JPS63238048A - Manufacture of substituted benzaldehydes - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing substituted benzaldehydes and novel compounds for use in the process. In particular, the present invention provides the following steps: a) 4-amino-3,5-dibromobenzaldehyde or its cyclic acetal or oxime is reacted with an alkali metal lower alkoxide in the presence of copper and a protonatable organic solvent to form a reaction product. or b) 4-bromo-2,6-di-(lower alkoxy)-
N,N-dimethylaniline as the metallizing agent and then
The present invention relates to a method for producing 4-dimethylamino-3,5-di(lower alkoxy)benzaldehyde, which comprises reacting with a formylating agent.

Lower alkoxy groups and lower alkanols are preferably straight-chain and have up to 6 carbon atoms. Methoxy is the preferred alkoxy group.

The reaction of 4-amino-3,5-dibromobenzaldehyde or its cyclic acetal or oxime with the alkali metal alcoholate is advantageously carried out at elevated temperature, preferably at a temperature of about 80°C. The alkali metal alcoholate is advantageously used in excess, for example a 15- to 20-fold molar excess.

Copper can be used as metal powder, but preferably Cu(I) compounds, such as CuO1 or Cu(
I) Using salts, especially halides such as copper(I) iodide.

Cu(I) salts can be used in catalytic amounts, for example amounts of 2-3 mole %, preferably CuO1 is used in equimolar amounts. Possible protonatable organic solvents are in particular dimethylformamide or also nitrogen-containing organic solvents, such as pyridine or collidine.

In a preferred embodiment, a solvent mixture is used that is predominately a solvent such as dimethylformamide. The reaction is preferably carried out using a cyclic acetal of 4-amino-3,5-dibromobenzaldehyde. Examples of such cyclic acetals are ethylene acetal, 2,3-butylene acetal and 2,2-dimethyl-1,3-propylene acetal.

4-(5,5-dimethyl-1,3-dioxan-2-yl)-2,6-dibromoaniline is a preferred starting material.

As methylating agent, reagents such as formaldehyde/formic acid are preferably considered, but it is also possible to use other methylating agents, for example dimethyl sulfate.

As metallizing agents in process b) organolithium compounds, such as lithium alkyls, such as methylLi or butylLi: phenyllithium: or magnesium compounds, come into consideration. Examples of formylating agents are dimethylformamide, orthoformate and N-formylmorpholine. Metalization reaction with lithium or magnesium
This can be carried out under conditions known per se for organic compounds or Grignard compounds. In a preferred embodiment, 4-bromo-2,6-di(lower alkoxy)-
N,N-dimethylaniline in hexane at about -10°C
to react with butyllithium.

Dimethylformamide is the preferred formylating agent.

A further aspect of the invention is 4-amino-3,5-dibromo-benzaldehyde, especially 4-(5,5-dimethyl-1,3
Cyclic acetal of -dioxan-2-yl)-2,6-dibromoaniline and 3,5-dibromo-4-amino-
A process for producing benzaldehyde oxime, the process comprising a cyclic acetal of p-nitrobenzaldehyde, especially 2
-(4-nitrophenyl) -5,5-'; Methyl-1
．． 3-'; oxane, or 4-nitrobenzaldehyde oxime, respectively, as a cyclic acetal of p-aminobenzaldehyde, especially p-(5,5-dimethyl-m-dioxan-2-yl)aniline, or 4-amino-benzaldehyde oxime. or brominating the latter, or reacting p-nitrotoluene with lower alkyl nitrite in the presence of a base to form p-aminobenzaldehyde oxime and brominating this. The reduction of p-nitrobenzaldehyde acetal to p-aminobenzaldehyde acecure or the reduction of 4-nitrobenzaldehyde oxime to p-aminobenzaldehyde oxime is advantageous, for example in the presence of a Pt or Pd catalyst; or by catalytic reduction using Raney nickel. It will be held on. In the case of the reaction of p-nitrotoluene with lower alkyl nitrite, preference is given to using isoamyl nitrite and an alkali metal alcoholate as base, such as sodium ethylate in ethanol. Bromination can be carried out with elemental bromine in the presence of a proton acceptor such as butylene oxide.

