DD296481A5 - PROCESS FOR PREPARING N, N-DIMETHYLAMINO-METHYLARYL COMPOUNDS - Google Patents

Abstract

Ranitidine and other compounds of general formula I {N, N-dimethylaminomethylaryl compounds; ranitidine; phenyl; pyridyl; dimethylformamide; Hydroxymethylarylverbindung; Tetramethylformamidiniumsalz}

Description

-2- 296

The present invention relates to a special process for the preparation of Ν, Ν-Dimothylamino-mothylarylverbindungen of the general formula I.

I. ι

ArCHN (CH ₃ ) ₂

wherein R is a hydrogen atom or a methyl group and Ar is a optionally substituted phenyl group of the formula

wherein R ¹ denotes a hydrogen atom, chlorine atom or bromine atom or a Ct-e-alkyl group, an optionally substituted furyl group of the formula

R ²

wherein R ^{2 is} a hydrogen atom, a Ct-e-alkyl group or a group of the formula

HCNO ₀ Il 2 or CH

in which Me is a methyl group, or a possibly substituted pyridyl group of the formula

^ N ^^ ^ N

or

wherein R ^{3 is} a hydrogen atom or a C). _e alkyl group, or salts thereof.

The compounds of the general formula I are at least partially known and are partly suitable as intermediates for use in the pharmaceutical industry, partly as medicaments. A well-known drug that belongs to this class of compounds is ranitidine, which is an important antiulcer (gastric and duodenal ulcer) with the formula IV:

CHNO ₂ (CH ₂ ) ₀ NCH ₀ F \ CH ₀ SCH ₀ CH ₀ NHCNHCh, ^lv

There are a number of methods for preparing compounds of general formula I by reacting alcohols to dimethylamines, see e.g. Houben-Weyl, Methods of Organic Chemistry, XI / 1 (1957), 108-135 and ibid VI / 16 (1984), 914-916 (alcohols III); J. March, Adv. Orgn. Chem. (1985), 366.3. Output; Y. Tanigawa et al., Tetrahedron Letters (1975), 471; Organic Reactions 29 (1983), 1-162; E.H. White et al., JACS 87 (1965), 5261, p. I) and the references cited in these references.

All of these methods are either Mohr stage reactions - with isolation of intermediates or they use difficult to access reagents, require the use of a catalyst and / or find in extreme conditions such as e.g.

high temperatures or strong acidic environments instead.

From GB Patent Specification No. 1,565,966 various processes for the preparation of ranitidine are known. These methods use readily available raw materials, but require a variety of reaction steps and difficult to handle cleaning methods.

According to US Pat. No. 4,497,961, ranitidine is prepared by reacting a thiol of formula V.

with an alkylation center! the general formula Vl

CHNO ₀

I ² Vl

LCh ₂ CH ₂ NH-CNHCH ₃

wherein L is a leaving group, preferably a halogen atom. Since the yields, calculated with respect to the thiol V, are in the order of 20-30%, the overall yield, calculated on the accessible furan derivatives, will be very low.

U.S. Patent Specification No. 4,440,938 describes the preparation of ranitldine by the reaction of a thiol V with an azirldine compound (ethyleneimine compound) having the formula VIII:

NHCH ₃ -

and British Patent Specification No. 2,075,980 describes the preparation of ranitidine by the reaction of V with VIII; or related compounds wherein the nitrogen atom in V and VIII to which the methyl groups are attached are otherwise substituted. The GB patent discloses high yields of the reaction, usually more than 80% in this last reaction step to produce ranitidine.

Although it is said that these starting materials are obtainable with fairly good yields, this method is not suitable for use on an industrial scale since the aziridine VIII is used. Aziridines are generally very toxic, very reactive substances which mutagenize and carginogenically invade even at low concentrations. A technical production and use of such compounds will be very questionable and require expensive safety and control measures.

DK Publication No. 1,153,758 (European Patent No. 219,225) describes an ancestor for producing ranitidine. The process consists in reacting N- [2 - [[5- (hydroxymethyl) -2-furanyl] methyl] thio] ethyl-N'-methyl-2-nitro-1,1-ethenediamine of the formula IX

CHNO ₀

" ² IX

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

wherein Hal represents bromine or chlorine.

However, this method has the disadvantage that the starting material triphenylphosphine is expensive, and since it has a high molecular weight, the price per mole of this excipient becomes a burden on the price of the final product.

The aim of the invention is thus to provide a process for the preparation of the indicated compounds of general formula I, in which process one can convert arylmethanols by the use of inexpensive raw materials to the corresponding Ν, Ν-dimethylaminomethyl derivatives of formula I, under mild conditions ie at a weakly basic pH, and in good yields (56-88% isolated compound), a process which is very suitable for the production of ranitidine and the other compounds of formol I on an industrial scale.

This object is achieved in the process according to the invention, which process is characterized in that in dimethylformamide as a solvent Hydroxymethylarylverbindung the general formula

ArCHOH Il

where R and Ar have the meanings given above, with dimethylamine and a tetramethylformamidinium salt of the formula

III

wherein X is an anion such as. Chlorine, bromine or Fosyl called reacts, after which the formed compound, if desired, is converted into a salt thereof.

The invention according to the reaction temperature is preferably maintained at 80-13O ⁰ C, in particular at 90-100 ⁰ C. Also, it is expedient according to the invention, dimethylamine in an amount of 2 moles or more fo> each mole Hydroxymethylarylverbindung Il and III in TeWamethylformamidiniumsalz in an amount of 1 mole or more for each mole of hydroxymethylaryl compound II.

A particular advantage of the present process is that it is specific because any saturated aliphatic alcohols that may be present are not substituted.

As salts of the compounds of formula I, the salts normally used in the pharmaceutical industry are preferably prepared with inorganic and organic acids, such. As hydrochlorides, hydrobromides, phosphates, sulfates, picrates, tosylates or benzenesulfonates.

The process according to the invention is for the preparation of ranitidine according to the reaction scheme

NO ^ + ", ..

NMe Il H

Me ₂ NH

H H or 3- (N, N-dimethylamino) pyridine according to the scheme

CH ₉ OH,

+ ({Me, Me ₂ NH

HC-NMe ₂ Cr _DMp ^ N

very suitable.

In practice, it is advisable so that the alcohol is heated together with the Tetramethylformamldinlumsalz, diethylamine and dimethylformamide in a closed container at 80-12O ⁰ C for 8-64 hours. The dimethylaminomethylaryl compound formed is then achieved by distillation and / or precipitation in the form of a salt. The method according to the invention is described in more detail below by embodiments. The examples also contain reaction schemes, and in these schemes Me denotes methyl.

Starting material Tetramethvlformamldiniumchlorid

NMe ₀

Il ² HC-t

Me ₉ NCOCl + HCONMe ₉ > HC-NMe ₀ , C].

* ^Δ DMF ^&

120 ° C, 18 s 83%

Dimetbylcarbamylchlorid (108g, 1.00 mol) was dissolved in dimethylformamide (DMF; 400 ml) and heated to 12O ⁰ C for 18 hours. After cooling to room temperature, the crystals formed were filtered off, washed with DMF and dried in vacuo at 100 ⁰ C. This yielded 113 g (83%) of tetramethylformamidinium chloride as a white product. Melting point 143-146 ⁰ C.

Method according to the invention

Example 1 N, N-dimethylbenzylamines

⁺ NMe _o

/ ,, V CH + OH ₀ HC ₀ NMe, Cl s _n Z _V-9 CH NMe ₉

VV ^{2 l} DMF, Me ₂ NH vl / ^l *

DMF, Me ₂ NH

45 mmol 68 mmol 110 ° C, 64 S 88%

Benzyl alcohol (4,86g, 45mMol) and tetramethylformamidinium chloride (9.3 g, 68 mmol) were heated to 100 ⁰ C for 64 hours in an autoclave together with dimethylamine (9.0 g, 20OmMoI) and DMF (90ml). The reaction mixture was then cooled and added to water, after which it was extracted with hexane (2 × 200 ml). The combined organic extracts were washed with a 25% aqueous sodium chloride solution, dried over sodium sulfate and evaporated to an oil. The oil was distilled at 740mbar. The fraction which distilled at 166-17O ⁰ C, was collected and showed sit h from 5,34y (88%) Ν, Ν-dimethylbenzylamine to exist. Colorless oil no ° 1,4998. HPLC showed a purity of about 98%. For example, for C ₉ H ₁₆ N (MW 135.2): C, 79.95, H, 9.69, N, 10.36

Found: C 80.44 H 10.06 N 10.01%

Example 2 2-Chloro-N, N-dimethylbonzylam! N

Cl

/ - S ² - Me ₉ NH _ ^

/ -VcH ₀ OH + HC-NMe _0, Cl - Z ^ _V-9 CH NMe,

VV ^l DMF W ^ ^

This compound was prepared using 2-chlorobenzyl alcohol as in Example 1 in a yield of 86%. Melting point 16mBar94-98 ° C. Colorless oil ng ⁰ 1,5240

Calculated for C ₉ H ₁₂ CIN (MW 169.7): C 63.71 H 7,13 N 8,26

Found: C 64.87 H 7.39 M 7.91%

Example 3 N, N-Dimethyl-1-phonylethylamine

πf3Y * , ~

Z _V-CHOH + HC-NMe _0, Cl ν / V _n

W * DMF, Me ₂ NH 'Vl /

_n CHNMe DMF, 'V /

40 mmol 80 mmol oil 11O ⁰ C, 64 S 64%

(Picrate)

1-phenolethanol (4.88g, 40mMoI) and tetramethylformamidinium chloride (10.9g, 8OmMoI) were heated at 100 ° C for 64 hours in an autoclave along with dimethylamine (9.0g, 20OmMoI) and DMF (80ml). The reaction mixture was then cooled, 12N hydrochloric acid was added to pH 2, and the mixture was evaporated in a water-jet vacuum. To the residue was added 4N sodium hydroxide and it was then extracted with hexane (2 x 200 ml). The combined organic extracts were dried over sodium sulfate and then evaporated. The resulting residue

was dissolved in ethanol and picric acid (7.3 g, 32 mmol) in ethanol was added. The product formed was filtered off, washed and dried. This isolated 9.6 g (64%) of NN-dimethylM-phenylethylamine, picnic. Melting point 137.5-139 ⁰ C.

Calculated for C ₁₈ H ₁ ^ N ₄ O ₇ (MW 378.3): 0 50.79 H 4.79 N 14.81

Found: C 50.72 H Λ92 N 14.78%

Example 4 3- (N, N-Dimethylamnomethyl) -pyridine

σCH ₉ OH ⁺ NMe ₀ .. .CH ₀ NMe ₀

+ HCNM Cl Π

σ + HC-NMe, Cl

DMF, Me ₂ NH

30 mmol 60 mmol 110 ⁰ C, 64 s 88%

(Dipikrat)

3- (hydroxymethyl) pyridine (3.27 g, 30 mmol) and tetramethylformamidinium chloride (8.2 g, 60 mmol) were added to 110 ⁰ C during 64 hours in an autoclave together with dimethylamine (6.8 g, 15OmMoI) and DMF (60 ml) heated. The reaction mixture was then cooled, 12 N hydrochloric acid was added until pH 2, and the mixture was evaporated in a water-jet vacuum. To the residue was added 6N sodium hydroxide (100 ml) and it was then extracted with t-butyl methyl ether (2 x 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 picric acid (13.7 g, 6OmMoI) in ethanol was added. The product formed was filtered off, washed and dried. This isolated 15.6 g (8%) of 3- (N, N-dimethylaminomethyl) -pyridine, dipicrate. Melting point 188.5-192 ° C

Calculation for C ₂₀ H ₁₈ O ₁₃ (MW 594.4): C 40.41 H 3.05 N 18.85

Found: C 40.36 H 3.11 N 18.78%

Example 5 2- (N, N-Dlmothylamnomonothyl) -pyridine

II ² + HC-NMe ₀₁ Cl

a .. CH ₂ OH - ^ά DMF

74% (dipricrate)

was prepared as in Example 2 using 2- (hydroxymethyl) -pyr; jin in 74% yield. The Dipikrat melted at 166-168 ⁰ C.

Example 6 2,5-Blis (N, N-dimethylamino) -furan

HC Me ₂ -NMe ₂ Cl " me 2 NH ^ Me ₂ N " ° 80 mmol DMF 20 p 73% (dipricrate) 90 ⁰ C

40 mmol

5- (Dimethylaminomethyl) -furfuryl alcohol (6.20g, 40mMoI) and tetramethylformamidinium chloride (10.9g, 8OmMoI) were added to 9O ⁰ C for 20 hours in an autoclave together with dimethylamine (9.0g, 20OmMoI) and DMF (80ml) '.ützt. The reaction mixture was then cooled, 12N hydrochloric acid was added until pH 2, and the mixture was evaporated in a water-jet vacuum. The residue was added with 8N sodium hydroxide (100 ml) and then extracted with t-butyl methyl ether (2 × 150 ml). The combined organic extracts were washed with a 20% aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. The resulting residue was dissolved in ethanol and picric acid (16 g, 70 mmol) in ethanol was added. The product formed was filtered off, washed and dried. This isolated 18.6 g (73%) of 2,5-bis- (N, N-dimethylaminomethyl) -furan, dipicrate. Melting point 199-201.5 ⁰ C.

Calculated for C ₂₂ H ₂₄ N ₈ O _{) 6} (MW 640.4): C 41.26 H 3.77 N 17.50 Gofunden: C 41.14 H 3.75 N 17.43%

Example 7 NN - ^ - tlBtlDimothylaminol-methyll ^ -furanyll-mothyl-thlol-ethyl-N'-methyl ^ -nitro-i ^ -äthendiamin-HCKRanitidlnHCl)

NMe ₂ , Cl 60 mmol

Me ₂ NH DMF ^

90 ° C, 16S 56%

N- [2- (il5- (hydroxymethyl) -2-furanyl] methyl] -thio] ethyl] -N'-methyl-2-nitro-1,1-ethene-diamine (5.74g, 20mMoI) and tetramethylformamidinium chloride ( 8,2g, 6OmMoI) were at 9O ⁰ C for 16 hours in an autoclave zusamnen (with dimethylamine 6g 13OmMoI) and DMF (60ml) is heated. The reaction mixture was then evaporated in a water jet vacuum and represents residue was dissolved in a mixture of 20% aqueous sodium chloride (60 ml) and 1-butanol / toluene (1: 1, 90 ml) were added, and the pH was adjusted to 3.5 with 4N hydrochloric acid, the phases were separated and the aqueous phase was pH 9, b with 11N sodium hydroxide and extracted with butanol / toluene (1: 1; 2 x 90 ml).

The combined organic extracts were pre-evaporated in a water jet vacuum and dissolved in 2-propanol. This solution was filtered slowly through a pad of kleselgol (20 g). The filter layer was rinsed with 2-propanol. The filtrate was evaporated to about 50 ml and 8N hydrochloric acid was added to pH 4.5. The resulting residue wurdo washed at 1O ⁰ C filtered and washed with 2-propanol. The drying gave 3.9 g (56%) Raniticlin-HCl as a beige product with melting point 135-137 ⁰ C.

Calculated for C ₃ H ₃₂ N ₄ O ₃ S, HCI (MW 350.9): 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-Dimethylarninornethylarylverbindungen the general formula R
ArCHN (CH ₃ ) ₂ ' or salts thereof, in which formula R denotes a hydrogen atom or a methyl group, and Ar denotes an optionally substituted phenyl group of the formula R ¹ wherein R ¹ denotes a hydrogen atom, chlorine atom or bromine atom or a Ci _ $ - alkyl group, an optionally substituted furyl group of the formula wherein R ^{2 is} a hydrogen atom, a Ci_6-alkyl group or a group of formula HCNO ₀ Il ^l
or CH in which Me is a methyl group, or an optionally substituted pyridyl group of the formula wherein R ³ denotes a hydrogen atom or a C ₁ _ _€ alkyl group, characterized in that in dimethylformamide as a solvent Hydroxymethylarylverbindung the general formula ii ArCHOH where R and Ar have the meanings given above, with dimethylamine and a tetramethylformamidinium salt of the formula wherein X denotes chlorine, bromine or tosyl, after which the formed compound is converted, if desired, into a salt thereof. 2. The method according to claim 1, characterized in that the reaction temperature at 80-130 ⁰ C, preferably at 90-100 ⁰ C, is maintained. 3. The method according to claim 1 or 2, characterized in that dimethylamine is used in an amount of 2 moles or more for each mole Hydroxymethylarylverbindung Il and the Tetramethylformamidiniumsalz III is used in an amount of 1 mole or more for each mole Hydroxymethylarylverbindung Il.