TMBA

TMBA, a drug intermediate widely used for an antibiotic Trimethoprim, has been traditionally made from gallic acid (3,4,5-trihydroxy benzoic acid) or vanillin imported from China where they extract it from a particular bark of a tree. However, during the last decade or so, it has been more economically made from p-cresol... 

Following are the steps for synthesis of 3,4,5-TMBA from p-cresol [21] ... 

According to one Indian manufacturer 3,5-dimethoxy p-cresol is initially oxidized to 3,5-dimethoxy-4-hydroxy-benzaldehyde (syringe aldehyde) which is then methylated to 3,4,5-TMBA... 

China has heen producing 3,4,5-TMBA from gallic acid and vanillin which used to he extracted from the hark of a tree. However, China has also recently switched over to p-cresol and most of 3,4,5-TMBA is now made from p-cresol. Japan has introduced the technology for synthesis of 3,4,5-TMBA from p-cresol almost two decades ago. Otsuka Chemical is a key player producing approximately 300 tpa of TMBA. DSM, Andino, Holland, one of the largest manufacturers of Trimethoprim, has heen mostly importing TMBA from China, Japan, and India. 

Sulmetozin, an ulcustherapenticum, is a small volume application of 3,4,5-TMBA. This compound was introduced hack in 1970 and has apparently reached the top of its life cycle. No growth in demand is expected during the next decade. Total global demand of 3,4,5-TMBA is estimated at 2000 tpa. Five percent annual growth is projected [14,34]. 

In India, hoth synthesis of 3,4,5-TMBA and its conversion into Trimethoprim have heen carried out during the last two decades. M/s. Inventaa, Hyderabad produce almost 50 tpm or 600 tpa of 3,4,5-TMBA. Zora Pharma, Ahmedabad used to produce 25 tpm or 300 tpa of the material. Both Inventaa and Zora 3,4,5-TMBA production were based on p-cresol. One Bombay based drug co., namely. Alpha Drugs, produces TMBA from gallic acid imported from China. Indian production of 3,4,5-TMBA is estimated to the tune of 1200 tpa. Most of this quantity is captively consumed to make trimethoprim. However, some quantities of TMBA (300-400 tpa) are exported mostly to W. Europe. 

Synthesis of trimethoprim from 3,4,5-TMBA based on the conventional process would proceed as follows ... 

The conventional technology for synthesis of trimethoprim from 3,4,5-TMBA was introduced as early as 1970 USA, Canada, countries of W. Europe like UK, Germany, France, Switzerland, Spain, Denmark, Finland, etc. and also India, China and Japan in Asia were manufacturing this bulk drug. 

Since then major improvements have taken place in the technology front particularly in China and India where this drug is still very popular. For instance, considerable work has been carried out by the Department of Energy Utilization and Chemical Engineering, China University of Mining and Technology. They have reported that efficient synthesis of trimethoprim from 3,4,5-TMBA was accomplished by condensation with methanolic sodium methoxide, methanol and acrylonitrile via prior base-catalyzed 1,3-prototropic isomerization of cinnamonitrile converted into the enol ether, followed by addition with methanol at 90°C and cyclocondensation directly with guanidine in DMSO at 110°C with the removal of methanol. 

The bulk drug is made by Inventaa, Hyderabad and Alpha Drugs, Bombay. Zora Pharma, an Ahmedabad-based company, had facilities for manufacture of both 3,4,5-TMBA... 

TMBA Indian companies will continue to play a key role in supply of trimethoprim to the world market. 

A special film holder allows transportation of the film with various rates. Time marks are printed automatically on the film for correlating the X-ray patterns to specific times and temperatures in the TMBA curves. The temperature program of the X-ray camera furnace is regulated by the thermobalance heating control system. Up to the maximum temperature of 1200 °C usual heating rates can be varied from 0.2 to 4 °C/min. The temperature of the impact plates can be held constant between room temperature and 450 °C and is recorded during the... 

The method is limited however to the vacuum region <10-3 torr. Standard deviations of the temperature in the order of +5 °K and 1 °K were found at 1225 °K and at 300 °K respectively. This same method was also used by Wiedemann44 to follow continuously the evolution of gaseous decomposition products with simultaneous recording of the heating X-ray45 diffraction pattern (TMBA-X-ray method). 

The simultaneously recorded heating X-ray pattern of calcite in vacuum, the TMBA-curve and the mass spectrometric curve for C02 are shown in Fig. 60 and in Fig. 61. It can be seen that the decomposition of calcite in vacuum (10-4 torr) starts already at 420 °C and that it is complete at 660 °C. The equipment and experimental procedure for thermomolecular beam analysis has been discussed in detail in Section 2.4. 

Fig. 60. TMBA- and MS-curves of the decomposition of calcium carbonate. Heating rate...

TMBA-ICI4 is collected and dried in air, m.p. 106-125°C (decomp.). The salt loses Cl2 above 106°C and the final m.p. is that of TMBA-IClj. 

TMBA-IC12 (0.92 g, 2.64 mmol) is added with stirring at room temperature to the alkene (2.4 mmol) in CH2C12 (20 ml) and the solution is stirred until the orange colour has faded... 

TMBA-ICl2 (0.81 g, 2.3 mmol) is added to the enaminone (2.3 mmol) in CH2Cl2 (35 ml) and MeOH (25 ml). NaHCO, (1.3 g) is added and the mixture is stirred at room temperature until the orange colour disappears (10—40 min). The mixture is filtered and the filtrate is washed well with aqueous NaHCO, (sat. soln) and extracted with CHCl,... 

Method C (dichlorination) TMBA-IC14 (4.18 g, 10 mmol) is stirred with the acetophenone (5 mmol) in AcOH (50 ml) at 70°C for 5 h. BTMA-IC12 is collected by filtration from the cooled mixture and aqueous NaHS03 (5%, 10 ml) and NaHC03 (5%, 80 ml) are added to the concentrated filtrate. The aqueous mixture is extracted with Et20 (4 x 40 ml) and the dried (MgS04) extracts are evaporated to yield the dichloroacetyl derivative (Table 2.17). 

Using the procedure outlined in 2.3.22, but replacing TMBA-Br, with TMBA-IC12 (1.64 g, 4.71 mmol), gives the monoiodoarene (Table 2.19). 

Method A. Chlorination TMBA-IC14 (22.7 g, 54 mmol) is added to the alkylbenzene (54 mmol) and AIBN (0.89 g, 5.4 mmol) in CC14 (300 ml) and the solution is refluxed. Precipitated TMBA-ICl, is removed from the cooled solution and the filtrate is concentrated. n-C6H 4 (30 ml) is added to the concentrate and the chlorinated products isolated by chromatography from silica. 

Method B TMBA-Br3 (see Table 2.22) and CaCO, (2 g) is added to the aniline (5.37 mmol) in CH2C12 (50 ml) and MeOH (20 ml). The mixture is stirred for 30 min until the orange colour fades, then filtered. The filtrate is concentrated, H20 (20 ml) is added, and the mixture is extracted with Et20 (4 x 40 ml). The dried (MgS04) extracts are evaporated to yield the brominated aniline. 

TMBA-ICI4 (1.3 g, 3.1 mmol) is added to the acetanilide (3.1 mmol) in AcOH (30 ml) and the mixture is stirred for 24 h at room temperature. The precipitated TMBA-ICI2 is collected and the filtrate is evaporated under vacuum. The residue is washed with NaHSO, (5%, 10 ml), NaHCO, (5%, 15 ml) and extracted with CH.CI, (3 x 20 ml). The organic extracts are filtered through A120, and evaporated to yield the chlorinated acetanilide. 

TMBA-IC12 (1.77 g, 5.1 mmol) and anhydrous ZnCl2 (1 g) is added to the aryl ether in AcOH (30 ml) and the mixture is stirred at room temperature for ca. 3 h. When the yellow solution has turned to reddish brown, H20 (20 ml) and aqueous NaHSO, (5%, 20 ml) are added and the aqueous mixture is extracted with n-C6H14 (3 x 50 ml). The dried (MgS04), extracts are evaporated to yield the iodophenyl ether. 

Monohalogenation Acridine or acridone (2 mmol) and TMBA-X, (2 mmol using TMBA-Br, for bromination, TMBA-IC14 for chlorination, TMB A-IC12 for iodination) are... 

Dihalogenation Acridine or acridone (1 mmol) and TMBA-X (2 mmol) are stirred in MeOH (20 ml) (AcOH (50 ml) for acridone] at 80°C for 2 h (8 h for acridone). The mixture is cooled to room temperature and the precipitated dihalo derivative is collected (3,7-dibromoacridine 70% 3,7-dibromoacridone 80% 3,7-dichloroacridone 65%). 

TMBA-Br3 (1.95 g, 5 mmol) is added to aqueous NaOH (0.25 M, 20 ml) over a period of 30 min at 0°C. The amide (5 mmol) is then added and the mixture stirred at 0°C for4 h. The precipitate is collected, washed well with aqueous AcOH (10%), and dried under vacuum to yield the A-bromoamide (e.g. n-C7H 5CONHBr, 77% PhCH2CONHBr, 63% PhCONHBr, 53% 4-ClC6H4CONHBr, 86% 4-02NC6H4CONHBr, 82%). 

B1 uses TBA-Br, B uses Aliquat. 94% with 1 mmol of catalyst. 99% when 0.16 g TiO, added. 93% when 0.16 g TiO, added. 92% with t mmol of catalyst.1 Using TMBA-C1. 

Tetra-n-butylammonium chlorochromate TBA-CICr03 and benzyltrimethylammonium chlorochromate TMBA-CICr03... 

Using procedure 10.3.5.F."97% using TMBA-CICrO,. 3 1 ratio of K,Cr 0, alcohol.J 60% yield after 90 min. 97% using TMB A-( (tOt. Nerol produces 95% neral under the same conditions. 83% using TMBA-CICrO,. 83% using TMBA-ClCtO,. 

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