JPS5839145B2 - 2↓-[N↓-(2↓-hydroxyethyl)↓-N↓-lower alkylaminomethyl]↓-benzhydrol production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 2-(N-(2-hydroxyethyl)N-methylaminomethyl]-benzhytrol (I).

The benzhitrol product according to the method of the invention is a valuable physiologically active substance, the corresponding phenylbenzyl (
f) Can be directly converted to -2,5-oxazosine.

See US Pat. No. 3,830,803, US Pat. No. 3,978,085, British Patent No. 1,148,717, and Canadian Patent No. 8,633,49.

It has been known that the following (■) type compounds can be directly produced from (n) type compounds.

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 (eg GB 1 148 717).
(see specification).

However, reduction with lithium aluminum hydride is not a practical synthetic method for large-scale reactions on an industrial basis.

The solvents to be used are flammable, the lithium aluminum hydride itself is extremely dangerous, and its price is prohibitively high.

On the other hand, the method of the invention may be industrially feasible and advantageous.

They use less hazardous solvents, can be considerably less expensive, and can produce products of excellent purity in high yields.

The present invention relates to 2-CN-(2-
Provided is a method for producing (hydroxyethyl)-N-methylaminomethyliobenzhydrol, which method comprises adding a compound of the general formula (wherein the formula is a halogen) to an alkanoic acid in an inert solvent. consisting of reduction with sodium borohydride in the presence of sodium borohydride.

Preferably, the compound of general formula (m) is obtained by treating a compound of general formula with a logogenating agent in an inert solvent.

The reduction of the following types of amides to amines with sodium borohydride in the presence of an alkanoic acid is performed using sodium acyloxyborohydride as reducing agents.
ide as New Reducing Agent
s) “(Tetrahedron Letters A, 10 No. 7
63-766) and Reduction of A
m1des with Sodium Borohydr
ide “(Pentron alembic CVentron
Alembic) Isshu end, pages 6-7 of 9), this is the no. of our general formula (III).
This appears to be different from the reduction of rogogenated compounds.

That is, the reductions described in the prior art require large excesses of sodium borohydride, with loss of efficiency due to H20 evolution and possibly amine-borane formation, and the reductions can be carried out as described above by the alkyloxyborohydride method. proceed.

On the other hand, the reduction of the present invention proceeds readily with much smaller excesses of sodium borohydride in a wide range of solvents;
The presence of halogen D is essential, without which the reaction will fail, and in a preferred procedure the compound of general formula (I[) and the alkanoic acid are added gradually into the reaction mixture containing all of the sodium borohydride. However, there is no H2 evolution after the initial small amount of acid addition.

The product (I) is usually recovered from the reaction mixture by the method of aqueous mixing in solution in an inert solvent.

It can be obtained as a pure substance by removing the solvent by conventional methods, or the solution can be used directly, for example in the preparation of physiologically active phenylbenzo(f)2.5-oxazosine.

The starting materials (n) for the process of the invention are generally known in the art (see the British and Japanese patents mentioned above).

The first (logenation) step of the process is carried out in an inert solvent, such as a chlorinated hydrocarbon, such as dichloromethane or dichloroethane, or an aromatic hydrocarbon, such as toluene, benzene, etc.

A preferred solvent is dichloroethane. Suitable halogenating agents include phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, and thionyl chloride.

Phosphorous trichloride is currently preferred due to its relatively low cost.

Generally, an equivalent amount or a small excess of up to about 10% halogenating agent is used.

The required temperature may be e.g. 20-90°C depending on time constraints.
This is a medium-sized one.

At 55-80°C, the reaction is complete in about 1 to about 4 hours.

Excessive reaction temperatures and reaction times should be avoided to minimize the possibility of side reactions.

This reaction is generally monitored by chromatography.

Preferably, the reaction mixture is cooled, neutralized with an aqueous base solution, separated and dried.

This reduction reaction is easily and economically performed, with high yields (
For example, 80 to 100% of the theoretical amount) can be obtained.

Unlike the prior art, which uses the strong reducing agent lithium aluminum hydride and difficult and dangerous reaction conditions, the reduction process of the present invention can be easily controlled even when carried out on a large scale.

This reaction is carried out in the presence of an alkanoic acid, preferably a lower alkanoic acid containing up to 4 carbon atoms, such as acetic acid.

If this acid is omitted, little or no desired product is obtained.

The amount of alkanoic acid used may be, for example, from about 0.1 to about 1.0 moles per mole of sodium borohydride.

This reduction is suitably carried out in an inert aliphatic chlorinated hydrocarbon solvent with a reflux temperature above 60°C, preferably dichloroethane.

The reaction temperature is preferably the reduction temperature of the reaction mixture.

Starting the reaction at temperatures below 60°C can be dangerous.

