CN108658961A - A kind of preparation method of Azilsartan - Google Patents
A kind of preparation method of Azilsartan Download PDFInfo
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- CN108658961A CN108658961A CN201810604579.0A CN201810604579A CN108658961A CN 108658961 A CN108658961 A CN 108658961A CN 201810604579 A CN201810604579 A CN 201810604579A CN 108658961 A CN108658961 A CN 108658961A
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- 0 COc1nc2cccc(*3)c2[n]1[*@]3C=CC=C(C=C)c(cccc1)c1C(N1)=NOC1O Chemical compound COc1nc2cccc(*3)c2[n]1[*@]3C=CC=C(C=C)c(cccc1)c1C(N1)=NOC1O 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention belongs to pharmaceutical synthesis fields；A kind of preparation method of Azilsartan, it is characterised in that include the following steps：A kind of preparation method of Azilsartan, it is characterised in that including：1）Compound 5 is acted on hydroxylamine hydrochloride under alkaline condition, and heating reaction generates compound 6；2）Compound 6 is acted in triethylene diamine and carbonyl dimidazoles, and reaction generates compound 4；3）Hydrolysis occurs under alkaline condition for compound 4, obtains Azilsartan crude product；4）Azilsartan crude product is by being refining to obtain Azilsartan.The preparation method of Azilsartan of the present invention has the advantages that the reaction time is short, product purity is high, high income, is suitable for large-scale industrial production.
Description
Technical field
Present invention relates particularly to a kind of preparation methods of Azilsartan, belong to pharmaceutical synthesis field.
Background technology
Azilsartan, chemistry are entitled：2- ethyoxyls -1- [[2'- (4,5- dihydro -5- oxo -1,2,4- oxadiazole -3- bases)
Biphenyl -4- bases] methyl] benzimidazole -7- carboxylic acids.Japanese Wu Tian companies exploitation, in January, 2012, can in Japan's approval listing
With the combination of antagonizing angiotensin II and angiotensin-ii receptor.Peripheral vessels are made to the strength inhibition of vasoconstrictor effects
Drop in resistance generates antihypertensive effect.Concrete structure 1 is as follows：
The synthetic route of Azilsartan is numerous, such as：Patent US5243054 is with compound 2 for starting material and chloro-carbonic acid
Ethyl ester generates compound 3 under the action of DMP, and compound 3 reacts generationization under conditions of sodium methoxide does alkali with hydroxylamine hydrochloride
Object 4 is closed, compound 4 obtains Azilsartan by hydrolysis.Using ethyl chloroformate and sodium methoxide is arrived in synthetic route, industrializing
It can cause great security risk, therefore, be unfavorable for large-scale industrial production in production.
Patent US5243054 reports another synthetic route, with compound 5 and hydroxylamine hydrochloride under the action of sodium methoxide
Reaction generates compound 6, and compound 6 acts on ethyl chloroformate generate compound 4 again, and compound 4 arrives A Qi by hydrolysis
Sha Tan.It is applied equally to poison larger sodium methoxide and ethyl chloroformate.
Patent CN103242305 is reacted with hydroxylamine hydrochloride under the action of triethylamine with compound 5 generates compound 6, changes
It closes object 6 and acts on generation compound 4 with ethyl chloroformate again, compound 4 arrives Azilsartan by hydrolysis.Synthetic route with
US5243054 reports are identical, are only that conditional parameter is different.In 5 reaction process of compound, by-product is more,
Later stage, which need to pass through purifying, can just obtain qualified compound 6, cumbersome, be unfavorable for industrial operation.
Original grinds patent ZL93100006.8 with compound 7 as raw material and hydrazine hydrate, and iron chloride acts on obtaining compound 8, changes
It closes object 8 and compound 5 is obtained by the reaction with tetraethyl orthocarbonate again, compound 5 obtains chemical combination with hydroxylamine hydrochloride by oximation reaction again
Object 6, ethyl chloroformate and compound 6 act on cyclization and obtain compound 4, and compound 4 obtains compound 1 by basic hydrolysis, i.e., Ah
Qi Shatan.
