CN106866625A - The preparation method of ketanserin - Google Patents
The preparation method of ketanserin Download PDFInfo
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Abstract
The present invention relates to the preparation method of medical material ketanserin, more particularly to it is a kind of in high yield with the preparation method of the ketanserin of high-purity.The technical solution adopted in the present invention is：A kind of high-purity, the preparation method of ketanserin in high yield, the method comprise the following steps：There is condensation reaction and ketanserin crude product be obtained in (1) 3 (2 chloroethyl) 2,4 (1H, 3H) quinazoline diones and 4 (4 fluoro benzoyl) piperidine hydrochlorates；(2) ketanserin crude product obtained in step (1) is recrystallized, is obtained final product ketanserin sterling, reaction equation is as follows：
Description
Technical field
The present invention relates to the preparation method of medical material ketanserin, more particularly to it is a kind of in high yield with the ketanserin of high-purity
Preparation method.
Background technology
Ketanserin, its chemical name is 3- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -2,4
(1H, 3H)-quinazolinedione, the general entitled Ketanserin of medicine, its structural formula is as follows：
。
It is antihypertensive, but to normal person without antihypertensive effect.Clinic be mainly used in gently, moderate or serious blood high
Pressure, is also used for congestive heart failure and Raynaud's disease, and research is it has also been found that in miocardial infarction, inflammatory pain and sex dysfunction in addition
On have new purposes.
Existing patent application EP0098499A1 discloses the preparation method of ketanserin, by intermediate 4- (4- fluorobenzoyls
Base) simultaneously [2,3-B] quinazoline -5- reactive ketones are obtained for piperidines and 2,3- dihydro -5H- oxazoles, and reaction equation is as shown in Equation 1：
。
Or the ketanserin as disclosed in patent US4335127 is by (1H, the 3H)-quinoline azoles of intermediate 3- (2- chloroethyls) -2,4
Quinoline diketone and 4- (4- fluoro benzoyls) piperidine hydrochlorate are condensed to yield, and reaction equation is as shown in Equation 2：
。
But above-mentioned document does not record the purity of ketanserin, at the same the purity of the ketanserin product of in the market be 95 ~
98%, it is impossible to reach the quality standard (impurity content≤0.10%) of medical material medicine, additionally, being prepared using the technique shown in formula 2
Product yield is low, and only 27%, therefore prepare ketanserin in high yield with high-purity and be just particularly important.
The content of the invention
The technical problems to be solved by the invention are that the preparation method yield ketanserin that is low and obtaining of existing ketanserin is produced
The low problem of product purity, the present invention is prepared in high yield and high-purity by improving the ketanserin synthesis technique of prior art
Ketanserin product.The technical solution adopted in the present invention is：A kind of high-purity, the preparation method of ketanserin in high yield, should
Method comprises the following steps：
(1) (1H, the 3H)-quinazoline diones of 3- (2- chloroethyls) -2,4 contracts with 4- (4- fluoro benzoyls) piperidine hydrochlorate
Close reaction and ketanserin crude product is obtained；
(2) ketanserin crude product obtained in step (1) is recrystallized, is obtained final product ketanserin sterling, reaction equation is as follows：
Preferably, in step (1), reaction alkali used is natrium carbonicum calcinatum, addition and the 4- (4- fluoro benzoyls) of alkali
The amount ratio of the material of piperidine hydrochlorate is 4:1；
Preferably, in step (1), reaction dissolvent is 4-methyl-2 pentanone；
Preferably, in step (1), reaction temperature is 100 ± 2 DEG C, and the reaction time is 72 hours；
Preferably, in step (2), organic solvent used by re-crystallization step is the mixed solvent of methyl alcohol and dichloromethane；
Preferably, in step (2), the volume ratio 1 of organic solvent methyl alcohol and dichloromethane used by re-crystallization step:2；
Preferably, in step (2), the quality of ketanserin crude product is 1 with the volume ratio of organic solvent:24~30 (g/mL).
