CN117083277A - Preparation method of nalbuphine sebacate and intermediate thereof - Google Patents

Preparation method of nalbuphine sebacate and intermediate thereof Download PDF

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CN117083277A
CN117083277A CN202280021384.8A CN202280021384A CN117083277A CN 117083277 A CN117083277 A CN 117083277A CN 202280021384 A CN202280021384 A CN 202280021384A CN 117083277 A CN117083277 A CN 117083277A
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compound
acid
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董达文
许向阳
崔华
巩烨
刘延明
张玲
蒋钰
陈帅
蔡兆雄
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Suzhou Enhua Biomedical Technology Co ltd
Nhwa Pharmaceutical Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
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    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems

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Abstract

The invention provides a preparation method of nalbuphine sebacate and an intermediate thereof, which can prepare nalbuphine sebacate efficiently, conveniently and safely, remarkably improves the purity and the yield of the end product nalbuphine sebacate,

Description

Preparation method of nalbuphine sebacate and intermediate thereof
cross-reference to related patent applications
The patent application claims the priority of the prior patent application with the application number 202110276968.7 which is filed by the China national intellectual property office on 3-15 days of 2021 and the name of 'a preparation method of nalbuphine sebacate and an intermediate thereof'. The entire disclosure of this prior application is incorporated by reference herein.
Technical Field
The application belongs to the field of medicinal chemistry, and in particular relates to a preparation method of nalbuphine sebacate or pharmaceutically acceptable salt thereof and an intermediate thereof.
Background
The di-nalbuphine sebacate, also known as (Dinalbuphine sebacate, DNS), also known as nalbuphine sebacate (Nalbuphine sebacate) or sebacoyl-di-nalbuphine (Sebacoyl dinalbuphine ester, SDE), is known under the chemical name bis ((4R, 4aS,7S,12 bS) -3- (cyclobutylmethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methylbenzofuran [3, 2-e) ]Isoquinoline-9-yl) sebacate, which is an opioid 7-day long-acting analgesic injection developed by Taiwan Shunshiu, and has the trade name of nano-pain solutionCurrently, taiwan has been marketed for the treatment of moderate to severe postoperative pain. Nalbuphine sebacate is a prodrug of nalbuphine, and has the following structure after 12-24 hours of administration:
the current synthetic route of nalbuphine sebacate mainly comprises the following modes:
TW399056B discloses a method for preparing the di-nalbuphine sebacate by nalbuphine hydrochloride and sebacic acid, which takes the nalbuphine hydrochloride and sebacic acid as starting materials, and prepares the di-nalbuphine sebacate by esterification reaction of di (2-pyridine) carbonate and dimethylformamide pyridine (DMAP), but a large amount of di (2-pyridine) carbonate condensing agent is used, the price is high, and the reaction time is as long as 18 hours; in addition, the DMAP adopted by the novel protective mask is toxic when being contacted with skin, is easy to absorb through the skin, has a stimulation effect on eyes, skin and respiratory systems, and is not beneficial to safe and green production because protective clothing, gloves and protective masks are worn when the novel protective mask is used in a large amount.
US20120209002A1 discloses a process for the reduction of the 6-keto group of a morphine alkaloid to a 6-hydroxy group by hydrogenating the 6-keto group with gaseous hydrogen in the presence of a heterogeneous catalyst and one or more solvents to obtain a 6-hydroxy morphinan alkaloid. However, the method needs hydrogen reduction, has higher equipment requirement, simultaneously has explosion risk and has higher industrial production cost. Meanwhile, the patent application also discloses that if 6-keto group is reduced by borohydride, there is a problem in that scaling up to commercial scale production by borohydride reduction is difficult in industrial scale production, and borohydride is difficult to remove in purification.
Based on the actual conditions, the preparation method of the dimaleate needs to be provided, the method needs to overcome the defects of overlong reaction time, harsh reaction conditions and the like, is safe and environment-friendly, and the catalyst used is low in cost, easy to obtain, simple in reaction conditions, easy to operate, free of corrosion to production equipment, high in conversion rate and good in purity.
Disclosure of Invention
The invention provides a formula (1)A preparation method of the shown dinafop diacid ester or the pharmaceutically acceptable salt and the intermediate thereof.
A process for the preparation of a dimemorfan diacid ester of formula (1) or a pharmaceutically acceptable salt thereof comprising the steps ofThe compound is shown as a starting material and is prepared into the formula (2) through esterification reaction with an esterification reagentThe compound is reduced to 6-hydroxy by 6-keto group to prepare the dinafop diacid ester shown in the formula (1) or the pharmaceutically acceptable salt thereof.
The compound shown in the formula (III) is subjected to esterification reaction with an esterification reagent in an organic solvent (B) under the action of Lewis base, so that a compound shown in the formula (2) is prepared;
the compound shown in the formula (2) is subjected to reduction reaction in an organic solvent (A) under the action of acid and a reducing agent to prepare the compound shown in the formula (1).
In the compound represented by the formula (1), n is an integer of 3 to 10, preferably n is 6. When n is 6, the compound is hereinafter designated as formula (I), namely, dinaphthyl sebacate
In the compound represented by the formula (2), n is an integer of 3 to 10, preferably n is 6. When n is 6, the compound is hereinafter designated as formula (II), formula (I)
The esterifying reagent is selected from dicarboxylic acid HOOC-CH 2 -(CH 2 ) n -CH 2 -COOH, dibasic acid anhydrideOr binary acyl chloride ClOC-CH 2 -(CH 2 ) n -CH 2 COCl, wherein n is an integer from 3 to 10, preferably n is 6. Preferably, the esterification reagent is binary acyl chloride ClOC-CH 2 -(CH 2 ) n -CH 2 COCl, in particular sebacoyl chloride.
Wherein the compound of formula (III) may be of formula (IV)The compound is prepared by taking the compound as a starting material through reductive amination reaction.
The present invention also provides a compound represented by the formula (2)n is 3-10An integer, preferably n is 6. The compound represented by the formula (2) is used as an intermediate for the preparation of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
In some embodiments of the invention, the invention provides a preparation method of a dinaphthyl sebacate or a pharmaceutically acceptable salt thereof, which comprises the steps of preparing a compound shown in a formula (II) by an esterification reaction of a compound shown in a formula (III) as a starting raw material with sebacic acid, sebacic anhydride or sebacoyl chloride, and reducing 6-ketone group to 6-hydroxy group to prepare the dinaphthyl sebacate or the pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the present invention provides a process for preparing a dinafop-p-sebacic acid ester or a pharmaceutically acceptable salt thereof, and an intermediate thereof, which comprises preparing a compound represented by formula (III) from a compound represented by formula (IV) as a starting material by a reductive amination reaction, then preparing a compound represented by formula (II) by an esterification reaction with sebacoyl chloride, and then reducing 6-keto to 6-hydroxy to obtain a dinafop-sebacic acid ester or a pharmaceutically acceptable salt thereof.
The invention provides a preparation method of a compound shown in a formula (II) or pharmaceutically acceptable salt thereof, which comprises the following steps:
the compound shown in the formula (III) is subjected to esterification reaction with sebacoyl chloride in an organic solvent (B) under the action of Lewis base, so that the compound shown in the formula (II) is prepared.
The present invention further provides a process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising:
the compound shown in the formula (IV) is subjected to reductive amination reaction with cyclobutyl formaldehyde in an organic solvent (C) under the action of a transition metal catalyst, alkali and a hydrogen donor agent to prepare the compound shown in the formula (III).
The invention further provides a method for preparing a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, namely a method for preparing the dimaleate or pharmaceutically acceptable salt thereof, which comprises the following steps:
The compound shown in the formula (II) is subjected to reduction reaction in an organic solvent (A) under the action of acid and a reducing agent, so that the compound shown in the formula (I) is prepared.
The present application also provides a compound represented by the formula (II) as an intermediate for producing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict, the present disclosure provides definitions. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. All patents, published patent applications, and publications cited herein are incorporated by reference.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that such terms as "comprising" encompass the meaning of "consisting of …".
The terms "selected from …", "preferably …" and "more preferably …" refer to one or more elements of the group listed thereafter, independently selected, and may include combinations of two or more elements, with one element of the group listed thereafter being preferred in the present application.
The terms "optional," "optionally," or "optionally present" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with an amine" means that the amine may or may not be present.
The terms "substituted" and "substituted" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When it is described that a substituent is absent, it is understood that the substituent may be one or more hydrogen atoms, provided that the structure is such that the compound attains a stable state. When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, provided that the normal valency of all atoms in the group in the current case is not exceeded, and stable compounds are formed.
The term "acyloxyborohydride" refers to a compound having the structure In the present invention, each R 1 Is C 1-3 And are identical, for example methyl, ethyl and propyl; m is M + Can be matched withSalt-forming cations, M in the present invention + Sodium ion, potassium ion, lithium ion and ammonium ion;
when M + When the ammonium ion is the acyloxyborohydride compound, namely the acyloxyborohydride ammonium compound, wherein the ammonium ion isSaid each R 2 Is C 1-3 And are identical, for example methyl, ethyl and propyl. The acyloxy ammonium borohydride compound disclosed by the invention can be prepared by referring to patent CN 104072528A.
The term "benzene" is a compound containing only one benzene ring and optionally substituted for the benzene ring, such as benzene, toluene, chlorobenzene, xylene, and the like.
The term "hydrogen donor agent" is referred to in the present invention as being capable of donating H + The compounds of the present invention are preferably the corresponding organic or inorganic acids, such as formic acid, acetic acid, hydrochloric acid, etc.
