A process to prepare nitrophenyl mercaptoanaline (NPMA)

Abstract

A more cost competitive, environmentally friendly and safer process was developed to prepare nitrophenyl mercaptoanaline (NPMA) or 2-nitro-5-(phenylthio)aniline.

Description

[0001] TITLE

[0002] A Process to Prepare Nitrophenyl Mercaptoanaline (NPMA)

[0003] BACKGROUND

[0004] 2-nitro-5-(phenylthio)aniline (CAS No. 43156-47-4) also known as nitrophenyl mercaptoanaline (NPMA) is a useful synthetic intermediate. NPMA is a precursor to fenbendazole, a broad-spectrum anthelmintic.

[0005] Febantel is an anthelmintic.

[0006] It is used in veterinary medicine to treat dogs, cats, cattle, sheep, goats, pig, and poultry against roundworms and tapeworms. The metabolic pathway of febantel is converted directly to either fenbendazole or oxfendazole.

[0007] Oxfendazole is a broad spectrum benzimidazole anthelmintic. Its main use is for protecting livestock against roundworm, strongyles and pinworms. Oxfendazole is the sulfoxide metabolite of fenbendazole.

[0008] Oxfendazole and Febantel also use NPMA as a precursor.

[0009] Cortes et al., J. Heterocyclic Chem., 41, 273 (2004) and CN103242238 B disclose the preparation of fenbendazole from nitrophenyl mercaptoanaline (NPMA) via reduction of NMPA to 4- (phenylthio)benzene-l,2-diamine or amino-phenyl-mercapto-aniline (APMA) followed by conversion of APMA to fenbendazole.

[0010] CN116655554 discloses a green synthesis method of a flumioxazin key intermediate which begins with the formation of 5-fluoro-2-nitrophenol from 2, 4-difluoronitrobenzene. CN113045557 discloses a process of a flumioxazin herbicide which also begins with the formation of 5-fluoro-2- nitrophenol from 2, 4-difluoronitrobenzene. Neither reference discloses the synthesis of 5-fluoro-2- nitroaniline from 2, 4-difluoronitrobenzene.

[0011] US6552230 describes the synthesis of 2-nitro-5-(phenylthio)anilines utilizing 5-chloro-2- nitroaniline. The preparation of 5-chloro-2-nitroaniline from 2, 4-dichloronitrobenzene by chloroamine exchange, and then 2-nitro-5-(phenylthio)anilines by adding thiophenol is described. In the preparation of 5-chloro-2 -nitroaniline, a pressure of 4 - 30 bar is required for reaction. There is no disclosure utilizing 5-fluoro-2-nitroaniline.

[0012] SUMMARY OF INVENTION

[0013] A process to prepare 2-nitro-5-(phenylthio)aniline comprising a) reacting 2,4-difluoro-l -nitrobenzene urce to produce 5-fluoro-2-nitroanaline b) reacting 5-fluoro-2-nitroanaline with benzenethiol to produce 2-nitro-5-(phenylthio)aniline.

[0014] DESCRIPTION OF EMBODIMENTS

[0015] An improved process to make nitrophenyl mercaptoanaline (NPMA) or 2-nitro-5- (phenylthio)aniline has been developed. The new process utilizes 2,4-difluoro-l -nitrobenzene which is converted to 5-fluoro-2-nitroaniline which in turn is tranformed into NPMA. See Scheme 1.

[0016] The benefit of using 5-fluoro-2-nitroanaline to make NPMA is that this reaction can be carried out in water, rather than ethanol, which is cheaper, safer and more environmentally friendly. In addition, the synthesis of 5-fluoro-2-nitroanaline is more cost competitive, environmentally friendly and safer than prior art processes. 5-fluoro-2-nitroanaline was produced from 2,4-difluoro-l - nitrobenzene with milder reaction conditions with lower pressure (2.5-3.5 bar vs. 4-30 bar) and lower amount of ammonia (1-1.95 mol vs. 2-15 mol). Thus this new process of preparing NPMA, has many advantages because the starting material 5-fluoro-2-nitroanaline can be made safer and more cost-effective and using 5-fluoro-2-nitroanaline to make NPMA water can be used as a solvent to replace ethanol.

[0017] Scheme 1

[0018] US6552230 describes the preparation of 5-chloro-2-nitroaniline from 2, 4-dichloronitrobenzene by chloro-amine exchange, and then 2-nitro-5-(phenylthio)anilines by adding thiophenol. In the preparation of 5-chl oro-2 -nitroaniline, due to the low activity of chlorine, a pressure of 4 - 30 bar is required for reaction.

[0019] In contrast in the current inventive procedure, when 2, 4-difluoronitrobenzene is used as the starting material, the volume of ammonium hydroxide reduced by 1.5 V and the reaction condition milder. For example, the pressure of the inventive process is only 2.5-3.5 bar. This is compared to using 2, 4-dichloronitrobenzene such as in US6552230 where the pressure as noted above was 4 - 30 bar. Finally, no phase transfer catalyst was utilized in the inventive process.

[0020] An ammonium source is a compound that provides ammonia to the reaction. Examples are NH3.H2O, NH4HCO3 and (NH4)2CO3

[0021] In an embodiment, the ratio of the moles of ammonia source to the moles of 2,4-difluoro-l- nitrobenzene is 1 to 1.95.

[0022] In an embodiment, the base used in step a) is selected from NaOH, K2CO3, Na2CO3, KOH, TEA (triethyl amine), and DIEA (N,N - diisopropylethyl amine), preferably K2CO3.

[0023] In an embodiment, the base used in step b) is selected from NaOH, K2CO3, Na2CO3, KOH, TEA and DIEA, preferably NaOH.

[0024] In an embodiment, the solvent is step a) is selected from THF (tetrahydrofuran), MeOH, EtOH, toluene, MeCN, NMP (N-methyl-2-pyrrolidone), dioxane, IPA (isopropanol), EtOAc, n-hexane, DMF (dimethylformamide), DMSO (dimethyl sulfoxide) and DCM (di chloromethane), preferably toluene.

[0025] In another embodiment, the the solvent is step a) is THF (tetrahydrofuran).

[0026] In an embodiment, the solvent is step b) is selected from EtOH, MeOH, toluene, dioxane, THF and water, preferably water. In another embodiment, the product of the reaction of 2,4-difluoro- 1 -nitrobenzene with the ammonium source (i.e. 5-fluoro-2-nitroanaline ) is carried on to the reaction with benzenethiol with out purification. That is 2-nitro-5-(phenylthio)aniline is produced from 2,4-difluoro- 1 -nitrobenzene via 5-fluoro-2-nitroanaline in a one pot reaction. Another embodiment of the invention is a process to prepare fenbendazole comprising a) reacting 2,4-difluoro- 1 -nitrobenzene with an ammonium source to produce 5-fluoro-2-nitroanaline b) reacting 5-fluoro-2-nitroanaline with benzenethiol c) further reacting 2-nitro-5-(phenylthio)aniline to form fenbendazole. Another embodiment of the invention is a process to produce 5-fluoro-2-nitroanaline comprising with an ammonium source to produce 5-fluoro-2-nitroanaline. In an embodiment, the process is conducted at a pressure of between about 1 and less than about 4 bar, preferably between about 2.5 and about 3.5 bar.

[0027] In an embodiment, the ammonium source is selected from NH3.H2O, NH4HCO3 and (NH^COs, preferably NH3.H2O.

[0028] In an embodiment, the ratio of the moles of ammonia source to the moles of 2,4-difluoro-l- nitrobenzene is 1 to 1.95.

[0029] In an embodiment, the process further comprises a base and the base is selected from NaOH, K2CO3, Na2CO3, KOH, TEA, and DIEA, preferably K2CO3.

[0030] In an embodiment, the process is conducted in a solvent selected from THF, MeOH, EtOH, toluene, MeCN, NMP, dioxane, IP A, EtOAc, n-hexane, DMF, DMSO and DCM, preferably toluene.

[0031] Another embodiment of the invention is a process to prepare 2-nitro-5-(phenylthio)aniline luoro-2-nitroanaline with benzenethiol to produce 2-nitro-5-(phenylthio)aniline.

[0032] In an embodiment, the process further comprises a base, wherein the base is selected from NaOH, K2CO3, Na2CO3, KOH, TEA and DIEA, preferably NaOH.

[0033] In an embodiment, the process is conducted in a solvent selected from EtOH, MeOH, toluene, dioxane, THF and H2O, preferably H2O. EXAMPLES

[0034] Example 1 A - preparation of 5-fluoro-2-nitroanaline

[0035] To a mixture of 2, 4-difluoro-l -nitrobenzene (50.0 g, 314 mmol, 34.5 mL, 1.0 eq) in toluene (100 mL) was added K2CO3 (22.6 g, 163 mmol, 0.52 eq) and NH3.H2O (71.1 g, 487 mmol, 78.1 mL, 24% purity, 1.55 eq) in one portion. Then the mixture was stirred at 70°C (inner temperature) for 16 hrs in a 500 mL of autoclave. HPLC showed the reaction was completed. Concentrate the mixture under reduced pressure to remove toluene, the residue was added H2O (150 mL) and stirred at 15 °C for 1 hr. The mixture was filtered to give 49.1 g of solid with 97.8% purity by HPLC, and the assay yield was 96.2%. In an alterative example, the mixture was filtered and the wet cake was washed with 3N HC1 (6 V, 6.00 L) at 40-45°C for 8 hrs. Cool the mixture to 25-35 oC. Filter and wash the wet cake with H2O (10 V, 10.0 L) to give 1.84 Kg wet solid (with 50% 5-fluoro-2- nitroaniline and 99.6% purity). The assay yield was 94.4%.

[0036] Impurity profile of the reaction:

[0037] Exact Mass: 159.01 Exact Mass: 156.03 Exact Mass: 156.03 Exact Mass: 170.05 Exact Mass: 153.05 ypro uc t

[0038] The process of Example 1A was optimized with respect to solvents, ammonia source, the volume of NH3.H2O, base, the equivalent of base, the volume of solvent, and the reaction temperature. These results are presented in Examples IB to IE below.

[0039] Example I B - solvent screen

[0040] A variety of solvents were screened for use in the reaction from 2A to 3A See Table 1 below

[0041] Table 1

[0042] The results in Table 1 were obtained during solvents screening. After screening, toluene was selected for further process optimization. 96.2% was the yield after process optimization. Example 1C - ammonium source screening

[0043] Several ammonia sources were screened for use in the conversion of 2A to 3 A. See Table 2 below.

[0044] Table 2 Example ID - base screening

[0045] Several bases were screened for use in the conversion of 2A to 3 A. See Table 3 below.

[0046] Table 3 The results in Table 3 were obtained during base screening. After screening, K2CO3 was selected for further process optimization. 96.2% was the yield after process optimization.

[0047] Example IE - temperature screening

[0048] Several temperatures were screened for use in the conversion of 2A to 3 A. See Table 4 below.

[0049] Table 4

[0050] The condition NH3.H2O (1.5 V), K2CO3 (0.52 eq), toluene (2 V), 70 °C, 2.5 - 3.5 bar, 16 - 24 hrs gave the best result.

[0051] The HPLC method was developed for IPC from 2A to 3 A. Detailed information is shown below: HPLC conditions

[0052] RRT of major impurities in the HPLC graph

[0053] Example 2 - Preparation of 2-nitro-5-(phenylthio)aniline To a mixture of 5-fluoro-2-nitroaniline (40.0 g, 256 mmol, 1.0 eq) on H2O (184 mL) was added NaOH (6 M, 64.06 mL, 1.5 eq and thiophenol (34.1 g, 309.50 mmol, 31.63 mL, 1.21 eq), the mixture was stirred at 60 °C for 6 hrs at atmospheric pressure. HPLC showed the reaction was completed. The mixture was added H2O (240 mL), stirred at 25 °C for 16 hrs and then filtered to give the residue. The residue was triturated with n-heptane (160 mL) and stirred at 15 °C for 16 hrs and then filtered to give 61.0 g of solid with 98.3% purity by HPLC, and the assay yield was 96.7%. In an alternative example, the residue or wet cake was slurried with 3 N HC1 1-2 times at 40-45 °C for 2 to 4 hrs. Then the mixture was filtered, washed with water, and dried. 82.2 g solid was obtained with 95.0% assay, 99.7% purity. The assay yield is 99.0%. The overall assay yield for two steps was 93.0%.

[0054] HPLC method was developed and validated for NPMA. Detail information is shown below:

[0055] HPLC conditions RT of major impurities in the HPLC graph

[0056] The yield of first step was 96.2%, the yield of second step was 96.7%; the total yield of two steps was 93.0%.

[0057] Several different solvents (EtOH, MeOH, toluene, dioxane, THF and water) and bases (NaOH, K2CO3, NazCCh, KOH, TEA, DIEA) were found to give successful results with the reaction of 3 A to NMPA. The conditions of NaOH (1.5 eq), thiophenol (1.2 eq), H2O (4.6 V), 60 °C, and 6 - 24 hrs reaction time provided the best yield.

[0058] The major component of wastewater from first step is K2CO3 with trace amounts of 5-fluoro-2- nitroaniline, 4-nitrobenzene- 1,3 -diamine, 2,4-difluoro-l -nitrobenzene and 3-fluoro-4-nitroaniline. The major components of wastewater from second step are NaOH and thiophenol, with trace amounts of 3-fluoro-4-nitroaniline, 1,2-diphenyldisulfane, 5 -fluoro-2 -nitroaniline and NPMA. Furthermore, no phase transfer catalysts were used in either reaction.

[0059] Example 3 Preparation of fenbendazone from 2-nitro-5-(phenylthio)aniline

[0060] Fenbendazone is prepared from 2-nitro-5-(phenylthio)aniline as described below.

[0061] Step I. Reduction of NPMA to APMA solution

[0062] 1.24-1.47 liters of n-Butyl Acetate and 1 kg of NPMA are added to the reaction vessel and agitated for 0.5h. 0.58-0.71 liters of methanol and 0.009-0.019 kg (dry basis) of Raney Nickel catalyst (Raney Ni) are charged to the vessel. The vessel is heated to 20-70 °C and maintained for 2-3 hrs under hydrogen while keeping pressure no more than 1.0 MPa. The mixture in the vessel is heated to 55- 100 °C while maintaining the pressure hydrogen no more than 1.2 MPa. The mixture is agitated until the pressure in the reactor is stable when hydrogen is not introduced to the reactor. The vessel is then cooled to a temperature of no more than 45°C. A sample is obtained from the vessel and analyzed for reaction completion by HPLC.

[0063] The reaction mixture is allowed to settle for 1 h and is filtered to remove Raney Ni. 0.20 liters of n- Butyl acetate is used to wash the equipment and the filter cake. 0.207-0.625 (liters) of n-Butyl acetate, 2.382-3 145 (liters) of water and no more than 0.26 kg of sodium chloride are added to the filtrate. The mixture is heated to 35-45°C, and then agitated for 10-15 min. The mixture is allowed to settle for at least 30 min and separated into two layers. The bottom aqueous phase is discarded.

[0064] The organic solution from above is heated in a reactor to no more than 80 °C. The internal pressure is maintained at no less than -0.07MPa. The solution is refluxed for at least Ih. The solution is rectified while maintaining the internal temperature at no more than 80 °C and internal pressure at no less than -0.07MPa. After the distillate reaches 0.155-0.217 (liters), The solution in reactor to tested for benzene content by gas chromatogram (GC). Benzene level is no more than 2 ppm.

[0065] An aqueous solution of Sodium-EDTA and sodium hydrosulfite is prepared by charging 0.0005- 0.0450 kg of Sodium-EDTA, 0.0045-0.0050 kg of sodium hydrosulfite and no less than 0.091 liters of water. To this aqueous Sodium-EDTA and sodium hydrosulfite solution is charged 0.155-0.217 liters of n-butyl acetate, 0.0091 kg of diatomaceous earth, 0.01-0.20 kg of charcoal. The resulting mixture is heated to 45-80 °C, and agitated for 45-120 min. The mixture is cooled to 35-45 °C, The mixture is then filtered. The wet cake is washed with no less than 0.273 liters of n-Butyl acetate. The washing portions are combined with the filtrate. The obtained filtrate (APMA solution) is stored at no more thanlO °C until it is used in Step III (Cyclization).

[0066] Cyanamide Methyl Chloroformate (MCF) Cyanourethane

[0067] Chemical Formula:CH2N2Chemical Formula: C2H3C1O2Chemical Formula:C3H3N2O2Na

[0068] MW:42.04 MW:94.50 MW: 122 06

[0069] A sodium hydroxide solution is prepared by mixing no more than 0.938 liters of drinking water and no more than 0.462 (kg) of sodium hydroxide. A cyanamide solution is prepared by mixing no less than 0.85 (liters) of drinking water and 1.06-1.35 molar equivalents of cyanamide (based on NPMA). The temperature is adjusted to 5-20 °C and the solution is stirred for no less than 0.5 h. The cyanamide solution is add simultaneously to the sodium hydroxide solution with 1.12-1.38 molar equivalents of methyl chloroformate (based on NPMA) while keeping the reaction mixture pH at 8.1-9.6 and temperature at 5-20 °C.

[0070] Once methyl chloroformate is completely added, the reaction mixture is maintained at a temperature between 5-20 °C and pH of between 8.1-9.6, until the pH is stable within this range for at least 0.5 h without requiring addition of sodium hydroxide solution. The batch is held for at least an additional 1 h and then sampled to check for the absence of cyanamide.

[0071] After the reaction is completed, the cyanourethane solution is stored at no more than 20 °C for the first 5 h and at no more than 10 °C afterwards until it is used in Step III.

[0072] Step III Preparation of Fenbendazole

[0073] Reaction scheme

[0074] The temperature of the APMA solution prepared in Step I is adjusted to no more than 60 °C and the pH is adjusted to 2.0-5.0 by adding cone. HC1. The cyanourethane solution obtained in Step II is added to the APMA solution while keeping the pH between 3.4-4.0 by adding cone. HC1. The temperature is maintained at no more than 30 °C.

[0075] Once the cyanourethane solution transfer is completed, the mixture is heated to 40-50 °C, and the pH adjusted to 3.1-3.6 by adding cone. HC1.

[0076] The reaction mixture is agitated and heated to a temperature between 60-70 °C. The pH of the reaction mixture is maintained between 3.1-3.6 by adding cone. HC1. The reaction mixture is agitated until the pH of the mixture is stable between 3.1-3.6 for at least 1 hour without addition of cone. HC1. The reaction mixture is cooled to 40-50 °C, then adjust the pH to 6.5-7.5 by adding an aqueous sodium hydroxide solution. The reaction mixture is agitated for at least 1 h.

[0077] The mixture is filtered at 20-50 °C and then washed successively with no less than 0.90X (liters) of n-Butyl acetate, no less than 1.8 liters of purified water, no less than 1.011 liters of methanol and NLT 1.8 liters of purified water. The wet cake is washed with no less than 1.011 liters of methanol and dried at a temperature of no more than 80 °C under vacuum for at least 8 h. Expected yield: 75.0 %-85.0 % Fenbendazole (Calculated based on NPMA input)

Claims

CLAIMS1. A process to prepare 2-nitro-5-(phenylthio)anilinecomprising a) reacting 2,4-difluoro-l -nitrobenzenewith an ammonium source to produce 5-fluoro-2-nitroanaline; and b) reacting 5-fluoro-2-nitroanaline with benzenethiolto produce 2-nitro-5-(phenylthio)aniline.

2. The process of claim 1, wherein step a) is conducted at a pressure of between about 1 and less than about 4 bar, preferably between about 2.5 and about 3.5 bar.

3. The process of any one of claims 1-2, wherein the ammonium source is selected from NH3.H2O, NH4HCO3 and (NH4)2CO3, preferably NH3.H2O.

4. The process of any one of claim 1-3, wherein the ratio of the moles of ammonia source to the moles of 2,4-difluoro-l -nitrobenzene is 1 to 1.95.

5. The process of any one of claims 1-4, wherein step a) further comprises a base and the base is selected from NaOH, K2CO3, Na2CO3, KOH, TEA, and DIEA, preferably K2CO3.

6. The process of any one of claims 1-5, wherein step b) further comprises a base, wherein the base is selected from NaOH, K2CO3, Na2CO3, KOH, TEA and DIEA, preferably NaOH.

7. The process of any one of claims 1-6, wherein step a) is conducted in a solvent selected from THF, MeOH, EtOH, toluene, MeCN, NMP, dioxane, IP A, EtOAc, n-hexane, DMF, DMSO and DCM, preferably toluene.

8. The process of any one of claims 1-7, wherein step b) is conducted in a solvent selected from EtOH, MeOH, toluene, dioxane, THF and H2O, preferably H2O.

9. A process to prepare fenbendazole comprising a) reacting 2,4-difluoro-l -nitrobenzenewith an ammonium source to produce 5-fluoro-2-nitroanalineb) reacting 5-fluoro-2-nitroanaline with benzenethiolc) further reacting 2-nitro-5-(phenylthio)aniline to form fenbendazole.

10. A process to produce 5-fluoro-2-nitroanalinecomprising with an ammonium source to produce 5-fluoro-2-nitroanaline.

11. The process of claim 10 wherein the process is conducted at a pressure of between about 1 and less than about 4 bar, preferably between about 2.5 and about 3.5 bar.

12. The process of any one of claims 10-11, wherein the ammonium source is selected from NH3.H2O, NH4HCO3 and (NH4)2CO3, preferably NH3.H2O.

13. The process of any one of claim 10-12, wherein the ratio of the moles of ammonia source to the moles of 2, 4-difluoro-l -nitrobenzene is 1 to 1.95.

14. The process of any one of claims 10-13, wherein the process further comprises a base and the base is selected from NaOH, K2CO3, Na2COs, KOH, TEA, and DIEA, preferably K2CO3.

15. The process of any one of claims 10-14, wherein the process is conducted in a solvent selected from THF, MeOH, EtOH, toluene, MeCN, NMP, dioxane, IP A, EtOAc, n-hexane, DMF, DMSO and DCM, preferably toluene.

16. A process to prepare 2-nitro-5-(phenylthio)aniline luoro-2-nitroanaline with benzenethiolto produce 2-nitro-5-(phenylthio)aniline.

17. The process of claim 16, wherien the process further comprises a base, wherein the base is selected from NaOH, K2CO3, Na2CO3, KOH, TEA and DIEA, preferably NaOH.

18. The process of any one of claims 16-17, wherein the process is conducted in a solvent selected from EtOH, MeOH, toluene, dioxane, THF and H2O, preferably H2O.

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