CN108727444B - Synthesis method of morphine-6-beta-D-glucuronide and intermediate compound thereof - Google Patents
Synthesis method of morphine-6-beta-D-glucuronide and intermediate compound thereof Download PDFInfo
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Abstract
The invention discloses a synthetic method of morphine-6-beta-D-glucuronide and an intermediate compound thereof. The intermediate shown in formula (I) is adopted to synthesize morphine-6-beta-D-glucuronide, and the definition of each substituent is detailed in the specification. Compared with the prior art, the synthesis method can quickly finish the reaction in a short time, obtain the morphine-6-beta-D-glucuronide with high yield, high purity and easy industrialization, and shorten the reaction time of the glycosylation reaction to 2-10 h.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, relates to a synthetic method of analgesic, and particularly relates to a synthetic method of morphine-6-beta-D-glucuronide and an intermediate compound thereof.
Background
Morphine-6-beta-D-glucuronide (Morphine-6-beta-D-glucuronide, M6G for short) is an active metabolite of Morphine in vivo. Morphine, the opioid compound, is currently the most widely used narcotic analgesic for the treatment of moderate to severe pain, but studies have shown that morphine does not itself act as a narcotic analgesic. Morphine binds primarily to glucuronide in the liver and produces two metabolites: morphine-3-glucuronide (M3G) and morphine-6-beta-D-glucuronide (M6G). M6G can bind to opioid receptor, and animal experiments show that the analgesic effect is stronger than morphine and the adverse reaction is slight. M3G has low affinity with opioid receptors and no analgesic effect, and animal experiments show that M3G can resist the analgesic effect of morphine and M6G and possibly participate in the formation of morphine tolerance. The structural formula of morphine-6-beta-D-glucuronide (M6G) is shown in the specification.
At present, the synthesis methods of morphine-6-beta-D-glucuronide (M6G) mainly comprise the following steps:
the Conixis-Kernol (Koenigs-Knorr) glycosidation method is to perform a coupling reaction between a glycosyl halide and morphine under the catalysis of a metal salt or a Lewis acid to obtain morphine-O-glycoside, thereby realizing the glycosidation of the morphine. This method was first reported by Yoshimura in 1968 (chem. pharm. bull.1968, 16, 2114.). In addition, there are other groups that have reported relevance, for example, patent WO9305057A1 to Mertz et al also relates to this synthesis. However, the method has low yield, the bromo-sugar is unstable, and the long-term storage is difficult under normal storage conditions; meanwhile, the purification is difficult, and a small amount of heavy metal ions in the final product are difficult to remove, so that the method is not suitable for amplification and industrial production.
The trichloroacetimidate method is that trichloroacetimidate with sugar connected to one end is obtained through the reaction of trichloroacetonitrile and 1-position hydroxyl of sugar, and then coupled with 6-position hydroxyl of morphine to obtain the target product with protecting group. This method was first reported by Schmidt and Grundler in 1981 (Synthesis.1981, 885.). The Brown group improved the optimization of the method and applied for related patent WO9303051a1 in 1993. Although Brown's group reports that they can achieve 50% to 70% coupling reaction yield using this method, several other groups report that the results are difficult to replicate, and that there are also deficiencies in low yield, poor stereoselectivity, etc.
The thioglycoside method, Gutman et al, reported a strategy for the Synthesis of the M6G analog dihydromorphine-6- β -D-glucuronide using the thioglycoside method (Synthesis2000, 9, 1241.): the dihydromorphine with protected 3-hydroxyl is subjected to glycosylation reaction with thioglycoside under the catalysis of NIS and TfOH to synthesize the dihydromorphine-6-beta-D-glucuronide intermediate with the protecting group. The intermediate has simple synthesis method, high efficiency and good stereoselectivity. The synthesis of M6G by this method is also referred to in WO9938876A1, but it has several disadvantages: firstly, when synthesizing an intermediate of thioglycoside, namely the glucuronic acid methyl ester with protection, glucuronic acid lactone is subjected to ring opening to generate the glucuronic acid methyl ester, and then the glucuronic acid methyl ester reacts with acyl chloride, so that the yield is low, and the separation and the purification are not easy; secondly, the morphine-6-beta-D-glucuronide intermediate with the protecting group and the final product M6G are separated and purified by a column chromatography method, and are difficult to industrialize; third, no suitable deprotection and work-up methods are given.
The following synthetic route is reported in US20030083476a 1:
this route has the following disadvantages:
(1) perchloric acid in the catalyst is salified and precipitated with 3-pivaloyl morphine, so that the catalyst is deactivated.
(2) Column chromatography is adopted in the post-treatment of the glycosidation reaction to purify the product, and the feasibility of later amplification and industrialization is not high.
The literature reports only 29% yield for this glycosidation reaction. It can be seen that the conversion rate of this reaction is very low, and the raw material and product are not easily separated, and column chromatography is used to purify the product, so that the yield is further reduced, and the method has problems in industrialization.
Chinese patent CN201410116005.0 reports the following route:
in the route, Lewis acid is used for catalyzing the glycosylation reaction when the first-step reaction is carried out, the reaction speed is very low when the industrial amplification is carried out, and when P2 is acetyl or isobutyryl or pivaloyl, the glycosylation reaction needs to be finished after 120h to 200 h; even if P2 is trifluoroacetyl or trifluoromethanesulfonyl, the glycosidation reaction can be completed within 60 to 80 hours, and the application of the method in industrialization is seriously influenced due to the extremely long reaction time of the method. The following two impurities are easily generated in the reaction process, and the impurities are not easily and completely removed in the post-treatment process, which brings certain difficulty to the purification of the final product M6G.
In summary, the above methods for synthesizing M6G all have the same problems: (1) the conversion rate of the glycosidation reaction in the key step is low, or the reaction time is extremely long; (2) the purification of the product adopts a column chromatography mode, and the industrialization has problems. (3) The purity of the product and the residues on ignition are difficult to meet the quality requirements.
Disclosure of Invention
The inventor develops a synthesis method of a morphine-6-beta-D-glucuronide intermediate, which is simple in operation, mild in condition, capable of quickly finishing reaction in a short time, high in yield and purity and easy to industrialize, overcomes the defects in the prior art, and shortens the reaction time of glycosylation reaction to 2-10 h.
The invention aims to provide a synthesis method of morphine-6-beta-D-glucuronide.
It is another object of the present invention to provide intermediate compounds for the synthesis of morphine-6- β -D-glucuronide, for example, compounds represented by formula I, and the like.
Specifically, in an embodiment of the present invention, the present invention provides a method for the synthesis of morphine-6- β -D-glucuronide (i.e., a compound of formula V), comprising the steps of:
(1) the morphine base shown as the formula (II) is reacted with organic acid anhydride R in an organic solvent 1 containing water under the catalysis of a basic catalyst1-O-R1Or organic acid chlorides R1-Cl to produce a compound of formula (III);
(2) 3-R represented by the formula (III)1Morphine and acyl protected glucuronate shown as a formula (IV) react in an organic solvent 2 under the catalysis of Lewis acid to obtain an intermediate shown as a formula (I);
(3) removing protecting group from the intermediate shown in the formula (I) to obtain morphine-6-beta-D-glucuronide shown in the formula (V)
Wherein, the organic acid anhydride R1-O-R1Organic acid chloride R1-Cl, R in formula (I) and formula (III)1Is an electron-withdrawing group selected from CF3C(O)-，CF3S(O)2-, p-toluenesulfonyl, CH2ClC(O)-，CHCl2C(O)-，CCl3C(O)-，CH3OC(O)C(O)-，CH3OC(O)-，CH3CH2OC(O)-，CH3CH2OC (O) C (O) -, m-chlorobenzoyl, m-nitrobenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-chlorobenzoyl, o-nitrobenzoyl, dinitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, o-chlorobenzenesulfonyl, o-nitrobenzenesulfonyl, preferably dinitrobenzoyl, CF3C (O) -or CF3S(O)2-；
R in the formula (I) and the formula (IV)2Alkanoyl or benzoyl group of C2-C6, preferably selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl or benzoyl;
r in the formula (I) and the formula (IV)3Is C1-C6 alkyl or benzyl, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl;
r in the formula (IV)5Is R4-O-or halogen, where R4Is C1-C4 alkanoyl, C1-C6 sulfonyl, one or more halogen substituted C1-C4 alkanoyl, one or more halogen substituted C1-C6 sulfonyl, C1-C4 alkoxy C1-C4 alkanoyl, C1-C4 alkoxy C1-C4 alkanoyl C1-C4 alkanoyl, or substituted benzoyl, or substituted benzenesulfonyl, wherein the substituted benzoyl or substituted benzenesulfonyl is that one or more hydrogens on the benzene ring is substituted by nitro, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkanoyloxy; preferably, R5Selected from Br, CF3C(O)-O-，CF3S(O)2-O-, p-toluenesulfonyloxy, CH2ClC(O)-O-，CHCl2C(O)-O-，CCl3C(O)-O-，CH3OC(O)C(O)-O-，CH3OC(O)-O-，CH3CH2OC(O)-O-，CH3CH2OC (O) C (O) -O-, m-acetoxybenzoyloxy, nitrobenzoyloxy, dinitrobenzoyloxy, more preferably Br, CF3C (O) -O-or CF3S(O)2-O-。
In an embodiment of the present invention, the present invention provides a method for synthesizing morphine-6- β -D-glucuronide, wherein the organic solvent 1 of step (1) is acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, N-dimethylformamide, or N, N-dimethylacetamide; the volume ratio of water to the organic solvent 1 is 5: 95-95: 5.