This reduction combines acetic acid with sodium borohydride in dichloroethane and the precursor N-(2-haloethyl)N-methyl-
It can be carried out by adding to a mixture of 0-benzoylbenzamide (n).

Although this reaction is controllable, it is usually highly exothermic.

Alternatively (and preferably for large scale reactions) the reaction is initiated on a relatively small scale where all reaction components are present.

This initial reaction mixture, which contains the entire amount of sodium borohydride to be used in the large-scale reaction, is kept heated to reflux.

The remaining dichloroethane solution of precursor (III) and the alkanoic acid are slowly added together.

Using this alternative, less alkanoic acid is required (eg, less than 0.2 moles per mole of sodium borohydride).

Furthermore, the use of smaller amounts of sodium borohydride is also possible; for example, currently 1 mole per m as compared to the 2.0 mole per mole (m) used without this preferred method. It is preferred to use about 1.5 moles per (■).

This reaction may be carried out under an inert (eg nitrogen) atmosphere, although this is generally not necessary, as a safety measure and to minimize the possibility of side reactions.

After this reduction is complete (conveniently indicated by chromatographic analysis), the mixture is added gradually (cautiously at first) to water, then made basic and heated to reflux (to remove any remaining sodium borohydride). to destroy and neutralize alkanoic acids).

The product can then be isolated, or the organic layer containing the product separated and used in subsequent reactions to provide the pharmaceutically active phenylbenz(f)-2,5-oxazosine.

The following illustrative examples are presented to demonstrate how to practice the method of the invention.

Example 2 just illustrates the preparation of starting compound (m).

Example 1 A complete five-step synthetic route starting from commercially available materials and ending with pharmaceutically active phenylbenz(f)-2,5-oxazosine.

Steps (3) and (4) of this example illustrate the preferred method of the present invention as part of the sequence.

Step (1) - Preparation of acid chloride Phosphorus trichloride (35.4 ml, 0.46 mol) was added in one portion to a slurry of ortho-benzoylbenzoic acid (222,2P, 10 mol) in dichloroethane (230 m7). .

After stirring for one hour, the temperature reached a maximum of 39°C.

Stirring at room temperature was continued overnight and subsequent thin layer chromatography showed complete conversion to the acid chloride.

The product layer was separated by decantation.

Step (2) - Amide Formation Triethylamine in dichloroethane (400ml) (
A dichloroethane solution of the acid chloride from step (1) was added to a solution of 111,39S' (1.1 mol) and N-methylethanolamine (82,62P, 1.1 mol) at 5 to 12°C for 1 hour. and added dropwise.

After the addition was complete, the reaction mixture was stirred for an additional hour.
Thin layer chromatography analysis showed that complete conversion to N-(2-hydroxyethyl)-N-methyl-O-benzoylbenzamide had taken place by this time.

Step (3) -N-(2-chloroethyl)-N-methyl-
Phosphorus trichloride (35.4 ml:0.40
6 mol) was added.

This resulted in a 20°C temperature increase and made the slurry considerably thinner.

After warming to 55-60°C and holding at this temperature for 1 hour, thin layer chromatography analysis showed complete conversion to the desired product.

The reaction mixture was cooled to 0°C and diluted with water (500 yd) for 5 minutes keeping the temperature below 5°C.

The two-phase mixture was stirred for 5 minutes and the layers were separated.

The bottom organic layer is further diluted with water at a pH of 500 - below 10°C.
was washed with an amount of base (sodium hydroxide) to bring the volume up to ca. 7 and the bottom layer was dried over anhydrous sodium sulfate (91).

Step (4) - 180 TrL of a solution of N-(2-chloroethyl)N-methyl-0-benzoylbenzamide in reduced dichloroethane
Acetic acid (3.5 ml) was added warm to a slurry of 1.1 and sodium borohydride (28.4 f?, 0.75 mol).

After foaming and heat generation had finished, the temperature was raised to reflux temperature and kept for 15 minutes.

The remainder of the solution of the product of step (3) containing 9 TLl of acetic acid was added dropwise to this slurry heated to reflux with stirring over a period of 2 hours.

Although the temperature was maintained at reflux while gently warming the flask, the addition itself was quite exothermic.

After the addition was complete, the reaction mixture was stirred under reflux for an additional hour, at which time thin layer chromatography analysis showed complete conversion to the desired product.

This entire operation was carried out under a nitrogen atmosphere. 200 TLl of water was added warmly (very slowly at first) to the above slurry over a period of 1 hour at room temperature.

This addition resulted in fairly vigorous foaming and the temperature was 4.
The temperature rose to 5°C.

A 40% aqueous sodium hydroxide solution (75 m7) was added to the above diluted reaction mixture.

The temperature was increased to reflux and held for 45 minutes.

