CN108264499B - Preparation method of benzodiazepine derivative - Google Patents
Preparation method of benzodiazepine derivative Download PDFInfo
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- CN108264499B CN108264499B CN201810003775.2A CN201810003775A CN108264499B CN 108264499 B CN108264499 B CN 108264499B CN 201810003775 A CN201810003775 A CN 201810003775A CN 108264499 B CN108264499 B CN 108264499B
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a benzodiazepine
A preparation method of the derivative. Specifically, the invention relates to a method for preparing a compound shown in a formula (III) from a starting material compound shown in a formula (V), preparing a compound shown in a formula (II) after continuous reaction, and finally obtaining a benzodiazepine shown in a formula (I)
A process for the preparation of derivatives, pharmaceutically acceptable salts thereof and intermediates in the preparation and a process for the preparation thereof. The method shortens the reaction steps, improves the reaction yield, is simple and easy to control, and is beneficial to industrial expanded production, and the specific preparation method is as follows:
Description
Technical Field
The invention relates to a benzodiazepine
A preparation method of the derivative.
Background
The chemical name of the compound of formula (Ia) is (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives
-4-yl) propionic acid methyl ester,
patent WO0069836A1 reports on carboxylic acid esters and benzodiazepines
The structured compounds are short-acting Central Nervous System (CNS) inhibitors with sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. They can be used for intravenous administration in clinical treatment regimens: pre-operative sedation, anxiolytic and amnesic uses such as during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics; ICU tranquilization, etc. WO0069836A1 and WO2013029431A1 disclose a benzodiazepine
The preparation method of the derivative and the tosilate thereof comprises the following steps:
according to the method, reactants used in the preparation of the compound shown in the formula (4) need to be subjected to coupling reaction under a heating reflux condition and ring closure reaction under a basic condition, and an acid is added to remove a protecting group Fmoc, so that the yield is 55%; when the compound shown in the formula (6) is prepared, an inert gas protection reaction system is not carried out, the used strong base deprotonating agent is sodium hydride, and the yield is only 37%; the addition of DMSO, oxalyl chloride and methylene chloride used in the preparation of the compound of formula (Ia) is direct mixing, which is disadvantageous for industrial scale-up.
WO2011032692A1 discloses another benzodiazepine
The preparation method of the derivative comprises the following steps:
the method uses the starting reactants in the preparation of the compound shown as the formula (D)tBoc-Glu (OMe) -OH, reacting under the action of coupling agent DCC to obtain a compound shown in a formula (B), adding hydrochloric acid to remove Boc protecting group to obtain a compound shown in a formula (C), adding sodium bicarbonate to carry out cyclization reaction to obtain a compound shown in a formula (D), reacting with dimorpholinyl phosphinic chloride under the action of deprotonation reagent to obtain a compound shown in a formula (E), reacting with R-isopropanolamine with single configuration to obtain a compound shown in a formula (F), reacting with 1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoacyl-3 (1H) ketone (Dess-martin oxidant, Dess-Martinperiodinane) to obtain a compound shown in a formula (G), and adding hydrochloric acid to carry out cyclization reaction to obtain a compound shown in a formula (Ia); among them, isopropanolamine used in the reaction for preparing the compound represented by the formula (F) has a single R configuration, the yield is 56%, the chemical purity of the reaction for preparing the compound represented by the formula (Ia) is 93.91%, and the purity of the product obtained by the reaction with the single configuration R-isopropanolamine is low, so that there is a need for improving the existing preparation method.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing the compound shown in the formula (Ia), wherein the purity and the yield of the product are improved by changing the starting raw materials to improve the yield of an intermediate, optimizing reaction conditions such as reaction temperature and the like, and changing post-treatment methods and other ways; the method is simple and easy to control, reactants such as starting materials are simple and easy to purchase, the reaction conditions are simple and controllable, the post-reaction treatment method is simple, the reaction yield is obviously improved, and the method is beneficial to industrial expanded production.
