CN103864866A - Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide - Google Patents
Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide Download PDFInfo
- Publication number
- CN103864866A CN103864866A CN201410116005.0A CN201410116005A CN103864866A CN 103864866 A CN103864866 A CN 103864866A CN 201410116005 A CN201410116005 A CN 201410116005A CN 103864866 A CN103864866 A CN 103864866A
- Authority
- CN
- China
- Prior art keywords
- formula
- morphine
- methyl
- synthetic method
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC(C1**)OC(*2)C2C1OIPP Chemical compound CC(C1**)OC(*2)C2C1OIPP 0.000 description 1
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
Abstract
The invention discloses a synthesis method and an intermediate compound of morphine-6-Beta-D-glucuronide. The synthesis method comprises the following steps: (1) carrying out a reaction on 3-acetyl morphine and acyl-protected glucuronate in an organic solvent 1 under the catalysis of lewis acid so as to obtain an intermediate shown as a formula (IV); (2) hydrolyzing the intermediate shown as the formula (IV) with lithium hydroxide and neutralizing the intermediate shown as the formula (IV) with hydrobromic acid in a mixture solvent of C1-C4 alkanol and water; and washing the intermediate with the C1-C4 alkanol and drying, thereby obtaining the intermediate compound of the morphine-6-Beta-D-glucuronide, wherein the definitions of substituent groups in the formula (III) and the formula (IV) are shown in the specification. The synthesis method has the advantages of moderate condition and high yield, and is simple to operate and easy to industrialize.
Description
Technical field
The present invention relates to a kind of synthetic method of anodyne, belong to the synthetic field of pharmaceutical chemistry, be specifically related to synthetic method and the midbody compound thereof of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides.
Background technology
Morphine-6-β-D-Glucose aldehydic acid glycosides [Morphine-6-β-D-glucuronide is called for short M6G], shown in formula (I), is morphine active metabolite in vivo.Being the narcotic analgesics that is widely used in most at present treatment moderate and severe pain as the morphine of opioid compounds, is not itself but research shows that morphine plays analgesia effect.Morphine mainly in liver with glucuronidation and produce two kinds of meta-bolitess: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).M6G can be in conjunction with opiate receptor, and experimentation on animals shows that its analgesic activity is stronger than morphine, and untoward reaction is slighter.M3G and opiate receptor avidity are lower, there is no analgesic activity, and experimentation on animals shows that M3G can resist the analgesic activity of morphine and M6G, may participate in the formation of morphine.
At present, about the synthetic method of morphine-6-β-D-Glucose aldehydic acid glycosides (M6G) mainly contains following several:
Ke Nixisi-Ke Nuoer (Koenigs-Knorr) glycosidation method, the method is by the halides of glycosyl and morphine, linked reaction to occur under metal-salt or lewis acidic catalysis to obtain morphine-O-and join sugar, thereby realizes the glucosides of morphine.This method is reported (Chem.Pharm.Bull.1968,16,2114.) by Yoshimura in nineteen sixty-eight first.In addition, also have some other groups also to report relevant content, wherein the patent WO9305057 of the people such as Mertz application also relates to this synthetic method.But the productive rate of the method is lower, and bromo sugar is unstable, under normal storage condition, be difficult to long-time preservation; Also have the difficulty on purifying, in final product, a small amount of heavy metal ion is difficult to eliminate simultaneously, is not suitable for amplifying and suitability for industrialized production.
Trichloroacetimidate method, the method is must arrive one end by Trichloroacetonitrile with 1 hydroxyl reaction of sugar to be connected with sugared trichloroacetimidate, and then obtains the target product with blocking group with 6 hydroxyl couplings of morphine.This method by Schmidt and Grundler reported first (Synthesis.1981,885.) in 1981.Brown group improves and optimizates the method, and has applied for Patents WO9303051 in 1993.Although Brown group reports that they utilize the method linked reaction productive rate can reach 50%～70%, other several groups report that this result is difficult to repetition, and also have the deficiencies such as productive rate is low, stereoselectivity is poor.
Thioglycoside method; the people such as Gutman have reported the strategy (Synthesis2000 that utilizes the synthetic M6G analogue paramorphane-6-β-D-Glucose aldehydic acid glycosides of thioglycoside method; 9; 1241.): the paramorphane that 3 hydroxyls are protected under the catalysis of NIS and TfOH and thioglycoside generation glycosylation, the synthetic this intermediate of paramorphane-6-β-D-Glucose aldehydic acid glycosides obtaining with protecting group.This intermediate synthetic method is simple, efficient, stereoselectivity is good.Profit in this way synthetic M6G also has and relates in patent WO9938876, but also there is the deficiency of several respects simultaneously: first, in the time synthesizing the glucuronic acid methyl ester of the intermediate of thioglycoside-band protection, to utilize Glucuronic acid lactone open loop to generate after glucuronic acid methyl ester again and acyl chlorides effect, productive rate is lower, is difficult for separation and purification; The second, morphine-6-β-D-Glucose aldehydic acid glycosides intermediate and final product M6G with protecting group are the method separation and purification by column chromatography, are difficult to industrialization; The 3rd, do not provide suitable deprotection and the method for aftertreatment.
U.S. Pat 20030083476A1 has reported following synthetic route:
This route has following deficiency:
(1) perchloric acid in catalyzer and 3-pivaloyl morphine salify and separate out, causes catalyst deactivation.
(2) in the aftertreatment of reaction of guanosine, adopt column chromatography to carry out purified product, later stage amplification and industrialized feasibility are not high.
