CN106316885A - Preparation method of 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid - Google Patents
Preparation method of 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
Abstract
The invention provides a new preparation method of a medicament 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid for resisting muscular dystrophy and a new intermediate compound. The preparation method has a reasonable route design, and overcomes the disadvantages of high cost, low yield, low purity and the like in the prior preparation method which is bad for environmental protection; and the method has he advantages of cheap and easily available raw materials, good product yield, high purity, low cost, environmental protection, and industrialization.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field.In particular to a kind of anti-muscular dystrophy disease drug 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic preparation method.
Background technology
3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzoic acid is the experimental drug developed of PTC Therapeutics Inc. of the U.S. (PTC Therapeutics), English name Ataluren, another name PTC124 (the most also PTC124 is called in letter).As one effective nonsense mutation inhibitor, the clinical data of PTC124 shows that the duchenne muscular dystrophy to nonsense mutation (Duchenne Muscular Dystrophy) patient has positive therapeutic.
3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic structural formula is as follows:
Patent documentation US2004204461A1 reports a kind of preparation method of PTC124 at first, comprises the following steps: (1) 3-cyanobenzoic acid and iodomethane reaction, generates 3-cyano-benzoic acid methyl ester；(2) 3-cyano-benzoic acid methyl ester and azanol reaction, obtains 3-(N-hydroxyl amidino groups) essence of Niobe；(3) 3-(N-hydroxyl amidino groups) essence of Niobe reacts with 2-fluorobenzoyl chloride, obtains 3-[N-(2-fluorobenzoyl epoxide) amidino groups] essence of Niobe；(4) 3-[N-(2-fluorobenzoyl epoxide) amidino groups] essence of Niobe dehydration condensation, obtains 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] essence of Niobe；(5) hydrolysis of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] essence of Niobe, obtains 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid.Its chemical equation is as follows:
The raw material 3-cyanobenzoic acid price that this preparation method uses, iodomethane is poisonous reagent and belongs to controlled drug, and costly, production cost is the highest, is not suitable for industrialization for the price of gained 3-cyano-benzoic acid methyl ester.In embodiment, the HPLC purity of finished product is the highest, is 98%, is unfavorable for that the application of high standard preparation, total molar yield only have 57%.
Gupta, Puneet K.；Hussain, Mohd.Kamil et al. are at New Journal of Chemistry；vol.38；(2014)；P.3062-3070 the another kind of preparation method of PTC124 is disclosed in, comprise the following steps: (1) 2-fluobenzoic acid and 3-methylbenzene amitraz hydrochloride are at 2-(7-azo BTA)-N, N, react in the presence of N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU) and DIPEA (DIPEA), obtain 5-(2-fluorophenyl)-3-(3-aminomethyl phenyl)-1,2,4-diazole, molar yield 70%；(2) 5-(2-fluorophenyl)-3-(3-aminomethyl phenyl)-1,2,4-diazole are in the presence of pyridine, 3-[5-(2-fluorophenyl)-1 is obtained with potassium permanganate oxidation, 2,4-diazole-3-bases] benzoic acid, molar yield 40%.Its chemical equation is as follows:
This preparation method only has two-step reaction, but reaction selectivity is poor, post processing difficulty, needs column chromatography for separation, and total molar yield is low, and only 28%, second step uses potassium permanganate oxidation, serious three wastes, is unfavorable for environmental protection, it is difficult to industrialization.
In view of existing PTC124 preparation method all exists highway route design defect, cause cost height, yield is low, be unfavorable for environmental protection, be not suitable for the problems such as industrialization, it is thus desirable to improve PTC-124 preparation method, research and development reactions steps is few, quality is high, low cost, environmental protection, be suitable for industrialization new synthetic route.
Summary of the invention
For the deficiencies in the prior art, it is an object of the invention to provide the preparation method of a kind of new PTC124, and provide new key intermediate compound and preparation method thereof.
