WO2023143158A1 - Dérivé de phénol, forme cristalline de celui-ci et procédé de préparation associé - Google Patents

Dérivé de phénol, forme cristalline de celui-ci et procédé de préparation associé Download PDF

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WO2023143158A1
WO2023143158A1 PCT/CN2023/072277 CN2023072277W WO2023143158A1 WO 2023143158 A1 WO2023143158 A1 WO 2023143158A1 CN 2023072277 W CN2023072277 W CN 2023072277W WO 2023143158 A1 WO2023143158 A1 WO 2023143158A1
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formula
compound
reaction
preparation
iii
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PCT/CN2023/072277
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Chinese (zh)
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蒋海港
刘军华
孔石林
程应朝
李泽华
何锦
刘民强
赵晓勇
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天地恒一制药股份有限公司
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Priority to CN202380008068.1A priority Critical patent/CN116829523A/zh
Publication of WO2023143158A1 publication Critical patent/WO2023143158A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a phenol derivative, its crystal form and a preparation method, in particular to a solid intermediate for preparing the phenol derivative.
  • Propofol activates multiple gamma-aminobutyric acid type A (GABA A ) receptor subtypes and is widely used for induction and maintenance of general anesthesia.
  • GABA A gamma-aminobutyric acid type A
  • the remarkable pharmacokinetic and pharmacodynamic properties of propofol are rapid onset of action, short duration of action and rapid reversibility.
  • propofol quickly enters hyperperfused areas such as the heart, lungs, and liver from the blood, and its high fat solubility makes it easy for propofol to cross the blood-brain barrier and enter the brain to exert general anesthesia.
  • Patent WO2014180305 describes a class of phenol derivatives and their preparation methods and uses in the central nervous system, some of which have stronger GABA A agonistic activity than commercially available propofol, and can be predicted to have the effect of avoiding injection pain.
  • Patent CN202111122520.6 describes another class of phenol derivatives and their application in medicine. Some compounds disclosed in it have stronger medicinal effects and lower side effects.
  • the present invention provides another solid intermediate for synthesizing phenol derivatives, which has a structure shown in formula (I) or formula (II), wherein formula (II) is formed by introducing amino acid protecting groups and phenolic hydroxyl groups into esters
  • formula (II) is formed by introducing amino acid protecting groups and phenolic hydroxyl groups into esters
  • the solid intermediate formula (II) obtained by forming an ester of an amino acid protecting group and a phenolic hydroxyl group is compared with that obtained by forming a carbamate between (R)-(+)-1-phenylethyl isocyanate and a phenolic hydroxyl group in the prior art.
  • the solid intermediate obtained by the present invention has a good resolution effect, and the obtained product has high optical purity, and the raw materials used for introducing amino acid protecting groups are relatively cheap, the production cost is low, and industrial production is easy to realize.
  • the present invention provides an intermediate for the synthesis of phenol derivatives through a large number of creative experiments by the researchers. After studying its solid state, we found a solid state with obvious powder X-ray diffraction pattern characteristics form.
  • the intermediate provided by the invention has high optical purity, is more conducive to the synthesis of phenol derivatives with high optical purity, and has more industrial production value.
  • the method for splitting synthetic intermediates provided by the invention reduces the difficulty of splitting, has high splitting purity and high yield, and the compound is stable during the splitting process, and the compound can be recycled and utilized many times to achieve the optimization of material utilization.
  • the intermediate provided by the invention synthesizes the target product of the phenol derivative, and the cost is lower.
  • the present invention provides a compound represented by formula (I) or formula (II), or a stereoisomer thereof:
  • R is a hydroxyl protecting group, the hydroxyl protecting group is selected from amino acid protecting groups, and the amino acid protecting group is selected from Boc-amino acid protecting group, Cbz-amino acid protecting group, Fmoc-amino acid protecting group;
  • R is the following structural formula:
  • n is selected from 1,2,3.
  • the compound has the structure shown in the following formula (III):
  • n is selected from 1, 2, 3.
  • the compound has the structure shown in the following formula (IV) or formula (IV-I) or its isomer formula:
  • the compound has the structure shown in the following formula (III-I):
  • the present invention also provides the X-ray powder diffraction pattern of the crystal form of compound formula (III-I), whose values at 2 ⁇ are: 7.280, 10.847, 10.954, 13.641, 14.304, 14.419, 15.161, 15.683, 16.556, 17.659, 18.501 , 18.600, 19.301, 20.558, 20.663, 21.620, 22.060, 22.281, 22.663, 23.941, 25.461, 25.800, 26.500, 27.800, 28.079, 29.142, 29.498, 30.577, 3 Diffraction peaks at 0.819, 31.761, 34.979, 37.741, 42.400, 44.257 .
  • the X-ray powder diffraction pattern of the crystal form of the compound formula (III-I) also has a 2 ⁇ value of: 10.616, 15.583, 27.321, 29.902, 32.942, 33.503, 36.239, 39.601, 48.303 or There are many diffraction peaks.
  • the present invention also provides the X-ray powder diffraction pattern of the structure shown in compound formula (IV) or the crystal form of its isomer formula, and its value at 2 ⁇ is: 9.316, 12.121, 13.097, 13.599, 15.158, 16.037, 17.222, 18.239 , 18.659, 20.142, 20.519, 20.858, 21.279, 22.261, 23.123, 24.182, 25.002, 25.301, 25.981, 34.839 have diffraction peaks.
  • the X-ray powder diffraction pattern of the crystal form of the compound formula (IV) or its isomer formula also has a 2 ⁇ value of: 15.780, 19.499, 21.899, 27.542, 28.122, 35.338, 36.001 or There are many diffraction peaks.
  • the present invention also provides a preparation method of the compound represented by the formula (III), the method is obtained by the formula (V)
  • the compound is prepared by esterification with cyclic acid anhydride;
  • a solvent is used in the reaction, and the solvent is selected from any one of methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone one or a mixture of several proportions;
  • Described reaction adds catalyst, and catalyst is selected from DMAP;
  • alkaline reagent is added to the reaction, and the alkaline reagent is selected from triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, Any one or a mixture of any of sodium bicarbonate.
  • the present invention also provides a preparation method of the compound represented by formula (IV), which is prepared by performing condensation reaction between the compound of formula (VI) and Boc-D-alanine to form an ester;
  • a solvent is used in the reaction, and the solvent is selected from any one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone one or a mixture of several proportions;
  • a condensing agent is added in the reaction, and the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azobenzotriazole)-N,N, Any of N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole;
  • the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3- Any one of dimethylaminopropyl)-3-ethylcarbodiimide;
  • alkaline reagent is added to the reaction, and the alkaline reagent is selected from the bases: any one of DMAP, triethylamine, N,N-diisopropylethylamine, and pyridine.
  • the preparation method of the compound represented by the formula (VI) comprises the following steps:
  • Step a hydrolyzing the compound of formula (III-1) under basic conditions to generate the compound of formula (V);
  • Step b reducing the compound of formula (V) to generate the compound of formula (VI);
  • described basic reagent is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, described reaction solvent Any one selected from methanol, ethanol, tetrahydrofuran, water or a mixture of any ratio;
  • a reducing agent and a catalyst are used in the step b, the reducing agent is hydrogen, and the catalyst is (4R,5R)-(+)-O-[1-benzyl-1-(5-methyl- 2-Phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl](dicyclohexylphosphine)(1,5-cyclopentadiene)iridium(I)tetrakis(3, 5-Bis(trifluoromethyl)phenyl borate.
  • the present invention also provides a method for purifying the compound represented by formula (III),
  • the purification method is that the crude product of the compound of formula (III) is subjected to beating and purification in an organic solvent, and the organic solvent is selected from alkanes, Any one of cycloalkanes, aromatic hydrocarbons, and ether solvents or a mixture of any ratio;
  • the organic solvent is selected from a single solvent of n-hexane, n-heptane or toluene;
  • the organic solvent is selected from mixed solvents of n-hexane and methyl tert-butyl ether, n-heptane and methyl tert-butyl ether or toluene and methyl tert-butyl ether.
  • the present invention also provides a method for purifying the compound represented by formula (IV),
  • the purification method is that the crude product of the compound shown in formula (IV) is recrystallized in an organic solvent, and the organic solvent is selected from any one or a mixture of any ratio in alkane and cycloalkane solvents; preferably, the organic solvent For n-hexane or n-heptane.
  • the present invention also provides a compound represented by formula (VII), or its isomer formula (VII-I) or formula (VII-II):
  • the present invention also provides a preparation method of the compound represented by formula (VII), comprising the following steps:
  • Step c hydrolyzing the compound of formula (IV-I) under basic conditions to generate the compound of formula (VI);
  • Step d acylation of the compound of formula (VI) to generate the compound of formula (VII);
  • an alkaline reagent and a reaction solvent are used in the step c, the alkaline reagent is selected from sodium hydroxide, and the reaction solvent is selected from methanol and Tetrahydrofuran, methanol and water in any one or a mixture of several ratios;
  • an acylating agent, a catalyst and an alkaline agent are used, the acylating agent is selected from paraformaldehyde, the catalyst is selected from magnesium chloride, and the alkaline agent is selected from triethylamine.
  • the present invention also provides a preparation method of the compound shown in formula (XI), the preparation process comprising the following steps:
  • Step e Grignard reaction of the compound of formula (VII) to generate the compound of formula (IX);
  • Step f reacting the compound of formula (IX) with ethanethiol to generate the compound of formula (X);
  • Step g oxidizing the compound of formula (X) to generate the compound of formula (XI);
  • a Grignard reagent is used in the step e, and the Grignard reagent is selected from methylmagnesium chloride;
  • An acid reagent is used in the step f, and the acid reagent is selected from hydrochloric acid;
  • oxidizing agent in the described step g is selected from m-chloroperoxybenzoic acid.
  • amino acid protecting group in the present invention refers to the group after amino acid reacts with hydroxyl group and carboxylic acid removes hydroxyl group.
  • Boc-amino acid protecting group, Cbz-amino acid protecting group, and Fmoc-amino acid protecting group are respectively Boc-amino acid, Cbz-amino acid, Fmoc-amino acid reacting with hydroxyl group after the carboxylic acid removes the hydroxyl group.
  • Boc-amino acids include, but are not limited to, N-(tert-butoxycarbonyl)-L-glutamate-1-benzyl ester, Boc-L-proline, N-Boc-O-benzyl-L-serine, S- Acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N2-[tert-butoxycarbonyl]-N-(trityl base)-D-asparagine, Boc-D-alanine, N-Boc-N-nitro-L-arginine, tert-butoxycarbonyl-L-2,4-diaminobutyric acid, ( S)-3-amino-2-(tert-butoxycarbonylamino)propionic acid, Boc-glycine, N-tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester, N-Boc-N'-triphenyl Methyl-L-histidine,
  • Cbz-amino acids include but are not limited to N-benzyloxycarbonyl-L-arginine cyclohexylamine salt, N-benzyloxycarbonyl-glycyl-glycine, N-benzyloxycarbonyl-D-leucine, N-benzyloxycarbonyl Oxycarbonyl-L-glutamic acid-5-tert-butyl ester, N-benzyloxycarbonyl-L-leucine, N-[(benzyloxy)carbonyl]-1-(triphenylmethyl)-L -Histidine, N-alpha-benzyloxycarbonyl-L-2,3-diaminopropionic acid, Cbz-L-phenylglycine, N-benzyloxycarbonyl-O-tert-butyl-L-serine, Cbz-glycine Methyl Ester, N-Benzyloxycarbonyl-L-Tryptophan, Cbz
  • Fmoc-amino acids include, but are not limited to, Fmoc-O-tert-butyl-L-threonine, Fmoc-L-aspartic acid-beta-tert-butyl ester, Fmoc-O-tert-butyl-L-glutamine Amino acid, Fmoc-O-tert-butyl-L-tyrosine, N-alpha-fluorenylmethoxycarbonyl-N-epsilon-tert-butoxycarbonyl-L-lysine, Fmoc-Pbf-arginine, N -alpha-Fmoc-N-in-tert-Butoxycarbonyl-L-Tryptophan, Fmoc-L-Proline, N-Fmoc-L-Alanine, Fmoc-L-Valine acid, Fmoc-L-methionine, Fmoc-L-phenylalanine, F
  • Fig. 1 is the XRD pattern of formula (III-I) compound crystal form
  • Fig. 2 is the XRD pattern of formula (IV) compound crystal form
  • Fig. 3 is an ellipsoid diagram of the three-dimensional molecular structure of the compound of formula (IV).
  • Chemical purity test adopt high performance liquid chromatography (HPLC) to detect the chemical purity of the product;
  • Optical purity test chrial-HPLC test.
  • Powder X-ray diffraction (XRD) test The characteristic powder X-ray diffraction (XRD) peaks of the compound III-I crystal form prepared in Example 1 are shown in Table 1; the powder X-ray diffraction pattern is shown in Figure 1.
  • Powder X-ray diffraction (XRD) test The characteristic powder X-ray diffraction (XRD) peaks of the compound IV crystal form prepared in Example 5 are shown in Table 2; the powder X-ray diffraction pattern is shown in Figure 2.
  • compound X (200mg, 0.798mmol) was dissolved in DCM (10mL) and m-chloroperoxybenzoic acid (m-CPBA, 325mg, 1.60mmol, 2.0 eq) was added to the reaction, and the reaction was allowed to react at 10°C for 0.5 hours.
  • m-CPBA m-chloroperoxybenzoic acid
  • the SADABS program was used to perform empirical absorption correction on the data; the SHELXT2014 software was used to analyze the single crystal structure by the direct method, and the structure was refined by the least square method.
  • the isotropic calculation process is obtained, and the hydrogen atoms on C-H are obtained by calculation hydrogenation, and the riding model is used to refine it.
  • the Flack constant is 0.14 (11), the chirality can be confirmed, and C7 and C13 are R configurations ( Figure 3).

Abstract

La présente invention concerne un dérivé de phénol, une forme cristalline de celui-ci et un procédé de préparation associé, en particulier un intermédiaire solide utilisé pour préparer le dérivé de phénol, et concerne en particulier un composé représenté par la formule (I) ou la formule (II), un stéréoisomère de celui-ci, une forme cristalline de celui-ci et un procédé de préparation associé.
PCT/CN2023/072277 2022-01-26 2023-01-16 Dérivé de phénol, forme cristalline de celui-ci et procédé de préparation associé WO2023143158A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016188490A1 (fr) * 2015-05-28 2016-12-01 四川海思科制药有限公司 Procédé de préparation de 1,2-dicyclopropyléthylphénol et de son isomère optique
CN106187702A (zh) * 2015-05-28 2016-12-07 四川海思科制药有限公司 一种2‑[1‑环烷基乙烯基]苯酚的制备方法及其中间体
CN106278947A (zh) * 2015-05-19 2017-01-04 四川海思科制药有限公司 苯酚衍生物的晶型及其制备方法
CN113248482A (zh) * 2020-02-10 2021-08-13 中国药科大学 含苯并五元杂环结构的化合物及其制备方法与用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106278947A (zh) * 2015-05-19 2017-01-04 四川海思科制药有限公司 苯酚衍生物的晶型及其制备方法
WO2016188490A1 (fr) * 2015-05-28 2016-12-01 四川海思科制药有限公司 Procédé de préparation de 1,2-dicyclopropyléthylphénol et de son isomère optique
CN106187702A (zh) * 2015-05-28 2016-12-07 四川海思科制药有限公司 一种2‑[1‑环烷基乙烯基]苯酚的制备方法及其中间体
CN113248482A (zh) * 2020-02-10 2021-08-13 中国药科大学 含苯并五元杂环结构的化合物及其制备方法与用途

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