CN110305142B

CN110305142B - Stereoselective synthesis method of 6 beta-hydroxymorphine derivative

Info

Publication number: CN110305142B
Application number: CN201910631355.3A
Authority: CN
Inventors: 周皓; 郭建锋; 易斌; 李莉娥; 田峦鸢; 吕金良; 李禹琼; 汪淼; 李仕群; 杜文涛; 朱圣姬
Original assignee: Yichang Humanwell Pharmaceutical Co Ltd
Current assignee: Yichang Humanwell Pharmaceutical Co Ltd
Priority date: 2019-07-12
Filing date: 2019-07-12
Publication date: 2021-11-16
Anticipated expiration: 2039-07-12
Also published as: CN110305142A

Abstract

The invention discloses a stereoselective synthesis method of a 6 beta-hydroxymorphine derivative, which comprises the following steps: (i) reducing the compound shown in the formula VI into a compound shown in the formula VII by sodium borohydride in a hydrophilic organic solvent in the presence of catalytic amount of C1-C4 alkanoic acid; (ii) (ii) separating the compound of formula VII obtained in step (i) to obtain a compound of formula VIII; the definitions of the substituents in the formulae VI, VII and VIII are described in the specification.

Description

Stereoselective synthesis method of 6 beta-hydroxymorphine derivative

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a stereoselective synthesis method of a 6 beta-hydroxymorphine derivative.

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, the glucuronic acid morphine has obvious advantages compared with other opioids for patients with hepatic insufficiency. The structural formula is as follows:

M6G is relatively stable, but in the process of synthesizing M6G, the configuration is easy to turn over during the glycosylation reaction, so that the compound impurity shown in the formula (I-2) is easy to generate, and the impurity is difficult to remove in the subsequent purification process, so that the quality of the M6G product is not high, and great hidden danger is caused to the medication safety of people. The structure is not reported in the literature.

Furthermore, the following isomers of morphine and ethyl morphine I-3 and I-4 are also important in the corresponding product quality control:

disclosure of Invention

The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

The invention aims to overcome the defects of the prior art and provide a stereoselective synthesis method of a 6 beta-hydroxymorphine derivative, which does not need a chiral catalyst and has the advantages of simple operation, cheap and easily obtained raw materials, high yield and high purity.

In an embodiment of the present invention, the present invention provides a stereoselective synthesis method of 6 β -hydroxymorphine derivatives, wherein the 6 β -hydroxymorphine derivatives are represented by formula VIII, the synthesis method comprises the following steps:

(i) reducing the compound shown in the formula VI into a compound shown in the formula VII by sodium borohydride in a hydrophilic organic solvent in the presence of catalytic amount of C1-C4 alkanoic acid;

(ii) (ii) separating the compound of formula VII obtained in step (i) to obtain a compound of formula VIII;

here, the substituents R in the formulae VI, VII and VIII₁Is hydrogen, unsubstituted C1-C4 alkyl, cyclopropylmethyl, unsubstituted C2-C4 alkenyl, R₉-O-C (O) -, or R₇-C(O)-；R₃Is hydrogen, unsubstituted C1-C4 alkyl, cyclopropylmethyl, unsubstituted C2-C4 alkenyl, R₈-C (O) -or R₆-O-c (O) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₇And R₈Each independently selected from hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen; r₂And R₄Each independently is hydrogen or hydroxy;

the hydrophilic organic solvent in the step (i) is one or a mixed solution of more than two of methanol, absolute ethyl alcohol and tetrahydrofuran;

the C1-C4 alkanoic acid in step (i) is selected from one or more of formic acid, acetic acid, propionic acid, and butyric acid, preferably formic acid, acetic acid or propionic acid.

In the above embodiment, the catalytic amount means that the volume ratio of the C1-C4 alkanoic acid to the hydrophilic organic solvent is 0.2-0.6:100, preferably 0.3-0.5: 100.

In the above embodiments, the compound of formula VIII in the compound of formula VII obtained in step (i) is present in an amount greater than 50%, preferably greater than 90%.

In the above embodiments, the separation of step (ii) may be by chromatography.

In an embodiment of the invention, the unsubstituted C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; the unsubstituted C2-C4 alkenyl group is vinyl, propenyl, or allyl.