in an embodiment of the present invention, the present invention provides a method for synthesizing morphine-6-beta-D-glucuronide, wherein the organic acid anhydride R of the step (1)1-O-R1Is trifluoroacetic anhydride or trifluoromethanesulfonic anhydride; organic acid chloride R1-Cl is p-methylbenzenesulfonyl chloride, m-chlorobenzoyl chloride, m-nitrobenzoyl chloride, p-chlorobenzoyl chloride, p-nitrobenzoyl chloride, o-chlorobenzoyl chloride, o-nitrobenzoyl chloride, dinitrobenzoyl chloride, p-chlorobenzenesulfonyl chloride, m-nitrobenzenesulfonyl chloride, m-chlorobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-chlorobenzenesulfonyl chloride, or o-nitrobenzenesulfonyl chloride.
In the embodiment of the invention, the morphine-6-beta-D-glucuronide synthesis method provided by the invention is characterized in that the basic catalyst in the step (1) is one or more of sodium hydride, potassium tert-butoxide, potassium carbonate, sodium bicarbonate, triethylamine, pyridine and sodium hydroxide.
In the embodiment of the invention, the reaction temperature of the step (1) is-30-40 ℃, preferably 5-30 ℃.
In an embodiment of the present invention, the present invention provides a method for synthesizing morphine-6-beta-D-glucuronide, wherein in the step (1), the organic acid anhydride R1-O-R1Or organic acid chlorides R1-molar ratio of Cl to morphine base 1: 0.5 to 1.2.
In a particularly preferred embodiment of the present invention, the present invention provides a method for synthesizing morphine-6- β -D-glucuronide, wherein the step (1) is:
preparing 2.85kg of morphine base into a suspension by using 28.5L of mixed solvent of tetrahydrofuran, acetonitrile, acetone, methanol, ethanol, isopropanol, N-dimethylformamide or N, N-dimethylacetamide and water (the ratio of water to organic solvent is 5: 95-95: 5), adding 0.5-1.2 equivalents of one or more of sodium hydride, potassium tert-butoxide, potassium carbonate, sodium bicarbonate, triethylamine, pyridine or sodium hydroxide, controlling the internal temperature to be less than 30 ℃, dropwise adding 1 equivalent of trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, p-methylbenzenesulfonyl chloride, m-chlorobenzoyl chloride, m-nitrobenzoyl chloride, dinitrobenzoyl chloride, p-chlorobenzoyl chloride, p-nitrobenzoyl chloride, o-chlorobenzoyl chloride, o-nitrobenzoyl chloride, p-chlorobenzoyl chloride, m-nitrobenzoyl chloride and p-nitrobenzoyl chloride, after the reaction, the o-chlorobenzenesulfonyl chloride or o-nitrobenzenesulfonyl chloride is filtered and filtered at 45-65 ℃ and dried under reduced pressure, and the yield is 95-98% (wherein R in the compound of the formula (III)1Is CF3C(O)-，CF3S(O)2-, p-toluenesulfonyl, m-chlorobenzoyl, m-nitrobenzoyl, dinitrobenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-chlorobenzoyl, o-nitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, m-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl, o-chlorobenzenesulfonyl, o-nitrobenzenesulfonyl).
In an embodiment of the present invention, the present invention provides a method for synthesizing morphine-6- β -D-glucuronide, wherein the lewis acid in step (2) is a mixture of one or more of zinc bromide, copper bromide, boron trifluoride, zinc chloride, ferric chloride, aluminum chloride, silver carbonate or cuprous chloride.
In an embodiment of the present invention, the present invention provides a method for synthesizing morphine-6- β -D-glucuronide, wherein the organic solvent 2 of step (2) is one or more of tetrahydrofuran, 1, 2-dichloroethane, dimethylformamide, dichloromethane, acetonitrile, nitromethane, toluene, xylene or chloroform.
In the embodiment of the invention, the reaction temperature of the step (2) is 0-140 ℃, preferably 5-135 ℃.
In an embodiment of the present invention, the present invention provides a method for synthesizing morphine-6- β -D-glucuronide, wherein the compound of formula (IV) of step (2) can be synthesized by the following method:
r is to be5Is R4-O-、R2And R4Are all isobutyryl or pivaloyl or acetyl, R3Dissolving 2kg of a compound of formula (IV) which is methyl in 1kg of acetic acid, adding 1kg of trifluoroacetic anhydride or trifluoromethanesulfonic anhydride and 1L of boron trifluoride diethyl etherate solution, reacting at 50-60 ℃, pouring into ice water after the reaction is finished, filtering, and drying a filter cake at 45-50 ℃ under reduced pressure to obtain R used in the step (2)2Is isobutyryl, pivaloyl, acetyl, R3Is methyl, R5Is R4-O-、R4The compound of formula (IV) is trifluoroacetyl or trifluoromethanesulfonyl, and the yield is 85-95%; or
R is to be5Is R4-O-、R2And R4Are all isobutyryl or pivaloyl or acetyl, R3Dissolving 2kg of compound (IV) of formula (IV) which is methyl in 1kg of acetic acid, adding 1.5kg of hydrogen bromide acetic acid solution, stirring at room temperature for 24h, distilling off the acetic acid under reduced pressure, adding 30L of dichloromethane, neutralizing with saturated sodium bicarbonate, washing with saturated sodium chloride solution, and concentrating to obtain compound (R) of formula (IV) used in step (2)5Is bromine, R2And R4Are all isobutyryl or pivaloyl or acetyl, R3Is methyl); or
R is to be5Is R4-O-、R2And R4Is C2-C6 alkanoyl or benzoyl, R3Adding a C1-C6 alkyl or benzyl compound of formula (IV) into methanol or ethanol, adding 1 equivalent of hydroxylamine hydrochloride, reacting at 15-30 ℃, filtering, drying under reduced pressure at 45 ℃, adding a product of the reaction into tetrahydrofuran or acetonitrile, adding a basic catalyst such as triethylamine and the like, controlling the temperature to be below 30 ℃, and dropwise adding corresponding anhydride or acyl chloride to obtain the compound of formula (IV) used in the step (2)Compound (R)2Is isobutyryl, pivaloyl, acetyl, R3Is methyl, R5Is R4-O-、R4Is p-toluenesulfonyloxy, CH2ClC(O)-O-，CHCl2C(O)-O-，CCl3C(O)-O-，CH3OC(O)C(O)-O-，CH3OC(O)-O-，CH3CH2OC(O)-O-，CH3CH2OC (O), C (O) -O-, m-acetoxy benzoyloxy, nitrobenzoyloxy and dinitrobenzoyloxy) with a yield of 75-90%.
In the embodiment of the invention, the invention provides a method for synthesizing morphine-6-beta-D-glucuronide, wherein the process conditions of patent CN201410116005.0 can be adopted in the step (3); preferably, the intermediate shown in the formula (I) is hydrolyzed by lithium hydroxide in a mixture solvent of C1-C4 alkanol and water, neutralized by acetic acid, washed by C1-C4 alkanol and dried to obtain morphine-6-beta-D-glucuronide shown in the formula (V).