A further aspect of the present invention is that 2,6-di-(lower alkoxy)
4-bromo-2,6-di-(lower alkoxy)-N,N consisting of brominating aniline to produce 4-bromo-2.6-di-(lower alkoxy)aniline and methylating the latter. -Relating to a method for producing dimethylaniline. Bromination can be carried out by treatment with elemental bromine in a solvent such as a chlorinated hydrocarbon such as dichloromethane. Methylation can be accomplished by treatment with a methylating agent such as dimethyl sulfate.

The compound obtained in the above reaction, p-(5,5-dimethyl-1,3-dioxan-2-yl)aniline 4-(5,5-dimethyl-1,3-dioxan-2-yl-2,6- Dipromoaniline 4-bromo-2,6-dimethoxyaniline 4-bromo-
2,6-dimethoxy-N,N-dimethylaniline, 4-amino-3,5-dibromobenzaldehyde oxime and 4-amino-3,5-dimethoxybenzaldehyde oxime are new and also for the purposes of the present invention. be.

The 4-dimethylamino 3°5-di-(lower alkoxy)benzaldehyde obtained according to the invention is an intermediate in the preparation of pharmaceutically valuable benzylpyrimidines, for example DE 2.443. 6
See No. 82. The previously known methods for these benzylpyrimidines are uneconomical. The present invention allows the production of these compounds in a substantially cost-effective manner than previously. The process is accomplished by producing the required benzaldehyde derivative as the key intermediate in high yield from inexpensive starting materials using a simple reaction.

The invention will be further illustrated by the following examples. The temperature is 0C.

Example 1 4-nitrobenzaldehyde 7652.2-dimethyl-1,3-propanediol 537.52, p-1-
Luenesulfonic acid hydrate 0.58. ? and toluene 2
The mixture of 530+a1 was heated under reflux for 15 hours until the Hondori 85- was separated and the educt was no longer detectable. The reaction mixture was cooled and washed with 500 mA of water. The aqueous phase was dissolved in tert-butyl methyl ether 150%
0-, and the extract was diluted with saturated aqueous sodium chloride solution 10
Washed with 00+J and dried the organic phase over sodium sulfate. The solvent was distilled off at 50° O/15 mbar and the residual liquid was dried at 50° C. and 10.01 mbar. Melting point 81-8
1195.1 (99%) of beige crystals at 4° C. were obtained. Purity determined by gas chromatography was 98.5%. The crude product was recrystallized from n-hexane as pale yellow crystals with a melting point of 83-85°C, 2-(4-nitrophenyl)-5,5-dimethyl-1,
3-dioxane (1128) (94%) was obtained. Purity determined by gas chromatography was 100%.

Example 2 2-(4-nitrophenyl)-5,5-dimethyl-1
, 3-dioxane 1125JF, platinum supported on carbon 112. ! A mixture consisting of M and tetrahydro7ran 11250- was heated to 10 bar of H! Hydrogenation was carried out under pressure at 25° C. for 8 hours. This batch was processed as follows: All operations were carried out under N, bubbling. The catalyst was separated by filtration on a Dicalite pad, the filtrate was freed from solvent at 60 °C/15 mbar and the residue was dried at 60 °C and 10.1 mbar. Melting point 102-104. p- as beige crystals at °C
(5,5-dimethyl-1,3-dioxan-2-yl)
Aniline 945.21 (96°2%) was obtained.

Example 3 0-5 of bromine 16.789 in dichloromethane 500-
The pre-cooled solution to 1.°C was cooled with ice and stirred.
Within 5 hours, p-(5,
5-dimethyl-1,3-dioxan-2-yl)aniline 10.36. ? and butylene oxide 14.427.

The reaction was completed by stirring overnight at room temperature.

The reaction mixture was sequentially treated with stirring at room temperature with 28% aqueous sodium hydroxide solution 7.5-β and 1
Within 5 minutes, the organic phase was separated and the aqueous phase was treated with dichloromethane (250).
Back extracted twice. The combined organic phase was dissolved in sodium sulfate 302
the solvent was distilled off at 50°C/15 mbar,
The residue was dried at 50° C. and 10.01 mbar. Melting point 1
Beige crystals 17.41 (9
5.3%) was obtained. Purity determined by gas chromatography was 88.3%. The crude product was recrystallized from ethanol, melting point 156-157°C.
4-(5,5-dimethyl-1,3-
dioxan-2-yl)-2,6-dipromoaniline 1
2.81 (70%) was obtained.

Purity determined by gas chromatography is 100
%Met.

Example 4 30% methanolic sodium methylate solution 1235
From a solution of m1 and dimethylformamide 450-, 1
The solvent mixture was heated within 45 minutes at 03-18°C (bath temperature 120-140°C) with stirring and nitrogen bubbling.
was distilled. A white precipitate (Na methylate) formed at the end of the distillation. Temperature 80±2℃ (bath r!1L90~92
C.), the reaction mixture was treated in one portion with 16.62 g of copper iodide (finely ground). 4-(5,5-
dimethyl-1,3-dioxan-2-yl)-2,6-
About 52 portions of 121.61 dibromoaniline were added within 15 minutes. The reaction was continued at 80±2° C. for 3.5 hours with good stirring until starting material was no longer detected. The reaction mixture, cooled to room temperature, was poured into 1050° of water with stirring and cooling and heated to 60° C. for 4 hours.

The mixture cooled to room temperature was mixed with 52% activated carbon and 220% toluene.
Stirred with 0 mN for 15 minutes, filtered with suction over Dicalide. The aqueous phase was extracted twice with 900 g of toluene.

The solvent was distilled off at 10 °C/15 mbar and the residue was heated at 60 °C.
(Dried at !10.1 mbar.Residue (brownish oil 8
7.6. ? ') 98% formic acid 400I and 37-40
89-94°C (with 589% formaldehyde aqueous solution)
The mixture was heated to reflux for 180 minutes at a bath temperature of about 92-102°C. Then 23 mβ of 37% hydrochloric acid was added and the mixture was heated under reflux for a further 2 hours. Formaldehyde and formic acid were removed from the reaction mixture at 55-60°O/15 mbar.

Dilute the residue with 1140 ml of ice water, stir and add 10 to 15 ml of
While cooling to
m1. Extracted three times. The organic phase was washed with 240 °C of saturated aqueous sodium chloride solution, dried over sodium sulfate and diluted with toluene at 60°C/150°O/15 mbar.
Dry at 0°O 10.1 mbar.

67.12 of a yellow oil was obtained as a residue, which was
Distilled under high vacuum on a cm Bigelow column.

At 110-120 DEG C. and 10.1 mbar, 54.49 g of 4-(dimethylamino)-3,5-dimethoxybenzaldehyde was obtained as a pale yellow oil, which crystallized on standing. Purity determined by gas chromatography was 98% (46-47°C).

Example 5 A solution of 78.9'J of bromine in 8Q of dichloromethane was dissolved in 76' of 2,6-dimethoxyaniline in 8Q of dichloromethane.
The reagents were added dropwise at about 1°C to the solution of i at about 1°C, at which time the reagents were first added relatively quickly (750 m2 in 2 hours, and then added slowly to avoid perbromination. After about 6 hours) All reagents have been added. The mixture is then stirred for 25 minutes. The reaction mixture is washed twice with IN sodium hydroxide solution 2Q and sphagnum 1.2512, and the washings are washed twice with dichloromethane 1.2512. The combined organic phases were re-extracted and dried over sodium sulfate.
It was evaporated at C and the residue was dried. 4-Bromo2,6-dimethoxyaniline 114.2 as an amorphous brown mass
．． ? was gotten. Purity determined by gas chromatography was 97%. The crude product was dissolved in toluene 300- and filtered over silica gel 60-12,
It was then purified by elution with toluene 16 (2). The eluent was evaporated at a bath temperature of 80°C and the residue was dried. Melting point 71~
4-Bromo-2 as pale beige crystals with 99% purity as determined by gas chromatography at 73°C.
, 6-dimethoxyaniline 94°42 was obtained.

Example 6 4-Bromo-2,6-dimethoxyaniline 95°22°C was dissolved in 136°C of sodium bicarbonate in 200°C of water with vigorous stirring. ? This suspension was added to a suspension of 100% in a water bath.
Cooled to 0. Dimethyl sulfate 181'j was then added in one portion and the heterogeneous mixture was stirred vigorously for 2.5 hours at 10° C. until gas evolution and educts were no longer detected. The mixture was stirred to room temperature, treated with 90% 25% aqueous ammonia solution and stirred for an additional hour. The reaction mixture was extracted with 360 mA of dichloromethane, the organic phase was treated with 450 mJ2 of hydrochloric acid solution and the aqueous phase was washed with 180 mA of dichloromethane. ~68d of 28% aqueous sodium hydroxide solution was added dropwise to the hydrochloric acidic aqueous phase with stirring and cooling until the pH value reached 8.5 and the product began to crystallize. The suspension was cooled to O'C to complete crystallization. The white crystals were filtered off with suction, washed with 200ml of ice water to neutralize them, and
Dry overnight at 5060 under high vacuum at 50°C/150°O/15 mbar. 4-Bromo-2,6-dimethoxy-N,N- as white crystals with a melting point of 90-91'O
Dimethylaniline too-4,? was gotten. Purity determined by gas chromatography was 100%.

Example 7 4-bromo 2,6-dimethoxy-N,N-dimethylaniline 132 was dissolved in ether 185d under nitrogen.

Butyllithium 501 in hexane was added dropwise to this solution cooled to -10°C within 20 minutes and the resulting white suspension was stirred at -10°C for a further 30 minutes. ether 250m
A solution of 28.62 g of dimethylformamide in A was added dropwise within 1 hour at the same temperature with good internal mixing and the mixture was allowed to react for 4 hours at room temperature. Next, add 202 ml of concentrated hydrochloric acid to the mixture.
and poured onto ice 202 and hydrolyzed for 1 hour with thorough stirring (pH value approximately 1.2). The aqueous phase was heated to 5-10 °C (with cooling with ice) in a 28% sodium hydroxide solution with approx.
A pH value of 8.5 was achieved by addition of a+1. The aqueous phase was extracted with 480 °C of ether; the ether phase was washed with 120 °C of half-saturated sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was evaporated under water pump vacuum at a bath temperature of 50 °C; The residue was dried under high vacuum. 4 as oil
-(Dimethylamino)-3,5-dimethoxybenzaldehyde IO,5jF was obtained, which solidified into yellow crystals in the refrigerator. The purity measured by gas chromatography was 88.5%.

Example 8 4-Amino-benzaldehyde oxime 13°62 was dissolved in 300° of glacial acetic acid with stirring.

Lower the temperature to 0-2°C and add 3 bromine in 100°C of glacial acetic acid.
The solution of 5.21 was added dropwise from the dropping funnel within 20 minutes, ensuring that the temperature did not exceed the 15-20°C range. The reaction mixture was immediately mixed with a l:l mixture of ice/water at 10,100 O!
and stirred for 30 minutes.

Separate the precipitated crystals and make ice water moss 250+sj! , that is,
Total of 500 theories! The mixture was broken down twice and dried by suction.

The crystals were dried to constant weight over potassium hydroxide under vacuum with a water jet overnight at room temperature.
3,5-dibromo-4-aminobenzaldehyde oxime 20:J was obtained as yellowish brown crystals at 145°C. Purity determined by gas chromatography was 83%.

Example 9 30% methanolic sodium methylate solution 1527
- from a mixture of 562 mA of dimethylformamide,
The solvent mixture 810- was distilled off until sodium methylate began to precipitate. Temperature: 80±2°C (bath -82°C
), finely ground copper(I) iodide 21
．． 38. ? was added in one portion, which caused the mixture to turn dark blue and after stirring for 15 minutes, turned purple. A total of 1182 3,5-dibromo-4-aminobenzaldehyde oximes, about 1.52 each, are introduced within 5 minutes;
The mixture was stirred at 80° C. for 2 hours until no educt or monomethoxy intermediate could be detected. The reaction mixture, cooled to 60° C., was added within 15 minutes with 2.5 kg of l:l ice/water, and the mixture was brought to 60° C. and left with stirring for 8 hours. After that, the water-based salt 11 was cooled on ice while stirring the mixture.
000-. 1000 each of toluene for neutral components
1 and twice, ie, a total of 2000. The aqueous-acidic phase is treated with 700 mβ of a 28% aqueous sodium hydroxide solution at room temperature with the addition of ice chips until a pH value of approximately 9-10 is obtained, and the liberated 4-amino-3,5-dimethoxybenzaldehyde oxime is removed with toluene. Extraction was carried out three times at 1000° each, ie a total of 3000°. To remove precipitated components, silica gel 60 209 was added and the mixture was filtered with suction over a Dicalide pad. Aqueous phase transparent orange 2-
The phase was separated from the filtrate. The toluene phase was concentrated at 60° C./15 mbar and the residue was dried to constant weight at 60° C./10.1 mbar. 4-Amino-3,5-dimethoxybenzaldehyde oxime 78 as a brown-yellow solid mass
．． 62 was obtained. Purity determined by gas chromatography was 66.5%.

Example 10 4-Amino-3,5-dimethoxybenzaldehyde oxime (crude product according to Example 9) 78.62 to 98
The mixture was heated under reflux for 2 hours until no more educts were present. Then 31.8 or 35.5 JJ of concentrated hydrochloric acid were introduced and the mixture was heated under reflux for a further 2 hours. Excess formaldehyde solution and formic acid were removed from the reaction mixture, which had been cooled to room temperature, at 55° C./15 mbar. Place the residue in ice water 1
pH at 380I and adding ice strips at room temperature.
Treated with 28% aqueous sodium hydroxide solution 62- until the value reached 8.5. liberated 4-dimethylamino-3,
5-dimethoxybenzaldehyde to toluene 1000 each
3 times with a+1, that is 3000mj! Extracted with. The toluene phase was washed successively with saturated aqueous sodium chloride solution.

Discard the aqueous phase, combine the toluene phase, and add 20% sodium sulfate.
Dry on 07. The desiccant was filtered off with suction, dissolved twice with 100-.beta. of toluene, ie a total of 200, and dried with suction. The filtrate's solvent was distilled off at 60°C/15 mbar and the residue was dried to constant weight at 60°C and 10.1 mbar. 4-Dimethylamino-3,5-dimethoxybenzaldehyde as a yellow-brown oil with a purity of 96% determined by gas chromatography 54.2
1 was obtained.

Example 11 14.37 ml of copper iodide (■) was heated with 370 J of sodium methylate solution (2 mol) under reflux for 10 minutes and N
, 4-(5,
5-dimethyl-1,3-dioxan-2-yl)-2,
It was treated within 10 minutes with a solution of 6-dibromoaniline 36°52. Thereafter, the solvent 175- was distilled off. 80-1
After stirring at 08 °C for 90 min, the reaction mixture was cooled and
Approximately 200 m of methylene chloride in a round bottom flask with a volume of 2Q
1 and concentrated in a rotary evaporator at approximately 6°C/30 mbar. The brown-red solid residue was taken up in 750 mj2 of 3N sodium hydroxide solution and the suspension was stirred under reflux for 60 min, cooled to 60°C and diluted with 30 mj of ethyl acetate.
0-, stirred for 10 minutes and filtered over filter aid. The filtration residue was extracted three times with 100 mL each of ethyl acetate,
The aqueous phase was separated and back-extracted two more times with 100 mN each of ethyl acetate. The organic phase was washed successively with 250 ml of water, dried over 50 ml of magnesium sulfate, filtered, the filtration residue was washed twice with 50 mβ each of ethyl acetate, and the combined filtrate was washed with ca.
concentrated by rotary evaporator at 5°O/30 mbar,
This gave 32.17 g of 4-(5,5-dimethyl-1,3-dioxan-2-yl)-2,6-dimethoxyaniline as crude product. 31.69 of the crude product thus obtained was heated under reflux with stirring with 140 I62 of formic acid and 22.9.9 of formaldehyde solution. The brown solution was cooled to 0°C, washed four times with 100° each of methylene chloride while cooling with ice, the organic extract was extracted twice with 100° each of 3N hydrochloric acid, and the combined aqueous phase was reduced to 0°C.
Sodium hydroxide solution (2
The resulting emulsion was extracted with 550 mg of methylene chloride, and the extract was soaked with 250 l of cold water.
llN, the organic phase was dried over magnesium sulfate 502, filtered on a glass suction filter with silica gel 402, the filter bed was washed 6 times with 50° each of methylene chloride, and the combined filtrates were heated at 30° It was evaporated to constant weight in a rotary evaporator at 30 mbar. 4-Amino-3゜5-dimethoxybenzaldehyde 1 as a pale yellow oil
5.62 was obtained. Add 100% ether each to the filter bed.
The combined filtrates were evaporated to constant weight in a rotary evaporator at 30° O/30 mbar, thus giving a further 1.92 of the reaction product.

shaft

Claims (1)

[Claims] 1, a) 4-amino-3,5-dibromobenzaldehyde or its cyclic acetal or oxime is reacted with an alkali metal lower alkoxide in the presence of copper and a protonatable organic solvent, treating the product with a methylating agent and hydrolyzing the acetal or oxime groups present in the reaction product; or b) 4-bromo-2,6-di(lower alkoxy)-N,
4, characterized in that N-dimethylaniline is reacted with a metallating agent and thereafter with a formylating agent.
-Method for producing dimethylamino-3,5-di(lower alkoxy)benzaldehyde. 2. The method according to claim 1, wherein in a) a Cu(I) salt is used. 4-(5,5-
dimethyl-1,3-dioxan-2-yl)-2,6-
The method according to claim 1, using dibromoaniline. 4. The cyclic acetal of p-nitrobenzaldehyde is
- reduction of aminobenzaldehyde to a cyclic acetal;
The method according to any one of claims 1 to 3, wherein a cyclic acetal of 4-amino-3,5-dibromobenzaldehyde is produced by brominating the latter compound. 5,4-Nitrobenzaldehyde oxime is reduced to 4-aminobenzaldehyde oxime and the latter is brominated; alternatively, p-nitrotoluene is reacted with lower alkyl nitrite in the presence of a base and the 4-aminobenzaldehyde oxime thus obtained is A method according to claim 1, wherein 3,5-dibromo-4-amino-benzaldehyde oxime is prepared by brominating benzaldehyde oxime. in b) by brominating 6,2,6-di-(lower alkoxy)aniline to produce 4-bromo-2,6-di-(lower alkoxy)aniline and methylating the latter compound. 4-bromo-2,6- used
A method according to claim 1 for producing di-(lower alkoxy)-N,N-dimethylaniline. 7. The method according to claim 1, wherein an alkali metal methoxide is used as the alkali metal lower alkoxide in a). 8, p-(5,5-dimethyl-1,3-dioxane-2
−il) aniline. 9,4-(5,5-dimethyl-1,3-dioxane-2
-yl)-2,6-dibromoaniline. 10,4-bromo-2,6-dimethoxyaniline. 11,4-Bromo-2,6-dimethoxy-N,N-dimethylaniline. 12,4-amino-3,5-dibromobenzaldehyde oxime. 13,4-amino-3,5-dimethoxybenzaldehyde oxime.