Synthesis technique is prepared in ketanserin, two intermediate 3- (2- chloroethyls) -2,4 (1H, 3H)-quinazolines two
The condensation reaction of ketone and 4- (4- fluoro benzoyls) piperidine hydrochlorate and crude product is carried out into recrystallization is committed step, the present invention is specially
Door is studied the two steps, and below the two steps will be described in detail：
On step (1), this step is (1H, the 3H)-quinazoline diones of two intermediate 3- (2- chloroethyls) -2,4 and 4- (4- fluorine
Benzoyl) piperidine hydrochlorate condensation reaction, requirement of the step to solvent and alkali be higher, if the selection of alkali and solvent is uncomfortable
When, larger is influenceed on product quality, therefore, our selections to alkali and solvent have carried out detailed touching during technical study
Rope.Grope by many experiments, if our research staff have found that alkalescence is too strong, impurity content will increase in product, make technique
Post-processing operation is complicated, therefore alkali is preferably sodium carbonate；If solvent selection is improper, the color of reaction solution can deepen, serious shadow
Ring product outward appearance and quality, therefore solvent we be preferably 4-methyl-2 pentanone.Our research staff are to improve the step
The purity of yield and product, explores through many experiments, and the reaction time is 72 hours more suitable, temperature control at 100 ± 2 DEG C,
The material of 3- (2- chloroethyls) -2,4 (1H, 3H)-quinazoline diones and 4- (4- fluoro benzoyls) piperidine hydrochlorate is controlled simultaneously
Amount ratio be 1.05：1, the addition of alkali is 4 with the amount ratio of the material of 4- (4- fluoro benzoyls) piperidine hydrochlorate:1, using this
Process conditions, the yield of ketanserin crude product is 92.6%, far superior to the 27% of document report.
The step of on crude product is recrystallized, the step influences great, suitable recrystallisation solvent to the quality of product,
Rational crystallization operation improves product yield and purity plays an important role to reducing product impurity.Have been reported that in the prior art
Solvent used by the re-crystallization step of ketanserin crude product is (1H, the 3H)-quinazolines of two intermediate 3- (2- chloroethyls) -2,4
Solvent used in diketone and 4- (4- fluoro benzoyls) piperidine hydrochlorate step of condensation, but for ketanserin after recrystallization
Purity without report.Through many experiments, our research staff have found that the mixed solvent of methyl alcohol and dichloromethane is optimal knot
The volume ratio of brilliant solvent, methyl alcohol and dichloromethane is preferably 1:2, the mass volume ratio (g/mL) of ketanserin crude product and recrystallisation solvent
It is 1:24~1:30, the crystallization type of cooling is natural cooling, and crystallization time is not less than 5 hours.With this understanding, ketanserin sterling
Crystallisation recoveries need to only be crystallized once more than 85%, and the purity of ketanserin sterling reaches more than 99.90%.
The present invention is by improving (1H, the 3H)-quinazoline diones of intermediate 3- (2- chloroethyls) -2,4 and 4- (4- fluorobenzoyls
Base) piperidine hydrochlorate condensation reaction and ketanserin crude product recrystallization process conditions, be obtained in high yield with the ketanserin of high-purity
Product.
Brief description of the drawings
Fig. 1 is the HPLC datagrams of example IV ketanserin crude product, and impurity A refers to 4- (4- fluoro benzoyls) piperidinium salt in figure
Hydrochlorate, impurity B refers to (1H, the 3H)-quinazoline diones of 3- (2- chloroethyls) -2,4.
Fig. 2 is the nuclear magnetic data figure of example IV ketanserin sterling.
Fig. 3 is the HPLC datagrams of example IV ketanserin sterling.
Fig. 4 is the HPLC datagrams of the ketanserin crude product of embodiment five, and impurity A refers to 4- (4- fluoro benzoyls) piperidinium salt in figure
Hydrochlorate, impurity B refers to (1H, the 3H)-quinazoline diones of 3- (2- chloroethyls) -2,4.
Fig. 5 is the HPLC datagrams of the ketanserin sterling of embodiment five, and impurity B refers to (1H, the 3H)-quinolines of 3- (2- chloroethyls) -2,4
Oxazoline diketone.
Specific embodiment
The relevant substance detecting method of ketanserin
Chromatographic condition and system suitability：Use C18 posts；With phosphate（Take potassium dihydrogen phosphate 3.4g add water 50ml dissolving, plus
Triethylamine 10ml, then it is diluted with water to 1000ml）：Methyl alcohol=1:1（PH to 4.0 is adjusted with phosphoric acid）, Detection wavelength is 245nm；
Need testing solution：Precision weighs this product 10mg, in putting 100ml measuring bottles, plus flows phased soln and is diluted to scale；
Contrast solution：Precision measures need testing solution 1ml, and in putting 100ml measuring bottles, plus mobile phase is diluted to scale；
Determination method：The μ l of contrast solution 20 injection liquid chromatographs are taken, detection sensitivity is adjusted, makes the peak height at principal component peak be full amount
The 10% ~ 20% of journey.Precision measures need testing solution and each 20 μ l of contrast solution again, is injected separately into liquid chromatograph, records chromatogram
Figure is to 3 times of principal component peak retention time.If any impurity peaks in need testing solution chromatogram, the peak area of single impurity must not be big
In the 1/5 of contrast solution main peak area（0.2%）, main peak area that is each impurity peak area and cannot be greater than contrast solution
（1.0%）.
