CN105985296A - Industrializable refining process for lesinurad intermediate 1-naphthyltriazole thioketone - Google Patents
Industrializable refining process for lesinurad intermediate 1-naphthyltriazole thioketone Download PDFInfo
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Abstract
The invention discloses a synthesis process and refining process for a lesinurad intermediate 3-amino-4-(4-cyclopropylnaphthalen-1-yl)-1H-1,2,4-triazole-5(4H)-thione which can be used for preparation of gout treatment drugs. The process comprises the following steps: adding a sodium carbonate solution into a mixture prepared from a compound 1, a compound 2-B1, ethanol and water drop by drop; supplementing a proper amount of water after completion of reaction; and treating a crude product 3 of 3-M containing impurities with alkali in a solvent, hydrolyzing 3-M and subjecting the obtained crude solid of 3 to ethanol beating so as to obtain a high-purity product 3. The process has the advantages of suitability for large-scale industrial operation and capacity of producing the high-purity product.
Description
Technical field
The invention belongs to pharmaceutical technology field, particularly relate to one and may be used for preparing gout treatment medicine
The method of lesinurad intermediate 3-amino-4-(4-cyclopropyl naphthalene-1-base)-1H-1,2,4-triazole-5 (4H)-thioketones and
Its process for refining.
Background technology
Gout is a kind of causing so that hyperuricemia and monosodium urate salt (MSU) are deposited on the positions such as joint bitterly
The chronic metabolic disease that pain is principal character, main cause is purine metabolic disturbance and/or uric acid discharges obstacle.
Whole world patient with gout has tens million of at present.Lesinurad (RDEA 594) is a kind of to be developed by Ardea company
Uric acid transporter body in kidney (urate transporter 1, URAT1) can be suppressed to discharge the oral of uric acid in blood
Medicine, is developed by antiviral drugs RDEA806 of Valeant the earliest.Present lesinurad's is all
Ownership is in Astra Zeneca.
The principal synthetic routes (WO2014/008295 and US2013345271) of Lesinurad is as follows.Its
In, US2013345271 discloses and is synthesized through intermediate 2 by 4-cyclopropyl-1-naphthalenylisothiocyanate (1)
3-amino-4-(4-cyclopropyl naphthalene-1-base)-1H-1, the detailed process of 2,4-triazoles-5 (4H)-thioketones (3) (page 15,
Step E).This technique is made up of two steps altogether, and the first step (1 → 2) needs to react 15 hours, second step (2 →
3) need to react 60 hours, and the first step also relates to high boiling after the completion of reaction in processes
DMF is evaporated off, and product 3 finally also needs to column chromatography and purifies, and productivity is relatively low (to be only had by the merging yield of 1 to 3
49%).To sum up, disclosed in document by 1 preparation 3 technique shortcoming clearly: the reaction time is very
The operation that high boiling DMF is evaporated off using in length, technique is relatively difficult, column chromatography purifying has been arrived in use,
Yield is relatively low.
In order to solve the problem in above-claimed cpd 3 preparation process, patent CN201410340622.9 discloses
Article one, new synthetic route is (as follows.Wherein R is selected from C1-C10Alkyl, benzyl, on phenyl ring by F,
Cl、Br、I、NO2、R1O、C1-C10Alkyl and CF3Substituted benzyl, pi-allyl, wherein R1=C1-C10
Alkyl；X is selected from F, Cl, Br, I, OMs, OTs and OTf), this route substantially overcomes above-mentioned lacking
Point, has the advantages that the time is short, productivity is high and does not needs column chromatography purifying.
CN201410340622.9 is disclosed by the general routes outlined of 1 preparation 3:
CN201410340622.9 embodiment 1 is disclosed by the route of 1 preparation 3:
But the synthetic route of most potential 1 → 3 disclosed in patent CN201410340622.9
(i.e. the embodiment 1 of CN201410340622.9, now R=Bn, the productivity that this embodiment is reported for work and RX's
Cost is optimum in the disclosed all possible choice of technology) when furtheing investigate, especially in pilot scale level
And when studying in above scale, it was found that two are hindered the technical problem that this route industrially uses.The
One is, when by compound 1 and 2-B1, in the mixed solution of ethanol/water, reaction generates 2-C1 in the presence of a base,
Reaction system when proceeding to mid-term can separate out the jelly of extremely thickness, and these materials can be attached to paddle
On, make stirring be difficult to be smoothed out, extreme influence production safety；Second is, in pilot scale and above scale
During preparation, the sample of the compound 3 according to the technique institute isolated of embodiment 1 for the in-depth study discovery contains
Having a certain amount of impurity 3-M (structural formula is as follows), content is typically at about 10%-20%.3-M's is molten
Xie Du is poor, uses technique disclosed in CN201410340622.9 (making beating i.e. in ethanol) to be difficult to remove, right
The sample purity impact of compound 3 is very big.Attempt to use straight alcohol or ethyl acetate and hexane mixture etc.
