JP2005306782A - New method for synthesizing l-carnosine - Google Patents
New method for synthesizing l-carnosine Download PDFInfo
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- JP2005306782A JP2005306782A JP2004126272A JP2004126272A JP2005306782A JP 2005306782 A JP2005306782 A JP 2005306782A JP 2004126272 A JP2004126272 A JP 2004126272A JP 2004126272 A JP2004126272 A JP 2004126272A JP 2005306782 A JP2005306782 A JP 2005306782A
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 229940044199 carnosine Drugs 0.000 title claims 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 60
- 229960002885 histidine Drugs 0.000 claims abstract description 31
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 21
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 claims abstract description 21
- 108010087806 Carnosine Proteins 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- GLABFZPEHHFGDW-UHFFFAOYSA-N 3-aminopropanoyl chloride Chemical compound NCCC(Cl)=O GLABFZPEHHFGDW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 238000005917 acylation reaction Methods 0.000 claims abstract description 10
- 230000010933 acylation Effects 0.000 claims abstract description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 1
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 229940000635 beta-alanine Drugs 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 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 5
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- 239000000203 mixture Substances 0.000 description 5
- -1 that is Chemical compound 0.000 description 5
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- IUQJDHJVPLLKFL-UHFFFAOYSA-N 2-(2,4-dichlorophenoxy)acetate;dimethylazanium Chemical compound CNC.OC(=O)COC1=CC=C(Cl)C=C1Cl IUQJDHJVPLLKFL-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- NKSXAFUVSSNREK-ZSCHJXSPSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.OC(=O)[C@@H](N)CC1=CN=CN1 NKSXAFUVSSNREK-ZSCHJXSPSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KZLYQYPURWXOEW-UHFFFAOYSA-N 2-iodopropanoic acid Chemical compound CC(I)C(O)=O KZLYQYPURWXOEW-UHFFFAOYSA-N 0.000 description 1
- WBLZUCOIBUDNBV-UHFFFAOYSA-N 3-nitropropanoic acid Chemical group OC(=O)CC[N+]([O-])=O WBLZUCOIBUDNBV-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- WQVFQXXBNHHPLX-ZKWXMUAHSA-N Ala-Ala-His Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O WQVFQXXBNHHPLX-ZKWXMUAHSA-N 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PXLFVPUOFWMZAR-UHFFFAOYSA-N acetic acid cyanic acid Chemical compound OC#N.CC(O)=O PXLFVPUOFWMZAR-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003571 thiolactams Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、Ｌ−カルノシン、すなわちβ−アラニル−Ｌ−ヒスチジンの新規合成法に関する。 The present invention relates to a novel synthesis method of L-carnosine, that is, β-alanyl-L-histidine.
Ｌ−カルノシンイは筋肉中に発見される天然ジペプチドであって、筋ＡＴＰアーゼの活性化作用、抗酸化作用を有し、またその亜鉛との錯体は抗潰瘍剤として市販されている。最近では健康食品サプリメントとして欧米において広まっている。 L-carnosine is a natural dipeptide found in muscles, and has an activation and antioxidant effect on muscle ATPase, and its complex with zinc is commercially available as an anti-ulcer agent. Recently, it has spread in Europe and America as a health food supplement.
一般にジペプチドの合成法は、アミノ基を保護したＮ末端アミノ酸の反応性誘導体、例えば酸クロライドでＣ末端アミノ酸のアミノ基をアシル化し、アミノ基を脱保護することよりなる。これまで報告されているＬ−カルノシンの合成法の大部分はこの方法に従っており、β−アラニンの保護基としてフタルイミド、ベンシルオキシカルボニルなどが、また反応性誘導体として酸クロライドのほか、酸アジド、スクシンイミジル、エトキシカルボニルなどが用いられている。β−アラニンはキラル炭素原子を持たないため、β−ニトロもしくはヨードプロピオン酸の反応性誘導体でＬ−ヒスチジンをアシル化し、還元またはアンモニアとの反応によってＬ−カルノシンとする方法が報告されている。またβ−アラニンのラクタムまたはチオラクタムをＬ−ヒスチジンのアシル化剤とする方法も報告されている。最近Ｌ−ヒスチジンをシアン酢酸エステルでアシル化し、生成するＮ−シアノアセチル−Ｌ−ヒスチジンを接触還元してＬ−カルノシンを合成する方法が開示された。さらにＬ−ヒスチジンを遊離塩基の状態でアシル化すると副生成物が多く生成し、Ｌ−カルノシンの収率が低くなるため、メチルエステルなどのエステルとし、アシル化後Ｌ−カルノシンエステルを加水分解する方法も報告されている。 In general, a method for synthesizing a dipeptide comprises acylating the amino group of the C-terminal amino acid with a reactive derivative of the amino terminal-protected N-terminal amino acid, for example, acid chloride, and deprotecting the amino group. Most of the methods for synthesizing L-carnosine reported so far follow this method, and phthalimide, benzyloxycarbonyl and the like are used as protecting groups for β-alanine, and acid chloride, acid azide, Succinimidyl, ethoxycarbonyl and the like are used. Since β-alanine does not have a chiral carbon atom, a method has been reported in which L-histidine is acylated with a reactive derivative of β-nitro or iodopropionic acid to give L-carnosine by reduction or reaction with ammonia. In addition, a method of using β-alanine lactam or thiolactam as an acylating agent for L-histidine has also been reported. Recently, a method for synthesizing L-carnosine by acylating L-histidine with cyanate acetate and catalytically reducing the resulting N-cyanoacetyl-L-histidine was disclosed. Further, when acylating L-histidine in the state of free base, a large amount of by-products are formed and the yield of L-carnosine is lowered. A method has also been reported.
従来技術のＬ−カルノシン合成方法は、β−アラニンのアミノ基の保護および脱保護、後でアミノ基へ変換し得る基を有する前駆体を使用する場合はアミノ基への変換、シアノ基の還元などの付加工程を必要とし、工程が長くかつ収率も満足ではなかった。 Prior art L-carnosine synthesis methods include the protection and deprotection of the amino group of β-alanine, conversion to an amino group if a precursor having a group that can be subsequently converted to an amino group, reduction of the cyano group Such an additional process was required, and the process was long and the yield was not satisfactory.
〔参考文献〕
Ｂａｕｍａｎｎ，Ｌ．ｅｔ ａｌ．，Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，３５，２６３（１９１８）；
Ｂａｒｇｅｒ，Ｇ．ｅｔ ａｌ．，Ｂｉｏｃｈｅｍ．，１２，４０２（１９１８）；
Ｌｏｓｓｅ，Ｇ．ｅｔ ａｌ．，Ｂｅｒ．，９４，２７６８（１９６１）；
Ｔｕｒｎｅｒ，Ｒ．Ａ．，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７５，２３８８（１９５３）；
Ｓｈｆｆｅｒｄ，Ｒ．Ｈ．ｅｔ ａｌ．，Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，１０８，７３３（１９３５）；
Ｋｒｏｌｌ，Ｈ．ｅｔ ａｌ．，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７５，２５１１（１９５３）；
Ｒｉｎｄｅｒ Ｋｎｅｃｈｔ，Ｈ．ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．２９，１９６８（１９６４）；
ＲＵ２０３０４２２；
Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，２９，５８５９−５８６２（１９８８）；
Ｊ．Ｏｒｇ．Ｃｈｅｍ．，４８，３９２−３９３（１９８３）；
ＷＯ２００１／０６４６３８（特表２００４−５０９８３４）．
[References]
Baumann, L.M. et al. , J .; Biol. Chem. , 35, 263 (1918);
Barger, G .; et al. Biochem. , 12, 402 (1918);
Losse, G.M. et al. Ber. , 94, 2768 (1961);
Turner, R.A. A. , J .; Am. Chem. Soc. , 75, 2388 (1953);
Shferd, R.A. H. et al. , J .; Biol. Chem. , 108, 733 (1935);
Kroll, H .; et al. , J .; Am. Chem. Soc. 75, 2511 (1953);
Rinder Knecht, H.C. et al. , J .; Org. Chem. 29, 1968 (1964);
RU2030222;
Tetrahedron Lett. , 29, 5859-5862 (1988);
J. et al. Org. Chem. 48, 392-393 (1983);
WO2001 / 064638 (Special table 2004-509834).
