US3903098A - 3-Pyridyl phosphonates - Google Patents
3-Pyridyl phosphonates Download PDFInfo
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- US3903098A US3903098A US655448A US65544857A US3903098A US 3903098 A US3903098 A US 3903098A US 655448 A US655448 A US 655448A US 65544857 A US65544857 A US 65544857A US 3903098 A US3903098 A US 3903098A
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- US
- United States
- Prior art keywords
- pyridyl
- methylphosphonate
- mixture
- pyridol
- trimethylcyclohexyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- XFRKDTDMAUGWBD-UHFFFAOYSA-N OP(OC1=CC=CN=C1)=O Chemical class OP(OC1=CC=CN=C1)=O XFRKDTDMAUGWBD-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- -1 Cyclohexyl 3-pyridyl methylphosphonate Chemical compound 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 19
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical class OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- KQWAOLPZVUPXQI-UHFFFAOYSA-N 3-[methyl-(3,3,5-trimethylcyclohexyl)oxyphosphoryl]oxypyridine Chemical compound CP(OC1CC(CC(C1)C)(C)C)(OC=1C=NC=CC1)=O KQWAOLPZVUPXQI-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- BRRVXFOKWJKTGG-UHFFFAOYSA-N 3,3,5-trimethylcyclohexanol Chemical compound CC1CC(O)CC(C)(C)C1 BRRVXFOKWJKTGG-UHFFFAOYSA-N 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- SCLFRABIDYGTAZ-UHFFFAOYSA-N methylphosphonic acid dichloride Chemical compound CP(Cl)(Cl)=O SCLFRABIDYGTAZ-UHFFFAOYSA-N 0.000 claims description 4
- OSUKSSHOHKZSJC-UHFFFAOYSA-N 12591-02-5 Chemical compound ClP(=O)=O OSUKSSHOHKZSJC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 23
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 19
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- 229940076134 benzene Drugs 0.000 description 13
- 239000000047 product Substances 0.000 description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- GWTSOSYIMOYKNU-UHFFFAOYSA-N methyl(pyridin-3-yloxy)phosphinic acid Chemical compound N1=CC(=CC=C1)OP(O)(=O)C GWTSOSYIMOYKNU-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000001805 chlorine compounds Chemical group 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 231100001225 mammalian toxicity Toxicity 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- RTLLQQBEJNHPCH-UHFFFAOYSA-N 1-[chloro(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(Cl)=O RTLLQQBEJNHPCH-UHFFFAOYSA-N 0.000 description 1
- UNYZIFVAALQVKH-UHFFFAOYSA-N 1-[chloro(methyl)phosphoryl]oxyoctane Chemical compound CCCCCCCCOP(C)(Cl)=O UNYZIFVAALQVKH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NAFOPSBAMSOGMQ-UHFFFAOYSA-N [chloro(methyl)phosphoryl]oxycyclohexane Chemical compound CP(Cl)(=O)OC1CCCCC1 NAFOPSBAMSOGMQ-UHFFFAOYSA-N 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- XMQFTWRPUQYINF-UHFFFAOYSA-N bensulfuron-methyl Chemical compound COC(=O)C1=CC=CC=C1CS(=O)(=O)NC(=O)NC1=NC(OC)=CC(OC)=N1 XMQFTWRPUQYINF-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002575 chemical warfare agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- JVMPUTQDWDLULW-UHFFFAOYSA-N chloro(methyl)phosphinic acid Chemical compound CP(O)(Cl)=O JVMPUTQDWDLULW-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C06—EXPLOSIVES; MATCHES
- C06D—MEANS FOR GENERATING SMOKE OR MIST; GAS-ATTACK COMPOSITIONS; GENERATION OF GAS FOR BLASTING OR PROPULSION (CHEMICAL PART)
- C06D7/00—Compositions for gas-attacks
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- R is an alkyl group containing not more than three carbon atoms
- R" is selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl cyclohexyl groups containing not more than 16 carbon atoms
- R' is an alkyl group containing not more than eight carbon atoms
- X is selected from the class consisting of chloride, bromide and iodide.