Ethyl chloroformate and hydrazine hydrate are used in said synthesis route, are poisonous and harmful reagent, are caused in production process
Security risk, by-product is more in reaction process, and process route is long, therefore is unfavorable for large-scale industrial production.
In view of safety in production, the purpose of process stabilizing, inventor carries out process optimization on the basis of grinding route with reference to original, obtains one
Kind meets the Azilsartan production technology of industrialized production.
Summary of the invention
The ethyl chloroformate being more toxic is used in view of above-mentioned technique, and plurality of impurities is easy tod produce in technical process,
Technique take and post-process it is cumbersome, inventor with reference to original grind patent ZL93100006.8 on the basis of based on quality derived from design
Theory explores a kind of preparation method of more efficient convenient Azilsartan by many experiments, and this method is easy to operate, production
Product high income, product quality meet related quality criterion, and process stabilizing is suitble to industrialized production.
The technical solution adopted by the present invention is as follows：
A kind of preparation method of Azilsartan, it is characterised in that include the following steps：
1) under the conditions of 20-30 DEG C, sodium bicarbonate and hydroxylamine hydrochloride is added in dimethyl sulfoxide (DMSO) and stirred, 50- is warming up to
Salt is solved under the conditions of 60 DEG C, rear that compound 5 is added, after the reaction was complete, reaction solution is added into water for temperature reaction, is stirred, filtering
Product compound 6 is obtained after drying；
2) compound 6 and carbonyl dimidazoles (CDI) are added to stirring and dissolving in dichloromethane, and the two of triethylene diamine are added
Chloromethanes solution, after the completion of reaction, hydrochloric acid is adjusted to acidity, obtains product compound 4 after liquid separation after organic phase filtration drying；
3) compound 4 is hydrolyzing in the presence of alkali, and after the reaction was complete, hydrochloric acid is adjusted to acidity, and Ah is obtained after filtration drying
Qi Shatan crude products；
4) Azilsartan crude product is added in ethyl alcohol, is warming up to material dissolution, cool down crystallization, filters, ethanol rinse filter
Cake obtains Azilsartan.
Preferably 60~90 DEG C of reaction temperature described in step 1) described above, more preferable 75~85 DEG C, reaction time 7-
10h。
Reaction dissolvent preferred DMF, DMSO described in step 1) described above, more preferable DMSO.
Alkali used in reaction described in step 1) described above is potassium carbonate, sodium carbonate, sodium bicarbonate, preferably sodium bicarbonate.
Hydroxylamine hydrochloride dosage used in step 1) described above is 2.0~5.0 molar equivalents, preferably 3.0 molar equivalents.
Sodium bicarbonate dosage used in step 1) described above is 3.0~6.0 molar equivalents, preferably 4.0 molar equivalents.
Reaction temperature described in step 2) described above is preferably 25~30 DEG C, 2~3h of reaction time.
Carbonyl dimidazoles dosage used in step 2) described above is 1.2~3.5 molar equivalents, and preferably 1.6 moles are worked as
Amount.
Triethylene diamine dosage used in step 2) described above is 1.5~4.0 molar equivalents, and preferably 1.8 moles are worked as
Amount.
The preferred 1N hydrochloric acid of hydrochloric acid used in step 2) described above, pH value are adjusted to 3.
Reaction temperature described in step 3) described above is preferably 25~30 DEG C, 1~2h of reaction time.
Alkali used in reaction described in step 3) described above is sodium bicarbonate, potassium hydroxide, sodium hydroxide, preferably hydroxide
Sodium.
The preferred 1N hydrochloric acid of hydrochloric acid used in step 3) described above, pH value are adjusted to 3.
Reaction dissolvent described in step 4) described above is methanol, ethyl alcohol, preferred alcohol.
Reaction dissolvent consumption described in step 4) described above is 5~10 times of amounts.
