Preparation method, intermediate and application of deuterated propargylamine hydrochloride

Abstract

The invention relates to a preparation method of deuterated propargylamine and hydrochloride thereof. The method is easy to implement, high in total yield and low in reagent cost, and an obtained product is low in impurity content, easy to purify and suitable for industrial production.

Description

Preparation method of deuterated propargylamine hydrochloride, intermediates thereof and uses Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a preparation method of deuterated propargylamine hydrochloride, an intermediate thereof and use thereof. Background Art

[0002] Deuterated propargylamine and its hydrochloride are important intermediates in the pharmaceutical and chemical industries. Monique PC Mulder et al. disclosed a method for preparing 1,1-dideuterated-prop-2-yn-1-amine (1,1-d2-prop-2-yn-1-amine) hydrochloride. The step of forming the azanyl intermediate 13 in this method requires the use of an expensive organophosphorus oxide reagent NHBocPO(OEt)2; the route involves two rounds of Boc protection and deprotection; the route is cumbersome, and the total yield of the 5-6 steps is only 23.32%.

[0003] Summary of the Invention

[0004] The first aspect of the present invention provides a method for preparing a salt of Compound V, comprising the following steps f): distilling an organic solution of Compound V under normal pressure, collecting the distillate, and acidifying to obtain a salt of Compound V, wherein the organic solution of Compound V is selected from one or more of an alcohol solvent, an ester solvent, or an aromatic hydrocarbon solvent;

[0005] Wherein R1 is -H, -D, trimethylsilyl or trimethylgermanyl, preferably R1 is -H or -D.

[0006] In some embodiments of the present invention, the alcohol solvent is a C1-C6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, and isopropanol, more preferably methanol or ethanol.

[0007] In some embodiments of the present invention, the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene, and xylene, preferably toluene.

[0008] In some embodiments of the present invention, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

[0009] In some embodiments of the present invention, the salt of compound V is an inorganic acid salt or an organic acid salt of compound V, preferably a hydrochloride, a hydrobromide, a sulfate, or a phosphate, and more preferably a hydrochloride.

[0010] In some embodiments of the present invention, the acidification is as follows: cooling the distillate to 0-10° C., adding dropwise an acid solution in ethyl acetate, and slowly precipitating a solid.

[0011] In some embodiments of the present invention, the step of adding n-heptane for recrystallization is further included after the acidification. Preferably, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, and more preferably hydrochloric acid.

[0012] In some embodiments of the present invention, the method for preparing compound V comprises the following steps d:

[0013] Step d: Hydrazinolysis of compound III to obtain compound V

[0014] Wherein R1 is -H, -D, trimethylsilyl or trimethylgermanyl.

[0015] In some embodiments of the present invention, the compound V is compound V-2, and the organic solution of the compound V-2 is prepared by the following steps e:

[0016] Step e: dissolving compound V-1 in an alcohol solvent, adding a base, stirring at room temperature, filtering after the reaction is completed, and adding an aromatic hydrocarbon solvent to the obtained filtrate to obtain an organic solution of compound V-2.

[0017] Furthermore, the volume ratio of the alcohol solvent to the aromatic hydrocarbon solvent is 1:0.2-2, preferably 1:0.4-1;

[0018] The base is one or more of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide;

[0019] The molar ratio of the base to compound V-2 is 1:1 to 3;

[0020] The alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol. The aromatic hydrocarbon solvent is one or more of benzene, toluene, and xylene, preferably toluene.

[0021] The second aspect of the present invention provides a method for preparing compound V, comprising the following step d): hydrazinolysis of compound III to obtain compound V, wherein R1 is -H, -D or trimethylgermanium,

[0022] In some embodiments of the present invention, in step d, the reagent for hydrazinolysis is hydrazine hydrate;

[0023] In some embodiments of the present invention, in step d, the amount of hydrazine hydrate used is 2 to 5 molar equivalents of compound III, preferably 3 molar equivalents.

[0024] In some embodiments of the present invention, in step d, the reaction temperature of the hydrazinolysis is 0 to 30°C;

[0025] In some embodiments of the present invention, in step d, compound III is dissolved in an alcohol solvent, and a hydrazine hydrate solution is slowly added dropwise. After the addition is completed, the reaction is continued by stirring, and the mixture is filtered. The filter cake is rinsed with an ester solvent to obtain an organic solution of compound V.

[0026] In some embodiments of the present invention, in step d, the alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol, more preferably methanol;

[0027] In some embodiments of the present invention, in step d, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

[0028] In some embodiments of the present invention, the preparation of compound III comprises the following steps c:

[0029] Step c: In an organic solvent, compound II reacts with phthalimide in the presence of a phosphorus reagent and a nucleophilic reagent to obtain compound III.

