WO2023226900A1 - 2-(piperazine-2-yl) acetonitrile derivative, preparation method for, and use thereof - Google Patents

Abstract

The present invention discloses 2-(piperazine-2-yl) acetonitrile or a salt thereof, a derivative thereof and a synthesis method thereof. The process route of the method in the present invention is simple and efficient, has low costs and pollution and high safety, and does not involve column chromatography purification. The prepared target product has an HPLC purity larger than 98% and an ee value larger than 99%. Therefore, the preparation method is more suitable for industrial application.

Description

2-(Piperazin-2-yl)acetonitrile derivatives and preparation methods and applications thereof Technical field

The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method and application of 2-(piperazin-2-yl)acetonitrile or its salt and its derivatives.

Background technique

Lung cancer is one of the important causes of cancer death in humans. Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients. According to statistics, the global NSCLC market in 2016 was approximately US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China. Judging from current trends, the non-small cell lung cancer market has maintained continued growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018; 553(7689):446-454). KRAS mutations are frequently detected in lung cancer patients and account for approximately 32% of all oncogene mutations. Among them, KRAS ^G12C mutation accounts for 44% of all oncogene mutations in NSCLC. Since the KRAS ^G12C target protein is pathologically associated with a variety of diseases, novel KRAS ^G12C inhibitors are currently needed for clinical treatment. Highly selective and active KRAS ^G12C inhibitors can more effectively treat diseases such as cancer caused by KRAS ^G12C mutations, as well as have the potential to reduce off-target effects, so they have a more urgent clinical need.

KRASG12C inhibitors currently in clinical stages include AMG510, MRTX849, ARS-3248 and LY-3499446, among which MRTX849 has demonstrated good efficacy and safety in phase I clinical trials. MRTX849 uses the S-2-(piperazin-2-yl)acetonitrile structure to increase the binding of KRAS ^G12C protein, improve the pharmacokinetic properties and increase the inhibitory effect of KRAS ^G12C protein (J Med Chem. 2020 Apr 6.doi :10.1021/acs.jmedchem.9b02052.). In addition, 2-(piperazin-2-yl)acetonitrile is also widely used as an important pharmacophore group in PKC inhibitors (WO/2014/052699) and antibiotics (Journal of Heterocyclic Chemistry, 1992, 29(1), 55- 59) and other drug molecular structures.

On the other hand, deuteration strategies are often used in drug synthesis. By replacing the hydrogen in the drug molecule with deuterium, the metabolic site is blocked, the clearance rate in the organism is slowed down, and the half-life is extended, thereby improving the pharmacokinetic properties while reducing the generation of toxic metabolites. Ultimately, it is possible to reduce clinical dosage and reduce clinical toxic and side effects while ensuring efficacy. Therefore, deuteration of 2-(piperazin-2-yl)acetonitrile can block potential metabolic sites, improve pharmacokinetic properties and reduce potential toxic side effects.

Patents WO2014052699, WO2017201161, etc. report the preparation method of racemic 2-(piperazin-2-yl)acetonitrile derivatives. The synthesis method is as shown in Route 1.

Route one:

Route 1 uses allyl nitrile as the starting material, which is added with bromine to form A17 or added with bromine and then eliminated to form A07, which is then reacted with N1, N2-diphenylmethylethane-1,2- Diamine ring closure reaction gives A18, and debenzylation gives A19. This route can obtain racemic A19, but the existing synthesis method has low yield and requires at least two column chromatography purifications, so it is not suitable for industrial production.

Patent WO2017201161, US20180072723, etc. report the preparation method of chiral (S)-2-(piperazin-2-yl)acetonitrile derivatives. The synthesis method is as shown in Route 2.

Route two:

Route 2 uses B01 containing a chiral center as the starting material, first activates the hydroxyl group of B01, then replaces the activated hydroxyl group with a cyano group to introduce a cyano group, and finally removes protection to obtain A22. This synthesis route has the disadvantages of expensive starting material B01, highly toxic reagents used in the reaction, and multiple column chromatography purifications, so it is not suitable for industrial production.

In summary, the synthesis methods of racemic or chiral 2-(piperazin-2-yl)acetonitrile or its salts and their derivatives reported above all have the problems of high cost, high toxicity, high pollution, low yield, There are technical problems such as difficulty in mass production. Therefore, there is an urgent need to develop a simple, efficient, low-cost, low-pollution, column-free chromatography purification operation and a synthetic route suitable for industrial production.

Contents of the invention

In view of the problems in the background technology, the purpose of the present invention is to provide a synthesis method of 2-(piperazin-2-yl)acetonitrile or its salt and its derivatives. This compound is an intermediate of a KRAS G12C inhibitor, This synthesis method has low cost, safe and environmentally friendly process, and column-free chromatography operation, which is more suitable for industrial production.

In order to achieve the above objects, the present invention proposes the following technical solutions:

Contents of the invention

In view of the problems in the background technology, the purpose of the present invention is to provide a synthesis method of 2-(piperazin-2-yl)acetonitrile or its salt and its derivatives. This compound is an intermediate of a KRAS G12C inhibitor, This synthesis method has low cost, safe and environmentally friendly process, and column-free chromatography operation, which is more suitable for industrial production.

A first aspect of the present invention provides a method for preparing compound A22 or a salt thereof, the method comprising:

s1) In an inert solvent, compound A19 reacts with a chiral acid to obtain compound A20;

s2) In an inert solvent, compound A20 reacts with an amino protecting agent to obtain compound A21;

s3) In an inert solvent, compound A21 is deprotected to obtain compound A22 or a salt thereof;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

X ₁ , X ₂ , X ₃ and X ₄ are each independently none, organic acid or inorganic acid;

P ₁ and P ₂ are each independently an amino protecting group;

0<n≤10, preferably, 0<n≤8, more preferably, 0.5≤n≤5.

In another preferred example, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are all H.

In another preferred example, R ₁ and R ₂ are D, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are all H.

In another preferred example, R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ and R ₁₁ are H.

In another preferred example, R ₁ , R ₂ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₃ , R ₄ , R ₅ , R ₁₀ and R ₁₁ are H.

In another preferred example, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₁₀ and R ₁₁ are H.

In another preferred example, R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₁ , R ₂ , R ₁₀ and R ₁₁ are H.

In another preferred example, R ₃ , R ₄ , and R ₅ are D, and R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are H.

In another preferred example, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are D, and R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are H.

In another preferred example, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₃ , R ₁₀ and R ₁₁ are H.

In another preferred example, the amino protecting agent is selected from: di-tert-butyl dicarbonate, benzyl chloroformate, benzyl bromoformate, benzyl chloride, benzyl bromide, triphenyl chloride, triphenyl bromide, chlorine 9-fluorenylmethyl formate, 9-fluorenylmethyl bromoformate, allyl chloroformate, allyl bromoformate, 2,2,2-trifluoroacetyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride , Acetyl chloride, pivaloyl chloride, 1-(chloromethyl)-4-methoxybenzene, 1-(bromomethyl)-4-methoxybenzene, 1-(chloromethyl)-2,4- Dimethoxybenzene, 1-(bromomethyl)-2,4-dimethoxybenzene, o-(p-)nitrobenzenesulfonyl chloride.

In another preferred example, n is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 ,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4,3.5,3.6,3.7,3.8,3.9,4.0,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.0 .

