CN106316885B - A kind of preparation method of 3- [5- (2- fluorophenyl) -1,2,4- oxadiazoles -3- base] benzoic acid - Google Patents
A kind of preparation method of 3- [5- (2- fluorophenyl) -1,2,4- oxadiazoles -3- base] benzoic acid Download PDFInfo
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- CN106316885B CN106316885B CN201510386166.6A CN201510386166A CN106316885B CN 106316885 B CN106316885 B CN 106316885B CN 201510386166 A CN201510386166 A CN 201510386166A CN 106316885 B CN106316885 B CN 106316885B
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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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- C—CHEMISTRY; METALLURGY
- 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 present invention provides the new preparation method of anti-muscular dystrophy disease drug 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid and new midbody compounds.The preparation method highway route design is reasonable, overcomes that existing preparation method is at high cost, is unfavorable for environmental protection, the disadvantages such as yield is low, purity is low, has the advantages that raw material is cheap and easy to get, product yield is good, with high purity, at low cost, environmentally friendly, suitable industrialization.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical fields.In particular to a kind of anti-muscular dystrophy disease drug 3-
The preparation method of [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid.
Background technique
3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid, is PTC Therapeutics Inc. of the U.S. (PTC
Therapeutics) the experimental drug developed, English name Ataluren, alias PTC124 (also be called in this application by letter
PTC124).As a kind of effective nonsense mutation inhibitor, the clinical data of PTC124 shows the Du Shi flesh battalion to nonsense mutation
Supporting bad disease (Duchenne Muscular Dystrophy) patient has positive therapeutic.
The structural formula of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid is as follows:
Patent document US2004204461A1 reports a kind of preparation method of PTC124 at first, comprising the following steps: (1)
3- cyanobenzoic acid and iodomethane reaction generate 3- cyano-benzoic acid methyl ester；(2) 3- cyano-benzoic acid methyl ester and azanol reaction,
Obtain 3- (N- hydroxyl amidino groups) methyl benzoate；(3) 3- (N- hydroxyl amidino groups) methyl benzoate is reacted with 2- fluorobenzoyl chloride, is obtained
To 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] methyl benzoate；(4) 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzoic acid first
Ester dehydration condensation obtains 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] methyl benzoate；(5) 3- [5- (2- fluorobenzene
Base) -1,2,4- oxadiazoles -3- bases] methyl benzoate hydrolysis, obtain 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzene
Formic acid.Its chemical equation is as follows:
The raw material 3- cyanobenzoic acid price that the preparation method uses, iodomethane are poisonous reagents and belong to control medicine
Product, costly, the production cost is very high for the price of gained 3- cyano-benzoic acid methyl ester, is not suitable for industrialization.In embodiment, finished product
HPLC purity it is not high, be 98%, be unfavorable for the application of high standard preparation, total moles yield only has 57%.
Gupta, Puneet K.；Hussain, Mohd.Kamil et al. are in New Journal of Chemistry；
vol.38；(2014)；P.3062-3070 another preparation method of PTC124 is disclosed in, comprising the following steps: (1) 2- fluorine
Benzoic acid and 3- methyl benzamidine hydrochloride are in 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester
(HATU) and in the presence of n,N-diisopropylethylamine (DIPEA) it reacts, obtains 5- (2- fluorophenyl) -3- (3- aminomethyl phenyl) -1,
2,4- oxadiazoles, molar yield 70%；(2) 5- (2- fluorophenyl) -3- (3- aminomethyl phenyl) -1,2,4- oxadiazoles exist in pyridine
Under, 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid, molar yield 40% are obtained with potassium permanganate oxidation.Its
Chemical equation is as follows:
The preparation method only has two-step reaction, but reaction selectivity is poor, and post-processing is difficult, needs column chromatography for separation, always rubs
Your yield is low, and only 28%, second step uses potassium permanganate oxidation, and serious three wastes are unfavorable for environmental protection, it is difficult to industrialization.
All there is highway route design defect in view of existing PTC124 preparation method, causes that at high cost, yield is low, is unfavorable for
Environmental protection is not suitable for the problems such as industrialization, it is therefore desirable to the preparation method of PTC-124 is improved, research and development reaction step is few, quality is high,
New synthetic route that is at low cost, environmentally friendly, being suitble to industrialization.
