CN107652214A - A kind of preparation method of high fat of blood curative Ezetimibe - Google Patents
A kind of preparation method of high fat of blood curative Ezetimibe Download PDFInfo
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- CN107652214A CN107652214A CN201711082016.1A CN201711082016A CN107652214A CN 107652214 A CN107652214 A CN 107652214A CN 201711082016 A CN201711082016 A CN 201711082016A CN 107652214 A CN107652214 A CN 107652214A
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- ezetimibe
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of preparation method of high fat of blood curative Ezetimibe, belong to pharmaceutical synthesis field.It is raw material with compound 2, by being prepared into Ezetimibe 1 through the step synthesis step of carbonyl-protection, cyclisation, carbonyl reduction, oxidation etc. four.Compared to the method for existing literature report, the use of contaminative tiron is avoided, synthesis step is reduced, and technology stability is higher, is adapted to large-scale production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation side of high fat of blood curative Ezetimibe
Method.
Background technology
Ezetimibe (Ezetimibe), also known as ezetimibe, ezetimibe replace wheat according to pool, it is chemical it is entitled (3R,
4S) -1- (4- fluorophenyls) -3- { (3S) -3- (4- fluorophenyls) -3- hydroxypropyls } -4- (4- hydroxy phenyls) -2- azetidins
Ketone, entitled 1- (4-fluorophenyl) -3- [3- (the 4-fluorophenyl) -3-hydroxy-propy l] -4- (4- of English
Hydroxyphenyl)-azetidin-2-one, No. CAS：163222-33-1, character：White or off-white color crystalline powder,
Fusing point：164 DEG C -166 DEG C, molecular formula：C24H21F2NO3, molecular weight：409.43, dissolubility：It is soluble in ethanol, isopropanol, third
Ketone, methanol, ethyl acetate etc., it is insoluble in water, petroleum ether, ether etc..
Ezetimibe is a kind of new drop blood by Merck and the new cholesterol antagonist of Schering Plough company joint development
Fat medicine.The same period lists in the U.S. in German Initial Public Offering within 2002, be first obtain FDA approval listings there is selectivity
The new blood lipid-lowering medicine of cholesterol absorption inhibitory action, obtain widely should in more than 90 individual countries and regions at present
With trade name：Ezetrol, benefit fit pure, Zetia.Have the advantages that toxic side effect is small, evident in efficacy, wide market.
Ezetimibe acts locally on intestinal epithelial cell, optionally suppresses intestinal cholesterol and related sitosterol
Absorb, reduce the cholesterol of arrival liver, reduce cholesterol reserves in liver and increase cholesterol plasma clearance.
The main exogenous cholesterol of Ezetimibe has effect, and then unrestraint acts on to endogenous cholesterol.By Ezetimibe and
Two kinds of medicine composition compound medicines " Vytorin " of Simvastatin of Merck companies formally pass through FDA approval in August, 2004."
The single corresponding bodies of two kinds of Vytorin " can reduce serum cholesterol, the difference is that Simvastatin suppresses regulation and control cholesterol life in vivo
The enzyme of thing synthesis, and Ezetimibe then suppresses food-based enteral cholesterol absorption, both are shared then by external in vivo
Two kinds of approach effectively reduce cholesterol.Ezetimibe is single use statins by cholesterol with Statins use in conjunction
8 times of effect.China is increasing to the demand share of fall lipid drug, is particularly liked deeply by many patients and doctor
Newtype drug Ezetimibe, therefore, one economy of exploitation, environment-friendly, the synthesis work for the Ezetimibe that can be mass produced
Skill route is of great practical significance.
Therefore, on the basis of with reference to existing synthetic route, one process conditions of research are gentle well, production efficiency is high,
Low in input cost, operation is simple, it is just very necessary to be easy to industrial synthetic route.
The content of the invention
In order to solve the deficiencies in the prior art, the invention provides a kind of preparation side of high fat of blood curative Ezetimibe
Method.
A kind of preparation method of high fat of blood curative Ezetimibe, it is characterised in that comprise the following steps：With compound 2
For raw material, by being prepared into Ezetimibe after carbonyl-protection, cyclization, carbonyl reduction, oxidation.
Reaction equation is as follows：
Further, the protection step is to be obtained after compound 2 and 1-1.1eq ethylene glycol is reacted in n-hexane
Compound 3.
Further, the cyclisation step is, by compound 3 and the cyclization under the conditions of BSA and TBAF of compound 4
Compound 5.BSA is N, and the double trimethyl silicane yl acetamides of O- are write a Chinese character in simplified form.
Further, the compound 3, compound 4, BSA and TBAF equivalent proportions are 1-1.2:1-1.2:2:0.06.
Further, the carbonyl reduction steps are that in dichloromethane solvent, reaction temperature is -5 DEG C to 0 DEG C, is added
0.10-0.15eq (R)-MeCBS and 1.0-1.5eq BH3-S(CH3)2Asymmetric reduction is carried out to compound 5, obtains compound
6。
Further, the oxidation step is that the oxidation step is, in acetic acid, adds 1.5-2.0 equivalent hydrogen peroxide
Borate group in compound 6 is oxidized to hydroxyl, obtains crude product 1.
Further, the crude product 1 passes through ethyl acetate：Petroleum ether=1：2.4-3.0 (volume ratio) is recrystallized to give
The sterling 1 of purity more than 99.5%.
Further, the compound 4 synthesizes, by para-fluoroaniline and equivalent to aldehyde radical phenyl boric acid pinacol ester in first
Obtained in benzene after reflux water-dividing or obtain compound 4 after adding 4A molecular sieve dehydrations at room temperature.
The beneficial effect of invention：
1st, the use of contaminative tiron is avoided compared to the method for existing literature report, cyclization step, technique is greener
Colour circle is protected.
2nd, using implicit group of the borate as hydroxyl, when undergoing protection, cyclization, three step of reduction, do not detect
Accessory substance caused by borate group and impurity, after peroxidating, it is transformed into hydroxyl finally.
3rd, crude product 1 passes through ethyl acetate：After petroleum ether recrystallization, the product of purity more than 99.5% can be obtained.
4th, synthesis step of the present invention is few, and technology stability is higher, is more suitable for large-scale production.
Embodiment
Embodiment 1
In three-necked bottle, add compound 2 (3.55g, 10.0mmol), ethylene glycol (0.68g, 11mmol) and 30mL just oneself
Alkane adds in three-necked flask and forms suspension, is subsequently added into p-methyl benzenesulfonic acid (9.0mmol), 25 DEG C of reaction 6h.Add 0.5g
(6mmol) sodium acid carbonate, 30min is stirred, ice bath cooling is lower to be added dropwise the sodium hydroxide solutions of 30mL 10%.Confined reaction at 25 DEG C
1h, reaction are finished, and 20% citric acid is adjusted to pH=3-4 under ice bath, and ethyl acetate 40mL is extracted twice, and merge organic phase, and decompression is steamed
Ethyl acetate is evaporated, n-hexane recrystallizes to obtain 3.61g compound as white solid 3, yield 90.5%, fusing point:101-102℃,[α]25 D
=+54.1 ° of (c=1, CH2Cl2)；1H NMR(400MHz,DMSO-d6):1.43-1.57(m,2H),1.76-1.84(m,2H),
2.81 (dt, J=17.2,7.5Hz, 1H), 2.91 (dt, J=17.2,7.5Hz, 1H), 3.61-3.70 (m, 2H), 3.89-3.99
(m, 2H), 4.14 (dd, J=8.7,3.6Hz, 1H), 4.72 (t, J=8.7Hz, 1H), 5.44 (dd, J=8.7,3.6Hz, 1H),
7.12-7.16(m,2H),7.24-7.29(m,2H),7.29-7.35(m,1H),7.35-7.39(m,4H)。
By para-fluoroaniline (1.11g, 10mmol) with adding 150mL to aldehyde radical phenyl boric acid pinacol ester (2.32g, 10mmol)
Reflux in toluene divides water, after completion of the reaction, solvent evaporated, n-hexane and ethyl acetate 10:1 is recrystallized to give compound 4
(3.029g), yield 93.2%.
By the double trimethyl silicon substrate second of compound 3 (3.99g, 10.0mmol), compound 4 (3.25g, 10.0mmol) and N, O-
In acid amides (BSA, 4.06g, 20.0mmol) input toluene 300mL, it is warming up to 60 DEG C of stirrings to suspension and clarifies, add the tetrabutyl
Ammonium fluoride (TBAF, 0.1566g, 0.6mmol), it is incubated 60 DEG C of stirring 3h and is largely disappeared to raw material, 10mL acetic acid is added after cooling,
It is concentrated under reduced pressure and removes toluene, remaining grease is dried under vacuum, and obtains intermediate 5 (4.599g, yield 88.95%).
Under nitrogen protection, in dry three-necked bottle, dichloromethane 8mL, BH are added3-S(CH3)27.46mL (15mmol),
Controlling reaction temperature is -5 DEG C to 0 DEG C, and (R)-MeCBS 1M toluene solutions 1.5mL (1.5mmol) are added dropwise, intermediate is slowly added dropwise
5 (5.17g, 10.0mmol) dichloromethane solution 10mL, drip to finish and maintain temperature to continue to stir 3h at -5 DEG C to 0 DEG C, to having reacted
Quan Hou, methanol is then slowly added dropwise successively and is quenched, 4mol/L sulfuric acid solutions are washed, and are layered after stirring, and organic layer uses 0.5mol/ respectively
L sulfuric acid solutions 6m L, 5% sodium sulfite aqueous solution 22mL are washed, and organic layer is concentrated to dryness, and obtains tacky liquid, i.e., middle
Body 6 (4.775g, yield 92.01%, 98.4%dr).
In reaction bulb, 5.19g (10mmol) intermediate 6 is added in 30mL acetic acid, is slowly added to 25% hydrogen peroxide
2.72mL (20mmol), is stirred at room temperature 2h.After completion of the reaction, add saturation sodium hydrogensulfite and excessive hydrogen peroxide, acetic acid second is quenched
Ester extracting and demixing, the crude product 3.12g of object 1, yield 76.34% are obtained after concentration.
The method for recrystallizing and refining of crude product 1：The crude product of Ezetimibe 1 (4.09g, 10mmol) is taken, lower acetic acid second is stirred at room temperature
Ester (15mL) dissolves, and is slowly added to petroleum ether (45mL), is heated to 60 DEG C, stirs 2h, is cooled to room temperature suction filtration, gained solid vacuum
24h is dried, obtains Ezetimibe 3.52g, yield 86.23%, purity>99.9%, dr:>99.9%, mp:164.1-166.3℃,
[α]25 D=-27.5 (c=0.34, MeOH)；1H-NMR(400MHz,DMSO-d6):1.70-1.86(m,4H),3.07-3.08(m,
1H), 4.49-4.50 (m, 1H), 4.81 (d, J=2.0Hz, 1H), 5.27 (d, J=4.4Hz, 1H), 6.76 (d, J=8.3Hz,
2H),7.11-7.32(m,10H),9.50(s,1H)；ESI-MS m/z:calcd for C21H17ClN5[M+H]+410.3,
found 410.3.
Embodiment 2
In three-necked bottle, compound 2 (35.5g, 100.0mmol) is added, ethylene glycol (6.8g, 110mmol) and 300mL are just
Hexane adds in three-necked flask and forms suspension, is subsequently added into p-methyl benzenesulfonic acid (90mmol), reaction is stirred at room temperature.Add 5g
After (60mmol) sodium acid carbonate, ice bath cooling is lower to be added dropwise the sodium hydroxide solutions of 300mL 10%.Confined reaction 1h at 25 DEG C, reaction
Finish, 20% citric acid is adjusted to pH=3-4 under ice bath, and ethyl acetate 400mL is extracted twice, and merges organic phase, is evaporated under reduced pressure acetic acid
Ethyl ester, n-hexane recrystallize to obtain 36.07g compound as white solid 3, yield 90.42%, fusing point:101-102℃.
By para-fluoroaniline (11.1g, 100mmol) with being added to aldehyde radical phenyl boric acid pinacol ester (23.2g, 100mmol)
350mL reflux in toluene divides water, after completion of the reaction, solvent evaporated, n-hexane and ethyl acetate 10:1 is recrystallized to give compound 4
(30.23g), yield 93.0%.
By the double trimethyl silicon substrates of compound 3 (39.9g, 100.0mmol), compound 4 (32.5g, 100.0mmol) and N, O-
In acetamide (BSA, 40.6g, 200.0mmol) input toluene 1L, it is warming up to 60 DEG C of stirrings to suspension and clarifies, add the tetrabutyl
Ammonium fluoride (TBAF, 1.566g, 6mmol), it is incubated 60 DEG C of stirring 3h and is largely disappeared to raw material, cooling, add 100mL acetic acid, subtract
Pressure concentration removes toluene, and remaining grease is dried under vacuum, and obtains intermediate 5 (45.89g, yield 88.76%).
Under nitrogen protection, in dry three-necked bottle, dichloromethane 800mL, BH are added3-S(CH3)274.6mL
(150mmol), reaction temperature are -5 DEG C to 0 DEG C, and (R)-MeCBS 1M toluene solutions 15mL (15mmol) are added dropwise, is slowly added dropwise and contains
There is the dichloromethane solution 1L of intermediate 5 (51.7g, 100.0mmol), drip complete maintenance temperature and continue to stir 3- at -5 DEG C to 0 DEG C
5h, to after reacting completely, methanol is then slowly added dropwise successively and is quenched, dilution heat of sulfuric acid is washed, and organic layer uses 0.5mol/L sulphur respectively
Acid solution, the washing of 5% sodium sulfite aqueous solution, organic layer are concentrated to dryness, and obtain intermediate 6 (47.74g, yield 91.99%),
The next step is directly used in without purifying.
