US2980692A - 3-indolemethanephosphonic acid and its salts and preparation thereof - Google Patents

3-indolemethanephosphonic acid and its salts and preparation thereof Download PDF

Info

Publication number
US2980692A
US2980692A US751155A US75115558A US2980692A US 2980692 A US2980692 A US 2980692A US 751155 A US751155 A US 751155A US 75115558 A US75115558 A US 75115558A US 2980692 A US2980692 A US 2980692A
Authority
US
United States
Prior art keywords
acid
indolemethanephosphonic
salts
lower alkyl
indolemethanephosphonate
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
Application number
US751155A
Inventor
Noel F Albertson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
STWB Inc
Original Assignee
Sterling Drug Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sterling Drug Inc filed Critical Sterling Drug Inc
Priority to US751155A priority Critical patent/US2980692A/en
Application granted granted Critical
Publication of US2980692A publication Critical patent/US2980692A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention resides in the concept of a composition of matter having a molecular structure wherein a methanephosphonic acid radical, -CH PO H is attached to the 3-position of indole; the salts of such composition; a process for preparing the compositions; and intermediates in said process.
  • the phy'sical embodiments of the inventive concept have plant growth regulant properties.
  • they are inhibitors of heteroauxin (S-indoleacetic acid) and are thus useful as antagonists of plant growth;
  • the embodiment o'f'the inventive concept can be accomplished by interactingfa t'ri-lower alkyl phosphite and a 3-indole-methyl-quatern ary ammonium salt having the structural formula where B represents a member of the group, consisting of dimethyl, diethyl, and 1,5-pentylene (CH CH CH CH CH radicals, and An represents a member of the group consisting of the iodide radical and the methosulfate radical, to produce a di-lower alkyl 3-indolemethanephos phonate, which ester is then hydrolyzed to produce 3-indolemethanephosphonic acid; and this dibasic acid can, if desired, be interacted with-either one or two equivalents of an organic or inorganic base to form acor-responding organic or inorganic salt.
  • B represents a member of the group, consisting of dimethyl, diethyl, and 1,5-pentylene (CH CH CH CH CH
  • lower alkyl as used in the specification and claims represents in each instance branched and unbranched alkyl radicals-having 1-4 carbon atoms and accordingly includes methyl,.ethyl, isopropyl, n-butyl;:and the like.
  • the tri lower alkyl phosphites employed-asa starting material' are known and readily obtained compounds.
  • The-3-indole methyl-quaternary ammonium salt reactants ⁇ are known and readily obtained compounds.
  • The-3-indole methyl-quaternary ammonium salt reactants ⁇ are used to interacting an appropriate 3-(N,N-dis'ubstituted aminomethyl)indo1e, that is 3-(N,N-dimethylamino"- methyl) indole grami-ne) 3- (N ,N-diethylamirfomet-liyl indole, or 3-(piperidinomethyl)indole, with methyl'iddide' 2,980,692 Patented Apr. 18, 1961 action medium which facilitates stirring of the mixture.
  • This reaction is-preferably carried out at a temperature in-the' approximate range degrees centigrade to degrees centigrade, and at least several hours reaction time is required for optimum yields.
  • the di-lower alkyl 3'indolemethanephosphonates obtained as intermediates in my process are white solids which are practically insoluble in water and are moderately soluble in ethanol. They are hydrolyzed by aqueous alkaline solutions to the corresponding mono-lower alkyl esters which, like the di-lower alkyl esters, are hydrolyzed by strong mineral acid-glacial acetic acid mixtures to yield 3-indolemethanephosphonic acid.
  • the di-lower alkyl 3-indolemethanephosphonate resulting from the first'step is heated, conveniently at reflux temperature, for several hours or more with a mixture of glacial acetic acid and a strong mineral acid, such as hyrochloric acid, phosphoric acid, or sulfuric acid.
  • a strong mineral acid such as hyrochloric acid, phosphoric acid, or sulfuric acid.
  • EXAMPLE 1 Diethyl 3-indolemethanephosphonate 7.1 g. of inethyliodide was dripped into a stirred suspension of 8.7 g. of gramine in 65 g. of triethyl phosphite at room temperature (about 25 degrees centigrade) during a period of fifteen minutes, and the reaction mixture was then heated for ten hours on a steam bath. After this heating period, the reaction mixture was filtered to remove the solid material which had separated from solution, and the collected solid was washed with about 25 ml. of benzene.
  • This acid is soluble in water at 25 C. to the extent of about 0.5% (weight/volume).
  • the pH of a 0.5% solution was 2.2; when a 0.5% aqueous solution was adjusted to pH-7.0 by treatment with N/ sodium hydroxide solution, no precipitate was formed.
  • the acid was soluble in diethyl ether and fairly soluble in isopropyl alcohol.
  • My new compounds can be employed to combat the growth of unwanted vegetation by application to, the plants by the conventional methods, for instance dusting, spraying, and the like.
  • spraying I generally preferan aqueous solution of the monosodium or disodium salt'of 3-indolemethanephosphonic acid.
  • '3-indolemethanephosphonic' acid has a relatively low toxicity toward animals; for example, oral doses in the ormonkeys.
  • 3-indolemethanephosphonic acid having the structural formula range'l00-200 mg./kg. had no detectable effect on cats acid.
  • the process which comprises heating a mixture of a tri-lower alkyl phosphite and a 3-indolemethy1 quateifl nary ammonium salt having the structural formula where B represents a member of the group consisting of dimethyl, diethyl, and 1,5-pentylene radicals and An represents a member of the group consisting of the iodide radical and the methosulfate radical, to produce a dilower alkyl 3-indolemethanephosphonate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Description

