JP2005154430A - Method for producing pyrimidine derivative, intermediate for the same, and method for producing the intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for advantageously producing a pyrimidine derivative useful as an enzyme inhibitor and intermediates for synthesizing the same. <P>SOLUTION: This method comprises hydrolyzing a compound (I) (P is an alkyl or the like; R<SP>1</SP>and R<SP>2</SP>are each an alkyl or the like) to obtain a compound (II) (M is Na or the like), reacting the compound (II) with a reagent (III) (R<SP>3</SP>is an alkyl which may be substituted or the like; and X is a halogen or the like) to obtain a compound (IV), reacting the compound (IV) with a compound (V) (R<SP>5</SP>is an alkyl which may be substituted or the like; and R<SP>6</SP>is H or the like) to obtain a compound (VI), condensing the compound (VI) with a compound (XII) (R<SP>7</SP>is an aralkyl which may be substituted or the like; and Y is a heteroaryl which may be substituted or the like) to obtain a compound (XI), and subjecting the compound (XI) to deprotection, preferably, by enzyme reaction to obtain a compound (XV). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel method for producing pyrimidine derivatives useful as enzyme inhibitors such as elastase inhibitors and chymase inhibitors. Furthermore, this invention relates to the novel intermediate body in the said manufacturing method, and its manufacturing method.

  General formula (XVI):

(Wherein R ¹¹ represents a hydrogen atom, an acyl group, a formyl group, etc., R ¹² represents an optionally substituted phenyl group, an alkyl group, etc., and R ¹³ represents a substituent. An alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, etc., and R ¹⁴ may be a heterocyclic group which may have a substituent, an acyl group The compound group represented by haloalkyl group, etc.) is useful for the treatment and prevention of rheumatism, chronic obstructive pulmonary disease and the like as an enzyme inhibitor such as pharmaceuticals, particularly elastase inhibitors and chymase inhibitors. Have been reported (see Patent Documents 1 and 2).

  As a method for producing the compound represented by the general formula (6), which is one of the compounds represented by the general formula (XVI), a method shown in the following reaction scheme has been reported (see Patent Document 3).

(Wherein R ³ ′ is (1) a C1-4 alkyl group, (2) Cycl or (3) a C1-4 alkyl group substituted by Cycl (in which the Cycl is a C3-10 monocycle or A bicyclic carbocycle, a 3 to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms is shown. )

  In this method, when the compound represented by the general formula (4) and the compound represented by the formula (5) are subjected to an amidation reaction, 5 of the pyrimidine ring of the compound represented by the general formula (4) is obtained. Since an amino group is present at the position, a side reaction that generates a dimer of the compound represented by the general formula (4) by an amidation reaction with itself occurs, and is represented by the target general formula (6). There exists a problem that the yield and quality of a compound fall.

  In the above method, the amidation reaction between the compound represented by the general formula (3) and the compound represented by the formula (5) is carried out without deprotecting the benzoyl group of the compound represented by the general formula (3). If followed by deprotection of the benzoyl group, dimer formation can be avoided. However, deprotection of the benzoyl group after the amidation reaction requires harsh conditions such as strong base, reflux, and long time (see Example 4 of Patent Document 3). Under such conditions, since the 1,3,4-oxadiazole ring in the compound represented by the general formula (6) is decomposed, it is difficult to obtain the pyrimidine compound represented by the general formula (6). . Therefore, in order to avoid the dimerization reaction in the above method, it may be possible to protect the amino group of the compound represented by the general formula (4) with a protecting group that can be deprotected under mild conditions. This is not preferable because a deprotection step is further required.

In general, in the protection by acylation of an amino group, it is known that an aliphatic acyl such as acetyl can be hydrolyzed under milder conditions than an aromatic acyl such as benzoyl (Non-Patent Document). 1). Accordingly, if a compound in which the 2-position of the azlactone ring is an aliphatic group in the compound represented by the formula (1) is available instead of the raw material, the 5-position amino group is a fatty acid in the compound represented by the general formula (3). Since a compound protected with an aliphatic acyl group is obtained, the aliphatic acyl group is deprotected without deprotection after deamidation with a compound represented by formula (5) under milder conditions without decomposition. It may be possible to protect it.
However, an efficient method for producing a compound represented by the formula (1) in which the 2-position of the azlactone ring is an aliphatic group has not yet been reported.

  The present inventors use the Erlenmeyer method shown in the following reaction scheme, which is known as a general method for producing an azlactone compound, and is a compound represented by the formula (8) in which the 2-position of the azlactone ring is a methyl group I tried to synthesize.

However, in this method, a lot of by-products were generated, and the azlactone compound represented by the formula (8) was obtained only in a very low yield.
International Publication No. 98/24806 Pamphlet International Publication No. 98/09949 Pamphlet International Publication No. 02/051815 Pamphlet Theodore W. Green (Theodora W. Grrene), Peter G. M.M. Peter GM Wuts, “Protective Groups in Organic Synthesis” (USA), 2nd edition, A Wiley Interscience Publication, 1991, p. 349.

  The problem to be solved by the present invention is that of a pyrimidine derivative represented by the following general formula (XV) useful as an enzyme inhibitor or an N-protected form thereof (for example, N-formyl form, see Patent Document 2). It is to provide an advantageous manufacturing method. Furthermore, it is providing the novel synthetic intermediate required for the said manufacturing method, and its manufacturing method.

  As a result of diligent research to solve the above problems, the present inventors have found a method for advantageously producing a novel compound represented by the following general formula (IV), and the compound is used as a raw material or an intermediate compound. Thus, a novel and advantageous production method of the pyrimidine derivative represented by the general formula (XV) or an N-protected product thereof can be provided.

That is, the present invention is as follows.
(1) General formula (I):

(Wherein P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ¹ and R ² are the same or different and each represents an alkyl group, or A compound represented by a compound (hereinafter referred to as Compound (I)), which may form an aliphatic heterocyclic ring together with the adjacent nitrogen atom, and the wavy line indicates that it is a cis isomer, a trans isomer or a mixture thereof. Or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to give a compound of the general formula (II):

(Wherein, M represents a hydrogen atom, sodium, potassium, or lithium, and P and wavy lines are as defined above) (hereinafter, also referred to as compound (II));
The obtained compound (II) is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, an aryl group which may have a substituent, An aralkyl group, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b which may have a group, and X is a halogen atom, —OSO ₃ R ⁴ or —OCOR ^4a (where R ⁴ , R ^4a And R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. And a reagent represented by the following general formula (IV):

(In the formula, each symbol and wavy line have the same meanings as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (IV)).

(2) General formula (VI) characterized by comprising the following steps (a), (b) and (c):

(In the formula, R ⁵ represents an alkyl group which may have a substituent or a phenyl group which may have a substituent, R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group; A compound represented by the following formula (hereinafter also referred to as compound (VI)) or a salt thereof;
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is converted into the general formula (V):

(Wherein each symbol is as defined above) and a compound (VI) or a salt thereof is obtained by reacting with a compound (hereinafter also referred to as compound (V)) or a salt thereof.

(3) General formula (VII) characterized by comprising the following steps (a), (b), (c) and (d):

(Wherein each symbol is as defined above), a method for producing the compound (hereinafter also referred to as compound (VII));
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is reacted with compound (V) or a salt thereof to obtain compound (VI) or a salt thereof;
Step (d): The obtained compound (VI) or a salt thereof is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then condensed with N-hydroxysuccinimide to obtain a compound (VII).

(4) The production method according to any one of (1) to (3), wherein P is a methyl group, an ethyl group, or a benzyl group.
(5) The production method according to any one of (1) to (3), wherein R ³ is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group, or a trimethylsilyl group.

(6) General formula (IX) characterized by comprising the following steps (a), (b), (c), (d) and (e):

Wherein, R ⁷ represents a hydrogen atom, an optionally substituted alkyl group, which may have an optionally substituted aralkyl group or a substituted aryl group, R ⁸ Represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). The other symbols are as defined above. A compound represented by the following formula (hereinafter also referred to as compound (IX)) or a salt thereof;
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is reacted with compound (V) or a salt thereof to obtain compound (VI) or a salt thereof;
Step (d): The compound (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then condensed with N-hydroxysuccinimide to obtain a compound (VII);
Step (e): Compound (VII) obtained and general formula (VIII):

(Wherein each symbol has the same meaning as described above) (hereinafter also referred to as compound (VIII)) or a salt thereof is reacted to obtain compound (IX) or a salt thereof.

(7) A process for producing compound (IX) or a salt thereof, comprising the following steps (a), (b), (c) and (f):
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is reacted with compound (V) or a salt thereof to obtain compound (VI) or a salt thereof;
Step (f): The obtained compound (VI) or a salt thereof is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then condensed with the compound (VIII) or a salt thereof to give a compound (IX) or a salt thereof. Obtain its salt.

(8) The production method according to the above (6) or (7), wherein P is a methyl group, an ethyl group or a benzyl group.
(9) The production method according to the above (6) or (7), wherein R ³ is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group or a trimethylsilyl group.

(10) The compound (IX) obtained by the production method according to any one of (6) to (9) above or a salt thereof is deprotected, represented by the general formula (X):

(Wherein each symbol is as defined above), or a method for producing a salt thereof (hereinafter also referred to as compound (X)).
(11) The production method according to the above (10), wherein the deprotection is performed by an enzymatic reaction.
(12) The production method according to the above (10), wherein the deprotection is performed under acidic conditions.

(13) General formula (XV) characterized by comprising the following steps (j), (k) and (l):

(Wherein Y represents a heterocyclic group which may have a substituent, an acyl group or a haloalkyl group which may have a substituent, and other symbols are as defined above). A method for producing a compound represented by the formula (hereinafter also referred to as compound (XV)) or a salt thereof;
Step (j): The compound (X) obtained by the method according to any one of the above (10) to (12) or an amino group of a salt thereof is protected to give a general formula (XIII):

(Wherein Q represents a protecting group for an amino group other than an acyl group, and other symbols are as defined above) (hereinafter also referred to as compound (XIII)) or a salt thereof Obtain;
Step (k): A group represented by R ⁸ of the obtained compound (XIII) or a salt thereof is converted into a group represented by Y, and the compound represented by the general formula (XIV):

Wherein each symbol is as defined above (hereinafter also referred to as compound (XIV)) or a salt thereof;
Step (l): The obtained compound (XIV) or a salt thereof is deprotected to obtain a compound (XV) or a salt thereof.
(14) General formula (XI) characterized by comprising the following steps (a), (b), (c), (d), (e) and (g):

(Wherein each symbol is as defined above) or a method for producing a salt thereof (hereinafter also referred to as compound (XI));
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is reacted with compound (V) or a salt thereof to obtain compound (VI) or a salt thereof;
Step (d): The compound (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then condensed with N-hydroxysuccinimide to obtain a compound (VII);
Step (e): Compound (IX) or a salt thereof is obtained by reacting the obtained compound (VII) with compound (VIII) or a salt thereof;
Step (g): The group represented by R ⁸ of the obtained compound (IX) or a salt thereof is converted to a group represented by Y to obtain a compound (XI) or a salt thereof.
(15) A method for producing compound (XI) or a salt thereof, comprising the following steps (a), (b), (c), (f) and (g):
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is reacted with compound (V) or a salt thereof to obtain compound (VI) or a salt thereof;
Step (f): The obtained compound (VI) or a salt thereof is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then condensed with the compound (VIII) or a salt thereof to give a compound (IX) or a salt thereof. Obtaining its salt;
Step (g): The group represented by R ⁸ of the obtained compound (IX) or a salt thereof is converted to a group represented by Y to obtain a compound (XI) or a salt thereof.
(16) A method for producing compound (XI) or a salt thereof, comprising the following steps (a), (b), (c) and (h):
Step (a): Compound (II) or a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide to obtain Compound (II);
Step (b): The compound (II) obtained is reacted with the reagent (III) to obtain the compound (IV);
Step (c): The obtained compound (IV) is reacted with compound (V) or a salt thereof to obtain compound (VI) or a salt thereof;
Step (h): The obtained compound (VI) or a salt thereof is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then the general formula (XII):

(Wherein each symbol is as defined above) and condensed with a compound (hereinafter also referred to as compound (XII)) or a salt thereof to give compound (XI) or a salt thereof.

(17) The production method according to any one of (14) to (16), wherein P is a methyl group, an ethyl group, or a benzyl group.
(18) The production method according to any one of (14) to (16), wherein R ³ is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group, or a trimethylsilyl group.

(19) A method for producing compound (XV) or a salt thereof, which comprises deprotecting compound (XI) or a salt thereof obtained by the production method of any one of (14) to (18) above.
(20) The production method according to the above (19), wherein the deprotection is performed by an enzymatic reaction.
(21) The production method according to the above (19), wherein the deprotection is performed under acidic conditions.
(22) General formula (IV ′):

(In the formula, P and wavy lines are as defined above, and R ^3a has an optionally substituted alkyl group (except when P is an alkyl group or a benzyl group), and has a substituent. An aryl group which may be substituted, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b (wherein R ^4a and R ^4b are the same or different and are each independently And an aryl group which may have a substituent.) (Hereinafter also referred to as compound (IV ′)). ). (23) The compound described in (22) above, wherein P is a methyl group, an ethyl group or a benzyl group, and R ^3a is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group or a trimethylsilyl group.

(24) General formula (VII):

(Wherein each symbol is as defined above).
(25) The compound described in (24) above, wherein P is a methyl group, an ethyl group or a benzyl group, and R ⁵ is a methyl group or a phenyl group which may have a substituent.

(26) General formula (IX):

(Wherein each symbol is as defined above) or a salt thereof.
(27) P is a methyl group, an ethyl group or a benzyl group, R ⁵ is a methyl group or an optionally substituted phenyl group, R ⁷ is a methyl group, an isopropyl group or a benzyl group, The compound or a salt thereof according to the above (26), wherein R ⁸ is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, or —N (Me) —OMe.
(28) General formula (X):

(Wherein each symbol is as defined above) or a salt thereof.
(29) R ⁵ is a methyl group or an optionally substituted phenyl group, R ⁷ is a methyl group, an isopropyl group or a benzyl group, and R ⁸ is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group Or the compound or its salt of the said (28) description which is -N (Me) -OMe.

(30) A method for producing compound (X) or a salt thereof, which comprises deprotecting compound (IX) or a salt thereof by an enzymatic reaction.
(31) A method for producing compound (XV) or a salt thereof, which comprises deprotecting compound (XI) or a salt thereof by an enzymatic reaction.
(32) The production method according to the above (30) or (31), wherein P is a benzyl group which may have a substituent.
(33) The production method according to (30) or (31) above, wherein the enzyme is penicillin amidase.

  The present invention provides a novel compound represented by the general formula (IV) and an efficient production method thereof, and is a final target compound useful as an enzyme inhibitor by passing the compound as a raw material compound or an intermediate compound. Provided is a method for advantageously producing Compound (XV) or an N-protected form thereof.

In the compound (VI) produced through the novel compound (IV) of the present invention, since the amino group at the 5-position of the pyrimidine ring is protected with a protecting group that can be deprotected under mild conditions, the compound (XV) or its compound (XV) It can be easily deprotected without causing decomposition of the product at the final stage leading to the N-protected body.
Therefore, the production method of the present invention does not require deprotection of the protecting group prior to the amidation reaction as in the conventional method using an intermediate compound in which the 5-position of the pyrimidine ring is protected with a benzoyl group. As a result, side reactions such as dimerization by carrying out an amidation reaction while the amino group at the 5-position of the pyrimidine ring is in a free state can be suppressed, and a high-quality target compound can be obtained in high yield.

The present invention is described in detail below.
Definitions of symbols used in the present invention are as follows.

The “alkyl group” in P, R ¹ , R ² , R ⁶ , R ⁹ and R ¹⁰ is a linear or branched chain having preferably 1 to 20 carbon atoms, more preferably 1 to 7 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a lauryl group. Of these, a methyl group and an ethyl group are preferable.
The “optionally substituted alkyl group” in R ³ , R ⁴ , R ^4a , R ^4b , R ⁵ and R ⁷ is the above alkyl optionally substituted with one or more of the following substituents Examples of the substituent herein include, for example, a nitro group, a linear or branched alkoxy group (carbon number: 1 to 6, example: methoxy group), a halogen atom (example: chlorine atom, fluorine) Atoms), hydroxyl groups and the like.

  The “alkenyl group” in P is a linear or branched alkenyl group having preferably 2 to 20 carbon atoms, more preferably 2 to 7 carbon atoms, for example, vinyl group, allyl group, homoallyl group. And an oleyl group, among which a vinyl group and an allyl group are preferable.

The “aryl group optionally having substituent (s)” in R ³ , R ⁴ , R ^4a , R ^4b and R ⁷ is preferably an aryl group having 6 to 20 carbon atoms, more preferably 6 to 8 carbon atoms. And the aryl group may be substituted with one or more of the following substituents. Examples of the substituent here include a nitro group, a linear or branched alkoxy group (carbon number: 1 to 6, eg, methoxy group), a halogen atom (eg, chlorine atom, fluorine atom, etc.), linear or branched alkyl group (preferably a carbon number: 1-4, such as methyl group, ethyl group, propyl group and the like), a hydroxyl group and the like, have a "substituent R ⁵ Examples of the substituent in the “good phenyl group” include the same. Specific examples of the aryl group which may have a substituent or the phenyl group which may have a substituent include a phenyl group, o-, m- or p-nitrophenyl group, o-, m- or Examples include p-methoxyphenyl group, o-, m- or p-chlorophenyl group, o-, m- or p-fluorophenyl group, o-, m- or p-tolyl group. Among them, phenyl group, p- A fluorophenyl group and a p-tolyl group are preferred.
The “optionally substituted aryl group” for R ³ is preferably a 4-nitrophenyl group, a 2-nitrophenyl group, a 2,4-dinitrophenyl group, or the like.

The “aralkyl group” in R ⁶ is an aryl group having an aryl part of preferably 6 to 12, more preferably 6 to 8, and an alkyl part of preferably 1 to 6, more preferably 1 to 3. An aralkyl group which is a linear or branched alkyl group having the number of carbon atoms. As a specific example of the aralkyl group, a benzyl group is preferable.

