CN115404249A - 一种(s)-尼古丁中间体的制备方法及其应用 - Google Patents
一种(s)-尼古丁中间体的制备方法及其应用 Download PDFInfo
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- CN115404249A CN115404249A CN202110594146.3A CN202110594146A CN115404249A CN 115404249 A CN115404249 A CN 115404249A CN 202110594146 A CN202110594146 A CN 202110594146A CN 115404249 A CN115404249 A CN 115404249A
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- nicotine
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- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 100
- 229960002715 nicotine Drugs 0.000 title claims abstract description 100
- 229930182840 (S)-nicotine Natural products 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 102000004190 Enzymes Human genes 0.000 claims abstract description 44
- 108090000790 Enzymes Proteins 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 34
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 22
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 20
- 229940126062 Compound A Drugs 0.000 claims description 18
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 18
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- 150000002466 imines Chemical class 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 17
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- 239000005515 coenzyme Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 239000011664 nicotinic acid Substances 0.000 claims description 10
- 229960003512 nicotinic acid Drugs 0.000 claims description 10
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- 239000008363 phosphate buffer Substances 0.000 claims description 9
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 claims description 8
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
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- 230000007062 hydrolysis Effects 0.000 claims description 6
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
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- HHLJUSLZGFYWKW-UHFFFAOYSA-N triethanolamine hydrochloride Chemical compound Cl.OCCN(CCO)CCO HHLJUSLZGFYWKW-UHFFFAOYSA-N 0.000 claims 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
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- 108010050848 glycylleucine Proteins 0.000 description 9
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- 108010061238 threonyl-glycine Proteins 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 8
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
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- 230000003287 optical effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- BTBUEVAGZCKULD-XPUUQOCRSA-N Ala-Gly-His Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BTBUEVAGZCKULD-XPUUQOCRSA-N 0.000 description 6
- TZDNWXDLYFIFPT-BJDJZHNGSA-N Ala-Ile-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O TZDNWXDLYFIFPT-BJDJZHNGSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PHONXOACARQMPM-BQBZGAKWSA-N Gly-Ala-Met Chemical compound [H]NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O PHONXOACARQMPM-BQBZGAKWSA-N 0.000 description 6
