CN103724382B - A kind of easy process for purification of capecitabine intermediate - Google Patents
A kind of easy process for purification of capecitabine intermediate Download PDFInfo
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- CN103724382B CN103724382B CN201310674404.4A CN201310674404A CN103724382B CN 103724382 B CN103724382 B CN 103724382B CN 201310674404 A CN201310674404 A CN 201310674404A CN 103724382 B CN103724382 B CN 103724382B
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Abstract
The invention discloses a kind of easy removal of impurities of antineoplastic medicine capecitabine intermediate 2,3-dibenzoyl-5-deoxidation-5-fluorine cytidine synthesis reaction solution, crystallization method.It is characterized in that 2; acetic acid ethyl acetate extract after the chlorination of 3-dibenzoyl-5-deoxidation-5-fluorine cytidine, amination reaction first disposable removing impurity by means of precipitation under prescribed conditions; after its filtrate appropriateness is concentrated in original solvent a step crystallisation by cooling, and the highly purified target compound of disposable acquisition.Precipitated impurities can also as chlorination, aminating reaction raw materials recovery recycling simultaneously.The crude product concentrated residue that present method not only eliminates former technique is through the tediously long step of mixed solvent repeatedly recrystallization, and yield significantly improves, and preparation cost declines to a great extent, and is especially applicable to suitability for industrialized production.
Description
Technical field
The invention relates to a kind of antineoplastic medicine capecitabine intermediate---the easy process for purification of 2,3-dibenzoyl-5-deoxidation-5-fluorine cytidine synthesis crude product, belongs to organic or pharmaceutical synthesis field.
Background technology
Capecitabine (Capecitabine) is widely used in treatment at present clinically to the advanced primary of the drug ineffective such as taxol and Dx or the active drug of metastatic breast cancer and transitivity carcinoma of the colon and rectum.Therefore, to the research of its various synthesis techniques with improve and become current heat subject.
The chemosynthesis of capecitabine has many approach.Wherein, the synthesis technique being raw material with 5-'-Deoxy-5-fluorouridine, because protecting group reagent used is inexpensive, processing condition are easy to the advantages such as control and are still widely adopted.Its synthetic route is as follows:
In upper synthetic route, compound 3 is 2,3-dibenzoyl-5-deoxidation-5-fluorine cytidine (C
23h
21fN
3o
6) be that its purity height will directly affect follow-up synthesis and be separated with a key intermediate (calling intermediate in the following text) in the 5-'-Deoxy-5-fluorouridine operational path that is starting raw material synthesize capecitabine.According to Chen Yuelei; the intermediate 2 of Cen Junda report; synthesis technique (the Chinese pharmaceutical chemistry magazine 2004 of 3-dibenzoyl-5-deoxidation-5-fluorine cytidine; 14 (5) p.277 ~ 279; 28) condition; 2; after the chlorination of 3-dibenzoyl-5-'-Deoxy-5-fluorouridine, amination reaction terminate; first decompression steams solvent; resistates distributes in ethyl acetate and water; after dividing water-yielding stratum, organic phase uses dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt solution washing successively, steams most of solvent, separate out white solid after cooling after drying agent drying and dehydrating.This solid is again with obtaining intermediate 2,3-dibenzoyl-5-deoxidation-5-fluorine cytidine white plates crystal after ethyl acetate-light petrol recrystallization.
Imitating experiment shows: the solid crude product obtained according to aforesaid method is recrystallization less effective in ethyl acetate-light petrol mixed solvent.For obtaining the intermediate product of qualified purity, have to pass through more than 2 times and even 3 times recrystallization processes.As production technique, not only the cycle is long, solvent coefficient of losses is also high for the purification process of this poor efficiency, and the yield discount in addition in each treating process, makes refining cost rise step by step.