The “aralkyl group optionally having substituent (s)” in P, R ³ and R ⁷ refers to the above aralkyl group optionally substituted with one or more of the following substituents. Examples thereof include a nitro group, a linear or branched alkoxy group (carbon number: 1 to 6, eg methoxy group), a halogen atom (eg chlorine atom, fluorine atom etc.), a hydroxyl group and the like.

  The “haloalkyl group” in P and Y is preferably substituted with 1 or 2 or more of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), preferably having 1 to 5 carbon atoms, more preferably 1 to 3 carbon atoms. It is a linear or branched alkyl group, and examples thereof include a trifluoromethyl group, a trichloromethyl group, and a chloromethyl group, and a trifluoromethyl group is preferable.

  The “halogen atom” in X is a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom or a bromine atom.

The “aliphatic heterocycle” in which R ¹ and R ² may be formed together with the adjacent nitrogen atom includes a carbon atom and at least one nitrogen atom, and in addition, an oxygen atom, a sulfur atom, and Examples include 5 to 6-membered aliphatic heterocycles which may contain 1 to 3 heteroatoms selected from nitrogen atoms, such as pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine and the like.

The “trialkylsilyl group” in R ³ is a silyl group substituted with the same or different alkyl group as defined above. Examples thereof include a trimethylsilyl group, a tert-butyldimethylsilyl group, and a triisopropylsilyl group. Preferably, it is a trimethylsilyl group.

The “alkoxy group” in R ⁸ is linear or branched alkoxy having 1 to 20 carbon atoms, more preferably 1 to 7 carbon atoms, such as methoxy group, ethoxy group, n- Examples thereof include a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a lauryloxy group. Of these, a methoxy group and an ethoxy group are preferable.

Examples of the “aralkyloxy group” in R ⁸ include an aralkyloxy group having an aralkyl moiety defined above, and examples thereof include a benzyloxy group and a p-nitrobenzyloxy group.

The “heterocyclic group” of the “heterocyclic group optionally having a substituent” in Y includes 5 to 5 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the carbon atom. A 6-membered heterocyclic group, and a condensed heterocyclic group thereof, such as a pyrrolyl group (1-, 2- or 3-pyrrolyl group), a furyl group (2- or 3-furyl group), a thienyl group (2- Or 3-thienyl group), imidazolyl group (1-, 2-, 4- or 5-imidazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group), thiazolyl group (2-, 4- or 5) -Thiazolyl group), pyrazolyl group (1-, 3-, 4- or 5-pyrazolyl group), isoxazolyl group (3-, 4- or 5-isoxazolyl group), isothiazolyl group (3-, 4- or 5-isothiazolyl group) Group), oxadiazolyl (1,2,4-oxadiazol-3 or 5-yl group, 1,3,4-oxadiazol-2-yl group, 1,2,5-oxadiazol-3-yl group), thiadiazolyl Group, (1,2,4-thiadiazol-3 or 5-yl group, 1,3,4-thiadiazol-2-yl group, 1,2,5-thiadiazol-3-yl group), triazolyl group (1, 2,4-triazol-1,3,4,5-yl group, 1,2,3-triazol-1,2, or 4-yl group), indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group), benzofuryl group (2-, 3-, 4-, 5-, 6- or 7-benzofuryl group), benzothienyl group (2-, 3-, 4-, 5) -, 6- or 7-benzothienyl group), benzimidazolyl group (1-, 2-, 4-, 5-, -Or 7-benzimidazolyl group), benzoxazolyl group (2-, 4-, 5-, 6- or 7-benzoxazolyl group), benzothiazolyl group (2-, 4-, 5-, 6- Or 7-benzothiazolyl group), pyridyl group (2-, 3- or 4-pyridyl group), pyridine-1-oxide group (2-, 3- or 4-pyridine-1-oxide group), pyrimidinyl group (2- , 4- or 5-pyrimidinyl group), tetrazolyl group (1H-tetrazol-1 or 5-yl group, 2H-tetrazol-2 or 5-yl group), quinolyl group (2-, 3-, 4-, 5- , 6-, 7- or 8-quinolyl group) or isoquinolyl group (1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group), pyrrolidinyl group (1-, 2- or 3). -Pyrrolidinyl group), pyrazolidinyl group (1-, 3- or 4-pyrazolidinyl group), imidazolidinyl group (1-, 2- or 4-imidazolidinyl group), pyrrolinyl group (1-, 2- or 3-pyrrolinyl group), pyrazolinyl group (1-, 3- or 4- Pyrazolinyl group), imidazolinyl group (1-, 2-, 4- or 5-imidazolinyl group), tetrahydrofuryl group (2- or 3-tetrahydrofuryl group), tetrahydrothienyl group (2- or 3-tetrahydrothienyl group), Thiazolidinyl group (2-, 3-, 4- or 5-thiazolidinyl group), piperidinyl group (1-, 2-, 3- or 4-piperidinyl group), piperazinyl group (1- or 2-piperazinyl group), tetrahydropyrani Group (2-, 3- or 4-tetrahydropyranyl group), morpholinyl group (2-, 3- or 4-morpholinyl group), thiomo Folinyl group (2-, 3- or 4-thiomorpholinyl group), dioxolanyl group (2- or 4-dioxolanyl group), homopiperidinyl group (1-, 2-, 3- or 4-homopiperidinyl group), homopiperazinyl group (1- 2-, 5- or 6-homopiperazinyl group), indolinyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolinyl group), chromanyl group (2-, 3-, 4) -, 5-, 6-, 7- or 8-chromanyl group) and the like, and an oxadiazolyl group, a thiazolyl group, and a benzoxazolyl group are preferable, and a 1,3,4-oxadiazol-2-yl group, 2-thiazolyl group and 2-benzoxazolyl group are more preferable.
The heterocyclic group may be substituted with one or more of the following substituents. Examples of the substituent herein include a nitro group, a linear or branched alkoxy group (preferable carbon number: 1 to 6, example: methoxy group), a halogen atom (example: chlorine atom, fluorine atom, etc.). A linear or branched alkyl group (preferably having a carbon number of 1 to 4, eg, methyl group, ethyl group, propyl group, etc.), an alkoxycarbonyl group (eg: methoxycarbonyl group, ethoxycarbonyl group, etc.), etc. Can be mentioned.
Specific examples of the heterocyclic group which may have a substituent include 5-tert-butyl-1,3,4-oxadiazol-2-yl group, 2-thiazolyl group, and 5-methoxycarbonylbenzoxazole. -2-yl group and the like can be mentioned, among which 5-tert-butyl-1,3,4-oxadiazol-2-yl group is preferable.

  The “acyl group” of the “optionally substituted acyl group” in Y is a linear or branched acyl group having preferably 1 to 20 carbon atoms, such as acetyl Group, propionyl group, butyryl group, isobutyryl group and the like. The acyl group may be substituted with one or more of the following substituents. Examples of the substituent herein include a nitro group, a linear or branched alkoxy group (preferable carbon number: 1 to 6, example: methoxy group), a halogen atom (example: chlorine atom, fluorine atom, etc.). A linear or branched alkyl group (preferably having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, and a propyl group), a 2-pyridyloxy group, and the like. Specific examples of the “acyl group optionally having a substituent” include a 4- (2-pyridyloxy) butyryl group.

  The “protecting group for an amino group other than an acyl group” in Q is not particularly limited as long as it is other than an acyl group. For example, benzyloxycarbonyl group (Cbz group), tert-butoxycarbonyl group (Boc group), methoxycarbonyl group (Moc group), 9-fluorenylmethoxycarbonyl group (Fmoc group) and the like. Of these, a Cbz group, a Boc group, and the like that can be deprotected under mild conditions are preferable.

Next, a preferred embodiment of each symbol will be described.
P is preferably an alkyl group or an aralkyl group which may have a substituent, and more preferably a methyl group, an ethyl group or a benzyl group.

The alkyl group which may have a substituent for R ³ is preferably a methyl group or an ethyl group, and the aryl group which may have a substituent is preferably a nitrophenyl group, which has a substituent. preferably a benzyl group or a chlorobenzyl group as aralkyl group, preferably a trimethylsilyl group as a trialkylsilyl group, preferably an acetyl group or a propionyl group as -COR ^4a, as the -SO ₂ R ^4b, or methanesulfonyl group A p-toluenesulfonyl group is preferred.

  M is preferably sodium or potassium.

R ⁵ is preferably a phenyl group, a p-fluorophenyl group, or a methyl group.

R ⁶ is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom, a methyl group or a tert-butyl group.

R ⁷ is preferably an alkyl group which may have a substituent or an aralkyl group which may have a substituent, and more preferably a methyl group, an isopropyl group or a benzyl group.

R ⁸ is preferably a hydrogen atom, a hydroxyl group, a methoxy group, a tert-butoxy group, a benzyloxy group or —N (R ⁹ ) —OR ¹⁰ (where each symbol is as defined above), and a hydrogen atom, a methoxy group, a benzyl group An oxy group or -N (Me) -OMe is more preferable.

  Y represents 5-tert-butyl-1,3,4-oxadiazol-2-yl group, 2-thiazolyl group, trifluoromethyl group, 4- (2-pyridyloxy) butyryl group or 5-methoxycarbonylbenzo An oxazol-2-yl group is preferred.

  Compounds represented by general formula (I), (V), (VI), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV) Can form salts such as alkali metal salts (for example, potassium salt, sodium salt, lithium salt), organic amine salts (for example, triethylamine salt, dicyclohexylamine salt), etc. When having a group, it may form a salt such as an inorganic acid salt (eg, hydrochloride, sulfate, etc.), an organic acid salt (eg, acetate, trifluoroacetate, tosylate, mesylate, etc.) it can.

  The production method of the present invention is represented by the following reaction scheme.

(In the formula, each symbol is as defined above.)

  That is, the present invention includes general formulas (IV), (VI), (VII), (IX), (X), (XI) including a part of steps (a) to (m) shown in the above reaction scheme. Or it is the manufacturing method of the compound represented by (XV), and what is necessary is just to select the suitable route for manufacturing a desired compound suitably.

  The production method of the present invention includes a novel synthesis route for producing compound (IV), which is a novel azlactone derivative, step (a) and step (b), and high yielding of compound (IV) is achieved by this step. Can be manufactured efficiently and efficiently.

Fat which can deprotect the amino group at the 5-position of the pyrimidine ring under mild conditions by using the compound (IV) as a raw material for the enzyme inhibitor or its useful intermediate, the pyrimidine compound (XV) or (X) Since it is possible to go through compounds (VI), (VII), (IX) and (XI) which are synthetic intermediates protected with a group acyl, there is no decomposition or the like in step (i) or (m) Can be deprotected.
For this reason, it is not necessary to deprotect prior to steps (d), (e), (f), (g) and (h), and a secondary reaction such as dimerization by carrying out a condensation reaction with a free amino group. Since the reaction can be avoided and there is no need to replace the protecting group to avoid dimerization, the high-quality compound (X) or compound (XV) can be efficiently produced in a shorter process. Can be manufactured.

Further, in the present invention, it has been found that by using compound (IV) as a raw material, deprotection can be performed by an enzymatic reaction in step (i) or (m) which is a deprotection step. Since the enzyme reaction proceeds in a high yield under a mild condition of stirring at room temperature in the vicinity of neutrality, it can be suitably applied to the present invention.
Furthermore, the present inventors also found that the deprotection reaction proceeds at a high yield under mild conditions such as weak acidity and near room temperature without accompanying side reactions such as decomposition.

  Below, process (a)-(m) is demonstrated.

1. Step (a)
Step (a) is a method of obtaining compound (II) by hydrolyzing compound (I) in the presence of an alkali metal hydroxide. Specifically, for example, an alkali metal hydroxide, preferably an aqueous solution thereof, may be added to compound (I) in a solvent, but the addition order may be reversed or simultaneous.

As a method for producing compound (II), 4- (N, N-dimethylaminomethylene) -2-alkyl-2-oxazolin-5-one is reacted with sodium ethoxide in an ethanol solvent to give 4-hydroxy A method for producing methylene-2-alkyl-2-oxazolin-5-ones is known (Ind. J. Chem., 39B, 688-693 (2000)). There were problems such as the generation of decomposition products during neutralization.
In step (a), the use of alkali metal hydroxide is advantageous because compound (II) can be synthesized in a high yield under mild conditions.

  As the compound (II) produced in the step (a), since the salt form is stable, sodium, potassium, or lithium in which M is an alkali metal is preferable, and sodium is more preferable.

  Examples of the alkali metal hydroxide used in the step (a) include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide. The alkali metal hydroxide may be used in a solid state, but is preferably used as an aqueous solution, and the concentration in this case is in the range of 0.1N to 12N.

  The amount of alkali metal hydroxide used is usually 0.9 to 1.5 equivalents, preferably 1 to 1.2 equivalents, relative to compound (I).

As the solvent that can be used in the step (a), any solvent that does not inhibit this reaction may be used. For example, water, acetate esters (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.), Acetonitrile, tetrahydrofuran (THF), N, N-dimethylformamide and the like may be mentioned. These may be used alone or in combination of two or more, and a mixed solvent of water and an organic solvent miscible with water such as acetonitrile or acetone. Is more preferable, and among them, a mixed solvent of acetonitrile and water is preferable. The usage-amount of a solvent is 3-50 times weight normally with respect to compound (I), Preferably it is 10-20 times weight. In addition, when using alkali metal hydroxide aqueous solution, the quantity of the said water is contained in the usage-amount of a solvent.
In addition, when alcoholic solvents (for example, ethanol, isopropyl alcohol, n-butanol, etc.) are used, side reactions such as the opening of the azlactone ring of compound (I) tend to occur, so use alcoholic solvents. Is not preferred.

  Step (a) is usually performed within the range of the reflux temperature (preferably 0 to 20 ° C.) of the solvent used from −10 ° C. The reaction is usually completed within 30 minutes to overnight (preferably 2 hours to 20 hours) within the above temperature range.

After completion of the reaction in step (a), compound (II) is present in the form of an alkali metal salt (M = alkali metal). Therefore, when isolating the free form (M = hydrogen atom) of compound (II), an acid (for example, hydrochloric acid, sulfuric acid, etc.) is added to the reaction mixture to adjust the pH to 3.5 to 4.5, The free form of compound (II) can be isolated by a usual isolation and purification method, for example, by concentrating or crystallizing the reaction mixture, or subjecting to a silica gel column chromatography, but is not limited thereto. Not.
In the case of isolation in the form of an alkali metal salt, it is possible to isolate the alkali metal salt form of the compound (II) by concentrating or crystallizing the reaction mixture, for example, by a conventional isolation and purification method. it can.

In addition, the form of the alkali metal salt of compound (II) tends to form a hydrate, and when subjected to the step (b) as a hydrate, there is a possibility that adverse effects such as decomposition may occur due to the influence of water. It is preferable to form anhydrous crystals by high temperature slurry washing or high temperature drying in an organic solvent.
Among the compounds (II) obtained in step (a), those in the form of alkali metal salts are novel compounds.

Compound (I) which is a raw material of the step (a) can be produced by a known method.
For example, as in Reference Examples 1 to 3 below, N-acylglycine represented by the general formula: PC (═O) NHCH ₂ COOH (wherein P is as defined above) and the general formula : Compound (I) can be produced by reacting formamide represented by R ¹ R ² NCHO (wherein each symbol is as defined above) and phosphorus oxychloride (Ind. J. Chem., 39B, 688-693 (2000)).
Further, as in Reference Example 4 described later, an N-acylglycine represented by the general formula: PC (═O) NHCH ₂ COOH (wherein P is as defined above) is represented by the general formula: R Compound (I) is produced by reacting with formamide dimethyl acetal represented by ¹ R ² NCH (OMe) ₂ (wherein each symbol is as defined above) and N, N′-dicyclohexylcarbodiimide. (See J. Heterocyclic Chem., 34, 247 (1997)).

2. Step (b)
Step (b) is a method of obtaining compound (IV) by reacting compound (II) with reagent (III). In detail, it can carry out by adding reagent (III) to compound (II), for example in a solvent, However, The addition order may be reverse or simultaneous.

  In the Erlenmeyer method, which is a general method for producing an azlactone compound, the compound (IV) in which the 2-position of the azlactone ring is an aliphatic group produces many by-products, has a very low yield, and is difficult to isolate. The step (a) and the step (b) of the present invention are advantageous because the compound (IV) can be produced from the known compound (I) under a mild condition in a high yield.

  As the solvent that can be used in the step (b), any solvent that does not inhibit this reaction may be used. For example, acetates (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.), acetonitrile, Examples include THF, N, N-dimethylformamide, halogenated solvents (for example, chloroform, dichloromethane, etc.), acetone and the like. These may be used alone or in combination of two or more, N, N-dimethylformamide, acetonitrile. , Chloroform alone or a mixed solvent is preferable. The usage-amount of a solvent is 3-50 times weight normally with respect to compound (II), Preferably it is 5-20 times weight.

The reagent (III) used in the step (b) is not particularly limited as long as it can be defined by R ³ and X in the general formula (III), and specifically, dimethyl sulfate, diethyl sulfate, iodine Examples thereof include, but are not limited to, methyl iodide, ethyl iodide, benzyl chloride, benzyl bromide, benzyl iodide, p-toluenesulfonyl chloride, methanesulfonyl chloride, trimethylsilyl chloride, acetyl chloride, and acetic anhydride. From the viewpoint of yield and cost, dimethyl sulfate, diethyl sulfate, benzyl bromide, and trimethylsilyl chloride are preferable.

When compound (II) is a free form (M = hydrogen atom), it is preferable to add a base during the reaction. Such bases include inorganic bases (eg, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, etc.) or organic bases (eg, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, etc.), Organic bases, particularly triethylamine and diisopropylethylamine are preferred.
The amount of the base to be used is generally 0.5 to 5 equivalents, preferably 1 to 1.5 equivalents, relative to compound (II).

  The amount of reagent (III) used depends on the type of reagent used, but is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (II). When acetic anhydride is used in excess of the above amount, the part functions as a solvent.

  Step (b) is usually performed within the range of the reflux temperature (preferably 0 to 80 ° C.) of the solvent used from 0 ° C. The said reaction is normally complete | finished in 30 minutes-overnight (preferably 1 hour-20 hours) within the said temperature range.

