KR100330718B1 - A process for preparing thymine - Google Patents
A process for preparing thymine Download PDFInfo
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- KR100330718B1 KR100330718B1 KR1019990020006A KR19990020006A KR100330718B1 KR 100330718 B1 KR100330718 B1 KR 100330718B1 KR 1019990020006 A KR1019990020006 A KR 1019990020006A KR 19990020006 A KR19990020006 A KR 19990020006A KR 100330718 B1 KR100330718 B1 KR 100330718B1
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- thymine
- formula
- cyclization reaction
- acid
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- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 229940113082 thymine Drugs 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000004202 carbamide Substances 0.000 claims abstract description 11
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 9
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000012970 tertiary amine catalyst Substances 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 11
- -1 2-formylpropionic acid ester Chemical class 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- 239000010953 base metal Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 11
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 7
- 150000001340 alkali metals Chemical class 0.000 abstract description 7
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 6
- 150000001342 alkaline earth metals Chemical class 0.000 abstract description 5
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229940104302 cytosine Drugs 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical group O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- AFBXRHFIVUFPES-UHFFFAOYSA-N 5-methyl-1h-pyrimidine-2,4-dione Chemical compound CC1=CNC(=O)NC1=O.CC1=CNC(=O)NC1=O AFBXRHFIVUFPES-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- HWYJZXYVLPKDLM-UHFFFAOYSA-N methyl 2-methyl-3-oxopropanoate Chemical compound COC(=O)C(C)C=O HWYJZXYVLPKDLM-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003151 propanoic acid esters Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/122—Propionic acid
Abstract
본 발명은 다음 화학식 1로 표시되는 티민의 제조방법에 관한 것으로서, 더욱 상세하게는 2-포르밀프로피온산 에스테르를 원료로하여 산(acid)과 요소를 반응시킨 후에 연속적으로 고리화 반응을 수행하여 티민을 제조하되, 상기한 고리화 반응을 2급 또는 3급의 아민촉매와 알칼리금속 또는 알칼리토금속계 무기염기하에서 수행하여 고수율 및 고순도의 티민을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing thymine represented by the following formula (1), and more particularly to 2-thiylpropionic acid as a raw material to react with acid (urea) and urea followed by a cyclization reaction continuously To prepare, but the above-mentioned cyclization reaction is carried out under a secondary or tertiary amine catalyst and an alkali metal or alkaline earth metal-based inorganic base, and relates to a method for producing high yield and high purity thymine.
Description
본 발명은 다음 화학식 1로 표시되는 티민의 제조방법에 관한 것으로서, 더욱 상세하게는 2-포르밀프로피온산 에스테르를 원료로하여 산(acid)과 요소를 반응시킨 후에 연속적으로 고리화 반응을 수행하여 티민을 제조하되, 상기한 고리화 반응을 2급 또는 3급의 아민촉매와 알칼리금속 또는 알칼리토금속계 무기염기하에서 수행하여 고수율 및 고순도의 티민을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing thymine represented by the following formula (1), and more particularly to 2-thiylpropionic acid as a raw material to react with acid (urea) and urea followed by a cyclization reaction continuously To prepare, but the above-mentioned cyclization reaction is carried out under a secondary or tertiary amine catalyst and an alkali metal or alkaline earth metal-based inorganic base, and relates to a method for producing high yield and high purity thymine.
화학식 1Formula 1
상기 화학식 1로 표시되는 티민(Thymine; 5-메틸우라실)은 인체 DNA를 구성하는 주요 뉴클로오시드의 주요 염기중의 하나로서 최근에는 항바이러스계 의약품의 원료로 광범위하게 사용하고 있다. 티민을 원료로 사용하는 의약품으로는 AZT(Glaxo-Wellcome사)와 d4T(Bristol-Myers Squibb사) 등이 있으며, 이들 의약품은 HIV 바이러스의 리버스 트렌스크립타제 억제(Reverse-Transcriptase Inhibitor) 효과를 가지는 AIDS 치료제의 원료로 사용되고 있다.Thymine (5-methyluracil) represented by Chemical Formula 1 is one of the main bases of the major nucleosides constituting human DNA and has recently been widely used as a raw material for antiviral drugs. Drugs that use thymine as raw materials include AZT (Glaxo-Wellcome) and d4T (Bristol-Myers Squibb). It is used as a raw material for therapeutics.
이상에서 설명한 바와 같이, 티민의 산업적 용도가 광범위하므로 이를 보다 값싸게 합성하는 새로운 제조방법의 개발이 요구된다. 현재까지 알려져 있는 티민의 제조방법은 다음과 같다.As described above, since the industrial use of thymine is extensive, development of a new manufacturing method for synthesizing it cheaper is required. Known methods for producing thymine are as follows.
WO 9113064A에는 5-알킬-2,4-피리미딘온의 2- 또는 4-위치의 수산기를 메탄술포닐 클로라이드(MsCl)를 사용하여 치환한 후 Pd/C를 이용하여 이중 결합을 도입한 기술이 공개되어 있다. 그러나, 이 방법은 제조수율이 낮고 사용원료가 고가인 문제가 있다.WO 9113064A discloses a technique in which a hydroxyl group at the 2- or 4-position of 5-alkyl-2,4-pyrimidinone is substituted with methanesulfonyl chloride (MsCl) and then a double bond is introduced using Pd / C. It is open. However, this method has a problem in that the production yield is low and the raw material is expensive.
JP 1261378A에서는 시토신(Cytosine)을 황산으로 고온·고압반응시켜 티민을 제조하는 기술이 공개되어 있으나, 이 방법 역시 사용원료인 시토신이 고가이므로 경제적인 이점은 없다.JP 1261378A discloses a technique for preparing thymine by reacting cytosine with sulfuric acid at high temperature and high pressure. However, this method also has no economic advantage since cytosine, which is a raw material, is expensive.
티민 제조방법 중 가장 널리 이용되고 있는 방법이 JP 5603467A에 공개되어 있으며, 이는 SU 197597A 특허를 변경한 방법이다.The most widely used method of thymine production is disclosed in JP 5603467A, which is a modification of the SU 197597A patent.
SU 197597A 특허에서는 저온에서 다음 화학식 2로 표시되는 2-포르밀프로피온산 에스테르에 과량의 황산수용액에서 요소를 반응시켜 다음 화학식 3으로 표시되는 화합물을 합성한 후, 이를 가열하여 고리화 반응을 일용기 반응으로 수행하여 티민을 제조하고 있다.In the SU 197597A patent, urea is reacted in an excess sulfuric acid solution to a 2-formylpropionic acid ester represented by the following Chemical Formula 2 at a low temperature to synthesize a compound represented by the following Chemical Formula 3, and then heated to a cyclization reaction. It is carried out to prepare thymine.
이에 반하여, JP 5603467A에서는 다음 화학식 2로 표시되는 2-포르밀프로피온산 에스테르에 염산과 요소를 반응시켜 다음 화학식 3으로 표시되는 화합물을 합성하고 촉매인 묽은 염산 및 반응중 생성수를 제거하기 위한 증발 공정을 거친 후, NaOMe를 사용하여 고리화 반응시켜 티민을 제조하고 있다.On the contrary, in JP 5603467A, hydrochloric acid and urea are reacted with 2-formylpropionic acid ester represented by the following Chemical Formula 2 to synthesize a compound represented by the following Chemical Formula 3, and dilute hydrochloric acid as a catalyst, and an evaporation process for removing the generated water during the reaction. After passing through the cyclization reaction using NaOMe to prepare thymine.
상기한 SU 197597A와 JP 5603467A의 제조방법에서는 상업적으로 손쉽게 합성이 가능한 2-포르밀프로피온산 에스테르를 원료물질로 사용하고 있다는 점에서 경제적으로 우수성은 있다. 그러나, SU 197597A의 제조기술의 경우 합성공정은 비교적 간단하나 과량의 황산 사용으로 인하여 수율이 약 50%로 저조한 문제가 있다. 그리고, JP 5603467A 제조기술의 경우 수율은 비교적 높은 편이나 고리화 반응에서 수분에 민감한 NaOMe를 사용하기 때문에 상기 화학식 3으로 표시되는 화합물의 제조반응에서 생성되는 당량의 생성수 및 사용된 묽은 염산에 함유된 수분을 고리화 반응 이전에 수분을 완전히 제거하여야 만하는 공정의 번거로움이 있으며, 또한 고가의 NaOMe를 사용하므로 원가부담이 크다.In the manufacturing method of the above-described SU 197597A and JP 5603467A, it is economically superior in that 2-formylpropionic acid ester which is commercially easily synthesized is used as a raw material. However, in the case of the manufacturing technology of SU 197597A, the synthesis process is relatively simple, but the yield is low due to the use of excess sulfuric acid, which is about 50%. In the case of JP 5603467A manufacturing technology, the yield is relatively high, but since NaOMe is sensitive to moisture in the cyclization reaction, it is contained in the equivalent water produced in the reaction of the compound represented by Formula 3 and the diluted hydrochloric acid used. There is a hassle of the process of having to completely remove the moisture before the cyclization reaction, and the cost burden is high because expensive NaOMe is used.
또다른 방법으로서, 시토신[JP 1261378A]과 5-알킬오로트산[JP 58172377A]를 사용하여 티민을 제조하는 방법이 있으며, 이 방법은 2- 또는 4-위치의 아민기 혹은 카르복실기 등을 제거하고 이중 결합고리를 도입하여야 하는 어렵고 수율이 낮은 공정을 거쳐야 한다.Another method is to prepare thymine using cytosine [JP 1261378A] and 5-alkylorroic acid [JP 58172377A], which removes amine or carboxyl groups in 2- or 4-position, It is difficult and low yield process to introduce double bond ring.
또한, 고리화 반응 후에 5- 위치에 포름알데하이드와 아민을 이용하여 메틸화하는 기술도 공개되어 있으나[JP 63063668A호], 이 방법 역시 수율이 매우 저조하다.In addition, a technique of methylation using formaldehyde and an amine at the 5-position after the cyclization reaction is also disclosed [JP 63063668A], but this method also has a very low yield.
이외에도, 다른 출발물질 즉 프로피온산 에스테르가 아닌 2-알킬-2,3-디브로모프로피온산 유사물질을 사용하는 제법이 있으나[DD 222591A], 제법 자체의 수율도 그리 높지 않다.In addition, there are preparations using other starting materials, such as 2-alkyl-2,3-dibromopropionic acid, rather than propionic acid esters [DD 222591A], but the yield of the preparation itself is not so high.
본 발명은 상기한 SU 197597A와 JP 5603467A의 제조방법에서 제시된 문제점 특히, 고리화 반응에서의 저조한 수율 및 수분 민감성 시약의 사용을 배제시킬 수 있는 새로운 티민 제조방법을 개발하고자 연구 노력하였다. 그 결과, 별도의 수분 증발공정을 거치지 않고 상기 화학식 3으로 표시되는 화합물을 알칼리금속 또는 알칼리토금속계의 무기염기와 2급 또는 3급의 아민촉매하에서 고수율로서 고리화 반응시킴으로써 본 발명을 완성하였다.The present invention has tried to develop a new method for preparing thymine, which can eliminate the problems of the above-described methods for preparing SU 197597A and JP 5603467A, in particular, poor yield and water sensitive reagents in the cyclization reaction. As a result, the present invention was completed by subjecting the compound represented by Chemical Formula 3 to a high yield under a secondary or tertiary amine catalyst with an alkali or alkaline earth metal-based inorganic base without undergoing a separate water evaporation process. .
따라서, 본 발명은 고수율 및 고순도의 티민을 경제적으로 제조하는 방법을제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for economically preparing high yield and high purity thymine.
본 발명은 다음 화학식 2로 표시되는 2-포르밀프로피온산 에스테르에 산(acid)과 요소를 가하여 다음 화학식 3으로 표시되는 화합물을 제조한 후, 이를 고리화 반응시켜 다음 화학식 1로 표시되는 티민을 제조하는 방법에 있어서,In the present invention, an acid and urea are added to 2-formylpropionic acid ester represented by the following Formula 2 to prepare a compound represented by the following Formula 3, and then cyclized to produce thymine represented by the following Formula 1. In the way,
상기 고리화 반응을 알카리금속 또는 알카리토금속계의 무기염기와 2급 또는 3급의 아민촉매하에서 환류시켜 반응을 시킴으로써, 별도의 증발공정을 거치지 않고 일용기 반응을 고수율로 수행하는 것을 그 특징으로 한다.The cyclization reaction is carried out by refluxing an alkali metal or alkaline earth metal-based inorganic base group under a secondary or tertiary amine catalyst to perform a daily container reaction in a high yield without undergoing a separate evaporation process. do.
화학식 1Formula 1
상기 화학식 2와 3에서 : R은 탄소원자수 1 내지 6의 알킬기를 나타낸다.In Chemical Formulas 2 and 3, R represents an alkyl group having 1 to 6 carbon atoms.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 비교적 가격이 저렴하여 상업성이 우수한 상기 화학식 2로 표시되는 2-포르밀프로피온산 에스테르를 원료로하여 촉매량의 산과 요소를 이용하여 알려진 공정에 의하여 상기 화학식 3으로 표시되는 화합물을 제조하고, 다음으로 수행되는 고리화 반응에서는 2급 또는 3급의 아민촉매와 알카리금속 또는 알카리토금속계의 무기염기를 사용하여 값싸고 간단한 공정으로 진행시켜 목적으로 하는 상기 화학식 1로 표시되는 티민을 고수율 및 고순도로 제조하는 방법에 관한 것이다.The present invention is to prepare a compound represented by the formula (3) by a known process using a catalytic amount of acid and urea as a raw material using a 2-formylpropionic acid ester represented by the formula (2), which is relatively inexpensive and commercially good, and then In the cyclization reaction carried out by the secondary or tertiary amine catalyst and the inorganic base of the alkali metal or alkaline metal-based proceeds in a cheap and simple process to the target thymine represented by the formula (1) in high yield and high purity It relates to a method of manufacturing.
본 발명에 따른 고리화 반응은 상기 화학식 2로 표시되는 2-포르밀프로피온산 에스테르에 촉매량의 산과 요소를 가하여 상기 화학식 3으로 표시되는 화합물을 제조한 후, 연속적으로 값싼 알카리금속 또는 알카리토금속계의 무기염기와 2급 또는 3급의 아민을 촉매로 소량 사용하여 일용기반응(one-pot reaction) 시키는 것을 그 특징으로 하고 있다. 이로써 매우 우수한 수율을 보여주며 원료의 가격이 매우 저렴할 뿐만 아니라, 반응시 습기에 의한 수율에 미치는 악영향이 없고, 공정 또한 연속적으로 수행하므로 기존 제법과 비교시 월등한 경제성을 보여준다.In the cyclization reaction according to the present invention, after adding a catalytic amount of acid and urea to 2-formylpropionic acid ester represented by Chemical Formula 2 to prepare a compound represented by Chemical Formula 3, continuously inexpensive alkali metal or alkaline earth-based inorganic compounds It is characterized by a one-pot reaction using a small amount of a base and a secondary or tertiary amine as a catalyst. This shows a very good yield and the price of the raw material is very inexpensive, there is no adverse effect on the yield by the moisture during the reaction, and the process is performed continuously, showing superior economics compared to the existing manufacturing method.
JP 5603467A의 특허범위로 규정한 NaOH를 단독으로 사용하여 실험한 결과 40% 이하의 저조한 수율로 저순도의 티민이 얻었지며, 이 외에 유기염기를 단독으로 사용할 때에는 반응이 진행되지 않았다[표 2 참조]. 이에 반하여, 본 발명에 따른 제조방법에 의하여 2급 또는 3급의 아민을 촉매로 사용할 경우, NaOH, NaHCO3, Na2CO3, KOH, KHCO3, K2CO3, Ca(OH)2, CaO, CaCO3와 같은 값싼 알카리금속 또는 알카리토금속계의 무기염기를 사용하여도 90 ∼ 95%의 고수율로 고리화 반응이 가능하였다.As a result of experiments using NaOH specified in the patent scope of JP 5603467A alone, thymine of low purity was obtained with a low yield of 40% or less. In addition, the reaction did not proceed when using an organic base alone [see Table 2]. ]. On the contrary, when a secondary or tertiary amine is used as a catalyst by the preparation method according to the present invention, NaOH, NaHCO 3 , Na 2 CO 3 , KOH, KHCO 3 , K 2 CO 3 , Ca (OH) 2 , Inexpensive alkali metal or alkaline earth metal bases such as CaO and CaCO 3 were also able to cyclize at a high yield of 90 to 95%.