[0030] In some embodiments of the present invention, the phosphorus reagent is an alkylphosphine reagent or an arylphosphine reagent, preferably tributylphosphine or triphenylphosphine;

[0031] In some embodiments of the present invention, the nucleophile is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, and dibenzyl azodicarboxylate, preferably diisopropyl azodicarboxylate;

[0032] In some embodiments of the present invention, the amount of the phosphorus reagent is 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents; the amount of the nucleophilic reagent is 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents;

[0033] In some embodiments of the present invention, compound II, an organophosphorus reagent, and phthalimide are dissolved in an organic solvent, the reaction liquid temperature is lowered to -5°C to 0°C, a nucleophilic reagent is added dropwise, and the internal temperature is controlled not to exceed 5°C. After the addition is completed, the reaction is kept warm and then raised to room temperature for reaction. After the reaction is completed, the reaction solvent is concentrated and purified to obtain compound III.

[0034] In some embodiments of the present invention, in step c, the organic solvent is THF, and the molar volume ratio of compound II to the organic solvent is 0.1 to 1 mol / L, preferably 0.5 to 0.6 mol / L. In some embodiments, the compound III is compound III-3, and its preparation comprises the following steps i:

[0035] Step i: N-propynylphthalimide reacts with a deuterated reagent in heavy water in the presence of a base to obtain compound III.

[0036] In some embodiments of the present invention, the deuterated reagent is a deuterated alcohol reagent, preferably deuterated methanol;

[0037] In some embodiments of the present invention, the volume ratio of the deuterated reagent to heavy water is 1:1;

[0038] In some embodiments of the present invention, the base is NaOD or KOD;

[0039] In some embodiments of the present invention, the amount of the base is 0.05 to 2 molar equivalents of N-propynylphthalimide, preferably 0.05 to 0.20 molar equivalents;

[0040] In some embodiments of the present invention, the weight-to-volume ratio of the N-propynylphthalimide to the deuterated reagent is 1:5 to 1:20 g / mL, preferably 1:5 to 1:10 g / mL.

[0041] A third aspect of the present invention provides a method for preparing compound V, comprising the following steps:

[0042] Step g) Compound II is sulfonylated to obtain compound IV,

[0043] Step h) Compound IV is then subjected to an aminolysis reaction with an aminating agent to obtain compound V.

[0044] wherein R3 is an optionally substituted sulfonyl group, wherein the substituted substituent is an alkyl group (e.g., methyl, ethyl) or an aryl group (e.g., phenyl, tolyl); preferably, R3 is a methylsulfonyl group, an ethylsulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a trimethylphenylsulfonyl group or a nitrobenzenesulfonyl group,

[0045] R1 is -H, -D, trimethylsilyl or trimethylgermanyl.

[0046] In some embodiments of the present invention, the sulfonylation reagent is methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or p-methanesulfonic anhydride;

[0047] In some embodiments of the present invention, R3 is a methanesulfonyl group, and the sulfonylation reagent is methanesulfonyl chloride or methanesulfonic anhydride.

[0048] In some embodiments of the present invention, R3 is p-toluenesulfonyl, and the sulfonylation reagent is p-toluenesulfonyl chloride or p-methanesulfonic anhydride.

[0049] In some embodiments of the present invention, the amount of the sulfonylation reagent is 1.0 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents;

[0050] In some embodiments of the present invention, the aminating agent is aqueous ammonia; the amount of aqueous ammonia used is 1 to 5 molar equivalents of compound IV, preferably 1 to 2 molar equivalents.

[0051] In some embodiments of the present invention, the aminating agent is benzylamine; the amount of benzylamine used is 1 to 5 molar equivalents of compound IV, preferably 1 to 2 molar equivalents.

[0052] In some embodiments of the present invention, the temperature of the aminolysis reaction is 0-5°C.

[0053] In some embodiments of the present invention, the method for preparing compound II comprises the following steps:

[0054] Step a) In an organic solvent, compound I is reacted with LiAlD4 to generate compound II, wherein R2 is an optionally substituted -C1-C6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R2 is a C1-C3 alkyl group or a benzyl group; more preferably, R2 is a methyl group or an ethyl group.

[0055] In some embodiments of the present invention, the molar ratio of Compound I to LiAlD4 is 1:0.4 to 1, for example, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or any value or range therebetween.

[0056] In some embodiments of the present invention, the method for preparing compound II comprises the following steps:

[0057] Step b) Compound I is reacted with a metal reagent and a deuterated alcohol to generate Compound II, wherein R2 is an optionally substituted -C1-C6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R2 is a C1-C3 alkyl group or a benzyl group; more preferably, R2 is a methyl group or an ethyl group.

[0058] In some embodiments of the present invention, the metal reagent is Na or K, and the deuterated alcohol reagent is CH3OD or CH3CH2OD; the molar ratio of the compound I to the metal reagent is 1:0.5~5, preferably 1:1~5, for example, 1:1, 1:2, 1:3, 1:4, 1:5 or any value or range therebetween; the molar ratio of the compound I to the deuterated alcohol reagent is 1:0.5~5, preferably 1:1~5, for example, 1:1, 1:2, 1:3, 1:4, 1:5 or any value or range therebetween.

[0059] In some embodiments of the present invention, the organic solvent is tetrahydrofuran.

[0060] In some embodiments of the present invention, the concentration of Compound I in the organic solvent is 0.3-1.8 mol / L.

[0061] A fourth aspect of the present invention provides a method for preparing the hydrochloride of compound V-2, comprising the following steps:

[0062] Step d: Compound III-1 is hydrazine-hydrated to give compound V-1:

[0063] Step e: dissolving compound V-1 in methanol, adding K2CO3, stirring at room temperature, filtering after the reaction is completed, and adding toluene to the obtained filtrate to obtain an organic solution of compound V-2;

[0064] Step f: distilling the organic solution of compound V-2 under normal pressure, collecting the distillate, and acidifying to obtain the salt of compound V-2.

[0065] Preferably, compound III-1 is prepared by a one-pot method of steps d, e, and f to obtain the hydrochloride salt of compound V-2.

[0066] A fifth aspect of the present invention provides a method for preparing the hydrochloride of compound V-2, comprising the following steps:

[0067] Step g: Compound II-1 is sulfonylated to obtain compound IV-1.

[0068] Step h: Compound IV-1 is then subjected to an aminolysis reaction with an aminating agent to obtain compound V-1.

[0069] Step e: dissolving compound V-1 in methanol, adding K2CO3, stirring at room temperature, filtering after the reaction is completed, and adding toluene to the obtained filtrate to obtain an organic solution of compound V-2;

[0070] Step f: distilling the organic solution of compound V-2 under normal pressure, collecting the distillate, and acidifying to obtain the salt of compound V-2.

[0071] Wherein, R3 is methylsulfonyl or p-toluenesulfonyl;

[0072] Preferably, compound II-1 is prepared in one pot by steps g, h, e, and f to obtain the hydrochloride salt of compound V-2.

[0073] Another aspect of the present invention provides a compound I, wherein R1 is trimethylgermanium, R2 is -H, -C1-C3 alkyl or benzyl,

[0074] Another aspect of the present invention provides a compound II-2,

[0075] Another aspect of the present invention provides compound III-2, compound III-3, and compound III-4.

[0076] In another aspect, the present invention provides compound IV-2, compound IV-3, and compound IV-4.

[0077] In another aspect, the present invention provides compound V-3 and compound V-4.

[0078] In another aspect, the present invention provides the use of Compound I, Compound II-2, Compound III-2, Compound III-3, Compound III-4, Compound IV-2, Compound IV-3, Compound IV-4, Compound V-3 or Compound V-4 in the preparation of deuterated propargylamine and its hydrochloride.

[0079] The deuterated propargylamine prepared in the present invention can be further prepared into deuterated propargylamine hydrochloride by conventional methods in the art. Beneficial effects:

[0080] 1) In the preparation process of the present invention, starting from compound I-1, a total of five reaction steps a, c to f are performed to obtain the hydrochloride of 1,1-dideuterated-prop-2-yn-1-amine (1,1-d2-prop-2-yn-1-amine, compound V-2) with a total yield of 61.3%. Compared with the prior art, the reaction yield is significantly improved. In addition, the present invention does not require the use of expensive NHBocPO(OEt)2 and does not require two rounds of Boc protection and deprotection steps, thereby improving atom economy, simplifying the reaction steps, lowering the price of reaction reagents, reducing production costs, and being more conducive to industrial production.

[0081] 2) During the post-treatment of deuterated propargylamine (Compound V), atmospheric distillation is used to collect the distillate, eliminating the need to introduce a protecting group Boc during the reaction, thereby simplifying the preparation steps and making the post-treatment simpler.

[0082] 3) In the reaction of introducing deuterium atoms, deuterated ethanol is preferably used as the deuteration reagent, which can avoid the shortcomings of LiAlD4, such as flammability, high cost, low reaction temperature, and high equipment requirements. DETAILED DESCRIPTION

[0083] Terms and descriptions:

[0084] Unless otherwise specified, the terms in this invention have the following meanings:

[0085] In the present invention, the term "eq" is an abbreviation of "equivalent", which refers to equivalent, and is a term used for the ratio of the amounts of substances when substances interact with each other.

[0086] Deuterated propargylamine refers to propargylamine Compounds wherein one or more H atoms are replaced by deuterium. Including but not limited to:

[0087] The term "sulfonyl" herein includes, but is not limited to, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-toluenesulfonyl, trimethylphenylsulfonyl, or nitrobenzenesulfonyl.

