JPH0730035B2 - Process for producing pyridazinone compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a novel method for producing a pyridazinone compound having a useful pharmacological action such as selective anxiolytic action and biological defense enhancing action. .

[Conventional technology]

JP-A-61-56169, JP-A-62-252789, JP-A-1-9991, JP-A-1-6278, JP-A1-228969, and JP-A-1-250383 have an anxiolytic effect or Various pyridazinone compounds having a biological defense enhancing action have been shown.

Meanwhile, Journal of Medicinal Chemistry, Vol. 14, p. 262 (1
(971) reported oxidation with bromine as a method of introducing a double bond at the 4,5-position of the pyridazinone ring, and British Patent No. 1168291 reported oxidation with sodium metanitrobenzenesulfonate. . In the above-mentioned publication, these methods are used as a method for introducing a double bond at the 4- and 5-positions of the pyridazinone ring.

[Problems to be Solved by the Invention]

However, in the method of introducing a double bond by oxidation with bromine, a brominated by-product is mixed, and in the oxidation with sodium metanitrobenzenesulfonate, the pyridazinone ring may be unstable and decomposed into alkali, which may be a problem. There are many problems to be solved.

[Means for Solving the Problems]

The present inventors have conducted extensive studies to solve these problems, and as a result, in the presence or absence of a sulfoxide such as dimethyl sulfoxide, in the 4,5-position of the pyridazinone ring under mild conditions by reaction with an acid. The inventors have found a novel method for introducing a double bond and have completed the present invention.

That is, the present invention has the general formula Wherein ring A benzene ring or thiophene ring, R ^1, R
² is the same or different and is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, lower alkyl, lower alkoxy or lower alkanoylamino, R ³ is hydrogen, alkyl having 1 to 8 carbons, hydroxy Substitution selected from halogen, hydroxy, amino, nitro, cyano, lower alkyl, lower alkoxy, lower alkanoylamino, haloalkyl, acyloxy, lower alkoxycarbonyl and carboxy on alkyl, alkanoyloxyalkyl, aryl, aralkyl, heteroaryl or aromatic ring. An aryl, aralkyl or heteroaryl having at least one group, X is O, S, SO, SO ₂ , CH ₂ or NR ⁴ (R ⁴ represents hydrogen, lower alkyl, acyl or benzenesulfonyl).
And n represents 1 or 2. ] The compound represented by the formula is reacted with an acid in the presence of a sulfoxide compound, if necessary. (In the formula, each symbol has the same meaning as defined above.) A method for producing a pyridazinone compound represented by

In the above definition, halogen is chlorine, bromine, fluorine and iodine, and lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc.
Lower alkoxy is methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, isobutoxy, tertiary butoxy and the like, lower alkanoylamino is acetylamino, propionylamino, butyrylamino, pivaloylamino and the like, and alkyl having 1 to 8 carbons is a straight or branched chain. , Methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl and the like, and hydroxyalkyl is hydroxymethyl, hydroxyethyl, hydroxy. Propyl, hydroxybutyl, etc. are alkanoyloxyalkyl and acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, propionyloxy. Ropyl, propionyloxybutyl, etc., aryl is phenyl, naphthyl, etc., aralkyl is benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, etc., and heteroaryl is pyridyl. , Thienyl, furyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, benzimidazolyl and the like, and haloalkyl is fluoromethyl, bromomethyl, chloromethyl, iodomethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2. -Trifluoroethyl, etc., acyloxy is acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, benzoyloxy, etc., and lower alkoxycarbonyl is methoxycarboxyl. Rubonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl and the like, and acyl means acetyl, propionyl, butyryl, isobutyryl, benzoyl and the like.

The method for producing the compound of general formula (I) according to the method of the present invention is as follows.

Method 1 General formula (In the formula, each symbol has the same meaning as defined above.) A sulfoxide compound represented by the following formula is used as a suitable acid (hydrobromic acid such as hydrobromic acid, hydrochloric acid or hydroiodic acid,
Alkylsulfonic acid such as methanesulfonic acid and trifluoromethanesulfonic acid, aliphatic carboxylic acid such as acetic acid, formic acid and trifluoroacetic acid, arylsulfonic acid such as p-toluenesulfonic acid, and the like, or a mixture thereof)
~ A method of reacting from 0 ° C to around the boiling point of the acid for several tens of hours.

