CN105524971A - Novel method for resolving 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline through enzyme catalysis - Google Patents
Novel method for resolving 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline through enzyme catalysis Download PDFInfo
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Abstract
The invention relates to a method for resolving 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline through enzyme catalysis dynamic kinetics. Specifically, the invention provides a method for resolving 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline racemate into a single configuration product (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline through dynamic kinetics and by utilizing cyclohexane oxidase and a mutant thereof, wherein (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline is a key intermediate for synthesizing the central antitussive drug dextromethorphan. The method has the outstanding characteristics of high yield, good stereoselectivity, mild reaction conditions and the like.
Description
Technical field
The present invention relates to novel method prepared by a kind of cough medicine key intermediate, be specifically related to enzyme catalysis Dynamic Kinetic Resolution and prepare dextromethorphan hydrobromide key intermediate (S)-1-(4-methoxy-benzyl)-1,2,3,4,5, the novel method of 6,7,8-octahydro isoquinoline 99.9.
Background technology
Dextromethorphan hydrobromide is dextromethorphan HBr again, chemistry (+)-3-methoxyl group-17-methyl-(9 α by name, 13 α, 14 α)-morphinan Hydrogen bromide monohydrate, be applicable to the dry cough of catching a cold, acute or chronic bronchitis, bronchial asthma, pharyngolaryngitis, pulmonary tuberculosis and other upper respiratory tract infection cause.
The synthetic method of dextromethorphan hydrobromide is a lot, as Chinese patent CN201310041846, CN201310051880, CN201210405684, CN201310004262, CN201410169133 and document [today pharmacy, 2008,18 (4), 63-64], [Helv.Chim.Acta1956,39,1,376 1386], major part preparation method all needs to use intermediate (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9.The method of this intermediate of tradition preparation is by the 1-(4-methoxy-benzyl)-1 to racemization, 2,3,4,5,6,7,8-octahydro isoquinoline 99.9 carries out chiral separation acquisition, as Chinese patent CN201210073513, US Patent No. 8148527 and document [Helv.Chim.Acta1956,39,1,376 1386].Not only yield is lower for the method, complex operation, and produces a large amount of waste water.Also report metal catalytic asymmetric reduction 1-(4-methoxy-benzyl)-3,4,5 is had, 6,7,8-six hydrogen isoquinoline preparation (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7, the method of 8-octahydro isoquinoline 99.9, as Chinese patent CN201410169133 and document [Tetrahedron:Asymmetry1998,9,4043 – 4054].
We find, in the technique existed at present, still not utilize the method for enzyme catalysis Dynamic Kinetic Resolution 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9.The present invention intends adopting hexahydroaniline oxydase and mutant thereof to realize 1-(4-methoxy-benzyl)-1 in conjunction with non-selective reductant agent, 2,3,4,5,6,7, the Dynamic Kinetic Resolution of 8-octahydro isoquinoline 99.9, this process has the distinguishing features such as reaction conditions gentleness, pollution-free and operational path be simple.
Summary of the invention
The object of the present invention is to provide a kind of novel preparation method of dextromethorphan hydrobromide key intermediate (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9.
Technology contents of the present invention is: enzyme catalysis Dynamic Kinetic Resolution 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 preparation (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9, is characterized in that:
(1) expression of hexahydroaniline oxydase and mutant thereof
The successful recombinant bacterial strain that checks order lines LB(containing 100 μ g/mL penbritins) flat board on, after 12-14h cultivated by 37 ° of C incubators, colony growth is to enough large.Picking list bacterium colony, is inoculated in 5mL selectivity LB(containing 100 μ g/mL penbritins) in liquid nutrient medium, 37 DEG C, 200rpm/min shaking culture is spent the night.The bacterium liquid of overnight incubation is inoculated 500mL(1:50 by next day) selectivity LB(is containing 100 μ g/mL penbritins) in liquid nutrient medium 37 DEG C, when 200rpm/min shaking culture is to OD600=0.6-0.8.Add 1mol/LIPTG in bacterium liquid, make IPTG final concentration be 0.5mM, 25 DEG C, 200rpm/min shaking culture 10h.