- ULXYQAJWJGLCNR-YUMQZZPRSA-N Leu-Asp-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O ULXYQAJWJGLCNR-YUMQZZPRSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
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- 239000000706 filtrate Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
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- DKJPOZOEBONHFS-ZLUOBGJFSA-N Ala-Ala-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O DKJPOZOEBONHFS-ZLUOBGJFSA-N 0.000 description 5
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 5
- KUFVXLQLDHJVOG-SHGPDSBTSA-N Ala-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C)N)O KUFVXLQLDHJVOG-SHGPDSBTSA-N 0.000 description 5
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 5
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 108010031719 prolyl-serine Proteins 0.000 description 1
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
Abstract
本发明涉及一种(S)‑尼古丁中间体的制备方法及其在制备(S)‑尼古丁中的应用,制备方法包括:式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)‑尼古丁中间体;鉴于现有技术中已公开的制备(S)‑尼古丁的策略大多需要甲基化方式才能得到(S)‑尼古丁,或者不经甲基化使用酶催化得不到(S)‑尼古丁,(S)‑尼古丁的制备策略还十分有限,本发明创造性地开发了全新的直接将甲基经酶催化带入产物中的策略,实现了无需甲基化过程即可高效制备(S)‑尼古丁,即先将上述式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)‑尼古丁中间体;后续可进一步反应得到(S)‑尼古丁。该策略操作简单、安全可靠,收率高,纯度高,且可降低制备成本。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种(S)-尼古丁中间体的制备方法及其应用,尤其涉及一种利用生物催化制备(S)-尼古丁中间体的方法及其在制备(S)-尼古丁中的应用。
背景技术
(S)-尼古丁(烟碱)是一种存在于茄科植物(茄属)中的生物碱,也是烟草的重要成分。烟叶中含有1.5%-3.5%的(S)-尼古丁,从烟叶从提取烟碱是目前获取烟碱的最主要方法,虽然已经有化学合成法的相关报道,但是化学合成方法还不成熟,其成本远高于提取法。目前已经报道的化学合成方法包括化学拆分法、不对称氢化法、手性辅助试剂法等。
专利WO2014174505公开了使用亚胺还原酶(iminereductase enzyme)催化pseudooxynicotine得到尼古丁,该专利使用的亚胺还原酶包括sp.GF3546、sp.GF3546,且其催化只能制备得到(R)-尼古丁,没有公开如何制备(S)-尼古丁。
专利US10913962B公开了使用酶催化麦思明制备(S)-去甲烟碱,再对(S)-去甲烟碱甲基化最后得到(S)-尼古丁。该发明使用生物催化制备(S)-去甲烟碱解决了成本高的问题,而且能够得到高收率的(S)-去甲烟碱,同时在甲基化过程中需要甲醛提供甲基来源,需要甲酸作为还原剂。
为了解决现有技术需要甲基化方式才能制备(S)-尼古丁,或者不经甲基化使用酶催化得不到(S)-尼古丁的问题,需要开发一种新的制备(S)-尼古丁的策略。
发明内容
针对现有技术的不足,本发明的目的在于提供一种(S)-尼古丁中间体的制备方法及其应用,尤其提供一种利用生物催化制备(S)-尼古丁中间体的方法及其在制备(S)-尼古丁中的应用。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种(S)-尼古丁中间体的制备方法,所述(S)-尼古丁中间体的制备方法包括:式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)-尼古丁中间体;
鉴于现有技术中已公开的制备(S)-尼古丁的策略大多需要甲基化方式才能得到(S)-尼古丁,或者不经甲基化使用酶催化得不到(S)-尼古丁,(S)-尼古丁的制备策略还十分有限,本发明创造性地开发了全新的直接将甲基经酶催化带入产物中的策略,实现了无需甲基化过程即可高效制备(S)-尼古丁,即先将上述式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)-尼古丁中间体;后续可进一步反应得到(S)-尼古丁。该策略操作简单、安全可靠,收率高,纯度高,且可降低制备成本。
优选地,所述生物酶催化的方法包括:在辅酶循环系统的条件下,以亚胺还原酶为催化剂进行催化。
优选地,所述亚胺还原酶包括SEQ ID No.2-9所示的氨基酸序列,优选SEQ IDNo.2、SEQ ID No.4、SEQ ID No.5所示的氨基酸序列。
与其他亚胺还原酶类型相比,具有SEQ ID No.2-9所示氨基酸序列的亚胺还原酶能更显著地使式Ⅲ所示化合物转化成式Ⅱ所示(S)-尼古丁中间体,其中具有SEQ ID No.2、SEQ ID No.4、SEQ ID No.5所示氨基酸序列的亚胺还原酶使式Ⅲ所示化合物转化成式Ⅱ所示(S)-尼古丁中间体的效率更高,超过50%。