Summary of the invention
In view of the deficiencies of the prior art, the object of the present invention is to provide the preparation methods of new PTC124 a kind of, and provide
New key intermediate compound and preparation method thereof.
Purpose according to the present invention, the present invention provides a kind of new midbody compound 3- [N- for being used to prepare PTC124
(2- fluorobenzoyl oxygroup) amidino groups] benzonitrile, shown in structural formula such as formula (II):
The present invention also provides one kind of the formula (II) compound 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile
Preparation method, comprising the following steps:
Step (1): m-dicyanobenzene and azanol or the acceptable reactant salt of azanol obtain formula (I) compound 3- (N- hydroxyamidines
Base) benzonitrile
Step (2): formula (I) compound 3- (N- hydroxyl amidino groups) benzonitrile reacts in the presence of a base with 2- fluorobenzoyl chloride,
Obtain formula (II) compound 3- [N- (2- fluorobenzoyl oxygroup) 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 azanol, preferably pharmaceutically acceptable salt, such as selected from hydroxylamine hydrochloride or hydroxylamine sulfate；
In step (1), m-dicyanobenzene is 1: 0.8~1: 2 with the molar ratio of azanol or the acceptable salt of azanol；
Step (1) reaction dissolvent be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, acetonitrile, toluene or
Methylene chloride；
Step (1) reaction temperature is 30~100 DEG C, preferably 40~50 DEG C；
Step (1), when using aqueous hydroxylamine solution, without adding alkali.When using azanol acceptable salt, need to be added with
Its equivalent or excessive alkali, make system be maintained at alkaline environment, used in alkali be selected from carbonate, bicarbonate, phosphoric acid
Salt, hydrophosphate or organic amine are preferably selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen phosphate, sodium phosphate, potassium phosphate, three
Ethamine, pyridine or diisopropylethylamine；
Step (2) alkali is selected from carbonate, bicarbonate, phosphate, hydrophosphate or organic amine, is preferably selected from carbonic acid
Sodium, potassium carbonate, sodium bicarbonate, potassium hydrogen phosphate, sodium phosphate, potassium phosphate, triethylamine, pyridine or diisopropylethylamine；
In step (2), the molar ratio of formula (I) compound 3- (N- hydroxyl amidino groups) benzonitrile and 2- fluorobenzoyl chloride is 1:
0.9~1: 2；
Step (2) reaction dissolvent is selected from chloralkane, highly polar aprotic solvent or apolar aprotic solvent, preferably selects
From methylene chloride, acetonitrile, ethyl acetate, tetrahydrofuran, toluene or n,N-Dimethylformamide；
Step (2) reaction temperature is 0~50 DEG C, preferably 0~10 DEG C.
After the reaction was completed, product passes through this field for the step of above-mentioned formula (II) compounds process for production thereof (1) or step (2)
Routine techniques is isolated and purified, such as filtering, concentration, extraction, recrystallization etc..
Purpose according to the present invention, the present invention provides the preparation methods of PTC124 a kind of, comprising the following steps:
Step (a): formula (II) compound 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile dehydration condensation obtains formula
(III) compound 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
Step (b): formula (III) compound 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile exists in acid
Lower hydrolysis obtains 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
In the preferred embodiment of above-mentioned PTC124 preparation method:
Step (a) reaction dissolvent is selected from chlorinated aromatic hydrocarbons or fragrant alkane, is preferably selected from toluene, dimethylbenzene or chlorobenzene；
Step (a) reaction temperature is 60 DEG C~solvent reflux temperature；
Step (a) reaction time is 2~20 hours, preferably 4~8 hours；
Step (b) acid is selected from sulfuric acid, nitric acid or hydrochloric acid；
Step (b) acid and (III) compound 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
Molar ratio is 3: 1~50: 1, preferably 6: 1~20: 1；
Step (b) reaction dissolvent is selected from or mixtures thereof water, formic acid, acetic acid；
Step (b) reaction temperature is 50~120 DEG C, preferably 60~100 DEG C.
After the reaction was completed, product passes through the conventional skill of this field for the step of above-mentioned PTC124 preparation method (a) or step (b)
Art is isolated and purified, such as filtering, concentration, recrystallization etc..