United States PatentC 'ice S-INDOLEMETHANEPHOSPHONIC ACID AND ITS SALTS AND PREPARATION THEREOF Noel F. Albertson, Castleton on Hudson, 'N.Y., assignmto Sterling'Di-ug I'ne, New York, N.Y., a eorporanon of Delaware No Drawing. Filed'July- 28, 1958, SenNo. 751,155- 8 Claims. or. 260-319) This invention relates to- I i-substituted indoles.
The present invention resides in the concept of a composition of matter having a molecular structure wherein a methanephosphonic acid radical, -CH PO H is attached to the 3-position of indole; the salts of such composition; a process for preparing the compositions; and intermediates in said process.
The phy'sical embodiments of the inventive concept have plant growth regulant properties. In particular, they are inhibitors of heteroauxin (S-indoleacetic acid) and are thus useful as antagonists of plant growth;
The embodiment o'f'the inventive concept can be accomplished by interactingfa t'ri-lower alkyl phosphite and a 3-indole-methyl-quatern ary ammonium salt having the structural formula where B represents a member of the group, consisting of dimethyl, diethyl, and 1,5-pentylene (CH CH CH CH CH radicals, and An represents a member of the group consisting of the iodide radical and the methosulfate radical, to produce a di-lower alkyl 3-indolemethanephos phonate, which ester is then hydrolyzed to produce 3-indolemethanephosphonic acid; and this dibasic acid can, if desired, be interacted with-either one or two equivalents of an organic or inorganic base to form acor-responding organic or inorganic salt.
The term lower alkyl as used in the specification and claims represents in each instance branched and unbranched alkyl radicals-having 1-4 carbon atoms and accordingly includes methyl,.ethyl, isopropyl, n-butyl;:and the like.
In the first step. of-the process of my invention, the tri lower alkyl phosphites employed-asa starting material'are known and readily obtained compounds.- The-3-indole methyl-quaternary ammonium salt reactants} ,a'rereadily obtained by interacting an appropriate 3-(N,N-dis'ubstituted aminomethyl)indo1e, that is 3-(N,N-dimethylamino"- methyl) indole grami-ne) 3- (N ,N-diethylamirfomet-liyl indole, or 3-(piperidinomethyl)indole, with methyl'iddide' 2,980,692 Patented Apr. 18, 1961 action medium which facilitates stirring of the mixture. This reaction is-preferably carried out at a temperature in-the' approximate range degrees centigrade to degrees centigrade, and at least several hours reaction time is required for optimum yields.
The di-lower alkyl 3'indolemethanephosphonates obtained as intermediates in my process are white solids which are practically insoluble in water and are moderately soluble in ethanol. They are hydrolyzed by aqueous alkaline solutions to the corresponding mono-lower alkyl esters which, like the di-lower alkyl esters, are hydrolyzed by strong mineral acid-glacial acetic acid mixtures to yield 3-indolemethanephosphonic acid.
In the second, or acid hydrolysis, step of my proces the di-lower alkyl 3-indolemethanephosphonate resulting from the first'step is heated, conveniently at reflux temperature, for several hours or more with a mixture of glacial acetic acid and a strong mineral acid, such as hyrochloric acid, phosphoric acid, or sulfuric acid. This procedure removes both of the lower alkyl groups and produces the free dibasic acid, 3-ind0lernethanephosphonic acid. This white'crystalline product is readily isolated and easily purified. It can be used as such or converted to any desired salt by conventional treatment with the appropriate organic or inorganic base.
My invention is'illustrated by the following examples without, howevenbeing limited thereto.
