Methiomeprazine

 Methiomeprazine is an antiemetic drug.

PATENT

FR 2705 M 19640831.

The title compd. and its derivs. are prepd. and can be used in the prepn. of antiemetic compns.  A soln. of 2.280 g. 3-methylthio-10-(3-dimethylamino-2-methylpropyl)phenothiazine (I) in 12 l. EtOH is heated to 70° and added to a soln. (60°) of 969 g. d-tartaric acid in 27 l. EtOH, the soln. kept overnight and filtered, and the mother liquors from the 1st and 2nd crystns. combined and evapd.  The residue (2.352 g.) is dissolved in H₂O, the soln. made alk. with 700 ml. NaOH (d. 1.33) and extd. with 4 l. CH₂Cl₂, the org. phase sepd., the aq. phase extd. with 1 l. CH₂Cl₂, and the exts. combined and evapd. at ∼20 mm.  The residue (1.183 g.) is taken up in 7 l. EtOH at 60°, the soln. added to 370 g. maleic acid in 1.7 l.  EtOH (60°), and the mixt. kept overnight to give 1.192 g. I acid maleate (II), m. 176-7° (EtOH), [α]²⁴_D -21.2° ± 1.5° (c 2, CHCl₃).  II (300 g.) is added to a mixt. of 1 l. H₂O and 2 l.  CH₂Cl₂, 150 ml. NaOH (d. 1.33) added, and the org. phase sepd. and distd. to give 185 g. (-)-3-methylthio-10-(3-dimethylamino-2-methylpropyl)phenothiazine (III), m. 84-5° (iso-PrOH), [α]²³_D -45° ± 3° (c 2.5, C₆H₆).

PAPER

Journal of Organic Chemistry (1960), 25, 944-7.

cf. CA 54, 15391b.  The prepn. of various 10-aminoalkyl derivs. of the following phenothiazines was described: 2-hydroxyphenothiazine (I), 2-methylthiophenothiazine (II), 2-methylsulfonylphenothiazine (III), 2-trifluoromethylsulfonylphenothiazine (IV), 2-trifluoromethylthiophenothiazine (V), 2-azaphenothiazine (VI), and 8-chloro-2-azaphenothiazine (VII).  The direct alkylation of I was not attempted.  Instead, 2-benzoyloxyphenothiazine was alkylated with NaNH₂ in xylene and the ester group removed by basic hydrolysis during the workup.  The alkylation of IV with 3-(4-methylpiperazinyl)propyl chloride required 48 hrs.  VI (15 g.), 6.8 g. NaNH₂, and 500 ml. PhMe refluxed 45 min. under N, treated with 21 g. 3-chloro-1-(1-formyl-4-piperazinyl)propane-HCl and 300 ml. PhMe, the mixt. cooled, 150 ml. H₂O added, the PhMe layer extd. with dil. HCl, the acid exts. made alk., extd. with C₆H₆, and the solvent evapd. gave 21 g. oil.  The oil dissolved in 250 ml. alc., 60 ml. H₂O and 7 ml. 40% NaOH, the mixt. refluxed 2 hrs., the solvents removed, the residual oil dissolved in C₆H₆, the soln. extd. with HCl, made alk., extd. with C₆H₆, and the whole distd. gave 11 g. 10-[3-(1-piperazinyl)propyl]-2-azaphenothiazine.  The distd. material was dissolved in 250 ml. MeOH and refluxed 1.5 hrs. with 1.8 g. ethylene oxide, the solvent evapd., the residue dissolved in 250 ml. C₆H₆, the soln. azeotropically distd. during 1 hr., cooled, and refluxed 1 hr. with 6.5 g. AcCl, the solvents evapd., the gum treated with 10% NaOH, and the C₆H₆ evapd. gave 4.3 g. 4-[3-(2-azaphenothiazin-10-yl)propyl]-1-piperazineëthanol; acetate dimaleate m. 147-8° (decompn.) (EtOAc).  1-Piperazinepropanol (57.6 g.) refluxed 1 hr. with 48 g. HCO₂Me, the excess HCO₂Me removed, and the residue distd. gave 65.3 g. oil, b_1.1 174.5-7.0°, n²⁴_D 1.5072.  This oil (42.8 g.) in 300 cc. CHCl₃ treated with excess HCl, then 19 g. SOCl₂, the mixt. refluxed 0.5 hr., 3 g. SOCl₂ added, refluxing continued 2.5 hrs., and the solvents removed gave a cryst. HCl salt.  Conversion of this to the free base gave 60% 1-formyl-4-(3-chloropropyl)piperazine, yellow oil, b_0.4 144.5-8.5°, n²⁵_D 1.5053.  By starting with I-VII the following 2,10-disubstituted phenothiazines were obtained (substituents at 2, 10, b.p./mm., and % yield given); SMe, (CH₂)₃NMe₂, 220-3°/0.7 (HCl salt m. 149-50°), 88; SMe, CH₂CHMeCH₂NMe₂, 218-21°/0.1 (HCl salt m. 173-4°), 93; SMe, (CH₂)₃N.(CH₂)₂.NMe.CH₂.CH₂, 239-42°/0.1 (di-HCl salt m. 224-5°), 92; SMe, CH₂CHMeCH₂N.(CH₂)₂.  NMe.CH₂.CH₂, 200-20°/0.03 (dimaleate m. 174-5°), 44; SMe, (CH₂)₃N.(CH₂)₂.N[(CH₂)₂OAc].CH₂.CH₂ – (dimaleate m. 165-6°), 33; SO₂Me, (CH₂)₃NMe₂, 115-16° (HCl salt m. 112-15°), 62; SO₂Me, CH₂CHMeCH₂NMe₂, 255-60°/0.2 (HCl salt m. 234-5°), 60; SCF₃, (CH₂)₃NMe₂, 153-7°/0.1, 64; SCF₃, CH₂CHMeCH₂NMe₂, 153-7°/0.1 (picrate m. 158.5-9.5°), 54; SCF₃, I (CH₂)₃N.(CH₂)₂.NMe.CH₂.CH₂, 220-3°/0.3 (dimaleate m. 182-3°), 63; SO₂CF₃, (CH₂)₃NMe₂, 235-40°/0.04 (HCl salt m. 174-5°), 15; SO₂CF₃, CH₂CHMeCH₂NMe₂, 182-4°/0.2 (picrate m. 203-4°), 19; SO₂CF₃, (CH₂)₃N.(CH₂)₂.NMe.CH₂.CH₂, – [di-HCl salt m. 249.5° (decompn.)], 16; OH, (CH₂)₃NMe₂, 220-5°/0.05, m. 90-1° (dimaleate m. 132-3°), 49.  The following 8,10-substituted 2-azaphenothiazines were similarly prepd. (8,10 substituents, m.p. or b.p., % yield given): H, (CH₂)₃NMe₂, 165-70°/0.007 [di-HCl salt m. 240.5-4.5° (decompn.)], 63; H, CH₂CHMeCH₂NMe₂, 190-5°/0.6 (di-HCl salt m. 234-5°), 82; H, (CH₂)₃N.(CH₂)₂.N[(CH₂)₂OAc].CH₂.CH₂, – (dimaleate m. 147-8° (decompn.), 9; Cl, (CH₂)₃NMe₂, 215-20°/1 (di-HCl salt m. 249-50°), 66.

