US2911430A - Quaternary salts of dialkyl thiophosphate esters - Google Patents

Quaternary salts of dialkyl thiophosphate esters Download PDF

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US2911430A
US2911430A US708966A US70896658A US2911430A US 2911430 A US2911430 A US 2911430A US 708966 A US708966 A US 708966A US 70896658 A US70896658 A US 70896658A US 2911430 A US2911430 A US 2911430A
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Howard M Fitch
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/1651—Esters of thiophosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

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  • This-invention relates to quaternary ammonium salts of dialkylaminoethyl thiophosphate esters and to the treatment of conditions of disease therewith.
  • novel compounds of the invention are quaternary ammonium salts of dialkylaminoethyl thiophosphate esters of the general formula.
  • R, R and R are alkyl groups, R is hydrogen,
  • X is sulfur or oxygen, at least one X being sulfur, andn is an integer from 1 to 3.
  • the compounds of the invention show a prolonged ino hibition of cholinesterase, making them particularly suitable for causing a prolonged miosis and fall in intraocular pressure on topical application to the eye.
  • the preferred compounds for such use are the quaternary ammonium salts of S-B-dialkylaminoethyl dialkyl thiophosphates and particularly of S-B-di-methylaminoethyl-0,0-diethyl thiophosphate. useful in the treatment of myasthenia gravis, preferably by oral administration.
  • the quaternary ammonium salts of the invention are also useful insecticidal agents.
  • One method for preparing the bases of the compounds of the invention comprises causing an alkali'metal salt of a B-dialkylaminoethanol or a substituted Bdialkylaminoethanol to react with a thionophosphoryl halide.
  • the alkali metal salt may be dissolved or suspended in an inert solvent, such as benzene, toluene, or the like, and an excess of the fl-dialkylaminoethanol may in some cases be used to aid in solution of the alkali metal salt and facilitate the reaction.
  • Relatively low reaction temperatures in the range of 3 to C. are preferred, since the products tend to decompose at high temperatures.
  • the thionophosphoryl halide may be a thionophosphoryl trihalide, a monoalkyl thionophosphoryl dihalide or a dialkyl thionophosphoryl monohalide, giving rise to prod ucts containing three, two or one ,B-dialkylaminoethyl ester groups, respectively.
  • Crude mixtures of monoalkyl thionophosphoryl dihalides and dialkyl thionophosphoryl monohalides, obtained by causing a thionophosphoryltrihalide to react with an alcohol or an alkali metal alcoholate, may also be employed.
  • An alternative method comprises causing a B-halogenoethanol or an alkali metal B-halogenoethylate to react with
  • the compounds of the invention are also ice r ties of tertiary aliphatic amines. They react readily with organic or inorganic acids to'form salts and with alkyl halides or sulfates to form quaternary ammonium salts.
  • the free bases tend to decompose on heating, particularly at temperatures above 100 C., although many of them can be distilled with relatively little decomposition at pressures of 1-2 mm. or less.
  • the ,B-dialkylaminoethyl thionophosphates of the formula R1 in general, readily isomerize to the corresponding thiols of formula R a, o I ll /NCH;CHS P (01m R1 in on heating, or even on standing at room temperature for long periods. While the thiol esters may be separated from the thionophosphates by physical methods, such as fractional crystallization, the facile rearrangement of the thionophosphates into the corresponding thiol esters makes it difficult to obtain or maintain the thionophosphates free of the isomeric thiol esters. Usually the thionophosphates as obtained by the methods of the invention will contain greater-or lesser amounts of the isomeric thiol esters.
  • the amounts of the thiol ester contained a thionophosphate preparation may readily be determined by hydrolysing the thiol ester with dilute alkali under mild conditions and titrating the hydrolysate idometrically for mercaptan under the following conditions:
  • the percent of thiol isomers in thesample of ester is obtained by multiplying the molecular weight of the ester by twice the number of cc. 0.02 'N potassium iodate required for the titration, and dividing by the weight of the sample in milligrams.
  • the thiol esters may also be prepared by causing an I alkali metal salt of a dialkylaminoethylmercaptan to react with a phosphoryl halide or with a thionophosphoryl halide, or by causing a dialkylaminoethyl halide to react with a thiothionophosphate ester. The latter two procedures produce thiothionophosphate esters.
  • the acid oxalate salt prepared in absolute alcohol by adding an equivalent of oxalic acid dihydrate and purified by crystallization from isopropanol, is obtained as large White plates, M.P. 131-2 0., containing about 0.8 mole percent of the isomeric thiol.
  • the methomethylsulfate prepared by adding an excess of dimethylsulfate to a cold solution of the base in acetone and purified by crystallization from a 2 percent solution of isopropanol in ethylacetate, is obtained as flat, white needles, M.P. 92.5-3.5 C., containing about 3.8 mole percent of the isomeric thiol.