According to the object of the invention, the invention provides a kind of new midbody compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile for preparing PTC124, shown in its structural formula such as formula (II):
Present invention also offers a kind of preparation method of described formula (II) compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, comprise the following steps:
Step (1): m-dicyanobenzene and azanol or the acceptable reactant salt of azanol, obtains formula (I) compound 3-(N-hydroxyl amidino groups) benzonitrile
Step (2): formula (I) compound 3-(N-hydroxyl amidino groups) benzonitrile reacts in the presence of a base with 2-fluorobenzoyl chloride, obtains formula (II) compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
In the preferred embodiment of above-mentioned formula (II) compounds process for production thereof:
Step (1) described azanol may be from commercially available aqueous hydroxylamine solution, and wherein the mass content of azanol is 10%-50%；The acceptable salt of described azanol, preferably pharmaceutically acceptable salt, it is selected from hydroxylamine hydrochloride or hydroxylamine sulfate；
In step (1), m-dicyanobenzene is 1: 0.8～1: 2 with the mol ratio of azanol or the acceptable salt of azanol；
Step (1) reaction dissolvent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, acetonitrile, toluene or dichloromethane；
Step (1) reaction temperature is 30～100 DEG C, preferably 40～50 DEG C；
Step (1), when using aqueous hydroxylamine solution, it is not necessary to add alkali.When using the acceptable salt of azanol, need to add and its equivalent or the alkali of excess, system is made to be maintained at alkaline environment, the alkali wherein used, selected from carbonate, bicarbonate, phosphate, hydrophosphate or organic amine, is preferably selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen phosphate, sodium phosphate, potassium phosphate, triethylamine, pyridine or diisopropylethylamine；
Step (2) described alkali, selected from carbonate, bicarbonate, phosphate, hydrophosphate or organic amine, is preferably selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen phosphate, sodium phosphate, potassium phosphate, triethylamine, pyridine or diisopropylethylamine；
In step (2), formula (I) compound 3-(N-hydroxyl amidino groups) benzonitrile is 1: 0.9～1: 2 with the mol ratio of 2-fluorobenzoyl chloride；
Step (2) reaction dissolvent, selected from chloralkane, highly polar aprotic solvent or apolar aprotic solvent, is preferably selected from dichloromethane, acetonitrile, ethyl acetate, oxolane, toluene or DMF；
Step (2) reaction temperature is 0～50 DEG C, preferably 0～10 DEG C.
After the step (1) of above-mentioned formula (II) compounds process for production thereof or step (2) have been reacted, product carries out isolated and purified by the ordinary skill in the art, such as, filter, concentrate, extract, recrystallization etc..
According to the object of the invention, the invention provides the preparation method of a kind of PTC124, comprise the following steps:
Step (a): formula (II) compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile dehydration condensation, obtain formula (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzonitrile
Step (b): formula (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzonitrile hydrolyzes in presence of an acid, obtains 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzoic acid
In the preferred embodiment of above-mentioned PTC124 preparation method:
Step (a) reaction dissolvent, selected from chlorinated aromatic hydrocarbons or fragrance alkane, is preferably selected from toluene, dimethylbenzene or chlorobenzene；
Step (a) reaction temperature is 60 DEG C～solvent reflux temperature；
Step (a) response time is 2～20 hours, preferably 4～8 hours；
The described acid of step (b) is selected from sulphuric acid, nitric acid or hydrochloric acid；
The described acid of step (b) is 3: 1～50: 1 with the mol ratio of (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, preferably 6: 1～20: 1；
Step (b) reaction dissolvent is selected from water, formic acid, acetic acid or its mixture；
Step (b) reaction temperature is 50～120 DEG C, preferably 60～100 DEG C.
After the step (a) of above-mentioned PTC124 preparation method or step (b) have been reacted, product carries out isolated and purified by the ordinary skill in the art, such as, filter, concentrate, recrystallization etc..
