WO2020052545A1

WO2020052545A1 - Method for preparing brivaracetam and intermediates thereof

Info

Publication number: WO2020052545A1
Application number: PCT/CN2019/105111
Authority: WO
Inventors: 郭朋; 刘凤伟; 任建笑; 朱文峰
Original assignee: 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
Priority date: 2018-09-12
Filing date: 2019-09-10
Publication date: 2020-03-19
Also published as: CN112739683B; WO2020051796A1; CN112739683A

Abstract

A method for preparing Brivaracetam, intermediates thereof and a method for preparing the intermediates. The raw materials for the method have simple structures, low price and are easy to access. All the steps have mild reaction conditions and are easy to operate, do not have requirements for low temperature or strictly anhydrous and anaerobic conditions, do not have special separation means, and are suitable for industrial production.

Description

Preparation method of bovaacetam and its intermediate

This application claims priority from PCT application PCT / CN2018 / 105203, filed on September 12, 2018. The contents of that application are incorporated herein by reference in its entirety.

Technical field

The present application relates to the field of medicinal chemistry, and in particular to a method for preparing bovaracetam (I) and its related intermediates.

Background technique

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). The results of clinical trials show that bovaracetam can significantly reduce the frequency of partial seizures and improve the response rate. It has good antiepileptic activity and high safety.

There are two chiral centers in the structure of Boisacetam, and the overall synthesis is difficult. WO2017 / 076738 and WO2005 / 028435 report the following synthetic methods to obtain a mixture of diastereomers of bovaracetam by condensation, amination, and hydrogenation. Although it uses asymmetric hydrogenation conditions, the chiral selectivity is not high, and still requires chiral separation to obtain optically pure bovaracetam.

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. However, 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.

Summary of the Invention

In one aspect, the invention relates to a method for preparing boisacetam of formula I, which method comprises steps (A)-(D):

(A) reacting an alcohol of formula R ₁ OH with a compound of formula III to prepare a compound of formula IV

Wherein R ₁ is C _1-6 alkyl;

(B) Ammonialysis of a compound of formula IV to prepare a compound of formula V

(C) Preparation of a compound of formula VI from a compound of formula V

(D) Preparation of bovaracetam of formula I from a compound of formula VI

In one embodiment of the production method of the present invention, step (D) includes

Step (D-1): protecting the carboxyl group in the compound of formula VI to prepare a compound of formula VII

Where R ₂ is a protecting group with steric hindrance effect;

Step (D-2): reacting a compound of formula VII with 2-hydroxybutyronitrile to prepare a compound of formula VIII

Step (D-3): The compound of formula VIII is resolved to prepare a compound of formula IX

Step (D-4): intramolecular amidation of the compound of formula IX to prepare a compound of formula XI

Step (D-5): Hydrolyzing a compound of formula XI to prepare bovaracetam of formula I

In another optional embodiment of the preparation method of the present invention, step (D) includes

Step (D-i): preparing a compound of formula XIII from a compound of formula VI

Step (D-ii): Preparation of bovaracetam of Formula I from a compound of Formula XIII

In yet another aspect, the invention also relates to a method for preparing a compound of formula XIII, the method comprising steps (a)-(d):

Wherein R ₁ is C _1-6 alkyl;

(b) subjecting a compound of formula IV to ammonolysis to prepare a compound of formula V

(c) Preparation of a compound of formula VI from a compound of formula V

(d) Preparation of a compound of formula XIII from a compound of formula VI

detailed description

The technical content of the present invention will be described below through specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

General terms and definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the definition provided in this application shall prevail. When a trade name appears herein, it is intended to refer to its corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

The terms "about" and "approximately" when used in conjunction with a numerical variable generally mean that the value of the variable and all values of the variable are within experimental error (for example, within a 95% confidence interval for the mean) or within ± 10 of a specified value %, Or a wider range.

The term "optional" or "optionally present" means that the event or situation described later may or may not occur, and the description includes the occurrence or non-occurrence of the event or situation.

The expression "comprising" or similar expressions "including," "containing," and "having" are open-ended, and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of" excludes any element, step, or ingredient not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps or ingredients, plus elements, steps or ingredients that are optionally present and do not substantially affect the basic and new characteristics of the claimed subject matter. It should be understood that the expression "comprising" covers the expressions "consisting essentially of" and "consisting of".

The term "one or more" or "at least one" can mean one, two, three, four, five, six, seven, eight, nine (one) or more (A).

The ranges listed herein (such as numerical ranges) can encompass each value in the range and each sub-range formed by each value. For example, the expression "reaction temperature is -20 ° C to 25 ° C" 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. should also be understood in a similar manner. For example, 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.

Unless otherwise stated herein, the singular forms refer to “a”, “an”, and “the”, and include the plural referents. Unless otherwise stated, the concentration is by weight, the proportion of liquid in the mixed solution is calculated by volume, and 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. For a detailed description of the selection method of the protecting group, as well as the addition and removal, please refer to: T.W. Greene, Protecting Groups, Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. 1999.

The term "alkyl", as used herein, alone or in combination with other groups, refers to a saturated linear, branched, or cyclic hydrocarbon group. As used herein, the term "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. For example, "C _1-6 alkyl" may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo Amyl, 3-methylpentane-3-yl, hexyl (e.g. 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.

The term "olefin" refers to a non-aromatic linear, branched or cyclic hydrocarbon having one or more carbon-carbon double bonds. For example, as used herein, the term "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. Examples of 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.

The term "alkenyl", as used herein alone or in combination with other groups, 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. For example, an alkenyl group obtained by removing a hydrogen atom from a carbon atom of propylene is called a propenyl group. The term "C _2-6 alkenyl" refers to an alkenyl group having 2-6 (eg, 2, 3, 4, 5, 6) carbon atoms. Examples of C _2-6 alkenyl include, but are not limited to, 2-butenyl, 2-pentenyl, 2-hexenyl, 3-hexenyl, 2-methyl-2-pentenyl, isobutenyl, and Isopentenyl and the like.

The term "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.

The term "alkane-based" solvent refers to a solvent of a saturated linear, branched or cyclic hydrocarbon having 1 to 10 carbon atoms. Examples of the 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.

The term "ester" solvent refers to a solvent of an ester having 3 to 10 carbon atoms. Examples of the 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.

The term "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.

The term "aromatic" solvent refers to a solvent of an aromatic hydrocarbon having 6 to 14 carbon atoms. Examples of the aromatic solvent include, but are not limited to, benzene, toluene, xylene, ethylbenzene, or a combination thereof, preferably toluene.

The signs and common sense, diagrams, and examples used in the reaction are consistent with current scientific literature, such as those used in the Journal of the American Chemical Society or the Journal of Biochemistry. Unless otherwise stated, all starting materials used were purchased from market suppliers and used without further purification.

As is well known in the art, linkages between atoms and other atoms may lead to the presence of stereoisomers (such as chiral centers). For example, 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.).

The expression "optically pure" as used herein 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.

The expression "diastereomeric enrichment" as used herein 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.

The term "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. The expression "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.

Synthetic routes and intermediate compounds

In one aspect, the present invention relates to a method for preparing boisacetam of formula I, which method comprises the following steps (A)-(D):

Step (A): reacting an alcohol of formula R ₁ OH with a compound of formula III to prepare a compound of formula IV

Wherein R ₁ is C _1-6 alkyl.

In one embodiment, 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. In a preferred embodiment, R ₁ is C _1-3 alkyl, especially C ₁ alkyl (ie, R ₁ OH is methanol).

In one embodiment, step (A) is performed in a solvent. In a specific embodiment, the solvent is selected from the group consisting of aromatic solvents, ether solvents and mixed solvents thereof. In one embodiment, the aromatic solvent is toluene. In one embodiment, 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.

In a preferred embodiment, the quinine derivative catalyst is selected from:

In a particular embodiment, the quinine derivative catalyst is:

That is Q-BTBSA.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, the 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.

The process design of 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. When quinine derivative Q-BTBSA is used as a catalyst, the crude yield can reach 100%. The crude product is used in the next step of the ammonolysis reaction to obtain an optically pure compound of formula V (ee = 100%), so it is easy to achieve industrialized large-scale production.

In one embodiment of the preparation method of the present invention, 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 ') before step (A): preparing a compound of formula III from a compound of formula II

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. In one embodiment, the compound of formula II is dehydrated in an anhydride system. In another embodiment, the reaction temperature is from 100 ° C to 150 ° C. In yet another embodiment, the acid anhydride system is acetic anhydride.

Step (B): Ammonialyzing the compound of formula IV to prepare a compound of formula V

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.

In one embodiment, 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.

In one embodiment, the reaction using C ₁ -C ₆ alcohols (such as methanol) as the solvent. In another embodiment, the reaction is performed directly in an ammonia system without using a solvent.

In one embodiment, 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.

In another embodiment, the ammonolysis reaction is performed in the presence of an ammonium chloride catalyst. In a preferred embodiment, the reaction conditions are normal pressure reactions catalyzed by ammonium chloride.

In one embodiment, the reaction temperature of step (B) is 20 ° C to 60 ° C.

Step (C): Degrading the amide group of the compound of formula V to an amino group to prepare a compound of formula VI

In one embodiment, 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. In one embodiment, the molar equivalent of halogen relative to the compound of formula V is 1-5. In a preferred embodiment, the halogen is selected from bromine, chlorine and mixtures thereof.

In a preferred embodiment, 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.

In one embodiment, the reaction temperature is from 0 ° C to 100 ° C.

Step (D): Preparation of bovaracetam of formula I from a compound of formula VI

(I)

In one embodiment of the preparation method of the present invention, step (D) includes steps (D-1) to (D-5):

Among them, R ₂ is a protecting group having a steric hindrance effect.

In a preferred embodiment, 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.

In one embodiment, R ₂ is C _1-6 alkyl. In a preferred embodiment, R ₂ is C _3-5 alkyl, more preferably C ₄ alkyl, especially tert-butyl.

In one embodiment of step (D-1), the carboxyl group is protected by an esterification reaction.

In one embodiment, the compound of formula VI with an alcohol compound (R ₂ OH) prepared by reacting an acid of formula VII in the system. In a specific embodiment, the compound of formula VI is reacted with an alcohol (R ₂ OH) in an acidic system at 0 ° C to 100 ° C. In one embodiment, the acidic system is selected from the group consisting of sulfoxide, acetyl chloride, and hydrogen chloride / alcohol solution. In one embodiment, 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.

In another embodiment, 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. For example, in a specific embodiment, a compound of formula VI is reacted with an olefin under conditions of concentrated sulfuric acid at 0 ° C to 50 ° C. In one embodiment, the olefin is a C _2-6 olefin, preferably a C _3-5 olefin, especially a C ₄ olefin. In a particular embodiment, the olefin is isobutylene.

In one embodiment, the reaction is performed in the presence of a water-binding agent. Examples of 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.

In one embodiment, the reaction temperature of step (D-2) is 0 ° C to 50 ° C.

In one embodiment, 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. In one embodiment, the purification is performed by precipitation of a salt. In one embodiment, the precipitation of the salt is performed at -20 ° C to 40 ° C, preferably 0 ° C to 15 ° C. In one embodiment, the compound of formula IX is obtained by freeing the precipitated salt by alkali-adjusting the pH to 10-11.

In another embodiment, 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.

In one embodiment, the solvent used is an ether solvent, an alkane solvent, an ester solvent, or a mixed solvent thereof. In one embodiment, the ether-based solvent is selected from the group consisting of isopropyl ether, methyl tert-butyl ether, and mixtures thereof. In another embodiment, the alkane-based solvent is selected from heptane, hexane, and mixtures thereof. In one embodiment, the ester solvent is ethyl acetate.

In one embodiment, 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. In another embodiment, the chiral acid is selected from L-tartaric acid, L-dibenzoyltartaric acid, L-di-p-methylbenzotartaric acid, L-camphorsulfonic acid, and combinations thereof. In one embodiment, the chiral acid is selected from the group consisting of D-tartaric acid, D-dibenzoyltartaric acid, D-di-p-methylbenzotartaric 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.

In one embodiment, 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.

In one embodiment, the reaction temperature of step (D-4) is 0 ° C to 50 ° C.

In one embodiment, the reaction is performed under acidic conditions. Useful acids include, but are not limited to, sulfuric acid, hydrochloric acid, and mixtures thereof.

In one embodiment, the reaction temperature of step (D-5) is 30 ° C to 80 ° C.