Isolation and purification of compound (IV) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (IV) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc.) are added for crystallization or subjected to silica gel column chromatography to purify compound (IV) However, it is not limited to these.
In addition, compound (IV) can be subjected to the next step as a reaction mixture containing compound (IV) without isolation.

  A part of the compound (IV) obtained in the step (b), that is, the compound (IV ′) is a novel compound and is useful as an intermediate of the enzyme inhibitor of the present invention. It can also be used as an intermediate for the synthesis of ring derivatives (International Journal of Peptideb & protein Research, 45 (3), 266-71 (1995); JCS Parkin. Transaction 1, (17), 2813-16 (1998), etc. reference).

3. Step (c)
Step (c) is a method in which compound (IV) or a salt thereof is obtained by reacting compound (IV) with compound (V) or a salt thereof. This reaction is carried out in a solvent. Specifically, for example, compound (IV) or a solution thereof is added to compound (V) or a solution thereof (preferably dropwise in the case of a solution), and the mixture is heated and stirred. The order of addition may be reversed or simultaneous.

Compound (V) tends to decompose in a free form when R ⁶ is an alkyl group or an aralkyl group, and is usually isolated in the form of a stable salt as a solid. Examples of the salt of compound (V) include acid addition salts such as hydrochloride, sulfate, and trifluoroacetate. In the compound (V), when R ⁶ is a hydrogen atom, it forms a salt with an imino group in the molecule and exists stably, and also exists as a base addition salt such as sodium salt or potassium salt. . Therefore, when the free compound (V) is reacted with the compound (IV), an amount of base (for example, sodium ethoxide, potassium butoxide, sodium methoxide) required to convert the compound (V) into a base addition salt is used. Etc.) are preferably used.

  In step (c), the acid addition salt of compound (V) is preferably neutralized with a base in a solvent, once converted to a free form, and then reacted with compound (IV). Prior to the reaction, it is possible to dissolve the compound (V) salt and the compound (IV) in a solvent and add a base, for example. ) Is reduced. The base used for neutralization is not particularly limited, and examples thereof include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium methoxide, sodium ethoxide and the like. These bases may be used as an aqueous solution. Neutralization is usually carried out in a solvent. As the solvent, toluene, ethyl acetate or the like can be used. In this case, it is preferable to add water for dissolving the base, and the compound (V ) Free form can be separated and used. The amount of the base used is not particularly limited as long as the salt of compound (V) can be converted into a free form, but it is preferably 3 equivalents or less with respect to compound (V) from the economical viewpoint.

  As the solvent that can be used in the step (c), any solvent that does not inhibit this reaction may be used. For example, acetates (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.), hydrocarbons (For example, toluene, benzene, xylene, etc.), acetonitrile, THF, alcohols (for example, ethanol, isopropyl alcohol, n-butanol, etc.), N, N-dimethylformamide, and the like. The above may be used in combination, and acetonitrile, toluene, ethanol, isopropyl alcohol, and ethyl acetate are preferable. Acetonitrile, toluene, and isopropyl alcohol alone or a mixed solvent are more preferable, and among them, acetonitrile and toluene alone or a mixed solvent are preferable. The usage-amount of a solvent is 2-50 times weight normally with respect to compound (IV), Preferably it is 5-20 times weight.

  The amount of compound (V) to be used is generally 0.9 to 3 equivalents, preferably 1 to 1.3 equivalents, relative to compound (IV).

  When using the reaction mixture of the step (b) as the compound (IV), the amount of each reagent used can be within the above range based on the compound (II) used in the step (b).

  The reaction between compound (IV) and compound (V) is usually carried out within the range of the reflux temperature of the solvent used from 10 ° C (preferably 20 to 80 ° C). The reaction is usually completed within 1 to 20 hours (preferably 3 to 15 hours) within the above temperature range.

  Isolation and purification of compound (VI) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (VI) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or mixed solvents thereof, etc.) are added to crystallize or subject to silica gel column chromatography to purify compound (VI) However, it is not limited to these.

4). Step (d)
In step (d), compound (VI) or a salt thereof is converted to a carboxylic acid form by hydrolysis or the like when R ⁶ in compound (VI) is other than a hydrogen atom, and then condensed with N-hydroxysuccinimide. This is a method for obtaining compound (VII).
Compound (VII) is a novel compound and can be amidated directly with various amines as in the following step (e), so it is convenient as a versatile intermediate and free of amino acids. There is an advantage that it can be condensed with an amine having a carboxyl group without protecting the carboxyl group.

When R ⁶ of the compound (VI) is other than a hydrogen atom, that is, an alkyl group or an aralkyl group, first, the form of carboxylic acid (R ⁶ = hydrogen atom, hereinafter, by hydrolysis, acid treatment, hydrogenation, etc.) Simply referred to as carboxylic acid form). The hydrolysis, acid treatment, hydrogenation and the like may be performed by methods known to those skilled in the art. For example, hydrolysis is performed by reacting with a base (eg, sodium hydroxide, potassium hydroxide, etc.) or an acid (eg, hydrochloric acid, sulfuric acid, etc.) in a mixed solvent with alcohol or water such as methanol or ethanol. However, it is not limited to this.

For example, when R ⁶ is a tert-butyl group or the like, it can be converted into a carboxylic acid form by performing an acid treatment, for example, by treating with an acid such as trifluoroacetic acid in an organic solvent.

In addition, when R ⁶ is benzyl or the like, it can be converted into a carboxylic acid form by hydrogenolysis, for example, by catalytic reduction in the presence of a catalyst such as palladium carbon.

The method for condensing the carboxylic acid form with N-hydroxysuccinimide may be carried out by a method known to those skilled in the art and is not particularly limited. For example, a carboxylic acid form may be reacted with a chlorinating agent such as thionyl chloride or phosphorus pentachloride to be led to an acid chloride, and then condensed with N-hydroxysuccinimide. Since 1 amide exists, a method of activating the carboxylic acid form with a condensing agent and then condensing with N-hydroxysuccinimide is preferable.
The preferred embodiment will be described below, but the step (d) is not limited to this embodiment.

  Specifically, as a preferred embodiment, the carboxylic acid form is activated with an activator in a solvent and then condensed with N-hydroxysuccinimide.

  Examples of the activator include chloroformates (eg, ethyl chloroformate, isobutyl chloroformate, methyl chloroformate, etc.), carbodiimides (eg, N, N′-dicyclohexylcarbodiimide (DCC), N- (3-dimethylamino). Propyl) -N′-ethylcarbodiimide (EDC) and the like, carbodiimidazole (CDI), diphenylphosphoryl azide (DPPA) and the like, but are not limited thereto. Of these, chloroformate, DCC, EDC and the like are preferable, and ethyl chloroformate and isobutyl chloroformate are particularly preferable.

  The usage-amount of an activator is 0.9-1.5 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.3 equivalent.

When activating the carboxylic acid form, a base may be added as necessary. Such bases include inorganic bases (eg, sodium carbonate, potassium carbonate, etc.) or organic bases (eg, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, piperidine, etc.), and organic bases, particularly N- Methylmorpholine, triethylamine and pyridine are preferred.
The usage-amount of the said base is 0.9-2 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.5 equivalent.

  The solvent used for the activation of the carboxylic acid form may be any solvent as long as it does not inhibit this reaction. For example, acetate esters (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.) , Hydrocarbons (for example, toluene, benzene, xylene, etc.), acetonitrile, THF, dichloromethane, methyl-tert-butyl ether and the like. These may be used alone or in combination of two or more, acetonitrile, THF In addition, a single or mixed solvent such as ethyl acetate is more preferable. The usage-amount of a solvent is 3-50 times weight normally with respect to a carboxylic acid body, Preferably it is 5-20 times weight.

  The activation of the carboxylic acid is usually performed within the range of the reflux temperature of the solvent used from -40 ° C (preferably -10 to 10 ° C). The activation is usually completed within 5 minutes to 3 hours (preferably 10 minutes to 1 hour) within the above temperature range.

After activation of the carboxylic acid form, N-hydroxysuccinimide is added to the reaction mixture. The order of addition may be reversed or simultaneous.
The usage-amount of N-hydroxysuccinimide is 0.9-2 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.3 equivalent.

  The condensation with N-hydroxysuccinimide is usually carried out within the range of -50 to 40 ° C (preferably -20 to 20 ° C). The condensation is usually completed within 1 to 20 hours (preferably 2 to 5 hours) within the above temperature range.

  Isolation and purification of compound (VII) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (VII) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc.) are added for crystallization, or subjected to silica gel column chromatography to purify compound (VII) However, it is not limited to these.

5). Step (e)
Step (e) is a method in which compound (VII) and compound (VIII) or a salt thereof are reacted to obtain compound (IX) or a salt thereof. Specifically, for example, the compound (VII) or the solution thereof can be added to the solution of the compound (VIII) in a solvent, but the addition order may be reversed or simultaneous.

Step (e) is advantageous in that it can be carried out without side reactions such as self-polymerization of compound (VIII) even when R ⁸ is a hydroxyl group in compound (VIII).
Therefore, R ⁸ is a hydroxyl group, that is, a free amino acid can be suitably applied to compound (VIII) in step (e).

  As the solvent that can be used in the step (e), any solvent that does not inhibit this reaction may be used. For example, water, acetate esters (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.), Acetonitrile, THF, N, N-dimethylformamide, acetone and the like can be mentioned, and these may be used alone or in combination of two or more, and water, acetonitrile, THF or the like alone or a mixed solvent is more preferable. The amount of the solvent to be used is generally 2 to 50 times weight, preferably 5 to 20 times weight, relative to compound (VII).

  When the compound (VIII) is a free amino acid, it is preferably used in advance as an aqueous solution having a pH of 5 to 10 with an alkaline aqueous solution (for example, an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution). The amount of water in the aqueous solution is included in the amount of solvent used.

  The amount of compound (VIII) to be used is generally 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (VII).

  Step (e) is usually performed within the range of the reflux temperature (preferably 0 to 30 ° C.) of the solvent used from −20 ° C. The reaction is usually completed within 30 minutes to overnight (preferably 1 hour to 10 hours) within the above temperature range.

When R ⁸ is a hydroxyl group in compound (IX), it exists in the form of a carboxylate salt. Therefore, after adding an acid (eg, hydrochloric acid, sulfuric acid, etc.) to the reaction mixture to reduce the pH to 3 or less, for example, The reaction mixture is concentrated or a crystallization solvent (eg, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogenated solvents (eg, For example, dichloromethane (dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc. are added for crystallization or subjected to silica gel column chromatography to give compound (IX ) Free form can be purified, but is not limited thereto.

When R ⁸ is other than a hydroxyl group in compound (IX), it can be isolated and purified by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (IX) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) Compound (IX) is purified by crystallization by adding an alcohol (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, or subjecting to silica gel column chromatography. However, it is not limited to these.

6). Step (f)
In step (f), compound (VI) or a salt thereof is converted to a carboxylic acid form when R ⁶ in compound (VI) is other than a hydrogen atom, and then condensed with compound (VIII) to give compound (IX Or a salt thereof.
Compound (IX) synthesized in Step (e) and Step (f) is a novel compound, and is represented by R ⁸ in the state where the amino group of Compound (VIII) is protected in Step (g) described later. Since the group can be converted into a group represented by Y, it is useful as a synthetic intermediate that can efficiently produce the compound (XV) that is an enzyme inhibitor.

In step (f), it is not preferred that R ⁸ of compound (VIII) is a hydroxyl group because side reactions such as self-polymerization can occur.
Therefore, in step (f), R ⁸ of compound (VIII) is other than a hydroxyl group, that is, a hydrogen atom, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein each symbol is the same as described above). It shows the significance.

When R ⁶ of compound (VI) is other than a hydrogen atom, that is, an alkyl group or an aralkyl group, it is first converted to a carboxylic acid form by the same method as in step (d).

  As a method for condensing the carboxylic acid compound and the compound (VIII), the compound (VIII) or a salt thereof is used in place of the N-hydroxysuccinimide in the method of condensing the carboxylic acid compound and N-hydroxysuccinimide in the step (d). The same conditions can be used.

That is, in a preferred embodiment, compound (IX) can be produced by activating a carboxylic acid form with a activating agent in a solvent and then condensing with compound (VIII) or a salt thereof.
Although the said aspect is demonstrated below, a process (f) is not limited to this aspect at all.

Examples of the activator include those similar to those in the step (d), and chloroformates, particularly ethyl chloroformate, methyl chloroformate, isobutyl chloroformate and the like are preferable.
The usage-amount of an activator is 0.9-1.5 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.2 equivalent.

When activating the carboxylic acid form, a base may be added as necessary. Examples of such a base include the same bases as in step (d), and N-methylmorpholine, triethylamine, pyridine and piperidine are preferable.
The usage-amount of the said base is 0.9-2 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.2 equivalent.

  The solvent used for the activation of the carboxylic acid form may be any solvent as long as it does not inhibit this reaction. For example, acetate esters (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.) Hydrocarbons (eg, toluene, benzene, xylene, etc.), acetonitrile, THF, halogen solvents (eg, dichloromethane, chloroform, etc.), ether solvents (eg, diethyl ether, methyl-tert-butyl ether, etc.), etc. These may be used alone or in combination of two or more, and are preferably single or mixed solvents such as acetonitrile, THF, ethyl acetate, methyl-tert-butyl ether and the like. The usage-amount of a solvent is 3-50 times weight normally with respect to a carboxylic acid body, Preferably it is 5-20 times weight.

  Activation of a carboxylic acid body is normally performed within the range of -50-40 degreeC (preferably -20-20 degreeC). The activation is usually completed within 5 minutes to 5 hours (preferably 15 minutes to 2 hours) within the above temperature range.

After activation of the carboxylic acid compound, compound (VIII) is added to the reaction mixture. The order of addition may be reversed or simultaneous.
The amount of compound (VIII) to be used is generally 0.9 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to the carboxylic acid form.

When compound (VIII) is in the form of a salt, it is preferable to add a base similar to the base used in activating the carboxylic acid form for neutralization.
The amount of the base to be used is generally 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (VIII).

  The condensation with compound (VIII) is usually performed within the range of -50 to 40 ° C (preferably -20 to 20 ° C). The condensation is usually completed within 0.5 to 20 hours (preferably 1 to 3 hours) within the above temperature range.

  Isolation and purification of compound (IX) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an alkaline aqueous solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the resulting organic layer is concentrated. Thus, compound (IX) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc.) are added to crystallize or subject to silica gel column chromatography to give compound (IX). Although it can refine | purify, it is not limited to these.

As the compound (VIII) which is a raw material of the step (e) and the step (f), commercially available amino acids are used, or they are esterified by a known method, or a general formula: NH It can manufacture by condensing with the hydroxylamine derivative represented by (R < ⁹ >)-OR < ¹⁰ > (In formula, each symbol shows the same meaning as the above.).

7). Step (g)
Step (g) is a method of converting the group represented by R ⁸ of compound (IX) or a salt thereof into a group represented by Y to obtain compound (XI) or a salt thereof.
Step (g), as described above, the compound (IX), in a state where the amino group is protected, by converting the group represented by R ⁸ in the group represented by Y, the compound (XI) Therefore, compound (XV) can be produced efficiently and can be one of advantageous reaction routes.

The process (g) differs depending on the mode of Y, and the method for converting the group represented by R ⁸ into the group represented by Y will be described below.

7-1. When Y is a heterocyclic group which may have a substituent (hereinafter also referred to as step (g-1)).
Step (g-1) is a method of converting a group represented by R ⁸ into a heterocyclic group as shown in the following reaction scheme. Specifically, compound (IX) is represented by the general formula in a solvent. ^(XVIIa): Y ¹ -M 1 wherein, ^{Y 1} represents a heterocyclic group which may have a substituent group, ^{M 1} is lithium or MgX ¹ (wherein, ^{X 1} is a chlorine atom, a bromine atom Or an iodine atom). And a compound represented by the general formula (XI) wherein Y is a heterocyclic group which may have a substituent (hereinafter referred to as a reagent (XVIIa)). , Compound (XIa)).

(In the formula, each symbol is as defined above.)
R ⁸ of compound (IX) in step (g-1) is —N (R ⁹ ) —OR ¹⁰ (wherein each symbol is a symbol for preventing further reaction of reagent (XVIIa) with compound (XIa)). It is preferably a group represented by the same meaning as described above.

Reagent (XVIIa) is a compound represented by the general formula: Y ¹ -H or Y ¹ -X ¹ (wherein each symbol is as defined above) alkyllithiums (for example, n-butyllithium, Methyllithium, etc.) or lithium amides (eg, lithium diisopropylamide, etc.) and ether solvents (eg, THF, diethyl ether, methyl-tert-butyl ether (MTBE), etc.) at −90 to 20 ° C. or in general It can be obtained by reacting a compound represented by the formula: Y ¹ -X ¹ (wherein each symbol has the same meaning as described above) under conditions for producing magnesium and a normal Grignard reagent.

  As the solvent that can be used in the step (g-1), any solvent that does not inhibit this reaction may be used. For example, an ether solvent (for example, THF, diethyl ether, MTBE, etc.), a hydrocarbon solvent (for example, n- Hexane, toluene, and the like), and these may be used alone or in combination of two or more. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, relative to compound (IX).

  The amount of reagent (XVIIa) to be used is generally 1-10 equivalents, preferably 1-6 equivalents, relative to compound (IX).

  Step (g-1) is usually performed within the range of -90 to 30 ° C (preferably -80 to -20 ° C). The said reaction is normally complete | finished in 10 minutes-5 hours (preferably 30 minutes-2 hours) within the said temperature range.

In addition, when R ⁸ is a hydrogen atom, a reduced form (alcohol form) of compound (XIa) can be obtained, so that it is oxidized by a known method (for example, Dess Martin reagent, Swan oxidation, Pfitzner-Moffatt oxidation, etc.) Can lead to compound (XIa).

7-2. R ⁸ is a hydrogen atom, and Y is the general formula (XVIII):

(In the formula, a dotted line represents a double bond or a single bond, Z represents an oxygen atom or a sulfur atom, and R ¹⁵ and R ¹⁶ are the same or different and represent a group corresponding to a substituent of a heterocyclic group, Or a heterocyclic group (hereinafter referred to as heterocyclic group (XVIII)) represented by a heterocycle or heterocycle which may have a substituent together with adjacent carbon atoms. (Hereinafter also referred to as step (g-2)).

When R ⁸ is a hydrogen atom, according to the method described in Journal of Medicinal Chemistry, 44 (8), 1286-1296 (2001), the following steps (g-2a) to (g-2e) R ⁸ (hydrogen atom) of compound (IX) can be converted to a heterocyclic group (XVIII).

That is, as shown in the reaction scheme below,
Step (g-2a): a compound represented by general formula (IXa) in which R ⁸ is a hydrogen atom (hereinafter also referred to as compound (IXa)) or a salt thereof is converted to a cyanohydrin represented by general formula (XIX) ( Hereinafter referred to as cyanohydrin (XIX));
Step (g-2b): The obtained cyanohydrin (XIX) or a salt thereof is converted to an imidate represented by the general formula (XXI) (hereinafter also referred to as imidate (XXI)) or a salt thereof;
Step (g-2c): The obtained imidate (XXI) or a salt thereof is reacted with a compound represented by the general formula (XVIIIa) (hereinafter, also referred to as compound (XVIIIa)) or a salt thereof to give a general formula A compound represented by (XXII) (hereinafter also referred to as compound (XXII)) or a salt thereof;
Step (g-2d): Compound (IXa) or a salt thereof is reacted with a compound represented by the general formula (XVIIIb) (hereinafter also referred to as Compound (XVIIIb)) to obtain Compound (XXII) or a salt thereof. ;
Step (g-2e): A compound represented by the general formula (XIb) in which Y is a heterocyclic group (XVIII) (hereinafter referred to as compound (XIb) by oxidizing the obtained compound (XXII) or a salt thereof. Can also be obtained.

(In the formula, R ¹⁷ represents a trialkylsilyl group, R ¹⁸ represents an alkyl group, and other symbols and dotted lines are as defined above.)
The “group corresponding to the substituent of the heterocyclic group” in R ¹⁵ and R ¹⁶ corresponds to the substituent of the “heterocyclic group which may have a substituent” in Y, specifically Is, for example, a nitro group, a linear or branched alkoxy group (carbon number: 1 to 6, eg: methoxy group), a halogen atom (eg, chlorine atom, fluorine atom, etc.), linear or branched chain And alkyl groups (preferably having 1 to 4 carbon atoms, eg, methyl group, ethyl group, propyl group, etc.), alkoxycarbonyl groups (eg: methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like.

Examples of the homocyclic ring that R ¹⁵ and R ¹⁶ may form together include benzene, naphthalene, cyclohexane and the like.
Examples of the heterocyclic ring that R ¹⁵ and R ¹⁶ may form together include pyridine and piperidine.
Examples of the substituent that the homocyclic ring and the heterocyclic ring may have include those similar to the above-mentioned “group corresponding to the substituent of the heterocyclic group”.

The “trialkylsilyl group” in R ¹⁷ is a silyl group substituted with the same or different alkyl group, and examples thereof include a trimethylsilyl group.

The “alkyl group” in R ¹⁸ is linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, and an n-propyl group. A methyl group and an ethyl group are preferred.

7-2-1. Step (g-2a)
Step (g-2a) is realized, for example, by reacting compound (IXa) with cyanohydrins and a base in a solvent.

  As the solvent that can be used in the step (g-2a), any solvent that does not inhibit this reaction may be used. Examples thereof include dichloromethane, THF, diethyl ether, and the like. These may be used alone or in combination of two or more. Also good. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (IXa).

  Examples of cyanohydrins include acetone cyanohydrin. The amount of cyanohydrins to be used is generally 0.8-5 equivalents, preferably 1-3 equivalents, relative to compound (IXa).

  Examples of the base include triethylamine, pyridine, N-methylmorpholine and the like, and triethylamine is preferable. The amount of the base to be used is generally 0.5-3 equivalents, preferably 0.6-2 equivalents, relative to compound (IXa).

  A process (g-2a) is normally performed within 0-50 degreeC (preferably 10-30 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-8 hours) within the said temperature range.

  Isolation and purification of cyanohydrin (XIX) obtained in the step (g-2a) can be performed by a conventional method. For example, cyanohydrin (XIX) can be isolated by washing the reaction solution with a saline solution after completion of the reaction and concentrating the organic layer obtained by liquid separation. Furthermore, cyanohydrin (XIX) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-2-2. Step (g-2b)
In the step (g-2b), for example, cyanohydrin (XIX) is represented by the general formula (XX): R ¹⁸ OH (wherein R ¹⁸ is as defined above) in the presence or absence of a solvent. It is realized by reacting with alcohol (hereinafter also referred to as alcohol (XX)) and hydrochloric acid.

  As the solvent that can be used in the step (g-2b), any solvent that does not inhibit this reaction may be used. Examples thereof include chloroform, dichloromethane, THF, and the like. These may be used alone or in combination of two or more. Also good. When using a solvent, the amount of use is usually 5 to 50 times the weight, preferably 8 to 20 times the weight of cyanohydrin (XIX).

  Specific examples of the alcohol (XX) include methanol, ethanol, and propanol, and methanol or ethanol is preferable. The usage-amount of alcohol (XX) is 0.1-50 equivalent normally with respect to cyanohydrin (XIX), Preferably it is 1-20 equivalent.

  Hydrochloric acid may be introduced into the reaction system as a gas, may be added as a solution of alcohol (XX), or may be generated in the system by adding acetyl chloride, trimethylsilyl chloride or the like. The usage-amount of hydrochloric acid is 2-50 equivalent normally with respect to cyanohydrin (XIX), Preferably it is 5-30 equivalent.

  A process (g-2b) is normally performed within the range of -20-30 degreeC (preferably 0-20 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  The imidate (XXI) obtained in the step (g-2b) can be isolated and purified by a conventional method, but can also be subjected to the next step without particular purification.

7-2-3. Step (g-2c)
Step (g-2c) is realized, for example, by reacting imidate (XXI) with compound (XVIIIa) in a solvent.

  As a solvent that can be used in the step (g-2c), any solvent that does not inhibit this reaction may be used. Examples thereof include ethanol, acetonitrile, THF, and the like. These may be used alone or in combination of two or more. Also good. The usage-amount of a solvent is 5-50 times weight normally with respect to imidate (XXI), Preferably it is 8-20 times weight.

  Specific examples of the compound (XVIIIa) include 2-aminophenol, 2-aminothiophenol, 2-amino-3-hydroxypyridine, methyl 3-amino-4-hydroxybenzoate, aminoethanol, and the like. Methyl 3-amino-4-hydroxybenzoate is preferred. The amount of compound (XVIIIa) to be used is generally 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to imidate (XXI).

  In the step (g-2c), a base may be added to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, and triethylamine is preferable. The usage-amount of the said base is 0.5-5 equivalent normally with respect to imidate (XXI), Preferably it is 1-3 equivalent.

  The step (g-2c) is usually performed within the range of the reflux temperature of the solvent used from 0 ° C. (preferably 30 ° C. to reflux). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-8 hours) within the said temperature range.

7-2-4. Step (g-2d)
In step (g-2d), for example, as shown in the following scheme, compound (IXa) is reacted with compound (XVIIIb) in a solvent to give a compound represented by general formula (XXII ′) (hereinafter referred to as compound ( This is also realized by deprotecting the silyl ether of the obtained compound (XXII ′).

(In the formula, each symbol and dotted line are as defined above.)

  As the solvent that can be used in the step (g-2d), any solvent that does not inhibit this reaction may be used. Examples thereof include dichloromethane, chloroform, THF, and the like. These may be used alone or in combination of two or more. Good. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (IXa).

Specific examples of the compound (XVIIIb) include 2-trimethylsilylthiazole and 2-trimethylsilyloxazole, and 2-trimethylsilylthiazole is preferable. The amount of compound (XVIIIb) to be used is generally 0.8-3 equivalents, preferably 1-1.5 equivalents, relative to compound (IXa).
Compound (XVIIIb) can be obtained by the method described in J. Org. Chem. 58, 3196 (1993), or a commercially available product may be used.

  A process (g-2d) is normally performed within 0-50 degreeC (preferably 10-30 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-8 hours) within the said temperature range.

The obtained compound (XXII ′) can be deprotected by adding an acid (eg, hydrochloric acid, methanesulfonic acid, etc.) or a fluoride salt (eg, tetra-n-butylammonium fluoride, etc.) to the reaction solution. .
The amount of the acid or fluoride salt to be used is generally 1-10 equivalents, preferably 1-3 equivalents, relative to compound (IXa).

  The deprotection reaction is usually performed within a range of 0 to 50 ° C. (preferably 10 to 30 ° C.). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 30 minutes-8 hours) within the said temperature range.

  Isolation and purification of compound (XXII) obtained in step (g-2c) or step (g-2d) can be carried out by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XXII) can be isolated. Further, the compound (XXII) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-2-5. Step (g-2e)
Step (g-2e) is a method of obtaining compound (XIb) by oxidizing compound (XXII) by various known methods (for example, Dess Martin reagent, Swan oxidation, Pfitzner-Moffatt oxidation, etc.).
Hereinafter, Pfitzner-Moffatt oxidation (see J. Med. Chem., 30, 1617-1622 (1987)), which is a preferred embodiment, will be described, but the step (g-2e) is not limited thereto. .

  The Pfitzner-Moffatt oxidation in the step (g-2e) is realized by reacting the compound (XXII) with a carbodiimide condensing agent and an acid in, for example, dimethyl sulfoxide and another solvent.

  As the solvent that can be used in the oxidation reaction, any solvent that does not inhibit this reaction may be used. Examples thereof include toluene, chloroform, dichloromethane, and the like, and these may be used alone or in combination of two or more. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XXII).

  The amount of dimethyl sulfoxide to be used is generally 2-100 equivalents, preferably 2-80 equivalents, relative to compound (XXII).

  Examples of the carbodiimide condensing agent include N, N'-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), and EDC is preferable. The usage-amount of a carbodiimide type condensing agent is 1-5 equivalent normally with respect to compound (XXII), Preferably it is 1-3 equivalent.

  Examples of the acid include dichloroacetic acid and chloroacetic acid, and dichloroacetic acid is preferable. The amount of the acid to be used is generally 0.8 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (XXII).

  The said oxidation reaction is normally performed within 0-30 degreeC (preferably 0-20 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-5 hours) within the said temperature range.

7-3. When R ⁸ is a hydrogen atom and Y is an optionally substituted acyl group (hereinafter also referred to as step (g-3)).
When R ⁸ is a hydrogen atom, R ⁸ (hydrogen atom) of compound (IX) is substituted by the following steps (g-3a) to (g-3g) according to the method described in Patent Document 2. It can convert into the acyl group which may have a group.

That is, as shown in the reaction scheme below,
Step (g-3a): Compound (IXa) or a salt thereof is converted to cyanohydrin (XIX) or a salt thereof by the same method as in Step (g-2a);
Step (g-3b): By hydrolyzing the obtained cyanohydrin (XIX) or a salt thereof, a compound represented by the general formula (XXIII) (hereinafter also referred to as compound (XXIII)) or a salt thereof is obtained. ;
Step (g-3c): The obtained compound (XXIII) or a salt thereof is reacted with N, O-dimethylhydroxylamine or a salt thereof to give a compound represented by the general formula (XXIV) (hereinafter referred to as compound (XXIV) Or a salt thereof;
Step (g-3d): A compound represented by the general formula (XXV) (hereinafter also referred to as compound (XXV)) or a salt thereof by forming an oxazolidine ring in the obtained compound (XXIV) or a salt thereof. Obtain;
Step (g-3e): The obtained compound (XXV) or a salt thereof is reacted with a reagent represented by the general formula (XVIIb) (hereinafter also referred to as a reagent (XVIIb)) to give a compound represented by the general formula (XXVI) A compound represented by the formula (hereinafter also referred to as compound (XXVI)) or a salt thereof;
Step (g-3f): A compound represented by the general formula (XXVII) (hereinafter also referred to as compound (XXVII)) or a compound thereof by opening the oxazolidine ring of the obtained compound (XXVI) or a salt thereof. Obtaining salt;
Step (g-3g): By oxidizing the obtained compound (XXVII) or a salt thereof, a compound represented by the general formula (XIc) in which Y is an acyl group optionally having substituent (s) , Compound (XIc)).

(Wherein R ¹⁹ represents a group formed by removing a carbonyl group from an acyl group which may have a substituent represented by Y, and other symbols are as defined above.)
Examples of the “group formed by removing a carbonyl group from an optionally substituted acyl group” in R ¹⁹ include a 3- (2-pyridyloxy) propyl group.

7-3-1. Step (g-3a)
In step (g-3a), cyanohydrin (XIX) is obtained from compound (IXa) by the same method as in step (g-2a).

7-3-2. Step (g-3b)
Step (g-3b) is realized, for example, by hydrolyzing cyanohydrin (XIX) with an acid in a solvent.

  As the solvent that can be used in the step (g-3b), any solvent that does not inhibit this reaction may be used. Examples thereof include 1,4-dioxane, THF, MTBE, and the like. You may use together. The usage-amount of a solvent is 5-50 times weight normally with respect to cyanohydrin (XIX), Preferably it is 8-20 times weight.

  Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like, and hydrochloric acid is preferable. The usage-amount of an acid is 3-100 equivalent normally with respect to cyanohydrin (XIX), Preferably it is 5-30 equivalent.

  The step (g-3b) is usually performed within the range of the reflux temperature of the solvent used from 0 ° C (preferably 5 to 60 ° C). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of the compound (XXIII) obtained in the step (g-3c) can be performed by a conventional method. For example, after completion of the reaction, the compound (XXIII) can be isolated by washing the reaction solution with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and concentrating the organic layer obtained by liquid separation. Further, the compound (XXIII) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-3-3. Step (g-3c)
Step (g-3c) is realized by, for example, condensing compound (XXIII) and N, O-dimethylhydroxylamine with a condensing agent in a solvent.

  As the solvent that can be used in the step (g-3c), any solvent that does not inhibit this reaction may be used. Examples thereof include dichloromethane, THF, diethyl ether, and the like. These may be used alone or in combination of two or more. Also good. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XXIII).

  Examples of the condensing agent include carbodiimide condensing agents (for example, DCC, EDC, etc.), chloroformates (for example, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, etc.) and the like.

  The said condensation reaction is normally performed within the range of -20-20 degreeC (preferably 0-10 degreeC). The said reaction is normally complete | finished in 15 minutes-16 hours (preferably 0.5 hour-2 hours) within the said temperature range.

  Isolation and purification of compound (XXIV) obtained in step (g-3c) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XXIV) can be isolated. Further, the compound (XXIV) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-3-4. Step (g-3d)
Step (g-3d) is realized, for example, by reacting compound (XXIV) with acetone dimethyl acetal in the presence of an acid in a solvent or without a solvent.

  The solvent that can be used in the step (g-3d) may be any solvent as long as it does not inhibit this reaction. Examples thereof include acetone, ethyl acetate, THF, and the like. These may be used alone or in combination of two or more. Also good. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XXIV).

  The amount of acetone dimethyl acetal to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (XXIV).

  Examples of the acid include p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and the like, and p-toluenesulfonic acid is preferable. The amount of the acid to be used is generally 0.1-3 equivalents, preferably 0.3-2 equivalents, relative to compound (XXIV).

  The step (g-3d) is usually performed within a range of −20 to 40 ° C. (preferably 0 to 20 ° C.). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of the compound (XXV) obtained in the step (g-3d) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an alkaline aqueous solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the resulting organic layer is concentrated. Thus, compound (XXV) can be isolated. Further, the compound (XXV) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-3-5. Step (g-3e)
Step (g-3e) is realized, for example, by reacting compound (XXV) with reagent (XVIIb) in a solvent.

  As the solvent that can be used in the step (g-3e), any solvent that does not inhibit this reaction may be used. For example, an ether solvent (eg, THF, diethyl ether, MTBE, etc.), a halogen solvent (eg, chloroform, dichloromethane, etc.) These may be used alone or in combination of two or more. The usage-amount of a solvent is 5-50 times weight normally with respect to compound (XXV), Preferably it is 8-20 times weight.

Reagent (XVIIb) is the same as reagent (XVIIa) in the above-mentioned step (g-1) from a compound represented by general formula R ¹⁹ -X (wherein each symbol is as defined above). For example, 3- (2-pyridyloxy) propylmagnesium bromide, 3- (2-pyridyloxy) propyllithium and the like are preferable. The amount of reagent (XVIIb) to be used is generally 1-5 equivalents, preferably 1-3 equivalents, relative to compound (XXV).

  The step (g-3e) is usually performed within a range of −80 to 40 ° C. (preferably −78 to 20 ° C.). The said reaction is normally complete | finished in 15 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of the compound (XXVI) obtained in the step (g-3e) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XXVI) can be isolated. Further, the compound (XXVI) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-3-6. Step (g-3f)
Step (g-3f) is realized, for example, by reacting compound (XXVI) with an acid in a solvent.

  As the solvent that can be used in the step (g-3f), any solvent that does not inhibit this reaction may be used. Examples thereof include water, methanol, ethanol, and the like, and these may be used alone or in combination of two or more. Good. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XXVI).

  Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and p-toluenesulfonic acid and sulfuric acid are preferable. The amount of the acid to be used is generally 0.2-30 equivalents, preferably 1-20 equivalents, relative to compound (XXVI).

  Step (g-3f) is usually performed within the range of the reflux temperature of the solvent used from 20 ° C. The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 3 hours-16 hours) within the said temperature range.

  Isolation and purification of compound (XXVII) obtained in step (g-3f) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XXVII) can be isolated. Further, the compound (XXVII) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-3-7. Step (g-3g)
In step (g-3g), compound (XXVII) can be converted to compound (XIc) by the same method as in step (g-2e) (for example, Dess Martin reagent, Swan oxidation, Pfitzner-Moffatt oxidation, etc.) it can.

7-4. When R ⁸ is a hydroxyl group and Y is a trifluoromethyl group (hereinafter also referred to as step (g-4)).
When R ⁸ is a hydroxyl group, according to the method described in Tetrahedron Lett., 36 (42), 7761-7764 (1995), the following steps (g-4a) to (g-4d) R ⁸ (hydroxyl group) of IX) can be converted into a trifluoromethyl group.

That is, as shown in the following scheme:
Step (g-4a): a compound represented by general formula (IXb) wherein R ⁸ is a hydroxyl group (hereinafter also referred to as compound (IXb)) or a salt thereof and general formula (XXVIII): R ²⁰ CHO (wherein , R ²⁰ represents a hydrogen atom, an alkyl group (for example, a methyl group, an ethyl group, etc.), an aryl group (for example, a p-methoxyphenyl group, etc.) which may have a substituent. An aldehyde (hereinafter also referred to as aldehyde (XXVIII)) is reacted to obtain a compound represented by the general formula (XXIX) (hereinafter also referred to as compound (XXIX)) or a salt thereof;
Step (g-4b): The compound (XXIX) or a salt thereof obtained is reacted with trimethyl (trifluoromethyl) silane to give a compound represented by the general formula (XXX) (hereinafter also referred to as compound (XXX)). ) Or a salt thereof;
Step (g-4c): A compound represented by general formula (XXXI) (hereinafter also referred to as compound (XXXI)) or a salt thereof by deprotecting the trimethylsilyl group of the obtained compound (XXX) or a salt thereof. Obtain;
Step (g-4d): The compound represented by the general formula (XId) in which Y is a trifluoromethyl group by opening the oxazolidine ring of the obtained compound (XXXI) or a salt thereof (hereinafter referred to as the compound ( XId))) can be obtained.

(In the formula, each symbol is as defined above.)

7-4-1. Step (g-4a)
Step (g-4a) is realized, for example, by subjecting compound (IXb) and aldehyde (XXVIII) to a dehydration reaction in a solvent in the presence of an acid. The dehydration reaction can be performed, for example, by using a Dean-Stark tube to azeotrope water and solvent from the system and return only the solvent to the system.

  Examples of the solvent that can be used in the step (g-4a) include benzene, toluene, chloroform, diethyl ether, acetonitrile, and the like, and these may be used alone or in combination of two or more. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (IXb).

  Examples of the acid include p-toluenesulfonic acid and methanesulfonic acid, and p-toluenesulfonic acid is preferable. The amount of the acid to be used is generally 0.01-5 equivalents, preferably 0.03-1 equivalents, relative to compound (IXb).

  Examples of the aldehyde (XXVIII) include paraformaldehyde and acetaldehyde, and paraformaldehyde is preferable. The amount of aldehyde (XXVIII) to be used is generally 1-5 equivalents, preferably 1-3 equivalents, relative to compound (IXb).

  Step (g-4a) is usually performed at the reflux temperature of the solvent used. The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of compound (XXIX) obtained in step (g-4a) can be carried out by a conventional method. For example, after completion of the reaction, the compound (XXIX) can be isolated by washing the reaction solution with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and concentrating the organic layer obtained by liquid separation. Further, the compound (XXIX) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-4-2. Step (g-4b)
Step (g-4b) is realized, for example, by reacting compound (XXIX) with trimethyl (trifluoromethyl) silane in the presence of a fluoride salt in a solvent. In this case, it is preferable to apply ultrasonic waves to the reaction system in order to promote the reaction.

  The solvent that can be used in the step (g-4b) may be any solvent that does not inhibit this reaction, and examples thereof include THF, MTBE, and the like. These may be used alone or in combination of two or more. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XXIX).

  Examples of the fluoride salt include cesium fluoride and tetra-n-butylammonium fluoride, and cesium fluoride is preferable. The amount of the fluoride salt used may be a catalytic amount, usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (XXIX).

  The amount of trimethyl (trifluoromethyl) silane to be used is generally 0.8-5 equivalents, preferably 1-2 equivalents, relative to compound (XXIX).

  A process (g-4b) is normally performed within 0-80 degreeC (preferably 5-40 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of the compound (XXX) obtained in the step (g-4b) can be performed by a conventional method. For example, after completion of the reaction, the compound (XXX) can be isolated by washing the reaction solution with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and concentrating the organic layer obtained by liquid separation. Further, the compound (XXX) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-4-3. Step (g-4c)
Step (g-4c) is realized, for example, by treating compound (XXX) with a fluoride salt in a solvent. In this case, it is preferable to apply ultrasonic waves to the reaction system in order to promote the reaction.

  As the solvent that can be used in the step (g-4c), any solvent that does not inhibit this reaction may be used. Examples thereof include THF, MTBE, dichloromethane, chloroform, and the like. These may be used alone or in combination of two or more. May be. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 12 times weight, with respect to compound (XXX).

  Examples of the fluoride salt include cesium fluoride and tetra-n-butylammonium fluoride, and cesium fluoride is preferable. The amount of the fluoride salt to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (XXX).

  A process (g-4c) is normally performed within 0-80 degreeC (preferably 0-40 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of compound (XXXI) obtained in step (g-4c) can be performed by a conventional method. For example, after completion of the reaction, the compound (XXXI) can be isolated by washing the reaction solution with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and concentrating the organic layer obtained by liquid separation. Further, the compound (XXXI) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

7-4-4. Step (g-4d)
Step (g-4d) is realized, for example, by treating compound (XXXI) with an acid in a solvent.

  As the solvent that can be used in the step (g-4d), any solvent that does not inhibit this reaction may be used. Examples thereof include acetonitrile, THF, ethyl acetate, chloroform, and the like. These may be used alone or in combination of two or more. May be. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XXXI).

  Examples of the acid include strongly acidic ion exchange resins (for example, Amberlite (registered trademark) R-120, Amberlyst (registered trademark), etc.), and strong acid ion exchange resins are preferred. The amount of the acid to be used is generally 0.1 to 100 times weight, preferably 0.5 to 20 times weight, relative to compound (XXXI).

  A process (g-4d) is normally performed within 0-80 degreeC (preferably 20-50 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

7-5. When R ⁸ is a hydrogen atom and Y is a trifluoromethyl group (hereinafter also referred to as step (g-5)).
When R ⁸ is a hydroxyl group, according to the method described in Tetrahedron Lett., 36 (42), 7761-7764 (1995), the following steps (g-5a) to (g-5c) IX) R ⁸ (hydrogen atom) can be converted to a trifluoromethyl group.

That is, as shown in the following scheme:
Step (g-5a): The compound (IXa) or a salt thereof is reacted with trimethyl (trifluoromethyl) silane to obtain a compound represented by the general formula (XXXII) or a salt thereof;
Step (g-5b): The trimethylsilyl group of the obtained compound represented by the general formula (XXXI) or a salt thereof is deprotected to obtain a compound represented by the general formula (XXXIII) or a salt thereof;
Step (g-5c): The compound (XId) can be obtained by oxidizing the obtained compound represented by the general formula (XXXIII) or a salt thereof.

(In the formula, each symbol is as defined above.)
The step (g-5a) is the same as the step (g-4b), the step (g-5b) is the same as the step (g-4c), and the step (g-5c) is the same as the step (g-2e). Can be done.

  As described above, the isolation and purification of the compound (XI) obtained in the steps (g-1) to (g-5) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XI) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), acetic esters (eg, ethyl acetate, butyl acetate, etc.), water or a mixed solvent thereof, etc.) are added for crystallization or silica gel Compound (XI) can be purified by subjecting it to column chromatography, but is not limited thereto.

8). Step (h)
In step (h), when R ⁶ in compound (VI) is other than a hydrogen atom, compound (VI) or a salt thereof is converted to a carboxylic acid form, and then condensed with compound (XII) to give compound (XI) Or a salt thereof.
Step (h) has the advantage that compound (XI) can be produced in a short process by directly condensing compound (VI) and compound (XII).

When R ⁶ of compound (VI) is other than a hydrogen atom, that is, an alkyl group or an aralkyl group, it is first converted to a carboxylic acid form by the same method as in step (d).

  As a method of condensing the carboxylic acid compound and the compound (XII), the compound (XII) or a salt thereof is used in place of the N-hydroxysuccinimide in the method of condensing the carboxylic acid compound and N-hydroxysuccinimide in the step (d). The same conditions can be used.

That is, as a preferred embodiment, compound (XI) can be produced by activating a carboxylic acid form with a activating agent in a solvent and then condensing with compound (XII) or a salt thereof.
Although the said aspect is demonstrated below, a process (h) is not limited to this aspect at all.

Examples of the activator include the same ones as in step (d), and chloroformates, particularly ethyl chloroformate, methyl chloroformate, isobutyl chloroformate, and the like are preferable.
The usage-amount of an activator is 0.9-1.5 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.2 equivalent.

When activating the carboxylic acid form, a base may be added as necessary. Examples of such a base include the same bases as in step (d), and N-methylmorpholine, triethylamine, and pyridine are preferable.
The usage-amount of the said base is 0.9-2 equivalent normally with respect to a carboxylic acid body, Preferably it is 1-1.3 equivalent.

  The solvent used for the activation of the carboxylic acid form may be any solvent as long as it does not inhibit this reaction. For example, acetate esters (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.) , Hydrocarbons (for example, toluene, benzene, xylene, etc.), acetonitrile, THF, halogen-based solvents (for example, dichloromethane, dichloroethane, etc.) and the like. These may be used alone or in combination of two or more. Single or mixed solvents such as acetonitrile and THF are more preferable. The usage-amount of a solvent is 3-50 times weight normally with respect to a carboxylic acid body, Preferably it is 5-20 times weight.

  Activation of a carboxylic acid body is normally performed within the range of -30-40 degreeC (preferably 0-30 degreeC). The activation is usually completed within 5 minutes to 5 hours (preferably 10 minutes to 2 hours) within the above temperature range.

After activation of the carboxylic acid form, compound (XII) is added to the reaction mixture. The order of addition may be reversed or simultaneous.
The amount of compound (XII) to be used is generally 0.9 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to the carboxylic acid form.

When compound (XII) is in the form of a salt, it is preferable to add a base similar to the base used for activating the carboxylic acid form for neutralization.
The amount of the base to be used is generally 0.9 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (XII).

  The condensation with the compound (XII) is usually performed within a range of −30 to 40 ° C. (preferably −20 to 30 ° C.). The condensation is usually completed within 0.5 to 5 hours (preferably 1 to 3 hours) within the above temperature range.

  Isolation and purification of compound (XI) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XI) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or mixed solvents thereof, etc.) are added to crystallize or purify compound (XI) by silica gel column chromatography. However, it is not limited to these.

Compound (XII) which is a raw material of the step (h) is prepared by using the compound (VIII) as a raw material and protecting the amino group with a benzyloxycarbonyl group or a tert-butoxycarbonyl group by a known method, and then the step (g) It can be synthesized by converting the group represented by R ⁸ to the group represented by Y by the same method as described above and then deprotecting by a known method.

9. Step (i)
In step (i), P—C (═O) — (wherein P is as defined above) at the 5-position of the pyrimidine ring of compound (IX) is deprotected to give compound (X) or its This is a method for obtaining a salt.
For the deprotection reaction, a method known to those skilled in the art, for example, the amide deprotection method described in Non-Patent Document 1 can be applied without limitation, but in order to avoid side reactions such as decomposition, it is mild. These conditions are preferable.

  As a preferable aspect of process (i), (1) Deprotection by an enzyme reaction [Hereafter, it is also called process (i-1). ] Or (2) Deprotection under acidic conditions [hereinafter also referred to as step (i-2). ]. Hereinafter, the step (i-1) and the step (i-2) will be described in detail, but the step (i) is not limited to these embodiments.

9-1. Step (i-1)
In step (i-1), compound (X) can be produced by deprotection, for example, by reacting compound (IX) with an enzyme in a solvent.

The enzyme used in the step (i-1) is any enzyme that can deprotect P—C (═O) — (wherein P is as defined above) at the 5-position of the pyrimidine ring. There are no particular limitations, and examples include conventionally known enzymes derived from microorganisms such as bacteria, actinomycetes, fungi, or animals and plants, such as penicillin amidase, penicillin acylase, and the like.
In addition, it is preferable to use an enzyme immobilized on a resin or the like because it can be easily separated from a compound and easily reused. As these enzymes or immobilized enzymes, commercially available products can be used.

  The amount of the enzyme or microbial cell treatment solution used may be an amount (effective amount) that exhibits the intended effect, and this effective amount can be easily determined by a person skilled in the art by a simple preliminary test. In the case of a product enzyme solution, the amount is 0.01 ml to 2 ml with respect to 1 g of compound (IX) as a substrate.

  The protecting group of the starting compound (IX) may be appropriately selected depending on the substrate characteristics of the enzyme used. In the case of penicillin amidase, which is a suitable enzyme, P is benzyl, phenylacetyl group is preferable.

  As the solvent that can be used in the step (i-1), water or a hydrophilic solvent can be mixed with water as long as the enzyme activity is not impaired, and it is preferable to use only water. As the hydrophilic solvent, one or more of N, N-dimethylformamide, dimethyl sulfoxide, THF, acetone and the like can be used. The usage-amount of a solvent is 5-200 times weight normally with respect to compound (IX), Preferably it is 10-100 times weight.

The solvent is preferably adjusted to a pH optimum for the enzyme (for example, about pH 6 to 8) with a buffer component such as potassium dihydrogen phosphate and potassium monohydrogen phosphate.
The concentration of the buffer component in the solvent is not particularly limited as long as it does not inhibit the enzyme reaction, but is about 0.001M to 0.2M.
Moreover, you may adjust pH by adding a base suitably etc. during reaction.

  In step (i-1), a surfactant may be added as needed to promote the reaction. Examples of such a surfactant include Triton X-100 (Triton X-100 (registered trademark)) and Tween (Tween (registered trademark)), and Triton X-100 is preferable. The amount of the surfactant used is usually 0.001 to 0.05 times by weight, preferably 0.01 to 0.05 times by weight, relative to compound (IX).

  Step (i-1) is usually performed within a range of 20 to 50 ° C (preferably 30 to 40 ° C). The reaction is usually completed within 30 minutes to 1 week (preferably 1 hour to 20 hours) within the above temperature range.

  After completion of the reaction, the obtained compound (X) can be separated from the enzyme by a conventional method. For example, in the case of an immobilized enzyme, the compound (X) can be separated into the filtrate by adding a soluble solvent (for example, acetonitrile) of the compound (X) as necessary and filtering. In the case of an enzyme that is not immobilized, compound (X) can be separated as a filtrate by adding water to the reaction mixture as necessary to precipitate compound (X) and filtering. However, it is not limited to these.

  The separated compound (X) is, for example, a crystallization solvent (eg, ethers (eg, diethyl ether, THF), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.). , Adding a halogenated solvent (for example, dichloromethane, dichloroethane, etc.), alcohols (for example, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc. to cause crystallization, or subjecting to silica gel column chromatography Can purify the compound (X), but is not limited thereto.

9-2. Step (i-2)
In step (i-2), compound (X) can be produced by deprotection by adding an acid to compound (IX) for reaction in a solvent, for example. The order of addition may be reversed or simultaneous.

  The solvent that can be used in the step (i-2) may be any solvent that does not inhibit this reaction. However, when an acid is used, at least a protic solvent such as water or alcohol is present. is necessary. Examples of the solvent include acetates (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.), hydrocarbons (for example, toluene, benzene, xylene, etc.), acetonitrile, THF, alcohols (for example, , Methanol, ethanol, isopropyl alcohol, n-butanol, etc.), N, N-dimethylformamide, etc., and these may be used alone or in combination of two or more, methanol, ethanol, acetonitrile, isopropyl alcohol, water Among them, methanol, acetonitrile, water or the like alone or a mixed solvent is preferable. The amount of the solvent to be used is generally 3 to 50 times weight, preferably 5 to 20 times weight, relative to compound (IX).

  Examples of the acid used in the step (i-2) include inorganic acids (for example, hydrochloric acid, sulfuric acid, etc.), organic acids (for example, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc.), preferably hydrochloric acid. Etc.

The amount of the acid to be used is generally 1-50 equivalents, preferably 3-10 equivalents, relative to compound (IX).
The acid is preferably used as a solution of the solvent to be used, and may be added so that the amount of the solvent and acid used is within the above range.

  Step (i-2) is usually performed within the range of the reflux temperature (preferably 20 to 60 ° C.) of the solvent used from 0 ° C. The reaction is usually completed within 60 minutes to overnight (preferably 1 hour to 5 hours) within the above temperature range.

  After completion of the reaction, compound (X) is present in the reaction mixture in the form of a salt with the acid used. Therefore, the acid addition salt can be isolated by concentrating the reaction mixture. The isolated acid addition salt can be added to a crystallization solvent (eg, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen The acid addition salt of compound (X) is crystallized by adding a system solvent (eg, dichloromethane, dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, and the like. Can be purified.

  In order to isolate the free form of compound (X), alkali is added in a protic solvent such as water or alcohol, or after completion of the reaction, the reaction solution is washed with an aqueous alkaline solution (for example, saturated aqueous sodium hydrogen carbonate, brine, etc.). The compound (X) can be isolated by concentrating the organic layer obtained by washing and liquid separation. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (for example, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc.) are added for crystallization, or subjected to silica gel column chromatography to give the compound (X) Although a free body can be refine | purified, it is not limited to these.

Compound (X) produced in step (i) is a novel compound, and is useful as a highly versatile synthetic intermediate for producing other enzyme inhibitors in addition to compound (XV) (J. Med. Chem., 2001, 44, 1286-1296).
For example, compound (XV) can be produced by steps (j), (k) and (l) described below.

10. Step (j)
In step (j), compound (XIII) or a compound thereof is protected by protecting the amino group of compound (X) other than an acyl group by a known method, for example, the method listed on page 309 and thereafter of Non-Patent Document 1. This is a method for obtaining a salt.

  Hereinafter, the protection by the Cbz group, which is a preferred embodiment of the step (j), will be described, but the step (j) is not limited thereto.

  The protection by the Cbz group is realized, for example, by reacting the compound (X) with a benzyloxycarbonylating agent (hereinafter referred to as Cbzating agent) in a solvent.

  The solvent that can be used in the protection reaction may be any solvent as long as it does not inhibit this reaction. Examples thereof include water, acetonitrile, ethyl acetate, THF, chloroform, and the like. These may be used alone or in combination of two or more. May be. The usage-amount of a solvent is 5-50 times weight normally with respect to compound (X), Preferably it is 8-20 times weight.

  Examples of the Cbz agent include benzyloxycarbonyl chloride. The amount of the Cbz agent to be used is generally 0.9 to 2 equivalents, preferably 1 to 1.3 equivalents, relative to compound (X).

  In the protection reaction, a base (for example, sodium hydroxide, triethylamine, pyridine, sodium carbonate, etc.) may be added. The amount of the base to be used is generally 0.9 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (X).

  The said protection reaction is normally performed within the range of -20-40 degreeC (preferably 0-20 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of the resulting compound (XIII) can be performed by a conventional method. For example, after completion of the reaction, the reaction solution is washed successively with an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, etc.) and an aqueous alkaline solution (eg, saturated aqueous sodium bicarbonate, brine, etc.), and the organic layer obtained by liquid separation is concentrated. Thus, compound (XIII) can be isolated. Further, the compound (XIII) can be purified by crystallization or silica gel column chromatography, but is not limited thereto.

11. Step (k)
The step (k) is a step of obtaining the compound (XIV) or a salt thereof by converting the group represented by R ⁸ of the compound (XIII) or a salt thereof into a group represented by Y.
Step (k) can be carried out under the same method and reaction conditions as in step (g) above.

12 Step (l)
In the step (l), the protecting group Q of the compound (XIV) or a salt thereof is deprotected by a known method, for example, the method listed on page 309 and thereafter of Non-Patent Document 1, to thereby give the compound (XV) or a compound thereof. This is a method for obtaining a salt.

  The deprotection when Q is a Cbz group, which is a preferred embodiment of the step (l), will be described below, but the step (l) is not limited thereto.

  The deprotection reaction of the Cbz group is realized, for example, by hydrogenolysis of the compound (XIV) in a solvent.

  As the solvent that can be used in the hydrogenolysis reaction, any solvent that does not inhibit this reaction may be used, and examples thereof include ethanol, methanol, isopropanol, ethyl acetate, THF, and the like. You may use together. The amount of the solvent to be used is generally 5 to 50 times weight, preferably 8 to 20 times weight, with respect to compound (XIV).

  Examples of the catalyst used in the hydrocracking reaction include palladium carbon and palladium hydroxide. The usage-amount of the said catalyst is 0.01-0.5 times weight normally with respect to compound (XIV), Preferably it is 0.05-0.2 times weight.

  In the hydrocracking reaction, an acid (for example, hydrochloric acid, methanesulfonic acid, etc.) may be added to promote the reaction. The amount of the acid to be used is generally 0.05 to 1.5 equivalents, preferably 0.1 to 1 equivalents, relative to compound (XIV).

  The said reaction is normally performed within the range of 10-80 degreeC (preferably 20-50 degreeC). The said reaction is normally complete | finished in 30 minutes-24 hours (preferably 1 hour-16 hours) within the said temperature range.

  Isolation and purification of the resulting compound (XV) can be performed by a conventional method. For example, after completion of the reaction, the catalyst is removed by filtration or the like, and alkali is added in a protic solvent such as water or alcohol, or it is washed with an alkaline aqueous solution (for example, saturated sodium bicarbonate water, saline solution) and separated. By concentrating the obtained organic layer, compound (XV) can be isolated. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc.) are added for crystallization, or subjected to silica gel column chromatography to give the compound (XV). Although a free body can be refine | purified, it is not limited to these.

13. Process (m)
In step (m), P—C (═O) — (wherein P is as defined above) at the 5-position of the pyrimidine ring of compound (XI) is deprotected to give compound (XV) or its This is a method for obtaining a salt.
For the deprotection reaction, a method known to those skilled in the art, for example, the amide deprotection method described in Non-Patent Document 1 can be applied without limitation, but in order to avoid side reactions such as decomposition, it is mild. It is preferable to carry out under various conditions, for example, the same conditions as in step (i) above.

  As a preferred embodiment of the step (m), as in the step (i), (1) deprotection by enzymatic reaction [hereinafter also referred to as step (m-1). ] Or (2) Deprotection under acidic conditions [hereinafter also referred to as step (m-2). ]. Hereinafter, the step (m-1) and the step (m-2) will be described in detail, but the step (m) is not limited to these embodiments.

13-1. Step (m-1)
In the step (m-1), the compound (XV) can be produced by deprotecting, for example, by reacting the compound (XI) with an enzyme in a solvent.

Examples of the enzyme used in the step (m-1) include those similar to those in the step (i-1), and penicillin amidase, penicillin acylase and the like are preferable.
Moreover, it is preferable to use what was fixed to resin etc. as an enzyme like a process (i-1).

  The amount of the enzyme or microbial cell treatment solution used may be an amount (effective amount) that exhibits the intended effect, and this effective amount can be easily determined by a person skilled in the art by a simple preliminary test. In the case of a product enzyme solution, the amount is 0.01 ml to 2 ml with respect to 1 g of compound (XI) as a substrate.

  The protecting group of the starting compound (XI) may be appropriately selected depending on the substrate characteristics of the enzyme used. In the case of penicillin amidase which is a suitable enzyme, P is benzyl, and phenylacetyl is preferred. .

  As a solvent that can be used in the step (m-1), water or a hydrophilic solvent can be mixed with water as long as the enzyme activity is not impaired, and it is preferable to use only water. As a suitable hydrophilic solvent, one or more of dimethyl sulfoxide, acetone and the like can be used. The usage-amount of a solvent is 5-200 times weight normally with respect to compound (XI), Preferably it is 10-100 times weight.

The solvent is preferably adjusted to a pH optimum for the enzyme (for example, about pH 6 to 8) with a buffer component such as potassium dihydrogen phosphate and potassium monohydrogen phosphate.
The concentration of the buffer component in the solvent is not particularly limited as long as it does not inhibit the enzyme reaction, but is about 0.001M to 0.2M.
Moreover, you may adjust pH by adding a base suitably during reaction.

  In the step (m-1), a surfactant may be added as necessary to promote the reaction. Examples of such a surfactant include Triton X-100 (Triton X-100 (registered trademark)) and Tween (Tween (registered trademark)), and Triton X-100 is preferable. The amount of the surfactant used is usually 0.001 to 0.05 times by weight, preferably 0.01 to 0.05 times by weight, relative to compound (IX).

  A process (m-1) is normally performed within the range of 20-50 degreeC (preferably 30-40 degreeC). The reaction is usually completed within 30 minutes to 1 week (preferably 1 hour to 20 hours) within the above temperature range.

  After completion of the reaction, the obtained compound (XV) can be separated from the enzyme by a conventional method. For example, in the case of an immobilized enzyme, the compound (XV) can be separated into the filtrate by adding a soluble solvent (for example, acetonitrile) of the compound (XV) as necessary and filtering. In the case of an enzyme that is not immobilized, the compound (XV) can be separated as a filtrate by adding water to the reaction mixture as necessary to precipitate the compound (XV) and filtering. However, the present invention is not limited to this.

  The separated compound (XV) is, for example, a crystallization solvent (eg, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.) , Adding a halogenated solvent (for example, dichloromethane, dichloroethane, etc.), alcohols (for example, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc. to cause crystallization, or subjecting to silica gel column chromatography Can purify compound (XV), but is not limited thereto.

13-2. Step (m-2)
In the step (m-2), the compound (XV) can be produced by deprotection by adding an acid to the compound (XI) for reaction in a solvent, for example. The order of addition may be reversed or simultaneous.

  The solvent that can be used in the step (m-2) may be any solvent that does not inhibit this reaction. However, when an acid is used, at least a protic solvent such as water or alcohol is present. is necessary. Examples of the solvent include acetates (for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, etc.), hydrocarbons (for example, toluene, benzene, xylene, etc.), acetonitrile, THF, alcohols (for example, , Methanol, ethanol, isopropyl alcohol, n-butanol, etc.), N, N-dimethylformamide, etc., and these may be used alone or in combination of two or more, methanol, ethanol, acetonitrile, isopropyl alcohol, water Among them, methanol, acetonitrile, water or the like alone or a mixed solvent is preferable. The usage-amount of a solvent is 3-50 times weight normally with respect to compound (XI), Preferably it is 5-20 times weight.

  Examples of the acid used in the step (m-2) include inorganic acids (for example, hydrochloric acid, sulfuric acid, etc.), organic acids (for example, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc.), and preferably hydrochloric acid. Etc.

The usage-amount of an acid is 1-50 equivalent normally with respect to compound (XI), Preferably it is 3-10 equivalent.
The acid is preferably used as a solution of the solvent to be used, and may be added so that the amount of the solvent and acid used is within the above range.

  The step (m-2) is usually performed within the range of the reflux temperature of the solvent used from 0 ° C (preferably 20 to 60 ° C). The reaction is usually completed within 60 minutes to overnight (preferably 1 hour to 5 hours) within the above temperature range.

  After completion of the reaction, compound (XV) is present in the reaction mixture in the form of a salt with the acid used. Therefore, the acid addition salt can be isolated by concentrating the reaction mixture. The isolated acid addition salt can be added to a crystallization solvent (eg, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen The acid addition salt of compound (XV) is crystallized by adding a system solvent (for example, dichloromethane, dichloroethane, etc.), alcohols (for example, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, and the like. Can be purified.

  In order to isolate the free form of compound (XV), alkali is added in a protic solvent such as water or alcohol, or after the reaction is completed, the reaction solution is washed with an alkaline aqueous solution (for example, saturated aqueous sodium bicarbonate solution, saline solution, etc.). Compound (XV) can be isolated by concentrating the organic layer obtained by washing and liquid separation. Further, crystallization solvents (for example, ethers (eg, diethyl ether, THF, etc.), acetone, acetonitrile, hydrocarbon solvents (eg, toluene, benzene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane) , Dichloroethane, etc.), alcohols (eg, methanol, ethanol, isopropanol, etc.), water or a mixed solvent thereof, etc.) are added for crystallization, or subjected to silica gel column chromatography to give the compound (XV). Although a free body can be refine | purified, it is not limited to these.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Reference example 1
4- (N, N-dimethylaminomethylene) -2-methyl-5-oxazolinone N-acetylglycine (20.0 g, 171 mmol) was added to phosphorus oxychloride (67.0 g, 437 mmol) and N, N-dimethylformamide ( 33.0 g, 451 mmol) was added in an ice bath and stirred at 45 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure and added dropwise to 28% aqueous ammonia (150 ml) while maintaining the temperature at 10 ° C. or lower. The mixture was stirred for 1 hour in an ice bath and the precipitate was collected by filtration. The obtained crystals were washed successively with water and ethanol and dried to give the title compound crystals (20.2 g, 131 mmol).

¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.18 (3H, m), 3.47 (3H, s), 6.96 (1H, s).
MS (ESI) m / z [MH] + 155.2

Reference example 2
2-Benzyl-4- (N, N-dimethylaminomethylene) -5-oxazolinone Phenacetic acid (10.0 g, 51.8 mmol) in chloroform (30.0 ml), phosphorus oxychloride (20.0 g, 130 mmol) and N , N-dimethylformamide (10.0 g, 137 mmol) was added in an ice bath and stirred at 45 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure and added dropwise to 28% aqueous ammonia (65 ml) while maintaining the temperature at 10 ° C. or lower. The mixture was extracted with chloroform, and the organic layer was washed with water and saturated brine, and concentrated to dryness. The concentrate was washed with isopropyl alcohol, and the precipitate was filtered, washed with isopropyl alcohol and dried to give the title compound as crystals (9.90 g, 43.3 mmol).

¹ H-NMR (CDCl ₃ ) δ: 3.17 (3H, s), 3.48 (3H, m), 3.83 (2H, s), 6.97 (1H, s), 7.23-7.36 (5H, m)
MS (ESI) m / z [MH] + 231.5

Reference example 3
2-Methyl-4- (morpholinomethylene) -5-oxazolinone N-acetylglycine (0.50 g, 4.27 mmol) was added to phosphorus oxychloride (995 μl, 10.7 mmol) and N-formylmorpholine (1.23 g, 10 0.7 mmol) was added in an ice bath and stirred at 45 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure and added dropwise to 28% aqueous ammonia (5 ml) and water (5 ml) while maintaining the temperature at 10 ° C. or lower. The mixture was stirred for 1 hour in an ice bath and the precipitate was collected by filtration. The obtained crystals were washed successively with water and ethanol and dried to give the title compound crystals (0.52 g, 2.65 mmol).

¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.47 (2H, br), 3.79 (4H, t, J = 4.8Hz), 4.27 (2H, s), 6.92 (1H, s)
MS (ESI) m / z [MH] + 196.9

Reference example 4
2-Benzyl-4- (N, N-dimethylaminomethylene) -5-oxazolinone Phenacetic acid (1.00 g, 5.18 mmol) to toluene (10.0 ml) and N, N′-dicyclohexylcarbodiimide (1.07 g, 5.19 mmol) was added and stirred at room temperature overnight. The precipitate was filtered off, N, N-dimethylformamide dimethyl acetal (0.68 g, 5.71 mmol) was added, and the mixture was stirred overnight. The reaction mixture was washed with saturated brine and concentrated to dryness. Isopropyl alcohol was added to the concentrate for crystallization, and the precipitate was filtered. After washing with isopropyl alcohol and drying under reduced pressure, crystals of the title compound (0.78 g, 3.39 mmol) were obtained.

Example 1
4-hydroxymethylene-2-methyl-5-oxazolinone sodium salt 4- (N, N-dimethylaminomethylene) -2-methyl-5-oxazolinone (4.00 g, 26.0 mmol) in acetonitrile (50 ml) 2N aqueous sodium hydroxide solution (15 ml, 30.0 mmol) was added under ice cooling and allowed to stir overnight. Water was distilled off and acetonitrile (30 ml) was added and stirred. The precipitate was filtered, washed with acetonitrile, and then dried under reduced pressure to obtain crystals of the title compound (3.65 g, 24.5 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 2.00 (3H, s), 8.67 (3H, s)
MS (API-ES) m / z [MH] + 126.1

Example 2
2-Benzyl-4-hydroxymethylene-5-oxazolinone sodium salt monohydrate 2-Benzyl-4- (N, N-dimethylaminomethylene) -5-oxazolinone (10.8 g, 46.9 mmol) in acetonitrile (120 ml) was added 1N aqueous sodium hydroxide solution (53 ml, 53.0 mmol) under ice cooling and allowed to stir overnight. Acetonitrile was distilled off and crystallized under ice cooling. The precipitate was filtered and dried under reduced pressure to obtain the title compound crystal (5.99 g, 26.6 mmol). Differential scanning calorimetry (DSC) and thermogravimetry (TG) were measured with a thermal analyzer (manufactured by Rigaku Corporation, TAS-200). An endothermic peak was observed at 121.4 ° C., and weight loss was observed at 116.1-126.9 ° C. The chart is shown in FIG.

¹ H-NMR (DMSO-d ₆ ) δ: 3.66 (2H, s), 7.22-7.32 (5H, m), 8.71 (1H, s)
MS (ESI) m / z [MH] -202.1

Example 3
2-Benzyl-4-hydroxymethylene-5-oxazolinone sodium salt / anhydride 2-Benzyl-4- (N, N-dimethylaminomethylene) -5-oxazolinone (1.00 g, 4.34 mmol) in acetonitrile (10 ml) 1N aqueous sodium hydroxide solution (5 ml, 5.00 mmol) was added under ice cooling and allowed to stir overnight. The reaction mixture was concentrated to dryness, acetonitrile (5 ml) was added and the precipitate was filtered and dried at 100 ° C. for 2 hours to give the title compound as crystals (0.90 g, 4.00 mmol). DSC and TG were measured with a thermal analyzer. No endothermic peak and no obvious weight change was observed up to 220 ° C. The chart is shown in FIG.

¹ H-NMR (DMSO-d ₆ ) δ: 3.66 (2H, s), 7.22-7.32 (5H, m), 8.71 (1H, s)
MS (ESI) m / z [MH] -202.1

Example 4
2-Benzyl-4-hydroxymethylene-5-oxazolinone 4-N, N′-dimethylaminomethylene-2-benzyl-5-oxazolinone (350 mg, 6.65 mmol) in acetonitrile (15 ml) was added 2N aqueous sodium hydroxide (0 .92 ml) was added under ice cooling and allowed to stir overnight at room temperature. The reaction mixture was concentrated, acetonitrile was distilled off, washed with ethyl acetate (5 ml), and neutralized to pH 4 with 1N hydrochloric acid under ice cooling. The precipitate was filtered, washed with water, and dried under reduced pressure to give the title compound as crystals (1.03 g, 5.07 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 3.92 (2H, s), 7.29-7.38 (5H, m), 7.68 (1H, s)
MS (ESI) m / z [MH] -202.3

Example 5
4-methoxymethylene-2-methyl-5-oxazolinone 4-hydroxymethylene-2-methyl-5-oxazolinone sodium salt (3.00 g, 20.1 mmol) was added to N, N-dimethylformamide (30 ml) and dimethyl sulfate (2 20 ml, 23.2 mmol) was added and stirred at 60 ° C. for 5 hours. The solvent was distilled off, ethyl acetate was added and the precipitated salt was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.73 g, 12.2 mmol).

¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 4.11 (3H, s), 7.13 (1H, s)
MS (APCI) m / z [MH] + 142.1

Example 6
4-Ethoxymethylene-2-methyl-5-oxazolinone The title compound was obtained in the same manner as in Example 5 except that diethyl sulfate was used instead of dimethyl sulfate.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.1Hz), 2.29 (3H, s), 4.35 (2H, q, J = 7.1 Hz), 7.21 (1H, s)

Example 7
4-Benzyloxymethylene-2-methyl-5-oxazolinone 4-hydroxymethylene-2-methyl-5-oxazolinone sodium salt (0.42 g, 2.81 mmol) to N, N-dimethylformamide (5 ml) and benzyl bromide (0.53 g, 3.10 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated, toluene was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated to dryness, and isopropyl alcohol was added to the residue for crystallization. The precipitate was filtered, washed with isopropyl alcohol, and dried under reduced pressure to give the title compound as crystals (0.37 g, 1.70 mmol).

¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H, s), 5.26 (2H, s), 7.19-7.38 (6H, m)
MS (ESI) m / z [MH] + 218.3

Example 8
2-Benzyl-4-methoxymethylene-5-oxazolinone 2-Benzyl-4-hydroxymethylene-5-oxazolinone sodium salt (3.00 g, 13.3 mmol) in acetonitrile (30 ml) and dimethyl sulfate (1.64 ml, 17. 3 mmol) was added and the mixture was stirred at 60 ° C. for 4 hours. The solvent was distilled off, ethyl acetate and n-hexane were added, and the precipitated salt was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.99 g, 9.16 mmol).

¹ H-NMR (CDCl ₃ ) δ: 3.86 (2H, s), 4.10 (3H, s), 7.15 (1H, s), 7.25-7.37 (5H, m)
MS (ESI) m / z [MH] + 218.2

Example 9
2-Benzyl-4-ethoxymethylene-5-oxazolinone 2-Benzyl-4-hydroxymethylene-5-oxazolinone sodium salt (3.00 g, 13.3 mmol) in acetonitrile (30 ml) and diethyl sulfate (2.28 ml, 17. 4 mmol) was added and the mixture was stirred at 60 ° C. for 12 hours. Ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated to dryness to give the title compound (2.60 g, 11.2 mmol).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1Hz), 3.86 (2H, s), 4.28 (2H, q, J = 7.1Hz), 7.21 (1H, s), 7.24- 7.35 (5H, m)
MS (ESI) m / z [MH] + 231.8

Example 10
2-benzyl-4-ethoxymethylene-5-oxazolinone 4-hydroxymethylene-2-benzyl-5-oxazolinone (0.56 g, 2.76 mmol) to acetonitrile (6 ml), triethylamine (0.5 ml, 3.60 mmol) and Diethyl sulfate (0.47 ml, 3.60 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated to dryness to give the title compound (0.54 g, 2.34 mmol).

Example 11
2-Benzyl-4-benzyloxymethylene-5-oxazolinone 2-Benzyl-4-hydroxymethylene-5-oxazolinone sodium salt (0.60 g, 2.66 mmol) in acetonitrile (6 ml) and benzyl bromide (0.48 g, 2.81 mmol) was added, and the mixture was stirred at 80 ° C. for 7 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated to dryness to give the title compound (0.69 g, 2.35 mmol).

¹ H-NMR (CDCl ₃ ) δ: 3.86 (2H, s), 5.28 (2H, s), 7.26-7.39 (11H, m)
MS (ESI) m / z [MH] + 294.6

Example 12
(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetic acid N- (carboxymethyl) phenylamidine (0.40 g, 2.25 mmol) in isopropyl alcohol (8 ml) and 21% sodium ethoxide / ethanol solution (0.73 g, 2.26 mmol) was added and stirred for 0.5 hour. Thereafter, 4-benzyloxymethylene-2-methyl-5-oxazolinone (0.49 g, 2.25 mmol) crystals were added in 4 portions at 50 ° C. over 1 hour. The mixture was stirred overnight at 80 ° C., and the reaction mixture was concentrated. Ethyl acetate (5 ml) and water (5 ml) were added for liquid separation, and the aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl acetate. Hexane was added to the organic layer for crystallization, and the precipitate was filtered and dried under reduced pressure to give the title compound as yellow crystals (0.44 g, 1.53 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 2.15 (3H, s), 4.52 (2H, s), 7.48-7.56 (5H, m), 8.83 (1H, s), 9.58 (1H, s)
MS (ESI) m / z [MH] + 288.2, [MH]-286.1

Example 13
(6-Oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetic acid 4-benzyloxymethylene-2-methyl-5-oxazolinone instead of 2-benzyl-4-benzyl The title compound was obtained in the same manner as in Example 12 except that oxymethylene-5-oxazolinone was used.

¹ H-NMR (DMSO-d ₆ ) δ: 3.84 (2H, s), 4.52 (2H, s), 7.25-7.27 (1H, m), 7.31-7.34 (4H, m), 7.47-7.55 (5H, m), 8.83 (1H, s), 9.72 (1H, s)
MS (ESI) m / z [MH] + 364.0, [MH]-361.6

Example 14
1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine N- (tert-butoxycarbonylmethyl) phenylamidine hydrochloride (2.00 g, 7. 39 mmol) and sodium carbonate (2.30 g, 21.7 mmol) were added to toluene (25 ml) and water (10 ml), and the mixture was vigorously stirred, and the organic layer was washed with saturated brine. To this organic layer, a solution of 4-ethoxymethylene-2-benzyl-5-oxazolinone (1.38 g, 5.97 mmol) in acetonitrile (5 ml) was dropped and stirred at 80 ° C. overnight. The reaction solution was cooled to room temperature, washed with a 1N hydrochloric acid aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated hot water, respectively, and then concentrated under reduced pressure. Hexane was added to the residue for crystallization, and the precipitate was filtered and dried under reduced pressure to give the title compound as pale yellow crystals (2.03 g, 4.84 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40 (9H, s), 3.81 (2H, s), 4.58 (2H, s), 7.33-7.44 (5H, m), 7.53-7.67 (5H, m) , 8.02 (1H, s), 9.10 (1H, s)
MS (ESI) m / z [MH] + 420.4

Example 15
1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine (1) 2-benzyl-4-methanesulfonyloxymethylene-5-oxazolinone 2-benzyl -4-Hydroxymethylene-5-oxazolinone sodium salt (100 mg, 0.444 mmol) was suspended in chloroform (3 ml), methanesulfonyl chloride (34.3 μl, 0.443 mmol) was added, and the mixture was stirred at room temperature for 6 hours. . A part of the reaction mixture was sampled and analyzed by ¹ H-NMR, and it was confirmed that 2-benzyl-4-methanesulfonyloxymethylene-5-oxazolinone was contained.
¹ H-NMR (CDCl ₃ ) δ: 3.67 (2H, s), 3.87 (1.5H, s), 3.90 (1.5H, s), 7.28-7.33 (6H, m)

(2) 1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine N- (tert-butoxycarbonylmethyl) -phenylamidine hydrochloride (155 mg, 0.57 mmol), sodium carbonate (200 mg, 1.89 mmol), toluene (2 ml) and water (2 ml) were stirred for 10 minutes. The organic layer was washed with saturated brine, triethylamine (62 μl, 0.445 mmol) was added to the organic layer, the reaction mixture of Example 15 (1) was further added, and the mixture was stirred at 80 ° C. overnight. The reaction solution was washed successively with 1N aqueous hydrochloric acid and saturated brine. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound as crystals (84 mg, 0.20 mmol).

Example 16
1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine (1) 2-benzyl-4-trimethylsilyloxymethylene-5-oxazolinone 2-benzyl- 4-hydroxymethylene-5-oxazolinone sodium salt (100 mg, 0.444 mmol) was suspended in chloroform (3 ml), trimethylsilyl chloride (61.9 μl, 0.498 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a part of the reaction mixture was sampled and analyzed by ¹ H-NMR to confirm that 2-benzyl-4-trimethylsilyloxymethylene-5-oxazolinone was contained.
¹ H-NMR (CDCl ₃ ) δ: 0.30 (9H, s), 3.82 (2H, s), 7.20-7.27 (6H, m)
(2) 1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine N- (tert-butoxycarbonylmethyl) -phenylamidine hydrochloride (155 mg, 0.57 mmol), sodium carbonate (200 mg, 1.89 mmol), toluene (2 ml) and water (2 ml) were stirred for 10 hours. The organic layer was washed with saturated brine, and the reaction mixture of Example 16 (1) was further added, followed by stirring at 80 ° C. overnight. The reaction solution was washed successively with 1N aqueous hydrochloric acid and saturated brine. The organic layer was concentrated and purified by silica gel chromatography to give the title compound as crystals (121 mg, 0.288 mmol).

Example 17
1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine (1) 4-acetoxymethylene-2-benzyl-5-oxazolinone 2-benzyl-4 Acetic anhydride (0.5 ml, 5.29 mmol) was added to -hydroxymethylene-5-oxazolinone (100 mg, 0.492 mmol), and the mixture was stirred at room temperature for 1 hour. Cold water was added to the reaction solution for washing, and ethyl acetate and saturated brine were added for washing. The organic layer was dried under reduced pressure to give 4-acetoxymethylene-2-benzyl-5-oxazolinone.
¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s), 4.08 (2H, s), 7.28-7.37 (5H, m), 8.11 (1H, s)
MS (ESI) m / z [MH] + 264.1, [MH]-261.9

(2) 1- (tert-Butoxycarbonylmethyl) -6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidine N- (tert-butoxycarbonylmethyl) -phenylamidine hydrochloride (155 mg, 0.572 mmol), sodium carbonate (200 mg, 1.89 mmol), toluene (2 ml) and water (2 ml) were stirred for 10 hours. The organic layer was washed with saturated brine, and 4-acetoxymethylene-2-benzyl-5-oxazolinone obtained in Example 17 (1) was added to the organic layer, followed by stirring at 80 ° C. overnight. The reaction solution was washed with 1N hydrochloric acid and saturated brine. The organic layer was concentrated and purified by silica gel column chromatography to give the title compound as crystals (70.0 mg, 0.167 mmol).

Example 18
5-acetylamino-6-oxo-2-phenyl-1- (succinimidooxycarbonylmethyl) -1,6-dihydropyrimidine (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1 -Yl) acetic acid (300 mg, 1.04 mmol), acetonitrile (5 ml) and N-methylmorpholine (121 mg, 1.20 mmol) were mixed, ethyl chloroformate (125 mg, 1.15 mmol) was added, and 30 minutes under water cooling Stir. N-hydroxysuccinimide (148 mg, 1.29 mmol) was added and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated to dryness. The slurry was washed with water (5 ml), the precipitate was filtered, and the crystals were dried to give the title compound as pale yellow crystals (0.31 g, 0.81 mmol).

¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.88 (4H, s), 4.94 (2H, s), 7.50-7.56 (5H, m), 8.04 (1H, s), 9.10 (1H , s)
MS (ESI) m / z [MH] + 385.2, [MH]-383.2

Example 19
(S) -2- [2- (5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetylamino] -3-phenylpropionic acid L-phenylalanine (100 mg, 0 .61 mmol) was added to 50% acetonitrile water (3 ml), and adjusted to pH 8 with 6N aqueous sodium hydroxide solution and dissolved. To this solution, 5-acetylamino-6-oxo-2-phenyl-1- (succinimidooxycarbonylmethyl) -1,6-dihydropyrimidine (176 mg, 0.46 mmol) was dissolved in acetonitrile (1 ml) and ice-cooled. The solution was added dropwise and stirred for 2 hours. The mixture was further stirred at room temperature for 3 hours. The reaction solution was concentrated and crystallized by adjusting the pH to 2 with an aqueous hydrochloric acid solution. The precipitate was filtered, washed and dried under reduced pressure to obtain the title compound as white crystals (190 mg, 0.44 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 2.14 (3H, s), 2.84-2.87 (1H, dd, J1 = 13.8Hz, J2 = 5.0Hz), 3.01 (1H, dd, J1 = 13.8Hz, J2 = 8.7Hz), 4.41-4.48 (3H, m), 7.12-7.14 (2H, d, J = 7.8Hz), 7.21-7.25 (3H, m), 7.43-7.52 (5H, m), 8.53 (1H, d, J = 7.8Hz), 8.80 (1H, s), 9.52 (1H, s)
MS (ESI) m / z [MH] + 435.2, [MH]-433.3

Example 20
(S) -2-[(6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetylamino] -3-phenylpropionic acid 5-acetylamino-6-oxo Instead of 2-phenyl-1- (succinimidooxycarbonylmethyl) -1,6-dihydropyrimidine, 6-oxo-2-phenyl-5-phenylacetylamino-1- (succinimidooxycarbonylmethyl) -1,6 -Crystals of the title compound were obtained in the same manner as in Example 19 except that dihydropyrimidine was used.

¹ H-NMR (DMSO-d ₆ ) δ: 2.85 (1H, dd, J1 = 14.1Hz, J2 = 5.1Hz), 3.02 (1H, dd, J1 = 14.1Hz, J2 = 5.1Hz), 3.83 (2H, s), 4.45 (3H, m), 7.15-7.52 (15H, m), 8.53 (1H, d, J = 7.8Hz), 8.80 (1H, s), 9.64 (1H, s)
MS (ESI) m / z [MH] + 511.3, [MH]-509.4

Example 21
(S) -2- [2- (5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetylamino] -3-methylbutyrate (5-acetylamino-6 To -oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetic acid (250 mg, 0.87 mmol) was added tetrahydrofuran (5 ml) and N-methylmorpholine (0.10 ml, 0.91 mmol). After dissolution, ethyl chloroformate (85.3 μl, 0.91 mmol) was added under ice cooling, and the mixture was stirred for 20 minutes. L-valine methyl ester hydrochloride (146 mg, 0.87 mmol) and N-methylmorpholine (0.10 ml, 0.91 mmol) were added and stirred for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was concentrated to dryness to give the title compound (0.18 g, 0.45 mmol). .

¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, d, J = 6.9Hz), 0.94 (3H, d, J = 6.9Hz), 2.16-2.19 (1H, m), 2.21 (3H, S), 3.75 (3H, s), 4.58 (3H, m), 6.37 (1H, d, J = 8.6Hz), 7.43-7.50 (3H, m), 7.55-7.57 (2H, m), 8.01 (1H, s) 9.10 (1H, s)

Example 22
N- [2- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-methyl-2-oxoethyl]-(6-oxo-2-phenyl-5-phenylacetylamino) -1,6-dihydropyrimidin-1-yl) acetamide (6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetic acid (600 mg, 1.65 mmol) in tetrahydrofuran (8 ml) and N-methylmorpholine (0.20 ml, 1.82 mmol) were added and dissolved, and ethyl chloroformate (0.165 ml, 1.73 mmol) was added under ice cooling, followed by stirring for 20 minutes. 2-Amino-1- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-propanone hydrochloride (386 mg, 1.65 mmol) and N-methylmorpholine (0.20 ml, 1.82 mmol) was added and stirred for 1 hour. Methyl-tert-butyl ether was added to the reaction mixture, and the mixture was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was concentrated to dryness to give the title compound (0.61 g, 1.12 mmol). Got.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.53 (3H, d, J = 4.2Hz), 3.76 (2H, s), 4.57 (2H, s), 5.43-5.51 (1H, m ), 6.76 (1H, d, J = 6.8Hz), 7.25-7.32 (5H, m), 7.43-7.53 (5H, m), 8.05 (1H, s), 9.09 (1H, s)
MS (ESI) m / z [MH] + 543.4, [MH]-541.4

Example 23
N- [2- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-methyl-2-oxoethyl]-(5-acetylamino-6-oxo-2-phenyl- 1,6-dihydropyrimidin-1-yl) acetamide (6-acetyl-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetic acid instead of (5-acetylamino-6- The title compound was obtained in the same manner as in Example 22 except that oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetic acid was used.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.59 (3H, d, J = 7.3Hz), 2.23 (3H, s), 4.62 (2H, s), 5.48-5.54 (1H, m ), 6.79 (1H, d, J = 6.9Hz), 7.47-7.56 (5H, m), 8.02 (1H, s), 9.08 (1H, s)
MS (ESI) m / z [MH] + 467.2, [MH]-465.4

Example 24
N- [2-Methyl-1- (2-thiazolylcarbonyl) propyl]-(6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetamide (6- Oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetic acid (400 mg, 1.10 mmol) was added to tetrahydrofuran (6 ml) and N-methylmorpholine (0.133 ml, 1.21 mmol). ) Was added and dissolved, and ethyl chloroformate (0.11 ml, 1.15 mmol) was added under ice cooling, followed by stirring for 20 minutes. 2-Amino-3-methyl-1- (2-thiazolyl) -1-butanone hydrochloride (250 mg, 1.13 mmol) and N-methylmorpholine (0.133 ml, 1.21 mmol) were added and stirred for 1 hour. Ethyl-tert-butyl ether was added to the reaction mixture, and the mixture was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was concentrated to dryness to give the title compound (556 mg, 1.05 mmol). It was.

¹ H-NMR (CDCl ₃ ) δ: 0.76 (3H, d, J = 6.8Hz), 0.99 (3H, d, J = 6.8Hz), 2.37-2.45 (1H, m), 3.75 (2H, s), 4.11 (1H, dd, J1 = 14.3Hz, J2 = 7.1Hz), 4.60-4.70 (2H, m), 5.65-5.68 (1H, dd, J1 = 8.9Hz, J2 = 4.9Hz), 7.05 (1H, d , J = 8.9Hz), 7.23-7.53 (10H, m), 7.69 (1H, d, J = 3.0Hz), 7.99 (1H, d, J = 3.0Hz), 8.16 (1H, s), 9.08 (1H , s)
MS (ESI) m / z [MH] + 530.3, [MH]-528.3

Example 25
N- [2-Methyl-1- (2-thiazolylcarbonyl) propyl]-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide (6-oxo (2-acetyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) instead of acetic acid ) The title compound was obtained in the same manner as in Example 24 except for using acetic acid.

¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, d, J = 6.9Hz), 1.05 (3H, d, J = 6.9Hz), 2.22 (3H, s), 2.48 (1H, m), 4.61 ( 1H, d, J = 16Hz), 4.68 (1H, d, J = 16Hz), 5,67 (1H, dd, J1 = 8.8Hz, J2 = 4.8Hz), 6.78 (1H, d, J = 8.8Hz) , 7.41-7.46 (3H, m), 7.54-7.56 (2H, m), 7.73 (1H, d, J = 3.0Hz), 8.00 (1H, s), 8.04 (1H, d, J = 3.0Hz), 9.09 (1H, s)
MS (ESI) m / z [MH] + 454.2, [MH]-452.4

Example 26
(S) -N- [1-Benzyl-3-chloro-2-oxopropyl]-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide (6- (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-) instead of oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetic acid Yl) acetic acid, 2-amino-1- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-propanone instead of (S) -3-amino-1- The title compound was obtained in the same manner as in Example 22 except that chloro-4-phenyl-2-butanone hydrochloride was used.

¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 3.02-3.07 (1H, dd, J1 = 14.0Hz, J2 = 6.9Hz), 3.10-3.16 (1H, dd, J1 = 14.0Hz, J2 = 6.9Hz), 4.00 (1H, d, J = 16.1Hz), 4.15 (1H, d, J = 16.1Hz) 4.48 (1H, d, J = 15.6Hz), 4.56 (1H, d, J = 15.6Hz) ), 4.98-5.03 (1H, m), 6.51 (1H, d, J = 7.2Hz), 7.10-7.12 (2H, m), 7.26-7.29 (3H, m), 7.45-7.49 (5H, m), 7.96 (1H, s), 9.10 (1H, s)
MS (ESI) m / z [MH] + 467.2, [MH]-465.2

Example 27
(S) -2-[(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetylamino] -3-phenylpropionic acid (S) -2-[(6- Oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetylamino] -3-phenylpropionic acid (135 mg, 0.264 mmol), water (10 ml) and dihydrogen phosphate Potassium (155 mg, 1.14 mmol) was added, the pH was adjusted to 7.6 with an aqueous sodium hydroxide solution, penicillin amidase beads (Sigma, 23.0 mg) were added, and the mixture was stirred at 37 ° C. overnight. Acetonitrile was added to the resulting reaction solution, the precipitate was removed by filtration, and the filtrate was concentrated. A hydrochloric acid aqueous solution was added to adjust the pH to 2.0, and crystallization was performed. The precipitate was filtered, washed and dried under reduced pressure to give the title compound as crystals (85.0 mg, 0.217 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 2.83-2.88 (1H, m), 3.00-3.03 (1H, m), 4.33-4.47 (3H, m), 5.14 (2H, br), 7.14-7.45 ( 10H, m), 8.44 (1H, d, J = 7.8Hz)
MS (ESI) m / z [MH] + 393.3, [MH]-391.2

Example 28
N- [2-Methyl-1- (2-thiazolylcarbonyl) propyl]-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide N- [2- Methyl-1- (2-thiazolylcarbonyl) propyl]-(6-oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetamide (150 mg, 0.283 mmol). Suspended in 0.05 M potassium phosphate buffer (pH 7.4, 15.0 ml), Triton X-100 (registered trademark) (2.00 μl) and penicillin amidase aqueous solution (manufactured by Sigma) were added, Stir at 37 ° C. for 5 days. The resulting precipitate of the reaction solution was filtered, washed and dried under reduced pressure to obtain the title compound crystal (114 mg, 0.277 mmol).

¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, d, J = 6.8Hz), 1.05 (3H, d, J = 6.82Hz), 2.45-2.50 (1H, m), 4.04 (2H, s), 4.58 (1H, d, J = 15.5Hz), 4.66 (1H, d, J = 15.5Hz), 5.64 (1H, dd, J1 = 8.9Hz, J2 = 4.8Hz), 6.88 (1H, d, J = 8.9 Hz), 7.40-7.52 (6H, m), 7.72 (1H, d, J = 3.1Hz), 8.03 (1H, d, J = 3.1Hz)
MS (ESI) m / z [MH] + 412.2, [MH]-410.0

Example 29
N- [2- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-methyl-2-oxoethyl]-(5-amino-6-oxo-2-phenyl-1 , 6-Dihydropyrimidin-1-yl) acetamide N- [2- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-methyl-2-oxoethyl]-(6- Oxo-2-phenyl-5-phenylacetylamino-1,6-dihydropyrimidin-1-yl) acetamide (150 mg, 0.277 mmol) in 0.05 M potassium phosphate buffer (pH 7.4, 15.0 ml). The suspension was suspended, Triton X-100 (registered trademark) (2.00 μl) and penicillin amidase aqueous solution (manufactured by Sigma) were added, and the mixture was stirred at 37 ° C. overnight. The resulting precipitate of the reaction solution was filtered, washed and dried under reduced pressure to obtain the title compound crystal (114 mg, 0.269 mmol).

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.57 (3H, d, J = 7.3Hz), 4.48 (1H, d, J = 15.5Hz), 4.64 (1H, d, J = 15.5 Hz), 4.47 (1H, m), 7.01 (1H, d, J = 6.6Hz), 7.43-7.53 (6H, m)
MS (ESI) m / z [MH] + 425.3, [MH]-423.1

Example 30
(S) -2-[(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetylamino] -3-methylbutyric acid hydrochloride (S) -2-[( 5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetylamino] -3-methylbutyrate (100 mg, 0.25 mmol) was dissolved in methanol (5 ml) and 10 % Hydrogen chloride methanol solution (0.5 ml) was added and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, methyl-tert-butyl ether was added, filtered, washed with methyl-tert-butyl ether and dried to give the title compound as crystals (90.0 mg, 0.228 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 0.80 (3H, d, J = 3.0Hz), 0.82 (3H, d, J = 3.0Hz), 1.97-2.02 (1H, m), 3.64 (3H, s ), 4.20 (1H, dd, J1 = 8.4Hz, J2 = 6.2Hz), 4.53 (2H, s), 7.37 (1H, s), 7.48-7.55 (5H, m), 8.51 (1H, d, J = (8.4Hz)
MS (ESI) m / z [MH] + 359.4, [MH]-393.1

Example 31
N- [2-Methyl-1- (2-thiazolylcarbonyl) propyl]-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide hydrochloride N- [ 2-Methyl-1- (2-thiazolylcarbonyl) propyl]-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide (100 mg, 0.220 mmol) Was dissolved in methanol (5 ml), 10% hydrogen chloride methanol solution (0.5 ml) was added, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated to dryness, methyl-tert-butyl ether was added, filtered, washed with methyl-tert-butyl ether and dried to give the title compound as crystals (93.0 mg, 0.208 mmol).

¹ H-NMR (DMSO-d ₆ ) δ: 0.80 (3H, d, J = 6.9Hz), 0.87 (3H, d, J = 6.9Hz), 2.28-2.33 (1H, m), 4.62 (2H, s ), 5.45 (1H, dd, J1 = 8.1Hz, J2 = 5.5Hz), 7.51-7.62 (6H, m), 8.20 (1H, d, J = 3.0Hz), 8.30 (1H, d, J = 3.0Hz) ), 8.75 (1H, d, J = 8.1Hz)
MS (ESI) m / z [MH] + 412.3, [MH]-446.2

Example 32
(S) -N- [1-Benzyl-3-chloro-2-oxopropyl]-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide hydrochloride (S ) -2-[(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetylamino] -3-methylbutyrate instead of methyl (S) -N- [1 -Benzyl-3-chloro-2-oxopropyl]-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) acetamide and Example 30 In the same manner, crystals of the title compound were obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 2.78-2.84 (1H, m), 3.07-3.11 (1H, m), 4.43 (2H, s), 4.55-4.60 (3H, m), 7.13-7.23 ( 5H, m), 7.43-7.58 (5H, m), 7.59-7.60 (1H, m), 8.96 (1H, d, J = 7.4Hz)
MS (ESI) m / z [MH] + 425.2, [MH]-459.2

Comparative Example 1
To a solution of 4-N, N-dimethylaminomethylene-2-benzyl-5-oxazolinone (242 mg, 1.05 mmol) in ethanol (8 ml) was added sodium hydroxide (50 mg, 1.25 mmol) under ice cooling, Stir at room temperature for 2 hours. The solvent was distilled off, water was added, and the mixture was neutralized with 2N hydrochloric acid. After completion of the reaction and after neutralization, HPLC and MS analysis revealed ethyl 2-phenylacetylamino-3-N, N-dimethylaminopropionate which was a ring-opened product.

2 is a chart showing the results of thermal analysis (DSC and TG) of the compound of Example 2. 4 is a chart showing the results of thermal analysis (DSC and TG) of the compound of Example 3.

Claims (33)

Formula (I):

(Wherein P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ¹ and R ² are the same or different and each represents an alkyl group, or An adjacent heterocyclic group may form an aliphatic heterocyclic ring, and the wavy line indicates that it is a cis- or trans-isomer or a mixture thereof. Hydrolysis in the presence of an alkali metal gives general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ has an alkyl group which may have a substituent and a substituent. An aryl group which may be substituted, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or —OCOR ^4a (here And R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above). General formula (VI), characterized by comprising the following steps (a), (b) and (c):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. A phenyl group which may be present, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group.)
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein each symbol has the same meaning as described above) is reacted with a compound represented by the general formula (VI) or a salt thereof. General formula (VII) characterized in that it comprises the following steps (a), (b), (c) and (d):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. A phenyl group that may be present; and a method for producing a compound represented by:
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein R ⁵ represents the same meaning as described above, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group) and a compound represented by the general formula (VI):

Wherein each symbol is as defined above, or a salt thereof;
Step (d): The compound represented by the general formula (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, then condensed with N-hydroxysuccinimide, and the above general formula A compound represented by the formula (VII) is obtained.   The manufacturing method as described in any one of Claims 1-3 whose P is a methyl group, an ethyl group, or a benzyl group. The production method according to any one of claims 1 to 3, wherein R ³ is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group or a trimethylsilyl group. General formula (IX), characterized in that it comprises the following steps (a), (b), (c), (d) and (e):

[Wherein, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. R ⁸ represents an aryl group, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). Group). Or a salt thereof;
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein R ⁵ represents the same meaning as described above, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group) and a compound represented by the general formula (VI):

Wherein each symbol is as defined above, or a salt thereof;
Step (d): When the compound represented by the general formula (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, it is condensed with N-hydroxysuccinimide to give a general formula (VII):

(Wherein each symbol is as defined above), a compound represented by
Step (e): the compound represented by the general formula (VII) and the general formula (VIII):

(Wherein each symbol has the same meaning as described above) is reacted with a compound represented by the general formula (IX) or a salt thereof. General formula (IX), characterized in that it comprises the following steps (a), (b), (c) and (f):

[Wherein, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. R ⁸ represents an aryl group, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). Group). Or a salt thereof;
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein R ⁵ represents the same meaning as described above, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group) and a compound represented by the general formula (VI):

Wherein each symbol is as defined above, or a salt thereof;
Step (f): The compound represented by the general formula (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then the general formula (VIII):

(Wherein each symbol has the same meaning as described above) is condensed with a compound represented by the above general formula (IX) or a salt thereof.   The manufacturing method of Claim 6 or 7 whose P is a methyl group, an ethyl group, or a benzyl group. The production method according to claim 6 or 7, wherein R ³ is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group or a trimethylsilyl group. General formula (IX) obtained by the production method according to any one of claims 6 to 9:

[Wherein, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. R ⁸ represents an aryl group, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). Group). A compound represented by the general formula (X):

(Wherein each symbol is as defined above), or a method for producing the salt thereof.   The production method according to claim 10, wherein the deprotection is performed by an enzymatic reaction.   The production method according to claim 10, wherein the deprotection is performed under acidic conditions. General formula (XV), characterized in that it comprises the following steps (j), (k) and (l):

(In the formula, R ⁵ represents an alkyl group which may have a substituent or a phenyl group which may have a substituent, and R ⁷ represents a hydrogen atom or an alkyl group which may have a substituent. Represents an aralkyl group which may have a substituent or an aryl group which may have a substituent, and Y 1 may have a heterocyclic group which may have a substituent, or a substituent. A good acyl group or haloalkyl group)) or a salt thereof;
Process (j): General formula (X) obtained by the method as described in any one of Claims 10-12:

[Wherein, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group) And other symbols are as defined above. And the amino group of the compound represented by the formula (XIII):

Wherein Q represents an amino-protecting group other than an acyl group, and other symbols are as defined above, or a salt thereof;
Step (k): Converting the group represented by R ⁸ of the compound represented by the general formula (XIII) or a salt thereof to the group represented by Y to produce the general formula (XIV):

Wherein each symbol is as defined above, or a salt thereof;
Step (l): The compound represented by the general formula (XIV) or a salt thereof obtained is deprotected to obtain the compound represented by the general formula (XV) or a salt thereof. General formula (XI), characterized in that it comprises the following steps (a), (b), (c), (d), (e) and (g):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. A aryl group, and Y represents a heterocyclic group which may have a substituent, an acyl group which may have a substituent or a haloalkyl group.) Or a salt thereof;
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein R ⁵ represents the same meaning as described above, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group) and a compound represented by the general formula (VI):

Wherein each symbol is as defined above, or a salt thereof;
Step (d): When the compound represented by the general formula (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, it is condensed with N-hydroxysuccinimide to give a general formula (VII):

(Wherein each symbol is as defined above), a compound represented by
Step (e): the compound represented by the general formula (VII) and the general formula (VIII):

[In the formula, R ⁷ is as defined above, and R ⁸ is a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group- or N (R ⁹ ) -OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or And each independently represents an alkyl group.). ] Or a salt thereof is reacted with the compound represented by the general formula (IX):

Wherein each symbol is as defined above, or a salt thereof;
Step (g): The compound represented by the general formula (IX) or a salt thereof obtained by converting the group represented by R ⁸ to the group represented by Y is represented by the above general formula (XI). Or a salt thereof. General formula (XI) characterized by comprising the following steps (a), (b), (c), (f) and (g):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. A aryl group, and Y represents a heterocyclic group which may have a substituent, an acyl group which may have a substituent or a haloalkyl group.) Or a salt thereof;
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein R ⁵ represents the same meaning as described above, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group) and a compound represented by the general formula (VI):

Wherein each symbol is as defined above, or a salt thereof;
Step (f): The compound represented by the general formula (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then the general formula (VIII):

[Wherein R ⁷ is as defined above, R ⁸ is a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group — or N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or And each independently represents an alkyl group.). A compound represented by the general formula (IX):

Wherein each symbol is as defined above, or a salt thereof;
Step (g): The compound represented by the general formula (IX) or a salt thereof obtained by converting the group represented by R ⁸ to the group represented by Y is represented by the above general formula (XI). Or a salt thereof. General formula (XI), characterized in that it comprises the following steps (a), (b), (c) and (h):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. A aryl group, and Y represents a heterocyclic group which may have a substituent, an acyl group which may have a substituent or a haloalkyl group.) Or a salt thereof;
Step (a): General formula (I):

Wherein P is as defined above, and R ¹ and R ² are the same or different and each represents an alkyl group or may form an aliphatic heterocyclic ring together with an adjacent nitrogen atom. , The wavy line indicates that the compound is a cis isomer, a trans isomer or a mixture thereof) or a salt thereof in the presence of an alkali metal hydroxide to give a general formula (II):

(Wherein M represents a hydrogen atom, sodium, potassium or lithium, and P and a wavy line have the same meanings as described above);
Step (b): The compound represented by the general formula (II) thus obtained is represented by the general formula: R ³ -X (III) [wherein R ³ is an alkyl group which may have a substituent, a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b , wherein X is a halogen atom, —OSO ₃ R ⁴ or -OCOR ^4a (wherein R ⁴ , R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent) .) And a reagent represented by the general formula (IV):

(Wherein each symbol and wavy line have the same meaning as described above) to obtain a compound represented by
Step (c): The obtained compound represented by the general formula (IV) is converted into the general formula (V):

(Wherein R ⁵ represents the same meaning as described above, and R ⁶ represents a hydrogen atom, an alkyl group or an aralkyl group) and a compound represented by the general formula (VI):

Wherein each symbol is as defined above, or a salt thereof;
Step (h): The compound represented by the general formula (VI) or a salt thereof obtained is converted to a hydrogen atom when R ⁶ is other than a hydrogen atom, and then the general formula (XII):

(Wherein each symbol is as defined above) is condensed with a compound represented by the general formula (XI) or a salt thereof.   The manufacturing method as described in any one of Claims 14-16 whose P is a methyl group, an ethyl group, or a benzyl group. R ³ is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group or a trimethylsilyl group, The process according to any one of claims 14 to 16. General formula (XI) obtained by the manufacturing method of any one of Claims 14-18:

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. Represents an aryl group, and Y represents a heterocyclic group which may have a substituent, an acyl group which may have a substituent or a haloalkyl group.) Or a salt thereof The general formula (XV):

(Wherein each symbol is as defined above), or a method for producing the salt thereof.   The production method according to claim 19, wherein the deprotection is performed by an enzymatic reaction.   The production method according to claim 19, wherein the deprotection is performed under acidic conditions. General formula (IV ′):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ^3a represents an alkyl group which may have a substituent (provided that P Is an alkyl group or a benzyl group), an aryl group which may have a substituent, an aralkyl group which may have a substituent, a trialkylsilyl group, —COR ^4a or —SO ₂ R ^4b Wherein R ^4a and R ^4b are the same or different and each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. A wavy line indicates a cis- or trans-isomer or a mixture thereof.) The compound according to claim 22, wherein P is a methyl group, an ethyl group or a benzyl group, and R ^3a is a methyl group, an ethyl group, a benzyl group, a methanesulfonyl group or a trimethylsilyl group. General formula (VII):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. A phenyl group which may have a compound represented by: The compound according to claim 24, wherein P is a methyl group, an ethyl group or a benzyl group, and R ⁵ is a methyl group or a phenyl group which may have a substituent. General formula (IX):

[Wherein, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. R ⁸ represents an aryl group, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). Group). Or a salt thereof. P is a methyl group, an ethyl group or a benzyl group, R ⁵ is a methyl group or an optionally substituted phenyl group, R ⁷ is a methyl group, an isopropyl group or a benzyl group, and R ⁸ is 27. The compound or a salt thereof according to claim 26, which is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, or -N (Me) -OMe. Formula (X):

[Wherein, R ⁵ represents an alkyl group which may have a substituent or a phenyl group which may have a substituent, and R ⁷ represents a hydrogen atom or an alkyl group which may have a substituent. Represents an aralkyl group which may have a substituent or an aryl group which may have a substituent, and R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group or —N (R ⁹ ) —OR. ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). Or a salt thereof. R ⁵ is a methyl group or an optionally substituted phenyl group, R ⁷ is a methyl group, an isopropyl group, or a benzyl group, and R ⁸ is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, or —N 29. The compound according to claim 28 or a salt thereof, which is (Me) -OMe. General formula (IX):

[Wherein, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. R ⁸ represents an aryl group, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, or —N (R ⁹ ) —OR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each independently represents an alkyl group). Group). A compound represented by the general formula (X):

(Wherein each symbol is as defined above), or a method for producing the salt thereof. General formula (XI):

(In the formula, P represents a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or a haloalkyl group which may have a substituent, and R ⁵ represents an alkyl group or a substituent which may have a substituent. R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent. An aryl group, and Y represents a heterocyclic group which may have a substituent, an acyl group which may have a substituent, or a haloalkyl group. General formula (XV), characterized by deprotection by:

(Wherein each symbol is as defined above), or a method for producing the salt thereof.   32. The production method according to claim 30 or 31, wherein P is an optionally substituted benzyl group.   The production method according to claim 30 or 31, wherein the enzyme is penicillin amidase.

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