It also is difficult to when solvent recrystallizes remove, it is intended to when using common column chromatography to separate 3-M and 3 also not
Easily success, because compound 3-M solubility is less, often separates out on a silica gel column and causes column chromatography procedure
Middle pillar blocks, and column chromatography does not often also use in large-scale production.
For two problems occurring in 1 → 3 technique disclosed in above-mentioned CN201410340622.9, we
Carry out substantial amounts of further investigation, disclosed one and can be suitable for heavy industrialization operation and can produce high-purity
The process of the product 3 of degree.
It should be strongly noted that compound 3 has two kinds of existence forms, i.e. thioketones formula 3-ONE and thiol
3-OL (as follows).Both forms are in the state of difference, in the solution made of different solvents and different
Present in the solution of concentration, ratio is different, but does not affect its use in synthetic reaction.
Content of the invention
The present invention be contemplated to solve prior art shortcoming, and provide one can be industrialized by compound
1 technique preparing compound 3, this technique has applicable heavy industrialization and operates and can produce highly purified
The advantage of product 3.
Of the present invention compound 1 is synthesized the process route of compound 3 and refined route is as follows.
In order to solve two problems occurring in 1 → 3 technique disclosed in patent CN201410340622.9, I
Done numerous studies.
For first problem (that is: compound 1 and 2B1 in the presence of a base in the mixed solution of ethanol/water anti-
When should generate 2-C1, reaction system when proceeding to mid-term can separate out the jelly of extremely thickness, these materials
Can be attached on paddle, make stirring be difficult to be smoothed out, extreme influence production safety), former technique uses
Once adding sodium carbonate liquor, the present invention has carried out 2 improvement after research, and first is: by sodium carbonate
Solution has changed into slowly dripping, and dropping process continues between 2-12 hour, preferably 3-5 hour；Second is:
Original 1/4～1/2 is had to change 1/1 into the volume ratio of second alcohol and water in reaction system before dropping sodium carbonate liquor,
Reaction is mended after completing again and is added water to 1/2 (disregarding the volume adding the water that aqueous sodium carbonate brings).Through ours
After improvement, when above-mentioned reaction proceeds to mid-term, system can separate out the jelly of extremely thickness, and reaction system stirs more
Add close friend, be more suitable for industrialized production.
For Second Problem, (that is:, when preparing in pilot scale and above scale, in-depth study discovery separates
Containing a certain amount of impurity 3-M in the sample of the compound 3 obtaining, content is typically at about 10%-20%.
The solubility of 3-M is poor, uses technique disclosed in CN201410340622.9 (making beating i.e. in ethanol) to be difficult to
Removing, the quality impact on compound 3 is very big.Attempt to use ethanol or ethyl acetate and hexane mixture
It also is difficult to when equal solvent recrystallizes remove, it is intended to when using common column chromatography to separate 3-M and 3 also
It is difficult to successfully, because compound 3-M solubility is less, often separates out on a silica gel column and cause column chromatography mistake
Pillar blocking in journey, and column chromatography does not often also use in large-scale production), our purifying to product 3
Mode has done numerous studies, has finally done significant improvement, it may be assumed that by the solid of the crude product 3 containing impurity 3-M
Use alkali process, 3-M is hydrolyzed, in post processing, then recalls to pH value again with acid, through routine after extraction
Process, the solid of 3 obtaining through ethanol pull an oar, i.e. can get highly purified product 3.The alkali being used
For NaOH or KOH.Product (i.e. 4-cyclopropyl-naphthalidine, benzyl mercaptan, the sulphur generation obtaining after 3-M hydrolysis
Sodium carbonate) i.e. water soluble (sodium thiocarbonate) or using ethanol to pull an oar in conventional process wherein
When be dissolved in ethanol and remove (4-cyclopropyl-naphthalidine and benzyl mercaptan).After our above-mentioned improvement, product 3
In the impurity 3-M that is difficult to remove thoroughly removed, improve the quality of product 3.