In reaction bulb, 51.9g (100mmol) intermediate 6 is added in 300mL acetic acid, is slowly added to 25% hydrogen peroxide
21.8mL (160mmol), is stirred at room temperature 5h.After completion of the reaction, add saturation sodium hydrogensulfite and excessive hydrogen peroxide, acetic acid second is quenched
Ester extracting and demixing, the crude product 33.81g of object 1, yield 82.64% are obtained after concentration.
The method for recrystallizing and refining of crude product 1：Ezetimibe crude product (120g, 0.293mol) is taken, lower acetic acid second is stirred at room temperature
Ester (1.5L) dissolves, and is slowly added to petroleum ether (4.5L), is heated to 60 DEG C, stirs 2h, is cooled to room temperature suction filtration, gained solid vacuum
24h is dried, obtains Ezetimibe 103g, yield 86.18%, purity>99.9%, dr:>99.9%, fusing point:164.1-166.3℃,
[α]25 D=-26.5 (c=0.34, MeOH)；1H-NMR(400MHz,DMSO-d6):1.70-1.86(m,4H),3.07-3.08(m,
1H), 4.49-4.50 (m, 1H), 4.81 (d, J=2.0Hz, 1H), 5.27 (d, J=4.4Hz, 1H), 6.76 (d, J=8.3Hz,
2H),7.11-7.32(m,10H),9.50(s,1H)；ESI-MS m/z:calcd for C21H17ClN5[M+H]+410.3,
found410.3.
Embodiment 3
In three-necked bottle, add compound 2 (3.55kg, 10.0mol), ethylene glycol (0.68kg, 11mol) and 30L just oneself
Alkane adds in three-necked flask and forms suspension, is subsequently added into p-methyl benzenesulfonic acid (90mmol), reaction is stirred at room temperature.Add 0.5kg
After (6mol) sodium acid carbonate, ice bath cooling is lower to be added dropwise the sodium hydroxide solutions of 30L 10%.Confined reaction 1h at 25 DEG C, reaction are finished,
20% citric acid is adjusted to pH=3-4 under ice bath, and ethyl acetate 40L is extracted three times, is merged organic phase, is evaporated under reduced pressure ethyl acetate,
N-hexane recrystallizes to obtain 3.599kg compound as white solid 3, yield 90.2%, fusing point:101-102℃.
By para-fluoroaniline (1.11kg, 10mol) with adding 75L first to aldehyde radical phenyl boric acid pinacol ester (2.32kg, 10mol)
Reflux water-dividing in benzene, after completion of the reaction, solvent evaporated, n-hexane and ethyl acetate 10:1 is recrystallized to give compound 4
(3.016kg), yield 92.8%.
By the double trimethyl silicon substrate second of compound 3 (3.99kg, 10.0mol), compound 4 (3.25kg, 10.0mol) and N, O-
In acid amides (BSA, 4.06kg, 20.0mol) input toluene 1L, it is warming up to 60 DEG C of stirrings to suspension and clarifies, add tetrabutyl fluorine
Change ammonium (TBAF, 1566g, 6mol), be incubated 60 DEG C of stirring 3h and largely disappeared to raw material, cooling, add 10L acetic acid, be concentrated under reduced pressure
Toluene is removed, remaining grease is dried under vacuum, and obtains intermediate 5 (4.59kg, yield 88.72%).
In a kettle, under nitrogen protection, dichloromethane 80L, BH are added3-S(CH3)27.46L (15mol), control reaction
Temperature be -5 DEG C to 0 DEG C, add (R)-MeCBS 1M toluene solutions 1.5L (1.5mol), be slowly added dropwise intermediate 5 (5.17kg,
10mol) dichloromethane solution 1L, drip and finish maintenance temperature after -5 DEG C to 0 DEG C are continued to stir and extremely reacted completely, it is then slow successively
Be added dropwise methanol 25L be quenched, 4mol/L sulfuric acid solutions are washed, and are layered after stirring, organic layer respectively with 0.5mol/L sulfuric acid solutions 60L,
5% sodium sulfite aqueous solution 22L is washed, and organic layer filtrate is concentrated to dryness, and obtains intermediate 6 (4.77kg, yield 91.88%),
The next step is directly used in without purifying.