Summary of the invention
Based on the related defects of above-mentioned documents; applicant has developed a kind of by intermediate and other all raw materials do not acted on and the short-cut method synthesizing magazins' layout; that is: 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridine and Dimethylamino pyridine, phosphorus oxychloride, pyridine, strong aqua are carried out chlorination, amination reaction.After reaction terminates, reaction solution is concentrated, then with ethyl acetate and water extraction.After removing water layer, acetic acid ethyl acetate extract is clean and dry, then under the concentration, temperature condition of regulation, leave standstill appropriate time, all impurity primary sedimentations are separated out.After filtering precipitation filtrate is concentrated into suitable concentration and at suitable temperature direct crystallization, thus direct acquisition high-quality target product.
Main technique technical qualification of the present invention are:
1. first acetic acid ethyl acetate extract is diluted with identical solvent before heavy assorted and the concentration being settled to intermediate between 56mg/ml ~ 62mg/ml;
2. the optimal temperature making all impurity fully precipitate, time conditions are: temperature 0 DEG C ~ 3 DEG C, time: 12 ~ 15h;
3. again by between the concentration adjustment of intermediate to 85mg/ml ~ 90mg/ml after the concentrating filter liquor after the precipitation that filters out impurities, decolouring;
4. high purity, high productivity obtain the temperature of One-step crystallization from removal of impurities mother liquor, time conditions is: temperature-3 DEG C ~-6 DEG C, digestion time 9 ~ 12h;
5. One-step crystallization mother liquor through vacuum concentration to be about original volume 1/2 after direct bleaching, crystallization, high-quality target product can be obtained;
6. synthesis in obtain all dirt throw out can be used as chlorination, aminating reaction raw material is back in next batch chlorination, aminating reaction.
First removing impurity by means of precipitation of the present invention is the method for direct crystallization and documents Measures compare again, has the advantage that separation efficiency is high, process is easy, yield is high, with low cost, is particularly suitable for suitability for industrialized production.
The method of this first removing impurity by means of precipitation, again direct crystallization of the present invention is also applicable to by 2; 3-diacetyl-5-deoxidation-5-fluorine cytidine or 2,3-position hydroxyl by other ester classes or alkoxyl group ethers or silane ethers protecting group the easy removal of impurities of 5-deoxidation-5-fluorine cytidine class synthesis reaction solution protected and crystallization.
Embodiment
In order to explain the difference of enforcement of the present invention and embodiment and documents better, following preparation method's embodiment being provided and copying documents embodiment of the method.These embodiments are only explain, and do not limit the scope of the invention.
embodiment 1
1.2; the preparation feedback of 3-dibenzoyl-5-deoxidation-5-fluorine cytidine: 44.5g (0.363mol) Dimethylamino pyridine is suspended in 280ml acetonitrile and 29.5ml(0.364mol) pyridine in, under 8 DEG C of conditions, drip 33.7g (0.22mol) phosphorus oxychloride.Finish; 2 DEG C are down to after continuing stirring reaction 65min in 23 DEG C ~ 25 DEG C; slowly drip 33.07g (pure 0.073mol) 2; the solution that 3-dibenzoyl-5-'-Deoxy-5-fluorouridine (compound 2) and 187ml acetonitrile are made; dropwise; be warming up to 23 DEG C ~ 25 DEG C, and continue stirring reaction 3.5h.Be cooled to 5 DEG C ~ 7 DEG C again, and drip 176ml strong aqua in this solution, be about 70min in 23 DEG C ~ 25 DEG C stirring reactions, and with TLC method Indicator Reaction terminal.Developping agent: ethyl acetate: sherwood oil=7.5:2.5; Stationary phase: GF254.
2. extract, wash: after reaction terminates, in hot water bath, reclaim under reduced pressure solvent is to clean, obtains orange-yellow half solid fraction enriched material.Then use 450ml ethyl acetate and the ultrasonic extraction of 350ml distilled water, after leaving standstill 15min, divide water-yielding stratum.The dilute hydrochloric acid 165ml of organic phase priority 2mol/L, saturated sodium carbonate solution 150ml respectively washs once.Finally use saturated common salt water washing three times (200ml+140ml+100ml).Add wherein by 50g anhydrous sodium sulphate after dividing water purification layer, jolting is left undisturbed overnight in a moment.Obtain the acetic acid ethyl acetate extract 378ml that dry yellow is clear and bright after filtering siccative, then add diluted ethyl acetate to 450ml, the concentration that intermediate is surveyed in sampling is 59.5mg/ml.Chlorination, amination 2 step reaction total conversion rate: 80.69%.