The reaction route that the present invention prepares PTC124 can be summarized as follows, including four steps: (1) m-dicyanobenzene and azanol
Or the acceptable reactant salt of azanol, obtain 3- (N- hydroxyl amidino groups) benzonitrile (I)；(2) 3- (N- hydroxyl amidino groups) benzonitrile (I) with
2- fluorobenzoyl chloride reacts in the presence of a base, obtains 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile (II)；(3)3-[N-
(2- fluorobenzoyl oxygroup) amidino groups] benzonitrile (II) dehydration condensation, obtain 3- [- 1,2,4- oxadiazoles -3- of 5- (2- fluorophenyl)
Base] benzonitrile (III)；(4) 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile (III) water in presence of an acid
Solution, obtains 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid (PTC124)
It is to prepare PTC124 in view of formula (II) compound 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile in the present invention
Key intermediate, therefore formula (I) compound 3- (N- hydroxyl amidino groups) benzonitrile and formula (III) compound 3- [5- (2- fluorobenzene
Base) -1,2,4- oxadiazoles -3- bases] benzonitrile can use in the preparation of PTC124 as midbody compound.
The present invention develops new intermediate 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzene first for PTC124 preparation
Nitrile (II), and then develop the new preparation method of PTC124.Synthetic route design of the present invention is reasonable, compared with prior art,
It has selected m-dicyanobenzene cheap and easy to get for starting material, has been conducive to that cost is greatly lowered, reaction step of the present invention is few, technique
Easy to operate, reaction condition is mild, is not necessarily to special installation, environmental-friendly, is suitble to industrialization production.Key intermediate 3- [N- (2-
Fluorobenzoyl oxygroup) amidino groups] benzonitrile (II) have in high yield, high-purity and low cost, molar yield > 80%, HPLC purity
>=99.5%, it can satisfy requirement of the pharmaceutical field to high quality intermediate.Product PTC124 have in high yield, high-purity and low
Cost, total moles yield > 70%, HPLC purity >=99.5% can satisfy requirement of the pharmaceutical field to high quality bulk pharmaceutical chemicals.
Specific embodiment
It will be helpful to further understand the present invention by the following examples, but be not used in the limitation contents of the present invention.
Various reagents used in embodiment are all commercially available.
" room temperature " described in embodiment refers to 10 DEG C~30 DEG C.
Test analytical instrument and condition in embodiment:
1H-NMR test equipment: AV-400 Nuclear Magnetic Resonance (German Bruker company)；
HPLC test equipment: LC-20AT type high performance liquid chromatograph (Japanese Shimadzu Corporation)；
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；Mobile phase: methanol: water (20mmol/L sodium dihydrogen phosphate phosphoric acid tune pH
=3.5)=70%: 30%.
Embodiment 1
(1) preparation of 3- (N- hydroxyl amidino groups) benzonitrile
It in 500mL flask, is added m-dicyanobenzene 25.6g (0.2mol), 200mL dehydrated alcohol, nitrogen protection is warming up to
It 50 DEG C, being added dropwise 50% aqueous hydroxylamine solution of 13.2g (0.2mol), then insulation reaction 4 hours, HPLC shows raw material fully reacting,
Concentration and recovery etoh solvent 150mL is added the dilution of 200mL water, precipitating is precipitated, stirs 30 minutes, filtering, and filter cake washing is taken out
Dry, 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 oxygroup) amidino groups] benzonitrile
In 500mL flask, 3- (N- hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 200mL acetonitrile, under stirring is added
11.2g triethylamine is added, ice-water bath is cooled to 5 DEG C, 16.6g (0.105mol) 2- fluorobenzoyl chloride is added dropwise, then insulation reaction 2
Hour, HPLC shows raw material fully reacting.
40 DEG C of water-bath vacuum concentration recycling acetonitrile 150mL, residue pour into ice water, precipitating are precipitated, filters, washes, takes out
Dry, recrystallisation from isopropanol obtains 26.3g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile, and molar yield 93%, HPLC is pure
Degree 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- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
26.3g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile is added in 250mL flask, 115mL toluene rises
Warm reflux water-dividing reacts 8h, and HPLC is monitored to raw material less than 0.5%, stops reaction.
It is cooled to room temperature, is stirred 3 hours, filtering obtains 22.6g 3- [- 1,2,4- oxadiazoles -3- of 5- (2- fluorophenyl)
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) preparation of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
13.3g 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile is added in 250mL flask
The 20mL concentrated sulfuric acid is added dropwise in (0.05mol), acetic acid 133mL, 10mL water, is warming up to 100 DEG C, keeps the temperature 5 hours, and HPLC shows raw material
Fully reacting, the reaction was continued 2 hours, and reaction is completed.
20 DEG C are cooled to, insulated and stirred 3 hours, filtering, filter cake acetone washing was drained, and 60 DEG C are dried in vacuo 12 hours,
Obtain 13.5g off-white color crystal 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] 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, it is added m-dicyanobenzene 25.6g (0.2mol), 15.4g hydroxylamine hydrochloride (0.22mol), 200mL
Methanol, nitrogen protection are warming up to 50 DEG C, are added dropwise 22g triethylamine (0.22mol), then insulation reaction 4 hours, and HPLC display is former
Expect fully reacting, concentration and recovery solvent methanol 150mL is added the dilution of 200mL water, precipitating is precipitated, stir 30 minutes, filters, filter
Cake washing, is drained, 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 oxygroup) amidino groups] benzonitrile
In 500mL flask, 3- (N- hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 200mL acetonitrile, under stirring is added
11.2g triethylamine is added, ice-water bath is cooled to 10 DEG C, 15.8g (0.1mol) 2- fluorobenzoyl chloride is added dropwise, then insulation reaction 2
Hour, HPLC shows raw material fully reacting.
40 DEG C of water-bath vacuum concentration recycling acetonitrile 150mL, residue pour into ice water, precipitating are precipitated, filters, washes, takes out
Dry, recrystallized from acetonitrile obtains 26.3g 3- [N- (2- fluorobenzoyl oxygroup) 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- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
Addition 26.3g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile in 250mL flask, 115mL dimethylbenzene,
Temperature rising reflux divides water, reacts 8h, and HPLC is monitored to raw material less than 0.5%, stops reaction.
It is cooled to room temperature, is stirred 3 hours, filtering, acetone washing is dried in vacuo, obtains 23.3g 3- [5- (2- fluorobenzene
Base) -1,2,4- oxadiazoles -3- bases] 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) preparation of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
13.3g 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile is added in 250mL flask
50mL concentrated nitric acid is added dropwise in (0.05mol), acetic acid 133mL, 10mL water, is warming up to 100 DEG C, keeps the temperature 5 hours, and HPLC shows raw material
Fully reacting, the reaction was continued 2 hours, and reaction is completed.
20 DEG C are cooled to, insulated and stirred 3 hours, filtering, filter cake acetone washing was drained, and 60 DEG C are dried in vacuo 12 hours,
Obtain 13.7g off-white color crystal 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] 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
It in 500mL flask, is added m-dicyanobenzene 25.6g (0.2mol), 200mL dehydrated alcohol, nitrogen protection is warming up to
It 40 DEG C, is added dropwise 50% aqueous hydroxylamine solution of 15.8g (0.24mol), then insulation reaction 3 hours, HPLC shows that raw material has reacted
Entirely, concentration and recovery etoh solvent 150mL is added the dilution of 200mL water, precipitating is precipitated, stirs 30 minutes, filtering, and filter cake washing is taken out
Dry, 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 oxygroup) amidino groups] benzonitrile
In 500mL flask, 3- (N- hydroxyl amidino groups) benzonitrile 16.1g (0.1mol), 200mL toluene, under stirring is added
14g triethylamine is added, ice-water bath is cooled to 0 DEG C, 19.4g (0.12mol) 2- fluorobenzoyl chloride is added dropwise, then insulation reaction 1 is small
When, HPLC shows raw material fully reacting.
100mL water extracting and demixing is added, organic phase saturated salt solution washed once, and water phase abandons, and organic phase concentration is done molten
Agent toluene, residue obtain 26.0g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile with recrystallisation from isopropanol, mole receipts
Rate 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- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
26.3g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile is added in 250mL flask, 115mL toluene rises
Temperature reacts 20h to 100 DEG C, and HPLC is monitored to raw material less than 2.5%, stops reaction.
It is cooled to room temperature, is stirred 3 hours, filtering obtains 23.6g 3- [- 1,2,4- oxadiazoles -3- of 5- (2- fluorophenyl)
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) preparation of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
13.3g 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile is added in 250mL flask
60mL sulfuric acid is added dropwise in (0.05mol), acetic acid 133mL, 20mL water, is warming up to 70 DEG C, keeps the temperature 18 hours, and HPLC shows that raw material is anti-
Should completely, the reaction was continued 2 hours, and reaction is completed.
20 DEG C are cooled to, insulated and stirred 3 hours, filtering, filter cake acetone washing was drained, and 60 DEG C are dried in vacuo 12 hours,
13.3g white solid 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid is obtained, molar yield 93%, HPLC is pure
Degree: 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
It in 500mL flask, is added m-dicyanobenzene 25.6g (0.2mol), 200mL anhydrous acetonitrile, nitrogen protection is warming up to
It 50 DEG C, being added dropwise 50% aqueous hydroxylamine solution of 13.2g (0.2mol), then insulation reaction 4 hours, HPLC shows raw material fully reacting,
Concentration and recovery solvent acetonitrile 150mL is added the dilution of 200mL water, precipitating is precipitated, stirs 30 minutes, filtering, and filter cake washing is drained,
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 is pure
Degree 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 oxygroup) amidino groups] benzonitrile
In 500mL flask, 3- (N- hydroxyl amidino groups) benzonitrile 16.1g (0.1mol) is added, 150mL methylene chloride stirs
Lower addition 18g diisopropylethylamine is mixed, ice-water bath is cooled to 0 DEG C, and 19.4g (0.12mol) 2- fluorobenzoyl chloride is added dropwise, then protects
Temperature reaction 1 hour, HPLC shows raw material fully reacting.
100mL water extracting and demixing is added, organic phase saturated salt solution washed once, and water phase abandons, and organic phase concentration is done molten
Agent methylene chloride, residue obtain 26.9g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile with recrystallized from acetonitrile, mole
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- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
26.3g 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile is added in 250mL flask, 160mL toluene rises
Warm reflux water-dividing reacts 10h, and HPLC is monitored to raw material less than 0.5%, stops reaction.
It is cooled to room temperature, is stirred 3 hours, filtering obtains 22.6g 3- [- 1,2,4- oxadiazoles -3- of 5- (2- fluorophenyl)
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) preparation of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
13.3g 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile is added in 250mL flask
60mL hydrochloric acid is added dropwise in (0.05mol), acetic acid 133mL, 10mL water, is warming up to 70 DEG C, keeps the temperature 18 hours, and HPLC shows that raw material is anti-
Should completely, the reaction was continued 2 hours, and reaction is completed.
20 DEG C are cooled to, insulated and stirred 3 hours, filtering, filter cake acetone washing was drained, and 60 DEG C are dried in vacuo 12 hours,
Obtain 13.5g off-white color crystal 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] 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 reaction kettle, 20L dehydrated alcohol is added, m-dicyanobenzene 2.56kg is warming up to 50 DEG C, the drop in 2-3 hours
Add 50% aqueous hydroxylamine solution of 1.32kg, then insulation reaction 4 hours, HPLC shows raw material fully reacting, concentration and recovery solvent second
Alcohol 17L is added the dilution of 20L purified water, precipitating is precipitated, stirs 30 minutes, filtering, and filter cake washing is drained, 50 DEG C are dried under vacuum to
Constant weight obtains 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 oxygroup) amidino groups] benzonitrile
In 50L reaction kettle, 3- (N- hydroxyl amidino groups) benzonitrile 1.6kg, 14L acetonitrile is added, is added with stirring 1.12kg
Triethylamine, ice-water bath are cooled to 10 DEG C, 1.66kg2- fluorobenzoyl chloride are added dropwise, then insulation reaction 3 hours, and HPLC shows raw material
Fully reacting.
40 DEG C of water-bath vacuum concentration recycling acetonitrile 12L, are added 20L drinking water, precipitating are precipitated, stir 1 hour, filtering, water
It washes, drains, 10L recrystallisation from isopropanol obtains 2.68kg3- [N- (2- fluorobenzoyl oxygroup) 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- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile
4.3kg 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile, 30L toluene, heating are added in 50L reaction kettle
Reflux water-dividing reacts 10h, and HPLC is monitored to raw material less than 1.0%, stops reaction.