The mixture is then cooled and the layers separated to give 2-(N
A dichloroethane solution of -(2-hydroxyethyl)-N-methylamine methyl]benzhytrol was obtained.

Step (5) - Cyclization The benzhydrol (still in dichloroethane solution) from step (4) was cyclized using aqueous hydrobromic acid by the method of US Pat. No. 3,978,085.

This reaction resulted in 131.5S' 5-methyl-1-phenylate 3,4,6-tetrahydro-5H-benz (f
)-2,5-oxazosine hydrobromide, melting point 259~
A temperature of 261°C was obtained.

Its melting point, thin layer chromatography analysis and infrared spectroscopy all indicate pure product.

The overall yield of the five steps (starting from orthobenzoylbenzoic acid) was 60-65% of theory.

Example 2 N-(2-hydroxyethyl)-N-methyl O-benzoylbenzamide (56,66 kg, 200 mol), toluene (10 liters) and phosphorus trichloride (10,07 k
g, 10% excess) was gently warmed until the exothermic reaction ensured the formation of a hot melt at 77°C.

After 0.5 hour at 75-77°C, thin layer chromatography analysis showed complete formation of N(2-chloroethyl)-N-methyl-0-benzoylbenzamide.

Inglopanol (90 liters) was quickly added, the reaction vessel was rapidly cooled, seeded with crystal nuclei, and cooled to below 0°C.

The product was collected, washed with cold impropat tool (2X 10 liters) and dried to yield 50.6 kg (83.3%
) product, melting point 85.5-86.2°C was obtained.

Example 3 144klij of N(
A solution of 2-chloroethyl)-N-methyl-0-penzoylbenzamide (481 mol) was prepared.

50 kg of this solution, sodium borohydride (273
kg, 721.5 mol, 1.5 eq.) and dichloroethane (120 liters) was treated with acetic acid (0.5 kg) at 46°C.

The temperature rose steadily to reflux at 86°C.

The remaining dichloroethane solution was slowly added, and the exotherm kept the mixture at reflux even though no heat was applied during the addition, which was completed 2 hours after the addition.

Thin layer chromatography analysis was used to check the completion of the reaction (if the reaction was found to be incomplete then further addition of a small amount of sodium borohydride could be carried out).

The complex was then heated under reflux temperature by careful slow addition of 100 liters of water and then 40% (W/W) of the next 50 liters.
) separation by addition of aqueous sodium hydroxide solution, 2
-(N-(2-hydroxyethyl)-N-methylaminomethyl]benzhydrol was formed in cyclolethane.

The benzhydrol in dichloroethane was washed with water until pH 8, and then 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz(f) was added to J:5.
)-2.5 oxazosine: The organic phase was separated and cooled to 20°C: stirred for half an hour while cooling and keeping the temperature below 50°C.
~50% (224 kg, 149.2 liters) of hydrogen bromide was added.

The mixture was warmed gently to reflux temperature, heated at reflux for 2.5 hours, cooled to room temperature, then cooled to 0°C.

The product was collected by centrifugation and centrifuged to dry.
ry), washed with a total amount of 110 liters of acetone, and centrifuged again to dry.

The wet product was pre-coated with toluene (242,8 liters),
Returning to a clean container containing tap water (110,4 liters) and granular sodium hydroxide (20,4 kg), the mixture was stirred and heated to 60°C, and the stirring was continued for 1 hour at 60°C.
/2 hours and then left for 1/2 hour to separate.

The lower aqueous alkaline layer is washed away, and the toluene layer is
Washed with 2 x 561 J tttle of tap water at 70°C to pH 7.

The toluene was distilled off under reduced pressure and the remaining oil was cooled to room temperature.
It was then diluted with acetone (220 liters).

The solution was clarified by passing it through a cartridge filter into a clean container.

0.5 to this stirred, water-cooled, clear acetone solution.
Hydrochloric acid (38,02 kg, 31
．． (88 liters) was added (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 thoroughly with acetone (total volume 1101 Jtu), suction dried, and then dried overnight in a vacuum oven at 50-60°C.

Claims (1)

[Claims] 1. A process consisting of reducing a compound of the general formula (wherein R is methyl and -D is a halogen) with sodium borohydride in the presence of an alkane m in an inert solvent, General formula % formula %) Method for producing thylaminomethyl]benzhyttrol. 2. The manufacturing method according to claim 1, wherein the alkanoic acid is acetic acid. 3 D is chlorine, claim 1 or 2
The manufacturing method described in any of paragraphs. 4. The reduction is carried out by mixing the sodium borohydride with a portion of the alkanoic acid and the compound of the general formula (■), and then gradually adding the remaining alkanoic acid and the compound of the general formula (III) to the reaction mixture. A manufacturing method according to any one of claims 1 to 3, which is carried out by: