WO1991001314A1

WO1991001314A1 - Process for the preparation of methyl-quinoline derivatives

Info

Publication number: WO1991001314A1
Application number: PCT/HU1990/000049
Authority: WO
Inventors: Zoltán Salamon; József JEKO^'; Ilona Imre; Magdolna CZELLÉR
Original assignee: Alkaloida Vegyészeti Gyár
Priority date: 1989-07-25
Filing date: 1990-07-20
Publication date: 1991-02-07
Also published as: AU6074190A; FI911403A0; HUT54363A; FI911402A0; BG60031A3; EP0435993A1; EP0435995A1; AU619129B2; US5166354A; WO1991001315A1; US5175297A

Abstract

The present invention relates to a process for the preparation of methyl-quinoline derivatives of general formula (I), or salts thereof, wherein X1 stands for hydrogen or a non-binding electron pair, R1 stands for hydrogen or a group of general formula (II), R2 stands for acyloxy or hydroxyl and the dotted line is an optionally aromatic ring. The invention is carried out by rearranging an N-oxide derivative of general formula (III), wherein R1 is as given above - with an organic carboxylic acid derivative containing halogen, preferably a halogen substituted aliphatic or aromatic carboxylic acid anhydride or carboxylic acid halide containing 1 to 8 carbon atoms, and reducing the obtained ester of general formula (IV), wherein R1 is as given above, and Ac stands for acyl - after or before the solvolysis of the ester group.

Description

PROCESS FOR THE PREPARATION OF METHYL-QUINOLINE DERIVATIV

The present invention relates to a process for preparation of methyl-quinoline derivatives of the gen formula (I)

and salts thereof. The compounds of the general for (I) can be prepared by rearranging an N-oxide derivat of the general formula (III)

with an organic carboxylic acid derivative containing ha gene, preferably with a halogene substituted C, -. alipha

70385-123-KY/KmO or aromatic carboxylic anhydride or carboxylic acid halide and by reducing the obtained ester of the general formula

after or before solvoliziπg the ester group. The definition of the substituents in the present application is as fol- lows

X stands for hydrogen or a non-binding electron pair, R stands for hydrogen or a group of the formula (II)

R stands for acyloxy or hydroxyl,

R stands for a group of the formula (II) and

Ac stands for an acyl group and the dotted line indicates an optionally aromatic ring.

The compounds prepared according to the present inven- tioπ are novel important intermediates for the prepara¬ tion of pharmaceutically active compounds. Thus erithro- -alfa-2-piperidyl-2,8-bis(trifluoro-methyl)-quinoline-4- -methanol-hydrochloride (meflocin) can be prepared from the above compounds. This active ingredient can be used as antimalaria substance.

Meflocin has been first prepared (J. Med. Che . ______

926 (1971)) by hydratiπg 2-pyridyl-2 ,8-bis(trifluoro-methy -quinolyl-ketone ("Ketoπe" hereinafter) above Adams cataly and 2-pyridyl-2 ,8-bis(trifluor-methyl)-quinolyl-ketone is obtained from 2 , 8-bis(trifluoro-methyl)-quinoline-4-carbox acid syπthetized in three steps with 2-lithio-pyridiπe. Starting from the above quiπoline carboxylic acid inter¬ mediate "ketoπe" has been obtained also by reacting same w 2-bromo-magπesium-pyridine (DOS 29 40443) which analogousl was hydrated to meflocin in the presence of platiπa-charco catalyst. (2-pyridyl)-2,8-bis(trifluoro-methyl)-quinoline- -4-methaπol which is an unisolated intermediate of the red tion step is called hereinafter "Oxy-methane". This Oxy-met can be also obtained by subjecting 2,8-bis(trifluoro-methy -4-bromo-quinoline to lithiatioπ and by reacting the forme 4-lithio-quinoliπe derivative with 2-pyridine-aldehyde (DO 28066909). According to a recent solution the metallatioπ step is eliminated and thereby the use of a starting materi being cheeper than quinoline intermediates became possible. By reacting 2, 8-bis(trifluoro-methyl)-4-chloro-quinoline with 2-pyridyl-aceto-nitrile or 2-pyridyl-methyl-phosphoniu salt "ketone" is obtained by oxidating the formed intermedi According to the authors for the nucleophil substitution of the halogen of the quinoline in four-position the pyri- dine derivative has to contain an electron withdrawing substituent on the methyl group (such as the above mentione carbonitrile or phosphoπium group) (EP 0049776).