Reaction solution temperature described in step 4) described above is 65~70 DEG C.
Reaction-crystallization temperature described in step 4) described above is 0~10 DEG C, preferably 0~5 DEG C, 2~3h of stirring and crystallizing.
Innovation of the present invention：
The prior art uses poisonous and hazardous sodium methoxide, ethyl chloroformate and hydrazine hydrate, and yield is generally relatively low, total to receive
Rate 10~15%.The problem of for technique, the present invention grind patented method with reference to original, shorten process route and to technique into
Row improvement, specially in Azilsartan synthetic route, carbonyl dimidazoles are replaced with by the ethyl chloroformate in step 3, and
Alkali is done using triethylene diamine, greatly improves reactivity, avoids the generation of by-product, post-processing operation is reduced and shortens post-processing
Time.
10 feather weight process certifications work is completed in the present invention at present, meets the big production requirement of industry, and route total recovery reaches
To 40%~50%, 99.9% or more purity meets related quality criterion.
For the technique without especial equipment requirements, no special reaction parameter is easy to operate, while improving finished product yield, production
Quality meets related quality criterion, suitable for industrialized production.
Description of the drawings
Fig. 1 is the powder diffraction spectrum of Azilsartan；
Fig. 2 is that the hydrogen spectrogram of Azilsartan is composed；
Fig. 3 is that the carbon spectrogram of Azilsartan is composed；
Specific implementation mode
With reference to test example and specific implementation mode, the present invention is described in further detail.But this should not be understood
Range to invent above-mentioned theme is only limitted to embodiment below, all to belong to this hair based on the technology that the content of present invention is realized
Bright range.
Embodiment 1：
19.76kg (235.0mol) sodium bicarbonates and 12.24kg (176.3mol) hydroxylamine hydrochloride are added to 110.kg
It being stirred in DMSO and is warming up to 50~60 DEG C, 25.04kg (58.8mol) compound 5 is added into above-mentioned reaction solution by stirring 1h,
75~85 DEG C of insulated and stirreds are warming up to react 7~10 hours.Reaction solution is added to 200.16kg purified waters after reaction, 20
1h is stirred under the conditions of~30 DEG C, is centrifuged, and filter cake 12.24kg purify water wash, dries, obtains 22.23kg compounds 6, yield
82.5%,.
22.10kg (48.2mol) compound 6 and 12.50kg (77.1mol) carbonyl dimidazoles are added to 146.41kg bis-
In chloromethanes, 9.73kg (100.9mol) triethylene diamines and 87.85kg dichloromethanes is added in stirring and dissolving, 25~30 DEG C of temperature control
The mixed liquor of alkane reacts 2~3h under the conditions of 25~30 DEG C, and after the reaction was complete, pH=3, liquid separation are adjusted with 196.52kg 1N hydrochloric acid
After discard water phase, organic phase filtering 10.04kg eluent methylene chloride filter cakes, it is dry after 19.60kg compounds 4, yield
87.7%.
19.50kg (40.2mol) compound 4 is added into 78.14kg methanol, 20% sodium hydroxides of 9.76kg are added
Aqueous solution finishes, and is stirred 1 hour after reaction solution clarification.With 18.64kg 1N salt acid for adjusting pH to 3, there are a large amount of white solids to analyse
Go out, centrifuge, filter cake is eluted with 7.86kg methanol, it is dry, obtain product 15.55kg, yield 84.6%.
15.40kg (33.7mol) Azilsartan crude product is added in 61.68kg absolute ethyl alcohols, is warming up to 65~70 DEG C
Dissolving stirring 1 hour, 50~55 DEG C of temperature control stirring and crystallizing 1 hour are cooled to 0~10 DEG C of stirring and crystallizing 2~3 hours, centrifugation,
6.25kg absolute ethyl alcohols elute filter cake, dry white crystals sprills Azilsartan 12.69kg, yield 82.4%, related object
Matter purity 99.92%.It is operated by embodiment 1, Azilsartan entirety total recovery is 50.4%.
Embodiment 2：
29.43kg (350.3mol) sodium bicarbonates and 20.42kg (293.8mol) hydroxylamine hydrochloride are added to 110.kg
It being stirred in DMSO and is warming up to 50~60 DEG C, 25.00kg (58.8mol) compound 5 is added into above-mentioned reaction solution by stirring 1h,
75~85 DEG C of insulated and stirreds are warming up to react 7~10 hours.Reaction solution is added to 200.16kg purified waters after reaction, 20
1h is stirred under the conditions of~30 DEG C, is centrifuged, and filter cake 12.24kg purify water wash, dries, obtains 21.84kg compounds 6, yield
81.1%,.
21.80kg (47.5mol) compound 6 and 26.98kg (166.4mol) carbonyl dimidazoles are added to 146.41kg
In dichloromethane, 21.33kg (190.2mol) triethylene diamines and 87.85kg dichloros is added in stirring and dissolving, 25~30 DEG C of temperature control
The mixed liquor of methane reacts 2~3h under the conditions of 25~30 DEG C, and after the reaction was complete, pH=3 is adjusted with 410.61kg 1N hydrochloric acid, point
Water phase is discarded after liquid, organic phase filtering 10.90kg eluent methylene chloride filter cakes obtain 20.96kg compounds 4, yield after dry
91.0%.
20.90kg (43.1mol) compound 4 is added into 83.75kg methanol, 20% sodium hydroxides of 10.46kg are added
Aqueous solution finishes, and is stirred 1 hour after reaction solution clarification.With 19.98kg 1N salt acid for adjusting pH to 3, there are a large amount of white solids to analyse
Go out, centrifuge, filter cake is eluted with 10.02kg methanol, it is dry, obtain product 16.75kg, yield 85.1%.
16.50kg (36.1mol) Azilsartan crude product is added in 132.04kg absolute ethyl alcohols, is warming up to 65~70 DEG C
Dissolving stirring 1 hour, 50~55 DEG C of temperature control stirring and crystallizing 1 hour are cooled to 0~10 DEG C of stirring and crystallizing 2~3 hours, centrifugation,
8.25kg absolute ethyl alcohols elute filter cake, dry white crystals sprills Azilsartan 12.35kg, yield 74.8%, related object
Matter purity 99.96%.It is operated by embodiment 2, Azilsartan entirety total recovery is 47.0%.
Embodiment 3：
14.81kg (176.3mol) sodium bicarbonates and 8.17kg (117.5mol) hydroxylamine hydrochloride are added to 110.kg
It being stirred in DMSO and is warming up to 50~60 DEG C, 25.00kg (58.8mol) compound 5 is added into above-mentioned reaction solution by stirring 1h,
75~85 DEG C of insulated and stirreds are warming up to react 7~10 hours.Reaction solution is added to 200.16kg purified waters after reaction, 20
1h is stirred under the conditions of~30 DEG C, is centrifuged, and filter cake 12.25kg purify water wash, dries, obtains 19.93kg compounds 6, yield
74.0%,.
19.80kg (43.2mol) compound 6 and 8.40kg (51.8mol) carbonyl dimidazoles are added to 146.41kg bis-
In chloromethanes, the mixed liquor of 7.27kg (64.8mol) and 87.85kg dichloromethane is added in stirring and dissolving, 25~30 DEG C of temperature control,
2~3h is reacted under the conditions of 25~30 DEG C, after the reaction was complete, adjusts pH=3 with 176.1kg 1N hydrochloric acid, water phase is discarded after liquid separation,
Organic phase filtering 10.00kg eluent methylene chloride filter cakes, 16.32kg compounds 4, yield 78.0% are obtained after dry.
16.00kg (33.0mol) compound 4 is added into 64.11kg methanol, 20% sodium hydroxides of 8.01kg are added
Aqueous solution finishes, and is stirred 1 hour after reaction solution clarification.With 15.30kg 1N salt acid for adjusting pH to 3, there are a large amount of white solids to analyse
Go out, centrifuge, filter cake is eluted with 7.84kg methanol, it is dry, obtain product 12.81kg, yield 85.0%.
12.70kg (27.8mol) Azilsartan crude product is added in 50.80kg absolute ethyl alcohols, is warming up to 65~70 DEG C
Dissolving stirring 1 hour, 50~55 DEG C of temperature control stirring and crystallizing 1 hour are cooled to 0~10 DEG C of stirring and crystallizing 2~3 hours, centrifugation,
5.04kg absolute ethyl alcohols elute filter cake, dry white crystals sprills Azilsartan 10.41kg, yield 81.9%, related object
Matter purity 99.93%.
It is operated according to embodiment 3, Azilsartan entirety total recovery is 40.2%.
Comparative example (ZL93100006.8)：
By 10g compounds 7 and FeCl3·6H2The mixture of O (0.1g) and activated carbon (1g) is in methanol (100mL) and tetrahydrochysene
It is heated at reflux 30min in the mixture of furans (50mL), hydrazine hydrate (7.2mL) is added dropwise into reaction mixture, then heats back
Flow 14h.Insoluble substance is filtered out, filtrate is concentrated and dried.Sodium bicarbonate aqueous solution, mixture acetic acid second are added into residue
Ester extracts, and extract is washed with water and is dried and evaporated solvent to doing, purifies residue through silica gel column chromatography after, gained crystal is used
Isopropyl ether recrystallizes, and obtains pale yellow needles 6.0g, yield 64%, i.e. compound 8.
Into the solution of the tetraethyl orthocarbonate (5mL) of compound 8, acetic acid (0.37g) is added, mixture is in 80 DEG C of stirrings
1h concentrates reaction mixture, and residue is dissolved in ethyl acetate, solution sodium bicarbonate aqueous solution and washing, solvent evaporated,
It obtains crystal to be recrystallized with ethylacetate-hexane, obtains clear crystal 2.01g, yield 86%, i.e. compound 5.
Into mixture of the hydroxylamine hydrochloride (6.95g) in dimethyl sulfoxide (DMSO) (DMSO) (80mL), at room temperature, side stirring
The methanol solution of 28% sodium methoxide is added in side, and mixture stirs 10min, is charged with compound 5 at room temperature
(8.22g) then stirs mixture 4h at 90 DEG C, and at room temperature, into the reaction mixture of stirring plus water (50mL) filtering is received
Collect the crystal precipitation generated, is washed with water and dries, obtain white powder 8.0g, yield 90%, i.e. compound 6.
Compound 6 is added in triethylamine (0.2g) and tetrahydrofuran (THF, 30mL) mixture, stirring, ice water cooling
Lower dichloromethane (2mL) solution that ethyl chloroformate (0.22g) is added dropwise.Mixture stirs 2h at room temperature, filters out insoluble matter, filter
Liquid is concentrated to dryness, and ethyl acetate (5mL) is added into concentrate, then filters out insoluble matter, and filtrate is concentrated and dried, the mixing of residue
Object is heated at reflux 1.5h in dimethylbenzene (10mL).Add ethyl acetate into reaction mixture, be washed with water, dry, concentration is residual
Excess is purified through silica gel column chromatography, obtains crude product.With ethyl acetate-isopropyl ether recrystallization, colourless prism 0.22g, yield are obtained
23%, i.e. compound 4.
Compound 4 (0.165g) is dissolved in methanol (12mL), then adds the lithium hydroxide aqueous solution (1mL) of 2N, is then returned
Stream heating 3h, pH=3, solvent evaporated are adjusted with 2N hydrochloric acid.Residue is allocated in water (20mL) and chloroform (50mL), with
After organic layer and drying, solvent evaporated is washed with water, gained crystallized product re-crystallizing in ethyl acetate obtains colourless prism
0.135g, yield 84%, i.e. Azilsartan.