The yield of this step reaction of guanosine bibliographical information also only has 29%.Visible, the transformation efficiency of this reaction is very low, and raw material and product are not easily separated, adopt column chromatography to carry out purified product, and yield is further reduced, and these method industrialization existing problems.
In sum, the several method of above-mentioned M6G is all to have identical problem: (1) committed step reaction of guanosine low conversion rate.(2) purifying of product has all adopted the mode of column chromatography, industrialization existing problems.(3) purity of product and residue on ignition are difficult to conform to quality requirements.
Summary of the invention
It is high and be easy to the synthetic method of industrialized morphine-6-β-D-Glucose aldehydic acid glycosides that the inventor has developed a kind of simple to operate, mild condition, yield after deliberation, overcome the deficiencies in the prior art.
The object of this invention is to provide the synthetic method of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides.
Another object of the present invention is to provide for morphine-6-β-D-Glucose aldehydic acid glycosides synthetic intermediate compound.
In embodiments of the invention, the invention provides the synthetic method of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides (being formula I compound), comprise the steps:
(1) in organic solvent 1, react under Louis acid catalysis with the glucuronate of the acyl group protection shown in the 3-acetylmorphine shown in formula (II) and formula (III), obtain the intermediate shown in formula (IV);
(2) intermediate shown in formula (IV) is in the admixture solvent of C1-C4 alkane alcohol and water, use lithium hydroxide is hydrolyzed, and Hydrogen bromide neutralizes, and washs with C1-C4 alkanol, dry, obtain the morphine shown in formula (I)-6-β-D-Glucose aldehydic acid glycosides;
In above-mentioned formula II, substituent A c is ethanoyl;
In above-mentioned formula III and formula IV, substituent R is C1-C6 alkyl or benzyl, is preferably selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl; Be more preferably methyl, ethyl;
Substituting group P1 is alkyloyl or the benzoyl of C2-C6, is preferably selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group or benzoyl, is more preferably ethanoyl or isobutyryl;
Substituting group P2 is alkyloyl, the R of C2-C6
1-C (O)-, R
1-S (O)
2-or R
1-C (O)-C (O)-, R
1for C1-C4 alkyl, phenyl or substituted-phenyl that C1-C4 alkoxyl group, one or more halogen replace, here, described substituted-phenyl refers to that the one or more hydrogen on phenyl ring are replaced by C1-C4 alkyl, C1-C4 alkoxyl group or C1-C4 alkanoyloxy; Preferably, P2 is selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group, CF
3c (O)-, CF
3s (O)
2-, p-toluenesulfonyl, CH
2clC (O)-, CHCl
2c (O)-, CCl
3c (O)-, CH
3oC (O) C (O)-, CH
3oC (O)-, CH
3cH
2oC (O)-, CH
3cH
2oC (O) C (O)-, benzoyl, an acetoxy benzoyl, is more preferably ethanoyl or isobutyryl, CF
3cO-, CF
38O
2-.
In a kind of preferred embodiment of the present invention, morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides synthetic method, comprises the steps:
(1) 3-acetylmorphine (compound shown in formula (II)) and the compound shown in formula (III) are dissolved with organic solvent 1, add Lewis acid at 10～25 ℃, 10～60 ℃ are reacted complete to raw material reaction; Reaction solution is poured into water, with and the immiscible organic solvent 2 of water extract, be concentrated into dryly, obtain the intermediate shown in formula (IV);
(2) intermediate shown in formula IV is dissolved with the mixed solvent of C1-C4 alkane alcohol and water, 10～25 ℃ add lithium hydroxide to be hydrolyzed, and 25～30 ℃ are reacted complete to raw material reaction; Be neutralized to pH4～6 with Hydrogen bromide, 40～60 ℃ of concentrating under reduced pressure, wash with C1-C4 alkanol, and 25～60 ℃ of drying under reduced pressure, obtain morphine-6-β-D-Glucose aldehydic acid glycosides;
Here, in formula (II), formula (III) and formula (IV) each substituent definition as above, and P1 and P2 can be identical or different.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, described Lewis acid in step (1) is one or more the mixture in zinc bromide, cupric bromide, boron trifluoride, zinc chloride, iron(ic) chloride, aluminum chloride or cuprous chloride, preferably, be zinc bromide or zinc chloride.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, the organic solvent 1 of step (1) is one or more the mixture in tetrahydrofuran (THF), methyl tertiary butyl ether, dimethyl formamide, methylene dichloride, acetonitrile, Nitromethane 99Min. or trichloromethane, preferably, be methyl tertiary butyl ether or methylene dichloride.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, the extraction of step (1) be one or more the mixture in methyl tertiary butyl ether, methylene dichloride, trichloromethane or ethyl acetate with organic solvent 2, preferred, is methyl tertiary butyl ether.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, the temperature of reaction of step (1) is 10～60 ℃, is preferably 25～40 ℃.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, the part by weight of the C1-C4 alkane alcohol and water in the admixture solvent of the C1-C4 alkane alcohol and water of step (2) is 10: 1～1: 10, is preferably 7: 3～4: 6.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, C1-C4 alkanol in the admixture solvent of the C1-C4 alkane alcohol and water of step (2) is one or more the mixture in methyl alcohol, ethanol or Virahol, preferably, be a kind of in methyl alcohol or ethanol or both mixtures.
In the synthetic method of morphine provided by the invention-6-β-D-Glucose aldehydic acid glycosides, wherein, the C1-C4 alkanol of removing lithiumbromide for washing of step (2) is one or more mixture of methyl alcohol, ethanol or Virahol, preferably, be a kind of in methyl alcohol or ethanol or both mixtures.