[0088] The term "nucleophile" in the present invention includes but is not limited to diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate.

[0089] The term "ammonolysis reaction" in the present invention refers to the process in which organic compounds containing various functional groups generate amine compounds under the action of an aminating agent; aminating agents include liquid ammonia, ammonia water, urea, ammonium salts and organic amines.

[0090] In the present invention, the term "-C1-C6 alkyl" includes alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl or n-hexyl; the term "-C1-C3 alkyl" includes alkyl groups containing 1 to 3 carbon atoms, specifically methyl, ethyl, n-propyl and isopropyl.

[0091] The term "substituted" in the present invention means that any one or more hydrogen atoms on the designated atom are replaced by a substituent selected from the designated group, and the result of the substitution is to produce a stable compound.

[0092] The term "organic solvent" in the present invention includes but is not limited to any one or more combinations of tetrahydrofuran, ethyl acetate, dichloromethane, methanol, and ethanol.

[0093] The term "distillation" in the present invention includes but is not limited to simple distillation, rectification, special distillation, etc.

[0094] In the present invention, "room temperature" refers to 20 to 30°C.

[0095] In the present invention, "ice water bath" refers to -5 to 5°C.

[0096] In the present invention, hydrogen proton nuclear magnetic resonance spectrum ( 1 H NMR) was measured by Bruker AVANCE 400 at 400 MHz.

[0097] In the present invention, mass spectrometry (LC-MS) was measured by Agilent HPLC 1260 Infinity II and G6125C LC / MSD.

[0098] The meanings of some abbreviations in the present invention are as follows: Boc tert-butyloxycarbonyl TMS trimethylsilyl DIAD diisopropyl azodicarboxylate DEAD diethyl azodicarboxylate DIPEA N,N-diisopropylethylamine THF tetrahydrofuran LiAlD4 deuterated lithium aluminum hydride Ph3P triphenylphosphine MsCl methanesulfonyl chloride TsCl p-toluenesulfonyl chloride DCM dichloromethane

[0099] Unless otherwise specified, in the present invention, the alcohol solvent is a C1-C6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, and isopropanol, more preferably methanol or ethanol.

[0100] Unless otherwise specified, in the present invention, the aromatic hydrocarbon solvent is one or more of benzene, toluene, and xylene, preferably toluene.

[0101] Unless otherwise specified, in the present invention, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

[0102] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention more clearly understood, the present invention is further described below in conjunction with specific embodiments. However, it should be understood that the embodiments do not limit the scope of this application.

[0103] The reagents and solvents used in the present invention were purchased from commercial sources. Unless otherwise specified in the present application, all reagents and solvents were used directly without treatment.

[0104] The hydrazine hydrate used in the present invention includes but is not limited to an aqueous solution of hydrazine hydrate. In some embodiments, the concentration of the solution is 80%.

[0105] Example 1: Step a

[0106] LiAlD4 (8.0 g, 0.54 eq) was added to the bottle, and anhydrous THF (600 mL) was added and stirred to dissolve. The reaction solution temperature was lowered to -70 to -60 ° C with a dry ice ethanol bath, and nitrogen was replaced three times. Stirring was continued for 30 minutes, and a solution of 3-(trimethylsilyl)propiolic acid ethyl ester (60 g, 0.35 mol, 1 eq) in THF (200 mL) was added dropwise under temperature control for about 1.5 hours. After the addition was completed, the reaction was kept warm for 1.5 hours, and then the temperature was slowly raised to room temperature for about 1 hour. The reaction was continued at room temperature until the raw materials were basically reacted. The reaction solution was cooled to about 0 ° C, 1N HCl (180 mL) solution was added dropwise to quench the reaction, and water (600 mL) and DCM (600 mL) were added and stirred for 10 minutes. 1N The pH of the system was adjusted to about 3-4 with HCl (420 mL) solution, and the mixture was allowed to stand for separation. The aqueous phase was extracted once with DCM (600 ml). The organic phases were combined, washed twice with water, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound II-1 (110 g), which was directly used in the next reaction. The yield was calculated as 100%.

[0107] 1 H NMR (400MHz, CDCl3): δ=0.17 (9H).

