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Synthesis of 3-amino-4-hydroxyl benzoic acid phosphate.

Byline: Baoxue Quan and Wenwei Jiang

Abstract 3-amino-4-hydroxyl benzoic acid phosphate was synthesized from 4-chloro benzoic acid through three steps, the whole process was cost-effective in which the materials in each step were reused. More importantly, phosphoric acid medium did no harm to Pd-C catalyst in the hydrogenation and the Pd-C catalyst could be recycled for ten times at least without decrease in catalytic activity. In addition, product could meet the requirement of polymerization reaction of producing poly(2,5-benzoxazole) without dehydrochlorogenation. In this process, good conversion, high overall yield (79.28%) and high purity (99.30% by HPLC) were achieved.

Key words: Synthesis, 3-amino-4-hydroxyl benzoic acid phosphate, Pd-C, recycle.


In 1950s, poly(benzoxazole)s and copolymers thereof were firstly synthesized and reported. [1] In the subsequent studies, researchers found the copolymers thereof were involved in photosensitive materials. [2-4] Most importantly, poly(2,5-benzoxazole) [5-7] as one kind of aromatic heterocyclic polymers which have excellent properties such as high strength, high module, and excellent thermal stability got much attention. [8, 9] 3-amino-4-hydroxyl benzoic acid (3,4-AHBA) is known as monomer of poly(2,5-benzoxazole). Except for in materials science, [10-14] 3,4-AHBA is applied in medicinal chemistry, [15-18] biology, [19,20] and dye stuff [21] as well. Especially, Joseph Chege found out that 3,4-AHBA and derivative thereof can be used in the preparation of medicament for treating retroviral infection, particularly for treating HIV infection.[22]

Pharmacologists and biologists found out that natural 3,4-AHBA exists in microorganism, [23- 25] but it is hard to separate 3,4-AHBA from microorganism. In 1988, synthetic method for 3,4- AHBA was reported by DOW, 3,4-AHBA could be obtained through electrolytic reduction of 3-nitro-4- hydroxyl benzoic acid (3,4-NHBA) in alkaline medium. [26-28] However, equipment required is complex and production capacity of electrochemical reduction is very small compared with chemical reduction and catalytic reduction. In 1990, Dow invented another process to synthesize 3,4-AHBA starting with methyl 4-hydroxy benzoate through nitration, esterolysis and reduction. [29, 30] A similar process was reported, beginning with 4-hydroxyl benzoic acid instead. However, many side reactions take place in the nitration, because of the vulnerable hydroxyl group and decarboxylization, which results in poor yield and purity.[31]

In 1989, Zenon Lysenko, Midland and Mich figured out a process to prepare 3,4-AHBA from 4-chloro benzoic ac id (4-CBA) through nitration, hydrolyzation, and hydrogenation [32] and it deserves to be mentioned that hydrogenation in acidic medium is much better than basic medium, because the free amino group on the benzene ring is vulnerable while exposing to air. This synthetic route is valuable, however, the total yield is poor and the process is not economical and not environment friendly as well. Here we report an optimized process with high yield and purity which is more economical and environmental friendly. In addition, phosphoric acid medium that does no harm to Pd-C catalyst is reported firstly in hydrogenation of 3,4-NHBA, and the product 3,4-AHBA H3PO4 meets requirement of polymerization reaction of poly(2,5-benzoxazole) directly without dehydrochlorogenation. Intermediates and products were monitored by HPLC.


NMR spectra were recorded on Bruker spectrometer 400MHz, for 1H and 13C, respectively, and the chemical shifts were reported as d values in parts per million relative to tetramethylsilane (TMS) as an internal standard. Infrared (IR) spectra were obtained using a SHIMADZU FTIR-8400S IR spectrometer. Mass spectra were recorded on TSQ Quantum Ultra liquid chromatographymass spectrometer. Melting points were recorded on YUHUA SX-4 melting point apparatus which was uncorrected. DTA and DTG were recorded on SHIMADZU DTG-60A. SEM was recorded using JEOL JSM-7500F. All solvents and reagents were obtained from commercial sources and used without further purification.

Preparation of 3,4-NCBA 4-CBA (200g, 1.286mol) was added into concentrated sulfuric acid (98%, 350ml). The nitrating agent that was prepared by mixing concentrated sulfuric acid (98%, 95ml) and concentrated nitric acid (65%, 95ml) was added into system dropwise. The temperature of reaction mixture was kept below 30 while adding nitrating agent. After adding the system was heated to 35, and 6 hours with stirring was kept. Then reaction mixture was filtered, 3,4-NCBA was washed in water, drying at 80 as white powder. Yield: 97.56%, purity: 99.46% by HPLC (buffered solution of H3PO4-NaH2PO4 (pH = 3)/CH3OH : 65/35), and mp: 182~183. IR (KBr cm-1): 3086~2535 (O-H in COOH, stretching), 1691 (C=O stretching),1600, 1485 and 1434 (aromatic C=C), 1546 and 1363 (N=O stretching), 1051 (C-Cl on benzene ring, stretching).

