DE2402577C3 - Process for the preparation of benzylamines - Google Patents
Process for the preparation of benzylaminesInfo
- Publication number
- DE2402577C3 DE2402577C3 DE19742402577 DE2402577A DE2402577C3 DE 2402577 C3 DE2402577 C3 DE 2402577C3 DE 19742402577 DE19742402577 DE 19742402577 DE 2402577 A DE2402577 A DE 2402577A DE 2402577 C3 DE2402577 C3 DE 2402577C3
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- chlorine
- denotes
- preparation
- bromine atom
- 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
Links
- 150000003939 benzylamines Chemical class 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims 4
- 238000002360 preparation method Methods 0.000 title claims 4
- 150000001875 compounds Chemical class 0.000 claims description 7
- -1 hydroxycyclohexyl Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- YZCKVEUIGOORGS-UHFFFAOYSA-N hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 239000011780 sodium chloride Substances 0.000 claims 2
- 230000000954 anitussive Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000000875 corresponding Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 description 2
- OJGDCBLYJGHCIH-UHFFFAOYSA-N Bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 2
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 2
- JGRVPGDTWHHRAL-UHFFFAOYSA-M [Br-].NC1=C(C[N+]2=CC=CC=C2)C=C(C=C1Br)Br Chemical compound [Br-].NC1=C(C[N+]2=CC=CC=C2)C=C(C=C1Br)Br JGRVPGDTWHHRAL-UHFFFAOYSA-M 0.000 description 2
- DYJSUCXNMLSPHE-UHFFFAOYSA-M [I-].NC1=C(C[N+](C)(C)C)C=C(C=C1Br)Br Chemical compound [I-].NC1=C(C[N+](C)(C)C)C=C(C=C1Br)Br DYJSUCXNMLSPHE-UHFFFAOYSA-M 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N Benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 1
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
Description
-CX-CX
CH7-XCH 7 -X
HaiShark
NH2 NH 2
45 in der Hai und R1 wie eingangs definiert sind und X einen Trialkylammonium- oder Pyridiniumrest darstellt, mit einem Amin der allgemeinen Formel III 45 in which Hal and R 1 are as defined at the outset and X represents a trialkylammonium or pyridinium radical, with an amine of the general formula III
in der R2 und R;1 wie eingangs definiert sind, bei Temperaturen zv/ischen 100 und 200° C, vorzugsweise bei Temperaturen zwischen 140 und 1600C, in An- oder Abwesenheit eines Lösungsmittels umsetzt. 1 are as defined at the outset, zv 100 and 200, preferably at temperatures / regard ° C at temperatures between 140 and 160 0 C, in the presence or absence of a solvent, in which R 2 and R.
2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß die Umsetzung in einem Überschuß des verwendeten Amins der allgemeinen Formel 111 durchgeführt wird.2. The method according to claim 1, characterized in that the reaction in an excess of the amine of the general formula III used is carried out.
In den britischen Patentschriften 968 254, 1098 140 und 11 78 034 werden unter anderem Benzylamine Η —ΝBritish patents 968 254, 1098 140 and 11 78 034 include benzylamines Η —Ν
(ΠΙ)(ΠΙ)
55 in der R2 und R3 wie eingangs definiert sind, bei Temperaturen zwischen 100 und 200'C, vorzugsweise bei Temperaturen zwischen 140 und 1600C, in An- oder Abwesenheit eines Lösungsmittels umsetzt. Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formel Il lassen sich beispielsweise durch Umsetzung eines entsprechenden Benzylamins mit einem entsprechenden Alkylierungsmittel, wie Methyljodid, oder durch Umsetzung eines entsprechenden Benzylhalogenids mit Pyridin herstellen. 55 3 are as hereinbefore defined in which R 2 and R, at temperatures between 100 and 200'C, preferably at temperatures between 140 and 160 0 C, in the presence or absence of a solvent. The compounds of the general formula II used as starting materials can be prepared, for example, by reacting a corresponding benzylamine with a corresponding alkylating agent, such as methyl iodide, or by reacting a corresponding benzyl halide with pyridine.
Eine als Ausgangsstoff verwendete Verbindung der allgemeinen Formel Il enthält somit eine freie Aminogruppe und gleichzeitig eine quartäre Ammoniumgruppe. Aus der Literatur ist jedoch bekannt, daß quartäre Ammoniumverbindungen mäßig starke Alkylierungsmittel darstellen (siehe Organic Reactions, Band VlI, 1953, Seite 138, bzw. Houben — Weyl, Methoden der organischen Chemie, BandXI/2, 4. Auflage, 1958, Seite 633 und 634). Eine Verbindung der allgemeinen Formel II müßte daher bei erhöhten Temperaturen mit sich selbst reagieren und somit für die gewünschte Umsetzung verlorengehen, überraschenderweise ist dies jedoch nicht der Fall, vielmehr läßt sich eine Verbiadung der allgemeinen Formel H praktisch in quantitativer Ausbeute mit einem Amin der allgemeinen Formel III in das gewünschte Endprodukt überführen. Dies ist um so überraschender, da der Fachmann aus der Lehre der britischen Patentschriften 9 68 254, 10 98 140 und 11 78 034 entnehmen mußte, daß sich die Benzylamine der allgemeinen Formel I mittels Alkylierung durch ein Benzylkation nur durch Umsetzung eines entsprechenden Diacylamino-benzylhalogenids mit einem entsprechenden Amin und anschließender Hydrolyse herstellen lassen, also durch Umsetzung eines Amino-benzylhalogenids dessen Aminogruppe während der Umsetzung durch eine oder mehrere Schutzgruppen geschützt ist.A compound of the general formula II used as a starting material thus contains a free amino group and at the same time a quaternary ammonium group. However, it is known from the literature that quaternary ammonium compounds are moderately strong alkylating agents (see Organic Reactions, Volume VlI, 1953, page 138, or Houben - Weyl, Methods of Organic Chemistry, VolumeXI / 2, 4th edition, 1958, pages 633 and 634). A compound of the general formula II would therefore have to be react with themselves at elevated temperatures and are thus lost for the desired implementation, Surprisingly, however, this is not the case; rather, a linkage of the general Formula H practically in quantitative yield with an amine of the general formula III in transfer the desired end product. This is all the more surprising since the skilled person from the Teaching of British patents 9 68 254, 10 98 140 and 11 78 034 had to infer that the benzylamines of the general formula I by means of alkylation by a benzyl cation only by reaction a corresponding diacylamino-benzyl halide with a corresponding amine and then Let hydrolysis be produced, that is, by reacting an amino-benzyl halide thereof Amino group is protected by one or more protective groups during the reaction.
Die nachfolgenden Beispiele sollen die Erfindung näher erläutern:The following examples are intended to explain the invention in more detail:
2-Amino-3,5-dibroni-N-(trans-4-hydroxycyclohexyl)-benzylarnin 2-amino-3,5-dibroni-N- (trans-4-hydroxycyclohexyl) benzylamine
4,5 g (0,01 Mol) N-(2-Amino-3,5-dibrom-benzyl)-trimeihylammoniumjodid werden mit 10 g trans-4-Amino-cyclohexanol 1 Stunde auf 150 C erhitzt. Anschließend kühlt man das Reaktionsgemisch etwas ab, versetzt mit Chloroform und 2 n-Natronlauae und schüttelt intensiv. Die organische Phase wird abgetrennt und die alkalische Phase noch.nals mit Chloroform ausgeschüttelt. Man trocknet die Chloroformphasen mit Natriumsulfat und engt im Wasserstrahlvakuum ein. Zur Charakterisierung löst man den Rückstand in absolutem Äthanol und etwas Äther und säuert mit äthanolischer Salzsäure an, wonach das 2-Amino-3,5-dibrom-N-(trans-4-hydroxy-cyclohexylj-benzylamin-hydrochiorid krista'ili-S siert.4.5 g (0.01 mol) of N- (2-amino-3,5-dibromobenzyl) trimethylammonium iodide are heated to 150 ° C. for 1 hour with 10 g of trans-4-amino-cyclohexanol. The reaction mixture is then cooled somewhat, and chloroform and 2N sodium hydroxide are added and shakes intensely. The organic phase is separated and the alkaline phase noch.nals with Shaken out chloroform. The chloroform phases are dried with sodium sulfate and concentrated in a water-jet vacuum one. For characterization, the residue is dissolved in absolute ethanol and a little Ether and acidify with ethanolic hydrochloric acid, after which the 2-amino-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl-benzylamine-hydrochloride Krista'ili-S siert.
Ausbeute: 3,9 g (94,0% der Theorie).
Schmelzpunkt: 233—234,5C C (Zers.).Yield: 3.9 g (94.0% of theory).
Melting point: 233-234.5 C (dec.).
2-Amino-N-cyclohexyl-3,5-dibrom-N-methyl-benzylamin 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine
Schmelzpunkt des Hydrochlorids: 233—234,5"C (Zers.). Hergestellt aus N-(2-Amino-3,5-dibrom-benzyl)-trimethylammoniurnjodid und N-Methyl-cyclohexylamin analog Beispiel 1.Melting point of the hydrochloride: 233-234.5 "C (dec.). Prepared from N- (2-amino-3,5-dibromobenzyl) -trimethylammonium iodide and N-methyl-cyclohexylamine analogous to Example 1.
Ausbeute: 92,7% der Theorie.Yield: 92.7% of theory.
2-Amino-N-cyclohexyl-3,5-dibrom-N-methyl-benzylamin 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine
7,5 g N - (2 - Amino - 3,5 - dibrom - benzyl) - pyridiniumbromid werden mit 20 ml N-Methyl-cyclohexylamin 3 Stunden auf 1400C erhitzt. Nach dem Abkühlen wird mit Wasser versetzt und mit Chloroform ausgeschüttelt. Die organische Phase wird mit Wasser gewaschen, dann über Natriumsulfat getrocknet und im Vakuum zur Trockene eingedampft. Der ölige Rückstand wird in absolutem Äthanol gelöst und mit äthanolischer Salzsäure das Hvdrochlorid gefällt. Man erhält 5,94 g (81.3% der Theorie) 2-Amino-N - cyclohexyl - 3,5 - dibrom - N - methyl - benzylaminhydrochlorid mit einem Schmelzpunkt von 233— 234,5° C (Zers.).7.5 g of N - (2 - amino - 3,5 - dibromo - benzyl) - pyridinium bromide are heated for 3 hours at 140 0 C with 20 ml of N-methyl-cyclohexylamine. After cooling, water is added and the mixture is extracted by shaking with chloroform. The organic phase is washed with water, then dried over sodium sulfate and evaporated to dryness in vacuo. The oily residue is dissolved in absolute ethanol and the hydrochloride is precipitated with ethanolic hydrochloric acid. 5.94 g (81.3% of theory) of 2-amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine hydrochloride with a melting point of 233-234.5 ° C. (decomp.) Are obtained.
2-Amino-3,5-dibrom-N-(trans-4-hydroxycyclohexyl)-benzylamin 2-Amino-3,5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine
Schmelzpunkt des Hydrochlorids: 233—234,5 C (Zers.). Hergestellt aus N-(2-Amino-3,5-dibrom-benzyl)-pyridiniumbromid
und trans-4-Amino-cyclohexanol analog Beispiel 3.
«5 Ausbeute: 87,5% der Theorie.Melting point of the hydrochloride: 233-234.5 C (dec.). Prepared from N- (2-amino-3,5-dibromobenzyl) pyridinium bromide and trans-4-amino-cyclohexanol analogously to Example 3.
«5 Yield: 87.5% of theory.
Claims (1)
Gegenstand der Erfindung ist daher ein VerfahrenThis is because the compounds of the above general formula I and their acid addition salts have valuable pharmacological properties, in particular an antitussive, secretolytic and / or breath-stimulating effect.
The invention therefore relates to a method
Priority Applications (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742402577 DE2402577C3 (en) | 1974-01-19 | Process for the preparation of benzylamines | |
| AT651074A AT327876B (en) | 1974-01-19 | 1974-08-08 | PROCESS FOR THE PRODUCTION OF HALOGENATED 2-AMINO-BENZYLAMINES AND THEIR ACID ADDITION SALTS |
| HUBO001513 HU167562B (en) | 1974-01-19 | 1974-08-08 | |
| NL7410822A NL7410822A (en) | 1974-01-19 | 1974-08-13 | PROCESS FOR PREPARING BENZYLAMINS. |
| FI247174A FI60552C (en) | 1974-01-19 | 1974-08-22 | NYTT FOERFARANDE FOER FRAMSTAELLNING AV 2-AMINO-3,5-DIBROM-BENZYLAMINER |
| ES429772A ES429772A2 (en) | 1974-01-19 | 1974-09-05 | Procedure for the preparation of bencilamines. (Machine-translation by Google Translate, not legally binding) |
| YU239374A YU37110B (en) | 1974-01-19 | 1974-09-05 | Process for preparing 2-amino-benzylamines |
| DK473174A DK473174A (en) | 1974-01-19 | 1974-09-06 | |
| CA208,639A CA1050541A (en) | 1974-01-19 | 1974-09-06 | Process for the preparation of benzylamines |
| JP10286174A JPS50101329A (en) | 1974-01-19 | 1974-09-06 | |
| CH1218874A CH612663A5 (en) | 1974-01-19 | 1974-09-06 | Process for the preparation of benzylamines |
| SE7411314A SE439157B (en) | 1974-01-19 | 1974-09-06 | NEW METHOD FOR PREPARING BENZYLAMINES. |
| BG2765674A BG22385A4 (en) | 1974-01-19 | 1974-09-07 | |
| PL17395974A PL91730B1 (en) | 1974-01-19 | 1974-09-07 | |
| CS631374A CS167213B2 (en) | 1974-01-19 | 1974-09-13 | |
| JP7769277A JPS5353624A (en) | 1974-01-19 | 1977-06-29 | Novel preparation of benzineamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742402577 DE2402577C3 (en) | 1974-01-19 | Process for the preparation of benzylamines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2402577A1 DE2402577A1 (en) | 1975-12-18 |
| DE2402577B2 DE2402577B2 (en) | 1976-09-02 |
| DE2402577C3 true DE2402577C3 (en) | 1977-04-28 |
Family
ID=
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