JPS6043059B2 - New method for producing benzyl alcohol derivatives - Google Patents

Description

Detailed Description of the Invention The present invention relates to benzyl alcohol derivatives represented by the general formula (wherein R represents a benzyloxy group or a lower alkoxy group, and ring A represents a phenyl group having 1 to 3 methoxy groups) and its acid. Concerning a new method for producing addition salts.

Conventional methods for synthesizing benzyl alcohol derivatives include:
For example, (a) a method of reacting an α-halogenoacetophenone derivative with a phenethylamine derivative to produce an α-phenethylaminomethyl acetophenone derivative, and reducing this with sodium borohydride or catalytic reduction (
Special Publication No. 53-11097 U.S. Patent No. 2900415;
No. 3135797, J. A. C. S. 76,3l49
(1954), U.S. Patent No. 707293, U.S. Patent No. 707
3(1)) (b) A method of reacting the sodium salt of an α-hydroxy-α-sulfoacetophenone derivative with a phenethylamine derivative (Japanese Patent Publication No. 10973/1983) (
c) Many methods are known, including a method of reacting a phenylglyoxal derivative and a phenethylamine derivative in the presence of an alkali metal borohydride (Japanese Patent Publication No. 6657/1983).

However, as a result of various studies, the present inventors have completed an industrially advantageous method for producing the benzyl alcohol derivative [1] using a novel reaction method that is completely different from the conventional method. .

According to the present invention, the target compound [1] can be obtained by reacting the corresponding benzaldehyde derivative [2] with phenylacetic acid halide [3] in the presence of metal cyanide, as shown in the reaction formula below. It can be prepared by preparing the cyanohydrin derivative shown and then reducing it with a reaction product of an alkali metal borohydride and an organic carboxylic acid or with diborane. (However, the symbol X in the above formula
represents a halogen atom, M represents a metal atom, R and ring A have the same meanings as above) In the above general formula [2], examples of the symbol R include methoxy group, ethoxy group, propoxy group, isopropoxy Examples include lower alkoxy groups having 1 to 4 carbon atoms such as n-butoxy groups, isobutoxy groups, and benzyloxy groups, and these lower alkoxy groups or benzyloxy groups are located at the 2nd and 3rd positions on the benzene ring.
It may be substituted at any position from position 4 to position 4.

On the other hand, in general formula [3], examples of ring A include 2-methoxyphenyl group, 3-methoxyphenyl group, 4
- a monomethoxyphenyl group such as a methoxyphenyl group;
2,3-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 2,6-dimethoxyphenyl group,
Dimethoxyphenyl group such as 3,5-dimethoxyphenyl group; or 2,3,4-trimethoxyphenyl group, 3
, 4,5-trimethoxyphenyl group, 2,4,5-trimethoxyphenyl group, etc.
A phenyl group having 1 to 3 methoxy groups can be mentioned, and examples of the symbol X include halogen atoms such as brome and chromium. Hereinafter, the method of the present invention will be explained in detail according to the above reaction formula.

[2]+[3]→[4] The reaction between the above raw material compounds [2] and [3] is preferably carried out in an appropriate solvent in the presence of metal cyanide.

Examples of metal cyanides include alkali metal cyanides such as potassium cyanide and sodium cyanide, copper cyanide,
Transition metal cyanide such as zinc cyanide can be suitably used. As the reaction solvent, for example, polar aprotic solvents such as acetonitrile, dimethylformamide, hexamethylene phosphoric triamide, etc. can be used as appropriate. The reaction proceeds suitably at around -10°C to 30°C. j[4]→[5]→[1] Compound [4] thus produced can be isolated and purified, or can be subjected to the reduction reaction as a crude product without being isolated and purified.