SEQ ID No.2:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGEAIAASDITLVCVDNYAVSQQLLDEASDAVAGKLLVQLSTGSPQGARSLESWCHTRGARYLDGAILCFPDQIGTTDASIICSGASTAFSEAEPVLRLLAPPLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEVEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ。
SEQ ID No.3:
MRHLSVIGLGAMGSALATTLLKAGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQLLLDEASDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPAQIGTSDASIICSGASAAFSEAEPVLSLLAPTLDHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAQ。
SEQ ID No.4:
MRHLSVIGLGAMGSALATTLIKGGHPVTVWNRSAAKAAPLQALGATLAPSVGAAIAASDITLVCVDNYAVSQQLLDEARDAVAGKLLVQLSTGSPQGARALESWSHARGARYLDGAILCFPDQIGTSDASIICSGASAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLAGHATDAGIDSRFPRFAADLFEEGVAQGFGQQEVSALIKVLRARNGAAL。
SEQ ID No.5:
MRPISVIGLGAMGSALATTLLKAGHPVTVWNRSAAKATPLIALGAILAPSVSEAIAAGDITLICVDNYAVSQQLLDEASNAVTGKLVVQLSTGSPLGARTLESWCHARGACYLDGAILCFPDQIGTTDASIICSGANAAFREAEPVLRLLAPTLEHVAEAVGAAAAQDCAVAAYFAGGLLGALHGALICEAEGLPVAKVCAQFSELSPILGGDVAHLGKTLASGDFDHPYASLKTWSAAISRLTDHAADAGIDNSFPRFAADLFEEGVEQGLGQQEVSALIKVLRARNGAAQ。
SEQ ID No.6:
MSKQSVTVIGLGPMGQAMVNTFLDNGHEVTVWNRTASKAEALVARGAVLAPTVEDALSANELIVLSLTDYDAVYAILEPVTGSLSGKVIANLSSDTPDKAREAAKWAAKHGAKHLTGGVQVPPPLIGKPESSTYYSGPKDVFDAHEDTLKVLTNADYRGEDAGLAAMYYQAQMTIFWTTMLSYYQTLALGQANGVSAKELLPYATMMTSMMPHFLELYAQHVDSADYPGDVDRLAMGAASVDHVLHTHQDAGVSTVLPAAVAEIFKAGMEKGFAENSFSSLIEVLKKPAV。
SEQ ID No.7:
MTVLGLGAMGTALVEAFLAGGHATTVWNRTPGKADGVVARGAVVAETVAEAVAASPLVVVCLWDDAVVRDVLHPVADALAGRVVVNLTNGTPAQAREMAAWAAEHGVEYVDGGIMAIPPGIGTEHAFVLYSGAEAAFEAHREVLERLGAAKYLGADAGLAALFDLALLSGMYGTFAGLWHSLAMVRTENVSAAEFVPMLGPWMQAMIGGNLDRLAHQLDTGDYGHEVVSNLAMQAAAFPNIVQASLDQGIRPDLMAPIQRLMDQAVAAGHGAEDVAVVVDLLKN。
SEQ ID No.8:
MTDLGKSAVTVLGLGAMGTALAEALLAAGHPTTVWNRSPARTAGPAQRGAAVAAATAEAIAASRLIVVCLLDHTSVHAVLDGQELTGRIVVNLTSGTPGQARELDARVAERGGDHLDGAVLAVPSMIGTPDASVLYSGSRGAFDTHRPVLEVFGAADYVGADPGAASLQDAALLSAMYGQVAGVLHAFALVRSAGVTATEFLPRLVGWLTAMGGFPADAARRIDARAYADDVDAALTMQVTAVRNLVRAAREQGVSAELIAPLVPVMQRRIDDGDGGDDLAALVEVITAEEVA。
SEQ ID No.9:
MTDKPPVTVLGLGAMGTALARTLLNAGYPTTVWNRTASKTAPLTELGAHAADSPADAIARGELVLACLLDYDSVHQTLAGTGDALRGKAFVNLTNGTPEQARALAGKLDTAYLDGGIMAVPPMIGSPGAFLFYSGEIAVFEQYRPVLESFGEAIEVGTDPGLAALHDLALLSAMYGMFGGVLQAFALTGSAGVSAASLAPLLHRWLDGMSGFIAQSAAQLDSGDFATGVVSNLAMQDTGFANLFRAAKEQGISTGQLEPLGALIRRRVEDGHGAEDLAGIVEYLKIGANA。
在本发明中,所述辅酶循环系统包括辅酶、葡萄糖和葡萄糖脱氢酶。
优选地,所述辅酶包括NADP盐和/或NAD盐,优选NADP盐。
优选地,所述葡萄糖脱氢酶包括SEQ ID No.1所示的氨基酸序列。
SEQ ID No.1:
MYKDLEGKVVVITGSSTGLGKSMAIRFATEKAKVVVNYRSKEDEANSVLEEIKKVGGEAIAVKGDVTVESDVINLVQSAIKEFGKLDVMINNAGLENPVSSHEMSLSDWNKVIDTNLTGAFLGSREAIKYFVENDIKGTVINMSSVHEKIPWPLFVHYAASKGGMKLMTETLALEYAPKGIRVNNIGPGAINTPINAEKFADPEQRADVESMIPMGYIGEPEEIAAVAAWLASSEASYVTGITLFADGGMTQYPSFQAGR。
优选地,所述反应在15-45℃下进行,例如15℃、20℃、25℃、30℃、35℃、40℃、45℃等,该数值范围内的其他具体点值均可选择,在此便不再一一赘述。
优选地,所述反应在缓冲液体系中进行,所述缓冲液包括磷酸盐缓冲液、三羟甲基甲胺-盐酸缓冲液或三乙醇胺-盐酸缓冲液。
优选地,所述反应在pH=6.0-8.0下进行,例如pH=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等,该数值范围内的其他具体点值均可选择,在此便不再一一赘述。
第二方面,本发明提供一种如第一方面所述的(S)-尼古丁中间体的制备方法在制备(S)-尼古丁中的应用。
第三方面,本发明提供一种(S)-尼古丁的制备方法,所述(S)-尼古丁的制备方法包括:以第一方面所述的(S)-尼古丁中间体的制备方法制得式Ⅱ所示的(S)-尼古丁中间体;式Ⅱ所示的(S)-尼古丁中间体再与氯化剂混合反应,然后调节反应体系的pH值,得到式Ⅰ所示的(S)-尼古丁;其反应式如下所示:
优选地,所述氯化剂包括氯化亚砜、甲磺酰氯、对甲苯磺酰氯或对硝基苯磺酰氯。
优选地,所述pH值调节至12-14,例如pH=12、pH=12.5、pH=13、pH=13.5、pH=14等,该数值范围内的其他具体点值均可选择,在此便不再一一赘述。
式Ⅲ所示的化合物可以通过现有技术中公开的合成技术和策略进行制备,示例性地,可以由包括如下步骤的合成路线制备得到:
(1)将烟酸与甲醇混合,在强酸性或强碱性环境中进行酯化反应,得到化合物A;
(2)化合物A与γ-丁内酯反应,得到化合物B;
(3)化合物B发生开环水解,得到式Ⅲ所示的化合物;
其反应式如下所示:
优选地,步骤(3)所述开环水解的具体操作包括:化合物B与硫酸混合,回流反应,调节反应体系的pH值至10-12,例如pH=10、pH=10.5、pH=11、pH=11.5、pH=12等,该数值范围内的其他具体点值均可选择,在此便不再一一赘述即得。
作为本发明的优选技术方案,所述(S)-尼古丁的制备方法具体包括如下步骤:
(1)将烟酸与甲醇混合,在强酸性或强碱性环境中进行酯化反应,得到化合物A;
(2)化合物A与γ-丁内酯反应,得到化合物B;
(3)化合物B发生开环水解,得到式Ⅲ所示的化合物;
(4)式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)-尼古丁中间体;所述生物酶催化的方法为:在辅酶循环系统的条件下,以亚胺还原酶为催化剂进行催化;所述亚胺还原酶包括SEQ ID No.2-9所示的氨基酸序列,优选SEQ ID No.2、SEQ ID No.4、SEQ ID No.5所示的氨基酸序列;
(5)式Ⅱ所示的(S)-尼古丁中间体再与氯化剂混合反应,然后调节反应体系的pH值,得到式Ⅰ所示的(S)-尼古丁;其反应式如下所示:
相对于现有技术,本发明具有以下有益效果:
鉴于现有技术中已公开的制备(S)-尼古丁的策略大多需要甲基化方式才能得到(S)-尼古丁,或者不经甲基化使用酶催化得不到(S)-尼古丁,(S)-尼古丁的制备策略还十分有限,本发明创造性地开发了全新的直接将甲基经酶催化带入产物中的策略,实现了无需甲基化过程即可高效制备(S)-尼古丁,即将式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)-尼古丁中间体;后续可进一步反应得到(S)-尼古丁。该策略操作简单、安全可靠,收率高,纯度高,且可降低制备成本。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
NADP盐为购自于尚科生物医药(上海)有限公司;
酶2的来源为自制;酶1、3-11的来源为自制。
制备例1-1
本制备例制备化合物A:
向500mL反应瓶中加入烟酸50g,甲醇250g,启动搅拌,向反应瓶中滴加浓硫酸60g,滴加完毕后升温至回流反应18小时后降温到45℃减压浓缩,蒸出甲醇,待无馏分蒸出后,浓缩残留物降温至20℃,向浓缩残留物中加入乙酸乙酯250g,水250g,搅拌溶清后用20%氢氧化钠水溶液调节pH至7.5,静置分层,收集有机层,水层再用乙酸乙酯250g萃取一次,合并有机层,用无水硫酸钠干燥后,减压蒸除溶剂得无色透明液体55.2g,纯度99%,收率99%,该液体冷却后固化。
对制得的化合物A进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.22(1H,d),8.77(1H,dd),8.29(1H,dt),7.39(1H,dd),3.95(3H,s)。表明化合物A被成功合成。
制备例1-2
本制备例制备化合物A:
向500mL反应瓶中加入烟酸50g,甲醇250g,开启搅拌,升温至回流后向反应瓶中滴加氯化亚砜120.5g(2.5eq),滴加完毕后保持回流反应9小时后,40℃减压浓缩,蒸出甲醇,待无馏分蒸出后,浓缩残留物降温至10℃,向浓缩残留物中加入二氯甲烷200g,水100g,搅拌溶清后用15%氢氧化钠水溶液调节pH至8,静置分层,收集有机层,水层用200g二氯甲烷再萃取一次,合并有机层,用5%氢氧化钠水溶液100g洗涤一次,有机层用无水硫酸钠干燥后,减压蒸除溶剂得浅黄色透明液体44.8g,纯度99%,收率81%,该液体冷却后固化即得。
对制得的化合物A进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.22(1H,d),8.77(1H,dd),8.29(1H,dt),7.39(1H,dd),3.95(3H,s)。表明化合物A被成功合成。
制备例1-3
本制备例制备化合物A:
向100mL反应瓶中加入烟酸5g,原甲酸三甲酯5.2g(1.2eq),甲醇25g,四氯化锆0.48g(0.05eq),启动搅拌,升温至回流反应17小时后降温到25℃,加入乙醇钠0.55g(0.2eq)中和后,过滤,滤液减压浓缩,蒸出甲醇,得无色透明液体5.5g,纯度98.1%,收率99%,该液体冷却后固化即得。
对制得的化合物A进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.22(1H,d),8.77(1H,dd),8.29(1H,dt),7.39(1H,dd),3.95(3H,s)。表明化合物A被成功合成。
制备例1-4
本制备例制备化合物A:
向100mL反应瓶中加入烟酸5g,原甲酸三甲酯5.2g(1.2eq),甲醇25g,四氯化锆0.1g(0.01eq),启动搅拌,升温至回流反应36小时后降温到30℃,加入乙醇钠0.11g(0.04eq)中和后,过滤,滤液减压浓缩,蒸出甲醇,得无色透明液体5.3g,纯度91.6%,收率95%,该液体冷却后固化即得。
对制得的化合物A进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.22(1H,d),8.77(1H,dd),8.29(1H,dt),7.39(1H,dd),3.95(3H,s)。表明化合物A被成功合成。
制备例1-5
本制备例制备化合物A:
向100mL反应瓶中加入烟酸5g,原甲酸三甲酯5.2g(1.2eq),甲醇25g,四氯化锆0.19g(0.02eq),启动搅拌,升温至回流反应30小时后降温到20℃,加入乙醇钠0.22g(0.08eq)中和后,过滤,滤液减压浓缩,蒸出甲醇,得无色透明液体5.4g,纯度93.9%,收率97%,该液体冷却后固化即得。
对制得的化合物A进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.22(1H,d),8.77(1H,dd),8.29(1H,dt),7.39(1H,dd),3.95(3H,s)。表明化合物A被成功合成。
制备例1-6
本制备例制备化合物A:
