CN105566374B - A kind of slurry bed system continuous producing method of Ezetimibe intermediate - Google Patents
A kind of slurry bed system continuous producing method of Ezetimibe intermediate Download PDFInfo
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- CN105566374B CN105566374B CN201511016609.9A CN201511016609A CN105566374B CN 105566374 B CN105566374 B CN 105566374B CN 201511016609 A CN201511016609 A CN 201511016609A CN 105566374 B CN105566374 B CN 105566374B
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- 0 C*(CC[C@@](*(*)C(N(C(NC)OC1)[C@]1c1ccccc1)=O)[C@](*c(cc1)ccc1F)c(cc1)ccc1O*)c(cc1)ccc1I Chemical compound C*(CC[C@@](*(*)C(N(C(NC)OC1)[C@]1c1ccccc1)=O)[C@](*c(cc1)ccc1F)c(cc1)ccc1O*)c(cc1)ccc1I 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Abstract
This application discloses a kind of Ezetimibe intermediate 3 [(2R, 5S) 5 (4 fluorophenyl) 2 [(S) [(4 fluorophenyls (amino)]] [4 R1Oxygroup] phenyl] methyl] 1 oxo 5 [(trimethyl silicane) oxygen] phenyl] 4 phenyl (4S) 2 oxazolidone continuous producing method, it is characterized in that, by the raw material containing compound A and compound B, with solid acid catalyst haptoreaction in paste state bed reactor, the Ezetimibe intermediate is prepared.By using solid acid catalyst instead of original titanium tetrachloride and isopropyl titanate catalyst, and the successive reaction in paste state bed reactor, reduce environmental pollution and the requirement to production equipment, it solves the problems, such as the separation of catalyst and recycling, makes it possible the large-scale continuous production of Ezetimibe.
Description
Technical field
This application involves a kind of Ezetimibe intermediate 3- [(2R, 5S) -5- (4- fluorophenyls) -2- [(S)-[(4- fluorophenyls
(amino)]] [4-R1Oxygroup] phenyl] methyl] -1- oxos -5- [(trimethyl silicane) oxygen] phenyl] -4- phenyl-(4S) -2- oxazoles
The preparation method of alkanone, belongs to pharmaceutical synthesis field.
Background technology
Ezetimibe piece is a kind of new cholesterol-lowering drug, is a kind of selective cholesterol absorption inhibitor, main to hinder
The exogenous absorption features of disconnected cholesterol.It inhibits the absorption of enteron aisle inner cholesterol by acting on cholesterol transporter.And
And Ezetimibe f hardlyes pass through cytochrome P 450 enzymes metabolism, the interaction between other drugs is lacked, security and tolerance
Property is good.
Ezetimibe (Ezetimibe) alias according to ezetimibe, ezetimibe, earliest by Schering Plough (Schering-
Plough) company and Merck (Merck) company develop success jointly.U.S. FDA approval listing on October 25th, 2002, business
The name of an article is Ai ZetingIt has been listed in Canada, Japan, European Union, China etc. afterwards.Commodity in Discussion on Chinese Listed
Entitled benefit is suitable pureDosage form is tablet, specification：10mg/ pieces, for primary hypercholesterolemia, homozygosis
The treatment of sub-family hypercholesterolemia, homozygote Sitosterolemia.
The synthesis of Ezetimibe and its intermediate is mainly using titanium tetrachloride and isopropyl titanate as the homogeneous catalysis of catalyst
Methodology of organic synthesis, requirement there are of high cost, environmental pollution, to production equipment and feed moisture content is high, it is continuous anti-to be difficult to
Should, catalyst the problems such as being difficult to recycle.
The content of the invention
According to the one side of the application, a kind of Ezetimibe intermediate 3- [(2R, 5S) -5- (4- fluorophenyls) -2- are provided
[(S)-[(4- fluorophenyls (amino)]] [4-R1Oxygroup] phenyl] methyl] -1- oxos -5- [(trimethyl silicane) oxygen] phenyl] -4- benzene
The slurry bed system continuous producing method of base-(4S) -2- oxazolidones, by using solid acid catalyst instead of original four chlorination
Titanium and isopropyl titanate catalyst, and the successive reaction in paste state bed reactor reduce environmental pollution and production equipment are wanted
It asks, solves the problems, such as the separation of catalyst and recycling, make it possible the large-scale continuous production of Ezetimibe.
Ezetimibe intermediate described herein, through the following steps that the intermediate of production Ezetimibe technique：
The first step：Condensation reaction
Second step：Ring-closure reaction
3rd step：Hydrolysis
4th step：Recrystallization purification
With organic dissolution to the crude product after hydrolysis, recrystallization purification is carried out, obtains the Ezetimibe of high-purity.
The preparation method of herein described Ezetimibe intermediate is the first step in above-mentioned steps, which is characterized in that
By the raw material containing compound A and compound B, in paste state bed reactor with solid acid catalyst haptoreaction, described in preparation
Ezetimibe intermediate；
The compound A is (4S) -3- [(5S) -5- (4- fluorophenyls) -5- hydroxypentanoyls base] -4- phenyl -1,3- oxygen nitrogen
Heterocycle pentane -2- ketone, structural formula is shown in formula I：
Formulas I
The compound B is 4- (4- fluorophenyls imines) methylphenol, and structural formula is as shown in Formula II：
Formula II
The Ezetimibe intermediate is 3- [(2R, 5S) -5- (4- fluorophenyls) -2- [(S)-[(4- fluorophenyls (amino)]]
[4-R1Oxygroup] phenyl] methyl] -1- oxos -5- [(trimethyl silicane) oxygen] phenyl] -4- phenyl-(4S) -2- oxazolidones, structure
Formula is as shown in formula III：
Formula III
Wherein, R1Selected from least one of group with structural formula shown in formula IV：
Formula IV
Wherein, R11, R12, R13Separately it is no more than 10 alkyl selected from carbon number.
Preferably, the R in formula IV11, R12, R13In at least one be methyl.It is further preferred that the R in formula IV11,
R12, R13It is methyl.
Preferably, the solid acid catalyst be selected from H-ZSM-5 molecular sieve catalysts, Co-ZSM-5 molecular sieve catalysts,
SO4 2-/TiO2Solid acid catalyst, AlCl3/SiO2At least one of catalyst.
Preferably, in the H-ZSM-5 molecular sieve catalysts, the weight percentage of H-ZSM-5 molecular sieves is not less than
30%.It is further preferred that in the H-ZSM-5 molecular sieve catalysts, the weight percentage of H-ZSM-5 molecular sieves is 50%
~100%.
Preferably, the sial atomic ratio Si/Al in the H-ZSM-5 molecular sieves is no more than 50.It is it is further preferred that described
Sial atomic ratio Si/Al in H-ZSM-5 molecular sieves is 25~50.
Preferably, in the Co-ZSM-5 molecular sieve catalysts, the weight percentage of Co-ZSM-5 molecular sieves is not less than
30%.It is further preferred that in the Co-ZSM-5 molecular sieve catalysts, the weight percentage of Co-ZSM-5 molecular sieves is
50%~100%.
The Co-ZSM-5 molecular sieves are obtained by ion-exchange or infusion process.
Preferably, weight percentage of the cobalt element in Co-ZSM-5 molecular sieves is in the Co-ZSM-5 molecular sieves
0.1~5wt%.It is further preferred that weight hundred of the cobalt element in Co-ZSM-5 molecular sieves in the Co-ZSM-5 molecular sieves
It is 0.5~2wt% to divide content.
Preferably, the sial atomic ratio Si/Al in the Co-ZSM-5 molecular sieves is no more than 50.It is further preferred that institute
It is 25~50 to state the sial atomic ratio Si/Al in Co-ZSM-5 molecular sieves.
Preferably, it is described in paste state bed reactor with the catalytic mass space velocity of solid acid catalyst for 0.1~
10h-1；Preferably, described is 1~3h with the catalytic mass space velocity of solid acid catalyst in paste state bed reactor-1。
Preferably, cooling tube, the cooling tube and the reactant in the slurry bed system are contained in the paste state bed reactor
System contacts, and coolant is led in the cooling tube, and the cooling tube controls the temperature of reaction system in the paste state bed reactor
At -30 DEG C~-20 DEG C.
Preferably, the molar ratio of compound A and compound B are 1 in the raw material:1~3.It is further preferred that the original
The molar ratio of compound A and compound B are 1 in material:2~3.
Also contain organic amine, hydroxy-protecting agent and organic solvent in the raw material.Those skilled in the art, can basis
The needs of actual production and the needs of concrete technology, select the addition of suitable organic amine, hydroxy-protecting agent and organic solvent
Amount.Preferably, the weight ratio of organic amine and compound A are 0.2~1 in raw material:1；Hydroxy-protecting agent：(compound A+ chemical combination
Object B) molar ratio be 1~2:1；The weight ratio of organic solvent and compound A are 4~10：1.It is further preferred that raw material
The weight ratio of middle organic amine and compound A are 0.5~0.8:1；Hydroxy-protecting agent：The molar ratio of (compound A+ compound B)
Example is 1.2~1.6:1；The mass ratio of organic solvent and compound A are 5~8：1.
Preferably, the organic amine in triethylamine, n,N-diisopropylethylamine, pyridine, piperidines, morpholine at least one
Kind.
Preferably, the organic solvent is selected from least one of dichloromethane, chloroform, tetrahydrofuran, toluene.
Preferably, the hydroxy-protecting agent, which is selected from, has at least one of compound of structural formula shown in Formula V：
Formula V
Wherein, R11, R12, R13Separately it is no more than 10 alkyl selected from carbon number；X is in halogen
It is at least one.It is further preferred that the hydroxy-protecting agent is trim,ethylchlorosilane.
Preferably, the raw material and the catalytic reaction temperature of solid acid catalyst are -30 DEG C~-20 DEG C.Further
Preferably, the raw material and the catalytic reaction temperature of solid acid catalyst are -30 DEG C~-25 DEG C.
As a preferred embodiment, the preparation method of the Ezetimibe intermediate, including at least following steps：
A) compound A and compound B are dissolved in organic solvent, system temperature is down to less than -20 DEG C, adds in organic amine
And hydroxy-protecting agent, obtain raw material；
B) at -30 DEG C~-20 DEG C, by raw material obtained by step a) with after solid acid catalyst haptoreaction, adding in acid solution
Terminate reaction；
C) N is added in, the double trimethylsilyl acetamides of O- after extracted concentration, add in crystallization solvent, and crystal is precipitated through drying,
Up to the Ezetimibe intermediate.
Preferably, acid solution is selected from least one of formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid in step b).
Preferably, the step c) crystallization solvents are made of normal heptane and ethyl acetate, the body of normal heptane and ethyl acetate
Product is than being 2~3:1.
Preferably, 30~40 DEG C of double trimethylsilyl acetamides of addition N, O- in step c), when reflux 1~3 is small after, in 40~
50 DEG C addition crystallization solvents, stirring no less than 1 it is small when after be cooled to 10~20 DEG C of crystallizations, gained crystal is done through 40~50 DEG C of air blast
It is dry, you can to obtain the Ezetimibe intermediate.
The advantageous effect of the application includes but not limited to：
(1) method provided herein, by using solid acid catalyst instead of original titanium tetrachloride and isopropyl
Alcohol titanium catalyst reduces environmental pollution and the requirement to production equipment.
(2) method provided herein, catalyst can recycle use convenient for separation.
(3) method provided herein, using solid catalyst, making the large-scale continuous production of Ezetimibe, become can
Energy.
(4) method provided herein using paste state bed reactor, can be mass produced continuously.
Specific embodiment
The application is described in detail with reference to embodiment, but the application is not limited to these embodiments.
The preparation of 1 catalyst of embodiment
The preparation of CAT-1：
The ammonium nitrate that ZSM-5 molecular sieve (silica alumina ratio Si/Al=25) the addition 500mL concentration for weighing 10g is 2mol/L is molten
In liquid, when 80 DEG C of stirred in water bath 2 are small, ion exchange is carried out.After exchanging three times repeatedly, the solid sample that is centrifugally separating to obtain,
After being dried at deionized water is washed 3 times, 100 DEG C, when roasting 4 is small at 550 DEG C, gained H-ZSM-5 sieve samples are denoted as
CAT-1。
The preparation of CAT-2：
The ammonium nitrate that ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) the addition 500mL concentration for weighing 10g is 2mol/L is molten
In liquid, when 80 DEG C of stirred in water bath 2 are small, ion exchange is carried out.After exchanging three times repeatedly, washed 3 times, 100 DEG C through deionized water
After lower drying, when roasting 4 is small at 550 DEG C, gained H-ZSM-5 sieve samples are denoted as CAT-2.
