CN110054656B - Synthesis method of 10-carbonyl/hydroxymorphine-6-glucuronide - Google Patents

Abstract

The invention provides a method for synthesizing 10-carbonyl/hydroxymorphine-6-glucuronide, which comprises the steps of oxidizing a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (IV), and then converting the compound with the structure shown in the formula (IV) into 10-carbonyl morphine-6-glucuronide.

Description

Synthesis method of 10-carbonyl/hydroxymorphine-6-glucuronide

Technical Field

The invention relates to the field of organic synthesis, in particular to a method for synthesizing 10-carbonyl/hydroxymorphine-6-glucuronide.

Background

Morphine-6-glucuronide (M6G) is the major metabolite of morphine, and its mechanism of action is similar to other opioids, and is a central nervous system μ -receptor opioid agonist. Compared to morphine, M6G analgesia has a slower onset but longer duration and fewer side effects, especially lower incidence of nausea, vomiting and respiratory depression. In addition, as the glucuronic acid morphine is not metabolized by the liver, compared with other opioids, the glucuronic acid morphine has obvious advantages for patients with hepatic insufficiency, and the structural formula is as follows:

M6G is stable in itself but can be oxidized in aqueous solution, the oxidation reaction is a radical reaction, oxygen in air, sunlight and ultraviolet radiation or iron ions can promote the reaction, and patent WO2004016633a1 discloses that the oxidation impurities of M6G are:

however, the present patent does not disclose the preparation method and structure identification information of these two impurities, and the present inventors have referred to the synthesis method of 10-carbonyl/hydroxymorphine-6-glucuronide of Die Pharmazie (1984), 39(10), 687-8 and Pharmazie (1978), 33(9), 609 to synthesize 10-carbonyl/hydroxymorphine-6-glucuronide as an impurity, but have not produced a product of 10-carbonyl/hydroxymorphine-6-glucuronide. Therefore, the research and synthesis of the oxidized impurity of M6G for the quality detection of medicines are of great significance.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a method for synthesizing 10-carbonyl/hydroxymorphine-6-glucuronide, which can easily oxidize the 10-position of M6G into carbonyl or hydroxyl to obtain M6G oxidized impurities.

Compared with the prior art, the invention provides a synthesis method of 10-carbonyl/hydroxymorphine-6-glucuronide, which comprises the steps of oxidizing a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (IV), and then converting the compound with the structure shown in the formula (IV) into 10-carbonyl morphine-6-glucuronide.

Drawings

FIG. 1 is a drawing showing the synthesis of 10-carbonylmorphine-6-glucuronide¹H-NMR chart;

FIG. 2 is an HPLC plot of 10-carbonylmorphine-6-glucuronide;

FIG. 3 is a drawing showing the synthesis of 10-hydroxymorphine-6-glucuronide¹H-NMR chart;

FIG. 4 is an HPLC plot of 10-hydroxymorphine-6-glucuronide;

FIG. 5 shows the results of LC-MS measurement of the reaction solution provided in the comparative example.

Detailed Description

The invention provides a method for synthesizing 10-carbonyl morphine-6-glucuronide, which comprises the following steps:

1) oxidizing the compound with the structure of the formula (III) to obtain a compound with the structure of the formula (IV),

wherein R is a formula (R-1) or a formula (R-2),

according to the invention, the compound with the structure of formula (III) is oxidized to obtain the compound with the structure of formula (IV), the oxidizing agent is preferably one or two of chromium trioxide and manganese dioxide, the oxidation also comprises an oxidation auxiliary agent, and the oxidation auxiliary agent is trifluoroacetic acid or trifluoromethanesulfonic acid; the solvent for the reaction is dichloromethane or chloroform; the reaction temperature is 0-30 ℃, and more preferably 10-25 ℃; in order to better perform the reaction, the reaction is preferably performed for 1-1.5 hours at the temperature of 5-10 ℃, and then the reaction is performed for 3-5 hours at the temperature of 20-25 ℃ to obtain the product.

In the compound of the formula (III), R is₁Preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octylA group, trifluoromethyl or trifluoroethyl, more preferably trifluoromethyl, methyl, ethyl or propyl; the R is₂Preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, trifluoromethyl or trifluoroethyl, more preferably trifluoromethyl, trifluoroethyl, methyl, ethyl or propyl.