In another preferred example, P ₁ and P ₂ are each independently tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, trityl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trifluoroacetyl, benzene sulfonyl Acyl, p-toluenesulfonyl, acetyl, pivaloyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, o-(p-)nitrobenzenesulfonyl.

In another preferred example, X ₁ , X ₂ , X _{3 and} Sulfonic acid, camphorsulfonic acid, oxalic acid, malic acid, citric acid, or combinations thereof.

In another preferred example, compound A22 is compound A'22, and its preparation method includes:

s'2) Diastereomeric salt of (S)-2-(piperazin-2-yl)acetonitrile and chiral acid (compound A'20) and di-tert- Butyl dicarbonate reacts to generate di-tert-butyl (S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (compound A'21);

s'3) Di-tert-butyl (S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (compound A'21) reacts with hydrogen chloride to obtain 2-(piperazine- 2-yl)acetonitrile hydrochloride (Compound A'22).

In another preferred example, in step s1), the molar equivalent ratio of the chiral acid to compound A19 is 0.1 to 10 equivalents; preferably, it is 0.5 to 5 equivalents.

In another preferred example, in step s1), when compound A19 is a salt, the solution of the salt of compound A19 is first adjusted to neutral or alkaline with a base, then a chiral acid is added, and finally compound A20 is precipitated (i.e., (S)-2-(Piperazin-2-yl)acetonitrile diastereomeric salt with chiral acid).

In another preferred embodiment, the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, hydrogen Sodium oxide, potassium hydroxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or a combination thereof; preferably, the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, methanol Sodium, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof; more preferably, the base is selected from: sodium carbonate, sodium ethoxide, sodium hydroxide , potassium hydroxide, or combinations thereof.

In another preferred example, in step s1), when compound A19 is a salt, the solution of the salt of compound A19 is first adjusted to neutral or alkaline with a base, wherein the molar equivalent ratio of the base to compound A19 is 1.0~ 3.0:1, preferably 1.5～2.0:1, more preferably 1.5～1.8:1.

In another preferred example, in step s1), the reaction temperature is -50°C to solvent reflux temperature, preferably the reaction temperature is -30°C to 100°C, more preferably, the reaction temperature is -15°C to 50°C, more preferably, The reaction temperature is 20°C to 50°C, for example, 25 to 50°C.

In another preferred embodiment, compound A20 is (S)-2-(piperazin-2-yl)acetonitrile salt, which is selected from the D-tartrate salt of (S)-2-(piperazin-2-yl)acetonitrile. , D-malic acid of (S)-2-(piperazin-2-yl)acetonitrile, R-(-)-citramalic acid of (S)-2-(piperazin-2-yl)acetonitrile, or its combination.

In another preferred example, the chiral acid is selected from: L-tartaric acid, D-tartaric acid, dibenzoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, di-p-toluoyl-L-tartaric acid, Di-p-toluoyl-D-tartaric acid, L-dipivaloyl tartaric acid, L-malic acid, D-malic acid, R-(-)-citramalic acid, S-(+)-citramalic acid, R-( -)-mandelic acid, S-(+)-mandelic acid, D-(+)-10-camphorsulfonic acid, L-(-)-10-camphorsulfonic acid, D-camphoric acid, or combinations thereof; preferably , the chiral acid is selected from: D-tartaric acid, D-malic acid, dibenzoyl-D-tartaric acid, R-(-)-citramalic acid, R-(-)-mandelic acid, or a combination thereof; More preferably, the chiral acid is selected from: D-tartaric acid, D-malic acid, R-(-)-citramalic acid, or combinations thereof.

In another preferred example, in step s2), the molar equivalent ratio of compound A20 to the amino protecting agent is 1.0:0.1-10 equivalents, preferably 1.0:0.5-5.0, more preferably 1.0:1.0-3.0.

In another preferred example, in step s2), the reaction temperature is -50°C to the solvent reflux temperature, preferably the reaction temperature is -30°C~100°C, more preferably, the reaction temperature is -5°C~50°C, more preferably Preferably, the reaction temperature is 20 to 25°C.

In another preferred example, in step s2), the solution of the salt of compound A20 is first adjusted to neutral or alkaline (for example, pH=5-11, preferably 6-10) with a base.

In another preferred example, in step s3), the reaction temperature is -20°C to the solvent reflux temperature, preferably the reaction temperature is -10°C ~ 100°C, more preferably, the reaction temperature is 0°C ~ 60°C, more preferably Ground, the reaction temperature is 20~25℃.

In another preferred example, in step s3), compound A21 is deprotected under acidic conditions to obtain compound A22, wherein the acid is selected from: hydrogen chloride, hydrogen bromide, hydrogen fluoride, phosphoric acid, sulfuric acid, acetic acid, Trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malic acid, citric acid, or combinations thereof; the molar equivalent ratio of compound A21 to acid is 1.0:0.1-20 equivalents, preferably 1.0:0.5～10.0, more preferably 1.0:1.0～5.0.

In another preferred embodiment, the method further includes adding a base to obtain the free base of compound A22.

In another preferred example, the purity of compound A20 or compound A22 is greater than 95%, preferably, greater than 97%, more preferably, greater than 98%.

In another preferred example, the chiral purity of compound A20 or compound A22 is greater than 95%, preferably greater than 97%, more preferably greater than 99%.

In another preferred example, A19 is 2-(piperazin-2-yl)acetonitrile or its hydrochloride, and its preparation method includes the steps:

Route one:

(i) In dichloromethane, compound A06 reacts with bromine reagent to obtain compound A17;

(ii) In an inert solvent, in the presence of a base, at 45-50°C, compound A17 and N ¹ , N ² -diphenylmethylethane-1,2-diamine Reaction to obtain compound A18;

(iii) In an inert solvent, compound A18 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A’19;

Route two:

(i') In an inert solvent, the compound reacts with a bromine reagent, and then performs an elimination reaction in the presence of a base to obtain compound A07; wherein the molar equivalent of the base is 0.5-5.0 equivalents, preferably 1.0-3.0 equivalents;

(ii') In the presence of a base, at 20-25°C, compound A17 and N ¹ , N ² -diphenylmethylethane-1,2-diamine Reaction to obtain compound A18;

(iii’) In an inert solvent, compound A18 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A’19.

In another preferred example, A19 is 2-(piperazin-2-yl)acetonitrile-d ₂ or its hydrochloride, 2-(piperazin-2-yl-5,5,6,6-d ₄ ) Acetonitrile or its hydrochloride, 2-(piperazin-2-yl-2,3,3,5,5,6,6-d ₇ )acetonitrile-d ₂ or its hydrochloride, its preparation method includes the steps: :

Route one:

(i") In an inert solvent, compound A01 reacts with a deuterated reducing agent to obtain compound A02;

(ii") In an inert solvent, compound A02 reacts with a halogenated reagent to obtain compound A03;

(iii") In an inert solvent, compound A03 reacts with sodium cyanide or potassium cyanide to obtain compound A04;

(iv”) In an inert solvent, compound A04 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A05;

Route two:

(i”’) In an inert solvent, compound A06 reacts with a bromine reagent, and then an elimination reaction occurs under the action of a base to obtain compound A07;

(ii"') In an inert solvent, compound A07 and N ¹ , N ² -dibenzylethane-d ₄ -1,2-diamine Reaction to obtain compound A08;

(iii”’) In an inert solvent, compound A08 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A09;

Route three:

(i"") In an inert solvent, compound A10 is reacted with a bromine reagent to obtain;

(ii"") In an inert solvent, compound A11 reacts with N ¹ , N ² -dibenzylethane-d ₄ -1,2-diamine to obtain compound A12;

(iii"") In an inert solvent, compound A12 reacts with a deuterated reducing agent to obtain compound A13;

(iv””) In an inert solvent, compound A13 reacts with a halogenated reagent to obtain compound A14;

(v””) In an inert solvent, compound A14 reacts with sodium cyanide or potassium cyanide to obtain compound A15;

(v””) In an inert solvent, the protecting group of compound A15 is removed in the presence of 1-chloroethyl chloroformate to obtain compound A16.