In a second aspect, in an embodiment of the present invention, the present invention provides intermediate compounds for the synthesis of morphine-6- β -D-glucuronide, represented by formula (I):
wherein the content of the first and second substances,
substituent R1Is an electron-withdrawing group selected from CF3C(O)-，CF3SO2-, p-toluenesulfonyl, CH2ClC(O)-，CHCl2C(O)-，CCl3C(O)-，CH3OC(O)C(O)-，CH3OC(O)-，CH3CH2OC(O)-，CH3CH2Oc (o) c (o) -, m-chlorobenzoyl, m-nitrobenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-chlorobenzoyl, o-nitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, m-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl, o-chlorobenzenesulfonyl, dinitrobenzoyl, or o-nitrobenzenesulfonyl; preferably dinitrobenzoyl, CF3C (O) -or CF3S(O)2-；
Substituent R2Alkanoyl or benzoyl group of C2-C6, preferably selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl or benzoyl;
substituent R3Is C1-C6 alkyl or benzyl, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
In a preferred embodiment of the present invention, the intermediate compound represented by formula (I) for the synthesis of morphine-6- β -D-glucuronide provided by the present invention is selected from one of the following compounds:
in an embodiment of the present invention, the present invention also provides an intermediate compound represented by formula (III) for use in the synthesis of an intermediate compound of morphine-6- β -D-glucuronide of formula (I):
wherein R is1Is an electron-withdrawing group selected from CF3C(O)-，CF3S(O)2-, p-toluenesulfonyl, CH2ClC(O)-，CHCl2C(O)-，CCl3C(O)-，CH3OC(O)C(O)-，CH3OC(O)-，CH3CH2OC(O)-，CH3CH2OC (O), C (O) -, m-chlorobenzoyl, m-nitrobenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-chlorobenzoyl, o-nitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, m-chlorobenzenesulfonyl, p-nitrobenzoylBenzenesulfonyl, o-chlorobenzenesulfonyl, or o-nitrobenzenesulfonyl, dinitrobenzoyl, preferably dinitrobenzoyl, CF3C (O) -or CF3S(O)2-。
In an embodiment of the present invention, the present invention also provides intermediate compounds represented by formula (IV) useful for the synthesis of intermediate compounds of morphine-6- β -D-glucuronide of formula (I):
wherein the content of the first and second substances,
R2alkanoyl or benzoyl group of C2-C6, preferably selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl or benzoyl;
R3is C1-C6 alkyl or benzyl, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl;
R5is R4-O-or halogen, where R4Is C1-C4 alkanoyl, C1-C6 sulfonyl, one or more halogen substituted C1-C4 alkanoyl, or substituted benzoyl, wherein the substituted benzoyl means that one or more hydrogens on the phenyl ring is substituted with C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkanoyloxy; preferably, R5Selected from Br, CF3C(O)-O-，CF3S(O)2-O-, p-toluenesulfonyloxy, CH2ClC(O)-O-，CHCl2C(O)-O-，CCl3C(O)-O-，CH3OC(O)C(O)-O-，CH3OC(O)-O-，CH3CH2OC(O)-O-，CH3CH2OC (O) C (O) -O-, m-acetoxybenzoyloxy, more preferably Br, CF3C (O) -O-or CF3S(O)2-O-。
In the study of the synthesis method of the compound represented by the formula (I), different R's were found1The substituent group has a great influence on the reaction speed of the next glycosylation when R is1The reaction speed is gradually increased when the compounds are respectively pivaloyl, isobutyryl and acetyl, but the change is notParticularly obvious; when R is1In the case of a phenylacyl group, the reaction rate is remarkably accelerated, but the reaction rate which is industrially required cannot be satisfied, and the reaction time still needs about 50 hours. The invention is realized by selecting R1Electron-withdrawing substituents such as trifluoroacetyl group and the like are used, the glycosidation reaction can be completed within 2h to 10h, impurities 1 and 2 cannot be generated, the post-treatment is simple, a relatively pure compound shown in formula I can be obtained through simple recrystallization, the purity of HPLC is over 98 percent, the yield is over 95 percent, great convenience is brought to the synthesis of a final product M6G, the production cost is greatly reduced, and the quality of the product is improved.
The inventors' reference US6737518 hydrolyzes intermediate (I) using sodium hydroxide, found that the anhydrate impurities were high, about 15% by HPLC, and the impurities were difficult to remove; and sodium chloride produced after neutralization by using hydrochloric acid is difficult to remove cleanly, and the burning residues are very large and about 2 percent according to the detection of the method in the Chinese pharmacopoeia 2010 edition (CP2010) appendix.
The reference US20030083476 hydrolyzes the intermediate (I) using calcium hydroxide, the reaction time is long, and the reaction is not complete after three days; after the neutralization by using sulfuric acid, the generated calcium sulfate is difficult to completely remove, and the ignition residue is still about 3 percent after multiple purifications.
The synthesis of the glycoside compound of formula (I), which is the key step, according to the method provided in CN201410116005.0, has a very long reaction time, and is prone to generate impurity 1 and impurity 2, which are difficult to remove, thus seriously affecting the industrial application.
However, the burning residue of the synthesis method of morphine-6-beta-D-glucuronide provided by the invention is less than 0.1 percent. Compared with the literature, the synthesis method shortens the reaction route, simplifies the operation steps and the treatment process, greatly shortens the reaction time of glycosylation reaction in the key step, shortens the reaction time of the step from the original 120-200 h to 2-10 h, avoids the generation of impurities 1 and 2, improves the product yield and purity, also improves the total yield and purity of the final product M6G, reduces the cost of industrial production, has extremely strong feasibility of industrial operation, can reach 99.9% of the purity of HPLC detection, has smaller dehydrated substance impurities (shown in formula VI) generated when glycoside is hydrolyzed into M6G (the HPLC content is 0.02%), is simple to operate, mild in conditions, good in reproducibility and safer for human body medication.
Drawings
FIG. 1 shows the morphine-6-beta-D-glucuronide intermediate product (compound of formula I, wherein R is1Is trifluoroacetyl, R2Is acetyl, R3Methyl) in the sample.
Figure 2 shows the morphine-6-beta-D-glucuronide intermediate product (compound of formula III, wherein R is as shown in the figure) of example 1 of the present invention1Trifluoroacetyl group) was used.
Figure 3 shows an HPLC profile of morphine-6- β -D-glucuronide product (compound of formula V) of example 1 of the present invention.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
In an embodiment of the present invention, it is,1the H-NMR detector is a Bruker Fourier300 nuclear magnetic resonance spectrometer.
Example 1
(1) A compound of formula (III) (R)1Is trifluoroacetyl group) of a compound
Adding 2.85kg of morphine base (namely the compound shown in the formula (II)) into 28.5L of mixed solvent of acetonitrile and water (the acetonitrile accounts for 5 vol% and the water accounts for 95 vol%), adding 2.02kg of triethylamine, cooling to below 5 ℃, controlling the temperature to be within 30 ℃, dropwise adding 2.1kg of trifluoroacetic anhydride, reacting for 0.5h at 0-10 ℃ after dropwise adding, performing suction filtration after the reaction is finished, washing with water, and drying under reduced pressure at 45 ℃ to obtain 3.6kg of white solid, wherein the yield is 95%, and the HPLC (high performance liquid chromatography) is 99.93%.
1H-NMR(300MHz，d6-DMSO)：＝1.65～1.89(m，2H)，1.95～2.04(m，1H)，2.28(s，3H)，2.36～2.42(m，2H)，2.75～3.05(m，2H)，4.56～4.61(m，2H)，5.59～5.85(m，1H)，5.90～5.95(m,1H)，6.18(s，1H)，6.58～6.61(d，1H)，6.72～6.74(d，1H)
The purity of the product compound of formula (III) was analyzed by means of waters2695 type High Performance Liquid Chromatography (HPLC), wherein the column was Agilent ZORBAX Eclipse XDB-phenyl, mobile phase a: 10mg of monopotassium phosphate, and adjusting the pH value to 3.0 by phosphoric acid; mobile phase B: acetonitrile phase, wavelength: 210nm, and gradient elution with gradient of
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 45 | 15 | 85 |
| 45.1 | 90 | 10 |
The analysis results are shown in FIG. 1.
(2) A compound of formula (I) (R)1Is trifluoroacetyl, R2Is acetyl, R3Is methyl) synthesis
3.8kg of 3-trifluoroacetylmorphine (compound of the formula (III), R)1Trifluoroacetyl group) and 4.5kg of a compound of the formula (IV) (R)5Is R4-O-、R2And R4Are all acetyl, R3Methyl) is added into 38L tetrahydrofuran, 3.8L boron trifluoride ether solution is added, the mixture reacts for 8 hours at the temperature of 5-10 ℃, after the reaction is finished, the mixture is poured into 5L water, neutralized by sodium bicarbonate, extracted by 7.6L dichloromethane, washed by 5L saturated sodium chloride, concentrated and recrystallized by 2L isopropanol, 6.7kg of white solid is obtained, the yield is 96.1 percent, and the HPLC purity is 99.78 percent.
1H-NMR(300MHz，d6-DMSO)：＝1.64～1.90(m，2H)，2.03(s，10H)，2.27(s，3H)，2.48～2.74(m，3H)，2.78～3.11(m，2H)，3.67(s，3H)，3.81～4.26(m，1H)，4.81～4.84(m，1H)，4.98～5.02(m，1H)，5.65～5.60(m，4H)，5.95～5.99(m，3H)，，6.47～6.60(d，1H)，6.64～6.74(d，1H)。
The purity of the compound of the product (I) was analyzed by means of a waters2695 High Performance Liquid Chromatograph (HPLC) with an Agilent ZORBAX Eclipse XDB-phenyl column and a mobile phase A: 10mg of monopotassium phosphate, and adjusting the pH value to 3.0 by phosphoric acid; mobile phase B: acetonitrile phase, wavelength: 210nm, and gradient elution with gradient of
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 45 | 15 | 85 |
| 45.1 | 90 | 10 |
The analysis results are shown in FIG. 2.