In the invention, the compound with the structure of the formula (III) is prepared according to the following method: reacting a compound with a structure shown in a formula (II) with RX to obtain a compound with a structure shown in a formula (III), wherein the ROCOX is preferably methyl chloroformate, ethyl chloroformate or isopropyl chloroformate; the solvent for the reaction is preferably dichloromethane or chloroform; a reaction auxiliary agent is also added in the reaction, the reaction auxiliary agent is alkali, and the alkali is preferably sodium bicarbonate, sodium carbonate, potassium carbonate or potassium bicarbonate; the solvent for the reaction is preferably one or more of chloroform, dichloromethane, nitromethane and 1, 2-dichloroethane, and more preferably chloroform or dichloromethane; the reaction temperature is preferably 40-105 ℃, more preferably 50-85 ℃, and most preferably 55-60 ℃;

according to the invention, the compound with the structure of formula (IV) is converted into the compound with the structure of formula (I), namely 10-carbonyl morphine-6-glucuronide; in particular, the method comprises the following steps of,

firstly, reacting a compound with a structure shown in a formula (IV) with a methylating agent to obtain a compound with a structure shown in a formula (V), wherein the methylating agent is preferably formaldehyde; the catalyst for the reaction is preferably acetic acid and sodium cyanoborohydride; the reaction is preferably carried out at room temperature; the invention has no special requirements on the dosage of each raw material, and a person skilled in the art can adjust the proper proportion according to the needs of the reaction.

The invention also converts the compound with the structure of the formula (V) into the compound with the structure of the formula (I); dissolving a compound with a structure shown in a formula (V) in an aqueous solution of alcohol, and then adding alkali for hydrolysis to obtain a compound with a structure shown in a formula (I); wherein the aqueous solution of the alcohol is a methanol aqueous solution, and the methanol aqueous solution is 85-90% by volume of the methanol aqueous solution; the alkali is one or more of lithium hydroxide, sodium hydroxide, barium hydroxide, calcium hydroxide and potassium hydroxide, and is more preferably lithium hydroxide; the hydrolysis temperature is preferably-20-0 ℃, and more preferably-15-10 ℃.

The invention also provides a synthetic method of 10-hydroxymorphine-6-glucuronide, which comprises the following steps:

A) reacting the compound with the structure of the formula (V) with a reducing agent to obtain a compound with the structure of the formula (VI);

B) converting the compound with the structure of the formula (VI) into a compound with the structure of the formula (VII), namely 10-hydroxymorphine-6-glucuronide,

in the invention, the compound with the structure of formula (V) reacts with a reducing agent to obtain the compound with the structure of formula (VI); wherein the reducing agent is one or two of sodium borohydride and sodium triacetoxyborohydride; the solvent for the reaction is preferably one or both of acetic acid and tetrahydrofuran.

In the invention, the compound with the structure of formula (VI) is converted into the compound with the structure of formula (VII), namely 10-hydroxymorphine-6-glucuronide, specifically, the alkali used in the conversion process is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and barium hydroxide, and preferably lithium hydroxide.

More specifically, the reaction scheme of the 10-carbonyl morphine-6-glucuronide is as follows:

the reaction process of the 10-hydroxymorphine-6-glucuronide is as follows:

the invention provides a synthesis method of 10-carbonyl/hydroxymorphine-6-glucuronide, which comprises the steps of oxidizing a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (IV), and then converting the compound with the structure shown in the formula (IV) into 10-carbonyl morphine-6-glucuronide.

The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The instrument comprises the following steps:

¹the H-NMR detector is a Bruker Fourier 300 nuclear magnetic resonance spectrometer

Water 2695 High Performance Liquid Chromatography (HPLC) for product purity

The chromatographic column is Agilent ZORBAX Eclipse XDB-phenyl

The mobile phase is A: 10mg of monopotassium phosphate, and adjusting the pH value to 3.0 by phosphoric acid; mobile phase B: acetonitrile phase

Column temperature: 35 deg.C

Wavelength: 210nm

Using gradient elution with a gradient of

Time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	90	10
35	15	85
			60	15	85

EXAMPLE 1 preparation of Compound of formula (I)

1) Preparation of the Compound of formula (III)

