CN110305142A - A kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives - Google Patents
A kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives Download PDFInfo
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- CN110305142A CN110305142A CN201910631355.3A CN201910631355A CN110305142A CN 110305142 A CN110305142 A CN 110305142A CN 201910631355 A CN201910631355 A CN 201910631355A CN 110305142 A CN110305142 A CN 110305142A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
Abstract
The invention discloses a kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives, the synthetic method includes the following steps: (i) Formula IV compound in hydrophilic organic solvent, it is Formula VII compound by sodium borohydride reduction in the presence of catalytic amount C1-C4 alkanoic acid;(ii) the Formula VII compound for obtaining step (i) separates, and obtains Formula VIII compound;Here, substituent group definition is detailed in specification in Formula IV, Formula VII and VIII.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, three-dimensional more particularly to a kind of 6 beta-hydroxy morphine derivatives is selected
Property synthetic method.
Background technique
Morphine-6-glucuronide (M6G) is the main metabolites of morphine, mechanism of action and other opiates medicines
Species are central nervous system μ-receptor opioid agonist seemingly.Compared with morphine, M6G analgesic effect works relatively slow but continues
Time is longer, and side effect is lighter, and the incidence of especially Nausea and vomiting and respiration inhibition is lower.Additionally, due to glucose
Aldehydic acid morphine does not pass through liver metabolism, therefore compared with other opioid drugs, has for dyshepatia patient bright
Aobvious advantage.Structural formula is as follows:
M6G itself is more stable, but in the technique of synthesis M6G, since configuration is easy overturning when carrying out glycosylation reaction, easily
Compound impurities shown in production (I-2), and the impurity is difficult to remove in subsequent purifying process, causes the matter of M6G product
Amount is not high, causes very big hidden danger to the drug safety of the people.The structure there is no literature reported on.
In addition, the following isomers I-3 and I-4 of morphine and dionin is also very heavy in corresponding control of product quality
It wants:
Summary of the invention
It is the general introduction to the theme being described in detail herein below.This general introduction is not the protection model in order to limit claim
It encloses.
The purpose of the present invention is to overcome the shortcomings of the existing technology, provides a kind of three-dimensional choosing of 6 beta-hydroxy morphine derivatives
Selecting property synthetic method, this method do not need chiral catalyst, and with easy to operate, raw material is cheap and easily-available, high income, purity
High advantage.
In embodiments of the invention, the present invention provides a kind of stereoselectivity conjunctions of 6 beta-hydroxy morphine derivatives
At method, as shown in Formula VIII, the synthetic method includes the following steps: the 6 beta-hydroxy morphine derivatives
(i) Formula IV compound is in hydrophilic organic solvent, in the presence of catalytic amount C1-C4 alkanoic acid, by sodium borohydride reduction
For Formula VII compound;
(ii) the Formula VII compound for obtaining step (i) separates, and obtains Formula VIII compound;
Here, substituent R in Formula IV, Formula VII and VIII1For hydrogen, unsubstituted C1-C4 alkyl, Cvclopropvlmethvl, do not take
C2-C4 alkenyl, the R in generation9- O-C (O)-or R7-C(O)-;R3For hydrogen, unsubstituted C1-C4 alkyl, Cvclopropvlmethvl, unsubstituted
C2-C4 alkenyl, R8- C (O)-or R6-O-C(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-C4 alkyl;R7
And R8It is each independently selected from hydrogen, unsubstituted C1-C4 alkyl and the phenyl optionally replaced, the phenyl optionally replaced is
Refer to one or more hydrogen on the phenyl replaced following groups: methoxyl group, nitro and halogen;R2And R4It is each independently
Hydrogen or hydroxyl;
Hydrophilic organic solvent described in step (i) in methanol, dehydrated alcohol, tetrahydrofuran it is one or two kinds of with
On mixed solution;
C1-C4 alkanoic acid described in step (i) is one or more in formic acid, acetic acid, propionic acid and butyric acid, it is preferable that is
Formic acid, acetic acid or propionic acid.
In the above-described embodiment, the catalytic amount refers to the volume ratio of C1-C4 alkanoic acid Yu the hydrophilic organic solvent
For 0.2-0.6:100, it is preferable that be 0.3-0.5:100.
In the above-described embodiment, the Formula VII compound compound of formula VIII content that step (i) obtains is greater than 50%,
It is preferably greater than 90%.
In the above-described embodiment, the separation of step (ii) can use chromatography.
In embodiments of the invention, the unsubstituted C1-C4 alkyl be methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group or tert-butyl;The unsubstituted C2-C4 alkenyl is vinyl, acrylic or allyl.
In some embodiments, substituent R in Formula IV, Formula VII and VIII1For R9- O-C (O)-or R7-C(O)-;R3For
R6- O-C (O)-or R8-C(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-C4 alkyl;R7And R8It is respectively independent
Ground is selected from hydrogen, methyl, isopropyl and dinitrophenyl group;R2And R4It is each independently hydrogen or hydroxyl.