In another preferred embodiment, the deuterated reducing agent is lithium deuterated aluminum tetrahydrogen.

In another preferred embodiment, the halogenating reagent is sulfoxide chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, or a combination thereof.

In another preferred embodiment, in each step, the inert solvent is selected from: ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dimethyl Tetrahydrofuran, methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) ), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), acetonitrile, acetone, benzene, toluene, chlorobenzene, methanol, ethanol, tert-butanol, isopropyl Alcohol, n-propanol, n-butanol, water, or combinations thereof.

In another preferred embodiment, the bromine reagent is selected from: bromine or tribromopyridinium salt.

In another preferred embodiment, step (i') also includes distillation under reduced pressure to obtain purified compound A07.

In another preferred embodiment, step (ii) or (ii') also includes recrystallizing compound A18 using a crystallization solvent to obtain purified compound A18, wherein the crystallization solvent is selected from: methanol, ethanol, petroleum ether, n-heptane, cyclohexane, n-hexane, methylcyclohexane, pentane, or combinations thereof.

In another preferred embodiment, in step (i'), the inert solvent is selected from: tert-butyl alcohol, isopropyl alcohol, petroleum ether, n-heptane, cyclohexane, n-hexane, methylcyclohexane, pentane, Or a combination thereof; preferably, the inert solvents tert-butanol and petroleum ether (v/v=1:1~6, such as 1:3).

In another preferred example, in step (i'), the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, tert-butyl Potassium alkoxide, sodium tert-amyloxide, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidine, Lithium hexamethyldisilazide (LHMDS), potassium hexamethyldisilamide (KHMDS), or a combination thereof; preferably, the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, tert. Potassium butoxide, sodium tert-amyloxide, lithium 2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilamide (LHMDS), potassium hexamethyldisilamide (KHMDS), or Combinations thereof; more preferably, the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, or combinations thereof.

In another preferred embodiment, in step (ii) or (ii'), the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate Esters, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethyl Formamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, Chlorobenzene, or a combination thereof; preferably, the inert solvent is selected from: toluene, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane , acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), or combinations thereof; more preferably, the inert solvent Selected from: toluene, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide (DMF), or combinations thereof.

In another preferred embodiment, in step (ii) or (ii'), the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine , 1-methylpyrrolidine, 1-methylpiperidine, dimethylisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2 ,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0] Undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), or a combination thereof; preferably, the base is selected from: sodium carbonate , potassium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 1-methylpyrrolidine, 1-methylpiperidine, dimethylisopropylamine, N,N-diisopropylamine Propylethylamine, N-methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), or combinations thereof; more preferably, the The base is selected from: potassium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, or a combination thereof.

In another preferred embodiment, in step (iii) or (iii'), the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate Esters, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethyl Formamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, Chlorobenzene, or a combination thereof; preferably, the inert solvent is selected from: toluene, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, N,N-dimethylacetamide (DMA), or a combination thereof; more preferably, the inert solvent is selected from: toluene, 1,2-dichloroethane, chloroform, or a combination thereof.

In another preferred example, in step (iii) or (iii'), the reaction temperature is 25-120°C, preferably 50-110°C, and more preferably 70-100°C.

In another preferred embodiment, step (iii) or (iii') further includes adding a base to obtain the free base of compound A19.

In a second aspect, the present invention provides a method for preparing compound A20, which method includes the steps:

s1) In an inert solvent, compound A19 reacts with a chiral acid to obtain compound A20;

X ₁ and X ₂ are each independently free, organic acid or inorganic acid;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.

In another preferred example, compound A20 is a diastereomeric salt of (S)-2-(piperazin-2-yl)acetonitrile and chiral acid, and its preparation method includes the steps

0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5;

First use a base to adjust the solution of 2-(piperazin-2-yl)acetonitrile hydrochloride (A'19) to neutral or alkaline, then add chiral acid, and finally precipitate (S)-2-(piperazine) -2-yl) Diastereomeric salts of acetonitrile and chiral acids (A'20).

In another preferred example, the molar equivalent ratio of the chiral acid to compound A19 is 0.1 to 10 equivalents; preferably, the molar equivalent ratio is 0.5 to 5 equivalents.

In another preferred embodiment, the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, hydrogen Sodium oxide, potassium hydroxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or a combination thereof; preferably, the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, methanol Sodium, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof; more preferably, the base is selected from: sodium carbonate, sodium ethoxide, sodium hydroxide , potassium hydroxide, or combinations thereof.

In another preferred example, the molar equivalent ratio of the base to compound A'19 is 1.0-3.0:1, preferably 1.5-2.0:1, more preferably 1.5-1.8:1.

In another preferred example, the reaction temperature is -50°C to the solvent reflux temperature, and the preferred reaction temperature is -30°C. to 100°C, more preferably, the reaction temperature is -15°C to 50°C, more preferably, the reaction temperature is 20°C to 50°C, such as 25 to 50°C.

In another preferred example, compound A'20 is selected from the group consisting of D-tartrate salt of (S)-2-(piperazin-2-yl)acetonitrile, (S)-2-(piperazin-2-yl)acetonitrile. D-malic acid, R-(-)-citrimalic acid of (S)-2-(piperazin-2-yl)acetonitrile, or combinations thereof

In a third aspect, the present invention provides a compound A20, which is prepared by the method described in the second aspect.

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.

The fourth aspect of the present invention provides a compound represented by formula I or a salt, enantiomer, diastereomer, or racemate thereof,

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D; the limiting condition is R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are not hydrogen at the same time.

In another preferred embodiment, the compound of formula I has the structure shown in formula I'

Among them, * indicates R or S configuration,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are defined as above.

In another preferred embodiment, the compound is selected from:

In another preferred embodiment, the compound is selected from:

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

Detailed ways

After extensive and in-depth research, the inventor has developed an intermediate of KRAS G12C inhibitor. This synthesis method has low cost, safe and environmentally friendly process, and column-free chromatography operation, which is more suitable for industrial production. On this basis, the present invention was completed.

the term

In the present invention, "inert solvent" refers to a reagent that does not react with the reaction substrate.

Intermediates

Intermediates refer to semi-finished products, which are products formed during the production of the required products. Typically, inventors can proceed to the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby increasing the yield and saving time and cost.

Preferably, the intermediate of the present invention is selected from compound A20

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D; the qualification is R ₁ , R ₂ , R _3. R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are not hydrogen at the same time;

0<n≤10, preferably, 0<n≤8, more preferably, 0.5≤n≤5, for example, n is 1-3.

Preferably, the chiral acid is D-tartaric acid.