Taking 14.1g of a dried compound shown as a formula (II), dissolving the compound with 100ml of anhydrous chloroform, adding 20g of potassium bicarbonate, dropwise adding 28g of methyl chloroformate at room temperature, after the dropwise adding, reacting at 55-60 ℃ until the reaction is finished, cooling to room temperature, filtering, washing a filter cake with 100ml of chloroform, draining, combining filtrates, concentrating to dryness, recrystallizing with 15ml of ethyl acetate, crystallizing at 0-5 ℃ for 16-20 h, performing suction filtration, washing the filter cake with a small amount of ethyl glacial acetate, and drying at 40-45 ℃ for 6-10 h to obtain 8.32g of the compound shown as a formula (III). Yield: 55.5 percent

2) Preparation of Compound of formula (IV)

Dissolving 7.63g of the compound shown in the formula (III) by using 100ml of dichloromethane, cooling to 0-10 ℃, adding 4.8g of trifluoroacetic acid in batches, reacting for 20-30 min, adding 4.95g of chromium trioxide, reacting for 1h at 10 ℃, reacting for 3-5 h at 25 ℃, pouring the reaction liquid into 50ml of ice water, separating liquid, extracting a water layer by using 100ml of dichloromethane, combining organic layers, drying for 5-8 h by using anhydrous magnesium sulfate, filtering, concentrating the filtrate, carrying out column chromatography separation on the residue, eluting with methanol to acetone (5: 2), eluting at equal degree, and concentrating the eluent to obtain 3.9g of a product. Yield: 50.2%, HPLC purity: 94.18 percent.

3) Preparation of Compound of formula (V)

3.82g of the compound represented by the formula (IV) was dissolved in 50mL of dichloromethane, and washed with 20mL of a 10% aqueous solution of sodium carbonate with stirring, and the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the residue was added with 0.5mL of 37% formaldehyde, 0.3g of acetic acid, and 0.6g of sodium cyanoborohydride, placed in a 50mL reaction flask, added with 30mL of methanol, and reacted at room temperature for 12 hours. After the reaction, 10mL of saturated sodium carbonate solution was added, followed by extraction with 10mL of dichloromethane for 3 times, organic phases were combined, washed with 10mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography and acetone recrystallization to obtain 2.41g of the compound represented by formula (V). Yield: 66.9%, melting point: 152-158 ℃ C

¹H-NMR(d₆-DMSO，ppm)：8.12～8.16(m，2H)，7.62～7.72(m，2H)，7.11(d，1H)；5.90～6.02(m，4H)；5.40～5.60(m，2H)；4.98～5.02(d，1H)；4.80～4.82(d，1H)；4.23～4.25(m，1H)；3.85～3.87(m，1H)；3.71(s，3H)；2.41～2.72(m，3H)；2.26(s，3H)；2.03(s，9H)；1.85～1.88(m，2H)

4) Preparation of Compounds of formula (I)

Dissolving 3.6g of the compound shown in the formula (V) by using 50m 185% methanol aqueous solution at room temperature under stirring, cooling to-15 ℃, adding 1.05g of lithium hydroxide monohydrate in batches, reacting for 3-5 h under heat preservation, returning to 20-25 ℃ until the reaction is finished, adjusting the pH value to 6-7 by using acetic acid, filtering, concentrating the filtrate, performing column chromatography separation on the concentrate, wherein an eluent is dichloromethane and methanol (1: 5), concentrating the eluent, and 1.8g of yellow solid. Yield: 75.6%, melting point: 188-192 ℃.

The obtained compounds were identified and the results are shown in FIGS. 1 to 2; FIG. 1 is a drawing showing the synthesis of 10-carbonylmorphine-6-glucuronide¹H-NMR chart; FIG. 2 is an HPLC plot of 10-carbonylmorphine-6-glucuronide;

as can be seen from the figure 1 of the drawings,¹H-NMR(d₆-DMSO，ppm)：6.53～6.97(AB，2H，Mo-H1，Mo-H2)；5.74(d，1H，J_7，8＝10Hz，Mo-H8)；5.24(d，，H，J_7，8＝10Hz，Mo-H7)；4.97(d，1H，J＝6Hz，Glu-HI)；4.49(d，1H，Mo-H5)；4.34(S，1H，Mo-H6)；3.35(g，1H，Mo-H9)；3.0～3.2(m，2H，Glu-H5，Glu-H3)；3.15(S，3H，N-Me)；2.1～2.7(m，3H；Mo-H14，H16)；1.83～2.28(AB，2H，Mo-H15)；

from the high performance liquid chromatography data, the purity of the compound obtained by the present invention was 98.66%.