In embodiment of the present invention, the synthetic method of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides provided by the invention, wherein, shown in the 3-acetylmorphine using and formula III, the synthetic method of compound is as follows:
1,3-acetylmorphine (compound shown in formula II) is synthetic
In reaction flask, add 40g (0.14mol) morphine and 3.77L10% sodium hydrogen carbonate solution, then 5 ℃ drip 100mL (1mol) diacetyl oxide.Dropwise rear stirring 30min, TLC shows after completion of the reaction, adds 2L methylene dichloride, layering, and dichloromethane layer salt water washing, anhydrous sodium sulfate drying, underpressure distillation removes desolventizing and obtains white dope 41.3g, and productive rate is 90%.
2, compound shown in formula III (P1 and P2 are identical protecting group) is synthetic
In 20L reaction flask, add 15L methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol or benzylalcohol and 6g sodium hydroxide, stirring and dissolving.Start to add 2000gD-Glucuronic acid lactone in batches, after feeding in raw material, keep 30 ℃ of reactions 8 hours.45 ℃ of concentrating under reduced pressure obtain sorrel sticky solid.Upwards walking in residuum adds 2L pyridine to dissolve and 45 ℃ of heating for dissolving, then reaction solution is transferred in the reactor of 50L, then in reactor, add 10L methylene dichloride, cooling down to 0 ℃, start to drip 10L Acetyl Chloride 98Min., diacetyl oxide, propionyl chloride, isopropyl acyl chlorides, butyryl chloride, isobutyryl chloride, benzoyl oxide or pivaloyl chloride, in dropping process, control temperature below 15 ℃.After dropwising, stirring at normal temperature is spent the night.Then 60 ℃ of back flow reaction 7 hours, stopped reaction.Slowly drip 4L methyl alcohol, in control dropping process, temperature of reaction is below 20 ℃.Add again 10L water, separate organic layer.Organic layer is used 15L10%HCl successively, 10L10% sodium hydrogen carbonate solution, saturated nacl aqueous solution washing.45 ℃ of concentrating under reduced pressure of organic phase obtain sorrel sticky solid, use 5L dissolve with ethanol, freezing crystallization.Decompress filter is also used frozen ethanol drip washing, and 60 ℃ of normal pressure forced air dryings, obtain white or off-white color solid.Yield 85% left and right.
Or compound shown in formula III (P1 and P2 are different protecting groups) can synthesize with reference to following method:
For example; P1 and P2 are to compound 20g shown in the formula III that isobutyryl R is methyl to be dissolved in acetic acid; 10g trifluoroacetic anhydride; add boron trifluoride 0.1ml, 30～40 ℃ of reactions, pour in frozen water; filter; 45～50 ℃ of drying under reduced pressure of filter cake, obtaining P1 is that isobutyryl, R are methyl, P2 be trifluoroacetyl group compound 20.5g shown in formula III, yield 97.6%.
On the other hand, in embodiments of the invention, the invention provides for midbody compound shown in the synthetic formula III of morphine-6-β-D-Glucose aldehydic acid glycosides:
Here, substituent R is C1-C6 alkyl or benzyl, is preferably selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl;
Substituting group P1 is alkyloyl or the benzoyl of C2-C6, is preferably selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group or benzoyl.
Substituting group P2 is R
1-C (O)-, R
1-S (O)
2-or R
1-C (O)-C (O)-, R
1for C1-C4 alkyl or substituted-phenyl that C1-C4 alkoxyl group, one or more halogen replace, here, described substituted-phenyl refers to that the one or more hydrogen on phenyl ring are replaced by C1-C4 alkyl, C1-C4 alkoxyl group or C1-C4 alkanoyloxy; Preferably, P2 is selected from CF
3c (O)-, CF
3s (O)
2-, p-toluenesulfonyl, CH
2clC (O)-, CHCl
2c (O)-, CCl
3c (O)-, CH
3oC (O) C (O)-, CH
3oC (O)-, CH
3cH
2oC (O)-, CH
3cH
2oC (O) C (O)-, an acetoxy benzoyl, is more preferably CF
3cO-or CF
3sO
2-.
In a kind of preferred embodiment of the present invention, the invention provides for midbody compound shown in the synthetic formula III of morphine-6-β-D-Glucose aldehydic acid glycosides:
Here, substituent R is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl;
Substituting group P1 is selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group or benzoyl;
Substituting group P2 is CF
3cO-or CF
3sO
2-.
The inventor uses sodium hydroxide to be hydrolyzed to intermediate compound IV according to document US6737518, finds that dehydrate impurity is larger, and HPLC detects and reaches 15% left and right, and is difficult to remove this impurity; And in use hydrochloric acid, be difficult to remove totally with the sodium-chlor of rear production, detect according to Chinese Pharmacopoeia version (CP2010) appendix method in 2010, its residue on ignition is very large, in 2% left and right.
Use calcium hydroxide to be hydrolyzed to intermediate compound IV according to document US20030083476, the reaction times is longer, and reaction is carried out not reacting completely yet for three days; Use in sulfuric acid and after, the calcium sulfate of its generation is difficult to thoroughly remove, after purifying repeatedly, its ignition residue is still in 3% left and right.
But, the synthetic method of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides provided by the invention, ignition residue is less than 0.3%.With respect to document, synthetic method of the present invention has shortened reaction scheme, operation steps and treatment process are simplified, improve product yield, there is the feasibility of extremely strong industrialization operation, the purity 99.83% that HPLC detects, and simple to operate, mild condition, favorable reproducibility, make human body medication safer.