Preferably, the intermediate of the present invention is And A'20 is prepared by the following method

First use a base to adjust the solution of 2-(piperazin-2-yl)acetonitrile hydrochloride (A'19) to neutral or alkaline, then add chiral acid, and finally precipitate (S)-2-(piperazine) -2-yl) Diastereomeric salt of acetonitrile and chiral acid (A'20);

Wherein, 0<n≤10, preferably, 0<n≤8, more preferably, 0.5≤n≤5, for example, n is 1-3, and the chiral acid is D-tartaric acid.

Preferably, the intermediate of the present invention is selected from compounds represented by formula (I) or salts thereof,

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D; the limiting condition is R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are not hydrogen at the same time.

Preferably, the salt of the compound of formula (I) may be an HCl salt.

Preferably, in compound A20, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ can all be H.

Preferably, R ₁ and R ₂ are D, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are all H.

Preferably, R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ and R ₁₁ are H.

Preferably, R ₁ , R ₂ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₃ , R ₄ , R ₅ , R ₁₀ and R ₁₁ are H.

Preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₁₀ and R ₁₁ are H.

Preferably, R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₁ , R ₂ , R ₁₀ and R ₁₁ are H.

Preferably, R ₃ , R ₄ , and R ₅ are D, and R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are H.

Preferably, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are D, and R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are H.

Preferably, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are D, and R ₃ , R ₁₀ and R ₁₁ are H.

Preparation method of compound A20

In the present invention, the preparation method of compound A20 includes

s1) In an inert solvent, compound A19 reacts with a chiral acid to obtain compound A20;

X ₁ and X ₂ are each independently inorganic, organic or inorganic acid;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.

Preferably, the preparation method includes

In an inert solvent, compound A’19 reacts with a chiral acid to obtain compound A’20;

0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.

Preferably, the method further includes

Route one:

(1) In methylene chloride, allyl nitrile is reacted with bromine or tribromopyridinium salt to obtain 2,3-dibromopropionitrile;

(2) At 45~50℃, 2,3-dibromopropionitrile and N ¹ ,N ² -diphenylmethylethane-1,2-diamine ring closure reaction to obtain 2-(1,4-diamine Benzylpiperazin-2-yl) acetonitrile; in this step, purified 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile can be obtained by recrystallization; the crystallization solvent is selected from methanol, Ethanol, petroleum ether, n-heptane, cyclohexane, n-hexane, methylcyclohexane, pentane, or combinations thereof.

(3) Use 1-chloroethyl chloroformate to remove the protecting group of 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile to obtain 2-(piperazin-2-yl)acetonitrile salt acid salt;

Route two:

(1') Allyl nitrile and bromine or tribromopyridinium salt are first added to the reaction, and then the elimination reaction is carried out with a suitable amount of base (such as sodium ethoxide) to obtain 3-bromoacrylonitrile; where, the mole of the base The equivalent is 0.5-1.5 equivalents, preferably 1.0-1.1 equivalents; after optimization and adjustment, the appropriate amount of alkali is obtained, so that the pure product of A07 can be obtained by distillation under reduced pressure in this step, so that it can be applied to large-scale production;

(2')3-Bromoacrylonitrile reacts with N ¹ , N ² -diphenylmethylethane-1,2-diamine ring closure to obtain 2-(1,4-diphenylmethylpiperazine-2- base) acetonitrile; in this step, purified 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile can be obtained by recrystallization; the crystallization solvent is selected from methanol, ethanol, petroleum ether, n-heptane , cyclohexane, n-hexane, methylcyclohexane, pentane, or combinations thereof;

(3') 2-(1,4-Diphenylmethylpiperazin-2-yl)acetonitrile removes benzyl protection to obtain 2-(piperazin-2-yl)acetonitrile hydrochloride;

Or the method also includes

Route three:

(1"') Methyl 1,4-dibenzylpiperazine-2-carboxylate reacts with lithium deuterated tetrahydrogen aluminum to obtain (1,4-dibenzylpiperazine-2-yl)methane-d ₂ -Alcohol;

(2"')(1,4-dibenzylpiperazin-2-yl)methane-d ₂ -ol undergoes halogenation reaction to obtain 1,4-dibenzyl-2-(chloromethyl-d ₂ ) Piperazine;

(3"')1,4-dibenzyl-2-(chloromethyl-d2)piperazine reacts with sodium cyanide or potassium cyanide to obtain 2-(1,4-dibenzylpiperazine-2- Base) acetonitrile-d ₂ ;

(4"') Utilize 1-chloroethyl chloroformate to remove the protecting group of 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile-d ₂ to obtain 2-(piperazine-2- Base) acetonitrile-d ₂ hydrochloride;

Route four:

(1"") But-3-enenitrile undergoes an addition reaction before bromine or tribromopyridinium salt, and then undergoes an elimination reaction under the action of a base to obtain 4-bromobut-2-enenitrile;

(2"")4-bromobut-2-enenitrile reacts with N ¹ , N ² -dibenzyl ethane-d ₄ -1,2-diamine ring closure to obtain 2-(1,4-dibenzyl Piperazin-2-yl-5,5,6,6-d ₄ )acetonitrile;

(3"") Use 1-chloroethyl chloroformate to remove the protecting group of 2-(1,4-dibenzylpiperazin-2-yl-5,5,6,6-d ₄ )acetonitrile to obtain 2 -(Piperazin-2-yl-5,5,6,6-d ₄ )acetonitrile hydrochloride;

Route five:

(1""') Addition reaction between d ₃ -methyl acrylate and bromine or tribromopyridinium salt to obtain 2,3-dibromopropionic acid-2,3,3-d ₃ -methyl ester;

(2""') 2,3-dibromopropionic acid-2,3,3-d ₃ -methyl ester and N ¹ , N ² -dibenzyl ethane-d ₄ -1,2-diamine in ring reaction Obtain 1,4-dibenzylpiperazine-2-carboxylic acid-2,3,3,5,5,6,6-d ₇ -methyl ester;

(3""')1,4-dibenzylpiperazine-2-carboxylic acid-2,3,3,5,5,6,6-d ₇ -methyl ester is obtained by reduction reaction with deuterated lithium aluminum tetrahydrogen (1,4-dibenzylpiperazine-2-yl-2,3,3,5,5,6,6-d ₇ )methane-d ₂ -ol;

(4""')(1,4-dibenzylpiperazine-2-yl-2,3,3,5,5,6,6-d ₇ )methane-d ₂ -alcohol and thionyl chloride Chlorination reaction yields 1,4-dibenzyl-2-(chloromethyl-d2)piperazine-2,3,3,5,5,6,6-d _7;

(5""')1,4-dibenzyl-2-(chloromethyl-d2)piperazine-2,3,3,5,5,6,6-d ₇ with sodium cyanide or potassium cyanide The reaction yields 2-(1,4-dibenzylpiperazin-2-yl-2,3,3,5,5,6,6-d ₇ )acetonitrile-d _2;

(6""') Use 1-chloroethyl chloroformate to remove 2-(1,4-dibenzylpiperazin-2-yl-2,3,3,5,5,6,6-d ₇ ) the protecting group of acetonitrile-d ₂ gives 2-(piperazin-2-yl-2,3,3,5,5,6,6-d ₇ )acetonitrile-d ₂ hydrochloride.

In the present invention, in each step, the ratio of each reaction material is not particularly limited, and the molar ratio of the reactants can be 5.0-0.5:1 (such as 2:1, 3:1, 1.5:1 or 1:1, etc.).

