Preparation method of cis-trans isomers of spiro[cyclobutane 1,4′-isoquinolinol]one derivatives

Abstract

The present invention provides a novel method for preparing cis and trans isomers of spiro[cyclobutane-1,4'-isoquinoline]-3'-ketone derivatives, particularly a method for selectively synthesizing the cis and trans isomers of 6'-chloro-3-amino-2'-methyl-1', 2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-ketone. The method comprises first isolating cis-6'-chloro-3-hydroxy-2'-methyl-1', 2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-ketone, and then using the cis-6'-chloro-3-hydroxy-2'-methyl-1', 2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-ketone as a raw material, combining the mitsunobu reaction, substitution reaction, reduction reaction, and other steps. The method provided by the present invention significantly improves the yield of the target compound, has a simple operation method, and is suitable for industrial production applications.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis, and specifically relates to a novel method for preparing cis- and trans-isomers of spiro[cyclobutane 1,4′-isoquinoline]-one derivatives, and in particular relates to a method for preparing cis- and trans-isomers of 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivatives. Background Art

[0002] NMDAR (N-methyl-D-aspartate receptor) is an ionotropic glutamate receptor that primarily responds to Ca 2+ Ion-permeable, they become activated upon binding to glycine and glutamate, playing a crucial role in excitatory synaptic plasticity. Physiologically, they activate and trigger the opening of ion channels, generating an input current that inactivates only slowly. In pathological conditions, they can lead to NMDAR overactivation, a key mechanism of receptor excitotoxicity.

[0003] The physiological activity of NMDAR is essential for normal neural function. Excessive activation of NMDAR is involved in acute neurological diseases, such as stroke or traumatic brain injury, and in chronic stress disorders, such as neurodegenerative diseases. Many pathologies are believed to be related to excessive NMDAR activity and are therefore potentially sensitive to NMDAR antagonists ([J]. Journal of neurochemistry, 2006, 97(6):1611-1626.).

[0004] In addition, NMDAR may also mediate peripheral sensitization and visceral pain ([J]. Nature, 2005, 438(7071):1162.) A large amount of preclinical data supports that NMDAR antagonists may treat opioid-induced refractory pain, postoperative pain, and cancer pain.

[0005] PCT / CN2020 / 129826 discloses a series of 1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′-one derivatives, among which 3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′-one and its isomers are a new type of reversible NMDAR antagonist, which belongs to the channel pore blocker (TMD site) and can inhibit the channel opening caused by excessive activation of NMDAR under pathological conditions, thereby avoiding Ca 2+ Compared with the NMDAR antagonists already on the market, this drug not only has significant analgesic and antidepressant activity, but also has the advantage of significantly reducing psychotomi- cal adverse reactions, making it of great clinical value.

[0006] PCT / CN2020 / 129826 also discloses a method for preparing trans-3-amino-6'-chloro-2'-methyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one and cis-3-amino-6'-chloro-2'-methyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one: 3-amino-6'-chloro-2'-methyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one is first synthesized and then the isomers are separated by preparative HPLC to obtain trans and cis isomers, respectively. This method has low separation efficiency and is not suitable for industrial production applications. Summary of the Invention

[0007] The present invention aims to provide a method for preparing cis- or trans-isomers of 1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′-one derivatives at a lower cost and higher conversion rate. Another object of the present invention is to provide a simple method for preparing compound AFaO2.

[0008] First, the first aspect of the present invention provides a method for preparing compound AFa02, comprising the following steps: converting compound AFa00 into compound AFa02 through a cyclization reaction with paraformaldehyde:

[0009]

[0010] Wherein, R1 is hydrogen, methyl or ethyl.

[0011] Preferably, the solvent system for the cyclization reaction of the compound AFa00 with paraformaldehyde is concentrated sulfuric acid, acetic anhydride and acetic acid system, or methanesulfonic acid and phosphorus pentoxide system, or Eaton's reagent.

[0012] In a preferred embodiment, the method for preparing the compound AFa02 comprises the following steps: subjecting the compound AFa00 to a cyclization reaction with paraformaldehyde in the presence of Eaton's reagent as a solvent to convert the compound AFa00 into the compound AFa02.

[0013] Furthermore, in the preparation method of the compound AFa02, the weight ratio of the compound AFa00 to Eaton's reagent is 1:2.5-10, and the reaction temperature is 40-80°C.

[0014] Furthermore, in the preparation method of compound AFa02, the weight ratio of compound AFa00 to Eaton's reagent is 1:4.5 to 9, preferably 1:6 to 9. The reaction temperature is 40 to 80°C, preferably 60 to 80°C.