The preparation (infusion process) of CAT-3：
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) for weighing 10g adds in the nitric acid that 500mL concentration is 1mol/L
In ammonium salt solution, when 80 DEG C of stirred in water bath 2 are small, the solid sample three times, being centrifugally separating to obtain is exchanged repeatedly, is washed through deionization
It washs at 3 times, 100 DEG C after drying, by obtained solid sample using equi-volume impregnating, 4h is impregnated in cobalt acetate solution, through 110
DEG C drying 16h, at 550 DEG C roast 4 it is small when, be prepared cobalt element weight percentage be 0.1wt% Co-ZSM-5
Sieve sample is denoted as CAT-3.
The preparation of CAT-4：
10g titanium sulfates is taken to add in four-hole boiling flask, after adding in 500mL deionized water dissolvings, add in 1g glycol monoethyl ethers,
Be vigorously stirred it is lower be quickly heated to reflux, after azeotropic to hydrolysising balance, be added dropwise unsaturated carbonate hydrogen ammonium salt solution to system pH to 7, stop
It only heats, after being cooled to room temperature, after centrifuging solid and being washed with deionized three times, is dried at 100 DEG C, obtained solid
It adds in the 1mol/L sulfuric acid solutions of 200mL, impregnates 14h, be centrifugally separating to obtain solid sample, dried at 80 DEG C, at 500 DEG C
3h is roasted to get SO4 2-/TiO2Solid acid catalyst is denoted as CAT-4.
The preparation of CAT-5：
By γ-Al2O3After when roasting 2 is small at 500 DEG C, 500 DEG C of system temperature is kept, is passed through CCl4Steam, with γ-
Al2O3Reaction generation AlCl3Steam, the AlCl of generation3Steam is carried by nitrogen, at 200 DEG C with by roasting 2 is small at 500 DEG C when
Carrier S iO2(specific surface area 300m2/ g, pore volume 0.9mL/g) contact 3h.1h is purged with nitrogen, after being cooled to room temperature to obtain the final product
AlCl3/SiO2Catalyst is denoted as CAT-5.
2 paste state bed reactor of embodiment is reacted
Reaction raw materials
According to the proportioning of table 1, compound A and compound B are dissolved in organic solvent respectively, system temperature is down to -20
DEG C, it adds in organic amine and hydroxy-protecting agent, obtained reaction raw materials is as shown in table 1.
1 reaction raw materials of table
Note*：A is compound A；B is compound B.
Paste state bed reactor
200g reaction raw materials are added in paste state bed reactor, according still further to table 2, catalyst is crushed and whole grain is to 0.03mm
The particle of~0.05mm, is added in paste state bed reactor.Cooling tube in paste state bed reactor is passed through coolant, by slurry bed system
Interior temperature is controlled in the temperature shown in table 2, slurry bed system everywhere without temperature gradient.The material entrance of paste state bed reactor
10 micron filters are equipped with, raw material is passed through reactor with air speed shown in table 2, while there is material outflow in outlet.
Reaction 1#~reaction 5#Reaction condition be shown in Table 2.
Table 2
| Reaction number | Catalyst and total dosage | Mass space velocity* | Reaction temperature |
| Reaction 1# | CAT-1；100g | 0.1h-1 | -30℃ |
| Reaction 2# | CAT-2；100g | 1h-1 | -25℃ |
| Reaction 3# | CAT-3；100g | 2h-1 | -20℃ |
| Reaction 4# | CAT-4；100g | 3h-1 | -25℃ |
| Reaction 5# | CAT-5；100g | 10h-1 | -25℃ |
Note*：Mass space velocity WHSV
Reaction
Reaction 1#~reaction 5#Under 2 corresponding reaction condition of table, raw material is passed through in reactor, is contacted with catalyst instead
Should, after stable reaction 30min, the acid solution in outlet material addition table 3 is reacted with terminating.Add in N, the double trimethylsilyl acetyl of O-
Amine after extracted concentration, adds in the crystallization solvent in table 3, and crystal is precipitated through 45 DEG C of forced air dryings to get in the Ezetimibe
Mesosome.
Table 3
Note*：Mass space velocity WHSV
The above is only several embodiments of the application, any type of limitation is not done to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, make a little variation using the technology contents of the disclosure above or modification is equal to
Case study on implementation is imitated, is belonged in the range of technical solution.