Thalline after abduction delivering, with the centrifugal 5min of 6000rpm, is collected after thalline with the DEAEBindingbuffer of the ratio of 10:1 (thalline in 10mL bacterium liquid adds 1mL damping fluid) pH6.5.The high-pressure homogeneous crusher machine thalline of the resuspended rear use of thalline, specific procedure is the broken 800Mp fragmentation twice of 400Mp, then with 14000rpm high speed centrifugation 30min, gets supernatant, uses 0.45 membrane filtration.Adopt AKTApurifier10 to carry out protein purification, first DEAE-FF post rinses pillar with 100%DEAEElutionbuffer elutriant and goes out decon, then balances with DEAEBindingbuffer.Start loading after balance, the supernatant after filtration is loaded in DEAE-FF post with 1mL/min, rinses until 280nm uv-absorbing line is walked flat with the flow velocity of 2mL/min with Bindingbuffer.With the unconjugated foreign protein of Elutionbuffer gradient elution of 50%, then adopt in the method 30min time of linear elution, Elutionbuffer concentration rises to 80% by 50%.Be in charge of the elution peak collected and occur in Elutionbuffer concentration uphill process with the volume of 2mL/ pipe, collect the eluted protein of yellow color and SDS-page detects purification effect.
(2) Dynamic Kinetic Resolution of 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9
Enzyme catalysis Dynamic Kinetic Resolution 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 adopts following reaction system: 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9, enzyme and reductive agent, after reaction for some time.Liquid chromatography monitoring reaction process, to reacting end, obtains product through aftertreatment, by liquid chromatographic detection and standard substance Determination product ee value, and determines to produce configuration by measuring product specific rotatory power.
The Dynamic Kinetic Resolution of chemical equation 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9
Hexahydroaniline oxydase of the present invention can be its mutant, also can be other monoamine oxidase that amino acid sequence homology is greater than 80%.
Enzyme of the present invention can be genetic engineering bacterium, broken bacterium liquid, pure enzyme or immobilized enzyme viable cell.
Reductive agent of the present invention can be boron amide, sodium borohydride, POTASSIUM BOROHYDRIDE and other can make the reductive agent of imine reduction.
Accompanying drawing explanation
The HPLC figure of Fig. 1 (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 and raceme thereof;
Fig. 2 (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9
1hNMR;
Fig. 3 (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9
13cNMR.
Embodiment
Further illustrate below by way of specific embodiment, its object is to better understand summary of the invention, but these embodiments are not construed as limiting the invention.
The Dynamic Kinetic Resolution of embodiment 1:1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9
1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 (100mg), get 8g wet thallus after mutant Y321I bacteria break supernatant 50mL(expression is centrifugal and be dissolved in 100mM, after the phosphoric acid buffer mesohigh fragmentation of pH6.5, the centrifugal 30min of 12000 × g gets supernatant) and boron ammonium (80mg), react at 25 DEG C, carry out in the shaking table of 200rpm.Liquid chromatography monitoring reaction process, after 32h, reaction terminates, and regulates pH then to use dichloromethane extraction three times (50mL × 3) to 10 with the sodium hydroxide of 5M.Extraction liquid is concentrated to 25mL and mixes with the hydrochloric acid soln of 25mL1M.The sodium hydroxide being separated the aqueous phase 5M obtained regulates pH then to use dichloromethane extraction three times (25mL × 3) to 10.Organic extraction, after anhydrous sodium sulfate drying, is spin-dried for and obtains product 76.5mg, and isolated yield is 76.5%, shows that product ee value is 93.5% by liquid chromatographic detection.Polarimetry result is [α]
20 d=-152 (c=1.0, methanol), and (R)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 [α] of bibliographical information
20 d=139 (c=1.0, methanol) [Helv.Chim.Acta1956,39,1,376 1386], therefore determine that product is S configuration., by liquid chromatographic detection and standard substance Determination product ee value, and determine to produce configuration by measuring product specific rotatory power.Liquid chromatographic detection condition is: adopt OJ-H chromatographic column, moving phase is normal hexane: the solution of Virahol (containing 0.5% thanomin)=9:1, and flow velocity is 0.8mL/min, column temperature 25 DEG C (accompanying drawing 1).