1H NMR (400 MHz (CD3)2SO ppm): d: 13.81 (br, 1H), 8.48 (m, J = 7.2 Hz 1H), 8.16 (m, J = 13.6 Hz 1H), 7.89 (m, J=17.6 Hz 1H). 13C NMR (400 MHz (CD3)2SO ppm): d: 1 65.29, 147.91, 134.44, 132.71, 131.61, 129.92, 126.64. MS/EI m/z = 199.98(100%), 201.98(31.89%), 200.98(7.89%), 155.98(4.24%), 202.98(2.52%), 158.01(1.47%).

Preparation of 3,4-NHBA

3,4-NCBA(201.57g, 1mol) was added into solution(1000g) containing sodium hydroxide (150g, 3.75mol). Reaction was carried out at 95 and kept for 10h. When the reaction completed, the reaction mixture was cooled to room temperature, part of 3,4- NHBA-2Na precipitated as crystal. The crystal was separated by filtrating. The filtrate was analyzed and reused. The crude 3,4-NHBA was washed in dilute hydrochloric acid solution (pH=1~2), drying at 40. Yield: 47.36%, Purity: 99.10% by HPLC (buffered solution of H3PO4-NaH2PO4 (pH=3)/CH3OH: 65/35). In the cycle experiment, the feeding amount of each substance was based on the content of key components in filtrate, and the content of component was achieved by analyzing filtrate. In the five times of cycle experiment, the total was 91.83%, average purity was 99.57% (by HPLC).

The mp: 183~185. IR (KBr, cm-1): 3300 (O-H stretching), 3080~2560(O-H in COOH stretching), 1684(C=O stretching), 1627 and 1441 (aromatic C=C), 1538 and 1338 (N=O stretching), 1173 (C-O in Ar-OH stretching). 1H NMR (400 MHz (CD3)2SO, ppm): d 13.15 (br, 1H), 11.89 (br, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.04 (m, J=10.8Hz 1H), 7.20(d, J=8.4Hz 1H). 13C NMR (400 MHz (CD3)2SO, ppm): d: 165.55, 155.49, 136.62, 135.40, 126.76, 121.61, 119.16. MS/EI m/z = 182.02 (100%), 183.02 (8.29%), 138.02(4.81%), 184.03(1.45%), 108.03(0.84%).

Preparation of Pd-C catalyst

Activated carbon was washed in hydrochloric acid, then washed in water at 80, and dried at 110. Palladium chloride (1.77g) was dissolved in hydrochloric acid (30g, 15%wt) and chelated with EDTA-2Na (1.5g), then activated carbon (9.5g) and a little pure water (135g) was added. Mixture was kept stirring at 40 for 2h and then filtered, filter cake was washed in water for times. After that the filter cake was dispersed in pure water, and sodium formate (60g, 2.5%wt) was added dropwise under nitrogen, keeping stirring for 1h. Then the mixture was heated to 60 and kept stirring for 4h. Finally Pd-C catalyst was obtained by filtering and washing in water. Used Pd-C catalyst was washed with sodium hydroxide solution and pure water and then reused in the next reaction directly.

Preparation of 3,4-AHBAH3PO4.

3,4-NHBA (66.7g, 0.3645mol) was added into phosphoric acid (1080g, 20% wt) in autoclave, reaction was carried under hydrogen with the presence of Pd-C (10% wt) at 95. Keep rotating speed at 500r/min and press of hydrogen 1MPa~1.4MPa. When hydrogen absorption was completed, extra 3 hours was kept. The reaction mixture was filtered at 65, Pd-C was washed and reused, and filtrate was kept for 10h at 0 to precipitate crystal. The crystal was separated by filtrating and dried at 80 in a vacuum. Snow-white product was obtained, yield was 60.22%, and purity was 99.17% (by HPLC). In the cycle experiment, filtrate containing phosphoric acid from the last reaction was reused, 3,4-NHBA (40g), phosphoric acid (15ml, 85%wt), H2O (10ml~30ml) and Pd-C catalyst was added. The reaction was carried out with the same condition described above.

In the ten times of cycle experiments, the total yield was 88.50%, and purity was 99.30% by HPLC. DTG (under nitrogen): A weight loss of 21% of happens rapidly between 200 and 250, it indicates the evaporation of H3PO4 partially and the product 3,4-AHBA H3PO4 turns to (3,4-AHBA)2 H3PO4. The weight loss is a little more than 19.5% (theoretic value) which shows that there is excessive phosphoric acid in product. IR (KBr, cm-1):3150~2590 (N-H, O-H and COOH stretching), 1688 (C=O stretching), 1647 and 1522 (aromatic C=C), 1277 (C-N in Ar-NH2 stretching), 1134 (C-O in Ar-OH stretching). 1H NMR (400 MHz (CD3)2SO, ppm): d: 8.33 (br, 4H), 7.21(d, J=1.2Hz 1H), 7.07 (m, J=6.8Hz 1H), 6.68(d, J=5.6Hz, 1H). 13C NMR (400 MHz (CD3)2SO, ppm) d: 167.66, 148.88, 134.94, 121.67, 119.97, 115.93, 113.73. MS/EI m/z = 152.05 (100%), 188.01(43.15%), 194.96(36.26%), 210.96(14.55%), 292.95(14.32%), 250.02(9.48%), 132.95(8.49%).

In the nitration of 4-CBA, the molar ratio of nitric acid to 4-CBA was reduced to 1.05, the utilization rate of nitric acid was 95.24%. In order to get complete conversion, 6 hours of vigorous stirring was required. When nitration completed, the reaction mixture was filtered rather than poured into crashed ice which made it easy to concentrate and recycle sulfuric acid. The reduction of nitric acid consumption not only cut the cost of material but also increased dehydrating value of sulfuric acid (DVS) of system. A higher DVS (7.334) ensured almost full conversion of 4-CBA and high purity of crude 3,4- NCBA.

Since the carboxyl group (-COOH) turned into carboxyl anion (COO-) in alkaline medium. Carboxyl anion increases the electron density around benzene ring which was negative for hydrolysis of 3,4-NCBA. Therefore big consumption of sodium hydroxide was involved to achieve full conversion, the molar ratio of sodium hydroxide to 3,4-NCBA preferred 4.5 (theoretic ratio: 3.0). When reaction completed, instead of Acidifying the reaction mixture directly, the reaction mixture was cooled down and filtered to get the crystal of 3-nitro-4-hydroxyl benzoic acid disodium salt (3,4-NHBA-2Na) and initial filtrate. After analyzed, the initial filtrate was recycled. The feeding amounts of materials in cycle experiments were based on the amounts of 3,4- NHBA-2Na and sodium hydroxide in the filtrate from the last reaction. The amounts of 3,4-NHBA- 2Na (n1) and the amount of sodium hydroxide (n2) in the filtrate were determined by titration and UV spectrophotometer analysis.

In addition, the feeding amounts also should ensure that when the reaction completed, the amounts of 3,4-NHBA-2Na and sodium hydroxide in reaction mixture were kept just the same as initial reaction (Entry 2) to ensure the quality of the products.


The total molar ratio of sodium hydroxide to 3,4-NCBA in experiments from Entry 2 to Entry 7 was 3.4, the utilization rate of sodium hydroxide was 88.26%. It can be predicted that as the cycle experiment carries on, the utilization rate of sodium hydroxide will improve further.

In acidic medium with existence of chloride ion, the palladium dispersed on activated carbon is ionized partially and slowly, this results in inactivation of Pd-C catalyst. However, Pd-C gets much higher stability in phosphoric acid medium. So hydrogenation of 3,4-NHBA was carried out in phosphoric acid instead of hydrochloric acid which extended lifespan of Pd-C greatly. The Pd-C made by ourselves showed high activity, even after used 10 times. In hydrogenation, the concentration of phosphoric acid preferred 20% wt and the molar ratio of phosphoric acid to 3,4-NHBA preferred 6.0. Since the product was soluble in aqueous medium, the poor yield of the initial reaction (Entry 8) was 60.22%. In order to improve the yield and cut the cost, the used phosphoric acid and Pd-C must be recycled. In each cycle experiment, 60% of the feeding amount of 3,4- NHBA in Entry 8 was added. It indicated materials were recycled well.

In the experiments from Entry 8 to Entry 18, the total yield was 88.50% which theoreticall y would reach 92% and the average purity of products was 99.3%. The washing of catalyst which absorbed products and analysis of the liquid sample containing products lowered the total yield.

Pictures from SEM show that after using 10 times the surface and channels of Pd-C did not change too much compared with fresh catalyst's, this is the reason why Pd-C keeps high activity.

Table: Experimental data





















3,4-AHBA H3PO4 is synthesized from 4- CBA through an cost-effective process with good conversion and high total yield,recycle of materials in each step works well. The Pd-C catalyst we made for hydrogenation keeps high activity and stability in phosphoric acid medium.


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Date:Aug 31, 2015
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