Claims (14)
1. a kind of continuous producing method of Ezetimibe intermediate, which is characterized in that by the original containing compound A and compound B
Material, with solid acid catalyst haptoreaction in paste state bed reactor, prepares the Ezetimibe intermediate；
The compound A is (4S) -3- [(5S) -5- (4- fluorophenyls) -5- hydroxypentanoyls base] -4- phenyl -1,3- oxazas
Pentane -2- ketone, structural formula is shown in formula I：
The compound B is 4- (4- fluorophenyls imines) methylphenol, and structural formula is as shown in Formula II：
The Ezetimibe intermediate is 3- [(2R, 5S) -5- (4- fluorophenyls) -2- [(S)-[(4- fluorophenyls (amino)]] [4-R1
Oxygroup] phenyl] methyl] -1- oxo -5- [R1Oxygroup] phenyl] -4- phenyl-(4S) -2- oxazolidones, structural formula such as formula III institute
Show：
Wherein, R1Selected from least one of group with structural formula shown in formula IV：
Wherein, R11, R12, R13Separately it is no more than 10 alkyl selected from carbon number；
The solid acid catalyst is selected from H-ZSM-5 molecular sieve catalysts, Co-ZSM-5 molecular sieve catalysts, SO4 2-/TiO2Solid
Acid catalyst, AlCl3/SiO2At least one of catalyst.
2. according to the method described in claim 1, it is characterized in that, described connect in paste state bed reactor with solid acid catalyst
The mass space velocity for touching reaction is 0.1~10h-1。
3. according to the method described in claim 2, it is characterized in that, described connect in paste state bed reactor with solid acid catalyst
The mass space velocity for touching reaction is 1~3h-1。
It is 4. described cold according to the method described in claim 1, it is characterized in that, contain cooling tube in the paste state bed reactor
But pipe is contacted with the reaction system in the slurry bed system, logical coolant in the cooling tube, and the cooling tube is by the slurry bed system
Temperature of reaction system in reactor is controlled at -30 DEG C~-20 DEG C.
5. according to the method described in claim 1, it is characterized in that, R in formula IV11, R12, R13In at least one be methyl.
6. according to the method described in claim 5, it is characterized in that, R in formula IV11, R12, R13It is methyl.
7. according to the method described in claim 1, it is characterized in that, the molar ratio of compound A and compound B are in the raw material
1:1~3.
8. the method according to the description of claim 7 is characterized in that the molar ratio of compound A and compound B are in the raw material
1:2~3.
9. according to the method described in claim 1, it is characterized in that, containing organic amine, hydroxy-protecting agent and have in the raw material
Solvent；The organic amine is selected from triethylamine, at least one of N, N- diisopropylethylamine, pyridine, piperidines, morpholine；
The organic solvent is selected from least one of dichloromethane, chloroform, tetrahydrofuran, toluene；
The hydroxy-protecting agent, which is selected from, has at least one of compound of structural formula shown in Formula V：
Wherein, R11, R12, R13Separately it is no more than 10 alkyl selected from carbon number；X in halogen at least
It is a kind of.
10. according to the method described in claim 1, it is characterized in that, the raw material and the catalytic reaction temperature of catalyst
For -30 DEG C~-20 DEG C.
11. according to the method described in claim 10, it is characterized in that, the raw material and the catalytic reaction temperature of catalyst
For -30 DEG C~-25 DEG C.
12. the method according to claim 1 or 9, which is characterized in that including at least following steps：
A) compound A and compound B are dissolved in organic solvent, system temperature is down to less than -20 DEG C, adds in organic amine and hydroxyl
Base protective agent, obtains raw material；
B) at -30 DEG C~-20 DEG C, raw material obtained by step a) is terminated into reaction with after catalyst haptoreaction, adding in acid solution；
C) add in N, the double trimethylsilyl acetamides of O- after extracted concentration, add in crystallization solvent, be precipitated crystal through it is dry to get
The Ezetimibe intermediate.
13. according to the method for claim 12, which is characterized in that in step b) acid solution be selected from formic acid, acetic acid, hydrochloric acid,
At least one of sulfuric acid, perchloric acid；Step c) the crystallization solvents are made of normal heptane and ethyl acetate, normal heptane and acetic acid
The volume ratio of ethyl ester is 2~3:1.
14. according to the method for claim 12, which is characterized in that 30~40 DEG C of double trimethylsilyls of addition N, O- in step c)
Acetamide, reflux 1~3 it is small when after, in 40~50 DEG C add in crystallization solvents, stirring no less than 1 it is small when after be cooled to 10~20 DEG C
Crystallization, gained crystal is through 40~50 DEG C of forced air dryings, you can obtains the Ezetimibe intermediate.
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