In some embodiments, substituent R in formula VI, formula VII, and VIII₁Is R₉-O-C (O) -or R₇-C(O)-；R₃Is R₆-O-C (O) -or R₈-c (o) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₇And R₈Each independently selected from hydrogen, methyl, isopropyl, and 2, 4-dinitrophenyl; r₂And R₄Each independently hydrogen or hydroxy.

In some embodiments, substituent R in formula VI, formula VII, and VIII₁Is methyl, ethyl, cyclopropylmethyl, allyl, acetyl, isobutyryl, 2, 4-dinitrobenzoyl or R₉-O-C(O)-；R₃Is methyl, cyclopropylmethyl, allyl, acetyl, 2, 4-dinitrobenzoyl or R₆-O-c (O) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₂And R₄Each independently hydrogen or hydroxy.

In one embodiment, the substituent R in formula VI, formula VII, and formula VIII₁Is R₉-O-C(O)-；R₃Is R₆-O-c (O) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₂And R₄Each independently hydrogen.

In a preferred embodiment, the present invention provides a method for synthesizing morphine-6-beta-O-beta-D-glucuronide represented by the formula I-2,

the synthesis method comprises the following steps:

(i) reducing the compound of formula VI-2 by sodium borohydride in a hydrophilic organic solvent in the presence of a catalytic amount of C1-C4 alkanoic acid to form a compound of formula VII-2;

(ii) (ii) separating the compound of formula VII-2 obtained in step (i) to obtain a compound of formula VIII-2;

here, the substituents R in the formulae VI-2, VII-2 and VIII-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen; preferably, R₇Is methyl or isopropyl.

In the above embodiment, the present invention provides a method for synthesizing morphine-6- β -O- β -D-glucuronide represented by formula I-2, which further comprises the following steps:

(iii) reacting a compound of formula VIII-2 with formula III-1 to provide a compound of formula IV:

alternatively, the compound of formula VIII-2 is reacted with formula III-2 to provide a compound of formula IV:

alternatively, the compound of formula VIII-3 is reacted with formula III-2 to provide the compound of formula IV:

(iv) deprotection of a compound of formula IV to give a compound of formula I-2

Wherein the substituent R in the formula III-1, the formula III-2, the formula III-3 and the formula IV₅Is C1-C6 alkyl, or benzyl, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl; more preferably methyl, ethyl;

substituent P1 in formula III-1, formula III-2, formula III-3 and formula IV is alkanoyl or benzoyl having C2-C6, preferably selected from acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pivaloyl or benzoyl, more preferably acetyl, or isobutyryl;

the substituent P2 in the formula III-1 is alkanoyl of C2-C6, R₁₀-C(O)-、R₁₀-S(O)₂-, or R₁₀-C(O)-C(O)-，R₁₀Is C1-C4 alkoxy, one or more halogen substituted C1-C4 alkyl, phenyl, or substituted phenyl, wherein the substituted phenyl is one or more hydrogens on the phenyl ring substituted with C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkanoyloxy; preferably, P2 is selected from acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pivaloyl, 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) -, benzoyl, m-acetoxybenzoyl, more preferably acetyl, or isobutyryl, CF₃CO-、CF₃SO₂-；

The substituent P3 in the formula III-1 is C1-C6 alkyl, phenyl-substituted C1-C6 alkyl or aryl (such as phenyl);

the substituents R in the formulae IV and VIII-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen; preferably, R₇Is methyl, isopropyl or 3, 5-dinitrophenyl.

(1-i) morphine base or its salt (such as morphine sulfate), anhydride R₇-C(O)-O-(O)C-R₇Or acyl chlorides R₇-C (O) -Cl is used as a raw material, and a compound of a formula II is obtained through esterification reaction;

(2-i) oxidizing the compound of formula II obtained in step (1-i) to a compound of formula VI-2;

here, the substituents R in the formulae II and VI-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen; preference is given toEarth, R₇Is methyl, isopropyl, or 3, 5-dinitrophenyl;

the acid anhydride R₇-C(O)-O-(O)C-R₇Or acyl chlorides R₇R in (C), (O) -Cl₇As defined above.

