DK161513B - PROCEDURE FOR PREPARING N, N-DIMETHYLAMINOMETHYLARYL COMPOUNDS - Google Patents

Description

DK 161513B

The present invention relates to a particular process, characterized by the characterizing part of claim 1, for the preparation of ranitidine and other N, N-dimethylaminomethylaryl compounds of the general formula I

R

Ar 1 HN (CH 3) and I

wherein R represents a hydrogen atom or a methyl group and Ar 10 represents an optionally substituted phenyl group of formula -or 15 wherein R 1 represents a hydrogen atom, chlorine atom or bromine atom or a C 1-6 alkyl group, an optionally substituted furyl group of formula O '*

20 NCK

wherein R 2 represents a hydrogen atom, a C 1-6 alkyl group, a group of the formula HCNO 2 CHaN (CH3) a or CHaSCHaCHaNHCNHCH3, or an optionally substituted pyridyl group of the formula

30 I

* <1 '»m-jT or * 3-0 1 wherein R 3 represents a hydrogen atom or a C 1-6 alkyl group, or salts thereof.

Compounds of general formula X are at least 2

DK 161513B

partly known and suitable partly as intermediates for use in the pharmaceutical industry and partly as pharmaceuticals. A well-known drug belonging to this class of compounds is ranitidine, which is an important remedy for ulcers (gastric ulcer 5 and duodenal ulcer) and has the formula / T \ chno2

(CHaJaNCHa ^ O ^ 'CHaSCHaCHaNHCNHCHa IV

10

A number of methods are known for preparing compounds of general formula I by converting alcohols to dimethylamines, see, e.g., Houben-Weyl. Methods 15 of Organic Chemistry, XI / 1 (1957), 108-235 and ibid., VI / 16.

(1984), 914-916 (Alcohols III); J. March. Adv. Orgn. Chem.

(1985), 366, 3rd ed .; Y. Tanigawa et al., Tetrahedron Letters (1975), 471; Organic Reactions 29 (1983), 1-162? E. H. White et al., JACS 87 (1965), 5261, S, -I) and references therein.

All of these processes yield low yields, are multi-stage reactions with isolation of intermediates, or employ readily available reagents, require the use of a catalyst, and / or take place under extreme conditions such as high temperature or highly acidic environment.

Danish Patent Specification No. 137,898 discloses an analogous process for the preparation of 3- (4, -bromophenyl) -3- (3,2-pyridyl) -1-dimethylaminopropane of the formula

br

I I CH

/ 3 ^^ -> hch2ch2n Cl C «3 35 by reacting the corresponding aliphatic alcohol with dimethylamine. This is evident from, among other things, the only example of scripture that the process itself is known. Specifically,

DK 161513 B

3 the sign is known from the above-mentioned article in the Methoden der organischen Chemie. This known process can be illustrated by the reaction scheme

5 1) ROH + p-TsCl -> R-OTS

pyridine 2) R-OTs + (CH3) aNH -> RN (CH3) a 10 where Ts represents tosyl.

The yield of the reaction according to the example is 0.8 g of pure product, i.e. ca. 25% after chromatographic purification.

A characteristic feature of the process of the present invention is that it can be carried out only on a hydroxymethylaryl compound or certain hydroxymethyl aromatic heterocyclic compounds, but not on aliphatic compounds such as RCHCHaCHaOH.

20 From DK patent specification 148,258 are variously known

analogous methods for the preparation of ranitidine. These processes use readily available raw materials but require a number of reaction steps and cumbersome purification processes. According to U.S. Patent No. 4,497,961, ranitidine can be prepared by reacting a thiol of formula V

(ch3) 2Nch2 ^ CH2sh

30 V

with an alkylating agent of the general formula VI

CHNOa

LCHaCHaNH-? NHCH3 VI

4

DK 161513B

wherein L is a leaving group, preferably a halogen atom. Since the yields calculated from thiol V are of the order of 20-30%, the total yield calculated from readily available furan derivatives will be very low.