向2L反应瓶中加入烟酸200g,原甲酸三甲酯207g(1.2eq),甲醇1000g,四氯化锆9.5g(0.025eq),启动搅拌,升温至回流反应20小时后降温到25℃,加入乙醇钠11.06g(0.1eq)中和后,过滤,滤液减压浓缩,蒸出甲醇,得无色透明液体220.6g,纯度98.5%,收率99%,该液体冷却后固化即得。
对制得的化合物A进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.22(1H,d),8.77(1H,dd),8.29(1H,dt),7.39(1H,dd),3.95(3H,s)。表明化合物A被成功合成。
制备例2-1
本制备例制备式Ⅲ所示化合物:
向100mL反应瓶中加入制备例1-1制得的化合物A 5g,四氢呋喃50mL,叔丁醇钾8.1g(2.0eq),γ-丁内酯3.1g(1.0eq),启动搅拌,升温至55℃,反应18小时后,降温至25℃,得化合物B反应液,不进行任何处理直接进行后续反应。
向上述反应液中加入30%硫酸水溶液25g,升温到常压蒸出溶剂,直至内温达到105℃后,回流反应19小时后降温至5℃,用4%氢氧化钠水溶液调节pH至11后用乙酸乙酯100g分四次萃取,合并有机层,减压浓缩得式Ⅲ所示化合物3.8g,为棕色油状物,纯度56%,收率63%。
对制得的式Ⅲ所示化合物进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.07(1H,d),8.65-8.66(1H,dd),8.16-8.19(1H,dt),7.34-7.37(1H,m),3.80(1H,s),3.65-3.69(2H,t),3.05-3.09(2H,t),1.91-1.98(2H,m)。表明式Ⅲ所示化合物被成功合成。
制备例2-2
本制备例制备式Ⅲ所示化合物:
向500mL反应瓶中加入制备例1-2制得的化合物A 20g,四氢呋喃200g,甲醇钠23.6g(3eq),γ-丁内酯15.1g(1.2eq),启动搅拌,升温至回流,反应6小时后,降温至25℃,得化合物B反应液,不进行任何处理直接进行后续反应。
向上述反应液中加入30%硫酸水溶液100g,升温到常压蒸出溶剂,直至内温达到110℃后,回流反应17小时后降温至0℃,用4%氢氧化钠水溶液调节pH至10后用乙酸乙酯400g分四次萃取,合并有机层,减压浓缩得式Ⅲ所示化合物21.2g,为棕色油状物,纯度69.8%,收率88.2%。
对制得的式Ⅲ所示化合物进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.07(1H,d),8.65-8.66(1H,dd),8.16-8.19(1H,dt),7.34-7.37(1H,m),3.80(1H,s),3.65-3.69(2H,t),3.05-3.09(2H,t),1.91-1.98(2H,m)。表明式Ⅲ所示化合物被成功合成。
制备例2-3
本制备例制备式Ⅲ所示化合物:
向500mL反应瓶中加入制备例1-3制得的化合物A 100g,四氢呋喃1000g,甲醇钠87.8g(2.2eq),γ-丁内酯75.3g(1.2eq),启动搅拌,升温至回流,反应18小时后,降温至25℃,得化合物B反应液,不进行任何处理直接进行后续反应。
向上述反应液中加入30%硫酸水溶液385g,升温到常压蒸出溶剂,直至内温达到110℃后,回流反应17小时后降温至10℃,用4%氢氧化钠水溶液调节pH至12后用乙酸乙酯2000g分四次萃取,合并有机层,减压浓缩得式Ⅲ所示化合物102g,为棕色油状物,纯度92%,收率85%。
对制得的式Ⅲ所示化合物进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.07(1H,d),8.65-8.66(1H,dd),8.16-8.19(1H,dt),7.34-7.37(1H,m),3.80(1H,s),3.65-3.69(2H,t),3.05-3.09(2H,t),1.91-1.98(2H,m)。表明式Ⅲ所示化合物被成功合成。
制备例2-4
本制备例制备式Ⅲ所示化合物:
向50L反应釜中加入制备例1-4制得的化合物A 1.68kg,四氢呋喃16.81kg,甲醇钠1.48kg(2.2eq),γ-丁内酯1.26kg(1.2eq),启动搅拌,升温至回流,反应12小时后,降温至25℃,得化合物B反应液,不进行任何处理直接进行后续反应。
向上述反应液中加入30%硫酸水溶液1.9kg,升温到常压蒸出溶剂,直至内温达到105℃后,回流反应19小时后降温至5℃,用4%氢氧化钠水溶液调节pH至11后用乙酸乙酯39kg分四次萃取,合并有机层,减压浓缩得式Ⅲ所示化合物1.85kg,为棕色油状物,纯度89%,收率91%。
对制得的式Ⅲ所示化合物进行核磁氢谱表征,数据为:1H-NMR(400MHz,CDCl3):δppm 9.07(1H,d),8.65-8.66(1H,dd),8.16-8.19(1H,dt),7.34-7.37(1H,m),3.80(1H,s),3.65-3.69(2H,t),3.05-3.09(2H,t),1.91-1.98(2H,m)。表明式Ⅲ所示化合物被成功合成。
制备例3-1
本制备例制备如SEQ ID No.1所示氨基酸序列的葡萄糖脱氢酶:
将来源于Priestia megaterium(NCBI登录号AUO12718.1)的葡萄糖脱氢酶氨基酸序列(SEQ ID No.1)送至南京金斯瑞公司进行密码子优化和全基因合成,连接入质粒pET30a(+)中;将重组质粒转入大肠杆菌BL21(DE3)感受态细胞,获得含有葡萄糖脱氢酶基因的重组菌。
将上述重组菌接种于5mL含有50μg/mL卡那霉素的LB液体培养基中,置于37℃下培养过夜;取1mL菌液接种于125mL含有50μg/mL卡那霉素的LB液体培养基中,置于37℃下培养3h,然后加入125μL 1M IPTG,25℃下诱导过夜;离心(4000rpm,4℃,10min)收集菌体,加入4倍体积的磷酸缓冲液(pH=7.0)重悬,重悬后对细胞进行超声破碎,离心(4000rpm,4℃,10min)取上清溶液进行冷冻干燥,获得葡萄糖脱氢酶酶粉。
制备例3-2
本制备例制备以下10种亚胺还原酶:
将NCBI上报道的亚胺还原酶氨基酸序列(SEQ ID No.2-11,信息见下表)送至南京金斯瑞公司进行密码子优化和全基因合成,连接入质粒pET30a(+)中;将重组质粒转入大肠杆菌BL21(DE3)感受态细胞,获得含有亚胺还原酶基因的重组菌。
将上述重组菌接种于5mL含有50μg/mL卡那霉素的LB液体培养基中,置于37℃下培养过夜;取1mL菌液接种于125mL含有50μg/mL卡那霉素的LB液体培养基中,置于37℃下培养3h,然后加入125μL 1M IPTG,25℃下诱导过夜;离心(4000rpm,4℃,10min)收集菌体,加入4倍体积的磷酸缓冲液(pH=7.0)重悬,重悬后对细胞进行超声破碎,离心(4000rpm,4℃,10min)取上清溶液进行冷冻干燥,获得亚胺还原酶酶粉。