(3) Synthesis of Compound of formula (V)
An intermediate (R) shown as a formula (I)1Is trifluoroacetyl, R2Is acetyl, R3Methyl) 7.0kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is decompressed and dried at the temperature of 25-35 ℃ to obtain 4.4kg of white solid, the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
The residue on ignition was 0.03% according to the test method attached to CP 2010.
1H-NMR：(300MHz，D2O)＝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)。
Analyzing the purity of the product morphine-6-beta-D-glucuronide by using a waters2695 type High Performance Liquid Chromatograph (HPLC), wherein a chromatographic column is Agilent ZORBAX Eclipse XDB-phenyl, and a mobile phase is A: 10mg of monopotassium phosphate, and adjusting the pH value to 3.0 by phosphoric acid; mobile phase B: acetonitrile phase, wavelength: 210nm, and gradient elution with gradient of
The analysis results are shown in FIG. 3.
Example 2
1) A compound of formula (III) (R)1Is trifluoromethanesulfonyl) synthesis
Adding 2.85kg of morphine base (namely the compound shown in the formula (II)) into 28.5L of mixed solvent of acetone and water (the acetone accounts for 15 percent by volume and the water accounts for 85 percent by volume), adding 2.7kg of potassium carbonate, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 2.8kg of trifluoromethanesulfonic anhydride, reacting for 1h, after the reaction is finished, performing suction filtration, washing with water, and drying at 45 ℃ under reduced pressure to obtain 3.9kg of white solid with the yield of 94 percent.
1H-NMR(300MHz，d6-DMSO)：＝1.67～1.87(m，2H)，2.01～2.04(m，1H)，2.28(s，3H)，2.32～2.40(m，1H)，2.81～3.10(m，2H)，4.13～4.15(m，1H)，4.56～4.58(m，1H)，5.55～5.59(m，1H)，6.18(s，1H)，6.28～6.32(m，1H)，6.68～6.70(d，1H)，6.75～6.80(d，1H)
(2) A compound of formula (I) (R)1Is trifluoromethanesulfonyl, R2Is butyryl, R3Is ethyl) synthesis
4.2kg of 3-trifluoromethanesulfonylmorphine, i.e. the compound of formula (III), and 9.1kg of the compound of formula (IV) (R)2Is butyryl, R5Is R4-O-、R4Is trifluoromethanesulfonyl, R3Ethyl) is added into 38L of acetonitrile, 4kg of anhydrous zinc bromide is added, the reaction is carried out for 2h at the temperature of 20-30 ℃, after the reaction is finished, the mixture is poured into 5L of water, neutralized by sodium bicarbonate, extracted by 7.6L of dichloromethane, washed by 5L of saturated sodium chloride, concentrated and recrystallized by 1.6L of methanol to obtain 7.6kg of white solid, the yield is 94.1%, and the HPLC purity is 99.88%.
1H-NMR(300MHz，d6-DMSO)：＝0.89～0.99(t，9H)，1.19～1.22(t，3H)，1.62～1.69(m，6H)，2.01～2.04(m，1H)，2.27(s，3H)，2.36～2.42(m，8H)，2.78～3.05(m，2H)，4.22～4.34(m，3H)，5.01～5.03(d，1H)，5.56～5.59(m，2H)，5.95～6.01(m，3H)，6.66～6.68(d，1H)，6.79～6.81(d，1H)。
(3) Synthesis of Compound of formula (V)
Reacting an intermediate (R) of formula (I)1Is trifluoromethanesulfonyl, R2Is butyryl, R3Ethyl) 7.0kg of methanol 8.5L anddissolving 1.5L of water, adding 21kg of lithium hydroxide at the temperature of below 20 ℃, adjusting the pH value to 4-5 by using acetic acid after the reaction is finished, concentrating under reduced pressure to dryness, adding methanol for crystallization, washing off lithium salt generated by neutralization, and drying under reduced pressure at the temperature of 25-35 ℃ to obtain 4.4kg of white solid, wherein the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 3
1) A compound of formula (III) (R)1Is trichloroacetyl group)
Adding 2.85kg of morphine base (namely the compound shown in the formula (II)) into 28.5L of mixed solvent of tetrahydrofuran and water (the tetrahydrofuran accounts for 25% by volume and the water accounts for 75% by volume), adding 1.4kg of pyridine, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 2.46kg of trichloroacetic anhydride, reacting at 0-10 ℃ for 1.5h after the dropwise adding is finished, filtering, washing with water, and drying at 45 ℃ under reduced pressure to obtain 4.2kg of white solid with the yield of 97%.
1H-NMR(300MHz，d6-DMSO)：＝1.65～1.89(m，2H)，1.95～2.04(m，1H)，2.28(s，3H)，2.36～2.42(m，2H)，2.75～3.05(m，2H)，4.56～4.61(m，2H)，5.59～5.85(m，1H)，5.90～5.95(m,1H)，6.18(s，1H)，6.58～6.61(d，1H)，6.72～6.74(d，1H)
(2) A compound of formula (I) (R)1Is trichloroacetyl, R2Is isobutyryl, R3Is isopropyl) synthesis
4.3kg of 3-trichloroacetylmorphine (compound of formula (III)) and 6.5kg of compound of formula (IV) (R)2Is isobutyryl, R5Is R4-O-、R4Is trifluoroacetyl, R3Isopropyl) is added into 38L of dichloromethane, 4.2kg of anhydrous copper bromide is added, the reaction is carried out for 10h at the temperature of 10-20 ℃, after the reaction is finished, the mixture is poured into 5L of water, neutralized by sodium bicarbonate, extracted by 7.6L of dichloromethane, washed by 5L of saturated sodium chloride, concentrated and recrystallized by 1.6L of methanol, 8.1kg of white solid is obtained, the yield is 94.8 percent, and the HPLC purity is 99.89 percent.
1H-NMR(300MHz，d6-DMSO)：＝1.13～1.21(d，24H)，1.63～1.67(m，2H)，2.01～2.03(m，1H)，2.25(s，3H)，2.36～2.75(m，3H)，2.79～3.03(m，2H)，4.21～4.26(m，1H)，4.82～5.03(m，3H)，5.56～5.59(m，3H)，5.95～6.02(m，4H)，6.56～6.61(d，1H)，6.69～6.73(d，1H)。
(3) Synthesis of Compound of formula (V)
Reacting an intermediate (R) of formula (I)1Is trichloroacetyl, R2Is isobutyryl, R3Isopropyl) 8.6kg is dissolved by 8.5L methanol and 1.5L water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the solution is concentrated under reduced pressure to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the solution is dried under reduced pressure at the temperature of 25-35 ℃ to obtain 4.4kg of white solid, the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 4
1) A compound of formula (III) (R)1Is m-chlorobenzoyl) synthesis
Adding 2.85kg of morphine base (namely the compound shown in the formula (II)) into 28.5L of a mixed solvent of isopropanol and water (the isopropanol accounts for 35% by volume, and the water accounts for 65% by volume), adding 3.4kg of sodium carbonate, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 1.8kg of m-chlorobenzoyl chloride, reacting at 10-20 ℃ for 0.5h after the dropwise adding is finished, filtering, washing with water, and drying at 45 ℃ under reduced pressure to obtain 4.1kg of white solid with the yield of 97%.
1H-NMR(300MHz，d6-DMSO)：＝1.61～1.85(m，2H)，2.01～2.04(m，1H)，2.28(s，3H)，2.36～2.52(m，3H)，2.81～3.13(m，2H)，4.55～4.64(m，2H)，5.59～5.65(m，1H)，5.91～5.97(m，1H)，6.18(s，1H)，6.67～6.79(d，1H)，6.82～6.84(d，1H)，7.54～7.75(m，2H)，8.11～8.14(m，1H)，8.16(s，1H)
(2) A compound of formula (I) (R)1Is m-chlorobenzoyl, R2Is pivaloyl, R3N-butyl) synthesis
4.3kg of 3-m-chlorobenzoylmorphine, i.e. the compound of formula (III), and 8.3kg of the compound of formula (IV) (R)2Is pivaloyl, R5Is R4-O-、R4Is trichloroacetyl, R3N-butyl) is added into 38L1, 2-dichloroethane, 3.2kg of anhydrous zinc chloride is added, the reaction is carried out for 6h at the temperature of 0-10 ℃, the mixture is poured into 5L water after the reaction is finished, the mixture is neutralized by sodium bicarbonate, and 7.6LExtraction with dichloromethane, washing with 5L of saturated sodium chloride, concentration, and recrystallization with 1.6L of methanol gave 8.6kg of white solid with a yield of 95.8% and a HPLC purity of 99.79%.