- the new compounds of the present invention may be represented by the following general formulas:
- R is an open chain alkyl group which contain not more than 3 carbon atoms
- R" is an open chain alkyl group containing not more than 8 carbon atoms, a cyclohexyl group, or an alkyl-cyclohexyl group con taining not more than 16 carbon atoms
- R' is an alkyl group containing not more than 8 carbon atoms
- X is chloride, bromide or iodide.
- These compounds are useful as chemical warfare agents. They have an extremely high anticholinesterase activity and a mammalian toxicity of an entirely different magnitude than superficially similar compounds such as the 3-pyridyl dialkyl phosphates disclosed in British Pat. No. 666,596.
- the compounds of the British Patent differ from those claimed herein in that R in the above structural formulae is an alkoxy group rather than the alkyl group of our compounds.
- the mammalian toxicity of the phosphates is not sufficiently high to make them useful for our purposes.
- Our compounds may be utilized in any munitions suitable for handling a relatively non-volatile toxic agent, such as bombs, shells, spray tanks, aerosol generators, etc.
- the present invention also includes a process for the manufacture of 3-pyridyl 'phosphonates of the above general formula I by reacting on alkali metal derivative of 3'pyridol, having the formula with an alkyl or cycloalkyl alkylphosphonhalidate having the formula
- M represents an alkalimetal, preferably sodium or potassium
- X represents halogen, preferably chlorine
- R and R" have the same meaning as in general formulas I and ll.
- the reaction may best be conducted in solution or suspension in an anhydrous inert solvent such as, for example, absolute ethyl alcohe] or other anhydrous alcohols, or a hydrocarbon, e.g., benzene, xylene or a petroleum fraction.
- the reaction is exothermic and should be carried out with cool-
- the invention also includes a second, but closely related, process for the manufacture of the 3-pyridyl phosphonates.
- 3- pyridol itself is reacted with the alkyl or cyeloalkyl alkylphosphonohalidate, preferably in a hydrocarbon solvent such as benzene, xylene, or a petroleum fraction, in the presence of an amine-type HCl acceptor,
- triethylamine for example triethylamine, other trialkyl amines, pyridine, diethyl aniline, or other tertiary amines.
- the resulting alkyl 3-pyridyl alkylphosphonates may be converted to the quaternary salts of general formula ll by the usual methods employed for producing quaternary pyridinium compounds, e.g. by reaction with the proper alkyl halide.
- the quaternary salts are water soluble and in some cases may be preferred for that reason.
- alkyl alkylphosphonhalidates employed as reactants are:
- EXAMPLE 1 3-Mcthylcyclohexyl 3-pyridyl methylphosphonate An ethanolie solution of the sodium salt of 3pyridol was prepared by adding 3-pyridol (9.5 g., 0.1 M) to a solution of sodium ethoxide, made by dissolving metallie sodium (2.3 g., 0.1 M) in absolute ethanol (l ml.). 3 Methylcyclohexyl methylphosphonochloridate (21.1 g., 0.1 M) was added over a period of minutes while stirring and cooling.
- the reaction temperature was maintained at'35C.,- and the mixture allowed to stir for an additional 1 V2 hours at C.'
- pyriclol itself may be used as the reactant, the reaction being carried out in the presence of an amine type HCl acceptor, preferably triethylamine.
- an amine type HCl acceptor preferably triethylamine.
- Example 3 the low melting isomer of 3.3,S-trimethylcyclohexanol was used as the starting material. We have also carried outthe same preparation using the high melting'isomer, but find that the compound produced is much less toxic than that derived from the lowmelting isomer. The differences in structure in the final compounds which are responsible for these differences in toxicity are not known to us. Accordingly we designate the compound of Example 3 simply as 3,3,S-trimethylcyclohexyl 3-pyridyl methylphosphonatc derived from the low-melting isomer of 3,3,5-trimethylcyclohexanol. i
- EXAMPLE 4'- EXAMPLE 5 Cyclohexyl 3-Pyridyl Methylphosphonate Sodium metal (5.75 g., 0.25 mole) was dissolved in 200 ml. of absolute ethanol and 3-pyridol (23.8 g., 0.25 mole) was added. After stirring at room temp. for 1 hr., cyclohexyl methylphosphonochloridate (49.2 g., 0.25 mole) was added slowly while the mixture was stirred. An exothermic reaction occurred and cooling was necessary to maintain the reaction temp. at 35. After stirring for an additional 2 hrs and standing overnight, the solvent was stripped off at reduced pressure. The residue was dissolved in a mixture containing ml.
- EXAMPLE 7 Ethyl 3-Pyridyl Methylphosphonate Metallic sodium is dissolved in absolute ethanol to form a solution of sodium ethoxide 3-Pyridol is then added slowly at a temperature of 50C. with good stirring. Ethyl methylphosphonochloridate is then added slowly with continuous stirring and cooling, a temperature of about 30C. being maintained. Stirring is continued for an additional hour at the same temperature. The reaction product is then treated in the same manner as Example 1.
- the product is recovered as set out in Example
- the compounds of our general formula l are easily converted to the quaternary compounds of general formula II by simply adding the proper alkyl halide, preferably in excess, to a hydrocarbon solution of the pyridyl phosphonate.
- the quaternary compounds are insoluble in and of higher density than the hydrocarbon and settle out, forming a layer which is readily separated.
- R' is methyl we prefer, under laboratory conditions, to use methyl iodide as the halide, because of the very low boiling point of the chloride and bromide.
- Methyl bromide or methyl chloride may, however, be utilized by carrying out the reaction in an autoclave. For higher members, the cheaper chlorides or bromides may conveniently be used.
- the other compounds of our invention may be prepared by the same methods simply substituting the proper alkyl alkylphosphonohalidate andiin' the case of the quaternary compounds, the proper alkyl halide.
- a process for preparing a pyridyl alkylphosphonate of'the formula I 0 V 1 Y R-P-O, l l H 0R1! which comprises mixing an alkylphosphonochloridate of the formula 8 inv an inert soljyerit with a compound selected from the class consisting of 3-pyridol'and its sodium and potassium salts; R in the above formulas being an alkyl group containing'not more than three carbon atoms and R" being selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl substituted cyclohexy'l groups containing not more than sixteen carbon atoms, while cooling the resulting mixture.
- a process as defined inclaim 9 which comprises mixing said phospho'n'o'ehloridate with atleast one of said'salts'of 3-pyridol in solution in anhydrousalcohol. If].
- a process defined in claim 9 whichcomprises mixing s'ai'd'alkylphosphonochloridate with pyridol in a hyc'lroc'arbc'm solution in" the presence of a tertiar amine.
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Abstract
1. A compound selected from the class consisting of
wherein R'' is an alkyl group containing not more than three carbon atoms, R'''' is selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl cyclohexyl groups containing not more than 16 carbon atoms, R'''''' is an alkyl group containing not more than eight carbon atoms, and X is selected from the class consisting of chloride, bromide and iodide.
wherein R'' is an alkyl group containing not more than three carbon atoms, R'''' is selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl cyclohexyl groups containing not more than 16 carbon atoms, R'''''' is an alkyl group containing not more than eight carbon atoms, and X is selected from the class consisting of chloride, bromide and iodide.
Description
United States Patent [1 1 Dawson et al.
[451 Sept. 2, 1975 3-PYRIDYL PHOSPHONATES [75] Inventors: Thomas P. Dawson, Bel Air; Charles E. Williamson, Edgewood, both of Md.
[22] Filed: Apr. 26, 1957 [21] App]. No.: 655,448
Related U.S. Application Data [63] Continuation-in-part of Ser. No. 564,584, Feb. 9,
1956, abandoned [52] U.S. Cl. 260/297 P; 260/999; 424/200 [51] Int. Cl. C07D 213/44 [58] Field of Search ..260/269, 290, 297.5,
[5 6] References Cited FOREIGN PATENTS OR APPLICATIONS 666,596 2/1952 United Kingdom 260/290 Primary Examiner-Leland A. Sebastian Attorney, Agent, or Firm-Nathan Edelberg; Robert P. Gibson; Kenneth P. Van Wyck EXEIVIPLARY CLAIM l. A compound selected from the class consisting of wherein R is an alkyl group containing not more than three carbon atoms, R" is selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl cyclohexyl groups containing not more than 16 carbon atoms, R' is an alkyl group containing not more than eight carbon atoms, and X is selected from the class consisting of chloride, bromide and iodide.
14 Claims, No Drawings 3-PYRIDYL PHOSPHONATES The invention described herein may be manufactured and used by or for the Government of the United States of America for governmental purposes without the payment to us of any royalty thereon.
This is a continuation-in-part of application Ser. No. 564,584, filed Feb. 9, 1956 and now abandoned This invention relates to 3-pyridyl phosphonates and quaternary salts thereof. It also relates to a process for manufacturing these compounds.
The new compounds of the present invention may be represented by the following general formulas:
wherein R is an open chain alkyl group which contain not more than 3 carbon atoms, R" is an open chain alkyl group containing not more than 8 carbon atoms, a cyclohexyl group, or an alkyl-cyclohexyl group con taining not more than 16 carbon atoms, R' is an alkyl group containing not more than 8 carbon atoms, and X is chloride, bromide or iodide.
These compounds are useful as chemical warfare agents. They have an extremely high anticholinesterase activity and a mammalian toxicity of an entirely different magnitude than superficially similar compounds such as the 3-pyridyl dialkyl phosphates disclosed in British Pat. No. 666,596. The compounds of the British Patent differ from those claimed herein in that R in the above structural formulae is an alkoxy group rather than the alkyl group of our compounds. The mammalian toxicity of the phosphates is not sufficiently high to make them useful for our purposes.
Our compounds may be utilized in any munitions suitable for handling a relatively non-volatile toxic agent, such as bombs, shells, spray tanks, aerosol generators, etc.
The present invention also includes a process for the manufacture of 3-pyridyl 'phosphonates of the above general formula I by reacting on alkali metal derivative of 3'pyridol, having the formula with an alkyl or cycloalkyl alkylphosphonhalidate having the formula In these formulae M represents an alkalimetal, preferably sodium or potassium, X represents halogen, preferably chlorine, and R and R" have the same meaning as in general formulas I and ll. The reaction may best be conducted in solution or suspension in an anhydrous inert solvent such as, for example, absolute ethyl alcohe] or other anhydrous alcohols, or a hydrocarbon, e.g., benzene, xylene or a petroleum fraction. The reaction is exothermic and should be carried out with cool- The invention also includes a second, but closely related, process for the manufacture of the 3-pyridyl phosphonates. According to this modification, 3- pyridol itself is reacted with the alkyl or cyeloalkyl alkylphosphonohalidate, preferably in a hydrocarbon solvent such as benzene, xylene, or a petroleum fraction, in the presence of an amine-type HCl acceptor,
for example triethylamine, other trialkyl amines, pyridine, diethyl aniline, or other tertiary amines.
The resulting alkyl 3-pyridyl alkylphosphonates may be converted to the quaternary salts of general formula ll by the usual methods employed for producing quaternary pyridinium compounds, e.g. by reaction with the proper alkyl halide. The quaternary salts are water soluble and in some cases may be preferred for that reason.
Examples of preferred alkyl alkylphosphonhalidates employed as reactants are:
Ethyl methylphoshonochloridate [sopropyl methylphosphonochloridate Cyclohexyl methylphosphonochloridate 3-Methylcyclohexyl methylphosphonochloridate 3,3,5-Trimethylcyclohexyl methylphosphonochloridate (Derived from the lowmelting isomer of 3,3,5- trimethyl cyclohexanol) These intermediates have been prepared according to the general reaction.
The procedure employed in each case was as follows: The methylphosphonic dichloride and triethylamine, 2 percent excess of each, were dissolved in 125 ml. of nhexane (0.5 mole run). The alcohol, R OH, 0.5 mole previously dissolved in ml' of dry hexane, was then added dropwise with stirring and cooling during a 15 min. period at a reaction temperature of 10 to 15C. The reaction mixture was then allowed to warm to room temperature and finally heated to 4045 C for 1 hour. In some cases the resulting solution was used directly in the main reaction. In others the triethylamine hydrochloride was removed by filtration and the filtrate was distilled. After stripping of the hexane, the last traces under a vacuum (2mm Hg, abs), the phosphonochloridate was obtained in good yield and adequate purity for use in the main reaction for the preparation of our novel compounds.
The following examples illustrate how the process of the invention may be carried into effect:
EXAMPLE 1 3-Mcthylcyclohexyl 3-pyridyl methylphosphonate An ethanolie solution of the sodium salt of 3pyridol was prepared by adding 3-pyridol (9.5 g., 0.1 M) to a solution of sodium ethoxide, made by dissolving metallie sodium (2.3 g., 0.1 M) in absolute ethanol (l ml.). 3 Methylcyclohexyl methylphosphonochloridate (21.1 g., 0.1 M) was added over a period of minutes while stirring and cooling. The reaction temperature was maintained at'35C.,- and the mixture allowed to stir for an additional 1 V2 hours at C.'The solvent was then distilled'off at reduced pressure and the residual oil dissolvedin xylene (50 ml). It was then washed with 5 percent sodiumhydroxide solution ("6 X 85 ml.), 5 percent sodium chloride solution (2 X 85 ml.) and water (2 X 85 ml.). After removal of the solvent at reduced pressure the product was evacuated to 2 mm. Hg. at 5055C. for 3 hours. The unvaporized material constituted the product. The yield was 14.5 g. (=54 percent). g I 7 EXAMPLE 2 v 3.3,5-Trimethylcyclohexyl 3-Pyridyl Methylphosphonate This compound was prepared in a manner similar to that of Example 1 from 3-pyridol (23.8 g., 0.25), sodium (5.75 g., 0.25 M), absolute ethanol (200 ml.) and 3,3,S-trimethylcyclohexyl methylphosphonochloridate (59.7 g., 0.25 M). The yield was 55.6 g. (=74.8%).
Instead of employing the alkali metal salt of pyridol, pyriclol itself may be used as the reactant, the reaction being carried out in the presence of an amine type HCl acceptor, preferably triethylamine. The following example shows a typical preparation of a compoundby this method.
EXAMPLE 3 3,3,5-Trimethylcyclohexyl 3-Pyridyl Methylphosphonate Mcthylphosphonic dichloride (33.2 g., 0.25 M) and triethylamine (25.3 g., 0.25 M) were dissolved in 200 ml. of benzene and the low melting isomer of 3,3,S-trimcthylcyclohexanol (35.5 g., 0.25 M) was added slowly while stirring and cooling. A reaction temperature of l()l5C. was maintained' It 'was then heated to 40C. for an additional hour. This mixture is now essentially a benzene solution of 3,3,5-trimethylcyclohexyl methylphosphonochloridate. Triethylamine (25.3 g., 0.25 M) was again added to the reaction mixture and 3-pyridol (23.8 g., 0.25 M) was added slowly while stirring and cooling. A reaction-temperature of C. was maintained. After stirring for an additional hour at room temperature the mixture was washed with 5 percent sodium hydroxidesolution (5 X 100 ml.) followed by water (3 X 100 ml.). The solvent was then removed'by distillation at reduced pressure. A yield of 66.0 g. (=88.8 percent) of product remained.
It will be noted that in Example 3, the low melting isomer of 3.3,S-trimethylcyclohexanol was used as the starting material. We have also carried outthe same preparation using the high melting'isomer, but find that the compound produced is much less toxic than that derived from the lowmelting isomer. The differences in structure in the final compounds which are responsible for these differences in toxicity are not known to us. Accordingly we designate the compound of Example 3 simply as 3,3,S-trimethylcyclohexyl 3-pyridyl methylphosphonatc derived from the low-melting isomer of 3,3,5-trimethylcyclohexanol. i
" EXAMPLE 4'- EXAMPLE 5 Cyclohexyl 3-Pyridyl Methylphosphonate Sodium metal (5.75 g., 0.25 mole) was dissolved in 200 ml. of absolute ethanol and 3-pyridol (23.8 g., 0.25 mole) was added. After stirring at room temp. for 1 hr., cyclohexyl methylphosphonochloridate (49.2 g., 0.25 mole) was added slowly while the mixture was stirred. An exothermic reaction occurred and cooling was necessary to maintain the reaction temp. at 35. After stirring for an additional 2 hrs and standing overnight, the solvent was stripped off at reduced pressure. The residue was dissolved in a mixture containing ml. of xylene and 100 ml. of 5% NaQH solution. The xylene solution containing the desired product was then washed with 57: NaOH solution (5 X 200 ml.) and an equal amountof water. The solvent was stripped off at reduced'prcssure and the residue wassubmitted for analy 1 i A yield of l .4 g. (46.6 percent) was obtained. Anal. Calcd. for c,,,H ,,No,P; (7.58.9; H, 7.5; v1.5.2; P, 11.5 Foundz C, 58.2 H, 7.5; N 4.8; P, 11.5.
EXAMPLE'6 Methyl 3-Py ridyl Methylphosphonate Equimolar quantities :of methyl methylphosphonoehloridate and tributylamin'e are dissolved in xylene. An equimolar quantity of 3-pyridol in xylene is slowly added with constant stirring andfcooling The mixture is stirred -for an additional'fhour; A reaction temperature of about 30-C is maintained by cooling. The reaction mixture is then treated in thesame manner as given in Example 3.
EXAMPLE 7 Ethyl 3-Pyridyl Methylphosphonate Metallic sodium is dissolved in absolute ethanol to form a solution of sodium ethoxide 3-Pyridol is then added slowly at a temperature of 50C. with good stirring. Ethyl methylphosphonochloridate is then added slowly with continuous stirring and cooling, a temperature of about 30C. being maintained. Stirring is continued for an additional hour at the same temperature. The reaction product is then treated in the same manner as Example 1.
EXAMPLE 8 An -(j) Mcthylphosphona te l Equimolar,==-,quantities of n-octyl methylphosphonochloridate .and tricthylamine are dissolvedin benzene. An ee uimolara.:lq-uantityv of 3-pyridol is then added Equimolar quantities of;diisopropylcarbiinyl methylpl'ios phonochloridate and triethylarnin e are dissolved in benzene. An equimolar quantity of 3;pyrido l' is then added slowly with constant stirring; the temperature being maintained at about 30C. The mixture is then stirred for" an additional htiur at the same temperature and theproduc't is recovered the mariner "set out in Example 3. Q
. EXAMPLE l H Ethyl 3-Pyridyl Ethylphosphonate Equimolar quantities of ethyl ethylphosplionochloridate and triethylamine are diissolve d in benzene? Ari equimo lar quantity of 3 pyridol is added slowly with constant stirring. The temperature ismai ritained' at about35C by coolirig. After all the pyridol has been added them'ix ture is stirred at room temperature for anotherj hour. The product is then separated in the manner. given Example 3. v i
EXAMPLE I l Cyclohexyl 3Pyridyl Ethylphosphonate Equimolar quantities of cyclohexyl ethylphosphonochloridate and triethylamine .are dissolved in benzene. An equimolar quantity of 3- pyridol.-is then added slowly with constant stirring. The temperature is maintained at about 30C. by cooling... After allthe 'pyridol has been added the stirring is continued for'an additio nal hour at room temperature. a
The product is recovered as set out in Example The compounds of our general formula l are easily converted to the quaternary compounds of general formula II by simply adding the proper alkyl halide, preferably in excess, to a hydrocarbon solution of the pyridyl phosphonate. The quaternary compounds are insoluble in and of higher density than the hydrocarbon and settle out, forming a layer which is readily separated. When R' is methyl we prefer, under laboratory conditions, to use methyl iodide as the halide, because of the very low boiling point of the chloride and bromide. Methyl bromide or methyl chloride may, however, be utilized by carrying out the reaction in an autoclave. For higher members, the cheaper chlorides or bromides may conveniently be used.
EXAMPLE l2 Z-Methycyclohexyl 3-Pyridyl Methylphosphonate Methiodide Fifteen grams of Z-mcthylcyclohexyl 3-pyridyl methylphosphonate was dissolved in 75 ml. of dry ben- Zene. and 30 ml. of methyl iodide was added. After standing overnight. a benzene-insoluble layer was formed which was removed and washed three times with dry benzene. To remove the last trace of benzene, the product was evacuated to 2mm. Hg at 45 for 3 hrs. The product on analysis was found to contain 28.3 percent iodine, (theoretical-30.86 percent).
EXAMPLE l3 3,3,5-Trimethylcyclohexyl 3-Pyridyl Methylphosphonate Methiodide The procedure of Example 12 was repeated exactly, except that 3,3,5-trimethylcyclohexyl 3-pyridyl methylphosphonate used as th e reactant. The product was an oil containing by analysis 30.97 percent iodine (theoretical, 28.89 percent).
a EXAMPLE l4 3;3,5 Trifnethylcyclohexyl 3- Py ridyl H iMethy lphosp'honate Ethobromide Fifteen grams of 3,3,5-trimethylcyclohexyl 3-py rid'yl methylphonate is dissolved in a ml. benzene and 30 mLof ethylbromideadded. The mixture is then treated in the same-manner as given in Example 12 a I '1 EXAMPLE 15 lsopropyli3- lyridyl Methylphosphonate Butochloride Fifteen grains of isopropyl 3-py'ridyl methylphosphonate is dissolved in 75 ml. of benzene and 30 ml. of n-butyl chlorideis added. The mixture is then treated l 3 I v1 1n the same manner as given in Example 12.
The other compounds of our invention may be prepared by the same methods simply substituting the proper alkyl alkylphosphonohalidate andiin' the case of the quaternary compounds, the proper alkyl halide.
We have found that the identity of the alkyl groups, particularly R, has a marked influence on the toxicity of the compounds.- Particularly outstanding results are secured when is methyl and R" is cyclohexyl or substituted cyclohexylThe presence of substituents in the cyclohexyl ring further effects the toxicity. ln compound'siJfthe formula the variation of toxicity with various cyclohexyl radicals as R was found to be as follows:
Increasing R Toxicity Cyelohcxyl 4-Methylcyclohexyl Z-Methylcyclohexyl 3-Methylcyclohexyl 3.3.5-Trimethylcyclohexyl (from the low melting isomer of 3.3.S-trimethylcyclohexanol) 4-Cyclohexylcyelohexyl Maximum wherein R is an alkyl group containing not more than three carbon atoms, R is selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl cyclohexyl groups containing notmorc than -16 carbon atoms, R'
is an .a lkyl group containing not more than eight carbon atoms, and X? is $e1 rearr the class consisting of chloridebrom ideargcliodide i 2. Cyelohexyl 3-pyridyl methylphosphonate. 3. 3-Methylcyclohexyl 3 -py'ridylmethylphosphonate.
4. 4-Methylcyclohexyl 3-pyridyl methylphosphonate.
5. 3,3 ,5-Trimethyleyclohexyl 3-pyridyl methylphosp o -l v 6. 'lsopro pyl 3-pyridyl'methylphdsphonate." I 7. 2 Met hylcyelo'he xyl"3-pyridyl methylphosphonate methiodide.
8. 3,3,5 Trimethylcyclohexyi"3-pyridyl methyl pliosphonate methiodide'. I
9. A process for preparing a pyridyl alkylphosphonate of'the formula I 0 V 1 Y R-P-O, l l H 0R1! which comprises mixing an alkylphosphonochloridate of the formula 8 inv an inert soljyerit with a compound selected from the class consisting of 3-pyridol'and its sodium and potassium salts; R in the above formulas being an alkyl group containing'not more than three carbon atoms and R" being selected from the class consisting of open chain alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkyl substituted cyclohexy'l groups containing not more than sixteen carbon atoms, while cooling the resulting mixture.
' 105 A process as defined inclaim 9 which comprises mixing said phospho'n'o'ehloridate with atleast one of said'salts'of 3-pyridol in solution in anhydrousalcohol. If]. A process defined in claim 9 whichcomprises mixing s'ai'd'alkylphosphonochloridate with pyridol in a hyc'lroc'arbc'm solution in" the presence of a tertiar amine. i 1
12. A process as defined in claim 11 wherein said amine is triethylamine. I I
13. -3,3,S-Trimethylcyclohexyl 3-pyridyl methylphosphonate derived from thelow' melting isomerof 3,3,5- t'rimethyl cyclohexanol by mixing said 3,3,5-trimethylcyelohexanol with methylphosphonic dichloride in an inert solvent in the presence of a teritary amine HCl aceeptor while 'cooling said mixture, thereafter heating said mixture to a'temperatureof about40 C, and adding 3-pyridol tosaid mixture in-the presence of a teri- ,thereafter heating said-mixture to a temperature of about,4 0C,, and add ing 3-pyridol to, said mixture in the presence of a tertiary amine, HCl acceptor while stirring and cooling sai cl mixture'
Claims (14)
1. A COMPOUND SELECTED FROM KTHE CLASS CONSISTING OF
2. Cyclohexyl 3-pyridyl methylphosphonate.
3. 3-Methylcyclohexyl 3-pyridyl methylphosphonate.
4. 4-Methylcyclohexyl 3-pyridyl methylphosphonate.
5. 3,3,5-Trimethylcyclohexyl 3-pyridyl methylphosphonate.
6. Isopropyl 3-pyridyl methylphosphonate.
7. 2-Methylcyclohexyl 3-pyridyl methylphosphonate methiodide.
8. 3,3,5-Trimethylcyclohexyl 3-pyridyl methylphosphonate methiodide.
9. A process for preparing a pyridyl alkylphosphonate of the formula
10. A process as defined in claim 9 which comprises mixing said phosphonochloridate with at least one of said salts of 3-pyridol in solution in anhydrous alcohol.
11. A process as defined in claim 9 which comprises mixing said alkylphosphonochloridate with pyridol in a hydrocarbon solution in the presence of a tertiary amine.
12. A process as defined in claim 11 wherein said amine is triethylamine.
13. 3,3,5-Trimethylcyclohexyl 3-pyridyl methylphosphonate derived from the low melting isomer of 3,3,5-trimethyl cyclohexanol by mixing said 3,3,5-trimethylcyclohexanol with methylphosphonic dichloride in an inert solvent in the presence of a teritary amine HCl acceptor while cooling said mixture, thereafter heating said mixture to a temperature of about 40* C, and adding 3-pyridol to said mixture in the presence of a teritary amine HCl acceptor while stirring and cooling said mixture.
14. The process of preparing 3,3,5-trimethylcyclohexyl 3-pyridyl methylphosphonate consisting essentially of mixing the low-melting isomer of 3,3,5-trimethylcyclohexanol with methylphosphonic dichloride in an inert solvent in the presence of a tertiary amine HCl acceptor while cooling said mixture, thereafter heating said mixture to a temperature of about 40*C., and adding 3-pyridol to said mixture in the presence of a tertiary amine HCl acceptor while stirring and cooling said mixture.
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