Preferably, the compound of the general formula (II) -1 is heated under reflux in trifluoroacetic acid for 15 to 25 hours, stirred in acetic acid in the presence of hydrogen bromide at room temperature, or in methanesulfonic acid. It can be produced by stirring at 60 to 80 ° C for 15 minutes to several tens of hours.

Method 2 General formula (In the formula, each symbol has the same meaning as described above.), A compound represented by the following formula is used as a sulfoxide (dimethyl sulfoxide, diphenyl sulfoxide, phenyl vinyl sulfoxide, dibenzyl sulfoxide, p-tolyl sulfoxide, methylphenyl sulfoxide, resorcinol sulfoxide, etc.). A method of stirring in the presence of a suitable acid (the same as in Method 1) at 0 ° C. to the reflux temperature of the solvent for several minutes to several tens hours.

Preferably, the compound of the general formula (II) -2 is dissolved in methanesulfonic acid, and in the presence of 4 equivalents of dimethylsulfoxide.
It can be produced by stirring at 80 to 90 ° C for 10 to 25 hours.

The compound of general formula (II) can be produced by the method described in the publication of the prior art.

[Operation and effect of the invention]

According to the method of the present invention, the pyridazinone ring of
A double bond can be efficiently introduced at the 4,5-position, and the brominated by-product found in the conventional bromine oxidation method is not mixed. Therefore, the method of the present invention is an industrially advantageous method for the compound represented by the general formula (I).

In addition, the obtained compound of the general formula (I) has anxiolytic action, biological defense enhancing action and the like, and is useful as a medicine.

〔Example〕

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto.

Example 1 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydrothieno [2 ', 3': 2,3] thiepino [4,5-c] pyridazin-3 (2H) -one 7- A solution of 5.6 g of oxide in 50 ml of methanesulfonic acid is kept at 60 ° C. for 2 hours. After that, the reaction solution is poured into ice water, extracted with chloroform, washed with water, and dried with magnesium sulfate. Distill off the chloroform,
The obtained residue was subjected to silica gel column chromatography, and crude crystals obtained from the fraction eluted with a mixed solvent of chloroform and methanol (100: 1) were recrystallized from ethyl acetate to give a white powder with a melting point of 140 to 142 ° C. 2- (4 as crystals
-Chlorophenyl) -5,6-dihydrothieno [2 ', 3':
2,3] thiepino [4,5-c] pyridazin-3 (2H) -one
2.2 g are obtained.

Example 2 2- (4-chlorophenyl) -4,4a used in Example 1,
5,6-Tetrahydrothieno [2 ', 3': 2,3] thiepino [4,5-c] pyridazin-3 (2H) -one 9-Bromo-2- (4-methoxyphenyl) instead of 7-oxide ) -4,4a, 5,6-Tetrahydrothieno [2 ', 3': 2,3]
Thiepino [4,5-c] pyridazin-3 (2H) -one 7
By the same reaction and treatment with -oxide, 9-bromo-2- (4-methoxyphenyl) -5,6-dihydrothieno [2 ', 3': 2 was obtained as white crystals having a melting point of 148 to 150 ° C. , 3] Thiepino [4,5-c] pyridazine-
3 (2H) -one is obtained.

Example 3 2- (4-chlorophenyl) -4,4a used in Example 1,
5,6-Tetrahydrothieno [2 ', 3': 2,3] thiepino [4,5-c] pyridazin-3 (2H) -one 7-oxide instead of 9-ethyl-2- (4-methoxyphenyl) ) -4,4a, 5,6-Tetrahydrothieno [2 ', 3': 2,3]
Thiepino [4,5-c] pyridazin-3 (2H) -one 7
By performing the same reaction and treatment with -oxide, 9-ethyl-2- (4-methoxyphenyl) -5,6-dihydrothieno [2 ', 3': 2] was obtained as white crystals having a melting point of 141-143 ° C. , 3] Thiepino [4,5-c] pyridazine-
3 (2H) -one is obtained.

Example 4 2- (4-chlorophenyl) -4,4a used in Example 1
5,6-Tetrahydrothieno [2 ', 3': 2,3] thiepino [4,5-c] pyridazin-3 (2H) -one 2- (4-methoxyphenyl) -9-instead of 7-oxide Methyl-4,4a, 5,6-tetrahydrothieno [2 ', 3': 2,3]
Thiepino [4,5-c] pyridazin-3 (2H) -one 7
-By performing the same reaction and treatment with oxide, 2- (4-
Methoxyphenyl) -9-methyl-5,6-dihydrothieno [2 ', 3': 2,3] thiepino [4,5-c] pyridazine-
3 (2H) -one is obtained.