EXAMPLE 1 A. Diethyl 3-indolemethanephosphonate 7.1 g. of inethyliodide was dripped into a stirred suspension of 8.7 g. of gramine in 65 g. of triethyl phosphite at room temperature (about 25 degrees centigrade) during a period of fifteen minutes, and the reaction mixture was then heated for ten hours on a steam bath. After this heating period, the reaction mixture was filtered to remove the solid material which had separated from solution, and the collected solid was washed with about 25 ml. of benzene. The filtrate and wash liquor were combined and concentratedunder reduced pressure, and the residue thus obtained, which weighed 25 g., was shaken with a mixture of ether and water. The ether layer was separated and concentrated, and then distilled. 'Aftera small fore-run of triethyl phosphite had distilled, the
boilin-gpoint of the residual liquid ro'se rapidly. The f.
CHn-P\ I] 0 023. N
it A nalysia Calculated for c H' om; Nitregen,
5.24%;oxygen', 17.96%. Found: Nitrogn,[5.2 1%; ox'y gen, 17;90% 1 When equivalent" amounts of 3 -diethylaminoinetl1yD indole and 3-(piperidinomethyl')indoleare substituted for the gramine reactant in the above" procedure, there is obtained in each instance the same product as above described, nam'elydiethyl 3-indolemetlianepliosphonate.
H5 3-'i izdolemethaizephbsplionic acid solved in a mixture of 25 ml. of acetic acid and 25 ml.
5.1 of diethyl 3 indolernethanephospho'nate wasdisessence J 1 of concentrated hydrochloric acid, and the resulting solution was refluxed for nine hours. The reaction was then concentrated under reduced pressure. The crystalline residue thus obtained was recrystallized from 30 ml. of water and then from 13 ml. of water, thereby yielding 2.1 g. of almost-white crystals which melted at 216.8- 218.4 C. (corn). This product was 3-indolemethanephosphonic acid, having the structural formula Analysis-Calculated for C H NO P: Nitrogen,
6.63%; neutral equivalent, 106. 6.54%; neutral equivalent, 110.
This acid is soluble in water at 25 C. to the extent of about 0.5% (weight/volume). The pH of a 0.5% solution was 2.2; when a 0.5% aqueous solution was adjusted to pH-7.0 by treatment with N/ sodium hydroxide solution, no precipitate was formed. The acid was soluble in diethyl ether and fairly soluble in isopropyl alcohol.
3indolemethanephosphonic acid reacted with inorganic andorganic bases to form the corresponding monoor di-salts, depending on whether one or two equivalents of Lbase was employed. The water-soluble alkali metal salts and the ammonium salts are especially useful and economical forms for many purposes, but other salts are also readily obtained and maybe preferred in some instances,*for example: the alkaline earth metal salts,
Found: Nitrogen,
for. instancethe calcium, magnesium, and barium salts; the copper, mercury, and arsenic salts; and substituted-- amomnium salts, for instance the dimethylammonium EXAMPLE 2 7 A. Monoethyl 3-ind0lemethanephosphonate .Alkaline hydrolysis of diethyl 3-indolemethanephosphonate, for-instance by heating it for several. hours with 5% --sod ium- -hyd roxide solution, produces ethyl sodium 3-indolemethanephosphonate. which on treatment with one equivalent ofhydrochloric acid or other strong acid isfco'nverted to monoethyl 3-indolemethanephosphonate,
136-137 (3., having the structural formula B. 3-indolemethanephosphonic acid Acid hydrolysis of the monoethyl S-indoI'emetha'nephosphonate described in part A above,,-using thev samehydrolysis conditions as described in part B of Example 1, produces S-indolemethanephosphonic acid, identical with the product from the acid hydrolysis of the diethyl ester.
" EXAMPLE 3 A. Di-n-butyl 3 indolemethanephosphonate By substituting 98 g. of tri-n-butyl phosphite for the triethyl phosphite and 6.3 g. of dimethyl sulfate for the methyliodide in'the procedure described in part'A of 4 7 M Example -1, there is obtained di-n-butyl 3-indolemethanephosphonate, having the structural formula B. Mono-rt-butyl 3-indolemethanephosphonate By hydrolysis of -di-n-butyl 3-indolemethanephosphonate with aqueous potassium hydroxide solution to pro- .duce n-butyl potassium 3-indolemethanephosphonateand treating this ester-salt with strong acid, there is obtained C. 3-indolemethanephosphonic acid inhibition can be readily determined by means of stand- For instance, the following method is used. An aqueous solution containing ard biological test procedures.
10- of heteroauxin per ml. is employed as a control. A series of aqueous'test solutions containing 3-indolemethanephosphonic acid, or mono or disodium salt thereof, at concentrations of 1 up to 1000 per m1., is prepared and to each solution there is added suflicient heteroauxin so that. its concentration in thesolution is l0- 'y per ml.
These solutions are then applied to the roots of a test plant, such as Lepidium sativum, and the plants are incubated at 27 C. in the dark for 12-18 hrs. By measuring the root lengths before and after the test and comparing thecontrols with the test solutions, the antagonistic eifect of the various concentrations of 3-indolemethanephosphonic acid, or salt thereof, can be calculated in terms of the percentage difference in root lengths.
The normal stimulation of root growth by the heteroauxin is diminished by the presence of the 3-indolemethanephosphonic compound, so that the root lengths are shorter in the test solutions thanin the controls.
My new compounds can be employed to combat the growth of unwanted vegetation by application to, the plants by the conventional methods, for instance dusting, spraying, and the like. When spraying is used, I generally preferan aqueous solution of the monosodium or disodium salt'of 3-indolemethanephosphonic acid.
'3-indolemethanephosphonic' acid has a relatively low toxicity toward animals; for example, oral doses in the ormonkeys.
I claim: I
--1. 3-indolemethanephosphonic acid, having the structural formula range'l00-200 mg./kg. had no detectable effect on cats acid.
2. alkalimetal salt of 3 -indolemethanephosphonic 0; A sodium salt of 3-indolemethanephosphonic acid.
i w cm 4. The process which comprises: heating a mixture of a tri-lower alkyl phosphite and a 3-indolemethyl-quaternary ammonium salt having the structural formula CH: CHr-l T=B in it 6. The process which comprises heating a mixture of a tri-lower alkyl phosphite and a 3-indolemethy1 quateifl nary ammonium salt having the structural formula where B represents a member of the group consisting of dimethyl, diethyl, and 1,5-pentylene radicals and An represents a member of the group consisting of the iodide radical and the methosulfate radical, to produce a dilower alkyl 3-indolemethanephosphonate.
7. A compound of the group consisting of mono-lower alkyl 3-indolemethanephosphonates and di-lower alkyl 3- indolemethanephosphonates.
8. Diethyl 3-indolemethanephosphonate.
References Cited in the file of this patent UNITED STATES PATENTS 2,447,545 Snyder et a1. Aug.'24, 1948 2,847,442 Sallmann Aug. 12, 1958 2,849,454 Szmuszkovicz Aug. 26, 1958 UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 2, 980 692 April 18 1961 Noel F, Albertson It is hereby certified that error appears in the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.
Column 1, lines 30 to 33 column 5, lines 4 to 7. and column 6, lines' 3 to 6, the right-hand portion of the formulas, each occurrence, should appear as shown below instead of as in the patent:
column 2, line 64, for "3 -diethylaminomethyl)" read 3(diethylaminomethyl) column l line 30, for "salt" read salts Signed and sealed this 26th day of September 1961 (SEAL) Attest:
ERNEST W. SWIDER DAVID L., LADD Atte'sting Officer Commissioner of Patents