The term "eq" is used to denote the amount of a substance, as generally understood in the art, referred to as "equivalent", also called molar equivalent, in the sense that the eq number in the present invention is equal to the molar ratio.
The term "amine compound" refers to an ammonia molecule (NH 3 ) The organic compounds formed by substituting hydrogen of (1-3) N atoms (such as 1,2 and 3N atoms) and 1-12C atoms (such as 1-3, 2-6 and 3-12) are fatty amines; for example, primary amines having 1 to 2N atoms, e.g. NH 2 -R 3 And NH 2 -R 3 -NH 2 ，R 3 Is C 1-5 Saturated or unsaturated hydrocarbon groups of (a) such as methylamine, ethylamine, ethylenediamine, propylenediamine, propylamine and the like; for example, secondary amines having 1 to 2N atoms, e.g. R 4 -NH-R 3 Or R is 4 -NH-R 5 -NH-R 3 ，R 3 And R is 4 Each independently is C 1-5 Saturated or unsaturated hydrocarbon radicals, R 5 Is C 1-5 Saturated or unsaturated hydrocarbylene radicals of (2) such as dimethylamine, diethylamine, dipropylamine, N-methylethylamine, N 1 ,N 2 -dimethyl-ethyl-1, 2-diamine and N 1 ,N 2 -diethyl-ethyl-1, 2-diamine, and the like; for example, tertiary amines having 1 to 2N atoms, e.gR 3 、R 4 、R 6 And R is 7 Each independently is C 1-5 Saturated or unsaturated hydrocarbon radicals, R 5 Is C 1-5 Saturated or unsaturated alkylene groups of (a), such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine (DIPEA), diisopropylmethylamine, and the like.
The term "nitrogen-containing heterocycle" refers to a mono-or bi-cyclic ring system (four to twelve membered, five to ten membered, four to seven membered, five to six membered) containing N atoms and having, for example, 4 to 12 (suitably 5 to 11) ring atoms, wherein at least one ring atom (e.g., 1,2 or 3) is selected from N, the other heteroatoms are heteroatoms selected from N, O and S, and the remaining ring atoms are C. The ring system may be saturated or unsaturated (i.e., having one or more double bonds within the ring), and may be aromatic or non-aromatic. The "nitrogen-containing heterocycle" of the present invention may optionally be substituted with an amine and C 1-3 Is substituted with an alkyl group, the amine being as defined above.
The term "hydrocarbylene", when used herein alone or in combination with other groups, refers to a straight or branched chain, saturated or unsaturated, divalent hydrocarbon group. For example, the term C 1-5 Saturated or unsaturated alkylene of (C) refers to saturated or unsaturated alkylene having 1 to 5 carbon atoms, e.g., methylene (-CH) 2 (-), ethylene (-CH) 2 -CH 2 (-) propenylidene (-CH) 2 -CH＝CH-)。
The compound of formula (III) as used in the context of the present invention includes its free base form, hydrate form, such as the dihydrate of the compound of formula (III), solvated form, and salt form, such as the hydrochloride salt of the compound of formula (III), and the like.
Process for preparing compounds of formula (2) or pharmaceutically acceptable salts thereof
The invention provides a preparation method of a compound shown in a formula (2) or pharmaceutically acceptable salt thereof, which comprises the following steps:
and (3) carrying out esterification reaction on the compound shown in the formula (III) and an esterification reagent in an organic solvent (B) under the action of Lewis base to prepare the compound shown in the formula (2).
Wherein in the compound shown in the formula (2), n is an integer of 3-10, preferably n is 6;
the esterifying reagent is selected from dicarboxylic acid HOOC-CH 2 -(CH 2 ) n -CH 2 -COOH, dibasic acid anhydrideOr binary acyl chloride ClOC-CH 2 -(CH 2 ) n -CH 2 COCl, wherein n is an integer from 3 to 10, preferably n is 6. Preferably, the esterification reagent is binary acyl chloride ClOC-CH 2 -(CH 2 ) n -CH 2 COCl, in particular sebacoyl chloride.
Process for preparing compounds of formula (II) or pharmaceutically acceptable salts thereof
The invention provides a preparation method of a compound shown in a formula (II) or pharmaceutically acceptable salt thereof, which comprises the following steps:
the compound shown in the formula (III) is subjected to esterification reaction with sebacoyl chloride in an organic solvent (B) under the action of Lewis base, so that the compound shown in the formula (II) is prepared.
Wherein: the Lewis base is selected from goldBelongs to weak acid salt compounds, amine and C 1-3 Optionally substituted alkyl-containing heterocycles, preferably amines and amines, C 1-3 Optionally substituted alkyl containing heterocycles; the organic solvent (B) is selected from C 1-3 Halogenated hydrocarbon solvents, nitrile solvents, ether solvents and C 2-5 Saturated carboxylic acid ester solvents of (C) are preferred 1-3 Is a halogenated hydrocarbon solvent.
In one embodiment of the invention, the metal weak acid salt compound is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal monohydrogenphosphates, alkali metal acetates, etc., such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium monohydrogenphosphate, sodium dihydrogen phosphate, sodium phosphate, potassium monohydrogenphosphate, potassium dihydrogen phosphate, potassium phosphate, sodium acetate, potassium acetate and cesium carbonate, preferably sodium carbonate and potassium carbonate, such as sodium carbonate.
In one embodiment of the invention, the amine compound is selected from C 1-5 Primary amine compound of (C) 2-10 Secondary amine compounds and C 3-10 Tertiary amine compounds of (C) are preferred 3-10 Tertiary amine compounds of (a).
In one embodiment of the invention, the C 1-5 The primary amine compounds of (a) are selected from the group consisting of methylamine, ethylamine, ethylenediamine, propylamine and propylenediamine, with methylamine, ethylamine and ethylenediamine being preferred.
In one embodiment of the invention, the C 2-10 The secondary amine compounds of (a) are selected from dimethylamine, diethylamine, dipropylamine, dibutylamine, N-methylethylamine and N-ethylethylamine, preferably diethylamine, dipropylamine and N-methylethylamine.
In one embodiment of the invention, the C 3-10 The tertiary amine compound of (2) is selected from the group consisting of trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-dimethylethylamine, tetramethylethylenediamine and tetramethylpropylenediamine, preferably triethylamine, tetramethylethylenediamine and diisopropylethylamine, for example triethylamine.
In a more preferred embodiment of the invention, the amine compound is selected from the group consisting of tetramethyl ethylenediamine, triethylamine and diisopropylethylamine, such as triethylamine.
In one embodiment of the invention, the amine, C 1-3 Optionally substituted nitrogen-containing heterocyclic compounds selected from the group consisting of pyridine, piperidine, 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, pyrrolidine, triethylenediamine (DBACO) and 1, 8-diazabicyclo [ 5.4.0) ]Undec-7-ene (DBU), preferably 4-dimethylaminopyridine and DBU, such as 4-dimethylaminopyridine.
In one embodiment of the invention, the amine, C 1-3 The optionally substituted nitrogen-containing heterocyclic compound of (C) is preferably substituted by alkyl 3-10 Tertiary amine of C 1-3 Optionally substituted alkyl containing heterocycles.
In a preferred embodiment of the invention, the lewis base is selected from sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethyl ethylenediamine, 4-dimethylaminopyridine, DBACO and DBU, preferably sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine and 4-dimethylaminopyridine, more preferably diisopropylethylamine, sodium carbonate and triethylamine, for example triethylamine.
In one embodiment of the invention, the C 1-3 The halogenated hydrocarbon solvent of (2) is selected from halogenated methane solvents selected from dichloromethane and tetrachloromethane, preferably dichloromethane.
In one embodiment of the invention, the nitrile solvent is selected from acetonitrile and propionitrile, preferably acetonitrile.
The ether solvent is selected from tetrahydrofuran, methyl tert-butyl ether, dioxane, tert-butyl ether, n-butyl ether and tetrahydropyran, preferably tetrahydrofuran and methyl tert-butyl ether, such as tetrahydrofuran.
In one embodiment of the invention, the C 2-5 The saturated carboxylic acid ester solvent is selected from methyl formate, methyl acetate, ethyl formate, ethyl acetate, propyl formate, methyl propionate, ethyl propionate and propyl acetateEthyl acetate is preferred.
In one embodiment of the invention, the organic solvent (B) is selected from acetonitrile, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether and dichloromethane, preferably dichloromethane.
In one embodiment of the invention, the molar ratio of the lewis base to the compound of formula (III) is selected from 1:1 to 10:1, preferably 1:1 to 5:1, more preferably 1:1 to 3:1, for example 1:1 to 2:1.
In a preferred embodiment of the present invention, the molar ratio of triethylamine to the compound of formula (III) is selected from 1:1 to 10:1, preferably 1:1 to 5:1, more preferably 1:1 to 3:1, for example 1:1 to 2:1
In one embodiment of the invention, the molar ratio of the compound of formula (III) to the esterifying reagent is selected from 1:1 to 2:1, preferably 1.5:1 to 2:1, for example 1.8:1.
In a preferred embodiment of the invention, the molar ratio of the compound of formula (III) to sebacoyl chloride is selected from 1:1 to 2:1, preferably 1.5:1 to 2:1, for example 1.8:1.
In still another embodiment of the present invention, in the above-mentioned process for producing the compound represented by the formula (2), it is necessary to maintain a specific reaction temperature at the time of adding the esterifying reagent, the reaction temperature being selected from the group consisting of-25 to 40 ℃, for example, -20 to-10 ℃, and-5 to 30 ℃, preferably, for example, -20 to 10 ℃,0 to 25 ℃,0 to 10 ℃, and more preferably, -20 to-10 ℃.
In a preferred embodiment of the present invention, in the above-mentioned process for preparing the compound represented by the formula (II), it is also necessary to maintain a specific reaction temperature at the time of addition of sebacoyl chloride, the reaction temperature being selected from the group consisting of-25 to 40 ℃, for example, -20 to-10 ℃, and-5 to 30 ℃, preferably, for example, -20 to 10 ℃,0 to 25 ℃,0 to 10 ℃, more preferably, -20 to-10 ℃.
In a preferred embodiment of the present invention, there is provided a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:
the compound shown in the formula (III) is subjected to esterification reaction with sebacoyl chloride in an organic solvent (B) under the action of Lewis base, so that a compound shown in the formula (II) is prepared;
wherein the lewis base is selected from triethylamine, tetramethyl ethylenediamine or diisopropylethylamine, preferably triethylamine; the organic solvent (B) is selected from dichloromethane, THF, acetonitrile or ethyl acetate, preferably dichloromethane; the reaction requires maintaining a specific reaction temperature when adding sebacoyl chloride, wherein the reaction temperature is selected from-25 to 40 ℃, preferably-20 to-10 ℃; the molar ratio of the Lewis base to the compound shown in the formula (III) is 1:1-3:1; the molar ratio of the compound shown in the formula (III) to the sebacoyl chloride is 1.5:1-2:1.
The present invention provides a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:
mixing a compound shown in a formula (III), triethylamine and dichloromethane, adding a mixed solvent of sebacoyl chloride and dichloromethane at a temperature of-25-40 ℃, for example, 0-10 ℃, preferably-20-10 ℃, and reacting to obtain a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof, wherein the molar ratio of the triethylamine to the compound shown in the formula (III) is 1:1-3:1; the molar ratio of the compound shown in the formula (III) to the sebacoyl chloride is 1.5:1-2:1.
The process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof from a compound of formula (III) as described in the context of the present invention optionally further comprises a post-treatment comprising purification by one or more steps of pH adjustment, extraction, filtration, adsorption, crystallization, recrystallization, concentration, etc., after completion of the reaction, which steps may be performed sequentially or in an alternating manner, or a purification process such as crystallization or recrystallization may be performed a plurality of times. In a preferred embodiment of the present invention, the post-treatment process comprises, after the reaction, adding an aqueous ammonium chloride solution, filtering, and adding an organic solvent to crystallize, wherein the crystallization comprises one or more of adding an inert solvent to crystallize, cooling to crystallize, or stirring to crystallize.
Process for preparing compounds of formula (III) or pharmaceutically acceptable salts thereof
The invention provides a preparation method of a compound shown in a formula (III) or pharmaceutically acceptable salt thereof, which comprises the following steps:
the compound shown in the formula (IV) is subjected to reductive amination reaction with cyclobutyl formaldehyde in an organic solvent (C) under the action of a transition metal catalyst, alkali and a hydrogen donor agent to prepare a compound shown in the formula (III);
wherein: the transition metal catalyst is selected from transition metal complex catalysts, such as bis (4-cymene) ruthenium (II) dichloride ([ RuCl) 2 (p-cymene)] 2 ) Triruthenium dodecacarbonyl (Ru) 3 (CO) 12 ) Bis (triphenylphosphine) cyclopentadienyl ruthenium (II) chloride (Cp (PPh) 3 ) 2 RuCl), tris (triphenylphosphine) ruthenium (II) chloride (RuCl) 2 (PPh 3 ) 3 ) Ruthenium (II) dichloro tetra (triphenylphosphine) (RuCl) 2 (PPh 3 ) 4 ) And rhodium (III) dichloro (pentamethylcyclopentadienyl) ([ Rh (C) 5 Me 5 )Cl 2 ] 2 ) Preferably dichlorobis (4-cymene) ruthenium (II); the organic solvent (C) is selected from C 1-3 Saturated monohydric alcohol solvents, ether solvents and amide solvents; the alkali is selected from metal weak acid salt compounds and tertiary amine compounds; the hydrogen donor agent is selected from C 1-3 Carboxylic acid, hydrochloric acid and boric acid.
In yet another embodiment of the present invention, the transition metal catalyst is selected from ruthenium-based catalysts The ruthenium catalyst is selected from dichloro bis (4-cymene) ruthenium (II) ([ RuCl) 2 (p-cymene)] 2 ) Triruthenium dodecacarbonyl (Ru) 3 (CO) 12 ) Bis (triphenylphosphine) cyclopentadienyl ruthenium (II) chloride (Cp (PPh) 3 ) 2 RuCl), tris (triphenylphosphine) ruthenium (II) chloride (RuCl) 2 (PPh 3 ) 3 ) And tetrakis (triphenylphosphine) ruthenium (II) (RuCl) 2 (PPh 3 ) 4 ) Preferably dichlorobis (4-cymene) ruthenium (II).
In one embodiment of the invention, the C 1-3 The saturated monohydric alcohol is selected from methanol, ethanol and isopropanol, preferably methanol and ethanol, for example methanol.
In one embodiment of the invention, the ethereal solvent is selected from tetrahydrofuran, methyl tert-butyl ether, dioxane, tert-butyl ether, n-butyl ether and tetrahydropyran, preferably tetrahydrofuran and methyl tert-butyl ether, such as tetrahydrofuran.
In one embodiment of the invention, the amide-based solvent is selected from the group consisting of N, N-Dimethylacetamide (DMAC) and N, N-Dimethylformamide (DMF), preferably DMF.
The metal weak acid salt compound is selected from alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal phosphates, alkali metal monohydrogenphosphates, alkali metal dihydrogenphosphates, alkali metal acetates, etc., such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium monohydrogenphosphate, sodium dihydrogenphosphate, sodium phosphate, potassium monohydrogenphosphate, potassium dihydrogenphosphate, potassium phosphate, sodium acetate, potassium acetate and cesium carbonate, preferably sodium carbonate and potassium carbonate, such as sodium carbonate.
In one embodiment of the present invention, the tertiary amine compound is selected from C 3-10 Tertiary amine compound of (C) 3-10 The tertiary amine compound of (2) is selected from the group consisting of trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-dimethylethylamine, tetramethylethylenediamine and tetramethylpropylenediamine, preferably triethylamine, tetramethylethylenediamine and diisopropylethylamine, for example triethylamine.
In one embodiment of the invention, the C 1-3 Is selected from formic acid, acetic acid, oxalic acid and propionic acid, preferably formic acid and acetic acid, for example formic acid.
In a preferred embodiment of the invention, the organic solvent (C) is selected from methanol, ethanol, isopropanol, THF and DMF, preferably methanol or THF, for example methanol.
In a preferred embodiment of the invention, the base is selected from sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine and trimethylamine, preferably triethylamine.
In a preferred embodiment of the invention, the hydrogen donor agent is selected from formic acid, acetic acid and hydrochloric acid, preferably formic acid.
In one embodiment of the invention, the molar ratio of base to compound of formula (IV) is selected from 1:1 to 10:1, preferably 1.5:1 to 6:1, for example preferably 2:1 to 5:1,3:1 to 5:1 or 3:1 to 4:1.
In a preferred embodiment of the present invention, the molar ratio of triethylamine to the compound of formula (IV) is selected from 1:1 to 10:1, preferably 1.5:1 to 6:1, for example preferably 2:1 to 5:1,3:1 to 5:1 or 3:1 to 4:1.
In one embodiment of the present invention, the molar ratio of the compound of formula (IV) to the transition metal catalyst is selected from 1:0.001 to 1:0.03, for example 1:0.001 to 1:0.01, preferably 1:0.001 to 1:0.005, more preferably 1:0.002 to 1:0.005.
In still another embodiment of the present invention, in the above-mentioned method for producing the compound represented by the formula (III), the reaction system is further maintained at a specific reaction temperature selected from the group consisting of 0 to 100℃or 0℃to the reflux temperature of the reaction solution, preferably 30 to 100℃or 30℃to the reflux temperature of the reaction solution, more preferably 60 to 80℃or the reflux temperature of the reaction solution, for example 60 to 65 ℃.
The present invention provides a process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising:
stirring and reacting a compound shown in a formula (IV), methanol and cyclobutyl formaldehyde at 60-80 ℃, cooling to room temperature, adding a mixed solvent of triethylamine, methanol and formic acid, and dichlorobis (4-cymene) ruthenium (II), and stirring and reacting at 60-80 ℃ to prepare a compound shown in a formula (III); wherein the molar ratio of triethylamine to the compound represented by formula (IV) is 2:1 to 5:1 (preferably 3:1 to 5:1); the molar ratio of the compound shown in the formula (IV) to the dichlorobis (4-cymene) ruthenium (II) is 1:0.002-1:0.005.
In yet another embodiment of the present invention, the preparation of the compound of formula (III) or a pharmaceutically acceptable salt thereof may further comprise a post-treatment process, such as extraction by an organic solvent commonly used in the art, washing by an aqueous solution of a saturated salt commonly used in the art; the extraction process and the washing process are sequentially or alternatively performed, and then one or more of concentrating the organic phase, adsorbing by activated carbon, crystallizing, recrystallizing and/or drying can be further included.
In a preferred embodiment of the present invention, the organic solvent may be selected with reference to a conventional solvent in the art, preferably C, during the post-treatment of the compound of formula (III) or a pharmaceutically acceptable salt thereof 2-5 More preferably ethyl acetate.
In a preferred embodiment of the present invention, the saturated salt solution may be selected with reference to a common solution in the art, preferably a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, during the post-treatment.
In a preferred embodiment of the present invention, the drying and/or concentration of the organic phase may be performed using anhydrous magnesium sulfate or anhydrous sodium sulfate.
Process for preparing compounds of formula (1) or pharmaceutically acceptable salts thereof
The compound shown in the formula (2) is subjected to reduction reaction in an organic solvent (A) under the action of acid and a reducing agent to prepare the compound shown in the formula (1).
Process for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof
The invention provides a method for preparing dinafop-buprenorphine sebacate (a compound shown in a formula (I)) or pharmaceutically acceptable salt thereof, which comprises the following steps:
the compound shown in the formula (II) is subjected to reduction reaction in an organic solvent (A) under the action of acid and a reducing agent, so that the compound shown in the formula (I) is prepared.
Wherein: the reducing agent is an acyloxyborohydride compound; the organic solvent (A) is selected from nitrile solvents, C 2-5 Saturated carboxylic ester solvent, benzene solvent, ether solvent, C 1-3 Saturated monohydric alcohol solvent and C 1-3 Preferably a nitrile solvent.
In one embodiment of the invention, the nitrile solvent is selected from acetonitrile and propionitrile, preferably acetonitrile.
In one embodiment of the invention, the C 2-5 The saturated carboxylic acid ester solvent of (a) is selected from methyl formate, methyl acetate, ethyl formate, ethyl acetate, propyl formate, methyl propionate, ethyl propionate and propyl acetate, preferably ethyl acetate.
In one embodiment of the invention, the benzene-based solvent is selected from toluene, ethylbenzene, 1, 2-xylene and 1, 3-xylene, preferably toluene.
In one embodiment of the invention, the C 1-3 The halogenated hydrocarbon solvent of (2) is selected from halogenated methane solvents selected from dichloromethane and tetrachloromethane, preferably dichloromethane.
The ether solvent is selected from tetrahydrofuran, methyl tert-butyl ether, dioxane, tert-butyl ether, n-butyl ether and tetrahydropyran, preferably tetrahydrofuran and methyl tert-butyl ether, such as tetrahydrofuran.
In one embodiment of the invention, the C 1-3 The saturated monohydric alcohol is selected from methanol, ethanol and isopropanol, preferably methanol and ethanol, for example methanol.
In one embodiment of the invention, the organic solvent (a) is selected from acetonitrile, ethyl acetate, tetrahydrofuran, toluene and dichloromethane, preferably acetonitrile.
In one embodiment of the present invention, the acyloxyborohydride compound is selected from the group consisting of acyloxy ammonium borohydride compounds, acyloxy sodium borohydride compounds, acyloxy potassium borohydride compounds, and acyloxy lithium borohydride compounds, preferably acyloxy ammonium borohydride compounds.
In one embodiment of the present invention, the sodium acyloxyborohydride compound is preferably sodium triacetoxyborohydride.
In one embodiment of the present invention, the potassium acyloxyborohydride compound is preferably potassium triacetoxyborohydride.
In one embodiment of the present invention, the acyloxy ammonium borohydride compound is selected from the group consisting of triacetoxy ammonium borohydride compounds, tripropionoyloxy ammonium borohydride compounds, tributyloxy ammonium borohydride compounds and tripentyloxy ammonium borohydride compounds, preferably triacetoxy ammonium borohydride compounds.
In one embodiment of the invention, the triacetoxyborohydride compound is selected from the group consisting of tetra-methyl-ammonium triacetoxyborohydride, tetra-ethyl-ammonium triacetoxyborohydride, tetra-propyl-ammonium triacetoxyborohydride and tetra-butyl-ammonium triacetoxyborohydride, preferably tetra-methyl-ammonium triacetoxyborohydride.
In one embodiment of the invention, the tripropionyloxyborohydride is selected from the group consisting of tripropionyloxyborohydride tetramethylammonium, tripropionyloxyborohydride tetraethylammonium, tripropionyloxyborohydride tetrapropylammonium and tripropionyloxyborohydride tetrabutylammonium, preferably tripropionyloxyborohydride tetramethylammonium.
In one embodiment of the invention, the tributyloxy ammonium borohydride compound is selected from the group consisting of tetrabutyloxy tetramethyl ammonium borohydride, tetrabutyloxy tetraethyl ammonium borohydride, tetrabutyloxy tetrapropyl ammonium borohydride and tributyloxy tetrabutyl ammonium borohydride, preferably tributyloxy tetramethyl ammonium borohydride.
In a preferred embodiment of the present invention, the acyloxyborohydride compound is an acyloxy borohydride ammonium compound, the acyloxy borohydride ammonium compound is a triacetoxy borohydride ammonium compound, and the triacetoxy borohydride ammonium compound is triacetoxy borohydride tetramethylammonium.
In one embodiment of the invention, the acid is selected from the group consisting of mineral acids selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, preferably hydrochloric acid, or organic acid solvents; the organic acid is selected from C 1-3 Saturated carboxylic acids of (2).
In one embodiment of the invention, the C 1-3 The saturated carboxylic acid of (2) is selected from formic acid, acetic acid, oxalic acid and malonic acid, preferably acetic acid.
In a preferred embodiment of the invention, the volume ratio of the organic solvent (A) to the acid is selected from 0.5:1 to 9:1, for example 1:1 to 9:1, preferably 1:1 to 5:1, more preferably 1:1 to 3:1, for example 1:1.
In a more preferred embodiment of the invention, the volume ratio of acetonitrile to acetic acid is selected from 0.5:1 to 9:1, for example 1:1 to 9:1, preferably 1:1 to 5:1, more preferably 1:1 to 3:1, for example 1:1.
In one embodiment of the invention, the molar ratio of the reducing agent to the compound of formula (2) is selected from 1:1 to 5:1, preferably 2:1 to 5:1, for example 2:1 to 3:1, or 3.1:1,3.2:1,3.3:1,3.4:1,3.5:1,3.6:1,3.7:1,3.8:1,3.9:1,4:1, etc.
In a preferred embodiment of the invention, the molar ratio of the reducing agent to the compound of formula (II) is selected from 1:1 to 5:1, preferably 2:1 to 5:1, for example 2:1 to 3:1, or 3.1:1,3.2:1,3.3:1,3.4:1,3.5:1,3.6:1,3.7:1,3.8:1,3.9:1,4:1, etc.
In a more preferred embodiment of the invention, the molar ratio of the tetramethylammonium triacetoxyborohydride to the compound of formula (II) is selected from 1:1 to 5:1, preferably 2:1 to 5:1, for example 2:1 to 3:1, or 3.1:1,3.2:1,3.3:1,3.4:1,3.5:1,3.6:1,3.7:1,3.8:1,3.9:1,4:1, etc.
In still another embodiment of the present invention, in the above-mentioned method for preparing the compound represented by the formula (1), it is necessary to maintain a specific reaction temperature at the time of adding the reducing agent, the reaction temperature being selected from the group consisting of-10 to 60 ℃, for example, -10 to 30 ℃,0 to 10 ℃,20 to 30 ℃, preferably-5 to 25 ℃, and most preferably-5 to 10 ℃.
In still another embodiment of the present invention, in the above-mentioned process for preparing the compound represented by the formula (I), it is also necessary to maintain a specific reaction temperature at the time of adding the reducing agent, the reaction temperature being selected from the group consisting of-10 to 60 ℃, for example, -10 to 30 ℃,0 to 10 ℃,20 to 30 ℃, preferably-5 to 25 ℃, most preferably-5 to 10 ℃.
The invention provides a method for preparing a dinafop sebacate (a compound shown in a formula (I)) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
dissolving a compound shown in a formula (II) in a mixed solvent of acetonitrile and acetic acid, adding tetraacetoxy tetramethylammonium borohydride at the temperature of-5-10 ℃ and reacting to prepare the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, wherein the volume ratio of acetonitrile to acetic acid is 1:1-3:1; the molar ratio of the tetraacetoxyborohydride to the compound shown in the formula (II) is 2:1-3:1 or 3:1-4:1.
In yet another embodiment of the present invention, the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof may further comprise a post-treatment process, such as extraction by an organic solvent commonly used in the art, washing by an aqueous solution of a saturated salt commonly used in the art; the extraction process and the washing process are sequentially or alternatively performed, and then the process of drying and/or concentrating the organic phase can be further included.
In a preferred embodiment of the present invention, the organic solvent may be selected with reference to a conventional solvent in the art, preferably a halogenated hydrocarbon solvent, more preferably dichloromethane, during the post-treatment of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the saturated salt solution may be selected with reference to a common solution in the art, preferably a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, during the post-treatment.
In a preferred embodiment of the present invention, the drying and/or concentration process may be performed using anhydrous magnesium sulfate or anhydrous sodium sulfate.
The invention provides a method for preparing a dinafop sebacate (a compound shown in a formula (I)) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
the compound shown in the formula (IV) is subjected to reductive amination reaction with cyclobutyl formaldehyde in an organic solvent (C) under the action of a transition metal catalyst, alkali and a hydrogen donor agent to prepare a compound shown in the formula (III); the compound shown in the formula (III) is subjected to esterification reaction with sebacoyl chloride in an organic solvent (B) under the action of Lewis base, so that a compound shown in the formula (II) is prepared; the compound shown in the formula (II) is subjected to reduction reaction in an organic solvent (A) under the action of acid and a reducing agent to prepare the compound shown in the formula (I);
wherein:
the reducing agent is an acyloxyborohydride compound, preferably an ammonium triacetoxyborohydride compound, more preferably tetramethylammonium triacetoxyborohydride; the organic solvent (A) is selected from nitrile solvents, C 2-5 Saturated carboxylic ester solvent, benzene solvent, ether solvent, C 1-3 Saturated monohydric alcohol of (C) 1-3 Preferably a nitrile solvent, more preferably acetonitrile;
the roadThe easy base is selected from metal weak acid salt compound, amine and C 1-3 Optionally substituted alkyl-containing heterocycles, preferably amines, more preferably C 3-10 Tertiary amine compounds of (C), in particular, the C 3-10 The tertiary amine compound of (2) is triethylamine; the organic solvent (B) is selected from C 1-3 Halogenated hydrocarbon solvents, nitrile solvents, ether solvents and C 2-5 Saturated carboxylic acid ester solvents of (C) are preferred 1-3 More preferably a halomethane solvent, in particular, dichloromethane;
the transition metal catalyst is selected from dichloro bis (4-cymene) ruthenium (II) ([ RuCl) 2 (p-cymene)] 2 ) Triruthenium dodecacarbonyl (Ru) 3 (CO) 12 ) Bis (triphenylphosphine) cyclopentadienyl ruthenium (II) chloride (Cp (PPh) 3 ) 2 RuCl), tris (triphenylphosphine) ruthenium (II) chloride (RuCl) 2 (PPh 3 ) 3 ) Ruthenium (II) dichloro tetra (triphenylphosphine) (RuCl) 2 (PPh 3 ) 4 ) And rhodium (III) dichloro (pentamethylcyclopentadienyl) ([ Rh (C) 5 Me 5 )Cl 2 ] 2 ) Preferably dichlorobis (4-cymene) ruthenium (II); the organic solvent (C) is selected from C 1-3 Saturated monohydric alcohols, ethereal solvents and amide solvents, preferably C 1-3 More preferably methanol; the alkali is selected from metal weak acid salt compounds and tertiary amine compounds, preferably tertiary amine compounds, in particular, the tertiary amine compounds are triethylamine; the hydrogen donor agent is selected from C 1-3 Carboxylic acids and hydrochloric acid, preferably C 1-3 More preferably formic acid.
The invention provides a method for preparing a dinafop sebacate (a compound shown in a formula (I)) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
stirring and reacting a compound shown in a formula (IV), methanol and cyclobutyl formaldehyde at 60-80 ℃, cooling to room temperature, adding a mixed solvent of triethylamine, methanol and formic acid and dichlorobis (4-cymene) ruthenium (II), and stirring and reacting at 60-80 ℃ to prepare a compound shown in a formula (III); wherein the molar ratio of triethylamine to the compound represented by formula (IV) is 2:1 to 5:1 (preferably 3:1 to 5:1); the molar ratio of the compound shown in the formula (IV) to the dichlorobis (4-cymene) ruthenium (II) is 1:0.002-1:0.005;
mixing a compound shown in a formula (III), triethylamine and dichloromethane, adding a mixed solvent of sebacoyl chloride and dichloromethane at a temperature of-25-40 ℃, for example, 0-25 ℃, preferably-20-10 ℃, and reacting to obtain a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof, wherein the molar ratio of the triethylamine to the compound shown in the formula (III) is 1:1-3:1; the molar ratio of the compound shown in the formula (III) to the sebacoyl chloride is 1.5:1-2:1;
Dissolving a compound shown in a formula (II) in a mixed solvent of acetonitrile and acetic acid, adding tetraacetoxy tetramethylammonium borohydride at the temperature of-5-10 ℃ and reacting to prepare the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, wherein the volume ratio of acetonitrile to acetic acid is 1:1-3:1; the molar ratio of tetramethylammonium triacetoxyborohydride to the compound of formula (II) is from 2:1 to 5:1, for example from 2:1 to 3:1.
Advantageous effects of the invention
Compared with the preparation method disclosed in the prior art, the preparation method of the dinafop-buprenorphine diacid ester shown in the formula (1) or the pharmaceutically acceptable salt thereof has the advantages that the starting materials are easy to obtain, the selectivity of the hydroxy esterification reaction is high, and the yield and the purity of the final product can be obviously improved. In particular to a novel preparation method of the dinafop-buprenorphine sebacate (a compound shown in a formula (I)) or the pharmaceutically acceptable salt thereof and a key intermediate (a compound shown in a formula (II) and a formula (III)) thereof, which can obviously improve the yield and the purity of a final product compared with the preparation method disclosed in the prior art. Compared with the prior art, the yield can reach 92% or higher, the purity reaches 98.8% or higher, the conversion rate is higher, and the subsequent purification difficulty and cost are reduced; in addition, the toxicity of the reagents used in the novel preparation method is low (the toxicity of triethylamine and methylene dichloride is lower than that of dimethylamine pyridine and di (2-pyridine) carbonate), the reaction time is obviously shortened (1 hour vs 18 hours), the method is environment-friendly, and is beneficial to large-scale medicine industrial production, the production cost and the production risk are obviously reduced, the labor protection requirement is low, the operability is strong, and the method is more suitable for industrial production.
Drawings
FIG. 1 shows an HPLC profile of the compound of formula III prepared in example 1;
FIG. 2 shows an HPLC profile of a compound of formula II prepared in method 6 of example 2;
FIG. 3 shows an HPLC profile of a compound of formula I prepared in method 2 of example 3;
FIG. 4 shows an HPLC profile of a compound of formula I prepared by the method of example 3.1.3;
FIG. 5 shows an HPLC profile of a crude compound of formula I prepared by the method of example 3.1.4;
FIG. 6 shows an HPLC profile of a crude compound of formula I prepared by the method of example 3.2.1;
FIG. 7 shows an HPLC profile of a crude compound of formula I prepared by the method of example 3.2.3;
FIG. 8 shows an HPLC profile of a crude compound of formula I prepared by the method of example 3.2.4.
Examples
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, the proportions, percentages, etc., referred to herein are by weight.
Test conditions of the instrument used for the experiment:
1. high performance liquid chromatography (High Performance Liquid Chromatograph, HPLC)
Instrument model: agilent 1260 (DAD) binary pump liquid chromatography
Chromatographic column: SHIMADZU VP-ODS C18 column (4.6X105 mm,5 μm)
Mobile phase:
a:0.01mol/L potassium dihydrogen phosphate, 1mol/L sodium octane sulfonate (pH adjusted to 4.2 with phosphoric acid)
B: acetonitrile
Flow rate: column temperature 0.8 ml/min: 40 DEG C
Wavelength: 278nm sample volume: 10 mu L
Gradient conditions (volume ratio):
raw materials and reagents used in the experiments:
the raw materials and reagents used in the patent are all commercially available, and the compound shown in the formula (IV) is purchased from Gansu pharmaceutical inspection plant Co.
Synthetic examples
Example 1 (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methylbenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one (Compound shown in formula (III))
Method 1
To a 1L single-necked flask, 14-hydroxydihydromorphone (20 g,1 eq) and absolute methanol (400 mL) were sequentially added, and nitrogen was replaced three times, 3eq of cyclobutyl formaldehyde was added, and the reaction was stirred at 70℃for 1 hour. The reaction solution was cooled to room temperature, 10eq of formic acid was slowly added to 100mL of anhydrous methanol of 4eq of triethylamine in another 250mL single-necked flask, stirred for 5 minutes, then added to the first single-necked flask, and a catalytic amount (113 mg) of bis (4-cymene) ruthenium (II) dichloride was added. The reaction was stirred at 70℃for 2.5 hours. After the reaction, saturated sodium bicarbonate (600 mL) and ethyl acetate (500 mL. Times.2) were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was slurried with ethyl acetate (50 mL) and filtered to obtain 20.8g of a pure white solid with a yield of 95% and a purity of 96.56%.
1 H NMR(400MHz,CDCl 3 )ppm 1.52-1.77(m,4H)1.81-2.00(m,3H)2.06-2.25(m,4H)2.26-2.45(m,2H)2.47-2.63(m,5H)2.83-3.06(m,2H)3.09(d,J＝18.4Hz,1H)4.68(s,1H)6.60(d,J＝8.4Hz,1H)6.72(d,J＝8.4Hz,1H)
Method 2
20g (0.07 mol,1 eq) of 14-hydroxydihydromorphone is dissolved in 180ml of methanol, 7.81g (0.085 mol,1.2 eq) of cyclobutyl formaldehyde is added, nitrogen is introduced, and the mixture is heated to an internal temperature of 60-65 ℃ and stirred for 1 hour. A vessel was prepared, 17.1g (0.37 mol,5.3 eq) of formic acid and 20ml of methanol were added thereto, the temperature was lowered to 0 to 5℃and 12.53g (0.124 mol,1.8 eq) of triethylamine formate was slowly dropped, a methanol mixed solution of triethylamine formate was added to the 14-hydroxydihydronormorphone reaction solution, and a catalytic amount of 0.11g (0.00018 mol, 0.003eq) of bis (4-methylisopropenyl) ruthenium (II) was added thereto, the internal temperature was raised to 65 to 68℃after the addition, the reaction was carried out for about 4 hours, HPLC monitoring was carried out, the reaction was completed, the reaction solution was concentrated at 40 to 45℃and pH=7 to 8 was adjusted with an aqueous sodium carbonate solution, 600ml of ethyl acetate was added for extraction, washing was carried out, and the organic phase was added to 2g of activated carbon, stirred for 1 hour, and then filtered and concentrated. After the concentration, 60ml of ethyl acetate is added, and the mixture is heated, refluxed, stirred, beaten and filtered to obtain 19.7g of off-white solid with the yield of 90 percent and the purity of 99.0 percent.
Method 3:
50.00g (0.155 mol,1.0 eq) of 14-hydroxydihydromorphone dihydrate is dissolved in 450mL of methanol, 10.50g (0.232 mol,1.5 eq) of cyclobutyl formaldehyde is added, nitrogen is introduced for deoxidization, the mixture is heated to an internal temperature of 60-65 ℃ and stirred for 1h, a container is additionally prepared, 42.65g (0.927 mol,6.0 eq) of formic acid and 50mL of methanol are added, the temperature is reduced to 0-10 ℃, 31.25g (0.309 mol,2.0 eq) of triethylamine is slowly added dropwise, a methanol mixed solution of triethylamine formate is quickly added to the 14-hydroxydihydromorphone reaction solution, and a catalytic amount of dichlorobis (4-methyl isopropyl phenyl) ruthenium (II) of 0.284g (0.00046 mol, 0.003eq) is added after the addition; raising the internal temperature to 60-65 ℃, reacting for 3.5h, and monitoring the reaction by HPLC; concentrating the reaction solution at 40-50 ℃; saturated aqueous sodium carbonate solution is added, stirred, filtered, extracted by adding 1.0L of dichloromethane, and added with active carbon, heated and refluxed, filtered by suction to obtain filtrate, concentrated, added with ethyl acetate for beating, filtered by suction, dried in vacuum to obtain 49.58g of off-white solid, the yield is 90%, and the purity is 99% (HPLC chart is shown in figure 1).
EXAMPLE 2 bis ((4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4 a-hydroxy-7-oxo-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methoxybenzofuran [3,2-e ] isoquinolin-9-yl) sebacate (Compound represented by formula (II))
Method 1
To a 1L single-necked flask were successively added (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methylbenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one (20 g,1 eq), 1.5eq triethylamine (8.56 g) and 100mL DCM, and replaced with nitrogen three times, and a dichloromethane solution (100 mL) of 0.55eq sebacoyl chloride (7.4 g) was added at 0℃and the reaction stirred at room temperature for 1 hour. After the reaction, aluminum oxide is added for filtration, and the filter cake is leached by methylene dichloride and then concentrated to obtain 23g of white solid product with the yield of 94%.
Method 2
To a 1L single-necked flask were successively added (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methylbenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one (20 g,1 eq), 1.5eq sodium carbonate (8.98 g) and 100mL acetonitrile, and replaced with nitrogen three times, and a methylene chloride solution (100 mL) of 0.55eq sebacoyl chloride (7.4 g) was added at 0℃and the reaction was stirred at room temperature for 1 hour. After the reaction, aluminum oxide is added for filtration, and the filter cake is leached by methylene dichloride and then concentrated to obtain 22.3g of white solid product with the yield of 91.1 percent.
Method 3
To a 1L single-necked flask were successively added (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methylbenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one (20 g,1 eq), 1.0eq DMAP (10.34 g) and 100mL tetrahydrofuran, and replaced with nitrogen three times, and a dichloromethane solution (100 mL) of 0.55eq sebacoyl chloride (7.4 g) was added at 0℃and the reaction was stirred at room temperature for 1 hour. After the reaction, aluminum oxide is added for filtration, and the filter cake is leached by methylene dichloride and then concentrated to obtain 19.4g of white solid product with the yield of 79.2 percent.
Method 4
To a 1L single-necked flask were successively added (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methylbenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one (20 g,1 eq), 1.5eq diisopropylethylamine (10.93 g) and 100mL ethyl acetate, and replaced with nitrogen three times, and a dichloromethane solution (100 mL) of 0.55eq sebacoyl chloride (7.4 g) was added at 0℃and the reaction was stirred at room temperature for 1 hour. After the reaction, aluminum oxide is added for filtration, and the filter cake is leached by methylene dichloride and then concentrated to obtain 23.3g of white solid product with the yield of 95.2 percent.
1 H NMR(400MHz,DMSO-d 6 )ppm 1.21-1.47(m,7H)1.56-1.72(m,4H)1.74-2.14(m,7H)2.34(td,J＝12.4,5.2Hz,1H)2.46(br.s.,2H)2.52-2.65(m,4H)2.80-2.96(m,2H)3.09(d,J＝19.07Hz,1H)4.84-5.11(m,2H)6.72(d,J＝8.4Hz,3H)6.78-6.86(m,1H)
Method 5
19g (0.053 mol,1 eq) of (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methoxybenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one 19g (0.053 mol,1 eq) was dissolved in 285ml of dichloromethane, 8.12g (0.008 mol,1.5 eq) of triethylamine was added, cooled to 0-5 ℃, 95ml of a solution of sebacoyl chloride 7.04g (0.0029 mol,0.55 eq) was added dropwise, the dropwise addition was maintained at 0-5 ℃ and ended at about 1H, the reaction was continued at 0 ℃ for 15min, 100ml of saturated ammonium chloride aqueous solution was added for two washes, and allowed to stand for delamination, organic coherence was concentrated to a semi-oily semi-solid state, 57ml of ethyl acetate was added, and then slowly added to 570ml (0-5 ℃) of cooled n-heptane, stirred for 2-3H, filtered, white solid was obtained, weighed, and dried, and 100% purity was 100% yield.
Method 6
10g (0.028 mol,1 eq) of (4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4a, 9-dihydroxy-2, 3, 4a,5, 6-hexahydro-1H-4, 12-methoxybenzofuran [3,2-e ] isoquinolin-7 (7 aH) -one (1 eq) is dissolved in 150mL of dichloromethane, 4.30g (0.042 mol,1.5 eq) of triethylamine is added, the temperature is reduced to-20 to-10 ℃, a solution of sebacoyl chloride (3.70 g (0.015 mol,0.55 eq) in 50mL of dichloromethane is added dropwise, and the reaction is continued at this temperature for 1H; monitoring the reaction completion of the raw materials by HPLC, and finishing the reaction; adding 200mL of saturated ammonium chloride aqueous solution, stirring, standing for layering, and concentrating the organic phase to a semi-oil semi-solid state; adding 10mL of acetone for dissolving and stirring, adding 200mL of methyl tertiary ether in batches, heating to 50-55 ℃ and stirring for 0.5h; filtering while hot, slowly cooling the filtrate to-10-0deg.C, precipitating a large amount of solid, filtering to obtain filter cake, and vacuum drying at 50deg.C to obtain 11.23g white solid with a yield of 98.9% and HPLC purity of 96.9% (shown in figure 2).
Example 2.1 temperature condition investigation experiment of the synthesis of the compound of formula (II) from the compound of formula (III):
with reference to the procedure of method 5 of example 2, the effect of different reaction temperatures on the purity of the product was examined, wherein the compound of formula III was dosed at 1.00g, sebacoyl chloride 0.55eq, triethylamine 1.5eq, solvent DCM (10 v/w) and the reaction time was 1.0-4.0 h (HPLC monitoring of the starting material reaction). The experimental results are shown in table 2.1.
TABLE 2.1 effects of different reaction temperatures on the product purity results
Numbering device Reaction temperature Compounds of formula III Compounds of formula II
2.1.1 -20～-10℃ 0.23％ 96.82％
2.1.2 0-10℃ 1.48％ 92.35％
2.1.3 20-25℃ 1.72％ 89.64％
2.1.4 30-40℃ 8.64％ 85.66％
As can be seen from Table 2.1, as the reaction temperature increases, the purity of the reaction target product decreases, wherein the reaction temperature is the optimum reaction temperature between-20 and-10 ℃, and at this time, both the reaction yield (95-100%) and the purity (HPLC. Gtoreq.96%) can be achieved, and the inventors have unexpectedly found that the reaction proceeds for about 1 hour under the temperature condition, and the raw materials can be reacted completely. When the reaction temperature is increased, in particular, to more than 40 ℃, the starting material (the compound represented by formula III) cannot be completely reacted even if the reaction time is prolonged. The compound shown in the formula II is used as a key intermediate of the dinafop-buprenorphine sebacate, the purity of the compound directly influences the quality control of the dinafop-buprenorphine sebacate, and the inventor finds that if the purity of the compound shown in the formula II is not high, particularly the compound shown in the formula III and/or a monoacylate are contained, the compound is extremely difficult to remove in the final product of the dinafop-buprenorphine sebacate, so that the prepared dinafop-buprenorphine sebacate bulk drug is difficult to meet the requirements of the quality standards related to drug registration.
The preparation method of the formula II, which is obtained by optimizing the process conditions, particularly optimizing the temperature and the feeding ratio, has the advantages of high purity, high yield and short reaction time of the prepared target product, and the prepared intermediate is used for preparing the dimaleate, so that the purity of the dimaleate bulk drug can be obviously improved.
Example 2.2 synthesis of compounds of formula (II) from compounds of formula (III):
with reference to the operating procedure of the method of example 2.1, the influence of different esterification reagents and different temperature conditions on the purity and yield of the product was examined,
the inventor replaces sebacoyl chloride in the operation steps of the method in example 2.1 with sebacoyl anhydride and sebacylic acid respectively, and conducts experimental study, and the research result shows that under the same reaction condition, the sebacoyl anhydride and the sebacylic acid can be used as esterification reagents to prepare the compound shown in the formula II, but the yield and the purity of the prepared compound shown in the formula II are superior to those of the sebacoyl anhydride and the sebacylic acid.
EXAMPLE 3 bis ((4R, 4aS,7S,12 bS) -3- (cyclobutylmethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methylbenzofuran [3,2-e ] isoquinolin-9-yl) sebacate (Compound of formula (I), dinafop-sebacate)
Method 1:
the compound bis ((4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4 a-hydroxy-7-oxo-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methoxybenzofuran [3,2-e ] isoquinolin-9-yl) sebacate (20 g,0.0248 mol) was dissolved in a mixed solution of acetonitrile (200 mL) and acetic acid (200 mL), and the mixture was stirred under nitrogen for 5 minutes to dissolve. The addition of tetra-methyl ammonium triacetoxyborohydride (18 g,0.0684 mol) was started at 0℃and the reaction was stirred for 1 hour after the addition was completed. The reaction solution was poured into a beaker, 300mL of water was added, 100mL of dichloromethane was separated, the aqueous phase was extracted 3 times with 100mL of dichloromethane, the organic phases were combined, the organic phases were washed twice with 100mL of saturated sodium bicarbonate solution and once with 100mL of saturated sodium chloride solution, the organic phases were dried and concentrated to give 18.4g of a white solid product, yield 92%, and HPLC showed a purity of 98.8%.
1 H NMR(400MHz,DMSO-d 6 )ppm 0.97-1.11(m,1H)1.27-1.40(m,6H)1.40-1.57(m,2H)1.58-1.71(m,4H)1.77-1.93(m,2H)1.95-2.19(m,4H)2.39-2.49(m,4H)2.53-2.67(m,3H)2.77(d,J＝6.0Hz,1H)3.05(d,J＝18.8Hz,1H)3.98-4.06(m,1H)4.23(d,J＝4.8Hz,1H)4.50(d,J＝4.2Hz,1H)4.79(s,1H)6.62(d,J＝8.4Hz,1H)6.78(d,J＝8.4Hz,1H)。
Method 2:
the compound bis ((4R, 4aS,7aR,12 bS) -3- (cyclobutylmethyl) -4 a-hydroxy-7-oxo-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methoxybenzofuran [3,2-e ] isoquinolin-9-yl) sebacate prepared in example 2, method 6 was dissolved in a mixed solution of acetonitrile (300 mL) acetic acid (100 mL), and the solution was purged with nitrogen. The reaction system was cooled to 0-10℃and was started to add 13.2g (0.05 mol,2 eq) of tetra-methyl ammonium triacetoxyborohydride, the temperature was controlled to 20-30℃and after the reaction was completed, the reaction solution was added to 300mL of water, 100mL of methylene chloride was added for extraction, the organic phases were combined, the organic phases were washed with 100mL of saturated sodium bicarbonate solution and then with 100mL of saturated sodium chloride solution, and the organic phases were dried and concentrated to give a product as a white solid 18g, yield 88.8% and HPLC showed a purity of 99.6% (as shown in FIG. 3).
Example 3.1 reducing agent equivalent investigation experiment for the Synthesis of Compounds of formula (I) from Compounds of formula (II):
acetonitrile (5.0 v/w) is added into a reaction bottle at room temperature, stirring is started, a compound II (1.00 g,1.0 eq) is added into the reaction bottle, after dissolution, the reaction system is cooled to 0-10 ℃, acetic acid (5.0 v/w) is added into the reaction system, tetramethyl triacetoxy ammonium borohydride is weighed, the reaction solution is added in batches, the temperature is controlled to 0-10 ℃, after the addition, the temperature is raised to 25+/-5 ℃ for reaction for 20 hours. The reaction mixture was added to water (30.0 v/w), and sodium carbonate was added to adjust the pH to 8-9, and stirred for 1 hour until the pH was unchanged, and samples were taken for HPLC purity measurement, and the measurement results are shown in Table 3.1.
Table 3.1 different reducing agent equivalents, purity of target product I in the reaction solution tested:
numbering device Reducing agent equivalent I (crude purity)
3.1.1 2.5eq 44.34％
3.1.2 3eq 67.83％
3.1.3 3.5eq 94.05％
3.1.4 4eq 93.75％
From the above experiments, the reducing agent equivalent is above 2.5eq, preferably greater than 3eq, the conversion is higher, the product impurities are fewer, particularly preferably around 3.5eq, for example when the reducing agent equivalent is 3.5 and 4, the crude product of formula I is obtained with HPLC purities of 94.05% (as shown in fig. 4) and 93.75% (as shown in fig. 5), respectively.
The crude products obtained by experiments with the numbers of 3.1.3 and 3.1.4 are purified according to the similar post-treatment method of the method 1 of the example 3, and the purity of the obtained dinafop sebacate (the compound of the formula I) is more than 99 percent.
Example 3.2 temperature condition investigation experiment for the synthesis of the compound of formula (I) from the compound of formula (II):
the reaction was examined at various reaction temperatures according to the reaction procedure and operating conditions of the previous example 3.1 at a reducing agent equivalent of 3.5eq, and the results are shown in the following table 3.2.
Table 3.2 effect of reaction temperature on experimental results:
numbering device Reaction temperature (. Degree. C.) I (crude purity) HPLC chart
3.2.1 0-10 92.80％ FIG. 6
3.2.2 20-30 94.05％ FIG. 4
3.2.3 35-40 92.50％ FIG. 7
3.2.4 50-60 93.03％ FIG. 8
From the above experimental results and FIGS. 4, 6-8, it can be seen that the reaction temperature can be selected between-10 and 60℃and that the conversion of formula (II) will be more complete at 0-30℃with relatively fewer product impurities. Too high a reaction temperature does not favor the improvement of the conversion rate of raw materials and the purity of products.
The inventors have further studied and found that the experimentally obtained formula I, numbered 3.2.2, is more prone to remove impurities during subsequent purification, and that the purity of the resulting dimibuprine sebacate (compound of formula I) is above 99% after purification according to a similar post-treatment method as described in method 1 of example 3 above.
Comparative example 1 preparation of Dinalbuphine sebacate Using nalbuphine hydrochloride as starting Material
Method 1
Specific preparation method the preparation was carried out as described in example 16 of patent TW399056B, with a yield of 43% for the buprenorphine sebacate, with an HPLC purity of 73.4% and with more buprenorphine sebacate monoester produced in the reaction, which is more difficult to remove.
Method 2
Specific preparation method the preparation was carried out as described in example 15 of patent TW399056B, with a yield of 57% for the buprenorphine sebacate, with an HPLC purity of 80.1% and with more buprenorphine sebacate monoester produced in the reaction, which is more difficult to remove.
Test results: in the novel preparation process of the nalbuphine sebacate, the compound shown in the formula (III) is used as a starting material for esterification to prepare the compound shown in the formula (II), and the compound shown in the formula (II) is reduced to prepare the dimaleate, compared with the method described by TW399056B, the method not only remarkably improves the yield and purity of the final product (92% vs 43-57%, 98.8% vs 73.4-80.1%), but also has mild and controllable reaction conditions, the toxicity of the used reagent is lower (the toxicity of triethylamine and dichloromethane is lower than that of the dimethylaminopyridine and the di (2-pyridine) carbonate), the reaction time (vs 18 hours) is remarkably shortened, and the method is not only green and environment-friendly, but also is beneficial to large-scale medicine industrial production, remarkably reduces the production cost and reduces the production risk.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims (11)

  1. A process for the preparation of a compound of formula (2) or a pharmaceutically acceptable salt thereof, comprising:
    the compound shown in the formula (III) is subjected to esterification reaction with an esterification reagent in an organic solvent (B) under the action of Lewis base, so that a compound shown in the formula (2) is prepared;
    wherein:
    in the compound represented by the formula (2), n is an integer of 3 to 10, preferably n is 6;
    the esterifying reagent is selected from dicarboxylic acid HOOC-CH 2 -(CH 2 ) n -CH 2 -COOH, dibasic acid anhydrideOr binary acyl chloride ClOC-CH 2 -(CH 2 ) n -CH 2 -COCl, wherein n is an integer from 3 to 10, preferably n is 6, in the dicarboxylic acids, dicarboxylic anhydrides and dicarboxylic chlorides; preferably, the esterification reagent is binary acyl chloride ClOC-CH 2 -(CH 2 ) n -CH 2 -COCl；
    The Lewis base is selected from metal weak acid salt compounds, amine and C 1-3 Optionally substituted alkyl containing heterocycles, preferably amines;
    the organic solvent (B) is selected from C 1-3 Halogenated hydrocarbon solvents, nitrile solvents, ether solvents and C 2-5 Saturated carboxylic acid ester solvents of (C) are preferred 1-3 Is a halogenated hydrocarbon solvent.
  2. The process for producing a compound represented by the formula (2) or a pharmaceutically acceptable salt thereof according to claim 1,
    the metal weak acid salt compound is selected from alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, alkali metal monohydrogen phosphate, alkali metal dihydrogen phosphate, alkali metal acetate, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium acetate, potassium acetate, and cesium carbonate, more preferably sodium carbonate and potassium carbonate;
    The amine compound is selected from C 1-5 Primary amine compound of (C) 2-10 Secondary amine compounds and C 3-10 Tertiary amine compounds of (C) are preferred 3-10 More preferably trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-dimethylethylamine, and tetramethylethyl amineDiamine or tetramethylpropanediamine, in particular, the C 3-10 The tertiary amine compound is triethylamine, tetramethyl ethylenediamine or diisopropylethylamine;
    the amine, C 1-3 Optionally substituted nitrogen-containing heterocycles selected from the group consisting of pyridine, piperidine, 4-dimethylaminopyridine, N-methylmorpholine, pyrrolidine, triethylenediamine (DBACO) and 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU), preferably 4-dimethylaminopyridine and DBU;
    the C is 1-3 The halogenated hydrocarbon solvent of (2) is selected from halogenated methane solvents selected from dichloromethane and tetrachloromethane, preferably dichloromethane;
    the nitrile solvent is selected from acetonitrile and propionitrile, preferably acetonitrile;
    the ether solvent is selected from tetrahydrofuran, methyl tertiary butyl ether, dioxane, tertiary butyl ether, n-butyl ether and tetrahydropyran, preferably tetrahydrofuran and methyl tertiary butyl ether;
    the C is 2-5 The saturated carboxylic acid ester solvent of (a) is selected from methyl formate, methyl acetate, ethyl formate, ethyl acetate, propyl formate, methyl propionate, ethyl propionate and propyl acetate, preferably ethyl acetate.
  3. The process for the preparation of a compound of formula (2) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the molar ratio of lewis base to compound of formula (III) is selected from 1:1 to 10:1, preferably 1:1 to 5:1, more preferably 1:1 to 3:1; the molar ratio of the compound shown in the formula (III) to the esterifying reagent is selected from 1:1-2:1, preferably 1.5:1-2:1.
  4. A process for the preparation of a compound of formula (2) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein a specific reaction temperature is required to be maintained at the time of addition of the esterifying reagent, said reaction temperature being selected from the group consisting of-25 to 40 ℃, preferably-5 to 30 ℃, more preferably-20 to-10 ℃.
  5. A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:
    mixing a compound shown in a formula (III), a Lewis base and an organic solvent, and adding the mixture of sebacoyl chloride and the organic solvent at-25-40 ℃, preferably-20-10 ℃ to react to obtain a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof, wherein the molar ratio of the Lewis base to the compound shown in the formula (III) is 1:1-3:1; the molar ratio of the compound shown in the formula (III) to the sebacoyl chloride is 1.5:1-2:1;
    the organic solvent is selected from acetonitrile, ethyl acetate, tetrahydrofuran, methyl tertiary butyl ether and dichloromethane, preferably dichloromethane;
    The lewis base is selected from sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine or 4-dimethylaminopyridine, preferably triethylamine.
  6. The production method according to any one of claims 1 to 5, wherein the compound represented by the formula (III) is produced by a method comprising:
    the compound shown in the formula (IV) is subjected to reductive amination reaction with cyclobutyl formaldehyde in an organic solvent (C) under the action of a transition metal catalyst, alkali and a hydrogen donor agent to prepare a compound shown in the formula (III);
    wherein:
    the transition metal catalyst is selected from dichloro bis (4-cymene) ruthenium (II), dodecacarbonyl triruthenium, bis (triphenylphosphine) cyclopentadienyl ruthenium (II) chloride, tris (triphenylphosphine) ruthenium (II) chloride, dichloro tetrakis (triphenylphosphine) ruthenium (II) and dichloro (pentamethyl cyclopentadienyl) rhodium (III), preferably dichloro bis (4-cymene) ruthenium (II);
    the organic solvent (C) is selected from C 1-3 Saturated monohydric alcohol solvents, ether solvents and amide solvents; preferably, the C 1-3 The saturated monohydric alcohol is selected from methanol, ethanol and isopropanol, more preferably methanol and ethanol; preferably, the ethereal solvent is selected from Tetrahydrofuran (THF), methyl tert-butyl ether, dioxane, tert-butyl ether, n-butyl ether and tetrahydropyran, more preferably tetrahydrofuran and methyl tert-butyl ether; preferably, the amide-based solvent is selected from the group consisting of N, N-Dimethylacetamide (DMAC) and N, N-Dimethylformamide (DMF), more preferably DMF;
    The alkali is selected from metal weak acid salt compounds and tertiary amine compounds; preferably, the metal weak acid salt compound is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal monohydrogenphosphates, alkali metal dihydrogenphosphates, alkali metal acetates, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium monohydrogenphosphate, sodium dihydrogenphosphate, sodium phosphate, potassium monohydrogenphosphate, potassium dihydrogenphosphate, potassium phosphate, sodium acetate, potassium acetate and cesium carbonate, more preferably sodium carbonate and potassium carbonate; preferably, the tertiary amine compound is selected from C 3-10 Tertiary amine compound of (C) 3-10 The tertiary amine compound of (2) is selected from trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-dimethylethylamine, tetramethyl ethylenediamine or tetramethyl propylenediamine, preferably triethylamine, tetramethyl ethylenediamine or diisopropylethylamine;
    the hydrogen donor agent is selected from C 1-3 Carboxylic acid, hydrochloric acid and boric acid; preferably, the C 1-3 The carboxylic acid of (a) is selected from formic acid, acetic acid, oxalic acid and propionic acid, preferably formic acid or acetic acid.
  7. The method according to claim 6, wherein,
    the base is selected from sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethyl ethylenediamine and trimethylamine, preferably triethylamine;
    The organic solvent (C) is selected from methanol, ethanol, isopropanol, THF and DMF, preferably methanol or THF;
    the hydrogen donor agent is selected from formic acid, acetic acid and hydrochloric acid, preferably formic acid;
    the molar ratio of the base to the compound of formula (IV) is selected from 1:1 to 10:1, preferably 2:1 to 5:1;
    the molar ratio of the compound shown in the formula (IV) to the transition metal catalyst is selected from 1:0.001-1:0.03, preferably 1:0.001-1:0.005.
  8. A process for preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof, comprising the steps of:
    the compound shown in the formula (2) is subjected to reduction reaction in an organic solvent (A) under the action of acid and a reducing agent to prepare a compound shown in the formula (1);
    wherein:
    in the compound represented by the formula (1), n is an integer of 3 to 10, preferably n is 6;
    in the compound represented by the formula (2), n is an integer of 3 to 10, preferably n is 6;
    the reducing agent is an acyloxyborohydride compound; preferably, the acyloxyborohydride compound is selected from the group consisting of acyloxy ammonium borohydride compounds, acyloxy sodium borohydride compounds, acyloxy potassium borohydride compounds, and acyloxy lithium borohydride compounds, preferably acyloxy ammonium borohydride compounds;
    The organic solvent (A) is selected from nitrile solvents, C 2-5 Saturated carboxylic ester solvent, benzene solvent, ether solvent, C 1-3 Saturated monohydric alcohol solvent and C 1-3 Preferably a nitrile solvent;
    optionally, the method further comprises a step of preparing a compound shown in a formula (2), wherein the preparation method of the compound shown in the formula (2) is as set forth in any one of claims 1 to 4;
    preferably, a specific reaction temperature is maintained at the time of adding the reducing agent, said reaction temperature being selected from-10 to 60 ℃, preferably-10 to 30 ℃, more preferably 0 to 10 ℃.
  9. The method for producing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to claim 8,
    the acyloxy ammonium borohydride compound is selected from the group consisting of triacetoxy ammonium borohydride compound, tripropionoyloxy ammonium borohydride compound, tributyloxy ammonium borohydride compound and tripentyloxy ammonium borohydride compound, preferably triacetoxy ammonium borohydride compound, more preferably triacetoxy tetramethyl ammonium borohydride, triacetoxy tetraethyl ammonium borohydride, triacetoxy tetrapropylammonium borohydride and triacetoxy tetrabutyl ammonium borohydride;
    the nitrile solvent is selected from acetonitrile and propionitrile, preferably acetonitrile;
    The C is 2-5 The saturated carboxylic acid ester solvent of (a) is selected from methyl formate, methyl acetate, ethyl formate, ethyl acetate, propyl formate, methyl propionate, ethyl propionate and propyl acetate, preferably ethyl acetate;
    the benzene solvent is selected from toluene, ethylbenzene, 1, 2-xylene and 1, 3-xylene, preferably toluene;
    the C is 1-3 The halogenated hydrocarbon solvent of (2) is selected from halogenated methane solvents selected from dichloromethane and tetrachloromethane, preferably dichloromethane;
    the ether solvent is selected from tetrahydrofuran, methyl tertiary butyl ether, dioxane, tertiary butyl ether, n-butyl ether and tetrahydropyran, preferably tetrahydrofuran or methyl tertiary butyl ether;
    the saturated monohydric alcohol is selected from methanol, ethanol and isopropanol, preferably methanol or ethanol;
    the acid is selected from inorganic acid or organic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid, preferably hydrochloric acid; the organic acid is selected from C 1-3 Saturated carboxylic acids of (2).
  10. A process for producing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to any one of claim 8 to 9,
    the acid is selected from formic acid, acetic acid, oxalic acid and malonic acid, preferably acetic acid;
    the organic solvent (a) is selected from acetonitrile, ethyl acetate, tetrahydrofuran, toluene and dichloromethane, preferably acetonitrile;
    The volume ratio of the organic solvent (A) to the acid is selected from 0.5:1 to 9:1, preferably 1:1 to 5:1, more preferably 1:1 to 3:1;
    the molar ratio of the reducing agent to the compound of formula (2) is selected from 1:1 to 5:1, preferably 2:1 to 5:1.
  11. Compounds of formula (2)Wherein n is an integer of 3 to 10;
    preferred compounds are those of formula (II)
CN202280021384.8A 2021-03-15 2022-03-10 Preparation method of nalbuphine sebacate and intermediate thereof Pending CN117083277A (en)

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