Example 5 2- (4-Methoxyphenyl) -4,4a, 5,6-tetrahydro [2 ', 3': 2,3] thiepino [4,5-c] pyridazine-
To a solution of 14.8 g of 3 (2H) -one in 100 ml of 30% hydrobromic acid, 6.1 ml of dimethyl sulfoxide was added with stirring at room temperature.
Then, after reacting for 4 hours at room temperature, the reaction solution is poured into water, extracted with chloroform, washed with water and dried. The crystals obtained were concentrated under reduced pressure, and the obtained crystals were recrystallized from a mixed solvent of toluene-isopropyl ether to give 2- (4-methoxyphenyl) -5,6-dihydrothieno [2 ', white crystals having a melting point of 126 to 128 ° C. 10 g of 3 ': 2,3] thiepino [4,5-c] pyridazin-3 (2H) -one are obtained.

Example 6 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydro- [1] benzothiepino [5,4-c] pyridazine-3 (2
A solution of 2 g of H) -one 7-oxide in trifluoroacetic acid is refluxed for 15 hours. After that, the reaction solution is poured into ice water, extracted with chloroform, washed with water, and dried with magnesium sulfate. Chloroform was distilled off, the obtained residue was subjected to silica gel column chromatography, and crude crystals obtained from the fraction eluted from chloroform were recrystallized from ethanol to give 2- () as white crystals having a melting point of 186 to 187 ° C. 0.9 g of 4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one are obtained.

Example 7 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydro- [1] benzothiepino [5,4-c] pyridazine-3 (2
H) -one (5 g) was added to methanesulfonic acid solution (4 equivalents), and the mixture was stirred at 70 to 90 ° C for 15 to 20 hours. After that, the reaction solution is poured into ice water, extracted with chloroform, washed with water, and dried with magnesium sulfate. Chloroform was distilled off, the obtained residue was subjected to silica gel column chromatography, and crude crystals obtained from the fraction eluted from chloroform were recrystallized from ethanol to give a melting point of 186-1.
2- (4-chlorophenyl) -5 as white crystals at 87 ° C,
4.3 g of 6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one are obtained.

Example 8 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydro- [1] benzothiepino [5,4-c] pyridazine-3 (2
A solution of 5 g of H) -one 7-oxide in methanesulfonic acid is stirred at 70 to 90 ° C. for 15 to 25 hours. After that, the reaction solution is poured into ice water, extracted with chloroform, washed with water, and dried with magnesium sulfate. Chloroform was distilled off, the obtained residue was subjected to silica gel column chromatography, and crude crystals obtained from the fraction eluted from chloroform were recrystallized from ethanol to give 2- () as white crystals having a melting point of 186 to 187 ° C. 4-chlorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3 (2
H) -one 4.2 g is obtained.

Example 9 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydro- [1] benzothiepino [5,4-c] pyridazine-3 (2
A solution of H) -one 7-oxide 2 g in hydrobromic acid was stirred at room temperature for 3 to 5 hours. After that, the reaction solution is poured into ice water, extracted with chloroform, washed with water, and dried with magnesium sulfate. Chloroform was distilled off, the obtained residue was subjected to silica gel column chromatography, and crude crystals obtained from the fraction eluted from chloroform were recrystallized from ethanol to give 2- () as white crystals having a melting point of 186 to 187 ° C. Four
1.8 g of -chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one are obtained.

Example 10 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydro- [1] benzothiepino [5,4-c] pyridazine-3 (2
H) on 5 g of hydrobromic acetic acid solution was stirred at room temperature for 15 to 25 minutes, 4 equivalents of dimethyl sulfoxide was added thereto, and the mixture was stirred at room temperature for 30 minutes, then the reaction solution was poured into ice water and extracted with chloroform. After that, it is washed with water and dried over magnesium sulfate. Chloroform was distilled off, the obtained residue was subjected to silica gel chromatography, and crude crystals obtained from the fraction eluted from chloroform were recrystallized from ethanol.
2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-] as white crystals at 186-187 ° C
4.5 g of c] pyridazin-3 (2H) -one are obtained.