实施例1
本实施例制备式Ⅱ所示的(S)-尼古丁中间体:
向10个5mL离心管中分别加入20mg制备例2-1制得的4-羟基-1-(3-吡啶基)-1-丁酮,加入2mL 0.1M的磷酸盐缓冲液,调节pH至6.0。再向反应瓶中加入32mg葡萄糖,13mg一甲胺盐酸盐,搅拌至完全溶解,再向其中分别加入30mg SEQ ID No.2-9所示氨基酸序列的酶1,酶3,酶4,酶5,酶6,酶7,酶10,酶11以及作为对比的SEQ ID No.10-11所示氨基酸序列的酶8,酶9。在另一个5mL离心管中加入3mL 0.1M的磷酸盐缓冲液,40mg SEQ ID No.1所示氨基酸序列的酶2和40mg NADP盐,搅拌至完全溶解。然后将第二个离心管中的溶液分别取0.1mL缓慢加入第一个离心管中,升温至25℃,以300r/min搅拌反应16h。分别取反应液0.1mL加入0.9mL的甲醇中振荡1min后过滤至1mL液相瓶中供高效液相分析,以(S)-4-(甲基氨基)-4-(3-吡啶基)-1-丁醇的面积比为转化率。
SEQ ID No.10:
MKPTLTVIGAGRMGSALIKAFLQSGYTTTVWNRTKAKSEPLAKLGAHLADTVRDAVKRSDIIVVNVLDYDTSDQLLRQDEVTRELRGKLLVQLTSGSPALAREQETWARQHGIDYLDGAIMATPDFIGQAECALLYSGSAALFEKHRAVLNVLGGATSHVGEDVGHASALDSALLFQMWGTLFGTLQALAISRAEGIPLEKTTAFIKLTEPVTQGAVADVLTRVQQNRLTADAQTLASLEAHNVAFQHLLALCEERNIHRGVADAMYSVIREAVKAGHGKDDFAILTRFLK。
SEQ ID No.11:
MVSSPYLNVTAYPKVRNLPWPVPGPIRVASQILELRPMTTIGFLGAGRMGSALVKSLLEAGHSVHVWNRTAEKAQALADFGAVPEPSAERAAGPAEIVIVNLLDYEASDAELRKPDVAEALKGKLLVQLTSGSPKTARETGRWAGDHGIAYLDGAIMATPNFIGGAETVILYSGSKTHFEKHEGLFKALGGKSAFVGEDFGTASALDSALLSQMWGTLFGTLQALAVCRAEGIEHDVYAGFLMSAQPMIDGAQQDLMERIRDGRDLADAQTLATVAVHNVAFHHLRDLIADRDLNPAFGDALGSLLETALRNDHQDDDFAVLARFMGAK。
结果如表1所示。
表1
酶 | 1 | 3 | 4 | 5 | 6 |
转化率% | 55.2 | 34.6 | 77.2 | 83.2 | 11.3 |
酶 | 7 | 8 | 9 | 10 | 11 |
转化率% | 5.2 | 0 | 0 | 44.3 | 13.6 |
由表1数据可知:相比于酶8和酶9,本发明所涉及的亚胺还原酶能够有效地将式Ⅲ所示化合物转化为式Ⅱ所示的(S)-尼古丁中间体,且酶1,酶4,酶5的转化率更高,转化率能达到55%以上。
实施例2
本实施例制备式Ⅱ所示的(S)-尼古丁中间体((S)-4-(甲基氨基)-4-(3-吡啶基)-1-丁醇):
向5000mL四口夹套瓶中加入200g制备例2-2制得的4-羟基-1-(3-吡啶基)-1-丁酮,加入2000mL 0.1M的磷酸盐缓冲液,调节pH至6.0。再向反应瓶中加入320g葡萄糖,150g一甲胺盐酸盐,搅拌至完全溶解。在另一个500mL三口圆底烧瓶中加入200mL 0.1M的磷酸盐缓冲液、20g SEQ ID No.5所示氨基酸序列的酶5、5g SEQ ID No.1所示氨基酸序列的酶2和1g NADP盐,搅拌至完全溶解。然后将第二个三口圆底烧瓶中的溶液缓慢加入第一个四口夹套瓶中,升温至25℃,以300r/min搅拌反应16h。反应完成后,加入硅藻土搅拌30min,过滤,滤液用氢氧化钠溶液调节至pH=10后用乙酸乙酯萃取,无水硫酸钠干燥,浓缩后得(S)-尼古丁中间体((S)-4-(甲基氨基)-4-(3-吡啶基)-1-丁醇)183g。纯度98.2%,光学纯度100%,收率83.9%。
对制得的(S)-4-(甲基氨基)-4-(3-吡啶基)-1-丁醇进行核磁氢谱表征,数据为:1H-NMR(400MHz,DMSO):δppm 8.58(1H,s),8.36(1H,dd),7.85(1H,dt),7.34-7.37(1H,m),3.82-3.87(1H,m),3.78(1H,t),3.26(1H,s),1.68-1.76(2H,m),1.43-1.46(2H,m)。表明式(S)-尼古丁中间体被成功合成。
实施例3
本实施例制备式Ⅱ所示的(S)-尼古丁中间体:
向500mL三口圆底烧瓶中加入20g制备例2-3制得的4-羟基-1-(3-吡啶基)-1-丁酮,加入200mL 0.1M的磷酸盐缓冲液,调节pH至6.0。再向反应瓶中加入32g葡萄糖,15g一甲胺盐酸盐,搅拌至完全溶解。在另一个50mL三口圆底烧瓶中加入20mL 0.1M的磷酸盐缓冲液、3g SEQ ID No.4所示氨基酸序列的酶4、1g SEQ ID No.1所示氨基酸序列的酶2和0.2gNADP盐,搅拌至完全溶解。然后将第二个三口圆底烧瓶中的溶液缓慢加入第一个烧瓶中,升温至30℃,以300r/min搅拌反应16h。后处理操作:反应完成后,加入硅藻土搅拌30分钟,过滤,滤液用氢氧化钠溶液调节至pH=10后用乙酸乙酯萃取,无水硫酸钠干燥,浓缩后,得(S)-尼古丁中间体18.7g。纯度96.7%,光学纯度100%,收率85.7%。
对制得的(S)-尼古丁中间体进行核磁氢谱表征,数据为:1H-NMR(400MHz,DMSO):δppm 8.58(1H,s),8.36(1H,dd),7.85(1H,dt),7.34-7.37(1H,m),3.82-3.87(1H,m),3.78(1H,t),3.26(1H,s),1.68-1.76(2H,m),1.43-1.46(2H,m。表明式(S)-尼古丁中间体被成功合成。
应用例1
本应用例制备式Ⅰ所示的(S)-尼古丁:
向500mL反应瓶中加入式Ⅱ所示的(S)-尼古丁中间体50g,二氯甲烷250g,氯化亚砜49.5g(1.5eq),启动搅拌,保温在20℃反应20小时后,用30%氢氧化钠水溶液调节反应体系pH到13后搅拌2h,静置分层,水层再用750g二氯甲烷分三次萃取,合并有机层,减压浓缩蒸出溶剂,得浅黄色油状物,减压蒸馏纯化后得无色透明油状物32.8g,纯度99%,光学纯度97%,收率73%。
对制备得到的(S)-尼古丁进行核磁氢谱表征,数据为: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)。表明(S)-尼古丁被成功合成。
应用例2
本应用例制备式Ⅰ所示的(S)-尼古丁:
