JP2809972B2 - Method for producing 5-trifluoromethyluracil - Google Patents
Method for producing 5-trifluoromethyluracilInfo
- Publication number
- JP2809972B2 JP2809972B2 JP5179415A JP17941593A JP2809972B2 JP 2809972 B2 JP2809972 B2 JP 2809972B2 JP 5179415 A JP5179415 A JP 5179415A JP 17941593 A JP17941593 A JP 17941593A JP 2809972 B2 JP2809972 B2 JP 2809972B2
- Authority
- JP
- Japan
- Prior art keywords
- trifluoromethyl
- trifluoromethyluracil
- dihydrouracil
- iodine
- reaction
- 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 - Fee Related
Links
- LMNPKIOZMGYQIU-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical compound FC(F)(F)C1=CNC(=O)NC1=O LMNPKIOZMGYQIU-UHFFFAOYSA-N 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- ACYJXCFDMOGNSM-UHFFFAOYSA-N 5-(trifluoromethyl)-1,3-diazinane-2,4-dione Chemical compound FC(F)(F)C1CNC(=O)NC1=O ACYJXCFDMOGNSM-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000005360 alkyl sulfoxide group Chemical group 0.000 claims description 5
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- 239000011630 iodine Substances 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VLSRKCIBHNJFHA-UHFFFAOYSA-N 2-(trifluoromethyl)prop-2-enoic acid Chemical compound OC(=O)C(=C)C(F)(F)F VLSRKCIBHNJFHA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- WJYJULOBJLLPER-UHFFFAOYSA-N copper(1+);trifluoromethane Chemical compound [Cu+].F[C-](F)F WJYJULOBJLLPER-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- ZXYAAVBXHKCJJB-UHFFFAOYSA-N uracil-5-carboxylic acid Chemical compound OC(=O)C1=CNC(=O)NC1=O ZXYAAVBXHKCJJB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は抗腫瘍作用、抗ウイルス
作用を有するトリフルオロメチルウラシルの製造法に関
する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing trifluoromethyluracil having an antitumor effect and an antiviral effect.
【０００２】[0002]
【従来の技術】トリフルオロメチルウラシルは核酸の塩
基であるウラシル、チミンとの関係で古くより注目され
ている化合物である。特にトリフルオロチミジン及びそ
の誘導体に代表される様に、その特異な物性及び作用か
ら制癌剤または抗ウイルス剤としてまた医薬品の重要な
原料として多くの製造法の検討がなされてきた。従来５
−トリフルオロメチルウラシルを製造する方法としては
（１）５−ヒドロキシカルボニルウラシルをＳＦ4と反
応させる方法［Ｍ．Ｐ．Ｍｅｒｉｔｅ，ｅｔ．ａｌ．，
Ｊ．Ｐａｈｒｍ．Ｓｃｉ．，５２，５０８（１９６
３）］、（２）５−ヨードウラシルをトリフルオロメチ
ル銅と反応させる方法［Ｙ．Ｋｏｂａｙａｓｈｉ，ｅ
ｔ．ａｌ．，Ｊ．Ｃ．Ｓ．Ｐｅｒｋｉｎ Ｉ，２７５５
（１９８０）］、（３）ウラシルとトリフルオロ酢酸を
電解反応に付す方法［Ｌ．Ｈｅｉｎ，Ｄ．Ｃｅｃｈ，
Ｚ．Ｃｈｅｍ．，１７，４１５（１９７７）］、（４）
５−トリフルオロメチル−５，６−ジヒドロウラシルと
臭素を反応させる方法［Ｃ．Ｈｅｉｄｅｒｂｅｒｇｅ
ｒ，ｅｔ．ａｌ．，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，７，１
（１９６４）；特開昭５８−１７４３７１］、（５）５
−トリフルオロメチル−５，６−ジヒドロウラシルとハ
ロゲン化第二銅を反応させる方法［特開昭６０−９４９
７１］などが知られている。2. Description of the Related Art Trifluoromethyluracil has been attracting attention for a long time in relation to uracil and thymine, which are bases of nucleic acids. In particular, as represented by trifluorothymidine and its derivatives, due to its unique physical properties and actions, many production methods have been studied as anticancer agents or antiviral agents and as important raw materials for pharmaceuticals. Conventional 5
- method as a method for producing a trifluoromethyl uracil is reacted with SF 4 to (1) 5-hydroxycarbonyl uracil [M. P. Merite, et. al. ,
J. Pahrm. Sci. , 52, 508 (196
3)], (2) a method of reacting 5-iodouracil with trifluoromethyl copper [Y. Kobayashi, e
t. al. , J. et al. C. S. Perkin I, 2755
(1980)], (3) A method of subjecting uracil and trifluoroacetic acid to an electrolytic reaction [L. Hein, D .; Cech,
Z. Chem. , 17, 415 (1977)], (4)
A method of reacting 5-trifluoromethyl-5,6-dihydrouracil with bromine [C. Heiderberg
r, et. al. , J. et al. Med. Chem. , 7,1
(1964); JP-A-58-174371], (5) 5
-Method of reacting trifluoromethyl-5,6-dihydrouracil with cupric halide [JP-A-60-949]
71] are known.
【０００３】しかし（１）の方法では毒性が高く危険な
ＳＦ4を用いなければならない欠点を有し、（２）の方
法では反応中間体が空気等に極めて敏感であるため反応
条件や収率に難があり、（３）の方法では収率電流効率
ともに悪くまたトリフルオロ酢酸に耐える電解設備が必
要になるという欠点があり、（４）の方法では理論量の
２倍以上の臭素を要する上に収率も悪い、（５）の方法
では反応後に大量の銅塩を含む残渣を生じ操作性や銅塩
の後処理などに大きな問題がある等の欠点を有してい
る。即ち従来のいずれの製造法においても医薬品におい
て重要であるトリフルオロメチルウラシルの安価で確実
な製造法とはいえず、更に改良された有益な製造法が望
まれていた。However a drawback that must be used high dangerous SF 4 toxicity in the method of (1), the reaction conditions and yield for the reaction intermediate is very sensitive to air or the like in the method (2) The method (3) has a drawback in that the yield current efficiency is poor and an electrolytic facility that can withstand trifluoroacetic acid is required. The method (4) requires twice or more the theoretical amount of bromine. In addition, the method (5) has disadvantages such as a poor yield and a large amount of a residue containing a copper salt after the reaction, resulting in a large problem in operability and post-treatment of the copper salt. That is, none of the conventional production methods can be said to be an inexpensive and reliable method for producing trifluoromethyluracil, which is important in pharmaceuticals, and a more improved and useful production method has been desired.
【０００４】[0004]
【発明が解決しようとする課題】そこで本発明者らは従
来の問題点を解決し安価かつ容易なトリフルオロメチル
ウラシルの製造法を確立すべく検討した結果、以下に示
す新しい脱水素法を見いだし本発明を完成した。The present inventors have studied to solve the conventional problems and to establish a cheap and easy method for producing trifluoromethyluracil, and as a result, have found the following new dehydrogenation method. The present invention has been completed.
【０００５】[0005]
【課題を解決するための手段】すなわち本発明は、５−
トリフルオロメチルウラシルを製造するにあたり５−ト
リフルオロメチル−５，６−ジヒドロウラシルとアルキ
ルスルホキシドをハロゲン類の存在下および酸触媒下に
反応させれることにより示される。That is, the present invention provides a 5-
In the production of trifluoromethyluracil, it is indicated by reacting 5-trifluoromethyl-5,6-dihydrouracil with alkyl sulfoxide in the presence of halogens and in the presence of an acid catalyst.
【０００６】本発明に原料として用いられる５−トリフ
ルオロメチル−５，６−ジヒドロウラシルはトリフルオ
ロメタクリル酸と尿素を反応させて容易に得る事のでき
る既知化合物である。［例えば、Ｔ．Ｆｕｃｈｉｇａｍ
ｉ，ｅｔ．ａｌ．，Ｓｙｎｔｈｅｓｉｓ，７６６（１９
８４）等。］本反応にはアルキルスルホキシドとしてジ
メチルスルホキシド、ジエチルスルホキシド等が用いら
れるが、アルキルスルホキシドのアルキル基はこれらに
限定されず、好ましくはＣ1〜Ｃ4の低級アルキル基であ
る。またアルキルスルホキシドの使用量は原料５−トリ
フルオロメチル−５，６−ジヒドロウラシルに対して１
当量以上の範囲で用いることが出来るが好ましくは２当
量以上１０当量以下が望ましい。また用いることの出来
るハロゲンとしてはヨウ素、臭素、一塩化ヨウ素等を挙
げることが出来るがヨウ素が最も好適である。用いるハ
ロゲンの量は原料５−トリフルオロメチル−５，６−ジ
ヒドロウラシルに対して０．０１当量以上１０当量以下
までの範囲で用いることが出来るが０．０７当量以上
０．５当量以下の範囲が最も好適である。用いる酸触媒
としては有機酸としてはトリフルオロ酢酸、カンファー
スルホン酸、ｐ−トルエンスルホン酸、無機酸としては
塩化トリメチルシラン、五酸化リン、硫酸、塩酸などが
あげられる。この中で酸触媒としては硫酸を用いるのが
最も望ましい。用いる酸の量は原料５−トリフルオロメ
チル−５，６−ジヒドロウラシルに対して０．０１当量
以上１当量以下までの範囲で用いることが出来るが０．
０７当量以上０．５当量以下の範囲が最も好適である。[0006] 5-trifluoromethyl-5,6-dihydrouracil used as a raw material in the present invention is a known compound which can be easily obtained by reacting trifluoromethacrylic acid with urea. [For example, T. Fuchigam
i, et. al. , Synthesis, 766 (19)
84) etc. In this reaction, dimethyl sulfoxide, diethyl sulfoxide and the like are used as the alkyl sulfoxide, but the alkyl group of the alkyl sulfoxide is not limited thereto, and is preferably a C 1 -C 4 lower alkyl group. The amount of the alkyl sulfoxide used is 1 to the starting material 5-trifluoromethyl-5,6-dihydrouracil.
Although it can be used in the range of equivalents or more, it is preferably 2 equivalents or more and 10 equivalents or less. Examples of the halogen that can be used include iodine, bromine, and iodine monochloride, with iodine being most preferred. The amount of the halogen to be used can be used in the range of 0.01 to 10 equivalents to the raw material 5-trifluoromethyl-5,6-dihydrouracil, but is in the range of 0.07 to 0.5 equivalents. Is most preferred. Examples of the acid catalyst used include trifluoroacetic acid, camphorsulfonic acid, and p-toluenesulfonic acid as organic acids, and trimethylsilane chloride, phosphorus pentoxide, sulfuric acid, and hydrochloric acid as inorganic acids. Among them, sulfuric acid is most preferably used as the acid catalyst. The amount of the acid used can be in the range of 0.01 equivalent or more and 1 equivalent or less based on the starting material 5-trifluoromethyl-5,6-dihydrouracil.
The range of not less than 07 equivalents and not more than 0.5 equivalents is most preferable.
【０００７】この反応では溶媒を用いても用いなくても
良い。溶媒としては、反応に影響を与えない限り限定さ
れないが、具体的には、クロロホルム、ベンゼン、トル
エン、１，２−ジメトキシエタン、ジメチルホルムアミ
ドなどの非プロトン性溶媒を用いることができる。好ま
しくは無溶媒またはジメチルホルムアミドを用いるのが
望ましい。反応温度は通常室温から溶媒の沸騰温度範
囲、好ましくは９０℃以上１５０℃以下である。反応時
間は通常０．５から７２時間である。本反応は以下に詳
しく実施例にて述べるが、安価でかつ操作性に優れ工業
的製造法として従来の方法に比べ格段の有意性が認めら
れるものである。In this reaction, a solvent may or may not be used. The solvent is not limited as long as it does not affect the reaction, and specifically, an aprotic solvent such as chloroform, benzene, toluene, 1,2-dimethoxyethane, and dimethylformamide can be used. Preferably, no solvent or dimethylformamide is used. The reaction temperature is usually in the range of room temperature to the boiling temperature of the solvent, preferably 90 ° C or higher and 150 ° C or lower. The reaction time is usually 0.5 to 72 hours. This reaction is described in detail in the Examples below, but it is inexpensive, has excellent operability, and has remarkable significance as an industrial production method as compared with conventional methods.
【０００８】[0008]
【実施例】以下に実施例をあげて本発明をさらに具体的
に説明する。 参考例１ ５−トリフルオロメチル−５，６−ジヒドロウラシルの
合成 尿素１３．５ｇを無水酢酸１６０ｍｌに懸濁し、ここへ
トリフルオロメタクリル酸３０ｇを加える．１００℃で
１時間反応後、そのまま反応液を減圧下に濃縮し得られ
た油状物を水１５０ｍｌから結晶化し同溶媒で再結晶し
て５−トリフルオロメチル−５，６−ジヒドロウラシル
２５．９ｇを得た。融点 ２０３−２０５℃The present invention will be described more specifically with reference to the following examples. Reference Example 1 Synthesis of 5-trifluoromethyl-5,6-dihydrouracil 13.5 g of urea was suspended in 160 ml of acetic anhydride, and 30 g of trifluoromethacrylic acid was added thereto. After reacting at 100 ° C. for 1 hour, the reaction solution was directly concentrated under reduced pressure, and the obtained oil was crystallized from 150 ml of water and recrystallized with the same solvent to give 25.9 g of 5-trifluoromethyl-5,6-dihydrouracil. I got 203-205 ° C
【０００９】実施例１ ５−トリフルオロメチル−５，６−ジヒドロウラシル
２５．２ｇをジメチルスルホキシド８８．７ｍｌに溶解
し、ヨウ素３．４７ｇ及び濃硫酸０．７６ｍｌを加え均
一に溶解する。そのまま１４０℃６時間攪拌する。室温
まで冷却し亜硫酸ナトリウム水溶液を加えてヨウ素を還
元する。そのまま減圧下に濃縮して水を加えて酢酸エチ
ルで３回抽出する。酢酸エチルを濃縮し水１００ｍｌか
ら再結晶して白色針状結晶の５−トリフルオロメチルウ
ラシル ２１．９ｇ（８８％）を得た。融点 ２３９−
２４１℃ ＮＭＲ：文献記載の値と一致した。Example 1 5-trifluoromethyl-5,6-dihydrouracil
25.2 g is dissolved in 88.7 ml of dimethyl sulfoxide, and 3.47 g of iodine and 0.76 ml of concentrated sulfuric acid are added and uniformly dissolved. Stir at 140 ° C. for 6 hours. Cool to room temperature and add aqueous sodium sulfite to reduce iodine. The mixture is concentrated under reduced pressure, water is added, and the mixture is extracted three times with ethyl acetate. Ethyl acetate was concentrated and recrystallized from 100 ml of water to obtain 21.9 g (88%) of 5-trifluoromethyluracil as white needle crystals. Melting point 239-
241 ° C NMR: consistent with the value described in the literature.
【００１０】実施例２ ５−トリフルオロメチル−５，６−ジヒドロウラシル
１０ｇをジメチルホルムアミド２４．７ｍｌに溶解しジ
メチルスルホキシド１２．８ｇ，ヨウ素１．４ｇ及び濃
硫酸０．５４ｇを加え均一に溶解する。そのまま１１７
℃で９時間攪拌する。室温まで冷却し亜硫酸ナトリウム
水溶液を加えてヨウ素を還元する。そのまま減圧下に濃
縮して水を加えて酢酸エチルで３回抽出する。酢酸エチ
ルを濃縮し水４０ｍｌから再結晶して白色針状結晶の５
−トリフルオロメチルウラシル７．２ｇ（７３％）を得
た。Example 2 5-trifluoromethyl-5,6-dihydrouracil
10 g is dissolved in 24.7 ml of dimethylformamide, and 12.8 g of dimethylsulfoxide, 1.4 g of iodine and 0.54 g of concentrated sulfuric acid are added and uniformly dissolved. 117 as it is
Stir at 9 ° C. for 9 hours. Cool to room temperature and add aqueous sodium sulfite to reduce iodine. The mixture is concentrated under reduced pressure, water is added, and the mixture is extracted three times with ethyl acetate. The ethyl acetate was concentrated and recrystallized from 40 ml of water to give white needle-like crystals.
7.2 g (73%) of trifluoromethyluracil were obtained.
【００１１】実施例３ ５−トリフルオロメチル−５，６−ジヒドロウラシル
２５．２ｇをジメチルスルホキシド７３．９ｍｌに溶解
し、ヨウ素２．４４ｇ及び濃硫酸０．５４ｍｌを加え均
一に溶解する。そのまま１５０℃８時間攪拌する。室温
まで冷却し亜硫酸ナトリウム水溶液を加えてヨウ素を還
元する。そのまま減圧下に濃縮して水を加えて酢酸エチ
ルで３回抽出する。酢酸エチル層を無水硫酸ナトリウム
で乾燥しを濃縮し減圧下に濃縮し得られた残渣をクロロ
ホルムにて結晶化してこれを水１００ｍｌから再結晶し
て白色針状結晶の５−トリフルオロメチルウラシル １
４．８ｇを得た。Example 3 5-trifluoromethyl-5,6-dihydrouracil
25.2 g is dissolved in 73.9 ml of dimethyl sulfoxide, and 2.44 g of iodine and 0.54 ml of concentrated sulfuric acid are added and uniformly dissolved. Stir at 150 ° C. for 8 hours. Cool to room temperature and add aqueous sodium sulfite to reduce iodine. The mixture is concentrated under reduced pressure, water is added, and the mixture is extracted three times with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated and concentrated under reduced pressure. The resulting residue was crystallized from chloroform and recrystallized from 100 ml of water to give 5-trifluoromethyluracil 1 as white needle crystals.
4.8 g were obtained.
【００１２】実施例４ ヨウ素１７．２ｇ及び濃硫酸３．６ｍｌをジメチルスル
ホキシド９３．６ｍｌに溶解しここへ５−トリフルオロ
メチル−５，６−ジヒドロウラシル ２５．２ｇを加え
均一に溶解した。そのまま１４０℃４時間攪拌し反応し
た。室温まで放冷し亜硫酸ナトリウム水溶液を加えてヨ
ウ素を還元、そのまま減圧下に濃縮して得られた残渣を
熱水１５０ｍｌに溶解し２日間冷蔵し析出した白色針状
結晶を濾取して乾燥し、５−トリフルオロメチルウラシ
ル１５．１ｇを得た。Example 4 17.2 g of iodine and 3.6 ml of concentrated sulfuric acid were dissolved in 93.6 ml of dimethyl sulfoxide, and 25.2 g of 5-trifluoromethyl-5,6-dihydrouracil was added thereto and uniformly dissolved. The mixture was stirred and reacted at 140 ° C. for 4 hours. After cooling to room temperature, an aqueous solution of sodium sulfite was added to reduce iodine, and the resulting residue was concentrated under reduced pressure. The residue was dissolved in 150 ml of hot water, refrigerated for 2 days, and the precipitated white needle crystals were collected by filtration and dried. 15.1-g of 5-trifluoromethyluracil was obtained.
【００１３】[0013]
【発明の効果】本発明の製造方法は従来の５−トリフル
オロメチルウラシルの製造技術における問題点がなく、
優れた方法である。The production method of the present invention has no problems in the conventional production technology of 5-trifluoromethyluracil,
This is an excellent method.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 Ｊ．ＩＮＤＩＡＮ．ＣＨＥＭ．ＳＯ Ｃ．，（1991），68，Ｐ367−368 (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 239/54 B01J 27/06 C07B 61/00 300 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＷＰＩＤＳ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuation of front page (56) References INDIAN. CHEM. SOC. , (1991), 68, P367-368 (58) Fields investigated (Int. Cl. 6 , DB name) C07D 239/54 B01J 27/06 C07B 61/00 300 CA (STN) REGISTRY (STN) WPIDS (STN) )
Claims (1)
ドロウラシルとアルキルスルホキシドをハロゲン類の存
在下および酸触媒下に反応させることを特徴とする５−
トリフルオロメチルウラシルの製造方法。1. A method comprising reacting 5-trifluoromethyl-5,6-dihydrouracil with an alkyl sulfoxide in the presence of a halogen and in the presence of an acid catalyst.
A method for producing trifluoromethyluracil.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5179415A JP2809972B2 (en) | 1993-07-20 | 1993-07-20 | Method for producing 5-trifluoromethyluracil |
| US08/275,455 US5532349A (en) | 1993-07-20 | 1994-07-15 | Process for producing 1-(2'-deoxy-β-D-erythro-pentofuranosyl)-5-trifluoromethyluracil derivatives |
| DE69431537T DE69431537T2 (en) | 1993-07-20 | 1994-07-20 | Process for the preparation of 5-trifluoromethyluracil derivatives |
| DE69424475T DE69424475T2 (en) | 1993-07-20 | 1994-07-20 | Process for the preparation of 1- (2'-deoxy-beta-D-erythropentofuranosyl) -5-trifluoromethyluracil derivatives |
| EP99122024A EP0990651B1 (en) | 1993-07-20 | 1994-07-20 | Process for producing 5-trifluoromethyluracil derivatives |
| EP94111294A EP0635517B1 (en) | 1993-07-20 | 1994-07-20 | Process for Producing 1-(2'-deoxy-beta-D-erythropentofuranosyl)-5-trifluoromethyluracil Derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5179415A JP2809972B2 (en) | 1993-07-20 | 1993-07-20 | Method for producing 5-trifluoromethyluracil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0733750A JPH0733750A (en) | 1995-02-03 |
| JP2809972B2 true JP2809972B2 (en) | 1998-10-15 |
Family
ID=16065471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5179415A Expired - Fee Related JP2809972B2 (en) | 1993-07-20 | 1993-07-20 | Method for producing 5-trifluoromethyluracil |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2809972B2 (en) |
-
1993
- 1993-07-20 JP JP5179415A patent/JP2809972B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| Ｊ．ＩＮＤＩＡＮ．ＣＨＥＭ．ＳＯＣ．，（１９９１），６８，Ｐ３６７−３６８ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0733750A (en) | 1995-02-03 |
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