TRANSLATED: Chinese 3,4,5 TMB article

[ning]

Please pardon the roughness of this translation. My chinese is about 2nd grade level.  It's a cool trick they're doing, though. Gallic acid --DMS--> 3,4,5-trimethoxybenzoic acid methyl ester --hydrazine--> some hydrazide/zone/?? --potassium ferricyanide--> 3,4,5-trimethoxybenzaldehyde.
Here's the goods:

Improved synthesis of 3,4,5-trimethoxybenzaldehyde


3,4,5-TMB is an antibacterial sulfa synergist expectorant asthma medicine important intermediate. Its synthesis starts with gallic acid for raw material, under alkaline conditions with
dimethyl sulfate process and (then?) under acidic conditions to obtain 3,4,5-trimethoxybenzoic acid methyl ester, which is then reacted with hydrazine, then with red prussiate to obtain 9the goods). [1]

| there was a picture here. |

(As is currently done) in the hydrazine reaction step uses 80-90% hydrazine hydrate in refluxing ethanol. Concentrated hydrazine hydrate has explosion danger, therefore work conditions are severe. In the conversion to aldehyde step, reaction medium is aqueous, volume is large (presumably because the precursor isn't very soluble), red prussiate (potassium ferricyanide, K3Fe(CN)6) consumption is large, and yield is only about 50%. (More recently,) organic solvent (benzene or toluene) has been added to augment reactant solubility, giving yields around 70%.[2]

For the sake of improving this and raising yields, we optimized these two steps. In the hydrazine reaction step,
we used 50% hydrazine hydrate and refluxed 3h to obtain a yield of 98%. In ferricyanide step, because the reaction was a two-phase mixture, we added the phase-transfer catalyst tetrabutylammonium bromide. After adopting PTC, ferricyanide amount could be reduced, while raising reaction yield to 83%.

1.1 - synthesis of 3,4,5-trimethoxybenzyl hydrazone(?)

345-TMO-benzoic acid methyl ester 22.6g (0.1 mol)and 50% hydrazine hydrate 27 ml (0.5 mol) are refluxed 3h until silica gel TLC indicates all reactant is consumed (eluting w/ petroleum ether:EtOAc 8:2). Water 35 ml is added, and as the mixture cools, copious amounts of white solids form. They are removed and filtered, washed with a small qty. of dilute( ethanol-water and dried under infrared(?) to yield white solid 22 g, 97.5% mp 128-130 C [3]

1.2 synthesis of 3,4,5-trimethoxybenzaldehyde

To a 17-20C solution consisting of 7.5 g (0.033mol) of previously made hydrazone mixed with 40 ml 20% ammonia water, 40 ml toluene, and 2g(!!) PTC tetrabutylammonium bromide (Bu4N+Br-) was added dropwise pottasium ferricyanide 16 g (.045 mol) dissolved in 50 ml water. The addition took 1h, and the mixture was agitated for an additional 30 minutes, then extracted & filtered, and the filtrate extracted twice with toluene. The pooled extracts were washed with water, dried with anhydrous Na2SO4, and the solvent evaporated. Recrystallized from 95% ethanol were obtained white needles 5.3 g, yield 83%. mp 75 - 76. [4]

Refs:
[1]: Organic drug synthesis handbook, shanghai
[2]: Takagi S, Japan patent 74 28184 (1974)
[3]: Kudryashova N I, Davidenkov L R, Khromov-Borisov N V. Zh. Obshch. Khim. 1959 (29): 1885
[4]: Organic synthesis chemical society journal(?) 1995 53(7): 650


That's it. Phew!  Who would have though such a little article could take so long?!  And why the hell do they use so much PTC? It's obscene!

Ning thinks gallic acid could be methylated in some aprotic solvent with KI and MeCl generated by H2SO4, salt, and methanol, then reacted like this to yield a most desireable precursor. Say, isn't that funky witch hazel stuff they always sell in pharmacies mostly made of tannins? Hmm....

[Rhodium]

Synthesis of 3,4,5-Trimethoxybenzaldehyde from Gallic Acid and other Alkoxybenzaldehydes
Hisashi Ishii, et. al.

Chem. Pharm. Bull. 31, 3024-3038 (1983)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/trimethoxybenzaldehydes.html)

Several benzaldehyde derivatives were prepared for use as synthetic starting materials:

1. 3,5-Dimethoxybenzaldehyde was prepared by methylation of 3,5-dihydroxybenzoic acid with dimethyl sulfate in acetone in the
presence of potassium carbonate followed by reduction with LiAlH4 and by oxidation with Collins reagent in 80.3% overall yield.

2. 3,4,5-Trimethoxybenzaldehyde was also prepared by methylation of gallic acid with the same reagent
followed by reduction with Vitride and by oxidation with pyridinium dichromate (PDC) in 80.7% overall yield.

3. 2-Methoxy-4,5-methylenedioxy-benzaldehyde and 2,4,5-trimethoxy-benzaldehyde were obtained
by Vilsmeier–Haack reaction of O-methylsesamol and 1,2,4-trimethoxybenzene, respectively.

4. 5-Methoxy-2,3-methylenedioxy- and 2,3,5-trimethoxy-benzaldehyde were derived from 5-methoxy-2,3-methylenedioxy-
and 2,3,5-trimethoxybromobenzene by treatment with ethyl lithium followed by formylation with N,N-dimethylformamide (DMF).