The Dynamic Kinetic Resolution of embodiment 2:1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9
1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 (129mg) is dissolved in 1mL methyl-sulphoxide, join mutant Y321I bacteria break supernatant 50mL(express centrifugal after get 10g wet thallus and be dissolved in 100mM, after the phosphoric acid buffer mesohigh fragmentation of pH6.5, the centrifugal 30min of 12000 × g gets supernatant) and boron ammonium (124mg), react at 25 DEG C, carry out in the shaking table of 200rpm.Liquid chromatography monitoring reaction process, after 20h, reaction terminates, and adds 6M hydrochloric acid termination reaction, regulates pH to 10, then use ethyl acetate High-speed centrifugal extraction three times (50mL × 3) with the sodium hydroxide of 5M.Organic extraction is after anhydrous sodium sulfate drying, and column chromatographic isolation and purification obtains product 100mg, and isolated yield is 78%, shows that product ee value is greater than 99%(accompanying drawing 1 by liquid chromatographic detection).Polarimetry result is [α]
20 d=-130 (c=1.0, methanol).
1hNMR (400MHz, CDCl3): δ=7.21 (d, J=8.6Hz, 2H), 6.85 (d, J=8.6Hz, 2H), 3.79 (s, 3H), 3.52 (br.s., 1H), 3.08 (dd, J=14.1,4.4Hz, 1H), 2.93-3.02 (m, 1H), 2.87 (dt, J=12.0,5.9Hz, 1H), 2.78 (dd, J=14.1,8.4Hz, 1H), 1.98-2.15 (m, 3H), 1.94 (br.s., 2H), 1.82 (m, 1H), 1.63-1.77 (m, 2H), 1.55 (m, 2H).
13cNMR (100MHz, CDCl3): δ=158.40,130.46,129.88,128.83,127.45,114.06,57.56,55.23,39.57,37.05,30.21,28.72,27.07,22.85,22.53(accompanying drawing 2 and accompanying drawing 3).
SEQUENCELISTING
<110> Tianjin Institute of Industrial Biotechnology, Chinese Accademy of Sciences
<120> enzyme catalysis Dynamic Kinetic Resolution 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,
The novel method of 8-octahydro isoquinoline 99.9
<130>MirzaIA,BurkDL,XiongB,IwakiH,HasegawaY,etal.(2013)
StructuralAnalysisofaNovelCyclohexylamineOxidasefrom
BrevibacteriumoxydansIH-35A.PLoSONE8(3):e60072.
doi:10.1371/journal.pone.0060072
<160>1
<170>PatentInversion3.3
<210>1
<211>1470
<212>DNA
<213>CHAO
<400>1
chaatgtgccgtagcaggcaagccgcaagatcgaaaagagaggaaagtgctttgacccat60
ctcaatacttacgagtcagttacccccgatcccgacgtcgatgtgatcatcatcggcgcg120
gggatctcaggcagcgccgcagccaaggccttgcatgatcaaggcgcgtccgttctcgtc180
gtcgaggcgaatgacaggatcggcggacggacctggacagaacaggagggcgcacccggg240
ggtccaatcgattatggcggcatgttcatcggggagacgcatacgcaccttattgaactt300
ggcacaagcctgggcttggagatgaccccatcgggcaagcccggcgatgacacttacatt360
gtggcgggcaatgtcttgagggctcctgacgaccaactggaccccaaccttcccttcgtt420
ccggagtttctctcctcccttaaggctcttgacgaattggcggacagcgtcggttgggac480
cagccttgggcatcgcctaacgcagcagcactcgacagcaagacggtagccacatggttg540
gcggagacgatcgagagcgaagaagtcagacggttgcacacggttatcgtcaataccctc600
ctcggcgccgacccctatgaggtttccctcctgtactgggcctactacgtcagtgagtgc660
gaagggatacagtcactcatgggcacccgggacggagcccaatgggcatggtggtttggc720
ggcgccgctcaggtgagctggcgaatcgccgatgccatcgggagggacaagttccttttg780
gagtggccggtcgaccgtatcgagcacgacgaatcgggggtgacacttttctccgggcag840
cggagcctgcgggcacgccatatcgtgatcgccatgtcacccttggcggcaaaccaaatc900
cgttttgaaccagccctaccgacatctcgagcgcaactccaggcgcgcgcaccgatgggc960
cgctattacaaggtgcaggcgcgctacccctcttcattctgggtcgagcagggctattcc1020
ggcgcgttgcttgacaccgaagacgtcggagtcttcctcctcgacggcacgaaacctacc1080
gatacgctagcgaccctaattgggttcatcggagggtcaaattacgaccgctgggcggcc1140
cacacaccccaagagcgcgagcgggctttcctggatcttctggtgaaggcgttcggtccg1200
caggcagcagaccccagctacttccatgagactgactggacccagcaggagtgggcaaag1260
ggaggccctgtcacctatatgcccccgggagtgttggccaactttggtgcagccctacgc1320
gatccggtcgggaaagtgcatttcgctggtaccgaagcgtcgttccaatggtccggctat1380
atggaaggtggcgtccgggcaggccagaaggccgccgctgcgattgccgaggagctcgaa1440
cgaaccgccaacaaaggagctctcgtatga1470