Accompanying drawing explanation
What Fig. 1 represented is the HPLC collection of illustrative plates of morphine of the present invention-6-β-D-Glucose aldehydic acid glycoside product.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment providing is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.
In an embodiment of the present invention,
1h NMR detecting instrument is Bruker Fourier300 nuclear magnetic resonance spectrometer.
Embodiment 1
(1) intermediate III (P1 and P2 are different protecting groups) is synthetic
By compound shown in formula III, (P1 and P2 are isobutyryl, R is methyl) 20g is dissolved in acetic acid, and 10g trifluoroacetic anhydride, adds boron trifluoride 0.1ml, 30～40 ℃ of reactions, pour in frozen water, filter 45～50 ℃ of drying under reduced pressure of filter cake, (P1 is isobutyryl, P2 is trifluoroacetyl group, and R is methyl) compound 20.5g shown in formula III, yield 97.6%;
1H-NMR：(300MHz，CDCl
3)δ=5.75(d，1H)，5.11～5.16(m，3H)，4.17(d，1H)，3.74(s，3H)，2.02(s，9H)。
(2) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 is isobutyryl, P2 is trifluoroacetyl group, R is methyl) 20g methyl tertiary butyl ether dissolves, 10～25 ℃ add zinc bromide 5g, 55～60 ℃ of reactions are to complete, filter, with dichloromethane extraction, water, saturated common salt water washing, be concentrated into dry, add normal hexane crystallization, filter 25～35 ℃ of drying under reduced pressure, (P1 is isobutyryl to obtain intermediate shown in formula (IV), R is methyl) white solid 21.4g, yield 95%, 188～189 ℃ of fusing points;
(3) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate shown in formula (IV), (P1 is isobutyryl; R is methyl) 10ml water and 1ml dissolve with methanol for 7.3g, 20 ℃ add lithium hydroxide 12g below, react complete; adjust pH4～5 with Hydrogen bromide; be evaporated to dryly, add ethanol crystallization, wash away lithiumbromide; 25～35 ℃ of drying under reduced pressure; obtain white solid 4.2g, yield 91.3%, fusing point: 253～255 ℃.
According to the detection method of CP2010 appendix, residue on ignition is 0.1%.
1H-NMR：(300MHz，D
2O)δ=6.65(d，1H)，6.60(d，1H)，5.74(d，1H)，5.34(d，1H)，5.18(d，1H)，4.60(d，1H)，4.49(m，1H)，4.10(m，1H)，3.60-3.65(m，1H)，3.40-3.48(m，2H)，3.21-3.34(m，3H)，3.02-3.15(m，2H)，2.89(m,4H)，2.20-2.23(m，1H),2.05-2.08(m，1H)。
Adopt the purity of waters2695 type high performance liquid chromatograph (HPLC) analysed preparation morphine-6-β-D-Glucose aldehydic acid glycosides, wherein, chromatographic column is Agilent ZORBAX Eclipse XDB-phenyl, and moving phase is A:10mg potassium primary phosphate, and phosphoric acid is adjusted PH3.0; Mobile phase B: acetonitrile phase, adopt gradient elution, gradient is
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 35 | 15 | 85 |
| 60 | 15 | 85 |
Its analytical results as shown in Figure 1.
Embodiment 2
1) intermediate III (P1 and P2 are different protecting groups) is synthetic
By compound shown in formula III, (P1 and P2 are ethanoyl, R is methyl) 20g is dissolved in phenylformic acid, and 12g trichlorine methylsulfonic acid acid anhydride, adds boron trifluoride 0.05ml, 30～40 ℃ of reactions, pour in frozen water, filter 50～60 ℃ of drying under reduced pressure of filter cake, (P1 is ethanoyl to obtain compound shown in formula III, P2 is trifyl, and R is methyl) 21.5g, yield 97.5%;
1H-NMR：(300MHz，CDCl
3)δ=6.42(d，1H)，5.24～5.79(m，3H)，4.44(d，1H)，3.73(s，3H)，2.46～2.54(m，3H)，1.12(d，18H)。
(2) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 is ethanoyl, P2 is trifyl, R methyl) 18g dissolves with methylene dichloride, 10～25 ℃ add boron trifluoride ether solution 15ml, 35～40 ℃ of reactions are to complete, filter, filtrate is extracted with ethyl acetate, and water, saturated common salt water washing, be concentrated into dry, add normal hexane crystallization, filter, 25～35 ℃ of drying under reduced pressure, (P1 is isopropyl acyl group to obtain intermediate compound IV, R methyl) white solid 17.5g, yield 89%;
(2) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate compound IV, (P1 is isopropyl acyl group; R methyl) 8ml water and 4ml dissolve with ethanol for 6.5g; 20 ℃ add lithium hydroxide 12g below, and room temperature reaction is complete, adjust pH4～5 with Hydrogen bromide; reducing pressure 40～45 ℃ is concentrated into dry; add Virahol crystallization, ethanol washes away lithiumbromide, 35～45 ℃ of drying under reduced pressure; obtain white solid 4.1g, yield 91%.
According to the detection method of CP2010 appendix, residue on ignition is 0.27%.