The preparation of embodiment one intermediate 4- (4- fluoro benzoyls) piperidine hydrochlorate
The preparation of step one 1- acetyl group -4- piperidine carboxylic acids
The g of raw material 4- piperidine carboxylic acids 300 (2.3 mol) are scattered in 1.5 L acetic anhydrides, are refluxed overnight, use TLC methods
(HSGF254 silica gel plates, solvent：VMethyl alcohol:VEthyl acetate=1:6) reaction process is monitored, after reaction terminating, acetic anhydride is reclaimed, to surplus
Add 500 mL methyl tertiary butyl ether(MTBE)s, agitation and filtration, filter cake to be washed with methyl tertiary butyl ether(MTBE) (100 mL × 2) in excess, dry
It is dry, obtain the g of white solid 330, yield 83%, 180 ~ 181 DEG C of mp.
The preparation of step 2 1- acetyl group -4- (4- fluoro benzoyls) piperidines
The g of 1- acetyl group -4- piperidine carboxylic acids 200 is slowly dissolved in 1.5 L thionyl chlorides, 4 h are stirred at room temperature, leaked with core
Bucket filtering, filtering will be protected, few ingress of air, be washed with 500 mL methyl tertiary butyl ether(MTBE)s, be vacuum dried (T=50 DEG C), obtain 1-
The g of acetyl group -4- piperidine formyls chlorine 213.Aluminum trichloride (anhydrous) 276g is scattered in 1L fluorobenzene, is slowly added under stirring condition
213g1- acetyl group -4- piperidine formyls chlorine (30 ~ 70 DEG C of temperature), add 3 h of backflow, and with TLC methods, (HSGF254 silica gel plates launch
Agent：VDichloromethane:VMethyl alcohol=40:3) reaction process is monitored, after reaction completely, room temperature is cooled to, is poured into frozen water and is quenched, use 2L dichloros
Methane is extracted, and the g of oil product 200 is done to obtain in concentration, and yield 68% (can be directly used for the next step).
The preparation of step 3 4- (4- fluoro benzoyls) piperidine hydrochlorate
1- acetyl group -4- (4- fluoro benzoyls) piperidines 200 g is dissolved in 600mL 6mol/L HCl/water solution, is refluxed
8 h, reaction is finished, and concentration removes water, is evaporated completely with up to water for 3 times with toluene band water, is beaten with dichloromethane, is cooled to 20
DEG C, filtering, filter cake is washed with dichloromethane, then uses VDichloromethane：VPetroleum ether=1：1 washes, and dries to obtain the g of yellow solid 174, yield 89%
(can be directly used for the next step).
The preparation of embodiment two intermediate 3- (2- chloroethyls) -2,4 (1H, 3H)-quinazoline diones
The preparation of step one 2- [(carbethoxyl group) amino] ethyl benzoate
870g raw material 2- benzocaines are dissolved in 7L toluene, backflow is heated to, ethyl chloroformate 626g is added dropwise, backflow is stirred
Mix overnight, with TLC methods (HSGF254 silica gel plates, solvent：VEthyl acetate:VPetroleum ether=1:20) reaction process is monitored, after reaction completely,
Room temperature is cooled to, is washed with 5L saturated sodium carbonates to alkalescence, concentration removes part toluene, cooling, crystallization filters to obtain 1.1kg products
Thing, yield 88%.
The preparation of step 2 3- (2- ethoxys) -2,4- (1H, 3H)-quinazoline diones
To 1.1kg 2- [(carbethoxyl group) amino] ethyl benzoates and 285g 2- ethylaminoethanols is added in reaction bulb, it is heated to
90 DEG C, it is refluxed overnight, with TLC methods (HSGF254 silica gel plates, solvent：VEthyl acetate:VMethyl alcohol=10:1) reaction process is monitored,
After completion of the reaction, 10 DEG C are cooled to, 2L dichloromethane is added, 30min is stirred, filter cake, 50 DEG C of bakings is washed in filtering with dichloromethane
Do to obtain white solid 800g, yield 83.7%.
The preparation of (1H, the 3H)-quinazoline diones of step 3 3- (2- chloroethyls) -2,4
To addition 670g 3- (2- ethoxys) -2,4- (1H, 3H)-quinazoline diones, 423g thionyl chlorides and 7L tri- in reaction bulb
Chloromethanes, is refluxed overnight, with TLC methods (HSGF254 silica gel plates, solvent：VEthyl acetate:VPetroleum ether=1:1) monitoring react into
Journey, after reaction completely, is cooled to less than 10 DEG C and filters, and filter cake is washed with dichloromethane, and 50 DEG C dry to obtain white solid 650g, receives
Rate 89.0%.
The preparation method technical study of the present invention of embodiment 3
(1H, the 3H)-quinazoline diones of 3- (2- chloroethyls) -2,4 is with 4- (4- fluoro benzoyls) piperidine hydrochlorate condensation reaction
The committed step of ketanserin is prepared, the step is larger on product quality and yield influence.Based on document US4335127 reported by
The low technical problem of this step synthesis ketanserin yield, our research staff are studied the technique in terms of three below
Improve.
First, we are screened to reaction dissolvent, explore the experimental program for using ketone or ethers as solvent,
When result finds to select methyl phenyl ethers anisole as solvent, reaction solution color is presented black, during from diphenyl ether or cyclohexanone as solvent,
Reaction solution color is presented yellow, and from 4-methyl-2 pentanone as solvent, reaction solution color is presented white, is aftertreatment technology
Simply we determined that 4-methyl-2 pentanone is used as solvent.
Secondly, found through test of many times, the low technical problem of ketanserin yield that document US4335127 is reported be due to
Raw material reaction is incomplete, accordingly, it is considered to the stronger potassium carbonate of alkalescence is used instead as base reagent, but when experiment is carried out to 7 ~ 8h
Impurity spot is more when experimental result finds that TLC is detected, therefore alkali still selects sodium carbonate.
Finally, we are investigated to the reaction time, and based on document US4335127, temperature is defined as 100 ± 2 by we
DEG C, when reaction is carried out to 24h, TLC detection unreacteds are complete；When reaction is carried out to 48h, TLC detection unreacteds are complete, but product
The significantly more than experiment of 24h；When reaction is carried out to 72h, TLC detection reactions are complete, and impurity spot is less；Therefore, the time we
It is set to 72h.
Additionally, quality influence of the re-crystallization step on product is great, the selection of recrystallisation solvent is the core of process for refining research
Intracardiac appearance, suitable recrystallisation solvent and rational crystallization operation serve important function to eliminating product impurity.
According to described we in document US4335127 first using 4-methyl-2 pentanone as recrystallization solvent, so
And ketanserin cannot be completely dissolved under heated reflux condition, therefore we have investigated methyl phenyl ethers anisole, diphenyl ether, cyclohexanone respectively again
Used as the situation of recrystallization solvent, above-mentioned three kinds of solvents ketanserin under heated reflux condition cannot be completely dissolved, therefore on
State the recrystallization that solvent is not particularly suited for ketanserin.
For the fat-soluble structure such as substituted benzene ring and saturation hexatomic ring is contained in ketanserin structure, by substantial amounts of experiment,
We determined that the mixed solvent of methyl alcohol and dichloromethane is used as ketanserin recrystallisation solvent.Then we are with methyl alcohol and dichloromethane
Mixed solvent investigated the influence of the usage amount of solvent and the volume ratio of both solvents to recrystallizing as recrystallization solvent.It is real
Result is tested to show：With methyl alcohol：Methylene chloride volume ratio is 1:2 used as recrystallisation solvent system, and ketanserin crude product quality is molten with crystallization
Agent volume ratio (mass volume ratio, g/mL) is 1:24~1:Between 30, the product in high yield with high-purity is obtained.
