JPH0332559B2 - - Google Patents
Info
- Publication number
- JPH0332559B2 JPH0332559B2 JP21574982A JP21574982A JPH0332559B2 JP H0332559 B2 JPH0332559 B2 JP H0332559B2 JP 21574982 A JP21574982 A JP 21574982A JP 21574982 A JP21574982 A JP 21574982A JP H0332559 B2 JPH0332559 B2 JP H0332559B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorine
- reaction
- formula
- fluorouridines
- methanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 239000011737 fluorine Substances 0.000 claims description 19
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 18
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 claims description 12
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 6
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 6
- 229940045145 uridine Drugs 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GFFMDHPYCOHCHJ-XWHACKQUSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-6-hydroxy-1,3-diazinane-2,4-dione Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)C1O GFFMDHPYCOHCHJ-XWHACKQUSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
本発明は５−フルオロウリジン類の製法に関
し、更に詳しくは新規な含フツ素ウリジン類から
５−フルオロウリジン類を製造する製法に関す
る。
従来、５−フルオロウリジン類は、制癌および
抗腫瘍剤としてよく知られている。その製法は、
例えば、５，６−ジヒドロ−５−フルオロ−６−
ヒドロキシウリジン類を強酸（HCl等）存在下で
加熱して脱水する（特開昭55−28926号公報）の
であるが、生成した５−フルオロウリジン類は、
主として反応幅生成物の為と思われるが結晶化し
にくく、再結晶法によつて精製し純度を上げるこ
とはできない。その為、シリカゲルおよび／また
はカチオン交換樹脂カラムを用いて精製しなけれ
ばならず、再結晶法に比べ工業的に不利なものと
なつている。
そこで本発明者らは再結晶法により精製を図る
べく研究を進めた結果、特定の含フツ素ウリジン
類とトリエチルアミン等の塩基とを有機溶媒中、
室温付近で反応させたところ収率もよく５−フル
オロウリジン類が生成し、かつその５−フルオロ
ウリジン類はメタノールで容易に再結晶による精
製が可能であることを見い出し本発明を完成する
に到つた。
すなわち本発明は、一般式：
〔式中、Ｒは低級アシル基、含フツ素低級アシル
基または含フツ素低級アシル基、Ｘは水素または
水酸基を示す。〕で表わされる含フツ素ウリジン
類と塩基とを有機溶媒中、０〜80℃で反応させる
ことからなる一般式：
〔式中、Ｘは前記と同じ〕で表わされる５−フル
オロウリジン類の製法を要旨とするものである。
本発明で原料として用いられる含フツ素ウリジ
ン類は、一般式：
〔式中、Ｒは低級アシル基、含フツ素低級アシル
基または含フツ素低級アルキル基、Ｘは水素、ま
たは水酸基を示す。〕
で表わされる新規な化合物で、この含フツ素ウリ
ジン類は、一般式：
〔式中、Ｘは前記と同じ。〕
で表わされるウリジン類とフツ素とを低級カルボ
ン酸、含フツ素低級カルボン酸または含フツ素低
級アルコール中で反応させることによつて製造す
ることが出来る。
本発明の製法で用いられる塩基は、トリエチル
アミン、ジエチルアミン、ピリジン、ピコリン等
の有機塩基またはアンモニア、重炭酸ソーダ等の
無機塩基であり、好ましくは前記アミン類が用い
られる。
本発明の製法で用いられる有機溶媒は、例えば
酢酸エチル等の低級カルボン酸のエステル、アセ
トン、アセトニトリルまたはジオキサンに低級ア
ルコールを50容量％以下混合したものなどで、好
ましく用いられるものは酢酸エチルにメタノール
を10容量％混合したものである。
本発明で採用される反応温度は、０〜80℃であ
り、好ましくは10〜30℃が採用される。
本発明の反応時間は、通常５〜24時間である。
次に実施例、参考例および比較例を示し、本発
明を具体的に説明する。
実施例 １
含フツ素ウリジン類(1) ３ｇ（8.29mmol）を、
トリエチルアミン：メタノール：酢酸エチル＝
３：４：20（容量）の混合液に溶解させ、20℃で
12時間撹拌、反応させる。反応後溶液を減圧濃縮
して得られた残渣をメタノールから再結晶化し、
白色の針状結晶1.78ｇ（5.88mmol）、収率70.9％）
を得た。
次に、この白色結晶の分析結果を示す。
The present invention relates to a method for producing 5-fluorouridines, and more particularly to a method for producing 5-fluorouridines from novel fluorine-containing uridines. Conventionally, 5-fluorouridines are well known as anticancer and antitumor agents. Its manufacturing method is
For example, 5,6-dihydro-5-fluoro-6-
Hydroxyuridines are dehydrated by heating in the presence of a strong acid (such as HCl) (Japanese Patent Application Laid-Open No. 1983-28926), but the 5-fluorouridines produced are
This is thought to be mainly due to the reaction width product, but it is difficult to crystallize and cannot be purified to increase its purity by recrystallization. Therefore, it must be purified using a silica gel and/or cation exchange resin column, which is industrially disadvantageous compared to the recrystallization method. Therefore, the present inventors conducted research to purify the product by a recrystallization method, and found that a specific fluorine-containing uridine and a base such as triethylamine were mixed in an organic solvent.
