CN102219817A - Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent - Google Patents
Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent Download PDFInfo
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- CN102219817A CN102219817A CN2011100900285A CN201110090028A CN102219817A CN 102219817 A CN102219817 A CN 102219817A CN 2011100900285 A CN2011100900285 A CN 2011100900285A CN 201110090028 A CN201110090028 A CN 201110090028A CN 102219817 A CN102219817 A CN 102219817A
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- carbalkoxylation
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- coupling agent
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- -1 fluorouracil compound Chemical class 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 37
- 239000007822 coupling agent Substances 0.000 title claims abstract description 22
- 238000005917 acylation reaction Methods 0.000 title claims abstract description 13
- 230000010933 acylation Effects 0.000 title abstract description 6
- 229960002949 fluorouracil Drugs 0.000 title abstract 4
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims abstract description 46
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229960004117 capecitabine Drugs 0.000 claims abstract description 39
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000002777 nucleoside Substances 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 239000000377 silicon dioxide Substances 0.000 claims description 8
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000002195 fatty ethers Chemical class 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- 239000012043 crude product Substances 0.000 claims 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 abstract description 28
- 239000003795 chemical substances by application Substances 0.000 abstract description 23
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 abstract description 17
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ZJIFDEVVTPEXDL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) hydrogen carbonate Chemical class OC(=O)ON1C(=O)CCC1=O ZJIFDEVVTPEXDL-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a method for carrying out carbalkoxylation acylation on fluorouracil compound with an active coupling agent, and applications thereof in synthesizing capecitabine. The method comprises the steps of carrying out N-4 site acylation reaction of coupling agent shown as the formula (1) and fluorouracil complex shown as the formula (8), introducing active carbonyl at N-4 site to obtain acylate, directly reacting the acylate with alcohol or phenol without separation, and carrying out N-4 site carbalkoxylation acylation reaction, thus obtaining carbalkoxylation acylate of fluorouracil compound. The carbalkoxylation acylation method can be used for preparing capecitabine. The method conducts acylation and carbalkoxylation acylation on cytidine by adopting coupling agent and alcohol or phenol, thus avoiding use of chlorocarbonic ester or phosgene acylating agent, being used for preparing capecitabine, and being stable and easy to obtain raw materials, high in product purity, safe and environment-friendly for operation environment, and easy for industrial operation.
Description
Technical field
The invention belongs to organic chemistry and pharmaceutical chemistry field; relate to a kind of method of fluoridizing the pyrimidine compound carbalkoxylation; particularly relate to the method that adopts active coupling agent to fluoridize pyrimidine compound N-4 acidylate and further carbalkoxylation, and the application of this method in synthesize capecitabine.
Background technology
Fluoridizing the miazines medicine is a present clinical antitumor line medicine commonly used, plays a part very important in malignant tumours such as treatment mammary cancer, nonsmall-cell lung cancer, cancer of the stomach and large bowel cancer.Capecitabine (Capecitabine, 3) is a kind of to the selective active oral cytotoxicity preparation of tumour cell for the up-to-date pyrimdinyl-amino formate ester medicine of fluoridizing, and chemistry is by name: 5 '-deoxidation-5-fluoro-N
4-[(pentyloxy) carbonyl] cytidine(C has the structure that is shown below:
It is a kind of novel targeted medicine.
The synthetic method of known capecitabine; disclosed as U.S. Pat 5476932, US5472949A; be to be starting raw material with 5 '-deoxidation-5-fluoro-cytidine (4); carry out the carbalkoxylation reaction of N-4 position with n-amyl chlorocarbonate; obtain capecitabine after removing protecting group, shown in the reaction formula I:
It is acylating agent that this method adopts n-amyl chlorocarbonate, and pyridine is an acid binding agent, and carrying out N-4 is carbalkoxylation, and toxicity is bigger, is unfavorable for suitability for industrialized production.
