WO2020051796A1 - Procédé de préparation de brivaracétam et de son intermédiaire - Google Patents

Procédé de préparation de brivaracétam et de son intermédiaire Download PDF

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WO2020051796A1
WO2020051796A1 PCT/CN2018/105203 CN2018105203W WO2020051796A1 WO 2020051796 A1 WO2020051796 A1 WO 2020051796A1 CN 2018105203 W CN2018105203 W CN 2018105203W WO 2020051796 A1 WO2020051796 A1 WO 2020051796A1
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formula
compound
acid
preparation
reaction
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PCT/CN2018/105203
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English (en)
Chinese (zh)
Inventor
郭朋
刘凤伟
任建笑
朱文峰
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上海宣泰医药科技有限公司
上海博璞诺科技发展有限公司
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Priority to PCT/CN2018/105203 priority Critical patent/WO2020051796A1/fr
Priority to CN201980059753.0A priority patent/CN112739683B/zh
Priority to PCT/CN2019/105111 priority patent/WO2020052545A1/fr
Publication of WO2020051796A1 publication Critical patent/WO2020051796A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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 present application relates to the field of medicinal chemistry, and in particular to a method for preparing bovaracetam (I) and its related intermediates.
  • Brivaracetam The chemical name of Brivaracetam is (S) -2-[(R) -3-propylpyrrolidin-1-yl] butanamide (formula I), which is produced by the Belgian pharmaceutical company UBS (UCB ) 3rd generation antiepileptic drug developed.
  • the drug can exert antiepileptic effects by binding to synaptic vesicle protein 2A (SV2A).
  • SV2A synaptic vesicle protein 2A
  • bovaracetam can significantly reduce the frequency of partial seizures and improve the response rate. It has good antiepileptic activity and high safety.
  • WO2007031263 reports the following synthetic route, where the first route uses chiral raw materials and requires chiral separation, and the second route performs two chiral separations resulting in lower overall yield, complicated operation, and higher cost.
  • US8076493 provides an asymmetric synthesis method of bovaracetam, in which the n-propyl R configuration chiral center on butyrolactam is selectively constructed by the Sharpless a hydroxylation of an olefin.
  • too many reaction steps limit its large-scale application.
  • US20080009638 discloses a method for the synthesis of diastereomeric enriched bovaracetam, in which the stereoselectivity of n-propyl on butyrolactam is not resolved.
  • WO2016191435 discloses a synthetic method for preparing optically pure bovaracetam, in which the chirality of n-propyl on butyrolactam is introduced by using chiral epichlorohydrin as a starting material.
  • bovaracetam The most critical difficulty in the synthesis of bovaracetam is the construction of the n-propyl R chiral center on butyrolactam. Almost all of the current preparation processes require chiral chromatography or use of chiral starting materials, which requires high equipment and low raw material utilization, which greatly increases production costs.
  • the invention relates to a method for preparing boisacetam of formula I, which method comprises steps (A)-(D):
  • R 1 is C 1-6 alkyl
  • step (D) includes
  • R 2 is a protecting group with steric hindrance effect
  • Step (D-3) The compound of formula VIII is resolved to prepare a compound of formula IX
  • step (D) includes
  • the invention also relates to a method for preparing a compound of formula XIII, the method comprising steps (a)-(d):
  • R 1 is C 1-6 alkyl
  • one or more or “at least one” can mean one, two, three, four, five, six, seven, eight, nine (one) or more (A).
  • reaction temperature is -20 ° C to 25 ° C
  • reaction temperature covers every point value and sub-range in the range from -20 ° C to 25 ° C, such as -20 ° C to 0 ° C, 0 ° C to 25 ° C, -10 ° C To 10 ° C, and -20 ° C, -10 ° C, 0 ° C, 5 ° C, 10 ° C, 15 ° C, 20 ° C, 25 ° C, and so on.
  • Other similar expressions such as “at -20 ° C to 40 ° C", "at 0 ° C to 100 ° C", etc.
  • the expression “molar equivalent is between 0.01-1.5” includes 0.01-0.1, 0.02-0.05, 0.03-0.05, 0.04-0.06, 0.1-0.5, 0.5-1.0, and 0.01, 0.03, 0.04, 0.05, 0.06, 0.07 , 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, etc.