The present invention prepares the reaction scheme of PTC124 and can be summarized as follows, including four steps: (1) m-dicyanobenzene and azanol or the acceptable reactant salt of azanol, obtains 3-(N-hydroxyl amidino groups) benzonitrile (I)；(2) 3-(N-hydroxyl amidino groups) benzonitrile (I) reacts in the presence of a base with 2-fluorobenzoyl chloride, obtains 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile (II)；(3) 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile (II) dehydration condensation, obtains 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile (III)；(4) 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzonitrile (III) hydrolyzes in presence of an acid, obtains 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzoic acid (PTC124)
In the present invention, in view of formula (II) compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile is the key intermediate preparing PTC124, therefore formula (I) compound 3-(N-hydroxyl amidino groups) benzonitrile and formula (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-bases] benzonitrile can use as midbody compound in the preparation of PTC124.
The present invention develops new intermediate 3-[N-(the 2-fluorobenzoyl epoxide) amidino groups] benzonitrile (II) prepared for PTC124, and then develops the new preparation method of PTC124.Synthetic route of the present invention is reasonable in design, and compared with prior art, have selected m-dicyanobenzene cheap and easy to get is initiation material, is conducive to cost is greatly lowered, reactions steps of the present invention is few, and technological operation is easy, and reaction condition is gentle, without special installation, environmental friendliness, it is suitable for industrialization and produces.Key intermediate 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile (II) has high yield, high-purity and low cost, molar yield ＞ 80%, HPLC purity >=99.5%, it is possible to meet the pharmaceutical field requirement to high-quality intermediate.Product PTC124 has high yield, high-purity and low cost, total molar yield ＞ 70%, HPLC purity >=99.5%, it is possible to meet the pharmaceutical field requirement to high-quality crude drug.
Detailed description of the invention
Will assist in by the following examples and be further appreciated by the present invention, but be not used in restriction present disclosure.
Various reagent used in embodiment are all commercially available.
" room temperature " described in embodiment refers to 10 DEG C～30 DEG C.
Test analytical instrument in embodiment and condition:
1H-NMR test instrunment: AV-400 nuclear magnetic resonance analyser (Bruker company of Germany)；
HPLC test instrunment: LC-20AT type high performance liquid chromatograph (Shimadzu Corporation of Japan)；
HPLC test condition: Phenomenon luna chromatographic column, C18,5 μm, 4.6mm × 250mm；Detection wavelength (UV) 242nm；Detection time 25min；Flow velocity 0.8mL/min；Flowing phase: methanol: water (20mmol/L sodium dihydrogen phosphate phosphoric acid adjusts pH=3.5)=70%: 30%.
Embodiment
1
(1) preparation of 3-(N-hydroxyl amidino groups) benzonitrile
In 500mL flask; add m-dicyanobenzene 25.6g (0.2mol); 200mL dehydrated alcohol, nitrogen is protected, is warmed up to 50 DEG C; dropping 13.2g 50% aqueous hydroxylamine solution (0.2mol); then insulation reaction 4 hours, HPLC display raw material reaction is complete, concentration and recovery etoh solvent 150mL; add the dilution of 200mL water; separate out precipitation, stir 30 minutes, filter; filter cake is washed; draining, 50 DEG C are dried under vacuum to constant weight, obtain 27.7g white solid 3-(N-hydroxyl amidino groups) benzonitrile; molar yield 86%, HPLC purity 99.0%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=8.0Hz), 7.86 (d, 1H, J=7.6Hz), 7.61 (t, 1H, J=7.6Hz), 6.00 (s, 2H).
(2) preparation of 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
In 500mL flask, add 3-(N-hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 200mL acetonitrile, stirring is lower adds 11.2g triethylamine, ice-water bath is cooled to 5 DEG C, dropping 16.6g (0.105mol) 2-fluorobenzoyl chloride, then insulation reaction 2 hours, HPLC display raw material reaction is complete.
40 DEG C of water-baths are concentrated in vacuo recovery acetonitrile 150mL, and residue is poured in frozen water, separates out precipitation, filter, washing, drain, recrystallisation from isopropanol obtains 26.3g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, molar yield 93%, HPLC purity 99.5%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.12-8.09 (m, 2H), 8.01 (d, 1H, J=8.0Hz), 7.73-7.09 (m, 2H), 7.41-7.34 (m, 2H), 7.01 (s, 2H).