That is, the reduction reaction of compound [4] is preferably carried out in a suitable solvent in the presence of a reaction product of an alkali metal borohydride and an organic carboxylic acid or diborane. The reaction product of the alkali metal borohydride and the organic carboxylic acid used in this reduction reaction has 1 to 4 carbon atoms per mole of the alkali metal borohydride, such as potassium borohydride and sodium borohydride. lower fatty acids (e.g. acetic acid, propionic acid, etc.), benzoic acid to halogenoacetic acid (
For example, it is easily prepared by reacting 1 to 3 molar equivalents of an organic acid such as monofluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, trichloroacetic acid, etc. at room temperature according to the method of JP-A-521-36606. In this reduction reaction, reaction products of halogenated acetic acids and sodium borohydride, such as monofluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, and trichloroacetic acid, can be particularly preferably used. As the reaction solvent, for example, ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc. can be used as appropriate.
The reaction proceeds particularly preferably at around 20°C to 100°C. Target compound [1] is produced via intermediate [5]. Note that this reduction reaction intermediate [5] can be directly isolated by adjusting the amount of the reducing agent used in the reduction reaction or the reaction temperature, for example, by adding the reducing agent to the compound [5] in the solvent. 4] Intermediate [5] can be produced by using 3 to 6 molar equivalents per mole and carrying out the reaction at 25°C or lower. Isolation of the compound is performed by extraction,
This can be carried out by subjecting it to known purification operations such as column chromatography and recrystallization. Moreover, this compound [5] can be easily induced to the target compound [1] by reacting under the same reduction reaction conditions as described above.
The target compound [1] thus produced can be easily isolated by appropriately subjecting it to known purification operations such as extraction, washing, concentration, and recrystallization. The target compound [1] thus obtained is subjected to a salt formation reaction in a conventional manner or further subjected to a salt exchange reaction to form a pharmacologically acceptable compound such as a hydrochloride, phosphate, nitrate, sulfate, Inorganic acid addition salts such as acetate, lactate, citrate, fumarate, maleate, oxalate, aspartate, methanesulfonate, benzoate, glycine salt, etc. can be converted to .

According to the method of the present invention, the desired benzyl alcohol [1
] can be synthesized in high yield by using an inexpensive benzaldehyde derivative [2] as a starting material in just two steps, and there is no need to isolate the intermediate purified product, so it is practically It is industrially very advantageous because it can be synthesized even by a one-step reaction.

Note that all of the target compounds represented by the general formula [1] obtained by the method of the present invention are useful pharmaceutical compounds as hypoglycemic agents, and in particular, among these compounds, ring A is a monomethoxyphenyl group or a trimethoxyphenyl group. The compound has the above-mentioned hypoglycemic effect and also has a platelet aggregation inhibiting effect, making it more desirable as a therapeutic agent for diabetes.

Example 1 To a solution of 2.12y of 2-benzyloxybenzaldehyde in 15ml of acetonitrile, 1.0ml of sodium cyanide was added.
Add y under stirring at room temperature.

After stirring at the same temperature for 30 minutes, 2.12y of 3,4-dimethoxyphenylacetic acid chloride and 1 acetonitrile were added.
Add 5 ml of solution dropwise over 45 minutes. After the dropwise addition, the reaction solution was stirred at room temperature for 17 hours, poured into ice water, and extracted with ethyl acetate. The extract was washed successively with water, diluted hydrochloric acid, and saturated brine, dried, and the solvent was distilled off to obtain crude α-(3,4-dimethoxyphenylacetyloxy)-2-benzyloxybenzylnitrile 4 as an oil. Get .0y. Sodium borohydride 3.86y
was suspended in 40 ml of tetrahydrofuran, and 20 ml of tetrahydrofuran containing 11.4 f of trifluoroacetic acid was added under ice cooling.
Add solution dropwise. After stirring at room temperature, a solution of 4.0 d of the above crude α-(3,4-dimethoxyphenylacetyloxy)-2-benzyloxybenzylnitrile in 30 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 3 hours. , stir under reflux for 6 hours. 4m of water in the reaction solution
After cooling with ice, the mixture was poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off, the resulting residue is dissolved in methanol, and 4 ml of 30% hydrochloric acid and methanol are added to this solution. Pour this solution into ice water and
Wash with ether. The aqueous layer is separated, made alkaline by adding potassium carbonate, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off and the resulting residue is crystallized with ether to obtain 2.63y of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol. . Yield 64.6y (total yield from 2-benzyloxybenzaldehyde) M. P
．． 95-9rC hydrochloride: M. p. l59℃～160℃(
Recrystallization from ethanol) Example 2 To a solution of 3.2 f of 4-pendioxybenzaldehyde in 20 mL of acetonitrile, 1.5 y of sodium cyanide and 3.0 y of sodium acid sulfite are added at room temperature with stirring.

After stirring at the same temperature, add 20ml of acetonitrile containing 3.3y of 3,4-dimethoxyphenylacetic acid chloride.
The solution is added dropwise over a period of 5 hours. Thereafter, the same procedure as in Example 1 was carried out to obtain 6.0V of crude α-(3,4-dimethoxyphenylacetyloxy)-4-benzyloxybenzylnitrile as an oil. Sodium borohydride6.
0 da was suspended in 65 ml of tetrahydrofuran, and 17.7 y of trifluoroacetic acid was added dropwise.

After stirring this solution at room temperature for 3 hours, the above crude α
-(3,4-dimethoxyphenylacetyloxy)-4
A solution of 6.0 y of -benzyloxybenzyl nitrile in 40 ml of tetrahydrofuran is added dropwise, stirred at room temperature for 3 hours, and then refluxed for 6 hours. Thereafter, α-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol 4.1y was obtained by the same treatment as in Example 1. Yield 67.4y (total yield from 4-benzyloxybenzaldehyde) M. p. lO8kiC
Hydrochloride: M. p. l68℃~170)C (ethanol/
Recrystallization from isopropyl ether) Example 3 In Example 1, 3-benzyloxybenzaldehyde was used instead of 2-benzyloxybenzaldehyde, and the same treatment as in Example 1 was performed to obtain α-(3,
4-dimethoxyphenethylaminomethyl)-3-benzyloxybenzyl alcohol is obtained.

Hydrochloride: M. p. 127°C to 1310°C (recrystallized from isopropanol ether) Colorless needle crystals Example 4 In Example 1, 3-methoxyphenylacetic acid chloride was used instead of 3,4-dimethoxyphenylacetic acid chloride, and the following Example 1 and By processing in the same way, α1(3
-methoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol is obtained.

M. p. 87C-83 diC 112 oxalate: M. p. l42nC~145
(Recrystallization from ethanol) Example 5 α-( 2
-methoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol is obtained.

M. p. 99 Hydrochloride: M. p. 134°C to 135°C (ethanol/
(Recrystallization from ether) Example 6 In Example 1, 4-methoxyphenylacetic acid chloride was used in place of 3,4-dimethoxyphenylacetic acid chloride, and the same procedure as in Example 1 was carried out to obtain α-(
4-methoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol is obtained.

Hydrochloride: M. p. 146℃~14TC (Recrystallized from ethanol) Example 7 The same procedure as in Example 1 was repeated except that 2,3,4-trimethoxyphenylacetic acid chloride was used instead of 3,4-dimethoxyphenylacetic acid chloride. By treatment, α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol is obtained.

M. p. 8OOC~82c Hydrochloride: M. p. l29°C-130°C (ethanol/
(Recrystallization from a mixture of ether) Example 8 In Example 1, 2-methoxybenzaldehyde was used in place of 2-benzyloxybenzaldehyde, and 2-methoxyphenylacetic acid chloride was used in place of 3,4-dimethoxyphenylacetic acid chloride. , and then treated in the same manner as in Example 1 to obtain α-(2-methoxyphenethylaminomethyl)-2-methoxybenzyl alcohol.

Hydrochloride: M. p. 18lC~182℃ (ethanol/
Recrystallization from ether) Example 9 In Example 1, 2-methoxybenzaldehyde was replaced with 2-benzyloxybenzaldehyde, and 3,4
Example 1 below using 3-methoxyphenylacetic acid chloride in place of -dimethoxyphenylacetic acid chloride.
By treating in the same manner as above, α-(3-methoxyphenethylaminomethyl)-2-methoxybenzyl alcohol is obtained.

