alkyne group which may be substituted with a non-reactive substituent, a cycloalkanediyl group which may have a non-reactive substituent, or a non-reactive a reactive substituent-substituted cycloalkenyldiyl group, an aryldiyl group which may be substituted with a non-reactive substituent, a heteroaryldiyl group which may be substituted with a non-reactive substituent, or a non-aromatic which may be substituted with a non-reactive substituent a heterocyclic diyl group; and γ is a single bond, an alkyl group which may be substituted with a non-reactive substituent, an alkenyl group which may be substituted with a non-reactive substituent, or an alkyne which may be substituted with a non-reactive substituent Base), if necessary, hydrolyzed to give a compound of formula (VIII): (wherein R1, R2, R3, and R4 are as defined in item 1 of the patent application; R7, 、, and 丫 have the same meaning as above). 5. For the application of the third or fourth method of the patent scope, the continuous implementation of the works C, D, A, and B 〇 6. For the production method of any one of the patent scopes 1 to 5, where (Π) The compound is obtained by crystallization. 7. The process according to any one of claims 1 to 6, wherein R1 is an alkyl group which may be substituted with a non-reactive substituent, R2 is a C-C2 alkyl group, and R3 is a C1-C3 alkyl group, R4 It is a hydrogen atom, and R5 is a C1-C2 alkyl group. The method of any one of claims 1 to 6, wherein R1 is an alkyl group which may be substituted with a non-reactive substituent, and R2 and R3 together with adjacent carbon atoms form a cyclooctene, and R4 is hydrogen. Atom, and R5 is C-C2 alkyl. 9. The method of claim 7 or 8, wherein the alcohol added is isopropyl-100-200835692 alcohol. 10. A method for preparing a crystal of a compound of the following formula (II) (wherein R1, R2, R3, and R4 are as defined in claim 1 of the patent application), characterized in that an alcohol is added to a solution containing the compound of the formula (II). 1 1. The method of claim 10, wherein the alcohol is isopropanol. -101 -