JPS645590B2 - - Google Patents
Info
- Publication number
- JPS645590B2 JPS645590B2 JP56144027A JP14402781A JPS645590B2 JP S645590 B2 JPS645590 B2 JP S645590B2 JP 56144027 A JP56144027 A JP 56144027A JP 14402781 A JP14402781 A JP 14402781A JP S645590 B2 JPS645590 B2 JP S645590B2
- Authority
- JP
- Japan
- Prior art keywords
- derivatives
- reaction
- pantethine
- cystamine
- pantothenic acid
- 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
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 claims description 13
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 claims description 13
- 229960000903 pantethine Drugs 0.000 claims description 13
- 235000008975 pantethine Nutrition 0.000 claims description 13
- 239000011581 pantethine Substances 0.000 claims description 13
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 9
- 235000019161 pantothenic acid Nutrition 0.000 claims description 9
- 239000011713 pantothenic acid Substances 0.000 claims description 9
- 229940055726 pantothenic acid Drugs 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 claims description 8
- 229940099500 cystamine Drugs 0.000 claims description 8
- 150000001718 carbodiimides Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- KXZSVYHFYHTNBI-UHFFFAOYSA-N 1h-quinoline-2-thione Chemical class C1=CC=CC2=NC(S)=CC=C21 KXZSVYHFYHTNBI-UHFFFAOYSA-N 0.000 claims description 3
- 150000004780 naphthols Chemical class 0.000 claims description 3
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical class SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 claims description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 3
- SEXOVMIIVBKGGM-UHFFFAOYSA-N naphthalene-1-thiol Chemical class C1=CC=C2C(S)=CC=CC2=C1 SEXOVMIIVBKGGM-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
- 238000006297 dehydration reaction Methods 0.000 description 6
- -1 dichloro-1-mercaptonaphthalene Chemical compound 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 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 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- GJCFRTZSTYVSCR-UHFFFAOYSA-N pentachloro(phenyl)-$l^{6}-sulfane Chemical compound ClS(Cl)(Cl)(Cl)(Cl)C1=CC=CC=C1 GJCFRTZSTYVSCR-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- MHTSJSRDFXZFHQ-UHFFFAOYSA-N quinoline-8-thiol Chemical compound C1=CN=C2C(S)=CC=CC2=C1 MHTSJSRDFXZFHQ-UHFFFAOYSA-N 0.000 description 2
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- WDDPYMZSEILGTQ-UHFFFAOYSA-N 2,3-dichloronaphthalen-1-ol Chemical compound C1=CC=C2C(O)=C(Cl)C(Cl)=CC2=C1 WDDPYMZSEILGTQ-UHFFFAOYSA-N 0.000 description 1
- OOXQIHPXUMNXJZ-UHFFFAOYSA-N 2,4,6-trichlorobenzenethiol Chemical compound SC1=C(Cl)C=C(Cl)C=C1Cl OOXQIHPXUMNXJZ-UHFFFAOYSA-N 0.000 description 1
- MHKRINONGZJSSL-UHFFFAOYSA-N 2,4-dinitrobenzenethiol Chemical compound [O-][N+](=O)C1=CC=C(S)C([N+]([O-])=O)=C1 MHKRINONGZJSSL-UHFFFAOYSA-N 0.000 description 1
- NULDEVQACXJZLL-UHFFFAOYSA-N 2-(2-aminoethyldisulfanyl)ethylazanium;chloride Chemical compound Cl.NCCSSCCN NULDEVQACXJZLL-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004806 hydroxypyridines Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- YBBJKCMMCRQZMA-UHFFFAOYSA-N pyrithione Chemical compound ON1C=CC=CC1=S YBBJKCMMCRQZMA-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- FNXKBSAUKFCXIK-UHFFFAOYSA-M sodium;hydrogen carbonate;8-hydroxy-7-iodoquinoline-5-sulfonic acid Chemical class [Na+].OC([O-])=O.C1=CN=C2C(O)=C(I)C=C(S(O)(=O)=O)C2=C1 FNXKBSAUKFCXIK-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 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
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、カルボジイミドの存在下で、パント
テン酸またはその塩類とシスタミンあるいはその
塩類とを脱水縮合させるパンテチンの製造方法に
関するものである。
本発明により製造されるパンテチンは生体内に
おけるエネルギー代謝に関与する重要な補酵素コ
エンザイムＡの前駆物質として有用な化合物であ
る。
パンテチンの製造方法は古くからいくつかの方
法が知られているが、パントテン酸またはその塩
とシスタミンまたはその塩とを脱水縮合剤の存在
下で直接反応せしめる直接法が、精製された原料
が工業的に得やすく、かつ製造工程が単一工程
で、しかも収率が比較的高い点で、最も優れた方
法ということができる。そして、この直接法を工
業的に有利に実施するための重要なポイントはこ
の反応に使用する脱水縮合剤等の選択である。
直接法に使用する脱水縮合剤等についてもすで
に各種の化合物が提案されている。これら公知の
脱水縮合剤等にはそれぞれ一長一短があるが、工
業的に安価に得やすく、取扱いが容易で、かつ反
応に際してクロル化等の副反応を起さない点で、
カルボジイミド（特公昭41−2896）が最も優れて
いる。しかし、脱水縮合剤としてカルボジイミド
のみを使用する場合は反応が遅く、完結度が低
い。この欠点を改善する目的で以下に例記するよ
うな反応促進剤（通常のペプチド合成においてよ
く用いられるもの。）の添加が提案され効果を挙
げている。すなわち、Ｎ−ヒドロキシ化合物（特
開昭52−144618）、置換フエノール類、ヒドロキ
シピリジン類、ヒドロキシキノリン類（特開昭53
−25520）等の反応促進剤を用いる方法である。
本発明者らは、カルボジイミドを脱水縮合剤と
する直接法において、さらに反応を効率的に遂行
させるべく鋭意研究の結果、前記の如き公知の反
応促進剤に比べて、工業的に入手しやすく、取扱
いが容易で、かつその性能において優れる特定の
反応促進剤を見い出し、本発明を完成するに到つ
た。
すなわち、本発明は、カルボジイミドの存在下
で、パントテン酸またはその塩類とシスタミンま
たはその塩類とを縮合反応せしめてパンテチンを
製造するに際して、この反応系に反応促進剤とし
てメルカプトベンゼン誘導体、メルカプトナフタ
レン誘導体、メルカプトピリジン誘導体、メルカ
プトキノリン誘導体もしくはナフトール誘導体の
うちの１種または２種以上の化合物を添加するこ
とによりパンテチンの製造を極めて効率的に行う
方法である。
本発明において使用される反応促進剤として
は、例えばペンタクロルメルカプトベンゼン、
２，４，６−トリクロル−１−メルカプトベンゼ
ンあるいは２，４−ジニトロ−１−メルカプトベ
ンゼンの如きメルカプトベンゼン誘導体、２，４
−ジクロル−１−メルカプトナフタレンの如きメ
ルカプトナフタレン誘導体、２−メルカプトピリ
ジン−Ｎ−オキサイドの如きメルカプトピリジン
誘導体、８−メルカプトキノリンの如きメルカプ
トキノリン誘導体、さらには２，４−ジニトロナ
フトールあるいは２，４−ジクロルナフトールの
如きナフトール誘導体を挙げることができる。こ
れらの化合物は医薬、農薬、染料その他の有機合
成薬品の原料または中間体としたよく知られ、工
業的規模で製造されているものが多いため、安価
に入手できるという利点があるとともに、毒性や
腐蝕性が少なく、性状からみて取扱いも容易であ
り、しかもそのペプチド合成における性能はきわ
めて優れているという点で画期的なものである。
本発明における反応促進剤の使用量は少量の添加
で有効であり、通常パントテン酸に対して10〜30
重量％で十分な効果が得られる。50％以上使用し
ても効果は変らない。
本発明方法は溶媒の存在下で実施されるが、こ
の反応に用いられる溶媒は公知の特公昭41−2896
号に記載されているピリジン、ジメチルホルムア
ミド、ジオキサン、テトラヒドロフラン、アセト
ニトリル、低級アルコール、水あるいはこれらの
混合物がそのまま使用できるが、反応を常に均一
系で実施するために、単一溶媒を用いるより反応
剤に応じて２以上の溶媒の適切な混合物を用いる
ことが望ましい。
反応温度は通常室温またはそれ以下が望まし
く、反応時間は数時間から数十時間、通常20〜30
時間が適当である。
原料のパントテン酸あるいはシスタミンはでき
るだけ遊離の形で用いることが反応を円滑に進め
る上で望ましいが、塩の形で用いることも可能で
あり、例えばパントテン酸はアルカリ金属塩、ア
ルカリ土類金属塩等が用いられるが、工業的な利
点からカルシウム塩が最適であり、シスタミンは
塩酸塩もしくは硫酸塩等が用いられる。
カルボジイミドの例としては、ペプチド合成等
で通常に用いられるジシクロヘキシルカルボジイ
ミドが最も好適であり、その使用量も公知の方法
どおり、原料パントテン酸に対して当量ないしは
若干過剰量を用いればよい。
本発明方法にしたがつて得られる反応物からパ
ンテチンを単離する方法についても、公知の方法
をそのまま採用すればよい。すなわち反応終了液
に水を加えて析出物を過し、液から溶媒を留
去したのち、更に折出結晶を過によつて除く。
次いで酢酸エチル等の溶剤で洗浄後、イオン交換
樹脂精製を行い、その処理液を減圧下に濃縮乾固
すれば高純度のパンテチンを得ることができる。
以下に本発明を実施例により更に詳しく説明す
る。
実施例 １
パントテン酸21.9ｇ、シスタミン7.30ｇ、ペン
タクロロメルカプトベンゼン5.5ｇを含水ピリジ
ン200ｇに溶解し、ジシクロロヘキシルカルボジ
イミド22.7ｇを氷冷下に加え、氷冷下２時間、つ
いで室温で24時間撹拌した。次に水250ｇを加え
析出したジシクロヘキシル尿素の結晶を別し
た。液中のピリジンを水との共沸により留去
し、更に折出したジシクロヘキシル尿素等の結晶
を別し、酢酸エチル100ｇで２回洗浄した。水
層に含まれる酢酸エチルを減圧にて除き、必要な
らば活性炭処理により脱色する。得られた液を強
酸性イオン交換樹脂 アンバーライトIR−120B
H+型50ml、強塩基性イオン交換樹脂 アンバー
ライトIRA−410 OH-型50mlの混床に通し脱塩
した。
次に処理液を減圧下に濃縮乾固して、パンテチ
ン22.7ｇ（シスタミンよりの理論収率85.3％）を
得た。本品は別途合成したパンテチン標品とIR、
TLCのRf値が一致した。
実施例 ２〜５
実施例１におけるペンタクロロメルカプトベン
ゼンのかわりに、２−メルカプトピリジン−Ｎ−
オキサイド2.5ｇ、２，４−ジクロル−１−メル
カプトナフタレン4.6ｇ、８−メルカプトキノリ
ン3.2ｇおよび２，４−ジニトロ−１−ナフトー
ル4.7ｇを用いたそれぞれの結果を第１表に示す。
The present invention relates to a method for producing pantethine, which comprises dehydrating and condensing pantothenic acid or a salt thereof and cystamine or a salt thereof in the presence of a carbodiimide. Pantethine produced according to the present invention is a compound useful as a precursor of coenzyme A, an important coenzyme involved in energy metabolism in vivo. Several methods for producing pantethine have been known for a long time, but the direct method, in which pantothenic acid or its salt and cystamine or its salt are directly reacted in the presence of a dehydration condensation agent, is the first method to produce pantethine. It can be said to be the most excellent method because it is easy to obtain, requires a single production process, and has a relatively high yield. An important point for industrially advantageous implementation of this direct method is the selection of the dehydration condensation agent used in this reaction. Various compounds have already been proposed as dehydration condensation agents used in the direct method. These known dehydration condensation agents have their own merits and demerits, but they are industrially easy to obtain at low cost, easy to handle, and do not cause side reactions such as chlorination during the reaction.
Carbodiimide (Special Publication No. 41-2896) is the best. However, when only carbodiimide is used as a dehydration condensation agent, the reaction is slow and the degree of completion is low. In order to improve this drawback, the addition of a reaction accelerator (commonly used in ordinary peptide synthesis) as exemplified below has been proposed and has been effective. Namely, N-hydroxy compounds (Japanese Unexamined Patent Publication No. 52-144618), substituted phenols, hydroxypyridines, hydroxyquinolines (Japanese Unexamined Patent Publication No. 1983-144618),
This method uses a reaction accelerator such as -25520). The present inventors have conducted extensive research in order to carry out the reaction more efficiently in a direct method using carbodiimide as a dehydration condensation agent, and have found that it is easier to obtain industrially than the known reaction accelerators mentioned above. We have discovered a specific reaction accelerator that is easy to handle and has excellent performance, and have completed the present invention. That is, the present invention provides a method for producing pantethine by condensing pantothenic acid or its salts with cystamine or its salts in the presence of a carbodiimide, and adding a mercaptobenzene derivative, a mercaptonaphthalene derivative, This method is an extremely efficient method for producing pantethine by adding one or more compounds selected from mercaptopyridine derivatives, mercaptoquinoline derivatives, and naphthol derivatives. Examples of the reaction accelerator used in the present invention include pentachloromercaptobenzene,
Mercaptobenzene derivatives such as 2,4,6-trichloro-1-mercaptobenzene or 2,4-dinitro-1-mercaptobenzene, 2,4
-mercaptonaphthalene derivatives such as dichloro-1-mercaptonaphthalene, mercaptopyridine derivatives such as 2-mercaptopyridine-N-oxide, mercaptoquinoline derivatives such as 8-mercaptoquinoline, and also 2,4-dinitronaphthol or 2,4- Mention may be made of naphthol derivatives such as dichlornaphthol. These compounds are well-known as raw materials or intermediates for pharmaceuticals, pesticides, dyes, and other organic synthetic drugs, and many of them are manufactured on an industrial scale, so they have the advantage of being available at low cost and are free from toxicity and It is revolutionary in that it is less corrosive, easy to handle considering its properties, and has extremely excellent performance in peptide synthesis.
The amount of reaction accelerator used in the present invention is effective when added in a small amount, and is usually 10 to 30% relative to pantothenic acid.
A sufficient effect can be obtained with the weight percentage. Even if you use more than 50%, the effect will not change. The method of the present invention is carried out in the presence of a solvent, and the solvent used in this reaction is known from Japanese Patent Publication No. 41-2896.
Pyridine, dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, lower alcohols, water, or mixtures thereof listed in the above issue can be used as they are, but in order to always carry out the reaction in a homogeneous system, the reactants should be used rather than using a single solvent. It is desirable to use a suitable mixture of two or more solvents depending on the situation. The reaction temperature is usually room temperature or lower, and the reaction time is several hours to several tens of hours, usually 20 to 30 hours.
The time is appropriate. Although it is desirable to use the raw material pantothenic acid or cystamine in as free a form as possible in order to proceed with the reaction smoothly, it is also possible to use it in the form of a salt; for example, pantothenic acid can be used in an alkali metal salt, an alkaline earth metal salt, etc. However, calcium salt is most suitable from the industrial advantage, and cystamine is used in the form of hydrochloride or sulfate. As an example of carbodiimide, dicyclohexylcarbodiimide, which is commonly used in peptide synthesis, etc., is most suitable, and the amount used may be equivalent to or slightly in excess of the raw material pantothenic acid, as in a known method. As for the method for isolating pantethine from the reaction product obtained according to the method of the present invention, a known method may be adopted as is. That is, water is added to the reaction-completed solution to filter out the precipitate, the solvent is distilled off from the solution, and then the precipitated crystals are further removed by filtration.
After washing with a solvent such as ethyl acetate, purification is performed using an ion exchange resin, and the treated solution is concentrated to dryness under reduced pressure to obtain highly pure pantethine. The present invention will be explained in more detail below with reference to Examples. Example 1 21.9 g of pantothenic acid, 7.30 g of cystamine, and 5.5 g of pentachloromercaptobenzene were dissolved in 200 g of hydrous pyridine, and 22.7 g of dicyclohexylcarbodiimide was added under ice cooling for 2 hours and then at room temperature for 24 hours. Stirred. Next, 250 g of water was added and the precipitated dicyclohexyl urea crystals were separated. The pyridine in the liquid was distilled off by azeotropic distillation with water, and the precipitated crystals of dicyclohexyl urea were separated and washed twice with 100 g of ethyl acetate. Ethyl acetate contained in the aqueous layer is removed under reduced pressure, and if necessary, decolorized by treatment with activated carbon. The obtained liquid was used as a strong acidic ion exchange resin Amberlite IR-120B.
Desalting was carried out through a mixed bed of 50 ml of H + type and 50 ml of strongly basic ion exchange resin Amberlite IRA-410 OH - type. Next, the treated solution was concentrated to dryness under reduced pressure to obtain 22.7 g of pantethine (theoretical yield from cystamine: 85.3%). This product consists of separately synthesized pantethine preparation and IR,
The TLC Rf values matched. Examples 2 to 5 Instead of pentachloromercaptobenzene in Example 1, 2-mercaptopyridine-N-
Table 1 shows the results using 2.5 g of oxide, 4.6 g of 2,4-dichloro-1-mercaptonaphthalene, 3.2 g of 8-mercaptoquinoline and 4.7 g of 2,4-dinitro-1-naphthol.
【表】
実施例 ６
パントテン酸カルシウム23.8ｇ、シスタミン塩
酸塩10.8ｇ、２，４，６−トリクロロメルカプト
ベンゼン5.1ｇをピリジン200ｇに溶解し、ジシク
ロヘキシルカルボジイミド22.7ｇを氷冷下加え
た。以下実施例１と同様に処理（但し、イオン交
換樹脂量をそれぞれ２倍に増量した。）してパン
テチン19.9ｇ（収率74.8％）を得た。
比較例 １〜３
実施例１のペンタクロロメルカプトベンゼンに
代えて１−ヒドロキシベンツトリアゾール、Ｎ−
ヒドロキシコハク酸イミド、メルカプトベンズイ
ミダゾールを用いる以外実施例１と同様に行なつ
た。その収率及び純度をTLCで確認した結果を
第２表に示した。[Table] Example 6 23.8 g of calcium pantothenate, 10.8 g of cystamine hydrochloride, and 5.1 g of 2,4,6-trichloromercaptobenzene were dissolved in 200 g of pyridine, and 22.7 g of dicyclohexylcarbodiimide was added under ice cooling. Thereafter, the same treatment as in Example 1 was carried out (however, the amount of ion exchange resin was doubled in each case) to obtain 19.9 g of pantethine (yield: 74.8%). Comparative Examples 1 to 3 In place of pentachloromercaptobenzene in Example 1, 1-hydroxybenztriazole, N-
The same procedure as in Example 1 was carried out except that hydroxysuccinimide and mercaptobenzimidazole were used. The yield and purity were confirmed by TLC and the results are shown in Table 2.
Claims (1)
たはその塩類とシスタミンまたはその塩類とを縮
合反応せしめてパンテチンを製造するに際して、
この反応系に反応促進剤としてメルカプトベンゼ
ン誘導体、メルカプトナフタレン誘導体、メルカ
プトピリジン誘導体、メルカプトキノリン誘導体
もしくはナフトール誘導体のうちの１種または２
種以上の化合物を添加することを特徴とするパン
テチンの製造方法。1. When producing pantethine by condensing pantothenic acid or its salts with cystamine or its salts in the presence of carbodiimide,
In this reaction system, one or two of mercaptobenzene derivatives, mercaptonaphthalene derivatives, mercaptopyridine derivatives, mercaptoquinoline derivatives, or naphthol derivatives are used as a reaction accelerator.
A method for producing pantethine, which comprises adding more than one compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56144027A JPS5846062A (en) | 1981-09-14 | 1981-09-14 | Preparation of pentethine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56144027A JPS5846062A (en) | 1981-09-14 | 1981-09-14 | Preparation of pentethine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5846062A JPS5846062A (en) | 1983-03-17 |
| JPS645590B2 true JPS645590B2 (en) | 1989-01-31 |
Family
ID=15352615
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56144027A Granted JPS5846062A (en) | 1981-09-14 | 1981-09-14 | Preparation of pentethine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5846062A (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51113821A (en) * | 1975-02-27 | 1976-10-07 | Sogo Yatsukou Kk | Preparation of pantethine |
| JPS5695162A (en) * | 1979-12-28 | 1981-08-01 | Nisshin Flour Milling Co Ltd | Novel synthesis of pantethine |
-
1981
- 1981-09-14 JP JP56144027A patent/JPS5846062A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5846062A (en) | 1983-03-17 |
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