1H-NMR(300MHz，d6-DMSO)：＝0.22(s，3H)，0.91(s，3H)，1.12～1.14(d，6H)，1.28(s，18H)，4.40～1.63(m，6H)，2.01～2.04(m，1H)，2.25(s，3H)，2.42～2.55(m，3H)，2.79～3.05(m，2H)，3.72～4.08(m，3H)，4.55～4.57(m，1H)，5.01～5.03(m，1H)，5.35～5.36(m，1H)，5.57～5.60(m，1H)，5.91～6.01(m，3H)，6.66～6.68(d，1H)，6.79～6.82(d，1H)，7.56～7.78(m，2H)8.19～8.24(m，2H)，8.33(s，1H)。
(3) Synthesis of Compound of formula (V)
Reacting an intermediate (R) of formula (I)1Is m-chlorobenzoyl, R2Is pivaloyl, R3N-butyl) is dissolved in 8.5L methanol and 1.5L water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the solution is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and decompressed and dried at the temperature of 25-35 ℃, 4.4kg of white solid is obtained, the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 5
1) A compound of formula (III) (R)1Is m-nitrobenzoyl) synthesis
Adding 2.85kg of morphine base (a compound shown in a formula II) into a mixed solvent of 28.5L N, N-dimethylformamide and water (the N, N-dimethylformamide accounts for 45% by volume, and the water accounts for 55% by volume), adding 0.4kg of sodium hydride, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 1.8kg of m-nitrobenzoyl chloride, reacting at 20-30 ℃ for 0.5h after dropwise adding, after the reaction is finished, performing suction filtration, washing with water, and drying at 45 ℃ under reduced pressure to obtain 4.2kg of white solid, wherein the yield is 96.8%.
1H-NMR(300MHz，d6-DMSO)：＝1.61～1.87(m，2H)，2.01～2.03(m，1H)，2.28(s，3H)，2.35～2.52(m，3H)，2.81～3.17(m，2H)，4.54～4.66(m，2H)，5.59～5.67(m，1H)，5.91～5.99(m，1H)，6.17(s，1H)，6.65～6.79(d，1H)，6.82～6.87(d，1H)，7.73～7.75(m，1H)，8.45～8.54(m，2H)，8.71(s，1H)。
(2) Synthesis of Compounds of formula I (R)1Is m-nitrobenzoyl, R2Is benzoyl, R3Is an isobutyl group)
4.9kg of 3-m-nitrobenzoyl morphine (compound of formula III) and 7.2kg of compound of formula IV (R)2Is benzoyl, R5 is R4-O-, R4Is methoxyacetyl, R3Isobutyl) is added into 38L nitromethane, 3.2kg of anhydrous cuprous chloride is added, the reaction is carried out for 8h at the temperature of 30-40 ℃, after the reaction is finished, the mixture is poured into 5L of water, neutralized by sodium bicarbonate, extracted by 7.6L of dichloromethane, washed by 5L of saturated sodium chloride, concentrated and recrystallized by 1.6L of methanol, 9.36kg of white solid is obtained, the yield is 95.8 percent, and the HPLC purity is 99.79 percent.
1H-NMR(300MHz，d6-DMSO)：＝0.93～0.96(d，6H)，1.60～2.05(m，3H)，2.25(s，3H)，2.36～2.75(m，3H)，2.77～3.08(m，2H)，3.96～3.98(d，2H)，4.24～4.27(m，1H)，4.81～4.83(d，1H)，5.01～5.03(d，1H)，5.55～5.63(m，2H)，5.90～6.03(m，5H)，6.66～6.68(d，1H)，6.79～6.84(d，1H)，7.53～7.61(m，6H)，7.62～7.77(m，4H)，8.01～8.05(m，6H)，8.42～8.49(m，1H)，8.51～8.56(m，1H)，8.75(s，1H)。
(3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is m-nitrobenzoyl, R2Is benzoyl, R3Isobutyl) 9.8kg of lithium hydroxide is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the solution is concentrated under reduced pressure to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the solution is dried under reduced pressure at the temperature of 25-35 ℃ to obtain 4.4kg of white solid, the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 6
1) A compound of formula III (R)1Is p-toluenesulfonyl group) synthesis
Adding 2.85kg of morphine base (a compound shown in a formula II) into 28.5L of mixed solvent of ethanol and water (ethanol accounts for 95 vol% and water accounts for 5 vol%), adding 2.4kg of sodium bicarbonate, cooling to below 5 ℃, controlling the temperature to be within 30 ℃, dropwise adding 1.8kg of p-toluenesulfonyl chloride, reacting at 30-40 ℃ for 1h, filtering after the reaction is finished, washing with water, and drying at 45 ℃ under reduced pressure to obtain 4.1kg of white solid with the yield of 94%.
1H-NMR(300MHz，d6-DMSO)：＝1.61～1.67(m，2H)，2.02～2.05(m，1H)，2.28(s，3H)，2.41～2.52(m，3H)，2.45(s，3H)，2.72～3.06(m，2H)，4.11～4.15(m，1H)，4.55～4.58(m，1H)，5.57～5.61(m，1H)，5.88～5.91(m，1H)，6.17(s，1H)，6.41～6.45(m，1H)，7.45～7.51(d，2H)，7.73～7.77(d，2H)。
(2) Synthesis of Compounds of formula I (R)1Is p-methylbenzenesulfonyl, R2 is benzoyl, R3 is tert-butyl)
Adding 4.4kg of 3-p-methyl benzenesulfonyl morphine (compound shown in formula III) and 7.3kg of compound shown in formula IV (R2 is benzoyl, R5 is R4-O-, R4 is benzoyl, and R3 is tert-butyl) into 38L of nitromethane, adding 4kg of anhydrous aluminum chloride, reacting at 50-60 ℃ for 2h, pouring the obtained product into 5L of water after the reaction is finished, neutralizing with sodium bicarbonate, extracting with 7.6L of dichloromethane, washing with 5L of saturated sodium chloride, concentrating, recrystallizing with 1.6L of acetone to obtain 9.1kg of white solid, wherein the yield is 93.1%, and the HPLC purity is 99.88%.
1H-NMR(300MHz，d6-DMSO)：＝1.40(s，9H)，1.62～1.95(m，2H)，2.03(m，1H)，2.26(s，3H)，2.36～2.51(m，3H)，2.44(s，3H)，2.78～3.15(m，2H)，4.34～4.36(m，1H)，5.01～5.05(m，1H)，5.53～5.61(m，2H)，5.91～6.21(m，4H)，6.38～6.42(m，2H)，7.41～7.62(m，8H)，7.67～7.79(m，5H)，8.02～8.05(d，6H)。
(3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is p-toluenesulfonyl, R2Is benzoyl, R3Tert-butyl) 9.8kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is concentrated under reduced pressure to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is dried under reduced pressure at the temperature of 25-35 ℃ to obtain 4.4kg of white solid, the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 7
(1) Synthesis of Compound of formula III (R)1Is trifluoromethanesulfonyl)
Adding 2.85kg of morphine base (a compound shown in a formula II) into 28.5L of mixed solvent of methanol and water (the methanol accounts for 65 vol% and the water accounts for 35 vol%), adding 2.32kg of potassium tert-butoxide, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 3.1kg of trifluoromethanesulfonic anhydride, reacting at 5-15 ℃ for 0.5 after the dropwise adding is finished, performing suction filtration, washing with water, and drying at 45 ℃ under reduced pressure to obtain 3.9kg of white solid with the yield of 94.5%.
1H-NMR(300MHz，d6-DMSO)：＝1.67～1.87(m，2H)，2.01～2.04(m，1H)，2.28(s，3H)，2.32～2.40(m，1H)，2.81～3.10(m，2H)，4.13～4.15(m，1H)，4.56～4.58(m，1H)，5.55～5.59(m，1H)，6.18(s，1H)，6.28～6.32(m，1H)，6.68～6.70(d，1H)，6.75～6.80(d，1H)。
(2) Synthesis of Compounds of formula I (R)1Is trifluoromethanesulfonyl, R2Is pivaloyl, R3Is benzyl)
4.2kg of 3-trifluoromethanesulfonylmorphine (compound of formula III) and 11.4kg of compound of formula IV (R)2Is pivaloyl, R5Is R4-O-，R4Is dichloroacetyl, R3Benzyl) is added into 38L of trichloromethane, 3kg of anhydrous ferric chloride is added, the reaction is carried out for 8h at the temperature of 40-50 ℃, after the reaction is finished, the anhydrous ferric chloride is poured into 5L of water, sodium bicarbonate is used for neutralization, 7.6L of dichloromethane is used for extraction, 5L of saturated sodium chloride is used for washing, concentration and 1.8L of methanol are used for recrystallization, 9.0kg of white solid is obtained, the yield is 96.1%, and the HPLC purity is 99.78%.