(3) preparation of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile
Adding 26.3g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, 115mL toluene in 250mL flask, temperature rising reflux divides water, reaction 8h, HPLC monitoring to be less than 0.5% to raw material, stopped reaction.
It is cooled to room temperature, stirs 3 hours, filter, obtain 22.6g 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, molar yield 92%, HPLC purity: 98.9%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.46 (s, 1H), (8.41 d, 1H, J=8.0Hz), (8.27 t, 1H, J=7.6Hz), (8.13 d, 1H, J=8.0Hz), 7.86-7.81 (m, 2H), 7.59-7.50 (m, 2H).
(4) 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic preparation
13.3g 3-[5-(2-fluorophenyl)-1 is added in 250mL flask, 2,4-diazole-3-base] benzonitrile (0.05mol), acetic acid 133mL, 10mL water, dropping 20mL concentrated sulphuric acid, being warmed up to 100 DEG C, be incubated 5 hours, HPLC display raw material reaction is complete, continuing reaction 2 hours, reaction completes.
It is cooled to 20 DEG C, insulated and stirred 3 hours, filter, filter cake washing with acetone, drain, 60 DEG C are vacuum dried 12 hours, obtain 13.5g off-white color crystal 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid, molar yield: 95%.HPLC purity: 99.6%.
1H NMR(CDCl3, 400MHz) and δ: 13.34 (s, 1H), 8.63 (s, 1H), 8.33 (d, 1H, J=7.6Hz), 8.27 (t, 1H, J=7.6Hz), 8.19 (d, 1H, J=7.6Hz), 7.81-7.73 (m, 2H), 7.58-7.48 (m, 2H).
Embodiment
2
(1) preparation of 3-(N-hydroxyl amidino groups) benzonitrile
In 500mL flask, add m-dicyanobenzene 25.6g (0.2mol), 15.4g oxammonium hydrochloride. (0.22mol), 200mL methanol, nitrogen is protected, it is warmed up to 50 DEG C, dropping 22g triethylamine (0.22mol), then insulation reaction 4 hours, HPLC display raw material reaction is complete, concentration and recovery solvent methanol 150mL, add the dilution of 200mL water, separate out precipitation, stir 30 minutes, filter, filter cake is washed, drain, 50 DEG C are dried under vacuum to constant weight, obtain 29.0g white solid 3-(N-hydroxyl amidino groups) benzonitrile, molar yield 90%, HPLC purity 98.9%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=8.0Hz), 7.86 (d, 1H, J=7.6Hz), 7.61 (t, 1H, J=7.6Hz), 6.00 (s, 2H).
(2) preparation of 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
In 500mL flask, add 3-(N-hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 200mL acetonitrile, stirring is lower adds 11.2g triethylamine, ice-water bath is cooled to 10 DEG C, dropping 15.8g (0.1mol) 2-fluorobenzoyl chloride, then insulation reaction 2 hours, HPLC display raw material reaction is complete.
40 DEG C of water-baths are concentrated in vacuo recovery acetonitrile 150mL, and residue is poured in frozen water, separates out precipitation, filter, washing, drain, recrystallized from acetonitrile obtains 26.3g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, molar yield 93%, HPLC purity 99.6%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.12-8.09 (m, 2H), 8.01 (d, 1H, J=8.0Hz), 7.73-7.09 (m, 2H), 7.41-7.34 (m, 2H), 7.01 (s, 2H).
(3) preparation of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile
Adding 26.3g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, 115mL dimethylbenzene in 250mL flask, temperature rising reflux divides water, reaction 8h, HPLC monitoring to be less than 0.5% to raw material, stopped reaction.
It is cooled to room temperature, stirs 3 hours, filter, washing with acetone, vacuum drying, obtain 23.3g 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, molar yield 95%, HPLC purity: 98.9%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.46 (s, 1H), (8.41 d, 1H, J=8.0Hz), (8.27 t, 1H, J=7.6Hz), (8.13 d, 1H, J=8.0Hz), 7.86-7.81 (m, 2H), 7.59-7.50 (m, 2H).
