1952-10-01

Abstract of GB680255 The invention comprises 7-chloro-4-[5-(N-ethyl - N - 2 - hydroxyethylamino) - 2 - pentyl]-aminoquinoline and acid addition salts thereof, and a method of preparing said compounds by heating 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine with a 4-halo-7-chloroquinoline preferably in the presence of phenol, and if necessary, converting the resulting base into acid addition salts thereof, or by heating a 1-halo-4-pentanone, e.g. 1-chloro-4-pentanone, with N-ethyl-N-hydroxyethylamine to yield 1 - (N - ethyl - N - 2 - hydroxyethylamino) - 4 - pentanone which is reductively aminated to 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine by contacting it with an excess of ammonia and hydrogen under pressure in the presence of a hydrogenation catalyst and the process is completed as above. 4-Halo-7-chloroquinolines that may be used are 4,7-dichloro-, 4-bromo-7-chloro- and 4-iodo-7-chloro-quinolines. Acids mentioned for salt formation are phosphoric, hydrochloric, hydrobromic, sulphuric sulphamic, tartaric, citric, succinic, acetic, benzoic and oleic acids. In the example, the above substituted quinoline and the diphosphate salt are prepared.

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1952-10-01

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GB19500015252 19500619

USX680255 19490723

1	7-chloro-4-[5-(n-ethyl-n-2-hydroxyethylamino)-2-pentyl]aminoquinoline and the preparation thereof
	Inventor:	Applicant: STERLING DRUG INC
	EC:	IPC:
	Publication info: GB680255 A - 1952-10-01

1	Quinoline nu-oxides
	Inventor: WERBEL LESLIE M; ELSLAGER EDWARD F	Applicant: PARKE DAVIS & CO
	EC:C07D215/60	IPC: C07D215/60;C07D215/00
	Publication info: US3136769 - 1964-06-09

What we claim is:-

1. A process of preparing an organic compound characterized by heating 5-(Nethyl - N - 2 - hydroxyethylamino) - 2pentylamine with a 4-halo7-chloroquinoline, and recovering the 7-chloro-4[5. - (N - ethyl - N - 2 - hydroxyethylamino) - 2 - pentyl]aminoquinoline which 210) is produced.

2. A process according to, Claim 1, characterized by using 4,7-dichloroquinoline.

3. A process according to Claim 1 or 2, 26 characterized by heating a 1-halo-4pentanone with N-ethyl-N-hydroxyethylamine to yield 1-(N-ethyl-N-2-hydroxyethylamino)-4-pentanone, and reductively aminating said 1-N-ethyl-N-2-hydroxyethylamino) - 4 - pentanone by simultaneously contacting it with an excess of ammonia and hydrogen under pressure in the presences of a. hydrogenation catalyst to yield the 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine. 356 4. A process according to Claim 3, characterized by the fact that 1-chloro-4pentanoneO is used in the first step.

5. A process according to any one of the preeeding Claims, characterized by 40 forming an acid-addition salt of the basic quinoline produced.

6. 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino) - 2 - pentyl]aminoquinoline and acid-addition salts thereof whenever 45 produced by a process aecording to any one of the preceding Claims.

7. 7-chloro-4-[5-(N-ethiyl-N-2-hydroxyethylamino) - 2 - pentyl]aminoquinoline; and acid-addition salts thereof. 60 8. 7-chloro-4- [ 5-(N-ethyl-N-2-lhydroxyethylamino) - 2 - pentyl]aminoquinoline diphosphate.

Dated the 19th day of June, 1949.

For: STERLING DRUG INC., Stevens, Langner, Parry & Rlollinson, Chartered Patent Agents, 5/9, Quality Court, Chancery Lane, London, W.1.2, and at 120, East 41st Street, New York, 17, New York, U.S.A.

Leamington Spa: Printed for Her Majesty's Stationery Office, by the Courier Press.-1952.

Published at The Patent Office, 25, Southampton Buildings, London, W.C.2. from which copies may be obtained.