向500mL反应瓶中加入式Ⅱ所示的(S)-尼古丁中间体50g,二氯甲烷250g,甲磺酰氯38.2g(1.2eq),三乙胺36.5g(1.3eq)启动搅拌,回流反应40小时后,用30%氢氧化钠水溶液调节反应体系pH到12后搅拌2h,静置分层,水层再用750g二氯甲烷分三次萃取,合并有机层,减压浓缩蒸出溶剂,得浅黄色油状物,减压蒸馏纯化后得无色透明油状物31.5g,纯度99%,光学纯度96%,收率70%。
对制备得到的(S)-尼古丁进行核磁氢谱表征,数据为: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)。表明(S)-尼古丁被成功合成。
应用例3
本应用例制备式Ⅰ所示的(S)-尼古丁:
向1000mL反应瓶中加入式Ⅱ所示的(S)-尼古丁中间体100g,二氯甲烷600g,二异丙基乙胺143.6g(2.0eq)启动搅拌,降温到0℃,滴加甲磺酰氯69.3g(1.1eq),滴加完毕后,升温到30℃反应。反应完全后,加入400mL水,静置分层,水层再用1200g二氯甲烷分三次萃取,合并有机层,减压浓缩蒸出溶剂,得浅黄色油状物,减压蒸馏纯化后得无色透明液体62.4g,纯度99%,光学纯度96%,收率75%。
对制备得到的(S)-尼古丁进行核磁氢谱表征,数据为: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)。表明(S)-尼古丁被成功合成。
申请人声明,本发明通过上述实施例来说明本发明的一种(S)-尼古丁中间体的制备方法及其应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
序列表
<110> 重庆博腾制药科技股份有限公司
<120> 一种(S)-尼古丁中间体的制备方法及其应用
<130> 2021
<160> 11
<170> SIPOSequenceListing 1.0
<210> 1
<211> 260
<212> PRT
<213> 人工序列(Artificial Sequence)
<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> 人工序列(Artificial Sequence)
<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> 人工序列(Artificial Sequence)
<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> 人工序列(Artificial Sequence)
<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> 人工序列(Artificial Sequence)
<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> 290
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Ser Lys Gln Ser Val Thr Val Ile Gly Leu Gly Pro Met Gly Gln
1 5 10 15
Ala Met Val Asn Thr Phe Leu Asp Asn Gly His Glu Val Thr Val Trp
20 25 30
Asn Arg Thr Ala Ser Lys Ala Glu Ala Leu Val Ala Arg Gly Ala Val
35 40 45
Leu Ala Pro Thr Val Glu Asp Ala Leu Ser Ala Asn Glu Leu Ile Val
50 55 60
Leu Ser Leu Thr Asp Tyr Asp Ala Val Tyr Ala Ile Leu Glu Pro Val
65 70 75 80
Thr Gly Ser Leu Ser Gly Lys Val Ile Ala Asn Leu Ser Ser Asp Thr
85 90 95
Pro Asp Lys Ala Arg Glu Ala Ala Lys Trp Ala Ala Lys His Gly Ala
100 105 110
Lys His Leu Thr Gly Gly Val Gln Val Pro Pro Pro Leu Ile Gly Lys
115 120 125
Pro Glu Ser Ser Thr Tyr Tyr Ser Gly Pro Lys Asp Val Phe Asp Ala
130 135 140
His Glu Asp Thr Leu Lys Val Leu Thr Asn Ala Asp Tyr Arg Gly Glu
145 150 155 160
Asp Ala Gly Leu Ala Ala Met Tyr Tyr Gln Ala Gln Met Thr Ile Phe
165 170 175
Trp Thr Thr Met Leu Ser Tyr Tyr Gln Thr Leu Ala Leu Gly Gln Ala
180 185 190
Asn Gly Val Ser Ala Lys Glu Leu Leu Pro Tyr Ala Thr Met Met Thr
195 200 205
Ser Met Met Pro His Phe Leu Glu Leu Tyr Ala Gln His Val Asp Ser
210 215 220
Ala Asp Tyr Pro Gly Asp Val Asp Arg Leu Ala Met Gly Ala Ala Ser
225 230 235 240
Val Asp His Val Leu His Thr His Gln Asp Ala Gly Val Ser Thr Val
245 250 255
Leu Pro Ala Ala Val Ala Glu Ile Phe Lys Ala Gly Met Glu Lys Gly
260 265 270
Phe Ala Glu Asn Ser Phe Ser Ser Leu Ile Glu Val Leu Lys Lys Pro
275 280 285
Ala Val
290
<210> 7
<211> 284
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Thr Val Leu Gly Leu Gly Ala Met Gly Thr Ala Leu Val Glu Ala
1 5 10 15
Phe Leu Ala Gly Gly His Ala Thr Thr Val Trp Asn Arg Thr Pro Gly
20 25 30
Lys Ala Asp Gly Val Val Ala Arg Gly Ala Val Val Ala Glu Thr Val
35 40 45
