Patented. Apr‘. 25, 1933
`
`UNITED STATES‘. ‘PATENT OFFICE‘
`
`JOHN A. AES'OH-LIMANN, OF BASEL, SWITZERLAND, ASSIGNOB TO‘ HOIFKAIN'N-LA. ROCHE
`INC., 01‘ NUTLEY, NEW JERSEY, A CORPORATION ‘OF NEW '_JERSEY_
`msnnsrrru'mn camsmrc ACID mm or runners oolrrair1mmv A. BASIC
`
`cons'rrruan'r
`
`'
`
`'
`
`'
`
`No Drawing. Application ?ledgApril 8, 1931, ‘Serial No. 528,708, and in Germany ‘Ianuary 2,“ 1981. I
`substituted phenol radical, R’ and R" and
`alkyl- or aryl group.
`'
`7
`As the new compoundsa's such are almost
`insoluble in water, it. is moreconvenient to
`use their salts or their ‘quaternary ammonium
`55
`
`compounds. I
`
`_
`
`'
`
`According to Stedman (Biochemical .our
`nal, Vol. 20, 1926, page 720) the myotlc ac
`tion of physostigmine (eserine) is connected
`with the presence of the methylcarbamic acid
`ester group. He prepared a great many
`monoalkyl- and monoarylcarbamic acid esters
`Example 1 '
`of basically substituted phenols, which had a
`myotic action on the cat’s eye (Biochemical
`To a solution of.13.7 parts of m-dimethyl
`J ournallvol. 20, 1926, page 719, volt. 23, 1929,
`amlnophenol and 5.6 parts of potassium hy
`page 17; Journal of the Chemical Society
`droxide in 100 parts of alcohol 716.9 parts of
`of London, vol. 135, 1929, page 609). Phys
`methylphenylcarbamic acid’ chloride are -
`ostigmine is decomposed on being heated in
`added. After a short period of boiling the
`vacuum; from the methylcarbamic acid ester
`mixture, which at ?rst showed an alkaline re
`group a phenol group is formed and eserohne
`action, has become almost neutral. The pre
`65
`is obtained (Strauss, Annalen der Chemie,
`cipitated potassium chloride is separated by
`vol, 401, 1913, page 352, 2nd paragraph).
`warm ?ltration and the alcohol distilled off.
`The monoalkyl- and monoarylcarbamlc {101d
`The ether solution of the residue is washed
`esters described by Stedman are also very
`with a solution of sodium hydroxide in order
`easily decomposed. Decomposition is par
`to ‘remove the unchanged dimet-hylamino
`ticularly marked on heating the aqueous solu~'
`phenol ‘and the ether is then evaporated.
`tions of their quaternary salts, whereby
`Hereafter the residue is distilled in Vacuum.
`methyl isocyanate is split off (Biochemical
`Boiling point 245°/18 mm.' The distillate,
`Journal, vol. 20, 1926, page 733, line 15).
`a viscous liquid, soon becomes crystalline and
`The present invention relates to disubsti
`by repeated recrystallization from alcohol is i
`75
`tuted carbamic acid esters of phenols con
`rendered pure ‘white; it melts at 84° C.
`taining a basic substituent, which also have
`The dimethylsulfate addition product, pre-v
`a very decided physos tigmine-like action.
`pared in the cold in acetone solution, melts
`The dissubstituted carbamic acid esters of
`after recrystallization from alcohol at 163°
`the basically substituted phenols may be dis
`C. and is easily soluble in water.
`,
`tilled in vacuum without decomposition.
`The, diphenylcarbaniic acid ester of m-di
`Their, aqueous solutions do not split off any
`methylaminophenol, obtained in the same
`isocyanate on heating and do not lose their
`manner, melts at 110° 0.; it is insoluble in
`activity.
`,
`water, soluble in hot alcohol and in an ex
`The disubstituted carbamic acid esters of
`cess of mineral acids.
`the basically substituted phenols may for
`E'wwmple 2
`instance be obtained by allowing the dialkyl-,
`arylalkyl- or diarylcarbamic acid halogenides
`2.16 parts of lamellated sodium are mixed
`' to react with the alkali salts of the basically
`with 100 parts of benzene and a solution of
`substituted phenols according to the follow
`16.9 parts of o-hydroxybenzyldiethylamine
`ing equation:
`in 20 parts of benzeneis added. With evolu
`R!
`/
`/R'
`‘
`. tion of hydrogen the sodium salt is quickly
`+ metal Hal
`1. R.O metal + Hal CO-—N
`= ROOO-N
`formed. 10 parts of dimethylcarbamic acid
`\R.
`.
`\R.
`chloride are added through the re?ux con
`or by treating the carbonic acid‘ esters of bas
`denser and the product is boiled on the steam
`ically substituted phenols with secondary
`bath. After cooling it is washed with wa
`amines according, to the following equation:
`ter and’ a solution of sodium hydroxide and
`'-
`' /R!
`/'R/
`the residue from the benzene is- distilled in
`, n. ROCOOR +HN = ROCON + ROH
`vacuum. 20 parts of the dimethylcarbamic
`acid ester of -o-hydroxybenzyldiethylamine
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`, In these equations It represents a basically
`
`00
`
`70
`
`80
`
`85
`
`90
`
`95
`
`100
`
`NOVARTIS EXHIBIT 2045
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 2
`
`

`

`2 ‘
`
`1,905,990
`
`an .
`
`JOHN A. AESCHLIMANN.
`
`15
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`are obtained as a mobile oil. The methio- tions, stable to heat, and having a physostig
`dide melts at 157° C.
`mine like action.
`Ewmpze 3
`2. The met-hylphenylcarbanviélqiagd ester of
`m - dimethylammophenol,
`forms
`A solution of S-hydroxyquinoline in the,
`crystals melting at 84° C. and can be distilled
`equivalent quantity of a triple normal solu
`in vacuum without decomposition and forms
`tion of potassium hydroxide is evaporated to
`a quaternary methylsulfate melting at 163°
`dryness in vacuum and the residue heated
`0., easily soluble in Water, forming solutions
`with the equimolecular quantity of dimethyl
`stable to heating, and having a physostig
`carbamic acid chloride in benzene on the
`10
`mine-like action.
`,steambath. The benzene solution is then
`h Ini witness whereof I have hereunto set my
`washed with water and a solution of sodium
`hydroxide, and distilled'in vacuum. The
`product melts after recrystallization from
`ether at 80° C. and forms a hydrochloride
`melting at 195° C. '
`From, m-dimethylaminophenol the di
`methylcarbamic ester may be prepared in a
`similar manner and boils at 190° C. at the
`water-pump. Its dimethylsulfate addition
`product melts at 143°.
`Example 4
`12 parts of tetramethyl-3, 3’-diamino
`phenylcarbonic acid ester are mixed with
`3.7 parts of piperidine and after 14 hours’
`standing heated to 90° C. for an hour.
`The following reaction occurs:
`(CH:)1NC¢H¢OOO0C¢H4N(CH;): + HNogHw =
`(CHa)2NCtH4'OCONC5H1o + HOCaH4N(CH;)z
`The mixture is then dissolved in ether and
`the m-dimethylaminophenol removed by
`shaking with a solution of sodium hydroxide.
`After drying the ether solution is evaporated.
`The residue crystallizes from ether after the
`addition of petroleum ether in heavy
`crystals melting at 56° C. The quaternary
`methylsulfate is obtained in acetone solution
`on addition of the theoretical quantity of di
`methylsulfate; it melts at 123° C.
`I claim:
`'
`1. The disubstituted carbamic acid esters
`of phenols containing a tertiary amino group,
`of the general formula,
`R!
`RoooN/
`
`70
`
`80
`
`95
`
`100
`
`105
`
`110
`
`R.
`R representing a phenyl radical with a
`tertiary amino group selected from the group
`which consists of a phenyl radical with a di
`alkyl amino group, a phenyl radical with a
`dialkyl amino alkyl group and a benzo
`heterocyclic radical; in whichv general
`formula the radicals R’ and B" may be alkyl
`radicals, or aryl radicals of the benzene se
`ries, or the group
`
`50
`
`55
`
`60
`
`may constitute part of a piperidine nucleus;
`Whlch products can be distilled in vacuo
`without decomposition. and form stable
`crystalline quaternary compounds or, salts
`easily soluble in water forming neutral solu
`
`65
`
`115
`
`120
`
`125
`
`130
`
`NOVARTIS EXHIBIT 2045
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 2
`
`