  • the methiodide prepared by adding an excess of methyl iodide to a cold solution of the base in methanol, thrown out of solution by adding ether and purified by dissolving in isopropanol and precipitating with ether, is obtained in the form of the monohydrate as white plates, M.P. 114-7 0, containing about 9.4 mole percent of the isomeric thiol.
  • the methobromide prepared by adding an excess of methyl bromide to a cold solution of base in acetone, thrown out of solution by adding ether and purified by dissolving in isopropanol and precipitating with ether, is obtained as very hygroscopic white needles, M.P. 76-81 C.
  • the methochloride prepared by bubbling methyl chloride through a cold solution of the base in acetone, thrown out of solution by adding ether and purified by dissolving in isopropanol and precipitating with ether, is obtained as deliquescent white needles, M.P. 58-60 C.
  • a sample of the crude base in isopropanol is treated with excess oxalic acid dihydrate, heated to boiling and filtered hot from insoluble material.
  • the acid oxalate salt precipitates from the filtrate on cooling and dilution with several volumes of ether. It is purified by crystallization from mixtures of isopropanol and ether and isopropanol and ethyl acetate and from isopropanol alone.
  • the pure acid oxalate is obtained as a white solid, M.P. 1111.5 C., gas evol., containing 97 mole percent thiol isomer.
  • a sample of distilled base in cold isopropanol is treated with excess methyl iodide, left at room temperature overnight, diluted with 5 volumes of ethyl acetate, and This is purified by crystallization from mixtures of isopropanol and ethyl acetate, filtering hot to remove an impurity of low solubility.
  • the pure methiodide is obtained as a white solid, M.P. 1244.5 C., containing 99 mole percent thiol isomer.
  • EXAMPLE v11 O,-O-di n butyl-S-B-dimethylaminoethyl thiophosphate This compound is prepared from the sodium salt of 1 3 3- -7 C., containing 95.5 percent thiol isomer.
  • EXAMPLE X Di-(fi-dimethylaminoethyl) ethyl thionophosphat e [(CH3)2NCH3CH20] P O C 11
  • EXAMPLE X1 Di-(fi-dimethylaminoethyl) isopropyl thionophosphate This compound is prepared from sodium ,B-dimethylaminoethylate and isopropyl thionophosphoryl dichloride as described in Example X. The di-ac'id oxalate, crystalpercent of thiol isomer.
  • the tri-acid oxalate salt purified by repeatedly dissolving in hot 50 percent alcohol and precipitating by adding 95 percent alcohol or absolute alcohol and cooling, crystallizes with three molecules of water as voluminous white needles, M.P. 1302 C., containing about 1.2 mole percent of thiol isomer.
  • the trimethiodide purified in the same manner, crystallizes with three molecules of water as White crystals that darken at about 185 C. and melt at 201-3 C., gas evolution, containing about 8.2 mole percent of thiol isomer.
  • the pure base obtained by treating the purified triacide oxalate with excess ammonium hydroxide and extracting into ether, is a colorless liquid, n 1.4708. ⁇ The base decomposes with a vigorous exothermic reaction on being heated to around'125 C. and decomposes on attempted distillation in vacuum.
  • EXAMPLE XIV fl-Diethylaminoethyl diethyl thionophosphate (C2H5)2NOH2CH2O%(QC:H5)I
  • the base prepared as described in Example I from sodium p-diethylaminoethylate and diethyl thionophosphoryl chloride, is obtained as a colorless liquid, B.P.
  • EXAMPLE XVII- p-Dimethylaminoethyl di-n-amyl thionophosphate The base is prepared as described in Example I from sodium fl-dimethylaminoethylate and di-n-amyl thionophosphoryl chloride.
  • the acid oxalate prepared from undistilled base and purified by crystallization from isopropanol, is obtained as a white solid, M.P. 106-7.5 C., containing no thiol isomer.
  • the mixture is stirred under nitrogen at room temperature for 7 hours and is left at room temperature for 4 days and filtered from a mixture of sodium and potassium chlorides.
  • the filtrate is added to a solution of 12.61 g. oxalic acid dihydrate in 100 cc. isopropanol.
  • 18.82 g. precipitate is removed by filtration.
  • the precipitate is purified by crystallization from a mixture of isopropanol and ethyl acetate, filtering hot to remove some material of low solubility, giving the acid oxalate as white plates, M.P. 124-5.5 C. 1
  • Example II- Methobromide From the oxalate of Example II- Methobromide, white crystals, M.P. 113-114 C. with gas evolution. a I Methochloride, white plates, M.P. 104-105 C. with gas evolution.
  • aqueous solutions of the quaternary salts of the invention 7 has been found to be efiective in reducing intraocular tension.