In reaction bulb, 5.19kg (10mol) intermediate 6 is added in 30L acetic acid, is slowly added to 30% hydrogen peroxide
4.08L (15mol), is stirred at room temperature 8h.After completion of the reaction, add saturation sodium hydrogensulfite and excessive hydrogen peroxide, ethyl acetate is quenched
Extracting and demixing, the crude product 3.28kg of object 1, yield 80.41% are obtained after concentration.
The method for recrystallizing and refining of crude product 1：Ezetimibe crude product (4.09kg, 10mol) is taken, ethyl acetate is used under being stirred at room temperature
(15L) dissolves, and is slowly added to petroleum ether (45L), is heated to 60 DEG C, stirs 3h, is cooled to room temperature suction filtration, the vacuum drying of gained solid
24h, obtain Ezetimibe 3.51kg, yield 86.12%, purity>99.6%, dr:>In 99.9%, HPLC product appearance time with
Standard items are consistent, and nuclear-magnetism structure is correct.
Embodiment above describes the general principle of the present invention, main features and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (8)
1. a kind of preparation method of high fat of blood curative Ezetimibe, it is characterised in that reaction equation is as follows：
Comprise the following steps：It is raw material with compound 2, is prepared by after carbonyl-protection, cyclization, carbonyl reduction, oxidation
Obtain Ezetimibe 1.
2. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 1, it is characterised in that：The protection step
Suddenly it is to obtain compound 3 after reacting compound 2 and 1-1.1eq ethylene glycol in n-hexane.
3. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 1, it is characterised in that：The cyclisation step
Suddenly it is that compound 3 and the cyclization under the conditions of BSA and TBAF of compound 4 are obtained into compound 5.
4. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 3, it is characterised in that：The compound
3rd, compound 4, BSA and TBAF equivalent proportions are 1-1.2:1-1.2:2:0.06.
5. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 1, it is characterised in that：The carbonyl is also
Former step is, in dichloromethane solvent, reaction temperature is -5 DEG C to 0 DEG C, adds 0.10-0.15eq (R)-MeCBS and 1.0-
1.5eq BH3-S(CH3)2Asymmetric reduction is carried out to compound 5, obtains compound 6.
6. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 1, it is characterised in that：The oxidation step
Suddenly it is in acetic acid, to add 1.5-2.0 equivalents hydrogen peroxide and the borate group in compound 6 is oxidized to hydroxyl, obtain product
1。
7. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 1, it is characterised in that：The product 1
By ethyl acetate：Petroleum ether=1：2.4-3.0 is recrystallized to give the sterling 1 of purity more than 99.5%.
8. according to a kind of preparation method of high fat of blood curative Ezetimibe in claim 1, it is characterised in that：The compound
4 synthesis, by para-fluoroaniline and equivalent aldehyde radical phenyl boric acid pinacol ester is obtained after reflux in toluene divides water or room temperature
Compound 4 is obtained after lower addition 4A molecular sieve dehydrations.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007119106A2 (en) * | 2005-12-22 | 2007-10-25 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of ezetimibe |
| CN104230978A (en) * | 2014-09-22 | 2014-12-24 | 上海现代制药股份有限公司 | Preparation midbody for Ezetimibe and preparation method of preparation midbody |
| CN104513187A (en) * | 2015-01-09 | 2015-04-15 | 安润医药科技（苏州）有限公司 | Ezetimibe synthesis method and Ezetimibe intermediate synthesis method |
| CN106397292A (en) * | 2016-09-20 | 2017-02-15 | 苏州普罗达生物科技有限公司 | Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe |
-
2017
- 2017-11-07 CN CN201711082016.1A patent/CN107652214A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007119106A2 (en) * | 2005-12-22 | 2007-10-25 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of ezetimibe |
| CN104230978A (en) * | 2014-09-22 | 2014-12-24 | 上海现代制药股份有限公司 | Preparation midbody for Ezetimibe and preparation method of preparation midbody |
| CN104513187A (en) * | 2015-01-09 | 2015-04-15 | 安润医药科技（苏州）有限公司 | Ezetimibe synthesis method and Ezetimibe intermediate synthesis method |
| CN106397292A (en) * | 2016-09-20 | 2017-02-15 | 苏州普罗达生物科技有限公司 | Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe |
Non-Patent Citations (2)
| Title |
|---|
| 朱丽娜: "降脂药物依替米贝的工艺优化", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
| 魏长勇: "依替米贝合成工艺优化", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
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Application publication date: 20180202 |