DE2356724A1 - High yield prepn. of 2-acylamino-benzylamines - by reaction of a benzoxazine with an amine; used for pharmacological purposes and/or as inters to pharmaceuticals - Google Patents

High yield prepn. of 2-acylamino-benzylamines - by reaction of a benzoxazine with an amine; used for pharmacological purposes and/or as inters to pharmaceuticals

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Publication number
DE2356724A1
DE2356724A1 DE2356724*A DE2356724A DE2356724A1 DE 2356724 A1 DE2356724 A1 DE 2356724A1 DE 2356724 A DE2356724 A DE 2356724A DE 2356724 A1 DE2356724 A1 DE 2356724A1
Authority
DE
Germany
Prior art keywords
reaction
acid
chlorine
bromine atom
general formula
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.)
Pending
Application number
DE2356724*A
Other languages
German (de)
Inventor
Joahnnes Dipl Chem Dr Keck
Gerd Dipl Chem Dr Krueger
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
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 Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Priority to DE19732337456 priority Critical patent/DE2337456A1/en
Priority to DE2356724*A priority patent/DE2356724A1/en
Publication of DE2356724A1 publication Critical patent/DE2356724A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/16—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with only hydrogen or carbon atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The following process is new: (where hal = Cl or Br; R1 = H, Cl or Br; R2 = H or lower alky (1-3C); R3 = cyclohexyl, hydroxycyclohexyl, isopropyl-aminocarbonylmethyl or morpholinocarbonylmethyl; R4 = aromatic organic acyl; R'4 = aryl). Physiologically acceptable salts of (I) with acids are included.

Description

Case 5/594 I
Dr.Pl./Kp.Case 5/594 I.
Dr.Pl./Kp.

DR. KARL THOMAE GMBH., BIBERACH AN DER RISSDR. KARL THOMAE GMBH., BIBERACH AN DER RISS

Neue BenzoxazineNew benzoxazines

/Ausscheidung aus Patentanmeldung P 23 37/ Removed from patent application P 23 37

Gegenstand der vorliegenden Anmeldung sind neue Benzoxazine der allgemeinen Formel I,The present application relates to new benzoxazines of the general formula I,

HaiShark

(D(D

in derin the

Hai ein Chlor- oder Bromatom,Shark a chlorine or bromine atom,

R1 ein Wasserstoff-, Chlor- oder Bromatom und Rh einen Arylrest bedeuten, deren Säureadditionssalze und ein Ver-'fahren zu ihrer Herstellung.R 1 is a hydrogen, chlorine or bromine atom and Rh is an aryl radical, their acid addition salts and a process for their preparation.

Die Verbindungen der allgemeinen Formel I stellen wertvolle Zwischenprodukte zur Herstellung von pharmazeutisch wertvollen Verbindungen dar, insbesondere zur Herstellung von 2-Benzoylamino-N-cyclohexyl-3i5--dibrom-N"methyl-benzyläinin, 2-Amino-N-cyclohexyl->3»5-dibrom-N-methyl-benzylaminJ 2-Benzoylamino-ö-chlor-N-methyl-N-Cmorpholino-carbonylmethyD-benzylamin, Z-Benzoylamino-ö-chlor-N-isopropyl-N-(morpholino-carbonylmethy1)-benzylamin, 2-Benzoylamino-3,5~dibrom-N-methyl-N-(morpholinocarbonylmethyD-benzylamin, 2-Benzoylamino-4-chlor-N-methyl-N-The compounds of the general formula I are valuable intermediates for the preparation of pharmaceutically useful compounds, in particular for the preparation of 2-benzoylamino-N-cyclohexyl-35-dibromo-N "methylbenzylamine, 2-amino-N-cyclohexyl-> 3 »5-dibromo-N-methyl-benzylamine J 2-benzoylamino-ö-chloro-N-methyl-N-cmorpholino-carbonylmethyD-benzylamine, Z-benzoylamino-ö-chloro-N-isopropyl-N- (morpholino-carbonylmethy1) -benzylamine, 2-benzoylamino-3,5 ~ dibromo-N-methyl-N- (morpholinocarbonylmethyD-benzylamine, 2-benzoylamino-4-chloro-N-methyl-N-

509807/1112509807/1112

(morpholino-carbonylmethyl)-benzylamin und 2—Benzoylamino-6-brom-N-methyl-N-(morpholino-carbonylmethyl)-benzylamin. (morpholino-carbonylmethyl) -benzylamine and 2- benzoylamino-6-bromo-N-methyl-N- (morpholino-carbonylmethyl) -benzylamine.