  • the singular forms refer to “a”, “an”, and “the”, and include the plural referents.
  • the concentration is by weight
  • the proportion of liquid in the mixed solution is calculated by volume
  • the ratio (including percentage) of the reaction reagent to the compound is by molar amount.
  • Protective group derivatives of the compounds herein can be prepared by methods well known to those skilled in the art.
  • the protecting group in the protecting group derivative can be removed by a method well known to those skilled in the art.
  • alkyl refers to a saturated linear, branched, or cyclic hydrocarbon group.
  • C 1-6 alkyl refers to a saturated straight-chain, branched-chain, or cyclic hydrocarbon group having 1-6 (eg, 1, 2, 3, 4, 5, or 6) carbon atoms.
  • C 1-6 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, Amyl, 3-methyl-3-pentyl, hexyl (eg, n-hexyl, cyclohexyl, etc.).
  • C 1-6 alkyl encompasses sub-ranges thereof, such as “C 1-3 alkyl", “C 2-3 alkyl", “C 4-6 alkyl", and the like.
  • olefin refers to a non-aromatic linear, branched or cyclic hydrocarbon having one or more carbon-carbon double bonds.
  • C 2-6 olefin refers to a straight, branched or cyclic hydrocarbon having 2 to 6 carbon atoms and one or more (preferably one) carbon-carbon double bonds, in particular C 4-6 olefins containing one carbon-carbon double bond.
  • C 2-6 olefins include, but are not limited to, 1-butene, 2-butene, 2-pentene, 2-hexene, 3-hexene, 2-methyl-1-propene, 2-methyl- 2-pentene, isobutylene, isoprene, etc.
  • alkenyl refers to a group derived from the corresponding monovalent olefin and having one hydrogen atom removed from a carbon atom containing a free valence electron.
  • a propenyl group an alkenyl group obtained by removing a hydrogen atom from a carbon atom of propylene is called a propenyl group.
  • C 2-6 alkenyl refers to an alkenyl group having 2-6 (eg, 2, 3, 4, 5, 6) carbon atoms.
  • C 2-6 alkenyl examples include, but are not limited to, 2-butenyl, 2-pentenyl, 2-hexenyl, 3-hexenyl, 2-methyl-2-pentenyl, isobutenyl, and Isopentenyl and the like.
  • steric hindrance effect refers to the steric hindrance effect caused by the proximity of certain atoms, atom groups or groups to each other in the molecular spatial structure.
  • a "protective group having a steric hindrance effect” refers to a group having a certain size and thus capable of preventing potential reaction sites from approaching each other.
  • alkane-based solvent refers to a solvent of a saturated linear, branched or cyclic hydrocarbon having 1 to 10 carbon atoms.
  • alkane-based solvent include, but are not limited to, n-pentane, n-hexane, cyclohexane, n-heptane, octane, or a combination thereof, preferably hexane or heptane.
  • ester solvent refers to a solvent of an ester having 3 to 10 carbon atoms.
  • ester-based solvent include, but are not limited to, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, pentyl acetate, or a combination thereof, and ethyl acetate is preferred.
  • ether-based solvent refers to a solvent of an ether having 2 to 10 carbon atoms.
  • examples of the ether-based solvent include, but are not limited to, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, or a combination thereof, preferably isopropyl ether, tetrahydrofuran, or methyl tert-butyl ether.
  • aromatic solvent refers to a solvent of an aromatic hydrocarbon having 6 to 14 carbon atoms.
  • aromatic solvents include, but are not limited to, benzene, toluene, xylene, ethylbenzene, or a combination thereof, with toluene being preferred.
  • stereoisomers such as chiral centers
  • the synthesis of bovaracetam may produce a mixture of different isomers (enantiomers, diastereomers).
  • These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotary chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.), and can also be purified by It can be obtained by chiral resolution by bonding with other chiral compounds (chemical bonding, etc.) or salt formation (physical bonding, etc.).
  • optically pure refers to a chiral center with a given configuration of more than 90%, preferably 95% or more, more preferably 99% or more, and most preferably 99.5% or more of a given compound.
  • diastereomeric enrichment refers to the content of one diastereomer of not less than 50% based on the weight of all kinds of diastereomers of a given compound.
  • racemate as used herein means that the mass content of one stereoisomer of the compound in question is equal to the content of the other stereoisomers of the compound.
  • make the alpha carbon of cyano group refers to changing the chirality of the carbon atom so that the content of the dominant stereoisomer of the compound is in the same direction as the content of other stereoisomers of the compound Variety.
  • the present invention relates to a method for preparing boisacetam of formula I, which method comprises the following steps (A)-(D):
  • R 1 is C 1-6 alkyl.
  • the compound of formula III is subjected to asymmetric ring opening with an alcohol of formula R 1 OH to give a compound of formula IV.
  • This step can be performed, for example, in the presence of a quinine derivative chiral catalyst.
  • R 1 is C 1-3 alkyl, especially C 1 alkyl (ie, R 1 OH is methanol).
  • step (A) is performed in a solvent.
  • the solvent is selected from the group consisting of aromatic solvents, ether solvents and mixed solvents thereof.
  • the aromatic solvent is toluene.
  • the ether-based solvent is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, and mixtures thereof, and is preferably methyl tert-butyl ether.
  • the quinine derivative catalyst is selected from:
  • the quinine derivative catalyst is:
  • the molar equivalent of the chiral catalyst relative to the compound of formula III is 0.01-1.5, preferably 0.01-1.0, more preferably 0.01-0.2, particularly preferably 0.02-0.1, and especially about 0.05.
  • the reaction temperature of step (A) is -20 ° C to 25 ° C. In a preferred embodiment, the reaction temperature of step (A) is -5 ° C to 5 ° C.
  • reaction time of step (A) is 4-48 hours. In a preferred embodiment, the reaction time of step (A) is 6-24 hours, such as 5-16 hours.
  • step (A) in the method of the present invention is reasonable, the conditions are mild, the reaction yield is high, and the optical selectivity is high. Especially when using quinine derivative Q-BTBSA as a catalyst, the crude product yield can reach 100%.
  • the compound of formula III can be prepared from a compound of formula II. Accordingly, in one embodiment, the method for preparing bovaracetam of formula I according to the present invention further comprises step (A ') to prepare a compound of formula III from a compound of formula II before step (A):
  • Step (A ') is a step of dehydration in the molecule to form an acid anhydride. This can be done by dehydration methods known in the art.
  • the compound of formula II is dehydrated in an anhydride system.
  • the reaction temperature is from 100 ° C to 150 ° C.
  • the acid anhydride system is acetic anhydride.
  • Step (B) is the ammonolysis of an ester compound of formula IV to an amide of a compound of formula V in an ammonia system.
  • the ammonia is selected from the group consisting of ammonia gas, liquid ammonia, and ammonia water. In a preferred embodiment, the ammonia is aqueous ammonia.
  • reaction using C 1 -C 6 alcohols (such as methanol) as the solvent.
  • reaction is performed directly in an ammonia system without using a solvent.
  • the reaction is performed under pressure.
  • the pressurizing condition can be implemented by, for example, a stuffing tank (0 to 20 Kg / cm 2 ). In another embodiment, the reaction is performed under atmospheric conditions.
  • the ammonolysis reaction is performed in the presence of an ammonium chloride catalyst.
  • the reaction conditions are normal pressure reactions catalyzed by ammonium chloride.
  • reaction temperature of step (B) is 20 ° C to 60 ° C.
  • this step is performed under basic conditions in the presence of a halogen.
  • the form of the halogen is not particularly limited, and may be a halogen (chlorine, bromine, iodine) molecule, or an agent capable of releasing a halogen, or an agent containing a halogen in the molecule.
  • the molar equivalent of halogen relative to the compound of formula V is 1-5.
  • the halogen is selected from bromine, chlorine and mixtures thereof.
  • the alkaline condition is selected from the group consisting of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, a sodium hypochlorite solution, a sodium hypobromite solution, and mixtures thereof.
  • the reaction temperature is from 0 ° C to 100 ° C.
  • step (D) includes steps (D-1) to (D-5):
  • R2 is a protecting group with a steric hindrance effect.
  • the protecting group is selected such that it is stable under alkaline conditions (at a pH of 10 to 11, and preferably at a pH of 14 or higher); and / or easily removed under acidic conditions.
  • R 2 is C 1-6 alkyl. In a preferred embodiment, R 2 is C 3-5 alkyl, preferably C 4 alkyl, especially tert-butyl.
  • step (D-1) the carboxyl group is protected by an esterification reaction.
  • the compound of formula VI with an alcohol compound (R 2 OH) prepared by reacting an acid of formula VII in the system.
  • the compound of formula VI is reacted with an alcohol (R 2 OH) in an acidic system at 0 ° C to 100 ° C.
  • the acidic system is selected from the group consisting of sulfoxide, acetyl chloride, and hydrogen chloride / alcohol solution.
  • R 2 is C 1-6 alkyl, preferably C 3-5 alkyl. In a particularly preferred embodiment, R 2 is C 4 alkyl, especially tert-butyl.
  • the compound of formula VI is added to an olefin under the catalysis of concentrated sulfuric acid to produce an ester compound of formula VII.
  • a compound of formula VI is reacted with an olefin under conditions of concentrated sulfuric acid at 0 ° C to 50 ° C.
  • the olefin is a C 2-6 olefin, preferably a C 3-5 olefin, especially a C 4 olefin.
  • the olefin is isobutylene.
  • the reaction is performed in the presence of a water-binding agent.
  • water-binding agents include, but are not limited to, anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves, calcium chloride, silica gel, or a combination thereof.
  • reaction temperature of step (D-2) is 0 ° C to 50 ° C.
  • Step (D-3) The compound of formula VIII is resolved to prepare a compound of formula IX
  • the compound of formula VIII is salted with a chiral acid in a solvent, purified, and then freed to obtain a compound of formula IX.
  • the purification is performed by precipitation of a salt.
  • the precipitation of the salt is performed at -20 ° C to 40 ° C, preferably 0 ° C to 15 ° C.
  • the compound of formula IX is obtained by freeing the precipitated salt by alkali-adjusting the pH to 10-11.
  • the purification further comprises a recrystallization process of the precipitated salt.
  • the recrystallization process of the salt can be repeated a desired number of times until the compound reaches the desired optical purity.
  • the solvent used is an ether solvent, an alkane solvent, an ester solvent, or a mixed solvent thereof.
  • the ether-based solvent is selected from the group consisting of isopropyl ether, methyl tert-butyl ether, and mixtures thereof.
  • the alkane-based solvent is selected from heptane, hexane, and mixtures thereof.
  • the ester solvent is ethyl acetate.
  • the chiral acid is selected from the group consisting of L-tartaric acid, L-dibenzoyltartaric acid, L-di-p-methylbenzoyltartaric acid, L-camphorsulfonic acid, D-tartaric acid, D-dibenzoyl Tartaric acid, D-di-p-methylbenzoyltartaric acid, D-camphorsulfonic acid, and combinations thereof.
  • Bases used to adjust pH include, but are not limited to, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • the reaction is performed under acidic conditions.
  • Acids that form acidic conditions include, but are not limited to, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and mixtures thereof, or solutions of acidic conditions that are the above acids.
  • reaction temperature of step (D-4) is 0 ° C to 50 ° C.
  • the reaction is performed under acidic conditions.
  • Useful acids include, but are not limited to, sulfuric acid, hydrochloric acid, and mixtures thereof.
  • reaction temperature of step (D-5) is 30 ° C to 80 ° C.
  • the method of the present invention optionally further comprises the following steps between steps (D-3) and (D-4):
  • the compound of formula X is a by-product isomer present in the crystallization mother liquor after the compound of formula VIII is resolved in step (D-3). See, for example, the following reaction route:
  • the alpha carbon of the cyano group is racemized under basic conditions, and then the carboxyl group is protected again with the R 2 group to obtain the compound of formula VIII.
  • the compound of formula X is deprotected in the presence of hydrochloric acid.
  • the compound of formula X (for example, after the crystallization mother liquor is concentrated) is added to a concentrated aqueous hydrochloric acid solution, and the protective group is removed at room temperature.
  • the cyano alpha carbon is racemic under basic and heating conditions.
  • the pH of the reaction system of the racemization reaction is 14 or more.
  • the reaction temperature of the racemization reaction is from 50 ° C to 60 ° C.
  • step (D-1) After the alpha carbon of the cyano group is racemic, the method of protecting the carboxyl group with the R 2 group can be referred to step (D-1).
  • an intermediate is obtained after isolation, and the intermediate is further protected to obtain a compound of formula VIII.
  • the obtained compound of formula VIII can be reused in step (D-3) to prepare a compound of formula IX.
  • the present invention also relates to an intermediate used for the preparation of bovaracetam of formula I, selected from:
  • R 2 is as defined above.
  • step (D) includes steps (D-i) to (D-ii):
  • the compound of formula VI is reacted with a diazotizing agent and further ring-closed to form a lactone compound of formula XIII.
  • diazotizing agents include, but are not limited to, sodium nitrite, nitrite (eg, isoamyl nitrite, t-butyl nitrite), sodium nitroprusside, or a combination thereof.
  • the temperature of the diazotization reaction is from -10 ° C to 10 ° C.
  • the ring-closure reaction is performed under heating conditions. In one embodiment, the ring-closure reaction temperature is from 50 ° C to 100 ° C. In one embodiment, the ring-closure reaction is performed under acidic conditions. In one embodiment, the ring-closure reaction is performed under basic conditions.
  • This step can be performed in accordance with the methods disclosed in Bio-catalytic, anti-epileptic, anti-epileptic, drug, Brivaracetam, Organic Process Research & Development 2016, vol. 20, pp. 1566-1575.
  • step (D-ii) includes
  • the reaction is performed in a hydrobromic acid solution.
  • the reaction is performed in the presence of a base and tetrabutylammonium iodide.
  • step (D) includes steps (D-I)-(D-II):
  • the compound of formula VI forms a compound of formula XIV in the presence of a condensing agent.
  • the condensing agent is selected from the group consisting of DCC, EDCI, CDI, and combinations thereof.
  • a compound of formula VI is itself ring-closed to a compound of formula XIV in the presence of an acid chloride-forming reagent.
  • the acid chloride-forming reagent is sulfoxide.
  • the ring closure reaction temperature of the compound of Formula VI is from 0 ° C to 50 ° C.
  • a compound of formula XIV is subjected to a condensation reaction with methyl 2-bromobutyrate in a solvent in the presence of NaH.
  • the resulting ester is then hydrolyzed to an amide, and then resolved by chiral preparative chromatography to obtain a compound of formula I.
  • the invention also relates to a method for preparing a compound of formula XIII.
  • Compounds of formula XIII can be used as intermediates to prepare bovaracetam of formula I (see step (D-ii)).
  • the method includes:
  • R 1 is C 1-6 alkyl.
  • the compound of formula III is subjected to asymmetric ring opening with an alcohol of formula R 1 OH to give a compound of formula IV.
  • This step can be performed, for example, in the presence of a quinine derivative chiral catalyst.
  • R 1 is C 1-3 alkyl, especially C 1 alkyl (ie, R 1 OH is methanol).
  • step (a) is performed in a solvent.
  • the solvent is selected from the group consisting of aromatic solvents, ether solvents and mixed solvents thereof.
  • the aromatic solvent is toluene.
  • the ether-based solvent is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, and mixtures thereof, and is preferably methyl tert-butyl ether.
  • the quinine derivative catalyst is selected from the following compounds:
  • the quinine derivative catalyst is:
  • the molar equivalent of the chiral catalyst relative to the compound of formula III is 0.01-1.5, preferably 0.01-1.0, more preferably 0.01-0.2, particularly preferably 0.02-0.1, and especially about 0.05.
  • the reaction temperature of step (a) is from -20 ° C to 25 ° C. In a preferred embodiment, the reaction temperature of step (a) is -5 ° C to 5 ° C.
  • reaction time of step (a) is 4-48 hours. In a preferred embodiment, the reaction time of step (a) is 6-24 hours, such as 5-16 hours.