PATENT

GB 802725

N-Aminoalkyl derivs. of I, where the alkyl is a straight or branched 2-5 C atom chain and the amino may be mono- or dialkylated or may be substituted by a pyrrolidino, piperidino, morpholino, or 4-alkyl-1-piperazinyl group, are prepd. by condensing I with the appropriate halo amine or by decompg. a phenothiazine-10-carboxylate of the appropriate amino alcohol.  I (4.9 g.) was heated in 50 cc. boiling anhyd. xylene with 0.88 g. sodamide 1 hr., 2.71 g. 3-dimethylamino-1-chloropropane added, the soln. boiled 6 hrs., treated with H₂O, then with dil. HCl, made alk. with NaOH, extd. with ether, and the solvent was evapd. in vacuo to give 4.5 g. 3-methylthio-10-(3-dimethylaminopropyl)phenothiazine (III), b_0.2 206-18°; III.2HCl m. 160° (acetone-ether); picrate m. 135° (acetone).  3-Methylthio-10-(3-dimethylamino-2-methylpropyl)phenothiazine, m. 88-9°, was prepd. from I and 3-dimethylamino-2-methyl-1-chloropropane; picrate m. 145° (EtOH).  The following were similarly prepd.: 3-methylthio-10-[3-(4-methyl-1-piperazinyl)propyl]phenothiazine, b_0.1 250-6° [dihydrochloride m. 220° (decompn.) (acetone-ether); dipicrate m. 252-3° (acetone-iso-PrOH); 3-methylthio-10 – (2 – dimethylaminopropyl)phenothiazine, b_0.2 202-6° (hydrochloride m. 205-6°; picrate m. 190°); 3-methylthio-10- (3-pyrrolidinopropyl)phenothiazine, b_0.9 261° (hydrochloride m. 161°).  I was phosgenated in toluene in the presence of pyridine to the 3-methylthiophenothiazine-10-carbonyl chloride (IV), m. 125°; IV heated in toluene with 3-(4- methyl-1-piperazinyl)-2-methylpropanol gave 3-(4-methyl-1- piperazinyl)-2-methylpropyl 3-methylthiophenothiazine-10- carboxylate (V) (dihydrochloride m. 225°).  A soln. of 13 7 g. V in 60 cc. ο-Cl₂C₆H₄ was boiled for 5 hrs. till CO₂ evolution ceased, the soln. cooled, 60 cc. ether added and the mixt. H₂O-washed, extd. with 10% HCl, made alk. with NaOH, and extd. with ether.  The ether soln. was dried over anhyd. Na₂SO₄ and distd. in vacuo to yield 11.25 g. crude base which gave, with an EtOH soln. of maleic acid, 12.7 g. 3-methylthio-10-[3-(4-methyl-1-piperazinyl)-2-methyl-propyl]phenothiazinecarboxylic acid dimaleate, m. 199°.  3-Methylthio-10- [2,3-bis(dimethylamino)propyl] phenothiazine neutral fumarate, m. 198°, was similarly obtained by decarboxylating 1,3-bis(dimethylamino)-2-propyl 3-methylthiophenothiazine-10-carboxylate and treating with fumaric acid.  3-Methylthio-10-(3-diethylaminopropyl)phenothiazine-HCl, m. 172°, was prepd. from 3-methylthio-10-[3-(p-toluenesulfonyloxy)propyl]phenothiazine (VI) and Et₂NH; 3-methylthio-10-(3-methylaminopropyl)phenothiazine (H oxalate m. 186°), from VI and MeNH₂.  VI heated with excess NH₃ in toluene gave 3-methylthio-10-(3-aminopropyl)phenothiazine (VII) (oxalate m. 198°).  VII in dioxane was neutralized with N HCl and treated with 30% aq. HCHO and PtO₂ to give III.  These compds. are antiemetics and potentiators of general anasthetics or neuroleptics.

SYN