KR20240019176A - 환원방식을 이용한 (s)-니코틴의 제조 방법 - Google Patents
환원방식을 이용한 (s)-니코틴의 제조 방법 Download PDFInfo
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- KR20240019176A KR20240019176A KR1020237045453A KR20237045453A KR20240019176A KR 20240019176 A KR20240019176 A KR 20240019176A KR 1020237045453 A KR1020237045453 A KR 1020237045453A KR 20237045453 A KR20237045453 A KR 20237045453A KR 20240019176 A KR20240019176 A KR 20240019176A
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- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 1
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- VCHDBLPQYJAQSQ-LOYHVIPDSA-N [(4s,5s)-5-(diphenylphosphanylmethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-diphenylphosphane Chemical compound C([C@H]1OC(O[C@@H]1CP(C=1C=CC=CC=1)C=1C=CC=CC=1)(C)C)P(C=1C=CC=CC=1)C1=CC=CC=C1 VCHDBLPQYJAQSQ-LOYHVIPDSA-N 0.000 description 1
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- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
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- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
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- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
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- 239000003638 chemical reducing agent Substances 0.000 description 1
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- 108010069495 cysteinyltyrosine Proteins 0.000 description 1
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- 108010073628 glutamyl-valyl-phenylalanine Proteins 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010090037 glycyl-alanyl-isoleucine Proteins 0.000 description 1
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- 108010010147 glycylglutamine Proteins 0.000 description 1
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- 150000007529 inorganic bases Chemical class 0.000 description 1
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 1
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- 108010030617 leucyl-phenylalanyl-valine Proteins 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 108010044348 lysyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010022588 methionyl-lysyl-proline Proteins 0.000 description 1
- 108010090114 methionyl-tyrosyl-lysine Proteins 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 108010089198 phenylalanyl-prolyl-arginine Proteins 0.000 description 1
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108700042769 prolyl-leucyl-glycine Proteins 0.000 description 1
- SGDIDUFQYHRMPR-UHFFFAOYSA-N pseudooxynicotine Chemical compound CNCCCC(=O)C1=CC=CN=C1 SGDIDUFQYHRMPR-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- AXMSEDAJMGFTLR-ZAQUEYBZSA-N trost ligand Chemical compound N([C@H]1CCCC[C@@H]1NC(=O)C=1C(=CC=CC=1)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 AXMSEDAJMGFTLR-ZAQUEYBZSA-N 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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Abstract
본 출원은 환원방식을 이용한 (S)-니코틴의 제조 방법에 관한 것이고, 상기 방법은 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 환원반응시켜 (S)-니코틴을 얻는다. 선행 기술에서 이미 개시한 (S)-니코틴을 제조하는 전략은 대부분 메틸화를 수행해야 (S)-니코틴을 얻을 수 있거나, 메틸화 없이 효소-촉매화를 사용하여서는 (S)-니코틴을 얻을 수 없다는 것을 감안하면, (S)-니코틴의 제조 전략은 여전히 매우 제한적이나, 본 발명은 메틸화 과정을 사용하지 않고 (S)-니코틴을 효율적으로 제조할 수 있는 새로운 방법을 창의적으로 개발하였으며, 즉, 상기 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 환원시키기만 하면 된다. 상기 합성방법은 작업이 간단하고, 안전하며 신뢰적이고, 수율이 높고 순도가 높다.
Description
본 출원은 유기합성 기술분야에 속하며, 구체적으로는 (S)-니코틴의 합성방법에 관한 것으로, 특히 환원방식을 이용한 (S)-니코틴의 제조 방법에 관한 것이다.
(S)-니코틴(Nicotine)은 가지과 식물(가지속(Solanum L.))에 존재하는 알칼로이드이고, 연초의 중요한 성분이기도 하다. 담배잎에는 1.5%-3.5%의 (S)-니코틴이 함유되어 있고, 담배잎에서 니코틴을 추출하는 것이 현재 니코틴을 획득하는 가장 주요한 방법인데, 화학적 합성 방법에 관한 보고가 있지만, 화학적 합성 방법은 아직 성숙하지 못하여, 추출 방법에 비해 그 비용이 훨씬 높다. 현재 이미 보고된 화학적 합성 방법은 화학적 분리법, 비대칭 수소화법, 키랄 보조제 방법 등을 포함한다.
특허 WO2014174505는 이민환원효소(Imine reductase)(케토리덕타제 효소((ketoreductase enzyme))를 사용하여 pseudooxynicotine을 촉매하는 것을 통해 니코틴을 획득하는 것을 개시하였고, 상기 특허에 사용된 이민환원효소는 Streptomyces sp. GF3546 및 Streptomyces sp. GF3587에서 각각 유래한 것이며, 또한 이들의 촉매작용은 (R)-니코틴만 제조하여 얻을 수 있고, (S)-니코틴의 제조방법에 대해서는 개시하지 않았다.
특허 US10913962B는 효소-촉매화된 미오스민(myosmine)을 사용하여 (S)-노르니코틴을 제조한 다음, (S)-노르니코틴을 메틸화하여 최종적으로 (S)-니코틴을 얻는 것을 개시하였다. 상기 발명은 생체촉매반응(biocatalysis)을 이용하여 (S)-노르니코틴을 제조함으로써 비용이 높은 문제를 해결하였고, 높은 수율의 (S)-노르니코틴을 얻을 수 있으며, 동시에 메틸화 과정에서 메틸 공급원을 제공하도록 포름알데히드가 필요하고, 포름산이 환원제로 사용되어야 한다.
선행 기술에서의 (S)-니코틴을 제조하기 위해 메틸화 과정이 필요하거나, 메틸화 없이 효소-촉매화를 사용하여서는 (S)-니코틴을 얻을 수 없는 문제를 해결하기 위해, 메틸화가 필요없이 (S)-니코틴을 제조하는 새로운 방법의 개발이 필요하다.
본 출원은 (S)-니코틴의 합성방법을 제공하며, 특히 환원방식을 이용한 (S)-니코틴의 제조 방법에 관한 것이다.
본 출원은 환원방식을 이용한 (S)-니코틴의 제조 방법을 제공하며, 상기 방법은, 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 환원반응시켜 (S)-니코틴을 얻는 단계를 포함한다:
.
선행 기술에서 이미 개시한 (S)-니코틴을 제조하는 전략은 대부분 메틸화를 수행해야 (S)-니코틴을 얻을 수 있거나, 메틸화 없이 효소 촉매화를 사용하여서는 (S)-니코틴을 얻을 수 없다는 것을 감안하면, (S)-니코틴의 제조 전략은 여전히 매우 제한적이나, 본 출원은 메틸화 과정을 사용하지 않고 (S)-니코틴을 효율적으로 제조할 수 있는 새로운 방법을 창의적으로 개발하였으며, 즉, 상기 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 환원시키기만 하면 된다. 상기 합성방법은 작업이 간단하고, 안전하며 신뢰적이고, 수율이 높고 순도가 높다.
본 출원에서, 상기 환원은 구체적으로 아래와 같이 두 가지 전략을 포함한다.
상기 환원반응은 생체효소 촉매화 방법(biocatalytic method)을 사용하고, 상기 방법은, 조효소 순환 시스템 조건에서, 이민환원효소를 촉매로 촉매화 환원반응을 수행하여, 식 I로 표시되는 에나민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 촉매 환원시켜 (S)-니코틴을 얻는 단계를 포함한다.
바람직하게는, 상기 조효소 순환 시스템은 조효소, 포도당 및 포도당 탈수소효소를 포함한다.
바람직하게는, 상기 조효소는 NADP 염 및/또는 NAD 염을 포함하며, 바람직하게는 NADP 염이다.
바람직하게는, 상기 포도당 탈수소효소는 서열번호 1로 표시되는 아미노산 서열을 포함한다.
서열번호 1:
MYKDLEGKVVVITGSSTGLGKSMAIRFATEKAKVVVNYRSKEDEANSVLEEIKKVGGEAIAVKGDVTVESDVINLVQSAIKEFGKLDVMINNAGLENPVSSHEMSLSDWNKVIDTNLTGAFLGSREAIKYFVENDIKGTVINMSSVHEKIPWPLFVHYAASKGGMKLMTETLALEYAPKGIRVNNIGPGAINTPINAEKFADPEQRADVESMIPMGYIGEPEEIAAVAAWLASSEASYVTGITLFADGGMTQYPSFQAGR.
바람직하게는, 상기 이민환원효소는 서열번호 2 내지 서열번호 6, 서열번호 8, 서열번호 11, 서열번호 12, 또는 서열번호 12와 적어도 95% 동일성을 갖는 아미노산 서열을 포함하고; 바람직하게는 서열번호 2 내지 서열번호 4, 서열번호 12, 또는 서열번호 12와 적어도 95% 동일성을 갖는 아미노산 서열이다.
서열번호 2:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGEAIAASDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARSLESWCHTRGARYLDGAILCFPDQIGTTDASIICSGASTAFSEAEPVLRLLAPPLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEVEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ.
서열번호 3:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ.
서열번호 4:
MRHLSVIGLGAMGSALATTLIKGGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQQLLDEARDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPDQIGTSDASIICSGASAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAL.
서열번호 5:
MRPISVIGLGAMGSALATTLLKAGHPVTVWNRSAAKATPLIALGAILAPSVSEAIAAGDITLICVDNYAVSQQLLDEASNAVTGKLVVQLSTGSPLGARTLESWCHARGACYLDGAILCFPDQIGTTDASIICSGANAAFREAEPVLRLLAPTLEHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLTDHAADAGIDNSFPRFAADLFEEGVEQGLGQQEVSALIKVLRARNGAAQ.
서열번호 6:
MRHLSVIGLGAMGSALATTLIKAGHPVTVWNRSAAKSAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQQLLDEASDAVAGKQLVQLSTGSPQGARALESWSHARGARYLDGAILCFPDQIGTSDASIICSGANTAFSDAEPVLRLLAPTLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVTKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ.
서열번호 7:
MGTALVEAFLAGGHATTVWNRTPGKADGVVARGAVVAETVAEAVAASPLVVVCLWDDAVVRDVLHPVADALAGRVVVNLTNGTPAQAREMAAWAAEHGVEYVDGGIMAIPPGIGTEHAFVLYSGAEAAFEAHREVLERLGAAKYLGADAGLAALFDLALLSGMYGTFAGLWHSLAMVRTENVSAAEFVPMLGPWMQAMIGGNLDRLAHQLDTGDYGHEVVSNLAMQAAAFPNIVQASLDQGIRPDLMAPIQRLMDQAVAAGHGAEDVAVVVDLLKN.
서열번호 8:
MKPTLTVIGAGRMGSALIKAFLQSGYTTTVWNRTKAKSEPLAKLGAHLADTVRDAVKRSDIIVVNVLDYDTSDQLLRQDEVTRELRGKLLVQLTSGSPALAREQETWARQHGIDYLDGAIMATPDFIGQAECALLYSGSAALFEKHRAVLNVLGGATSHVGEDVGHASALDSALLFQMWGTLFGTLQALAISRAEGIPLEKTTAFIKLTEPVTQGAVADVLTRVQQNRLTADAQTLASLEAHNVAFQHLLALCEERNIHRGVADAMYSVIREAVKAGHGKDDFAILTRFLK.
서열번호 9:
MVSSPYLNVTAYPKVRNLPWPVPGPIRVASQILELRPMTTIGFLGAGRMGSALVKSLLEAGHSVHVWNRTAEKAQALADFGAVPEPSAERAAGPAEIVIVNLLDYEASDAELRKPDVAEALKGKLLVQLTSGSPKTARETGRWAGDHGIAYLDGAIMATPNFIGGAETVILYSGSKTHFEKHEGLFKALGGKSAFVGEDFGTASALDSALLSQMWGTLFGTLQALAVCRAEGIEHDVYAGFLMSAQPMIDGAQQDLMERIRDGRDLADAQTLATVAVHNVAFHHLRDLIADRDLNPAFGDALGSLLETALRNDHQDDDFAVLARFMGAK.
서열번호 10:
MTDLGKSAVTVLGLGAMGTALAEALLAAGHPTTVWNRSPARTAGPAQRGAAVAAATAEAIAASRLIVVCLLDHTSVHAVLDGQELTGRIVVNLTSGTPGQARELDARVAERGGDHLDGAVLAVPSMIGTPDASVLYSGSRGAFDTHRPVLEVFGAADYVGADPGAASLQDAALLSAMYGQVAGVLHAFALVRSAGVTATEFLPRLVGWLTAMGGFPADAARRIDARAYADDVDAALTMQVTAVRNLVRAAREQGVSAELIAPLVPVMQRRIDDGDGGDDLAALVEVITAEEVA.
서열번호 11:
MTDKPPVTVLGLGAMGTALARTLLNAGYPTTVWNRTASKTAPLTELGAHAADSPADAIARGELVLACLLDYDSVHQTLAGTGDALRGKAFVNLTNGTPEQARALAGKLDTAYLDGGIMAVPPMIGSPGAFLFYSGEIAVFEQYRPVLESFGEAIEVGTDPGLAALHDLALLSAMYGMFGGVLQAFALTGSAGVSAASLAPLLHRWLDGMSGFIAQSAAQLDSGDFATGVVSNLAMQDTGFANLFRAAKEQGISTGQLEPLGALIRRRVEDGHGAEDLAGIVEYLKIGANA.
서열번호 12:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ.
당업자는 상기 서열번호 2 내지 서열번호 12의 아미노산 서열을 기초로 당업계의 통상적인 기술적 수단을 조합하여 서열 중 하나 이상의 아미노산을 돌연변이시키고, 추가로 이민환원효소 돌연변이체를 얻을 수 있으며, 또한, 본 출원에 관련된 기질(substrate)을 촉매화하여 (S)-니코틴을 얻을 수 있으면서 전환율과 거울상이성질체 과잉(ee 값)이 모두 실제 요구를 충족하는, 이민환원효소를 선별해낼 수 있다.
바람직하게는, 서열번호 12와 적어도 95% 동일성을 갖는 상기 아미노산 서열은 서열번호 12 서열과 비교하여, 아미노산 잔기에서 아래와 같은 차이: L73, S148 , V171 및 A172 중 어느 1종 또는 적어도 2종의 조합이 존재한다.
추가로 바람직하게는, 위치 73의 L이 Q 또는 V로 돌연변이되고, 위치 148의 S가 R로 돌연변이되며, 위치 171의 V가 Y, N, A 또는 S로 돌연변이되고, 위치 172의 A가 V 또는 F로 돌연변이된다.
추가로 바람직하게는, 서열번호 12와 적어도 95% 동일성을 갖는 상기 아미노산 서열은 서열번호 12 서열과 비교하여, 아미노산 잔기에서 아래와 같은 차이: A57, A176, Y230및 S241 중 어느 1종 또는 적어도 2종의 조합이 더 존재한다.
추가로 바람직하게는, 위치 57의 A가 R로 돌연변이되고, 위치 176의 A가 G로 돌연변이되며, 위치 230의 Y가 G, A 또는 T로 돌연변이되고, 위치 241의 S가 G 또는 A로 돌연변이된다.
예시적으로, 서열번호 12와 적어도 95% 동일성을 갖는 상기 아미노산 서열은 아래와 같을 수 있다:
서열번호 13:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQVLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAAAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 14:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLRLLAPTLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 15:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLRLLAPTLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPGASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 16:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAAVAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPTASLKTWSAAIGRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 17:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAAVAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAIGRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 18:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAAAAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAIGRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 19:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAVVAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAIGRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 20:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLRLLAPTLDHVAEAVGAAAAQDCAVAAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ;
서열번호 21:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLRLLAPTLDHVAEAVGAAAAQDCAVAAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAIARLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ; 또는
서열번호 22:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIARSDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLRLLAPTLDHVAEAVGAAAAQDCAVAAYFGGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPTASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ.
당업자는 상기 점 돌연변이의 임의의 조합에 당업계의 통상적인 기술적 수단을 결합하여 이민환원효소 돌연변이체를 얻을 수 있고, 본 출원에 관련된 기질을 촉매화하여 (S)-니코틴을 얻을 수 있으면서, 전환율이 99%이상이고, ee 값이 99%이상인 이민환원효소를 선별해낼 수 있다. 바람직하게는, 상기 촉매화 환원반응은 15-45℃에서 수행되며, 예를 들어 15℃, 20℃, 25℃, 30℃, 35℃, 40℃ 또는 45℃등이고, 상기 수치 범위 내의 기타 구체적인 포인트 값은 모두 선택될 수 있으며, 여기서 자세히 설명하지 않는다.
바람직하게는, 상기 촉매화 환원반응은 완충액(buffer solution) 시스템에서 수행되고, 상기 완충액은 인산염 완충액, 트리스히드록시메틸아민-염산염 완충액 또는 트리에탄올아민-염산염 완충액을 포함한다.
바람직하게는, 상기 촉매화 환원반응은 pH=6.0-8.0 에서 수행되며, 예를 들어 pH=6.0, pH=6.2, pH=6.5, pH=6.8, pH=7.0, pH=7.2, pH=7.5, pH=7.8 또는 pH=8.0 등이고, 상기 수치 범위 내의 기타 구체적인 포인트 값은 모두 선택될 수 있으며, 여기서 자세히 설명하지 않는다.
본 출원에서, 상기 환원반응은 키랄 금속 촉매(chiral metal catalyst)에 의한 촉매 방법을 사용하고, 상기 방법은, 수소가스 분위기에서, 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물이 키랄 금속 촉매에 의해 (S)-니코틴으로 촉매화 환원되는 단계를 포함한다.
바람직하게는, 상기 키랄 금속 촉매는 키랄 이리듐 촉매, 키랄 루테늄 촉매 또는 키랄 로듐 촉매을 포함하고, 바람직하게는 키랄 이리듐 촉매이다.
바람직하게는, 상기 촉매화 환원 시스템에 리간드를 더 첨가한다.
상기 리간드는 표 1 중 어느 1종 또는 적어도 2종의 조합으로부터 선택되고, 바람직하게는 (R,R)-f-SpiroPhos 및 (S,S)-Ph-BPE이다:
(S)-(+)-1-((R)-2-(Diphenylphosphino)ferrocenyl)ethyldi-t-butylphosphine (S)-(+)-1-((R)-2-(디페닐포스피노)페로세닐)에틸디-t-부틸포스핀 |
(S)-(+)-Neomenthyldiphenylphosphine (S)-(+)-네오멘틸디페닐포스핀, (S)-NMDPP |
(R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (R)-(+)-2,2'-비스(디페닐포스피노)-1,1'-비나프틸, (R)-(+)-BINAP |
(R,R)-(2-(4'-i-Propyloxazolin-2'-yl)ferrocenyl)diphenylphosphine (R,R)-(2-(4'-i-프로필옥사졸린-2'-일)페로세닐)디페닐포스핀 |
(R)-(-)-1-((S)-2-(Diphenylphosphino)ferrocenyl)ethyldicyclohexylphosphineethanoladduct (R)-(-)-1-((S)-2-(디페닐포스피노)페로세닐)에틸디시클로헥실포스핀에탄올, (R)-(S)-JOSIPHOS |
(R)-(-)-1-((S)-2-(Dicyclohexylphosphino)ferrocenyl)ethyldi-t-butylphosphine (R)-(-)-1-((S)-2-(디시클로헥실포스피노)페로세닐)에틸디-t-부틸포스핀, (R)-(S)-Cy2PF-P(tBu)2 |
(R)-(-)-1-((S)-2-(Diphenylphosphino)ferrocenyl)ethyldi-t-butylphosphine (R)-(-)-1-((S)-2-(디페닐포스피노)페로세닐)에틸디-t-부틸포스핀, (R)-(S)-PPF-P(tBu)2 |
(+)-1,2-Bis((2S,5S)-2,5-diphenylphospholano)ethane (+)-1,2-비스((2S,5S)-2,5-디페닐포스폴라노)에탄, (S,S)-Ph-BPE |
1,2-Bis((2S,5S)-2,5-Methylphospholano)ethane 1,2-비스((2S,5S)-2,5-메틸포스폴라노)에탄, (S, S)-Me-BPE |
(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolane (4S,5S)-2,2-디메틸-4,5-비스(디페닐포스피노메틸)-1,3-디옥솔란, (S,S)-DIOP |
(S)-(+)-(3,5-Dioxa-4-phospha-cyclohepta(2,1-a;3,4-a')dinaphthalen-4-yl)dimethylamine (S)-(+)-(3,5-디옥사-4-포스파-사이클로헵타(2,1-a;3,4-a')디나프탈렌-4-일)디메틸아민, (S)-MONOPHOS |
N,N'-(1S,2S)-1,2-Cyclohexanediylbis(2-(diphenylphosphino)benzamide) N,N'-(1S,2S)-1,2-사이클로헥산디일비스(2-(디페닐포스피노)벤즈아미드), (S,S)-DACH-Phenyl Trost Ligand |
(R)-(+)-5,5'-Bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole (R)-(+)-5,5'-비스(디페닐포스피노)-4,4'-비-1,3-벤조디옥솔, (R)-SEGPHOS |
S)-(-)-(6,6'-Dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine) (S)-(-)-(6,6'-디메톡시비페닐-2,2'-디일)비스(디페닐포스핀), (S)-MeO-BIPHEP |
(1S,2S)-(+)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (1S,2S)-(+)-N-(4-톨루엔술포닐)-1,2-디페닐에틸렌디아민, (S,S)-TsDPEN |
CAS: 1629646-88-3 (R,R)-f-SpiroPhos |
1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene 1,2-비스((2R,5R)-2,5-디에틸포스폴라노)벤젠, (R,R)-Et-Duphos |
바람직하게는, 상기 촉매화 환원반응은 50-100℃에서 수행되며, 예를 들어 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃ 또는 100℃ 등이고, 상기 수치 범위 내의 기타 구체적인 포인트 값은 모두 선택될 수 있으며, 여기서 자세히 설명하지 않는다.
바람직하게는, 상기 촉매화 환원반응 시스템에서의 수소는 1.0-6.0MPa로 유지되며, 예를 들어 1.0MPa, 2.0MPa, 3.0MPa, 4.0MPa, 5.0MPa 또는 6.0MPa 등이고, 상기 수치 범위 내의 기타 구체적인 포인트 값은 모두 선택될 수 있으며, 여기서 자세히 설명하지 않는다.
바람직하게는, 상기 촉매화 환원반응은 pH=4.0-13.0 에서 수행되며, 예를 들어 pH=4.0, 5.0, 6.0, pH=6.2, pH=6.5, pH=6.8, pH=7.0, pH=7.2, pH=7.5, pH=7.8, pH=8.0, pH=10.0, pH=12.0 또는 pH=13.0 등이고, 상기 수치 범위 내의 기타 구체적인 포인트 값은 모두 선택될 수 있으며, 여기서 자세히 설명하지 않는다.
본 출원에서, 상기 식 I로 표시되는 엔아민 화합물 또는 식 II로 표시되는 이미늄 양이온 화합물은 식 III으로 표시되는 화합물 또는 그 염이 탈염 및/또는 고리화를 거쳐 얻어진다:
.