In some embodiments, substituent R in Formula IV, Formula VII and VIII1For methyl, ethyl, Cvclopropvlmethvl, alkene
Propyl, acetyl group, isobutyryl, 2,4- dinitrobenzoyl or R9-O-C(O)-;R3For methyl, Cvclopropvlmethvl, allyl
Base, acetyl group, 2,4- dinitrobenzoyl or R6-O-C(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-
C4 alkyl;R2And R4It is each independently hydrogen or hydroxyl.
In one embodiment, substituent R in Formula IV, Formula VII and VIII1For R9-O-C(O)-;R3For R6-O-C
(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-C4 alkyl;R2And R4It is each independently hydrogen.
In a preferred embodiment, the present invention provides morphine -6- β-O- β-D-Glucose glycosides as shown in Formulas I -2
The synthetic method of acid,
The synthetic method includes the following steps:
(i) -2 compound of Formula IV is in hydrophilic organic solvent, in the presence of catalytic amount C1-C4 alkanoic acid, also by sodium borohydride
It originally was -2 compound of Formula VII;
(ii) -2 compound of Formula VII for obtaining step (i) separates, and obtains -2 compound of Formula VIII;
Here, substituent R in Formula IV -2, Formula VII -2 and VIII-21For R7-C(O)-;R3For methyl;Wherein, R7It is selected from
Hydrogen, unsubstituted C1-C4 alkyl and the phenyl optionally replaced, the phenyl optionally replaced refer to one on the phenyl or
Multiple hydrogen are replaced following groups: methoxyl group, nitro and halogen;Preferably, R7For methyl or isopropyl.
In the above-described embodiment, morphine -6- β-O- β-D-Glucose thuja acid provided by the invention as shown in Formulas I -2
Synthetic method, the synthetic method can further include following steps:
(iii) -2 compound of Formula VIII is reacted with formula III -1, to obtain formula IV compound:
Alternatively, -2 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
Alternatively, -3 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
(iv) formula IV compound is deprotected, and obtains -2 compound of Formulas I
Wherein, substituent R in formula III -1, formula III -2, formula III -3 and formula IV5For C1-C6 alkyl or benzyl, preferably
Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl or benzyl;More preferably methyl, ethyl;
Substituent group P1 is the alkanoyl or benzoyl of C2-C6 in formula III -1, formula III -2, formula III -3 and formula IV, preferably
Ground is selected from acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, pivaloyl group or benzoyl, more preferably second
Acyl group or isobutyryl;
Substituent group P2 is alkanoyl, the R of C2-C6 in formula III -110-C(O)-、R10-S(O)2Or R10- C (O)-C (O)-,
R10For C1-C4 alkyl, phenyl or substituted-phenyl that C1-C4 alkoxy, one or more halogens replace, here, the substituted benzene
Base refers to one or more hydrogen on phenyl ring replaced C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkanoyloxy;It is preferred that
Ground, P2 are selected from acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, pivaloyl group, CF3C (O)-, CF3S(O)2, right
Tosyl, CH2ClC (O)-, CHCl2C (O)-, CCl3C (O)-, CH3OC (O) C (O)-, CH3OC (O)-, CH3CH2OC
(O)-, CH3CH2OC (O) C (O)-, benzoyl, acetoxy benzoyl, more preferably acetyl group or isobutyryl,
CF3CO-、CF3SO2-;
Substituent group P3 is the C1-C6 that the alkyl of C1-C6, phenyl replace in formula III -1 alkyl or aryl (such as benzene
Base);
Substituent R in formula IV and VIII-21For R7-C(O)-;R3For methyl;Wherein, R7Selected from hydrogen, unsubstituted C1-C4
Alkyl and the phenyl optionally replaced, the phenyl optionally replaced refer to one or more hydrogen on the phenyl by following groups
It is replaced: methoxyl group, nitro and halogen;Preferably, R7For methyl, isopropyl or 3,5- dinitrophenyl.
In the above-described embodiment, morphine -6- β-O- β-D-Glucose thuja acid provided by the invention as shown in Formulas I -2
Synthetic method, the synthetic method can further include following steps:
(1-i) is with morphine base or its salt (such as morphine sulfate), acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7-C(O)-Cl
Formula II compound is obtained through esterification for raw material;
The Formula II compound oxidation that (2-i) obtains step (1-i) is -2 compound of Formula IV;
Here, substituent R in Formula II and Formula IV -21For R7-C(O)-;R3For methyl;Wherein, R7Selected from hydrogen, unsubstituted
C1-C4 alkyl and the phenyl optionally replaced, the phenyl optionally replaced refer to that one or more hydrogen on the phenyl are following
Replaced group: methoxyl group, nitro and halogen;Preferably, R7For methyl, isopropyl or 3,5- dinitrophenyl;
The acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7R in-C (O)-Cl7It is as defined above.
