Synthesis method of (S)-2-piperazinyl acetonitrile or salt thereof

Abstract

The invention provides a synthetic method of (S)-2-piperazinyl acetonitrile hydrochloride, chiral piperazinol protected by double BOC can be conveniently and efficiently synthesized according to a method reported in literature, the chiral piperazinol is used as a raw material to generate aldehyde through oxidation reaction, the aldehyde reacts with hydroxylamine hydrochloride to generate oxime, hydroxyl is activated and dehydrated into cyano, and the (S)-2-piperazinyl acetonitrile hydrochloride is obtained. And finally, carrying out deprotection under an acidic condition to obtain the (S)-2-piperazinyl acetonitrile salt. The purity of the intermediate (S)-2-piperazinyl acetonitrile salt obtained under the synthetic route is extremely high, the chiral purity reaches 99.9% or above, use of highly toxic potassium cyanide or sodium cyanide is avoided, the reaction condition of high-pressure hydrogenation deprotection is avoided, raw materials or reagents such as LiAlH4 which are not suitable for amplification are avoided, and the method is suitable for large-scale production. And the generation of chloride or sulfonate intermediates with potential genotoxicity is avoided.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound (pharmaceutical advanced intermediate) synthesis, and relates to (S)-2-piperazinyl acetonitrile or its salt, and in particular to a method for synthesizing (S)-2-piperazinyl acetonitrile or its salt, which avoids the use of highly toxic potassium cyanide or sodium cyanide and the reaction conditions of high-pressure hydrogenation deprotection and is efficient, mild, safe and suitable for large-scale production. Background Art

[0002] Adagrasib (KRAZATI) is an oral, potent, irreversible KRAS G12C mutant isomer small molecule inhibitor for the treatment of 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 necessary for cell growth, proliferation, and survival. It is the most common mutated oncogene in cancer, and about 25% of all types of tumors may have this mutation, especially in pancreatic cancer, colorectal cancer, and lung cancer. In recent years, many pharmaceutical companies have focused on the development of 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 structure for binding ligands, so the affinity through covalent binding is more advantageous; ③ About 12%-14% of NSCLCs have KRAS G12C mutations, and 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 are also directly related to production costs and production efficiency. Among them, (S)-2-piperazine acetonitrile or its salt is a key intermediate for the synthesis of Adgrasib (MRTX849), and its synthesis method has attracted much attention in the market.

[0004] The main synthesis methods are as follows:

[0005] 1. Publication No. WO2014052699A1, publication date 2014-04-03, invention named AZAQUINAZOLINE INHIBITORS OF ATYPICAL PROTEIN KINASE C, discloses the following route:

[0006]

[0007] This route is to synthesize piperazine through SN2 reaction of chemical formula 5 and 6, and then through LiAlH 4Reduction of ester to alcohol; chlorination, cyano group replacing chlorine, and finally reduction and debenzylation to obtain (S)-2-piperazinyl acetonitrile hydrochloride; the disadvantage of this route is that the raw materials are expensive, LiAlH 4 The reduction has high safety risks, using highly toxic potassium cyanide, and the intermediates involved in Chemical Formula 4 are genotoxic, with potential residual risks. In addition, the cost of hydrodebenzylation is high and is not suitable for industrial scale-up.

[0008] 2. Publication number CN112694475A, publication date 2021-04-23, entitled invention of cycloalkyl and heterocycloalkyl inhibitors and preparation methods and applications thereof, discloses the following routes:

[0009]

[0010] In this route, acrylonitrile is brominated and then reacted with N,N'-dibenzylethylenediamine (chemical formula 6) to form a piperazine ring, which is then debenzylated with ACECl to obtain (S)-2-piperazinylacetonitrile hydrochloride. Although this route has a short number of steps, the final product is a racemate and needs to be resolved by chirality, resulting in a loss of more than half of the yield. The overall synthesis efficiency is low and it is also not suitable for industrial scale-up.

[0011] 3. Publication No. WO2017201161A1, publication date 2017-11-23, invention named KRAS G12C INHIBITORS, discloses the following route:

[0012]

[0013] This route uses 3-hydroxymethylpiperazine-1-carbonate as a raw material, obtains sulfinic acid lactone through cyclization, is oxidized to sulfinic acid lactone, and then is replaced by cyano, and finally the Boc protecting group is removed by hydrochloric acid to obtain (S)-2-piperazinyl acetonitrile hydrochloride; the starting material of this route is very expensive, and it also requires multiple steps of reaction to prepare, and the subsequent synthetic route still requires the use of highly toxic KCN and expensive sodium periodate / ruthenium trichloride oxidation system. In addition, the overall yield of this route is low, and it is not suitable for industrial scale-up production.

