FI61311C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV 2-ACYLAMINO-BENTSYLAMINER - Google Patents

Description

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Patent patent

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Federal Republic of Germany (DE) P 2337 ^ 56.3 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken liyskland (DE) (72) Gerd Kruger, Johannes Keck, Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7U) Leitzinger Oy (5U) A new process for the preparation of 2-acylamino-benzylamines

The invention relates to a new process for the preparation of 2-acylamino-benzylamines of the general formula I.

Hai S 2 - «, R1 where

Hal is a chlorine or bromine atom, is a hydrogen, chlorine or bromine atom, R 2 is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R 1 is a cyclohexyl, hydroxycyclohexyl, isopropylaminocarbonylmethyl or morpholinocarbonylmethyl group; as well as their physiologically acceptable salts with inorganic or organic acids.

Surprisingly, it has now been found that the compounds of the formula I can be prepared by the novel process according to the invention in considerably better yields than the processes known from the prior art.

2 61311

The process according to the invention is characterized in that it is a benzoxazine of the general formula II

Hai - v (, i> h where

Hai and have the same meaning as above, and R41 represents a phenyl group, is reacted with an amine of the general formula III H - (III) in which R2 and R3 have the same meaning as above.

The process according to the invention can be carried out in an almost theoretical yield, which has not been possible by the methods known from GR patent 1 09R 140, U.S. patent 3,536,713 and FI patent application 1773/74. The preferred yield of the invention is surprising because, according to the literature, Heterocyclic Compunds can 6, page 574 would have been expected if the reaction of the invention had resulted in the corresponding 2-amino-benzylamine.

The reaction is conveniently carried out in a solvent such as tetralin or an excess of the amine of general formula III used at temperatures between 100 and 200 ° C, but most preferably at temperatures between 130 and 180 ° C. However, the reaction can also be carried out without a solvent.

The compounds of formula II used as starting materials can be prepared by the method described in patent application 801782.

The compounds of the general formula I obtained can, if desired, be subsequently converted into their physiologically acceptable salts with inorganic or organic acids. As the acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid or maleic acid have proved to be suitable.

The following examples further illustrate the invention:

Example 1 2-Benzoylamino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 11.2 g (0.025 moles) of 6, R-dibromo-2-phenyl-4H-3,1-benzoxazine hydrobromide and 17.0 g (0.15 mol) of N-methyl-cyclohexylamine are refluxed for 1.5 hours. The reaction mixture is then treated with 2N sodium hydroxide, shaken several times with ether, the organic phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in absolute ethanol and ether and acidified with ethanolic hydrochloric acid to crystallize 2-benzoylamino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine hydrochloride.

Yield: 12.1 g (93.7% of theory),

M.p .: 270-272 ° C (decomposes).

Example 2 2-Benzoylamino-6-chloro-N-methyl-N- (morpholinocarbonylmethyl) -benzylamine

M.p .: 122.5-123 ° C.

Prepared according to Example 1 from 5-chloro-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide.

Example 3 2-Benzoylamino-6-chloro-N-isopropyl-N- (morpholinocarbonylmethyl) -benzylamine

M.p .: 125-1270C.

Prepared according to Example 1 from 5-chloro-2-phenyl-4H-3,1-benzoxazine and N-isopropylglycine morpholide.

Example 4 4 61311 2-Benzoylamino-4-chloro-N-methyl-N- (isopropylamino-carbonylmethyl) -benzylamine

M.p .: 140-142 ° C.

Prepared according to Example 1 from 7-chloro-2-phenyl-4H-3,1-benzoxazine and sarcosine isopropylamide.

Example 5 2-Benzoylamino-6-bromo-N-methyl-N- (morpholino-carbonylmethyl) -benzylamine

M.p .: 159-161 ° C.

Prepared according to Example 1 from 5-bromo-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide.

Example 6 2-Benzoylamino-3,5-dibromo-N-methyl-N- (morpholinocarbonylmethyl) -benzylamine

M.p .: 164-166 ° C.

Prepared according to Example 1 from 6, R-dihromo-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide.

Claims (5)

1. Menetelmä valmistaa yleiskaavan I mukaisia 2-asyy1iamino-bentsyy-liamiineja Hai ✓ R2 R3 (I) »H - R4 R1 jossa Hai on chloro-tai bromiatomy, R ^ on vety-, chloro-tai bromiatomy, R2 on vetyatomi tai alempi aikyyliryhmä, jossa on 1-3 hiiliatomia, R ^ on cyclohexyl-, hydroxy-cyclohexyl-, isopropyyliaminokar-bonyylimethyl-tai-morpholinoinocarbonyylimethu-olayan, and R4 on bensoyyliryhmä jossa R ^ ja Hai tarkoittavat same kuin noble yes R4 'on fenyyliryhmä, saatetaan reagoimaan yleiskaavan III mukaisen amiinin chance H - N ^ (III) ^ R3 jossa R2 yes R ^ tarkoittavat same kuin noble, yes haluttaessa saatu yleiskaavan physiologisesti sopivaksi suolaksi epäorgaanisen tai organisenap hapon kanssa. * 61311 2. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, etä reacti suoritetaan liuottimessa. 3. Patenttivaatimuksen 1 tai 2 mucainen menetelmä, tunnettu siitä, one reactio suoritetaan passerpötiloissa velillä 100 ja 200 ° C. 4. Patent tivaatimuksen 1, 2 tai 3 mucainen menetelmä, tunnet-t u siitä, etä reactio suoritetaan yleiskaavan m mukaisen käytetyn amiinin ylimäärässä. A process for the preparation of 2-acylamino-benzylamines of the general formula I H 2 O 2 O 2 - R 2 - R 1 where H 2a represents a chlorine or bromine atom, R 2 represents a hydrogen atom or a lower alkyl group of 1-3 carbon atoms, R3 represents a cyclohexyl, hydroxycyclohexyl, isopropylaminocarbonylmethyl or morpholinocarbonylmethyl group and R4 represents a benzoyl group, and their physiologically suitable site with inorganic or organic acids, characterized in that benzoxazine according to the general formula II there and Hai is the same as before and R41 is a phenyl group, reacted with an amine of general formula III