Claims (5)
1. an enzyme catalysis Dynamic Kinetic Resolution prepares dextromethorphan hydrobromide key intermediate (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6, the novel method of 7,8-octahydro isoquinoline 99.9, is characterized in that utilizing hexahydroaniline oxydase and mutant thereof to realize 1-(4-methoxy-benzyl)-1 in conjunction with reductive agent, 2,3,4,5, Dynamic Kinetic Resolution preparation (S)-1-(4-methoxy-benzyl)-1 of 6,7,8-octahydro isoquinoline 99.9,2,3,4,5,6,7,8-octahydro isoquinoline 99.9, comprises the steps:
A) expression of hexahydroaniline oxydase and mutant thereof;
B) Dynamic Kinetic Resolution of hexahydroaniline oxydase and mutant catalysis 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 thereof.
2. a) step as claimed in claim 1, is characterized in that the expression of described hexahydroaniline oxydase and mutant thereof adopts conventional escherichia expression system.
3. b) step as claimed in claim 1, is characterized in that described hexahydroaniline oxydase and mutant thereof can be genetic engineering bacterium, broken bacterium liquid, pure enzyme or immobilized enzyme viable cell.
4. b) step as claimed in claim 1, is characterized in that described hexahydroaniline oxydase and mutant thereof can be other monoamine oxidase that amino acid sequence homology is greater than 80%.
5. b) step as claimed in claim 1, it is characterized in that described reductive agent can be boron amide, sodium borohydride, POTASSIUM BOROHYDRIDE and other can make the reductive agent of imine reduction.
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| CN109655553A (en) * | 2018-11-12 | 2019-04-19 | 江苏宝众宝达药业有限公司 | The impurity content of high effective liquid chromatography for measuring dextromethorphan hydrobromide fractionation salt |
| CN109971802A (en) * | 2017-12-28 | 2019-07-05 | 苏州同力生物医药有限公司 | A kind of method that Enzymatic Resolution prepares (S) -1,2,3,4- tetrahydroisoquinoline -1- formic acid and its derivative |
| CN110628841A (en) * | 2018-06-25 | 2019-12-31 | 中国科学院天津工业生物技术研究所 | Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetry |
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| CN106632038A (en) * | 2016-12-01 | 2017-05-10 | 暨明医药科技（苏州）有限公司 | Resolution method of octahydro isoquinoline |
| CN106632038B (en) * | 2016-12-01 | 2019-10-29 | 暨明医药科技（苏州）有限公司 | A kind of method for splitting of octahydro isoquinolin |
| CN109971802A (en) * | 2017-12-28 | 2019-07-05 | 苏州同力生物医药有限公司 | A kind of method that Enzymatic Resolution prepares (S) -1,2,3,4- tetrahydroisoquinoline -1- formic acid and its derivative |
| CN109971802B (en) * | 2017-12-28 | 2023-04-07 | 苏州同力生物医药有限公司 | Method for preparing (S) -1,2,3, 4-tetrahydroisoquinoline-1-formic acid and derivatives thereof by enzymatic resolution |
| CN110628841A (en) * | 2018-06-25 | 2019-12-31 | 中国科学院天津工业生物技术研究所 | Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetry |
| CN110628841B (en) * | 2018-06-25 | 2021-11-23 | 中国科学院天津工业生物技术研究所 | Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetry |
| CN109655553A (en) * | 2018-11-12 | 2019-04-19 | 江苏宝众宝达药业有限公司 | The impurity content of high effective liquid chromatography for measuring dextromethorphan hydrobromide fractionation salt |
| CN110643650A (en) * | 2019-09-20 | 2020-01-03 | 复旦大学 | Preparation method of (S) -1-benzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline compound |
| CN110643650B (en) * | 2019-09-20 | 2023-03-07 | 复旦大学 | Preparation method of (S) -1-benzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline compound |
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Application publication date: 20160427 |