EXAMPLE 2 preparation of the Compound of formula (I)

1) Preparation of the Compound of formula (III)

Taking 14.1g of a dried compound shown as a formula (II), dissolving the compound with 100ml of anhydrous dichloromethane, adding 20g of sodium bicarbonate, dropwise adding 29.5g of ethyl chloroformate at room temperature, after the dropwise adding is finished, reacting at 40-45 ℃ until the reaction is finished, cooling to room temperature, filtering, washing a filter cake with 100ml of dichloromethane, draining, combining filtrates, concentrating to dryness, recrystallizing with 15ml of ethyl acetate, crystallizing at 0-5 ℃ for 16-20 h, performing suction filtration, washing the filter cake with a small amount of ethyl glacial acetate, and drying at 40-45 ℃ for 6-10 h to obtain 8.65g of a compound shown as a formula (III). Yield: 56.6 percent.

2) Preparation of Compound of formula (IV)

Dissolving 7.75g of the compound shown in the formula (III) by using 100ml of dichloromethane, cooling to 0-10 ℃, adding 5.6g of trifluoromethanesulfonic acid in batches, reacting for 20-30 min, adding 7.5g of manganese dioxide, reacting for 1h at 10 ℃, reacting for 5-8 h at 25 ℃, pouring the reaction liquid into 50m1 ice water, separating, extracting a water layer by using 100ml of dichloromethane, combining organic layers, drying for 5-8 h by using anhydrous magnesium sulfate, filtering, concentrating the filtrate, performing column chromatography on the residue, eluting with methanol and acetone (5: 2) at equal intervals, and concentrating the eluent to obtain 4.2g of a product. Yield: 53.2 percent.

3) Preparation of Compound of formula (V)

3.82g of the compound represented by the formula (IV) was dissolved in 50mL of dichloromethane, and washed with 20mL of a 10% aqueous solution of sodium carbonate with stirring, the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the residue was taken up with 0.5mL of 37% formaldehyde, 0.3g of acetic acid, and 0.6g of sodium cyanoborohydride, and placed in a 50mL reaction flask, and 30mL of methanol was added to conduct a reaction at room temperature for 12 hours. After the reaction, 10mL of saturated sodium carbonate solution was added, followed by extraction with 10mL of dichloromethane for 3 times, organic phases were combined, washed with 10mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography and acetone recrystallization to obtain 2.41g of the compound represented by formula (V). Yield: 68.3 percent.

4) Preparation of Compounds of formula (I)

Dissolving 3.6g of the compound shown in the formula (V) by using 50m 185% methanol aqueous solution at room temperature under stirring, cooling to-30 ℃, adding 1.05g of sodium hydroxide in batches, reacting for 3-5 h under heat preservation, returning to 20-25 ℃ until the reaction is finished, adjusting the pH to 6-7 by using acetic acid, filtering, concentrating the filtrate, performing column chromatography separation on the concentrate, wherein an eluent is dichloromethane: methanol (1: 5), concentrating the eluent and 1.6g of yellow solid. Yield: 67.2 percent

EXAMPLE 3 preparation of the Compound of formula (I)

1) Preparation of the Compound of formula (III)

Taking 14.1g of a dried compound shown as a formula (II), dissolving the compound with 100ml of anhydrous nitromethane, adding 20g of potassium bicarbonate, dropwise adding 31g of isopropyl chloride at room temperature, reacting at 95-105 ℃ until the reaction is finished, cooling to room temperature, filtering, washing a filter cake with 150ml of dichloromethane, draining, combining filtrates, concentrating to dryness, recrystallizing with 15ml of ethyl acetate, crystallizing at 0-5 ℃ for 16-20 h, performing suction filtration, washing the filter cake with a small amount of ethyl glacial acetate, and drying at 40-45 ℃ for 6-10 h to obtain 8.86g of a compound shown as a formula (III). Yield: 56.9 percent.

2) Preparation of Compound of formula (IV)

Dissolving 7.75g of the compound shown in the formula (III) by using 100ml of dichloromethane, cooling to 0-10 ℃, adding 4.8g of trifluoroacetic acid in batches, reacting for 20-30 min, adding 5.08g of chromium trioxide, reacting for 1h at 10 ℃, reacting for 3-5 h at 25 ℃, pouring the reaction liquid into 50ml of ice water, separating liquid, extracting a water layer by using 100ml of dichloromethane, combining organic layers, drying for 5-8 h by using anhydrous magnesium sulfate, filtering, concentrating the filtrate, carrying out column chromatography separation on the residue, eluting with methanol to acetone (5: 2), eluting at equal degree, and concentrating the eluent to obtain 4.2g of a product. Yield: 53.2 percent.

3) Preparation of Compound of formula (V)

4.2g of the compound represented by the formula (IV) was dissolved in 50mL of dichloromethane, and washed with 20mL of a 10% aqueous potassium carbonate solution with stirring, and the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the residue was added with 0.5mL of 37% formaldehyde, 0.3g of acetic acid, and 0.6g of sodium cyanoborohydride, placed in a 50mL reaction flask, added with 30mL of methanol, and reacted at room temperature for 12 hours. After the reaction, 10mL of saturated sodium carbonate solution was added, followed by extraction with 10mL of dichloromethane for 3 times, organic phases were combined, washed with 10mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography and acetone recrystallization to obtain 2.45g of the compound represented by formula (V). Yield: 64.1 percent.

4) Preparation of Compounds of formula (I)

Dissolving 3.6g of the compound shown in the formula (V) by using 50ml of 85% methanol aqueous solution at room temperature through stirring, cooling to-15 ℃, adding 1.65g of calcium hydroxide in batches, reacting for 3-5 h under heat preservation, returning to 20-25 ℃ until the reaction is finished, adjusting the pH to 6-7 by using oxalic acid, filtering, concentrating the filtrate, performing column chromatography separation on the concentrate, wherein an eluent is dichloromethane and methanol (1: 5), concentrating the eluent, and 1.45g of yellow solid. Yield: 60.9 percent

EXAMPLE 4 preparation of the Compound of formula (I)

1) Preparation of the Compound of formula (III)

Taking 14.1g of a dried compound shown as a formula (II), dissolving the compound with 100ml of anhydrous 1, 2-dichloroethane, adding 20g of potassium bicarbonate, dropwise adding 28g of methyl chloroformate at room temperature, reacting at 80-90 ℃ until the reaction is finished, cooling to room temperature, filtering, washing a filter cake with 100ml of chloroform, draining, combining filtrates, concentrating to dryness, recrystallizing with 15ml of ethyl acetate, crystallizing at 0-5 ℃ for 16-20 h, performing suction filtration, washing the filter cake with a small amount of ethyl glacial acetate, and drying at 40-45 ℃ for 6-10 h to obtain 8.12g of the compound shown as a formula (III). Yield: 54.1 percent

2) Preparation of Compound of formula (IV)

Dissolving 7.82g of the compound shown in the formula (III) by using 100ml of dichloromethane, cooling to 0-10 ℃, adding 5.48g of trifluoromethanesulfonic acid in batches, reacting for 20-30 min, adding 4.95g of chromium trioxide, reacting for 1h at 10 ℃, reacting for 3-5 h at 25 ℃, pouring the reaction liquid into 50ml of ice water, separating liquid, extracting a water layer by using 100ml of dichloromethane, combining organic layers, drying for 5-8 h by using anhydrous magnesium sulfate, filtering, concentrating the filtrate, performing column chromatography on the residue, eluting with methanol and acetone (5: 2), isocratically eluting, and concentrating the eluent to obtain 4.5g of a product. Yield: 56.5 percent.

3) Preparation of Compound of formula (V)

3.89g of the compound represented by the formula (IV) was dissolved in 50mL of dichloromethane, and washed with 20mL of a 10% aqueous potassium carbonate solution with stirring, and the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the residue was added with 0.5mL of 37% formaldehyde, 0.3g of acetic acid, and 0.6g of sodium cyanoborohydride, placed in a 50mL reaction flask, added with 30mL of methanol, and reacted at room temperature for 12 hours. After the reaction, 10mL of saturated sodium carbonate solution was added, followed by extraction with 10mL of dichloromethane for 3 times, organic phases were combined, washed with 10mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography and acetone recrystallization to obtain 2.41g of the compound represented by formula (V). Yield: 65.8 percent.