Embodiment 3
(1) intermediate III (P1 and P2 are different protecting groups) is synthetic
By compound shown in formula III, (P1 and P2 are isopropyl acyl group, R is ethyl) 20g is dissolved in phenylformic acid, and 9g trifluoromethanesulfanhydride anhydride, adds zinc chloride 3g, 70～80 ℃ of reactions, pour in frozen water, filter 50～60 ℃ of drying under reduced pressure of filter cake, (P1 is isopropyl acyl group to obtain compound shown in formula III, P2 is trifyl, and R is ethyl) 20g, yield 96.5%;
(2) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 is isopropyl acyl group, P2 is trifyl, R is ethyl) 16g trichloromethane dissolves, 10～25 ℃ add aluminum chloride 12g, 40～45 ℃ of reactions are to complete, filter, filtrate is extracted with ethyl acetate, and water, saturated common salt water washing, be evaporated to dry, add normal hexane crystallization, filter, 40～45 ℃ of drying under reduced pressure, (P1 is isopropyl acyl group to obtain intermediate compound IV, R is ethyl) white solid 15g, yield 85%;
(3) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate compound IV, (P1 is isopropyl acyl group; R is ethyl) 4ml water and 7ml dissolve with methanol for 5.4g; 20 ℃ add lithium hydroxide 12g below, react complete, adjust pH5～6 with Hydrogen bromide; be evaporated to dry; add ethanol crystallization, wash away lithiumbromide, 45～50 ℃ of drying under reduced pressure; obtain white solid 3.9g, yield 87%.
According to the detection method of CP2010 appendix, residue on ignition is 0.15%.
Embodiment 4
(1) intermediate III (P1 and P2 are different protecting groups) is synthetic
By compound shown in formula III, (P1 and P2 are isobutyryl, R is methyl) 20g is dissolved in acetic acid, and 10g trifluoroacetic anhydride, adds boron trifluoride 0.1ml, 30～40 ℃ of reactions, pour in frozen water, filter 45～50 ℃ of drying under reduced pressure of filter cake, (P1 is isobutyryl, P2 is trifluoroacetyl group, and R is methyl) compound 20.5g shown in formula III, yield 97.6%;
(2) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 is isobutyryl, P2 is trifluoroacetyl group, R is methyl) 20g acetonitrile dissolves, 10～25 ℃ add zinc bromide 5g, 55～60 ℃ of reactions are to complete, filter, with dichloromethane extraction, water, saturated common salt water washing, be concentrated into dry, add normal hexane crystallization, filter 25～35 ℃ of drying under reduced pressure, (P1 is isobutyryl to obtain intermediate shown in formula (IV), R is methyl) white solid 21.8g, yield 95.2%, 188～189 ℃ of fusing points;
(3) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate shown in formula (IV), (P1 is isobutyryl; R is methyl) 10ml water and 1ml dissolve with methanol for 7.3g, 20 ℃ add lithium hydroxide 11.5g below, react complete; adjust pH4～5 with Hydrogen bromide; be evaporated to dryly, add ethanol crystallization, wash away lithiumbromide; 25～35 ℃ of drying under reduced pressure; obtain white solid 4.5g, yield 91.5%, fusing point: 253～255 ℃.
According to the detection method of CP2010 appendix, residue on ignition is 0.05%.
Embodiment 5
(1) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 and P2 are pivaloyl group, R is ethyl) 25g tetrahydrofuran (THF) dissolves, 10～25 ℃ add iron(ic) chloride 12.5g, 45～50 ℃ of reactions are to complete, filter, filtrate extracts with methyl tertiary butyl ether, water, saturated common salt water washing, be concentrated into dryly, add normal hexane crystallization, filter, 30～35 ℃ of drying under reduced pressure, obtain intermediate compound IV (P1 is pivaloyl group, and R is ethyl) white solid 24g, yield 92%;
(2) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate compound IV, (P1 is pivaloyl group; R is ethyl) 1ml water and 10ml dissolve with methanol for 8.5g; 20 ℃ add lithium hydroxide 15g below, react complete, adjust pH4～5 with Hydrogen bromide; be evaporated to dry; add ethanol crystallization, wash away lithiumbromide, 50～60 ℃ of drying under reduced pressure; obtain white solid 3.8g, yield 86.3%.
According to the detection method of CP2010 appendix, residue on ignition is 0.2%.
Embodiment 6:
(1) intermediate compound IV is synthetic
By compound shown in 3-acetylmorphine (compound shown in formula II) 10g and formula III, (P1 and P2 are isobutyryl, R methyl) 20g dissolves with dimethyl formamide, 10～25 ℃ add cupric bromide 13.5g, 25～35 ℃ of reactions are to complete, filter, filtrate is extracted with ethyl acetate, water, saturated common salt water washing, be evaporated to dryly, add normal hexane crystallization, filter, 40～45 ℃ of drying under reduced pressure, obtain intermediate compound IV ((P1 is isobutyryl, R methyl) white solid 19.8g, yield 89.8%;
(2) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate compound IV, ((P1 is isobutyryl; R methyl) 3ml water and the dissolving of 8ml Virahol for 7.3g; 20 ℃ add lithium hydroxide 12g below, react complete, adjust pH4～5 with Hydrogen bromide; be evaporated to dry; add ethanol crystallization, methyl alcohol washes away lithiumbromide, 30～40 ℃ of drying under reduced pressure; obtain white solid 4.1g, yield 91%.
According to the detection method of CP2010 appendix, residue on ignition is 0.12%.