[0014] 4. Publication number CN116410145A, publication date 2023-07-11, titled "Invention of a method for preparing an MRTX849 intermediate", discloses the following route:

[0015]

[0016] This route uses the acid salt of serine ester as a raw material, and undergoes condensation, deprotection, cyclization, reduction, adding a protecting group, condensation, substitution, deprotection and other reactions with protected glycine to obtain (S)-2-piperazinyl acetonitrile hydrochloride; this route goes through a chloro intermediate with genotoxicity and uses highly toxic potassium cyanide. At the same time, its synthesis steps are lengthy, the production efficiency is low, and it is not suitable for large-scale production.

[0017] 5. Publication No. CN116410145A, Publication Date 2023-09-19, entitled "A method for preparing (S)-2-(piperazine-2-yl)acetonitrile hydrochloride", discloses the following route:

[0018]

[0019] This route uses (R)-1-BOC-3-hydroxymethylpiperazine as the starting material, and the product is obtained by protecting the amino group with PMB, activating the hydroxyl group with ESCl, cyanating with TMSCN, and debenzylating with ACECl and BOC. The problem with this route is that the raw materials are expensive, and after the PMB protecting group is removed in the last step, methanol is heated to reflux under acidic conditions, the cyano group is unstable, and impurities are easily generated. The intermediate synthesized by this method is used for the synthesis of the raw material of Adagrasib, and its quality risk is high.

[0020] In summary, most of the synthetic strategies reported in the literature use highly toxic potassium cyanide or sodium cyanide, and undergo electrophilic intermediates such as chlorides and mesylate esters. These intermediates are potentially genotoxic, posing a great challenge to the quality research of APIs. In addition, most synthetic routes use a single N-protected piperazinol intermediate, which is relatively expensive and not conducive to cost control during commercial production. Summary of the invention

[0021] In order to solve the defects that most of the existing synthesis strategies use highly toxic potassium cyanide or sodium cyanide, have potential genotoxicity, high raw material prices, are not conducive to cost control during commercial production, and are not suitable for scale-up production, the present invention provides a highly efficient, mild, safe, and scale-up production-suitable synthesis method of (S)-2-piperazinyl acetonitrile hydrochloride, which avoids the use of highly toxic potassium cyanide or sodium cyanide, avoids the reaction conditions of high-pressure hydrogenation deprotection, and avoids LiAlH 4 The production of chlorinated or sulfonate intermediates with potential genotoxicity is avoided by using raw materials or reagents that are not suitable for scale-up.

[0022] The technical solution of the present invention is achieved as follows: According to the method reported in the document "Asymmetric syntheses of (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines, important5-HT2Cagonist precursors, Tetrahedron Letters (2018), 59(21), 2030-2033.", the chiral piperazinol with double BOC protection can be conveniently and efficiently synthesized. With this as a raw material, an aldehyde is generated by oxidation reaction, and then reacted with hydroxylamine hydrochloride to form an oxime. The hydroxyl group is activated and dehydrated to a cyano group, and finally deprotected under acidic conditions to obtain (S)-2-piperazinyl acetonitrile. The intermediate (S)-2-piperazinyl acetonitrile obtained under the synthetic route of the present invention has extremely high purity, and the chiral purity reaches more than 99.9%.

[0023] In order to achieve the above object, the present invention adopts the following technical solutions:

[0024] The present invention provides a method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof, the method comprising the following steps:

[0025] (a) the compound represented by formula I reacts with an oxidant in the presence of a base to obtain a compound represented by formula II;

[0026] (b) reacting the compound represented by formula II with hydroxylamine in the presence of a base to obtain a compound represented by formula III;

[0027] (c) activating the hydroxyl group in the compound represented by formula III with an activating agent and then hydrolyzing it, and then recrystallizing it with a solvent to obtain a compound represented by formula IV;

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

[0029] Wherein, the compound represented by formula I is:

[0030]

[0031] The compound shown in formula II:

[0032]

[0033] The compound shown in formula III:

[0034]

[0035] The compound shown in formula IV:

[0036]

[0037] The compound represented by formula V:

[0038] As a preferred embodiment of the present invention, the synthesis method is:

[0039] (a) dissolving the compound represented by formula I in a solvent, adding a base and an oxidant to react, and after the reaction is completed, quenching, centrifuging, layering, extracting, washing, drying and concentrating to obtain the compound represented by formula II;