Example 11 A solution of 2- (4-chlorophenyl) -2,3,4,4a-tetrahydro-5H- [1] benzothiopyrano [4,3-c] pyridazin-3-one 6-oxide 5g in trifluoroacetic acid was added to 23 By refluxing for a period of time and treating in the same manner as in Example 6, 2- (4-chlorophenyl) -having a melting point of 184 to 185 ° C.
2,3-Dihydro-5H- [1] benzothiopyrano [4,3-
c] Pyridazin-3-one 0.1 g is obtained.

Example 12 2- (4-chlorophenyl-3,4,4a, 5,6,7-hexahydro-2H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-one 0.5 g methanesulfone To 12.5 ml of the acid solution, 4 equivalents of dimethyl sulfoxide was added, and the mixture was stirred at 70 to 80 ° C for 29 hours and treated in the same manner as in Example 7 to give 2- (4-chlorophenyl) -3 having a melting point of 167 to 168 ° C. , 5,6,7
-Tetrahydro-2H-benzo [6,7] cyclohepta [1,2
0.14 g of -c] pyridazin-3-one are obtained.

Example 13 2- (4-chlorophenyl) -2,3,4,4a, 5,6-hexahydro [1] benzoxepino [5,4-c] pyridazine-
2- (4-Chlorophenyl) -2,3,5,6- 0.15 g of tetrahydro [1] benzoxepino [5,4-c] pyridazin-3-one are obtained.

Example 14 2-Phenyl-4,4a, 5,6-tetrahydrobenzo [h] cinnolin-3 (2H) -one 0.5g methanesulfonic acid solution
Add 4 equivalents of dimethylsulfoxide to 12.5 ml, 80-90 ℃
After stirring for 18 hours and treating in the same manner as in Example 7, 0.07 g of 2-phenyl-5,6-dihydrobenzo [h] cinnolin-3- (2H) -one having a melting point of 165 to 166 ° C was obtained. can get.

Example 15 2- (4-chlorophenyl) -4,4a, 5,6-tetrahydro- [1] benzothiepino [5,4-c] pyridazine-3 (2
H) -one was treated with hydrobromic acetic acid solution in the presence of diphenyl sulfoxide, phenyl vinyl sulfoxide, benzyl sulfoxide or p-tolyl sulfoxide in the same manner as in Example 10, respectively to give 2- (4-
It was confirmed by high performance liquid chromatography (HPLC) that chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one was produced. (Retention time: 5.4 minutes of raw material, 9.7 minutes of product) HPLC condition Equipment: LC-6AD (Shimadzu) Column: Shim-pack CLC (Shimadzu) Mobile phase: CH ₂ Cl ₂ , 0.4 ml / min Detection wavelength: 254 nm Example 16 2- (4-Methoxyphenyl) -4,4a, 5,6-tetrahydrothieno [2,3-h] cinnoline-3 (2H) -one 2.0 g
0.45 ml of dimethylsulfoxide is added to the 15% hydrogen bromide-acetic acid solution of (1) at room temperature, and the mixture is reacted at the same temperature for 50 minutes. Later,
Water is poured into the reaction solution and extracted with chloroform. The residue obtained by washing with water, drying over magnesium sulfate and concentration under reduced pressure is subjected to silica gel column chromatography. The crystals obtained from the fraction eluted with chloroform were washed with chloroform-
When recrystallized from a mixed solvent of ethanol, the melting point is 165-168.
2- (4-methoxyphenyl) -5 as white crystals at ℃,
6-dihydrothieno [2,3-h] cinnoline-3 (2H)-
Ong 1.0g is obtained.

The following compounds can be synthesized according to the above examples.