Embodiment 7
(1) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 and P2 are ethanoyl, R is benzyl) 20g dimethyl formamide dissolves, 10～25 ℃ add zinc chloride 10.3g, 25～35 ℃ of reactions are to complete, filter, filtrate chloroform extraction, water, saturated common salt water washing, be evaporated to dryly, add normal hexane crystallization, filter, 35～40 ℃ of drying under reduced pressure, obtain intermediate compound IV (P1 is ethanoyl, and R is benzyl) white solid 19.5g, yield 89.6%;
(2) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate compound IV, (P1 is ethanoyl; R is benzyl) 5ml water and 6ml dissolve with methanol for 7.3g; 20 ℃ add lithium hydroxide 12g below, react complete, adjust pH4～5 with Hydrogen bromide; be evaporated to dry; add ethanol crystallization, methyl alcohol washes away lithiumbromide, 28～40 ℃ of drying under reduced pressure; obtain white solid 3.8g, yield 89%.
According to the detection method of CP2010 appendix, residue on ignition is 0.1%.
Embodiment 8
(1) intermediate compound IV is synthetic
By compound shown in acetylmorphine (compound shown in formula II) 10g and formula III, (P1 and P2 are ethanoyl, R is benzyl) 20g Nitromethane 99Min. dissolves, 10～25 ℃ add cupric bromide 11.3g, 25～35 ℃ of reactions are to complete, filter, filtrate chloroform extraction, water, saturated common salt water washing, be evaporated to dryly, add normal hexane crystallization, filter, 35～40 ℃ of drying under reduced pressure, obtain intermediate compound IV (P1 is ethanoyl, and R is benzyl) white solid 20.5g, yield 89.8%;
(2) synthesizing of morphine-6-β-D-Glucose aldehydic acid glycosides (compound shown in formula I)
By intermediate compound IV, (P1 is ethanoyl; R is benzyl) 5ml water and 6ml dissolve with methanol for 7.3g; 20 ℃ add lithium hydroxide 12g below, react complete, adjust pH4～5 with Hydrogen bromide; be evaporated to dry; add ethanol crystallization, methyl alcohol washes away lithiumbromide, 28～40 ℃ of drying under reduced pressure; obtain white solid 3.5g, yield 87%.
According to the detection method of CP2010 appendix, residue on ignition is 0.07%.
Claims (10)
1. a synthetic method for morphine-6-β-D-Glucose aldehydic acid glycosides, comprises the steps:
(1) in organic solvent 1, react under Louis acid catalysis with the glucuronate of the acyl group protection shown in the 3-acetylmorphine shown in formula (II) and formula (III), obtain the intermediate shown in formula (IV);
(2) intermediate shown in formula (IV) is in the admixture solvent of C1-C4 alkane alcohol and water, use lithium hydroxide is hydrolyzed, and Hydrogen bromide neutralizes, and washs with C1-C4 alkanol, dry, obtain the morphine shown in formula (I)-6-β-D-Glucose aldehydic acid glycosides;
In above-mentioned formula II, substituent A c is ethanoyl;
In above-mentioned formula III and formula IV, substituent R is C1-C6 alkyl or benzyl, is preferably selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl;
Substituting group P1 is alkyloyl or the benzoyl of C2-C6, is preferably selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group or benzoyl;
Substituting group P2 is alkyloyl, the R of C2-C6
1-C (O)-, R
1-S (O)
2-or R
1-C (O)-C (O)-, R
1for C1-C4 alkyl, phenyl or substituted-phenyl that C1-C4 alkoxyl group, one or more halogen replace, here, described substituted-phenyl refers to that the one or more hydrogen on phenyl ring are replaced by C1-C4 alkyl, C1-C4 alkoxyl group or C1-C4 alkanoyloxy; Preferably, P2 is selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group, CF
3c (O)-, CF
3s (O)
2-, p-toluenesulfonyl, CH
2clC (O)-, CHCl
2c (O)-, CCl
3c (O)-, CH
3oC (O) C (O)-, CH
3oC (O)-, CH
3cH
2oC (O)-, CH
3cH
2oC (O) C (O)-, benzoyl, an acetoxy benzoyl, is more preferably ethanoyl or isobutyryl, CF
3cO-, CF
3sO
2-.
2. synthetic method as claimed in claim 1, wherein, Lewis acid described in step (1) is one or more the mixture in zinc bromide, cupric bromide, boron trifluoride, zinc chloride, iron(ic) chloride, aluminum chloride or cuprous chloride.
3. synthetic method as claimed in claim 1, wherein, the organic solvent 1 of step (1) is one or more the mixture in tetrahydrofuran (THF), methyl tertiary butyl ether, dimethyl formamide, methylene dichloride, acetonitrile, Nitromethane 99Min. or trichloromethane.
4. synthetic method as claimed in claim 1, wherein, the temperature of reaction of step (1) is 10～60 ℃, is preferably 25～40 ℃.
5. synthetic method as claimed in claim 1, wherein, the part by weight of the C1-C4 alkane alcohol and water in the admixture solvent of the C1-C4 alkane alcohol and water of step (2) is 10: 1～1: 10, is preferably 7: 3～4: 6.
6. synthetic method as claimed in claim 1, wherein, C1-C4 alkanol in the admixture solvent of the C1-C4 alkane alcohol and water of step (2) is one or more the mixture in methyl alcohol, ethanol or Virahol, preferably, is a kind of in methyl alcohol or ethanol or both mixtures.
7. synthetic method as claimed in claim 1, wherein, the C1-C4 alkanol for washing of step (2) is one or more mixture of methyl alcohol, ethanol or Virahol, preferably, is a kind of in methyl alcohol or ethanol or both mixtures.