[0040] (b) dissolving the compound represented by formula II in a solvent, adding a base and hydroxylamine, stirring while keeping warm, centrifuging after the reaction is completed, removing the solvent, adding a solvent for layered extraction, washing, drying, filtering, and concentrating to obtain the compound represented by formula III;

[0041] (c) dissolving the compound represented by formula III in a solvent, adding a base, and then dropping an activating reagent. After the dropwise addition is completed, the temperature is raised and kept to react. After the reaction is completed, water is added to quench, and the mixture is separated and extracted. The solvent is removed, and another solvent is replaced. The mixture is washed, concentrated, recrystallized, filtered, and dried to obtain the compound represented by formula IV;

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

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

[0044] As a preferred embodiment of the present invention, in step (a), the oxidant is trichloroisocyanuric acid, and the reaction temperature is 20°C-30°C.

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

[0046] As a preferred embodiment of the present invention, in step (c), the compound represented by formula III and N-methylmorpholine or pyridine are added during the activation reaction.

[0047] As a preferred embodiment of the present invention, in step (c), the activating agent comprises trichloroacetyl chloride, and the dropping temperature of the activating agent is 10°C-30°C.

[0048] As a preferred embodiment of the present invention, in step (c), the washing is washing with sodium carbonate aqueous solution, washing with citric acid aqueous solution and washing with 10% brine.

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

[0050] As a preferred embodiment of the present invention, in step (d), during the Boc removal, the insulation temperature is 15°C-35°C.

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

[0052] 1) In the process route adopted by the present invention, chirality is introduced by amino acids, and all process conditions are mild enough so that there is no racemization of the chiral center in the reaction. Therefore, a product with high chiral purity can be obtained in high yield, chiral separation is avoided, production costs are greatly reduced, and production efficiency is improved.

[0053] 2) The present invention avoids hydrogenation debenzylation of the protecting group and the use of the noble metal Pd, thereby reducing costs and enhancing the feasibility of production scale-up.

[0054] 3) The present invention avoids the use of highly toxic potassium cyanide or sodium cyanide, avoids the generation of chloro intermediates and sulfonate intermediates with genotoxicity, and the safety of the product is more guaranteed.

[0055] 4) The post-treatment process adopted by the present invention also does not need to use column chromatography to purify and separate the product, and most steps do not need to purify the crude product, which saves production time, improves production efficiency, and greatly reduces costs. It is suitable for industrial mass production and also suitable for small-scale preparation in the laboratory.

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

[0057] 6) The present invention provides a highly efficient, mild, safe and large-scale production-suitable synthesis method of (S)-2-piperazinylacetonitrile hydrochloride, which avoids the use of highly toxic potassium cyanide or sodium cyanide, avoids the reaction conditions of high-pressure hydrogenation deprotection, and avoids the use of LiAlH 4 The production of chlorinated or sulfonate intermediates with potential genotoxicity is avoided by using raw materials or reagents that are not suitable for scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0059] Figure 1 It is the synthesis route diagram of the present invention.

[0060] Figure 2 It is the chemical purity spectrum of the compound represented by Formula V in Example 1 of the present invention.

[0061] Figure 3 This is the chiral purity spectrum of the compound represented by Formula V in Example 1 of the present invention.

[0062] Figure 4 This is the H NMR spectrum of the compound represented by Formula V in Example 1 of the present invention. DETAILED DESCRIPTION

[0063] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0064] The invention provides a method for synthesizing (S)-2-piperazinyl acetonitrile hydrochloride that is efficient, mild, safe and suitable for large-scale production. The technical scheme of the invention is achieved as follows: According to the method reported in the document "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 piperazinol with double BOC protection can be conveniently and efficiently synthesized, and the chiral piperazinol is used as a raw material to generate an aldehyde through an oxidation reaction, and then reacted with hydroxylamine hydrochloride to form an oxime, and the hydroxyl group is dehydrated to form a cyano group after being activated, and finally deprotected under acidic conditions to obtain the (S)-2-piperazinyl acetonitrile salt. The intermediate (S)-2-piperazine acetonitrile salt obtained under the synthetic route has extremely high purity, and the chiral purity reaches more than 99.9%.