3. removing impurity by means of precipitation: be placed in by the acetic acid ethyl acetate extract of above-mentioned drying after refrigerating chamber is slowly cooled to 3 DEG C ~ 0 DEG C and leave standstill 12h, then filter, obtain the faint yellow solid throw out containing various impurity, dry weight: 8.24g, wherein, the content of intermediate is 3.32%.
4. One-step crystallization: by the mother liquor vacuum concentration after filtering out impurities to about original volume 1/2 time add 0.75g gac while hot and be placed on boiling water bath and filter carbon removal after reflux decolour 10min.Be settled to 300ml after destainer being added diluted ethyl acetate, the concentration recording intermediate is 87.8mg/ml.This solution is placed in refrigeration chamber and is slowly cooled to-3 DEG C ~-5 DEG C, and under equality of temperature quiescent crystallization 10h final vacuum suction strainer, and wash 2 times with a small amount of identical cold cut matchmaker.Filter cake to dry, is obtained 2, the 3-dibenzoyl-5-deoxidation-5-fluorine cytidine crystallisates that 23.27g white is glossy by vacuum-drying.Fusing point 198.0 DEG C ~ 198.9 DEG C.Content 99.56%(HPLC method).With 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridine meter, yield: 69.82%.
Results of elemental analyses:
Theoretical value: C60.92H4.45N9.27
Measured value C60.90H4.45N9.25.
5. in crystalline mother solution, reclaim intermediate: by One-step crystallization mother liquor vacuum concentration to about original volume 1/2 time add 0.95g gac; and in water-bath reflux decolour 10min; filtrate is placed in crystallisation by cooling 12h under 0 DEG C ~-2 DEG C conditions; vacuum filtration again; filter cake is dried to dry in accordance with the law after washing 3 times by ice-cold ethyl acetate; obtain 2,3-dibenzoyl-5 deoxidation-5-fluorine cytidine crystallizations of 2.02g white.Fusing point 198.2 ~ 199.3 DEG C.Content 99.27%(HPLC method).The ultimate production of twice crystallization is 25.29g.With 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridine meter, total recovery: 75.86%.
The comparative examples of embodiment 2(lower concentration extraction liquid)
In the present embodiment, diluted with identical solvent by dry for ethyl acetate liquid before removing impurity by means of precipitation and be settled to 500ml, the concentration recording intermediate in solution is 52.2mg/ml.Then by removing impurity by means of precipitation technique and the follow-up One-step crystallization condition implementation and operation of embodiment 1.Obtain contamination precipitation thing 7.20g, wherein, the content of intermediate is down to 1.03%.The output of One-step crystallization thing: 24.35, wherein, intermediates content: 92.48%.
The comparative examples of embodiment 3(high density extraction liquid)
In the present embodiment, before removing impurity by means of precipitation, a small amount of identical solvent of the dry liquid of ethyl acetate is settled to 400ml, the concentration recording intermediate in solution is 64.8mg/ml.Then by removing impurity by means of precipitation and the follow-up One-step crystallization condition implementation and operation of embodiment 1, obtain total impurities throw out 12.13g, wherein, intermediates content soars to 29.80%.The output of One-step crystallization thing: 19.67g(compares with example 1, production declining 16.6.%), fusing point 198.2 DEG C ~ 198.9 DEG C, content 99.63%.
Example 4(differing temps removing impurity by means of precipitation reference examples)
In the present embodiment, be promoted to by the precipitation temperature in removing impurity by means of precipitation process outside 4 DEG C ~ 3 DEG C, other processes are identical with example 1 with condition.Obtain total impurities throw out 6.63g, wherein, the content of intermediate drops to 2.42%.The output of One-step crystallization thing: 25.15g, content: 92.86%.
The different sedimentation time reference examples of embodiment 5()
In the present embodiment, will foreshorten to except 8h except the sedimentation time in removing impurity by means of precipitation process, other processes are identical with example 1 with condition.Gained contamination precipitation ultimate production 6.38g, wherein, the content of intermediate: 2.48%.The output of One-step crystallization thing: 25.02g, but product content drops to 92.21%.