8. synthetic method as claimed in claim 1, comprises the steps:
(1) compound shown in the 3-acetylmorphine shown in formula (II) and formula (III) is dissolved with organic solvent 1, add Lewis acid at 10～25 ℃, 10～60 ℃ are reacted complete to raw material reaction; Reaction solution is poured into water, with and the immiscible organic solvent 2 of water extract, be concentrated into dryly, obtain the intermediate shown in formula (IV);
(2) intermediate shown in formula IV is dissolved with the mixed solvent of C1-C4 alkane alcohol and water, 10～25 ℃ add lithium hydroxide to be hydrolyzed, and 25～30 ℃ are reacted complete to raw material reaction; Be neutralized to pH4～6 with Hydrogen bromide, 40～60 ℃ of concentrating under reduced pressure, wash away lithiumbromide with C1-C4 alkanol, and 25～60 ℃ of drying under reduced pressure, obtain morphine-6-β-D-Glucose aldehydic acid glycosides;
Wherein, in formula (II), formula (III) and formula (IV) each substituent definition as claim 1.
9. synthetic method as claimed in claim 8, wherein organic solvent 2 is one or more the mixture in methyl tertiary butyl ether, methylene dichloride, trichloromethane or ethyl acetate, is preferably methyl tertiary butyl ether.
10. for midbody compound shown in the synthetic formula III of morphine-6-β-D-Glucose aldehydic acid glycosides:
Here, substituent R is C1-C6 alkyl or benzyl, is preferably selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl;
Substituting group P1 is alkyloyl or the benzoyl of C2-C6, is preferably selected from ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, pivaloyl group or benzoyl;
Substituting group P2 is R
1-C (O)-, R
1-S (O)
2-or R
1-C (O)-C (O)-, R
1for C1-C4 alkyl or substituted-phenyl that C1-C4 alkoxyl group, one or more halogen replace, here, described substituted-phenyl refers to that the one or more hydrogen on phenyl ring are replaced by C1-C4 alkyl, C1-C4 alkoxyl group or C1-C4 alkanoyloxy; Preferably, P2 is selected from CF
3c (O)-, CF
3s (O)
2-, p-toluenesulfonyl, CH
2clC (O)-, CHCl
2c (O)-, CCl
3c (O)-, CH
3oC (O) C (O)-, CH
3oC (O)-, CH
3cH
2oC (O)-, CH
3cH
2oC (O) C (O)-, an acetoxy benzoyl, is more preferably CF
3cO-or CF
3sO
2-.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610366952.4A CN106008621B (en) | 2014-03-26 | 2014-03-26 | A kind of synthetic method and its midbody compound of morphine -6- β-D-Glucose aldehydic acid glycosides |
| CN201410116005.0A CN103864866B (en) | 2014-03-26 | 2014-03-26 | Synthetic method and the midbody compound thereof of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410116005.0A CN103864866B (en) | 2014-03-26 | 2014-03-26 | Synthetic method and the midbody compound thereof of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610366952.4A Division CN106008621B (en) | 2014-03-26 | 2014-03-26 | A kind of synthetic method and its midbody compound of morphine -6- β-D-Glucose aldehydic acid glycosides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103864866A true CN103864866A (en) | 2014-06-18 |
| CN103864866B CN103864866B (en) | 2016-05-25 |
Family
ID=50903927
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410116005.0A Active CN103864866B (en) | 2014-03-26 | 2014-03-26 | Synthetic method and the midbody compound thereof of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides |
| CN201610366952.4A Active CN106008621B (en) | 2014-03-26 | 2014-03-26 | A kind of synthetic method and its midbody compound of morphine -6- β-D-Glucose aldehydic acid glycosides |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610366952.4A Active CN106008621B (en) | 2014-03-26 | 2014-03-26 | A kind of synthetic method and its midbody compound of morphine -6- β-D-Glucose aldehydic acid glycosides |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN103864866B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106554377A (en) * | 2015-09-25 | 2017-04-05 | 宜昌人福药业有限责任公司 | Morphine derivatives crystal formation III and its production and use |
| CN106554376A (en) * | 2015-09-25 | 2017-04-05 | 宜昌人福药业有限责任公司 | Morphine derivatives crystal formation II and its production and use |
| CN107964030A (en) * | 2017-11-07 | 2018-04-27 | 宜昌人福药业有限责任公司 | A kind of synthetic method of morphine derivatives and application |
| CN108727444A (en) * | 2017-04-19 | 2018-11-02 | 宜昌人福药业有限责任公司 | The synthetic method and its midbody compound of morphine -6- β-D-Glucose aldehydic acid glycosides |
| CN110305142A (en) * | 2019-07-12 | 2019-10-08 | 宜昌人福药业有限责任公司 | A kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993003051A1 (en) * | 1991-08-06 | 1993-02-18 | Salford Ultrafine Chemicals And Research Limited | A process for making morphine-6-glucuronide or substituted morphine-6-glucuronide |
| EP0816375A1 (en) * | 1995-11-29 | 1998-01-07 | Rolabo Sl | Glycoconjugates of opiated substances |
| WO1999038876A1 (en) * | 1998-02-02 | 1999-08-05 | Cenes Limited | Glycosidation of 4,5-epoxymorphinan-6-ols |
| WO1999058545A1 (en) * | 1998-05-13 | 1999-11-18 | Cenes Limited | Process for preparation of 4,5-epoxymorphinan-6-oxyglucuronides |
| WO2013056096A1 (en) * | 2011-10-13 | 2013-04-18 | Angiochem Inc. | Polypeptide-opioid conjugates and uses thereof |