바람직하게는, 상기 염은 염산염, 이염산염(dihydrochloride), 브롬화수소산염(hydrobromide), 이브롬화수소산염(dihydrobromide), 황산염(sulfate) 또는 중황산염(bisulfate)을 포함한다.
상기 식 III으로 표시되는 화합물 또는 그 염은 무기 염기 및/또는 유기 염기와 중화되는 조건에서 탈염 및/또는 고리화 반응이 발생되어, 식 I로 표시되는 에나민 화합물 또는 식 II로 표시되는 이미늄 양이온 화합물을 얻는다.
본 출원에서, 식 III으로 표시되는 화합물의 염의 합성방법은 아래와 같은 단계를 포함한다:
화합물 A를 N-메틸피롤리돈 및 유기 염기와 혼합하여 반응시켜 화합물 D를 얻고; 화합물 D를 산과 혼합하여 반응시켜 식 III으로 표시되는 화합물의 염을 얻으며; 그 반응식은 아래와 같다:
.
또는, 식 III으로 표시되는 화합물의 염의 합성방법은 아래와 같은 단계를 포함한다:
화합물 A를 N-메틸피롤리돈 및 유기 염기와 혼합하여 반응시킨 후, 산을 첨가하여 pH=7-8로 중화시켜 화합물 B를 얻고; 화합물 B를 산과 혼합하고 반응시켜 식 III으로 표시되는 화합물의 염을 얻으며, 그 반응식은 아래와 같다:
.
본 출원에서, 상기 화합물 A의 합성방법은, 니코틴산과 메탄올을 혼합하고, 강산성 환경에서 에스테르화 반응을 수행하여 얻는 단계를 포함한다.
본 출원의 바람직한 기술방안으로서, (S)-니코틴을 제조하는 상기 방법은 아래와 같은 단계를 포함한다:
니코틴산과 메탄올을 혼합하고, 강산성 환경에서 에스테르화 반응을 수행하여 화합물 A를 얻고; 화합물 A를 N-메틸피롤리돈 및 유기 염기와 혼합하고 반응시킨 후, 선택적으로 산을 첨가하여 중화시켜 화합물 B 또는 D를 얻으며; 그 후 다시 산과 혼합하여 반응시켜 식 III으로 표시되는 화합물의 염을 얻고; 탈염 및 고리화가 일어나며, 최종적으로 생체효소 촉매화 방법 또는 키랄 금속 촉매에 의한 촉매화 방법을 사용하여 환원반응을 수행하여 (S)-니코틴을 얻으며, 그 반응식은 아래와 같다:
선행 기술과 비교하여, 본 출원은 아래와 같은 유익한 효과를 구비한다:
선행 기술에서 이미 개시한 (S)-니코틴을 제조하는 전략은 대부분 메틸화를 수행해야 (S)-니코틴을 얻을 수 있거나, 메틸화 없이 효소-촉매화를 사용하여서는 (S)-니코틴을 얻을 수 없다는 것을 감안하면, (S)-니코틴의 제조 전략은 여전히 매우 제한적이나, 본 출원은 메틸화 과정을 사용하지 않고 (S)-니코틴을 효율적으로 제조할 수 있는 새로운 방법을 창의적으로 개발하였으며, 즉, 상기 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 환원시키기만 하면 된다. 상기 합성방법은 작업이 간단하고, 안전하며 신뢰적이고, 수율이 높고 순도가 높으며, 또한 (S)-니코틴의 합성 전략을 풍부하게 만들었다.
도 1은 본 출원에 관련된 합성방법을 사용하여 제조된 (S)-니코틴의 핵자기 공명 스펙트럼이다.
도 2는 본 출원에 관련된 합성방법을 사용하여 제조된 화합물 III 염산염의 핵자기 공명 스펙트럼이다.
도 3은 본 출원에 관련된 합성방법을 사용하여 제조된 화합물 B의 핵자기 공명 스펙트럼이다.
도 2는 본 출원에 관련된 합성방법을 사용하여 제조된 화합물 III 염산염의 핵자기 공명 스펙트럼이다.
도 3은 본 출원에 관련된 합성방법을 사용하여 제조된 화합물 B의 핵자기 공명 스펙트럼이다.
이하, 구체적인 실시예를 통해 본 출원의 기술적 방안을 추가로 설명할 것이다. 상기 실시예는 단지 본 출원의 이해를 돕기 위한 것일 뿐, 본 출원에 대한 구체적인 제한으로 간주되어서는 안 된다는 점을 당업자는 이해해야 한다.
아래 제조예 및 실시예에서, 화합물 A의 순도 검출 방법은 고성능액체크로마토그래피이며; 수율 계산 방법은,
이고;
화합물 B의 순도 검출 방법은 고성능액체크로마토그래피이며, 수율 계산 방법은,
이며;
식 III으로 표시되는 화합물 또는 그 염의 순도 검출 방법은 고성능액체크로마토그래피이며, 수율 계산 방법은,
이고;
(S)-니코틴의 순도 검출 방법은 고성능액체크로마토그래피이고, 광학 순도 검출 방법은 고성능액체크로마토그래피이며; 수율 계산 방법은,
이다.
제조예 1-1
본 제조예는 화합물 A를 제조한다.
500mL 반응플라스크에 니코틴산 50g과 메탄올 250g을 첨가하고 교반을 시작하며, 반응플라스크에 농축 황산 60g을 적가하고, 적가완료 후 환류할 때까지 승온시켜 18시간 동안 반응시킨 후 45℃로 냉각시키고 감압농축하여 메탄올을 증류시키며, 유분(fraction)이 더이상 증발해 나오지 않으면, 농축 잔여물을 20℃로 냉각시키고, 농축 잔여물에 에틸아세테이트 250g 및 물 250g을 첨가하고 교반하여 녹인 후 20%의 수산화나트륨 수용액으로 pH를 7.5로 조절하고, 방치하여 분층시키고, 유기층을 수집하며, 수층은 에틸아세테이트 250g으로 다시 한 번 추출하고, 유기층을 합병하며, 무수황산나트륨으로 건조한 후, 용매를 감압증발시켜 무색 투명 액체 55.2g을 얻고 순도가 99%이고, 수율이 99%이며, 상기 액체를 냉각 후 고체화하여 얻는다.
제조예 1-2
본 제조예는 화합물 A를 제조한다.
500mL 반응플라스크에 니코틴산 50g과 메탄올 250g을 첨가하고 교반을 시작하며, 환류할 때까지 승온시킨 후 반응플라스크에 염화티오닐 120.5g(2.5eq)을 적가하고, 적가완료 후 9시간 동안 환류반응을 유지한 후, 40℃에서 감압농축하여 메탄올을 증류시키고, 유분(fraction)이 더이상 증발해 나오지 않으면, 농축 잔여물을 10℃로 냉각시키고, 농축 잔여물에 디클로로메탄 200g 및 물 100g을 첨가하고 교반하여 녹인 후 15%의 수산화나트륨 수용액으로 pH를 8로 조절하고, 방치하여 분층시키고, 유기층을 수집하며, 수층은 디클로로메탄 200g으로 다시 한 번 추출하고, 유기층을 합병하며, 5%의 수산화나트륨 수용액 100g으로 1회 세척하고, 유기층을 무수황산나트륨으로 건조시킨 후, 용매를 감압증발시켜 연황색 투명 액체 44.8g을 얻고 순도가 99%이고, 수율이 81%이며, 상기 액체를 냉각 후 고체화하여 얻는다.
제조예 1-3
본 제조예는 화합물 A를 제조한다.
100mL 반응플라스크에 니코틴산 5g, 트리메틸오르토포르메이트 (Trimethyl Orthoformate) 5.2g(1.2eq), 메탄올 25g, 사염화지르코늄 0.48g(0.05eq)을 첨가하고 교반을 시작하며, 환류할 때까지 승온시켜 17시간 동안 반응시킨 후 25℃로 냉각시키고, 소듐에톡사이드 0.55g(0.2eq)을 첨가하여 중화시킨 후, 여과하고 여액을 감압농축하여 메탄올을 증류시킨 후, 무색 투명 액체 5.5g을 얻고 순도가 98.1%이고, 수율이 99%이며, 상기 액체를 냉각 후 고체화하여 얻는다.
제조예 1-4
본 제조예는 화합물 A를 제조한다.
100mL 반응플라스크에 니코틴산 5g, 트리메틸오르토포르메이트 5.2g(1.2eq), 메탄올 25g, 사염화지르코늄 0.1g(0.01eq)을 첨가하고 교반을 시작하며, 환류할 때까지 승온시켜 36시간 동안 반응시킨 후 30℃로 냉각시키고, 소듐에톡사이드 0.11g(0.04eq)을 첨가하여 중화시킨 후, 여과하고 여액을 감압농축하여 메탄올을 증류시킨 후, 무색 투명 액체 5.3g을 얻고 순도가 91.6%이고, 수율이 95%이며, 상기 액체를 냉각 후 고체화하여 얻는다.
제조예 1-5
본 제조예는 화합물 A를 제조한다.
100mL 반응플라스크에 니코틴산 5g, 트리메틸오르토포르메이트 5.2g(1.2eq), 메탄올 25g, 사염화지르코늄 0.19g(0.02eq)을 첨가하고 교반을 시작하며, 환류할 때까지 승온시켜 30시간 동안 반응시킨 후 20℃로 냉각시키고, 소듐에톡사이드 0.22g(0.08eq)을 첨가하여 중화시킨 후, 여과하고 여액을 감압농축하여 메탄올을 증류시킨 후, 무색 투명 액체 5.4g을 얻고 순도가 93.9%이고, 수율이 97%이며, 상기 액체를 냉각 후 고체화하여 얻는다.
제조예 1-6
본 제조예는 화합물 A를 제조한다.
2L 반응플라스크에 니코틴산 200g, 트리메틸오르토포르메이트 207g(1.2eq), 메탄올 1,000g, 사염화지르코늄 9.5g(0.025eq)을 첨가하고 교반을 시작하며, 환류할 때까지 승온시켜 20시간 동안 반응시킨 후 25℃로 냉각시키고, 소듐에톡사이드 11.06g(0.1eq)을 첨가하여 중화시킨 후, 여과하고 여액을 감압농축하여 메탄올을 증류시킨 후, 무색 투명 액체 220.6g을 얻고 순도가 98.5%이고, 수율이 99%이며, 상기 액체를 냉각 후 고체화하여 얻는다.
제조예 2-1
본 제조예는 화합물 B를 제조한다.
반응플라스크에 제조예 1-1에서 제조한 화합물 A 102.0g, N-메틸피롤리돈 88.5g(1.2eq), 톨루엔 1.2kg, 칼륨 tert-부톡사이드 133.6g(1.6eq)을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 25°C로 냉각시키고, 5%의 염산으로 pH=7.5로 중화시키며, 방치하여 분층시키고, 수상을 디클로로메탄으로 추출한 후, 유기상을 합병하며, 감압농축시킴으로써 용매를 제거하여 황갈색의 액체, 즉, 화합물 B 121.0g을 얻고 순도가 94%이고, 수율이 80%이며; 정제처리 없이, 바로 다음 반응을 수행한다.
조생성물을 컬럼 크로마토그래피로 정제한 후, 핵자기 공명으로 검출하며, 생성물은 케톤 형태와 에놀 형태의 두 가지 형태로 공존하는데, 케톤 형태가 주요 형태이고, 케톤 형태와 에놀 형태의 비율은 약 10/1이다. 케톤 형태의 화합물의 수소 핵자기 스펙트럼의 데이터는 다음과 같다: δppm(400MHz, CDCl3)9.30(s, 1H), 8.77-8.80(m, 1H), 8.44(1H, dt, J=8.0, 2.0Hz), 7.43-7.47(m, 1H), 4.46(1H, dd, J=8.8, 3.2Hz), 3.36-3.46(m, 2H), 2.87(s, 3H), 2.67-2.75(m, 1H), 2.22-2.32(m, 1H). 수소 핵자기 스펙트럼의 스펙트럼은 도 3에 도시된 바와 같다.