The recycling of embodiment 6(precipitated impurities is tested)
The dry sediment 8.0g obtained in removing impurity by means of precipitation process in Example 1; in order to replace a part for chlorination in the present embodiment, aminating reaction raw material; remainder (25.47g, 0.0561mol) uses 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridines of fresh preparation.And the acetic acid ethyl acetate extract 386ml of intermediate is obtained according to the reaction of embodiment 1, extraction and wash conditions.Be settled to 450ml with identical solvent again, the concentration recording intermediate is 59.7mg/ml.Chlorination, aminating reaction transformation efficiency: 79.11%.
The constant volume liquid of above-mentioned concentration is done removing impurity by means of precipitation operation according to the condition of embodiment 1 again, and obtain dry sediment 8.32g, wherein, intermediates content is 3.36%.Its mother liquor is concentrated according to the method for embodiment 1, be settled to 300ml again after decolouring, and the content measuring intermediate is 87.5mg/ml.
2,3-dibenzoyl-5 deoxidation-5-fluorine cytidine crystallisates that 23.21g white is glossy are obtained after above-mentioned destainer being carried out One-step crystallization according to the condition of embodiment 1.Fusing point 197.9 ° ~ 198.8 DEG C, content 99.51%(HPLC method), with 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridine meter, yield: 69.61%.
Embodiment 7(copies embodiment by documents method)
1.2; the preparation feedback of 3-dibenzoyl-5-deoxidation-5-fluorine cytidine: 44.5g (0.363mol) Dimethylamino pyridine is suspended in 280ml acetonitrile and 29.5ml(0.364mol) pyridine in, under 8 DEG C of conditions, drip 33.7g (0.22mol) phosphorus oxychloride.Finish; stirring reaction 65min is continued in 23 DEG C ~ 25 DEG C; after be down to 2 DEG C; slowly drip 33.07g (pure 0.073mol) 2; the solution that 3-dibenzoyl-5-'-Deoxy-5-fluorouridine (compound 2) and 187ml acetonitrile are made; dropwise, be warming up to 23 DEG C ~ 25 DEG C, and continue stirring reaction 3.5h.Be cooled to 5 DEG C ~ 7 DEG C again, and drip 176ml strong aqua in this solution, be about 70min and with TLC method Indicator Reaction terminal in 23 DEG C ~ 25 DEG C stirring reactions.Developping agent: ethyl acetate: sherwood oil=7.5:2.5, stationary phase: GF254.
2. extract, wash: after reaction terminates, in hot water bath, reclaim under reduced pressure solvent is to clean, obtains orange-yellow half solid fraction enriched material.Then use 450ml ethyl acetate and the ultrasonic extraction of 350ml distilled water, after leaving standstill 15min, divide water-yielding stratum.The dilute hydrochloric acid 165ml of organic phase priority 2mol/L, saturated sodium carbonate solution 150ml respectively washs once.Finally use saturated common salt water washing three times (200ml+140ml+100ml).Add wherein by 50g anhydrous sodium sulphate after dividing water purification layer, jolting is left undisturbed overnight in a moment.The acetic acid ethyl acetate extract 390ml that dry yellow is clear and bright is obtained after filtering siccative.This extraction liquid to be placed in water-bath after vacuum concentration to 1/3 of original volume, to be cooled to 0 DEG C ~ 2 DEG C, solid is fully separated out.Filter and obtain white-yellowish solid 35.46g after vacuum-drying.Survey intermediates content: 75.81%(HPLC method, identical below), the chlorination of 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridine, amination reaction total conversion rate: 80.96%.
3. recrystallization: primary purification: get crude product 35.0g (pure 0.0584mol) and be placed in flask, once add ethyl acetate: sherwood oil (boiling range: 60 DEG C ~ 90 DEG C) mixed solvent (6.5:3.5) 410ml, heat in water-bath and reflux make molten, then the gac reflux decolour 10min again of 0.5% is added, destainer is chilled to 0 DEG C ~-2 DEG C, and static 10h, filter according to well-established law, wash and vacuum-drying, obtain off-white color crystallisate 26.22g, content: 86.98%.The pure yield 85.91% of primary purification.
