A method for synthesizing (s)-2-piperazinylacetonitrile or a salt thereof

Abstract

The application provides a synthesis method of (S)-2-piperazinylacetonitrile hydrochloride, according to the method reported in the literature, the chiral piperazine alcohol with double BOC protection can be conveniently and efficiently synthesized, the aldehyde is generated through an oxidation reaction, the oxime is generated through a reaction with hydroxylamine hydrochloride, the hydroxyl group is activated and then dehydrated to form a cyano group, and finally the (S)-2-piperazinylacetonitrile salt is obtained through deprotection under acidic conditions. The intermediate (S)-2-piperazinylacetonitrile salt obtained through the synthesis route of the application has very high purity, the chiral purity reaches more than 99.9%, the use of the highly toxic potassium cyanide or sodium cyanide is avoided, the reaction condition of high-pressure hydrogenation deprotection is avoided, the raw materials or reagents such as LiAlH4 which are not suitable for amplification are avoided, and the generation of the chloro compound or sulfonate intermediate with potential genotoxicity is avoided.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic matter (high-level intermediate of medicine) synthesis, and relates to (S)-2-piperazinylacetonitrile or a salt thereof, in particular to a synthesis method of (S)-2-piperazinylacetonitrile or a salt thereof which avoids the use of highly toxic potassium cyanide or sodium cyanide, avoids the reaction condition of high-pressure hydrogenation deprotection, and is high-efficiency, mild, safe and suitable for scale-up production. BACKGROUND

[0002] Adagrasib (KRAZATI) is an oral, potent, irreversible KRAS G12C mutant small molecule inhibitor for treating solid tumors containing KRAS G12C oncogenic driver mutations, including non-small cell lung cancer (NSCLC) and colorectal cancer. KRAS is a mediator of signaling pathways essential for cell growth, proliferation and survival, and is the most common mutated oncogene in cancer, which may occur in about 25% of all tumors, especially in pancreatic cancer, colorectal tumors and lung cancer. In recent years, many pharmaceutical companies have focused on developing covalent KRAS inhibitors targeting G12C mutations, which may be based on the following considerations: ① Targeting KRAS mutations can produce selective cytotoxicity to tumor cells; ② KRAS lacks a pocket-type structure for binding ligands, so covalent binding has an advantage in terms of affinity; ③ About 12%-14% of NSCLC patients have KRAS G12C mutations, and these patients will directly benefit from KRAS G12C inhibitors.

[0003] In the synthesis process of Adagrasib, the design and synthesis of intermediates are crucial. These intermediates not only affect the yield and purity of the final product, but also directly relate to production cost and production efficiency. Among them, (S)-2-piperazinylacetonitrile or a salt thereof as a key intermediate for synthesizing Adgrasib (MRTX849) has attracted much attention in the market.

[0004] Currently, there are several main synthesis methods:

[0005] 1. The invention with the publication number WO2014052699A1 and the publication date of 2014-04-03, named AZAQUINAZOLINE INHIBITORS OF ATYPICAL PROTEIN KINASE C, discloses the following route:

[0006]

[0007] This route is through the SN2 reaction of chemical formula 5 and 6 to cyclize piperazine, and then reduce the ester to alcohol by LiAlH4; chlorination, chloro-substituted cyano, and finally reduce the benzyl group to obtain (S)-2-piperazinyl acetonitrile hydrochloride; The disadvantages of this route are that the raw materials are expensive, the reduction of LiAlH4 has high safety risk, the use of highly toxic potassium cyanide, and the intermediates involved in chemical formula 4 have genotoxicity, which has potential residual risk. In addition, the cost of hydrogenation debenzyl is high, which is not suitable for industrial scale-up.

[0008] 2. The invention with publication number CN112694475A, publication date 2021-04-23, and name of Cycloalkyl and heterocycloalkyl inhibitors and methods of making and using the same, discloses the following route:

[0009]

[0010] This route brominates acrylonitrile, then reacts with N, N'-dibenzyl ethylenediamine (chemical formula 6) to cyclize to form a piperazine ring, and then uses ACECl to debenzyl to obtain (S)-2-piperazinyl acetonitrile hydrochloride; This route has a short step, but the final product is a racemate, which needs to be separated by chiral resolution, resulting in a loss of more than half of the yield, and the overall synthesis efficiency is low, which is also not suitable for industrial scale-up.

[0011] 3. The invention with publication number WO2017201161A1, publication date 2017-11-23, and name of KRAS G12C INHIBITORS, discloses the following route:

[0012]

[0013] This route uses 3-hydroxymethyl piperazine-1-carbonate as the starting material, cyclizes to obtain a sulfinic acid lactone, oxidizes to a sulfonic acid lactone, and then substitutes with cyano, and finally removes the Boc protecting group with hydrochloric acid to obtain (S)-2-piperazinyl acetonitrile hydrochloride; This route uses very expensive starting materials, which also need to be prepared by multiple steps, and the subsequent synthesis route still needs to use highly toxic KCN and expensive sodium periodate / ruthenium trichloride oxidation system. Not only that, the overall yield of this route is low, which is not suitable for industrial scale-up.