In the present invention, in each step, the base can be an organic base, an inorganic base, or a combination thereof, such as: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide , Potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), triethylamine (TEA), N,N -Diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or combinations thereof, the molar ratio of base and reactant is 1.0-8.0:1, such as 2.01:1, 3:1, 1.5:1 or 1:1 etc.

In the present invention, in each step, the reaction solvent, reaction temperature, reaction time, etc. can be selected according to the specific reactants. For example, the reaction solvent can be: ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloromethane, etc. Ethyl chloride, chloroform, carbon tetrachloride, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylmethane Amide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorine Benzene, methanol, ethanol, tert-butanol, isopropanol, n-propanol, n-butanol, water, or combinations thereof; the reaction temperature is -50°C to solvent reflux temperature, preferably the reaction temperature is -30°C to 100°C, especially The preferred reaction temperature is -15°C to 50°C, such as 45-50°C or 20-25°C; the reaction time can be 0-48h, preferably 0.1-24h, such as 10min, 1.5h, 3h, 4h or 6h, etc.

Compared with the prior art, the beneficial effects of the present invention are as follows:

1. The present invention provides a novel and efficient synthesis of 2-(piperazin-2-yl)acetonitrile or its salts and derivatives thereof;

2. The starting raw materials used in the process of the present invention are cheap and easy to obtain;

3. The process of the present invention avoids the use of highly toxic reagents to introduce cyano groups;

4. The process of the present invention avoids the use of multiple column chromatography purification operations;

5. The process of the present invention is simple to operate and easy to purify, and can obtain high-quality, high-purity intermediates and 2-(piperazin-2-yl)acetonitrile or its salts and derivatives thereof;

6. The present invention can prepare 2-(piperazin-2-yl)acetonitrile or its salts and derivatives thereof with high chiral purity;

7. The new route of the present invention has greater advantages and stronger industrialization prospects than the existing methods.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

For experimental methods without specifying specific conditions in the examples, follow conventional methods and conditions, or select according to product instructions.

Example 1 Preparation of 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile

At 20-25°C, add allyl nitrile (15g, 0.15mol, 1.0eq) and carbon tetrachloride (100mL) to the three-necked flask in sequence. Bromine (47.6g, 0.24mol, 2.0eq) was added to the above three-necked flask, stirred for 3 hours, concentrated under reduced pressure and then subjected to column chromatography to obtain 20.4g of 3,4-dibromobutyronitrile, with a yield of 60%. Add 3,4-dibromobutyronitrile (20g, 0.09mol, 1.0eq), N ¹ , N ² -diphenylmethylethane-1,2-diamine (24.0g, 0.10mol, 1.1eq), Add triethylamine (27.3g, 0.27mol, 3.0eq) and toluene (100mL) to a three-necked flask, adjust the temperature to 110°C, and stir for 3 hours. After concentration under reduced pressure and column chromatography, 13.7 g of the title compound was obtained with a purity of 95% and a yield of 50%.

¹ H NMR (400MHz, CDCl ₃ -d): δ7.40-7.23(m,10H), 3.85-3.76(m,1H), 3.54-3.44(m,3H), 3.07-2.96(m,1H), 2.94-2.84(m,1H),2.68-2.35(m,7H).

Example 2 Preparation of 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile

At 20-25°C, add allyl nitrile (15g, 0.22mol, 1.0eq) and dichloromethane (60mL) to the three-necked flask in sequence. Add bromine (37.6g, 0.24mol, 1.05eq) into the above three-necked flask, stir for 3 hours, and reserve the reaction solution for later use. Add N ¹ , N ² -diphenylmethylethane-1,2-diamine (53g, 0.22mol, 1.0eq), triethylamine (50g, 0.48mol, 2.2eq), and toluene (100mL) in sequence to three ports In the bottle, slowly add the previously reserved reaction solution, adjust the temperature to 45-50°C, stir for 1 hour, and solid will precipitate. Filter, distill the filtrate under reduced pressure to remove the solvent, add methanol (30 mL), adjust the temperature to 0-5°C and stir for 2 hours to precipitate a solid. Filter, take out the filter cake, and dry to obtain 47 g of the title compound, with a purity of 97% and a yield of 70%.

¹ H NMR (400MHz, CDCl ₃ -d): δ7.40-7.23 (m, 10H), 3.85-3.76 (m, 1H), 3.54-3.44(m,3H),3.07-2.96(m,1H),2.94-2.84(m,1H),2.68-2.35(m,7H).

Example 3 Preparation of 3-bromoacrylonitrile

At 20-25°C, add allyl nitrile (15g, 0.22mol, 1.0eq), tert-butanol (30mL), and n-heptane (30mL) to the three-necked flask in sequence. Add bromine (38g, 0.24mol, 1.05eq) into the above three-necked flask, then add sodium tert-butoxide (23g, 0.24mol, 1.05eq), and stir for 3 hours. Filtration, concentration of the filtrate, and column chromatography yielded 20.9 g of the title compound with a purity of 95% and a yield of 65%.

¹ H NMR (400MHz, CDCl ₃ -d): δ (E), 6.79 (td, J = 7.2, 16.0Hz, 1H), 5.63 (d, J = 16.0Hz, 1H), 4.00 (dd, J = 1.2 ,6.8Hz,2H); (Z),8＝6.66(td,J＝8.0,10.8Hz,1H),5.44(d,J＝10.8Hz,1H),4.16(dd,J＝0.8,8.0Hz, 2H).

Example 4 Preparation of 3-bromoacrylonitrile

At 20~25°C, add allyl nitrile (150g, 2.24mol, 1.0eq), tert-butanol (225mL), and petroleum ether (750mL) to the three-necked flask in sequence, and adjust the temperature to 0~5°C. Add bromine (376g, 2.35mol, 1.05eq) into the above three-necked flask, then add ethanol solution of sodium ethoxide (160g, 2.35mol, 1.05eq), and stir for 1.5 hours. Filtration, concentration of the filtrate, and distillation under reduced pressure yielded 236 g of the title compound, with a purity of 98% and a yield of 72%.

¹ H NMR (400MHz, CDCl ₃ -d): δ (E), 6.79 (td, J = 7.2, 16.0Hz, 1H), 5.63 (d, J = 16.0Hz, 1H), 4.00 (dd, J = 1.2 ,6.8Hz,2H); (Z),8＝6.66(td,J＝8.0,10.8Hz,1H),5.44(d,J＝10.8Hz,1H),4.16(dd,J＝0.8,8.0Hz, 2H).

Example 5 Preparation of 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile

At 20-25°C, add 3-bromoacrylonitrile (6.0g, 41.61mmol, 1.0eq) and N ¹ , N ² -diphenylmethylethane-1,2-diamine (10g, 41.61mmol, 1.0eq) in sequence. 1.0eq), triethylamine (8.4g, 83.21mmol, 2.0eq), toluene (100mL) into a three-necked flask, and stir for 16 hours. After concentration under reduced pressure and column chromatography, 6.4 g of the title compound was obtained with a purity of 95% and a yield of 50%.

¹ HNMR (400MHz, CDCl ₃ -d): δ7.40-7.23(m,10H),3.85-3.76(m,1H),3.54-3.44(m,3H),3.07-2.96(m,1H),2.94 -2.84(m,1H),2.68-2.35(m,7H).