  • step (a) in the method of the present invention is reasonable, the conditions are mild, the reaction yield is high, and the optical selectivity is high. Especially when using quinine derivative Q-BTBSA as a catalyst, the crude product yield can reach 100%.
  • Step (b) is the ammonolysis of an ester compound of formula IV to an amide of a compound of formula V in an ammonia system.
  • the ammonia is selected from the group consisting of ammonia gas, liquid ammonia, and ammonia water. In a preferred embodiment, the ammonia is aqueous ammonia.
  • reaction using C 1 -C 6 alcohols (such as methanol) as the solvent.
  • reaction is performed directly in an ammonia system without using a solvent.
  • the reaction is performed under pressure.
  • the pressurizing condition can be implemented by, for example, a stuffing tank (0 to 20 Kg / cm 2 ). In another embodiment, the reaction is performed under atmospheric conditions.
  • the ammonolysis reaction is performed in the presence of an ammonium chloride catalyst.
  • the reaction conditions are normal pressure reactions catalyzed by ammonium chloride.
  • reaction temperature of step (b) is 20 ° C to 60 ° C.
  • this step is performed under basic conditions in the presence of a halogen.
  • the form of the halogen is not particularly limited, and may be a halogen (chlorine, bromine, iodine) molecule, or an agent capable of releasing a halogen, or an agent containing a halogen in the molecule.
  • the molar equivalent of halogen relative to the compound of formula V is 1-5.
  • the halogen is selected from bromine, chlorine and mixtures thereof.
  • the alkaline condition is selected from the group consisting of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, a sodium hypochlorite solution, a sodium hypobromite solution, and mixtures thereof.
  • the reaction temperature is from 0 ° C to 100 ° C.
  • the compound of formula VI is reacted with a diazotizing agent and further ring-closed to form a lactone compound of formula XIII.
  • diazotizing agents include, but are not limited to, sodium nitrite, nitrite (eg, isoamyl nitrite, t-butyl nitrite), sodium nitroprusside, or a combination thereof.
  • the temperature of the diazotization reaction is from -10 ° C to 10 ° C.
  • the ring-closure reaction is performed under heating conditions. In one embodiment, the ring-closure reaction temperature is from 50 ° C to 100 ° C. In one embodiment, the ring-closure reaction is performed under acidic conditions. In one embodiment, the ring-closure reaction is performed under basic conditions.
  • the method for preparing bovaracetam according to the present invention has a simple raw material structure, low price and easy availability. All steps have mild reaction conditions, simple operation, no low temperature or strict anhydrous and anaerobic conditions, no special separation means, and are suitable for industrial production.
  • the second chiral center in the bovaracetam molecule was constructed by the salt-forming crystallization method, so that all raw materials do not need to be chiral. Moreover, after the preferred isomers are salted out, the non-preferred isomers present in the crystallization mother liquor can be continuously converted into the target configuration after recovery, racemization and re-salt crystallization, and the atomic economic utilization rate is high.
  • NMR spectra were recorded on a BRUKER AC250 Fourier Transform NMR spectrometer equipped with an Aspect 3000 computer and a 5 mm 1 H / 13 C dual probe. Compounds were studied in DMSO-d 6 (or CDCl 3 ) solution at a probe temperature of 313K. Lock the instrument on the deuterium signal of DMSO-d 6 (or CDCl 3 ). Chemical shifts are expressed in ppm of the low field of TMS with distance as an internal standard.
  • the analysis was performed using an Agilent Technologies HPLC system equipped with an Agilent Eclipse PLUS C18, 4.6 * 50mm, 3.5um column. In 3.5 minutes, a gradient elution of 95% 0.1% H 3 PO 4 aqueous solution and 5% acetonitrile to 5% 0.1% H 3 PO 4 aqueous solution and 95% acetonitrile was performed, and a 5% 0.1% H 3 PO 4 aqueous solution and 95% acetonitrile continued to elute for 1.5 minutes. The flow rate was set to 2.0 mL / min. The column temperature was set at 35 ° C. The detection wavelength was 210 nm.
  • the analysis was performed using an Agilent Technologies HPLC system equipped with an AD-H, 4.6 * 250mm, 5um column. In 25 minutes, it was eluted with 85% 1% trifluoroacetic acid n-hexane solution and 15% 1% trifluoroacetic acid ethanol solution. The flow rate was set at 0.5 mL / min. The detection wavelength was 205 nm.
  • the analysis was performed using an Agilent Technologies HPLC system equipped with an AD-H, 4.6 * 250mm, 5um column. In 20 minutes, it was eluted with 85% n-hexane solution and 15% ethanol solution. The flow rate was set at 0.5 mL / min. The detection wavelength was 205 nm.
  • the analysis was performed using an Agilent Technologies HPLC system equipped with an AD-H, 4.6 * 250mm, 5um column. In 25 minutes, it was eluted with a 90% n-hexane solution and a 10% ethanol solution. The flow rate was set at 0.5 mL / min. The detection wavelength was 210 nm.
  • the analysis was performed using an Agilent Technologies HPLC system equipped with an AD-H, 4.6 * 250mm, 5um column. In 20 minutes, it was eluted with 80% n-hexane solution and 20% ethanol solution. The flow rate was set at 0.5 mL / min. The detection wavelength was 210 nm.
  • the analysis was performed using an Agilent Technologies HPLC system equipped with an AD-H, 4.6 * 250mm, 5um column. In 40 minutes, it was eluted with 80% n-hexane solution and 20% ethanol solution. The flow rate was set at 0.5 mL / min. The detection wavelength was 210 nm.
  • the raw materials, reagents and equipment used in the specific implementation of the present invention are all commercially available products.
  • Reagents can be obtained from WuXi MingLanbo (Wuhan) Chemical Technology Co., Ltd., Shanghai Titan Technology Co., Ltd., Saen Chemical Technology (Shanghai) Co., Ltd., and Shanghai Aladdin Biochemical Technology Co., Ltd.
  • 3-N-propylglutaric acid (208 g, 1.2 mol) was added to acetic anhydride (600 ml), and the mixture was heated to reflux, and the reaction was stopped after about 3 hours. After the mixture was concentrated to remove most of the solvent, it was distilled under reduced pressure to obtain about 187 g of a colorless liquid with a yield of 96% and a GC purity of> 99%.
  • the solvent was removed by concentration, dichloromethane (250 ml) and 10% hydrochloric acid (250 ml) were added to the residue, the organic phase was discarded, and the aqueous phase was washed with dichloromethane (250 ml * 4).
  • the obtained aqueous phase was made alkaline with aqueous ammonia and extracted with dichloromethane (250 ml * 4).
  • the obtained organic phase was dried and concentrated to obtain a crude 9-aminodeoxyquinine.
  • the aqueous phase was then extracted with ethyl acetate (1 L) (the aqueous phase obtained after extraction was adjusted to pH 9 with ammonia water, and the solids precipitated, and filtered by suction to recover about 9 g of catalyst, recovery rate: 90%).
  • the obtained solid was recrystallized from isopropyl ether to obtain a DBTA salt of (R) -3- ⁇ [(S) -1-nitrilepropyl] aminomethyl ⁇ -hexanoic acid tert-butyl ester.
  • the obtained solid was added to a mixed solvent of water (40 ml) and methyl tert-butyl ether (60 ml), and the mixture was adjusted to a pH of 7 (aqueous layer) with a 0.6N sodium hydroxide solution while stirring. It was allowed to stand, separated, and the organic phase was washed with water (30 ml * 2), saturated brine (30 ml), and dried over anhydrous sodium sulfate.
  • the obtained solid was recrystallized from ethyl acetate / n-heptane to obtain (R)- Camphor sulfonate of tert-butyl 3- ⁇ [(S) -1-nitrilepropyl] aminomethyl ⁇ -hexanoate.
  • the obtained solid was added to a mixed solvent of water (10 ml) and methyl tert-butyl ether (20 ml), and the mixture was adjusted to a pH of 7 (aqueous layer) with a 0.6N sodium hydroxide solution while stirring.
  • the mother liquors obtained in the method 1 of Example 8 were combined and concentrated and added to a concentrated hydrochloric acid (36-38 wt%) aqueous solution, and stirred at room temperature until the protective group was completely removed.
  • the mixture was adjusted to pH 14 or higher with sodium hydroxide, stirred at 50 to 60 ° C. for about 6 hours, and then adjusted to pH 6 to 7 with 5% dilute hydrochloric acid in an ice-water bath.
  • the mixture was extracted three times with dichloromethane, and the organic phase was concentrated to remove most of the solvent to obtain a crude diastereoisomeric mixture (3R) -3- ⁇ [(1-nitrylpropyl) amino] methyl ⁇ -hexanoic acid .
  • the diastereomeric mixture was purified according to the method 1 of Example 8 to obtain chiral pure (R) -3- ⁇ [(S) -1-nitrilepropyl] aminomethyl ⁇ -hexanoic acid tert-butyl ester.
  • (R) -3- (aminomethyl) -hexanoic acid (290g, 2mol) was added to water (4L), and the mixture was adjusted to pH 10 with 4M sodium hydroxide, heated to 55 to 65 ° C, and sodium nitroprusside was added. (890g, 3mol), 4M sodium hydroxide solution was added dropwise during the addition to maintain the pH of the reaction solution at about 10. After the dropwise addition, the mixture was stirred at 55 to 65 ° C for 6 hours. The reaction was stopped, the mixture was cooled to 10 to 25 ° C, the reaction solution was filtered through celite, and the filtrate was adjusted to pH 1 with concentrated hydrochloric acid. Heat to 55 to 65 ° C and stir for 4 hours.
  • the resulting filtrates were combined, transferred to a reaction flask, heated to 50 to 60 ° C, and acetic acid (0.3g, 5mmol) was added dropwise. ). After the addition is complete, stir at 50 to 60 ° C for about 1 hour. After cooling to 15 to 25 ° C, suction filtration was performed. The filtrate was washed with water (10 ml * 2), saturated sodium bicarbonate solution (10 ml), saturated brine (10 ml) in this order, and dried over anhydrous sodium sulfate. It was concentrated to a volume of about 5 ml, and n-heptane (30 ml) was added dropwise under stirring, and the solid gradually precipitated.

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Abstract

La présente invention concerne un procédé de préparation de brivaracétam et de ses intermédiaires. Le procédé de préparation de brivaracétam selon la présente invention utilise des matières premières ayant une structure simple et un faible prix, et peuvent être facilement obtenues. Les étapes du procédé de préparation ont des conditions de réaction modérées, un mode opératoire simple, n'ont aucune exigence en termes de faible température ou de condition stricte anhydre et sans oxygène, aucun moyen de séparation spécial, et par conséquent le procédé de préparation est approprié pour une production industrielle.
PCT/CN2018/105203 2018-09-12 2018-09-12 Procédé de préparation de brivaracétam et de son intermédiaire WO2020051796A1 (fr)

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CN201980059753.0A CN112739683B (zh) 2018-09-12 2019-09-10 布瓦西坦的制备方法及其中间体
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CN112939900A (zh) * 2019-12-10 2021-06-11 广东东阳光药业有限公司 一种布瓦西坦中间体的制备方法
EP4282971A1 (fr) 2022-05-23 2023-11-29 Divi's Laboratories Limited Procédé amélioré de préparation de (r)-4-propyl pyrrolidine-2-one, un intermédiaire clé pour la synthèse du brivaracetam

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CN112143764A (zh) * 2020-09-24 2020-12-29 奥锐特药业股份有限公司 一种生物酶催化制备布瓦西坦中间体化合物的方法
EP4282971A1 (fr) 2022-05-23 2023-11-29 Divi's Laboratories Limited Procédé amélioré de préparation de (r)-4-propyl pyrrolidine-2-one, un intermédiaire clé pour la synthèse du brivaracetam
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JP7402935B2 (ja) 2022-05-23 2023-12-21 ディヴィズ・ラボラトリーズ・リミテッド ブリバラセタムの合成のための重要な中間体である（ｒ）－４－プロピルピロリジン－２－オンの調製のための改良されたプロセス
US11884623B2 (en) 2022-05-23 2024-01-30 Divi's Laboratories Ltd. Process for the preparation of (R)-4-propyl pyrrolidine-2-one, a key intermediate for synthesis of brivaracetam

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