[0065] The synthetic method of the present invention is:

[0066] (a) dissolving the compound represented by formula I in a solvent, adding a base and an oxidant to react, and after the reaction is completed, quenching, centrifuging, layering, extracting, washing, drying and concentrating to obtain the compound represented by formula II;

[0067] (b) dissolving the compound represented by formula II in a solvent, adding a base and hydroxylamine, stirring while keeping warm, centrifuging after the reaction is completed, removing the solvent, adding a solvent for layered extraction, washing, drying, filtering, and concentrating to obtain the compound represented by formula III;

[0068] (c) dissolving the compound represented by formula III in a solvent, adding a base, and then dropping an activating reagent. After the dropwise addition is completed, the temperature is raised and kept to react. After the reaction is completed, water is added to quench, and the mixture is separated and extracted. The solvent is removed, and another solvent is replaced. The mixture is washed, concentrated, recrystallized, filtered, and dried to obtain the compound represented by formula IV;

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

[0070] In the present invention, the compound represented by formula I can be prepared by 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-HT2 Cagonist precursors, Tetrahedron Letters (2018), 59(21),

[0071] The preparation method was synthesized according to the records of the literature review of the present invention. It can also be purchased from Shanghai Yuhan Chemical Co., Ltd. or Chengdu Feibai Pharmaceutical Technology Co., Ltd. Hydroxylamine hydrochloride was purchased from Jinan Quansheng Chemical Co., Ltd., Tempo was purchased from Shanghai Bangcheng Chemical Co., Ltd., trichloroisocyanuric acid was purchased from Shanghai MacLean Biochemical Technology Co., Ltd., N-methylmorpholine was purchased from Aladdin, MTBE (methyl tert-butyl ether) was purchased from Shanghai Bangcheng Chemical Co., Ltd., and the remaining reagents or equipment can be purchased from the market.

[0072] Example 1

[0073] See also Figure 1 , this embodiment provides a route for (S)-2-piperazinylacetonitrile hydrochloride, comprising:

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

[0075] 2) Methanol (284.8 g, 3V) and the compound shown in Formula II (120 g, 1.0 eq) were added to a 1000 mL three-necked flask, the reactor cover was opened, sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) were added under stirring, and the mixture was kept warm at 20°C-35°C for 2 h. After sampling and detection, the reaction was completed, centrifuged, the filtrate was desolventized, MTBE (444 g, 5V) and tap water (240 g, 2V) were added, stirred and separated, and the aqueous phase was extracted once with MTBE (177.6 g, 2V), the organic phases were combined, washed once with 10% (mass fraction) brine (240 g), dried over anhydrous sodium sulfate (30 g), filtered, and concentrated to obtain 107.0 g of the compound shown in Formula III, with a yield of 85.3% and a HPLC purity of 99.0%.

[0076] 3) Add dichloromethane (662.5 g, 5V), the compound represented by formula III (100 g, 1.0 eq) and N-methylmorpholine (100.1 g, 3.4 eq) into a 1000 mL three-necked flask, and add trichloroacetyl chloride (74.1 g, 1.4 eq) dropwise at 10°C-30°C. After the addition was completed, the mixture was kept warm for 2-6 hours. After sampling and detection, tap water (200 g, 2V) was added dropwise, the mixture was stirred and separated into layers. The aqueous phase was extracted once with dichloromethane (265 g, 2V). The organic phases were combined and desolventized. MTBE (370 g, 5V) was added. 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). After desolventization, n-heptane (204.9 g, 3V) was added, the mixture was heated to 80°C to dissolve, cooled to 0°C-10°C to recrystallize, filtered, and dried to obtain 86.1 g of the compound represented by formula IV, with a yield of 90.9% and a HPLC purity of 99.6%.

[0077] 4) Add anhydrous ethanol (56.7 g, 1.5V) and the compound represented by formula IV (47.9 g, 1.0 eq) to a 1000 mL three-necked flask, and add a 15% (mass fraction) hydrogen chloride ethanol solution (200 g) dropwise at 10°C-20°C. After the addition is complete, heat to 15°C-35°C and keep warm for 12h-16h. After sampling and testing, add anhydrous ethanol (264.6 g, 7V), stir for 1h-2h, cool to 0°C-10°C, keep warm for 1h, filter, and dry to obtain 24.8 g of the compound represented by formula V, with a yield of 85.1% and a HPLC chemical purity of 99.7% (see Figure 2 ), chiral purity 100% (see Figure 3 ), NMR spectroscopy see Figure 4 .

[0078] Example 2

[0079] See also Figure 1 , this embodiment provides a route for (S)-2-piperazinylacetonitrile hydrochloride, comprising:

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

[0081] 2) Methanol (284.8 g, 3V) and the compound shown in Formula II (120 g, 1.0 eq) were added to a 1000 mL three-necked flask, the reactor cover was opened, sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) were added under stirring, and the mixture was kept warm at 20°C-35°C for 2 h. After sampling and detection, the reaction was completed, centrifuged, the filtrate was desolventized, MTBE (444 g, 5V) and tap water (240 g, 2V) were added, stirred and separated, and the aqueous phase was extracted once with MTBE (177.6 g, 2V), the organic phases were combined, washed once with 10% (mass fraction) brine (240 g), dried over anhydrous sodium sulfate (30 g), filtered, and concentrated to obtain 107.0 g of the compound shown in Formula III, with a yield of 85.3% and an HPLC purity of 99.2%.

[0082] 3) Add dichloromethane (662.5 g, 5V), the compound represented by formula III (100 g, 1.0 eq) and N-methylmorpholine (100.1 g, 3.4 eq) into a 1000 mL three-necked flask, and add trichloroacetyl chloride (74.1 g, 1.4 eq) dropwise at 10°C-30°C. After the addition was completed, the mixture was kept warm for 2-6 hours. After sampling and detection, tap water (200 g, 2V) was added dropwise, the mixture was stirred and separated into layers. The aqueous phase was extracted once with dichloromethane (265 g, 2V). The organic phases were combined and desolventized. MTBE (370 g, 5V) was added. 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). After desolventization, n-heptane (204.9 g, 3V) was added, the mixture was heated to 80°C to dissolve, cooled to 0°C-10°C to recrystallize, filtered, and dried to obtain 86.1 g of the compound represented by formula IV, with a yield of 90.9% and a HPLC purity of 99.6%.

[0083] 4) Add anhydrous ethanol (56.7 g, 1.5V) and the compound represented by formula IV (47.9 g, 1.0 eq) to a 1000 mL three-necked flask, and add a 15% (mass fraction) hydrogen chloride ethyl acetate solution (200 g) dropwise at 10°C-20°C. After the addition is complete, heat to 15°C-35°C and keep warm for 12h-16h. After sampling and testing, add anhydrous ethanol (264.6 g, 7V), stir for 1h-2h, cool to 0°C-10°C, keep warm for 1h, filter, and dry to obtain 24.7 g of the compound represented by formula V, with a yield of 84.6%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0084] Example 3

[0085] See also Figure 1 , this embodiment provides a route for (S)-2-piperazinylacetonitrile hydrochloride, comprising:

[0086] 1) Add tap water (2129 g, 10V), the compound represented by formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11V) to a 10L glass reaction bottle, add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) under stirring, add TEMPO (2.0 g, 0.02 eq) at 10°C-20°C, after the addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20°C-30°C, and keep warm for 0.5h. After sampling and testing, filter, separate the filtrate, extract the aqueous phase once with dichloromethane (564.2 g, 2V), wash once with 5% (mass fraction) sodium carbonate aqueous solution (425.8 g), and wash once with 10% (mass fraction) saline solution (425.8 g). Dry over anhydrous sodium sulfate (50 g), filter and concentrate to obtain 191.5 g of the compound represented by formula II as a white solid with a yield of 90.5% and a HPLC purity of 99.3%.

[0087] 2) Methanol (189.8 g, 3V) and the compound shown in formula II (80 g, 1.0 eq) were added to a 500 mL three-necked flask, the reactor cover was opened, potassium carbonate (40.4 g, 1.2 eq) and hydroxylamine hydrochloride (20.3 g, 1.2 eq) were added under stirring, and the mixture was kept warm at 20°C-35°C for 2 h. After sampling and detection, the reaction was completed, centrifuged, the filtrate was desolventized, MTBE (296 g, 5V) and tap water (160 g, 2V) were added, stirred and separated, and the aqueous phase was extracted once with MTBE (118.4 g, 2V), the organic phases were combined, washed once with 10% (mass fraction) brine (160 g), dried over anhydrous sodium sulfate (25 g), filtered, and concentrated to obtain 70.4 g of the compound shown in formula III, with a yield of 84.2% and an HPLC purity of 99.4%.

[0088] 3) Dichloromethane (450.5 g, 5V), the compound represented by formula III (68 g, 1.0 eq) and N-methylmorpholine (68.1 g, 3.4 eq) were added to a 1000 mL three-necked flask, and trichloroacetyl chloride (50.4 g, 1.4 eq) was added dropwise at 10°C-30°C. After the addition was completed, the mixture was kept warm for 2-6 hours. After sampling and detection, tap water (136 g, 2V) was added dropwise, stirred and separated, and the aqueous phase was extracted once with dichloromethane (180.2 g, 2V). The organic phases were combined and desolventized. MTBE (450.5 g, 5V) was added, and the mixture was washed once with 5% (mass fraction) aqueous sodium carbonate solution (136 g), once with 20% (mass fraction) aqueous citric acid solution (272 g), and once with 10% (mass fraction) brine (136 g). After desolventization, n-heptane (139.3 g, 3V) was added, the mixture was heated to 80°C to dissolve, cooled to 0°C-10°C to recrystallize, filtered, and dried to obtain 57.1 g of the compound represented by formula IV, with a yield of 88.6% and a HPLC purity of 99.6%.

[0089] 4) Add anhydrous ethanol (56.7 g, 1.5V) and the compound represented by formula IV (47.9 g, 1.0 eq) to a 1000 mL three-necked flask, and add a 15% (mass fraction) hydrogen chloride ethanol solution (200 g) dropwise at 10°C-20°C. After the addition is complete, heat to 15°C-35°C and keep warm for 12h-16h. After sampling and testing, add anhydrous ethanol (264.6 g, 7V), stir for 1h-2h, cool to 0°C-10°C, keep warm for 1h, filter, and dry to obtain 24.8 g of the compound represented by formula V, with a yield of 85.1%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0090] Example 4

[0091] See also Figure 1 , this embodiment provides a route for (S)-2-piperazinylacetonitrile hydrochloride, comprising:

[0092] 1) Add tap water (2129 g, 10V), the compound represented by formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11V) to a 10L glass reaction bottle, add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) under stirring, add TEMPO (2.0 g, 0.02 eq) at 10°C-20°C, after the addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20°C-30°C, and keep warm for 0.5h. After sampling and testing, filter, separate the filtrate, extract the aqueous phase once with dichloromethane (564.2 g, 2V), wash once with 5% (mass fraction) sodium carbonate aqueous solution (425.8 g), and wash once with 10% (mass fraction) saline solution (425.8 g). Dry over anhydrous sodium sulfate (50 g), filter and concentrate to obtain 191.5 g of the compound represented by formula II as a white solid with a yield of 90.5% and a HPLC purity of 99.3%.

[0093] 2) Add ethanol (189.8 g, 3V) and the compound shown in formula II (80 g, 1.0 eq) to a 500 mL three-necked flask, open the reactor cover, add potassium carbonate (40.4 g, 1.2 eq) and hydroxylamine hydrochloride (20.3 g, 1.2 eq) under stirring, keep warm at 20°C-35°C for 2 h, take samples for detection after the reaction is completed, centrifuge, remove the solvent from the filtrate, add MTBE (296 g, 5V) and tap water (160 g, 2V), stir and separate, and extract the aqueous phase with MTBE (118.4 g, 2V) once, combine the organic phases, wash once with 10% (mass fraction) brine (160 g), dry with anhydrous sodium sulfate (25 g), filter, and concentrate to obtain 70.4 g of the compound shown in formula III, with a yield of 84.2% and an HPLC purity of 99.3%.

[0094] 3) Dichloromethane (450.5 g, 5V), the compound represented by formula III (68 g, 1.0 eq) and N-methylmorpholine (68.1 g, 3.4 eq) were added to a 1000 mL three-necked flask, and trichloroacetyl chloride (50.4 g, 1.4 eq) was added dropwise at 10°C-30°C. After the addition was completed, the mixture was kept warm for 2-6 hours. After sampling and detection, tap water (136 g, 2V) was added dropwise, stirred and separated, and the aqueous phase was extracted once with dichloromethane (180.2 g, 2V). The organic phases were combined and desolventized. MTBE (450.5 g, 5V) was added, and the mixture was washed once with 5% (mass fraction) aqueous sodium carbonate solution (136 g), once with 20% (mass fraction) aqueous citric acid solution (272 g), and once with 10% (mass fraction) brine (136 g). After desolventization, n-heptane (139.3 g, 3V) was added, the mixture was heated to 80°C to dissolve, cooled to 0°C-10°C to recrystallize, filtered, and dried to obtain 57.1 g of the compound represented by formula IV, with a yield of 88.6% and a HPLC purity of 99.6%.

[0095] 4) Add anhydrous ethanol (56.7 g, 1.5V) and the compound represented by formula IV (47.9 g, 1.0 eq) to a 1000 mL three-necked flask, and add a 15% (mass fraction) hydrogen chloride ethanol solution (200 g) dropwise at 10°C-20°C. After the addition is complete, heat to 15°C-35°C and keep warm for 12h-16h. After sampling and testing, add anhydrous ethanol (264.6 g, 7V), stir for 1h-2h, cool to 0°C-10°C, keep warm for 1h, filter, and dry to obtain 24.8 g of the compound represented by formula V, with a yield of 85.1%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0096] Example 5

[0097] See also Figure 1 , this embodiment provides a route for (S)-2-piperazinylacetonitrile hydrochloride, comprising:

[0098] 1) Add tap water (2129 g, 10V), the compound shown in Formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11V) to a 10L glass reaction bottle, add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) under stirring, add TEMPO (2.0 g, 0.02 eq) at 10°C-20°C, after the addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20°C-30°C, and keep warm for 0.5h. After sampling and detection, filter, separate the filtrate, extract the aqueous phase once with dichloromethane (564.2 g, 2V), wash once with 5% (mass fraction) sodium carbonate aqueous solution (425.8 g), and wash once with 10% (mass fraction) saline solution (425.8 g). Dry over anhydrous sodium sulfate (50 g), filter and concentrate to obtain 191.5 g of the compound represented by formula II as a white solid with a yield of 90.5% and a HPLC purity of 99.3%.

[0099] 2) Methanol (284.8 g, 3V) and the compound shown in Formula II (120 g, 1.0 eq) were added to a 1000 mL three-necked flask, the reactor cover was opened, sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) were added under stirring, and the mixture was kept warm at 20°C-35°C for 2 h. After sampling and detection, the reaction was completed, centrifuged, the filtrate was desolventized, MTBE (444 g, 5V) and tap water (240 g, 2V) were added, stirred and separated, and the aqueous phase was extracted once with MTBE (177.6 g, 2V), the organic phases were combined, washed once with 10% (mass fraction) brine (240 g), dried over anhydrous sodium sulfate (30 g), filtered, and concentrated to obtain 107.0 g of the compound shown in Formula III, with a yield of 85.3% and an HPLC purity of 99.2%.

[0100] 3) Add dichloromethane (662.5 g, 5V), the compound represented by formula III (100 g, 1.0 eq) and pyridine (78.3 g, 3.4 eq) into a 1000 mL three-necked flask, and add trichloroacetyl chloride (74.1 g, 1.4 eq) dropwise at 10°C-30°C. After the addition was completed, the mixture was kept warm for 2-6 hours. After sampling and detection, tap water (200 g, 2V) was added dropwise, the mixture was stirred and separated into layers. The aqueous phase was extracted once with dichloromethane (265 g, 2V). The organic phases were combined and desolventized. MTBE (370 g, 5V) was added. 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). After desolventization, n-heptane (204.9 g, 3V) was added, the mixture was heated to 80°C to dissolve, cooled to 0°C-10°C to recrystallize, filtered, and dried to obtain 86.1 g of the compound represented by formula IV, with a yield of 90.9% and a HPLC purity of 99.5%.

[0101] 4) Add anhydrous ethanol (56.7 g, 1.5V) and the compound represented by formula IV (47.9 g, 1.0 eq) to a 1000 mL three-necked flask, and add a 15% (mass fraction) dioxane solution (200 g) of hydrogen chloride dropwise at 10°C-20°C. After the addition is complete, heat to 15°C-35°C and keep warm for 12h-16h. After sampling and testing, add anhydrous ethanol (264.6 g, 7V), stir for 1h-2h, cool to 0°C-10°C, keep warm for 1h, filter, and dry to obtain 24.3 g of the compound represented by formula V, with a yield of 83.2%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0102] Example 6

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

[0104] 1) Add tap water (2129 g, 10V), the compound represented by formula I (212.9 g, 1.0 eq) and dichloromethane (3103 g, 11V) to a 10L glass reaction bottle, add sodium bicarbonate (162.4 g, 3.0 eq) and solid sodium bromide (6.6 g, 0.1 eq) under stirring, add TEMPO (2.0 g, 0.02 eq) at 10°C-20°C, after the addition, add trichloroisocyanuric acid (89.8 g, 0.6 eq) at 20°C-30°C, and keep warm for 0.5h. After sampling and testing, filter, separate the filtrate, extract the aqueous phase once with dichloromethane (564.2 g, 2V), wash once with 5% (mass fraction) sodium carbonate aqueous solution (425.8 g), and wash once with 10% (mass fraction) saline solution (425.8 g). Dry over anhydrous sodium sulfate (50 g), filter and concentrate to obtain 191.5 g of the compound represented by formula II as a white solid with a yield of 90.5% and a HPLC purity of 99.3%.

[0105] 2) Methanol (284.8 g, 3V) and the compound shown in Formula II (120 g, 1.0 eq) were added to a 1000 mL three-necked flask, the reactor cover was opened, sodium carbonate (46.5 g, 1.2 eq) and hydroxylamine hydrochloride (30.5 g, 1.2 eq) were added under stirring, and the mixture was kept warm at 20°C-35°C for 2 h. After sampling and detection, the reaction was completed, centrifuged, the filtrate was desolventized, MTBE (444 g, 5V) and tap water (240 g, 2V) were added, stirred and separated, and the aqueous phase was extracted once with MTBE (177.6 g, 2V), the organic phases were combined, washed once with 10% (mass fraction) brine (240 g), dried over anhydrous sodium sulfate (30 g), filtered, and concentrated to obtain 107.0 g of the compound shown in Formula III, with a yield of 85.3% and an HPLC purity of 99.2%.

[0106] 3) Add dichloromethane (662.5 g, 5V), the compound represented by formula III (100 g, 1.0 eq) and N-methylmorpholine (100.1 g, 3.4 eq) into a 1000 mL three-necked flask, and add trichloroacetyl chloride (74.1 g, 1.4 eq) dropwise at 10°C-30°C. After the addition was completed, the mixture was kept warm for 2-6 hours. After sampling and detection, tap water (200 g, 2V) was added dropwise, the mixture was stirred and separated into layers. The aqueous phase was extracted once with dichloromethane (265 g, 2V). The organic phases were combined and desolventized. MTBE (370 g, 5V) was added. 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). After desolventization, n-heptane (204.9 g, 3V) was added, the mixture was heated to 80°C to dissolve, cooled to 0°C-10°C to recrystallize, filtered, and dried to obtain 86.1 g of the compound represented by formula IV, with a yield of 90.9% and a HPLC purity of 99.5%.

[0107] 4) Add isopropanol (58.9 g, 1.5V) and the compound represented by Formula IV (50 g, 1.0 eq) to a 1000 mL three-necked flask, and add a 15% (mass fraction) dioxane solution (209 g) of hydrogen chloride dropwise at 10°C-20°C. After the addition is complete, heat to 15°C-35°C and keep warm for 12h-16h. After sampling and testing, add isopropanol (274.9 g, 7V), stir for 1h-2h, cool to 0°C-10°C, keep warm for 1h, filter, and dry to obtain 26.2 g of the compound represented by Formula V, with a yield of 86.2%, HPLC chemical purity of 99.7%, and chiral purity of 100%.

[0108] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and evolutions of the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

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 to obtain a compound represented by formula II; (b) reacting the compound represented by formula II with hydroxylamine in the presence of a base to obtain a compound represented by formula III; (c) activating the hydroxyl group in the compound represented by formula III with an activating agent and then hydrolyzing it, and then recrystallizing it with a solvent to obtain a compound represented by formula IV; (d) the compound represented by formula IV is deprotected under acidic conditions to obtain a compound represented by formula V; Wherein, the compound represented by formula I is: 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, characterized in that: The synthesis method is: (a) dissolving the compound represented by formula I in a solvent, adding a base and an oxidant 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 keeping warm, centrifuging after the reaction is completed, 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 dropping an activating reagent. After the dropwise addition is completed, the temperature is raised and kept to react. After the reaction is completed, water is added to quench, and the mixture is separated and extracted. The solvent is removed, and another solvent is replaced. 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 completed, centrifuging, and drying the wet product to obtain a compound represented by formula V.

3. A method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (a) and step (b), the base comprises one or both of sodium bicarbonate and potassium bicarbonate.

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

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

6. A 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.

7. A method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (c), the activating reagent comprises trichloroacetyl chloride, and the dropping temperature of the activating reagent is 10°C-30°C.

8. A 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 sodium carbonate aqueous solution, washing with citric acid aqueous solution and washing with 10% brine.

9. A method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (d), the acid comprises an ethanol solution of hydrogen chloride, a dioxane solution of hydrogen chloride or an ethyl acetate solution of hydrogen chloride.

10. A method for synthesizing (S)-2-piperazinylacetonitrile or a salt thereof according to claim 1 or 2, characterized in that: In step (d), during the Boc removal, the insulation temperature is 15°C-35°C.

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