제조예 2-2
본 제조예는 화합물 B를 제조한다.
반응플라스크에 제조예 1-2에서 제조한 화합물 A 102.0g, N-메틸피롤리돈 77.4g(1.05eq), 톨루엔 1.2kg, 칼륨 tert-부톡사이드 91.8g(1.1eq)을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 20°C로 냉각시키고, 5%의 염산으로 pH=7로 중화시키며, 방치하여 분층시키고, 수상을 톨루엔으로 추출한 후, 유기상을 합병하며, 감압농축시킴으로써 용매를 제거하여 황갈색의 액체, 즉, 화합물 B 118.0g을 얻고 순도가 93.5%이고, 수율이 78%이며; 정제처리 없이, 바로 다음 반응을 수행한다.
조생성물을 컬럼 크로마토그래피로 정제한 후, 핵자기 공명으로 검출하며, 생성물은 케톤 형태와 에놀 형태의 두 가지 형태로 공존하는데, 케톤 형태가 주요 형태이고, 케톤 형태와 에놀 형태의 비율은 약 10/1이다. 케톤 형태의 화합물의 수소 핵자기 스펙트럼의 데이터는 다음과 같다: δppm(400MHz, CDCl3)9.30(s, 1H), 8.77-8.80(m, 1H), 8.44(1H, dt, J=8.0, 2.0Hz), 7.43-7.47(m, 1H), 4.46(1H, dd, J=8.8, 3.2Hz), 3.36-3.46(m, 2H), 2.87(s, 3H), 2.67-2.75(m, 1H), 2.22-2.32(m, 1H).
제조예 2-3
본 제조예는 화합물 B를 제조한다.
반응플라스크에 제조예 1-3에서 제조한 화합물 A 102.0g, N-메틸피롤리돈 88.5g(1.2eq), 톨루엔 1.2kg, 나트륨 tert-부톡사이드 114.4g(1.6eq)을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 30°C로 냉각시키고, 5%의 염산으로 pH=8로 중화시키며, 방치하여 분층시키고, 수상을 에틸아세테이트로 추출한 후, 유기상을 합병하며, 감압농축시킴으로써 용매를 제거하여 황갈색의 액체, 즉, 화합물 B 117.8g을 얻고 순도가 95%이고, 수율이 78%이며; 정제처리 없이, 바로 다음 반응을 수행한다.
조생성물을 컬럼 크로마토그래피로 정제한 후, 핵자기 공명으로 검출하며, 생성물은 케톤 형태와 에놀 형태의 두 가지 형태로 공존하는데, 케톤 형태가 주요 형태이고, 케톤 형태와 에놀 형태의 비율은 약 10/1이다. 케톤 형태의 화합물의 수소 핵자기 스펙트럼의 데이터는 다음과 같다: δppm(400MHz, CDCl3)9.30(s, 1H), 8.77-8.80(m, 1H), 8.44(1H, dt, J=8.0, 2.0Hz), 7.43-7.47(m, 1H), 4.46(1H, dd, J=8.8, 3.2Hz), 3.36-3.46(m, 2H), 2.87(s, 3H), 2.67-2.75(m, 1H), 2.22-2.32(m, 1H).
제조예 2-4
본 제조예는 화합물 B를 제조한다.
반응플라스크에 제조예 1-4에서 제조한 화합물 A 102.0g, N-메틸피롤리돈 77.4g(1.05eq), 톨루엔 1.2kg, 나트륨 tert-부톡사이드 78.6g(1.1eq)을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 25°C로 냉각시키고, 5%의 염산으로 pH=7.5로 중화시키며, 방치하여 분층시키고, 수상을 톨루엔으로 추출한 후, 유기상을 합병하며, 감압농축시킴으로써 용매를 제거하여 황갈색의 액체, 즉, 화합물 B 108.7g을 얻고 순도가 93%이고, 수율이 72%이며; 정제처리 없이, 바로 다음 반응을 수행한다.
조생성물을 컬럼 크로마토그래피로 정제한 후, 핵자기 공명으로 검출하며, 생성물은 케톤 형태와 에놀 형태의 두 가지 형태로 공존하는데, 케톤 형태가 주요 형태이고, 케톤 형태와 에놀 형태의 비율은 약 10/1이다. 케톤 형태의 화합물의 수소 핵자기 스펙트럼의 데이터는 다음과 같다: δppm(400MHz, CDCl3)9.30(s, 1H), 8.77-8.80(m, 1H), 8.44(1H, dt, J=8.0, 2.0Hz), 7.43-7.47(m,1H), 4.46(1H, dd, J=8.8, 3.2Hz), 3.36-3.46(m, 2H), 2.87(s, 3H), 2.67-2.75(m, 1H), 2.22-2.32(m, 1H).
제조예 2-5
본 제조예는 화합물 B를 제조한다.
반응플라스크에 제조예 1-5에서 제조한 화합물 A 102.0g, N-메틸피롤리돈 88.5g(1.2eq), 톨루엔 1.2kg, 소듐에톡사이드 81.0g(1.6eq)을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 16시간 동안 반응시킨 후, 온도를 25°C로 냉각시키고, 5%의 염산으로 pH=7.5로 중화시키며, 방치하여 분층시키고, 수상을 톨루엔으로 추출한 후, 유기상을 합병하며, 감압농축시킴으로써 용매를 제거하여 황갈색의 액체, 즉, 화합물 B 127.0g을 얻고 순도가 92%이고, 수율이 84%이며; 정제처리 없이, 바로 다음 반응을 수행한다.
조생성물을 컬럼 크로마토그래피로 정제한 후, 핵자기 공명으로 검출하며, 생성물은 케톤 형태와 에놀 형태의 두 가지 형태로 공존하는데, 케톤 형태가 주요 형태이고, 케톤 형태와 에놀 형태의 비율은 약 10/1이다. 케톤 형태의 화합물의 수소 핵자기 스펙트럼의 데이터는 다음과 같다: δppm(400MHz, CDCl3)9.30(s, 1H), 8.77-8.80(m, 1H), 8.44(1H, dt, J=8.0, 2.0Hz), 7.43-7.47(m, 1H), 4.46(1H, dd, J=8.8, 3.2Hz), 3.36-3.46(m, 2H), 2.87(s, 3H), 2.67-2.75(m, 1H), 2.22-2.32(m, 1H).
제조예 2-6
본 제조예는 화합물 B를 제조한다.
반응플라스크에 제조예 1-6에서 제조한 화합물 A 102.0g, N-메틸피롤리돈 88.5g(1.2eq), 톨루엔 1.2kg, 수소화나트륨 47.6g(1.6eq, 오일 중 60% 수소화나트륨(Sodium hydride in oil))을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 25°C로 냉각시키고, 5%의 염산으로 pH=7로 중화시키며, 방치하여 분층시키고, 수상을 메틸 tert-부틸 에테르로 추출한 후, 유기상을 합병하며, 감압농축시킴으로써 용매를 제거하여 황갈색의 액체, 즉, 화합물 B 111.0g을 얻고 순도가 90%이고, 수율이 70%이며; 정제처리 없이, 바로 다음 반응을 수행한다.
조생성물을 컬럼 크로마토그래피로 정제한 후, 핵자기 공명으로 검출하며, 생성물은 케톤 형태와 에놀 형태의 두 가지 형태로 공존하는데, 케톤 형태가 주요 형태이고, 케톤 형태와 에놀 형태의 비율은 약 10/1이다. 케톤 형태의 화합물의 수소 핵자기 스펙트럼의 데이터는 다음과 같다: δppm(400MHz, CDCl3)9.30(s, 1H), 8.77-8.80(m, 1H), 8.44(1H, dt, J=8.0, 2.0Hz), 7.43-7.47(m, 1H), 4.46(1H, dd, J=8.8, 3.2Hz), 3.36-3.46(m, 2H), 2.87(s, 3H), 2.67-2.75(m, 1H), 2.22-2.32(m,1H).
제조예 3-1
본 제조예는 화합물 B를 원료로 사용하여 식 III으로 표시되는 화합물의 염산염을 제조한다.
반응플라스크에 제조예 2-1에서 제조한 화합물 B 100.0g, 농축 염산 500.0g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 55°C로 냉각시키고 감압농축하며, 잔여물에 메탄올 300.0g을 첨가하고 4℃로 냉각시킨 후, 여과하여 백색에 유사한 고체, 즉, 식 III으로 표시되는 화합물 92.2g을 얻으며 순도가 99%이고, 수율이 75%이다.
검출 후, 얻어진 화합물의 수소 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O):δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H). 스펙트럼은 도 2에 도시된 바와 같다.
제조예 3-2
본 제조예는 화합물 B를 원료로 사용하여 식 III으로 표시되는 화합물을 제조한다.
반응플라스크에 제조예 2-2에서 제조한 화합물 B 100.0g, 농축 염산 100.0g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 50°C로 냉각시키고 감압농축하며, 잔여물에 메탄올 100.0g을 첨가하고 8℃로 냉각시킨 후, 여과하여 백색에 유사한 고체, 즉, 식 III으로 표시되는 화합물 95.9g을 얻고 순도가 98.5%이고, 수율이 78%이다.
검출 후, 얻어진 화합물의 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O):δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H).
제조예 3-3
본 제조예는 화합물 B를 원료로 사용하여 식 III으로 표시되는 화합물을 제조한다.
반응플라스크에 제조예 2-3에서 제조한 화합물 B 100.0g, 농축 염산 300.0g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 50°C로 냉각시키고 감압농축하며, 잔여물에 에탄올 300.0g을 첨가하고 0℃로 냉각시킨 후, 여과하여 백색에 유사한 고체, 즉, 식 III으로 표시되는 화합물 100.8g을 얻고 순도가 99%이고, 수율이 82%이다.
검출 후, 얻어진 화합물의 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O):δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H).
제조예 3-4
본 제조예는 화합물 B를 원료로 사용하여 식 III으로 표시되는 화합물을 제조한다.
반응플라스크에 제조예 2-4에서 제조한 화합물 B 100.0g, 농축 염산 300.0g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 55°C로 냉각시키고 감압농축하며, 잔여물에 이소프로필알코올 500.0g을 첨가하고 4℃로 냉각시킨 후, 여과하여 백색에 유사한 고체, 즉, 식 III으로 표시되는 화합물 93.4g을 얻고 순도가 97.5%이고, 수율이 76%이다.
검출 후, 얻어진 화합물의 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O):δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H).
제조예 3-5
본 제조예는 화합물 B를 원료로 사용하여 식 III으로 표시되는 화합물을 제조한다.
반응플라스크에 제조예 2-5에서 제조한 화합물 B 100.0g, 농축 염산 500.0g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 55°C로 냉각시키고 감압농축하며, 잔여물에 이소프로필알코올 100.0g을 첨가하고 4℃로 냉각시킨 후, 여과하여 식 III으로 표시되는 화합물 103.3g을 얻고 순도가 96%이고, 수율이 84%인 백색에 유사한 고체이다.
검출 후, 얻어진 화합물의 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O):δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H).
제조예 4-1
본 제조예는 화합물 A를 원료로 사용하여 먼저 화합물 D를 제조한 후, 아래 식 III으로 표시되는 화합물을 제조한다.
반응플라스크에 제조예 1-1에서 제조한 화합물 A 120.0g, N-메틸피롤리돈 96.2g, 톨루엔 1.6kg, 칼륨 tert-부톡사이드 147g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 25°C로 냉각시키고, 여과하여 화합물 D(칼륨염)를 얻으며, 이를 다음 스텝의 반응에 직접 사용한다.
여과하여 얻은 D(칼륨염)을 농축 염산 650g에 첨가하고 반응이 완료될 때까지 100℃로 승온시킨다. 감압증류하여 대부분의 물을 제거하고, 잔여물에 95%의 에탄올 650mL를 첨가하며, 충분히 교반한 후 온도를 10℃로 냉각시키고, 여과 및 건조하여 백색에 유사한 고체, 즉, 식 III으로 표시되는 화합물 86g을 얻고 순도가 55.2%이고, 수율이 97.2%이다.
검출 후, 얻어진 화합물의 수소 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O): δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H).
제조예 4-2
본 제조예는 화합물 A를 원료로 사용하여 먼저 화합물 D를 제조한 후, 아래 식 III으로 표시되는 화합물을 제조한다.
반응플라스크에 제조예 1-2에서 제조한 화합물 A 153.0g, N-메틸피롤리돈 165g, 톨루엔 2kg, 나트륨 tert-부톡사이드 214.5g을 첨가하며, 물질을 첨가완료한 후 교반을 시작하고, 환류할 때까지 승온시키며; 반응이 합격된 후, 온도를 15°C로 냉각시키고, 여과하여 화합물 D(나트륨염)를 얻으며, 이를 다음 스텝의 반응에 직접 사용한다.
여과하여 얻은 D(나트륨염)을 농축 염산 960g에 첨가하고 반응이 완료될 때까지 100℃로 승온시킨다. 감압증류하여 대부분의 물을 제거하고, 잔여물에 이소프로필알코올 800mL를 첨가하며, 충분히 교반한 후 온도를 20℃로 냉각시키고, 여과 및 건조하여 백색에 유사한 고체, 즉, 식 III으로 표시되는 화합물 127g을 얻고 순도가 63.5%이고, 수율이 96.7%이다.
검출 후, 얻어진 화합물의 수소 핵자기 스펙트럼은 도시된 구조와 일치하며, 검출 데이터는 아래와 같다: 1H-NMR(400MHz, D2O):δppm 9.25(m, 1H), 9.0(dt, J=8.4Hz, 1.6Hz, 1H), 8.90-8.91(m, 1H), 8.13-8.17(m, 1H), 3.28(t, J=6.8Hz, 2H), 3.06(t, J=8.0Hz, 2H), 2.66(s, 3H), 2.02-2.09(m, 2H).
제조예 5-1
본 제조예는 서열번호 1로 표시된 바와 같은 아미노산 서열의 포도당 탈수소효소를 제조한다.
프리스티아 메가테리움(Priestia megaterium)(NCBI 등록번호 AUO12718.1)에서 유래된 포도당 탈수소효소 아미노산 서열(서열번호 1)을 Nanjing GenScript Company로 보내어 코돈(codon) 최적화와 유전자 합성(Gene Synthesis)을 수행하고, 플라스미드 pET30a(+)에 연결시키며; 재조합 플라스미드를 대장균(Escherichia coli) BL21(DE3) 컴피턴트 세포(competent cell)에 형질전환시켜, 포도당 탈수소효소 유전자를 함유한 재조합 박테리아를 획득한다.
상기 재조합 박테리아를 50μg/mL 카나마이신(Kanamycin)이 함유된 LB 액체배지 5mL에 접종하고, 37℃에 방치하여 밤새 배양하며; 균액 1mL를 취하여 50μg/mL 카나마이신이 함유된 LB 액체배지 125 mL에 접종하고, 37℃에 방치하여 3시간 동안 배양한 후, 125μL의 1M IPTG를 첨가하고, 25℃에서 밤새 유도하며; 원심분리(4,000rpm, 4℃, 10분)하여 균체를 수집하고, 4배 부피의 인산 완충액(pH=7.0)을 첨가하여 재현탁하며, 재현탁 후 세포를 초음파 처리하여 파쇄시키고, 원심분리(4,000rpm, 4℃, 10분) 한 후 상층액을 취해 동결건조하여 포도당 탈수소효소의 효소 분말을 획득한다.
제조예 5-2
본 제조예는 아래와 같이 11종의 이민환원효소를 제조하며, 차례로 효소 1, 효소 3-11, 효소 13으로 기록한다.
NCBI에 보고된 이민환원효소 아미노산 서열(서열번호 2 내지 서열번호 12, 정보는 아래 표를 참조)을 Nanjing GenScript Company로 보내어 코돈 최적화와 유전자 합성을 수행하고, 플라스미드 pET30a(+)에 삽입시키며; 재조합 플라스미드를 대장균 BL21(DE3) 컴피턴트 세포에 형질전환시켜, 이민환원효소 유전자를 함유한 재조합 박테리아를 획득한다.
상기 재조합 박테리아를 50μg/mL 카나마이신(Kanamycin)이 함유된 LB 액체배지 5mL에 접종하고, 37℃에 방치하여 밤새 배양하며; 균액 1mL를 취하여 50μg/mL 카나마이신이 함유된 LB 액체배지 125 mL에 접종하고, 37℃에 방치하여 3시간 동안 배양한 후, 125μL의 1M IPTG를 첨가하고, 25℃에서 16시간 동안 유도하며; 원심분리(4,000rpm, 4℃, 10분)하여 균체를 수집하고, 4배 부피의 인산 완충액(pH=7.0)을 첨가하여 재현탁하며, 재현탁 후 세포를 초음파 처리하여 파쇄시키고, 원심분리(4,000rpm, 4℃, 10분)한 후 상층액을 취해 동결건조하여 이민환원효소 분말을 획득한다.
본 제조예는 이하 10종의 이민환원효소를 더 제조하는데, 효소 14-효소 23으로 기록하며, 즉 서열번호 12의 아미노산 서열에 대해 위치지정 돌연변이를 수행하여 서열번호 13 내지 서열번호 22로 표시되는 이민환원효소 아미노산 서열을 획득하고, 이를 Nanjing GenScript Company로 보내어 코돈 최적화와 유전자 합성을 수행하고, 플라스미드 pET30a(+)에 삽입시키며; 재조합 플라스미드를 대장균 BL21(DE3) 컴피턴트 세포에 형질전환시켜, 이민환원효소 유전자를 함유한 재조합 박테리아를 획득한다. 상기 작업을 수행하여 최종적으로 이민환원효소 효소 분말을 획득한다.
제조예 5-3
본 제조예는 이하 효소를 제조하며, 효소 12로 기록한다.
이민환원효소(Imine reductase)(서열번호 2의 아미노산 서열)와 포도당 탈수소효소(서열번호 1의 아미노산 서열)를 차례로 플라스미드 pETDuet-1에 서브클로닝하고; 재조합 플라스미드를 대장균 BL21(DE3) 컴피턴트 세포에 형질전환시켜, 이민환원효소 유전자와 포도당 탈수소효소 유전자를 동시에 함유한 재조합 박테리아를 획득한다.
상기 재조합 박테리아를 100μg/mL 암피실린(ampicillin)이 함유된 LB 액체배지 5mL에 접종하고, 37℃에 방치하여 밤새 배양하며; 균액 1mL를 취하여 100μg/mL 암피실린이 함유된 LB 액체배지 125 mL에 접종하고, 37℃에 방치하여 3시간 동안 배양한 후, 125μL의 1M IPTG를 첨가하고, 25℃에서 밤새 유도하며; 원심분리(4,000rpm, 4℃, 10분)하여 균체를 수집하고, 4배 부피의 인산 완충액(pH=7.0)을 첨가하여 재현탁하며, 재현탁 후 세포를 초음파 처리하여 파쇄시키고, 원심분리(4,000rpm, 4℃, 10분)한 후 상층액을 취해 동결건조하여 효소 12의 효소 분말을 획득한다.
실시예 1
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
100mL 수소화 반응기(hydrogenation reactor)에 제조예 3-1에서 제조한 화합물 C 1.25g, 메탄올 50mL, 트리에틸아민 1.0g을 첨가한 후, 촉매인 1,5-사이클로옥타디엔이리듐클로라이드다이머 16.7mg, 리간드인 (S)-(-)-1-[(R)-2-디페닐포스핀페로세닐에틸디-tert-부틸포스핀 30mg을 첨가하고, 물질을 첨가완료한 후, 수소 가스를 투입하여 2.5MPa로 유지하며, 온도는 60℃로 조절한다. 반응이 완료된 후, 용매를 농축하여 제거하고, 잔여물을 n-헵탄으로 슬러리화한 후, 여과하고 농축하여 순도가 96%이고, 광학 순도가 72%인 목적 화합물을 얻는다.
도 1에 도시된 바와 같이, 제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 2
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
100mL 수소화 반응기에 제조예 3-2에서 제조한 화합물 C 1.25g, 메탄올 50mL, 트리에틸아민 1.0g을 첨가한 후, 촉매인 1,5-사이클로옥타디엔이리듐클로라이드다이머 16.7mg, 리간드인 (+)-1,2-비스((2S,5S)-2,5-디페닐포스폴라노)에탄 27mg을 첨가하고, 물질을 첨가완료한 후, 수소 가스를 투입하여 3.0MPa로 유지하며, 온도는 60℃로 조절한다. 반응이 완료된 후, 용매를 농축하여 제거하고, 잔여물을 n-헵탄으로 슬러리화한 후, 여과하고 농축하여 순도가 94%이고, 광학 순도가 80%인 목적 화합물을 얻는다.
제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 3
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
100mL 수소화 반응기에 제조예 3-3에서 제조한 화합물 C 1.25g, 메탄올 50mL, 트리에틸아민 1.0g을 첨가한 후, 촉매인 1,5-사이클로옥타디엔이리듐클로라이드다이머 16.7mg, 리간드인 (R,R)-f-SpiroPhos 38mg을 첨가하고, 물질을 첨가완료한 후, 수소 가스를 투입하여 5.5MPa로 유지하며, 온도는 80℃로 조절한다. 반응이 완료된 후, 용매를 농축하여 제거하고, 잔여물을 n-헵탄으로 슬러리화한 후, 여과하고 농축하여 순도가 90%이고, 광학 순도가 88%인 목적 화합물을 얻는다.
제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 4
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
그 제조방법과 실시예 3의 유일한 차이점은 촉매인 1,5-사이클로옥타디엔이리듐클로라이드다이머 16.7mg, 리간드 (R,R)-f-SpiroPhos 38mg을 Rh[(R,R)-DIPAMP](COD)BF4 45mg으로 대체한다는 점에 있으며, 기타 조건은 모두 변경되지 않는다. 이로부터 순도가 45%이고, 광학 순도가 27%인 목적 화합물을 얻는다.
제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 5
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
100mL 수소화 반응기에 제조예 3-4에서 제조한 화합물 C 1.25g, 에탄올 60mL, 트리에틸아민 1.0g을 첨가한 후, 촉매인 Rh[(R,R)-DIPAMP](COD)BF4 45mg을 첨가하고, 물질을 첨가완료한 후, 수소 가스를 투입하여 4.0MPa로 유지하며, 온도는 90℃로 조절한다. 반응이 합격된 후, 용매를 농축하여 제거하고, 잔여물을 n-헵탄으로 슬러리화한 후, 여과하고 농축하여 순도가 85%이고, 광학 순도가 58%인 목적 화합물을 얻는다.