In a particularly preferred embodiment, the present invention provides a method for the synthesis of morphine-6-beta-O-beta-D-glucuronide represented by formula I-2, comprising the steps of:

(i) (ii) reducing the compound of formula VI-2 obtained in step (i-2) with sodium borohydride in a hydrophilic organic solvent in the presence of a catalytic amount of C1-C4 alkanoic acid to form a compound of formula VII-2;

(iv) deprotection of a compound of formula IV to give a compound of formula I-2

Here, the substituent R₁、R₃、R₅P1, P2 and P3 are as defined above.

In an embodiment of the present invention, the present invention provides morphine-6-beta-O-beta-D-glucuronide represented by formula I-2, which can be used as a reference for M6G quality studies.

In a particularly preferred embodiment, the present invention provides a method for the synthesis of 6- β -hydroxy-morphine according to formula I-3, comprising the steps of:

(iii) deprotecting a compound of formula VIII-2 to provide a compound of formula I-3:

here, the substituents R in the formulae II, VI-2, VII-2 and VIII-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen; preferably, R₇Is methyl, isopropyl, or 3, 5-dinitrophenyl;

the acid anhydride R₇-C(O)-O-(O)C-R₇Or acyl chlorides R₇R in (C), (O) -Cl₇As defined above for the substituent R₁Is as defined above.

In a particularly preferred embodiment, the present invention provides a method for the synthesis of 6- β -hydroxy-ethylmorphine, as represented by formula I-4, comprising the steps of:

(2-i) oxidizing the raw material ethyl morphinine or the salt thereof to obtain a compound shown in the formula VI-3;

(i) (ii) reducing the compound of formula VI-3 obtained in step (i-2) with sodium borohydride in a hydrophilic organic solvent in the presence of a catalytic amount of a C1-C4 alkanoic acid to form a compound of formula VII-3;

(ii) (ii) separating the compound of formula VII-3 obtained in step (I) to obtain a compound of formula I-4;

the reaction and operating conditions in the above steps (2-i), (i) and (ii) may be the same as those in the above embodiments of the present application.

In the embodiment of the present invention, the addition amount of the catalytic amount of the C1-C4 alkanoic acid in the stereoselective oxidation step is a key step for controlling the preparation of the 6 β -hydroxymorphine derivative, the addition amount of the C1-C4 alkanoic acid is too small to complete the reaction, and the addition amount of the C1-C4 alkanoic acid is too large to achieve stereoselectivity, so that the pure product of the compound represented by formula (I-2) as the final product is not pure and the yield is low. The invention finally obtains the compound shown in the formula (I-2) with high purity, and the HPLC purity can reach more than 98%.

The method has the advantages that the compound shown in the formula (I-2) is obtained by taking morphine as a raw material and carrying out esterification, oxidation, reduction, resolution, glycosylation, hydrolysis and other nearly ten-step reactions and operations, the compound shown in the formula (I-2) with high purity is synthesized and can be used as an impurity standard product in M6G bulk drugs and preparation detection analysis, so that the accurate positioning and the qualification of the M6G bulk drugs and the preparation detection analysis on impurities are improved, the control on the impurities is favorably strengthened, and the quality of the M6G bulk drugs and the preparation is improved. The synthesized compound shown as the formula (I-2)After passing the melting point,¹H-NMR、¹³Confirmation of C-NMR, MS and the like.

Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.

Drawings

The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.

FIG. 1 shows morphine-6-beta-O-beta-D-glucuronide (compound represented by the formula (I-2)) in example 1¹An H-NMR spectrum;

FIG. 2 shows morphine-6-alpha-O-beta-D-glucuronide (M6G) of example 1¹H-NMR spectrum.

FIG. 3 shows morphine-6-beta-O-beta-D-glucuronide (compound represented by the formula (I-2)) in example 1¹³A C-NMR spectrum;

FIG. 4 shows an MS spectrum of morphine-6-beta-O-beta-D-glucuronide (a compound represented by the formula (I-2)) of example 1;

FIG. 5 shows an HPLC chromatogram of morphine-6-beta-O-beta-D-glucuronide (compound represented by the formula (I-2)) of example 1;

figure 6 shows an HPLC profile of morphine-6- α -O- β -D-glucuronide (M6G) of example 1.

Detailed Description

Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

The instrument comprises the following steps: low pressure preparative chromatograph (Teledyne ISCO), Bruker Fourier 500 NMR spectrometer, Fourier transform cyclotron resonance mass spectrometer (Bruker APEX IV), XPR-400P micro melting point apparatus, waters2695 type High Performance Liquid Chromatograph (HPLC)

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

morphine-6-beta-O-beta-D-glucuronide

S1: 33.4g (0.05mol) of morphine sulfate, 4g (0.1mol) of sodium hydroxide, 350mL of acetonitrile and 100mL of water are added into a 1L three-necked flask equipped with a thermometer, the temperature is reduced to 10 ℃, reaction is carried out, and 10.8g (0.05mol) of 3, 5-dinitrobenzoyl chloride is added dropwise. After the dropping is finished, slowly addingThe reaction was allowed to return to room temperature for 5 hours. After the reaction, the reaction solution was poured into 500ml of ethyl acetate, liquid separation was performed, the water layer was extracted 2 times with 200ml of ethyl acetate, the ethyl acetate layers were combined, washed with 5% sodium bicarbonate aqueous solution to neutrality, washed once with saturated sodium chloride, dried over anhydrous magnesium sulfate overnight, filtered, concentrated under reduced pressure at 45 ℃, and the residue was recrystallized from ethanol to obtain 20.4g of a white solid, i.e., a compound of formula II (R)₁Is 3, 5-dinitrobenzoyl, R₃Is methyl), yield: 85 percent of the total weight of the mixture,¹H-NMR(300MHz，d₆-DMSO)：

δ＝1.67～1.93(m，2H)，2.03(s，1H)，2.26(s，3H)，2.31～3.13(m，4H)，4.61～4.63(m，1H)，5.59～5.65(m，1H)，6.15(s，1H)，6.58～6.68(d，1H)，6.79～6.84(d，1H)，9.12～9.17(d，3H)。

s2: A1L three-necked flask was charged with 500ml of acetone and S1 to obtain a compound of formula II (R)₁Is 3, 5-dinitrobenzoyl, and R₃Methyl) is dissolved by stirring, the temperature is reduced to 0 ℃, 57.4ml of Jones reagent is dripped, the reaction temperature is controlled below 10 ℃ in the dripping process, 18ml of isopropanol is dripped to neutralize the unreacted Jones reagent after the reaction is finished, the reaction solution is poured into 500ml of water after being stirred for 30min, 800ml of dichloromethane is used for extraction, liquid separation is carried out, the water layer is extracted by 500ml of dichloromethane, the organic phase is combined, 300ml of saturated sodium bicarbonate aqueous solution and 300ml of saturated sodium chloride aqueous solution are used for washing, anhydrous magnesium sulfate is dried overnight, filtration and reduced pressure concentration are carried out, the residue is pulped by anhydrous ethanol and filtered, and the solid is dried under reduced pressure at 45 ℃ to obtain 18.6g of white solid, namely the compound of the formula VI-2 (R is₁Is 3, 5-dinitrobenzoyl, R₃Methyl) yield 92%.

S3: adding the compound of formula VI-2 (R) prepared in the previous step into a 1L three-necked flask₁Is 3, 5-dinitrobenzoyl, R₃Methyl group), 560ml of anhydrous methanol, 1.7ml of glacial acetic acid, 8.6g of sodium borohydride added in portions at room temperature, the reaction is completed at room temperature, the reaction solution is poured into 500ml of water, dichloromethane 500ml is respectively used for extraction twice, organic phases are combined, 300ml of saturated aqueous sodium chloride solution is used for washing, anhydrous magnesium sulfate is dried overnight, filtration is carried out, and concentration under reduced pressure is carried outTo dryness, 15.9g of formula VII-2 (R)₁Is 3, 5-dinitrobenzoyl, R₃Methyl) in 85.3% yield, which was used directly for the next resolution.

S4: preparation of formula VII-2 (R) from S3₁Is 3, 5-dinitrobenzoyl, R₃Methyl) is dissolved by 50ml of dichloromethane, 48g of silica gel (200-300 meshes) is added for sample mixing, the mixed material suspension is stirred, the mixture is concentrated under reduced pressure to be dry, and the mixture is separated and purified by a low-pressure preparative chromatograph for 0-15 min: methanol: dichloromethane (0% to 100%) is gradually changed to methanol: dichloromethane (5% -95%) is kept constant after 15 min. Formula VIII-2 (R)₁Is 3, 5-dinitrobenzoyl, R₃Methyl) is separated, the solution of the second peak is taken and concentrated to dryness under reduced pressure to obtain 13.7g of the formula VIII-2 (R)₁Is 3, 5-dinitrobenzoyl, R₃Methyl) yield 86.2%.

S5: VIII-2 (R) prepared by S4₁Is 3, 5-dinitrobenzoyl, R₃Methyl) and triacetyl bromo-D-glucuronic acid methyl ester (produced by Hongyang medicine science and technology Co., Ltd., Suzhou) 8.7g are added into 150mL of toluene, 17g of silver carbonate is added, the reaction is carried out for 2h at 130-140 ℃, after the reaction is finished, the filtration is carried out, the filtrate is poured into 100mL of water, 100mL of dichloromethane is respectively used for extraction for three times, dichloromethane layers are combined, 5L of saturated sodium chloride is used for washing, anhydrous magnesium sulfate is used for drying overnight, the filtration is carried out, the filtrate is concentrated, anhydrous ethanol is used for recrystallization, 18.5g of white solid is obtained (the compound shown in formula IV, P1 is acetyl, R is R₁Is 3, 5-dinitrobenzoyl, R₃Is methyl, R₅Methyl) yield 86.7% with HPLC purity 98.75%.

1H-NMR(300MHz，d6-DMSO)：δ＝1.54～1.62(m，2H)，2.02～2.15(m，1H)，2.19(s，9H)，2.26(s，3H)，2.88～3.04(m，3H)，3.28～3.31(m，2H)，3.57(s，3H)，4.17～4.19(d，1H)，4.89～4.97(m，2H)，5.53～5.58(m，2H)，5.93～6.18(m，4H)，6.57～6.60(d，1H)，6.66～6.68(d，1H),9.19～9.21(d，3H)。

S6: the compound shown as the formula IV prepared by S5 (P1 is acetyl, R₁Is 3, 5-dinitrobenzoyl, R₃Is methyl, R₅Methyl) is dissolved by 157mL of methanol and 27mL of water, 4.9g of lithium hydroxide monohydrate is added at 25 ℃, after the reaction is finished, the pH value is adjusted to 4-5 by acetic acid, reduced pressure concentration is carried out until the solution is dried, methanol is added for recrystallization, lithium salt generated by neutralization is washed off, and reduced pressure drying is carried out at 25-35 ℃ to obtain 8.9g of white solid morphine-6-beta-O-beta-D-glucuronide, the yield is 83.2%, and the melting point: 253-255 ℃ and the HPLC purity is 98.04%.

Morphine-6- β -O- β -D-glucuronide:¹H-NMR(500MHz，DMSO-d₆)：4.18-4.20(d，1H，6-H)

morphine-6- α -O- β -D-glucuronide (prepared in example 11 with reference to CN 201710257413.1):¹H-NMR(500MHz，DMSO-d₆)：5.10-5.11(d，1H，6-H)

morphine-6- β -O- β -D-glucuronide:¹³C-NMR(500MHz，DMSO-d₆)：173.80，146.11，138.82，130.88，129.57，127.63，123.27，118.90，116.68，99.83，90.17，74.23，73.13，72.39，72.34，71.77，58.54，45.74，42.38，41.17，33.30，20.96。

MS：460.2[M-H]⁺

EXAMPLE 26 preparation of beta-Hydroxymorphine

S1: 33.4g (0.05mol) of morphine sulfate, 4g (0.1mol) of sodium hydroxide, 350mL of acetonitrile and 100mL of water were added to a 1L three-necked flask equipped with a thermometer, the temperature was lowered to 10 ℃ to react, and 5.3g (0.05mol) of isobutyryl chloride was added dropwise. After the dropwise addition, the temperature was slowly returned to room temperature, and the reaction was carried out for 5 hours. After the reaction, the reaction solution was poured into 500ml of ethyl acetate, liquid separation was performed, the water layer was extracted 2 times with 200ml of ethyl acetate, the ethyl acetate layers were combined, washed with 5% sodium bicarbonate aqueous solution to neutrality, washed once with saturated sodium chloride, dried over anhydrous magnesium sulfate overnight, filtered, concentrated under reduced pressure at 45 ℃, and the residue was recrystallized from ethanol to obtain 16.4g of a white solid, i.e., a compound of formula II (R)₁Is isobutyryl, R₃Is methyl), yield: 92.3 percent.

S2: A1L three-necked flask was charged with 500ml of acetone and S1 to obtain a compound of formula II (R)₁Is isobutyryl, R₃Methyl), stirring to dissolve, cooling to 0 deg.C, adding 57.4ml Jones reagent dropwise, and filteringControlling the reaction temperature below 10 ℃, after the reaction is finished, dropwise adding 18ml of ethanol to neutralize the unreacted Jones reagent, stirring for 30min, pouring the reaction liquid into 500ml of water, extracting with 800ml of dichloromethane, separating liquid, extracting the water layer with 500ml of dichloromethane, merging organic phases, washing with 300ml of saturated sodium bicarbonate aqueous solution and 300ml of saturated sodium chloride aqueous solution, drying over night with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, pulping the residue with anhydrous ethanol, filtering, drying the solid under reduced pressure at 45 ℃ to obtain 14.1g of white solid, namely the compound of formula VI-2 (R)₁Is isobutyryl, R₃Methyl) yield 87%.

S3: adding the compound of formula VI-2 (R) prepared in the previous step into a 1L three-necked flask₁Is isobutyryl, R₃Methyl group), 560ml of anhydrous methanol, 1.5ml of formic acid, 8.6g of sodium borohydride are added in portions at room temperature, the reaction is completed at room temperature, the reaction solution is poured into 500ml of water, dichloromethane 500ml is used for extraction twice, organic phases are combined, 300ml of saturated aqueous sodium chloride solution is used for washing, anhydrous magnesium sulfate is used for drying overnight, filtration is carried out, and reduced pressure concentration is carried out until dryness, so as to obtain 12.2g of formula VII-2(R₁Is isobutyryl, R₃Methyl) in 86% yield, was used directly for the next resolution.

S4: preparation of formula VII-2 (R) from S3₁Is isobutyryl, R₃Methyl) is dissolved by 50ml of dichloromethane, 48g of silica gel (200-300 meshes) is added for sample mixing, the mixed material suspension is stirred, the mixture is concentrated under reduced pressure to be dry, and the mixture is separated and purified by a low-pressure preparative chromatograph for 0-15 min: methanol: dichloromethane (0% to 100%) is gradually changed to methanol: dichloromethane (5% -95%) is kept constant after 15 min. Formula VIII-2 (R)₁Is 3, 5-dinitrobenzoyl, R₃Methyl) is separated, the solution of the second peak is taken and concentrated to dryness under reduced pressure to obtain 10.4g of the formula VIII-2 (R)₁Is isobutyryl, R₃Methyl) yield 85%.

S5: preparation of S4 of formula VIII-2 (R)₁Is isobutyryl, R₃Methyl) is stirred with 150ml of methanol and 15ml of water to prepare suspension, the temperature is reduced to 0 ℃, 1.5g of lithium hydroxide monohydrate is added in batches, the reaction is kept at about 10 ℃ and stirred until the reaction is finished, the mixture is filtered and washed with water until the reaction is finishedDrying, and drying under reduced pressure at 60 ℃ to obtain 6.5g of 6-beta-hydroxymorphine, wherein the yield is as follows: 78.9 percent

6- β -hydroxymorphine:¹H-NMR(500MHz，DMSO-d₆)：4.58-4.65(m，1H，6-H)6.32(s，1H，6-OH)

morphine:¹H-NMR(500MHz，DMSO-d₆)：4.32-4.41(m，1H，6-H)6.27(s，1H，6-OH)

although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims

1. A stereoselective synthesis method of 6 beta-hydroxymorphine derivatives, wherein the 6 beta-hydroxymorphine derivatives are shown as a formula VIII, and the synthesis method comprises the following steps:

here, the substituents R in the formulae VI, VII and VIII₁Is hydrogen, unsubstituted C1-C4 alkyl, cyclopropylmethyl, unsubstituted C2-C4 alkenyl, R₉-O-C (O) -or R₇-C(O)-；R₃Is hydrogen, unsubstituted C1-C4 alkyl, cyclopropylmethyl, unsubstituted C2-C4 alkenyl、R₈-C (O) -or R₆-O-c (O) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₇And R₈Each independently selected from hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen; r₂And R₄Each independently is hydrogen or hydroxy;

(ii) the C1-C4 alkanoic acid in step (i) is selected from one or more of formic acid, acetic acid, propionic acid and butyric acid;

the catalytic amount refers to the volume ratio of the C1-C4 alkanoic acid to the hydrophilic organic solvent is 0.2-0.6: 100;

(ii) the compound of formula VII obtained in step (i) has a compound of formula VIII content of more than 50%.

2. The synthesis process according to claim 1, wherein in step (i) the C1-C4 alkanoic acid is formic acid, acetic acid or propionic acid.

3. The method of claim 1, wherein the catalytic amount is a volume ratio of the C1-C4 alkanoic acid to the hydrophilic organic solvent of 0.3-0.5: 100;

(ii) the compound of formula VII obtained in step (i) has a compound of formula VIII content of more than 90%.

4. The process of claim 1 wherein R is a substituent of formula VI, formula VII or formula VIII₁Is R₉-O-C (O) -or R₇-C(O)-；R₃Is R₆-O-C (O) -or R₈-c (o) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₇And R₈Each independently selected from hydrogen, methyl, isopropyl and 2, 4-dinitrophenyl; r₂And R₄Each independently is hydrogen or hydroxy; or

Substituent R in formula VI, formula VII and VIII₁Is methyl, ethyl, cyclopropylmethyl, allyl, acetyl, isobutyryl, 2, 4-dinitrobenzoyl or R₉-O-C(O)-；R₃Is methyl, cyclopropylmethyl, allyl, acetyl, 2, 4-dinitrobenzoyl or R₆-O-c (O) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₂And R₄Each independently is hydrogen or hydroxy; or

Substituent R in formula VI, formula VII and VIII₁Is R₉-O-C(O)-；R₃Is R₆-O-c (O) -; wherein R is₉And R₆Each independently selected from unsubstituted C1-C4 alkyl; r₂And R₄Each independently is hydrogen; or

Substituent R in formula VI, formula VII and VIII₁Acetyl, isobutyryl, 2, 4-dinitrobenzoyl; r₃Is methyl; r₂And R₄Each independently hydrogen.

5. A method for synthesizing morphine-6-beta-O-beta-D-glucuronide as shown in a formula I-2,

the synthesis method comprises the following steps:

(i) reducing the compound of formula VI-2 by sodium borohydride in a hydrophilic organic solvent in the presence of a catalytic amount of C1-C4 alkanoic acid to form a compound of formula VII-2; the catalytic amount refers to the volume ratio of the C1-C4 alkanoic acid to the hydrophilic organic solvent is 0.2-0.6: 100; (ii) the compound of formula VII-2 obtained in step (i) has a compound of formula VIII-2 content of more than 50%;

here, the substituents R in the formulae VI-2, VII-2 and VIII-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen;

alternatively, the compound of formula VIII-2 is reacted with formula III-3 to provide the compound of formula IV:

(iv) deprotection of a compound of formula IV to give a compound of formula I-2

Wherein the substituent R in the formula III-1, the formula III-2, the formula III-3 and the formula IV₅Is C1-C6 alkyl or benzyl;

the substituent P1 in the formula III-1, the formula III-2, the formula III-3 and the formula IV is alkanoyl or benzoyl of C2-C6;

the substituent P2 in the formula III-1 is alkanoyl of C2-C6, R₁₀-C (O) -or R₁₀-S(O)₂-，R₁₀Is C1-C4 alkoxy, one or more halogen substituted C1-C4 alkyl, phenyl or substituted phenyl, wherein the substituted phenyl is one or more hydrogens on the phenyl ring substituted with C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkanoyloxy;

the substituent P3 in the formula III-1 is C1-C6 alkyl, phenyl-substituted C1-C6 alkyl or aryl;

the substituents R in the formulae IV and VIII-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen.

6. The process of claim 5, wherein the substituent R in the formulae VI-2, VII-2 and VIII-2₁Is R₇-C (O) -, wherein R₇Is methyl or isopropyl.