  • 0.1% and 0.25% solutions of the S13-dimethylaminoethyl-O,O-diethylthiophosphate methiodide of Example II in isotonic saline solution have been found to be useful in controlling intraocular tension in glaucomatous eyes.
  • this compound has been found to have a longer duration of action than any of the commonly used miotics.
  • a quaternary salt of an S-fi-di-loweralkylaminoethyl-0,0-di-loweralkyl thiothionophosphate 8.
  • a quaternary salt of an S-fl-dimethylaminoethyl- 0,0-diethyl thiothionophosphate 11.
  • a quaternary salt of a fi-di-loweralkylaminoethyldi-loweralkyl thionophosphate 14.

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Description

QUATERNARY SALTS F DIALKYL THIOPHOSPHATE ESTERS Howard M. Fitch, Millburn, N.J., assignor to Campbell Pharmaceuticals, Inc., New York, N.Y., a corporation of Delaware No Drawing. Application January 15, 1958 Serial No. 708,966
14 Claims. (Cl. 260-461) This-invention relates to quaternary ammonium salts of dialkylaminoethyl thiophosphate esters and to the treatment of conditions of disease therewith.
The novel compounds of the invention are quaternary ammonium salts of dialkylaminoethyl thiophosphate esters of the general formula.
R R: X
I ll /NOHzOHX P(OR2)3-,, 1 n
wherein R, R and R are alkyl groups, R is hydrogen,
alkyl or substituted alkyl, including dialkylaminoalkyl, X y
is sulfur or oxygen, at least one X being sulfur, andn is an integer from 1 to 3.
The compounds of the invention show a prolonged ino hibition of cholinesterase, making them particularly suitable for causing a prolonged miosis and fall in intraocular pressure on topical application to the eye. The preferred compounds for such use are the quaternary ammonium salts of S-B-dialkylaminoethyl dialkyl thiophosphates and particularly of S-B-di-methylaminoethyl-0,0-diethyl thiophosphate. useful in the treatment of myasthenia gravis, preferably by oral administration.
The quaternary ammonium salts of the invention are also useful insecticidal agents.
One method for preparing the bases of the compounds of the invention comprises causing an alkali'metal salt of a B-dialkylaminoethanol or a substituted Bdialkylaminoethanol to react with a thionophosphoryl halide.
The alkali metal salt may be dissolved or suspended in an inert solvent, such as benzene, toluene, or the like, and an excess of the fl-dialkylaminoethanol may in some cases be used to aid in solution of the alkali metal salt and facilitate the reaction. Relatively low reaction temperatures in the range of 3 to C. are preferred, since the products tend to decompose at high temperatures. The thionophosphoryl halide may be a thionophosphoryl trihalide, a monoalkyl thionophosphoryl dihalide or a dialkyl thionophosphoryl monohalide, giving rise to prod ucts containing three, two or one ,B-dialkylaminoethyl ester groups, respectively. Crude mixtures of monoalkyl thionophosphoryl dihalides and dialkyl thionophosphoryl monohalides, obtained by causing a thionophosphoryltrihalide to react with an alcohol or an alkali metal alcoholate, may also be employed.
An alternative method comprises causing a B-halogenoethanol or an alkali metal B-halogenoethylate to react with The compounds of the invention are also ice r ties of tertiary aliphatic amines. They react readily with organic or inorganic acids to'form salts and with alkyl halides or sulfates to form quaternary ammonium salts. The free bases tend to decompose on heating, particularly at temperatures above 100 C., although many of them can be distilled with relatively little decomposition at pressures of 1-2 mm. or less.
The ,B-dialkylaminoethyl thionophosphates of the formula R1 in general, readily isomerize to the corresponding thiols of formula R a, o I ll /NCH;CHS P (01m R1 in on heating, or even on standing at room temperature for long periods. While the thiol esters may be separated from the thionophosphates by physical methods, such as fractional crystallization, the facile rearrangement of the thionophosphates into the corresponding thiol esters makes it difficult to obtain or maintain the thionophosphates free of the isomeric thiol esters. Usually the thionophosphates as obtained by the methods of the invention will contain greater-or lesser amounts of the isomeric thiol esters.
The amounts of the thiol ester contained a thionophosphate preparation may readily be determined by hydrolysing the thiol ester with dilute alkali under mild conditions and titrating the hydrolysate idometrically for mercaptan under the following conditions:
An accurately Weighed sample of 0.1 to 0.2 millimole is placed in 5 cc. 1 N sodium hydroxide solution. Ifthe sample does not dissolve readily, 5 cc. of ethanol is added. After standing two hours at room temperature, the mixture is chilled in an ice bath and treated with 3 cc. of
6 N hydrochloric acid. A small lump (ca. 0.2 g.) of po- 'tassium iodide is added and the mixture is immediately titrated with 0.02 N potassium iodate solution to a permanent pale yellow end point. The mole percent thiol (i.e.
the percent of thiol isomers in thesample of ester) is obtained by multiplying the molecular weight of the ester by twice the number of cc. 0.02 'N potassium iodate required for the titration, and dividing by the weight of the sample in milligrams.