Secondary refining: get primary purification product 25.0g(pure: 0.0478mol) be placed in flask, once add ethyl acetate: sherwood oil mixed solvent (6.5:3.5) 345ml, then the method according to a recrystallization makes secondary refining, obtain white crystals thing 20.38g, content: 93.56%, the pure yield 87.75% of second time treating process.
Refine for three times: get secondary fine goods 20.0g(pure: 0.0412mol) be placed in flask, once add ethyl acetate: sherwood oil mixed solvent (6.5:3.5) 215ml, then the method according to a recrystallization is done refining for the third time, obtain white crystals thing 16.16g, fusing point 197.8 DEG C ~ 199.5 DEG C, content: 99.28%.Separately from third time refinement mother liquor through concentrated, decolour after reclaim intermediate product 1.31g, content after crystallisation by cooling: 99.04%.Third time refines pure total recovery 92.6%.
With intermediate, imitative documents method prepares the process total recovery of intermediate 3: 56.66%.
In embodiment 1 ~ embodiment 7, precipitation, crystallization condition contrast with yield, purity data and see the following form:
Claims (3)
1. an easy process for purification for capecitabine intermediate, is characterized in that:
(1) capecitabine intermediate is 2,3-dibenzoyl-5-deoxidation-5-fluorine cytidine, by 2,3-dibenzoyl-5-'-Deoxy-5-fluorouridine and Dimethylamino pyridine, phosphorus oxychloride, pyridine, strong aqua carry out chlorination, amination reaction gained, after reaction terminates, reaction solution is carried out concentrate, then carry out the rear point water-yielding stratum of extraction with ethyl acetate and water, to organic phase washing, dewater, obtain water-free acetic acid ethyl acetate extract;
(2) Concentration Modulation: between the concentration adjustment of intermediate contained in acetic acid ethyl acetate extract to 56mg/ml ~ 62mg/ml;
(3) removing impurity by means of precipitation: will adjust the extraction liquid of concentration, is placed in ageing 12 ~ 15h under 0 DEG C ~ 3 DEG C conditions, then filters, and retains filtrate and solid sediment;
(4) decolouring, crystallization: add gac while hot and be placed on boiling water bath when filter vacuum being concentrated into 1/2 of about original volume and filter after reflux decolour, this solution is placed in-3 DEG C ~-5 DEG C, and crystallization 9 ~ 12h, obtain the intermediate after refining.
2. the method for claim 1, is characterized in that: all dirt throw out obtained can be used as chlorination, amination reaction raw material is back in next batch chlorination, amination reaction.
3. the purposes of the method for claim 1; it is characterized in that: can be applicable to 2; 3-dibenzoyl-5-deoxidation-5-fluorine cytidine or 2,3-position hydroxyl by other ester classes or alkoxyl group ethers or silylation ethers protecting group the removal of impurities of 5-deoxidation-5-fluorine cytidine class synthesis reaction solution protected and crystallization.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102260309A (en) * | 2010-05-24 | 2011-11-30 | 重庆福安药业(集团)股份有限公司 | Method for preparing high-purity capecitabine |
| CN102558262A (en) * | 2010-12-23 | 2012-07-11 | 天津泰普药品科技发展有限公司 | Preparation method of high-purity capecitabine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260309A (en) * | 2010-05-24 | 2011-11-30 | 重庆福安药业(集团)股份有限公司 | Method for preparing high-purity capecitabine |
| CN102558262A (en) * | 2010-12-23 | 2012-07-11 | 天津泰普药品科技发展有限公司 | Preparation method of high-purity capecitabine |
Non-Patent Citations (2)
| Title |
|---|
| 卡培他滨的合成.;周振轩等，;《化工时刊》;20130331;第28卷(第3期);第4-6页 * |
| 卡培他滨类似物的合成及体内抗肿瘤活性.;陈越磊，岑均达.;《中国药物化学杂志》;20041031;第14卷(第5期);第277-279页 * |
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