It is cooled to room temperature, is stirred 3 hours, filtering obtains 3.8kg 3- [- 1,2,4- oxadiazoles -3- of 5- (2- fluorophenyl)
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) preparation of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
3.7kg 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzonitrile, acetic acid are added in 50L flask
The 10L concentrated sulfuric acid is added dropwise in 18.5L, 2L water, is then warming up to 100 DEG C, keeps the temperature 10 hours, and HPLC shows raw material fully reacting, reaction
It completes.
20 DEG C are cooled to, insulated and stirred 3 hours, filtering, filter cake was washed with acetone 3L, drained, and it is anti-that filter cake is then added to 20L
It answers in kettle, 15L acetone is added, is stirred at room temperature 2 hours, filter, acetone washing, 60 DEG C of filter cake are dried in vacuo 12 hours, obtain
3.8kg off-white color crystal 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid.Molar yield: 96%, HPLC are pure
Degree: 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 (4)
1. a kind of formula (II) compound represented 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile:
The preparation side of a kind of (II) compound of formula described in claim 1 3- 2. [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile
Method, comprising the following steps:
Step (1): m-dicyanobenzene and azanol or the acceptable reactant salt of azanol obtain formula (I) compound 3- (N- hydroxyl amidino groups)
Benzonitrile
Step (2): formula (I) compound 3- (N- hydroxyl amidino groups) benzonitrile is reacted in the presence of a base with 2- fluorobenzoyl chloride, is obtained
Formula (II) compound 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile
Wherein, when using aqueous hydroxylamine solution, without adding alkali；When using azanol acceptable salt, be added with its equivalent or
Excessive alkali, the alkali are selected from carbonate, bicarbonate, phosphate, hydrophosphate or organic amine；Wherein,
In step (1): the acceptable salt of azanol is selected from hydroxylamine hydrochloride or hydroxylamine sulfate；M-dicyanobenzene and azanol or hydroxyl
The molar ratio of the acceptable salt of amine is 1:0.8~1:2；Reaction dissolvent be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol,
The tert-butyl alcohol, acetonitrile, toluene or methylene chloride；Reaction temperature is 30~100 DEG C；
In step (2): the alkali is selected from carbonate, bicarbonate, phosphate, hydrophosphate or organic amine；Formula (I) compound 3-
The molar ratio of (N- hydroxyl amidino groups) benzonitrile and 2- fluorobenzoyl chloride is 1:0.9~1:2；Reaction dissolvent is selected from chloralkane, second
Nitrile, ethyl acetate, tetrahydrofuran, toluene or N,N-dimethylformamide；Reaction temperature is 0~50 DEG C.
3. a kind of preparation method of 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid, comprising the following steps:
Step (a): formula (II) compound 3- [N- (2- fluorobenzoyl oxygroup) amidino groups] benzonitrile dehydration condensation obtains formula (III)
Compound 3- [5- (2- fluorophenyl) -1,2,4- oxadiazoles -3- base] benzonitrile
Step (b): formula (III) compound 3- [5- (2- fluorophenyl) -1,2,4- oxadiazoles -3- base] benzonitrile water in presence of an acid
Solution, obtains 3- [- 1,2,4- oxadiazoles -3- base of 5- (2- fluorophenyl)] benzoic acid
Wherein,
In step (a): reaction dissolvent is selected from chlorinated aromatic hydrocarbons or fragrant alkane；Reaction temperature is 60 DEG C~solvent reflux temperature；Instead
It is 2~20 hours between seasonable；
In step (b): the acid is selected from sulfuric acid, nitric acid or hydrochloric acid；It is described acid with (III) compound 3- [5- (2- fluorophenyl) -1,
2,4- oxadiazoles -3- base] benzonitrile molar ratio be 3:1~50:1；Reaction dissolvent is selected from or mixtures thereof water, formic acid, acetic acid；
Reaction temperature is 50~120 DEG C.
4. preparation method according to claim 3, which is characterized in that in step (a): the reaction dissolvent be selected from toluene,
Dimethylbenzene or chlorobenzene.
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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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| 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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| 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 |
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