◎ 2- (4-chlorophenyl) -10-methyl-2,3,5,
6-Tetrahydro [1] benzoxepino [5,4-c] pyridazin-3-one, melting point 172-173 ° C. 10-bromo-2- (4-chlorophenyl) 2,3,5,6
-Tetrahydro [1] benzoxepino [5,4-c] pyridazin-3-one, melting point 214-216 ° C ◎ 2- (4-methoxyphenyl) -2,3,5,6-tetrahydro [1] benzoxepino [5, 4-c] pyridazin-3-one, melting point 150-152 ° C ◎ 2-phenyl-5,6-dihydrobenzo [h] cinnolin-3 (2H) -one, melting point 155-157 ° C ◎ 2- (3-tri Fluoromethylphenyl) -5,6-
Dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 120-123 ° C ◎ 8-chloro-2- (4-chlorophenyl) -5,6-
Dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 201-203 [deg.] ◎ 8-chloro-2-phenyl-5,6-dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 122-124 ° C ◎ 9-chloro-2- (4-chlorophenyl) -5,6-
Dihydrobenzo [h] cinnolin-3 (2H) -one, melting point 205-207 ° C ◎ 9-chloro-2-phenyl-5,6-dihydrobenzo [h] cinnolin-3 (2H) -one, melting point 184-186 ° C ◎ 9-chloro-2- (4-nitrophenyl) -5,6-
Dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 258-259 ° C ◎ 9-chloro-2- (4-fluorophenyl) -5,6
-Dihydrobenzo [h] cinnoline-3 (2H) -one,
Melting point 174-177 ° C ◎ 9-Fluoro-2-phenyl-5,6-dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 180-181 ° C ◎ 2- (4-chlorophenyl) -9-fluoro- 5,6
-Dihydrobenzo [h] cinnoline-3 (2H) -one,
Melting point 176-179 ° C ◎ 9-chloro-2- (4-methylphenyl) -5,6-
Dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 184-186 ° C 2- (4-chlorophenyl) -9-methyl-5,6-
Dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 206-207 [deg.] C. 9-Methyl-2-phenyl-5,6-dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 173-175 ° C ◎ 9-methyl-2- (4-methylphenyl) -5,6-
Dihydrobenzo [h] cinnoline-3 (2H) -one, melting point 190-191 ° C 10-chloro-2- (4-chlorophenyl) -5,6-
Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, melting point 215-217 ° C 2- (4-chlorophenyl) -10-fluoro-5,6
-Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, melting point 184 ° C ◎ 2- (4-bromophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3 (2
H) -one, melting point 208-209 ° C. 2- (4-chlorophenyl) -10-methyl-5,6-
Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one hemihydrate, melting point 182-184 ° C ◎ 10-fluoro-2- [4-fluorophenyl) -5,
6-Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, melting point 169-171 ° C ◎ 2- (4-fluorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3 (2
H) -one, melting point 163-165 ° C. ◎ 8-chloro-2- (4-chlorophenyl) -5,6-
Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, melting point 166-168 ° C ◎ 2- (3,4-dichlorophenyl) -10-fluoro-
5,6-Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, melting point 156-157 ° C

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 495/04 111 111 116 495/14 FZ

Claims (3)

[Claims] 1. A general formula Wherein ring A benzene ring or thiophene ring, R ^1, R
² is the same or different and is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, lower alkyl, lower alkoxy or lower alkanoylamino, R ³ is hydrogen, alkyl having 1 to 8 carbons, hydroxyalkyl A substituent selected from halogen, hydroxy, amino, nitro, cyano, lower alkyl, lower alkoxy, lower alkanoylamino, haloalkyl, acyloxy, lower alkoxycarbonyl and carboxy on the alkanoyloxyalkyl, aryl, aralkyl, heteroaryl or aromatic ring. An aryl, aralkyl or heteroaryl having at least one of, X is O, S, SO, SO ₂ , CH ₂ or NR ⁴ (R ⁴ represents hydrogen, lower alkyl, acyl or benzenesulfonyl).
And n represents 1 or 2. ] The compound represented by the formula is reacted with an acid in the presence of a sulfoxide compound, if necessary. (In the formula, each symbol has the same meaning as defined above.) A method for producing a pyridazinone compound represented by 2. A sulfoxide is dimethyl sulfoxide, diphenyl sulfoxide, phenyl vinyl sulfoxide,
Dibenzyl sulfoxide, p-tolyl sulfoxide, methylphenyl sulfoxide or resorcinol sulfoxide, wherein the acid is hydrobromic acid, hydrochloric acid, hydrohalic acid of hydroiodic acid, methanesulfonic acid, alkylsulfonic acid of trifluoromethanesulfonic acid, The production method according to claim 1, which is an aliphatic carboxylic acid such as acetic acid, formic acid, or trifluoroacetic acid, an arylsulfonic acid such as p-toluenesulfonic acid, or a mixture thereof. 3. A sulfoxide is dimethyl sulfoxide, diphenyl sulfoxide, phenyl vinyl sulfoxide,
The method according to claim 1, wherein the method is dibenzyl sulfoxide or p-tolyl sulfoxide, and the acid is methanesulfonic acid, acetic acid or trifluoroacetic acid.