The technical scheme of the invention is as follows:
the invention provides a method for preparing a compound shown as a formula (III), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which is characterized by comprising the following steps:
the first step is that the compound shown in the formula (V) reacts with (2-amino-5-bromophenyl) (pyridine-2-yl) ketone in the presence of a coupling agent to obtain a compound shown in the formula (IV),
the second step is that the compound shown in the formula (IV) reacts under the alkali condition to obtain the compound shown in the formula (III),
wherein the content of the first and second substances,
r is hydrogen or an amino protecting group;
the amino protecting group is preferably an alkoxycarbonyl amino protecting group, an acyl amino protecting group, a sulfonyl amino protecting group or an alkyl amino protecting group,
the alkoxycarbonyl amino protecting group is selected from benzyloxycarbonyl (Cbz), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsiloxyethoxycarbonyl (Teoc), methoxycarbonyl or ethoxycarbonyl;
the acyl amino protecting group is selected from phthaloyl (Pht), trifluoroacetyl (Tfa), pivaloyl, benzoyl, formyl or acetyl;
the sulfonyl amino protecting group is selected from p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrobenzenesulfonyl (p-Ns);
the alkyl amino protecting group is selected from trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn).
In a preferred embodiment of the present invention, R is selected from an alkoxycarbonyl amino-protecting group, preferably benzyloxycarbonyl (Cbz), fluorenyl-methoxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), more preferably fluorenyl-methoxycarbonyl (Fmoc).
Preferably, the method is
More preferably, the method is
In the above scheme, the coupling agent of the first step reaction is selected from Dicyclohexylcarbodiimide (DCC), 2- (7-benzotriazole oxide) -N,n ', N' -tetramethyluronium Hexafluorophosphate (HATU), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl), propylphosphoric anhydride (T)3P), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop), N' -Carbonyldiimidazole (CDI), N-Diisopropylcarbodiimide (DIC) or isobutyl chloroformate, preferably Dicyclohexylcarbodiimide (DCC).
In the above scheme, the second step reaction is a cyclization reaction and a deprotection reaction under the condition of adding alkali into an organic solvent or a mixed organic solvent,
the organic solvent is selected from halogenated hydrocarbon solvents, ether solvents, amide solvents, nitrile solvents or alcohol solvents, the halogenated hydrocarbon solvents are preferably dichloromethane or chloroform, the ether solvents are preferably tetrahydrofuran or diethyl ether, the amide solvents are preferably N, N-dimethylformamide, the nitrile solvents are preferably acetonitrile, the alcohol solvents are preferably methanol or ethanol, the organic solvent mixture is selected from mixed solvents consisting of alcohols, ethers and nitrile solvents or mixed solvents consisting of halogenated hydrocarbons and nitriles, the organic solvent is preferably dichloromethane, the mixed organic solvent is preferably methanol/1, 4-dioxane/acetonitrile or dichloromethane/acetonitrile, the base is selected from morpholine, N-methylmorpholine, diisopropylethylamine, triethylamine, N-dimethylaniline, pyridine or alkali metal bicarbonate, preferably morpholine or triethylamine, the alkali metal bicarbonate is preferably sodium bicarbonate.
The invention also provides a method for preparing the compound shown as the formula (II), the pharmaceutically acceptable salt thereof or the stereoisomer thereof, which is characterized by comprising the following steps:
the first step of reaction is to react a compound shown as a formula (III) with dimorpholinyl phosphinic chloride in the presence of lithium bis (trimethylsilyl) amide (LiHMDS) to obtain a compound shown as a formula (II'),
the second step of reaction is to react the compound shown in the formula (II') with isopropanolamine to obtain the compound shown in the formula (II).
The method also comprises a step of adding acid for post-treatment, wherein the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and is more preferably hydrochloric acid; extracting the aqueous phase with organic solvent and then with saturated NaHCO3Aqueous solution, saturated NH4And washing the Cl aqueous solution and the purified water, and drying, filtering and concentrating the organic phase to obtain the product.
The above method further comprises a step of preparing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the compound shown in the formula (II) is firstly subjected to oxidation reaction and then subjected to cyclization reaction under acidic condition to obtain the compound shown in the formula (I), and the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and more preferably p-toluenesulfonic acid.
Preferably, the method is
In the scheme, the compound shown in the formula (IIIa) is dissolved in an organic solvent, lithium bis (trimethylsilyl) amide (LiHMDS) is added at a low temperature, stirring is carried out, dimorpholinyl phosphinic chloride is added, stirring and reacting are carried out at a low temperature, isopropanolamine is added, after the reaction is finished, a dilute hydrochloric acid aqueous solution is added into a reaction solution, a water phase is extracted by the organic solvent, and after an organic phase is dried, the organic phase is filtered and concentrated to obtain a product; the organic solvent is selected from ether organic solvents, and the ether organic solvent is preferably tetrahydrofuran.
In the scheme, dimethyl sulfoxide is added, oxalyl chloride is added at low temperature, stirring is carried out, a dichloromethane solution of the compound shown in the formula (II) is added, stirring is carried out, triethylamine is added, washing, drying, filtering and concentrating are carried out, the obtained residue is dissolved in an organic solvent, cyclization reaction is carried out under an acidic condition, and the compound shown in the formula (I) is obtained through concentration, washing, drying, filtering, concentrating and column chromatography purification; the organic solvent is selected from alcohols or ester solvents, the alcohols solvent is preferably methanol, and the ester solvent is preferably ethyl acetate; the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, more preferably p-toluenesulfonic acid.
The present invention further provides a method for preparing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the method comprises the steps of:
reacting a compound shown as a formula (V) with (2-amino-5-bromophenyl) (pyridine-2-yl) methanone in the presence of a coupling agent to obtain a compound shown as a formula (IV), reacting the compound shown as the formula (IV) under a base condition to obtain a compound shown as a formula (III), preferably morpholine, reacting the compound shown as the formula (III) with dimorpholinyl phosphinic chloride in the presence of bis (trimethylsilyl) lithium amide (LiHMDS) base to obtain a compound shown as a formula (II '), reacting the compound shown as the formula (II') with tert-butanolamine to obtain a compound shown as a formula (II), and cyclizing the compound shown as the formula (II) under an acidic condition firstly through an oxidation reaction to obtain a compound shown as a formula (I), preferably p-toluenesulfonic acid.
Preferably, the method is
More preferably, the method is
The invention also provides a method for preparing a pharmaceutically acceptable salt of the compound shown in the formula (Ia), which comprises the steps in the scheme and a step of preparing the pharmaceutically acceptable salt by reacting the compound shown in the formula (Ia) with acid, wherein the acid is selected from organic acid or inorganic acid, preferably organic acid; the organic acid is selected from acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
Detailed Description
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "amino protecting group" in the present invention refers to a group capable of protecting an amino group from reaction, and common amino protecting groups include, but are not limited to: formates (prepared by reacting amino with chloroformate, diazoformate or various carbonates), imines (prepared by reacting primary amine with aromatic aldehyde, aromatic ketone or aliphatic ketone), alkoxycarbonyls (prepared by reacting benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), methoxycarbonyl or ethoxycarbonyl), acyl (prepared by reacting amino with acyl chloride or anhydride, such as phthaloyl (Pht), trifluoroacetyl (Tfa), pivaloyl, benzoyl, formyl or acetyl), sulfonyls (aromatic sulfonamides such as p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrobenzenesulfonyl (p-Ns)) or alkyls (trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), P-methoxybenzyl (PMB) or benzyl (Bn)), wherein the terms "alkoxycarbonyl group, acyl group, and sulfonyl group" refer to R-O-C (O) -, R-S (O))2-, where R may be a hydrogen atom, an alkaneA group such as a phenyl group or an aryl group.
As used herein, "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 8 membered aryl group, more preferably a phenyl, anthracenyl or phenanthrenyl group.
The term "halo" as used herein means substituted with a "halogen atom" which means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.
The "alkyl" as used herein refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms, including, for example, "C1-6Alkyl group "," C1-4Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
The "amide organic solvent" in the present invention means that the hydroxyl group in the carboxyl group of the carboxylic acid molecule is substituted by an amino group or a hydrocarbylamino group (-NHR or-NR)2) A liquid compound resulting from substitution; can also be regarded as a liquid compound in which hydrogen on a nitrogen atom in ammonia or an amine molecule is substituted with an acyl group; specific examples include, but are not limited to: n, N-dimethylformamide, N-dimethylacetamide.
The "ether solvent" according to the present invention refers to a chain compound or a cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: propylene glycol methyl ether, tetrahydrofuran or 1, 4-dioxane.
The "ester solvent" according to the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.
The "alcoholic solvent" of the present invention refers to a group derived by substituting one or more hydrogen atoms on an "alkyl" group, as defined above, with one or more "hydroxy groups", and specific examples include, but are not limited to: methanol, ethanol, ethylene glycol, n-propanol or 2-propanol.
The "halogenated hydrocarbon solvent" in the present invention refers to a group derived by substituting one or more "halogen atoms" for one or more hydrogen atoms on an "alkyl group", wherein the "halogen atoms" and the "alkyl group" are as defined above, and specific examples include, but are not limited to: methyl chloride, dichloromethane, chloroform or carbon tetrachloride.
The "nitrile solvent" of the present invention refers to a group derived by substituting one or more hydrogen atoms of an "alkyl" group, as defined above, with one or more "cyano groups", and specific examples include, but are not limited to: acetonitrile or propionitrile.
The mixed solvent is a solvent formed by mixing one or more different organic solvents according to a certain proportion, or a solvent formed by mixing an organic solvent and water according to a certain proportion.
Advantageous effects of the invention
Compared with the prior art (WO0069836A1, published as 2000-11-23; WO2011032692A1, published as 2011-03-24), the technical scheme for preparing the compound shown in the formula (I) has the following advantages:
different from the starting raw materials in the prior art, the coupling reaction step in the process of preparing the compound of the formula (III) is simple, the ring-closing reaction and the deprotection reaction conditions can be carried out under the same conditions, and the obtained compound of the formula (III) has high purity; the post-treatment step of an intermediate is avoided in the step of preparing the compound of the formula (II), and the yield is improved on the premise of ensuring the purity; the invention shortens the reaction steps, avoids a multi-step post-treatment method, and has simpler operation method and easier operation compared with the prior art.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The experimental method of the present invention, in which the specific conditions are not specified, is generally carried out under the conventional conditions or the conditions recommended by the manufacturers of the raw materials or the commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift () at 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-500 NMR spectrometer using deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using FINNIGAN LCQ (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQDECA XPMAX).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Agilent Plus C18150X 4.6mm column).
Example 1, (S) -3- (7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [ e ]][1,4]Diaza derivatives
Preparation of methyl (3-yl) propionate
First step of
(2-amino-5-bromophenyl) (pyridin-2-yl) methanone
Tetrahydrofuran (44mL) is added into a reaction bottle, n-butyllithium (51mL) is added at-40 ℃, the internal temperature is controlled not to exceed-20 ℃, the temperature is reduced to-40 ℃, 2-bromopyridine (15.8g) is slowly dripped, the temperature is kept for 1 hour after dripping, a solution of 2-amino-5-bromo-benzoic acid (6.7g) dissolved in tetrahydrofuran (44mL) is dripped at the temperature below-40 ℃, and the temperature is naturally raised to about 0 ℃ after dripping for 3 hours. Slowly dropping saturated ammonium chloride solution (11mL) at the internal temperature of below 10 ℃, stopping the reaction, adding water (50mL), standing, separating, taking an organic layer, extracting an aqueous layer with ethyl acetate (50mL), combining the organic layers, washing with saturated sodium chloride aqueous solution (40mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain an oily substance, purifying by column chromatography (eluent PE: EA is 3:1-1:1, volume ratio), collecting the positive component, and concentrating to obtain a solid product (4.37g, yield 50.7%).
Second step of
(S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5- ((4-bromo-2-pyridinylphenyl) amino) -5-oxopentane
Acid methyl ester
Adding (2-amino-5-bromophenyl) (pyridine-2-yl) ketone (4g) and Fmoc-L-glutamic acid methyl ester (6.2g) into a reaction bottle, dissolving the mixture into dichloromethane (50mL), cooling to-10 ℃, dropwise adding a dichloromethane (8mL) solution of 1, 3-dicyclohexylcarbodiimide (3.0g), controlling the temperature to be-10 ℃ to-5 ℃, preserving the temperature to be-5 ℃ to 0 ℃ for reaction for 48 hours, filtering, concentrating the filtrate under reduced pressure to obtain an oily substance to obtain a crude product, and directly putting the crude product into the next step.
The third step
(S) -3- (7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [ e)][1,4]Diaza derivatives
-3-yl) propionic acid methyl ester
Adding 20% morpholine/dichloromethane (35mL) into the oily substance, stirring for dissolving, reacting at room temperature for about 20 hr, washing with water four times after the reaction is finished, washing with morpholine, drying, concentrating, and performing column chromatography (eluent: CH)2Cl2→CH2Cl2:CH3OH 100: 1-50: 1 by volume) to give crude product (3.7g, 63.7% yield, HPLC)>96%), isopropanol (15mL) was added and heated to a clear solution, crystallized at room temperature with stirring, and filtered to give the desired product (2.8g, 48.2% yield, HPLC: 99.84%).
Example 2, (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives
Preparation of (E) -4-yl) propionic acid methyl ester
First step of
3- ((3S) -7-bromo-2- ((2-hydroxypropyl) amino) -5- (pyridin-2-yl) -3H-benzo [ e][1,4]Diaza derivatives
-3-yl) propionic acid methyl ester
Under the protection of argon, adding phosphorus oxychloride (1.2kg) into toluene (6.4kg) in a reaction bottle, stirring to dissolve, cooling to 5 ℃, and dripping morpholine (2.68kg) into the reaction bottle within 2h, wherein the temperature is controlled to be not more than 20 ℃. After dropping, the reaction was carried out at room temperature for 3 hours. Filtering insoluble substances, washing with toluene for three times (1kg × 3), combining filtrates, concentrating under reduced pressure to obtain oily substance, adding toluene (1.92kg), heating to dissolve uniformly, adding petroleum ether (860g) under stirring (if insoluble substances exist, filtering while hot), adding petroleum ether (3.48kg), cooling to room temperature, filtering, washing filter cake with petroleum ether (1.2kg × 2), drying under reduced pressure to obtain dimorpholinyl hypophosphinic chloride solid (1.3kg), and drying for storage.
Adding (S) -3- (7-bromo-2-oxo-5- (pyridine-2-yl) -2, 3-dihydro-1H-benzo [ e) into a reaction bottle][1,4]Diaza derivatives
Methyl-3-yl) propionate (800g), tetrahydrofuran (6.8kg), dissolved with stirring under argon. The reaction solution was cooled to-30 ℃ and 2.4L of 1M lithium bis (trimethylsilyl) amide (LiHMDS) in THF (2.5kg) was added dropwise over 1 hour, the reaction was exothermic, the temperature was controlled not to exceed-20 ℃ during the dropwise addition, and stirring was continued at-20 ℃ for 1 hour. Then adding dimorpholinyl phosphinic chloride (1.2kg) in batches within 30min, and stirring for 4h at the temperature of minus 10-0 ℃.
And (3) dropwise adding isopropanolamine (524g) into the reaction solution, controlling the temperature to be not more than 0 ℃, controlling the temperature to be 0 ℃ after dropwise adding, reacting for 15h, supplementing isopropanolamine (149.4g), continuously stirring and reacting for 5h, and stopping the reaction.
And (3) quickly dropwise adding 1N HCl aqueous solution (5L) into the reaction solution, controlling the temperature to be not more than 30 ℃, stirring and reacting for 0.5h, separating liquid, and concentrating an organic layer. The aqueous layer was extracted with dichloromethane (5.4 kg. times.2), and the resulting organic phase was added to the concentrated residue together with a saturated aqueous sodium bicarbonate solution (6kg), sufficiently dissolved, and then separated. The organic phase was washed with saturated aqueous ammonium chloride (4.8kg) and purified water (3.6kg), respectively, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the resulting oil was purified by column chromatography (eluent petroleum ether: ethyl acetate 1:1 → ethyl acetate), the positive fraction was collected and concentrated at 45 ℃ under reduced pressure to give the product (730g, yield 80.0%, HPLC: 98.5%).
Second step of
(S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f]Imidazo [1,2-a ]][1,4]Diaza derivatives
-4-yl) propionic acid methyl ester
Dimethyl sulfoxide (493g) and dichloromethane (12.5kg) are added into a reaction bottle, stirred and cooled, oxalyl chloride (413g) is added dropwise at the temperature of-60 ℃ to-70 ℃, the reaction is kept for 1H after the addition, and 3- ((3S) -7-bromine-2- ((2-hydroxypropyl) amino) -5- (pyridin-2-yl) -3H-benzo [ e ] is added][1,4]Diaza derivatives
And (3) reacting a mixed solution of methyl (725g) and dichloromethane (1.9kg) for 3 hours under stirring at a constant temperature, dropwise adding triethylamine (924g), and naturally raising the temperature to room temperature after dropwise adding, and reacting for 3 hours under stirring. After the reaction was completed, the reaction system was washed with a saturated aqueous sodium bicarbonate solution (8.6kg), water (7kg) and a saturated aqueous sodium chloride solution (8.6kg) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness at 40 ℃ under reduced pressure to obtain a product.
The product obtained above was dissolved in methanol (4.49kg), p-toluenesulfonic acid (120g) was added, the reaction was stirred at 25 ℃ for 16 hours, and the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (10kg), washed successively with a saturated aqueous sodium hydrogencarbonate solution (8.6kg), water (7kg) and a saturated aqueous sodium chloride solution (8.6kg), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure at 40 ℃. The resulting oil was purified by column chromatography (eluent ethyl acetate: petroleum ether 1:1 → ethyl acetate), and the positive fraction was collected and concentrated under reduced pressure at 40 ℃ to give the objective product (526g, yield 75.9%, HPLC: 99.4%).
Example 3, (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives
Preparation of (E) -4-yl) propionic acid methyl ester tosylate
(1) Preparation of crude product
Adding (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives
-4-yl) propionic acid methyl ester (519g) and ethyl acetate (3.76kg) were dissolved with stirring, a methanol (416g) solution of p-toluenesulfonic acid (213.8g) was added dropwise over 30min, and after completion of the addition, the mixture was stirred at room temperature for 50min, filtered to obtain a cake, and dried under reduced pressure to obtain an off-white powdery solid (537g, yield 74.3%, HPLC: 99.81%).
(2) Purification of the product
Into a reaction flask, p- (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives
Adding purified water (6.38kg) at 80-90 ℃ to a crude tosylate (532g) of methyl-4-yl) propionate under stirring, stirring for 5min, filtering while the mixture is hot, carrying out water bath stirring crystallization on the filtrate for 20h, filtering, and drying under reduced pressure at 40 ℃ to obtain a white solid (356g, the yield is 66.9%, and the HPLC (high performance liquid chromatography): 99.89%).
MS m/z(ESI):439.09[M–C7H8SO3+1]
1H-NMR(500MHz,CD3OD)8.56-8.57(d,1H),8.14-8.16(d,1H),8.03-8.05(m,1H),7.99-8.01(dd,1H),7.80-7.82(d,1H),7.67-7.70(m,3H),7.57-7.59(m,1H),7.45(d,1H),7.20-7.22(d,2H),4.45-4.48(m,1H),3.69(s,3H),2.77-2.86(m,2H),2.67-2.74(m,1H),2.57-2.64(m,1H),2.49-2.49(s,3H),2.35(s,3H)。
Claims (16)
1. A process for preparing a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the steps of:
the first step of reaction is to react a compound shown as a formula (III) with dimorpholinyl phosphinic chloride in the presence of lithium bis (trimethylsilyl) amide to obtain a compound shown as a formula (II'),
the second step of reaction is to react the compound shown in the formula (II') with isopropanolamine to obtain the compound shown in the formula (II).
2. The method of claim 1, further comprising the step of post-treating with an acid.
3. The method of claim 2, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
4. The method of claim 3, wherein the acid is hydrochloric acid.
5. The method of claim 2, further comprising the step of preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the compound shown in the formula (II) is firstly subjected to oxidation reaction and then subjected to cyclization reaction under acidic condition to obtain the compound shown in the formula (I).
6. The method of claim 5, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
7. The method of claim 6, wherein the acid is p-toluenesulfonic acid.
8. The method of claim 1, wherein the method is
9. The method of any one of claims 5 to 7, wherein the method is
10. A process for preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the steps of:
reacting a compound shown in a formula (V) with (2-amino-5-bromophenyl) (pyridine-2-yl) methanone in the presence of a coupling agent to obtain a compound shown in a formula (IV), reacting the compound shown in the formula (IV) under a base condition to obtain a compound shown in a formula (III), reacting the compound shown in the formula (III) with dimorpholinyl phosphinic chloride in the presence of lithium bis (trimethylsilyl) amide base to obtain a compound shown in a formula (II '), reacting the compound shown in the formula (II') with isopropanolamine to obtain a compound shown in a formula (II), and performing oxidation reaction and cyclization reaction under an acidic condition to obtain a compound shown in a formula (I);
r is hydrogen or an amino protecting group.
11. The method of claim 10, wherein the method is
12. The method of claim 11, wherein the method is
13. A process for preparing a pharmaceutically acceptable salt of a compound of formula (Ia), comprising the steps of claim 12, and preparing a pharmaceutically acceptable salt thereof by reacting a compound of formula (Ia) with an acid selected from an organic acid or an inorganic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
14. The method of claim 13, wherein the acid is an organic acid.
15. The method of claim 14, wherein the organic acid is selected from the group consisting of acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, and methanesulfonic acid.
16. The method of claim 15, wherein the organic acid is p-toluenesulfonic acid.
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| ES2697918A1 (en) * | 2017-07-28 | 2019-01-29 | Moehs Iberica Sl | PROCEDURE FOR PREPARING METHYL ESTER OF ACID 3 - [(3S) -7-BROMO-2-OXO-5- (PYRIDIN-2-IL) -2,3-DIHYDRO-1H- [1,4] -BENZODIAZEPIN-3- IL] PROPIONIC, AND USEFUL COMPOUNDS IN THAT PROCEDURE (Machine-translation by Google Translate, not legally binding) |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
| CN112661759A (en) * | 2019-10-16 | 2021-04-16 | 浙江京新药业股份有限公司 | Benzodiazepine compound and preparation method thereof |
| KR102526590B1 (en) * | 2020-06-19 | 2023-04-28 | 하나제약 주식회사 | METHOD FOR PREPARATION OF 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1,2-a][1,4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER |
| CN112321594B (en) * | 2020-12-07 | 2022-05-20 | 扬子江药业集团有限公司 | Preparation method of benzodiazepine medicine |
| CN114644612B (en) * | 2020-12-17 | 2023-04-28 | 成都苑东生物制药股份有限公司 | Preparation method of benzodiazepine nerve inhibitor intermediate compound |
| CN114014839A (en) * | 2021-12-16 | 2022-02-08 | 上海再启生物技术有限公司 | Method for preparing key intermediate of remimazolam |
| WO2023194945A1 (en) | 2022-04-08 | 2023-10-12 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of remimazolam |
| CN115385891A (en) * | 2022-09-06 | 2022-11-25 | 上海药坦药物研究开发有限公司 | Preparation method of remazolam intermediate |
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| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
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| CN102753525A (en) * | 2009-09-18 | 2012-10-24 | Paion英国有限公司 | Process for preparing 3-[(4s)-8-bromo-1-methyl-6-(2-pyridinyl)-4h-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
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