Chen Yuelei etc. (" Chinese pharmaceutical chemistry magazine "; 2004; 277-299) reported a kind of method of fluoridizing the N-4 position carbalkoxylation of pyrimidines; with the cytidine (6) of hydroxyl protection is that the carbonyl acidylate is carried out in raw material and triphosgene and Fatty Alcohol(C12-C14 and C12-C18) reaction; behind the deprotection base, obtain capecitabine or its analogue then, shown in the reaction formula II:
（Ⅱ）
It is acylating agent that this method adopts triphosgene, and the danger that has hypertoxic phosgene to generate in the actually operating is unfavorable for the industrialization operation.
Chinese patent CN200610150161.4 discloses a kind of method of fluorine-containing pyrimidines carbalkoxylation; cytidine (8) with protection is a raw material; adopting pentyloxy formyl radical p-nitrophenyl phenolic ester (9) is acylating agent; carry out N-4 carbonyl acidylate; obtain capecitabine or its analogue through the deprotection base then, shown in the reaction formula III:
It is acylating agent that aforesaid method adopts pentyloxy formyl radical p-nitrophenyl phenolic ester, and aftertreatment needs silica gel chromatography, is unfavorable for suitability for industrialized production.
The present invention has found a kind of N-4 position carbalkoxylation method of effective fluorine-containing pyrimidines, and is applied to the preparation of capecitabine.
Summary of the invention
The object of the present invention is to provide a kind of method of fluoridizing the pyrimidine compound carbalkoxylation; with 5 ' of hydroxyl protection-deoxidation-5-fluoro-cytidine is raw material; adopt active coupling agent with cytidine N-4 acidylate; without separating directly and alcohol or phenol react, obtain the N-4 position carbalkoxylation reaction product of cytidine.
Another object of the present invention has been to provide a kind of synthetic method of antineoplastic medicine capecitabine.
The present invention adopts following technical scheme:
A kind of method of fluoridizing the pyrimidine compound carbalkoxylation; it is characterized in that: in aprotic solvent; coupling agent with structure shown in the formula (1) carries out N-4 position acylation reaction with the pyrimidine compound of fluoridizing with structure shown in the formula (8); the acylate of the structure shown in (10) that obtains having formula; described acylate (10) generates the N-4 position carbalkoxylation reaction product with structure shown in the formula (2) without separating directly and alcohol or phenol reaction:
R in the formula (1)
1, R
2Be at the same time or separately:
R is alkyl, alkenyl, aralkyl or aryl in the formula (2); R
3, R
4Be hydroxy-protecting agent, be selected from ethanoyl, benzoyl, substituted benzoyl, silica-based protecting group, as tertiary butyl dimethyl silica-based (TBS), trimethyl silicon based (TMS), or R
3, R
4Be combined into the propylidene base.
The invention provides a kind of formula preparation method who fluoridizes the pyrimdinyl-amino formic ether compounds as the formula (2); to have the pyrimidine compound of fluoridizing of formula (8) structure; be that 5 ' of hydroxyl protection-deoxidation-5-fluoro-cytidine is a raw material, make by N-4 position carbalkoxylation:
Wherein, R
3, R
4Described as defined above.
The described pyrimidine compound (8) of fluoridizing comprises 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides, 2 '; 3 '-two-O-(the dimethyl tertiary butyl is silica-based)-5 '-deoxidation-5-flurocytosine nucleosides or 2 '; 3 '-isopropylidene-5 '-deoxidation-5-flurocytosine nucleosides; preferred 2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides.Fluoridizing pyrimidine compound (8) can be synthetic according to known method; as 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a) can be with reference to (Zhu Renfa; Chen Shiyun; He Yong, the novel method of synthesize capecitabine, synthetic chemistry; 2008,16(1): 120-122) Ji Zai method is synthetic.