Hydrochloride: M. P. l4rC~148lC (ethanol/
(Recrystallization from ether) Example 10 In Example 1, 2-methoxybenzaldehyde was replaced with 2-benzyloxybenzaldehyde, and 3,4
4-methoxyphenylacetic acid chloride was used in place of -dimethoxyphenylacetic acid chloride, and the following Example 1 was prepared.
By treating in the same manner as above, α-(4-methoxyphenethylaminomethyl)-2-methoxybenzyl alcohol is obtained.

Hydrochloride: M. p. l54°C - 15C (decomposition) (recrystallized from ethanol and ether) Example 11 In Example 1, 2-ethoxybenzaldehyde was used instead of 2-benzyloxybenzaldehyde, and 3,4
4-methoxyphenylacetic acid chloride was used in place of -dimethoxyphenylacetic acid chloride, and the following Example 1 was prepared.
By treating in the same manner as above, α-(4-methoxyphenethylaminomethyl)-2-ethoxybenzyl alcohol is obtained.

Hydrochloride: M. p. 139'C to 140°C (recrystallized from ethanol) Example 12 In Example 1, 2-n-butoxybenzaldehyde was replaced with 2-benzyloxybenzaldehyde, and 3,
By using 4-methoxyphenylacetic acid chloride instead of 4-dimethoxyphenylacetic acid chloride and treating in the same manner as in Example 1, α-(4-methoxyphenethylaminomethyl)-2-n●butoxybenzyl alcohol is obtained. .

Hydrochloride: M. p. ll8℃～119℃(Ethanol・
(Recrystallization from ether) Example 13 α-(3,4-dimethoxyphenethylamino methyl)-2-methoxybenzyl alcohol is obtained.

M. p. 9l-C~92beC Hydrochloride: M. p.

147C to 143C (recrystallized from ethanol and ether) Example 14 By using 2-ethoxybenzaldehyde in place of 2-benzyloxybenzaldehyde in Example 1 and treating in the same manner as in Example 1, α-( 3,4-dimethoxyphenethylaminomethyl)-2-ethoxybenzyl alcohol is obtained.

Hydrochloride: M. p. 169beC to 170coC (recrystallized from isopropanol ether) Example 15 In Example 1, 4-ethoxybenzaldehyde was used instead of 2-benzyloxybenzaldehyde, and the following treatment was carried out in the same manner as in Example 1. , α-(3,4-
Dimethoxyphenethylaminomethyl)-4-ethoxybenzyl alcohol is obtained.

Hydrochloride: M. p. l46℃~148℃ (ethanol/
(Recrystallization from a mixture of acetone and ether) Example 16 3
,,4-dimethoxyphenethylaminomethyl)-2-n
・Obtain butoxybenzyl alcohol.

Hydrochloride: M. p. 128°C to 129°C (recrystallized from ethanol/ether) Example 17 α-( A solution of 0.2 q of 3,4-dimethoxyphenylacetyloxy)-2-benzyloxybenzylnitrile in 5 TIL of tetrahydrofuran is added dropwise, and the mixture is stirred at room temperature for 3 hours and then under reflux for 3 hours.

After the reaction solution was cooled, it was poured into ice water and extracted with methylene chloride. The extract was made acidic with hydrochloric acid and ether, and then allowed to stand for 3 minutes. After standing, the mixture is washed successively with water, a 10% aqueous potassium carbonate solution, and water, dried, and the solvent is distilled off. The resulting candy-like residue is purified using a silica gel column. (column solvent;
Crystallization from chloroformimethanol (30:1) ether yields α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol 0.6
Get 2y. M. p. 95 to C to 97oC Example 18 (1) 1.51y of sodium borohydride is suspended in 20ml of tetrahydrofuran, and a solution of 4.56y of trifluoroacetic acid in 10ml of tetrahydrofuran is added dropwise under ice cooling.

After stirring this solution at room temperature, α-(3,4-dimethoxyphenylacetyloxy)-2-benzyloxybenzyl nitrile obtained in the same manner as in Example 13.
A solution of 34y in 20 ml of tetrahydrofuran was added dropwise and stirred at room temperature for 5 hours. After cooling the reaction solution, it was poured into ice water and extracted with ethyl acetate. The extract is washed with water, dried, and then the solvent is distilled off. The resulting residue is dissolved in methanol, acidified with methanol chloride, and left to stand for 3 minutes. After standing, the solvent was distilled off and the resulting residue was dissolved in ethyl acetate, water,
After sequentially washing with a 10% aqueous potassium carbonate solution and water and drying, the solvent was distilled off and the resulting oil was purified using an alumina column. (Column solvent: benzene-chloroform) α
-(3,4-dimethoxyphenylacetamidomethyl)-
1.96 g of 2-benzyloxybenzyl alcohol is obtained. M. p. 99.51C to 100.5°C (recrystallized from a mixed solvent of ethyl acetate and n-hexane) (2) 0.38y of sodium borohydride was dissolved in 5m of tetrahydrofuran.
1, and a solution of 1.14 y of trifluoroacetic acid in 3Tn of tetrahydrofuran is added dropwise under ice-cooling.

After stirring at room temperature, the α-
(3,4-dimethoxyphenylacetamidomethyl)-2
-Benzyloxybenzyl alcohol 0. 5 ml of another solution of tetrahydrofuran was added dropwise, stirred at room temperature for 1 hour, and then refluxed for 6 hours while stirring. Example 1 below
By treating in the same manner as above, 0.60 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol is obtained. Yield 74.0%. M.
p. 95% C to 97 C0υ Example 19 1) α-(3,4-dimethoxyphenylacetamidomethyl)-2-benzyloxybenzyl alcohol 0.84y obtained in Example 18 (1) 3 in tetrahydrofuran
ml solution is added dropwise into 10 ml of a 1M solution of diborane (B2H6) in tetrahydrofuran under a nitrogen stream.

After stirring at room temperature for 1 hour, the mixture was refluxed for 3 hours while stirring. Hereinafter, by processing in the same manner as in Example 17, α
-(3,4-dimethoxyphenethylaminomethyl)-2
-0.58y of benzyloxybenzyl alcohol is obtained. Yield 71.4%. M. p. 95. C~97°C.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R represents a benzyloxy group or a lower alkoxy group, and ring A represents a phenyl group having 1 to 3 methoxy groups. ) is reduced with a reaction product of an alkali metal borohydride and an organic carboxylic acid or with diborane, and if necessary, the reduced reaction product is further converted into an acid addition salt thereof. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R and ring A have the same meanings as above) Production method 2 of benzyl alcohol derivatives or acid addition salts thereof General formula ▲ Numerical formulas, chemical formulas, tables, etc. etc. ▼ (However, R represents a benzyloxy group or a lower alkoxy group, and ring A represents a phenyl group having 1 to 3 methoxy groups) is combined with an alkali metal borohydride. General formulas that are characterized by reduction with a reaction product with an organic carboxylic acid or diborane, and if necessary, further converting the reduction reaction product into its acid addition salt ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, , R and ring A have the same meanings as above) Production method 3 of benzyl alcohol derivatives or acid addition salts thereof General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (However, R is benzyloxy group or lower alkoxy There are benzaldehyde derivatives represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (where X represents a halogen atom and ring A represents a phenyl group having 1 to 3 methoxy groups). A cyanohydrin derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R and ring A have the same meanings as above) is obtained by reacting the shown phenylacetic acid halide derivative in the presence of metal cyanide. and then reducing it with a reaction product of an alkali metal borohydride and an organic carboxylic acid or diborane, and if necessary, further converting the reduction reaction product into its acid addition salt. A method for producing a benzyl alcohol derivative or its acid addition salt represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R and ring A have the same meanings as above).