本発明者らは、無保護でβ−アラニンの酸クロライドとＬ−ヒスチジンを反応させてＬ−カルノシンを合成する方法を考え、アシル化試薬としてβ−アラニンクロライドの酸塩を使用することによってこれが可能であることを発見した。無保護のβ−アラニンを酸クロライドの形に活性化すると、アミノ基の求核性による分子間での自己縮合が考えられるが、求核性を抑制するため無保護のβ−アラニンクロライドを酸塩の形でアミノ基を４級化することにより副反応を抑えることができた。 The present inventors conceived a method of synthesizing L-carnosine by reacting an acid chloride of β-alanine and L-histidine without protection, and this was achieved by using an acid salt of β-alanine chloride as an acylating reagent. I found it possible. When unprotected β-alanine is activated in the form of acid chloride, self-condensation between molecules due to nucleophilicity of the amino group can be considered, but in order to suppress nucleophilicity, unprotected β-alanine chloride is converted into acid chloride. Side reactions could be suppressed by quaternizing the amino group in the form of a salt.
そこで本発明は、Ｌ−ヒスチジンのアシル化によるＬ−カルノシンの合成法において、アシル化試薬として無保護のβ−アラニンクロライド酸塩を使用することを特徴とするＬ−カルノシンの合成方法を提供する。 Accordingly, the present invention provides a method for synthesizing L-carnosine, which comprises using unprotected β-alanine chloride as an acylating reagent in a method for synthesizing L-carnosine by acylation of L-histidine. .
好ましい具体例では、Ｌ−ヒスチジンも酸塩の形でアシル化反応に使用される。これにより副生成物の生成およびラセミ化を抑制することができる。代りにＬ−ヒスチジンの溶液へ酸を加えてもよい。 In a preferred embodiment, L-histidine is also used in the acylation reaction in the form of an acid salt. Thereby, the production | generation and racemization of a by-product can be suppressed. Alternatively, acid may be added to the L-histidine solution.
塩を形成する酸は、塩酸、酢酸、メタンスルホン酸、トリフロロ酢酸、ｐ−トルエンスルホン酸などであるが、特に塩酸およびｐ−トルエンスルホン酸が好ましい。アシル化反応は、Ｌ−ヒスチジンの溶液へ粉末または固体の前記アシル化試薬を攪拌下に添加し、Ｌ−ヒスチジンの大部分が消費されるまで攪拌を継続することにより行われる。この際アシル化試薬を過剰、例えば少なくとも理論の１．５倍添加し、室温以下、例えば０℃の温度で行うのが好ましい。反応終了後、例えば反応液を水で希釈し、イオン交換樹脂処理によって不純分を除去した後、メタノール、エタノールのようなアルコールまたは含水アルコールを加えて結晶化することによって化学的および光学的純度の高いＬ−カルノシンを高収率で得ることができる。 The acid that forms the salt is hydrochloric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc., with hydrochloric acid and p-toluenesulfonic acid being particularly preferred. The acylation reaction is carried out by adding the powdered or solid acylating reagent to a solution of L-histidine under stirring and continuing stirring until most of the L-histidine is consumed. In this case, it is preferable to add an acylating reagent in excess, for example, at least 1.5 times the theory, and to carry out the reaction at a temperature below room temperature, for example, 0 ° C. After completion of the reaction, for example, the reaction solution is diluted with water, impurities are removed by ion-exchange resin treatment, and then an alcohol such as methanol or ethanol or a water-containing alcohol is added to crystallize to thereby improve the chemical and optical purity. High L-carnosine can be obtained in high yield.
ここに記載した本発明によれば、アミノ基の保護および脱保護、その他の付加工程なしで、β−アラニンとＬ−ヒスチジンとから高い純度のＬ−カルノシンを短かい工程で高収率で合成することが可能になる。 According to the present invention described here, high-purity L-carnosine is synthesized in high yield from β-alanine and L-histidine in a short process without the protection and deprotection of amino groups and other addition steps. It becomes possible to do.
本発明は、無保護β−アラニンクロライド（３−アミノプロピオン酸クロライド）の酸付加塩をＬ−ヒスチジンのアシル化試薬として使用する。このアシル化試薬はあらかじめ生成したβ−アラニンの酸付加塩に塩化チオニルを反応させて製造することができる。アシル化反応は、Ｌ−ヒスチジンの溶液に固体もしくは粉末状の前記アシル化試薬を添加し、攪拌することによって行われる。この際できるだけ多くのＬ−ヒスチジンがアシル化されるように、アシル化試薬を少なくとも１．５倍、特に２．０倍過剰に添加するのが好ましい。 In the present invention, an acid addition salt of unprotected β-alanine chloride (3-aminopropionic acid chloride) is used as an acylating reagent for L-histidine. This acylating reagent can be produced by reacting an acid addition salt of β-alanine produced in advance with thionyl chloride. The acylation reaction is performed by adding the solid or powdery acylating reagent to a solution of L-histidine and stirring. At this time, it is preferable to add the acylating reagent at least 1.5 times, particularly 2.0 times in excess so that as much L-histidine as possible is acylated.
Ｌ−ヒスチジンもやはり酸塩の形で反応させることが好ましく、これにより副生成物の量を減らすことができる。代って酸をＬ−ヒスチジンの溶液に加えても良い。 L-histidine is also preferably reacted in the form of an acid salt, whereby the amount of by-products can be reduced. Alternatively, an acid may be added to the L-histidine solution.
好ましい反応溶媒は、水、酢酸、ジメチルホルムアミド、ジメチルアセタミド、Ｎ−メチル−２−ピロリドンなどであるが、Ｌ−ヒスチジンの酸塩の代りにこれら溶媒に酸を加えても良い。例えば１Ｎ塩酸、リン酸緩衝液（ｐＨ２．８）、トリフルオロ酢酸／ジメチルホルムアミド混液、メタンスルホン酸／ジメチルホルムアミド混液、メタンスルホン酸／ジメチルアセタミド混液、メタンスルホン酸／Ｎ−メチル−２−ピロリドン混液等である。 Preferred reaction solvents are water, acetic acid, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and the like, but an acid may be added to these solvents instead of the acid salt of L-histidine. For example, 1N hydrochloric acid, phosphate buffer (pH 2.8), trifluoroacetic acid / dimethylformamide mixed solution, methanesulfonic acid / dimethylformamide mixed solution, methanesulfonic acid / dimethylacetamide mixed solution, methanesulfonic acid / N-methyl-2- Pyrrolidone mixed solution.
酸クロライドとアミンとの反応には生成する塩化水素を結合する塩基を使用するのが一般的であるが、本発明のアシル化反応では酸結合塩基の使用を省くことができる。もし使用するならば、３級アミン、例えばトリエチルアミン、Ｎ−メチルモルホリン、Ｎ，Ｎ−ジメチルアニリンを使用することができる。 In the reaction between an acid chloride and an amine, a base that binds the generated hydrogen chloride is generally used, but in the acylation reaction of the present invention, the use of an acid-bonded base can be omitted. If used, tertiary amines such as triethylamine, N-methylmorpholine, N, N-dimethylaniline can be used.
β−アラニンクロライドまたはＬ−ヒスチジンと塩を形成する酸には多数の無機および有機酸が含まれるが、実用上塩酸、酢酸、メタンスルホン酸、トリフルオロ酢酸、およびｐ−トルエンスルホン酸が好ましい。塩酸塩およびｐ−トルエンスルホン酸が最も好ましい。アシル化試薬およびＬ−ヒスチジンと塩を形成する酸と溶媒の最も好ましい組合わせは、β−アラニンクロラドのｐ−トルエンスルホン酸塩とＬ−ヒスチジンのｐ−トルエンスルホン酸塩をジメチルアセトアミドに溶解にして縮合させる方法である。無保護の反応では生成物の一部がラセミ化し、光学純度が低下する傾向があり、またはβ−アラニル−アラニル−ヒスチジンが主であるトリペプチド副生成物を生成する傾向があるが、上の組合わせによりラセミ化および副生成物の生成を最小に抑えるこができる。 The acid that forms salts with β-alanine chloride or L-histidine includes a number of inorganic and organic acids, but in practice, hydrochloric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid are preferred. Most preferred are hydrochloride and p-toluenesulfonic acid. The most preferred combination of acid and solvent that forms a salt with the acylating reagent and L-histidine is the dissolution of β-alanine chlorad p-toluenesulfonate and L-histidine p-toluenesulfonate in dimethylacetamide. This is a method of condensing. Unprotected reactions tend to racemize part of the product and reduce optical purity, or to produce tripeptide by-products that are predominantly β-alanyl-alanyl-histidine. The combination can minimize racemization and by-product formation.
好ましい反応温度は室温以下、最も好ましくは−１０℃〜０℃である。反応を不活性ガス、例えばアルゴン雰囲気中で実施することも好ましい。反応時間はＬ−ヒスチジンの少なくとも大部分、例えば９０％以上が反応に消費される時間である。これには例えば反応温度０℃附近の場合、少なくとも６時間を要するであろう。 The preferred reaction temperature is room temperature or lower, most preferably -10 ° C to 0 ° C. It is also preferred to carry out the reaction in an inert gas such as an argon atmosphere. The reaction time is a time during which at least a major part of L-histidine, for example, 90% or more is consumed in the reaction. This would take at least 6 hours, for example, near a reaction temperature of 0 ° C.
反応終了後、常法に従って反応液からＬ−カルノシンを回収することができる。例えば反応液を水で希釈し、強酸性イオン交換樹脂に吸着後、アンモニア水で溶出させ、溶出液を濃縮して弱酸性イオン交換樹脂に通液し、濃縮後エタノールを加えてＬ−カルノシンを結晶化する。 After completion of the reaction, L-carnosine can be recovered from the reaction solution according to a conventional method. For example, the reaction solution is diluted with water, adsorbed on a strongly acidic ion exchange resin, and then eluted with ammonia water. The eluate is concentrated and passed through a weakly acidic ion exchange resin. After concentration, ethanol is added to add L-carnosine. Crystallize.
以下実施例によって本発明を例証する。実施例中に使用した略号の意味は次のとおりである。
β−Ａｌａ：β−アラニン
β−ＡｌａＣｌ：β−アラニンクロライド
Ａｃ：アセチル
ＡｃＯＨ：酢酸
ＣＡＳ：Ｌ−カルノシン
ＤＭＡ：ジメチルアセタミド
Ｈｉｓ：Ｌ−ヒスチジン
ＭｓＯＨ：メタンスルホン酸
ＮＭＰ：Ｎ−メチル−２−ピロリドン
ｐ−ＴｓＯＨ：ｐ−トルエンスルホン酸
The following examples illustrate the invention. The meanings of the abbreviations used in the examples are as follows.
β-Ala: β-alanine β-AlaCl: β-alanine chloride Ac: acetyl AcOH: acetic acid CAS: L-carnosine DMA: dimethylacetamide His: L-histidine MsOH: methanesulfonic acid NMP: N-methyl-2- Pyrrolidone p-TsOH: p-toluenesulfonic acid
〔参考例１〕β−ＡｌａＣｌ・ＨＣｌの合成
β−Ａｌａ５０ｇ（０．５６ｍｏｌ）をトルエン４９０ｇと水２．８ｇの混液に懸濁させ、激しく攪拌しながら塩化水素ガスを８時間かけて吹き込み、β−Ａｌａ・ＨＣｌを生成させる。その後反応液に室温で塩化チオニル２４５ｍｌ（３．３７ｍｏｌ）を滴下し、１時間攪拌する。その後内温を５０℃に上げ、３８時間激しく攪拌する。反応後反応液をすばやく濾過し、得られた結晶をトルエン２００ｍｌで洗浄し、洗浄した結晶をトルエン２００ｍｌに懸濁させ、エバポレーターで濃縮し、褐色パウダー状のβ−ＡｌａＣｌ・ＨＣｌ ７３．３６ｇ（９０．８％）を得た。ＩＲ（ヌジョール）：１７９４ｃｍ-1（Ｃ＝０）
Reference Example 1 Synthesis of β-AlaCl · HCl 50 g (0.56 mol) of β-Ala was suspended in a mixture of 490 g of toluene and 2.8 g of water, and hydrogen chloride gas was blown in over 8 hours while stirring vigorously. -Generate Ala.HCl. Thereafter, 245 ml (3.37 mol) of thionyl chloride is added dropwise to the reaction solution at room temperature, followed by stirring for 1 hour. Thereafter, the internal temperature is raised to 50 ° C. and the mixture is vigorously stirred for 38 hours. After the reaction, the reaction solution was quickly filtered, and the obtained crystals were washed with 200 ml of toluene. The washed crystals were suspended in 200 ml of toluene, concentrated by an evaporator, and 73.36 g (90 of brown powdery β-AlaCl · HCl (90 8%). IR (Nujol): 1794 cm −1 (C = 0)
〔参考例２〕β−ＡｌａＣｌ・ｐ−ＴｓＯＨの合成
β−Ａｌａ５０ｇ（０．５６ｍｏｌ）を水１００ｍｌに溶かし、これにｐ−ＴｓＯＨ・Ｈ2 Ｏ １０６．８ｇ（０．５６ｍｏｌ）を加え、室温で３０分攪拌する。その後溶媒を留去し、トルエン１００ｍｌを加え、再び溶媒を留去すると定量的にβ−Ａｌａ・ｐ−ＴｓＯＨが得られる。次いでこれに室温でトルエン中チオニルクロライド２４５ｍｌ（３．３７ｍｏｌ）を滴下し、１時間攪拌する。その後温度を５０℃に上げ、３８時間激しく攪拌し、溶媒を減圧留去し、トルエンを加え、再び溶媒を留去し、パウダー状のβ−ＡｌａＣｌ・ｐ−ＴｓＯＨ １５５．９ｇ（９９．３％）を得た。ＩＲ（ヌジョール）：１７９０ｃｍ-1（Ｃ＝０）
[Reference Example 2] Synthesis of β-AlaCl · p-TsOH 50 g (0.56 mol) of β-Ala was dissolved in 100 ml of water, and 106.8 g (0.56 mol) of p-TsOH · H 2 O was added thereto at room temperature. Stir for 30 minutes. Thereafter, the solvent is distilled off, 100 ml of toluene is added, and when the solvent is distilled off again, β-Ala · p-TsOH is quantitatively obtained. Next, 245 ml (3.37 mol) of thionyl chloride in toluene is added dropwise thereto at room temperature, and the mixture is stirred for 1 hour. Thereafter, the temperature was raised to 50 ° C., and the mixture was vigorously stirred for 38 hours. The solvent was distilled off under reduced pressure, toluene was added, the solvent was distilled off again, and 155.9 g (99.3% of powdery β-AlaCl · p-TsOH) was obtained. ) IR (Nujol): 1790 cm -1 (C = 0)
〔参考例３〕Ｈｉｓ・２ｐ−ＴｓＯＨの合成
Ｈｉｓ １５５．１５ｇ（１．０ｍｏｌ）を水２５０ｍｌに溶かし、室温でｐ−ＴｓＯＨ・Ｈ2 Ｏ ３８０．４２ｇ（２．０ｍｏｌ）を加えて３０分攪拌する。その後反応液を濃縮し、トルエン２００ｍｌ×２を加えて濃縮すると、Ｈｉｓ・２ｐ−ＴｓＯＨ ４９５．２ｇ（９８．９％）が得られる。ＩＲ（ＫＢｒ）：１７３０ｃｍ-1（Ｃ＝０），１６２９ｃｍ-1（ａｒｏｍａｔｉｃ）
[Reference Example 3] Synthesis of His · 2p-TsOH 155.15 g (1.0 mol) of His was dissolved in 250 ml of water, and 380.42 g (2.0 mol) of p-TsOH · H 2 O was added at room temperature, followed by stirring for 30 minutes. To do. Thereafter, the reaction solution is concentrated, and 200 ml × 2 of toluene is added and concentrated to obtain 495.2 g (98.9%) of His · 2p-TsOH. IR (KBr): 1730 cm −1 (C = 0), 1629 cm −1 (aromatic)
〔実施例１〕β−ＡｌａＣｌ・ＨＣｌの使用
Ｈｉｓ ０．５ｇをＡｃＯＨ １０ｍｌまたは２０ｍｌに溶かし、室温でβ−ＡｌａＣｌ・ＨＣｌ ２当量を加えて３０分間攪拌する。反応液中の未反応Ｈｉｓ，生成したＣＡＳおよび副生したＡｃＨｉｓをそれぞれ定量し、出発Ｈｉｓに対する％を算出した。
[Example 1] Use of β-AlaCl · HCl 0.5 g of His is dissolved in 10 ml or 20 ml of AcOH, and 2 equivalents of β-AlaCl · HCl is added at room temperature and stirred for 30 minutes. Unreacted His, produced CAS and by-produced AcHis were quantified in the reaction solution, respectively, and the percentage relative to the starting His was calculated.
ＡｃＯＨ 反応時間 ＨＩＳ ＣＡＳ ＡｃＨｉｓ
１０ｍｌ ３０ｍｉｎ ３０．５％ ６８．０％ １．６％
２０ｍｌ ３０ｍｉｎ ３４．６％ ６４．７％ ０．７％
AcOH reaction time HIS CAS AcHis
10ml 30min 30.5% 68.0% 1.6%
20ml 30min 34.6% 64.7% 0.7%
〔実施例２〕β−ＡｌａＣｌ・ＨＣｌの使用
Ｈｉｓ ０．７８ｇを下表の溶媒に溶かして１０ｍｌとし、これにアルゴン雰囲気下、５℃でβ−ＡｌａＣｌ・ＨＣｌ ２当量を添加し、室温で４時間まで攪拌する。反応時間２時間後および４時間後、反応液の未反応Ｈｉｓ，ＣＡＳおよび副生したＡｌａ−Ａｌａ−Ｈｉｓを定量し、出発Ｈｉｓに対する％を算出した。またエタノールで析出させた粗ＣＡＳについて光学純度（％ｅｅ）を測定した。
[Example 2] Use of β-AlaCl · HCl Dissolve 0.78 g of His in a solvent shown in the following table to 10 ml, add 2 equivalents of β-AlaCl · HCl at 5 ° C under an argon atmosphere, and add 4 equivalent at room temperature. Stir until time. After 2 hours and 4 hours of reaction time, unreacted His, CAS and by-produced Ala-Ala-His in the reaction solution were quantified, and the percentage relative to the starting His was calculated. Further, the optical purity (% ee) of the crude CAS precipitated with ethanol was measured.
実験Ｎｏ． 溶媒 時間 Ｈｉｓ ＣＡＳ ％ｅｅ 副生成物
ｈ ％ ％
───── ───── ─── ───── ───── ───── ─────
１ １．０Ｍ ２ ４．１ ８０．２ ９１．２ ９．７
MsOH/DMA ４ １．４ ７９．４ ８６．６ １１．８
───────────────────────────────────────
２ ２．０Ｍ ２ ７．０ ７９．７ ８６．３ ７．７
MsOH/DMA ４ ２．２ ７９．７ ８１．６ ９．７
───────────────────────────────────────
３ ２．０Ｍ ２ １１．０ ７５．２ ９２．６ １１．３
MsOH/DMA ４ ４．２ ７８．５ ８５．８ １１．３
───────────────────────────────────────
Experiment No. Solvent Time His CAS% ee By-product
h%%
───── ───── ─── ───── ───── ───── ─────
1 1.0M 2 4.1 80.2 91.2 9.7
MsOH / DMA 4 1.4 79.4 86.6 11.8
───────────────────────────────────────
2 2.0M 2 7.0 79.7 86.3 7.7
MsOH / DMA 4 2.2 79.7 81.6 9.7
───────────────────────────────────────
3 2.0M 2 11.0 75.2 92.6 11.3
MsOH / DMA 4 4.2 78.5 85.8 11.3
───────────────────────────────────────
〔実施例３〕β−ＡｌａＣｌ・ｐＴｓＯＨおよびＨｉｓ・２ｐＴｓＯＨの使用
Ｈｉｓ・２ｐＴｓＯＨ １００ｇ（０．２ｍｏｌ）をＤＭＡ ４００ｍｌに溶解し、アルゴン雰囲気下−１０℃でβ−ＡｌａＣｌ・ｐＴｓＯＨ １１２ｇ（０．４ｍｏｌ）を１時間かけて添加し、０℃まで徐々に昇温し、攪拌する。反応終了後水を加えて残存するβ−ＡｌａＣｌを加水分解する。その後反応液を水で希釈し、強酸性イオン交換樹脂（ＳＫ−１Ｂ）に吸着後、２Ｎアンモニア水で溶出させ、溶出液を濃縮し、弱酸性イオン交換樹脂（ＷＫ−１１）に通液して濃縮し、８０％エタノールを加えて結晶化させ、乾燥してＣＡＳ２９．３ｇ（６４．７％）を得た。
化学純度９９．２％（ＵＬＴＲＯＮ ＶＸ−ＯＤＳ，Ｓｈｉｎｗａ Ｃｈｅｍｉｃａｌ Ｉｎｄｕｓｔｒｉｅｓ，Ｌｔｄ．使用），光学純度９９．３％ｅｅ（ＳＵＭＩＣＨＩＲＡＬ ＯＡ−５０００，住友化学工業（株）使用）
1 Ｈ−ＮＭＲ（Ｄ2 Ｏ，２００ＭＨｚ）：δ２．６２−２．６９（２Ｈ，ｍ，ＣＯＣＨ2 ）；２．６９（１Ｈ，ｄｄ，ＣＨ 2 ＣＨＣＯＯＨ）；２．９８（１Ｈ，ｄｄ，ＣＨ 2 ＣＨＣＯＯＨ）；３．２３（２Ｈ，ｔ，ＮＣＨ2 ）；４．４９（１Ｈ，ｄｄ，ＣＨＣＯＯＨ）；６．９６（１Ｈ，ｄ，ＮＨＣＨ）；７．７１（１Ｈ，ｄ，ＮＣＨ）
ＩＲ（ＫＢｒ）：１６４７ｃｍ-1，１５８５ｃｍ-1
Example 3 Use of β-AlaCl · pTsOH and His · 2pTsOH 100 g (0.2 mol) of His · 2pTsOH was dissolved in 400 ml of DMA and 112 g (0.4 mol) of β-AlaCl · pTsOH at −10 ° C. in an argon atmosphere. Is added over 1 hour, and the temperature is gradually raised to 0 ° C. and stirred. After completion of the reaction, water is added to hydrolyze the remaining β-AlaCl. Thereafter, the reaction solution is diluted with water, adsorbed on the strong acid ion exchange resin (SK-1B), and then eluted with 2N ammonia water. The eluate is concentrated and passed through the weak acid ion exchange resin (WK-11). The mixture was concentrated, crystallized by adding 80% ethanol, and dried to obtain 29.3 g (64.7%) of CAS.
Chemical purity 99.2% (using ULTRON VX-ODS, Shinwa Chemical Industries, Ltd.), optical purity 99.3% ee (using SUMICHIRAL OA-5000, Sumitomo Chemical Co., Ltd.)
1 H-NMR (D 2 O, 200 MHz): δ 2.62-2.69 (2H, m, COCH 2 ); 2.69 (1H, dd, C H 2 CHCOOH); 2.98 (1H, dd, C H 2 CHCOOH); 3.23 (2H, t, NCH 2 ); 4.49 (1H, dd, C H COOH); 6.96 (1H, d, NHC H ); 7.71 (1H, d) , NCH)
IR (KBr): 1647 cm −1 , 1585 cm −1
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| JP (1) | JP2005306782A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699668A (en) * | 2017-02-12 | 2017-05-24 | 江苏诚信药业有限公司 | Process system and method for preparing carnosine |
| CN111196837A (en) * | 2018-11-20 | 2020-05-26 | 皕达生物科技(上海)有限公司 | Preparation method of polaprezinc and polaprezinc preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2030422C1 (en) * | 1990-04-27 | 1995-03-10 | Фармацевтическое акционерное общество "Феррейн" | Method of synthesis of carnosine |
| WO2002000659A2 (en) * | 2000-06-23 | 2002-01-03 | Neotherapeutics, Inc. | Methods of synthesis for 9-substituted hypoxanthine derivatives |
-
2004
- 2004-04-22 JP JP2004126272A patent/JP2005306782A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2030422C1 (en) * | 1990-04-27 | 1995-03-10 | Фармацевтическое акционерное общество "Феррейн" | Method of synthesis of carnosine |
| WO2002000659A2 (en) * | 2000-06-23 | 2002-01-03 | Neotherapeutics, Inc. | Methods of synthesis for 9-substituted hypoxanthine derivatives |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699668A (en) * | 2017-02-12 | 2017-05-24 | 江苏诚信药业有限公司 | Process system and method for preparing carnosine |
| CN111196837A (en) * | 2018-11-20 | 2020-05-26 | 皕达生物科技(上海)有限公司 | Preparation method of polaprezinc and polaprezinc preparation |
| CN111196837B (en) * | 2018-11-20 | 2023-07-28 | 皕达生物科技(上海)有限公司 | Preparation method of polyprenone and polyprenone preparation |
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