[0015] In a preferred embodiment, a method for preparing compound AFa02 is provided, comprising the following steps: subjecting compound AFa00 to a cyclization reaction with paraformaldehyde under the action of Eaton's reagent to conversion into compound AFa02, wherein the molar ratio of compound AFa00 to paraformaldehyde is 1:1-2, preferably 1:1.5; the weight ratio of compound AFa00 to Eaton's reagent is 1:2.5-10, preferably 1:4.5-9, more preferably 1:6-9; the reaction temperature is 40-80°C, and the optimal reaction temperature is 60-80°C.

[0016] In a preferred embodiment, a method for preparing compound AFa02 is provided, comprising: reacting compound AFa00 with paraformaldehyde in Eaton's reagent as a solvent under nitrogen protection, heating to 60-80°C to obtain compound AFa02. The molar ratio of compound AFa00 to paraformaldehyde is 1:1-2, preferably 1:1.5, and the weight ratio of compound AFa00 to Eaton's reagent is 1:2.5-10, preferably 1:4.5-9, and more preferably 1:6-9.

[0017] The present invention further provides a method for preparing compound AFa00, comprising reacting compound AF001 with NH2CH2R1 under alkaline conditions:

[0018]

[0019] Wherein, R1 is hydrogen, methyl or ethyl.

[0020] In a preferred embodiment of the present invention, compound AF001 is reacted with NH2CH2R1 in an organic solvent to prepare compound AFa00. For example, NH2CH2R1 is added to compound AF001 and a suitable organic base such as triethylamine in a suitable solvent such as acetonitrile (CH3CN), followed by reaction at 65-75°C for 20-24 hours to obtain compound AFa00.

[0021] A second aspect of the present invention provides a method for preparing compound AFa03, comprising the following steps:

[0022] (a1) preparing compound AFa02 by the method of the present invention, that is, converting compound AFa00 into compound AFa02 through a ring-closure reaction;

[0023] (a2.1) Compound AFa02 is reacted with phthalimide via Mitsunobu reaction to convert it into compound AFa03.

[0024] Alternatively, (a2.2) compound AFa02 is converted into compound AFa04 through a substitution reaction, and then reacted with phthalimide and a base, or with an alkali metal salt of phthalimide, to convert it into compound AFa03;

[0025]

[0026] Wherein, R1 is hydrogen, methyl or ethyl, and LG is a leaving group;

[0027] In a preferred embodiment of the present invention, the step (a2.1) is to react compound AFa02 with phthalimide, triphenylphosphine and an activator to prepare compound AFa03; preferably, the activator is DIAD or DEAD.

[0028] In a preferred embodiment of the present invention, the base in step (a2.2) is selected from triethylamine, diisopropylethylamine, tert-butylisopropyllithium, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide.

[0029] In a preferred embodiment of the present invention, the leaving group LG is an alkylsulfonyl group, an alkenylsulfonyl group, an arylsulfonyl group, a benzyl group, a benzyloxymethyl group or an allyl group; the alkylsulfonyl group, the alkenylsulfonyl group or the arylsulfonyl group is optionally substituted by one or more substituents, wherein the substituents are C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5 Alkyl, nitro or amino;

[0030] Preferably, the leaving group LG is a methanesulfonyl group (Ms) or a p-toluenesulfonyl group (Ts).

[0031] In a third aspect of the present invention, a method for preparing compound AFa is provided, comprising the following steps:

[0032] (b1) preparing compound AFa03 by the method of the present invention;

[0033] (b2) Compound AFa03 is converted into compound AFa through a deprotection reaction;

[0034]

[0035] Wherein, R1 is hydrogen, methyl or ethyl.

[0036] Preferably, compound AFa03 is reacted with ethanolamine to convert it into compound AFa.

[0037] In a preferred embodiment of the present invention, a method for preparing compound AFa is provided, comprising the following steps: subjecting compound AFa00 to a cyclization reaction with paraformaldehyde under the action of Eaton's reagent to conversion into compound AFa02; subjecting compound AFa02 to a Mitsunobu reaction with phthalimide to conversion into compound AFa03, or subjecting compound AFa02 to a substitution reaction to conversion into compound AFa04, which is then reacted with phthalimide and a base, or with an alkali metal salt of phthalimide, to conversion into compound AFa03; and reacting compound AFa03 with ethanolamine to conversion into compound AFa.

[0038] Further preferably, the compound AFa02 is reacted with phthalimide through the Mitsunobu reaction to convert it into compound AFa03 by reacting compound AFa02 with phthalimide, triphenylphosphine and DIAD to prepare compound AFa03; for example, under nitrogen protection, at 0°C±5°C, in a suitable solvent such as THF, compound AFa02, phthalimide, triphenylphosphine and DIAD are added, and then the temperature is raised to room temperature to react to obtain compound AFa03.