(4) 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic preparation
13.3g 3-[5-(2-fluorophenyl)-1 is added in 250mL flask, 2,4-diazole-3-base] benzonitrile (0.05mol), acetic acid 133mL, 10mL water, dropping 50mL concentrated nitric acid, being warmed up to 100 DEG C, be incubated 5 hours, HPLC display raw material reaction is complete, continuing reaction 2 hours, reaction completes.
It is cooled to 20 DEG C, insulated and stirred 3 hours, filter, filter cake washing with acetone, drain, 60 DEG C are vacuum dried 12 hours, obtain 13.7g off-white color crystal 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid, molar yield: 96%.HPLC purity: 99.7%.
Nuclear magnetic data:1H NMR(CDCl3, 400MHz) and δ: 13.34 (s, 1H), 8.63 (s, 1H), 8.33 (d, 1H, J=7.6Hz), 8.27 (t, 1H, J=7.6Hz), 8.19 (d, 1H, J=7.6Hz), 7.81-7.73 (m, 2H), 7.58-7.48 (m, 2H).
Embodiment
3
(1) preparation of 3-(N-hydroxyl amidino groups) benzonitrile
In 500mL flask; add m-dicyanobenzene 25.6g (0.2mol); 200mL dehydrated alcohol, nitrogen is protected, is warmed up to 40 DEG C; dropping 15.8g 50% aqueous hydroxylamine solution (0.24mol); then insulation reaction 3 hours, HPLC display raw material reaction is complete, concentration and recovery etoh solvent 150mL; add the dilution of 200mL water; separate out precipitation, stir 30 minutes, filter; filter cake is washed; draining, 50 DEG C are dried under vacuum to constant weight, obtain 28.3g white solid 3-(N-hydroxyl amidino groups) benzonitrile; molar yield 88%, HPLC purity 98.8%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=8.0Hz), 7.86 (d, 1H, J=7.6Hz), 7.61 (t, 1H, J=7.6Hz), 6.00 (s, 2H).
(2) preparation of 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
In 500mL flask, add 3-(N-hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 200mL toluene, stirring is lower adds 14g triethylamine, ice-water bath is cooled to 0 DEG C, dropping 19.4g (0.12mol) 2-fluorobenzoyl chloride, then insulation reaction 1 hour, HPLC display raw material reaction is complete.
Adding 100mL water extracting and demixing, organic facies saturated aqueous common salt washed once, and aqueous phase abandons, organic facies concentrates dry solvent toluene, residue recrystallisation from isopropanol obtains 26.0g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, molar yield 92%, HPLC purity 99.6%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.12-8.09 (m, 2H), 8.01 (d, 1H, J=8.0Hz), 7.73-7.09 (m, 2H), 7.41-7.34 (m, 2H), 7.01 (s, 2H).
(3) preparation of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile
Adding 26.3g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, 115mL toluene in 250mL flask, be warmed up to 100 DEG C, reaction 20h, HPLC monitoring is less than 2.5% to raw material, stopped reaction.
It is cooled to room temperature, stirs 3 hours, filter, obtain 23.6g 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, molar yield 96%, HPLC purity: 98.5%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.46 (s, 1H), (8.41 d, 1H, J=8.0Hz), (8.27 t, 1H, J=7.6Hz), (8.13 d, 1H, J=8.0Hz), 7.86-7.81 (m, 2H), 7.59-7.50 (m, 2H).
(4) 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic preparation
13.3g 3-[5-(2-fluorophenyl)-1 is added in 250mL flask, 2,4-diazole-3-base] benzonitrile (0.05mol), acetic acid 133mL, 20mL water, dropping 60mL sulphuric acid, being warmed up to 70 DEG C, be incubated 18 hours, HPLC display raw material reaction is complete, continuing reaction 2 hours, reaction completes.
It is cooled to 20 DEG C, insulated and stirred 3 hours, filters, filter cake washing with acetone, draining, 60 DEG C are vacuum dried 12 hours, obtain 13.3g white solid 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid, molar yield 93%, HPLC purity: 99.6%.
1H NMR(CDCl3, 400MHz) and δ: 13.34 (s, 1H), 8.63 (s, 1H), 8.33 (d, 1H, J=7.6Hz), 8.27 (t, 1H, J=7.6Hz), 8.19 (d, 1H, J=7.6Hz), 7.81-7.73 (m, 2H), 7.58-7.48 (m, 2H).
Embodiment
4
(1) preparation of 3-(N-hydroxyl amidino groups) benzonitrile
In 500mL flask; add m-dicyanobenzene 25.6g (0.2mol); 200mL anhydrous acetonitrile, nitrogen is protected, is warmed up to 50 DEG C; dropping 13.2g 50% aqueous hydroxylamine solution (0.2mol); then insulation reaction 4 hours, HPLC display raw material reaction is complete, concentration and recovery solvent acetonitrile 150mL; add the dilution of 200mL water; separate out precipitation, stir 30 minutes, filter; filter cake is washed; draining, 50 DEG C are dried under vacuum to constant weight, obtain 27.4g white solid 3-(N-hydroxyl amidino groups) benzonitrile; molar yield 85%, HPLC purity 99.0%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=8.0Hz), 7.86 (d, 1H, J=7.6Hz), 7.61 (t, 1H, J=7.6Hz), 6.00 (s, 2H).
(2) preparation of 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
In 500mL flask, add 3-(N-hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 150mL dichloromethane, stirring is lower adds 18g diisopropylethylamine, ice-water bath is cooled to 0 DEG C, dropping 19.4g (0.12mol) 2-fluorobenzoyl chloride, then insulation reaction 1 hour, HPLC display raw material reaction is complete.
Add 100mL water extracting and demixing, organic facies saturated aqueous common salt washed once, aqueous phase abandons, organic facies concentrates dry methylene chloride, residue recrystallized from acetonitrile obtains 26.9g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, molar yield 95%, HPLC purity 99.7%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.12-8.09 (m, 2H), 8.01 (d, 1H, J=8.0Hz), 7.73-7.09 (m, 2H), 7.41-7.34 (m, 2H), 7.01 (s, 2H).
(3) preparation of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile
Adding 26.3g 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, 160mL toluene in 250mL flask, temperature rising reflux divides water, reaction 10h, HPLC monitoring to be less than 0.5% to raw material, stopped reaction.
It is cooled to room temperature, stirs 3 hours, filter, obtain 22.6g 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, molar yield 92%, HPLC purity: 98.9%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.46 (s, 1H), (8.41 d, 1H, J=8.0Hz), (8.27 t, 1H, J=7.6Hz), (8.13 d, 1H, J=8.0Hz), 7.86-7.81 (m, 2H), 7.59-7.50 (m, 2H).
(4) 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic preparation
13.3g 3-[5-(2-fluorophenyl)-1 is added in 250mL flask, 2,4-diazole-3-base] benzonitrile (0.05mol), acetic acid 133mL, 10mL water, dropping 60mL hydrochloric acid, being warmed up to 70 DEG C, be incubated 18 hours, HPLC display raw material reaction is complete, continuing reaction 2 hours, reaction completes.
It is cooled to 20 DEG C, insulated and stirred 3 hours, filter, filter cake washing with acetone, drain, 60 DEG C are vacuum dried 12 hours, obtain 13.5g off-white color crystal 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid, molar yield: 95%.HPLC purity: 99.6%.
1H NMR(CDCl3, 400MHz) and δ: 13.34 (s, 1H), 8.63 (s, 1H), 8.33 (d, 1H, J=7.6Hz), 8.27 (t, 1H, J=7.6Hz), 8.19 (d, 1H, J=7.6Hz), 7.81-7.73 (m, 2H), 7.58-7.48 (m, 2H).
Embodiment
5
(1) preparation of 3-(N--hydroxyl amidino groups) benzonitrile
In 50L reactor, add 20L dehydrated alcohol, m-dicyanobenzene 2.56kg, it is warmed up to 50 DEG C, in 2-3 hour, drips 1.32kg 50% aqueous hydroxylamine solution, then insulation reaction 4 hours, HPLC display raw material reaction is complete, concentration and recovery etoh solvent 17L, adds the dilution of 20L purified water, separates out precipitation, stir 30 minutes, filtering, filter cake is washed, and drains, 50 DEG C are dried under vacuum to constant weight, obtain 2.84kg white solid 3-(N-hydroxyl amidino groups) benzonitrile, molar yield 88%, HPLC purity 99.1%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=8.0Hz), 7.86 (d, 1H, J=7.6Hz), 7.61 (t, 1H, J=7.6Hz), 6.00 (s, 2H).
(2) preparation of 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
In 50L reactor, add 3-(N-hydroxyl amidino groups) benzonitrile 1.6kg, 14L acetonitrile, stirring is lower adds 1.12kg triethylamine, and ice-water bath is cooled to 10 DEG C, drips 1.66kg2-fluorobenzoyl chloride, then insulation reaction 3 hours, HPLC display raw material reaction is complete.
40 DEG C of water-baths are concentrated in vacuo recovery acetonitrile 12L, add 20L drinking water, separate out precipitation, stir 1 hour, filter, washing, drain, 10L recrystallisation from isopropanol obtains 2.68kg3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, molar yield 95%, HPLC purity 99.7%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.12-8.09 (m, 2H), 8.01 (d, 1H, J=8.0Hz), 7.73-7.09 (m, 2H), 7.41-7.34 (m, 2H), 7.01 (s, 2H).
(3) preparation of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile
Adding 4.3kg 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile, 30L toluene in 50L reactor, temperature rising reflux divides water, reaction 10h, HPLC monitoring to be less than 1.0% to raw material, stopped reaction.
It is cooled to room temperature, stirs 3 hours, filter, obtain 3.8kg 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, molar yield 94%, HPLC purity: 99.0%.
Nuclear magnetic data:1H NMR (400MHz, DMSO-d6) δ (ppm): 8.46 (s, 1H), (8.41 d, 1H, J=8.0Hz), (8.27 t, 1H, J=7.6Hz), (8.13 d, 1H, J=8.0Hz), 7.86-7.81 (m, 2H), 7.59-7.50 (m, 2H).
(4) 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic preparation
Adding 3.7kg 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile, acetic acid 18.5L, 2L water in 50L flask, drip 10L concentrated sulphuric acid, be then warmed up to 100 DEG C, be incubated 10 hours, HPLC display raw material reaction is complete, and reaction completes.
It is cooled to 20 DEG C, insulated and stirred 3 hours, filters, filter cake acetone 3L washs, and drains, and filter cake is then added in 20L reactor, add 15L acetone, it is stirred at room temperature 2 hours, filters, washing with acetone, filter cake 60 DEG C is vacuum dried 12 hours, obtain 3.8kg off-white color crystal 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid.Molar yield: 96%, HPLC purity: 99.7%.
1H NMR(CDCl3, 400MHz) and δ: 13.34 (s, 1H), 8.63 (s, 1H), 8.33 (d, 1H, J=7.6Hz), 8.27 (t, 1H, J=7.6Hz), 8.19 (d, 1H, J=7.6Hz), 7.81-7.73 (m, 2H), 7.58-7.48 (m, 2H).
Claims (9)
1. compound 3-[N-(the 2-fluorobenzoyl epoxide) amidino groups] benzonitrile shown in a formula (II):
2. formula (II) compound 3-described in a claim 1 [N-(2-fluorobenzoyl epoxide) amidino groups] benzene first
The preparation method of nitrile, comprises the following steps:
Step (1): m-dicyanobenzene and azanol or the acceptable reactant salt of azanol, obtains formula (I) compound
3-(N-hydroxyl amidino groups) benzonitrile
Step (2): formula (I) compound 3-(N-hydroxyl amidino groups) benzonitrile is deposited at alkali with 2-fluorobenzoyl chloride
In lower reaction, obtain formula (II) compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile
Preparation method the most according to claim 2, it is characterised in that in step (1): described hydroxyl
The acceptable salt of amine is selected from hydroxylamine hydrochloride or hydroxylamine sulfate；M-dicyanobenzene is acceptable with azanol or azanol
The mol ratio of salt is 1: 0.8～1: 2；Reaction dissolvent selected from methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol,
The tert-butyl alcohol, acetonitrile, toluene or dichloromethane；Reaction temperature is 30～100 DEG C.
Preparation method the most according to claim 2, it is characterised in that in step (2): described alkali
Selected from carbonate, bicarbonate, phosphate, hydrophosphate or organic amine；Formula (I) compound 3-(N-
Hydroxyl amidino groups) mol ratio of benzonitrile and 2-fluorobenzoyl chloride is 1: 0.9～1: 2；Reaction dissolvent is selected from alkyl chloride
Hydrocarbon, highly polar aprotic solvent or apolar aprotic solvent, be preferably selected from dichloromethane, acetonitrile, acetic acid
Ethyl ester, oxolane, toluene or DMF；Reaction temperature is 0～50 DEG C.
5. the benzoic preparation method of 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base], including following
Step:
Step (a): formula (II) compound 3-[N-(2-fluorobenzoyl epoxide) amidino groups] benzonitrile dehydration condensation,
Obtain formula (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile
Step (b): formula (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile is in acid
In the presence of hydrolyze, obtain 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzoic acid
Preparation method the most according to claim 5, it is characterised in that in step (a): react molten
Agent, selected from chlorinated aromatic hydrocarbons or fragrance alkane, is preferably selected from toluene, dimethylbenzene or chlorobenzene；Reaction temperature is 60 DEG C
～solvent reflux temperature；Response time is 2～20 hours.
Preparation method the most according to claim 5, it is characterised in that in step (b): described acid
Selected from sulphuric acid, nitric acid or hydrochloric acid；Described acid and (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole
-3-base] mol ratio of benzonitrile is 3: 1～50: 1；Reaction dissolvent is selected from water, formic acid, acetic acid or its mixture；
Reaction temperature is 50～120 DEG C.
8. formula (I) compound 3-(N-hydroxyl amidino groups) benzonitrile is at 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-
Base] in benzoic preparation as the purposes of midbody compound
9. formula (III) compound 3-[5-(2-fluorophenyl)-1,2,4-diazole-3-base] benzonitrile is at 3-[5-(2-
Fluorophenyl)-1,2,4-diazole-3-bases] in benzoic preparation as the purposes of midbody compound
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| PCT/CN2016/000305 WO2017004964A1 (en) | 2015-07-03 | 2016-06-12 | Preparation method of 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid |
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| CN101535284A (en) * | 2006-09-08 | 2009-09-16 | Ptc医疗公司 | Processes for the preparation of 1,2,4-oxadiazole benzoic acids |
| CN101605542A (en) * | 2006-12-12 | 2009-12-16 | 艾博特公司 | Pharmaceutical composition with and using method |
| WO2010138600A2 (en) * | 2009-05-29 | 2010-12-02 | Abbott Laboratories | Pharmaceutical compositions for the treatment of pain |
| CN102089297A (en) * | 2008-06-06 | 2011-06-08 | 雅培制药有限公司 | Novel 1,2,4 oxadiazole compounds and methods of use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101535284A (en) * | 2006-09-08 | 2009-09-16 | Ptc医疗公司 | Processes for the preparation of 1,2,4-oxadiazole benzoic acids |
| CN101605542A (en) * | 2006-12-12 | 2009-12-16 | 艾博特公司 | Pharmaceutical composition with and using method |
| CN102089297A (en) * | 2008-06-06 | 2011-06-08 | 雅培制药有限公司 | Novel 1,2,4 oxadiazole compounds and methods of use thereof |
| WO2010138600A2 (en) * | 2009-05-29 | 2010-12-02 | Abbott Laboratories | Pharmaceutical compositions for the treatment of pain |
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