In a kind of particularly preferred embodiment, the present invention provides the Portugals morphine -6- β-O- β-D- as shown in Formulas I -2
The synthetic method of polyglycoside acid, the synthetic method include the following steps:
(1-i) is with morphine base or its salt (such as morphine sulfate), acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7-C(O)-Cl
Formula II compound is obtained through esterification for raw material;
The Formula II compound oxidation that (2-i) obtains step (1-i) is -2 compound of Formula IV;
(i) -2 compound of Formula IV for obtaining step (i-2) is deposited in hydrophilic organic solvent in catalytic amount C1-C4 alkanoic acid
It is -2 compound of Formula VII by sodium borohydride reduction under;
(ii) -2 compound of Formula VII for obtaining step (i) separates, and obtains -2 compound of Formula VIII;
(iii) -2 compound of Formula VIII is reacted with formula III -1, to obtain formula IV compound:
Alternatively, -2 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
Alternatively, -3 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
(iv) formula IV compound is deprotected, and obtains -2 compound of Formulas I
Here, substituent R1、R3、R5, P1, P2, P3 be as defined above.
In embodiments of the invention, the present invention provides morphine -6- β-O- β-D-Glucose glycosides as shown in Formulas I -2
Acid, the compound may be used as M6G quality research reference substance.
In a kind of particularly preferred embodiment, the present invention provides the conjunctions of the beta-hydroxy of the 6- as shown in Formulas I-3-morphine
At method, which includes the following steps:
(1-i) is with morphine base or its salt (such as morphine sulfate), acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7-C(O)-Cl
Formula II compound is obtained through esterification for raw material;
The Formula II compound oxidation that (2-i) obtains step (1-i) is -2 compound of Formula IV;
(i) -2 compound of Formula IV for obtaining step (i-2) is deposited in hydrophilic organic solvent in catalytic amount C1-C4 alkanoic acid
It is -2 compound of Formula VII by sodium borohydride reduction under;
(ii) -2 compound of Formula VII for obtaining step (i) separates, and obtains -2 compound of Formula VIII;
(iii) -2 compound of Formula VIII is through being deprotected, to obtain -3 compound of Formulas I:
Here, substituent R in Formula II, Formula IV -2, Formula VII -2 and Formula VIII -21For R7-C(O)-;R3For methyl;Wherein,
R7Selected from hydrogen, unsubstituted C1-C4 alkyl and optionally the phenyl that replaces, the phenyl optionally replaced refer on the phenyl
One or more hydrogen are replaced following groups: methoxyl group, nitro and halogen;Preferably, R7For methyl, isopropyl or 3,5-
Dinitrophenyl;
The acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7R in-C (O)-Cl7It is as defined above substituent R1Definition such as
On.
In a kind of particularly preferred embodiment, the present invention provides the beta-hydroxy of the 6- as shown in Formulas I-4-dionins
Synthetic method, which includes the following steps:
(2-i) is aoxidized using dionin alkali or its salt as raw material, obtains -3 compound of Formula IV;
(i) -3 compound of Formula IV for obtaining step (i-2) is deposited in hydrophilic organic solvent in catalytic amount C1-C4 alkanoic acid
It is -3 compound of Formula VII by sodium borohydride reduction under;
(ii) -3 compound of Formula VII for obtaining step (i) separates, and obtains -4 compound of Formulas I;
In the reaction and operating condition of above-mentioned step (2-i), (i) and (ii) and the condition of the application the embodiment above
It can be identical.
In embodiments of the invention, the additional amount of catalytic amount C1-C4 alkanoic acid is control in stereoselective oxidation step
The committed step of system 6 beta-hydroxy morphine derivatives of preparation, C1-C4 alkanoic acid additional amount is very few, is difficult fully reacting, C1-C4 alkane
Acid is added excessively, cannot achieve stereoselectivity, and cause pure compounds shown in final product formula (I-2) impure, and yield
It is very low.The present invention finally obtains compound shown in the formula (I-2) of high-purity, and HPLC purity can reach 98% or more.
The invention has the following advantages that the present invention is using morphine as raw material, through esterification, oxidation, reduction, fractionation, glycosylation, water
Solution, etc. the reaction of nearly ten step and operation obtain compound shown in formula (I-2), synthesizing compound shown in the formula (I-2) of high-purity can make
For M6G bulk pharmaceutical chemicals and preparation test and analyze in contamination levels product, to promote M6G bulk pharmaceutical chemicals and preparation is tested and analyzed to impurity
Accurate positionin and qualitative, be conducive to reinforce the control to the impurity, and then promote M6G bulk pharmaceutical chemicals and the quality of the pharmaceutical preparations, this hair
The method raw material of bright offer is cheap and easily-available, easy to operate, HPLC purity >=98%.The warp of compound shown in synthesized formula (I-2)
Crossed fusing point,1H-NMR、13The confirmation of the methods of C-NMR, MS.