제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 6
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
100mL 수소화 반응기에 제조예 3-5에서 제조한 화합물 C 1.25g, 메탄올 50mL, 디이소프로필에틸아민 1.2g을 첨가한 후, 촉매인 (-)-1,2-비스((2R,5R)-2,5-디메틸포스피노)에탄(사이클로옥타디엔)로듐 테트라플루오로보레이트 39mg을 첨가하고, 물질을 첨가완료한 후, 수소 가스를 투입하여 1.5MPa로 유지하며, 온도는 100℃로 조절한다. 반응이 완료된 후, 용매를 농축하여 제거하고, 잔여물을 메틸 tert-부틸 에테르로 슬러리화한 후, 여과하고 농축하여 순도가 64%이고, 광학 순도가 82%인 목적 화합물을 얻는다.
제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m),3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 7
본 실시예는 키랄 금속 촉매를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
100mL 수소화 반응기에 제조예 4-1에서 제조한 화합물 C 1.25g, 메탄올 50mL, 트리에틸아민 1.0g을 첨가한 후, 촉매인 [(R)-(+)-2,2'-비스(디페닐포스피노)-1,1'-비나프틸]디클로로루테늄 35mg을 첨가하고, 물질을 첨가완료한 후, 수소 가스를 투입하여 3.0MPa로 유지하며, 온도는 90℃로 조절하고, 공정 내(In Process) 반응이 완료된 후, 반응액을 바로 농축하여 용매를 제거하고, 잔여물을 메틸 tert-부틸 에테르로 슬러리화한 후, 여과하고 농축하여 순도가 59%이고, 광학 순도가 66%인 목적 화합물을 얻는다.
제조된 (S)-니코틴을 컬럼 크로마토그래피로 정제한 후 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 8
본 실시예는 생물학적 효소를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
5mL 원심분리관 10 개에 제조예 4-2에서 제조한 화합물 C 30mg을 첨가하고, 0.1M 인산 완충액 2mL를 첨가하여 pH를 6.0으로 조절한다. 그 후 반응플라스크에 포도당 32mg을 첨가하고, 완전히 용해될 때까지 교반한 후, 이에 제조예 5-2에서 제조한, 아미노산 서열을 차례로 서열번호 2 내지 서열번호 22로 나타낸 이민환원효소 30mg을 각각 첨가한다. 다른 하나의 5mL 원심분리관에 0.1M 인산 완충액 3mL, 제조예 5-1에서 제조한 아미노산 서열이 서열번호 1로 나타낸 효소 240mg과 NADP 염 40mg을 첨가하고, 완전히 용해될 때까지 교반한다. 그 후 두 번째 원심분리관 중의 용액 0.1mL을 각각 취하여 첫 번째 원심분리관에 천천히 첨가하고, 온도를 25℃로 승온시킨 후, 300r/분으로 16시간 동안 교반한다. 반응액 0.1mL를 각각 취하여 메탄올 0.9mL를 첨가하고 1분 동안 진탕한 후 1mL 액상병으로 여과하여 고성능액체크로마토그래피 분석에 공급하며, (S)-니코틴의 면적비는 전환율이다.
전환율 데이터는 표 2에 도시된 바와 같다.
효소 | 전환율(%) | ee 값(%) | 배열(Configuration) |
1 | 99.5 | 99.4 | S |
3 | 99.6 | 100 | S |
4 | 94.6 | 99.1 | S |
5 | 89.5 | 85.5 | S |
6 | 88.6 | 95.3 | S |
7 | 0 | / | / |
8 | 56.4 | 88.1 | S |
9 | 83.2 | 99.2 | R |
10 | 77.9 | 87.6 | R |
11 | 23.5 | 99.5 | S |
13 | 99.5 | 99.9 | S |
14 | 99.5 | 99.5 | S |
15 | 99.8 | 99.8 | S |
16 | 99.5 | 99.7 | S |
17 | 99.5 | 99.7 | S |
18 | 99.8 | 99.5 | S |
19 | 99.5 | 99.3 | S |
20 | 99.3 | 99.5 | S |
21 | 99.5 | 99.3 | S |
22 | 99.9 | 99.9 | S |
23 | 99.3 | 99.2 | S |
표 2의 데이터로부터: 기타 효소와 비교하여, 효소 1, 효소 3, 효소 4, 효소 13-18 및 효소 22의 촉매 효과가 가장 우수하고, 전환율이 94.6% 이상에 도달할 수 있음을 알 수 있다.
실시예 9
본 실시예는 생물학적 효소를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
50mL 삼구 둥근바닥 플라스크에 제조예 4-1에서 제조한 화합물 C 4.5g을 첨가하고, 0.1M 인산 완충액 20mL를 첨가하여 pH를 7.0으로 조절한다. 그 후 반응플라스크에 포도당 4.8g을 첨가하고, 완전히 용해될 때까지 교반한다. 이어서 다른 하나의 50mL 플라스크에 0.1M 인산 완충액 10mL, 제조예 5-2에서 제조한 효소 1 0.3g, 제조예 5-1에서 제조한 효소 2 0.04g과 NADP 염 0.008g을 첨가하고, 완전히 용해될 때까지 교반한다. 그 후 두 번째 플라스크 중의 용액을 첫 번째 플라스크에 천천히 첨가하고, 온도를 30℃로 승온시킨 후, 300r/분으로 16시간 동안 교반한다. 이어서 여과하고, 여액을 수산화나트륨 수용액으로 pH=10으로 조절한 후 메틸 tert-부틸 에테르로 추출하며, 무수황산나트륨으로 건조하고, 농축하여 (S)-니코틴 2.6g을 얻는다. 순도는 99%이고, 광학 순도는 100%이며, 수율은 89.5%이다.
제조된 (S)-니코틴에 대해 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 10
본 실시예는 생물학적 효소를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
50mL 삼구 둥근바닥 플라스크에 제조예 3-1에서 제조한 화합물 C 4.5g을 첨가하고, 0.1M 인산 완충액 20mL를 첨가하여 pH를 6.0으로 조절한다. 그 후 반응플라스크에 포도당 4.8g을 첨가하고, 완전히 용해될 때까지 교반한다. 이어서 다른 하나의 50mL 플라스크에 0.1M 인산 완충액 10mL, 제조예 5-2에서 제조한 효소 3 0.4g, 제조예 5-1에서 제조한 효소 2 0.04g과 NADP 염 0.008g을 첨가하고, 완전히 용해될 때까지 교반한다. 그 후 두 번째 플라스크 중의 용액을 첫 번째 플라스크에 천천히 첨가하고, 온도를 35℃로 승온시킨 후, 300r/분으로 16시간 동안 교반한다. 이어서 여과하고, 여액을 수산화나트륨 수용액으로 pH=10으로 조절한 후 에틸아세테이트로 추출하며, 무수황산나트륨으로 건조하고, 농축하여 (S)-니코틴 2.4g을 얻는다. 순도는 99%이고, 광학 순도는 99.4%이며, 수율은 82.6%이다.
제조된 (S)-니코틴에 대해 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
실시예 11
본 실시예는 생물학적 효소를 사용하여 촉매화 환원을 통해 (S)-니코틴을 제조한다.
50mL 삼구 둥근바닥 플라스크에 제조예 3-1에서 제조한 화합물 C 4.5g을 첨가하고, 0.1M 인산 완충액 20mL를 첨가하여 pH를 6.0으로 조절한다. 그 후 반응플라스크에 포도당 4.8g을 첨가하고, 완전히 용해될 때까지 교반한다. 이어서 다른 하나의 50mL 플라스크에 0.1M 인산 완충액 10mL, 제조예 5-3에서 제조한 효소 12 0.4g과 NADP 염 0.008g을 첨가하고, 완전히 용해될 때까지 교반한다. 그 후 두 번째 플라스크 중의 용액을 첫 번째 플라스크에 천천히 첨가하고, 온도를 35℃로 승온시킨 후, 300r/분으로 16시간 동안 교반한다. 이어서 여과하고, 여액을 수산화나트륨 수용액으로 pH=10으로 조절한 후 에틸아세테이트로 추출하며, 무수황산나트륨으로 건조하고, 농축하여 (S)-니코틴 2.3g을 얻는다. 순도는 99%이고, 광학 순도는 99.6%이며, 수율은 79.2%이다.
제조된 (S)-니코틴에 대해 수소 핵자기 스펙트럼의 특성화를 수행하며, 데이터는 다음과 같다: 1H-NMR(400MHz, CDCl3):δppm 8.54(1H, d), 8.50(1H, dd), 7.70(1H, dt), 7.24-7.27(1H, m), 3.22-3.27(1H, m), 3.08(1H, t), 2.27-2.34(1H, m), 2.17-2.24(1H, m), 2.16(3H, m), 1.91-2.02(1H, m), 1.79-1.87(1H, m), 1.68-1.76(1H, m). 이는 (S)-니코틴이 성공적으로 합성되었음을 나타낸다.
본 출원인은, 본 출원에서 상기 실시예를 통해 본 출원의 환원방식을 이용한 (S)-니코틴의 제조 방법을 설명하지만, 본 출원이 상기 실시예에 제한되지 않으며, 즉, 이는 본 출원이 반드시 상기 실시예에 의존해야만 실시될 수 있다는 것을 의미하지 않음을 선언한다. 본 출원에 대한 모든 개선, 본 출원 제품의 각 원료의 동등한 대체 및 보조성분의 첨가, 구체적인 방식의 선택 등은, 모두 본 출원의 보호 범위와 개시 범위 내에 속한다는 것을 당업자는 이해해야 한다.
이상, 본 출원의 바람직한 실시예를 상세히 설명하였지만, 본 출원은 상기 실시방식 중의 구체적인 내용에 한정되는 것은 아니며, 본 출원의 기술사상 범위 내에서, 본 출원의 기술적 방안에 대해 여러 가지 간단한 변형을 수행할 수 있으며, 이러한 간단한 변형은 모두 본 출원의 보호범위에 속한다.
또한, 상기 구체적인 실시방식에 설명된 여러 가지 구체적인 기술적 특징은, 모순되지 않는 한, 임의의 적절한 방식으로 조합될 수 있으며, 불필요한 반복을 방지하기 위해, 본 출원은 여러 가지 가능한 조합에 대해 더 이상 설명하지 않을 것을 유의해야 한다.
<110> PORTON PHARMA SOLUTIONS LTD.