The thiol esters may also be prepared by causing an I alkali metal salt of a dialkylaminoethylmercaptan to react with a phosphoryl halide or with a thionophosphoryl halide, or by causing a dialkylaminoethyl halide to react with a thiothionophosphate ester. The latter two procedures produce thiothionophosphate esters.
EXAMPLE I fi-Dimethylaminoethyl diethyl thionophosphate S (CH NCHzOH2OI E (OCzH )g To a solution of 53.5 g. fi-dimethylaminoethanol (0.60 mole) in 200 cc. dry benzene is added 6.90 g. sodium (0.30 mole) with stirring during one-half hour. When the initial reaction has subsided, the mixture is stirred at 60-65 C. for about two hours until all the sodium has reacted. The solution of sodium p-dimethylaminoethylate thus obtained is cooled to about 3 C., and a solution of 56.6 g. diethyl thionophosphoryl chloride (0.30
mole) in cc. dry benzene is added with stirring at 34 C. during two hours. The mixture is stirred allowed to warm to room temperature during twoaddi Patented Nov. 3, 1959.. Y
' tional hours, and is washed with 35 cc. and 10 cc. portions of water and with 25 cc. saturated brine and dried over anhydrous calcium sulfate. After removing calcium sulfate by filtration and solvent and excess fi-dimethylaminoethanol by distillation at about 15 to 60 mm. pressure, the residue is distilled in vacuo. The product is 56.2 g. (78 percent theory) of crude fi-dimethylaminoethyl thionophosphate as a colorless liquid boiling at 8292 C./0.3 mm.
The acid oxalate salt, prepared in absolute alcohol by adding an equivalent of oxalic acid dihydrate and purified by crystallization from isopropanol, is obtained as large White plates, M.P. 131-2 0., containing about 0.8 mole percent of the isomeric thiol.
The methomethylsulfate, prepared by adding an excess of dimethylsulfate to a cold solution of the base in acetone and purified by crystallization from a 2 percent solution of isopropanol in ethylacetate, is obtained as flat, white needles, M.P. 92.5-3.5 C., containing about 3.8 mole percent of the isomeric thiol.
A suspension of 23.2 g. purified acid oxalate (0.07 mole) in 110 cc. water is treated with 15.0 cc. concentrated ammonium hydroxide and extracted with 150 cc. and then with 100 cc. ether. The ether extracts are combined, dried over calcium sulfate and filtered. The filtrate is stirred in an ice bath, and 9.34 g. dimethyl sulfate (0.074 mole) is slowly added. A precipitate forms rapidly. The mixture is left in an ice bath for two hours and at room temperature overnight and is filtered. The precipitate is 23.0 g. methomethyl sulfate (89 percent theory). Three crystallizations from a 2 percent solution of isopropanol in ethyl acetate yield 20.8 g. flat white needles, M.P. 92.594 C., containing no thiol isomer.
The methiodide, prepared by adding an excess of methyl iodide to a cold solution of the base in methanol, thrown out of solution by adding ether and purified by dissolving in isopropanol and precipitating with ether, is obtained in the form of the monohydrate as white plates, M.P. 114-7 0, containing about 9.4 mole percent of the isomeric thiol.
A solution of 5.0 g. purified acid oxalate (0.015 mole) in 35 cc. water is treated with 5.0 cc. concentrated ammonium hydroxide andextracted with 35 cc. benzene. The benzene extract is washed with saturated brine, dried over calcium sulfate and filtered. The filtrate is stirred in an ice bath, and 2.70 g. methyl iodide (0.019 mole) is slowly added. The mixture is left at room temperature overnight, diluted with 50 cc. 30-60 C. petroleum ether and filtered from 5.15 g. methiodide (90'percent theory). Two crystallizations from a solution of 10 percent isopropanol in ethyl acetate and one crystallization from a solution of 5 percent isopropanol in ethyl acetate yield 3.0 g. white plates, M.P. 1179.5 C., containing 1.8 mole percent thiol isomer.
The methobromide, prepared by adding an excess of methyl bromide to a cold solution of base in acetone, thrown out of solution by adding ether and purified by dissolving in isopropanol and precipitating with ether, is obtained as very hygroscopic white needles, M.P. 76-81 C.
The methochloride, prepared by bubbling methyl chloride through a cold solution of the base in acetone, thrown out of solution by adding ether and purified by dissolving in isopropanol and precipitating with ether, is obtained as deliquescent white needles, M.P. 58-60 C.