Brief description
Fig. 1 is the monocrystalline figure of the X-ray diffraction of compound 3-M.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only
It for illustrating, and is not intended to limit the present invention.Those skilled in the art are made according to the teachings of the present invention
Various changes all should be within the protection domain required by the application claim.
Embodiment 1 is based on the enlarged experiment of process route in CN201410340622.9
The synthesis of step 1. compound 2-C1
The glass reaction kettle of one 20L adds 182.28g (2mol) thiosemicarbazides 2-A, with 2097mL
Anhydrous alcohol solution, lower dropping 342.06g (2mol) cylite of ice-water bath cooling, drip off in 10 minutes.Drip
Adding after finishing, reactant mixture temperature rising reflux 30 minutes, TLC checks that discovery reaction completes, and then reaction is mixed
Compound is cooled to room temperature, the ethanol solution being 2-B1 now obtaining.
It is sequentially added into 8388mL water and 450.62g (2mol) compound 1 in reactant mixture, then stirring
Mix and add the saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water next time.Add
After complete, reactant mixture at room temperature (20 DEG C-35 DEG C) uses mechanical agitation to stir, and adds about about 1.5 hours
Rear system produces the jelly of a large amount of extremely thickness, and these jelly major parts stick on paddle and bottle wall
On, now stirring becomes more difficulty, strengthens and stirs horsepower continuation stirring, and frequently uses instrument to process adhesion
Dope on paddle and bottle wall, prevents security incident.After continuing stirring 24-36 hour, obtain
One light yellow syrup.
Reaction system suction filtration, filter cake (with certain viscosity) at room temperature vacuum (5mmHg) is dried 5 hours,
Obtain compound 2-C1,634.25g, yield 78%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
In the glass reaction kettle of one 20L add 609.86g (1.5mol) compound 2-C1 and 6099mL without
Water-ethanol, then temperature rising reflux 1 hour, TLC checks that reaction completes.
Reactant mixture is cooled to room temperature, continues stirring 3 hours under room temperature, obtains a light yellow brilliant slurry.
Collected by suction solid, is dried 5 hours under vacuum (5mmHg), is compound 3,381.19g, productivity 90%.
Analyze through HPLC, wherein contain impurity 3-M 18% (mass ratio).
Take out the above-mentioned crude Compound of 20g 3, attempt using ethyl alcohol recrystallization, and follow the tracks of compound with HPLC
The content of impurity 3-M in 3, acquired results is as shown in the table.
Table 1 uses ethanol to carry out the result of the test of crystallization and purification to crude Compound 3
| Crystallisation times is numbered | Ethanol volume | Yield after crystallization | 3-M content |
| 1 | 200mL | 18.34g | 17% |
| 2 | 183mL | 16.11g | 16% |
| 3 | 161mL | 14.04g | 15% |
| 4 | 140mL | 12.36g | 15% |
As can be seen from the above table, ethanol is used to carry out to crude product 3 recrystallizing to removing impurity 3-M therein
It is failed, because continuous 4 recrystallizations are very limited to the attenuating of the 3-M content in crude product 3.Use
When the mixed solvent of ethyl acetate and n-hexane crystallizes, have also been obtained similar result.
The impurity 3-M sample of a small amount of sterling is isolated by careful repeatedly column chromatography from crude product 3, to
Identify its accurate structural, and find the refined method removing 3-M accordingly.3-M sterling, white solid, molten
Point: 155-157 DEG C；HR-MS, m/z=350.1029.3-M's1H NMR and13C NMR spectra all compares
Strange, occur in that multiple bulge shape signal, it is impossible to for the determination of structure.Take 100mg 3-M and be dissolved in 10mL
In the mixture of absolute ethyl alcohol and 5mL dichloromethane, at room temperature slowly volatilize, obtain after 3 days being suitable for X-
The monocrystalline of x ray diffraction.Use X-ray single crystal diffractometer to carry out diffraction, collect data according to conventional operation
And data are resolved, obtain the accurate structural of 3-M, as shown in Figure 1.3-M structure contains one
Dithiocarbamate structure, it is concluded that destroy this structure perhaps by hydrolyzed under basic conditions,
And the product destroying can be dissolved in water or can be removed by making beating in usual vehicle.3-M structure accurate
Determine that finding use alkali of the present invention for us processes the crude product of 3 and serve key to remove 3-M
Effect.
Technique after embodiment 2 present invention improvement
The synthesis of step 1. compound 2-C1
In the round-bottomed flask of one 10L add 182.28g (2mol) thiosemicarbazides 2-A, with 2097mL without
Water-ethanol dissolves, lower dropping 342.06g (2mol) cylite of ice-water bath cooling, drips off in 10 minutes.Dropping
After finishing, reactant mixture temperature rising reflux 30 minutes, TLC checks that discovery reaction completes, then reaction mixing
Thing is cooled to room temperature, the ethanol solution being 2-B1 now obtaining.
It is sequentially added into 2097mL water and 450.62g (2mol) compound 1 in reactant mixture, then stirring
Mix down and slowly drip the saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water, drip
Continue 4 hours between the added-time.After dropping finishes, reactant mixture at room temperature (20 DEG C-35 DEG C) uses machinery to stir
Mix and be stirred overnight, obtain a light yellow brilliant slurry, whole during do not produce the mucilage binding thing of thickness.Toward instead
Answer and mixture is slowly added 2097mL water, drip off in 10 minutes, add rear reactant mixture and be further continued for stirring
Mix 3 hours.
Reaction system suction filtration, filter cake at room temperature vacuum (5mmHg) is dried 5 hours, obtains compound 2-C1,
658.64g, yield 81%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
In the glass reaction kettle of one 20L add 650.51g (1.6mol) compound 2-C1 and 6505mL without
Water-ethanol, then temperature rising reflux 1 hour, TLC checks that reaction completes.
Reactant mixture is cooled to room temperature, adds 6505mL n-hexane, continues stirring 3 hours under room temperature,
Obtain a light yellow brilliant slurry.Collected by suction solid, preliminarily dried 1 hour under vacuum (20mmHg), i.e.
For the crude product of compound 3, analyze through HPLC, wherein contain impurity 3-M 15% (mass ratio).
Above-mentioned crude product all joins in 4000mL absolute ethyl alcohol, stirring, adds 300mL's 30%
NaOH solution, mixture temperature rising reflux 10 minutes, TLC checks that discovery 3-M consumes completely, then reacts
Mixture is cooled to room temperature.
Reactant mixture joins in 16L frozen water, stirring, regulates pH=7 with concentrated hydrochloric acid, uses 2L × 3 two
Chloromethanes extracts.Merging extraction phase, 1L 10%NaCl solution washs, and anhydrous sodium sulfate is dried.Suction filtration removes
Drier, filtrate is concentrated under vacuum to do, and adds 2000mL ethanol, room in the solid residue obtaining
It is stirred overnight under Wen, obtain a white crystalline substance slurry, collected by suction solid, under vacuum (5mmHg), be dried 5
Hour, obtain compound 3, white solid, 365.94g, yield 81% (2-C1 → 3), HPLC purity
99.41%, do not detect 3-M.1H NMR(DMSO-d6,400MHz),12.85(bs,1H,
D2O-exchangable), 8.51 (d, 1H, J=8.8Hz), 7.66 (t, 1H, J=7.2Hz), 7.57 (t, 1H, J=
7.4Hz), 7.37 (s, 2H), 7.31 (d, 1H, J=8.0Hz), 5.84 (bs, 2H, D2O-exchangable),
1.11-1.15(m,2H),0.81-0.83(m,2H).
Technique after embodiment 3 present invention improvement
The synthesis of step 1. compound 2-C1
In the round-bottomed flask of one 10L add 182.28g (2mol) thiosemicarbazides 2-A, with 2097mL without
Water-ethanol dissolves, lower dropping 342.06g (2mol) cylite of ice-water bath cooling, drips off in 10 minutes.Dropping
After finishing, reactant mixture temperature rising reflux 30 minutes, TLC checks that discovery reaction completes, then reaction mixing
Thing is cooled to room temperature, the ethanol solution being 2-B1 now obtaining.
It is sequentially added into 2097mL water and 450.62g (2mol) compound 1 in reactant mixture, then stirring
Mix down and slowly drip the saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water, drip
Continue 2 hours between the added-time.After dropping finishes, reactant mixture at room temperature (20 DEG C-35 DEG C) uses machinery to stir
Mix and be stirred overnight, obtain a light yellow brilliant slurry.2097mL water is slowly added in reactant mixture,
Drip off in 10 minutes, add rear reactant mixture and be further continued for stirring 3 hours.
Reaction system suction filtration, filter cake at room temperature vacuum (5mmHg) is dried 5 hours, obtains compound 2-C1,
666.77g, yield 82%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
In the glass reaction kettle of one 20L add 650.51g (1.6mol) compound 2-C1 and 6505mL without
Water-ethanol, then temperature rising reflux 1 hour, TLC checks that reaction completes.
Reactant mixture is cooled to room temperature, adds 6505mL n-hexane, continues stirring 3 hours under room temperature,
Obtain a light yellow brilliant slurry.Collected by suction solid, preliminarily dried 1 hour under vacuum (20mmHg), i.e.
For the crude product of compound 3, analyze through HPLC, wherein contain impurity 3-M 14% (mass ratio).
Above-mentioned crude product all joins in 4000mL absolute ethyl alcohol, stirring, adds 300mL's 30%
NaOH solution, mixture temperature rising reflux 10 minutes, TLC checks that discovery 3-M consumes completely, then reacts
Mixture is cooled to room temperature.
Reactant mixture joins in 16L frozen water, stirring, regulates pH=7 with concentrated hydrochloric acid, uses 2L × 3 two
Chloromethanes extracts.Merging extraction phase, 1L 10%NaCl solution washs, and anhydrous sodium sulfate is dried.Suction filtration removes
Drier, filtrate is concentrated under vacuum to do, and adds 2000mL ethanol, room in the solid residue obtaining
It is stirred overnight under Wen, obtain a white crystalline substance slurry, collected by suction solid, under vacuum (5mmHg), be dried 5
Hour, obtain compound 3, white solid, 361.42g, yield 80% (2-C1 → 3), HPLC purity
99.43%, do not detect 3-M.1H NMR spectra is consistent with embodiment 2.
Technique after embodiment 4 present invention improvement
The synthesis of step 1. compound 2-C1
In the round-bottomed flask of one 10L add 182.28g (2mol) thiosemicarbazides 2-A, with 2097mL without
Water-ethanol dissolves, lower dropping 342.06g (2mol) cylite of ice-water bath cooling, drips off in 10 minutes.Dropping
After finishing, reactant mixture temperature rising reflux 30 minutes, TLC checks that discovery reaction completes, then reaction mixing
Thing is cooled to room temperature, the ethanol solution being 2-B1 now obtaining.
It is sequentially added into 2097mL water and 450.62g (2mol) compound 1 in reactant mixture, then stirring
Mix down and slowly drip the saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water, drip
Continue 12 hours between the added-time.After dropping finishes, reactant mixture at room temperature (20 DEG C-35 DEG C) uses machinery to stir
Mix and be stirred overnight, obtain a light yellow brilliant slurry.2097mL water is slowly added in reactant mixture,
Drip off in 10 minutes, add rear reactant mixture and be further continued for stirring 3 hours.
Reaction system suction filtration, filter cake at room temperature vacuum (5mmHg) is dried 5 hours, obtains compound 2-C1,
662.71g, yield 81.5%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
In the glass reaction kettle of one 20L add 650.51g (1.6mol) compound 2-C1 and 6505mL without
Water-ethanol, then temperature rising reflux 1 hour, TLC checks that reaction completes.
Reactant mixture is cooled to room temperature, adds 6505mL n-hexane, continues stirring 3 hours under room temperature,
Obtain a light yellow brilliant slurry.Collected by suction solid, preliminarily dried 1 hour under vacuum (20mmHg), i.e.
For the crude product of compound 3, analyze through HPLC, wherein contain impurity 3-M 13.7% (mass ratio).
Above-mentioned crude product all joins in 4000mL absolute ethyl alcohol, stirring, adds 300mL's 30%
NaOH solution, mixture temperature rising reflux 10 minutes, TLC checks that discovery 3-M consumes completely, then reacts
Mixture is cooled to room temperature.
Reactant mixture joins in 16L frozen water, stirring, regulates pH=7 with concentrated hydrochloric acid, uses 2L × 3 two
Chloromethanes extracts.Merging extraction phase, 1L 10%NaCl solution washs, and anhydrous sodium sulfate is dried.Suction filtration removes
Drier, filtrate is concentrated under vacuum to do, and adds 2000mL ethanol, room in the solid residue obtaining
It is stirred overnight under Wen, obtain a white crystalline substance slurry, collected by suction solid, under vacuum (5mmHg), be dried 5
Hour, obtain compound 3, white solid, 365.94g, yield 81% (2-C1 → 3), HPLC purity
99.45%, do not detect 3-M.1H NMR spectra is consistent with embodiment 2.