In another embodiment, the method of the present invention optionally further comprises the following steps between steps (D-3) and (D-4):

Step (D-3 '): preparing a compound of formula VIII from a compound of formula X which is a by-product of step (D-3)

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:

In one embodiment, after the compound of formula X is deprotected from the R ₂ group, 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. In one embodiment, the compound of formula X is deprotected in the presence of hydrochloric acid. In a preferred embodiment, 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. In one embodiment, the cyano alpha carbon is racemic under basic and heating conditions. In one embodiment, the pH of the reaction system of the racemization reaction is 14 or more. In another embodiment, the reaction temperature of the racemization reaction is from 50 ° C to 60 ° C.

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).

In one embodiment, after deprotection of the compound of formula X and racemization under basic conditions, 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.

In another aspect, the present invention also relates to an intermediate used for the preparation of bovaracetam of formula I, selected from:

Where R _{2 is} as defined above.

(II)

In another optional embodiment of the preparation method of the present invention, step (D) includes steps (D-i) to (D-ii):

Step (D-i): preparing a compound of formula XIII from a compound of formula VI

In one embodiment, the compound of formula VI is reacted with a diazotizing agent and further ring-closed to form a lactone compound of formula XIII. Examples of diazotizing agents include, but are not limited to, sodium nitrite, nitrite (eg, isoamyl nitrite, t-butyl nitrite), sodium nitroprusside, or a combination thereof. In one embodiment, the nitrosate is an alkyl nitrite.

In one embodiment, the temperature of the diazotization reaction is from -10 ° C to 10 ° C.

In one embodiment, 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.

In an exemplary embodiment, step (D-ii) includes

(1) Reaction of a compound of formula XIII in a hydrogen bromide solution to open a ring to prepare (R)-(γ) -bromo-3-propylbutyric acid

In one embodiment, the reaction is performed in a hydrobromic acid solution.

(2) reacting (R)-(γ) -bromo-3-propylbutyric acid with ethanol to prepare (R)-(γ) -bromo-3-propylbutyric acid ethyl ester

(3) reacting (R)-(γ) -bromo-3-propylbutyric acid ethyl ester with (S) -2-aminobutyramide hydrochloride to prepare bovaracetam

In one embodiment, the reaction is performed in the presence of a base and tetrabutylammonium iodide.

(III)

In another optional embodiment of the preparation method of the present invention, step (D) includes steps (D-I)-(D-II):

Step (D-I): Closing the compound of formula VI itself to form a lactam compound of formula XIV

In one embodiment, the compound of formula VI forms a compound of formula XIV in the presence of a condensing agent. In one embodiment, the condensing agent is selected from the group consisting of DCC, EDCI, CDI, and combinations thereof. In another embodiment, the compound of formula VI closes itself to the compound of formula XIV in the presence of an acid chloride-forming reagent. In one embodiment, the acid chloride-forming reagent is sulfoxide.

In one embodiment, the ring closure reaction temperature of the compound of Formula VI is from 0 ° C to 50 ° C.

Step (D-II): Preparation of bovaracetam of formula I from a compound of formula XIV

In one embodiment, 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.

Method for preparing compound of formula XIII

In yet another aspect, 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:

Wherein R ₁ is C _1-6 alkyl.

In a preferred embodiment, the quinine derivative catalyst is selected from the following compounds:

In a particular embodiment, the quinine derivative catalyst is:

That is Q-BTBSA, (N-((S)-(6-methoxyquinolin-4-yl) ((1S, 2S, 4S, 5R) -5-vinylquinuclidin-2-yl) methyl) -3,5-bis ( trifluoromethyl) benzenesulfonamide).

In one embodiment, 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.

The process design of 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 crude product is used in the next step of the ammonolysis reaction to obtain an optically pure compound of formula V (ee = 100%), so it is easy to achieve industrialized large-scale production.

In one embodiment, the reaction temperature of step (b) is 20 ° C to 60 ° C.

In one embodiment, the reaction temperature is from 0 ° C to 100 ° C.

Step (d): preparing a compound of formula XIII from a compound of formula VI

Beneficial effect

Compared with the prior art, the method described in this application has the advantages of high yield, simple method, high chiral purity, and low production cost:

1. 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.

An asymmetric ring opening was used to construct the absolute configuration of the chiral carbon center at the n-propyl position. High optical selectivity, quantitative reaction conversion, catalyst recovery, no need to use expensive and toxic precious metals. It also avoids the difficult to separate isomers, eliminates the high-cost preparative chiral separation operation, and is suitable for industrial production.

3. 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.

Examples

The following examples are provided for illustrative purposes only and should not be construed as limiting the invention.

NMR spectra were recorded on a BRUKER AC 250 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.

HPLC conditions

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.

GC conditions

An Agilent GC 7890B system equipped with an Agilent DB-624 30m × 0.320mm, 1.8um column was used for analysis. The column temperature rise mode was: from 50 ° C to 260 ° C at a rate of 15 ° C / min.

Chiral HPLC conditions (compound (S) -3-n-propylglutaric acid monoamide)

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.

Chiral HPLC conditions (compound (R) -3- (aminomethyl) -hexanoic acid, compound (R) -3- (aminomethyl) -hexanoic acid methyl ester hydrochloride)

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.

Chiral HPLC conditions (Compound 2-[(R) -2-oxo-4-n-propylpyrrole-1-yl] -butyronitrile, compound (S) -2-[(R) -2-oxo- 4-n-propylpyrrole-1-yl] -butyronitrile)

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.

Chiral HPLC conditions (Compound (3R) -3-{[(1-Nitrilpropyl) amino] methyl} -hexanoic acid tert-butyl ester, Compound (R) -3-{[(S) -1-nitrilepropyl (Amino) aminomethyl} -hexanoic acid tert-butyl ester, compound 2-[(R) -2-oxo-4-n-propylpyrrole-1-yl] -methyl butyrate)

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.

Chiral HPLC conditions (Boisacetam)

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.

Example 1 : Preparation of 3-n-propylglutaric anhydride

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%. ¹ H NMR (CDCl ₃ , 400 MHz): δ = 2.90 (dd, J = 17.6 Hz, J = 4.8 Hz, 2H), 2.44 (dd, J = 17.2 Hz, J = 10.0 Hz, 2H), 2.17-2.21 ( m, 1H), 1.37-1.42 (m, 4H), 0.96 ppm (t, J = 5.2 Hz, 3H).

