KR960010102B1 - Process for the preparation of prostaglandin for pharmaceutical - Google Patents
Process for the preparation of prostaglandin for pharmaceutical Download PDFInfo
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- KR960010102B1 KR960010102B1 KR1019890019932A KR890019932A KR960010102B1 KR 960010102 B1 KR960010102 B1 KR 960010102B1 KR 1019890019932 A KR1019890019932 A KR 1019890019932A KR 890019932 A KR890019932 A KR 890019932A KR 960010102 B1 KR960010102 B1 KR 960010102B1
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- pgf
- pge
- tetrahydrofuran
- organic solvent
- mono
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- 238000000034 method Methods 0.000 title claims abstract description 11
- 150000003180 prostaglandins Chemical class 0.000 title 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 159000000000 sodium salts Chemical class 0.000 claims abstract 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- BGKHCLZFGPIKKU-UHFFFAOYSA-N (13E,15S)-15-hydroxy-9-oxo-prosta-10,13-dienoic acid Natural products CCCCCC(O)C=CC1C=CC(=O)C1CCCCCCC(O)=O BGKHCLZFGPIKKU-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000007796 conventional method Methods 0.000 claims 1
- 239000003791 organic solvent mixture Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 abstract 1
- 229960002986 dinoprostone Drugs 0.000 abstract 1
- 229940035423 ethyl ether Drugs 0.000 abstract 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000005906 menstruation Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- -1 etc. Chemical compound 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 분만 촉진 및 유산에 사용되는 다음 구조식의 PGF2αPGE2의 분리 정제 기술에 관한 것이다.The present invention relates to a technique for separating and purifying PGF 2α PGE 2 of the following structural formulas used for labor of labor and lactic acid.
여기에서, X=0 혹은
상기 구조식 화합물에서 X=0, R1=R2=H(수소)일 때 PGE2로 알려진 광학적 활성 화합물, X가
이 PGE2, PGF2α는 여러가지 약릭학적, 의학적 목적으로 유용하게 알려진 바, 예를 들면 인간을 포함한 임신한 동물에 있어서의 분만 촉진 및 유산, 또 인간을 포함하여 임신 혹은 임신 않는 동물에 있어서의 월경 조절등이다. 이러한 목적에서 보통 처방 방도는 정맥주사나 주입방법이 사용되고 있고, 또한 구경경로는 분만 촉진에 사용되고, 질 및 자궁내 경로로는 유산과 월경 조절에 사용되고 있다.These PGE 2 and PGF 2α are useful for various pharmacological and medical purposes, for example, to promote delivery and miscarriage in pregnant animals, including humans, and menstruation in pregnant or non-pregnant animals, including humans. Adjustment light. For this purpose, the prescription is usually used for intravenous injection or infusion. Also, the caliber is used for palpation and the vaginal and intrauterine routes are used for abortion and menstruation.
일반적으로 테트라 하이드로 퓨란을 탈보호 하기 위해 사용되는 방법으로는 THF(테트라 하이드로 퓨란)와 아세트산(1.0M 수용액 : pH=2.4), 물을 이용하는 방법과 PPTS(피리디늄 파라 톨루엔 설폰네이트) 1.0M 수용액 : pH=3을 촉매로 하여 합성하는 방법이다(J.O.C vol 42, No 23, 1977). 이때 사용되는 용매는 메탄올, 에탄올, 이소프로필 알코올 등이다. 이 두 방법 중 어느 방법에 의해 합성하였던 부산물로는 2개의 PGF2α-모노 테트라 하이드로 퓨란이 생성되며, 분리정제하기 위해서는 반응에 사용된 용매를 농축한 다음 물과 포솨 소금으로 추출한 후, 농축하여 칼럼 크로마토그래피에 의해 분리하는 방법을 사용하였다.In general, methods used to deprotect tetrahydrofuran include THF (tetrahydrofuran) and acetic acid (1.0M aqueous solution: pH = 2.4), water and PPTS (pyridinium paratoluene sulfonate) 1.0M aqueous solution. : Synthesis by using pH = 3 as a catalyst (JOC vol 42, No 23, 1977). The solvent used at this time is methanol, ethanol, isopropyl alcohol and the like. As a by-product synthesized by either of these two methods, two PGF 2α -mono tetrahydrofuran are produced.In order to separate and purify, the solvent used in the reaction is concentrated, extracted with water and fortune salt, and then concentrated by column. The method of separation by chromatography was used.
그러나 이와 같은 방법으로 PGE2, PGF2α을 분리할 경우 많은 시간과 용매가 필요하며, 또 분리된 PGE2나 PGF2α의 일부분은 부산물인 PGE2-모노 테트라 하이드로 퓨란, PGF2α-모노 테트라 하이드로 퓨란과 혼합된 상태로 존재함으로 순도가 떨어지며, PGE2, PGF2α는 상당히 불안정하므로 값싼 실리카겔 칼럼은 사용하지 못하고, 값이싼 산으로 세척한 실리카겔 칼럼을 사용해야 하는 단점이 있다.However, when PGE 2 and PGF 2α are separated by this method, a lot of time and solvent are required, and a part of the separated PGE 2 or PGF 2α is a byproduct of PGE 2 -mono tetrahydrofuran, PGF 2α -mono tetrahydrofuran Purity is lowered by being mixed with, and PGE 2 and PGF 2α are very unstable, so a cheap silica gel column cannot be used, and a silica gel column washed with a cheap acid should be used.
더우기 PGF2α은 저융점의 납상의 고체이므로 응고 및 정제하기 어려우며, 염기성 수용액에 용해되는 속도도 느리다.Furthermore, since PGF 2α is a low melting lead-like solid, it is difficult to coagulate and purify, and the rate of dissolution in basic aqueous solution is also slow.
본 발명자들은 종래 기술의 문제점을 해결하여 효과적으로 순도를 높게 분리정제하는 방법을 찾기 위하여 오랜 연구를 행한 결과 본 발명을 완성하게 되었다. 본 발명에스는, PGE2와 PGF2α는 카르복시산이므로 염기의 수용액에 용해될 때의 염이 형성될 것이므로, 여러가지 염기를 사용하여 염의 형성 실험을 해 보았다. 여기서 사용한 염기는 수산화나트륨, 탄산나트륨, 탄산수소나트륨 등을 사용하였고, 용매로는 디클로로메탄, 에틸에테르, 에틸아세테이트, 클로로포름, 벤젠, 톨루엔 등을 사용하였다. 여기서 탄산수소나트륨 수용액 안에서 PGE2, PGF2α만이 선택적으로 염이 형성되고, PGE2-모노 테트라 하이드로 퓨란, PGE2-디 테트라 하이드로 퓨란, PGF2α-모노 테트라 하이드로 퓨란, PGF2α-디테트라 하이드로 퓨란은 염이 형성되지 않았다. 또한 탄산나트륨 수용액 안에서는 PGE2, PGF2α는 물론 PGE2-모노 테트라 하이드로 퓨란, PGE2-디 테트라 하이드로 퓨란, PGF2α-모노 테트라 하이드로 퓨란, PGF2α-디 테트라 하이드로 퓨란의 일부분이 염을 형성하였다.The present inventors have completed the present invention as a result of a long research to solve the problems of the prior art to find a method of effectively separating and purifying high purity. In the present invention, since PGE 2 and PGF 2α are carboxylic acids, salts will be formed when dissolved in an aqueous solution of a base. Thus, salt formation experiments were conducted using various bases. The base used herein was sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, etc., and dichloromethane, ethyl ether, ethyl acetate, chloroform, benzene, toluene, and the like were used as the solvent. In the aqueous solution of sodium bicarbonate, only PGE 2 and PGF 2α selectively form salts, PGE 2 -mono tetrahydrofuran, PGE 2 -di tetrahydrofuran, PGF 2α -mono tetrahydrofuran, PGF 2α -ditetra hydrofuran Silver salt did not form. Also inside sodium carbonate solution PGE 2, PGF 2α, as well as PGE 2 - mono tetrahydrofuran, PGE 2 - di tetrahydrofuran, PGF 2α - mono tetrahydrofuran, PGF 2α - D to form the salt portion of tetrahydrofuran.
따라서 수산화나트륨이나 탄산나트륨, 탄산수소나트륨과 같은 염기를 사용할 때, 단지 탄산수소나트륨만이 선택적으로 PGE2, PGF2α만을 형성할 수 있다는 것을 발견하였고, PGE2-디 테트라 하이드로 퓨란, PGF2α-디 테트라 하이드로 퓨란, PGE2-모노 테트라 하이드로 퓨란, PGF2α-모노 테트라 하이드로 퓨란은 염이 형성되지 않는 것을 발견하였다. 따라서 PGE2, PGF2α는 탄산수소나트륨을 사용할 때, 선택적으로 염을 형성할 수 있는 장점이 있으며, 기존의 여러가지 단점을 보완해 순도를 높일 수 있는 장점이 있다.Thus, when using bases such as sodium hydroxide, sodium carbonate and sodium bicarbonate, it was found that only sodium bicarbonate could selectively form PGE 2 , PGF 2α , and PGE 2 -di tetrahydrofuran, PGF 2α -di Tetra hydrofuran, PGE 2 -mono tetra hydrofuran, PGF 2α -mono tetra hydrofuran were found to not form salts. Therefore, PGE 2 and PGF 2α have the advantage of selectively forming a salt when using sodium hydrogen carbonate, and has the advantage of increasing the purity to compensate for the various disadvantages of the existing.
즉, PGF2α-디 테트라 하이드로 퓨란 혹은 PGE2-디 테트라 하이드로 퓨란을 피리디늄 파라 톨루엔 설포네이트를 촉매로 사용하여, 에탄올, 메탄올, 이소프로필 알코올과 같은 유기용매에서 반응을 시켜 PGF2α-디테트라 하이드로 퓨란, 2개의 PGF2α-모노 테트라 하이드로 퓨란, PGF2α혼합물 혹은 PGE2-디 테트라 하이드로 퓨란, 2개의 PGE2-모노 테트라 하이드로 퓨란, PGF2혼합물을 형성시킨다. 반응조건으로는, 온도는 30~70℃를 유지하게 하고, 반응시간은 3에서 8시간이 적당하다. 반응 종료 후, 에탄올, 메탄올, 이소프로필 알코올과 같은 용매를 농축시키고, 여기에 포화 탄산수소나트륨을 이용해 염을 형성케한 다음, 디클로로 메탄, 에틸에테르, 에틸아세테이트, 클로로 포름, 벤젠, 톨루엔 등과 같은 용매로 추출하였다. 이때 포화 탄산수소나트륨은 충분한 양을 사용햐여야 한다. 적은 양을 사용하면, PGF2α혹은 PGE2가 완전히 염이 형성되지 않는다. 즉 1~5배의 포화탄산수소나트륨을 사용하는 것이 바람직하다. 유기층은 모아두고, 수층을 받아내어 염산, 아세트산, 질산, 황산 등을 사용하여 pH 2~6으로 맞추어 산성화 시켰다. 이 수층을 위에 사용된 용매를 사용해 추출하여 순수한 PGF2α, PGE2을 얻을 수 있었다. 이때 pH의 범위가 2~6의 범위를 벗어날 시에는 얻고자 하는 PGE2α, PGE2의 염이 석출되지 않는다.That is, PGF 2α -ditetrahydrofuran or PGE 2 -ditetrahydrofuran is reacted in an organic solvent such as ethanol, methanol or isopropyl alcohol by using pyridinium para toluene sulfonate as a catalyst, and then PGF 2α - ditetra Hydrofuran, two PGF 2α -mono tetra hydrofurans, a PGF 2α mixture or PGE 2 -di tetra hydrofuran, two PGE 2 -mono tetra hydrofurans, a PGF 2 mixture are formed. As reaction conditions, temperature is maintained at 30-70 degreeC, and reaction time is suitable for 3 to 8 hours. After completion of the reaction, solvents such as ethanol, methanol and isopropyl alcohol are concentrated, and salts are formed therein with saturated sodium hydrogen carbonate, and then dichloromethane, ethyl ether, ethyl acetate, chloroform, benzene, toluene, and the like. Extracted with solvent. At this time, saturated sodium bicarbonate should be used in sufficient quantity. If a small amount is used, PGF 2α or PGE 2 will not be fully salted. That is, it is preferable to use 1-5 times of saturated sodium hydrogen carbonate. The organic layer was collected, and the aqueous layer was collected and acidified by adjusting the pH to 2-6 using hydrochloric acid, acetic acid, nitric acid, sulfuric acid, and the like. This aqueous layer was extracted using the solvent used above to obtain pure PGF 2α , PGE 2 . At this time, when the pH is out of the range of 2 ~ 6, the salt of PGE 2α , PGE 2 to be obtained is not precipitated.
다음의 실시예로서 본 발명을 더욱 상세히 설명한다.The present invention is explained in more detail by the following examples.
[실시예 1]Example 1
PGF2α-디 테트라 하이드로 퓨란 132㎎을 피리디늄 파라 톨루엔 설포네이트 0.5eq을 촉매로 하여 에탄올 30㎖에 녹여 55~60℃에서 5시간 동안 교반하여 PGF2α-디 테트라 퓨란, 2개의 PGF2α-모노 테트라하이드로 퓨란, PGF2α혼합물이 형성되었다. 반응 종료 후 에탄올을 제거하고, 포화 탄산수소나트륨을 사용해 염을 형성케 한다(pH를 8~10으로 조절). 디클로로메탄으로 추출한 다음, 수층은 1N 염산을 사용하여 pH를 2~6으로 맞추어 산성화 시킨다. 에틸 아세테이트를 사용하여 추출하고, 용매를 제거한 후에 순수한 PGF2α68㎎, 73%의 수율로 얻었다. IR 흡수 스펙트라(KBr) :VOH: 3350㎝-1,VC=0 :: 1708㎝-1, NMR 스펙트라(CDCl3) : 3.91~4.1ppm(1H1-OH 3H), 5.3~5.6ppm(4H : C=C bond).PGF 2α - di tetrahydrofuran 132㎎ the pyridinium p-toluenesulfonate as a catalyst to the 0.5eq the mixture was stirred at 55 ~ 60 ℃ dissolved in ethanol for 5 hours 30㎖ PGF 2α - di-tetrahydro furan, 2 PGF 2α - mono Tetrahydrofuran, PGF 2α mixture was formed. After the reaction is completed, ethanol is removed and a salt is formed using saturated sodium bicarbonate (pH is adjusted to 8-10). After extraction with dichloromethane, the aqueous layer is acidified by adjusting the pH to 2-6 with 1N hydrochloric acid. Extraction using ethyl acetate and removal of solvent gave a pure PGF 2α 68 mg, 73% yield. IR absorption spectra (KBr): VOH : 3350 cm -1 , VC = 0: 1708 cm -1 , NMR spectra (CDCl 3 ): 3.91 to 4.1 ppm ( 1 H 1 -OH 3H), 5.3 to 5.6 ppm (4H : C = C bond).
[실시예 2]Example 2
PGF2α대신에 PGE2를 사용해 실시예 1의 반응에 따라서 PGE2를 제조하였다.Using the PGE 2 PGF 2α in place according to the reaction of Example 1 was prepared in PGE 2.
[비교실시예 1]Comparative Example 1
실시예 1과 같은 방법으로 PGF2α혼합물을 만든 다음, 탄산나트륨으로 염 형성 실험을 해 본 결과, PGF2α및 PGF2α-모노 테트라 하이드로 퓨란, PGF2α-디 테트라 하이드로 퓨란의 일부분이 염을 형성하였다.After the PGF 2α mixture was prepared in the same manner as in Example 1, salt formation experiments were performed with sodium carbonate. As a result, a portion of PGF 2α and PGF 2α -mono tetra hydrofuran and PGF 2α -di tetrahydrofuran formed a salt.
[비교실시예 2]Comparative Example 2
실시예 1과 같은 방법으로 PGF 혼합물을 만든 다음, 수산화나트륨으로 염 형성 실험을 해 본 결과 PGF2α는 잘 염을 형성하지 않았다.The PGF mixture was prepared in the same manner as in Example 1, and then salt formation experiments were performed with sodium hydroxide, and PGF 2α did not form salts well.
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