- The reaction is carried out in an atmosphere of nitregen. To a solution of 4.60 g. sodium (0.20 mole) 1n cc. of methanol is added 14.17 g. ,B-dimethylamino- I ethyl mercaptan hydrochloride (0.10 mole), rinsed in filtered from the methiodide salt.
with 10 cc. methanol. Solvent is removed at a waterpump vacuum while blowing with a slow stream of nitrogen to 100 C./20 mm. To the residue suspended in 150 cc. benzene and cooled in an ice bath is added 17.25 g. diethylchlorophosphate (0.10 mole) in 3 portions at 10 minute intervals, After each addition, the temperature increases from about 4 to about 14 C. and then falls. The mixture is stirred in an ice bath for one-half hour and while warming to room temperature during 2 hours is washed with 35 and 5 cc. portions of water with two 10 cc. portions of saturated brine and is dried over calcium sulfate and filtered. After removal of solvent by distillation under reduced pressure to 55 C./20 mm., the residue is 23.0 g. crude base percent theory) as a pale yellow liquid. A sample of the crude base distills with some decomposition at 105-12 C./0.8 mm.
A sample of the crude base in isopropanol is treated with excess oxalic acid dihydrate, heated to boiling and filtered hot from insoluble material. The acid oxalate salt precipitates from the filtrate on cooling and dilution with several volumes of ether. It is purified by crystallization from mixtures of isopropanol and ether and isopropanol and ethyl acetate and from isopropanol alone. The pure acid oxalate is obtained as a white solid, M.P. 1111.5 C., gas evol., containing 97 mole percent thiol isomer.
A sample of distilled base in cold isopropanol is treated with excess methyl iodide, left at room temperature overnight, diluted with 5 volumes of ethyl acetate, and This is purified by crystallization from mixtures of isopropanol and ethyl acetate, filtering hot to remove an impurity of low solubility. The pure methiodide is obtained as a white solid, M.P. 1244.5 C., containing 99 mole percent thiol isomer.
EXAMPLE III fi-Dimethylaminoethyl dimethyl thionophospha te (CH!) aNCHaOHzO 1 (0 CH B-Dimethylaminoethyl di-n-propyl thionophosphate.
(CH3)3NCHjCH2Oi: (OCaH7)2 The base, prepared as described in Example I from sodium fi-dimethylaminoethylate and di-n-propyl thionophosphoryl chloride, is obtained as a colorless liquid boiling at 92-112 C./ 0.3 mm. The acid oxalate crystallizes from a mixture of isopropanol and ether as white plates, M.P. 1224 C., containing about 2 mole percent of thiol isomer. The methiodide crystallizes from a mixture of isopropanol and ether as fine white needles, M.P. 100-3 C., containing about 9 mole percent of thiol isomer.
EXAMPLE V p-Dimethylaminoethyl di-isopropyl thionophosphale i /CH; (CHa)2NCH2CH2O P O CH CH: 1 The base, prepared as described in Example I from sodium fi-dimethylaminoethylate and di-isopropyl thionophosphoryl chloride, is obtained as a colorless liquid,
7 white plates,
fB.l,. 83 -9,3' C./ 0.6 "The methiodide crystallizes from a mixture of isopropanol'and etheras fine white needles, M.P. 121.5-3 C., gas evolution, containing about 1.4 mole percent of the thiol isomer.-
' EXAMPLE V1 fi-Dimethylaminoethyl di-n-butyl thionophosphate s ounmcmomoi womg The base, prepared as described in Example I from .sodium ,liwdimethylaminoethylate and di-n-butyl thionophosphoryl chloride, is obtained as .a colorless liquid, B.P. 103-20" C./0.3 mm. The acid oxalate crystallizes from isopropanol as White plates melting indefinitely at 101-13 0., containing about 3.7 mole percent of the thiol isomer. The methiodide crystallizes from amixture of benzene and 30-60 C. petroleum ether as fine somewhatwaxy crystals, M.P. 77-9 0, containing about 7.2 mole percent of the thiol isomer.. 22.7 grams of crude undistilled base (0.076 mole) is added to a solution of 10.1 g. oxalic acid dihydrate (0.0.8 mole) in 100 cc. :isopropanojl; On dilution with 400 cc. ether 21 copious precipitate iorms. This is filtered ofr and crystallized three times by dissolving in 100 cc; hot isopropanol,
adding 250 cc. hot ethyl acetate, cooling-and filtering.
14.8 grams of purified acid oxalate is obtained as large isom r.
5.81 grams of the pure acid oxalate (15 millimoles) in 50 cc. water is treated with 18 cc. 2 N ammonium hydroxide solution and extracted with 50 cc. benzene.
M.P. 10l..52.5 0., containing no thiol The benzene extra-ct is washed with 10 cc. saturated brine, dried over calcium sulfate and filtered. To the filtrate is added 2.55 g. methyl iodide (18 millimoles). After standing atroom temperature overnight, the solutiouis diluted with .300 cc. -60 C. petroleum ether and ;fi -lter =.d.v The precipitate is purified by crystallization mixtures of ethyl acetate and 30-60 C. petroleum. ether and from ethyl acetate alone, yielding 4.51 g..pure.
methiodide a s flat white needles, M.P. 93-4 0., contaiui gno thiolisomer,
EXAMPLE v11 O,-O-di n butyl-S-B-dimethylaminoethyl thiophosphate This compound is prepared from the sodium salt of 1 3 3- -7 C., containing 95.5 percent thiol isomer.
, EXAMPLE VIII a-Methyl-p-dimthylaminoethyl diethyl thionvophosphate i a on, s
(ciinmcutbnoiwomm The base, prepared as described inExample I from -t h e sodium salt of 1 dimethylamino-Z-propanol and diethyl thionophos'p'horyl chloride, is obtained as a color- .less liquid, B.P. 77-87 C./0.5 mm. The acid oxalate, crystallized from isopropanol, melts at 120-1 C., and is free from thiol isomer. The methiodide,crystallized from isopropanol, melts at 134'-5 C. and is free from thiol isomer.
6 EXAMPLE IX 1,3abisdimethylamino-2-propyl. diethyl thionoph'osphate cHmNcm] crroi to 0.115 2 removed at 100 C./0.5 mm. To the residual sodium salt suspended in 100 cc. benzene is added a solution of 12.65 g. diethyl thionophosphoryl chloride (0.067 mole) in '50 cc. benzene with stirring at 35 'C. during about one hour. The mixture is stirred foran additional hour in an ice bath and during three hours-while slowly Warming to room temperature and left overnight. After washing with 10:cc. and-3 cc. portions of water and with 15 ccfsaturated brine'and drying over anhydrous calcium sulfate, solvent is removed by distillation under reduced pressure to 100 'C./ 10 mm. The residue is 14.45 g. dark amber oil. This is placed in 350 cc. ether, let stand for three days and filtered from ether-insoluble material. The residue after distillation of ether from the filtrate is 8.60 gfamber liquid. This on treating a solution in 60 cc. isopropanol' with 7.60 g. oxalic acid dihydrate and precipitatingby adding ether gives 8.73 g. crude oxalate salt. Purification by several crystallizations from absolute alcohol gives the di-acid oxalate as white crystals, M.P. 114- 5" C., containing about 1.6 mole percent of thiol isomer. A sample of the di-acid oxalate converted to the base and treated with methyl iodide gives the methiodide, which on purification by crystallization from absolute alcohol is obtained as White needles, M.P. 136.5 "--8.5- 0., gas evol., containing about 4.6 mole percent of thiol isomer.
EXAMPLE X Di-(fi-dimethylaminoethyl) ethyl thionophosphat e [(CH3)2NCH3CH20] P O C 11 EXAMPLE X1 Di-(fi-dimethylaminoethyl) isopropyl thionophosphate This compound is prepared from sodium ,B-dimethylaminoethylate and isopropyl thionophosphoryl dichloride as described in Example X. The di-ac'id oxalate, crystalpercent of thiol isomer.
EXAMPLE Xli -D i-(fl-dimethylarhinoethyl) n-octyl thz'onophosphate S [(OH3)2NCH2CH20] P00311 7 2 This 'compound is prepared from sodium ,B-dimethylaminoethylate and n-octylthionophosphoryl dichloride The dimethiodide, crystallized lized from absolute alcohol, is obtained as white crystals, M.P. 156-8 C., gas evolution, containing about 1 mole 103-6 C./0.3 mm.
EXAMPLE XIII Tri-(fi-dimethylaminoethyl) thionophosphate To 44.6 g. fl-dimethylaminoethanol (0.50 mole) in 200 ,cc. benzene is added 10.59 g. sodium (046 mole).- When the initial reaction has subsided, the mixture is stirred at 75-83 C. under reflux for about five hours until all the sodium has reacted. After cooling, 25.40 g. thiophosphoryl chloride, 0.15 mole) in 50 cc. benzene is added with stirring at 48 C. during 1 /2 hours. The mixture is stirred while warming to room temperature during three hours, left overnight, stirred foreight hours longer, and left for three days at room temperature. After washing with 100 cc. and two 25 cc. portions of water and with 20 cc. saturated brine and drying over anhydrous calcium sulfate, solvent isremoved by distillation under reduced pressure to 80 C./ 60 mm. The residue is 30.1 g. of crude base as a yellow liquid.
The tri-acid oxalate salt, purified by repeatedly dissolving in hot 50 percent alcohol and precipitating by adding 95 percent alcohol or absolute alcohol and cooling, crystallizes with three molecules of water as voluminous white needles, M.P. 1302 C., containing about 1.2 mole percent of thiol isomer. The trimethiodide, purified in the same manner, crystallizes with three molecules of water as White crystals that darken at about 185 C. and melt at 201-3 C., gas evolution, containing about 8.2 mole percent of thiol isomer. 1 The pure base, obtained by treating the purified triacide oxalate with excess ammonium hydroxide and extracting into ether, is a colorless liquid, n 1.4708. {The base decomposes with a vigorous exothermic reaction on being heated to around'125 C. and decomposes on attempted distillation in vacuum.
EXAMPLE XIV fl-Diethylaminoethyl diethyl thionophosphate (C2H5)2NOH2CH2O%(QC:H5)I The base, prepared as described in Example I from sodium p-diethylaminoethylate and diethyl thionophosphoryl chloride, is obtained as a colorless liquid, B.P.
EXAMPLE XV S-fl-diezhylaminethyl-0,0-diethyl thiophosphate a mixture of acetone and ethyl acetate, is obtained as a hygroscopic white solid, M.P. 72-4 C., containing 97 mole percent of the thiol isomer.
' EXAMPLE XVI B-Dimethylaminoethyl ethyl n-butyl thionophosphate S O C2H5 (CHshNCHgCHgO I) The base, prepared as described in Example I from sodium S-dimethylaminoethylate and ethyl n-butyl thionophosphoryl chloride, is obtained as a colorless liquid, B.P. 8696 C./0.2 mm. The acid oxalate crystallizes from isopropanol as White plates, M.P. lO7.58.5 C., containing about 1 mole percent of thiol isomer. The methiodide,
crystallized from a mixture of benzene and 30-60". C. petroleum ether, melts at'98.5100 C. and contains about 8 mole percent'of thiol isomer. v
EXAMPLE XVII- p-Dimethylaminoethyl di-n-amyl thionophosphate The base is prepared as described in Example I from sodium fl-dimethylaminoethylate and di-n-amyl thionophosphoryl chloride. The acid oxalate, prepared from undistilled base and purified by crystallization from isopropanol, is obtained as a white solid, M.P. 106-7.5 C., containing no thiol isomer.
7 EXAMPLE XVIII B-Dimethylaminoethyl di-n-octyl thionophosphate S (CHDgNCHzCHzO 1 (0 CQH fl The base is prepared as described in Example I from sodium B-dimethylaminoethylate and di-n-octyl thionophosphoryl chloride. The acid oxalate, prepared from undistilled base and purified by crystallization from a mixture of ethyl acetate and ether and from ethyl acetate, is obtained as a white solid, M.P. 102-6 C., containing no thiol isomer.
' EXAMPLE XIX 0,0-diethyl-S-fl-dimethylaminoethyl thiothionophosphate EXAMPLE XX 'O,"O-diis0pr0pyl-S-fl-dimethylaminoethyl thiothionophosphate 2.30 grams sodium (0.10 mole) is dissolved in cc. hot isopropanol. To the cooled solution is added 25.24 g. potassium 0,0-diisopropyl thiothionophosphate (0.10 mole) and 14.41 g. B-dimethylaminoethyl chloride hydrochloride (0.10 mole). The mixture is stirred under nitrogen at room temperature for 7 hours and is left at room temperature for 4 days and filtered from a mixture of sodium and potassium chlorides. The filtrate .is added to a solution of 12.61 g. oxalic acid dihydrate in 100 cc. isopropanol. After adding 600 cc. ether, 18.82 g. precipitate is removed by filtration. The precipitate is purified by crystallization from a mixture of isopropanol and ethyl acetate, filtering hot to remove some material of low solubility, giving the acid oxalate as white plates, M.P. 124-5.5 C. 1
The following additional typical quaternary salts of the invention made from the purified oxalates of the bases indicated:
From the oxalate of Example II- Methobromide, white crystals, M.P. 113-114 C. with gas evolution. a I Methochloride, white plates, M.P. 104-105 C. with gas evolution.
Ethiodide, white needles, M.P. 9090.5 C. with gas evolution.
2-phenylethiodide, very viscous oil.
Benzylbromide, very hygroscopic waxy white crystals, M.P. 55-65 C. with gas evolution.
3,4-dichlorobenzylchloride, white solid, M.P. 198- 199 C. with gas evolution.
p-Nitrobenzylchloride, white solid, M.P. 202-203 C. with gas evolution.
From the base of Example XIV Methomethylsulfate, hygroscopic white solid, M.P. 72-74 C.
From the oxalate of Example XX Methiodide, white plates, M.P. 121-122 C. with gas evolution.