-J

PATENT SPECIFICATION

680,255 Date of Application and filing Complete Specification: June 19, 1950.

No. 15252/50.

Application made in United States of America on July 23, 1949.

Complete Specification Published: Oct. I, 1952.

Index at acceptance:-Class 2(iii), Clf2(a3: c5: d3), C2b3(al:d: g7), C2b9.

COMPLETE SPECIFICATION

7-Chloro-4- [5- (N-Ethyl-N-2-Hydroxyethylamino) -2Pentyl] aminoquinoline and the Preparation thereof We, STERLING DRUG INC., a. corporation organised under the laws of the State of Delaware, United States of America, of 170, Varick Street, New York, State of 6 New York, United States of America, do hereby declare the invention, for which we pray that a patent may be, granted to us, and the method by which it is to be performed, to, be particularly described in and by the following statement:-

This invention relates to 7-chloro-4[5-(N-ethyl - N - 2. - hydroxyethylamino)2 - pentyl]aminoquinoline having the formula CH3 CHCCHCOH !wiHCI4CNCH HN( fe \CH2CH3 and to its preparation. The compound is useful as an antimalarial agent, and for this purpose can be used either in the free base form, or in the form of its acid-addition salts. This invention comprises a process of preparing an organic compound characterised by heating 5-(N-ethyl-N-2.hydroxyethylamine)-2-pentylamine with CH3C00H2CH120H2-halogen + HN< CHCHo0H11 CH3COCIH2CH2CHoN < CH12H1 CHC1(CH0H),N< CH2CH,OH I CHCH., NH, [I - h a 4-halo-7-chloroquinoline and recovering the 7-chloro-4- [5-(N-ethyl-N-2-hydroxyv- 26 ethylamino) - 2 - pentyl]aminoquinoline which is produced.

We have prepared this new quinoline compound by the, series of steps illustrated by the following equations: 30 CH2CH20I C1120113 H--0IHCOIl2C012C;IH2N < C02CHXO0E C112C0-3 11t C21 0.11 011 --> CH3CCHCHXCH2C/N< NH3 NHI CH2CH3 NHI Cl CH3 CH2CH2OH ,Nó 3NHCH(CH2)3N + I'N hIN CH2CH3 - I.C-IO fe In the above illustrated synthesis, a 1 - halo - 4 - pentanone, preferably the 1-chlore ketone, is heated with N-ethyl-N2-hydroxyethylamine to yield 1-(N-ethylN-2-hydroxyethylamino) - 4 - pentanone, which, when reductively aminated, by simultaneously contacting it with an -excess of ammonia and hydrogen under pressure in the presence of a hydrogenation catalyst, yields, the basic side chain, 5-(N - ethyl - N - 2 - hydiroxyethylamino)2-pentylamine. Then, in the last step, the condensation of this basic side chain with 4,7-dichloroquinoline yields the desired 16 product, 7 - chloro - 4 - [5 - (N - ethyl - N2 - hydroxyethylamino,)-2-pentyl]aminoquinoline. This condensation step is run preferably in the presence of phenol, although its presence is not essential.

It was convenient to isolate and use the basic quinoline of the invention as the water-soluble phosphoric acid-addition salt. It is, of course, understood that other acid addition salts, particularly the 26 water-soluble salts, such as those derived from other nontoxic inorganic acids, including hydrochloric acid, hydrobromic acid, sulphuric acid, and sulphamic acid, and nontoxic organic acids, including tartaric acid, citric acid, succinic, acid, acetic acid, benzoic acid and oleic acid will serve the same purpose and are within the scope of the invention.

The invention is further illustrated as 86 follows:1-(N-LrHYL-N-2-tYnDRoxYETHYLAlINo)4-PwrTAxNoE-.