[0014] 4. The invention with publication number CN116410145A, publication date 2023-07-11, and name of A preparation method of an intermediate of MRTX849, discloses the following route:

[0015]

[0016] The route takes the acid salt of serine ester as a raw material, and protects glycine to obtain (S)-2-piperazinyl acetonitrile hydrochloride through condensation, deprotection, cyclization, reduction, protection of the base, condensation, substitution, deprotection and other reactions; the route has a genotoxic chloro intermediate, and uses the toxic cyanide potassium, and at the same time, the synthesis steps are long, the production efficiency is low, and the production is not suitable for expansion.

[0017] 5. The invention with the publication number CN116410145A and the publication date of 2023-09-19, entitled Preparation method of (S)-2-(piperazin-2-yl)acetonitrile hydrochloride, discloses the following route:

[0018]

[0019] The route takes (R)-1-BOC-3-hydroxymethylpiperazine as a starting material, protects the amino group through PMB, activates the hydroxyl group through ESCl, cyanates through TMSCN, and removes the benzyl group and BOC through ACECl to obtain the product; the problem of the route is that the raw material is expensive, after removing the PMB protection group in the last step, the cyan group is unstable under the methanol acid condition and heating reflux, and impurities are easily generated, and the intermediate synthesized by the method is used for the synthesis of Adagrasib, and the quality risk is great.

[0020] In summary, in the synthesis strategies reported in the literature, toxic cyanide potassium or sodium is used, and electrophilic intermediates such as chloro and methanesulfonate are used, which have potential genotoxicity, and pose a great challenge to the quality research of the drug substance. In addition, most of the synthesis routes use a single N-protected piperazine alcohol intermediate, which is relatively expensive, and is not conducive to cost control in commercial production. SUMMARY

[0021] In order to solve the defects that toxic cyanide potassium or sodium is used in the existing synthesis strategy, there is potential genotoxicity, the raw material is expensive, which is not conducive to cost control in commercial production, and is not suitable for expansion production, the present application provides a synthesis method of (S)-2-piperazinyl acetonitrile hydrochloride, which is efficient, mild, safe and suitable for expansion production. The method avoids the use of toxic cyanide potassium or sodium, avoids the reaction conditions of high-pressure hydrogenation deprotection, avoids the use of LiAlH4 and other raw materials or reagents that are not suitable for expansion, and avoids the generation of chloro or sulfonate intermediates with potential genotoxicity.

[0022] The technical scheme of the present application is implemented as follows: according to the method reported in the literature Asymmetric syntheses of (R)-4-halo-6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino [1, 2-a] [1, n] naphthyridines, important 5-HT2C agonist precursors, Tetrahedron Letters (2018), 59 (21), 2030-2033, a chiral piperazine alcohol with double BOC protection can be conveniently and efficiently synthesized, and then the aldehyde is generated through an oxidation reaction, and then the oxime is generated through a reaction with hydroxylamine hydrochloride, the hydroxyl group is dehydrated into a cyano group after being activated, and finally the (S)-2-piperazinyl acetonitrile salt is obtained through deprotection under acidic conditions. The intermediate (S)-2-piperazinyl acetonitrile salt obtained in the synthesis route of the present application has extremely high purity, and the chiral purity reaches more than 99.9%.

[0023] In order to achieve the above-mentioned purpose, the present application adopts the following technical scheme:

[0024] The present application provides a synthesis method of (S)-2-piperazinyl acetonitrile or a salt thereof, which comprises the following steps:

[0025] (a) the compound shown in formula I is reacted with an oxidizing agent under the participation of a base to obtain a compound shown in formula II;

[0026] (b) the compound shown in formula II is reacted with hydroxylamine under the participation of a base to obtain a compound shown in formula III;

[0027] (c) the hydroxyl group in the compound shown in formula III is activated by an activating agent and then hydrolyzed, and recrystallization is performed using a solvent to obtain a compound shown in formula IV;

[0028] (d) the compound shown in formula IV is deprotected under acidic conditions to obtain a compound shown in formula V;

[0029] wherein the compound shown in formula I is:

[0030]

[0031] the compound shown in formula II is:

[0032]

[0033] the compound shown in formula III is:

[0034]

[0035] the compound shown in formula IV is:

[0036]

[0037] a compound shown in formula V:

[0038] As a preferred scheme of the present application, the synthetic method is:

[0039] (a) dissolving a compound shown in formula I in a solvent, adding a base and an oxidizing agent to react, after the reaction is completed, quenching, centrifuging, separating layers, extracting, washing, drying and concentrating to obtain a compound shown in formula II;

[0040] (b) dissolving a compound shown in formula II in a solvent, adding a base and hydroxylamine, stirring, after the reaction is completed, centrifuging, desolventizing, separating layers, extracting, washing, drying, filtering, concentrating to obtain a compound shown in formula III;

[0041] (c) dissolving a compound shown in formula III in a solvent, adding a base, then adding an activating agent dropwise, after the dropwise addition is completed, warming and reacting, after the reaction is completed, quenching with water, separating layers, desolventizing, replacing another solvent, washing, concentrating, recrystallizing, filtering and drying to obtain a compound shown in formula IV;

[0042] (d) dissolving a compound shown in formula IV in a solvent, adding an acid to react, after the reaction is completed, adding a solvent, centrifuging and drying the wet product to obtain a compound shown in formula V.

[0043] As a preferred scheme of the present application, in step (a) and step (b), the base includes one or both of sodium bicarbonate or potassium bicarbonate.

[0044] As a preferred scheme of the present application, in step (a), the oxidizing agent is trichloroisocyanuric acid, and the reaction temperature is 20-30°C.

[0045] As a preferred scheme of the present application, in step (b), the hydroxylamine includes hydroxylamine hydrochloride, and the reaction temperature is 20-35°C.

[0046] As a preferred scheme of the present application, in step (c), the activating reaction is carried out by adding a compound shown in formula III and N-methylmorpholine or pyridine.

[0047] As a preferred scheme of the present application, in step (c), the activating agent includes trichloroacetyl chloride, and the dropwise addition temperature of the activating agent is 10-30°C.

[0048] As a preferred scheme of the present application, in step (c), the washing includes sodium carbonate aqueous solution washing, citric acid aqueous solution washing and 10% saline washing.

[0049] As a preferred scheme of the present application, in step (d), the acid comprises hydrogen chloride in ethanol, hydrogen chloride in dioxane or hydrogen chloride in ethyl acetate.

[0050] As a preferred scheme of the present application, in step (d), the temperature for the Boc removal is 15-35℃.

[0051] Compared with the prior art, the present application has the following beneficial effects:

[0052] 1) In the process route adopted by the present application, chirality is introduced by amino acid, and all the process conditions are mild enough to avoid racemization of chiral center in the reaction, so that the product with high chiral purity can be obtained in high yield, avoiding chiral resolution, greatly reducing the production cost and improving the production efficiency.

[0053] 2) The present application avoids the use of hydrogenation to remove the benzyl protecting group and the use of noble metal Pd, thereby reducing the cost and enhancing the feasibility of production scale-up.

[0054] 3) The present application avoids the use of toxic potassium cyanide or sodium cyanide and the generation of genetically toxic chlorinated intermediates and sulfonate intermediates, so that the safety of the product is more guaranteed.

[0055] 4) The post-treatment process adopted by the present application also does not need to use column chromatography to purify and separate the product, and most of the steps can be carried out without purification of the crude product, thereby saving the production time, improving the production efficiency, greatly reducing the cost, being suitable for industrial mass production, and also being suitable for small-scale preparation in the laboratory.

[0056] 5) The process route of the present application is different from the prior art, and is a novel synthesis strategy that can realize industrial scale-up production.

[0057] 6) The present application provides a synthesis method of (S)-2-piperazinylacetonitrile hydrochloride, which is efficient, mild, safe and suitable for scale-up production, avoids the use of toxic potassium cyanide or sodium cyanide, avoids the reaction conditions of high-pressure hydrogenation to remove the protecting group, avoids the use of raw materials or reagents such as LiAlH4 which are not suitable for scale-up, and avoids the generation of chlorinated compounds or sulfonate intermediates which have potential genetic toxicity. BRIEF DESCRIPTION OF DRAWINGS

[0058] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed in the following embodiment or prior art description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0059] Figure 1is a synthetic route map of the present application.

[0060] Figure 2 is a chemical purity spectrum of the compound shown as formula V in embodiment 1 of the present application.

[0061] Figure 3 is a chiral purity spectrum of the compound shown as formula V in embodiment 1 of the present application.

[0062] Figure 4 is a nuclear magnetic hydrogen spectrum of the compound shown as formula V in embodiment 1 of the present application. DETAILED DESCRIPTION

[0063] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0064] The present application provides a synthesis method of (S)-2-piperazinylacetonitrile hydrochloride which is efficient, mild, safe and suitable for scale-up production. The technical solution of the present application is realized as follows: according to the method reported in the literature “Asymmetric syntheses of (R)-4-halo-6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino[1, 2-a][1, n]naphthyridines, important 5-HT2C agonist precursors, Tetrahedron Letters (2018), 59 (21), 2030-2033.”, the double-BOC-protected chiral piperazine alcohol can be conveniently and efficiently synthesized. The aldehyde is generated by oxidation reaction from the raw material, and then the oxime is generated by reaction with hydroxylamine hydrochloride. After activation of the hydroxyl group, dehydration is carried out to form a cyano group. Finally, the (S)-2-piperazinylacetonitrile salt is obtained by deprotection under acidic conditions. The intermediate (S)-2-piperazinylacetonitrile salt obtained by the synthesis route has extremely high purity, and the chiral purity reaches more than 99.9%.

[0065] The synthesis method of the present application is as follows:

[0066] (a) the compound shown as formula I is dissolved in a solvent, a base and an oxidizing agent are added for reaction, after the reaction is completed, quenching, centrifugation, separation of layers, washing and drying are carried out, and then concentration is carried out to obtain the compound shown as formula II;

[0067] (b) the compound shown as formula II is dissolved in a solvent, a base and hydroxylamine are added, and then incubation and stirring are carried out, after the reaction is completed, centrifugation is carried out, and then desolventization is carried out, and then layer separation extraction is carried out by adding a solvent, and then washing, drying, filtration and concentration are carried out to obtain the compound shown as formula III;

[0068] (c) dissolving the compound shown in formula III in a solvent, adding a base, then adding an activating reagent dropwise, after the dropwise addition is completed, warming and incubating for reaction, after the reaction is completed, quenching with water, separating layers, desolventizing, replacing another solvent, washing, concentrating, recrystallizing, filtering, and drying to obtain a compound shown in formula IV;

[0069] (d) dissolving the compound shown in formula IV in a solvent, adding an acid dropwise for reaction, after the reaction is completed, adding a solvent, centrifuging, and drying the wet product to obtain a compound shown in formula V.

[0070] In the present application, the compound shown in formula I can be synthesized according to the description in the literature “Asymmetric syntheses of (R)-4-halo-6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino[1, 2-a][1, n]naphthyridines, important 5-HT2C agonist precursors, Tetrahedron Letters (2018), 59 (21),

[0071] 2030-2033. https: / / doi.org / 10.1016 / j.tetlet.2018.04.030”, or can be purchased from Shanghai Yuhuan Chemical Co., Ltd. or Chengdu Bo Bo Pharmaceutical Technology Co., Ltd., hydroxylamine hydrochloride is purchased from Jinan Quansheng Chemical Co., Ltd., Tempo is purchased from Shanghai Bangcheng Chemical Co., Ltd., trichloroisocyanuric acid is purchased from Shanghai Maikelin Biochemical Technology Co., Ltd., N-methyl morpholine is purchased from Aldrin, MTBE (methyl tert-butyl ether) is purchased from Shanghai Bangcheng Chemical Co., Ltd., and the rest of the reagents or equipment can be purchased from the market.

[0072] Example 1

[0073] Referring to Figure 1 , the present embodiment provides a route of (S)-2-piperazinyl acetonitrile hydrochloride, which comprises:

[0074] 1) To a 10 L glass reactor flask, add tap water (2129 g, 10 V), compound of Formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11 V), add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) with stirring, add TEMPO (2.0 g, 0.02 eq) at 10-20 °C, after addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20-30 °C, keep for 0.5 h, take sample to check reaction completion, filter, separate the layers of the filtrate, extract the aqueous phase with dichloromethane (564.2 g, 2 V) once, wash with 5% (mass fraction) sodium carbonate aqueous solution (425.8 g) once, wash with 10% (mass fraction) sodium chloride aqueous solution (425.8 g) once. Dry over anhydrous sodium sulfate (50 g), filter, and concentrate to obtain 191.5 g of compound of Formula II, white solid, yield 90.5%, HPLC purity 99.3%.

[0075] 2) To a 1000 mL three-necked flask, add methanol (284.8 g, 3 V), compound of Formula II (120 g, 1.0 eq), open the reactor cap, add sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) with stirring, keep at 20-35 °C for 2 h, take sample to check reaction completion, centrifuge, remove the solvent from the filtrate, add MTBE (444 g, 5 V) and tap water (240 g, 2 V), stir and separate the layers, extract the aqueous phase with MTBE (177.6 g, 2 V) once, combine the organic phases, wash with 10% (mass fraction) sodium chloride (240 g) once, dry over anhydrous sodium sulfate (30 g), filter, and concentrate to obtain 107.0 g of compound of Formula III, yield 85.3%, HPLC purity 99.0%.

[0076] 3) To a 1000 mL three necked flask was added dichloromethane (662.5 g, 5V), compound of formula III (100 g, 1.0 eq) and N-methylmorpholine (100.1 g, 3.4 eq), trichloroacetyl chloride (74.1 g, 1.4 eq) was added drop wise at 10-30 °C. After the addition was complete, the reaction was allowed to warm to 20-30 °C for 2-6 h. After the reaction was complete, as indicated by sampling, tap water (200 g, 2V) was added drop wise, the mixture was stirred and the layers were separated. The aqueous layer was extracted with dichloromethane (265 g, 2V) once. The organic layers were combined and stripped of solvent. MTBE (370 g, 5V) was added, the mixture was washed with 5% (w / w) aqueous sodium carbonate (200 g) once, 20% (w / w) aqueous citric acid (400 g) once, and 10% (w / w) brine (200 g) once. The mixture was stripped of solvent and n-heptane (204.9 g, 3V) was added. The mixture was warmed to 80 °C to dissolve, then cooled to 0-10 °C to recrystallize. The mixture was filtered and dried to give 86.1 g of compound of formula IV, 90.9% yield, 99.6% HPLC purity.

[0077] 4) To a 1000 mL three necked flask was added absolute ethanol (56.7 g, 1.5V) and compound of formula IV (47.9 g, 1.0 eq). 15% (w / w) hydrogen chloride in ethanol (200 g) was added drop wise at 10-20 °C. After the addition was complete, the reaction was allowed to warm to 15-35 °C for 12-16 h. After the reaction was complete, as indicated by sampling, absolute ethanol (264.6 g, 7V) was added. The mixture was stirred for 1-2 h, then cooled to 0-10 °C for 1 h. The mixture was filtered and dried to give 24.8 g of compound of formula V, 85.1% yield, 99.7% HPLC chemical purity (see Figure 2 ), 100% chiral purity (see Figure 3 ), and 1H NMR (see Figure 4 .

[0078] Example 2

[0079] See Figure 1 , this example provides a route to (S)-2-piperazinylacetonitrile hydrochloride salt, comprising:

[0080] 1) Into a 3L 3-necked flask, add tap water (1500g, 10V), compound of Formula I (150g, 1.0 eq) and dichloromethane (2186.3g, 11V), add sodium bicarbonate (114.4g, 3.0 eq) and solid potassium bromide (5.4g, 0.1 eq) with stirring, add TEMPO (1.4g, 0.02 eq) at 10-20°C, after addition, add TCCA (63.3g, 0.6 eq) at 20-30°C and keep for 0.5h, after reaction is completed by sampling, filter, separate the layers of the filtrate, extract the aqueous phase with dichloromethane (397.5g, 2V) once, wash with 5% (mass fraction) sodium carbonate aqueous solution (300g) once, wash with 10% (mass fraction) salt water solution (300g) once. Dry over anhydrous sodium sulfate (40g), filter and concentrate to obtain 133.1g of compound of Formula II, white solid, yield 89.3%, HPLC purity 99.2%.

[0081] 2) Into a 1000mL 3-necked flask, add methanol (284.8g, 3V), compound of Formula II (120g, 1.0 eq), open the cap of the reactor, add sodium carbonate (46.5g, 1.2 eq) and hydroxylamine hydrochloride (30.5g, 1.2 eq) with stirring, keep for 2h at 20-35°C, after reaction is completed by sampling, centrifuge, remove the solvent from the filtrate, add MTBE (444g, 5V) and tap water (240g, 2V), stir and separate the layers, extract the aqueous phase with MTBE (177.6g, 2V) once, combine the organic phases, wash with 10% (mass fraction) salt water (240g) once, dry over anhydrous sodium sulfate (30g), filter and concentrate to obtain 107.0g of compound of Formula III, yield 85.3%, HPLC purity 99.2%.

[0082] 3) Into a 1000mL 3-necked flask, add dichloromethane (662.5g, 5V), compound of Formula III (100g, 1.0 eq) and N-methylmorpholine (100.1g, 3.4 eq), add trichloroacetyl chloride (74.1g, 1.4 eq) dropwise at 10-30°C. After dropwise addition is completed, keep for 2-6h, after reaction is completed by sampling, add tap water (200g, 2V) dropwise, stir and separate the layers, extract the aqueous phase with dichloromethane (265g, 2V) once, combine the organic phases, remove the solvent, add MTBE (370g, 5V), wash with 5% (mass fraction) sodium carbonate aqueous solution (200g) once, wash with 20% (mass fraction) citric acid aqueous solution (400g) once, wash with 10% (mass fraction) salt water (200g) once, remove the solvent, add n-heptane (204.9g, 3V), dissolve at 80°C, cool to 0-10°C and recrystallize, filter and dry to obtain 86.1g of compound of Formula IV, yield 90.9%, HPLC purity 99.6%.

[0083] 4) Into a 1000 mL three-necked flask, add anhydrous ethanol (56.7 g, 1.5 V) and the compound of Formula IV (47.9 g, 1.0 eq), drop 15% (mass fraction) hydrogen chloride ethyl acetate solution (200 g) at 10-20 °C. After the drop is completed, warm to 15-35 °C for 12-16 h, take sample to detect the reaction is complete, add anhydrous ethanol (264.6 g, 7 V), stir for 1-2 h, cool to 0-10 °C, incubate for 1 h, filter, dry to obtain 24.7 g of the compound of Formula V, yield 84.6%, HPLC chemical purity 99.7%, chiral purity 100%.

[0084] Example 3

[0085] Referring to Figure 1 , the present embodiment provides a route of (S)-2-piperazinyl acetonitrile hydrochloride, comprising:

[0086] 1) Into a 10 L glass reaction flask, add tap water (2129 g, 10 V), the compound of Formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11 V), add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) with stirring, add TEMPO (2.0 g, 0.02 eq) at 10-20 °C, after adding, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20-30 °C and incubate for 0.5 h, take sample to detect the reaction is complete, filter, separate the filtrate into layers, extract the aqueous phase with dichloromethane (564.2 g, 2 V) once, wash with 5% (mass fraction) sodium carbonate aqueous solution (425.8 g) once, wash with 10% (mass fraction) salt aqueous solution (425.8 g) once. Dry with anhydrous sodium sulfate (50 g), filter, concentrate to obtain 191.5 g of the compound of Formula II, white solid, yield 90.5%, HPLC purity 99.3%.

[0087] 2) Into a 500 mL three-necked flask, add methanol (189.8 g, 3 V), the compound of Formula II (80 g, 1.0 eq), open the reactor cap, add potassium carbonate (40.4 g, 1.2 eq) and hydroxylamine hydrochloride (20.3 g, 1.2 eq) with stirring, incubate at 20-35 °C for 2 h, take sample to detect the reaction is complete, centrifuge, remove the solvent from the filtrate, add MTBE (296 g, 5 V) and tap water (160 g, 2 V), stir to separate the layers, extract the aqueous phase with MTBE (118.4 g, 2 V) once, combine the organic phases, wash with 10% (mass fraction) salt water (160 g) once, dry with anhydrous sodium sulfate (25 g), filter, concentrate to obtain 70.4 g of the compound of Formula III, yield 84.2%, HPLC purity 99.4%.

[0088] 3) Into a 1000 mL three-necked flask, add dichloromethane (450.5 g, 5V), compound of formula III (68 g, 1.0 eq) and N-methylmorpholine (68.1 g, 3.4 eq), drop in trichloroacetyl chloride (50.4 g, 1.4 eq) at 10-30 °C. After dropwise addition, keep for 2-6 h, take sample to check reaction completion, drop in tap water (136 g, 2V), stir to separate layers, extract aqueous phase with dichloromethane (180.2 g, 2V) once, combine organic phases, remove solvent, add MTBE (450.5 g, 5V), wash with 5% (mass fraction) sodium carbonate aqueous solution (136 g) once, 20% (mass fraction) citric acid aqueous solution (272 g) once, 10% (mass fraction) brine (136 g) once, remove solvent, add n-heptane (139.3 g, 3V), dissolve at 80 °C, cool to 0-10 °C, recrystallize, filter, and dry to obtain 57.1 g of compound of formula IV, with a yield of 88.6% and HPLC purity of 99.6%.

[0089] 4) Into a 1000 mL three-necked flask, add absolute ethanol (56.7 g, 1.5V) and compound of formula IV (47.9 g, 1.0 eq), drop in 15% (mass fraction) hydrogen chloride in ethanol (200 g) at 10-20 °C. After dropwise addition, warm to 15-35 °C and keep for 12-16 h, take sample to check reaction completion, add absolute ethanol (264.6 g, 7V), stir for 1-2 h, cool to 0-10 °C, keep for 1 h, filter, and dry to obtain 24.8 g of compound of formula V, with a yield of 85.1%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0090] Example 4

[0091] Referring to Figure 1 , the present example provides a route of (S)-2-piperazinylacetonitrile hydrochloride, which comprises:

[0092] 1) To a 10 L glass reactor flask, add tap water (2129 g, 10 V), compound of Formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11 V), add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) with stirring, add TEMPO (2.0 g, 0.02 eq) at 10-20 °C, after addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20-30 °C, and incubate for 0.5 h, take sample to check reaction completion, filter, separate layers of filtrate, extract aqueous phase with dichloromethane (564.2 g, 2 V) once, wash with 5% (mass fraction) aqueous sodium carbonate solution (425.8 g) once, and wash with 10% (mass fraction) aqueous salt solution (425.8 g) once. Dry over anhydrous sodium sulfate (50 g), filter, and concentrate to obtain 191.5 g of compound of Formula II, white solid, yield 90.5%, HPLC purity 99.3%.

[0093] 2) To a 500 mL three-necked flask, add ethanol (189.8 g, 3 V), compound of Formula II (80 g, 1.0 eq), open the reactor cap, and add potassium carbonate (40.4 g, 1.2 eq) and hydroxylamine hydrochloride (20.3 g, 1.2 eq) with stirring, incubate at 20-35 °C for 2 h, take sample to check reaction completion, centrifuge, remove solvent from the filtrate, add MTBE (296 g, 5 V) and tap water (160 g, 2 V), stir to separate layers, extract the aqueous phase with MTBE (118.4 g, 2 V) once, combine the organic phases, wash with 10% (mass fraction) salt water (160 g) once, dry over anhydrous sodium sulfate (25 g), filter, and concentrate to obtain 70.4 g of compound of Formula III, yield 84.2%, HPLC purity 99.3%.

[0094] 3) Into a 1000 mL three-necked flask, add dichloromethane (450.5 g, 5V), compound of formula III (68 g, 1.0 eq) and N-methylmorpholine (68.1 g, 3.4 eq), drop in trichloroacetyl chloride (50.4 g, 1.4 eq) at 10-30 °C. After dropwise addition, keep for 2-6 h, take sample to check reaction completion, drop in tap water (136 g, 2V), stir to separate layers, extract aqueous phase with dichloromethane (180.2 g, 2V) once, combine organic phases, remove solvent, add MTBE (450.5 g, 5V), wash with 5% (mass fraction) sodium carbonate aqueous solution (136 g) once, 20% (mass fraction) citric acid aqueous solution (272 g) once, 10% (mass fraction) brine (136 g) once, remove solvent, add n-heptane (139.3 g, 3V), dissolve at 80 °C, cool to 0-10 °C, recrystallize, filter, and dry to obtain 57.1 g of compound of formula IV, with a yield of 88.6% and HPLC purity of 99.6%.

[0095] 4) Into a 1000 mL three-necked flask, add absolute ethanol (56.7 g, 1.5V) and compound of formula IV (47.9 g, 1.0 eq), drop in 15% (mass fraction) hydrogen chloride in ethanol (200 g) at 10-20 °C. After dropwise addition, warm to 15-35 °C and keep for 12-16 h, take sample to check reaction completion, add absolute ethanol (264.6 g, 7V), stir for 1-2 h, cool to 0-10 °C, keep for 1 h, filter, and dry to obtain 24.8 g of compound of formula V, with a yield of 85.1%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0096] Example 5

[0097] Referring to Figure 1 The present example provides a route for (S)-2-piperazinylacetonitrile hydrochloride, which comprises:

[0098] 1) To a 10 L glass reactor flask, add tap water (2129 g, 10 V), compound of Formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11 V), add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) with stirring, add TEMPO (2.0 g, 0.02 eq) at 10-20 °C, after addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20-30 °C, and incubate for 0.5 h, take sample to check reaction completion, filter, separate layers of filtrate, extract aqueous phase with dichloromethane (564.2 g, 2 V) once, wash with 5% (mass fraction) aqueous sodium carbonate solution (425.8 g) once, and wash with 10% (mass fraction) aqueous salt solution (425.8 g) once. Dry over anhydrous sodium sulfate (50 g), filter, and concentrate to obtain 191.5 g of compound of Formula II, white solid, yield 90.5%, HPLC purity 99.3%.

[0099] 2) To a 1000 mL three-necked flask, add methanol (284.8 g, 3 V), compound of Formula II (120 g, 1.0 eq), open the reactor cap, and add sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) with stirring, incubate at 20-35 °C for 2 h, take sample to check reaction completion, centrifuge, remove solvent from the filtrate, add MTBE (444 g, 5 V) and tap water (240 g, 2 V), stir to separate layers, extract the aqueous phase with MTBE (177.6 g, 2 V) once, combine the organic phases, wash with 10% (mass fraction) salt water (240 g) once, dry over anhydrous sodium sulfate (30 g), filter, and concentrate to obtain 107.0 g of compound of Formula III, yield 85.3%, HPLC purity 99.2%.

[0100] 3) To a 1000 mL three-necked flask was added dichloromethane (662.5 g, 5V), compound of Formula III (100 g, 1.0 eq) and pyridine (78.3 g, 3.4 eq), and trichloroacetyl chloride (74.1 g, 1.4 eq) was added dropwise at 10 °C to 30 °C. After the addition was completed, the reaction was allowed to warm to 20 °C to 30 °C for 2 to 6 h. After the reaction was completed, as determined by sampling, tap water (200 g, 2V) was added dropwise, and the mixture was stirred and partitioned. The aqueous phase was extracted with dichloromethane (265 g, 2V) once, and the organic phases were combined and stripped of solvent. MTBE (370 g, 5V) was added, and the mixture was washed with 5% (w / w) aqueous sodium carbonate (200 g) once, 20% (w / w) aqueous citric acid (400 g) once, and 10% (w / w) aqueous brine (200 g) once. The mixture was stripped of solvent, and n-heptane (204.9 g, 3V) was added. The mixture was warmed to 80 °C to dissolve, and then cooled to 0 °C to 10 °C to recrystallize. The mixture was filtered, and the solid was dried to give 86.1 g of compound of Formula IV, in 90.9% yield, with a HPLC purity of 99.5%.

[0101] 4) To a 1000 mL three-necked flask was added absolute ethanol (56.7 g, 1.5V) and compound of Formula IV (47.9 g, 1.0 eq). A 15% (w / w) solution of hydrogen chloride in dioxane (200 g) was added dropwise at 10 °C to 20 °C. After the addition was completed, the mixture was warmed to 15 °C to 35 °C and allowed to stir for 12 h to 16 h. After the reaction was completed, as determined by sampling, absolute ethanol (264.6 g, 7V) was added, and the mixture was stirred for 1 h to 2 h. The mixture was cooled to 0 °C to 10 °C, and the mixture was allowed to stir for 1 h. The mixture was filtered, and the solid was dried to give 24.3 g of compound of Formula V, in 83.2% yield, with a HPLC chemical purity of 99.7% and a chiral purity of 100%.

[0102] Example 6

[0103] See Figure 1 This example provides a route for (S)-2-piperazinylacetonitrile hydrochloride, comprising:

[0104] 1) To a 10 L glass reactor flask, add tap water (2129 g, 10 V), compound of Formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11 V), add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) with stirring, add TEMPO (2.0 g, 0.02 eq) at 10-20 °C, after addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20-30 °C, and incubate for 0.5 h, take sample to check reaction completion, filter, separate layers of filtrate, extract aqueous phase with dichloromethane (564.2 g, 2 V) once, wash with 5% (mass fraction) aqueous sodium carbonate solution (425.8 g) once, and wash with 10% (mass fraction) aqueous salt solution (425.8 g) once. Dry over anhydrous sodium sulfate (50 g), filter, and concentrate to obtain 191.5 g of compound of Formula II, white solid, yield 90.5%, HPLC purity 99.3%.

[0105] 2) To a 1000 mL three-necked flask, add methanol (284.8 g, 3 V), compound of Formula II (120 g, 1.0 eq), open the reactor cap, and add sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) with stirring, incubate at 20-35 °C for 2 h, take sample to check reaction completion, centrifuge, remove solvent from filtrate, add MTBE (444 g, 5 V) and tap water (240 g, 2 V), stir to separate layers, extract aqueous phase with MTBE (177.6 g, 2 V) once more, combine organic phases, wash with 10% (mass fraction) salt water (240 g) once, dry over anhydrous sodium sulfate (30 g), filter, and concentrate to obtain 107.0 g of compound of Formula III, yield 85.3%, HPLC purity 99.2%.

[0106] 3) Into a 1000 mL three-necked flask, dichloromethane (662.5 g, 5V), compound of formula III (100 g, 1.0 eq) and N-methylmorpholine (100.1 g, 3.4 eq) were added, and trichloroacetyl chloride (74.1 g, 1.4 eq) was added dropwise at 10-30 °C. After the dropwise addition was completed, the mixture was incubated for 2-6 h, and tap water (200 g, 2V) was added dropwise after the reaction was completed. The mixture was stirred, and the layers were separated. The aqueous phase was extracted once with dichloromethane (265 g, 2V). The organic phases were combined, and solvent was removed. MTBE (370 g, 5V) was added, and the mixture was washed once with 5% (mass fraction) aqueous sodium carbonate solution (200 g), once with 20% (mass fraction) aqueous citric acid solution (400 g), and once with 10% (mass fraction) brine (200 g). Solvent was removed, and n-heptane (204.9 g, 3V) was added. The mixture was dissolved at 80 °C, and recrystallized at 0-10 °C. The mixture was filtered, and dried to obtain 86.1 g of compound of formula IV, with a yield of 90.9% and an HPLC purity of 99.5%.

[0107] 4) Into a 1000 mL three-necked flask, isopropanol (58.9 g, 1.5V) and compound of formula IV (50 g, 1.0 eq) were added, and 15% (mass fraction) hydrogen chloride in dioxane (209 g) was added dropwise at 10-20 °C. After the dropwise addition was completed, the mixture was incubated at 15-35 °C for 12-16 h. After the reaction was completed, isopropanol (274.9 g, 7V) was added, and the mixture was stirred for 1-2 h. The mixture was cooled to 0-10 °C, and incubated for 1 h. The mixture was filtered, and dried to obtain 26.2 g of compound of formula V, with a yield of 86.2%, an HPLC chemical purity of 99.7%, and a chiral purity of 100%.

[0108] The above description is only the preferred embodiment of the present application, and is not intended to limit the present application in any form or in essence. It should be noted that those skilled in the art can make some improvements and supplements without departing from the method of the present application, and these improvements and supplements should also be considered as the protection scope of the present application. For those skilled in the art, some slight changes, modifications and equivalent changes made by utilizing the technical content disclosed above without departing from the spirit and scope of the present application are equivalent embodiments of the present application; meanwhile, any equivalent changes, modifications and evolution made by utilizing the essential technology of the present application to the above embodiments are still within the scope of the technical solutions of the present application.

Claims

1. A method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof, characterized in that: The synthesis method comprises the following steps: (a) the compound represented by formula I reacts with an oxidant in the presence of a base, sodium bromide and TEMPO to obtain a compound represented by formula II; the base is sodium bicarbonate and the oxidant is trichloroisocyanuric acid; (b) reacting the compound represented by formula II with hydroxylamine in the presence of a base to obtain the compound represented by formula III; (c) activating the hydroxyl group in the compound represented by Formula III with an activating reagent and then hydrolyzing it, followed by recrystallization using a solvent to obtain a compound represented by Formula IV; (d) deprotecting the compound represented by Formula IV under acidic conditions to obtain the compound represented by Formula V; the acid is a solution of hydrogen chloride in ethanol, a solution of hydrogen chloride in dioxane, or a solution of hydrogen chloride in ethyl acetate; Among them, the compound represented by formula I: ; The compound shown in formula II: ; The compound shown in formula III: ; The compound shown in formula IV: ; The compound represented by formula V: .

2. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1, wherein: The synthesis method is: (a) dissolving the compound represented by formula I in a solvent, adding sodium bicarbonate, trichloroisocyanuric acid, sodium bromide and TEMPO to react, and after the reaction is completed, quenching, centrifuging, layering, extracting, washing, drying and concentrating to obtain the compound represented by formula II; (b) dissolving the compound represented by Formula II in a solvent, adding a base and hydroxylamine, stirring while maintaining the temperature, centrifuging after the reaction is complete, removing the solvent, adding a solvent for layered extraction, washing, drying, filtering, and concentrating to obtain the compound represented by Formula III; (c) dissolving the compound represented by Formula III in a solvent, adding a base, and then dropwise adding an activating reagent. After the dropwise addition is complete, the temperature is raised and kept to react. After the reaction is complete, water is added to quench the reaction, and the mixture is separated and extracted. The solvent is removed and replaced with another solvent. The mixture is washed, concentrated, recrystallized, filtered, and dried to obtain the compound represented by Formula IV. (d) dissolving the compound represented by Formula IV in a solvent, adding an acid dropwise to react, adding a solvent after the reaction is complete, centrifuging, and drying the wet product to obtain the compound represented by Formula V; the acid is a solution of hydrogen chloride in ethanol, a solution of hydrogen chloride in dioxane, or a solution of hydrogen chloride in ethyl acetate.

3. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (a), the reaction temperature is 20°C-30°C.

4. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (b), the hydroxylamine is hydroxylamine hydrochloride, and the reaction temperature is 20°C-35°C.

5. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (c), the compound represented by formula III and N-methylmorpholine or pyridine are added during the activation reaction.

6. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (c), the activation reagent is trichloroacetyl chloride, and the temperature for adding the activation reagent dropwise is 10°C-30°C.

7. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (c), the washing is washing with a sodium carbonate aqueous solution, washing with a citric acid aqueous solution and washing with 10% brine.

8. The method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1, characterized in that: In step (d), during the deprotection, the reaction temperature is 15°C-35°C.

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