They discovered that 5-fluorouridines were produced in good yield when the reaction was carried out at around room temperature, and that the 5-fluorouridines could be easily purified by recrystallization with methanol, leading to the completion of the present invention. Ivy. That is, the present invention is based on the general formula: [In the formula, R represents a lower acyl group, a fluorine-containing lower acyl group, or a fluorine-containing lower acyl group, and X represents hydrogen or a hydroxyl group. A general formula consisting of reacting a fluorine-containing uridine represented by ] with a base in an organic solvent at 0 to 80°C: The gist of this invention is a method for producing 5-fluorouridines represented by the formula [wherein X is the same as above]. The fluorine-containing uridine used as a raw material in the present invention has the general formula: [In the formula, R represents a lower acyl group, a fluorine-containing lower acyl group, or a fluorine-containing lower alkyl group, and X represents hydrogen or a hydroxyl group. ] A novel compound represented by the following, and this fluorine-containing uridine has the general formula: [In the formula, X is the same as above. ] It can be produced by reacting a uridine represented by the following with fluorine in a lower carboxylic acid, a fluorine-containing lower carboxylic acid, or a fluorine-containing lower alcohol. The base used in the production method of the present invention is an organic base such as triethylamine, diethylamine, pyridine, or picoline, or an inorganic base such as ammonia or sodium bicarbonate, and preferably the above-mentioned amines are used. The organic solvent used in the production method of the present invention is, for example, a mixture of a lower carboxylic acid ester such as ethyl acetate, acetone, acetonitrile, or dioxane with 50% by volume or less of a lower alcohol, and preferably used is ethyl acetate and methanol. It is a mixture of 10% by volume. The reaction temperature employed in the present invention is 0 to 80°C, preferably 10 to 30°C. The reaction time of the present invention is usually 5 to 24 hours. Next, examples, reference examples, and comparative examples will be shown to specifically explain the present invention. Example 1 3 g (8.29 mmol) of fluorine-containing uridines (1),
Triethylamine: methanol: ethyl acetate =
Dissolve in a 3:4:20 (volume) mixture and heat at 20℃.
Stir and react for 12 hours. After the reaction, the solution was concentrated under reduced pressure, and the resulting residue was recrystallized from methanol.
1.78 g (5.88 mmol) of white needle-like crystals, yield 70.9%)
I got it. Next, the analysis results of this white crystal will be shown.
【表】【table】
【表】
上記分析結果より反応生成物を既知化合物の前
記５−フルオロウリジン類(2)と同定した。
実施例 ２
含フツ素ウリジン類(3)を 2.78ｇ（8.01mmol）
を原料として用いた他は実施例１と同様の操作で
反応、再結晶および分析を行つた。白色針状結晶
1.77ｇ（6.18mmol、収率77.1％）を得た。次にこ
の白色結晶の分析結果を示す。[Table] From the above analysis results, the reaction product was identified as the known compound 5-fluorouridine (2). Example 2 2.78g (8.01mmol) of fluorine-containing uridines (3)
The reaction, recrystallization and analysis were carried out in the same manner as in Example 1, except that the following was used as the raw material. white needle crystals
1.77 g (6.18 mmol, yield 77.1%) was obtained. Next, the analysis results of this white crystal are shown.
【表】
上記分析結果より反応生成物を既知化合物の前
記５−フルオロウリジン類(4)と同定した。
参考例
実施例２で得た５−フルオロウリジン類(4)1.77
ｇ（6.18mmol）をCF3COOH90重量％の水溶液
10mlに溶解させ室温で１時間撹拌、反応させる。
反応後溶液を減圧濃縮して得られた残渣について
メタノールから再結晶化し既知化合物の5′−デオ
キシ−５−フルオロウリジン(5)1.40ｇ
（5.69mmol、収率92.1％）の白色結晶を得た。次
の分析結果より生成物を前記と同定した。[Table] From the above analysis results, the reaction product was identified as the known compound 5-fluorouridine (4). Reference example 5-fluorouridine (4) obtained in Example 2 1.77
g (6.18 mmol) of CF 3 COOH in 90% by weight aqueous solution
Dissolve in 10 ml and stir at room temperature for 1 hour to react.
After the reaction, the solution was concentrated under reduced pressure and the resulting residue was recrystallized from methanol to yield 1.40 g of the known compound 5'-deoxy-5-fluorouridine (5).
(5.69 mmol, yield 92.1%) white crystals were obtained. The product was identified as above based on the following analytical results.
【表】
比較例 １
含フツ素ウリジン類(6) ３ｇ（8.64mmol）を
トリエチルアミン：メタノール：酢酸エチル＝
３：４：20（容量）の混合液に溶解させ、20℃で
12時間撹拌、反応させた。反応後溶液を減圧濃縮
して得られた残渣についてメタノールから再結晶
化を試みたが再結晶化しなかつた。
比較例 ２
含フツ素ウリジン類(8) ３ｇ（10.7mmol）の
水10ml溶液に濃塩酸10mlを加え、80℃で30分間撹
拌、反応させた。反応後溶液を減圧濃縮して得ら
れた残渣についてメタノールから再結晶化を試み
たが再結晶化しなかつた。[Table] Comparative example 1 Fluorine-containing uridines (6) 3g (8.64mmol) was mixed with triethylamine:methanol:ethyl acetate=
Dissolve in a 3:4:20 (volume) mixture and heat at 20℃.
The mixture was stirred and reacted for 12 hours. After the reaction, the solution was concentrated under reduced pressure, and the resulting residue was attempted to be recrystallized from methanol, but recrystallization failed. Comparative example 2 To a solution of 3 g (10.7 mmol) of fluorine-containing uridines (8) in 10 ml of water was added 10 ml of concentrated hydrochloric acid, and the mixture was stirred and reacted at 80° C. for 30 minutes. After the reaction, the solution was concentrated under reduced pressure, and the resulting residue was attempted to be recrystallized from methanol, but recrystallization failed.
Claims (1)
基または含フツ素低級アルキル基、Ｘは水素、ま
たは水酸基を示す。〕 で表わされる含フツ素ウリジン類と塩基とを有機
溶媒中、０〜80℃で反応させることからなる一般
式： 〔式中、Ｘは前記と同じ。〕 で表わされる５−フルオロウリジン類の製法。[Claims] 1. General formula [In the formula, R represents a lower acyl group, a fluorine-containing lower acyl group, or a fluorine-containing lower alkyl group, and X represents hydrogen or a hydroxyl group. ] A general formula consisting of reacting a fluorine-containing uridine represented by the following with a base in an organic solvent at 0 to 80°C: [In the formula, X is the same as above. ] A method for producing 5-fluorouridines represented by:
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21574982A JPS59106499A (en) | 1982-12-09 | 1982-12-09 | Production of 5-fluorouridine |
| US06/558,913 US4542209A (en) | 1982-12-09 | 1983-12-07 | Fluorine-containing uridine derivative and preparation and use thereof |
| DE8383112293T DE3362821D1 (en) | 1982-12-09 | 1983-12-07 | Fluorine-containing uridine derivative and preparation and use thereof |
| EP83112293A EP0111299B1 (en) | 1982-12-09 | 1983-12-07 | Fluorine-containing uridine derivative and preparation and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21574982A JPS59106499A (en) | 1982-12-09 | 1982-12-09 | Production of 5-fluorouridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59106499A JPS59106499A (en) | 1984-06-20 |
| JPH0332559B2 true JPH0332559B2 (en) | 1991-05-13 |
Family
ID=16677574
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21574982A Granted JPS59106499A (en) | 1982-12-09 | 1982-12-09 | Production of 5-fluorouridine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59106499A (en) |
-
1982
- 1982-12-09 JP JP21574982A patent/JPS59106499A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59106499A (en) | 1984-06-20 |
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