[0039] Further preferably, the conversion of compound AFa02 into compound AFa04 through a substitution reaction is carried out by reacting compound AFa02 with methanesulfonyl chloride under organic base conditions to convert it into the corresponding mesylate compound AFa04, and then reacting it with an alkali metal salt of phthalimide (such as potassium salt, sodium salt, etc. of phthalimide) to convert it into compound AFa03. More preferably, for example, under nitrogen protection, compound AFa02, triethylamine and methanesulfonyl chloride are added to a suitable solvent such as dichloromethane at 0°C±5°C, and the temperature is controlled at 20-25°C to react to obtain a mixture of mesylate compound AFa04. After evaporating the solvent, the mixture is dissolved in a suitable solvent such as dimethylformamide without separation, and phthalimide and a base (such as potassium carbonate or cesium carbonate) are added, and the temperature is raised to 70-145°C for reaction to obtain compound AFa03; or the obtained mesylate compound AFa04 mixture is purified through one or more steps of extraction, washing, concentration, crystallization, etc., and then added to a suitable solvent such as cyclopentane, and an alkali metal salt of phthalimide (such as potassium salt, sodium salt, etc. of phthalimide) and KI are added and the temperature is raised to 70-145°C for reaction to obtain compound AFa03.

[0040] Compound AFa03 is reacted with a deprotecting agent such as ethanolamine to convert it into compound AFa. More preferably, compound AFa03 is reacted with ethanolamine at 60-70°C to convert it into compound AFa.

[0041] More preferably, the reagent used in the substitution reaction is a sulfonyl compound, a substituted sulfonyl compound, or an alkyl halide. Preferably, the reagent used in the substitution reaction is methanesulfonyl chloride or p-toluenesulfonyl chloride.

[0042] The reaction scheme is summarized as follows:

[0043]

[0044] Wherein, R1 is hydrogen, methyl or ethyl, and LG is a leaving group.

[0045] The organic base in the above method is selected from triethylamine, diisopropylethylamine, tert-butylisopropyllithium, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS); preferably triethylamine;

[0046] The inorganic base is selected from sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium carbonate or cesium carbonate;

[0047] The leaving group LG is an alkylsulfonyl group, an alkenylsulfonyl group, an arylsulfonyl group, a benzyl group, a benzyloxymethyl group or an allyl group; the alkylsulfonyl group, the alkenylsulfonyl group or the arylsulfonyl group is optionally substituted by one or more substituents, wherein the substituent is C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5 Alkyl, nitro or amino;

[0048] Preferably, the leaving group LG is a methanesulfonyl group (Ms) or a p-toluenesulfonyl group (Ts).

[0049] The fourth aspect of the present invention also provides a method for preparing compound ASa03, comprising the following steps:

[0050] (c1) preparing compound AFa02 by the method of the present invention;

[0051] (c2) Compound AFa02 is converted into compound ASa02 by Mitsunobu reaction.

[0052] (c3) Compound ASa02 is converted into compound ASa03 through substitution reaction with phthalimide;

[0053]

[0054] Wherein, R1 is hydrogen, methyl or ethyl, and LG is a leaving group.

[0055] More preferably, the leaving group LG is an alkylsulfonyl group, an alkenylsulfonyl group, an arylsulfonyl group, a benzyl group, a benzyloxymethyl group or an allyl group; the alkylsulfonyl group, the alkenylsulfonyl group or the arylsulfonyl group is optionally substituted by one or more substituents, wherein the substituents are C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5 Alkyl, nitro or amino;

[0056] More preferably, the leaving group LG is a methanesulfonyl group (Ms) or a p-toluenesulfonyl group (Ts).

[0057] In the above method, preferably, the Mitsunobu reaction of the compound AFa02 in step (c2) is a reaction of the compound AFa02 with MsOH or p-toluenesulfonic acid under the catalysis of triphenylphosphine and an activating agent; the activating agent is preferably DIAD or DEAD;

[0058] In step (c3), the substitution reaction of compound ASa02 with phthalimide is carried out under alkaline conditions; or phthalimide is first reacted with a base to convert it into a corresponding alkaline salt, and then reacted with Asa02 to convert it into compound ASa03;

[0059] The base in step (c3) is triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.

