Journal of Medicinal Chemistry, 1971, Vol. 14, *Yo. ? 593
GENERAL ANESTHETICS.2
of syrup which crystd from PhH giving 3.01 g of yellow crystals, once from EtOH, gave 0.90 g (27.5%), the salt mp 210-212' mp 149-151.5'. Two recrystns, once from EtOAc and once dec. Anal. (CUHMCINO~S) C, H, C1, N, S. from EtOH, yielded 1.55 g (45%) of nearly white crystals, mp 3-Benzoyl-4-chlorobenzenesulfonyl Chloride (15).-To a cold 192-193' dec. Anal. (CirHi?N30&3)C, H, N, S. soln (0-5") of 23.8 g of (0.073 mole) of 2-chloro-5-aminobenzo1,3-Dihydro-l-methyl-7-(N-methylmethanesulfonamido)-5phenone in 73 ml of AcOH and 25 ml of concd HC1 was added phenyl-2H-1,4-benzodiazepin-2-one(17).-A soln of 1.88g (0.0055 slowly 5.58 g (0.685 mole) of NaNOz in 9.5 ml of H20. This mole) of 16 in 35 ml of MeOH was converted to the Na salt with mixt was stirred for 0.5 hr at 0-5". Then was added 17.3 g 1.4 g (0.0066 mole) of 25% NaOMe and evapd to dryness in (0.27 mole) of SO2 in 51 ml of AcOH contg 2.9 g (0.017 mole) of vacuo. The residue was dissolved in 30 ml of D M F and 1.5 ml CuClz in 5.2 ml of HtO. This mixt was allowed to warm to room of Me1 was added dropwise with stirring for 2.0 hr a t room temp. temp with stirring during 1 hr and poured into ice water. The The soln was poured into 300 ml of ice water giving 1.45 g of solid was collected yielding 21.27 g (92.50j0)of pale yellow solid, solid, mp 162-166' dec. Recrystn from i-PrOH gave 1.25 g mp 86.549'. A sample was recrystd from methylcyclohexane, (70.5%) of nearly white crystals, mp 174-176' dec. AnaZ. mp 90.5-92'. Anal. (Cl3HsClrO&3)C, H, C1, S. 1,t-Dihydro-7-(methanesulfonamido)-1-methyl-5-phenyl-2H- (CisHi9NaOaS) C, H, N, S. 1,4-benzodiazepin-2-one (16).-To a slurry of 2.65 g (0.01 mole) of 7-amino-l,3-dihydro-l-methyl-5-phenyl-2HllPbenzodiazepin- Acknowledgments.-The authors wish to thank the 2-one" in 20 ml of dry pyridine was added portionwise 1.37 g following people who contributed to this work: our (0.012 mole) of MeSOzCl. The mixt was stirred for 1.0 hr at Department of Physical and Analytical Chemistry, room temp and then warmed on a steam bath for 0.5 hr. Evapn for analytical and spectral data; Mr. William Veldof the reaction mixt in vacuo gave a syrup which was taken up in kamp for pharmacological data; Mr. R. F. Tripp, CHC13, washed (HzO),dried (MgS04),and reevapd to give 4.3 g (11) 0.Keller, N. Steiger, and L. H. Sternbach, U. 9. Patent 3,121,114 (1964); Chem. Abslr., 61, 1333b (1964).
General Anesthetics.
Mr. H. J. Triezenberg, and Mr. W. Friis for technical assistance.
2. Halogenated Methyl Isopropyl Ethers
LOUISESPEERS,*ALEXJ. SZUR,Ross C. TERRELL, JOHN TREADWELL, AND THOMAS U. UCCIARDI Central Research Laboratories, Air Reduction Company, Incorporated, Murray Hill, New Jersey 07974 Received November $3, 1970 Twenty-two new halogenated methyl isopropyl ethers have been synthesized for evaluation as general inhalant anesthetics. Sixteen stable compounds were evaluated using mice. Twelve of these compounds had anesthetic activity but were irritating and toxic, making them unsuitable for further study or clinical trials. (CF3)zCHOCH3 +(CFS)zCHOCHzCl+ The first study of the anesthetic properties of fluorin1 2782% ated hydrocarbons was reported by Robbins' in 1946. (CF3)zCHOCHCh +(CF3)zCHOCClS Since that time many fluorinated compounds, both 3, 58% 4, 100% hydrocarbons and ethers, have been found to have anesthetic properties in laboratory animals and several amount of monochloro product being formed with have progressed t o clinical trials in human^.