It is operated according to comparative example 1, Azilsartan entirety total recovery is 9.6%.
By embodiment 1,2,3, it is found that this patent institute inventive method grinds patent compared to original compared with comparative example 1,
Process route is short, and technological operation is simple, and total recovery is obviously improved, while avoiding ethyl chloroformate, hydrazine hydrate and sodium methoxide etc.
The use of poisonous and harmful reagent.
The Azilsartan compound is in X-ray powder diffraction pattern 9.126, and 12.608,14.824,15.283,16.142,
There is absorption peak at 21.386,22.443 and 23.416 ± 0.2 degree of 2 θ.1HNMR(400MHz,dDMSO)δ:1.3075~1.4058
(t,3H,-CH3), 4.5680~4.62 (q, 2H ,-OCH2CH3),5.7042(s,2H,ArCH2Ar), 7.0654~7.6960 (m,
11H,ArH),12.7478(brs,1H,-OH)。
13C~NMR (100Hz, CDCl3) δ:167.5713,159.5159,158.3235,158.3037,141.6885,
140.7536,137.7584,137.2285,131.8745,131.3248,130.6795,130.2231,128.8857,
127.8143,126.6623,123.5256,122.1908,121.4777,120.7058,116.6248,66.5160,
46.3950,14.3685。
Claims (7)
1. a kind of preparation method of Azilsartan, it is characterised in that including：
1) compound 5 is acted on hydroxylamine hydrochloride under alkaline condition, and heating reaction generates compound 6；
2) compound 6 is acted in triethylene diamine and carbonyl dimidazoles, and reaction generates compound 4；
3) hydrolysis occurs under alkaline condition for compound 4, obtains Azilsartan crude product；
4) Azilsartan crude product is by being refining to obtain Azilsartan
2. according to the method described in claim 1, it is characterized in that：Reaction temperature described in step 1) described above is 60~90
℃；The reaction dissolvent is DMF, DMSO；Alkali used in the reaction is potassium carbonate, sodium carbonate or sodium bicarbonate；The salt used
Sour azanol dosage is 2.0~5.0 molar equivalents；The base amount used is 3.0~6.0 molar equivalents.
3. according to the method described in claim 1, it is characterized in that：Reaction temperature described in step 2) described above is 25~30
℃；Carbonyl dimidazoles dosage used is 1.2~3.5 molar equivalents；Triethylene diamine dosage used is 1.5~4.0 moles
Equivalent, preferably 1.8 molar equivalents.
4. according to the method described in claim 3, it is characterized in that：Step 2) post-processing hydrochloric acid used described above is 1N salt
Acid, pH value are adjusted to 3.
5. according to the method described in claim 1, it is characterized in that：Reaction temperature described in step 3) described above is 25~30
℃；Alkali used in the reaction is sodium bicarbonate, potassium hydroxide, sodium hydroxide.
6. according to the method described in claim 5, it is characterized in that：The preferred 1N salt of step 3) post-processing described above hydrochloric acid used
Acid, pH value are adjusted to 3.
7. according to the method described in claim 1, it is characterized in that：Reaction dissolvent described in step 4) described above be methanol,
Ethyl alcohol；The reaction dissolvent consumption is 5~10 times of amounts；The reaction solution temperature is 65~70 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386928A (en) * | 2019-08-26 | 2019-10-29 | 海南皇隆制药股份有限公司 | A kind of Azilsartan synthesis technology |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601723A (en) * | 2013-11-19 | 2014-02-26 | 合肥远志医药科技开发有限公司 | Industrial production method of azilsartan |
| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
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2018
- 2018-06-13 CN CN201810604579.0A patent/CN108658961A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601723A (en) * | 2013-11-19 | 2014-02-26 | 合肥远志医药科技开发有限公司 | Industrial production method of azilsartan |
| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386928A (en) * | 2019-08-26 | 2019-10-29 | 海南皇隆制药股份有限公司 | A kind of Azilsartan synthesis technology |
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