Ala Glu Ala Val Ala Ala Ser Pro Leu Val Val Val Cys Leu Trp Asp
50 55 60
Asp Ala Val Val Arg Asp Val Leu His Pro Val Ala Asp Ala Leu Ala
65 70 75 80
Gly Arg Val Val Val Asn Leu Thr Asn Gly Thr Pro Ala Gln Ala Arg
85 90 95
Glu Met Ala Ala Trp Ala Ala Glu His Gly Val Glu Tyr Val Asp Gly
100 105 110
Gly Ile Met Ala Ile Pro Pro Gly Ile Gly Thr Glu His Ala Phe Val
115 120 125
Leu Tyr Ser Gly Ala Glu Ala Ala Phe Glu Ala His Arg Glu Val Leu
130 135 140
Glu Arg Leu Gly Ala Ala Lys Tyr Leu Gly Ala Asp Ala Gly Leu Ala
145 150 155 160
Ala Leu Phe Asp Leu Ala Leu Leu Ser Gly Met Tyr Gly Thr Phe Ala
165 170 175
Gly Leu Trp His Ser Leu Ala Met Val Arg Thr Glu Asn Val Ser Ala
180 185 190
Ala Glu Phe Val Pro Met Leu Gly Pro Trp Met Gln Ala Met Ile Gly
195 200 205
Gly Asn Leu Asp Arg Leu Ala His Gln Leu Asp Thr Gly Asp Tyr Gly
210 215 220
His Glu Val Val Ser Asn Leu Ala Met Gln Ala Ala Ala Phe Pro Asn
225 230 235 240
Ile Val Gln Ala Ser Leu Asp Gln Gly Ile Arg Pro Asp Leu Met Ala
245 250 255
Pro Ile Gln Arg Leu Met Asp Gln Ala Val Ala Ala Gly His Gly Ala
260 265 270
Glu Asp Val Ala Val Val Val Asp Leu Leu Lys Asn
275 280
<210> 8
<211> 293
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
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> 9
<211> 290
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
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> 10
<211> 291
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
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> 11
<211> 329
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
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
Claims (10)
2.如权利要求1所述的(S)-尼古丁中间体的制备方法,其特征在于,所述生物酶催化的方法包括:在辅酶循环系统的条件下,以亚胺还原酶为催化剂进行催化;
优选地,所述亚胺还原酶包括SEQ ID No.2-9所示的氨基酸序列,优选SEQ ID No.2、SEQ ID No.4、SEQ ID No.5所示的氨基酸序列。
3.如权利要求2所述的(S)-尼古丁中间体的制备方法,其特征在于,所述辅酶循环系统包括辅酶、葡萄糖和葡萄糖脱氢酶;
优选地,所述辅酶包括NADP盐和/或NAD盐,优选NADP盐;
优选地,所述葡萄糖脱氢酶包括SEQ ID No.1所示的氨基酸序列。
4.如权利要求1-3中任一项所述的(S)-尼古丁中间体的制备方法,其特征在于,所述反应在15-45℃下进行;
优选地,所述反应在缓冲液体系中进行,所述缓冲液包括磷酸盐缓冲液、三羟甲基甲胺-盐酸缓冲液或三乙醇胺-盐酸缓冲液;
优选地,所述反应在pH=6.0-8.0下进行。
5.如权利要求1-4中任一项所述的(S)-尼古丁中间体的制备方法在制备(S)-尼古丁中的应用。
7.如权利要求6所述的(S)-尼古丁的制备方法,其特征在于,所述氯化剂包括氯化亚砜、甲磺酰氯、对甲苯磺酰氯或对硝基苯磺酰氯;
优选地,所述pH值调节至12-14。
9.如权利要求8所述的(S)-尼古丁的制备方法,其特征在于,步骤(3)所述开环水解的具体操作包括:化合物B与硫酸混合,回流反应,调节反应体系的pH值至10-12,即得。
10.如权利要求6-9中任一项所述的(S)-尼古丁的制备方法,其特征在于,所述(S)-尼古丁的制备方法具体包括如下步骤:
(1)将烟酸与甲醇混合,在强酸性或强碱性环境中进行酯化反应,得到化合物A;
(2)化合物A与γ-丁内酯反应,得到化合物B;
(3)化合物B发生开环水解,得到式Ⅲ所示的化合物;
(4)式Ⅲ所示的化合物在生物酶催化下与甲胺或其盐反应,得到式Ⅱ所示的(S)-尼古丁中间体;所述生物酶催化的方法为:在辅酶循环系统的条件下,以亚胺还原酶为催化剂进行催化;所述亚胺还原酶包括SEQ ID No.2-9所示的氨基酸序列,优选SEQ ID No.2、SEQ IDNo.4、SEQ ID No.5所示的氨基酸序列;
(5)式Ⅱ所示的(S)-尼古丁中间体再与氯化剂混合反应,然后调节反应体系的pH值,得到式Ⅰ所示的(S)-尼古丁;其反应式如下所示:
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Cited By (2)
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CN115627282A (zh) * | 2022-12-16 | 2023-01-20 | 山东金城医药化工有限公司 | (s)-烟碱及其中间体的合成方法 |
CN115820762A (zh) * | 2023-02-20 | 2023-03-21 | 山东金城医药化工有限公司 | 合成(s)-烟碱及其中间体的方法 |
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