DE1083273B - Process for the preparation of quaternary ammonium compounds of the tetrahydrofuran series - Google Patents

Description

GERMAN

The invention relates to processes for the production of quaternary ammonium compounds of the tetrahydrofuran series, that of the general formula

Method of manufacture

of quaternary ammonium compounds

the tetrahydrofuran series

R »-

At

in which η is an integer from 0 to 4, R is a low molecular weight alkyl, oxyalkyl or alkoxyalkyl radical or the phenyl radical, R ₁ and R _{2 are} aliphatic hydrocarbon _{radicals, R 3 is} an aliphatic or araliphatic hydrocarbon radical and Αη ^{Θ is} a monovalent anion, in particular a hydrohalic acid, or a normal equivalent of a polyvalent anion.

These compounds have valuable neurophysiological properties. They have muscarinic parasympathicomimetic Effect (standstill of the heart activity in the isolated frog heart) and represent a synthetic is an easily accessible class of compounds that has a direct effect corresponding to that of muscarin. The parasympathicomimetics used in practice act indirectly by being cholinesterase inhibitors are and in this way the breakdown of the responsible for the parasympathicomimetic effect in the organism Prevent acetylcholine. In contrast, the new compounds are direct irritants that cause the Acetylcholine does not affect mechanism of action.

Their production is z. B. characterized in that there is a tertiary base of the general formula

35, R ₁

■ n:

¹ R ₂

with a reactive ester of an aliphatic or araliphatic alcohol of the general formula

R ₃ -An ',

where n, R, R ₁ , R ₂ and R _{3 have} the meanings given above and An 'denotes the acid radical of a hydrohalic acid, alkylsulfuric acid or arylsulfonic acid, reacts and then optionally replaces Αη' ^Θ with another anion.

The quaternization of the tertiary bases can be carried out in an or In the absence of organic solvents, if necessary with heating. As a solvent are for example diethyl ether, acetone,

Applicant: J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. F. Zumstein and Dipl.-Chem. Dr. rer. nat. E. Assmann, Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority: Switzerland from March 28 and June 14, 1956

Dr. Conrad H. Eugster, Wallisellen, Zurich, Dr. Rolf Denss, Dr. Franz Häfliger, Basel, Dr. Bruno Hofer, Münchenstein, Basel,

Dr. Rudolf Poster, Basel,

and Dr. Markus Zimmermann, Riehen, Basel (Switzerland), have been named as the inventor

Called butanone, ethyl acetate, tetrahydrofuran and benzene. The exchange of one anion for another can e.g. B. by means of double implementation, e.g. B. an iodide of an ammonium base defined above with a silver salt, z. B. with a silver chloride suspension or a silver nitrate solution. On the other hand, you can too Mix solutions of ammonium salts according to the definition with acids or with salts, the anions of which with the quaternary ammonium bases form sparingly soluble salts. Finally, a large number of salts are obtained by that the base is set free from one of its salts, e.g. B. by means of an anion exchange resin or, when using a halide, e.g. B. also by means of moist silver oxide, and then the base with any Acid neutralized.

Another production process consists in that one tetrahydrofuran of the general formula

-At"

in the "an" denotes a reactive substituent such as ζ. B. a halogen atom, and R and η as above

003 530/532

- C -CN ^ -R ₂

C Γ

I I

OH OH

3 4

have given meaning, such individual optically active stereoisomers in mixing with a tertiary amine

the general formula in a manner known per se, for. B. by transferring the

J ^ quaternary ammonium bases in salts optically more active

/ - acids, win.

Ν \ ~ · ^ 2 5 The following examples are intended to facilitate the implementation

R ₃ explain the method according to the invention in more detail.

in which R ₁ , R ₂ and R _{3 have} the meaning given above in Example 1

have implemented and, if necessary, then the

An anion "is replaced by another anion. Io Ig S-dimethylamino-S-ethyl-tetrahydrofuran (Kp _u.

Finally, one can also, if necessary, through 60 to 62 ° C) is in 5 ecm dry ether with 1 ecm one to four radicals R substituted salt of a quaternary methyl iodide are added, with heating of the ether a-2-ammoniobutane-1,4-diol of the general formula occurs and the quaternary salt crystallizes out. After two

Allowing to stand for hours, the reaction mixture ® 15 is refluxed for a few minutes, the precipitate

. e sucked off and made from ethanol-ether or from isopro-

panol — ether recrystallized. The methiodide of 3-dimethylamino-5-ethyl-tetrahydrofuran, is a white, readily water-soluble salt and melts at 140.5 to ao 141 ⁰ C.

By treating the quaternary iodide with a silver chloride suspension in water, _{the very hygroscopic quaternary chloride is obtained in the usual manner in which R, R 1} , R ₂ , R ₃ and An® have the meaning given above, with a ring-closing agent that only after careful drying in a high vacuum, in particular phosphoric acid, sulfuric acid or bromine can be obtained in crystalline form from ethanol-ether, hydrochloric acid, if necessary with replacement of the anion F. 150 to 151 ° C.
by that of the ring-closing acid. The tetrachloroaurate of the quaternary base crystallizes

The tertiary bases up to 117 ° C, which can be used as starting materials for the first-mentioned manufacture from water in fine, yellow flakes from the F. 116 longitudinal process into consideration.
can be produced by methods known per se. 30 ■ _. . . _

As a reactive ester of aliphatic and arali- ^

Phatic alcohols can e.g. B. Halides, such as Me- 1.03 g of 3-dimethylamino-tetrahydrofuran of bp ₈₀

ethyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, 77 to 78 ° C (hydrochloride mp 138 to 140 ° C) n-amyl-, isoamyl-, n-hexyl-, n-octyl-, allyl-, crotyl-, dissolved in 5 ecm dry ether and with 1 ecm Methallyl chloride, bromide or iodide, dimethyl sulfate 35 methyl iodide added. The reaction disappears quickly and diethyl sulfate, p-toluenesulfonic acid methyl ester, Ben- heating and crystallization of the N-tetrahydrofurylzyl-, p-chlorobenzyl-, p-methoxybenzyl-, p-methylbenzyl- (3) -trimethylammonium iodide. After 2 hours and jS-phenylethyl chloride and bromide, use leave to stand and then briefly boil Find. Reflux, the quaternary salt is sucked off and off

The 3-halogeno-ethanol ether, which continues to serve as starting materials, recrystallizes. You get it in shape Some tetrahydrofurans are known, or they can come from long prismatic needles from 226 to 226.5 ° C. also prepared by methods known per se. The quaternary chloride can be prepared from the iodide z. B.

will. by shaking with a suspension of silver chloride

Suitable tertiary amines are, for example, tri- in _50/0 methanol, filtration and evaporation, the obtained methyl amine, triethylamine, dimethyl-n-butylamine, di 45 ° methanolic solution. From absolute methyl-allylamine, dimethyl-benzylamine or dimethyl-isopropanol-acetone, it crystallizes in long colorless {(S-phenyl-ethyl) -amine. Needles from 298 to 299 ° C, which are extremely hygroscopic

For processes for the production of starting materials and are water-soluble.

is no patent protection within the scope of the invention The tetrachloroaurate is obtained by adding gold

t claimed. 50 hydrochloric acid for the aqueous solution of the chloride

Obtained in the tetrahydrofuran ring is not further substituted ammonium and crystallized from 50 ammonium salts ° / ₀ methanol in the form or their quarters of poorly soluble, shining leaflets underlying the-refractory at 228 ammonium bases are naturally in two to 229 ° C melt, after browning at 220 ° C.
enantiomorphic forms; the introduction of sub-

substituents in the tetrahydrofuran ring occurs. Example 3

of pairs of stereoisomers with different physical properties. Can tetrametriezentren SS-tetramethyl-S-dimethylamino-in reactions at Asymmetry 0.2 g djl ^^., The quantitative ratio of the liydrofuran (bp. 56-57 ° C _n) are dissolved in 1 cc of acetone resulting stereoisomers by Reaktionsbedin- and mixed with 0.09 ecm of methyl iodide. That influences d, lN-genes and may result in a single 60 [2,2,5,5-tetramethyl-tetrahydrofuryl- (3)] trimethyl-am pair of enantiomorphic stereoisomers. Monium iodide soon begins to fade after grinding - especially if it crystallizes next to a center of asymmetry, its melting point is 255 ° C.
a negative substituent, e.g. B. an oxo group, ■ Analogously from! ^^, SS-tetramethyl-S-dimethylamiis a conversion of a single or a small no-tetrahydrofuran ([a] f = -0.722 ° ± 0.02 ° undiluted) number of Pairs of stereoisomers in a larger number 65 with methyl iodide make the IN- [2,2,5,5-tetramethyl-tetrahydro-such possible by racemization. Mixtures of furyl (3)] trimethylammonium iodide with a melting point of 160 ° C. and several pairs of stereoisomers can, for example, contain [a] f = -23.0 ° ± 0.5 ° (c = 10 in water). Precisely by fractional crystallization or distillation, or if in an analogous manner, the d, l-2,2,5,5-T can be separated by distribution processes. Furthermore, traäthyl-3-dimethylamino-tetrahydrofuran of bp _u can be obtained from individual pairs of stereoisomers or from 70 110 to 112 ° C with methyl iodide the d, lN- [2,2,5,5-tetra-

5 6

ethyl-tetrahydrofuryl- (3)] trimethylammonium iodide from the examples

M.p. 208 ° C, mitBenzylchloriddasd.l-N-P ^ .SjS-Tetraäthyl- - A crude mixture of stereoisomeric 3-dimethylaminotetrahydrofuryl- (3)] - N-benzyl-N, N-dimethyl-ammonium-5- (a-oxyethyl) -tetrahydrofurans (light brown oil) is dissolved in chloride with a temperature of 181 ° C and with dimethyl sulfate the 20 ecm of dry ether and then with 2 ecm d, l-N- [2,2,5,5-tetraethyl-tetrahydrofuryl- (3)] -trimethyl-5 methyl iodide left to stand for about 14 hours. Subsequent ammonium methyl sulfate at a temperature of 130 ° C., the reaction mixture is boiled for 2 hours

Reflux, decanted the ether from the excreted

Example 4 Mixture of stereoisomeric quaternary iodides from and leads

the latter by shaking with an aqueous silver

90mg3-Dimethylamino-5-methyl-tetrahydrofuranwer- io chloride suspension in the appropriate mixture of dissolved in 1 ecm of acetone and tri-added with 0.5 ecm of methyl iodide stereoisomeric N- [5- (a-oxyethyl) tetrahydrofuryl- (3)]. While the solution is heated, methylammonium chlorides are soon poured over. After evaporation Separation of the N- [5-methyl-tetrahydrofuryl- (3)] - tri- the aqueous solution and drying of the residue in methyl-ammonium iodide, which crystallizes the quaternary chloride mixture after recrystallization from a high vacuum. Isopropyl alcohol melts at 128 to 132 ° C. 15 When recrystallizing from isopropanol — acetone

In an analogous manner, with allyl bromide, one obtains fine needles that are united to form tufts N-fS-methyl-tetrahydrofuryl-ß ^ -N-allyl- ^ N-dimethyl- at 149 to 150 ° C and after renewed recrystallization ammonium bromide with a melting point of 126 to 128 ° C (from acetone - melting at 154 to 155 ° C and extremely hygroscopic Methanol) and from which are 3-diethylamino-tetrahydrofuran.

from _{b.p. lo} 62 to 63 ° C with methyl iodide the N-tetrahydro-20. By fractional crystallization of the mixture of furyl- (3) -N-methyl-N, N-diethylammonium iodide from the stereoisomers after conversion into the tetrachloroaurate F. 168 to 171 ° C; from the S-dimethylamino-S-phenyl- obtained the pure isomeric tetrachloroaurate from tetrahydrofuran by Kp. _lo 134.5 to 136.5 ° C, the F. 114.5 to 115 ° C and from 151 to 152.5 ° F. C.
N- [5-phenyl-tetrahydrofuryI- (3)] -trimethyl-ammonium-

iodide with a melting point of 116 to 120 ° C; from the 2-ethyl-3-dimethyl- 25 example 7

amino-tetrahydrofuran, bp. 52-53 ° C _lo the

N- [2 -ethyl-tetrahydrofuryl] (3)] -trimethyl- ammonium- 2,5-dimethyl-2,5-diethyl-3-dimethylamino-tetrahydro-

iodide from m.p. 112 to 116 ° C; from the 2,5-dimethyl-3-di-furan (light brown liquid with a basic odor) methylamino-tetrahydrofuran of bp ₁₂ 48 to 51 ⁰ C that is dissolved in ether and with excess methyl iodide N- [2,5-dimethyl- tetrahydrofuryl- (3)] -trimethyl-ammo-30 added. The precipitated N- [2,5-dimethyl-2,5-diniumjodid, mp 162 to 164 ⁰ C (from methanol-ethyl ethyl-tetrahydrofuryl (3)] - trimethyl-ammoniumjodidwird acetate); recrystallized from 3- (N-methyl-Nn-butylamino) -tetra- from isopropanol-ether, whereby it is in hydrofuran with a bp. ", ₀₄ 84 to 85 ° C the N-tetrahydro-form of pale yellow needles from M. 172 to 174 ° C furyl- (3) -Nn-butyl-N, N-dimethylammonium iodide is obtained from.
F. 144 to 146 ° C (from acetone-isopropyl alcohol mixture) 35 Beismel 8

and from the 3- (N-methyl-N-benzylamino) -tetrahydro- '

furan, bp. _{0, 01} 84 up to 85 ° C, the N-tetrahydrofuryl 15.1 g of 3-bromo-tetrahydrofuran in an autoclave

(3) -N-benzyl-N, N-dimethyl-ammonium iodide, melting at 164 with 135 g of a 15 ° / _o by weight solution of trimethylamine in benzene to 167 ° C. 8 hours heated to 13Q ° C to 120th After beBeispiel 5 ⁴ ° ^{ene (ieter} reaction and the crystallized reaction

product filtered off, washed several times with benzene

2.03 g dl ^ S ^ S-Dmethyl-dihydroxy-S-dimethyl- aminohexane and thereto from an isopropyl alcohol-acetone mixture, a water-white viscous oil of boiling point. _0, recrystallized _0025th The very hygroscopic tetrahydro-60 to 65 ° C, are dissolved in 10 ecm acetone and mixed with furyl- (3) -trimethylammonium bromide melts in an evacuated 0.67 ecm methyl iodide. The d, lN- [2 ', 5'-dimethyl-45 ated tube at 249 to 251 ° C with decomposition.
2 ', 5'-dihydroxy-hexyl (3')] trimethylammonium iodide.

crystallizes out immediately, its melting point is. Example y

293 ° C. 0.6 g of 3-bromo-5- (a-oxyethyl) tetrahydrofuran are in

0.165 g of this quaternary ammonium iodide are dissolved in 3 ecm of absolute methanol, dissolved with 1.5 ecm of trimethyl-5 ecm of water, and the resulting solution is very 50 amine and slowly passed through a column of 1 g of the under the in the fused tube for 20 hours loading heated to 6O ⁰ C. Then at 50 to 60 ⁰ C drawing Amberlite IR 120 in the market, the volatile components are sold in a stream of nitrogen, the ion exchanger (Η-form) is added and the residue is left to run with ether and the latter is decanted after the column is washed with water until the run-off neutral some standing from the separated viscous oil. reacted. Now it is eluted with 5 ecm of ln-sulfuric acid 55 This represents the crude bromide of the N- [5- (a-oxyethyl) - and the column again with water up to the neutral tetrahydrofuryl- (3)] - trimethylammonium base.
Washed reaction. The sulfuric acid eluate is. .

concentrated in vacuo to a syrup consistency, then. Example IU

with 1 cc of 33 ° / _o sulfuric acid was added and 2 hours 1 g of 3 - dimethylamino - 5 - oxymethyl - tetrahydrofuran

heated to 95 ° C. The light brown reaction mixture is 60 by Kp. _U 122 to 12O ⁰ C is dissolved in 5 cc acetone diluted ecm with water to 20, very slowly added over a and 1 cc of methyl iodide to give warming column of 9 g of the commercial product Amberlite LRJV B enters . The reaction solution is allowed to filter for about 4 hours (OH form) and it is left to stand with distilled water, excess methyl iodide is then evaporated and washed until the reaction is neutral. The eluate solvent is removed and the oily residue is dried in a high vacuum with 0.1n hydroiodic acid. The non-crystallizing N- [5-oxymethyl must be put in place and the whole tetrahydrofuryl- (3)] -trimethylammonium iodide is evaporated to dryness in vacuo. The residue crystallizes immediately and characterization with the same amount of acetic anhydride is triturated four times with acetone. The 1 hour thus obtained is shaken with gentle warming at times, IN- [2,2,5,5-tetramethyl-tetrahydrofuryl- (3)] trimethyl. Then, evaporate the acetic acid and ammonium iodide melts at 249 ° C. 70 excess acetic anhydride in vacuo at 50 to 6O ⁰ C

and the residue is dried in a high vacuum. After recrystallizing twice from methanol-ethyl acetate, the N- [5-acetoxymethyltetrahydrofuryl- (3)] -trimethylammonium iodide thus obtained melts at 177 to 180 ^° C.

Claims (3)

Patent claims: 1. Process for the preparation of quaternary ammonium compounds of the tetrahydrofuran series general formula in which η is an integer from 0 to 4, R is a low molecular weight alkyl, oxyalkyl or alkoxyalkyl radical or the phenyl radical, R ₁ and R _{2 are} aliphatic hydrocarbon _{radicals, R 3 is} an aliphatic or araliphatic hydrocarbon radical and An® is a monovalent anion or a normal equivalent of one mean polyvalent anion, characterized in that one is a tertiary base of the general formula , R ₁ R _n - -n: 30th with a reactive ester of an aliphatic or araliphatic alcohol of the general formula 35 in the An 'denotes the acid residue of a hydrohalic acid, alkylsulfuric acid or arylsulfonic acid, reacted and, if appropriate, then replaced Αη' ^Θ by another anion. 2. Process for the preparation of the compounds designated in claim 1, characterized in that that one is a tetrahydrofuran derivative of the general formula -At" in the an "denotes a reactive substituent with a tertiary amine of the general formula converts and optionally then the anion Αη " ^Θ replaced by another anion. 3. A method for the preparation of the compounds designated in claim 1, characterized in that that one optionally substituted by 1 to 4 radicals R of a quaternary 2-ammoniobutane-1,4-diol the general formula - C CN ^ R ₂ - C— —C - OH OH On ⁶ with a ring-closing agent, optionally with replacement of the anion by that of the ring-closing agent Acid, treated. Considered publications:
German Patent Nos. 696 779,700 036, 704 300; U.S. Patent No. 2,123,653;
Journal of the American Chemical Society, 67, 1945, pp. 415, 416. © 009 530/532 6.60