특히, JP 5603467A의 기술은 비교적 고가인 NaOMe의 손실을 최소화하기 위하여 상기 화학식 3으로 표시되는 화합물을 제조하기 위해 사용한 염산중에 포함된 수분과 반응 결과로 생성된 당량의 생성수를 제거하여야 하며, 이에 용매로 사용한 알콜과 함께 전량 증발시켜야 하는 공정상의 불편이 있으나, 본 발명에 따른 제조방법에 의해 값싼 알카리금속 또는 알카리토금속계의 무기염기와 2급 또는 3급의 아민을 촉매로 사용할 경우 계내에 다소의 수분이 포함되어 있어도 반응에 아무 지장이 없었다. 황산을 사용하여 상기 화학식 3으로 표시되는 화합물을 제조하여도 당량의 물이 생성수로 생성되나, 본 발명에 따른 제조방법에 의해 연속적으로 고리화 반응을 수행하여도 여전히 고수율 및 고순도의 티민을 제조할 수 있었다.In particular, the technique of JP 5603467A should remove the equivalent amount of water generated as a result of the reaction with the water contained in the hydrochloric acid used to prepare the compound represented by Formula 3 in order to minimize the loss of relatively expensive NaOMe, Although it is inconvenient for the process to evaporate the whole amount with the alcohol used as a solvent, in the case of using a cheap alkali metal or alkaline earth-based inorganic base and secondary or tertiary amine as a catalyst by the production method according to the present invention somewhat Even if the water contained in the reaction did not interfere. Even when the compound represented by Chemical Formula 3 is prepared using sulfuric acid, an equivalent amount of water is produced as generated water. However, even though the cyclization reaction is continuously performed by the preparation method according to the present invention, thymine of high yield and high purity is still obtained. Could be manufactured.
본 발명에 따른 제조방법에서 사용될 수 있는 아민촉매는 2급 또는 3급의 지방족 또는 방향족 아민이다. 이를 보다 구체적으로 예시하면, 4-디메틸아미노피리딘, 이미다졸, 하이드록시벤조트리아졸, 1,2,3-벤조트리아졸, 벤조이미다졸,1,2,4-트리아졸, 1,2,3-트리아졸, 티아졸, 벤조티아졸, 트리에틸아민, 피리딘, 디메틸아닐린 등이 있으며, 특히 4-디메틸아미노피리딘과 하이드록시벤조트리아졸이 매우 우수한 결과를 나타내었다. 상기한 아민촉매의 사용량은 사용된 상기 화학식 3으로 표시되는 화합물 당량에 대하여 10 mg ∼ 10 g, 보다 바람직하기로는 100 mg ∼ 1 g 범위에서 사용한다.The amine catalysts that can be used in the production process according to the invention are secondary or tertiary aliphatic or aromatic amines. To illustrate this more specifically, 4-dimethylaminopyridine, imidazole, hydroxybenzotriazole, 1,2,3-benzotriazole, benzoimidazole, 1,2,4-triazole, 1,2,3 -Triazoles, thiazoles, benzothiazoles, triethylamine, pyridine, dimethylaniline, etc., especially 4-dimethylaminopyridine and hydroxybenzotriazole showed very good results. The amount of the amine catalyst described above is used in the range of 10 mg to 10 g, more preferably 100 mg to 1 g, based on the equivalent of the compound represented by Formula 3 above.
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법에서는 상기 화학식 3으로 표시되는 화합물의 고리화 반응의 조건을 특정 조건으로 변경 설정하므로써 용매의 제거나 수분의 제거없이 일용기 반응(one-pot reaction)시킬 수 있어 획기적으로 공정이 단순화되어 월등히 경제성 높게 티민을 합성할 수 있었다.As described above, in the production method according to the present invention, by changing the conditions of the cyclization reaction of the compound represented by Chemical Formula 3 to specific conditions, one-pot reaction is performed without removing solvent or removing water. The process was greatly simplified and the thymine could be synthesized with high economic efficiency.
이와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바 본 발명이 이에 한정되는 것은 아니다.The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.
실시예 1 ∼ 20 및 비교예 1Examples 1-20 and Comparative Example 1
1ℓ 4구 둥근바닥 플라스크에 메틸 2-포르밀프로피오네이트 46.4 g, 메탄올 200 ㎖, 황산 4 g 및 요소 36 g을 가하고 50 ∼ 60℃로 4시간 동안 가열하였다. 반응동안 반응액은 변함이 없었다. 4시간 후 메탄올 200 ㎖와 다음 표 1에 나타낸 아민촉매 0.04 g 및 염기 32 g을 반응기내에 쏟아 부었다. 이때 온도가 70℃이상 상승하며 이후 온도를 가하여 메탄올이 환류되도록 하였다. 반응 1시간 후 상온으로 냉각한 후 생성된 염과 티민 염을 같이 여과하여 걸러내었다. 염을 건조한 후, 물 300 g을 가하고 가열하여 완전히 용해시켰다. 완전히 용해된 것을 확인하고 다시 상온으로 냉각하였다. 얼음 중탕하에서 35% HCl을 천천히 가하여 중화한 후, 생성된 티민을 여과하였다.To a 1 L four-necked round bottom flask was added 46.4 g of methyl 2-formylpropionate, 200 ml of methanol, 4 g of sulfuric acid and 36 g of urea and heated to 50-60 ° C. for 4 hours. The reaction solution did not change during the reaction. After 4 hours, 200 ml of methanol and 0.04 g of amine catalyst and 32 g of base shown in Table 1 were poured into the reactor. At this time, the temperature was raised to more than 70 ℃ and then added to the temperature to reflux the methanol. After 1 hour of reaction, the mixture was cooled to room temperature, and the resulting salt and thymine salt were filtered together. After the salt was dried, 300 g of water were added and heated to dissolve completely. It was confirmed that completely dissolved and cooled to room temperature again. After neutralization by slow addition of 35% HCl under ice bath, the resulting thymine was filtered off.
다음 표 1의 결과에 따르면, 본 발명에 따른 아민촉매와 무기염기를 사용하는 실시예 1 ∼ 20에서는 90%이상의 고수율 및 99.0 area%(HPLC)이상의 고순도의 티민을 얻을 수 있었다. 이에 반하여 아민촉매 사용없이 무기염기만을 사용하고 있는 비교예 1은 40%의 저조한 수율을 나타내었다.According to the results of Table 1, in Examples 1 to 20 using the amine catalyst and the inorganic base according to the present invention it was possible to obtain a high yield of more than 90% and high purity of more than 99.0 area% (HPLC). In contrast, Comparative Example 1, in which only inorganic bases were used without using an amine catalyst, showed a poor yield of 40%.
실시예 21 및 비교예 2 ∼ 6Example 21 and Comparative Examples 2-6
화학식 3으로 표시되는 화합물(R=Me) 63.2 g, 메탄올 200 ㎖ 및 다음 표 2에 나타낸 아민촉매와 염기를 반응기에 가한 후 1시간동안 가열 환류시켰다. 상온으로 냉각 후 티민 염을 여과하였다. 여과한 염을 건조 후 물 300 g에 가열 용해시킨뒤 냉각하면서 35% HCl로 중화하여 생성된 티민을 여과하였다.63.2 g of a compound represented by Formula 3 (R = Me), 200 ml of methanol, and the amine catalyst and base shown in the following Table 2 were added to the reactor and heated to reflux for 1 hour. After cooling to room temperature, the thymine salt was filtered off. The filtered salt was dried and dissolved in 300 g of water and neutralized with 35% HCl while cooling to filter the resulting thymine.
다만, 비교예 3은 JP 5603467A에서 예시한 방법에 의한 것으로서, 무수의 조건하에서 가열 환류 반응시켰다. 그 결과 본 발명과 유사한 수율 및 순도의 티민을 얻을 수 있었으나, 무수의 반응조건이 요구되는 등의 공정상의 번거로움으로 인하여 공업적으로 적용하기에는 많은 문제가 있다.However, Comparative Example 3 was obtained by the method exemplified in JP 5603467A, and was heated to reflux under anhydrous conditions. As a result, thymine of similar yield and purity could be obtained, but there are many problems in industrial application due to the cumbersome process conditions such as requiring anhydrous reaction conditions.
이상에서 설명한 바와 같이, 본 발명에서는 상기 화학식 3으로 표시되는 화합물의 고리화 반응 조건을 특정함으로써 공정을 단순화시키면서도 제조수율 및 순도 향상 효과가 우수하며, 또한 사용되는 원료물질 및 시약의 가격이 비교적 저렴하므로 경제성 역시 우수하다. 따라서, 본 발명은 티민의 공업적 생산에 매우 유용하다.As described above, in the present invention, by simplifying the process by specifying the cyclization reaction conditions of the compound represented by Chemical Formula 3, the production yield and purity are excellent, and the raw materials and reagents used are relatively inexpensive. Therefore, economics are also excellent. Thus, the present invention is very useful for the industrial production of thymine.
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