In the treatment of glaucoma, topical application of aqueous solutions of the quaternary salts of the invention 7 has been found to be efiective in reducing intraocular tension. For example, 0.1% and 0.25% solutions of the S13-dimethylaminoethyl-O,O-diethylthiophosphate methiodide of Example II in isotonic saline solution have been found to be useful in controlling intraocular tension in glaucomatous eyes. In particular, this compound has been found to have a longer duration of action than any of the commonly used miotics.
This application is a'continuation-in-part of my now abandoned application Serial No. 533,495, filed September 9, 1955, which is a continuation-in-part of my now abandoned application Serial No. 509,096, filed May 17, 1955.
I claim:
1. The quaternary salts of di-lower alkylaminoethyl thiophosphate esters of the I general formula wherein R, R and R are lower alkyl groups, R is selected from hydrogen, lower alkyl, and di-loweralkylaminoloweralkyl, X is selected from sulfur and oxygen at least one X being sulfur, and n is an integer from 1 to 3.
2. A quaternary salt of an S fi-di-loweralky1amino- I 7. S B dimethylaminoethyl 0,0 dibutylthiophosphate methiodide.
8. A quaternary salt of an S-fi-di-loweralkylaminoethyl-0,0-di-loweralkyl thiothionophosphate.
9. A quaternary salt of an S-B-diethylaminoethyl- 0,0-diethyl thiophosphate.
10.v S fl diethylaminoethyl 0,0 diethylthiophosphate methomethylsulfate.
11. A quaternary salt of an S-fl-dimethylaminoethyl- 0,0-diethyl thiothionophosphate.
12. S fl dimethylarninoethyl -,0,0 diethy1thionophosphate methiodide.
13. A quaternary salt of a fi-di-loweralkylaminoethyldi-loweralkyl thionophosphate.
14. fi-Dimethylaminoethyldiethylthionophosphate methiodide.
References Cited in the file of this patent UNITED STATES PATENTS Morrison et al. May 12, 1953 Gaetzi et a1 Feb. 28, 1956

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1. THE QUATERNARY SALTS OF DI-LOWER ALKYLAMINOETHYL THIOPHOSPHATE ESTERS OF THE GENERAL FORMULA
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2980581A (en) * 1956-12-21 1961-04-18 Bayer Ag Thiophosphoric acid esters and process for their manufacture
US3337658A (en) * 1964-04-27 1967-08-22 Dow Chemical Co Method for the manufacture of s-substituted phosphoro-dichloridothioates
US3369063A (en) * 1964-10-27 1968-02-13 Pennsalt Chemicals Corp O, o-bis[2-(disubstituted-amino)ethyl] dithiophosphates
US3480698A (en) * 1966-10-27 1969-11-25 Universal Oil Prod Co Aminoalkyl phosphites
US3681495A (en) * 1969-08-25 1972-08-01 American Home Prod Freeze dried echothiophate iodide compositions
US4083692A (en) * 1970-06-04 1978-04-11 The United States Of America As Represented By The Secretary Of The Army Detection and estimation of microquantities of alkylating agents
WO2015114470A1 (en) * 2014-01-31 2015-08-06 Shilpa Medicare Limited Echothiophate iodide process

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2638478A (en) * 1949-05-04 1953-05-12 Hoffmann La Roche Phosphorus-containing derivatives of m-amino-phenols
US2736726A (en) * 1952-03-28 1956-02-28 Geigy Ag J R Basic phosphoric acid esters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2638478A (en) * 1949-05-04 1953-05-12 Hoffmann La Roche Phosphorus-containing derivatives of m-amino-phenols
US2736726A (en) * 1952-03-28 1956-02-28 Geigy Ag J R Basic phosphoric acid esters

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2980581A (en) * 1956-12-21 1961-04-18 Bayer Ag Thiophosphoric acid esters and process for their manufacture
US3337658A (en) * 1964-04-27 1967-08-22 Dow Chemical Co Method for the manufacture of s-substituted phosphoro-dichloridothioates
US3369063A (en) * 1964-10-27 1968-02-13 Pennsalt Chemicals Corp O, o-bis[2-(disubstituted-amino)ethyl] dithiophosphates
US3480698A (en) * 1966-10-27 1969-11-25 Universal Oil Prod Co Aminoalkyl phosphites
US3681495A (en) * 1969-08-25 1972-08-01 American Home Prod Freeze dried echothiophate iodide compositions
US4083692A (en) * 1970-06-04 1978-04-11 The United States Of America As Represented By The Secretary Of The Army Detection and estimation of microquantities of alkylating agents
WO2015114470A1 (en) * 2014-01-31 2015-08-06 Shilpa Medicare Limited Echothiophate iodide process
US9708352B2 (en) 2014-01-31 2017-07-18 Shilpa Medicare Limited Echothiophate iodide process

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