Other features and advantages of the present invention will be illustrated in the following description, also, partly becomes from specification
It obtains it is clear that understand through the implementation of the invention.The objectives and other advantages of the invention can be by specification, right
Specifically noted structure is achieved and obtained in claim and attached drawing.
Detailed description of the invention
Attached drawing is used to provide to further understand technical solution of the present invention, and constitutes part of specification, with this
The embodiment of application technical solution for explaining the present invention together, does not constitute the limitation to technical solution of the present invention.
Fig. 1 shows be embodiment 1 morphine -6- β-O- β-D-Glucose thuja acid (compound shown in formula (I-2))1H-
NMR spectra;
What Fig. 2 was indicated is morphine -6- α-O- β-D-Glucose thuja acid (M6G) of embodiment 11H-NMR map.
What Fig. 3 was indicated is morphine -6- β-O- β-D-Glucose thuja acid (compound shown in formula (I-2)) of embodiment 113C-
NMR spectra;
That Fig. 4 is indicated is morphine -6- β-O- β-D-Glucose thuja acid (compound shown in formula (I-2)) MS of embodiment 1
Map;
What Fig. 5 was indicated is morphine -6- β-O- β-D-Glucose thuja acid (compound shown in formula (I-2)) of embodiment 1
HPLC map;
What Fig. 6 was indicated is morphine -6- α-O- β-D-Glucose thuja acid (M6G) HPLC map of embodiment 1.
Specific embodiment
It, hereinafter will be to the embodiment of the present invention for the purposes, technical schemes and advantages of the application are more clearly understood
It is described in detail.It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can
With mutual any combination.
Instrument: low pressure preparative chromatograph (Teledyne ISCO), 500 nuclear magnetic resonance chemical analyser of Bruker Fourier,
Fourier transform synchrometer (Bruker APEX IV), XPR-400P micro-meldometer, waters2695 type are efficient
Liquid chromatograph (HPLC)
Chromatographic column is Agilent ZORBAX Eclipse XDB-phenyl
Mobile phase is A:10mg potassium dihydrogen phosphate, phosphoric acid tune pH3.0;Mobile phase B: acetonitrile phase
Column temperature: 35 DEG C
Wavelength: 210nm
Using gradient elution, gradient is
Time (min) | Mobile phase A (%) | Mobile phase B (%) |
0 | 90 | 10 |
35 | 15 | 85 |
60 | 15 | 85 |
Embodiment 1
Morphine -6- β-O- β-D-Glucose thuja acid
33.4g (0.05mol) morphine sulfate, 4g (0.1mol) hydrogen-oxygen are added in the 1L there-necked flask of S1: Xiang Peiyou thermometer
Change sodium and 350mL acetonitrile and 100ml water, be cooled to 10 DEG C of reactions, 10.8g (0.05mol) 3,5- dinitrobenzoyl chloride is added dropwise.
It is added dropwise, slowly restores to room temperature, react 5 hours.After completion of the reaction, reaction solution is poured into 500ml ethyl acetate, point
Liquid, water layer are extracted 2 times with 200ml ethyl acetate, and combined ethyl acetate layer is washed with 5% sodium bicarbonate aqueous solution to neutrality, are satisfied
Primary with NaCl, ethyl acetate is dried overnight with anhydrous magnesium sulfate, filtering, 45 DEG C of reduced pressures, residue ethyl alcohol
Recrystallization, obtains 20.4g white solid, i.e. Formula II compound (R1For 3,5- dinitrobenzoyl, R3For methyl), yield:
85%,1H-NMR (300MHz, d6- DMSO):
δ=1.67~1.93 (m, 2H), 2.03 (s, 1H), 2.26 (s, 3H), 2.31~3.13 (m, 4H), 4.61~4.63
(m, 1H), 5.59~5.65 (m, 1H), 6.15 (s, 1H), 6.58~6.68 (d, 1H), 6.79~6.84 (d, 1H), 9.12~
9.17 (d, 3H).
S2: Formula II compound (R made from acetone 500ml, S1 is added in 1L there-necked flask1For 3,5- dinitro benzoyl
Base and R3For methyl), it stirs to dissolve, is cooled to 0 DEG C, Jones reagent 57.4ml is added dropwise, process control reaction temperature is added dropwise
10 DEG C of degree is added dropwise isopropanol 18ml to neutralize unreacted Jones reagent, after stirring 30min, will react hereinafter, end of reaction
Liquid pours into 500ml water, is extracted with 800ml methylene chloride, liquid separation, and water layer uses 500ml methylene chloride to extract again, merges organic
Phase is washed with saturated sodium bicarbonate aqueous solution 300ml, saturated sodium-chloride water solution 300ml, and anhydrous magnesium sulfate is dried overnight, mistake
Filter is concentrated under reduced pressure, and residue is beaten with dehydrated alcohol, filters, 45 DEG C of solid are dried under reduced pressure, and obtain white solid 18.6g, i.e. formula
VI-2 compound (R1For 3,5- dinitrobenzoyl, R3For methyl), yield 92%.
S3: -2 compound (R of Formula IV of previous step preparation is added into 1L there-necked flask1For 3,5- dinitrobenzoyl, R3
For methyl), sodium borohydride 8.6g is added portionwise in anhydrous methanol 560ml, glacial acetic acid 1.7ml under room temperature, reacts at room temperature to complete
Finish, reaction solution is poured into 500ml water, is extracted twice respectively with methylene chloride 500ml, merge organic phase, is saturated chlorine with 300ml
Change sodium water solution washing, anhydrous magnesium sulfate is dried overnight, and is filtered, is concentrated to dryness, obtains -2 (R of 15.9g Formula VII1For 3,5- bis-
Nitro benzoyl, R3For methyl), yield 85.3% is directly used in the fractionation of next step.
S4: (the R of Formula VII -2 prepared by S31For 3,5- dinitrobenzoyl, R3For methyl) it is molten with 50ml methylene chloride
Solution is added 48g silica gel (200~300 mesh) and mixes sample, is stirred material suspension, is concentrated to dryness, with low pressure preparative chromatograph
Isolate and purify, 0~15min: methanol: methylene chloride (0%~100%) gradually becomes methanol: methylene chloride (5%~95%),
The constant rate is maintained after 15min.(the R of Formula VIII -21For 3,5- dinitrobenzoyl, R3For methyl) after separation, take the
The solution at two peaks is concentrated to dryness, and obtains -2 (R of 13.7g Formula VIII1For 3,5- dinitrobenzoyl, R3For methyl), yield
86.2%.
S5: VIII-2 (R prepared by S41For 3,5- dinitrobenzoyl, R3For methyl) and the Portugal triacetyl bromo-D-
Grape uronic acid methyl esters (production of Suzhou Hong Yang Pharmaceutical Technology Co., Ltd) 8.7g is added in 150mL toluene, and 17g carbonic acid is added
Silver, 130~140 DEG C of reaction 2h, end of reaction, filtering, filtrate are poured into 100mL water, respectively with 100mL methylene chloride extraction three
It is secondary, merge dichloromethane layer, saturated sodium-chloride 5L washing, anhydrous magnesium sulfate is dried overnight, filters, filtrate concentration, dehydrated alcohol
Recrystallization, obtaining white solid 18.5g, (compound shown in formula IV, P1 are acetyl group, R1For 3,5- dinitrobenzoyl, R3For first
Base, R5For methyl), yield 86.7%, HPLC purity is 98.75%.
1H-NMR (300MHz, d6-DMSO): δ=1.54~1.62 (m, 2H), 2.02~2.15 (m, 1H), 2.19 (s,
9H), 2.26 (s, 3H), 2.88~3.04 (m, 3H), 3.28~3.31 (m, 2H), 3.57 (s, 3H), 4.17~4.19 (d, 1H),
4.89~4.97 (m, 2H), 5.53~5.58 (m, 2H), 5.93~6.18 (m, 4H), 6.57~6.60 (d, 1H), 6.66~
6.68 (d, 1H), 9.19~9.21 (d, 3H).
S6: by compound shown in the formula IV of S5 preparation, (P1 is acetyl group, R1For 3,5- dinitrobenzoyl, R3For first
Base, R5For methyl) it is dissolved with 157ml methanol and 27mL water, -25 DEG C of one hydronium(ion) lithia 4.9g of addition, end of reaction uses second
Acid adjusts pH to 4~5, is concentrated to dryness, and recrystallizing methanol is added, and washes away the lithium salts for neutralizing and generating, and 25~35 DEG C are dried under reduced pressure,
White solid morphine -6- β-O- β-D-Glucose thuja acid 8.9g, yield 83.2%, fusing point: 253~255 DEG C, HPLC purity
98.04%.
Morphine -6- β-O- β-D-Glucose thuja acid:1H-NMR (500MHz, DMSO-d6): 4.18-4.20 (d, 1H, 6-H)
Morphine -6- α-O- β-D-Glucose thuja acid (is prepared) with reference to CN201710257413.1 embodiment 11:1H-NMR
(500MHz, DMSO-d6): 5.10-5.11 (d, 1H, 6-H)
Morphine -6- β-O- β-D-Glucose thuja acid:13C-NMR (500MHz, DMSO-d6): 173.80,146.11,
138.82,130.88,129.57,127.63,123.27,118.90,116.68,99.83,90.17,74.23,73.13,
72.39,72.34,71.77,58.54,45.74,42.38,41.17,33.30,20.96.
MS:460.2 [M-H]+
The preparation of 2 6- beta-hydroxy morphine of embodiment
33.4g (0.05mol) morphine sulfate, 4g (0.1mol) hydrogen-oxygen are added in the 1L there-necked flask of S1: Xiang Peiyou thermometer
Change sodium and 350mL acetonitrile and 100ml water, be cooled to 10 DEG C of reactions, 5.3g (0.05mol) isobutyryl chloride is added dropwise.It is added dropwise, delays
It is slow to restore to room temperature, it reacts 5 hours.After completion of the reaction, reaction solution is poured into 500ml ethyl acetate, liquid separation, water layer is used
200ml ethyl acetate extracts 2 times, and combined ethyl acetate layer is washed with 5% sodium bicarbonate aqueous solution to neutrality, saturated sodium-chloride
It washed once, ethyl acetate is dried overnight with anhydrous magnesium sulfate, filtering, and 45 DEG C of reduced pressures, residue ethyl alcohol recrystallization obtains
16.4g white solid, i.e. Formula II compound (R1For isobutyryl, R3For methyl), yield: 92.3%.
S2: Formula II compound (R made from acetone 500ml, S1 is added in 1L there-necked flask1For isobutyryl, R3For first
Base), stir to dissolve, be cooled to 0 DEG C, Jones reagent 57.4ml is added dropwise, 10 DEG C of process control reaction temperature is added dropwise hereinafter,
End of reaction is added dropwise ethyl alcohol 18ml to neutralize unreacted Jones reagent, after stirring 30min, reaction solution is poured into 500ml water
In, it is extracted with 800ml methylene chloride, liquid separation, water layer uses 500ml methylene chloride to extract again, merges organic phase, with unsaturated carbonate hydrogen
Sodium water solution 300ml, saturated sodium-chloride water solution 300ml washing, anhydrous magnesium sulfate are dried overnight, and are filtered, and are concentrated under reduced pressure, residual
Object is beaten with dehydrated alcohol, and filtering, 45 DEG C of solid are dried under reduced pressure, and obtain white solid 14.1g, i.e. -2 compound (R of Formula IV1It is different
Bytyry, R3For methyl), yield 87%.
S3: -2 compound (R of Formula IV of previous step preparation is added into 1L there-necked flask1For isobutyryl, R3For methyl), nothing
Sodium borohydride 8.6g is added portionwise in water methanol 560ml, formic acid 1.5ml under room temperature, reacts at room temperature to finishing, by reaction solution
It pours into 500ml water, is extracted twice respectively with methylene chloride 500ml, merge organic phase, with 300ml saturated sodium-chloride water solution
Washing, anhydrous magnesium sulfate are dried overnight, and are filtered, are concentrated to dryness, obtain -2 (R of 12.2g Formula VII1For isobutyryl, R3For first
Base), yield 86% is directly used in the fractionation of next step.
S4: (the R of Formula VII -2 prepared by S31For isobutyryl, R3For methyl) it is dissolved with 50ml methylene chloride, 48g is added
Silica gel (200~300 mesh) mixes sample, is stirred material suspension, is concentrated to dryness, is isolated and purified with low pressure preparative chromatograph, 0
~15min: methanol: methylene chloride (0%~100%) gradually becomes methanol: methylene chloride (5%~95%), maintains after 15min
The constant rate.(the R of Formula VIII -21For 3,5- dinitrobenzoyl, R3For methyl) separation after, take the molten of second peak
Liquid is concentrated to dryness, and obtains -2 (R of 10.4g Formula VIII1For isobutyryl, R3For methyl), yield 85%.
S5: (the R of Formula VIII -2 prepared by S41For isobutyryl, R3For methyl) it is made with 150ml methanol and the stirring of 15ml water
For suspension, it is cooled to 0 DEG C, a hydronium(ion) lithia 1.5g is added portionwise, 10 DEG C or so is maintained at and is stirred to react to finishing, mistake
Filter, and it is washed to dry, 60 DEG C are dried under reduced pressure, and obtain 6- beta-hydroxy morphine 6.5g, yield: 78.9%
6- beta-hydroxy morphine:1H-NMR (500MHz, DMSO-d6): 4.58-4.65 (m, 1H, 6-H) 6.32 (s, 1H, 6-OH)
Morphine:1H-NMR (500MHz, DMSO-d6): 4.32-4.41 (m, 1H, 6-H) 6.27 (s, 1H, 6-OH)
Although embodiment disclosed by the application is as above, the content only for ease of understanding the application and use
Embodiment is not limited to the application.Technical staff in any the application fields, is taken off not departing from the application
Under the premise of the spirit and scope of dew, any modification and variation, but the application can be carried out in the form and details of implementation
Scope of patent protection, still should be subject to the scope of the claims as defined in the appended claims.