Die neuen Verbindungen der allgemeinen Formel I lassen sich nach folgendem Verfahre.n herstellen:The new compounds of the general formula I can be prepared according to the following process:

Umsetzung eines Benzylalkohol der allgemeinen Formel II,Implementation of a benzyl alcohol of the general formula II,

HaiShark

CH2-OHCH 2 -OH

NH-R4'NH-R 4 '

(ID(ID

in derin the

R1 und Hai wie eingangs definiert sind und R1^' einen aromatischen organischen Acylrest bedeutet, in Gegenwart, einer Säure.R 1 and Hai are as defined at the outset and R 1 ^ 'denotes an aromatic organic acyl radical, in the presence of an acid.

Für Rn1 kommt insbesondere die Bedeutung des Benzoyl-, 2-Chlorbenzoyl- oder 4-Methylbenzoylrestes in Betracht.For Rn 1 , the meaning of the benzoyl, 2-chlorobenzoyl or 4-methylbenzoyl radical is particularly suitable.

Die Umsetzung wird vorzugsweise in einem Lösungsmittel wie Äther, Tetrahydrofuran oder Dioxan in Gegenwart einer Mineralsäure wie Chlorwasserstoff, Schwefelsäure, Phosphorsäure oder Bromwasserstoff, zweckmäßigerweise bei Temperaturen zwischen 0 und 5H0C, vorzugsweise jedoch bei Temperaturen zwischen 15 und 25 C, durchgeführt. The reaction is preferably carried out in a solvent such as ether, tetrahydrofuran or dioxane in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrogen bromide, conveniently at temperatures between 0 and 5H 0 C, but preferably at temperatures between 15 and 25 ° C is performed.

Die als Ausgangsstoffe verwendeten Benzy!alkohole der allgemeinen Formel II erhält man beispielsweise durch Umsetzung des ent sprechenden 2-Amino-benzylalkohols, welcher durch Reduktion des entsprechenden Benzaldehyds mit Natriumborhydrid erhalten wird, durch Umsetzung mit einem entsprechenden aromatischen Säurehalogenid in Pyridin und anschließende alkalische Verseifung des entstandenen Esters.The benzyl alcohols of the general formula II used as starting materials are obtained, for example, by reacting the corresponding 2-aminobenzyl alcohol, which is obtained by reducing the corresponding benzaldehyde with sodium borohydride, by reacting with a corresponding aromatic acid halide in pyridine and subsequent alkaline saponification of the resulting ester.

Die nachfolgenden Beispiele sollen die Erfindung nSher erläutern:The following examples are intended to explain the invention in greater detail:

509 807/1112509 807/1112

Beispiel 1example 1

6,8-Oibrom-2-phenyl-^H-3,1-benzoxazin6,8-Oibromo-2-phenyl- ^ H-3,1-benzoxazine

11 g 2-Benzoylamino-3,5-dibrom-benzylalkohol werden mit 600 ml absolutem Äther versetzt. In das Gemisch wird unter Rühren Minuten lang Bromwasserstoff-Gas eingeleitet. Dabei geht das Ausgangsprodukt in Lösung, und 6,8-Dibrom-2-phehyl-1IH-3,lbenzoxazin-hydrobromid .fällt aus. Nach sechsstündigem Rühren wird der Niederschlag abgesaugt und aus absolutem Äthanol umkristallisiert.
Schmelzpunkt des Hydrobromids: 2l8-221°C.11 g of 2-benzoylamino-3,5-dibromobenzyl alcohol are mixed with 600 ml of absolute ether. Hydrogen bromide gas is passed into the mixture for minutes with stirring. The starting product goes into solution and 6,8-dibromo-2-phenyl- 1 IH-3, benzoxazine hydrobromide precipitates out. After stirring for six hours, the precipitate is filtered off with suction and recrystallized from absolute ethanol.
Melting point of the hydrobromide: 218-221 ° C.

Beispiel 2Example 2

Schmelzpunkt: 88,5-89,5°C. Hergestellt aus 2-Benzoylamino-6-chlor-benzylalkohol analog Beispiel 1.Melting point: 88.5-89.5 ° C. Prepared from 2-benzoylamino-6-chlorobenzyl alcohol analogous to the example 1.

509807/1 1 1509807/1 1 1

Claims (2)

PatentansprücheClaims 1. Neue Benzoxazine der allgemeinen 'Formel I,1. New benzoxazines of the general formula I, HaiShark (D(D in derin the Hai ein,Chlor- oder Bromatom,Shark one, chlorine or bromine atom, R. ein Wasserstoff-, Chlor- oder Bromatom und R^ einen Arylrest bedeuten, und deren Säureadditionssalze.Usually a hydrogen, chlorine or bromine atom and R ^ mean an aryl radical, and their acid addition salts. 2. Verfahren zur Herstellung von neuen Benzoxazinen der allgemeinen Formel I,2. Process for the preparation of new benzoxazines of the general Formula I, HaiShark (D(D in der Hal ein Chlor- oder Bromatom, R1 ein Wasserstoff-, Chlor- oder Bromatom und Rj, einen Arylrest bedeuten, sowie von deren Säureadditionssalzen, dadurch gekennzeichnet, daß ein Benzylalkohol der allgemeinen Formel II,in which Hal is a chlorine or bromine atom, R 1 is a hydrogen, chlorine or bromine atom and Rj is an aryl radical, as well as their acid addition salts, characterized in that a benzyl alcohol of the general formula II, 509807/11509807/11 CH-OHCH-OH (ii)(ii) NH-R4 1 NH-R 4 1 in derin the R1 und Hal wie eingangs definiert sind und Rj,1 einen aromatischen organischen Acylrest bedeutet, an wart einer Säure umgesetzt wird.R 1 and Hal are as defined at the outset and Rj, 1 denotes an aromatic organic acyl radical on which an acid is reacted. .3. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, daß die Umsetzung in einem Lösungsmittel und bei Temperaturen zvrischen 0 und 500C durchgeführt wird..3. A method according to claim 2, characterized in that the reaction zvrischen in a solvent and at temperatures is carried out 0 and 50 0 C. H. Verfahren gemäß Anspruch 2 und 3, dadurch gekennzeichnet, daß die Umsetzung in Gegenwart einer Säure wie Chlorwasserstoff, Bromwasserstoff, Sehwefeisäure oder Phosphorsäure durchgeführt wird. H. Process according to Claims 2 and 3, characterized in that the reaction is carried out in the presence of an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid. ORIGINAL INSPECTEDORIGINAL INSPECTED 509807/11509807/11
DE2356724*A 1973-07-24 1973-07-24 High yield prepn. of 2-acylamino-benzylamines - by reaction of a benzoxazine with an amine; used for pharmacological purposes and/or as inters to pharmaceuticals Pending DE2356724A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE19732337456 DE2337456A1 (en) 1973-07-24 1973-07-24 NEW PROCESS FOR THE PRODUCTION OF 2-ACYLAMINO-BENZYLAMINES
DE2356724*A DE2356724A1 (en) 1973-07-24 1973-07-24 High yield prepn. of 2-acylamino-benzylamines - by reaction of a benzoxazine with an amine; used for pharmacological purposes and/or as inters to pharmaceuticals

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19732337456 DE2337456A1 (en) 1973-07-24 1973-07-24 NEW PROCESS FOR THE PRODUCTION OF 2-ACYLAMINO-BENZYLAMINES
DE2356724*A DE2356724A1 (en) 1973-07-24 1973-07-24 High yield prepn. of 2-acylamino-benzylamines - by reaction of a benzoxazine with an amine; used for pharmacological purposes and/or as inters to pharmaceuticals

Publications (1)

Publication Number Publication Date
DE2356724A1 true DE2356724A1 (en) 1975-02-13

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ID=32963216

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DE19732337456 Pending DE2337456A1 (en) 1973-07-24 1973-07-24 NEW PROCESS FOR THE PRODUCTION OF 2-ACYLAMINO-BENZYLAMINES
DE2356724*A Pending DE2356724A1 (en) 1973-07-24 1973-07-24 High yield prepn. of 2-acylamino-benzylamines - by reaction of a benzoxazine with an amine; used for pharmacological purposes and/or as inters to pharmaceuticals

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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1094864B (en) * 1978-05-29 1985-08-10 Tosi Franco Ist BROMEXIN DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION

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