[0108] Example 2: Step a

[0109] LiAlD4 (0.2 g, 0.8 eq) was added to the bottle, anhydrous THF (20 mL) was added, and the mixture was stirred to dissolve. The reaction temperature was lowered to -70 to -60 ° C with a dry ice ethanol bath, and nitrogen was replaced three times. Stirring was continued for 30 minutes, and a solution of 3-(trimethylsilyl)propiolic acid ethyl ester (1.0 g, 5.9 mmol, 1 eq) in THF (10 mL) was added dropwise with temperature control for about 0.5 h. After the addition was completed, the mixture was kept warm for 1.5 h, and then the temperature was slowly raised to room temperature for about 1 h. The reaction was continued at room temperature until the raw materials were basically reacted. The reaction solution was cooled to about 0 ° C, 1N HCl (20 mL) solution was added dropwise to quench the reaction, and water (20 mL) and DCM (10 mL) were added and stirred for 10 min. The pH of the system was adjusted to about 3 to 4 with 1N HCl (20 mL) solution, and the layers were allowed to stand. The aqueous phase was treated with DCM (10 ml). Extract once, combine the organic phases, wash twice with water, dry over anhydrous Na2SO4, filter, and concentrate to obtain II-1 (0.9 g), which was used directly in the next reaction. The yield was calculated as 100%.

[0110] Example 3: Step b

[0111] Ethyl 3-(trimethylsilyl)propiolate (60 g, 0.35 mol, 1 eq) was added to a bottle, followed by anhydrous n-heptane (1 L) and EtOD (74.15 g, 1.58 mol, 4.5 eq). The mixture was cooled in an ice-water bath, and then sodium dispersion (mass fraction 40%, 90.56 g, 1.58 mol, 4.5 eq) was added. The reaction was stirred under nitrogen protection and the reaction temperature was slowly raised to room temperature. After the reaction was complete, 1N HCl (1.6 L) solution was added dropwise to quench the reaction. The mixture was allowed to stand for stratification, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain II-1 (45.6 g), which was used directly in the next reaction. The yield was calculated as 100%.

[0112] Example 4: Step c

[0113] Compound II-1 (45.9 g, 0.35 mol, 1 eq) was added to a bottle, and anhydrous THF (600 mL) was added and stirred to dissolve. Ph3P (101.7 g, 1.1 eq) and phthalimide (57 g, 1.1 eq) were added separately and stirred to dissolve. The reaction solution was cooled to about 0°C, and DIAD (78.4 g, 1.1 eq) was added dropwise while controlling the internal temperature not to exceed 5°C. After the addition was complete, the reaction was kept warm for 4 hours, then raised to room temperature for 18 hours. The reaction solvent was concentrated, and the crude product was purified by column chromatography to obtain 65.3 g of compound III-1 with a yield of 71.3%.

[0114] LC-MS[M+H] + :260.00.

[0115] Example 5: Step c

[0116] Compound II-2 (58.08 g, 1 mol, 1 eq) was added to a bottle, and anhydrous THF (1.5 L) was added and stirred to dissolve. Ph3P (288.52 g, 1.1 eq) and phthalimide (161.84 g, 1.1 eq) were added separately and stirred to dissolve. The reaction solution was cooled to about 0°C, and DIAD (222.42 g, 1.1 eq) was added dropwise while controlling the internal temperature not to exceed 5°C. After the addition was complete, the reaction was kept warm for 4 hours, then raised to room temperature for 18 hours. The reaction solvent was concentrated, and the crude product was purified by column chromatography to obtain 149.75 g of compound III-2 with a yield of 80%.

[0117] LC-MS[M+H] + :188.04.

[0118] Example 6: Steps d to f

[0119] Step d: Add compound III-1 (72 g, 0.28 mol, 1 eq) into a bottle, add methanol (800 mL) and stir to dissolve, slowly add hydrazine hydrate (35 mL, 3 eq) solution dropwise, and complete the addition in about 1 hour. Continue stirring for about 20 hours, filter, and rinse the filter cake with ethyl acetate (300 mL). The filtrate is the organic solution of compound V-1.

[0120] Step e: Concentrate the filtrate to obtain compound V-1. Add methanol (210 mL) to the bottle, stir to dissolve, add anhydrous K2CO3 (55 g, 1.5 eq), stir at room temperature for 3 h, filter, and add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.

[0121] Step f: Distill under normal pressure and collect the distillate. The distillate was cooled in an ice-water bath, and a 2M HCl-ethyl acetate solution (200 mL) was added dropwise to slowly precipitate a solid. The mixture was stirred for approximately 2 h, and then concentrated to remove the solvent. Then, n-heptane (300 mL) was added, stirred for approximately 1 h, and filtered. The filter cake was rinsed with n-heptane (50 mL) and dried to obtain 22.4 g of the hydrochloride salt of compound V-2 (86% yield).

[0122] 1 H NMR (400MHz, DMSO-d6): δ = 8.55 (3H), 3.58 (1H).

[0123] Example 7: Steps d, f

[0124] Step d: Add compound III-2 (46.80 g, 0.25 mol, 1 eq) into a bottle, add methanol (800 mL) and stir to dissolve, slowly add hydrazine hydrate (32 mL, 3 eq) solution dropwise, and complete the addition in about 1 hour. Continue stirring for about 20 hours, filter, and rinse the filter cake with ethyl acetate (300 mL). The filtrate is the organic solution of compound V-2.

[0125] Step f: Rectification under atmospheric pressure, collecting the distillate, yielding 14.28 g of compound V-2. Compound V-2 was dissolved in ethyl acetate (100 mL), cooled in an ice-water bath, and a 2M HCl solution in ethyl acetate (200 mL) was added dropwise. A solid slowly precipitated, and the mixture was stirred for approximately 2 h. The solvent was then concentrated to remove the solvent, and n-heptane (300 mL) was added. The mixture was stirred for approximately 1 h and filtered. The filter cake was rinsed with n-heptane (50 mL) and dried to yield 23.40 g of the hydrochloride salt of compound V-2, with a yield of 90%.

[0126] Example 8: Step g

[0127] Step g: Add compound II-1 (13.03 g, 0.1 mol, 1 eq) to a bottle, add dichloromethane (200 mL) and triethylamine (15.18 g, 1.5 eq) respectively, stir to dissolve, cool the reaction solution to about 0°C, add MsCl (12.60 g, 1.1 eq) dropwise while controlling the internal temperature not to exceed 5°C, and keep the reaction warm for 2 hours after the addition is complete.

[0128] Step h: Slowly add aqueous ammonia (13.60 g, 2 eq) solution to the reaction solution, and continue stirring for about 2 h after the addition is complete.

[0129] Step e: Concentrate to remove the solvent, add methanol (150 mL) to the bottle, stir to dissolve, add anhydrous K2CO3 (20.73 g, 1.5 eq), stir at room temperature for 3 h, filter, and add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.

[0130] Step f: atmospheric distillation, collecting the distillate, cooling the obtained distillate in an ice-water bath, adding HCl ethyl acetate solution (2M, 100 mL) dropwise, slowly precipitating a solid, stirring for about 2 h, concentrating to remove the solvent, then adding n-heptane (100 mL), stirring for about 1 h, filtering, rinsing the filter cake with n-heptane (20 mL), and drying the filter cake to obtain 3.26 g of the hydrochloride salt of compound V-2, with a yield of 35%.

[0131] Example 9

[0132] Step g: Add compound II-1 (13.03 g, 0.1 mol, 1 eq) to a bottle, add dichloromethane (200 mL) and triethylamine (15.18 g, 1.5 eq) respectively, stir to dissolve, cool the reaction solution to about 0°C, add TsCl (20.97 g, 1.1 eq) dichloromethane solution dropwise while controlling the internal temperature not to exceed 5°C, and keep the reaction warm for 2 hours after the addition is complete.

[0133] Step h: Slowly add aqueous ammonia (13.60 g, 2 eq) solution to the reaction solution, and continue stirring for about 2 h after the addition is complete.

[0134] Step e: Concentrate to remove the solvent, add methanol (150 mL) to the bottle, stir to dissolve, add anhydrous K2CO3 (20.73 g, 1.5 eq), stir at room temperature for 3 h, filter, and add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.

[0135] Step f: Distill under normal pressure and collect the distillate. The distillate was cooled in an ice-water bath, and a 2M HCl ethyl acetate solution (100 mL) was added dropwise to slowly precipitate a solid. The mixture was stirred for approximately 2 h, and then concentrated to remove the solvent. Then, n-heptane (100 mL) was added, stirred for approximately 1 h, and filtered. The filter cake was rinsed with n-heptane (20 mL) and dried to obtain 2.58 g of the hydrochloride salt of compound V-2 (yield 28%).

[0136] Example 10

[0137] Step i: Add N-propynylphthalimide (10 g, 54 mmol, 1 eq) to a bottle, add deuterated methanol (100 mL) and heavy water (100 mL) and stir to dissolve, then add NaOD solution (5.4 mmol, 0.1 eq), stir for about 24 h, add dilute hydrochloric acid solution (about 6 mmol, 0.11 eq), continue stirring for about 15 minutes, and concentrate the reaction solution to obtain compound III-3.

[0138] Step d: Methanol (100 mL) was added to the above solid, and hydrazine hydrate (8 mL, 3 eq) solution was slowly added dropwise over about 1 h. The mixture was stirred for about 20 h, filtered, and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was an organic solution of compound V-3.

[0139] Step f: Atmospheric distillation was performed, and the distillate was collected to obtain 2.88 g of compound V-3. The obtained compound V-3 was dissolved in ethyl acetate (20 mL), cooled in an ice-water bath, and HCl ethyl acetate solution (2M, 25 mL) was added dropwise to slowly precipitate a solid. The mixture was stirred for about 2 h, concentrated to remove the solvent, and then n-heptane (50 mL) was added. The mixture was stirred for about 1 h and filtered. The filter cake was rinsed with n-heptane (50 mL) and dried to obtain 4.70 g of the hydrochloride salt of compound V-3, with a yield of 92%.

[0140] LC-MS[M+H] + :59.07.

Claims

1. A method for preparing a salt of compound V, characterized in that: The following steps are included: Step f: distilling the organic solution of compound V under normal pressure, collecting the distillate, and acidifying to obtain the salt of compound V, wherein the organic solution of compound V is selected from one or more of an alcohol solvent, an ester solvent or an aromatic hydrocarbon solvent, Wherein R1 is -H, -D, trimethylsilyl or trimethylgermanyl, preferably R1 is -H or -D.

2. The preparation method according to claim 1, characterized in that: The salt of compound V is an inorganic acid salt or an organic acid salt of compound V, preferably a hydrochloride, a hydrobromide, a sulfate, a phosphate, and more preferably a hydrochloride; Preferably, the acidification comprises: cooling the distillate to 0-10°C, adding dropwise an ethyl acetate solution of an acid, and slowly precipitating a solid. More preferably, the acidification further comprises the step of adding n-heptane for recrystallization; Preferably, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, more preferably hydrochloric acid; Preferably, the alcohol solvent is a C1-C6 alkyl alcohol, preferably selected from one or more of methanol, ethanol, propanol, isopropanol, more preferably methanol or ethanol. Preferably, the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene and xylene, more preferably toluene. Preferably, the ester solvent is ethyl acetate or methyl acetate, more preferably ethyl acetate.

3. The preparation method according to claim 1, characterized in that: The preparation method of the compound V comprises the following steps d: Step d: Compound III is subjected to hydrazinolysis to obtain compound V Wherein R1 is -H, -D, trimethylsilyl or trimethylgermanyl.

4. The preparation method according to claim 3, characterized in that: The compound V is compound V-2, and the organic solution of compound V-2 is prepared by the following steps e: Step e: dissolving compound V-1 in an alcohol solvent, adding a base, stirring at room temperature, filtering after the reaction is completed, and adding an aromatic hydrocarbon solvent to the obtained filtrate to obtain an organic solution of compound V-2. Furthermore, the volume ratio of the alcohol solvent to the aromatic hydrocarbon solvent is 1:0.2-2, preferably 1:0.4-1; The base is one or more of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; The molar ratio of the base to the compound V-1 is 1:1 to 3; The alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol; The aromatic hydrocarbon solvent is selected from one or more of benzene, toluene and xylene, preferably toluene.

5. A method for preparing compound V, characterized in that: Contains the following steps: Step d: Compound III is subjected to hydrazinolysis to obtain compound V, wherein R1 is -H, -D or trimethylgermanium, 6. The preparation method according to claim 3 or 5, characterized in that: In step d, the reagent for hydrazinolysis is hydrazine hydrate; In step d, the amount of hydrazine hydrate used is 2 to 5 molar equivalents of compound III, preferably 3 molar equivalents; In step d, the reaction temperature of the hydrazinolysis is 0 to 30°C; In step d, compound III is dissolved in an alcohol solvent, and a hydrazine hydrate solution is slowly added dropwise. After the addition is completed, the reaction is continued by stirring, and the filter cake is washed with an ester solvent to obtain an organic solution of compound V. Further, in step d, the alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol, more preferably methanol; In step d, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

7. The preparation method according to claim 6, characterized in that: The preparation of the compound III comprises the following steps c: Step c: In an organic solvent, compound II reacts with phthalimide in the presence of a phosphorus reagent and a nucleophilic reagent to obtain compound III. Further, the phosphorus reagent is an alkyl phosphorus reagent or an aryl phosphorus reagent, preferably tributylphosphine or triphenylphosphine; The nucleophilic agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, and dibenzyl azodicarboxylate, preferably diisopropyl azodicarboxylate; The amount of the phosphorus reagent used is 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents; the amount of the nucleophilic reagent used is 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents; Preferably, the step c comprises the following steps: dissolving compound II, an organophosphorus reagent and phthalimide in an organic solvent, lowering the temperature of the reaction solution to -5°C to 0°C, dropping a nucleophilic reagent, and controlling the internal temperature not to exceed 5°C, and after the dropwise addition is completed, keeping the temperature for reaction, and then warming the temperature to room temperature for reaction, and after the reaction is completed, concentrating the reaction solvent, purifying, and obtaining compound III; Preferably, the organic solvent is THF, and the molar volume ratio of compound II to the organic solvent is 0.1 to 1 mol / L, more preferably 0.5 to 0.6 mol / L.

8. The preparation method according to claim 6, characterized in that: The compound III is compound III-3, and its preparation comprises the following steps i: Step i: N-propynylphthalimide reacts with a deuterated reagent in heavy water in the presence of a base to obtain compound III. Preferably, the deuterated reagent is a deuterated alcohol reagent, preferably deuterated methanol; The volume ratio of the deuterated reagent to heavy water is 1:1 to 1:2; The base is NaOD or KOD; The amount of the base used is 0.05 to 2 molar equivalents of N-propynylphthalimide, preferably 0.05 to 0.20 molar equivalents, and the weight volume ratio of N-propynylphthalimide to the deuterated reagent is 1:5 to 1:20 g / mL, preferably 1:5 to 1:10 g / mL.

9. A method for preparing compound V, characterized in that: The following steps are involved: Step g) Compound II is sulfonylated to obtain compound IV, Step h) Compound IV is then subjected to an aminolysis reaction with an aminating agent to obtain Compound V, wherein R3 is an optionally substituted sulfonyl group, wherein the substituted substituent is an alkyl group or an aryl group; preferably, R3 is a methanesulfonyl group, an ethanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a trimethylbenzenesulfonyl group or a nitrobenzenesulfonyl group, more preferably, R3 is a methanesulfonyl group or a p-toluenesulfonyl group, R1 is -H, -D, trimethylsilyl or trimethylgermanyl.

10. The preparation method according to claim 9, characterized in that: The sulfonylation reagent is methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or p-methanesulfonic anhydride; The amount of the sulfonylation reagent used is 1.0 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents; The aminating agent is aqueous ammonia; the amount of aqueous ammonia used is 1 to 5 molar equivalents of compound IV, preferably 1 to 2 molar equivalents; The aminating agent is benzylamine; the amount of benzylamine used is 1 to 5 molar equivalents of compound IV, preferably 1 to 2 molar equivalents; The temperature of the ammonolysis reaction is 0-5°C.

11. The preparation method according to any one of claims 7, 9 or 10, characterized in that: The preparation method of the compound II comprises the following steps a: Step a: In an organic solvent, compound I is reacted with LiAlD4 to generate compound II, wherein R2 is an optionally substituted -C1-C6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R2 is a C1-C3 alkyl group or a benzyl group; more preferably, R2 is a methyl group or an ethyl group. Preferably, the molar ratio of compound I to LiAlD4 is 1:0.4-1.

12. The preparation method according to any one of claims 7, 9 or 10, characterized in that: The preparation method of the compound II comprises the following steps b: Step b: Compound I is reacted with a metal reagent and a deuterated alcohol to generate compound II, wherein R2 is an optionally substituted -C1-C6 alkyl, wherein the substituted substituent is H or phenyl; preferably, R2 is a C1-C3 alkyl or a benzyl; more preferably, R2 is a methyl or ethyl group. Preferably, the metal reagent is Na or K, the deuterated alcohol reagent is CH3OD or CH3CH2OD; the molar ratio of the compound I to the metal reagent is 1:0.5-5, preferably 1:1-5; Preferably, the organic solvent is tetrahydrofuran. Preferably, the concentration of compound I in the organic solvent is 0.3-1.8 mol / L.

13. A method for preparing the hydrochloride of compound V-2, characterized in that: The following steps are involved: Step d: Compound III-1 is hydrazine-hydrated to give compound V-1: Step e: dissolving compound V-1 in methanol, adding K2CO3, stirring at room temperature, filtering after the reaction is completed, and adding toluene to the obtained filtrate to obtain an organic solution of compound V-2; Step f: distilling the organic solution of compound V-2 under normal pressure, collecting the distillate, and acidifying to obtain the salt of compound V-2. Preferably, compound III-1 is prepared by a one-pot method of steps d, e, and f to obtain the hydrochloride salt of compound V-2.

14. A method for preparing the hydrochloride of compound V-2, characterized in that: The following steps are involved: Step g: Compound II-1 is sulfonylated to obtain compound IV-1. Step h: Compound IV-1 is then subjected to an ammonolysis reaction with an aminating agent to obtain compound V-1. Step e: dissolving compound V-1 in methanol, adding K2CO3, stirring at room temperature, filtering after the reaction is completed, and adding toluene to the obtained filtrate to obtain an organic solution of compound V-2; Step f: distilling the organic solution of compound V-2 under normal pressure, collecting the distillate, and acidifying to obtain the salt of compound V-2. Wherein, R3 is methanesulfonyl or p-toluenesulfonyl; Preferably, compound II-1 is prepared by a one-pot method of steps g, h, e and f to obtain the hydrochloride salt of compound V-2.

15. A compound I, wherein R1 is trimethylgermanyl, R2 is -H, -C1-C3 alkyl or benzyl, 16. A compound II-2, 17. Compound III-2, Compound III-3, Compound III-4, 18. Compound IV-2, Compound IV-3, Compound IV-4, 19. Compound V-3, Compound V-4, 20. Use of compound I, compound II-2, compound III-2, compound III-3, compound III-4, compound IV-2, compound IV-3, compound IV-4, compound V-3 or compound V-4 in the preparation of deuterated propargylamine and its hydrochloride.