Claims (10)
1. a kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives, the 6 beta-hydroxy morphine derivatives such as Formula VIII
Shown, the synthetic method includes the following steps:
(i) Formula IV compound is in hydrophilic organic solvent, is formula by sodium borohydride reduction in the presence of catalytic amount C1-C4 alkanoic acid
VII compound;
(ii) the Formula VII compound for obtaining step (i) separates, and obtains Formula VIII compound;
Here, substituent R in Formula IV, Formula VII and VIII1For hydrogen, unsubstituted C1-C4 alkyl, Cvclopropvlmethvl, unsubstituted
C2-C4 alkenyl, R9- O-C (O)-or R7-C(O)-;R3For hydrogen, unsubstituted C1-C4 alkyl, Cvclopropvlmethvl, unsubstituted
C2-C4 alkenyl, R8- C (O)-or R6-O-C(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-C4 alkyl;R7With
R8It is each independently selected from hydrogen, unsubstituted C1-C4 alkyl and the phenyl optionally replaced, the phenyl optionally replaced refers to
One or more hydrogen on the phenyl are replaced following groups: methoxyl group, nitro and halogen;R2And R4It is each independently hydrogen
Or hydroxyl;
Hydrophilic organic solvent described in step (i) is selected from one of methanol, dehydrated alcohol, tetrahydrofuran or two or more
Mixed solution;
C1-C4 alkanoic acid described in step (i) is one or more in formic acid, acetic acid, propionic acid and butyric acid, it is preferable that is first
Acid, acetic acid or propionic acid.
2. synthetic method as described in claim 1, wherein the catalytic amount refers to C1-C4 alkanoic acid and the hydrophilic organic
The volume ratio of solvent is 0.2-0.6:100, it is preferable that is 0.3-0.5:100;
The Formula VII compound compound of formula VIII content that step (i) obtains is greater than 50%, it is preferable that is greater than 90%.
3. synthetic method as described in claim 1, wherein substituent R in Formula IV, Formula VII and VIII1For R9- O-C (O)-or
R7-C(O)-;R3For R6- O-C (O)-or R8-C(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-C4 alkyl;R7
And R8It is each independently selected from hydrogen, methyl, isopropyl and dinitrophenyl group;R2And R4It is each independently hydrogen or hydroxyl;
Or
Substituent R in Formula IV, Formula VII and VIII1For methyl, ethyl, Cvclopropvlmethvl, allyl, acetyl group, isobutyryl, 2,
4- dinitrobenzoyl or R9-O-C(O)-;R3For methyl, Cvclopropvlmethvl, allyl, acetyl group, 2,4- dinitrobenzene first
Acyl group or R6-O-C(O)-;Wherein, R9And R6It is each independently selected from unsubstituted C1-C4 alkyl;R2And R4It is each independently
Hydrogen or hydroxyl;Or
Substituent R in Formula IV, Formula VII and VIII1For R9-O-C(O)-;R3For R6-O-C(O)-;Wherein, R9And R6Each independently
Selected from unsubstituted C1-C4 alkyl;R2And R4Be each independently hydrogen or;
Substituent R in Formula IV, Formula VII and VIII1For acetyl group, isobutyryl, 2,4- dinitrobenzoyl;R3For methyl;R2
And R4It is each independently hydrogen.
4. morphine -6- β-O- β-D-Glucose thuja acid synthetic method as shown in Formulas I -2,
The synthetic method includes the following steps:
(i) -2 compound of Formula IV in the presence of catalytic amount C1-C4 alkanoic acid, is by sodium borohydride reduction in hydrophilic organic solvent
- 2 compound of Formula VII;
(ii) -2 compound of Formula VII for obtaining step (i) separates, and obtains -2 compound of Formula VIII;
Here, substituent R in Formula IV -2, Formula VII -2 and VIII-21For R7-C(O)-;R3For methyl;Wherein, R7Selected from hydrogen, do not take
The C1-C4 alkyl in generation and the phenyl optionally replaced, the phenyl optionally replaced refer to one or more hydrogen quilts on the phenyl
Replaced following groups: methoxyl group, nitro and halogen;Preferably, R7For methyl or isopropyl.
5. synthetic method as claimed in claim 4, further includes following steps:
(iii) -2 compound of Formula VIII is reacted with formula III -1, to obtain formula IV compound:
Alternatively, -2 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
Alternatively, -3 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
(iv) formula IV compound is deprotected, and obtains -2 compound of Formulas I
Wherein, substituent R in formula III -1, formula III -2, formula III -3 and formula IV5For C1-C6 alkyl or benzyl, it is preferably chosen from
Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl or benzyl;More preferably methyl, ethyl;
Substituent group P1 is the alkanoyl or benzoyl of C2-C6 in formula III -1, formula III -2, formula III -3 and formula IV, is preferably selected
From acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, pivaloyl group or benzoyl, more preferably acetyl group,
Or isobutyryl;
Substituent group P2 is alkanoyl, the R of C2-C6 in formula III -110-C(O)-、R10-S(O)2Or R10- C (O)-C (O)-, R10For
C1-C4 alkyl, phenyl or the substituted-phenyl that C1-C4 alkoxy, one or more halogens replace, here, the substituted-phenyl is
Refer to one or more hydrogen on phenyl ring replaced C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkanoyloxy;Preferably, P2
Selected from acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, pivaloyl group, CF3C (O)-, CF3S(O)2, to toluene
Sulfonyl, CH2ClC (O)-, CHCl2C (O)-, CCl3C (O)-, CH3OC (O) C (O)-, CH3OC (O)-, CH3CH2OC (O)-,
CH3CH2OC (O) C (O)-, benzoyl, acetoxy benzoyl, more preferably acetyl group or isobutyryl,
CF3CO-、CF3SO2-;
The alkyl or aryl (such as phenyl) for the C1-C6 that substituent group P3 replaces in formula III -1 for alkyl, the phenyl of C1-C6;
Substituent R in formula IV and VIII-21For R7-C(O)-;R3For methyl;Wherein, R7Selected from hydrogen, unsubstituted C1-C4 alkyl,
The phenyl optionally replaced, the phenyl optionally replaced refer to that one or more hydrogen on the phenyl are taken by following groups
Generation: methoxyl group, nitro and halogen;Preferably, R7For methyl or 3,5- dinitrophenyl.
6. synthetic method as claimed in claim 4, wherein -2 compound of Formula IV can be prepared using following steps:
(1-i) is with morphine base or its salt, acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7- C (O)-Cl is raw material, anti-through being esterified
It answers, obtains Formula II compound;
The Formula II compound oxidation that (2-i) obtains step (1-i) is -2 compound of Formula IV;
Here, substituent R in Formula II and Formula IV -21For R7-C(O)-;R3For methyl;Wherein, R7Selected from hydrogen, unsubstituted C1-C4
Alkyl and the phenyl optionally replaced, the phenyl optionally replaced refer to one or more hydrogen on the phenyl by following groups
It is replaced: methoxyl group, nitro and halogen;Preferably, R7For methyl or 3,5- dinitrophenyl;
The acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7R in-C (O)-Cl7It is as defined above.
7. synthetic method described in any one of claim 4-6, the synthetic method include the following steps:
(1-i) is with morphine base or its salt, acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7- C (O)-Cl is raw material, anti-through being esterified
It answers, obtains Formula II compound;
The Formula II compound oxidation that (2-i) obtains step (1-i) is -2 compound of Formula IV;
(i) -2 compound of Formula IV for obtaining step (i-2) is in hydrophilic organic solvent, in the presence of catalytic amount C1-C4 alkanoic acid,
It is -2 compound of Formula VII by sodium borohydride reduction;
(ii) -2 compound of Formula VII for obtaining step (i) separates, and obtains -2 compound of Formula VIII;
(iii) -2 compound of Formula VIII is reacted with formula III -1, to obtain formula IV compound:
Alternatively, -2 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
Alternatively, -3 compound of Formula VIII is reacted with formula III -2, to obtain formula IV compound:
(iv) formula IV compound is deprotected, and obtains -2 compound of Formulas I
Here, substituent R1、R3、R5, P1, P2, P3 be as defined above.
8. morphine -6- β-O- β-D-Glucose thuja acid as shown in Formulas I -2:
9. the beta-hydroxy of the 6- as shown in Formulas I-3-morphine synthetic method, the synthetic method include the following steps:
(1-i) is with morphine base or its salt, acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7- C (O)-Cl is raw material, anti-through being esterified
It answers, obtains Formula II compound;
The Formula II compound oxidation that (2-i) obtains step (1-i) is -2 compound of Formula IV;
(i) -2 compound of Formula IV for obtaining step (i-2) is in hydrophilic organic solvent, in the presence of catalytic amount C1-C4 alkanoic acid,
It is -2 compound of Formula VII by sodium borohydride reduction;
(ii) -2 compound of Formula VII for obtaining step (i) separates, and obtains -2 compound of Formula VIII;
(iii) -2 compound of Formula VIII is through being deprotected, to obtain -3 compound of Formulas I:
Here, substituent R in Formula II, Formula IV -2, Formula VII -2 and Formula VIII -21For R7-C(O)-;R3For methyl;Wherein, R7It is selected from
Hydrogen, unsubstituted C1-C4 alkyl and the phenyl optionally replaced, the phenyl optionally replaced refer to one on the phenyl or
Multiple hydrogen are replaced following groups: methoxyl group, nitro and halogen;Preferably, R7For methyl or 3,5- dinitrophenyl;
The acid anhydrides R7-C(O)-O-(O)C-R7Or acyl chlorides R7R in-C (O)-Cl7It is as defined above substituent R1It is as defined above.
10. the beta-hydroxy of the 6- as shown in Formulas I-4-dionin synthetic method, the synthetic method include the following steps:
(2-i) is aoxidized using dionin alkali or its salt as raw material, obtains -3 compound of Formula IV;
(i) -3 compound of Formula IV for obtaining step (i-2) is in hydrophilic organic solvent, in the presence of catalytic amount C1-C4 alkanoic acid,
It is -3 compound of Formula VII by sodium borohydride reduction;
(ii) -3 compound of Formula VII for obtaining step (i) separates, and obtains -4 compound of Formulas I;
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