7. The process of claim 5, wherein the substituent R in the formulae III-1, III-2, III-3 and IV₅Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.

8. The process of claim 7, wherein the substituent R in the formulae III-1, III-2, III-3 and IV₅Is methyl or ethyl.

9. The synthesis process according to claim 5, wherein the substituent P1 in formula III-1, formula III-2, formula III-3 and formula IV is selected from acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pivaloyl or benzoyl.

10. The method of claim 9, wherein the substituent P1 in formula III-1, formula III-2, formula III-3, and formula IV is acetyl or isobutyryl.

11. The process of claim 5 wherein the substituent P2 in formula III-1 is selected from the group consisting of acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pivaloyl, CF₃C(O)-，CF₃S(O)₂-, p-toluenesulfonyl, CH₂ClC(O)-，CHCl₂C(O)-，CCl₃C(O)-，CH₃OC(O)-，CH₃CH₂OC (O) -, benzoyl, m-acetoxybenzoyl.

12. The process of claim 11 wherein the substituent P2 in formula III-1 is acetyl or isobutyryl, CF₃CO-、CF₃SO₂-。

13. The method of claim 5, wherein the substituent P3 in formula III-1 is phenyl.

14. The process as claimed in claim 5, wherein the substituents R in the formulae IV and VIII-2₁Is R₇-C (O) -, wherein R₇Is methyl or 3, 5-dinitrophenyl.

15. The method of claim 5, wherein the compound of formula VI-2 is prepared by:

(1-i) morphine base or its salt, anhydride R₇-C(O)-O-(O)C-R₇Or acyl chlorides R₇-C (O) -Cl is used as a raw material, and a compound of a formula II is obtained through esterification reaction;

here, the substituents R in the formulae II and VI-2₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen;

16. The process of claim 15 wherein R is a substituent of formula II or VI-2₁Is R₇-C (O) -, wherein R₇Is methyl or 3, 5-dinitrophenyl.

17. The method of synthesis of any one of claims 5-16, comprising the steps of:

(i) reducing the compound of formula VI-2 obtained in the step (2-i) in a hydrophilic organic solvent by sodium borohydride in the presence of a catalytic amount of C1-C4 alkanoic acid to obtain a compound of formula VII-2; the catalytic amount refers to the volume ratio of the C1-C4 alkanoic acid to the hydrophilic organic solvent is 0.2-0.6: 100; (ii) the compound of formula VII-2 obtained in step (i) has a compound of formula VIII-2 content of more than 50%;

(iv) deprotection of a compound of formula IV to give a compound of formula I-2

Here, the substituent R₁、R₃、R₅P1, P2 and P3 are as defined above.

18. A method for synthesizing 6-beta-hydroxy-morphine as shown in formula I-3, comprising the steps of:

here, the substituents in the formulae II, VI-2, VII-2 and VIII-2R₁Is R₇-C(O)-；R₃Is methyl; wherein R is₇Selected from the group consisting of hydrogen, unsubstituted C1-C4 alkyl, and optionally substituted phenyl, said optionally substituted phenyl meaning that one or more hydrogens on the phenyl group are replaced with: methoxy, nitro and halogen;

the acid anhydride R₇-C(O)-O-(O)C-R₇Or acyl chlorides R₇R in (C), (O) -Cl₇As defined above in the substituent R₁The definition in (1).

19. The process of claim 18 wherein the substituent R in formula II, formula VI-2, formula VII-2 and formula VIII-2₁Is R₇-C (O) -, wherein R₇Is methyl or 3, 5-dinitrophenyl.

20. The synthesis method of 6-beta-hydroxy-ethyl morphine as shown in the formula I-4 comprises the following steps:

(i) reducing the compound of formula VI-3 obtained in the step (2-i) in a hydrophilic organic solvent by sodium borohydride in the presence of a catalytic amount of C1-C4 alkanoic acid to obtain a compound of formula VII-3; the catalytic amount refers to the volume ratio of the C1-C4 alkanoic acid to the hydrophilic organic solvent is 0.2-0.6: 100; (ii) the compound of formula VII-3 obtained in step (I) has a compound of formula I-4 content of more than 50%;