Author Topic: A great TMBA patent.  (Read 640 times)

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Antoncho

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A great TMBA patent.
« on: October 08, 2003, 12:19:00 PM »
I decided to post this separately since this patent contains an admixture of several useful methods applicable to making our beeloved aldehydes - the common among them being that the preferred goal for the researchers is 3,4,5-TMBA.

Basically, what they do is to make a mixed anhydride from 3,4,5-triMeO-benzoic acid (with ethyl chloroformate), then hydrogenate it to the 3,4,5-triMeO-BzOH and lastly oxidize it to the aldehyde using a variety of methods. None of the rxns proceeds in less than 90% yield.

Now there are some other methods for reducing acids to alcohols which don't require a Parr shaker, among them are LAH or NaBH4/iodine (see

Post 403516

(Antoncho: "Acids to alcohols: a one(two)-step NaBH4 reduction", Novel Discourse)
), so the reduction part may seem relatively uninteresting.

But the array of TMBzOH --> TMBA oxidation methods - easy, high-yielding and essntially OTC is very neat, IMHO.


Here goes:





Patent US4239702




EXAMPLE I

3,4,5-trimethoxybenzoyl-ethyl-carbonate.

g 10.8 (0.10 moles) of ethylchloroformate in 100 ml tetrahydrofuran are added, under stirring and by cooling at 5 DEG-10 DEG C. and during 10-30 minutes to a solution of 21.2 g (0.10 moles) of 3,4,5-trimethoxy benzoic acid and 12.12 (0.12 moles) of triethylamine in 200 ml tetrahydrofuran. At the end of the addition the mixture is kept at room temperature for 2 hours under stirring.

The formed precipitate is filtered, throughtly washed with tetrahydrofuran and discarded.

On the joined reaction solution and washing liquids we can directly proceed to the catalytic reduction for the preparation of 3,4,5-trimethoxy benzyl alcohol (Example II). The 3,4,5-trimethoxybenzoyl-ethyl-carbonate may also be isolated evaporating under a vacuum at a temperature between 50 DEG and 70 DEG C. The residual is a white microcristalline solid; g 26.7, yield 94% with following characteristics: m.p. 92 DEG-94 DEG C.

IR spectrum=1810 and 1710 cm@-1

NMR spectrum (CD3)2 SO .delta. 7.4 (s, 2H, aromatics); 4.4 (q, 2H, CH2 --CH3); 3.9 (s, 6H, 3.5--OCH3); 3,8 (s,3H, 4--OCH3); 1.35 (t, 3H, CH2 --CH3)

Anal. C=54.85%, H=5.34%.

The product is remarcably stable and keeps well also at room temperature. It is not affected by moisture.

EXAMPLE II

3,4,5 trimethoxybenzyl alcohol.

To a solution of 3,4,5-trimethoxybenzoyl-ethyl-carbonate (0.1 moles), prepared as described in example I, 100 ml of glacial acetic acid and 5 g of 5% palladium on C (5% Pd/C ENGELHARD) are added.

The mixture is reduced in a PARR type apparatus during 10 hours at 60 DEG C. under a pressure of (200 psi 14 tm) hydrogen. The catalyst is filtered off and washed with 100 ml of tetrahydrofuran. The joined filtrates are treated with 500 ml cold water, adjusted at pH 5 and saturated with NaCl. The organic solution of tetrahydrofuran which is separated, is concentrated in a vacuum. A yellow, semisolid product of 30.46 g is obtained. The TLC chromatography show the presence, in this mixture, of 3,4,5-trimethoxy benzyl alcohol and of 3,4,5-trimethoxy benzoic acid plus traces of 3,4,5-trimethoxy benzaldehyde.

The crude product is treated with 200 ml of CHCl3 and 200 ml of 5% NaOH solution.

The isolated acid fraction contains g 2.58 (12%) of 3,4,5-trimethoxy benzoic acid, whereas the organic phase of chloroform contains a non acid fraction consisting chiefly of 3,4,5-trimethoxy benzyl alcohol. After evaporation of the solvent, g 16.30 (83%) of a dense, slightly yellow liquid are obtained. B.P. 225 DEG C./25 mm Hg, d=1.23.

The substance has following NMR characteristics (CDCl3):

.delta. 6.59 (s, 2H, aromatics); 4.2 (d, 2H, CH2 --OH); 3.90 (s, 9H, 3 OCH3); and 2.1 (t, iH,--OH)

EXAMPLE III

3,4,5-trimethoxybenzaldehyde (from 3,4,5-trimethoxybenzyl alcohol)

33.9 g (0.34 moles) of chromic anhydride are slowly dissolved under efficient stirring in 500 ml of glacial acetic acid and heating at 90 DEG-100 DEG C.

To this oxydation mixture, g 19.8 of 3,4,5-trimethoxy benzyl alcohol dissolved in 160 ml of glacial acetic acid are very slowly added under continuous stirring. The mixture is kept reacting during 30' after the end of the addition and is then cooled, diluted with water and extracted with CHCl3 (3 fractions of 200 ml each).

The organic fractions are then joined and concentrated under a vacuum. Obtained are g 17.60 (90%).

M.P. 38 DEG-40 DEG C.; B.P., 168 DEG-170 DEG C./12 mm.

NMR spectrum: (CDCl3) .delta. 9.82 (s, 1H, --CHO); 7.1 (s, 2H, aromatics) and 3.95 (s, 9H, 3 OCH3).

EXAMPLE IV

3,4,5-trimethoxybenzaldehyde (from 3,4,5-trimethoxybenzyl alcohol)

g 63.2 of KMnO4 are dissolved at room temperature and under stirring in 1500 ml H2 O. A solution containing 150 g of Na2 SO3.7H2 O in 400 ml water is slowly added. The mixture is stirred at room temperature during 2 hours and the MnO2 formed is filtered in order to obtain a nearly dry product. The MnO2 is suspended in ml 450 of CHCl3.

To this suspension 39.6 g (0.2 moles) of 3,4,5-trimethoxy benzyl alcohol are directly added and the mixture is stirred during 8 hours at 25 DEG C.

The solid is filtered and discarded whereas the organic solution is concentrated in a vacuum to dryness. 37.7 g of a semi solid product having the same characteristics of the one described in example III are obtained.

EXAMPLE V

Benzoyl-ethyl-carbonate

10.8 g (0.10 moles) of ethylchloroformiate dissolved in 100 ml of tetrahydrofuran are added to a solution of tetrahydrofuran (200 ml) containing 12.2 g (0.10 moles) of benzoic acid and 12.12 g (0.12 moles) of triethylamine.

We proceed as in Example I.

We obtain 17.8 g (yield 92%) of a product having the following characteristics:

Elementary analysis C=61.85% H=5.19%

Spectrum NMR: (CD3)2 SO .delta. 8.2-7.4 (m, 5H, aromatics); 4.4 (q, 2H, --CH2 --CH3) 1.3 (t, 3H, --CH2 --CH3)

EXAMPLE VI

Benzyl alcohol

100 ml of glacial acetic acid and 5 g of 5% palladium on charcoal are added to a solution of benzoyl-ethyl carbonate (20.8 g=0.1 moles) in 300 ml of tetrahydrofuran.

The mixture is reduced in a PARR type device for 10 hours at 60 DEG C. and under a pressure of 200 psi (14 atm.) of H2. We proceed as in Example II. We obtain 8.6 g (yield 80%) of a liquid, having the following characteristics:

B.P.=205 DEG C.

d=1,045

nD =1.5403

Spectrum NMR: .delta. 7.3 (s, 5H aromatics); 4.7 (s, 2H, --CH2 --OH); 1.8 (s, 1H, --CH2 --OH).

EXAMPLE VII

Toluyl-ethyl carbonate

10.8 g (0.10 moles) of ethychloroformiate dissolved in 100 ml of tetrahydrofuran are added to a solution of tetrahydrofuran (100 ml) containing 13.6 g (0.10 moles) of toluic acid and 12.12 g (0.12 moles) of triethylamine. We proceed as in Example I.

We obtain g 18.7 (yield 90%) of a product having the following characteristics:

Elementary analysis C=63.45%, H=5.80%.

Spectrum NMR: (CD3)2 SO .delta.=8.0 (d, 2H, aromatics); 7.2 (d, 2H, aromatics); 2.4 (s, 1H, CH3 --); 4.4 (q, 2H, --CH2 --CH3); 1.3 (t, 3H, --CH2 --CH3).

EXAMPLE VIII

Methyl-benzyl alcohol

100 ml of glacial acetic acid and 5 g of 5% Pd on C are added to a solution of toluyl-ethyl-carbonate (20.8 g=0.10 moles) in 300 ml of tetrahydrofuran. The mixture is reduced in a PARR apparatus for 10 hours at 60 DEG C. and under a pressure of 200 psi (14 atm) of H2.

We proceed as in Example II.

We obtain 9.7 g (yield 80%) of a product having the following characteristics:

M.P. 59 DEG-61 DEG C.

Spectrum NMR: (DMSO) .delta. 7.2 (s, 4H, aromatics); 4.6 (s, 2H, --CH2 --OH); 2.3 (s, 3H, --CH3); 1.9 (s, 1H, --CH2 --OH).

EXAMPLE IX

p-chlorobenzoyl-ethyl carbonate

10.8 g (0.10 moles) of ethylchloroformiate dissolved in 100 ml of tetrahydrofuran are added to a solution of tetrahydrofuran (200 ml) containing 15.6 g (0.10 moles) of p-chloro-benzoic acid and g 12.12 (0.12 moles) of triethylamine. We proceed as in Example I.

We obtain g 21 (yield 92%) of a product having the following characteristics:

Elementary analysis C=52.53%, H=3.96%.

Spectrum NMR: (CD3)2 SO .delta.=7.9 (d, 2H, aromatics); 7.4 (d, 2H, aromatics); 4.4 (q, 2H, --CH2 --CH3); 1.3 (t, 3H, --CH2 --CH3).

EXAMPLE X

p-chlorobenzyl-alcohol

100 ml of glacial acetic acid and 5 g of 5% Pd on C are added to a solution of p-chlorobenzoyl-ethyl carbonate (22.8 g=0.1 moles). The mixture is reduced in a PARR apparatus for 10 hours at 60 DEG and under a pressure of 200 psi (14 atm) of H2. We proceed as in Example II. We obtain 11.7 g (82%) of a product having the following characteristics:

M.P. 70 DEG-72 DEG C.

Spectrum NMR: (DMSO) .delta.=7.2 (s, 4H aromatics) 4.6 (s, 2H, CH2 --OH) 2.1 (s, 1H, CH2 --OH)

It was found, moreover, that it was advantageous, both because of the lower cost of the oxidizer and of the substantial absence of problems of pollution, to carry out the oxidation of step (3) from alcohol to aldehyde using as oxidizing agent an aqueous solution of a compound which liberates, in solution, hypochlorite (ClO@-) in the presence of a phase transfer catalyst.

This catalyst is preferably choosen among the quaternary ammonic salts formed by three hydrocarbonyl C8 -C10 and by a methylic group.

Catalysts of this kind are, for instance, the ones put onto the market by Fluka with the trademark ALIQUAT-336 and by Aldrich with the trademark ADOGEN-464. One skilled in the art will be able to find, on the basis of what is above taught, other phase transfer catalysts suitable for use in the present process among the ones available on the market at present. In these recent years the phase transfer catalysis has been the object of a remarkable interest, above all with reference to the fact that, utilizing the above methods, reactions that otherwise would require the use of costly anhydrous solvents are made economically convenient. The conditions of the phase transfer, instead, require that the reactions are carried out, generally in mild conditions, in a diphasic ambient water/organic solvent. In practice, in most of its appliances, a cation having sufficiently lipophilic characteristics (generally ammonium-ion, but also phosphonium, solphonium ions, etc.) transfers from the aqueous to the organic phase an anion which, reacting, leaves the cation free to carry out its work again.

According to this scheme, numerous reactions were described, among which various oxidation reactions wherein MnO4@-, HCrO4@- ions were transferred from the aqueous phase to the organic phase, as salts with quaternary ammonium ions. Also the oxidation of alcohols with ClO@- in conditions of phase transfer was described. In this connection see, for instance: "Phase Transfer Catalyzed Oxidations of Alcohols and Amines by Acqueous Hypochlorite", G. A. Lee, H. H. Freedman Tetrahedron Letters, (20) 1641; 1967.

In this article, the teachings of which are incorporated by reference in the present specification, a different transfer catalyst is used, however, as well as different operation conditions with respect to the ones being the object of the present invention.

The following further non-limitative examples are an elucidation of this variant of the process of the present invention.

EXAMPLE XI

Preparation of benzaldehyde.

5 g (46.24 mmoles) of benzyl alcohol dissolved in 100 ml of CH2 Cl (RPE Carlo Erba) were added to 300 ml of a commercial solution (RPE Carlo Erba) of NaOCl (about 462.5 mmloes) containing 2.80 g (about 6.94 mmoles) of Aliquat-336. The mixture was heated to 40 DEG C. under stirring for 2 hours. It was let return to room temperature, was extracted by Et2 O washing with H2 O to neutrality.

It was anhydrized with Na2 SO4 and a solution containing benzaldehyde was obtained with a yield of 85%. The pure benzaldehyde was obtained by fractioned distillation (total yield 75%).

EXAMPLE XII

Preparation of 3,4,5- trimethoxy-benzaldehyde

(A) 5 g (25.25 mmoles) of 3,4,5-trimethoxybenzyl alcohol dissolved in 65 ml of CHCl3 (RPE Carlo Erba) were added to 164 ml of a commercial solution (RPE Carlo Erba) of NaOCl (about 252.5 mmoles) containing 1.52 g (3.79 mmoles) of Aliquat-336. The reaction mixture was kept at 60 DEG C. under stirring for 1 hour. It was let to get back to room temperature, extracted with Et2 O washing with H2 O to neutrality.

It was anhydrized on Na2 SO4 and led to dryness by Rotavapor. 4.630 g of a white raw substance with M.P. 60 DEG-63 DEG C. were obtained.

(B) The reaction was carried out in the conditions mentioned in the previous example, using the same ratios of reagent and solvent but utilizing as phase transfer catalyst Adogen-464. A raw product (about 4.58 g) with M.P. 59 DEG-62 DEG C. was obtained.







Antoncho

hest

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HI
« Reply #1 on: October 08, 2003, 04:24:00 PM »

Now there are some other methods for reducing acids to alcohols which don't require a Parr shaker, among them are LAH or NaBH4/iodine



NaBH4/I will generate HI with then will cut some of the ethergroups, not good. (ben there done that)