1H-NMR(300MHz，d6-DMSO)：＝1.25(s，27H)，1.64～1.90(m，2H)，2.01(m，1H)，2.27(s，3H)，2.48～2.60(m，3H)，2.78～3.11(m，3H)，3.67(s，3H)，3.81(m，2H)，4.54(m，1H)，4.98～5.02(m，2H)，5.25～5.30(m，2H)，5.53～5.61(m，2H)，5.95(m，1H)，6.67～6.71(d，1H)，6.84～6.86(d，1H)，7.33(s，5H)。
3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is trifluoromethanesulfonyl, R2Is pivaloyl, R3Benzyl group) 9.4kg is dissolved by 8.5L methanol and 1.5L water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the solution is concentrated to be dry under reduced pressure, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the solution is dried under reduced pressure at the temperature of 25-35 ℃ to obtain 4.6kg of white solid, the yield is 98%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 8
(1) Synthesis of Compound of formula III (R)1Is m-chlorobenzoyl)
Adding 2.85kg of morphine base (a compound shown in a formula II) into a mixed solvent of 28.5L N, N-dimethylacetamide and water (the N, N-dimethylacetamide accounts for 85% by volume, and the water accounts for 15% by volume), adding 2.32kg of potassium tert-butoxide, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 2.1kg of m-chlorobenzoyl chloride, reacting at 5-15 ℃ for 0.5 after dropwise adding, after the reaction is finished, performing suction filtration, washing with water, and drying under reduced pressure at 45 ℃ to obtain 3.9kg of white solid with the yield of 92.5%.
1H-NMR(300MHz，d6-DMSO)：＝1.61～1.85(m，2H)，2.01～2.04(m，1H)，2.28(s，3H)，2.36～2.52(m，3H)，2.81～3.13(m，2H)，4.55～4.64(m，2H)，5.59～5.65(m，1H)，5.91～5.97(m，1H)，6.18(s，1H)，6.67～6.79(d，1H)，6.82～6.84(d，1H)，7.54～7.75(m，2H)，8.11～8.14(m，1H)，8.16(s，1H)。
(2) Synthesis of Compounds of formula I (R)1Is m-chlorobenzoyl, R2Is butyryl, R3Is methyl group)
4.2kg of 3-m-chlorobenzoylmorphine (compound of formula III) and 9.2kg of compound of formula IV (R)2Is butyryl, R5Is R4-O-,R4Is p-toluenesulfonyl, R3Methyl) is added into 38L of trichloromethane, 3kg of anhydrous ferric chloride is added, the reaction is carried out for 8h at the temperature of 40-50 ℃, after the reaction is finished, the mixture is poured into 5L of water, neutralized by sodium bicarbonate, extracted by 7.6L of dichloromethane, washed by 5L of saturated sodium chloride, concentrated and recrystallized by 2L of ethanol, 7.5kg of white solid is obtained, the yield is 94.2%, and the HPLC purity is 99.78%.
1H-NMR(300MHz，d6-DMSO)：＝0.95(t，9H)，1.64～1.72(m，8H)，2.01(m，1H)，2.27(s，3H)，2.38～2.54(m，9H)，2.78～3.11(m，2H)，3.67(s，3H)，4.27(m，1H)，4.84(m，1H)，4.98～5.02(d，1H)，5.55～5.60(m，2H)，5.93～6.21(m，4H)，6.67～6.69(d，1H)，6.84～6.86(d，1H)，7.53～7.55(m，1H)，7.65～7.68(m，1H)，8.02～8.05(m，1H)，8.12(s，1H)。
3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is m-chlorobenzoyl, R2Is butyryl, R3Methyl) 8.2kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is decompressed and dried at the temperature of 25-35 ℃ to obtain 4.6kg of white solid, the yield is 98%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 9
(1) Synthesis of Compound of formula III (R)1Is trichloroacetyl)
Adding 2.85kg of morphine base (a compound shown in a formula II) into a mixed solvent of 28.5L N, N-dimethylacetamide and water (the N, N-dimethylacetamide accounts for 85% by volume, and the water accounts for 15% by volume), adding 2.32kg of potassium tert-butoxide, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 3.1kg of trichloroacetic anhydride, reacting at 5-15 ℃ for 0.5 after dropwise adding, after the reaction is finished, performing suction filtration, washing with water, and drying under reduced pressure at 45 ℃ to obtain 4.0kg of white solid with the yield of 93.8%.
1H-NMR(300MHz，d6-DMSO)：＝1.65～1.89(m，2H)，1.95～2.04(m，1H)，2.28(s，3H)，2.36～2.42(m，2H)，2.75～3.05(m，2H)，4.56～4.61(m，2H)，5.59～5.85(m，1H)，5.90～5.95(m,1H)，6.18(s，1H)，6.58～6.61(d，1H)，6.72～6.74(d，1H)。
(2) Synthesis of Compounds of formula I (R)1Is trichloroacetyl, R2 is propionyl, R5 is bromo, R3 is ethyl)
4.3kg of 3-trichloroacetylmorphine (compound of formula III) and 6.3kg of the compound of formula IV (R)2Is propionyl, R5Is bromine, R3Is ethyl) Adding the mixture into 76L of toluene, adding 6kg of silver carbonate, reacting at 110-120 ℃ for 3h, pouring the mixture into 5L of water after the reaction is finished, extracting by 7.6L of dichloromethane, washing by 5L of saturated sodium chloride, concentrating, and recrystallizing by 2L of ethanol to obtain 6.7kg of white solid, wherein the yield is 96.1%, and the HPLC purity is 99.78%.
1H-NMR(300MHz，d6-DMSO)：＝1.21～1.25(t，12H)，1.64～1.90(m，2H)，2.03(m，1H)，2.27(s，3H)，2.29～2.45(m，9H)，2.78～3.11(m，2H)，4.21～4.54(m，4H)，4.81～4.83(d，1H)，5.95～6.30(m，5H)，6.57～6.61(d，1H)，6.74～6.76(d，1H)。
3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is trichloroacetyl, R2Is propionyl, R3Ethyl) 8.0kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is decompressed and dried at the temperature of 25-35 ℃ to obtain 4.6kg of white solid, the yield is 98%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 10
(1) Synthesis of Compound of formula III (R)1Is m-nitrobenzoyl)
Adding 2.85kg of morphine base (a compound shown in a formula II) into a mixed solvent of 28.5L N, N-dimethylacetamide and water (the N, N-dimethylacetamide accounts for 85% by volume, and the water accounts for 15% by volume), adding 2.32kg of potassium tert-butoxide, cooling to below 5 ℃, controlling the temperature within 30 ℃, dropwise adding 2.0kg of m-nitrobenzoyl chloride, reacting at 5-15 ℃ for 0.5 after dropwise adding, after the reaction is finished, performing suction filtration, washing with water, and drying at 45 ℃ under reduced pressure to obtain 4.1kg of white solid with the yield of 95%.
1H-NMR(300MHz，d6-DMSO)：＝1.61～1.87(m，2H)，2.01～2.03(m，1H)，2.28(s，3H)，2.35～2.52(m，3H)，2.81～3.17(m，2H)，4.54～4.66(m，2H)，5.59～5.67(m，1H)，5.91～5.99(m，1H)，6.17(s，1H)，6.65～6.79(d，1H)，6.82～6.87(d，1H)，7.73～7.75(m，1H)，8.45～8.54(m，2H)，8.71(s，1H)。
(2) A compound of the formula ISynthesis of substance (R)1Is m-nitrobenzoyl, R2Is isobutyryl, R3Is methyl group)
4.3kg of 3-m-nitrobenzoyl morphine (compound of formula III) and 5.5kg of compound of formula IV (R)2Is isobutyryl, R5Is iodine, R3Methyl) is added into 76L of toluene, 6kg of silver carbonate is added, the mixture reacts for 2 hours at 130-140 ℃, after the reaction is finished, the mixture is poured into 5L of water, 7.6L of dichloromethane is used for extraction, 5L of saturated sodium chloride is used for washing, the mixture is concentrated, 2L of ethanol is used for recrystallization, 6.7kg of white solid is obtained, the yield is 96.1%, and the HPLC purity is 99.78%.