Claims (1)

1. 3-INDOLEMETHANEPHOSPHONIC ACID, HAVING THE STRUCTURAL FORMULA
US751155A 1958-07-28 1958-07-28 3-indolemethanephosphonic acid and its salts and preparation thereof Expired - Lifetime US2980692A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US751155A US2980692A (en) 1958-07-28 1958-07-28 3-indolemethanephosphonic acid and its salts and preparation thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US751155A US2980692A (en) 1958-07-28 1958-07-28 3-indolemethanephosphonic acid and its salts and preparation thereof

Publications (1)

Publication Number Publication Date
US2980692A true US2980692A (en) 1961-04-18

Family

ID=25020725

Family Applications (1)

Application Number Title Priority Date Filing Date
US751155A Expired - Lifetime US2980692A (en) 1958-07-28 1958-07-28 3-indolemethanephosphonic acid and its salts and preparation thereof

Country Status (1)

Country Link
US (1) US2980692A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3198807A (en) * 1961-07-25 1965-08-03 Substitutes carboxamide indoles and indolines
US3260729A (en) * 1957-09-30 1966-07-12 Roussel Uclaf Benzoate of 1-(6'-methoxy-3'-indolyl)-2-propylamine
US3461120A (en) * 1965-09-27 1969-08-12 Sterling Drug Inc N-((1-piperidyl)-lower-alkyl)-n-((3-,2-,and 1-indolyl)-lower-alkyl) amines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2447545A (en) * 1944-10-21 1948-08-24 Merck & Co Inc Synthesis of tryptophane and intermediates therefor
US2847442A (en) * 1954-03-05 1958-08-12 Ciba Ltd New compounds containing nitrogen and phosphorus
US2849454A (en) * 1957-06-27 1958-08-26 Upjohn Co Gamma (3-indolyl)-gamma-keto-propyl phosphonic acids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2447545A (en) * 1944-10-21 1948-08-24 Merck & Co Inc Synthesis of tryptophane and intermediates therefor
US2847442A (en) * 1954-03-05 1958-08-12 Ciba Ltd New compounds containing nitrogen and phosphorus
US2849454A (en) * 1957-06-27 1958-08-26 Upjohn Co Gamma (3-indolyl)-gamma-keto-propyl phosphonic acids

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3260729A (en) * 1957-09-30 1966-07-12 Roussel Uclaf Benzoate of 1-(6'-methoxy-3'-indolyl)-2-propylamine
US3198807A (en) * 1961-07-25 1965-08-03 Substitutes carboxamide indoles and indolines
US3415934A (en) * 1961-07-25 1968-12-10 Ile De France Methods for the treatment of emesis
US3496275A (en) * 1961-07-25 1970-02-17 Ile De France Method of treatment of nervous tensions in mammals with certain substituted indoles and indolines
US3461120A (en) * 1965-09-27 1969-08-12 Sterling Drug Inc N-((1-piperidyl)-lower-alkyl)-n-((3-,2-,and 1-indolyl)-lower-alkyl) amines

Similar Documents

Publication Publication Date Title
EP0085321B1 (en) Diphosphonic acid derivatives and pharmaceutical preparations containing them
US3032584A (en) p-bis-(2-chloroethyl) aminophenylalanine and the process for the production thereof
US4327039A (en) Process for the production of 3-amino-1-hydroxypropane-1,1-diphosphonic acid
US4746654A (en) Anti-inflammatory products derived from methylene-diphosphonic acid, and process for their preparation
NO970653L (en) Process for Purification of 1,4,7,10-Tetraazacyclododecan-1,4,7,10-Tetra (Methylene Phosphonic Acid)
US4006204A (en) Phosphoric acid diesters
US2980692A (en) 3-indolemethanephosphonic acid and its salts and preparation thereof
US3223514A (en) Process for the control of plant growth
US2901481A (en) Process for preparing dialkyldithiophosphoric acid ester derivatives having two amide groups in the molecule and the insecticidal compounds obtained thereby
PL140912B1 (en) Process for preparing n-phosphonomethylglycine
US3163670A (en) Aromatic p, p'-diorthophosphoric acid monoesters
CS239903B2 (en) Processing of aminomethyl phosphoric acid derivatives
US4046774A (en) Process for N-phosphorylation of heterocyclic amines
US2906770A (en) Production of phosphoric and thiophosphoric-dialkyl ester-hydrazides
US5099056A (en) Process for the production of n-substituted-aminomethylphosphonic acid dialkylesters and of the corresponding acids
JPS63122694A (en) Production of 2-amino-4-phosphinyl butanoic acid
US2849454A (en) Gamma (3-indolyl)-gamma-keto-propyl phosphonic acids
US4368162A (en) Process for producing aminomethylphosphonic acid
US4182759A (en) Arylalkyl and aryloxyalkyl phosphonates and use as antiviral agents
US3694474A (en) Higher alkano yl-propanediol-(1,3)-phosphoric acid-choline esters
US3432503A (en) Method of reducing the cholinesterase activity of phosphoric acid esters
Macomber et al. Reactions of oxaphospholenes. 2. Hydrolysis of neopentyl esters, phenyl esters, and amides
US3873535A (en) 2-substituted-3,4-dihydro-3-oxo-2h-1,4-benzothiazine-4-acetic acid and esters thereof
US4457873A (en) Process for preparing phosphonomethylated amino acids
US5220021A (en) Geminal bisphosphonic acids and derivatives as anti-arthritic agents