The preparation of the ketanserin of embodiment 4
The preparation of step one ketanserin crude product
By 10g 4- (4- fluoro benzoyls) piperidine hydrochlorate, (1H, the 3H)-quinazoline diones of 9.7g 3- (2- chloroethyls) -2,4,
17.5g Na2CO3It is added in 150mL 4-methyl-2 pentanones, is heated to reflux 72h, TLC detection reactions is complete, are cooled to room
Temperature, pours into 500 mL water, and filtering, solid 50mL × 3 are washed, and drying obtains white solid 15g, yield 92.6%, purity
(HPLC)98.43%。
The preparation of step 2 ketanserin sterling
(V during ketanserin crude product 15g is dissolved in into 450mL methyl alcohol and dichloromethane mixed solutionMethyl alcohol：VDichloromethane=1:2), 45 ~ 50 DEG C
20min is refluxed, is filtered while hot, remove insoluble solid, liquid concentration to 150mL is filtered, and obtains ketanserin sterling 14g, this
Docking step total recovery 86.4%, purity (HPLC) 99.93%.
The comparative example of embodiment 5
By 4.5 g 4- (4- fluoro benzoyls) piperidine hydrochlorate (0.02mol), 4.9 g 3- (2- chloroethyls) -2,4 (1H,
3H)-quinazoline diones (0.02mol), 8 g Na2CO3It is added in 80mL 4-methyl-2 pentanones, 7 ~ 8h of heating stirring, reacts
Finish, appropriate amount of water is poured into cooling, is stirred, filtering, dry the g of ketanserin crude product 4.6, purity (HPLC) 98.32%.With 4- methyl-
2 pentanone is recrystallized, and must crystallize 2.2g, this docking step total recovery 27%, purity (HPLC) 99.22%.
Claims (7)
1. a kind of preparation method of ketanserin, the method comprises the following steps：
(1) (1H, the 3H)-quinazoline diones of 3- (2- chloroethyls) -2,4 contracts with 4- (4- fluoro benzoyls) piperidine hydrochlorate
Close reaction and ketanserin crude product is obtained；
(2) ketanserin crude product obtained in step (1) is recrystallized, is obtained final product ketanserin sterling.
2. the method for claim 1, it is characterised in that in step (1), reaction alkali used is natrium carbonicum calcinatum,
The addition of alkali is 4 with the amount ratio of the material of 4- (4- fluoro benzoyls) piperidine hydrochlorate:1.
3. the method for claim 1, it is characterised in that in step (1), reaction dissolvent is 4-methyl-2 pentanone.
4. the method for claim 1, it is characterised in that in step (1), reaction temperature is 100 ± 2 DEG C, during reaction
Between be 72 hours.
5. the method for claim 1, it is characterised in that in step (2), organic solvent used by re-crystallization step is first
The mixed solvent of alcohol and dichloromethane.
6. the method for claim 1, it is characterised in that in step (2), organic solvent methyl alcohol used by re-crystallization step
With the volume ratio 1 of dichloromethane:2.
7. the method for claim 1, it is characterised in that in step (2), the quality and organic solvent of ketanserin crude product
Volume ratio be 1:24~30 (g/mL).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112142760A (en) * | 2020-10-20 | 2020-12-29 | 江苏法安德医药科技有限公司 | Ketanserin intermediate and preparation method of ketanserin |
| WO2023133524A1 (en) * | 2022-01-06 | 2023-07-13 | Terran Biosciences, Inc. | A process for synthesizing ketanserin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335127A (en) * | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
-
2017
- 2017-01-17 CN CN201710029847.6A patent/CN106866625B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335127A (en) * | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
Non-Patent Citations (2)
| Title |
|---|
| HOSSEIN FAKHRAIAN，ET AL.: "Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HCl) via 3-(2-Chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) or Dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1)", 《J. HETEROCYCLIC CHEM.》 * |
| JEFF L. HERNDON,ET AL.: "Ketanserin Analogues: Structure-Affinity Relationships for 5-HT2 and 5-HT1c Serotonin Receptor Binding", 《J. MED. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112142760A (en) * | 2020-10-20 | 2020-12-29 | 江苏法安德医药科技有限公司 | Ketanserin intermediate and preparation method of ketanserin |
| WO2023133524A1 (en) * | 2022-01-06 | 2023-07-13 | Terran Biosciences, Inc. | A process for synthesizing ketanserin |
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Denomination of invention: Preparation method of ketoselin Effective date of registration: 20220321 Granted publication date: 20191213 Pledgee: Shanghai rural commercial bank Limited by Share Ltd. Zhangjiang Branch of science and technology Pledgor: SHANGHAI DINGYA PHARMACEUTICAL CHEMICALS CO.,LTD. Registration number: Y2022310000049 |
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