^^^ Fluoraddition of one C1 and so forth. Neither the perhalooxene (CF3CH20CH=CH2), halothane (CF3CHC1Br), genated product, (CF3)2CC10CCla,nor any isomers with and methoxyflurane (CH3OCF2CHC12) are presently C1 on the isopropyl group were found. in clinical use. Chlorination of 5 was carried only to the first step, The synthesis and pharmacological properties of similarly replacing only the H on the methyl group. some methyl ethyl ethers have been reported r e ~ e n t l y . ~ , ~ CFa(CFzCl)CHOCH3 +CF3(CFzCl)CHOCHzCl We have continued this investigation by synthesizing 5 6 22 new halogenated methyl isopropyl ethers; 16 of these have been evaluated as general anesthetics in mice The isomer, CF3(CF2C1)CC10CH3,was prepared by (Table I). The remaining were too unstable to test. chlorination of the pentafluoroisopropenyl ether. The Synthesis.-The chloro compounds were synthesized physical properties of this dichloro ether were signifiby photochlorination of four fluorinated isopropyl cantly different from those of 6.8 methyl ethers. Chlorination of 1, following the pubThe chlorination of 7 was similar to that of 5 and lished p r o ~ e d u r e ,gave ~ ! ~ only three products resulting only the methyl group was chlorinated. from substitution on the methyl group. The chlorina(CFzCl)zCHOCH3+ [(CFzCl)rCHOCHzCl] + tion is described as follows where the percentages in the 7 equation represent the maximum percentage of a given (CFzC1)zCHOCHClz+(CFzCl)zCHOCC13 product in any chlorination mixture, the maximum 8
(1) B. H. Robbins, J . Pharmacol. E z p . Ther., 86, 197 (1946). (2) J. C. Krantr, Jr., and F. G. Rudo. in "Handbook of Experimental Pharmacology," Vol. X X / I , 0. Eichler, A. Farah, H. Herken, and A . D. Welch, Ed., Springer, Berlin, 1966, pp 501-564. (3) E. R . Larsen, Fluorine Chem. R e v . , 3, 1 (1969). (4) R. C. Terrell, U. S. Patent 3,469,011 (to Air Reduction Co., Inc., New York, N . Y . ) ,Sept 23, 1969; Chem. Abstr., 72, 30253' (1970). (5) R . C. Terrell, L. Speers, A. J. Sam, J. Treadwell, and T. R. Ucciardi, J . M e d . Chem., 14,517 (1971). (6) J. D. Park, D. M. Griffin, and J. R. Lacher, J . A m e r . Chem. SOC.,74, 2293 (1952). (7) J. D.Park, B. Stricklin, and J. R . Lacher, ibid., 76, 1387 (1954).
9
Chlorination of 10 gave essentially only one monochloro product 11 and only one dichloro product 12. Further chlorination gave complex mixtures of products from which three trichloro products, 13, 14, and 15, and one tetrachloro product, 16, were isolated. Substitution of F for C1 in the ethers 3, 4, 8, 12, 13, and 14 was done using SbF3 or anhyd HF. SbClS was (8) Unpublished work, Air Reduction Co., 1965.
SPEERS,et al.
594 Journal of Medicinal Chemistry, 1971, Vol. 14, No. 7
TABLE I BP, 'C
No.
Compd
(mm)
Anal.=
n*D
Pharmacology
c, H, F
Very weak anesthetic at 2 . 5 7 , , ~ excitation a t 10.07, 1.3140 78 Good anesthesia at 1.25%, irritat(CFa)zCHOCHzCld C, H, C1 2 ing Too unstable to test 1.3385 94 C, H, C1 3 (CFa)zCHOCHClz 1.3575 C, H, C1; nmr Anesthetic a t 1.25% with con4 68 (149) (CFa)zCHOCCL vulsions 1.3203 Anesthetic at 2.00j,,f irritating CFa(CFzCl)CHOCH3 80e C, H, C1 5 Deep anesthesia a t 1.0% 1.3552 110 CF3(CFzCl)CHOCHzCld C, H, C1 6 Anesthetic at 1.070, opisthotonus, 110 (CFZCl)zCHOCH3 1.3636 7 C, H, C1 irritating 62 (24) 1.4071 No anesthesia at 0.6Yc, convulC, H, C1 8 (CFzC1)zCHOCHCls sions, toxic 1.4200 N o anesthesia at O.27,, toxic 9 C, H, C1; nmr (CFzC1)zCHOCCls 44 (4) Light anesthesia a t 3% 10 1.3062 47.8 CFa (CHs)CHOCHs c, H, F 1.3515 11 89 CFa(CHs)CHOCHzCl Too unstable to test 9 12 113 CF3(CHs)CHOCHClz C , H , F ; nmr Too unstable to test 1.3785 13 128 C , H ; nmr Too unstable to test 1.3975 CF3(CHs)CHOCCL 152 14 Too unstable to test 1.4130 CF3(CHzCl)CHOCHClz C, H , F ; nmr 131 15 CFa(CH3)CClOCHClz 1.3970 C, H, F ; nmr Too unstable to test 16 163 1.4260 C , H , F ; nmr Too unstable to test CFa(CH&l)CHOCC13 17 67.2 1.3006 Anesthetic at 1.25%, irritating (CF3)zCHOCHFCld C, H, C1 41.5 1.2604 Good anesthetic at 5.0% 18 (CF3)zCHOCHFzd c, H, F 19 75 1.3175 Light anesthesia at 2.5%, toxic (CFa)zCHOCClzF C, H, C1 45 Very light anesthesia at 7.5Tc, 20 1.2770 (CFa)&HOCClFz C, H, C1 toxic 21 1,3415 Anesthesia at 1 .25yo, irritating, 99 C, H, C1 (CFzCl)zCHOCHF2 toxic Anesthetic a t 5.097, 22 48