Described its structure of active coupling agent is as the formula (1):
Wherein, R
1, R
2Described as defined above, preferred R
1, R
2Be imidazolyl simultaneously, promptly described its structure of coupling agent is shown in the formula (1-1):
In aprotic solvent; carry out N-4 position acylation reaction with coupling agent (1) and the described pyrimidine compound (8) of fluoridizing; introduce the acylate of the active carbonyl group structure shown in (10) that obtains having formula in the N-4 position; acylate (10) need not to separate directly and alcohol or phenol reaction, carries out N-4 position carbalkoxylation prepared in reaction and obtains formula (2) compound:
Wherein R, R
3, R
4Described as defined above.The preferred C3-7 alkyl of described R, aralkyl.
Described mol ratio of fluoridizing pyrimidine compound (8) and coupling agent (1) and alcohol or phenol is 1:1.5～3.0:1.5～3.0, preferred 1:2.0～3.0:2.0～3.0.
The method according to this invention, the above-mentioned N-4 position active carbonyl group of fluoridizing pyrimidine compound (8) is introduced and the carbalkoxylation reaction is all carried out in aprotic solvent.Described aprotic solvent is selected from aromatic hydrocarbon, halohydrocarbon, fatty ether or polar aprotic solvent, include but not limited to, aromatic hydrocarbon solvent toluene, dimethylbenzene, halogenated hydrocarbon solvent chloroform, methylene dichloride, ethylene dichloride, fatty ether kind solvent methyl tertiary butyl ether, tetrahydrofuran (THF) or 1,4-dioxane, polar aprotic solvent such as methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide etc., or their mixture.The preferred methylene dichloride of described aprotic solvent.
In the described method, the N-4 position active carbonyl group of fluoridizing pyrimidine compound (8) introduce and the temperature of reaction of carbalkoxylation reaction at 0～40 ℃, preferred 20～30 ℃, 6～36 hours reaction times.
Above-mentionedly fluoridize that pyrimidine compound N-4 position active carbonyl group is introduced and the carbalkoxylation reaction can be used for the synthetic of capecitabine (3).
Another object of the present invention is to provide a kind of preparation method of new capecitabine (3), may further comprise the steps:
Step 1) is in aprotic solvent; formula (8) is fluoridized pyrimidine compound and formula (1) coupling agent carries out acylation reaction; introduce active carbonyl group in the N-4 position of formula (8) compound and obtain formula (10) acylate; acylate (10) need not to separate directly and the Pentyl alcohol reaction, carries out the carbalkoxylation reaction of N-4 position and makes formula (2-1) compound:
Step 2) formula (2-1) compound deprotection base is made capecitabine (3):
Wherein: R
1, R
2Be at the same time or separately:
R
3, R
4Be hydroxy-protecting agent, be selected from ethanoyl, benzoyl, substituted benzoyl or silica-based protecting group, or R
3, R
4Be combined into the propylidene base.
Described coupling agent (1) is preferred 1,1-carbonyl dimidazoles (1-1), i.e. R
1, R
2Be imidazolyl simultaneously.
The described pyrimidine compound (8) of fluoridizing is 2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides, 2 ', 3 '-two-O-(the dimethyl tertiary butyl is silica-based)-5 '-deoxidation-5-flurocytosine nucleosides or 2 ', 3 '-isopropylidene-5 '-deoxidation-5-flurocytosine nucleosides; Preferred 2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a), promptly in the said structure formula, R
3, R
4Be ethanoyl.
In the described step 1), fluoridize pyrimidine compound (8) and coupling agent (1) and introduce, obtain acylate through N-4 position active carbonyl group, need not to separate directly and Pentyl alcohol carry out N-4 position carbalkoxylation react formula (2-1) compound.The N-4 position penta oxygen carbonyl acylate (2-1) of fluoridizing pyrimidine compound removes protecting group and can obtain object capecitabine (3).According to R
3, R
4The difference of blocking group can be selected different deprotection based methods for use.
Remove protecting group, can adopt stepped approach, promptly earlier from reaction mixture, isolate 4 penta oxygen carbonyls of intermediate N acylate (2-1), carry out deprotection reaction again and obtain capecitabine (3); Perhaps 4 penta oxygen carbonyls of intermediate N acylate (2-1) can separate, and reaction mixture directly carries out deprotection reaction and obtains capecitabine (3).
One of ordinary skill in the art will readily recognize that according to the inventive method above-mentioned deprotection reaction can adopt routine techniques means of the prior art to carry out according to the hydroxyl protecting group of fluoridizing in the pyrimidine compound (8).For example, for the acyl group protecting group, can under alkaline condition, remove reaction.
According to the preparation method of capecitabine of the present invention (3), R
1, R
2Preferred imidazolyl, R
3, R
4Be preferably ethanoyl, the alcoxyl acylation product is formula (2-1a) compound, and this compound can be under alkaline condition, and selectivity deacetylate protecting group obtains capecitabine, and its reaction process is shown in following equation (IV):
Compound (2-1a) is under the NaOH condition, and the reaction that is hydrolyzed removes ethanoyl protection, and hydrolysising reacting temperature can be at-30 ℃～30 ℃, carries out under preferred-25 ℃～-15 ℃.
Reaction products resulting can obtain the capecitabine product through post-processing steps such as acidifying, extraction, desolventizings after removing protecting group; Product can adopt recrystallization method to carry out purifying, makes purity pure product of capecitabine of (HPLC) more than 99.7%.
Method of fluoridizing the pyrimidine compound carbalkoxylation of the present invention; cytidine with hydroxyl protection is a raw material; adopt active coupling agent with cytidine N-4 acidylate; acylate direct and alcohol or phenol reaction; obtain fluoridizing the N-4 position carbalkoxylation reaction product of pyrimidine compound; in reaction process, adopt coupling agent and alcohol or phenol that cytidine is carried out acidylate and carbalkoxylation, avoid using bigger chloro-formic ester of toxicity or phosgene class acylating agent and pyridine acid binding agent.Method according to carbalkoxylation of the present invention prepares capecitabine, and raw material is easy to get, the yield height, and the product aftertreatment is easy, is easy to purifying, and purpose product capecitabine quality is higher, and purity can reach (HPLC) more than 99.7%.Preparation method's reaction conditions gentleness of the present invention, easy to control, the operation environment safety environmental protection, technological process and equipment are simple, but are a kind of capecitabine production methods of industrial applications.
Describe the present invention below by embodiment, described embodiment helps the understanding of the present invention and enforcement, is not to be construed as limiting the invention; Protection scope of the present invention is limited by claim.Except as otherwise noted, the percentage ratio among the present invention is meant weight percentage.
Embodiment
Embodiment 1:2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-preparation of cytidine(C (2-1a).
Under the room temperature; with 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a) (10g; 30mmol), add 1,1 '-carbonyl dimidazoles (1-1) (9.7g with methylene dichloride 400ml stirring and dissolving; 60mmol); TLC to react completely (developping agent: methylene chloride=12:1), add Pentyl alcohol (6.6ml, 60mmol); TLC is to (the developping agent: methylene chloride=12:1) that reacts completely; water 50ml * 3 washings, the organic phase anhydrous sodium sulfate drying filters; filtrate is concentrated into dried; yellow oil, i.e. compound (2-1a) 10.7g, yield 80.5%.
Embodiment 2:2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-preparation of cytidine(C (2-1a).
Under the room temperature; with 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a) (10g; 30mmol), add 1,1 '-carbonyl dimidazoles (1-1) (13.2g with methylene dichloride 400ml stirring and dissolving; 80mmol); TLC to react completely (developping agent: methylene chloride=12:1), add Pentyl alcohol (8.7ml, 80mmol); TLC is to (the developping agent: methylene chloride=12:1) that reacts completely; water 50ml * 3 washings, the organic phase anhydrous sodium sulfate drying filters; filtrate is concentrated into dried; yellow oil, i.e. compound (2-1a) 10.8g, yield 81.5%.
Embodiment 3:2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-preparation of cytidine(C (2-1a).
Room temperature condition, with formula (8a) compound (10g, 30mmol) with methylene dichloride 400ml stirring and dissolving, add N, and N'-two succinimidyl carbonates (DSC) (15.4g, 60mmol), TLC is to (the developping agent: methylene chloride=12:1) that reacts completely, the filtering white solid, in filtrate, add Pentyl alcohol (6.6ml, 60mmol), TLC is to (the developping agent: methylene chloride=12:1) that reacts completely, water 50ml * 3 washings, the organic phase anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, yellow oil, i.e. compound (2-1a) 9.2g, yield 68.7%.
Embodiment 4:5 '-deoxidation-5-fluoro-N
4The preparation of-[(pentyloxy) carbonyl] cytidine(C (capecitabine, 3).
With embodiment 1 obtain 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine(C (2-1a) (8.9g; 20mmol); methyl alcohol 150ml stirring and dissolving; under-25 ℃～-20 ℃; drip the sodium hydroxide solution 50ml of 2mol/L, TLC is to (the developping agent: methylene chloride=9:1), regulate pH5.0-6.0 with concentrated hydrochloric acid that reacts completely; methylene dichloride 200ml * 3 extractions; merge organic phase, use anhydrous sodium sulfate drying, filter; filtrate is concentrated into dried; re-crystallizing in ethyl acetate obtains white solid, i.e. purpose compound capecitabine (3) 6.2g; yield 86.1%; HPLC:99.97%, fusing point: 113～116 ℃, specific optical rotation: 98.10 °.
Embodiment 5:5 '-deoxidation-5-fluoro-N
4The preparation of-[(pentyloxy) carbonyl] cytidine(C (capecitabine, 3).
With embodiment 1 obtain 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine(C (2-1a) (8.9g; 20mmol) be dissolved among the methylene dichloride 200ml; under-20 ℃～-15 ℃; drip the sodium hydroxide solution 50ml of 2mol/L, TLC is to (the developping agent: methylene chloride=9:1), add 50ml methyl alcohol that reacts completely; reaction mixture is regulated pH5.0-6.0 with concentrated hydrochloric acid; layering, water layer merges organic phase with methylene dichloride 10ml * 3 extractions; anhydrous sodium sulfate drying; filter, filtrate is concentrated into dried, re-crystallizing in ethyl acetate; obtain white solid; be purpose compound capecitabine (3) 5.8g, yield 81.1%, HPLC:99.71%; fusing point: 113～116 ℃, specific optical rotation: 98.91 °.
Embodiment 6:2 ', 3 '-isopropylidene-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-preparation of cytidine(C (2-1b).
Under the room temperature, with 2 ', 3 '-isopropylidene-5 '-deoxidation-5-flurocytosine nucleoside compound (8.58g, 30mmol), add 1,1 '-carbonyl dimidazoles (1-1) (9.7g with methylene dichloride 400ml stirring and dissolving, 60mmol), TLC to react completely (developping agent: methylene chloride=12:1), add Pentyl alcohol (6.6ml, 60mmol), TLC is to (the developping agent: methylene chloride=12:1) that reacts completely, water 50ml * 3 washings, the organic phase anhydrous sodium sulfate drying filters, filtrate decompression is concentrated into dried, yellow oil, i.e. compound (2-1b) 9.5 g, yield 79.5 %.
Embodiment 7:5 '-deoxidation-5-fluoro-N
4The preparation of-[(pentyloxy) carbonyl] cytidine(C (capecitabine, 3).
With embodiment 6 obtain 2 ', 3 '--isopropylidene-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine(C (2-1b) (9.5g, 24mmol) in methylene dichloride 100mL, and adding 50ml water, transfer about pH to 2 with 2%～3%HBr aqueous solution, 60～70 ℃ of insulation reaction, (developping agent: methylene chloride=12:1), filter concentrates TLC to reacting completely, re-crystallizing in ethyl acetate obtains white solid, be purpose compound capecitabine (3) 6.7 g, yield 79.2 %, HPLC:99.80%, fusing point: 113～116 ℃, specific optical rotation: 98.72 °.
Embodiment 8:2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(butoxy) carbonyl]-cytidine(C (2-2) preparation.
Under the room temperature; with 2 '; (10g 30mmol) with methylene dichloride 200ml stirring and dissolving, adds 1 to 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a); 1 '-carbonyl dimidazoles (9.7g; 60mmol), TLC is to (the developping agent: methylene chloride=12:1), add propyl carbinol (6.0 ml that reacts completely; 60mmol); (developping agent: methylene chloride=12:1), wash, the organic phase anhydrous sodium sulfate drying by water 50ml * 3 to reacting completely for TLC; filter; filtrate decompression is concentrated into dried, gets yellow oil, gets yellow oil; be compound (2-2) 9.6g, yield 75.0%.
Embodiment 9:2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[2-methyl-butoxy) carbonyl]-cytidine(C (2-3) preparation.
Under the room temperature; with 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a) (10g; 30mmol) use the DMF400ml stirring and dissolving, add 1,1 '-carbonyl dimidazoles (9.7 g; 60mmol); TLC to react completely (developping agent: methylene chloride=12:1), add 2-methyl-1-butene alcohol (6.6 ml, 60mmol); TLC is to (the developping agent: methylene chloride=12:1) that reacts completely; water 100ml * 3 washings, the organic phase anhydrous sodium sulfate drying filters; filtrate is concentrated into dried; faint yellow blister solid, i.e. title compound 10.9g, yield 82.5%.
Embodiment 10:2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(benzyloxy) carbonyl]-preparation of cytidine(C (2-4).
Under the room temperature; with 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a) (10g; 30mmol), add 1,1 '-carbonyl dimidazoles (13.2g with DMF 400ml stirring and dissolving; 80mmol); TLC to react completely (developping agent: methylene chloride=12:1), add phenylcarbinol (7.3 ml, 70mmol); TLC is to (the developping agent: methylene chloride=12:1) that reacts completely; water 50ml * 3 washings, the organic phase anhydrous sodium sulfate drying filters; filtrate is concentrated into dried; faint yellow oily thing, i.e. title compound 11.3g, yield 81.2%.
Claims (12)
1. method of fluoridizing the pyrimidine compound carbalkoxylation; it is characterized in that: in aprotic solvent; coupling agent with structure shown in the formula (1) carries out N-4 position acylation reaction with the pyrimidine compound of fluoridizing with structure shown in the formula (8); the acylate of the structure shown in (10) that obtains having formula; described acylate (10) generates the N-4 position carbalkoxylation reaction product with structure shown in the formula (2) without separating directly and alcohol or phenol reaction:
R in the formula (1)
1, R
2Be at the same time or separately:
R is alkyl, alkenyl, aralkyl or aryl in the formula (2); R
3, R
4Be hydroxy-protecting agent, be selected from ethanoyl, benzoyl, substituted benzoyl or silica-based protecting group, or R
3, R
4Be combined into the propylidene base.
2. the method for carbalkoxylation according to claim 1, it is characterized in that: described coupling agent (1) is 1, the 1-carbonyl dimidazoles.
3. the method for carbalkoxylation according to claim 1; it is characterized in that: the described pyrimidine compound (8) of fluoridizing is 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides, 2 '; 3 '-two-O-(the dimethyl tertiary butyl is silica-based)-5 '-deoxidation-5-flurocytosine nucleosides or 2 ', 3 '-isopropylidene-5 '-deoxidation-5-flurocytosine nucleosides.