Example 2 : Preparation of a catalyst

Quinine (16g, 0.049mol) and triphenylphosphine (16g, 0.06mol) were added to THF (250ml), the mixture was cooled to 0 to 5 ° C, DEAD (10g, 0.059mol) was added, and DPPA (17g 0.059mol) of THF (100ml) solution into the system. After the dropwise addition is complete, the mixture is warmed to room temperature and stirred for 12 hours. The mixture is then heated to 45 to 55 ° C and stirred for 2 hours. Triphenylphosphine (17g, 0.065 mol), stirring was continued at 45 to 55 ° C for about 4 hours. The mixture was cooled to room temperature, water (5 ml) was added, and the mixture was stirred at room temperature for 12 hours. 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 obtained 9-aminodeoxyquinine was added to DCM (150 ml), sulfonyl chloride (16 g, 0.052 mol) and triethylamine (5.6 g, 0.055 mol) were added, and the mixture was stirred at 15 to 30 ° C for 16 hours. Water (100 ml) was added to quench the reaction. The organic phase was separated, dried, and concentrated. The residue was purified by column chromatography (eluted with ethyl acetate) to obtain about 22 g of a white solid, HPLC purity: 98%, optical rotation: [α] D ²⁰ = + 16.3 (c = 1.0 , CHCl ₃ ), yield: 74%. ¹ H NMR (DMSO-d ⁶ , 400MHz): δ = 8.48 (d, J = 4.8Hz, 1H), 7.59-7.80 (m, 4H), 7.38-7.47 (m, 3H), 5.88 (dd, J = 16.4Hz, J = 5.2Hz 1H), 5.26 (d, J = 10.0Hz 1H), 5.04-5.12 (m, 2H), 4.01 (s, 3H), 3.40-3.66 (m, 2H), 2.97-3.06 ( m, 2H), 2.50-2.56 (m, 1H), 1.76-1.83 (m, 3H), 1.50-1.54 (m, 1H), 1.26-1.36 ppm (m, 2H).

Example 3 : Preparation of (R) -3-n-propylglutaric acid monomethyl ester

method 1

Q-BTBSA (5.7g, 0.01mol) was added to methyl tert-butyl ether (1.5L), stirred to fully dissolve, 3-n-propylglutaric anhydride (30g, 0.19mol) was added, and the mixture was cooled to- 5 to 5 ° C, methanol (62g, 1.9mol) was added dropwise, and the mixture was stirred at -5 to 5 ° C for about 6 hours. The solvent was concentrated and removed. Ethyl acetate (1L) was added to the mixture, and the mixture was washed with 1M hydrochloric acid (600ml). 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 organic layers were combined and used. It was washed with saturated brine (500 ml), dried over anhydrous sodium sulfate, and concentrated to obtain 36 g of crude product. The crude product yield was 100%, which was directly used in the next reaction. Chiral analysis of the next product revealed that the two-step reaction product ee = 100%. ¹ H NMR (CDCl ₃ , 400 MHz): δ = 3.69 (s, 3H), 2.39-2.41 (m, 5H), 1.35-1.37 (m, 4H), 0.93 ppm (t, J = 5.2 Hz, 3H).

Method 2

Quinine (3.6 g, 11 mmol) was added to toluene (50 ml), which was fully dissolved under stirring, 3-n-propylglutaric anhydride (1.5 g, 9.6 mmol) was added, and the mixture was cooled to -60 to -70 ° C. Methanol (2.4 g, 76.5 mmol) was added dropwise, and the mixture was stirred at -60 to -70 ° C for about 12 hours. The solvent was removed by concentration, methyl tert-butyl ether (60 ml) was added, and 2M hydrochloric acid (20 ml * 3) was used, followed by saturation. The solution was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The concentrated solution was purified by column chromatography to obtain 1.6 g of a colorless liquid, GC purity: 97%, ee = 61%, and yield: 89%.

Method 3

Propargylquinine (8.2g, 22mmol) was added to toluene (64ml), and it was fully dissolved under stirring. 3-N-propylglutaric anhydride (5g, 32mmol) was added, and the mixture was cooled to -15 to -10 ° C. Methanol (10g, 320mmol) was added dropwise, and the mixture was stirred at -15 to -10 ° C for about 8 hours. The solvent was concentrated and removed. Methyl tert-butyl ether (150ml) was added, followed by 2M hydrochloric acid (40ml * 3) and saturated common salt. It was washed with water (20 ml), dried over anhydrous sodium sulfate, and concentrated. The concentrated solution was purified by column chromatography to obtain 5.6 g of a colorless liquid, GC purity: 96%, ee = 24%, and yield: 93%.

Example 4 : Preparation of (S) -3-n-propylglutaric acid monoamide

(R) -3-N-propyl glutaric acid monomethyl ester (35 g, 0.19 mol) was added to aqueous ammonia (300 ml), ammonium chloride (11.2 g, 0.21 mol) was added, and the mixture was stirred at 40 to 50 ° C. After about 16 hours of reaction, HPLC showed that the starting material (R) -3-n-propylglutaric acid monomethyl ester had almost disappeared. The reaction was stopped, the mixture was cooled to 0 to 15 ° C, and the pH was adjusted to 2 with concentrated hydrochloric acid. The solid precipitated and was filtered off with suction to obtain a white solid.

The obtained solid was added to a mixed solvent of ethyl acetate (160 ml) and water (15 ml), and the mixture was heated to 55-65 ° C. After the solid was completely dissolved, the temperature was maintained and stirred for 0.5 hours. After cooling to 0-10 ° C, the solid was precipitated and filtered by suction to obtain 22 g of a white solid, purity: 98.0%, ee = 100%, two-step yield: 70%. ¹ H NMR (DMSO-d6, 400MHz): δ = 12.03 (s, 1H), 7.29 (s, 1H), 6.76 (s, 1H), 1.98-2.24 (m, 5H), 1.24-1.31 (m, 4H ), 0.86ppm (t, J = 5.2Hz, 3H).

Example 5 : Preparation of (R) -3- (aminomethyl) -hexanoic acid

Sodium hydroxide (12.2g, 0.3mol) was added to water (40ml). After dissolving, the mixture was cooled to 15-25 ° C, and (S) -3-n-propylglutaric acid monoamide (10g, 0.06mol) was added. After the solution is completely dissolved, the mixture is cooled to -5 to 5 ° C, and bromine (13.4g, 0.08mol) is added dropwise. During the dropwise addition, the solution changes from clear to turbid. After the drop, the solution becomes a light yellow clear solution. After stirring at -5 to 5 ° C for 10 minutes, heat to 60 to 70 ° C and stir for about 0.5 hours. TLC showed that the intermediate state (isocyanate) of the starting material completely disappeared, and the reaction was stopped. The mixture was cooled to 30 to 40 ° C, extracted once with methyl tert-butyl ether (40 ml), the organic phase was discarded, the aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid, and concentrated. The resulting concentrated solution was subjected to dichloromethane / methanol (30ml / 10ml) after pulping, suction filtration, and the filtrate was concentrated to obtain about 9.2g of brown liquid, GC purity: 98%, ee = 100%. Yield: 100%, used directly in the next reaction. ¹ H NMR (D ₂ O, 400MHz): δ = 2.85-2.96 (m, 2H), 2.15-2.28 (m, 2H), 2.01-2.05 (m, 1H), 1.24-1.31 (m, 4H), 0.83 ppm (t, J = 5.2Hz, 3H).

Example 6 : Preparation of (R) -3- (aminomethyl) -hexanoic acid tert-butyl ester

(R) -3- (aminomethyl) -hexanoic acid (6.4 g, 0.04 mol) was added to 1,4-dioxane (80 ml), concentrated sulfuric acid (5 ml) was added, and the mixture was stirred and cooled to 0. At 10 ° C, isobutylene (60 ml) was quickly added, and the reaction was sealed in the reactor for about 16 hours. Cool to 0 to 10 ° C, open the reactor to release the pressure, adjust the pH to 9 with 5N sodium hydroxide solution, extract with methyl tert-butyl ether (100ml * 3), combine the organic phases, and use water (100ml) and saturated brine (100 ml), and dried over anhydrous sodium sulfate. Concentration gave 7.2 g of a pale yellow liquid, yield: 82%. ¹ H NMR (CDCl ₃ , 400MHz): δ = 3.17 (s, 2H), 2.72-2.80 (m, 2H), 2.27-2.29 (m, 2H), 1.90-1.96 (m, 1H), 1.43 (s, 9H), 1.24-1.40 (m, 4H), 0.89ppm (t, J = 6.8Hz, 3H).

Example 7 : Preparation of (3R) -3-{[(1-Nitrilpropyl) amino] methyl} -hexanoic acid tert-butyl ester

(R) -3- (Aminomethyl) -hexanoic acid tert-butyl ester (6.9 g, 0.035 mol) was added to methanol (70 ml), and anhydrous sodium sulfate (21 g, 0.15 mol) and 2-hydroxybutyronitrile ( 3.0 g, 0.035 mol), and the mixture was stirred at 10 to 25 ° C. for about 6 hours to stop the reaction. After suction filtration, the filtrate was concentrated to obtain 7.7 g of a colorless liquid in a yield of 82%. Chiral HPLC: RS / RR / SS / SR = 50/50/0/0, ¹ H NMR (CDCl ₃ , 400 MHz) epimer mixture: δ = 3.40-3.48 (m, 2 * 1H), 2.91 (dd, J = 11.2 Hz, J = 6.0 Hz, 1H), 2.73 (dd, J = 12.0 Hz, J = 4.4 Hz, 1H), 2.63 (dd, J = 11.6 Hz, J = 6.8 Hz, 1H), 2.41 (dd, J = 11.2 Hz, J = 3.6 Hz, 1H), 2.25-2.32 (m, 2 * 2H), 1.96-2.01 (m, 2 * 1H), 1.72-1.81 (m, 2 * 2H), 1.45 (s, 2 * 9H), 1.32-1.36 (m, 2 * 4H), 1.08 (t, J = 7.6Hz, 2 * 3H), 0.91ppm (t, J = 6.0Hz, 2 * 3H).

Example 8 : Preparation of (R) -3-{[(S) -1-nitrilepropyl] aminomethyl} -hexanoic acid tert-butyl ester

method 1

(3R) -3-{[(1-Nitrilopropyl) amino] methyl)}-tert-butylhexanoate (4.5g, 0.017mol) was added to isopropyl ether (30ml), and D-(+) was added -Dibenzoyltartaric acid (DBTA) (4.2g, 0.012mol). After completely dissolving, cool the mixture to 0 to 15 ° C, add a small amount of seeds to induce, and the solid gradually precipitates. Stir the mixture at 0 to 15 ° C. 4 After hours, suction filtration was performed and the solid was washed twice with isopropyl ether (10 ml). 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. Concentrated to give 1.1 g of a colorless liquid, yield: 24%. Chiral HPLC: RS / RR / SS / SR = 99.5 / 0.5 / 0/0, ¹ H NMR (CDCl ₃ , 400 MHz): δ = 3.47 (t, J = 6.8 Hz 1H), 2.93 (dd, J = 11.6 Hz, J = 6.0 Hz, 1H), 2.46 (dd, J = 11.6 Hz, J = 6.0 Hz, 1H), 2.24-2.29 (m, 2H), 1.96-2.04 (m, 1H), 1.77-1.83 (m , 2H), 1.47 (s, 9H), 1.28-1.37 (m, 4H), 1.10 (t, J = 7.2 Hz, 3H), 0.92 ppm (t, J = 6.8 Hz, 3H).

Method 2

(3R) -3-{[(1-Nitrilpropyl) amino] methyl)}-hexanoic acid tert-butyl ester (0.7 g, 2.6 mmol) was added to ethyl acetate (7 ml), and L-camphorsulfonic acid was added (0.21g, 2.6mmol), after the solid is completely dissolved, the mixture is heated to 55 to 65 ° C, n-heptane (7ml) is added, the mixture is cooled to 0 to 15 ° C and stirred, the solid gradually precipitates, and the mixture is at 0 to After stirring at 15 ° C for 4 hours, suction filtration was performed. The solid was washed twice with ethyl acetate / n-heptane = 1/1 (2 ml). 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. It was allowed to stand, separated, and the organic phase was washed with water (10 ml * 2), saturated saline (1 ml), and dried over anhydrous sodium sulfate. Concentrated to obtain 0.4 g of colorless liquid, yield: 57%. Chiral HPLC: RS / RR / SS / SR = 70/30/0/0.

Method 3

(3R) -3-{[(1-Nitrilopropyl) amino] methyl)}-hexanoic acid tert-butyl ester (0.1 g, 0.37 mmol) was added to methyl tert-butyl ether (2 ml), and S- After the mandelic acid (0.071 g, 0.47 mmol) is completely dissolved, the mixture is heated to 45 to 55 ° C, n-heptane (2 ml) is added, and the mixture is cooled to 0 to 15 ° C. The mixture is stirred at this temperature and the solid gradually precipitates The mixture was stirred at 0 to 15 ° C for 4 hours, and then filtered with suction. The solid was washed twice with methyl tert-butyl ether / n-heptane = 1/1 (1 ml) to obtain (R) -3-{[(S) 1-Nitrilepropyl] aminomethyl} -t-butylhexanoate mandelate. The obtained solid was added to a mixed solvent of water (5 ml) and methyl tert-butyl ether (10 ml), and the mixture was adjusted to pH 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 (10 ml * 2), saturated saline (1 ml), and dried over anhydrous sodium sulfate. Concentrated to obtain 0.06 g of colorless liquid, yield: 60%. Chiral HPLC: RS / RR / SS / SR = 44/56/0/0.

Method 4

(3R) -3-{[(1-Nitrilopropyl) amino] methyl)}-t-hexanoic acid tert-butyl ester (1.1 g, 0.04 mol) was added to isopropyl ether (10 ml), and (-) DBTA ( 1.1g, 0.04mol), after completely dissolving, the mixture was cooled to 0 to 15 ° C, and the solid gradually precipitated. The mixture was stirred at 0 to 15 ° C for 4 hours and then filtered with suction. The mother liquor was concentrated and recrystallized in isopropyl ether. This time, the DBTA salt of tert-butyl (R) -3-{[(S) -1-nitrilepropyl] aminomethyl} -hexanoate was obtained. 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. It was allowed to stand, separated, and the organic phase was washed with water (10 ml * 2), saturated brine (10 ml), and dried over anhydrous sodium sulfate. Concentrated to obtain 0.35 g of colorless liquid, yield: 20%. Chiral HPLC: RS / RR / SS / SR = 98/2/0/0.

Example 9 : Recovery of (R) -3-{[(S) -1-nitrilepropyl] aminomethyl} -tert-butylhexanoate crystallization mother liquor

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 . This crude product was obtained in accordance with the method of Example 6 to obtain a diastereomeric mixture (3R) -3-{[(1-nitrylpropyl) amino] methyl} -hexanoic acid tert-butyl ester.

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.

Example 10 : Preparation of (S) -2-[(R) -2-oxo-4-n-propylpyrrole-1-yl] -butyronitrile

(R) -3-{[(S) -1-Nitrilepropyl] aminomethyl} -hexanoic acid tert-butyl ester (1.5 g, 5.6 mmol) was added to dichloromethane (40 ml), and trifluoroacetic acid ( 6.4 g, 56 mmol), the mixture was stirred at 10 to 25 ° C. for about 6 hours, the reaction was stopped, and concentrated. The obtained concentrated solution was dissolved in ethyl acetate (50 ml), washed with water (20 ml) and saturated brine (20 ml), dried, and concentrated. 0.96 g of a pale yellow liquid was obtained, yield: 89%. HPLC purity: 95%, chiral HPLC: RS / RR / SS / SR = 99.5 / 0.5 / 0/0. ¹ H NMR (CDCl ₃ , 400MHz): δ = 5.01 (t, = 5.6Hz, 1H), 3.51 (dd, J = 8.8Hz, J = 7.6Hz, 1H), 3.12 (dd, J = 8.8Hz, J = 7.6Hz, 1H), 2.56 (dd, J = 16.8Hz, J = 8.4Hz, 1H), 2.36-2.48 (m, 1H), 2.12 (dd, J = 16.8Hz, J = 8.4Hz, 1H), 1.87-1.93 (m, 1H), 1.74-1.80 (m, 1H), 1.33-1.49 (m, 4H), 1.03 (t, J = 7.2Hz, 3H), 0.94ppm (t, J = 7.2Hz, 3H ).

Example 11 : Preparation of bovaracetam

(S) -2-[(R) -2-oxo-4-n-propylpyrrole-1-yl] -butyronitrile (0.95g, 5mmol) was added to dichloromethane (2ml), and 95% sulfuric acid was added (1.1 ml, 18 mmol). The mixture was heated to 50 to 60 ° C, and the reaction was stopped after stirring for about 5 minutes. The mixture was cooled to 10 to 25 ° C, water (10 ml), methyl tert-butyl ether (30 ml) were added, and the liquid was separated. The organic phase was sequentially water (10 ml), 5% sodium hydroxide solution (10 ml), and saturated brine (10 ml). ), And dried over anhydrous sodium sulfate. Concentrated to a volume of about 5ml, n-heptane (30ml) was added dropwise to the concentrated solution under stirring, and the solid gradually precipitated. After stirring for about 16 hours, suction filtration was performed to obtain 0.8 g of off-white solid, which was bovaracetam. : 75%. HPLC purity 99%, chiral HPLC: RS / RR / SS / SR = 99.6 / 0.4 / 0/0, ¹ H NMR (CDCl ₃ , 400 MHz): δ = 6.13 (s, 1H), 5.24 (s, 1H) , 4.42 (dd, J = 8.8 Hz, J = 6.8 Hz, 1H), 3.49 (dd, J = 10.0 Hz, J = 8.0 Hz, 1H), 3.00 (dd, J = 10.0 Hz, J = 8.0 Hz, 1H ), 2.58 (dd, J = 17.2 Hz, J = 9.2 Hz, 1H), 2.30-2.37 (m, 1H), 2.07 (dd, J = 17.2 Hz, J = 9.2 Hz, 1H), 1.91-1.98 (m , 1H), 1.63-1.75 (m, 1H), 1.28-1.44 (m, 4H), 0.89-0.93 ppm (m, 6H).

Example 12 : Preparation of (R) -4-n-propylpyrrole-2-one

(R) -3- (aminomethyl) -hexanoic acid (6g, 0.04mol) was added to dichloromethane (80ml), and thionyl chloride (4.3ml, 0.06mol) was added dropwise. After the dropwise addition was completed, the mixture was mixed. Stir at 15 to 35 ° C for about 20 hours. After TLC showed that the raw materials had disappeared, the mixture was concentrated. The resulting concentrated solution was added with dichloromethane (60 ml), washed with saturated sodium bicarbonate solution (25 ml * 2), saturated brine (25 ml), dried, and concentrated to obtain a yellow oily liquid. 4.6 g, HPLC purity: 95%, yield: 90%. ¹ H NMR (CDCl ₃ , 400MHz): δ = 6.25 (s, 1H), 3.48-3.52 (m, 1H), 3.03 (dd, J = 9.6Hz, J = 7.2Hz, 1H), 2.42-2.52 (m , 2H), 1.27-1.49 (m, 4H), 0.93 ppm (t, J = 6.8 Hz, 3H).

Example 13 : Preparation of bovaracetam

Under nitrogen protection, NaH (60%, 0.64g, 16mmol) was added to tetrahydrofuran (20ml) at -5 to 0 ° C, and (R) -4- was added dropwise to the mixture at -5 to 0 ° C. A solution of n-propylpyrrole-2-one (1.3 g, 10 mmol) in tetrahydrofuran (1.5 ml). After the dropwise addition, the mixture was stirred at -5 to 0 ° C for 1 hour. At 0 to 10 ° C, a solution of methyl 2-bromobutyrate (2.4g, 13mmol) in tetrahydrofuran (1.5ml) was added dropwise. After the dropwise addition was complete, the mixture was stirred at 0 to 10 ° C for 1 hour, and then heated to 15 ° C. It was stirred at 25 ° C for 3 hours. The reaction was quenched with saturated ammonium chloride (20 ml), and the organic solvent was removed by concentration. The aqueous phase was extracted with ethyl acetate (40 ml * 2). The organic phases were combined, washed with saturated brine (20 ml), dried, and concentrated. 2 g of a pale yellow liquid was obtained, which was methyl 2-[(R) -2-oxo-4-n-propylpyrrole-1-yl] -butyrate, and the yield was 88%. HPLC: 98%, chiral HPLC: RS / RR / SS / SR = 50/50/0/0. ¹ H NMR (CDCl ₃ , 400 MHz) epimer mixture: δ = 4.71 (dd, J = 10.8 Hz, J = 5.2 Hz, 2 * 1H), 3.73 (s, 2 * 3H), 3.62 (dd, J = 9.2Hz, J = 8.0Hz, 1H), 3.43 (dd, J = 9.2Hz, J = 7.6Hz, 1H), 3.14 (dd, J = 9.2Hz, J = 6.8Hz, 1H), 2.97 (dd , J = 8.8Hz, J = 6.0Hz, 1H), 2.55-2.61 (m, 2 * 1H), 2.32-2.44 (m, 2 * 1H), 1.98-2.18 (m, 2 * 2H), 1.43-1.73 (m, 2 * 1H), 1.20-1.42 (m, 2 * 4H), 0.82-0.98ppm (m, 2 * 6H).

According to the method of US20090318708, 2-[(R) -2-oxo-4-n-propylpyrrole-1-yl] -butyric acid methyl ester can be successfully converted into bovaracetam diastereomers under the action of ammonia The structure can be obtained by chiral preparative chromatography (DAICEL CHIRALPAK AD 20μm, 100 * 500mm column at 30 ° C. 50% EtOH-50% Heptane).

Example 14 : Preparation of (R) -4-propyl-dihydro-furan-2-one

method 1

(R) -3- (aminomethyl) -hexanoic acid (110g, 760mmol) was added to 1M sulfuric acid (1.6L, 1.6mol). After stirring and completely dissolved, the mixture was cooled to -5 to 5 ° C, and sub- A solution of sodium nitrate (220 g, 3.2 mol) in water (1 L). After the dropwise addition, the mixture was stirred at -5 to 5 ° C for 1 hour, then heated to 10 to 25 ° C for about 16 hours, and then heated to 55 to 65 ° C for about 4 hours. The reaction was stopped, extracted with methyl tert-butyl ether (2L * 2), the organic phases were combined, washed with water (500ml * 2), saturated brine (500ml), and dried over anhydrous sodium sulfate. The solvent was removed by concentration, and 46 g of a colorless liquid was obtained through rectification. The GC purity was 96% and the yield was 47%. ¹ H NMR (CDCl ₃ , 400MHz): δ = 4.41 (dd, J = 8.8Hz, J = 7.6Hz, 1H), 3.91 (dd, J = 8.8Hz, J = 6.4Hz, 1H), 2.55-2.64 ( m, 2H), 2.17 (q, J = 8.0 Hz, 1H), 1.43-1.47 (m, 2H), 1.32-1.37 (m, 2H), 0.93 ppm (t, J = 7.2 Hz, 3H).

Method 2

(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 reaction was stopped, the mixture was cooled to 10 to 25 ° C, ethyl acetate (6L) was added and stirred for about 5 minutes, and then filtered through celite. The resulting filtrate was allowed to stand, and the organic phase was separated with water (3L * 2), saturated brine ( 3L) After washing, it was dried over anhydrous sodium sulfate. The solvent was removed by concentration, and 170 g of a colorless liquid was obtained through rectification. The GC purity was 99% and the yield was 77%. The NMR data of the product were consistent with those obtained by Method 1.

Example 15 : Preparation of (R)-(γ) -bromo-3-propylbutyric acid

A solution of (R) -4-propyl-dihydro-furan-2-one (2g, 15.6mmol) in acetic acid (3ml) was dropped to 33% hydrobromide under nitrogen at 0-10 ° C. In solution. After the dropwise addition, the mixture was heated to 75 to 85 ° C and stirred for about 2.5 hours. Stop the reaction, cool the mixture to 10 to 25 ° C, add water (12ml), extract with dichloromethane (12ml * 2), combine the organic phases, wash with water (12ml * 3), saturated brine (12ml), and anhydrous sodium sulfate dry. After concentration, 2.4 g of a brown liquid was obtained with a yield of 74%, which was directly used in the next reaction.

Example 16 : Preparation of (R)-(γ) -bromo-3-propylbutyric acid ethyl ester

(R)-(γ) -Bromo-3-propylbutyric acid (2.4 g, 11.5 mmol) was added to ethanol (10 ml), and concentrated hydrochloric acid (0.25 ml, 3 mmol) was used to catalyze. The mixture was stirred at 35 to 45 ° C. The reaction was stopped after stirring for about 20 hours. The solvent was removed by concentration, and ethyl acetate (20 ml) was added to the residue. The mixture was washed with a 2% sodium hydroxide solution (w / w, 10 ml), water (10 ml * 2), and saturated brine (10 ml) in this order, and anhydrous Dry over sodium sulfate. It was concentrated to obtain 2.3 g of a yellow liquid, GC purity: 87%, yield: 84%, which was directly used in the next reaction. ¹ H NMR (CDCl ₃ , 400MHz): δ = 4.11 (q, J = 7.2Hz, 2H), 3.53 (dd, J = 10.0, 4.0Hz, 1H), 3.46 (dd, J = 10.0, 4.8Hz, 1H ), 2.45 (dd, J = 16.0, 7.2 Hz, 1H), 2.31 (dd, J = 16.0, 6.0 Hz, 1H), 2.24-2.10 (m, 1H), 1.49-1.26 (m, 4H), 1.23 ( t, J = 7.2 Hz, 3H), 0.89 ppm (t, J = 7.2 Hz, 3H).

Example 17 : Preparation of bovaracetam

(R)-(γ) -Bromo-3-propylbutyric acid ethyl ester (2.3 g, 9.7 mmol) was added to isopropyl acetate (20 ml), and (S) -2-aminobutyramide hydrochloride (2.1 g, 15 mmol), sodium carbonate (4.2 g, 40 mmol), tetrabutylammonium iodide (1.1 g, 3 mmol) were subsequently added separately. The mixture was heated to reflux and the reaction was stopped after stirring for about 30 hours. The mixture was cooled to 10 to 25 ° C, filtered, and the filter cake was washed with isopropyl acetate (6ml * 2). 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. The mixture was stirred for about 16 hours, and then filtered with suction to obtain 0.9 g of an off-white solid. Yield: 38%. HPLC purity 99%, chiral HPLC: RS / RR / SS / SR = 99.6 / 0.4 / 0/0. The product characterization NMR data was consistent with that obtained in Example 11.

Although the invention has been illustrated and described with typical embodiments, the invention is not limited to the details. Since various possible modifications and substitutions do not depart from the spirit of the present invention, those skilled in the art can use the variations and equivalents of the present invention that can be conceived by routine experimentation. Therefore, all these variations and equivalents fall within the definition of the following claims. Within the spirit and scope of the present invention.

Claims

A method for preparing boisacetam of formula I, the method comprising:

(A) reacting an alcohol of formula R 1 OH with a compound of formula III to prepare a compound of formula IV

Wherein R 1 is C 1-6 alkyl;

(B) Ammonialysis of a compound of formula IV to prepare a compound of formula V

(C) Preparation of a compound of formula VI from a compound of formula V

(D) Preparation of bovaracetam of formula I from a compound of formula VI
The method of claim 1, wherein step (D) comprises:

(D-1) Preparation of a compound of formula VII from a compound of formula VI

Wherein R 2 is a protecting group with a steric hindrance effect;

(D-2) reacting a compound of formula VII with 2-hydroxybutyronitrile to prepare a compound of formula VIII

(D-3) Resolving a compound of formula VIII to prepare a compound of formula IX

(D-4) Intramolecular amine transesterification of a compound of formula IX to prepare a compound of formula XI

(D-5) Hydrolyzing a compound of formula XI to prepare bovaracetam of formula I
The method of any one of claims 1-2, wherein:

R 2 is C 1-6 alkyl, preferably C 3-5 alkyl, and most preferably tert-butyl.
The method of any one of claims 1-3, wherein

The compound of formula III is prepared by step (A '):
The method of any one of claims 1-4, wherein

Step (A) is performed in the presence of a chiral catalyst, which is a quinine derivative selected from

Preferred
The method of claim 5 wherein

The molar equivalent of the catalyst relative to the compound of formula III is 0.01-1.0, preferably 0.01-0.2, and particularly preferably 0.02-0.1.
The method of any one of claims 1-6, wherein

Step (A) is performed in a solvent selected from the group consisting of aromatic solvents, ether solvents and mixed solvents thereof, preferably toluene, tetrahydrofuran, methyl tert-butyl ether or a mixed solvent thereof.
The method of any one of claims 1-7, wherein

The ammonia used in the step (B) for the ammonialysis reaction is selected from the group consisting of ammonia gas, liquid ammonia, and aqueous ammonia.
The method of any one of claims 1-8, wherein

The reaction conditions of step (C) include:

Under alkaline conditions;

Carried out in the presence of a halogen, preferably the molar equivalent of the halogen relative to the compound of formula V is 1-5; and / or

The reaction temperature is from 0 ° C to 100 ° C.
The method according to any one of claims 2 to 9, wherein the following steps are further included between step (D-3) and step (D-4):

(D-3 ') preparing a compound of formula VIII from a compound of formula X

And optionally a compound of formula VIII is used as a raw material for step (D-3) to participate in the reaction.
The method of any one of claims 2-10, wherein

Step (D-2) is performed in the presence of a water-binding agent,

The water binding agent is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieve, calcium chloride, silica gel, and mixtures thereof.
The method of any one of claims 2-11, wherein

Step (D-3) comprises precipitating the compound of formula VIII and a chiral acid in a solvent, and then freeing the compound of formula IX,

The chiral acid is selected from L-tartaric acid, L-dibenzoyltartaric acid, L-di-p-methylbenzoyltartaric acid, L-camphorsulfonic acid, D-tartaric acid, D-dibenzoyltartaric acid, D- Di-p-toluene tartaric acid, D-camphorsulfonic acid and mixtures thereof.
The method of any one of claims 2-12, wherein

Step (D-4) and / or step (D-5) are performed under acidic conditions.
The method of claim 1, wherein step (D) comprises:

(D-i) Preparation of a compound of formula XIII from a compound of formula VI

(D-ii) Preparation of bovaracetam of formula I from a compound of formula XIII
The method of claim 14 wherein

Step (D-i) is performed in the presence of a diazotizing agent selected from the group consisting of sodium nitrite, nitrite, sodium nitrosoferrocyanide, and combinations thereof.
An intermediate for preparing bovaracetam of formula I, selected from:

Wherein R 2 is as defined in claims 2-13.
A method for preparing a compound of formula XIII, the method comprising:

(a) reacting an alcohol of formula R 1 OH with a compound of formula III to prepare a compound of formula IV

Wherein R 1 is C 1-6 alkyl;

(b) subjecting a compound of formula IV to ammonolysis to prepare a compound of formula V

(c) Preparation of a compound of formula VI from a compound of formula V

(d) Preparation of a compound of formula XIII from a compound of formula VI