U.S. Patent No. 4,440,938 discloses the preparation of ranitidine by reacting the thiol V with an aziridine compound (ethyleneimine compound) of formula VIII: CH2 HCNO2

\ II

N-C-NHCHa VIII

CHs and GB Patent 2,075,980 disclose the preparation of ranitidine by reaction of V with VIII; or of related compounds wherein the nitrogen atom of V and VIII to which the methyl groups are attached is substituted differently. The GB patent indicates high yields of the reaction, namely usually above 80% in this last reaction step for the preparation of ranitidine.

Although the two starting materials are stated to be capable of yielding wine in reasonably good yields, this process is not suitable for technical application, using aziridine VIII. Azi * v ridins are generally highly toxic, highly reactive substances which, even at low concentrations, appear mutagenic and carcinogenic. Technical preparation and use of such compounds will be extremely questionable and will necessitate costly security and control measures.

An improved method for the preparation of ranitidine is described in DK Publication No. 153,758. It consists in reacting N- [2 - [[[5- (hydroxymethyl) -2-furanyl] methyl] thio] -ethyl] -N'-methyl-2-nitro-1,1- ethylenediamine of formula IX

> T \\ fN0-

35 HOCHa CH2SCH2CH2NHCNHCH3 IX

5

DK 161513B

in an organic solvent with dimethylamine and a (N, N-dimethylamino) triphenylphosphonium halide of formula X

(CeHs) 3P + N (CH3) z, Hal + X

5 wherein Hal represents bromine or chlorine.

However, this known process has the disadvantage that the reagent of formula X is expensive to prepare, approx. four times as expensive per moles such as the tetramethylformamidinium salt of the present invention used with the formula III shown below. This salt is prepared by a one-step process in good yield, and when used as a reagent in the preparation of, for example, ranitidine, no undesirable by-products are produced, the DMF formed by the reaction being the same as the solvent (DMF).

The compound of formula X is prepared from expensive triphenylphosphine according to the reaction scheme (wherein Hal is represented by Br): 20 + NH (CH3) 2 (C6H5) P + Br2 “MF * (C6H5) 3P Br, Br 'DMF> (C6H5) P + N (CH3) 2, Br "25 When using this salt to prepare, for example, ranitidine, triphenyloxide is formed as a by-product, which significantly impairs work-up * The reaction scheme for this reaction is with ranitin as example: + 4 NH (CH2) 30 (W3P N (CH3) 2, Br + R4CH2OH 2>

R4CH2N (CH3) 2 + (C6H5) 3PO

where R · 4 represents the group 35

DK 161513 B

6 '^ O / XCH2SCH2CH2NHCNHCH3 CHNOa

It is therefore an object of the invention to provide a process for the preparation of the compounds of general formula I by which aryl methanols can be converted into the corresponding N, N-dimethylaminomethyl derivatives of formula I from mild raw materials. conditions, namely at low basic pH, and in good yields (56-88% isolated compound), a process suitable for the preparation of ranitidine and the other compounds of formula I on a technical scale.

This is achieved by the process according to the invention which is characterized by reacting in dimethylformamide as solvent a hydroxymethylaryl compound of the general formula

R

ArdlHOH II

Wherein R and Ar have the meanings given above, with dimethylamine and a tetramethylformaroidinium salt of the formula / N (CH 3) a \ + [yct x-

25. \ \ / III

N (CH 3) 2 / where X represents an anion such as, for example, chlorine, bromine or tosyl, and the compound formed, if desired, is converted to a salt thereof.

According to the invention, the reaction temperature is preferably maintained at 80-130 ° C, especially at 90-110 ° C. Also according to the invention, it is convenient to use dimethylamine in an amount of 2 moles or more for each mole of hydroxymethylaryl compound II and the tetramethylformamidinium salt III in an amount of 1 mole or more for each mole of hydroxymethylaryl compound II.

A particular advantage of the present method

DK 161513 B

7 is that it is specific in that any saturated aliphatic alcohols present will not be substituted.

As salts of the compounds of formula I, the conventional salts of inorganic and organic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, picrates, tosylates or benzenesulfonates are suitably prepared.

The process of the invention is excellently suitable for the preparation of, for example, ranitidine according to the reaction scheme 10 yo 2 W> HOCH 2 ^ <vO '> Vs'CH DMF (CH3) 2NCH2O- ^ CH2SCH2CH2NHCNHCH3 20 or 3- (N, N-dimethylaminomethyl) pyridine according to the scheme ^^ CH2 ° h I f * ff (CB3> 2 ΓΥ 2 3 2 25 HC-N (CH3) In practice, the alcohol is conveniently so heated that the alcohol is sealed in a sealed container together with the tetramethylformamidinium salt, dimethylamine and dimethylformamide 30 to 80-120 ° C for 8-64 hours. The resulting dimethylaminomethylaryl compound is then worked up by distillation. and / or by precipitation in the form of a salt.

The process according to the invention will now be described in more detail by some exemplary embodiments. They also show 35 reaction schemes.

DK 161513 B

8 A. Starting material Tetramethylformamidinium chloride (CH-J-NH {j (CH3) 2 (CH3) 2NCO1 + HCON (CH3) 2 - - - HC-N (CH3) 2, C1

DMF

120 ° C, 18 to 83% 10

Dimethylcarbamyl chloride (108 g, 1.00 mol) was dissolved in dimethyl formamide (-DMF; 400 ml) and heated to 120 ° C for 18 hours. After cooling to room temperature, the crystals formed were filtered off, washed with DMF and dried in vacuo at 110 ° C. There was obtained 113 g (83%) of tetramethylformamidinium chloride as a white product. Mp. 143-146 ° C.

Method of the Invention Example 1 N, N-Dimethylbenzylamine / T \ -CH, OH + HC-H (CH2, Cr, C, N (GH,), 25 W 2; 32 DMF, (CH3) 2h1 VV 2 3 2 .45 mmol 68 mmol 110 ° C, 64 t 88%

Benzyl alcohol (4.86 g, 45 mmol) and tetramethylformaminium chloride (9.3 g, 68 mmol) were heated to 110 ° C for 30 h in an autoclave with dimethylamine (9.0 g, 200 mmol) and DMF (90 ml). The reaction mixture was then cooled and water (90 ml) was added and extracted with hexane (2 x 200 ml). The combined organic extracts were washed with 25% aqueous sodium chloride solution, dried over sodium sulfate and evaporated to an oil. The oil was distilled at 740 mbar. The fraction distilled at 166-170 ° C was collected and found to consist of 5.34 g (88%) of N, N-dimethyl ether.

DK 161513 B

9 benzylamine. Colorless oil nDao 1.4998. HPLC indicated approx.

98% purity.

Calcd for C 18 H 29 N (MV 135.2): C 79.95 H 9.69 N 10.36

Found: C 80.44 H 10.06 N 10.01% 5

Example 2 2-Chloro-NN-dimethylbenzylamine 10-Cl + N (CH3) 2 (CH3) 2NH / Cl-O2_CH2OH + HC-N (CH3) 2, Cl "DMF * / O \ -CH2N (CH3) 2 86% This compound was prepared as described in Example 1 from 2-chlorobenzyl alcohol in 86% yield.

94-98 ° C (16 mbar). Colorless oil nD2 ° 1.5240.

Calcd for CbH2CIN (MV 169.7): C 63.71 H 7.13 N 8.26

Found: C 64.87 H 7.39 N 7.91% 20

Example 3 N, N-Dimethyl-1-phenylethylamine ch3 + n (ch3) 2 <Jh3 25 {+> - CHOH + HC-N (CH3) 2, cr (O> CH «<CH3.2 40 mmol 80 mmol 110 ° C, 64 t 64% (picrate) 30 1-Phenylethanol (4.88 g, 40 mmol) and tetramethylformamidinium chloride (10.9 g, 80 mmol) were heated to HO (9.0 g, 200 mmol) and DMF (80 ml) The reaction mixture was then cooled, added with 12N hydrochloric acid to pH 2 and evaporated in water jet vacuum.

The residue was added 6N sodium hydroxide (100 ml) and then extracted with hexane (2 x 200 ml). The combined organic extracts were dried over sodium sulfate and then evaporated.

DK 161513B

or pet. The resulting residue was dissolved in ethanol and picric acid (7.3 g, 32 mmol) in ethanol was added. The resulting product was filtered off, washed and dried. 9.6 g (64%) of N, N-dimethyl-1-phenylethylamine, picrate was isolated.

M.p. 137.5-139 AD.

Calcd. For C 6 H 6 N 2 O 3 (MV 378.3): C 50.79 H 4.79 N 14.81 Found: C 50.72 H 4.92 N 14.78%.

Example 4 10 ---------- 3- (N, N-Dimethylaminomethyl-pyridine, CH2OH + H (CH3) 2 ^^. CH2N (O) 3) 2 [1] + HC-N ( CH) cT - - [I] J z DMF, (CHJ9NH 30 mmol 60 mmol 110 ° C, 64 t 88% (dipicrate) 3- (Hydroxymethyl) pyridine (3.27 h, 30 mmol) methylformamidinium chloride (8.2 g, 60 mole) was heated to 110 ° C for 64 hours in an autoclave together with dimethylamine (6.8 g, 150 mmol) and DMF (60 ml). The reaction mixture was then cooled, added with 12 N hydrochloric acid. to pH 2 and evaporated in anhydrous crude living vacuum. The residue was added 6 N sodium hydroxide (100 ml) and then extracted with t-butyl methyl ether (2 x 25 200 ml). The combined organic extracts were washed with a 20% aqueous sodium chloride solution and then evaporated. to 5 g of oil The oil was dissolved in ethanol and added with picric acid (13.7 g, 60 mmol) in ethanol, the resulting product was filtered off, washed and dried to isolate 15.6 g (88%) of 3- (N, N-dimethylaminomethyl) -pyridine, dipicrate.

188.5-1928 C.

Calcd. For CaoHxSNsOxa (MV 594.4): C 40.41 H 3.05 N 18.85 Found: C 40.36 H 3.11 N 18.78%.

Example 5

DK 161513 B

11 2- (N.N-Dimethylaminomethyl) pyridine

5 (CHJ.NH

Γ jl + HC “N (CH CH) 9 / C1 - \ I Il

WtlAcH, OH DMF ViN- (CH2NiCH3) 2 74% (dipicrate) 10 was prepared in a similar manner as described in Example 2 from 2- (hydroxymethyl) pyridine in 74% yield. The dipyrate melted at 166-168 ° C.

Example 6 ---------- 2.5-Bis- (NN-dimethylaminomethyl) -furan / λ XN (CH 2) 2 (CH 3) 2 NH / CH 2 (CH 3) 2NCH 2 ch 2 OH + HC-N (CH 3 2) C1 (αΐ3,2? ΚΒ2 CB2N (CH3) 2 40 nmol 80 imol 90 ° C, 20t?, 3% (dipicrate) 1 2 3 4 5 6 7 8 9 10 11 5- (Dimethylaminomethyl) -furfuryl alcohol ( 6.20 g, 40 2 mmol) and tetramethylformamidinium chloride (10.9 g, 80 mmol) 3 were heated to 90 ° C for 20 hours in an autoclave together with dimethylamine (9.0 g, 200 mmol) and DMF ( The reaction mixture was then cooled and 12N hydrochloric acid 6 was added to pH 2 and evaporated in water jet vacuum. To the residue 7 was added 8N sodium hydroxide (100ml) and then extracted with t-butyl methyl ether. (2 x 150 ml) The combined 9 organic extracts were washed with 20% aqueous sodium chloride solution, dried over sodium sulfate and then evaporated.

11

The resulting residue was dissolved in ethanol and picric acid (16 g, 70 mmol) in ethanol was added. The resulting product was filtered off, washed and dried. Thereby r

DK 161513 B

12 isolated 18 * 6 g (73%) of 2,5-bis (N, N-dimethylaminomethyl) furan, dipicrate. Mp. 199 to 201.5 ° C.

Calcd for CaaHa + NaOis (MV 640.4): C 41.26 H 3.77 N 17.50 Found: C 41.14 H 3.75 N 17.43%. j

Example 7 N- [2- [[[5- [(Dimethylamino) -methyl] -2-furanyl] -methyl] -thio] -ethyl-N1-methyl-2-nitro-1,1-ethylenediamine-HCl tranitidine -HCl) HCjNO, + N (CH3) 2 _ hoch2 ^ <o> ^ ch2sch2ch2nhcnhch3 + hc-n (ch3) 2, ci 20 mmol 60 mmol (CH3) 2NH _ 'HCNO, - - DMF (CH3) 2NCH2O2> -CH2SCH2CH2NHCNHCH3 90 ° C, 16h 56% 20 (HCl salt) N- [2 - [[[5- (Hydroxymethyl) -2-furanyl] methyl] thio] ethyl ] -N'-methyl-2-nitro-1,1-ethylenediamine (5.74 g, 20 mmol) and tetramethylformamidinium chloride (8.2 g, 60 mmol) were heated for 16 hours to 90 ° C in a autoclave together with dimethylamine (6 g, 130 mmol) and DMF (60 ml). Then, the reaction mixture was evaporated in water jet vacuum and the residue dissolved in a mixture of 20% aqueous sodium chloride (60 ml) and 1-butanol-toluene (1: 1? 90 ml). After adjusting pH 30 to 3.5 with 4N hydrochloric acid, the phases were separated. The water phase. was adjusted to pH 9.5 with 11 N sodium hydroxide and extracted with 1-butanol-toluene (1: 1; 2 x 90 ml).

The combined organic extracts were evaporated in water jet vacuum and dissolved in 2-propanol. This solution 35 was slowly filtered through a layer of silica gel (20 g). The filter layer was rinsed with 2-propanol. The filtrate was evaporated to ca. 50 ml and 8N hydrochloric acid was added to the pH

DK 161513B

13 4.5. The resulting precipitate was filtered off at 10 ° C and washed with 2-propanol. Drying gave 3.9 g (56%) of ranitidine HCl as a beige product with m.p. 135-137 "C.

Calcd for Ca.3H23iN4O3S, HCl (MV 350.9): 5 C 44.50 H 6.61 N 15.97

Found: C, 44.35; H, 6.63; N, 15.81%.

Claims (3)

1. A process for the preparation of N, N-dimethylamino-methyl-aryl compounds of general formula 5? ArCHN (CH3) 2 I or salts thereof, in which formula R represents a hydrogen atom or a methyl group and Ar represents an optionally substituted phenyl group of formula -cr 15 wherein R x represents a hydrogen atom, chlorine atom or bromine atom or a C x e alkyl group , an optionally substituted furyl group of formula 20 / -v Q 25 wherein R 2 represents a hydrogen atom, a C 1-4 alkyl group or a group of the formula H 2 NO 2 CH 2 N (CH 3) 2 or CH 2 Wherein R3 represents a hydrogen atom or a C1-6 alkyl group characterized by reacting in dimethylformamide as solvent a hydroxymethylaryl compound of the general formula R R ArCHOH II wherein R and Ar have the meanings given above with dimethyl 10 and a tetramethylformidinium salt of the formula / N (CH 3) 2 + + (hc 2) X - III \ N (CH 3) 2/15 if desired, the compound is converted to a salt thereof. Process according to claim 1, characterized in that the reaction temperature is maintained at 80-130 ° C, preferably 90-110 ° C. Process according to claim 1 or 2, characterized in that dimethylamine is used in an amount of 2 moles or more for each mole of hydroxymethylaryl compound II and the tetramethylformamidinium salt III in an amount of 1 mole or more for each mole of hydroxymethylaryl compound 1I. j