The industrial realization of the above described processes have several disadvantages, such as the mentioned metallation steps and the expensive quinoline intermediates, such as 2,8-bis(trifluoro-methyl)-4-bromo-quinoline or the corresponding quinoline-4-carboxylic acid (due to the use of the expensive and not easily available pyridiπe derivativ as disclosed above.

These disadvantages could be eliminated by the process of the invention, according to which quinoline intermediate of the general formula (III) obtained by our method disclose in USP 45 99 345 and USP 46 59 834 suitable for the industri synthesis of 2,8-bis(trifluoro-methyl)-4-chloro-quinoline and 2-methyl-pyridine-N-oxide. In the course of our experiments we have found that as opposed to the above said (EP 0 049 776) there is no need to have an electron withdrawing substituent on the methyl group of picoline and a cheeper and easier available 2-methyl-pyridine-N-oxide can be reacted without this substi tueπt. The preparation of the N-oxide compounds is protected in our Hungarian patent application No. 3736/89 whereas according to the present invention the oxymethane derivative is obtained by rearranging the above compounds.

According to the present invention an N-oxyde of the general formula (III) is reacted with trifluoro-acetic acid anhydride.

One may also proceed by reacting an N-oxyde of the general formula (III) with an optionally halogen substituted C, _□ saturated or uπsaturated alkanoyl halide or aroyl or heteroaroyl halide. The use of acid chlorides is preferred The reaction is preferably carried out without solvents or in an aprotic polar or aprotic apolar organic solvent, preferably in trichloroethane, in dichloroethane or toluen The intermediate ester is solvolized in an aqueous or an¬ hydrous C, alcohol in the presence of alkali metal hydr¬ oxide, ammonia or amines, or alkali alcoholates or carbona preferably with sodium methylate in methaπol. One may also proceed by performing the solvolyzis of the intermediate ester in alcohols by using inorganic acid catalysis, preferably in aqueous hydrochloric acid in etha

In the course of the process a product of appropriate purity is obtained, if in the reaction only the compound of the formula (IV) or only the compound of the formula (V

is isolated. A very pure product is obtained if N-oxide derivative of the general formula (III) is rearranged with trifluoro-acetic acid anhydride and then the compound of the general formula (V) is isolated from the reaction mix- ture without isolating the compound of the general formula (IV) and it is reduced in the presence of alkanol.

The ester is solvolized in water or alcohols, or in the mixture thereof with ammonia or amines or alkoxides, preferably with sodium-methylate or triethyl-amine in methan under mild conditions, such as room temperature or by acid catalysis in water in aqueous organic solvent, preferably in aqueous ethanol containing hydrochloric acid.

The starting N-oxides of the general formula (III) can be used without isolation in situ if they were prepared according to our co-pending Hungarian patent application No. 3738/89.

The present invention further provides novel compounds such as the compounds of the general formula (III), their salts with strong inorganic acids as well as compounds of • the general formulae (IV) and (VI).

(V

The further details of our invention are illustrated by the following examples.