Technique after embodiment 5 present invention improvement
The synthesis of step 1. compound 2-C1
In the round-bottomed flask of one 10L add 182.28g (2mol) thiosemicarbazides 2-A, with 2097mL without
Water-ethanol dissolves, lower dropping 342.06g (2mol) cylite of ice-water bath cooling, drips off in 10 minutes.Dropping
After finishing, reactant mixture temperature rising reflux 30 minutes, TLC checks that discovery reaction completes, then reaction mixing
Thing is cooled to room temperature, the ethanol solution being 2-B1 now obtaining.
In reactant mixture add 450.62g (2mol) compound 1, then under agitation slowly drip by
105.99g (1mol) sodium carbonate and the saturated solution of sodium carbonate of 321mL water preparation, it is little that time for adding continues 4
When.After dropping finishes, reactant mixture at room temperature (20 DEG C-35 DEG C) uses mechanical agitation to be stirred overnight,
To a light yellow brilliant slurry.Slowly add 2097 × 2mL water in reactant mixture, drip off in 10 minutes,
Add rear reactant mixture to be further continued for stirring 3 hours.
Reaction system suction filtration, filter cake at room temperature vacuum (5mmHg) is dried 5 hours, obtains compound 2-C1,
670.84g, yield 82.5%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
In the glass reaction kettle of one 20L add 650.51g (1.6mol) compound 2-C1 and 6505mL without
Water-ethanol, then temperature rising reflux 1 hour, TLC checks that reaction completes.
Reactant mixture is cooled to room temperature, adds 6505mL n-hexane, continues stirring 3 hours under room temperature,
Obtain a light yellow brilliant slurry.Collected by suction solid, preliminarily dried 1 hour under vacuum (20mmHg), i.e.
For the crude product of compound 3, analyze through HPLC, wherein contain impurity 3-M 13.4% (mass ratio).
Above-mentioned crude product all joins in 4000mL absolute ethyl alcohol, stirring, adds 300mL's 30%
NaOH solution, mixture temperature rising reflux 10 minutes, TLC checks that discovery 3-M consumes completely, then reacts
Mixture is cooled to room temperature.
Reactant mixture joins in 16L frozen water, stirring, regulates pH=7 with concentrated hydrochloric acid, uses 2L × 3 two
Chloromethanes extracts.Merging extraction phase, 1L 10%NaCl solution washs, and anhydrous sodium sulfate is dried.Suction filtration removes
Drier, filtrate is concentrated under vacuum to do, and adds 2000mL ethanol, room in the solid residue obtaining
It is stirred overnight under Wen, obtain a white crystalline substance slurry, collected by suction solid, under vacuum (5mmHg), be dried 5
Hour, obtain compound 3, white solid, 369.10g, yield 81.7% (2-C1 → 3), HPLC purity
99.49%, do not detect 3-M.1H NMR spectra is consistent with embodiment 2.
Claims (5)
1. the process for refining being prepared high-purity compound 3 by compound 1, it is characterised in that:
1) sodium carbonate liquor is added drop-wise to by mixing that compound 1 and compound 2-B1 mix with second alcohol and water and make
In compound；
2) drip the volume ratio of second alcohol and water in reaction system before sodium carbonate liquor be 1:1 to straight alcohol, reacted
The volume ratio that Cheng Houzai benefit adds water to second alcohol and water is 1:2；
3) crude product 3 containing impurity 3-M is used in a solvent alkali process, 3-M is hydrolyzed, thus obtained
The crude solid of 3 is pulled an oar through ethanol, i.e. obtains highly purified product 3.
2. technique as claimed in claim 1, the time wherein dripping aqueous sodium carbonate is 2-12 hour.
3. technique as claimed in claim 2, the time wherein dripping aqueous sodium carbonate is 3-5 hour.
4. technique as claimed in claim 1, wherein drips the body of second alcohol and water in reaction system before sodium carbonate liquor
Long-pending ratio is 1:1.
5. technique as claimed in claim 1, the alkali that wherein process crude product 3 is used is NaOH or KOH.
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