A mixture of 323 g. of 1-ohloro-4pentanone, 480 g. of N-ethyl-N-2hydroxyethylamine and 400 g. of sodium chloride (to aid in subsequent filtration) in 1.3 liters of xylene was heated with stirring on a steam bath for two hours and then refluxed for three hours. After standing overnight, the mixture was filtered and the filter cake washed with xylene. The filtrate was fractionally distilled, yielding 207.3 g. of a fraction distilling at 89-90 (. at 0.35 mm.; n 25 1.4600. This fraction, 1-(N-ethyl-N-2hydroxyethylamino)-4-pentanone, was used in the next step of the synthesis. A sample of said fraction was, further purified by distillation through a column and gave an analytically pure sample of 1-(N - ethyl - N - 2 - hydroxyethylamino)4-pentanone, boiling at 85-879 a. at 0.4 mm., nD, 1.4583.

5-(N-ETHYL-N-2-HYDRoxYBTHYLAMINo)2-rENTYLAMINIn.

The, 1 - (N - ethyl - N-2-hydroxyethylamino)-4-pentanone from above (284.2 g.) was dissolved in 300 g. of 28%' ammoniacal methanol and reduced catalytically with Raney nickel (at an initial pressure do of 1000 pounds) at room temperature.

After 24 hours the catalyst was filtered off and the product distilled in 'acuo through a column, yielding 254 g. of a fraction distilling at; 88.5-9619 C. at 0.3 mm. and 70 oomprising mainly 5 - (N - ethyl - N - 2hydroxyethylamino)-2- pentylamine. An analytical sample of this fraction distilled at 93 a. at 0.6 mm.; n 25, 1.4'703.

7-csLnono-4- [5-N-ETYi-LN-2-nYDRoxyETHYLAmINo)-2-PSENT:LJ]AINoQuINOLINE DIOPHOSPHATE.

A mixture of 90 g. of 4,7-dichloroquinoline, 90 g. of phenol, 1 g. of potassilum iodide and 132 g. of 5-(N-ethyl-N-2hydroxyethylamino)-2-pentylamine from above was heated with stirring for 18 hours at 125-1309 C. Methanol (1.9 liters) was added and the mixture was filtered with charcoal. The filtrate was 86 treated with 270' cc. of a solution of 100 g.

of phosphoric acid in 300 cc. of methanol, the walls of the flask containing the filtrate were scratched with a glass rod and the mixture was allowed to, stand for 90 two days. The solid was filtered off, washed with methanol and dried, yielding 101 g.

of crude 7-chloro-4- [5-.(N-ethyl-N-2hydroxyethylamino') - 2 - pentyl]aminoquinoline diphosphate, m.p. 155-156 96 0. Additional quinoline diphosphate was obtained as a gummy mass from the filtrate by concentrating the latter to about half its volume and adding acetone.

The, crude gummy diphosphate was dissolved in water, basified with ammonium hydroxide and the resulting liberated basic quinoline, extracted with chloroform.

After removal of the chloroform by distillation, the residue was dissolved in 105 ether and crystallization was induced by scratching the walls of the flask with the glass rod. About 30 g. of the crude quinoline base, melting at 77-829 C., separated. Recrystallization of the 110 material from ethylene dichloride or ethyl acetate yielded the, purified 7-chloro-4-[5N - ethyl - N - 2 - hydroxyethylamino)2-pentyl]aminoquinoline, m.p. 89-91" O.

The above crude quinoline diphosphate 116 (101 g.) was purified by dissolving it in co. of water, adding 200 cc. of ethanol, and filtering the solution with charcoal.

To the hot filtrate was, added an additional 400 cc. of ethanol and crystallization was induced as above by scratching the wall of the flask with a glass rod. The separated product was dried at 100W Ci. for three hours, yielding 85 g. of 7-chloro-4[5-(N-ethyl - N - 2 - hydroxyethylamino)- 126 680,255 680,255 2 - pentyl]aminoquinoline diphosphate, m.p. 162-164 C. An additional 10 g. of the basic quinoline was recovered from the filtrate by using the procedure, already 6 described hereinabove.

Instead of using 4,7-dichloroquinoline in the above condensation 4-bromo-7chloroquinoline or 4-iodo-7-chloroquinoline can be used, but their use offers no advantage and these starting materials are somewhat more difficult to obtain.