Example 1

0.78 ml of acetyl-chloride are added dropwise in 10 dichloro-methane to a solution of 3.70 g (N-oxy-2-pyridyl) -2,8-bis(trifluoro-methyl)-quiπoline-4-methane in 50 ml of dichloro-methane at 0 C. After four days at room tempe ture the mixture is poured on ice, neutralized with solid potassium carbonate, the two layers are separated and the aqueous layer is extracted with 3 x 40 ml of dichloro-meth The combined organic layer is dried above sodium sulphate and evaporated. 3.80 g of residual oil is crystallized fro hexane. 2.55 g of 2-pyridyl-2,8-bis(trifluoro-methyl)-quiπ liπe-4-methanol-acetate are obtained, and after recrystall tion from isopropanol or hexane the product melts at 104 - 106 °C.

Example 2

1.54 g of benzoyl-chloride are added dropwise to a solution of 3.70 g (N-oxy-2-pyridyl)-2 , 8-bis(trifluoro- -methyl)-4-quinoliπe-methane in 50 ml dichloro-methane at 0 °C. The further proceeding is similar to that disclosed in Example 1 but the residue of the dichloro-methane extra is boiled with 230 ml of hexane and allowed to cool to roo temperature and the precipitated crystalline substance is recrystallized from 1.62 g of methanol. 1.4 g of ^-2- -pyridyl-2,8-bis(trifluoro-methyl)-quinoline-4-methanol- -benzoate are obtained. Mp.: 139 - 140 C. Example 3

20 g of (N-oxy-2-pyridyl)-2,8-bis(trifluoro-methyl)- -quinoliπe-4-methane are mixed with 250 ml of 1,2-dichloro- -ethane. Under external cooling at 25 °C 6.5 ml of ethyl- -chloroformiate are added dropwise, followed by 8 ml of triethyl-amine. The mixture is allowed to stand overnight and the precipitated triethyl-amine-hydrochloride is filtered and the filtrate is evaporated at reduced pressure. The residue is recrystallized from isopropaπol. 20.6 g of ethyl- (</.-2-pyridyl-2,8-bis-(trifluoro-methyl)-quinoliπe-4-methaπol -carbonate are obtained. Yield: 86.2 %, M.p.: 128 - 130 °C. Example 4

6 ml of trifluoro-acetic-acid are diluted with 40 ml of toluene and at room temperature the mixture is added dropwise to 3.72 g of (N-oxy-2-pyridyl)-2 ,8-bis(trifluoro- -methyl)-quinoline-4-methane in 50 ml of toluene at room temperature. The mixture is allowed to stand for 1 day, poured on icy water and neutralized with solid sodium hydrog carbonate and the two layers are separated. The organic layer is dried above sodium-sulphate, evaporated to 15 ml, cooled and the precipitated product is filtered and dried. 2.70 g of ^(-2-pyridyl-2,8-bis(trifluoro-methyl)-quinoline- -4-methanol are obtained. M-.p.: 133 - 135 °C. Example 5 20 g of (N-oxy-2-pyridyl)-2,8-bis(trifluoro-methyl)- -quinoline-4-methane are dissolved at 30 °C in 25 ml of acetonitrile and 15 ml of trifluoro-acetic acid anhydride are added. After 1 hour 5 ml of water are added dropwise, the solution is evaporated at reduced temperature to 34 g and it is crystallized from isopropanol. 16.56 g of -2- -pyridyl-2,8-bis(trifluoro-methyl)-quinoline-4-methanol trifluoro-acetate are obtained, m.p.: 133 - 135 °C. Example 6

The reaction is carried out according to Example 5 in 250 ml of dichloro-ethane or 250 ml of dichloro-methane but 8.6 ml of trifluoro-acetic acid anhydride are used onl To the mixture 8.6 g of potassium-carbonate dissolved in 10 ml of water are added, the two layers are separated and the organic layer is clarified by charcoal, evaporated to about 1/5 and cooled.

The precipitated product is filtered and recrystalliz from isopropanol. 12.63 g of .<-2-pyridyl-2 , 8-bis(trifluor methyl)-quinoline-4-methanol are obtained, melting at 138 - 140 °C. Example 7

Ethyl-(«^. -2-pyridyl-2, 8-bis-(trifluoro-me hyl)-quinol -4-methaπol)-carboπate obtained according to Example 3 is boiled in 2.2 g (30 ml) of methanol in the presence of 2.8 g of potassium-carbonate for 6 hours. The mixture is cooled to room temperature, the inorganic salt is filtered and the filtrate is acidified with glacial acetic acid (pH= and cooled. The precipitated product s isolated as describ above. 1.4 g of < .-2-pyridyl-2 , 8-bis(trifluoro-methyl)- -quinoliπe-4-methanol is obtained (76 %), melting point: 138 - 140 °C. Example 8

2 g of (N-oxy-2-pyridyl)-2,8-bis(trifluoro-methyl)- -quiπoline-4-methaπe are stirred for 1.5 hours at 50 - 55 °C in 20 ml of propionic acid chloride. The reaction mixture is evaporated at an inert temperature of up to 70 °C at reduced pressure and the residue is poured on ice, extracted with chloroform and the evaporated residue is crystallized or recrystallized from hexane. 1.27 g of Λ -2-pyridyl-2 ,8- -bis(trifluoro-methyl)-quinoline-4-methanol-propionate are obtained.

NMR data: quinoline sceletone proton shifts: 8.60 pieces, 5; 8.13 pieces, 7; 8.00 s, 3; 7.72 dd, 6; pyri- dine-protone shifts:- 8.55 d , 6; 7.65 d , 4; 7.55 dm, 3; 7.24 d , 5; Other: 7.65 s, methiπe; 2.60 q, methylene; 1.22 t methyl. Example 9

One may proceed as given in Example 8 but 20 ml of butiric acid chloride are used. 1.72 g of ύ -2-pyridyl-2 ,8- -bis(trifluoro-methyl)-quiπoline-4-methaπol-butirate are obtained, m.p.: 68 - 71 °C. Example 10

10 g of di(2,8-bis(trifluoro-methyl)-4-quinolyl)-(N- -oxi-2-pyridyl)-methane are dissolved in 90 ml of acetic acid anhydride and the mixture is stirred for 2 hours at 60 °C. It is evaporated at reduced pressure, the residue is poured on ice and neutralized with potassium carbonate and extracted with chloroform. The organic layer is dried, evaporated and the residue is crystallized from a mixture of chloroform and hexane. Yield: 6.3 g (79.1 %). The obtai , -di(2,8-bis(trifluor-methyl)-4-quinolyl)-pyridine-2- -methanol-acetate melts at 228 - 230 C. Example 11 1 g of JL, -X -di(2,8-bis(trifluor-methyl)-4-quinolyl)-

-pyridine-2-methanol-acetate is dissolved in 10 ml of anhy methanol and to the solution 0.1 ml of 5 mole methanolic sodium methylate is added at room temperature under nitrog streem. The mixture is allowed to stand overnight and is neutralized with glacial acetic acid, evaporated in vacuo and the residue is crystallized from a mixture of hexane and chloroform by hot clarification. The obtained product is filtered and 0.74- g of < , Λ -di-(2,8-bis(trifluor-methyl -4-quinolyl)-pyridiπe-2-methanol is obtained. Yield: 78.9 % M.p.: 200 - 202 °C. Example 12

1.4 g of ,£-2-pyridyl-2,8-bis(trifluor-methyl)-quinolin -4-methaπol-acetate is boiled under reflux for 3 hours in 20 ml of 95 % ethanol in the presence of 20 ml of 36 _ hydr chloric acid. The mixture is clarified hot with active char coal, cooled and added to a suspension of 0.9 g 10 % Pt/C catalyst (Aldrich) prehydrated in 80 ml of 95 % ethanol. The mixture is stirred vigorously in hydrogen atmosphere under normal pressure for 6 hours (hydrogen consumption 240 ml). The catalyst is filtered, evaporated at reduced pressure and the 1.24 g residue is recrystallized from acet nitrile. 0.96 g of erythro- o -(2-piperidyl)-2 , 8-bis(trifluo -methyl)-quiπoline-4-methaπol-hydrochloride is obtained. M.p.: 26^ - 264 °C. Example 13

1.0 g of -2-pyridyl-2,8-bis(trifluor-methyl)-quinolin -4-methanol is added to a suspension of 0. g of 5 % Pt/C catalyst prehydrated in 100 ml 95 % ethanol and 2 ml of 36.0 % hydrochloric acid. The hydration is carried out as disclosed in Example 12 and the product is isolated. After recrystallization 1.0 g of erithro-^ -2-pyperidyl-2,8-bis- (trifluor-methyl)-quinoline-4-me hanol-acetate hydrochloride is obtained. Yield: 90.7 %. M.p.: 211 - 212 °C. Example 14

1.0 g of erythro- /.-2-piperidil-2,8-bis(trifluor-methyl -quinoliπe-4-methanol-acetate hydrochloride is dissolved in 5 ml if 95 % ethanol, 1.00 ml of concentrated hydrochlori acid is added and the mixture is boiled under reflux for 2 hours. It is evaporated to dryness at reduced pressure, triturated with minimal amount of acetonitrile and 0.86 g, 94.7 % of erithro-f -2-piperidyl-2,6-bis(trifluor-methyl)- -quinoliπe-4-methanol-hydrochloride is obtained. M.p.: 259 - 261 °C.

Claims

C l a i s

1. Process for the preparation of methyl-quinoline- derivatives of the general formula (I)

or salts thereof, wherein

X stands for hydrogen or a non-binding electron pair, R stands for hydrogen or a group of the general formula (ID

R stands for acyloxy or hydroxyl and the dotted line is an optionally aromatic ring, which comprises rearranging an N-oxide derivative of the general formula ( III )

wherein R is as given above - with an organic carboxylic acid derivative containing halo¬ gen, preferably a halogen substituted aliphatic or aromatic carboxylic acid anhydride or carboxylic acid halide contain- ing 1 to 8 carbon atoms, and reducing the obtained ester of the general formula (IV)

wherein R is as given above and Ac stands for acyl - after or before the solvolysis of the ester group.

2. A process as claimed in claim 1 which comprises rearranging an N-oxide of the general formula (III) with trifluoro-acetic-acid anhydride.

3. A process as claimed in claim 1 which comprises reacting an N-oxide of the general formula (III) wherein

R is as given above - with an optionally halogen substitu C, g saturated or unsaturated alkanoyl halide or aroyl or heteroaroyl halide.

4. A process as claimed in any of claims 2 or 3 which comprises reacting the components without solvent or in an aprotic polar or aprotic apolar organic solvent, prefer ably in dichloromethane or dichloroethane or toluene.

5. A process as claimed in claim 1 which comprises performing the solvolysis of the intermediate ester in aqueous or anhydrous C, _* alcohols in the presence of an alkali metal hydroxide, ammonia or amine or alkali alcoho- lates or carbonates, preferably with sodium-methylate in methanol .

6. A process as claimed in claim 1 which comprises performing the solvolysis of the intermediate ester in alcohols and by inorganic acid catalysis, preferably with aqueous hydrochloric acid in ethanol.

7. A process as claimed in claim 1 which comprises isolating in the course of the reaction only compounds of the general formula (IV) or only compounds of the genera formula (V)

8. A process as claimed in claim 1 which comprises rearranging an N-oxide derivative of the general formula (III), wherein R is as given above - with trifluoro-acetic acid anhydride and isolating from the reaction mixture a compound of the general formula (V), wherein R is as given above.

9. Compounds of the general formula (III) and salts thereof formed with strong inorganic acids - R stands for hydrogen or a group of the general formula (II).

10. Compounds of the general formula (IV), wherein

1

R^x stands for hydrogen or a compound of the formula (II), Ac stands for acyl, except acetyl if R = hydrogen.

11. Compounds of the general formula (VI)

wherein R stands for a group of formula (II)