4) Preparation of Compounds of formula (I)

Dissolving 3.6g of the compound shown in the formula (V) in 50m 185% methanol water solution at room temperature by stirring, cooling to-15 ℃, adding 5.05g of barium hydroxide in batches, reacting for 3-5 h under heat preservation, returning to 20-25 ℃ until the reaction is finished, adjusting the pH to 6-7 by using sulfuric acid, filtering, concentrating the filtrate, performing column chromatography separation on the concentrate, wherein an eluent is dichloromethane and methanol (1: 5), concentrating the eluent, and 1.71g of yellow solid. Yield: 71.8 percent.

Example 5 preparation of Compound of formula (VII)

1) Preparation of the Compound of formula (VI)

Taking 7.2g of the compound shown in the formula (V), dissolving the compound with 100ml of acetic acid, controlling the temperature to be 0-10 ℃, adding 6g of sodium borohydride in batches, slowly heating to room temperature after the sodium borohydride is added, stirring until the reaction is finished, pouring the mixture into 300ml of ice water, extracting the mixture three times with 100ml of dichloromethane, combining dichloromethane layers, washing the dichloromethane layers with 100ml of 10% potassium carbonate solution, drying the dichloromethane, filtering, concentrating the filtrate, performing column chromatography on the concentrate, and concentrating the eluent to obtain 5.7g of dark yellow solid, wherein the eluent is dichloromethane to methanol (1: 5). Yield: 78.9%, melting point: 151-157 deg.C

¹H-NMR(d₆-DMSO，ppm)：8.15～8.17(d，2H)，7.61～7.72(m，2H)，7.11～7.12(d，1H)；5.93～6.02(m，4H)；5.78(s，1H)；5.41～5.60(m，2H)；4.97～5.02(d，1H)；4.81～4.82(d，1H)；4.24～4.25(m，1H)；3.82～3.87(m，1H)；3.77(s，3H)；2.42～2.72(m，3H)；2.28(s，3H)；2.05(s，9H)；1.81～1.89(m，2H)

2) Preparation of the Compound of formula (VII)

Dissolving 3.6g of the compound shown in the formula (VI) by using 50ml of 85% methanol aqueous solution at room temperature under stirring, cooling to-15 ℃, adding 1.08g of lithium hydroxide monohydrate in batches, reacting for 3-5 h under heat preservation, returning to 20-25 ℃ until the reaction is finished, adjusting the pH value to 6-7 by using acetic acid, filtering, concentrating the filtrate, performing column chromatography separation on the concentrate, wherein an eluent is dichloromethane: methanol (1: 5), concentrating the eluent, and obtaining 1.15g of yellow solid with the yield: 48.3%, its melting point: 179 to 184 DEG C

The resulting compounds were identified and the results are shown in FIGS. 3 to 4; FIG. 3 is a drawing showing the synthesis of 10-hydroxymorphine-6-glucuronide¹H-NMR chart; FIG. 4 is an HPLC plot of 10-hydroxymorphine-6-glucuronide;

as can be seen from the view in figure 3,¹H-NMR(d₆-DMSO，ppm)：6.65～6.78，(AB，2H，Mo-H1，Mo-H2)；5.50～5.63(d，1H，J_7，8＝10Hz，Mo-H8)；5.38～5.50(d，H，J_7，8＝10Hz，Mo-H7)；4.945.05(d，1H，J＝6Hz，Glu-HI)；4.49(d，1H，Mo-H5)；4.32(S，1H，Mo-H6)；4.20(s，Mo-OH)3.39～3.44(g，1H，Mo-H9)；3.03-3.16(m，2H，Glu-H5，Glu-H3)；3.15(S，3H，N-Me)；2.17-2.40(m，3H；Mo-H14，H16)；1.96～2.15(AB，2H，Mo-H15)；

from the high performance liquid chromatography data, the purity of the obtained compound was 98.0%.