<120> METHOD FOR USING REDUCTION TO PREPARE (S)-NICOTINE
<130> BY22DX0700FPPC-CN
<150> CN 202110594149.7
<151> 2021-05-29
<150> CN 202210575265.9
<151> 2022-05-24
<160> 22
<170> KoPatentIn 3.0
<210> 1
<211> 260
<212> PRT
<213> Artificial Sequence
<220>
<223> glucose dehydrogenase
<400> 1
Met Tyr Lys Asp Leu Glu Gly Lys Val Val Val Ile Thr Gly Ser Ser
1 5 10 15
Thr Gly Leu Gly Lys Ser Met Ala Ile Arg Phe Ala Thr Glu Lys Ala
20 25 30
Lys Val Val Val Asn Tyr Arg Ser Lys Glu Asp Glu Ala Asn Ser Val
35 40 45
Leu Glu Glu Ile Lys Lys Val Gly Gly Glu Ala Ile Ala Val Lys Gly
50 55 60
Asp Val Thr Val Glu Ser Asp Val Ile Asn Leu Val Gln Ser Ala Ile
65 70 75 80
Lys Glu Phe Gly Lys Leu Asp Val Met Ile Asn Asn Ala Gly Leu Glu
85 90 95
Asn Pro Val Ser Ser His Glu Met Ser Leu Ser Asp Trp Asn Lys Val
100 105 110
Ile Asp Thr Asn Leu Thr Gly Ala Phe Leu Gly Ser Arg Glu Ala Ile
115 120 125
Lys Tyr Phe Val Glu Asn Asp Ile Lys Gly Thr Val Ile Asn Met Ser
130 135 140
Ser Val His Glu Lys Ile Pro Trp Pro Leu Phe Val His Tyr Ala Ala
145 150 155 160
Ser Lys Gly Gly Met Lys Leu Met Thr Glu Thr Leu Ala Leu Glu Tyr
165 170 175
Ala Pro Lys Gly Ile Arg Val Asn Asn Ile Gly Pro Gly Ala Ile Asn
180 185 190
Thr Pro Ile Asn Ala Glu Lys Phe Ala Asp Pro Glu Gln Arg Ala Asp
195 200 205
Val Glu Ser Met Ile Pro Met Gly Tyr Ile Gly Glu Pro Glu Glu Ile
210 215 220
Ala Ala Val Ala Ala Trp Leu Ala Ser Ser Glu Ala Ser Tyr Val Thr
225 230 235 240
Gly Ile Thr Leu Phe Ala Asp Gly Gly Met Thr Gln Tyr Pro Ser Phe
245 250 255
Gln Ala Gly Arg
260
<210> 2
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 2
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Glu Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ser Leu Glu Ser Trp Cys His Thr Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Asp Gln Ile Gly Thr Thr Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Thr Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Pro Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Val Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 3
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 3
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Leu Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 4
<211> 258
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 4
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Ile Lys Gly Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Arg Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Asp Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Tyr Phe Ala Gly Gly
130 135 140
Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu Gly Leu
145 150 155 160
Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro Ile Leu
165 170 175
Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly Asp Phe
180 185 190
Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile Ser Arg
195 200 205
Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe Pro Arg
210 215 220
Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe Gly Gln
225 230 235 240
Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn Gly Ala
245 250 255
Ala Leu
<210> 5
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 5
Met Arg Pro Ile Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Thr Pro Leu Ile Ala Leu Gly Ala Ile Leu Ala
35 40 45
Pro Ser Val Ser Glu Ala Ile Ala Ala Gly Asp Ile Thr Leu Ile Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asn
65 70 75 80
Ala Val Thr Gly Lys Leu Val Val Gln Leu Ser Thr Gly Ser Pro Leu
85 90 95
Gly Ala Arg Thr Leu Glu Ser Trp Cys His Ala Arg Gly Ala Cys Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Asp Gln Ile Gly Thr Thr Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Asn Ala Ala Phe Arg Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Glu His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Thr Asp His Ala Ala Asp Ala Gly Ile Asp Asn Ser Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Glu Gln Gly Leu
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 6
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 6
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Ile Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ser Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Gln Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Asp Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Asn Thr Ala Phe Ser Asp Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Thr Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 7
<211> 276
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 7
Met Gly Thr Ala Leu Val Glu Ala Phe Leu Ala Gly Gly His Ala Thr
1 5 10 15
Thr Val Trp Asn Arg Thr Pro Gly Lys Ala Asp Gly Val Val Ala Arg
20 25 30
Gly Ala Val Val Ala Glu Thr Val Ala Glu Ala Val Ala Ala Ser Pro
35 40 45
Leu Val Val Val Cys Leu Trp Asp Asp Ala Val Val Arg Asp Val Leu
50 55 60
His Pro Val Ala Asp Ala Leu Ala Gly Arg Val Val Val Asn Leu Thr
65 70 75 80
Asn Gly Thr Pro Ala Gln Ala Arg Glu Met Ala Ala Trp Ala Ala Glu
85 90 95
His Gly Val Glu Tyr Val Asp Gly Gly Ile Met Ala Ile Pro Pro Gly
100 105 110
Ile Gly Thr Glu His Ala Phe Val Leu Tyr Ser Gly Ala Glu Ala Ala
115 120 125
Phe Glu Ala His Arg Glu Val Leu Glu Arg Leu Gly Ala Ala Lys Tyr
130 135 140
Leu Gly Ala Asp Ala Gly Leu Ala Ala Leu Phe Asp Leu Ala Leu Leu
145 150 155 160
Ser Gly Met Tyr Gly Thr Phe Ala Gly Leu Trp His Ser Leu Ala Met
165 170 175
Val Arg Thr Glu Asn Val Ser Ala Ala Glu Phe Val Pro Met Leu Gly
180 185 190
Pro Trp Met Gln Ala Met Ile Gly Gly Asn Leu Asp Arg Leu Ala His
195 200 205
Gln Leu Asp Thr Gly Asp Tyr Gly His Glu Val Val Ser Asn Leu Ala
210 215 220
Met Gln Ala Ala Ala Phe Pro Asn Ile Val Gln Ala Ser Leu Asp Gln
225 230 235 240
Gly Ile Arg Pro Asp Leu Met Ala Pro Ile Gln Arg Leu Met Asp Gln
245 250 255
Ala Val Ala Ala Gly His Gly Ala Glu Asp Val Ala Val Val Val Asp
260 265 270
Leu Leu Lys Asn
275
<210> 8
<211> 291
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 8
Met Lys Pro Thr Leu Thr Val Ile Gly Ala Gly Arg Met Gly Ser Ala
1 5 10 15
Leu Ile Lys Ala Phe Leu Gln Ser Gly Tyr Thr Thr Thr Val Trp Asn
20 25 30
Arg Thr Lys Ala Lys Ser Glu Pro Leu Ala Lys Leu Gly Ala His Leu
35 40 45
Ala Asp Thr Val Arg Asp Ala Val Lys Arg Ser Asp Ile Ile Val Val
50 55 60
Asn Val Leu Asp Tyr Asp Thr Ser Asp Gln Leu Leu Arg Gln Asp Glu
65 70 75 80
Val Thr Arg Glu Leu Arg Gly Lys Leu Leu Val Gln Leu Thr Ser Gly
85 90 95
Ser Pro Ala Leu Ala Arg Glu Gln Glu Thr Trp Ala Arg Gln His Gly
100 105 110
Ile Asp Tyr Leu Asp Gly Ala Ile Met Ala Thr Pro Asp Phe Ile Gly
115 120 125
Gln Ala Glu Cys Ala Leu Leu Tyr Ser Gly Ser Ala Ala Leu Phe Glu
130 135 140
Lys His Arg Ala Val Leu Asn Val Leu Gly Gly Ala Thr Ser His Val
145 150 155 160
Gly Glu Asp Val Gly His Ala Ser Ala Leu Asp Ser Ala Leu Leu Phe
165 170 175
Gln Met Trp Gly Thr Leu Phe Gly Thr Leu Gln Ala Leu Ala Ile Ser
180 185 190
Arg Ala Glu Gly Ile Pro Leu Glu Lys Thr Thr Ala Phe Ile Lys Leu
195 200 205
Thr Glu Pro Val Thr Gln Gly Ala Val Ala Asp Val Leu Thr Arg Val
210 215 220
Gln Gln Asn Arg Leu Thr Ala Asp Ala Gln Thr Leu Ala Ser Leu Glu
225 230 235 240
Ala His Asn Val Ala Phe Gln His Leu Leu Ala Leu Cys Glu Glu Arg
245 250 255
Asn Ile His Arg Gly Val Ala Asp Ala Met Tyr Ser Val Ile Arg Glu
260 265 270
Ala Val Lys Ala Gly His Gly Lys Asp Asp Phe Ala Ile Leu Thr Arg
275 280 285
Phe Leu Lys
290
<210> 9
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 9
Met Val Ser Ser Pro Tyr Leu Asn Val Thr Ala Tyr Pro Lys Val Arg
1 5 10 15
Asn Leu Pro Trp Pro Val Pro Gly Pro Ile Arg Val Ala Ser Gln Ile
20 25 30
Leu Glu Leu Arg Pro Met Thr Thr Ile Gly Phe Leu Gly Ala Gly Arg
35 40 45
Met Gly Ser Ala Leu Val Lys Ser Leu Leu Glu Ala Gly His Ser Val
50 55 60
His Val Trp Asn Arg Thr Ala Glu Lys Ala Gln Ala Leu Ala Asp Phe
65 70 75 80
Gly Ala Val Pro Glu Pro Ser Ala Glu Arg Ala Ala Gly Pro Ala Glu
85 90 95
Ile Val Ile Val Asn Leu Leu Asp Tyr Glu Ala Ser Asp Ala Glu Leu
100 105 110
Arg Lys Pro Asp Val Ala Glu Ala Leu Lys Gly Lys Leu Leu Val Gln
115 120 125
Leu Thr Ser Gly Ser Pro Lys Thr Ala Arg Glu Thr Gly Arg Trp Ala
130 135 140
Gly Asp His Gly Ile Ala Tyr Leu Asp Gly Ala Ile Met Ala Thr Pro
145 150 155 160
Asn Phe Ile Gly Gly Ala Glu Thr Val Ile Leu Tyr Ser Gly Ser Lys
165 170 175
Thr His Phe Glu Lys His Glu Gly Leu Phe Lys Ala Leu Gly Gly Lys
180 185 190
Ser Ala Phe Val Gly Glu Asp Phe Gly Thr Ala Ser Ala Leu Asp Ser
195 200 205
Ala Leu Leu Ser Gln Met Trp Gly Thr Leu Phe Gly Thr Leu Gln Ala
210 215 220
Leu Ala Val Cys Arg Ala Glu Gly Ile Glu His Asp Val Tyr Ala Gly
225 230 235 240
Phe Leu Met Ser Ala Gln Pro Met Ile Asp Gly Ala Gln Gln Asp Leu
245 250 255
Met Glu Arg Ile Arg Asp Gly Arg Asp Leu Ala Asp Ala Gln Thr Leu
260 265 270
Ala Thr Val Ala Val His Asn Val Ala Phe His His Leu Arg Asp Leu
275 280 285
Ile Ala Asp Arg Asp Leu Asn Pro Ala Phe Gly Asp Ala Leu Gly Ser
290 295 300
Leu Leu Glu Thr Ala Leu Arg Asn Asp His Gln Asp Asp Asp Phe Ala
305 310 315 320
Val Leu Ala Arg Phe Met Gly Ala Lys
325
<210> 10
<211> 293
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 10
Met Thr Asp Leu Gly Lys Ser Ala Val Thr Val Leu Gly Leu Gly Ala
