Afloqualone, アフロクアロン

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Afloqualone.pngChemSpider 2D Image | Afloqualone | C16H14FN3OAfloqualone.svg

Afloqualone

Molecular Formula: C16H14FN3O
Molecular Weight: 283.306 g/mol

6-amino-2-(fluoromethyl)-3-(2-methylphenyl)quinazolin-4-one

HQ 495C033541, QA-3735, UNII:CO4U2C8ORZ

4(3H)-Quinazolinone, 6-amino-2-(fluoromethyl)-3-(2-methylphenyl)- [ACD/Index Name]
4831
56287-74-2 [RN], アフロクアロン

Afloqualone; 56287-74-2; Arofuto; Aroft; Afloqualon; Afloqualone [INN:JAN]

Afloqualone (Arofuto) is a quinazolinone family GABAergic drug and is an analogue of methaqualone developed in the 1970s by a team at Tanabe Seiyaku.[1] It has sedative and muscle-relaxant effects resulting from its agonist activity at the β subtype of the GABAareceptor ,[2] and has had some clinical use, although it causes photosensitization as a side-effect that can cause skin problems such as dermatitis.[3]

 

PATENT

CN 106496145

PATENT

CN 106496144

https://patents.google.com/patent/CN106496144A/en

Example 1:

[0027] A-fluoro-quinolin-one process, comprising the steps of:

[0028] A. To the hydrogenation apparatus 10g 6- nitro-2- (fluoromethyl) -3- (2-methylphenyl) -4- (3H) -1,3- phthalazinone , 150ml acid content of 0.1 ~ 0.4N n-butanol solution of acetic acid, lg palladium ruthenium bimetallic catalyst, hydrogen pressure 0.02 ~ 0.4MPa, reaction temperature of 25-50 ° C, after 1 hour, filtered to give the filtrate ;

[0029] B. washed catalyst with ethanol, at normal temperature, under reduced pressure to obtain a solution ⑴;

[0030] C. was added to the filtrate and the solution ⑴ water, 0.1N sodium hydroxide solution was added, the pH adjusted to 10.2 to 11.0, and stirred at 50-60 ° C 0.5 h, cooled to room temperature and filtered to give the crude fluoro-quinolin-one;

[0031] D.-fluoro-quinolin per gram of the recrystallization solvent was added 5 ~ 15ml crude ketone, wherein the recrystallization solvent is a volume ratio of 1: 1: 0.2 in a solution of isopropanol (m), a solution of acid butyl ester (II ) and water mixture; crystallized at room temperature, filtered to give a fluorine methaqualone.

[0032] Example 2:

[0033] A-fluoro-quinolin-one process, comprising the steps of:

[0034] A. hydrogenation apparatus added to 20g 6- nitro _2_ (fluoromethyl) -3- (2_-methylphenyl) -4- (3-1,3-phthalazinone buckle, acid content of the acid-containing 240ml 0.1 ~ 0.4N ethanol solution of hydrochloric acid, lg palladium ruthenium bimetallic catalyst, hydrogen pressure 0.02 ~ 0.4MPa, reaction temperature of 25-50 ° C. after 0.5 hours the reaction was filtered to obtain filtrate;

[0035] B. washed catalyst with ethanol, at normal temperature, under reduced pressure to obtain a solution ⑴;

[0036] C. was added to the filtrate and the solution ⑴ water, 0.1N sodium hydroxide solution was added, the pH adjusted to 10.2 to 11.0, and stirred at 50-60 ° C 1 hour, cooled to room temperature and filtered to give the crude fluoro-quinolin-one;

[0037] D.-fluoro-quinolin added per gram of crude ketone was recrystallized from 5 ~ 15ml of the solvent, wherein the recrystallization solvent is a volume ratio of 1: o.2: methanol solution of i (m), an ethyl acetate solution (II ) and water mixture; crystallized at room temperature, filtered to give a fluorine methaqualone.

[0038] Example 3:

[0039] – quinolin-fluoro-one kind of process, comprising the steps of:

[0040] A. Add 5g 6- nitro apparatus _2_ hydride (fluoromethyl) -3- (2-methylphenyl) -4- (3-1,3-Perot phthalazinone, 80ml methanol containing an acid in an amount of 0.1 ~ 0.4N solution of sulfuric acid, lg palladium ruthenium bimetallic catalyst, hydrogen pressure 0.02 ~ 0.4MPa, reaction temperature of 25-50 ° C. after 1.5 hours the reaction was filtered to obtain filtrate;

[0041] B. the catalyst was washed with ethanol, normal temperature under reduced pressure to obtain a solution (the I);

[0042] C. was added to the filtrate and the solution (I) water, 0.1N sodium hydroxide solution was added, the pH adjusted to 10.2 to 11.0, and stirred at 50-60 ° C 1 hour, cooled to room temperature and filtered to give fluoro-quinolin-one Crude;

[0043] D. methaqualone fluorine per gram of crude product were added 5 ~ 15ml recrystallization solvent, wherein the recrystallization solvent is a volume ratio of 1: 0.2: 0.2 ethanol solution (m), carboxylic acid butyl ester (II) and water mixture; crystallization at room temperature, and filtered to give fluoro-quinolin-one.

PAPER

6-Amino-2-(fluoromethyl)-3-(2-methylphenyl)quinazolin-4(3H)-one
Acta Crystallographica, Section E: Structure Reports Online (2007), 63, (7), o3109

http://scripts.iucr.org/cgi-bin/paper?S1600536807026670

PAPER

Synthesis of the metabolites of afloqualone and related compounds
Chemical & pharmaceutical bulletin (1983), 31, (4), 1158-65.

Seven main metabolites (3-9) of afloqualone (1, 6-amino-2-fluoromethyl-3-(o-tolyl)-4 (3H)-quinazolinone and related 4 (3H)-quinazolinone derivatives were synthesized. The metabolites 4 and 5 containing a sulfur atom were prepared by the reaction of 6-acetamido-2-chloromethyl-3-(o-tolyl)-4 (3H)-quinazolinone (11) with NaSCH3 followed by oxidation with H2O2. Reaction of 11 and N-acetyl-L-cysteine gave the mercapturic acid-conjugated metabolite 6. Condensation of 2-fluoroacetamido-5-nitrobenzoic acid (19) and 2-amino-benzyl alcohol (20) with dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxy-benzotriazole afforded 2-fluoromethyl-3-(o-hydroxymethylphenyl)-6-nitro-4 (3H)-quinazolinone (21), which was converted to the metabolites 7 and 8. Treatment of the 2-bromomethyl-4 (3H)-quinazolinone (24) with AgBF4-H2O in dimethylsulfoxide (DMSO) gave the 2-hydroxymethyl metabolite 9. None of the main metabolites (2-9) showed significant central nervous system depressant activity

https://www.jstage.jst.go.jp/article/cpb1958/31/4/31_4_1158/_article

References

  1. Jump up^ US Patent 3966731 – 2-Fluoromethyl-3-o-tolyl-6-amino-4(3H)-quinazolinone
  2. Jump up^ Ochiai T, Ishida R. Pharmacological studies on 6-amino- 2-fluoromethyl- 3-(O-tolyl)- 4(3H)- quinazolinone (afloqualone), a new centrally acting muscle relaxant. (II) Effects on the spinal reflex potential and the rigidity. Japanese Journal of Pharmacology. 1982 Jun;32(3):427-38.
  3. Jump up^ Ishikawa T, Kamide R, Niimura M. Photoleukomelanodermatitis (Kobori) induced by afloqualone. Journal of Dermatology. 1994 Jun;21(6):430-3.
Afloqualone
Afloqualone.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
  • none
Legal status
Legal status
  • US: Unscheduled
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C16H14FN3O
Molar mass 283.3
3D model (JSmol)

//////////////Afloqualone, HQ 495, アフロクアロン , C033541, QA-3735, UNII:CO4U2C8ORZ, 4831

CC1=CC=CC=C1N2C(=NC3=C(C2=O)C=C(C=C3)N)CF

Afloqualone

    • ATC:M03A
  • Use:muscle relaxant
  • Chemical name:6-amino-2-(fluoromethyl)-3-(2-methylphenyl)-4(3H)-quinazolinone
  • Formula:C16H14FN3O
    • MW:283.31 g/mol
    • CAS-RN:56287-74-2
    • LD50:397 mg/kg (M, p.o.);
      249 mg/kg (R, p.o.)

    Derivatives

    hydrochloride

    • Formula:C16H14FN3O • xHCl
    • MW:unspecified
    • CAS-RN:56287-75-3

    Substance Classes

    Synthesis Path

    Substances Referenced in Synthesis Path

    CAS-RN Formula Chemical Name CAS Index Name
    108-24-7 C4H6O3 acetic anhydride Acetic acid, anhydride
    69123-71-3 C7H5ClN2O3 2-amino-5-nitrobenzoyl chloride Benzoyl chloride, 2-amino-5-nitro-
    23076-31-5 C14H13N3O3 N-(2-amino-5-nitrobenzoyl)-o-toluidine Benzamide, 2-amino-N-(2-methylphenyl)-5-nitro-
    56287-72-0 C16H14FN3O4 2-[(fluoroacetyl)amino]-N-(2-methylphenyl)-5-nitrobenzamide Benzamide, 2-[(fluoroacetyl)amino]-N-(2-methylphenyl)-5-nitro-
    359-06-8 C2H2ClFO fluoroacetyl chloride Acetyl chloride, fluoro-
    56287-73-1 C16H12FN3O3 2-(fluoromethyl)-3-(2-methylphenyl)-6-nitro-4(3H)-quinazolinone 4(3H)-Quinazolinone, 2-(fluoromethyl)-3-(2-methylphenyl)-6-nitro-
    616-79-5 C7H6N2O4 5-nitroanthranilic acid Benzoic acid, 2-amino-5-nitro-
    95-53-4 C7H9N o-toluidine Benzenamine, 2-methyl-

    Trade Names

    Country Trade Name Vendor Annotation
    J Aflomus Hishiyama
    Airomate SawaiNippon Chemiphar
    Arofuto Tanabe

    Formulations

    • tabl. 20 mg

    References

      • Tani, J. et al.: J. Med. Chem. (JMCMAR) 22, 95 (1979).
      • DOS 2 449 113 (Tanabe; appl. 15.10.1974; J-prior. 15.10.1973).
      • US 3 966 731 (Tanabe; 29.6.1976; J-prior. 15.10.1973)
    Title: Afloqualone
    CAS Registry Number: 56287-74-2
    CAS Name: 6-Amino-2-(fluoromethyl)-3-(2-methylphenyl)-4(3H)-quinazolinone
    Additional Names: 6-amino-2-fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone
    Manufacturers’ Codes: HQ-495
    Trademarks: Arofuto (Tanabe)
    Molecular Formula: C16H14FN3O
    Molecular Weight: 283.30
    Percent Composition: C 67.83%, H 4.98%, F 6.71%, N 14.83%, O 5.65%
    Literature References: A centrally acting muscle relaxant. Prepn: I. Inoue et al., DE 2449113eidem, US 3966731 (1975, 1976 to Tanabe); J. Tani et al., J. Med. Chem. 22, 95 (1979). Pharmacology: T. Ochiai, R. Ishida, Jpn. J. Pharmacol. 31, 491 (1981); 32,427 (1982). Metabolism: N. Otsuka et al., J. Pharmacobio-Dyn. 5, S-59 (1982); S. Furuuchi et al., Drug Metab. Dispos. 11, 371 (1983).
    Properties: Pale yellow prisms from 2-propanol, mp 195-196°. LD50 in mice (mg/kg): 315.1 i.p. (Tani).
    Melting point: mp 195-196°
    Toxicity data: LD50 in mice (mg/kg): 315.1 i.p. (Tani)
    Therap-Cat: Muscle relaxant (skeletal).
    Keywords: Muscle Relaxant (Skeletal).
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