EXAMPLE 6 preparation of Compound of formula (VII)

1) Preparation of the Compound of formula (VI)

Taking 7.2g of the compound shown in the formula (V), dissolving the compound with 100ml of tetrahydrofuran, controlling the temperature to be 0-10 ℃, adding 8g of sodium triacetoxyborohydride in batches, slowly returning to room temperature after the addition is finished, stirring until the reaction is finished, pouring the mixture into 300ml of ice water, extracting the mixture three times with 100ml of dichloromethane, combining dichloromethane layers, washing the dichloromethane layers with 100ml of 10% potassium carbonate solution, drying the obtained product with anhydrous magnesium sulfate, filtering, concentrating the obtained filtrate, carrying out column chromatography separation on the concentrate, wherein an eluent is dichloromethane and methanol (1: 5), concentrating the eluent, and obtaining 5.9g of a dark yellow solid. Yield: 81.7 percent.

2) Preparation of the Compound of formula (VII)

Dissolving 3.6g of the compound shown as the formula (VI) in 50ml of 85% methanol aqueous solution at room temperature by stirring, cooling to-15 ℃, adding 1.25g of calcium hydroxide in batches, reacting for 3-5 h under heat preservation, returning to 20-25 ℃ until the reaction is finished, adjusting the pH to 6-7 by using oxalic acid, filtering, concentrating the filtrate, performing column chromatography separation on the concentrate, wherein an eluent is dichloromethane and methanol (1: 5), concentrating the eluent and 0.85g of yellow solid. Yield: 35.7 percent.

Comparative example 1

The synthesis of the key intermediate of the impurity 10-carbonyl/hydroxymorphine-6-glucuronide was carried out according to the synthesis method for 10-carbonyl/hydroxymorphine described in reference to Die Pharmazie (1984), 39(10), 687-8 and Pharmazie (1978), 33(9), 609, the synthetic route being as follows:

the method comprises the following specific steps: adding 14.1g of a compound shown in a formula (II), 29ml of acetonitrile and 7ml of glacial acetic acid into a reaction bottle, controlling the reaction temperature to be 10-15 ℃, dropwise adding 35ml of trifluoroacetic acid, controlling the temperature to continue stirring for reaction for 30min, cooling to 5 ℃, adding 2.7g of chromium trioxide in batches, stirring for 2h at the temperature, naturally returning to 26 ℃, continuing stirring for 3 h, detecting by TLC (thin layer chromatography), detecting no new spot, stirring for reaction for 24 h at 30 ℃, detecting the new spot by TLC, taking the reaction solution, and performing LC-MS (liquid chromatography-mass spectrometry) detection, wherein the result is shown in figure 5, the figure 5 is the LC-MS detection result of the reaction solution provided by the comparative example, and the figure shows that the reaction solution has neither the molecular weight of the compound shown in the formula (II) nor the molecular weight of the compound shown in the formula (V).

The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (6)

1. A method for synthesizing 10-carbonyl morphine-6-glucuronide comprises the following steps:

reacting the compound with the structure of the formula (II) with RX to obtain the compound with the structure of the formula (III),

x is halogen or hydroxy;

1) oxidizing the compound with the structure of the formula (III) to obtain a compound with the structure of the formula (IV),

wherein R is a formula (R-1) or a formula (R-2),

R₁、R₂independently selected from C1-C8 alkylOr a halogenated C1-C8 alkyl group;

the oxidizing agent is one or two of chromium trioxide and manganese dioxide;

the oxidizing further comprises a pro-oxidant; the pro-oxidant is trifluoroacetic acid or trifluoromethanesulfonic acid;

2-1) reacting the compound with the structure of the formula (IV) with a methylating agent to obtain the compound with the structure of the formula (V),

the methylating agent is formaldehyde;

2-2) converting the compound with the structure of the formula (V) into the compound with the structure of the formula (I);

2. the method of synthesis of claim 1, wherein R is₁、R₂Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, trifluoromethyl or trifluoroethyl.

3. The synthesis method according to claim 1, wherein the catalysts for the reaction of step 2-1) are acetic acid and sodium cyanoborohydride.

4. A method for synthesizing 10-hydroxymorphine-6-glucuronide, which comprises the following steps:

A) reacting a compound of formula (V) prepared according to claim 1 with a reducing agent to obtain a compound of formula (VI);

B) converting the compound with the structure of the formula (VI) into a compound with the structure of the formula (VII), namely 10-hydroxymorphine-6-glucuronide,

5. the synthetic method according to claim 4, wherein the reducing agent is sodium borohydride or sodium triacetoxyborohydride.

6. The synthesis method according to claim 4, wherein the alkali for the conversion reaction in step B) is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and barium hydroxide.

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