Example 6 Preparation of 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile

At 20-25°C, add N ¹ , N ² -diphenylmethylethane-1,2-diamine (196g, 0.82mol, 1.0eq) and triethylamine (165g, 1.63mol, 2.0eq) in sequence. , toluene (500mL) was added to a three-necked flask, and a toluene solution of 3-bromoacrylonitrile (119g, 0.82mol, 1.0eq, 200mL of toluene) was added. After stirring for 16 hours, a solid precipitated. Filter, remove the solvent from the filtrate under reduced pressure, add methanol (200 mL) to the concentrate, and stir for 1 hour at 0 to 5°C to precipitate a white solid. Filter, take out the filter cake, and dry to obtain 200 g of the title compound, with a purity of 97% and a yield of 80%.

¹ HNMR (400MHz, CDCl ₃ -d): δ7.40-7.23(m,10H),3.85-3.76(m,1H),3.54-3.44(m,3H),3.07-2.96(m,1H),2.94 -2.84(m,1H),2.68-2.35(m,7H).

Example 7 Preparation of 2-(piperazin-2-yl)acetonitrile hydrochloride

At 20-25°C, add 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile (100g, 0.33mol, 1.0eq) and 1,2-dichloroethane (500mL) in sequence. Then slowly add the 1,2-dichloroethane solution of 1-chloroethyl chloride (283g, 1.98mol, 6.0eq), adjust the temperature to 90~95°C and stir for 24 hours. The solvent was distilled off under reduced pressure, methanol (1.5L) was added, and the mixture was stirred at 65°C for 2 hours. Then water (200mL) was slowly added, and the mixture was cooled to room temperature to precipitate a solid. Filter, take out the filter cake, and obtain 48 g of the title compound after drying, with a yield of 74%.

¹ H NMR (400MHz, D ₂ O): δ4.01-3.96 (m, 1H), 3.81-3.67 (m, 3H), 3.46-3.27 (m, 3H), 3.09 (d, J = 6.0HZ, 2H ).

According to the same synthesis method as in Example 7, N ¹ , N ² -dibenzyl ethane-d ₄ -1,2-diamine is substituted for N ¹ , N ² -dibenzyl ethane-1,2-diamine to obtain the following Compounds:

Example 7A 2-(piperazin-2-yl-5,5,6,6-d ₄ )acetonitrile hydrochloride

LCMS(m/z)：130(M+H) ⁺

Example 7B 2-(piperazin-2-yl)acetonitrile-d ₂ hydrochloride

Step 1: (1,4-Dibenzylpiperazin-2-yl)methane-d ₂ -ol

Under nitrogen protection, 1,4-dibenzylpiperazine-2-carboxylic acid methyl ester (3.00g, 9.25mmol) was added in batches to a suspension of deuterated aluminum lithium hydride (1.7g, 40.6mmol) in tetrahydrofuran at room temperature. The obtained reaction solution was refluxed for 3 hours, then cooled to 0°C, and then water (1.5 mL), 4N NaOH aqueous solution (1.5 mL) and water (4.5 mL) were added in sequence. The obtained mixture was stirred for 1 hr and then filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (2.76 g, quantitative yield). It was used directly in the next reaction without purification.

LCMS(m/z)：299(M+H) ⁺

Step 2: 1,4-dibenzyl-2-(chloromethyl-d ₂ )piperazine

To a solution of thionyl chloride (1.63 mL, 22.4 mmol) in CCl ₄ (30 mL), (1,4-dibenzylpiperazin-2-yl)methane-d ₂ -ol (2.76 g, 9.25 mmol) was slowly added dropwise. CCl ₄ solution. The resulting mixture was reacted at 80°C for 2 hr, then cooled to room temperature, and ice water (20 mL) was added. After the aqueous phase was collected, the pH was adjusted to 12 with 4N NaOH aqueous solution, and then extracted with chloroform. The organic phases were combined and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (2.63 g, 90% yield).

LCMS(m/z)：317(M+H) ⁺

Step 3: 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile-d ₂

A solution of 1,4-dibenzyl-2-(chloromethyl-d ₂ )piperazine (1.71g, 0.0054mol) in ethanol (2mL) was added dropwise to the refluxing KCN (0.46g, 0.007mol) in water (2mL) ) solution. The obtained mixture was reacted under reflux for 3 hours, and then concentrated under reduced pressure. The residue was dissolved in chloroform and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was crystallized with n-hexane/diethyl ether to obtain the target product (0.83 g, 50% yield).

LCMS(m/z)：308(M+H) ⁺

Step 4: 2-(piperazin-2-yl)acetonitrile-d ₂ hydrochloride

At 20~25°C, add 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile-d ₂ (0.8g, 0.0026mol, 1.0eq), 1,2-dichloroethane ( 4mL), then slowly add the 1,2-dichloroethane solution of 1-chloroethyl chloride (2.23g, 0.0156mol, 6.0eq), adjust the temperature to 90~95°C and stir for 24 hours. The solvent was evaporated under reduced pressure, methanol (12 mL) was added, stirred at 65°C for 2 hours, and then water (1.6 mL) was slowly added. After cooling to room temperature, a solid precipitated. Filter, take out the filter cake, and dry to obtain the target compound (0.36 g, yield 70%).

LCMS(m/z)：128(M+H) ⁺

Example 7C 2-(piperazin-2-yl-3,3,5,5,6,6-d ₆ )acetonitrile-d ₂ hydrochloride

Step 1: Methyl 2,3-dibromopropionate-2,3,3-d ₃

At 0°C, a solution of liquid bromine (1.74g, 11mmol) in DCM (2mL) was added dropwise to a solution of acrylic acid-d ₃ methyl ester-2,3,3 (0.89g, 10mmol) in DCM (10mL). The mixture was reacted at 0°C for 12 hr, then quenched with saturated sodium thiosulfate (1 mL) and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (2.5 g, quantitative yield). It was used directly in the next reaction without purification.

Step 2: Methyl 1,4-dibenzylpiperazine-2-carboxylate-2,3,3,5,5,6,6-d ₇

Methyl 2,3-dibromopropionate-2,3,3-d ₃ (2.5g, 10mmol) and Et ₃ N (2.9mL) obtained in the previous step were dissolved in toluene (20mL), and then heated to 50°C , then N ¹ , N ² -dibenzylethane-d ₄ -1,2-diamine (2.44g, 10mmol) was added dropwise. The reaction solution was refluxed overnight and then cooled to room temperature, and then extracted with 2N HCl aqueous solution. After the aqueous phase was separated, it was neutralized with 4N NaOH aqueous solution and extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the target product (1.66 g, 50% yield).

LCMS(m/z)：332(M+H) ⁺

Steps 3 to 6: Synthesize the following compounds according to the same method as Example 7B:

LCMS(m/z)：135(M+H) ⁺

Example 8 Preparation of (S)-2-(piperazin-2-yl)acetonitrile D-tartrate

Dissolve 2-(piperazin-2-yl)acetonitrile hydrochloride (10g, 50.5mmol, 1.0eq) in water (250mL) at 20~25°C, dissolve clearly, and add sodium hydroxide aqueous solution (4.0 g, 101mmol, 2.0eq, 250mL of water), stir for 10 minutes, then add the aqueous solution of D-tartaric acid (114g, 101mmol, 2.0eq) into the above solution, adjust the temperature to 25~50°C, and cool naturally to 0~25 ℃, a white solid precipitated. Filter, take out the filter cake, and dry to obtain 11.6 g of the title compound. Calculated as free 2-(piperazin-2-yl)acetonitrile, the resolution yield is 40%, the purity is 96.0%, and the chiral purity is 97%.

Example 9 Preparation of (S)-2-(piperazin-2-yl)acetonitrile D-tartrate

Dissolve 2-(piperazin-2-yl)acetonitrile hydrochloride (100g, 505mmol, 1.0eq) in water (250mL) at 20~25°C, dissolve clearly, and add sodium hydroxide aqueous solution (30g, 758mmol, 1.5eq, 250mL of water), stir for 10 minutes, then add the aqueous solution of D-tartaric acid (114g, 758mmol, 1.5eq) into the above solution, adjust the temperature to 25~50℃, and naturally cool to 0~25℃. A white solid precipitated. Filter, take out the filter cake, and obtain 89 g of the title compound after drying. Take out the above solid (10g), add water (130mL), adjust the temperature to 25~50°C, slowly add ethanol (130mL) dropwise, and naturally cool to 10~25°C to precipitate a white solid. Filter, take out the filter cake, and dry to obtain 8 g of the title compound. Calculated as free 2-(piperazin-2-yl)acetonitrile, the resolution yield is 35%, the purity is 99.0%, and the chiral purity is 99.7%.

¹ H NMR (400MHz, D ₂ O): δ4.48(s,4H,D-tartatic acid),4.01-3.96(m,1H),3.81-3.67(m,3H),3.46-3.27(m,3H) ),3.09(d,J＝6.0HZ,2H).

Example 10 Preparation of (S)-2-(piperazin-2-yl)acetonitrile hydrochloride

At 20 to 25°C, 22 g of the D-tartrate salt of (S)-2-(piperazin-2-yl)acetonitrile (which contains free (S)-2-(piperazin-2-yl)acetonitrile), 17.6mmol, 1.0eq) was added to water (20mL), slowly add sodium hydroxide aqueous solution (2mol/L) until the reaction solution pH=9, add di-tert-butyl dicarbonate (12g, 53mmol, 3.0eq) Tetrahydrofuran solution (tetrahydrofuran 20 mL), stir for 2 hours. Add ethyl acetate (100mL) for extraction, distill the solvent under reduced pressure, then add hydrogen chloride in ethyl acetate solution (4mol/L 100mL), and stir for 1 hour. The solvent was distilled off under reduced pressure, methyl tert-butyl ether (100 mL) was added, and the mixture was stirred for 30 minutes to precipitate a white solid. After filtration and drying, the title compound (32g) was obtained. The yield calculated based on free (S)-2-(piperazin-2-yl)acetonitrile was 90%, and the chiral purity was 99.5%.

¹ H NMR (400MHz, D ₂ O): δ4.01-3.96 (m, 1H), 3.81-3.67 (m, 3H), 3.46-3.27 (m, 3H), 3.09 (d, J = 6.0HZ, 2H ).

Example 11 Preparation of (S)-2-(piperazin-2-yl)acetonitrile-d ₂ D-tartrate

Dissolve 2-(piperazin-2-yl)acetonitrile-d ₂ hydrochloride (5g, 25mmol, 1.0eq) in water (10mL) at 20~25°C, dissolve clearly, and add sodium hydroxide aqueous solution ( 1.5g, 38mmol, 1.5eq, 20mL of water), stir for 10 minutes, then add the aqueous solution of D-tartaric acid (7.5g, 50mmol, 2.0eq) into the above solution, adjust the temperature to 50~80°C, and slowly add ethanol ( 20mL), naturally cooled to 0~25°C, and a white solid precipitated. Filter, take out the filter cake, and obtain 6.3 g of the title compound after drying. Take out the above solid (5g), add water (25mL), adjust the temperature to 80~85°C, slowly add ethanol (25mL) dropwise, and naturally cool to 20~25°C to precipitate a white solid. Filter, take out the filter cake, and dry to obtain 4.8 g of the title compound. Calculated as free 2-(piperazin-2-yl)acetonitrile-d ₂ , the resolution yield is 27% and the chiral purity is 99.5%.

¹ H NMR (400MHz, D ₂ O): δ4.48 (s, 10H, D-tartatic acid), 4.01-3.96 (m, 1H), 3.81-3.67 (m, 3H), 3.46-3.27 (m, 3H ).

Example 12 Preparation of 2-(piperazin-2-yl-5,5,6,6-d ₄ )acetonitrile D-tartrate

Dissolve 2-(piperazin-2-yl-5,5,6,6-d ₄ )acetonitrile hydrochloride (5g, 25mmol, 1.0eq) in water (10mL) at 20~25°C. Clear, add sodium hydroxide aqueous solution (1.5g, 38mmol, 1.5eq, 20mL of water), stir for 10 minutes, then add D-tartaric acid (7.5g, 5mmol, 2.0eq) aqueous solution to the above solution, adjust the temperature to 30 ~50℃, naturally cool to 0~25℃, and a white solid will precipitate. Filter, take out the filter cake, and obtain 6.4 g of the title compound after drying. Take out the above solid (5g), add water (25mL), adjust the temperature to 30-60°C, and naturally cool to 0-25°C to precipitate a white solid. Filter, take out the filter cake, and dry to obtain 5g of the title compound. Calculated based on free 2-(piperazin-2-yl-5,5,6,6-d ₄ )acetonitrile, the yield of separation is 28%. Chiral purity 99.5%.

Example 13 Preparation of 2-(piperazin-2-yl-2,3,3,5,5,6,6-d ₇ )acetonitrile-d ₂ D-tartrate

At 20-25°C, 2-(piperazin-2-yl-2,3,3,5,5,6,6-d ₇ )acetonitrile-d ₂ hydrochloride (5g, 24mmol, 1.0eq) Dissolve in water (10 mL), dissolve clear, add sodium hydroxide aqueous solution (1.4g, 36mmol, 1.5eq, 20mL of water), stir for 10 minutes, then add D-tartaric acid (72g, 5mmol, 2.0eq) to the above solution medium, adjust the temperature to 80-85°C, slowly add ethanol (20 mL), and naturally cool to 20-25°C to precipitate a white solid. Filter, take out the filter cake, and obtain 6.4 g of the title compound after drying. Take out the above solid (5g), add water (25mL), adjust the temperature to 80~85°C, slowly add ethanol (25mL) dropwise, and naturally cool to 20~25°C to precipitate a white solid. Filter, take out the filter cake, dry to constant weight to obtain 5g of the title compound, and dissolve it with free 2-(piperazin-2-yl-2,3,3,5,5,6,6-d ₇ )acetonitrile- _{d 2} Calculated, the resolution yield is 27% and the chiral purity is 99.5%.

All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (15)

1. A method for preparing compound A22 or a salt thereof, characterized in that the method includes:
   

   s1) In an inert solvent, compound A19 reacts with a chiral acid to obtain compound A20;

   s2) In an inert solvent, compound A20 reacts with an amino protecting agent to obtain compound A21;

   s3) In an inert solvent, compound A21 is deprotected to obtain compound A22 or a salt thereof;

   R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

   X ₁ , X ₂ , X ₃ and X ₄ are each independently none, organic acid or inorganic acid;

   P ₁ and P ₂ are each independently an amino protecting group;

   0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.
2. The preparation method according to claim 1, characterized in that R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are all H.
3. The preparation method according to claim 1 or 2, characterized in that P ₁ and P ₂ are each independently tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, trityl, fluorenylmethoxycarbonyl, allyloxy Carbonyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, acetyl, pivaloyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, o-(p-)nitrobenzenesulfonate acyl group.
4. The preparation method according to claim 1, wherein A19 is 2-(piperazin-2-yl)acetonitrile or its hydrochloride, and its preparation method includes the steps:

   Route one:
   

   (i) In dichloromethane, compound A06 reacts with bromine reagent to obtain compound A17;

   (ii) In an inert solvent, in the presence of a base, at 45-50°C, compound A17 and N ¹ , N ² -diphenylmethylethane-1,2-diamine Reaction to obtain compound A18;

   (iii) In an inert solvent, compound A18 removes the protecting group in the presence of 1-chloroethyl chloroformate, Obtain compound A'19;

   Route two:
   

   (i’) react the compound with a bromine reagent in an inert solvent, and then perform an elimination reaction in the presence of a base to obtain compound A07; wherein the molar equivalent of the base is 0.5-5.0 equivalents, preferably 1.0-3.0 equivalents;

   (ii') In the presence of a base, at 20-25°C, compound A17 and N ¹ , N ² -diphenylmethylethane-1,2-diamine Reaction to obtain compound A18;

   (iii’) In an inert solvent, compound A18 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A’19.
5. The preparation method according to claim 1, wherein A19 is 2-(piperazin-2-yl)acetonitrile-d ₂ or its hydrochloride, 2-(piperazin-2-yl-5,5, 6,6-d ₄ ) Acetonitrile or its hydrochloride, 2-(piperazin-2-yl-2,3,3,5,5,6,6-d ₇ ) Acetonitrile- _{d 2} or its hydrochloride , its preparation method includes steps including:

   Route one:
   

   (i") In an inert solvent, compound A01 reacts with a deuterated reducing agent to obtain compound A02;

   (ii") In an inert solvent, compound A02 reacts with a halogenated reagent to obtain compound A03;

   (iii") In an inert solvent, compound A03 reacts with sodium cyanide or potassium cyanide to obtain compound A04;

   (iv”) In an inert solvent, compound A04 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A05;

   Route two:
   

   (i"') In an inert solvent, compound A06 reacts with bromine reagent, and then is eliminated under the action of alkali Reaction to obtain compound A07;

   (ii"') In an inert solvent, compound A07 and N ¹ , N ² -dibenzylethane-d ₄ -1,2-diamine Reaction to obtain compound A08;

   (iii”’) In an inert solvent, compound A08 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A09;

   Route three:
   

   (i"") In an inert solvent, compound A10 is reacted with a bromine reagent to obtain;

   (ii"") In an inert solvent, compound A11 reacts with N ¹ , N ² -dibenzylethane-d ₄ -1,2-diamine to obtain compound A12;

   (iii"") In an inert solvent, compound A12 reacts with a deuterated reducing agent to obtain compound A13;

   (iv””) In an inert solvent, compound A13 reacts with a halogenated reagent to obtain compound A14;

   (v””) In an inert solvent, compound A14 reacts with sodium cyanide or potassium cyanide to obtain compound A15;

   (v””) In an inert solvent, compound A15 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A16.
6. The preparation method of claim 1, wherein compound A22 is compound A'22, and its preparation method includes:
   

   The diastereomeric salt of s'2)(S)-2-(piperazin-2-yl)acetonitrile and chiral acid (compound A'20) reacts with di-tert-butyl dicarbonate to form Di-tert-butyl(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (compound

   A’21);

   s'3) Di-tert-butyl (S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (compound A'21) reacts with hydrogen chloride to obtain 2-(piperazine- 2-yl)acetonitrile hydrochloride (Compound A'22).
7. The preparation method of claim 1, wherein compound A20 is (S)-2-(piperazine-2- base) acetonitrile salt, which is selected from the D-tartrate salt of (S)-2-(piperazin-2-yl)acetonitrile, the D-malic acid salt of (S)-2-(piperazin-2-yl)acetonitrile, (S)-2-(piperazin-2-yl)acetonitrile, R-(-)-citramalic acid, or combinations thereof.
8. The preparation method according to claim 1, characterized in that the reaction temperature is -50°C to the solvent reflux temperature, preferably the reaction temperature is -30°C~100°C, and more preferably, the reaction temperature is -5°C~50°C , more preferably, the reaction temperature is 20 to 25°C.
9. The preparation method according to claim 1, characterized in that in step s3), the reaction temperature is -20°C to the solvent reflux temperature, preferably the reaction temperature is -10°C to 100°C, and more preferably, the reaction temperature is 0 ℃～60℃, more preferably, the reaction temperature is 20～25℃;

   Alternatively, in step s3), compound A21 is deprotected under acidic conditions to obtain compound A22, wherein the acid is selected from: hydrogen chloride, hydrogen bromide, hydrogen fluoride, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methyl Sulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malic acid, citric acid, or combinations thereof; the molar equivalent ratio of compound A21 to acid is 1.0:0.1~20 equivalents, preferably 1.0:0.5~10.0 , more preferably 1.0:1.0～5.0.
10. A method for preparing compound A20, characterized in that the method includes the steps:
    

    s1) In an inert solvent, compound A19 reacts with a chiral acid to obtain compound A20;

    X ₁ and X ₂ are each independently free, organic acid or inorganic acid;

    R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

    0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.
11. The preparation method of claim 10, wherein compound A20 is a diastereomeric salt of (S)-2-(piperazin-2-yl)acetonitrile and a chiral acid, and its preparation method includes the steps
    

    0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5;

    First use a base to adjust the solution of 2-(piperazin-2-yl)acetonitrile hydrochloride (A'19) to neutral or alkaline, then add chiral acid, and finally precipitate (S)-2-(piperazine) -2-yl) Diastereomeric salts of acetonitrile and chiral acids (A'20).
12. The preparation method according to any one of claims 1 to 11, wherein the chiral acid is selected from: L-tartaric acid, D-tartaric acid, dibenzoyl-L-tartaric acid, dibenzoyl-tartaric acid D-tartaric acid, di-p-toluoyl-L-tartaric acid, di-p-toluoyl-D-tartaric acid, L-dipivaloyl tartaric acid, L-malic acid, D-malic acid, R-(-)-citrimalic acid, S-(+)-citromalic acid, R-(-)-mandelic acid, S-(+)-mandelic acid, D-(+)-10- Camphorsulfonic acid, L-(-)-10-camphorsulfonic acid, D-camphoric acid, or combinations thereof; preferably, the chiral acid is selected from: D-tartaric acid, D-malic acid, dibenzoyl- D-tartaric acid, R-(-)-citramalic acid, R-(-)-mandelic acid, or combinations thereof; more preferably, the chiral acid is selected from: D-tartaric acid, D-malic acid, R- (-)-Citral malic acid, or combinations thereof.
13. A compound A20, characterized in that the compound is prepared by the method as claimed in claim 10
    

    R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D;

    0<n≤10, preferably, 0<n≤8, more preferably, n is 0.5≤n≤5.
14. A compound represented by formula I or its enantiomer or its salt,
    

    Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently H or D; the limiting condition is R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are not hydrogen at the same time.
15. The compound or enantiomer or salt thereof according to claim 14, characterized in that the compound is selected from: