JPH09216886A - Production of triazolopyridazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply, safely and industrially advantageously obtain a triazolopyridazine derivative useful as antiallergic agent, etc., in high purity and good yield by a new method carrying out reaction in the presence of a metal alkoxide. SOLUTION: A compound of formula I (R<1> is H or an alkyl; R<2> and R<3> are each H or an alkyl or R<2> and R<3> may form a 5-7 membered ring together with adjacent C=C; Z<1> is a leaving group) or its salt is reacted with a compound of formula II [R<4> and R<5> are each H or a cyclic hydrocarbon, etc.; Z<2> is a leaving group; X is O or S(O)p (P is 0-2); Y is a group of formula III (R<6> and R<7> are each H or a lower alkyl), a divalent group derived from a 3-7-membered homocycle or heterocycle; (m) and (n) are each 0-4] or its salt and a metal alkoxide of the formula R<8> OM (R<8> is a branched alkyl; M is an alkali metal) (preferably sodium tert-butoxide) to provided the objective compound of formula IV. The compound of formula II and the metal alkoxide are preferably used in mounts of 1-2mol and 1-3mol, respectively, based on 1mol compound of formula I.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION General Formula

Embedded image [Wherein R ¹ represents a hydrogen atom or an alkyl group which may have a substituent, and R ² and R ³ each represent a hydrogen atom or an alkyl group which may have a substituent, or
Alternatively, R ² and R ³ may form a 5- to 7-membered ring with adjacent —C═C—, and R ⁴ and R ⁵ are each a hydrogen atom, an alkyl group which may have a substituent or a substituted group. Represents a cyclic hydrocarbon group which may have a group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom may form a nitrogen-containing heterocyclic group which may be substituted, and X represents oxygen. An atom or S (O) p (p is an integer of 0 to 2), and Y is the formula (1)

Embedded image [Wherein, R ⁶ and R ⁷ each represent a hydrogen atom or a lower alkyl group which may have a substituent] or (2) 3 to 7 which may have a substituent. A divalent group derived from a membered homocycle or heterocycle, m
Represents an integer of 0 to 4, and n represents an integer of 0 to 4. ] Or a salt thereof is useful as an anti-PAF agent, an eosinophil chemoattractant inhibitor, an anti-asthma agent, an anti-allergic agent, a prophylactic / therapeutic agent for allergic rhinitis, a prophylactic / therapeutic agent for atopic dermatitis. Is known (JP-A-6-27)
9447). The present invention relates to a novel industrially extremely advantageous production method capable of producing the compound represented by the formula [III] or a salt thereof in a high yield, easily and safely.

[0002]

PRIOR ART [III] or its salt and formula

Embedded image [In the formula, each symbol has the same meaning as described above. ] The method for producing the compound represented by the formula (1) or a salt thereof is already known (JP-A-6-279447). However, 60% oily sodium hydride having a high risk is used, and the operation is complicated. Therefore, it cannot be said that the yield is sufficient. When 60% oily sodium hydride is used, a large amount of explosive hydrogen gas is generated, so it is necessary to make the inside of the reactor an inert gas atmosphere. Also, since a large amount of gas is generated, 60% oily sodium hydride cannot be added at once to the reactor,
It is necessary to divide and add several times. Also, the formula that is the substrate for carrying out the reaction

Embedded image [Wherein R ¹ represents a hydrogen atom or an alkyl group which may have a substituent, and R ² and R ³ each represent a hydrogen atom or an alkyl group which may have a substituent, or
Alternatively, R ² and R ³ may form a 5- to 7-membered ring with adjacent —C═C—, and Z ¹ represents a leaving group. ], The hydrogen gas is generated during the addition, and the liquid level rises with the generation of hydrogen gas. It is necessary to divide and add the compound represented by the formula [I]. Since hydrogen gas is always generated during this addition, it is necessary to take safety measures against hydrogen gas. In addition to that, it is necessary to adjust the amount of the compound of formula [I] added once. It is also necessary to control the rise of the liquid level by. Further, when a compound represented by the formula [III] or [V] or a salt thereof is produced by a method using 60% oily sodium hydride, a product having a high HPLC area percentage is obtained, but it is produced by analysis with a capillary GC. 60 in things
A large amount of oil content of% oily sodium hydride is detected. Therefore, it is necessary to remove the oil content of 60% oily sodium hydride, but even if the oil removal operation is carried out in multiple stages, the oil content in the product cannot be completely removed.
About 00 ppm of oil remains in the product. From these facts, the manufacturing methods known so far cannot be said to be very satisfactory as an industrial manufacturing method of pharmaceuticals.

[0003]

The known methods for producing the compound represented by the formula [III] or [V] or salts thereof are known to be very satisfactory as industrial production methods. However, there is a need for a method of synthesizing in a higher purity, a higher yield, a simpler and safer method. As a result of diligent studies on a large number of reaction conditions, the present inventors have shown that the compound is represented by the formula [III] or [V] with a high purity, a good yield, a simple and safe method, and an industrially advantageous method. The inventors have found a method for synthesizing a compound or a salt thereof and completed the present invention.

[0004]

That is, a compound represented by the formula [I] or a salt thereof is represented by the formula:

Embedded image [Wherein R ⁴ and R ⁵ are each a hydrogen atom, an alkyl group which may have a substituent or a cyclic hydrocarbon group which may have a substituent, or R ⁴ and R ⁵ are A nitrogen-containing heterocyclic group which may be substituted with an adjacent nitrogen atom may be formed, Z ² is a leaving group, X is an oxygen atom or S (O) p (p is an integer of 0 to 2). , And Y is the expression (1).

Embedded image [Wherein each of R ⁶ and R ⁷ represents a hydrogen atom or an alkyl group which may have a substituent] or (2) a 3 to 7-membered optionally having a substituent Represents a divalent group derived from a homocycle or a heterocycle, m is 0
To 4 and n is an integer of 0 to 4. ] 1 to 2 mol of the compound represented by the formula or a salt thereof and 1 to 3 mol of a metal alkoxide as a base are heated in an ether such as tetrahydrofuran or dioxane or an amide such as dimethylformamide at a temperature of 50 to 70 ° C. Preferably 1 to 1 at 60 to 65 ° C
By stirring for 0 hour, preferably for 2 to 5 hours, the compound represented by the formula [III] or a salt thereof and the compound represented by the formula [V] or a salt thereof can be produced in high purity with high yield, safely, and industrially. They found that they can be synthesized by an advantageous method, and as a result of further research, they completed the present invention.

The present invention includes (1) a compound represented by the formula [I] or a salt thereof and a compound represented by the formula [I:
I] or a salt thereof and a formula

Embedded image [In the formula, R ⁸ represents a branched C _3-6 alkyl group and M represents an alkali metal. ] The manufacturing method of the compound or its salt represented by Formula [III] characterized by making it react with the metal alkoxide represented by these, (2) The compound or its salt represented by Formula [I], or its salt. I
A compound represented by formula [V] or a salt thereof is reacted with a metal alkoxide, and a method for producing the compound represented by formula [V] or a salt thereof,

(3) R ¹ is a hydrogen atom or 1 to 4 selected from amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-carbonyloxy. if it represents a C _1-6 alkyl group which may have a substituent, or R ² and R ³ are each a hydrogen atom or an amino, nitro, mono- - or di -C _1-6 alkylamino, C _{1- 6} alkoxy and C _1-6 alkyl-carbonyloxy represents a C _1-6 alkyl group optionally having 1 to 4 substituents, and R ² and R ³ are adjacent to each other -C = C- With other than carbon atom, for example, a nitrogen atom,
A 5- to 7-membered ring optionally containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and the like, Z
¹ is a showing halogen, a C _6-10 arylsulfonyloxy or C _1-4 alkylsulfonyloxy (1) or (2) The process according,

(4) R ⁴ and R ⁵ are each selected from a hydrogen atom, amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-carbonyloxy. To C _1-6 alkyl groups optionally having 4 substituents, amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-carbonyloxy A C _3-6 cycloalkyl group optionally having 1 to 4 substituents selected from the following, or (i) amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl - 1 selected from carbonyloxy to four may have a substituent group C _1-6 alkyl, selected from (ii) C _1-6 alkyl and 5- to 7-membered cyclic amino With one or two substituents Be an amino, (iii) acetamide, (iv) nitro, (v) C _1-6 alkoxy and (vi)
C _1-6 alkyl-carbonyloxy represents a C _6-14 aryl group _optionally having 1 to 5 substituents, or R ⁴ and R ⁵ are (i) together with an adjacent nitrogen atom. C _1- which may have 1 to 4 substituents selected from amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-carbonyloxy. ₆ alkyl, (ii) C _1-6 alkyl and amino optionally having 1 or 2 substituents selected from 5 to 7 membered cyclic amino, (iii) nitro and (iv) C _1-6 alkoxy May have 1 to 5 substituents selected from

Embedded image , Z ² represents a hydrogen atom or an alkali metal, and Y 2
Is the expression

[Chemical 21] [Wherein R ⁶ and R ⁷ are each a hydrogen atom or amino, nitro, mono- or di-C _1-6 alkylamino,
C _1-6 alkoxy and C _1-6 alkyl - group or (i) amino represented by 1 to selected from carbonyloxy shows four optionally substituted C _1-6 alkyl group] , nitro, mono- - or di -C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl - which may have 1 selected from carbonyloxy to 4 substituents C _1-6 From alkyl, (ii) C _1-6 alkyl and amino optionally having 1 or 2 substituents selected from 5 to 7 membered cyclic amino, (iii) nitro and (iv) C _1-6 alkoxy May have 1 to 5 substituents selected

Embedded image The method according to (1) or (2) above, wherein

(5) The production method according to the above (1) or (2), wherein R ¹ and R ² each represent a hydrogen atom or a lower alkyl group, and R ³ represents an alkyl group, (6) R ⁴ and R ⁵ Are each a hydrogen atom or a lower alkyl group, and Y is a formula

Embedded image [In the formula, R ⁶ ′ and R ⁷ ′ each represent a hydrogen atom or a lower alkyl group. ] The group represented by these, m is an integer of 1 to 3, and n is an integer of 1 to 4, The manufacturing method as described in said (1) or (2), (7) R ⁴ and R ⁵ are hydrogen The production method according to (6) above, wherein atom, m and n are 1, (8) the production method according to (1) or (2) above, wherein the metal alkoxide is sodium tert-butoxide.

(9) 6-Chloro-7-methyl-s-triazolo [1,5-b] pyridazine or its salt and 3-aminosulfonyl-2,2-diethyl-1-propanol or its salt and sodium tert- React with butoxide 6- (2,2-diethyl-
3-sulfamoyl-1-propoxy) -7-methyl-s-triazolo [1,5-b] pyridazine or a salt thereof, as described in (1) above, and (10) 6-chloro-7 -Isopropyl-s-triazolo [1,5-
b] Pyridazine or a salt thereof and 3-aminosulfonyl-2,2-
Dimethyl-1-propanol or its salt and sodium ter
The method for producing 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl-s-triazolo [1,5-b] pyridazine or a salt thereof by reacting with t-butoxide, 1) The production method according to 1) is provided.

The term "cyclic hydrocarbon group" as used herein includes, for example, cyclopropyl, cyclobutyl,
C _3-6 cycloalkyl group such as cyclopentyl and cyclohexyl, for example, cyclopropenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl,
C _3-6 cycloalkenyl group such as 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, etc., for example, phenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4-, or 9-
A C _6-14 aryl group (preferably phenyl) such as phenanthryl, 1-, 2-, 4-, 5- or 6-azulenyl is used. The term “alkyl group” as used herein includes, for example, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl,
A C _1-15 alkyl group such as pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and the like are used. The term "lower alkyl group" used in the present specification means, for example, a linear or branched C _1-6 alkyl group. _{Examples of the} C _1-6 alkyl group include methyl, ethyl, n-propyl, i
-Propyl, n-butyl, i-butyl, tert-butyl,
N-pentyl, n-hexyl and the like are used. Examples of the substituent which the “alkyl group”, “lower alkyl group”, “cycloalkyl group” and “cycloalkenyl group” may have include, for example, amino, nitro, mono- or di-lower alkylamino (eg, , Mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino etc.), lower alkoxy (eg methoxy, ethoxy,
1 to 4 selected from C _1-6 alkoxy such as propoxy and hexyloxy) and lower alkylcarbonyloxy (eg C _1-6 alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy).
Are used.

Examples of the substituent which the "aryl group" may have include lower alkyl which may have a substituent, amino which may have a substituent, acetamide, nitro and lower alkoxy. 1 to 5 selected from (for example, C _1-6 alkoxy such as methoxy, ethoxy and propoxy) and lower alkyl-carbonyloxy (such as C _1-6 alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy). Is used. Here, examples of the substituent which lower alkyl (eg, C _1-6 alkyl group such as methyl, ethyl, n-propyl) may have include, for example, amino, mono- or di-lower alkylamino (eg, Mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino etc. and lower alkoxy (eg C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy etc.) ) And the like are used.
Examples of the substituent that the amino group may have include C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.). ) Or the like is used. As the term "halogen" used in the present specification, for example, fluorine, chlorine, bromine, iodine and the like are used.

The term "5- to 7-membered ring formed together with adjacent -C = C-" means, for example, 1 selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to the carbon atom.
To 5 to 7 which may contain 4 to 4 heteroatoms
It means a member ring. Specifically, in particular, C _5-7 cycloalkene such as cyclopentene, cyclohexene and cycloheptene, a 5- to 7-membered aromatic hydrocarbon such as benzene, for example, 5 or 6 consisting of carbon atom and nitrogen atom such as pyrrole, pyridine and piperidine. Member nitrogen-containing heterocycles are often used. The term "3- to 7-membered homocyclic ring" means, for example, a 3- to 7-membered cyclic hydrocarbon consisting of only carbon atoms. Specifically, for example, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, C _3-7 cycloalkene such as cyclopropene, cyclobutene, cyclopentene, cyclohexene and cycloheptene, benzene and the like. A 5- to 7-membered aromatic hydrocarbon is often used. The divalent group derived from the "3- to 7-membered homocyclic ring" means one to two hydrogen atoms from one carbon atom in the above-mentioned 3- to 7-membered cyclic hydrocarbon, or two different hydrogen atoms. It means a divalent group in which one hydrogen atom is removed from each carbon atom. Specifically, for example,

Embedded image Etc. are used, and preferably

Embedded image And more preferably

Embedded image And so on.

The term "3- to 7-membered heterocycle" refers to the above-mentioned "3- to 7-membered homocycle", for example, other than carbon atom,
For example, it means a 3- to 7-membered heterocyclic ring optionally containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like. Specifically, for example, aziridine, dioxane, oxetane, tetrahydrofuran, furan, tetrahydropyran, pyrrole, azetidine, pyrrolidine, pyridine, piperidine, piperazine,
Tetrahydrothiophene, thiophene, homopiperidine, morpholine, etc. are used. The divalent group derived from the “3- to 7-membered heterocycle” means two hydrogen atoms from the same carbon atom in the aforementioned 3- to 7-membered heterocycle,
Alternatively, it means a divalent group obtained by removing one hydrogen atom from each of two different atoms. Specifically, for example,

Embedded image Are used. The term “nitrogen-containing heterocyclic group” includes, for example, one nitrogen atom and may further include, for example, 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like 3 To a 13-membered nitrogen-containing heterocycle or the like, which means a group obtained by removing one hydrogen atom from a nitrogen atom in a ring or a group which forms a quaternary ion on the nitrogen atom. Specifically, for example,

Embedded image A 3- to 9-membered (preferably 3- to 6-membered) nitrogen-containing heterocyclic group such as is commonly used.

The "3 to 7 membered homocyclic ring", "3 to 7
Examples of the substituent that the “membered heterocycle” and “nitrogen-containing heterocyclic group” may have include lower alkyl that may have a substituent, amino that may have a substituent, nitro and Lower alkoxy (eg methoxy, ethoxy,
1 to 5 selected from C _1-6 alkoxy such as propoxy) and the like are used. Here, lower alkyl (eg, C _1-6 such as methyl, ethyl, n-propyl, etc.)
Examples of the substituent which the alkyl group) may have include, for example, amino-, nitro-, mono- or di-lower alkylamino (for example, mono- or di-amino such as methylamino, ethylamino, propylamino, dimethylamino and diethylamino). -C _1-6 alkylamino, etc., lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, hexyloxy, etc.) and lower alkylcarbonyloxy (eg C _1-, such as acetyloxy, ethylcarbonyloxy, etc. 1 to 4 selected from ( ₆ alkyl-carbonyloxy etc.) and the like are used.
Examples of the substituent that the amino group may have include C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.) and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.). ) Or the like is used.

In the above formulas [I], [III] and [V], R ¹ represents a hydrogen atom or an alkyl group which may have a substituent which does not participate in the reaction in the production process of the present invention. R ¹ is preferably, for example, a hydrogen atom or C _1-6 alkyl (preferably C _1-3 alkyl such as methyl, ethyl, n-propyl, etc.), and a hydrogen atom is particularly often used. In the above formulas [I], [III] and [V], R ² and R ³ each represent a hydrogen atom or an alkyl group which may have a substituent which does not participate in the reaction in the production method of the present invention, or R ² and R ³ may form a 5- to 7-membered ring with adjacent —C═C—. R
Preferred examples of ² include a hydrogen atom, C _1-6 alkyl (preferably C _1-3 alkyl such as methyl, ethyl, n-propyl, etc.) and the like. Especially, hydrogen atom is widely used. As R ³ , for example, a hydrogen atom or a C _1-6 alkyl group is preferable, and a branched C _3-6 alkyl group (for example,
Isopropyl, isobutyl, tert-butyl, etc.) are more preferable, and particularly isopropyl group, tert-butyl group, etc. are widely used, and for example, isopropyl group is most preferable. Further, it is also preferable that R ² and R ³ form a 5- to 7-membered cyclic hydrocarbon together with the adjacent —C═C—, particularly cyclohexene and benzene. In the above formulas [II] and [III], X represents an oxygen atom or S (O) p (p represents an integer of 0 to 2).
As X, for example, an oxygen atom or S is preferable,
In particular, oxygen atoms are commonly used. The above formulas [II] and [I
II], [IV] and [V], Y is the formula

Embedded image [In the formula, R ⁶ and R ⁷ each represent a hydrogen atom or an alkyl group which may have a substituent. ] Or a divalent group derived from a 3- to 7-membered homocycle or heterocycle which may have a substituent. As the “substituent” which the “alkyl group” represented by R ⁶ and R ⁷ may have, the same substituents as the above “alkyl” may be used. Substituents that do not participate in the reaction in the production method of the invention are preferred. As Y,
Expression

Embedded image [In the formula, R ⁶ ′ and R ⁷ ′ each represent a hydrogen atom or a lower alkyl group. ] The group etc. which are represented by these are preferable.
The “lower alkyl group” represented by R ⁶ ′ and R ⁷ ′ is C such as methyl, ethyl, n-propyl and i-propyl.
_1-3 alkyl is preferred. Preferable R ⁶ ′ and R ⁷ ′ include a hydrogen atom or C _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.), and especially R ⁶ ′ and R ⁷ ′ are the same or different and are C. _1-3 alkyl (eg, methyl, ethyl, n-propyl, etc.) and the like are preferable, and it is particularly preferable that both R ⁶ ′ and R ⁷ ′ are methyl or ethyl. Further, it is also preferable that Y is a divalent group derived from a 3- to 7-membered homocyclic ring or heterocyclic ring which may have a substituent which does not participate in the reaction in the production method of the present invention.

Embedded image And more preferably

Embedded image Are commonly used, especially

Embedded image Are most commonly used.

In the above formulas [II], [III], [IV] and [V], R ⁴ and R ⁵ each have a hydrogen atom, an optionally substituted alkyl group or a substituent. And R ⁴ and R ⁵ may form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom. The "cyclic hydrocarbon group" is preferably a C _3-6 cycloalkyl group or a C _6-14 aryl group. Examples of R ⁴ and R ⁵ include a hydrogen atom and lower C _1-6 alkyl (preferably methyl, ethyl, n-
C _1-3 alkyl such as propyl) and the like are preferable, and especially a hydrogen atom and the like are widely used. The above formulas [II] and [II
In I], [IV] and [V], m is 0 to 4
Indicates an integer. As m, an integer of 1 to 4 is preferable, an integer of 1 to 3 is particularly used, and 1 is generally used. n represents an integer of 0 to 4, and as n, an integer of 1 to 4 is preferable, and 1 or the like is particularly widely used. Above all, it is most preferable that both m and n are 1.

Compounds [I prepared by the method of the present invention
As the salt of II] or [V], a physiologically acceptable acid addition salt is particularly preferable. For such salt,
For example, salts with inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.), or organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid,
Tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.) and the like salts are used. Furthermore, when the compound [III] or [V] of the present invention or a compound derived from these has an acidic group as a substituent, the compound [III] or [V] is an inorganic base (eg, sodium, potassium). ,
A salt may be formed with an alkali metal or alkaline earth metal such as calcium or magnesium, ammonia, etc.) or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine).

Next, the manufacturing method of the present invention will be described in detail. (A) Compound [I produced by the production method of the present invention
II] or a salt thereof has the formula

Embedded image [Wherein R ¹ represents a hydrogen atom or an alkyl group which may have a substituent, and R ² and R ³ each represent a hydrogen atom or an alkyl group which may have a substituent, or
Alternatively, R ² and R ³ may form a 5- to 7-membered ring with adjacent —C═C—, and Z ¹ represents a leaving group. ] Or a salt thereof represented by the formula

Embedded image [Wherein R ⁴ and R ⁵ are each a hydrogen atom, an alkyl group which may have a substituent or a cyclic hydrocarbon group which may have a substituent, or R ⁴ and R ⁵ are A nitrogen-containing heterocyclic group which may be substituted with an adjacent nitrogen atom may be formed, Z ² is a leaving group, X is an oxygen atom or S (O) p (p is an integer of 0 to 2). , And Y is the expression (1).

Embedded image [Wherein, R ⁶ and R ⁷ each represent a hydrogen atom or a lower alkyl group which may have a substituent] or (2) 3 to 7 which may have a substituent. A divalent group derived from a membered homocycle or heterocycle, m
Represents an integer of 0 to 4, and n represents an integer of 0 to 4. ] Or a salt thereof represented by the formula

Embedded image [In the formula, R ⁸ represents a branched C _3-6 alkyl group and M represents an alkali metal. ] It can be obtained by reacting with a metal alkoxide represented by. Examples of the leaving group represented by Z ¹ include halogen (eg, chlorine, bromine,
Iodine), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-tolylsulfonyloxy), C _1-4 alkylsulfonyloxy (eg,
(Methanesulfonyloxy) and the like (preferably halogen such as chlorine) are used. As the leaving group represented by Z ² , when X is an oxygen atom or a sulfur atom, for example, a hydrogen atom or an alkali metal such as sodium or potassium (preferably hydrogen) is used, and X is −
When SO − or —SO ₂ —, for example, sodium,
An alkali metal such as potassium is used. In this reaction, the compound [III] or a salt thereof is used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [II] or a salt thereof.

Examples of the branched C _3-6 alkyl group represented by R ⁸ include isopropyl, isobutyl, tert-butyl and the like, and the tert-butyl group is particularly preferable. Examples of the alkali metal represented by M include sodium and potassium, with sodium being particularly preferable. This reaction includes alcohols such as methanol and ethanol, ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile and the like. Can be carried out in an inert solvent such as nitriles, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, or pyridines. As the inert solvent, for example, ethers such as dioxane and tetrahydrofuran are preferable,
Tetrahydrofuran is particularly preferred. Further, in this reaction, it is not necessary to add the compound [I] as a substrate or a salt thereof in divided portions. Further, the compound [I] may be added to the reaction product after the reaction of the compound [II] with the metal alkoxide, but it is also possible to simultaneously mix all the reaction reagents, and the reaction temperature is usually 10 to 10 200 ° C, preferably 50 to 100 ° C, more preferably 50 to 7
It is 0 ° C, most preferably 60 to 65 ° C. The reaction time is generally 30 minutes to 24 hours, preferably 1 to 10 hours, more preferably 1 to 6 hours, most preferably 2 to 5 hours.

Further, (B) the compound [V] or its salt produced by the production method of the present invention has the formula

Embedded image [In the formula, each symbol has the same meaning as described above. ] Or a salt thereof represented by the formula

Embedded image [In the formula, each symbol has the same meaning as described above. ] It can be obtained by reacting a compound represented by the following formula or a salt thereof with a metal alkoxide. "Metal alkoxide" includes sodium methoxide, sodium ethoxide,
Alkali metal C _1-6 such as sodium tert-butoxide
Alkoxides (preferably alkali metal C _3-6 alkoxides) are mentioned, and sodium tert-butoxide is particularly preferable. This reaction includes alcohols such as methanol and ethanol, ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile and the like. Can be carried out in an inert solvent such as nitriles, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, or pyridines. As the inert solvent, for example, ethers such as dioxane and tetrahydrofuran are preferable,
Tetrahydrofuran is particularly preferred. Further, in this reaction, it is not necessary to add the compound [I] as a substrate or a salt thereof in divided portions. Further, usually, the compound [I] is added to the reaction product after the reaction of the compound [IV] with the metal alkoxide.

Embedded image [In the formula, each symbol has the same meaning as described above. ] When using the compound represented by the above formula, all reaction reagents can be mixed at the same time, and by doing so, the reaction process can be simplified and the reaction time can be shortened, which is advantageous. The reaction temperature is generally 10 to 200 ° C, preferably 50 to 100 ° C, more preferably 50 to 70 ° C, most preferably 60 to 65 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 1 to 10 hours,
More preferably 1 to 6 hours, most preferably 2 to 5 hours. The compound [III] or [V] thus obtained can be converted into a salt according to a conventional method in the case of a free form, or can be converted into a free form or other salt according to a conventional method when forming a salt. it can. The compound [III] or [V] or salt thereof thus obtained is
Known means such as solvent extraction, liquid conversion, phase transfer, salting out,
It can be isolated and purified by crystallization, recrystallization, chromatography and the like. Compound [III] or [V]
Alternatively, when the salt is an optically active substance, it can be separated into a d-form and an l-form by a usual optical resolution means.

Next, the starting compounds [I] and [I] used for the production of the compound [III] or [V] or a salt thereof.
A method for producing I] and [IV] or salts thereof will be described. Examples of salts of these compounds include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid). Acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and salts thereof are used. Furthermore, when these compounds have an acidic group that does not participate in the reaction in the production method of the present invention as a substituent, an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium, etc., Ammonia) or organic bases (eg tri-C such as triethylamine)
_1-3 alkylamine and the like).

The starting compound [I] or a salt thereof can be prepared, for example, by the journal of organic chemistry (J. Or
g. Chem.) 39, 2143 (1987), JP-A-3-223287, or a method analogous thereto. Starting compounds [II] and [I
V] or a salt thereof is, for example, Chemish Berichte (Ch
em. Ber.) 91, 2130 (1958), Journal of Organic Chemistry (J. Org. Ch.
em.) 52, p. 2162 (1987), JP-A-3
It can be synthesized by the method described in -223287 or the like or a method similar thereto.

These starting compounds or salts thereof thus obtained can be isolated and purified by known means such as solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. However, it may be directly used as a raw material for the next step without isolation. Further, in each of the reactions of the present invention and each reaction of the synthesis of the raw material compounds, when the raw material compounds have an amino group as a substituent, a protecting group generally used in peptide chemistry or the like was introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include formyl, optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl (eg, , Methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl), trityl, phthaloyl, N, N-
Dimethylaminomethylene or the like is used. These substituents include C _1-6 alkyl-carbonyl (eg,
(Methyl carbonyl, ethyl carbonyl, butyl carbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. As a method for removing the protecting group, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride And a method of treating with palladium acetate or the like.

The compound [III] or [V] or a salt thereof obtained by the production method of the present invention has excellent anti-allergic action, anti-inflammatory action and anti-PAF (platelet activating factor) action, Since it has low toxicity (acute toxicity: LD ₅₀ > 2 g / kg), it can be used as a safe anti-asthma agent for mammals (human, mouse, dog, rat, cow, etc.). The above-mentioned compounds or their salts may be used in the form of bulk powder, but they are usually administered in the form prepared with a pharmaceutical carrier. Specific examples thereof include tablets, capsules, granules, fine granules, powders, syrups, injections,
Inhalants are used. These preparations are prepared according to a conventional method. As the oral pharmaceutical carrier, substances commonly used in the oral pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium carboxymethyl cellulose and the like can be used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in pharmaceutical preparations can be appropriately added. The dosage of these preparations varies depending on the age, body weight, symptoms, administration route, number of administrations, etc., but is usually 0.1 to 100 mg / kg, preferably 1 to 50 mg / kg per day for an adult. More preferably, 1 to 10 mg / kg should be administered once or twice a day in divided doses. The administration route may be oral or parenteral.

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0026]

【Example】

Example 1 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-methyl-s-triazolo [1,5-
b] Preparation tetrahydrofuran 260L sodium tert- butoxide (NaOC (CH _{3) 3)} pyridazine 16.9kg and stirred charged at room temperature. 3-aminosulfonyl-2,2-diethyl-1-propanol 15.7k with stirring at room temperature
g was added. The mixture was stirred at about 60 ° C. for 30 minutes, and 13.6 kg of 6-chloro-7-methyl-s-triazolo [1,5-b] pyridazine was added. The mixture was stirred at about 60 ° C for about 2 hours. After cooling to about 25 ° C., 110 L of water was added. The pH was adjusted to 7 by adding about 8.2 L of concentrated hydrochloric acid. About 5 under reduced pressure
After distilling tetrahydrofuran off at 0 ° C., 310 L of water was added. Stirred at room temperature for about 1 hour. The precipitated crystals were centrifuged, and the crystals were washed with 100 L of water. The crystals were dried under reduced pressure at about 50 ° C. for 17 hours. 21.5k for the title compound
g was obtained. The yield of the title compound based on 6-chloro-7-methyl-s-triazolo [1,5-b] pyridazine was 8
The content was 1.4% and the content was 100% (HPLC).

Example 2 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl-s-triazolo [1,
Preparation of 5-b] pyridazine Sodium tert-butoxide (NaOC (C
H _{3) 3)} was dissolved 1.01g of tetrahydrofuran 20 mL. 3-aminosulfonyl-2,2-dimethyl-1
-Add 836 mg of propanol and add 1 in a 70 ° C water bath.
Stirred for hours. Cooled, 6-chloro-7-isopropyl-s-triazolo [1,5-b] pyridazine 983 mg.
Was added and the mixture was refluxed for 2 hours. After cooling, add 30 mL of ice water,
Tetrahydrofuran was distilled off under reduced pressure. 1N for residue
Hydrochloric acid was added to adjust the pH to 5.0 to precipitate crystals.
The precipitated crystals were collected by filtration and washed well with water. The crystal was dried to obtain 1.5 g of the title compound. The title compound, 6-chloro-7-isopropyl-s-triazolo [1,5-
b] The yield based on pyridazine was 91.7%.

Example 3 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl-s-triazolo [1,
Preparation of 5-b] pyridazine 6-chloro-7-isopropyl-s-triazolo [1,
5-b] pyridazine 197 g, 3-aminosulfonyl-
2,2-dimethyl-1-propanol 176g and sodium tert- butoxide (NaOC (CH _{3) 3)}
202 g was suspended in 3 L of tetrahydrofuran. 60
Stir at 80 ° C. for 80 minutes. Add 2 kg of ice water to the reaction mixture,
The pH was adjusted to 4.0 using 107 mL of concentrated hydrochloric acid. Tetrahydrofuran was distilled off, and the precipitated crystals were collected by filtration and washed with 1 L of cold water and 1 L of cold acetone-water (1: 1). The crystals were dried to give 291.6 g of the title compound. The yield of the title compound based on 6-chloro-7-isopropyl-s-triazolo [1,5-b] pyridazine was 89.2.
%, The content was 99.7% (HPLC).

Reference Example 1 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-methyl-s-triazolo [1,5-
b] Preparation of pyridazine 15 L of tetrahydrofuran was injected into the reactor. The inside of the reactor was replaced with argon gas. While stirring under an argon stream, 1 part of 434 g of NaH (60%, in oil) was added.
Added over 0 minutes. While stirring at room temperature under a stream of argon, 3-aminosulfonyl-2,2-diethyl-1-
975 g of propanol was added over 1 hour. The mixture was heated to about 53 ° C. with stirring under a stream of argon. 53-57
6-chloro-7-methyl-s-triazolo [1,5-b] pyridazine 76 with stirring under argon flow at 60 ° C.
5.2 g was added over 4 hours. The mixture was stirred at about 65 ° C for 2.5 hours. After completion of the reaction, while stirring under an argon stream,
An aqueous solution prepared by dissolving 59.3 g of ammonium chloride in 1 L of water was added dropwise to the reaction solution over 1 hour. Further, 9 L of water was dropped. Tetrahydrofuran was distilled off under reduced pressure. The residue was cooled to 20 ° C. While maintaining the temperature below 25 ° C, 525 ml of concentrated hydrochloric acid was added dropwise to adjust the pH to 7.2. The precipitated crystals were collected by filtration and washed with 10 L of water twice for repulping. Further, the repulp was washed with 2 L of acetone. The obtained crystals were dried under reduced pressure at about 40 ° C. The crystal was analyzed and found to contain 8.0% of liquid paraffin. The crystals were suspended in 3.3 L of a mixed solution of hexane-ethyl acetate (10: 1) and stirred for 5 hours at room temperature. The crystals were collected by filtration.
The same wet crystals were mixed with hexane-ethyl acetate (10: 1) as a mixture 3.
It was suspended in 3 L and stirred for 3 hours at room temperature. The crystals were collected by filtration, and the crystals were mixed with hexane-ethyl acetate (10: 1) 1.
Washed with 1 L. The obtained crystals were dried under reduced pressure at about 40 ° C. Analysis of the crystals revealed that the liquid paraffin was 4000.
ppm was contained. The crystals were mixed with acetone-water (10:
1) It was dissolved in 23.5 L of the mixed solution under reflux. Activated carbon 10
g, and stirred under reflux for 10 minutes. The activated carbon was separated, and the activated carbon was washed with 1 L of a mixed solution of acetone-water (10: 1). 21 L of water was added to the filter / washing solution, and at room temperature for 1 hour,
The mixture was further stirred at 5 ° C or lower for 2 hours. The crystals were separated, and the crystals were mixed with acetone-water (10: 1) 2 L and then with water 1.
Wash with L (twice). The wet crystals were suspended in 2.7 L of water, stirred at 60 ° C for 3 hours, and then cooled to room temperature. The crystals were separated and washed with 4 L of water. Crystals under reduced pressure at about 50 ℃
And dried. 1039 g of the title compound was obtained. The title compound, 6-chloro-7-methyl-s-triazolo [1,5-
The yield based on b] pyridazine was 69.5%.
The liquid paraffin content was 1000 ppm.

Reference Example 2 6- (2,2-Dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl-s-triazolo [1,
Preparation of 5-b] pyridazine 60% oily sodium hydride (0.336 g) was suspended in tetrahydrofuran (30 ml) to give 3-hydroxy-2,
2-Dimethylpropane-1-sulfonamide 0.669
g was added and the mixture was heated to reflux for 1 hour. After cooling, 6-chloro-7
0.748 g of isopropyltriazolo [1,5-b] pyridazine was added, and the mixture was heated under reflux for 4 hours. After cooling, ice water was added, the pH was adjusted to 6.0 with 1N hydrochloric acid, and the mixture was extracted with tetrahydrofuran ethyl acetate (1: 1). The extract was washed with saturated brine and dried over magnesium sulfate. Concentrate under reduced pressure and chromatograph the residue on silica gel with dichloromethane:
Elution was performed with ethyl acetate: methanol = 10: 10: 1.
The target fractions were collected and the obtained crystals were recrystallized from acetone-water to obtain 1.10 g of the title compound.

[0030]

INDUSTRIAL APPLICABILITY According to the method of the present invention, a compound represented by the formula [III] or [V] or a salt thereof is highly purified,
It can be produced in high yield, easily and safely by an industrially advantageous method.

Claims (10)

[Claims] (1) Formula (1) [Wherein R ¹ represents a hydrogen atom or an alkyl group which may have a substituent, and R ² and R ³ each represent a hydrogen atom or an alkyl group which may have a substituent, or
Alternatively, R ² and R ³ may form a 5- to 7-membered ring with adjacent —C═C—, and Z ¹ represents a leaving group. ] The compound or its salt represented by these, and a formula: [Wherein R ⁴ and R ⁵ are each a hydrogen atom, an alkyl group which may have a substituent or a cyclic hydrocarbon group which may have a substituent, or R ⁴ and R ⁵ are A nitrogen-containing heterocyclic group which may be substituted with an adjacent nitrogen atom may be formed, Z ² is a leaving group, X is an oxygen atom or S (O) p (p is an integer of 0 to 2). , And Y is the formula (1) [Wherein, R ⁶ and R ⁷ each represent a hydrogen atom or a lower alkyl group which may have a substituent] or (2) 3 to 7 which may have a substituent. A divalent group derived from a membered homocycle or heterocycle, m
Represents an integer of 0 to 4, and n represents an integer of 0 to 4. ] The compound or its salt represented by these, and a formula: [In the formula, R ⁸ represents a branched C _3-6 alkyl group and M represents an alkali metal. ] It is a formula characterized by reacting with a metal alkoxide [In the formula, each symbol has the same meaning as described above. ] Or a salt thereof. 2. The formula: [In the formula, each symbol has the same meaning as in claim 1. ] The compound or its salt represented by these, and a formula: [Wherein the symbols have the same meanings as in claim 1.] ] The compound represented by the formula or a salt thereof is reacted with a metal alkoxide. [In the formula, each symbol has the same meaning as described above. ] Or a salt thereof. 3. R ¹ is (1) a hydrogen atom or (2) amino, nitro, mono- or di-C _1-6 alkylamino,
C _1-6 alkoxy and C _1-6 alkyl - or shows a one to four may have a substituent group C _1-6 alkyl group selected from carbonyloxy, or R ² and R ³ are each ( 1) hydrogen atom or (2) amino, nitro,
Mono - from 1 selected from carbonyloxy to four may have a substituent group C _1-6 alkyl group - or di -C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl Shown or R ² and R ³ are adjacent -C = C
Together with-may form a 5- to 7-membered ring which may contain 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom, and Z ¹
Is halogen, C _6-10 arylsulfonyloxy or C
Claim 1 or 2 which shows _1-4 alkylsulfonyloxy
Production method as described. 4. R ⁴ and R ⁵ are each (1) a hydrogen atom, (2) amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-carbonyl. C _1-6 alkyl group optionally having 1 to 4 substituents selected from oxy, (3) amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _3-6 cycloalkyl group optionally having 1 to 4 substituents selected from C _1-6 alkyl-carbonyloxy, or (4) (i) amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-
1 selected from carbonyloxy to four may have a substituent group C _1-6 alkyl, 1 or 2 selected from (ii) C _1-6 alkyl and 5- to 7-membered cyclic amino
1 to 5 selected from amino optionally having 1 substituent, (iii) acetamide, (iv) nitro, (v) C _1-6 alkoxy and (vi) C _1-6 alkyl-carbonyloxy. Or an optionally substituted C _6-14 aryl group, or R ⁴ and R ⁵ together with the adjacent nitrogen atom are (i) amino, nitro, mono- or di-C _1-6
Alkylamino, C _1-6 alkoxy and C _1-6 alkyl - 1 selected from carbonyloxy to four may have a substituent group C _1-6 alkyl, (ii) C _1-6 alkyl and 5 To amino optionally having 1 or 2 substituents selected from a to 7-membered cyclic amino, (iii) nitro and (iv) having 1 to 5 substituents selected from C _1-6 alkoxy May be embedded , Z ² represents a hydrogen atom or an alkali metal, and Y 2
Is the formula (1) [Wherein R ⁶ and R ⁷ are (i) a hydrogen atom or (ii) amino, nitro, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and C _1-6 alkyl-carbonyloxy, respectively. Represents a C _1-6 alkyl group optionally having 1 to 4 substituents selected from the following] or (2) (i) amino, nitro, mono- or di-C _{1- 6} alkylamino, C _1-6 alkoxy and C _1-6 alkyl-
1 selected from carbonyloxy to four may have a substituent group C _1-6 alkyl, 1 or 2 selected from (ii) C _1-6 alkyl and 5- to 7-membered cyclic amino
Optionally substituted with 1 to 5 selected from amino, (iii) nitro and (iv) C _1-6 alkoxy.
Optionally have 4 substituents The manufacturing method of Claim 1 or 2 which shows these. 5. R ¹ and R ² each represent a hydrogen atom or a lower alkyl group, and R ³ represents an alkyl group.
Or the production method according to 2. 6. R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group, and Y is a compound of the formula: [In the formula, R ⁶ ′ and R ⁷ ′ each represent a hydrogen atom or a lower alkyl group. ] The manufacturing method of Claim 1 or 2 which shows the group represented by these, m shows the integer of 1-3, and n shows the integer of 1-4. 7. R ⁴ and R ⁵ are hydrogen atoms, and m and n are 1
The manufacturing method of Claim 6 which shows. 8. The method according to claim 1, wherein the metal alkoxide is sodium tert-butoxide. 9. 6-Chloro-7-methyl-s-triazolo [1,5-
b] Pyridazine or a salt thereof and 3-aminosulfonyl-2,2-
Diethyl-1-propanol or its salt and sodium ter
A method for producing 6- (2,2-diethyl-3-sulfamoyl-1-propoxy) -7-methyl-s-triazolo [1,5-b] pyridazine or a salt thereof by reacting with t-butoxide 1. The production method according to 1. 10. 6-Chloro-7-isopropyl-s-triazolo [1,5-b] pyridazine or a salt thereof and 3-aminosulfonyl-2,2-dimethyl-1-propanol or a salt thereof and sodium tert-butoxide. React with 6- (2,2-dimethyl-
3-sulfamoyl-1-propoxy) -7-isopropyl-s-
The production method according to claim 1, which is a production method of triazolo [1,5-b] pyridazine or a salt thereof.