1 5 10 15
Met Gly Thr Ala Leu Ala Glu Ala Leu Leu Ala Ala Gly His Pro Thr
20 25 30
Thr Val Trp Asn Arg Ser Pro Ala Arg Thr Ala Gly Pro Ala Gln Arg
35 40 45
Gly Ala Ala Val Ala Ala Ala Thr Ala Glu Ala Ile Ala Ala Ser Arg
50 55 60
Leu Ile Val Val Cys Leu Leu Asp His Thr Ser Val His Ala Val Leu
65 70 75 80
Asp Gly Gln Glu Leu Thr Gly Arg Ile Val Val Asn Leu Thr Ser Gly
85 90 95
Thr Pro Gly Gln Ala Arg Glu Leu Asp Ala Arg Val Ala Glu Arg Gly
100 105 110
Gly Asp His Leu Asp Gly Ala Val Leu Ala Val Pro Ser Met Ile Gly
115 120 125
Thr Pro Asp Ala Ser Val Leu Tyr Ser Gly Ser Arg Gly Ala Phe Asp
130 135 140
Thr His Arg Pro Val Leu Glu Val Phe Gly Ala Ala Asp Tyr Val Gly
145 150 155 160
Ala Asp Pro Gly Ala Ala Ser Leu Gln Asp Ala Ala Leu Leu Ser Ala
165 170 175
Met Tyr Gly Gln Val Ala Gly Val Leu His Ala Phe Ala Leu Val Arg
180 185 190
Ser Ala Gly Val Thr Ala Thr Glu Phe Leu Pro Arg Leu Val Gly Trp
195 200 205
Leu Thr Ala Met Gly Gly Phe Pro Ala Asp Ala Ala Arg Arg Ile Asp
210 215 220
Ala Arg Ala Tyr Ala Asp Asp Val Asp Ala Ala Leu Thr Met Gln Val
225 230 235 240
Thr Ala Val Arg Asn Leu Val Arg Ala Ala Arg Glu Gln Gly Val Ser
245 250 255
Ala Glu Leu Ile Ala Pro Leu Val Pro Val Met Gln Arg Arg Ile Asp
260 265 270
Asp Gly Asp Gly Gly Asp Asp Leu Ala Ala Leu Val Glu Val Ile Thr
275 280 285
Ala Glu Glu Val Ala
290
<210> 11
<211> 290
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 11
Met Thr Asp Lys Pro Pro Val Thr Val Leu Gly Leu Gly Ala Met Gly
1 5 10 15
Thr Ala Leu Ala Arg Thr Leu Leu Asn Ala Gly Tyr Pro Thr Thr Val
20 25 30
Trp Asn Arg Thr Ala Ser Lys Thr Ala Pro Leu Thr Glu Leu Gly Ala
35 40 45
His Ala Ala Asp Ser Pro Ala Asp Ala Ile Ala Arg Gly Glu Leu Val
50 55 60
Leu Ala Cys Leu Leu Asp Tyr Asp Ser Val His Gln Thr Leu Ala Gly
65 70 75 80
Thr Gly Asp Ala Leu Arg Gly Lys Ala Phe Val Asn Leu Thr Asn Gly
85 90 95
Thr Pro Glu Gln Ala Arg Ala Leu Ala Gly Lys Leu Asp Thr Ala Tyr
100 105 110
Leu Asp Gly Gly Ile Met Ala Val Pro Pro Met Ile Gly Ser Pro Gly
115 120 125
Ala Phe Leu Phe Tyr Ser Gly Glu Ile Ala Val Phe Glu Gln Tyr Arg
130 135 140
Pro Val Leu Glu Ser Phe Gly Glu Ala Ile Glu Val Gly Thr Asp Pro
145 150 155 160
Gly Leu Ala Ala Leu His Asp Leu Ala Leu Leu Ser Ala Met Tyr Gly
165 170 175
Met Phe Gly Gly Val Leu Gln Ala Phe Ala Leu Thr Gly Ser Ala Gly
180 185 190
Val Ser Ala Ala Ser Leu Ala Pro Leu Leu His Arg Trp Leu Asp Gly
195 200 205
Met Ser Gly Phe Ile Ala Gln Ser Ala Ala Gln Leu Asp Ser Gly Asp
210 215 220
Phe Ala Thr Gly Val Val Ser Asn Leu Ala Met Gln Asp Thr Gly Phe
225 230 235 240
Ala Asn Leu Phe Arg Ala Ala Lys Glu Gln Gly Ile Ser Thr Gly Gln
245 250 255
Leu Glu Pro Leu Gly Ala Leu Ile Arg Arg Arg Val Glu Asp Gly His
260 265 270
Gly Ala Glu Asp Leu Ala Gly Ile Val Glu Tyr Leu Lys Ile Gly Ala
275 280 285
Asn Ala
290
<210> 12
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 12
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Leu Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 13
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 13
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Val Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Ala Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 14
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 14
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 15
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 15
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Ala Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Ala
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Gly Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 16
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 16
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Leu Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Ala Val Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Thr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Gly Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 17
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 17
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Leu Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Ala Val Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Gly Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 18
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 18
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Leu Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Ala Ala Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Gly Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 19
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 19
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Leu Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Ser Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Val Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Gly Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 20
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 20
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 21
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 21
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Tyr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ala Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
<210> 22
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> imine reductase
<400> 22
Met Arg His Leu Ser Val Ile Gly Leu Gly Ala Met Gly Ser Ala Leu
1 5 10 15
Ala Thr Thr Leu Leu Lys Ala Gly His Pro Val Thr Val Trp Asn Arg
20 25 30
Ser Ala Ala Lys Ala Ala Pro Leu Gln Ala Leu Gly Ala Thr Leu Ala
35 40 45
Pro Ser Val Gly Ala Ala Ile Ala Arg Ser Asp Ile Thr Leu Val Cys
50 55 60
Val Asp Asn Tyr Ala Val Ser Gln Gln Leu Leu Asp Glu Ala Ser Asp
65 70 75 80
Ala Val Ala Gly Lys Leu Leu Val Gln Leu Ser Thr Gly Ser Pro Gln
85 90 95
Gly Ala Arg Ala Leu Glu Ser Trp Ser His Ala Arg Gly Ala Arg Tyr
100 105 110
Leu Asp Gly Ala Ile Leu Cys Phe Pro Ala Gln Ile Gly Thr Ser Asp
115 120 125
Ala Ser Ile Ile Cys Ser Gly Ala Ser Ala Ala Phe Ser Glu Ala Glu
130 135 140
Pro Val Leu Arg Leu Leu Ala Pro Thr Leu Asp His Val Ala Glu Ala
145 150 155 160
Val Gly Ala Ala Ala Ala Gln Asp Cys Ala Val Ala Ala Tyr Phe Gly
165 170 175
Gly Gly Leu Leu Gly Ala Leu His Gly Ala Leu Ile Cys Glu Ala Glu
180 185 190
Gly Leu Pro Val Ala Lys Val Cys Ala Gln Phe Ser Glu Leu Ser Pro
195 200 205
Ile Leu Gly Gly Asp Val Ala His Leu Gly Lys Thr Leu Ala Ser Gly
210 215 220
Asp Phe Asp His Pro Thr Ala Ser Leu Lys Thr Trp Ser Ala Ala Ile
225 230 235 240
Ser Arg Leu Ala Gly His Ala Thr Asp Ala Gly Ile Asp Ser Arg Phe
245 250 255
Pro Arg Phe Ala Ala Asp Leu Phe Glu Glu Gly Val Ala Gln Gly Phe
260 265 270
Gly Gln Gln Glu Val Ser Ala Leu Ile Lys Val Leu Arg Ala Arg Asn
275 280 285
Gly Ala Ala Gln
290
Claims (12)
- 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 환원반응시켜 (S)-니코틴을 얻는, 환원방식을 이용한 (S)-니코틴의 제조 방법:
.
- 제 1 항에 있어서,
상기 환원반응은 생체효소 촉매화 방법을 사용하고, 상기 방법은,
조효소 순환 시스템 조건에서, 이민환원효소를 촉매로 촉매화 환원반응을 수행하여, 식 I로 표시되는 에나민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물을 촉매 환원시켜 (S)-니코틴을 얻는 단계; 를 포함하는, 제조 방법.
- 제 2 항에 있어서,
상기 조효소 순환 시스템은 조효소, 포도당 및 포도당 탈수소효소를 포함하고;
바람직하게는, 상기 조효소는 NADP 염 및/또는 NAD 염을 포함하며, 바람직하게는 NADP 염이고;
바람직하게는, 상기 포도당 탈수소효소는 서열번호 1로 표시되는 아미노산 서열을 포함하는, 제조 방법.
- 제 2 항에 있어서,
상기 이민환원효소는 서열번호 2 내지 서열번호 6, 서열번호 8, 서열번호 11, 서열번호 12, 또는 서열번호 12와 적어도 95% 동일성을 갖는 아미노산 서열을 포함하고; 바람직하게는 서열번호 2 내지 서열번호 4, 서열번호 12, 또는 서열번호 12와 적어도 95% 동일성을 갖는 아미노산 서열인, 제조 방법.
- 제 2 항에 있어서,
상기 촉매화 환원반응은 15-45℃에서 수행되며;
바람직하게는, 상기 촉매화 환원반응은 완충액 시스템에서 수행되고, 상기 완충액은 인산염 완충액, 트리스히드록시메틸아민-염산염 완충액 또는 트리에탄올아민-염산염 완충액을 포함하며;
바람직하게는, 상기 촉매화 환원반응은 pH=6.0-8.0 에서 수행되는, 제조 방법.
- 제 1 항에 있어서,
상기 환원반응은 키랄 금속 촉매에 의한 촉매 방법을 사용하고, 상기 방법은 수소가스 분위기에서, 식 I로 표시되는 엔아민 화합물 및/또는 식 II로 표시되는 이미늄 양이온 화합물이 키랄 금속 촉매에 의해 (S)-니코틴으로 촉매화 환원되는 단계; 를 포함하는, 제조 방법.
- 제 6 항에 있어서,
상기 키랄 금속 촉매는 키랄 이리듐 촉매, 키랄 루테늄 촉매 또는 키랄 로듐 촉매을 포함하고, 바람직하게는 키랄 이리듐 촉매이고;
바람직하게는, 상기 촉매화 환원 시스템에 리간드를 더 첨가하며;
바람직하게는, 상기 촉매화 환원반응은 50-100℃에서 수행되고;
바람직하게는, 상기 촉매화 환원반응 시스템에서의 수소가스는 1.0-6.0MPa로 유지되며;
바람직하게는, 상기 촉매화 환원반응은 pH=4.0-13.0 에서 수행되는, 제조 방법.
- 제 1항 내지 제 7 항 중 어느 한 항에 있어서,
상기 식 I로 표시되는 엔아민 화합물 또는 식 II로 표시되는 이미늄 양이온 화합물은 식 III으로 표시되는 화합물 또는 그 염이 탈염 및/또는 고리화를 거쳐 얻어지는, 제조 방법:
;
바람직하게는, 상기 염은 염산염, 이염산염, 브롬화수소산염, 이브롬화수소산염, 황산염 또는 중황산염을 포함한다.
- 제 8 항에 있어서,
식 III으로 표시되는 화합물의 염의 합성방법은,
화합물 A를 N-메틸피롤리돈 및 유기 염기와 혼합하여 반응시켜 화합물 D를 얻고; 화합물 D를 산과 혼합하여 반응시켜 식 III으로 표시되는 화합물의 염을 얻는 단계; 를 포함하고, 그 반응식은 아래와 같은, 제조 방법:
.
- 제 8 항에 있어서,
식 III으로 표시되는 화합물의 염의 합성방법은,
화합물 A를 N-메틸피롤리돈 및 유기 염기와 혼합하여 반응시킨 후, 산을 첨가하여 pH=7-8로 중화시켜 화합물 B를 얻고; 화합물 B를 산과 혼합하고 반응시켜 식 III으로 표시되는 화합물의 염을 얻는 단계; 를 포함하고, 그 반응식은 아래와 같은, 제조 방법:
.
- 제 9 항 또는 제 10 항에 있어서,
상기 화합물 A의 합성방법은, 니코틴산과 메탄올을 혼합하고, 강산성 환경에서 에스테르화 반응을 수행하여 얻는 단계; 를 포함하는, 제조 방법.
- 제 1 항 내지 제 11 항 중 어느 한 항에 있어서,
상기 방법은,
니코틴산과 메탄올을 혼합하고, 강산성 환경에서 에스테르화 반응을 수행하여 화합물 A를 얻고; 화합물 A를 N-메틸피롤리돈 및 유기 염기와 혼합하고 반응시킨 후, 선택적으로 산을 첨가하여 중화시켜 화합물 B 또는 D를 얻으며; 그 후 다시 산과 혼합하여 반응시켜 식 III으로 표시되는 화합물의 염을 얻고; 탈염 및 고리화가 일어나며, 최종적으로 생체효소 촉매화 방법 또는 키랄 금속 촉매에 의한 촉매화 방법을 사용하여 환원반응을 수행하여 (S)-니코틴을 얻는 단계; 를 포함하고, 그 반응식은 아래와 같은, 제조 방법:
.
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