1H-NMR(300MHz，d6-DMSO)：＝1.12～1.14(d，18H)，1.64～1.90(m，2H)，2.01(m，1H)，2.27(s，3H)，2.38～2.62(m，3H)，2.78～3.11(m，2H)，3.67(s，3H)，4.11(m，1H)，4.84～4.86(m，1H)，4.98～5.02(m，1H)，5.59～5.70(m，2H)，5.93～56.11(m，2H)，6.62～6.67(d，1H)，6.81～6.84(d，1H)，7.71～7.73(m，1H)，8.43～8.45(m，1H)，8.53～8.56(m，1H)，8.72(s，1H)。
3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is m-nitrobenzoyl, R2Is isobutyryl, R3Methyl) 8.3kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is decompressed and dried at the temperature of 25-35 ℃ to obtain 4.6kg of white solid, the yield is 98%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 11
(1) Synthesis of Compound of formula III (R)1Is 3,5 dinitrobenzoyl)
Adding 2.85kg of morphine base (a compound shown in a formula II) into a mixed solvent of 28.5L N, N-dimethylacetamide and water (the N, N-dimethylacetamide accounts for 85% by volume, and the water accounts for 15% by volume), adding 2.32kg of potassium tert-butoxide, cooling to-30 ℃, controlling the temperature to be within-20 ℃, dropwise adding 2.3kg of 3, 5-dinitrobenzoyl chloride, reacting at 0-20 ℃ for 3.5 hours after dropwise adding, after the reaction is finished, performing suction filtration, washing with water, and drying under reduced pressure at 45 ℃ to obtain 4.5kg of white solid with the yield of 93%.
1H-NMR(300MHz，d6-DMSO)：
＝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)。
(2) Synthesis of Compounds of formula I (R)1Is 3, 5-dinitrobenzoyl, R2Is acetyl, R5Is bromine, R3Is methyl group)
4.8kg of 3, 5-di-n-nitrobenzoylmorphine (compound of formula III) and 7.5kg of compound of formula IV (R)2Is acetyl, R5Is bromine, R3Methyl) is added into 76L of toluene, 6kg of silver carbonate is added, the mixture reacts for 2 hours at 130-140 ℃, after the reaction is finished, the mixture is poured into 5L of water, 7.6L of dichloromethane is used for extraction, 5L of saturated sodium chloride is used for washing, the mixture is concentrated, 2L of ethanol is used for recrystallization, 7.5kg of white solid is obtained, the yield is 96.2%, and the HPLC purity is 99.78%.
1H-NMR(300MHz，d6-DMSO)：＝1.64～1.82(m，2H)，2.02(m，1H)，2.18(s，9H)，2.27(s，3H)，2.48～3.10(m，3H)，2.78～3.01(m，2H)，3.67(s，3H)，4.18～4.23(m，2H)，4.99～5.02(m，1H)，5.56～5.65(m，2H)，5.95～6.20(m，4H)，6.67～6.70(d，1H)，6.87～6.89(d，1H),9.21～9.23(d，3H)。
3) Synthesis of Compounds of formula V
Reacting an intermediate (R) of formula (I)1Is 3, 5-di-nitrobenzoyl, R2Is acetyl, R3Methyl) 8.0kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is decompressed and dried at the temperature of 25-35 ℃ to obtain 4.6kg of white solid, the yield is 98%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 12
1) A compound of formula (III) (R)1Is2, 6-dinitrobenzoyl) synthesis
Adding 2.85kg of morphine base (namely the compound shown in the formula (II)) into 28.5L of mixed solvent of isopropanol and water (the isopropanol accounts for 35% by volume, and the water accounts for 65% by volume), adding 3.4kg of sodium carbonate, cooling to below-20 ℃, controlling the temperature to be within-10 ℃, dropwise adding 2kg of 2, 6-dinitrobenzoyl chloride, reacting for 0.5h at 10-20 ℃ after dropwise adding, after the reaction is finished, performing suction filtration, washing with water, and drying under reduced pressure at 45 ℃ to obtain 4.5kg of white solid with the yield of 95%.
1H-NMR(300MHz，d6-DMSO)：
＝1.65～1.91(m，2H)，2.05(s，1H)，2.24(s，3H)，2.32～3.15(m，4H)，4.62～4.65(m，1H)，5.58～5.65(m，1H)，6.17(s，1H)，6.59～6.67(d，1H)，6.79～6.86(d，1H)，8.12～8.15(m，1H)8.77～8.82(d，2H)。
(2) A compound of formula (I) (R)1Is2, 6-dinitrobenzoyl, R2Is isobutyryl, R3Is methyl) synthesis
4.8kg of 2, 6-di-n-nitrobenzoylmorphine (compound of formula III) and 5.5kg of compound of formula IV (R)2Is isobutyryl, R5Is bromine, R3Methyl) is added into 76L of dichloromethane, 4kg of boron trifluoride ether solution is added, the mixture reacts for 2 hours at the temperature of 20-40 ℃, after the reaction is finished, the mixture is poured into 5L of water, the sodium bicarbonate solution is neutralized, the dichloromethane is washed by 5L of saturated sodium chloride, the mixture is concentrated, 2L of ethanol is recrystallized, 8.3kg of white solid is obtained, the yield is 94.1%, and the HPLC purity is 99.78%.
1H-NMR(300MHz，d6-DMSO)：＝1.10～1.13(d，18H)，1.64～1.71(m，2H)，2.02(m，1H)，2.27(s，3H)，2.48～2.55(m，5H)，2.78～3.01(m，2H)，3.67(s，3H)，4.18～4.23(m，1H)，4.81～4.84(m，1H)，4.99～5.02(m，1H)，5.56～5.61(m，2H)，5.95～6.20(m，5H)，6.67～6.70(d，1H)，6.87～6.89(d，1H),8.36-8.38(m，1H)，8.71～8.73(d，2H)。
(3) Synthesis of Compound of formula (V)
Reacting an intermediate (R) of formula (I)1Is2, 6-dinitrobenzoyl, R2Is isobutyryl, R3Methyl) 8.8kg of lithium hydroxide was dissolved in 8.5L of methanol and 1.5L of water, and 21kg of lithium hydroxide was added at a temperature of 20 ℃ or lowerAfter the reaction is finished, adjusting the pH value to 4-5 with acetic acid, concentrating under reduced pressure until the reaction is dry, adding methanol for crystallization, washing off lithium salt generated by neutralization, and drying under reduced pressure at 25-35 ℃ to obtain 4.4kg of white solid, wherein the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Example 13
1) A compound of formula (III) (R)1Is2, 4-dinitrobenzoyl) synthesis
Adding 2.85kg of morphine base (namely the compound shown in the formula (II)) into 28.5L of a mixed solvent of isopropanol and water (acetonitrile accounts for 35 vol%, and water accounts for 65 vol%), adding 5.7kg of potassium carbonate, cooling to below-10 ℃, controlling the temperature within 0 ℃, dropwise adding 2.3kg of 2, 4-dinitrobenzoyl chloride, reacting for 0.5h at 10-20 ℃ after dropwise adding, after the reaction is finished, performing suction filtration, water washing, and drying under reduced pressure at 45 ℃ to obtain 4.6kg of white solid with the yield of 97%.
1H-NMR(300MHz，d6-DMSO)：
＝1.65～1.91(m，2H)，2.05(s，1H)，2.24(s，3H)，2.32～3.15(m，4H)，4.62～4.65(m，1H)，5.58～5.65(m，1H)，6.17(s，1H)，6.59～6.67(d，1H)，6.79～6.86(d，1H)，8.35～8.37(d，1H)8.77～8.79(m，1H)，8.95(s，1H)。
(2) A compound of formula (I) (R)1Is2, 4-dinitrobenzoyl, R2Is pivaloyl, R3Is methyl) synthesis
4.8kg of 2, 4-dinitrobenzoyl morphine, i.e. the compound of formula (III), and 6.8kg of the compound of formula (IV) (R)2Is pivaloyl, R5Is R4-O-、R4Is p-toluenesulfonyl R3Methyl) is added into 38L1, 2-dichloroethane, 3.2kg of anhydrous zinc chloride is added, the reaction is carried out for 6h at the temperature of 0-10 ℃, the reaction is finished, the mixture is poured into 5L of water, sodium bicarbonate is used for neutralization, 7.6L of dichloromethane is used for extraction, 5L of saturated sodium chloride is used for washing, concentration and 1.6L of methanol is used for recrystallization, 7.7kg of white solid is obtained, the yield is 95.8 percent, and the HPLC purity is 99.79 percent.
1H-NMR(300MHz，d6-DMSO)：＝1.27(s，27H)，1.61～1.88(m，2H)，2.02(m，1H)，2.28(s，3H)，2.49～2.61(m，3H)，2.77～3.10(m，3H)，3.71(s，3H)，3.81～3.83(m，2H)，4.54～4.57(m，1H)，4.98～5.02(m，2H)，5.24～5.33(m，2H)，5.51～5.62(m，2H)，5.95(m，1H)，6.65～6.69(d，1H)，6.84～6.86(d，1H)，8.36～8.37(d，1H)8.78～8.84(m，1H)，8.92(s，1H)。
(3) Synthesis of Compound of formula (V)
Reacting an intermediate (R) of formula (I)1Is2, 4-dinitrobenzoyl, R2Is pivaloyl, R3Methyl) 8.8kg of the solid is dissolved by 8.5L of methanol and 1.5L of water, 21kg of lithium hydroxide is added at the temperature below 20 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, the mixture is decompressed and concentrated to be dry, methanol is added for crystallization, lithium salt generated by neutralization is washed off, and the mixture is decompressed and dried at the temperature of 25-35 ℃ to obtain 4.4kg of white solid, the yield is 96%, and the melting point is as follows: 253-255 ℃ and the HPLC purity is 99.95%.
Comparative example with patent CN 201410116005.0:
comparative example 1 after amplification according to the example of patent CN201410116005.0
Mixing acetylmorphine (compound shown in formula III, R)1Acetyl group) 1.0kg and a compound (R) of formula IV2Is isobutyryl, R5Is R4-O-，R4Is trifluoroacetyl, R3Methyl) 2.0g is dissolved by dichloromethane, 5.0kg of zinc bromide is added at 10-25 ℃, reaction is carried out for 150h at 55-60 ℃, filtration is carried out, dichloromethane is used for extraction, water and saturated saline solution are used for washing, concentration is carried out until dryness, n-hexane is added for crystallization, filtration is carried out, and reduced pressure drying is carried out at 25-35 ℃ to obtain an intermediate (R) shown in formula (I)1Is acetyl, R2Is isobutyryl, R3Methyl) white solid 21.4kg, yield 95% (with impurity 1 containing 15.3% and impurity 2 containing 10.5%);
comparative example 2
Mixing acetylmorphine (compound shown in formula III, R)1Acetyl group) 1.0kg and a compound (R) of formula IV2Is acetyl, R5Is R4-O-,R4Is acetyl, R3Methyl) 1.8kg of the compound is dissolved in acetonitrile, 1.5L of boron trifluoride diethyl etherate solution is added at the temperature of 10-25 ℃, the mixture reacts for 200 hours at the temperature of 35-40 ℃, the mixture is filtered, filtrate is extracted by ethyl acetate, washed by water and saturated salt water and concentratedDrying, adding n-hexane for crystallization, filtering, and drying under reduced pressure at 25-35 deg.C to obtain intermediate IV (R)1、R2Is acetyl, R3Methyl) white solid 17.5kg, yield 89% (where impurity 1 contains 12.8%, impurity 2 contains 10.3%);
the above embodiments are not exhaustive of the details of the invention, as the protecting group for morphine 3-OH is an electron withdrawing group (i.e., R)1Electron withdrawing groups) are within the scope of the invention.
Claims (19)
1. A method for synthesizing morphine-6-beta-D-glucuronide comprises the following steps:
(1) the morphine base shown as the formula (II) is reacted with organic acid anhydride R in an organic solvent 1 containing water under the catalysis of a basic catalyst1-O-R1Or organic acid chlorides R1-Cl to produce a compound of formula (III);
(2) 3-R represented by the formula (III)1Morphine and acyl protected glucuronate shown as a formula (IV) react in an organic solvent 2 under the catalysis of Lewis acid to obtain an intermediate shown as a formula (I);
(3) removing protecting group from the intermediate shown in the formula (I) to obtain morphine-6-beta-D-glucuronide shown in the formula (V)
Wherein, the organic acid anhydride R1-O-R1Organic acid chloride R1-Cl, R in formula (I) and formula (III)1Is an electron-withdrawing group selected from CF3C(O)-，CF3S(O)2-, p-toluenesulfonyl, CH2ClC(O)-，CHCl2C(O)-，CCl3C (O) -, m-chlorobenzoyl, m-nitrobenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-chlorobenzoyl, o-nitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, m-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl, o-chlorobenzenesulfonyl, o-nitrobenzenesulfonyl, dinitrobenzoyl;
r in the formula (I) and the formula (IV)2Is C2-C6 alkanoyl or benzoyl;
r in the formula (I) and the formula (IV)3Is C1-C6 alkyl or benzyl;
r in the formula (IV)5Is R4-O-or halogen, where R4Is C1-C4 alkanoyl, C1-C6 sulfonyl, one or more halogen substituted C1-C4 alkanoyl, one or more halogen substituted C1-C6 sulfonyl, C1-C4 alkoxy C1-C4 alkanoyl, C1-C4 alkoxy C1-C4 alkanoyl C1-C4 alkanoyl, or substituted benzoyl, or substituted benzenesulfonyl, wherein the substituted benzoyl or substituted benzenesulfonyl is that one or more hydrogens on the benzene ring is substituted by nitro, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkanoyloxy.
2. The method of claim 1 wherein the organic anhydride R is1-O-R1Organic acid chloride R1-Cl, R in formula (I) and formula (III)1Is dinitrobenzoyl, CF3C (O) -or CF3S(O)2-。
3. The synthetic method of claim 1, wherein R in formula (I) and formula (IV)2Acetyl, propionyl, n-butyryl, isobutyryl, pivaloyl or benzoyl.
4. The synthetic method of claim 1, wherein R in formula (I) and formula (IV)3Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
5. The synthetic method of claim 1, wherein R5Is Br, CF3C(O)-O-，CF3S(O)2-O-, p-toluenesulfonyloxy, CH2ClC(O)-O-，CHCl2C(O)-O-，CCl3C(O)-O-，CH3OC(O)C(O)-O-，CH3OC(O)-O-，CH3CH2OC(O)-O-，CH3CH2OC (O) C (O) -O-, or m-acetoxybenzoyloxy.
6. The synthetic method of claim 5, wherein R5Is Br, CF3C (O) -O-or CF3S(O)2-O-。
7. The synthesis method according to any one of claims 1 to 6, wherein the organic solvent 1 of step (1) is acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, N-dimethylformamide, or N, N-dimethylacetamide; the volume ratio of water to the organic solvent 1 is 5: 95-95: 5.
8. the synthesis method according to any one of claims 1 to 6, wherein the basic catalyst in step (1) is one or more of sodium hydride, potassium tert-butoxide, potassium carbonate, sodium bicarbonate, triethylamine, pyridine and sodium hydroxide.
9. The synthesis method according to any one of claims 1 to 6, wherein the reaction temperature in step (1) is-30 to 40 ℃.
10. The synthesis method according to claim 9, wherein the reaction temperature in step (1) is 5-30 ℃.
11. The synthesis process according to any one of claims 1 to 6, wherein in step (1), the organic acid anhydride R1-O-R1Or organic acid chlorides R1-molar ratio of Cl to morphine base 1: 0.5 to 1.2.
12. The synthesis of any one of claims 1 to 6, wherein the Lewis acid in step (2) is a mixture of one or more of zinc bromide, copper bromide, boron trifluoride, zinc chloride, ferric chloride, aluminum chloride, silver carbonate or cuprous chloride.
13. The synthesis process according to any one of claims 1 to 6, wherein the organic solvent 2 of step (2) is a mixture of one or more of tetrahydrofuran, 1, 2-dichloroethane, dimethylformamide, dichloromethane, acetonitrile, nitromethane, toluene, xylene or trichloromethane.
14. A morphine-6-beta-D-glucuronide intermediate compound is shown in the following formula (I):
wherein the content of the first and second substances,
substituent R1Is an electron-withdrawing group selected from CF3C(O)-，CF3S(O)2-, p-toluenesulfonyl, CH2ClC(O)-，CHCl2C(O)-，CCl3C (o) -, m-chlorobenzoyl, m-nitrobenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-chlorobenzoyl, o-nitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, m-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl, o-chlorobenzenesulfonyl, dinitrobenzoyl, or o-nitrobenzenesulfonyl;
substituent R2Is C2-C6 alkanoyl or benzoyl;
substituent R3Is C1-C6 alkyl or benzyl.
15. The morphine-6- β -D-glucuronide intermediate compound as claimed in claim 14, wherein the substituent R is1Is dinitrobenzoyl, CF3C (O) -or CF3S(O)2-。
16. The morphine-6- β -D-glucuronide intermediate compound as claimed in claim 14, wherein the substituent R is2Acetyl, propionyl, n-butyryl, isobutyryl, pivaloyl or benzoyl.
17. The morphine-6- β -D-glucuronide intermediate compound as claimed in claim 14, wherein the substituent R is3Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
18. A compound useful in the synthesis of the intermediate compound of claim 14, represented by formula (III):
wherein R is1Is an electron-withdrawing group selected from CF3C (O) -, p-toluenesulfonyl, CH2ClC(O)-，CHCl2C(O)-，CCl3C (O) -, m-chlorobenzoyl, m-nitrobenzoyl, o-nitrobenzoyl, p-chlorobenzenesulfonyl, m-nitrobenzenesulfonyl, m-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl, o-chlorobenzenesulfonyl, o-nitrobenzenesulfonyl and dinitrobenzoyl.
19. A compound for use in the synthesis of an intermediate compound as claimed in claim 18, wherein R is1Is dinitrobenzoyl or CF3C(O)-。
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| Synthesis of new morphine derivatives. II. The preparation O-benzoylmorphines with analgesic action and an O-benzylmorphine with a morphine-potentiating effect;Selmeci, Gyorgy，等;《CA》;19681231;第70:88011卷;第303-307页 * |
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