FI67536C - PROCEDURE FOR FRAMSTATION OF AV 2- (N- (2-HYDROXETYL) -N-ALKYLAMINOMETHYL) -BENOHYDROLDERIVAT - Google Patents

Description

It 'fcrTi ΓηΛ «« NOTICE OF PUBLICATION, „l 3 (1) UTLÄGGNINGSSICRIFT 675 3 6 ^ ^ ^ (51) K * .lk? / TatCt3 C 07 C 91/22, 93/06 FINLAND — FINLAND pi) ι ^ ιιιιι ^ -ι ^ μμιβμαι 782404 (22) H «k« mtapilv »- An» »knlnf» daj 04.08.78 '* (23) AlkupdUvft — GHti (h * t * dag 04.08.78 (41) Translators | ulklMksl - BllvK ofUntkj 02/06/79

National Board of Patents and Registration .... ______. . .

• (44) Date of NlhcMkdpanon | a kimL | ulkalayn— 31 η Η

Patent and registration authorities of the United Kingdom of Great Britain and Northern Ireland (32) (33) (31) muolkmi.-BegSrd prlorfcm 05.08.77

Engl anti-England (GB) 33006/77 (71) Riker Laboratories, Inc., 19901 Nordhoff Street, Northridge,

California 91324, USA (72) Peter Gordon Watson, Loughborough, Leicestershire, England-England (GB) (74) Oy Koister Ab (54) Method 2- [N- (2-hydroxyethyl) -N-alkylaminomethyl] benzhydrol derivatives for the preparation of framstä11 Ning av 2- / N - (2-hydroxety1) -Na Iky laminomethyl l_7benzohydrol der i vat

The invention relates to a process for the preparation of 2- (2-hydroxyethyl) -N-alkylaminomethyl / benzhydrolols of the formula 0------ xn

% —0T "0H

XCH0N (CH_) _OH Z | Z Z

R

wherein R represents methyl or ethyl, X is fluorine, chlorine, bromine or methyl, Y is fluorine, chlorine, methyl or methoxy and m and n are independently 0, 1 or 2.

_________ li ___ 2 67536

The benzhydrol compounds prepared by the process of the invention can be directly converted into the corresponding phenylbenz (f) -2,5-oxazokines, which are valuable physiologically active substances, cf. U.S. Patent 3,830,803, U.S. Patent 3,978,085, GB Patent 1,148,717 and CA Patent 863,349.

It is known that compounds of formula I can be prepared directly from a compound of formula ΓοΥ_-χ

Ym "" r Cl II

C-N- (CH 2) OH 11 I 22 O R

wherein R, X, Y, m and n have the same meaning as above.

This known reaction is carried out by treating the starting compound with a metal hydride reducing agent such as lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran or ether (see e.g. GB Patent 1,148,717). However, reduction with lithium aluminum hydride is not a useful commercial synthesis method on a large scale.

The solvents used are flammable and the lithium aluminum hydride itself is very dangerous and the cost is too high.

Instead, the manufacturing method now invented can be used easily and inexpensively on a commercial scale. It uses less hazardous solvents, is relatively inexpensive, and products of good purity are obtained in good yields.

The process according to the invention is characterized in that the compound of formula 3,67536

o "I --------- X

I \ n i / Xv "'··'"

NIGHT

m K ^ \

'C-N (CH _) - R

Π Δ Z.

U

wherein D is halogen, is reduced in an inert solvent with sodium borohydride in the presence of acetic acid, the reduction being carried out by mixing sodium borohydride with a portion of acetic acid and a compound of formula III, followed by the gradual addition of acetic acid-Posta and a compound of formula III to the reaction mixture.

Compounds of formula III are preferably obtained by treating a compound of formula II above with a halogenating agent in an inert solvent.

The reduction of certain amides to amines with sodium borohydride in the presence of alkanoic acid is described in "Sodium Acyloxyborohydride as New Reducing Agents", Tetrahedron Letter 1976, No. 10, pages 763-766 and "Reduction of amides with Sodium Borohydride", Ventue Alembic, Isson no. and 7. However, this process differs from the process of the present invention in which a halogenated compound of formula III is reduced. The known reduction methods in question require a large excess of sodium borohydride at the expense of efficiency due to the evolution of hydrogen and the likely formation of amine-borane, as the reduction has been shown to proceed through alkyloxyborohydride. Instead, the reduction of the present invention is readily accomplished in a variety of solvents with a smaller excess of sodium borohydride. The presence of halogen D is essential because the reaction does not take place without it. Since the compound of formula III and acetic acid are gradually added to the reaction mixture containing sodium borohydride, no evolution of hydrogen occurs after the first small acid addition.

The product of formula I is usually recovered from reaction I.

4 67536 of the mixture by treating the inert solvent with water. The product is obtained as a pure substance by removing the solvent in a manner known per se and the solution can be used as such, for example in the preparation of physiologically active phenylbenz (f) -2,5-oxazokines.

The compounds of the formula II are generally known (see GB and CA patents mentioned above). To prepare compounds of formula III, a compound of formula II is halogenated in an inert solvent such as a chlorinated hydrocarbon, for example dichloromethane or dichloroethane, or an aromatic hydrocarbon such as toluene, benzene or the like. The preferred solvent is dichloroethane. Suitable halogenating agents include phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and thionyl chloride. Phosphorus trichloride is preferred because of its relatively low cost. Generally, an equivalent amount or a small excess of up to 10 percent halogenating agent is used.

The reaction temperature is reasonable, for example, 20 to 90 ° C, depending on the desired reaction time. At 55-80 ° C, the reaction is complete after about 1-4 hours. Higher reaction temperatures and longer reaction times should generally be avoided to minimize the possibility of side reactions. The completion of the reaction is generally monitored by chromatography. The reaction mixture is preferably cooled, neutralized with aqueous base, then separated and dried.

The reduction reaction according to the invention can be carried out easily and economically in a high yield (e.g. 80-100% of the theoretical yield). In contrast to known methods using a strong reducing agent, lithium aluminum hydride, and cumbersome and hazardous reaction conditions, the reduction of the invention can be easily controlled, even when using the method on a large scale.

The amount of acetic acid to be used may be, for example, about 0.1 to 1.0 mole per mole of sodium borohydride. The reaction is conveniently carried out in an inert, aliphatic, chlorinated hydrocarbon solvent having a reflux temperature above 60 ° C, preferably dichloroethane. The reaction temperature is preferably the reflux temperature of the reaction mixture. It may be dangerous to start the reaction at temperatures below 60 ° C.

5,67536

The reaction is carried out, for example, by maintaining the initial reaction mixture containing all of the amount of sodium borohydride and a portion of the acetic acid and the compound of formula III at reflux temperature. The remainder of the compound of formula III and acetic acid in dichloroethane are then gradually added. The amount of acetic acid may, for example, be less than 0.2 moles per mole of sodium borohydride. The amount of sodium borohydride is preferably about 1.5 moles per mole of the compound of formula III. The reaction may be carried out in an inert atmosphere, for example nitrogen, as a precaution and also to minimize the possibility of side reactions, although this is generally not necessary.

Upon completion of the reaction (usually indicated by chromatography), the mixture is gradually added, initially carefully, to water, then basified and refluxed to destroy any remaining sodium borohydride and neutralize the acetic acid. The product can then be isolated or, alternatively, the organic layer containing the product can be separated and further used to prepare the pharmaceutically active phenylbenz (f) -2,5-oxazokine.

The following examples further illustrate the method of the invention. Example 2 shows the preparation of a starting material of formula III.

Example 1

The following is a 5-step synthetic chain starting from commercially available materials and ending with the pharmaceutically active phenylbenz (f) -2,5-oxazokine.

Step 4 comprises the method according to the invention.

Step 1 - Preparation of acid chloride

To a solution of o-benzoylbenzoic acid (222.2 g, 1.0 mol) in dichloroethane (230 mL) is carefully added phosphorus trichloride (35.4 mL, 0.46 mol) in one portion. After stirring for one hour, the temperature has reached a maximum of 39 ° C. Stirring at room temperature is continued overnight, after which thin layer chromatographic examination showed complete conversion to the acid chloride. The product layer is separated by decantation.

Step 2 - Amide formation

To a solution of triethylamine (111.39 g, 1.1 mol) and N-methylethanol-6,67536 amine (82.62 g, 1.1 mol) in dichloroethane (400 ml) is added dropwise a solution of the acid chloride-dichloroethane from step 1 over 5 hours. At -12 ° C. After the addition was complete, the reaction mixture was stirred for an additional 1 hour, after which time analysis by thin layer chromatography showed complete conversion to N- (2-hydroxyethyl) -N-methyl-o-benzoylbenzamide.

Step 3 - Preparation of N- (2-chloroethyl) -N-methyl-o-benzoylbenzamide

Phosphorus trichloride (35.4 mL, 0.0406 mol) is added to the slurry of the product from Step 2 at room temperature over 5 minutes. This causes a temperature rise of 20 ° C and the sludge thins considerably. Upon heating to 55-60 ° C and maintaining this temperature for one hour, thin layer chromatographic analysis showed complete conversion to the desired product. The reaction mixture is cooled to 0 ° C and diluted with water (500 mL) over 5 minutes, keeping the temperature below 5 ° C. The biphasic mixture is stirred for 5 minutes and the phases are allowed to separate. The lower organic phase is washed with water (500 ml) and a sufficient amount of base (sodium hydroxide) is added to raise the pH to about 7 at a temperature below 10 ° C and the lower layer is dried over anhydrous sodium sulfate (90 g).

Step 4 - Reduction

To a slurry containing a portion of the solution from Step 3 (108 mL) and sodium borohydride (28.4 g, 0.75 mol) is added dropwise acetic acid (3.5 mL). At the end of the foaming and heat generation, the temperature is raised to reflux temperature and held for 15 minutes. To this refluxing slurry is added dropwise with stirring over 2 hours the remainder of the product solution from step 3 containing 9 ml of acetic acid. The temperature is maintained at reflux temperature by heating the cooking vessel slightly, as the addition itself is slightly exothermic. At the end of the addition, the reaction mixture is refluxed with stirring for another hour, after which thin layer chromatographic analysis showed complete conversion to the desired product. This treatment is carried out in its entirety under a nitrogen atmosphere.

200 ml of water are added dropwise to the above slurry at room temperature over one hour (initially relatively slowly).

Il 7 67536

The addition causes a relatively strong effervescence and the temperature rises to 45 ° C. To the above diluted reaction mixture is added 40% aqueous sodium hydroxide solution (75 ml). The temperature is raised to reflux temperature and held for 3 quarters. The mixture is then cooled and the layers separated to give a solution of 2- [β- (2-hydroxyethyl) -N-methylaminomethyl] benzene in dichloroethane.

Step 5 - cyclization

The benzhydrol obtained from step 4 (stable in dichloroethane solution) is cyclized with aqueous hydrobromic acid using the method disclosed in U.S. Patent 3,978,085. The reaction gives 131.5 g of 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz (f) -2,5-oxazokine, m.p. 259-261 ° C. Melting point, thin layer chromatographic analysis and infrared spectral analysis all indicated that the product was pure.

The total yield of the five steps (starting from o-benzoylbenzoic acid) was 60-65% of theory.

Example 2

A mixture of N- (2-hydroxyethyl) -N-methyl-o-benzoylbenzamide (56.66 g, 200 moles), toluene (10 liters) and phosphorus trichloride (10.07 kg, 10% excess) was heated gently until the exothermic reaction resulted in the formation of a warm melt at 77 ° C. After half an hour from 75 to 77 ° C, thin layer chromatography analysis showed the N- (2-chloroethyl) -N-methyl-o-bentsoyylibentsamidin complete formation. Isopropanol (90 L) was added rapidly and the mixture was rapidly cooled, seeded and cooled below 0 ° C. The product was collected, washed with cold isopropanol (2 x 10 liters) and dried to give 50.6 kg (83.3%) of product, mp 85.5-86.2 ° C.

Example 3

A solution of 144 kg of N- (2-chloroethyl) -N-methyl-o-benzoylbenzamide (481 moles) in 378 kg of dichloroethane was prepared. A mixture of 50 kg of this solution, sodium borohydride (273 kg, 721.5 moles, 1.5 equivalents) and dichloroethane (120 liters) was treated at 46 ° C with acetic acid (0.5 kg). The temperature gradually rose to reflux temperature, 86 ° C. The remainder of the dichloroethane solution was added slowly, keeping the exo-thermal of the mixture at reflux temperature without heating during the addition and for two hours after the addition. Thin layer chromatographic analysis was used to determine the complete reaction (if the reaction had proved incomplete, it would have been advantageous to add a little more sodium borohydride to the mixture). The complex was then decomposed by the careful and slow addition of 100 liters of water at reflux temperature and then 50 liters of 40% by weight aqueous sodium hydroxide solution to give 2- [β- (2-hydroxyethyl) -N-methylaminomethyl / benzhydrol in dichloroethane. The dichloroethane solution of benzhydrol was washed with water to pH 8, followed by cyclization to form 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz (f) -2,5-oxazokine as follows:

The organic phase was separated and cooled to 20 ° C. Was added 48-50% HBr (224 kg, 149.2 liters) with stirring under cooling to maintain the temperature for half an hour at 50 ° C, below. The mixture was carefully warmed to reflux, refluxed for 2 1/2 hours, cooled to room temperature and then to 0 ° C. The product was recovered by centrifugation, also dried by centrifugation, washed with a total of 110 liters of acetone and dried again by centrifugation. The wet product was again placed in a clean cooking vessel to which toluene (248.8 liters), tap water (110.4 liters) and sodium borohydroxide beads (20-4 kg) had been added and the mixture was stirred with heating to 60 ° C and stirring was continued for 1/2 hours at 60 ° C and the mixture was allowed to stand for 1/2 hour to separate. The lower aqueous alkaline layer was drained and the toluene layer was washed with tap water (2 x 56 liters) at 60-70 ° C to pH 7. The toluene was removed under reduced pressure and the residue was cooled to room temperature and then diluted with acetone (220 liters). The solution was clarified by passing it through a batch filter into a clean cooking vessel. To the stirred, water-cooled, clear acetone solution was slowly added hydrochloric acid (30.02 kg, 31.88 liters) over 1/2 to 1 hour (to pH 1); the resulting slurry was stirred and cooled to room temperature and then to 0 ° C. The product was collected by centrifugation, washed well with acetone (110 liters in total) and dried by suction and then in a vacuum oven overnight at 9,67536 at 50-60 ° C.

Other substituted 2- [N- (2-hydroxymethyl) -N-alkylaminomethyl] benzhydrolols which can be prepared in addition to the above examples by the process of the invention are shown in Table 1.

10 67536

table 1

Ex. No. Starting material ..... (formula II) Product C γτ-τ \ 4 ° CH ^ - ^ - \ υη3 ^ -CHpNCHpCr S \ 1 0 xNCH-, CH ,, OH CH, | 2 2 3 CH3

Cl Cl 5 / v ^ A ^ ci ίο "J = ° yci

_ "CH0H

[o

V'VC-IiCH2CH2OH \ h2NCH2CH2OH

0 CH 2 CH 3 6 Cl Cl

1 I

Θ Φ

—-- C = O CHOH

O o

C-NCiL / JILOH OH ^ IICH-CH-OH

Il, E E 2, 2 2 o ch3 ch3

II

and 67536

Table 1 continued

Eg, no Starting material (formula II) -

7 f F

CO fo O J ^

C-NCH2CH2OH-CH2NCH2CH2OH

0 CE-5 ch3 a f3 f * ^ο ^ ΓοΊ VV — ch5 T "CH3

_C = 0 -CHOH

o! ^^^ C-NCH2CH2OH ^ ch2nch2ch2oh 0 CH3 ch3 ro

V V

C = O CHOH

CK3Cr ^ C-NCH2CH2 ° H ch ^ O NvCH2MCH2CH2OH

0 CH2CH3 CH2CH3 “Θ. Ψ> i = o -choh 1 °!

O I__C-KCHoCHo0H

V / 'Vi I 1 o fcH. ch, ^ 3

Claims (2)

A process for the preparation of 2- [N- (2-hydroxyethyl) -N-alkylaminomethyl] -benzhydrol derivatives of the formula ίο] -x ^ n I XOH Ym-iQl X CH-N (CH -) - 0H 2j 2 2 R wherein R represents methyl or ethyl, X is fluorine, chlorine, bromine or methyl, Y is fluorine, chlorine, methyl or methoxy and m and n are independently 0, 1 or 2, characterized in that the compound of formula [O) -Xn 111 y — 'qT' '' CN (CH ") - D n 22 wherein D is halogen and X, Y, R, m and n are as defined above, is reduced in an inert solvent with sodium borohydride in the presence of acetic acid, whereby the reduction is carried out by mixing sodium borohydride with a portion of acetic acid and a compound of formula III, after which the remainder of the acetic acid and the compound of formula III are gradually added to the reaction mixture.