4. the method for carbalkoxylation according to claim 1 is characterized in that: described mol ratio of fluoridizing pyrimidine compound (8) and coupling agent (1) and alcohol or phenol is 1:1.5～3.0:1.5～3.0.
5. the method for carbalkoxylation according to claim 1, it is characterized in that: described aprotic solvent is selected from aromatic hydrocarbon, halohydrocarbon, fatty ether or polar aprotic solvent, or the mixture of above-mentioned solvent.
6. the method for carbalkoxylation according to claim 5; it is characterized in that: described aromatic hydrocarbon is selected from toluene or dimethylbenzene; halohydrocarbon is selected from methylene dichloride, chloroform or ethylene dichloride; fatty ether is selected from methyl tertiary butyl ether, tetrahydrofuran (THF) or 1; the 4-dioxane; polar aprotic solvent is selected from methyl-sulphoxide, N, dinethylformamide or N,N-dimethylacetamide.
7. the method for carbalkoxylation according to claim 1 is characterized in that: the N-4 position active carbonyl group of fluoridizing pyrimidine compound (8) introduce and the temperature of reaction of carbalkoxylation reaction at 0～40 ℃, 6～36 hours reaction times.
8. the preparation method of a capecitabine may further comprise the steps:
Step 1) is in aprotic solvent; formula (8) is fluoridized pyrimidine compound and formula (1) coupling agent carries out acylation reaction; introduce active carbonyl group in the N-4 position of formula (8) compound and obtain formula (10) acylate; acylate (10) need not to separate directly and the Pentyl alcohol reaction, carries out the carbalkoxylation reaction of N-4 position and makes formula (2-1) compound:
Step 2) formula (2-1) compound deprotection base is made capecitabine (3):
Wherein: R
1, R
2Be at the same time or separately:
R
3, R
4Be hydroxy-protecting agent, be selected from ethanoyl, benzoyl, substituted benzoyl or silica-based protecting group, or R
3, R
4Be combined into the propylidene base.
9. the preparation method of capecitabine according to claim 8, it is characterized in that: described coupling agent formula (1) is 1,1-carbonyl dimidazoles (1-1).
10. the preparation method of capecitabine according to claim 8, it is characterized in that: the described pyrimidine compound (8-1) of fluoridizing is 2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-flurocytosine nucleosides (8a).
11. the preparation method of capecitabine according to claim 10 is characterized in that: described step 2), reaction mixture-30 ℃～30 ℃, removes the ethanoyl reaction under alkaline condition.
12. the preparation method of capecitabine according to claim 10 is characterized in that: prepared capecitabine crude product carries out purifying through recrystallization method.
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| CN103897005B (en) * | 2012-12-27 | 2017-07-28 | 鲁南制药集团股份有限公司 | Method for continuously synthesizing capecitabine |
| US10435429B2 (en) | 2017-10-03 | 2019-10-08 | Nucorion Pharmaceuticals, Inc. | 5-fluorouridine monophosphate cyclic triester compounds |
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| WO2019143860A1 (en) * | 2018-01-19 | 2019-07-25 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
| US11427550B2 (en) | 2018-01-19 | 2022-08-30 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
| CN109320563A (en) * | 2018-11-30 | 2019-02-12 | 河南福萌商贸有限公司 | A kind of preparation method of high yield capecitabine impurity F |
| CN109485684A (en) * | 2018-11-30 | 2019-03-19 | 河南福萌商贸有限公司 | A kind of preparation method of capecitabine impurity F |
| US12110311B2 (en) | 2019-07-17 | 2024-10-08 | Nucorion Pharmaceuticals, Inc. | Cyclic deoxyribonucleotide compounds |
| US11566041B2 (en) | 2020-04-21 | 2023-01-31 | Ligand Pharmaceuticals, Inc. | Nucleotide prodrug compounds |
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