[0060] In a fifth aspect of the present invention, a method for preparing compound Asa is provided, comprising the following steps:

[0061] Compound AFa00 is reacted with paraformaldehyde in the presence of Eaton's reagent to undergo a cyclization reaction to convert it into compound AFa02; compound AFa02 is converted into compound ASa02 through a Mitsunobu reaction; compound ASa02 is converted into compound ASa03 through a substitution reaction with phthalimide; and compound ASa03 is converted into compound ASa through a deprotection reaction. The reaction scheme is summarized as follows:

[0062]

[0063] Wherein, R1 is hydrogen, methyl or ethyl, and LG is a leaving group;

[0064] Preferably, the leaving group LG is an alkylsulfonyl group, an alkenylsulfonyl group, an arylsulfonyl group, a benzyl group, a benzyloxymethyl group or an allyl group; the alkylsulfonyl group, the alkenylsulfonyl group or the arylsulfonyl group is optionally substituted by one or more substituents, wherein the substituent is C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5Alkyl, nitro or amino;

[0065] More preferably, the leaving group LG is a methanesulfonyl group (Ms) or a p-toluenesulfonyl group (Ts).

[0066] In a preferred embodiment of the present invention, the Mitsunobu reaction of compound AFa02 is a reaction of compound AFa02 with MsOH or p-toluenesulfonic acid in the presence of triphenylphosphine and an activating agent (preferably DIAD or DEAD) for catalysis.

[0067] Further preferably, under nitrogen protection, at 0°C±5°C, in a suitable solvent such as THF, compound AFaO2, methanesulfonic acid, triphenylphosphine and an active agent (such as DIAD or DEAD) are added, and the reaction is warmed to room temperature to react and convert into compound ASaO2.

[0068] In a preferred embodiment of the present invention, the substitution reaction of the compound ASa02 with phthalimide is achieved by a substitution reaction under alkaline conditions; or phthalimide is first reacted with a base to convert it into the corresponding alkaline salt, and then reacted with Asa02 to convert it into compound ASa03.

[0069] In a preferred embodiment of the present invention, the conversion of compound ASa03 into compound ASa through a deprotection reaction is achieved by reacting compound ASa03 with ethanolamine.

[0070] In the above method, the base is preferably triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate. According to the method provided by the present invention, those skilled in the art can appropriately adjust the type and amount of the base according to the actual needs of the reaction.

[0071] Terms and abbreviations:

[0072] DIAD: diisopropyl azodicarboxylate;

[0073] DEAD: diethyl azodicarboxylate

[0074] PPh3: triphenylphosphine;

[0075] PhthNH: phthalimide

[0076] PhthNK: Phthalimide potassium salt

[0077] MsCl: methanesulfonyl chloride

[0078] TsCl: p-toluenesulfonyl chloride;

[0079] The term "halogen" as used herein refers to F, Cl, Br or I. In a preferred embodiment of the present invention, the halogen X is selected from Cl, Br or I.

[0080] The term "leaving group" as used herein is independently selected from sulfonyl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl, alkyl, benzyl, benzyloxymethyl or allyl, etc., wherein the alkylsulfonyl, alkenylsulfonyl and arylsulfonyl are optionally substituted with one or more substituents, wherein the substituents are C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5 Alkyl, nitro or amino, etc.; in a preferred embodiment of the present invention, the leaving group LG is independently selected from mesyl, toluenesulfonyl, trifluoromethanesulfonate, nitrobenzenesulfonyl (nosyD), bromobenzenesulfonyl (brosyl), aminosulfonyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, etc., with mesyl and p-toluenesulfonyl being particularly preferred.

[0081] The term "C 1-5 "Alkyl" refers to a straight-chain or branched alkane containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, etc.;

[0082] The term "C 1-5 The term "alkoxy" includes methoxy, ethoxy, propoxy, butoxy, 2-methylpropoxy, tert-butoxy, butoxy and the like; preferably methoxy, ethoxy, propoxy or tert-butoxy.

[0083] The beneficial effects of the present invention are:

[0084] First, the present invention proposes for the first time a method for preparing the compound AFa02 enriched in the cis isomer, which is simple to operate, has high separation efficiency and high yield;

[0085] Secondly, the present invention proposes for the first time a selective synthesis method for preparing compounds AFa and Asa enriched in cis or trans isomers. Compared with the prior art method of first synthesizing a racemate and then separating the isomers from the racemate, this method has high preparation efficiency and saves costs, and is particularly advantageous for the industrial preparation of the trans isomer AFa with higher activity.

[0086] Third, the present invention provides a scheme for converting compound AFa00 into compound AFa02 by reacting compound AFa00 with polyformaldehyde using Eaton's reagent as a solvent for a cyclization reaction. By optimizing the amount of Eaton's reagent and the reaction temperature, the yield of the key chiral intermediate AFa02 is significantly improved, which is beneficial to the improvement of the total yield and preparation of subsequent compounds AFa and Asa. DETAILED DESCRIPTION

[0087] It should be noted that, unless there is any conflict, the embodiments and features in the embodiments of this application can be combined with each other.

[0088] Example 1: Preparation of cis-6′-chloro-3-hydroxy-2′-methyl-1′, 2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′-one (AFb02):

[0089]

[0090] (1): Preparation of cis-4-(3-chlorophenyl)-2-oxabicyclo[2.1.1]hexan-3-one (AF001)

[0091] At 0°C, 37.5 kg of a 2M solution of isopropylmagnesium chloride in THF (2.2 eq) was added to a dry 100-L reactor. A 6-L tetrahydrofuran solution containing 6 kg of m-chlorophenylacetic acid was slowly added to the reactor, causing a large amount of white solid to precipitate. The reaction was then heated to 40°C for 1 hour. The mixture was cooled to 0°C, and 5.855 kg of epichlorohydrin was added dropwise. The reaction was continued at 25°C for 3 hours. The mixture was then cooled to 0°C, and 34.2 kg of a 2M solution of isopropylmagnesium chloride in THF (2.0 eq) was added. The reaction was then heated to 60°C overnight. After complete reaction of the starting materials, the mixture was cooled to 0°C, quenched by the addition of water, and extracted with ethyl acetate. The aqueous phase was adjusted to a pH of 4-5 with dilute sulfuric acid, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 7.5 kg of crude product as a white solid in a 94.3% yield.

[0092] In a 50-L reactor, 4.25 kg of the white solid obtained above was dissolved in 30 L of tetrahydrofuran. The temperature was lowered to 0°C, and 2.28 kg of triethylamine was added. 2.04 kg of ethyl chloroformate was then added dropwise, resulting in the precipitation of a large amount of white solid. The reaction was allowed to proceed at 0°C for 1 hour and then at room temperature for 20 hours. The reaction was monitored by TLC (PE / EA = 5). After completion of the reaction, water was added to quench the reaction, and the mixture was concentrated and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 4.25 kg of crude AF001, a yield of 108%.

[0093] (2): Preparation of cis-1-(3-chlorophenyl)-3-hydroxy-N-methylcyclobutane-1-carboxamide (AF00b)

[0094] In a 500ml single-necked flask, dissolve 21g of intermediate AF001 (101mmol) and 20.4g of methylamine hydrochloride (303mmol) in 180ml of acetonitrile. Cool to -20°C and slowly add 45g of triethylamine (450mmol) dropwise. Stir at this temperature for 1 hour, then raise the temperature to 70°C and stir overnight. After the reaction, add 300ml of water and 400ml of ethyl acetate for extraction. The organic phase is dried and concentrated under reduced pressure to obtain 16g of the title compound in a 65% yield.

[0095] (3): cis-6′-chloro-3-hydroxy-2′-methyl-1′, 2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (AFb02)

[0096] In a 250 ml single-necked flask, 16 g of the intermediate AF00b (66.9 mmol) and 3 g of paraformaldehyde (100 mmol) were dissolved in 96 g of Eaton's reagent. The temperature was raised to 80°C, and then the heating was turned off. The reaction was allowed to react at the residual temperature for about 0.5 to 1 hour. The reaction was monitored by TLC. After the temperature dropped to 0 to 10°C, the reaction solution was poured into 300 mL of ice water and extracted with 400 mL of ethyl acetate. The organic phase was dried and concentrated under reduced pressure using a column chromatography to obtain 14.3 g of the title compound in an 85% yield.

[0097] Comparative Example: Preparation of Compound AFb02 from Compound AF00b under Different Conditions

[0098] The following comparative examples 1.1 to 1.5 further verify the advantages of the technical solution of the present invention by listing some experiments conducted by the inventors on screening reaction conditions during the research and development process.

[0099]

[0100] Comparative Example 1.1: AF00b (1 eq) was reacted with paraformaldehyde (1.5 eq) in the presence of methanesulfonic acid (6 eq) and phosphorus pentoxide at 80°C. After the reaction, the temperature was cooled to room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain the title compound in a yield of 19%.

[0101] Comparative Example 1.2: AF00b (1 eq) was reacted with paraformaldehyde (1.5 eq) in polyphosphoric acid (5 eq) at 180°C. After the reaction, the temperature was cooled to room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain the title compound in a yield of 7%.

[0102] Comparative Example 1.3: AF00b (1 eq) was reacted with paraformaldehyde (1.5 eq) in concentrated sulfuric acid, acetic anhydride, and acetic acid at 140°C. After the reaction, the temperature was cooled to room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain the title compound in a yield of 35%.

[0103] Comparative Example 1.4: Based on the above experiments, the inventors further studied the effect of the amount of Eaton's reagent on the reaction. The test results showed that:

[0104] When the amount of Eaton reagent is less than 2.5 times the amount of AF00b (weight ratio), the reaction stirring effect is poor, resulting in extended reaction time, incomplete reaction of the raw materials, and a more complex reaction, with a reaction yield of about 62%; when the amount of Eaton reagent is greater than 10 times the amount of AF00b (weight ratio), the reaction rate is slow, and the reaction time needs to be extended to 6-8 hours, resulting in a more complex reaction, and a large amount of waste acid will be produced during post-processing, which is not suitable for large-scale industrial production. An Eaton reagent dosage of 4.5 to 9 times is more appropriate, with a short reaction time and a high yield, especially when the Eaton reagent dosage is 6 times, it is the optimal dosage.

[0105] Comparative Example 1.5: Effect of reaction temperature on test results:

[0106] Compound AF00b (66.9 mmol) and 3 g of paraformaldehyde (100 mmol) were dissolved in 30 mL of Eaton's reagent for reaction. The effects of different reaction temperatures on the experimental results were investigated. The effects of reactions at room temperature (25±5°C), 40°C±5°C, 60°C and 80°C±5°C on the reaction results were studied. The experimental results showed that at room temperature (25±5°C), there was basically no reaction; within the same reaction time, when the temperature was below 40°C, the reaction was incomplete and the reaction yield was low. Even with extended reaction time, the reaction still could not be completed; when the temperature was above 80°C, the reaction products were more mixed and the product purity was lower. 40-80°C was a more suitable reaction temperature, among which 60-80°C was the optimal reaction temperature. At this time, the reaction time was short, and the product purity and yield were the most ideal.

[0107] Example 2: Preparation of trans-6′-chloro-3-amino-2′-methyl-1′, 2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (AFb)

[0108]

[0109] (1): Preparation of cis-6′-chloro-2′-methyl-3′-oxo-2′, 3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinolinyl]-3-yl methanesulfonate (AFb04)

[0110] Under nitrogen protection, DCM (35.00 kg), TEA (1.25 kg), and AFbO2 (2.57 kg) were added to the reactor, cooled to 0-5 ° C, and MsCl (1.44 kg) was added dropwise, and the temperature was controlled at 0-25 ° C. After the addition was completed, the temperature was raised to 20-25 ° C and stirred. After the reaction was completed, (5.43 kg) of purified water was added to the reaction solution, stirred, and then allowed to stand for stratification. The aqueous phase was extracted with DCM and the organic phases were combined. It was washed with 2N sodium hydroxide aqueous solution and purified water. After the organic phase was concentrated, n-heptane (9.00 kg) was added and stirred at 15-35 ° C for 1-2 hours. Filtered and the filter cake was dried to obtain 3.32 kg of compound AFbO4, with a yield of 97.48% and a purity of 98%.

[0111] (2): Preparation of 2-trans-6′-chloro-2′-methyl-3′-oxo-2′, 3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinolin]-3-yl)isoindoline-1,3-dione (AFb03)

[0112] Under nitrogen protection, cyclopentane (40.00 kg), PhthNK (2.20 kg), KI (0.33 kg), and AFb04 (3.30 kg) were added to the reactor at 15-35 ° C., the temperature was raised to 140-145 ° C, and stirred. After the reaction was completed, the reaction solution was cooled to 40-45 ° C. At the same time, purified water (66.80 kg) was added to another reactor, the reaction solution was added to pure water, stirred at 15-35 ° C for 1-2 hours, centrifuged, and the filter cake was washed with purified water. The wet filter cake was added to purified water, stirred for 1-2 hours, centrifuged, and the filter cake was washed with purified water. The wet filter cake was added to DCM, stirred for 14-16 hours, centrifuged, and the filter cake was washed with DCM. After filtration, the filter cake was dried to obtain 2.21 kg of compound AFb03, with a yield of 58.2% and a purity of 99%.

[0113] (3): Preparation of trans-6′-chloro-3-amino-2′-methyl-1′, 2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (AFb)

[0114] Under nitrogen protection, MEA (12.00 kg) and AFbO3 (3.00 kg) were added to the reactor at 15-35 ° C, the temperature was raised to 60-65 ° C, and the mixture was stirred. After completion of the reaction, the reaction solution was cooled to 20-30 ° C, DCM (30.0 kg) and purified water (30.00 kg) were added, and the mixture was stirred at room temperature for 20-30 minutes. The mixture was then allowed to stand and separate. The aqueous phase was extracted with DCM, the organic phases were combined, and washed with purified water. The organic phase was concentrated under reduced pressure at 35-40 ° C under vacuum until no solvent was distilled off to obtain 1.96 kg of compound AFb with a yield of 99% and a purity of 97.9%.

[0115] Example 3: Preparation of trans-6′-chloro-3-amino-2′-methyl-1′, 2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (AFb)

[0116]

[0117] (1): Preparation of 2-trans-6′-chloro-2′-methyl-3′-oxo-2′, 3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinolin]-3-yl)isoindoline-1,3-dione (AFb03)

[0118] In a 50 mL single-necked flask, 1.5 g of compound AFbO2 (5.97 mmol), 1.56 g of phthalimide (8.96 mmol), and 2.34 g of triphenylphosphine (8.96 mmol) were dissolved in 15 mL of THF. 1.81 g of DIAD (8.96 mmol) was added at 0°C, and the mixture was stirred at room temperature overnight under nitrogen. TLC indicated completion of the reaction. The reaction solution was extracted with 150 mL of ethyl acetate and 300 mL of water. The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to yield 760 mg of the title compound (34% yield).

[0119] (2): Preparation of trans-3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (AFb)

[0120] In a 50 mL single-necked flask, 760 mg of compound AFbO3 (2 mmol) and 5 mL of ethanolamine were added and stirred at 70°C. After the reaction, 80 mL of water and 200 mL of dichloromethane were added to extract the organic phase, which was concentrated under reduced pressure to obtain the crude product. Separation on a preparative plate afforded 350 mg of the title compound as a colorless oil, with a yield of 70% and a purity of 97.3%.

[0121] 1 H NMR(400MHz,Methanol-d4)δ7.58(d,J=4.0Hz,1H),7.26-7.20(m,2H),4.47(s,2 H),3.75-3.67(m,1H),3.10(s,3H),2.98-2.92(m,2H),2.20-2.13(m,2H);[M+H] + 251.1.

[0122] Example 4: Preparation of cis-6′-chloro-3-amino-2′-methyl-1′, 2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (ASb)

[0123]

[0124] (1): Preparation of trans-6′-chloro-2′-methyl-3′-oxo-2′, 3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinolinyl]-3-yl methanesulfonate (ASbO2)

[0125] In a 50ml single-necked flask, 2g of compound AFbO2 (7.97mmol), 1.1g of methanesulfonic acid (11.95mmol), 3.1g of triphenylphosphine (11.95mmol), and 1.61g of triethylamine (15.94mmol) were dissolved in 15mL of THF. 2.4g of DIAD (11.95mmol) was added at 0°C, and the mixture was stirred at room temperature overnight under nitrogen. After completion of the reaction, the reaction solution was extracted with 150mL of ethyl acetate and 300mL of water. The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to yield 2.5g of the crude title compound (95% yield).

[0126] (2): Preparation of 2-cis-6′-chloro-2′-methyl-3′-oxo-2′, 3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinolin]-3-yl)isoindoline-1,3-dione (ASbO3)

[0127] In a 50ml single-necked flask, 2.5g of the intermediate ASbO2 (7.5mmol), 1.65g of phthalimide (11.25mmol), and 3.1g of potassium carbonate (22.5mmol) were dissolved in 10mL of DMF and stirred at 110°C overnight. After the reaction was completed, the mixture was cooled to room temperature and extracted with 100mL of brine and 50mL of ethyl acetate. The organic layer was dried and concentrated using a column chromatography column to obtain 1.2g of the title compound (41% yield).

[0128] (3): Preparation of cis-3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinolin]-3′-one (ASb)

[0129] In a 50 mL single-necked flask, 1.2 g of the intermediate ASbO3 (3.2 mmol) and 10 mL of ethanolamine were added and stirred at 70°C. After the reaction, 100 mL of water and 200 mL of dichloromethane were added to extract the organic phase, which was then concentrated under reduced pressure to obtain the crude product. Preparative plate separation afforded 400 mg of the title compound as a colorless oil, with a yield of 50% and a purity of 97.06%.

[0130] 1H-NMR (400MHz, Methanol-d4) δ7.67 (d, J = 4.0Hz, 1H), 7.32-7.24 (m, 2H), 4.53 (s, 2H),4.12-4.03(m,1H),3.12(s,3H),3.05-3.02(m,2H),2.53-2.27(m,2H).;[M+H] + 251.1.

[0131] Comparative Example 2.1:

[0132] Compounds AFb and ASb were prepared with reference to steps 5 and 6 of Example 2-1 of PCT / CN2020 / 129826 and the method of Example 2-2, wherein the total yield of 3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinoline]-3′-one prepared by the two-step reaction of steps 5 and 6 of Example 2-1 was approximately 2.3%. By isomer separation, the final yields of AFb and ASb were 1.84% and 0.115% purity, respectively.

[0133] Comparative Example 2.2:

[0134] The racemate of 3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinoline]-3′-one was prepared by referring to steps 2 to 4 of Example 14 of PCT / CN2020 / 129826. The isomeric compounds AFb and ASb were then separated to obtain final yields of 4.5% and 0.6% for AFb and ASb, respectively, with purities of 97.4% and 94.9%, respectively.

[0135] The above is based on the ideal embodiment of this application. Based on the above description, relevant personnel can make various changes and modifications without departing from the technical scope of this application. The technical scope of this application is not limited to the content of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing compound AFa02, comprising the following steps: Wherein, R1 is hydrogen, methyl or ethyl; Compound AFa00 is reacted with paraformaldehyde in Eaton's reagent as a solvent to undergo a cyclization reaction to convert it into compound AFa02; The weight ratio of compound AFa00 to Eaton's reagent is 1:2.5-10, and the reaction temperature is 40-80°C.

2. The method according to claim 1, characterized in that Compound AFa00 is converted into: Wherein, R1 is hydrogen, methyl or ethyl.

3. A method for preparing compound AFa03, comprising the following steps: (a1) preparing compound AFa02 by the method according to any one of claims 1 to 2; (a2.1) Compound AFa02 is reacted with phthalimide via Mitsunobu reaction to convert it into compound AFa03. Alternatively, (a2.2) compound AFa02 is converted into compound AFa04 through a substitution reaction, and then reacted with phthalimide and a base, or with an alkali metal salt of phthalimide, to convert it into compound AFa03; Wherein, R1 is hydrogen, methyl or ethyl, and LG is a leaving group.

4. The method according to claim 3, characterized in that Step (a2.1): Compound AFa02 is reacted with phthalimide, triphenylphosphine and an activator to prepare compound AFa03.

5. The method according to claim 4, characterized in that: The active agent is DIAD or DEAD.

6. The method according to claim 3, characterized in that The base in step (a2.2) is selected from triethylamine, diisopropylethylamine, tert-butylisopropyllithium, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide; The alkali metal salt of phthalimide is selected from potassium phthalimide, sodium phthalimide, or lithium phthalimide; The leaving group LG is an alkylsulfonyl group, an alkenylsulfonyl group, an arylsulfonyl group, a benzyl group, a benzyloxymethyl group or an allyl group; the alkylsulfonyl group, the alkenylsulfonyl group or the arylsulfonyl group is optionally substituted by one or more substituents, wherein the substituent is C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5 Alkyl, nitro or amino.

7. The method according to claim 3, characterized in that The leaving group LG is a methanesulfonyl group or a p-toluenesulfonyl group.

8. A method for preparing compound AFa, comprising the following steps: (b1) preparing compound AFa03 by the method according to any one of claims 3 to 7; (b2) Compound AFa03 is converted into compound AFa through a deprotection reaction; Wherein, R1 is hydrogen, methyl or ethyl.

9. The method according to claim 8, wherein: Compound AFa03 reacts with ethanolamine to convert into compound AFa.

10. A method for preparing compound ASa03, comprising the following steps: (c1) preparing compound AFa02 by the method according to any one of claims 1 to 2; (c2) Compound AFa02 is converted into compound ASa02 by Mitsunobu reaction. (c3) Compound ASa02 is converted into compound ASa03 through substitution reaction with phthalimide; Wherein, R1 is hydrogen, methyl or ethyl, and LG is a leaving group.

11. The method according to claim 10, characterized in that: The leaving group LG is an alkylsulfonyl group, an alkenylsulfonyl group, an arylsulfonyl group, a benzyl group, a benzyloxymethyl group or an allyl group; the alkylsulfonyl group, the alkenylsulfonyl group or the arylsulfonyl group is optionally substituted by one or more substituents, wherein the substituent is C 1-5 Alkyl, C 1-5 Alkoxy, halogen, halogenated C 1-5 Alkyl, nitro or amino.

12. The method according to claim 10, characterized in that: The leaving group LG is a methanesulfonyl group or a p-toluenesulfonyl group.

13. The method according to claim 10, characterized in that: In step (c2), the compound AFaO2 is subjected to a Mitsunobu reaction with MsOH or p-toluenesulfonic acid under the catalysis of triphenylphosphine and an activator; In step (c3), the substitution reaction of compound ASa02 with phthalimide is carried out under alkaline conditions; or phthalimide is first reacted with a base to convert it into a corresponding alkaline salt, and then reacted with ASa02 to convert it into compound ASa03.

14. The method according to claim 13, characterized in that: The active agent is selected from DIAD or DEAD.

15. The method according to claim 13, characterized in that: The base in step (c3) is triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.

16. A method for preparing compound ASa, comprising the following steps: (d1) preparing compound ASa03 by the method according to any one of claims 10 to 15; (d2) Compound ASa03 is converted into compound ASa through a deprotection reaction; Wherein, R1 is hydrogen, methyl or ethyl.

17. The method according to claim 16, characterized in that: Step (d2) is to convert compound ASa03 into compound ASa by reacting with ethanolamine.

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