| CN103421063A (en) * | 2012-05-23 | 2013-12-04 | 宜昌人福药业有限责任公司 | Method for synthesizing morphine-6-Beta-D-glucuronide |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07206891A (en) * | 1993-12-02 | 1995-08-08 | Seikagaku Kogyo Co Ltd | Iduronic acid derivative and its production |
-
2014
- 2014-03-26 CN CN201410116005.0A patent/CN103864866B/en active Active
- 2014-03-26 CN CN201610366952.4A patent/CN106008621B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993003051A1 (en) * | 1991-08-06 | 1993-02-18 | Salford Ultrafine Chemicals And Research Limited | A process for making morphine-6-glucuronide or substituted morphine-6-glucuronide |
| EP0816375A1 (en) * | 1995-11-29 | 1998-01-07 | Rolabo Sl | Glycoconjugates of opiated substances |
| WO1999038876A1 (en) * | 1998-02-02 | 1999-08-05 | Cenes Limited | Glycosidation of 4,5-epoxymorphinan-6-ols |
| WO1999058545A1 (en) * | 1998-05-13 | 1999-11-18 | Cenes Limited | Process for preparation of 4,5-epoxymorphinan-6-oxyglucuronides |
| WO2013056096A1 (en) * | 2011-10-13 | 2013-04-18 | Angiochem Inc. | Polypeptide-opioid conjugates and uses thereof |
| CN103421063A (en) * | 2012-05-23 | 2013-12-04 | 宜昌人福药业有限责任公司 | Method for synthesizing morphine-6-Beta-D-glucuronide |
Non-Patent Citations (1)
| Title |
|---|
| IGOR RUKHMAN，等: "Selective synthesis of both isomers of morphine 6-β-D-glucuronide", 《TETRAHEDRON》, vol. 57, no. 6, 4 February 2001 (2001-02-04), pages 1083 - 1092, XP004316540, DOI: doi:10.1016/S0040-4020(00)01080-2 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106554377A (en) * | 2015-09-25 | 2017-04-05 | 宜昌人福药业有限责任公司 | Morphine derivatives crystal formation III and its production and use |
| CN106554376A (en) * | 2015-09-25 | 2017-04-05 | 宜昌人福药业有限责任公司 | Morphine derivatives crystal formation II and its production and use |
| CN106554377B (en) * | 2015-09-25 | 2019-04-12 | 宜昌人福药业有限责任公司 | Morphine derivatives crystal form III and its preparation method and application |
| CN106554376B (en) * | 2015-09-25 | 2019-04-12 | 宜昌人福药业有限责任公司 | Morphine derivatives crystal form II and its preparation method and application |
| CN108727444A (en) * | 2017-04-19 | 2018-11-02 | 宜昌人福药业有限责任公司 | The synthetic method and its midbody compound of morphine -6- β-D-Glucose aldehydic acid glycosides |
| CN107964030A (en) * | 2017-11-07 | 2018-04-27 | 宜昌人福药业有限责任公司 | A kind of synthetic method of morphine derivatives and application |
| CN107964030B (en) * | 2017-11-07 | 2020-04-03 | 宜昌人福药业有限责任公司 | Synthesis method and application of morphine derivative |
| CN110305142A (en) * | 2019-07-12 | 2019-10-08 | 宜昌人福药业有限责任公司 | A kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives |
| CN110305142B (en) * | 2019-07-12 | 2021-11-16 | 宜昌人福药业有限责任公司 | Stereoselective synthesis method of 6 beta-hydroxymorphine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106008621A (en) | 2016-10-12 |
| CN103864866B (en) | 2016-05-25 |
| CN106008621B (en) | 2019-02-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103864866A (en) | Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide | |
| EP2835376B1 (en) | New synthesis process of antiparasitic drug selamectin | |
| EP3406619B1 (en) | Method and intermediate for preparing tulathromycin | |
| CN106749446B (en) | A kind of intermediate of epirubicin hydrochloride compound V | |
| CN101863934B (en) | Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof | |
| Sugimoto et al. | Synthesis and structure–activity relationship of a novel class of 15-membered macrolide antibiotics known as ‘11a-azalides’ | |
| WO2015081778A1 (en) | Method for synthesizing saponin | |
| CN107286207B (en) | Synthesis method of gentiobiose | |
| CN102432642B (en) | Synthesis method of 1,2,3-O-triacetyl-5-deoxy-D-ribofuranose | |
| CN103694291B (en) | Synthesis method for valrubicin | |
| CN103374049B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN107964030B (en) | Synthesis method and application of morphine derivative | |
| CN109369736A (en) | A kind of preparation method of high-purity capecitabine key intermediate | |
| CN113480591A (en) | Ginsenoside derivative and synthesis method and application thereof | |
| CN107383137A (en) | A kind of synthetic method of chenodeoxycholic acid | |
| CN103421063B (en) | A kind of method of synthesizing morphine-6-β-D-Glucose aldehydic acid glycosides | |
| JP2015517535A (en) | Improved synthesis | |
| CN107325133A (en) | A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 | |
| CN114644679B (en) | Glucuronide compound, preparation method and application thereof | |
| WO2000077016A1 (en) | DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN | |
| CN108727444B (en) | Synthesis method of morphine-6-beta-D-glucuronide and intermediate compound thereof | |
| CN115611964B (en) | Ursolic acid saponin with inflammatory bowel disease treatment effect, derivative thereof, preparation method and application | |
| CN115505020B (en) | Ursolic acid saponin and its preparation method and use | |
| CN117105996B (en) | Preparation method of deoxyribose derivative | |
| CN114075161B (en) | Preparation method of alpha-pyrone compound for treating respiratory diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |