[go: up one dir, main page]

WO2025067218A1 - Preparation method for deuterated propargylamine hydrochloride, intermediate thereof, and use - Google Patents

Preparation method for deuterated propargylamine hydrochloride, intermediate thereof, and use Download PDF

Info

Publication number
WO2025067218A1
WO2025067218A1 PCT/CN2024/121032 CN2024121032W WO2025067218A1 WO 2025067218 A1 WO2025067218 A1 WO 2025067218A1 CN 2024121032 W CN2024121032 W CN 2024121032W WO 2025067218 A1 WO2025067218 A1 WO 2025067218A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
reagent
reaction
group
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/121032
Other languages
French (fr)
Chinese (zh)
Inventor
杨哲洲
蔡训志
李敏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Huahai Pharmaceutical Co Ltd
Shanghai Synergy Pharmaceutical Sciences Co Ltd
Original Assignee
Zhejiang Huahai Pharmaceutical Co Ltd
Shanghai Synergy Pharmaceutical Sciences Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Huahai Pharmaceutical Co Ltd, Shanghai Synergy Pharmaceutical Sciences Co Ltd filed Critical Zhejiang Huahai Pharmaceutical Co Ltd
Publication of WO2025067218A1 publication Critical patent/WO2025067218A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/22—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of other functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/67—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a preparation method of deuterated propargylamine hydrochloride, an intermediate thereof and application.
  • Deuterated propargylamine and its hydrochloride are important intermediates in the pharmaceutical and chemical industry.
  • Monique PCMulder 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 organic phosphorus oxide reagent NHBocPO(OEt) 2 , which is expensive; there are two rounds of Boc protection and deprotection steps in the route; the route is cumbersome, and the total yield of the 5-6 step reaction is only 23.32%.
  • 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,
  • R 1 is -H, -D, trimethylsilyl or trimethylgermanyl, preferably R 1 is -H or -D.
  • the alcohol solvent is a C 1 -C 6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, isopropanol, more preferably methanol or ethanol.
  • the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene and xylene, preferably toluene.
  • the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.
  • 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.
  • the acidification is as follows: cooling the distillate to 0-10° C., adding dropwise an ethyl acetate solution of an acid, and slowly precipitating a solid.
  • the step of adding n-heptane for recrystallization is further included after the acidification, and the acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and more preferably hydrochloric acid.
  • the method for preparing compound V comprises the following steps d:
  • Step d Compound III is subjected to hydrazinolysis to obtain compound V
  • R 1 is -H, -D, trimethylsilyl or trimethylgermanyl.
  • the compound V is compound V-2, and the organic solution of the 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.
  • 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-2 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 one or more of benzene, toluene, and xylene, preferably toluene.
  • 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 R 1 is -H, -D or trimethylgermanium,
  • the reagent for hydrazinolysis is hydrazine hydrate
  • the amount of hydrazine hydrate used is 2 to 5 molar equivalents of compound III, preferably 3 molar equivalents.
  • reaction temperature of the hydrazinolysis is 0 to 30°C;
  • step d compound III is dissolved in an alcohol solvent, hydrazine hydrate solution is slowly added dropwise, and after the addition is completed, the reaction is continued by stirring, and the filter cake is rinsed with an ester solvent to obtain an organic solution of compound V.
  • the alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol, more preferably methanol;
  • the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.
  • the preparation of 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.
  • the phosphorus reagent is an alkyl phosphorus reagent or an aryl phosphorus reagent, preferably tributylphosphine or triphenylphosphine;
  • the nucleophilic agent is diisopropyl azodicarboxylate, diethyl azodicarboxylate, One or more of dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, dibenzyl azodicarboxylate, preferably diisopropyl azodicarboxylate;
  • the phosphorus reagent is used in an amount of 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents;
  • the nucleophilic reagent is used in an amount of 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents;
  • compound II, an organophosphorus reagent and phthalimide are dissolved in an organic solvent, the temperature of the reaction solution 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 temperature is kept for reaction, and then the temperature is raised to room temperature for reaction. After the reaction is completed, the reaction solvent is concentrated and purified to obtain compound III.
  • 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.
  • 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.
  • the deuterated reagent is a deuterated alcohol reagent, preferably deuterated methanol;
  • the volume ratio of the deuterated reagent to heavy water is 1:1;
  • the base is NaOD or KOD
  • the base is used in an amount of 0.05 to 2 molar equivalents of N-propynylphthalimide, preferably 0.05 to 0.20 molar equivalents;
  • 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.
  • the third aspect of the present invention provides a method for preparing compound V, comprising the following steps:
  • 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,
  • R 3 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, R 3 is a methanesulfonyl group, an ethylsulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a trimethylbenzenesulfonyl group or a nitrobenzenesulfonyl group,
  • R 3 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, R 3 is a methanesulfonyl group, an ethyl
  • R1 is -H, -D, trimethylsilyl or trimethylgermanyl.
  • the sulfonylation reagent is methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or p-methanesulfonic anhydride;
  • R 3 is a methanesulfonyl group
  • the sulfonylation reagent is methanesulfonyl chloride or methanesulfonic anhydride.
  • R 3 is p-toluenesulfonyl
  • the sulfonylation reagent is p-toluenesulfonyl chloride or p-methanesulfonic anhydride.
  • 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;
  • 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 aminolysis reaction is 0-5°C.
  • the method for preparing compound II comprises the following steps:
  • Step a) Compound I is reacted with LiAlD 4 in an organic solvent to generate Compound II, wherein R 2 is an optionally substituted -C 1 -C 6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R 2 is a C 1 -C 3 alkyl group or a benzyl group; more preferably, R 2 is a methyl group or an ethyl group.
  • the molar ratio of compound I to LiAlD 4 is 1:0.4-1, such as 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or any value or range therebetween.
  • the method for preparing compound II comprises the following steps:
  • Step b) Compound I is reacted with a metal reagent and a deuterated alcohol to generate Compound II, wherein R 2 is an optionally substituted -C 1 -C 6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R 2 is a C 1 -C 3 alkyl group or a benzyl group; more preferably, R 2 is a methyl group or an ethyl group.
  • the metal reagent is Na or K
  • the deuterated alcohol reagent is CH 3 OD or CH 3 CH 2 OD
  • 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.
  • the organic solvent is tetrahydrofuran.
  • the concentration of Compound I in the organic solvent is 0.3-1.8 mol/L.
  • the fourth aspect of the present invention provides a method for preparing the hydrochloride of compound V-2, comprising the following steps:
  • Step d Compound III-1 is hydrazine-hydrated to give compound V-1:
  • Step e dissolving compound V-1 in methanol, adding K 2 CO 3 , stirring at room temperature, filtering after the reaction, 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.
  • 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.
  • the fifth aspect of the present invention provides a method for preparing the hydrochloride of compound V-2, comprising the following steps:
  • 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 K 2 CO 3 , stirring at room temperature, filtering after the reaction, 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.
  • R 3 is methanesulfonyl or p-toluenesulfonyl
  • 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.
  • Another aspect of the present invention provides a compound I, wherein R 1 is trimethylgermanyl, R 2 is -H, -C 1 -C 3 alkyl or benzyl,
  • Another aspect of the present invention provides a compound II-2,
  • Another aspect of the present invention provides compound III-2, compound III-3, compound III-4,
  • the present invention provides compound IV-2, compound IV-3, and compound IV-4.
  • the present invention provides compound V-3 and compound V-4.
  • 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.
  • the deuterated propargylamine prepared in the present invention can be further prepared into deuterated propargylamine hydrochloride by conventional methods in the art.
  • deuterated ethanol is preferably used as the deuteration reagent, which can avoid the shortcomings of LiAlD 4 , such as flammability, high cost, low reaction temperature and high equipment requirements.
  • eq in the present invention is an abbreviation of "equivalent”, which means equivalent, and is a term used for the ratio of the amounts of substances when substances interact with each other.
  • Deuterated propargylamine refers to propargylamine Compounds in which one or more H on the molecule is replaced by deuterium. Including but not limited to:
  • sulfonyl in the present invention includes, but is not limited to, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or p-toluenesulfonyl, trimethylbenzenesulfonyl or nitrobenzenesulfonyl.
  • nucleophile in the present invention includes, but is not limited to, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate.
  • aminating 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; the aminating agent includes liquid ammonia, ammonia water, urea, ammonium salts and organic amines.
  • the term "-C 1 -C 6 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 "-C 1 -C 3 alkyl” includes alkyl groups containing 1 to 3 carbon atoms, specifically methyl, ethyl, n-propyl and isopropyl.
  • substituted in the present invention means that any one or more hydrogen atoms on the designated atom are replaced by a substituent selected from a designated group, and the result of the substitution is to produce a stable compound.
  • 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.
  • distillation in the present invention includes but is not limited to simple distillation, rectification, special distillation, etc.
  • room temperature refers to 20 to 30°C.
  • ice water bath refers to -5 to 5°C.
  • mass spectrometry was measured by Agilent HPLC 1260 InfinityII and G6125C LC/MSD.
  • the alcohol solvent is a C 1 -C 6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, isopropanol, more preferably methanol or ethanol.
  • the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene, preferably toluene.
  • the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.
  • 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.
  • 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%.
  • LiAlD 4 (8.0 g, 0.54 eq) was added to a bottle, and anhydrous THF (600 mL) was added, stirred to dissolve, and the reaction liquid temperature was lowered to -70 to -60°C with a dry ice ethanol bath, and nitrogen was replaced three times, and stirring was continued for 30 minutes.
  • the reaction was continued at room temperature until the raw materials were basically reacted.
  • the reaction liquid was cooled to about 0°C, and a 1N HCl (180 mL) solution was added dropwise to quench the reaction.
  • 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 layers were separated by standing.
  • the aqueous phase was extracted once with DCM (600 ml), and 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%.
  • LiAlD 4 (0.2 g, 0.8 eq) was added to a bottle, and anhydrous THF (20 mL) was added, stirred and dissolved, and the reaction liquid temperature was lowered to -70 to -60 ° C with a dry ice ethanol bath, and nitrogen was replaced three times, and stirring was continued for 30 minutes.
  • a THF (10 mL) solution of 3-(trimethylsilyl)propiolic acid ethyl ester 1.0 g, 5.9 mmol, 1 eq
  • was added dropwise at a temperature control and the addition was about 0.5 h. After the addition was completed, the reaction 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 liquid was cooled to about 0 ° C, and 1N HCl (20 mL) solution was added dropwise to quench the reaction.
  • 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 Na 2 SO 4 , filter, and concentrate to obtain II-1 (0.9 g), which is directly used in the next reaction.
  • the yield is calculated as 100%.
  • Ethyl 3-(trimethylsilyl)propiolate 60 g, 0.35 mol, 1 eq was added to a bottle, and anhydrous n-heptane (1 L) and EtOD (74.15 g, 1.58 mol, 4.5 eq) were added in sequence.
  • the mixture was cooled in an ice-water bath, and sodium dispersion (mass fraction 40%, 90.56 g, 1.58 mol, 4.5 eq) was added.
  • the mixture 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.
  • the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain II-1 (45.6 g), which was directly used in the next step reaction. The yield was calculated as 100%.
  • 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, the addition is completed in about 1 hour, and stirring is continued for about 20 hours. Filter, rinse the filter cake with ethyl acetate (300 mL), and the filtrate is the organic solution of compound V-1.
  • Step e Concentrate the filtrate to obtain compound V-1. Add methanol (210 mL) to the bottle, stir to dissolve, add anhydrous K 2 CO 3 (55 g, 1.5 eq), stir at room temperature for 3 h, filter, add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.
  • Step f atmospheric distillation, collect the distillate.
  • the obtained distillate was cooled in an ice-water bath, HCl-ethyl acetate solution (2M, 200 mL) was added dropwise, solids were slowly precipitated, stirred for about 2 h, concentrated to remove the solvent, and then n-heptane (300 mL) was added, stirred for about 1 h, filtered, the filter cake was rinsed with n-heptane (50 mL), and the filter cake was dried to obtain 22.4 g of the hydrochloride of compound V-2, with a yield of 86%.
  • 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, the addition is completed in about 1 hour, and stirring is continued for about 20 hours. Filter, rinse the filter cake with ethyl acetate (300 mL), and the filtrate is the organic solution of compound V-2.
  • Step f Normal pressure distillation, collect the distillate, and obtain 14.28 g of compound V-2. Dissolve the obtained compound V-2 in ethyl acetate (100 mL), cool in an ice-water bath, add HCl ethyl acetate solution (2M, 200 mL) dropwise, slowly precipitate solid, stir for about 2 hours, The solvent was removed by concentration, and n-heptane (300 mL) was added, stirred for about 1 h, filtered, and the filter cake was rinsed with n-heptane (50 mL). The filter cake was dried to obtain 23.40 g of the hydrochloride of compound V-2 with a yield of 90%.
  • Step g Add compound II-1 (13.03 g, 0.1 mol, 1 eq) into 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 and control the internal temperature not to exceed 5°C. After the addition is complete, keep the reaction warm for 2 hours.
  • 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.
  • Step e Concentrate to remove the solvent, add methanol (150 mL) to the bottle, stir to dissolve, add anhydrous K 2 CO 3 (20.73 g, 1.5 eq), stir at room temperature for 3 h, filter, add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.
  • Step f distill under normal pressure, collect the distillate, cool the obtained distillate in an ice-water bath, add HCl ethyl acetate solution (2M, 100 mL) dropwise, slowly precipitate solid, stir for about 2 hours, concentrate to remove the solvent, add n-heptane (100 mL), stir for about 1 hour, filter, rinse the filter cake with n-heptane (20 mL), and dry the filter cake to obtain 3.26 g of the hydrochloride salt of compound V-2, with a yield of 35%.
  • Step g Add compound II-1 (13.03 g, 0.1 mol, 1 eq) into 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 and control the internal temperature not to exceed 5°C. After the addition is complete, keep the reaction warm for 2 hours.
  • 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.
  • Step e Concentrate to remove the solvent, add methanol (150 mL) to the bottle, stir to dissolve, add anhydrous K 2 CO 3 (20.73 g, 1.5 eq), stir at room temperature for 3 h, filter, add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.
  • Step f atmospheric distillation, collect the distillate.
  • the obtained distillate was cooled in an ice-water bath, HCl ethyl acetate solution (2M, 100 mL) was added dropwise, solids were slowly precipitated, stirred for about 2 hours, concentrated to remove the solvent, and then n-heptane (100 mL) was added, stirred for about 1 hour, filtered, the filter cake was rinsed with n-heptane (20 mL), and the filter cake was dried to obtain 2.58 g of the hydrochloride of compound V-2, with a yield of 28%.
  • Step i Add N-propynylphthalimide (10 g, 54 mmol, 1 eq) into 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.
  • Step d Add methanol (100 mL) to the above solid, slowly add hydrazine hydrate (8 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 (100 mL). The filtrate is the organic solution of compound V-3.
  • Step f distillation at normal pressure, collect the distillate, and 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 solids.
  • 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, filtered, and the filter cake was rinsed with n-heptane (50 mL).
  • the filter cake was dried to obtain 4.70 g of the hydrochloride of compound V-3, with a yield of 92%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

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

Description

氘代炔丙胺盐酸盐制备方法、其中间体和用途Deuterated propargylamine hydrochloride preparation method, intermediates and uses thereof 技术领域Technical Field

本发明涉及有机合成技术领域，尤其是涉及氘代炔丙胺盐酸盐的制备方法、其中间体和用途。The invention relates to the technical field of organic synthesis, in particular to a preparation method of deuterated propargylamine hydrochloride, an intermediate thereof and application.

背景技术Background Art

氘代炔丙胺及其盐酸盐是医药化工领域重要中间体。Monique P.C.Mulder等公开了一种制备1,1-二氘代-丙-2-炔-1-胺(1,1-d2-prop-2-yn-1-amine)盐酸盐的制备方法。该方法中形成氮烷基中间体13的步骤需要使用有机氧磷试剂NHBocPO(OEt)2，价格昂贵；路线中存在两轮Boc保护和脱保护的步骤；该路线步骤繁琐，5～6步反应的总收率仅为23.32％，
Deuterated propargylamine and its hydrochloride are important intermediates in the pharmaceutical and chemical industry. Monique PCMulder 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 organic phosphorus oxide reagent NHBocPO(OEt) 2 , which is expensive; there are two rounds of Boc protection and deprotection steps in the route; the route is cumbersome, and the total yield of the 5-6 step reaction is only 23.32%.

发明内容Summary of the invention

本发明第一方面提供了一种化合物Ⅴ的盐的制备方法，包括以下步骤f)：将化合物V的有机溶液常压蒸馏，收集馏出液，酸化，得到化合物V的盐，所述化合物V的有机溶液的选自醇类溶剂、酯类溶剂或芳香烃类溶剂中的一种或多种， 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,

其中R1为-H、-D、三甲基硅基或三甲基锗基，优选地R1为-H、-D。 Wherein R 1 is -H, -D, trimethylsilyl or trimethylgermanyl, preferably R 1 is -H or -D.

在本发明的一些实施方案中，所述醇类溶剂为C1-C6烷基醇，优选地选自甲醇、乙醇、丙醇、异丙醇中的一种或多种，更优选地为甲醇或乙醇。In some embodiments of the present invention, the alcohol solvent is a C 1 -C 6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, isopropanol, more preferably methanol or ethanol.

在本发明的一些实施方案中，所述芳香烃类溶剂选择苯、甲苯、二甲苯中的一种或多种，优选地为甲苯。In some embodiments of the present invention, the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene and xylene, preferably toluene.

在本发明的一些实施方案中，所述酯类溶剂为乙酸乙酯或乙酸甲酯，优选地为乙酸乙酯。In some embodiments of the present invention, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

在本发明的一些实施方案中，所述化合物V的盐为化合物V的无机酸盐或有机酸盐，优选地为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐，更优选地为盐酸盐。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, a phosphate, and more preferably a hydrochloride.

在本发明的一些实施方案中，所述酸化为：将馏出液冷却至0～10℃，滴加酸的乙酸乙酯溶液，缓慢析出固体。In some embodiments of the present invention, the acidification is as follows: cooling the distillate to 0-10° C., adding dropwise an ethyl acetate solution of an acid, and slowly precipitating a solid.

在本发明的一些实施方案中，所述酸化后还包含加入正庚烷重结晶的步骤，优选地所述酸为盐酸、氢溴酸、硫酸、磷酸，更优选地为盐酸。In some embodiments of the present invention, the step of adding n-heptane for recrystallization is further included after the acidification, and the acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and more preferably hydrochloric acid.

在本发明的一些实施方案中，，所述化合物V的制备方法，包含以下步骤d：In some embodiments of the present invention, the method for preparing compound V comprises the following steps d:

步骤d：化合物Ⅲ肼解，得到化合物ⅤStep d: Compound III is subjected to hydrazinolysis to obtain compound V

其中R1为-H、-D、三甲基硅基或三甲基锗基。 Wherein R 1 is -H, -D, trimethylsilyl or trimethylgermanyl.

在本发明的一些实施方案中，所述化合物V为化合物V-2，所述化合物V-2的有机溶液通过以下步骤e制备得到：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:

步骤e：将化合物V-1溶于醇类溶剂，加入碱，室温下搅拌，反应结束后，过滤，得到的滤液中加入芳香烃类溶剂，即为所述化合物V-2的有机溶液，
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.

进一步地，所述醇类溶剂和所述芳香烃类溶剂的体积比为1:0.2～2，优选为1:0.4～1； Furthermore, the volume ratio of the alcohol solvent to the aromatic hydrocarbon solvent is 1:0.2-2, preferably 1:0.4-1;

所述碱为碳酸钾、碳酸钠、氢氧化钠、氢氧化钾中的一种或多种；The base is one or more of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide;

所述碱与化合物V-2的摩尔比为1:1～3；The molar ratio of the base to the compound V-2 is 1:1 to 3;

所述醇类溶剂为甲醇、乙醇、丙醇、异丙醇中的一种或多种，优选地为甲醇或乙醇。所述芳香烃类溶剂选自苯、甲苯、二甲苯中的一种或多种，优选地为甲苯。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.

本发明第二方面提供了一种化合物Ⅴ的制备方法，包含以下步骤d)：化合物Ⅲ肼解，得到化合物Ⅴ，其中R1为-H、-D或三甲基锗基，
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 R 1 is -H, -D or trimethylgermanium,

在本发明的一些实施方案中，步骤d中，所述肼解的试剂为水合肼；In some embodiments of the present invention, in step d, the reagent for hydrazinolysis is hydrazine hydrate;

在本发明的一些实施方案中，步骤d中，所述水合肼的用量为化合物Ⅲ的2～5摩尔当量，优选为3摩尔当量。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.

在本发明的一些实施方案中，步骤d中，所述肼解的反应温度为0～30℃；In some embodiments of the present invention, in step d, the reaction temperature of the hydrazinolysis is 0 to 30°C;

在本发明的一些实施方案中，步骤d中，将化合物III溶解于醇类溶剂中，缓慢滴加水合肼溶液，滴加完毕继续搅拌反应，过滤，滤饼用酯类溶剂淋洗，得到化合物Ⅴ的有机溶液。In some embodiments of the present invention, in step d, compound III is dissolved in an alcohol solvent, hydrazine hydrate solution is slowly added dropwise, and after the addition is completed, the reaction is continued by stirring, and the filter cake is rinsed with an ester solvent to obtain an organic solution of compound V.

在本发明的一些实施方案中，步骤d中，所述醇类溶剂为甲醇、乙醇、丙醇、异丙醇中的一种或多种，优选地为甲醇或乙醇，更优选地为甲醇；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;

在本发明的一些实施方案中，步骤d中，所述酯类溶剂为乙酸乙酯或乙酸甲酯，优选地为乙酸乙酯。In some embodiments of the present invention, in step d, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

在本发明的一些实施方案中，所述化合物III的制备包含以下步骤c：In some embodiments of the present invention, the preparation of compound III comprises the following steps c:

步骤c：有机溶剂中，化合物II在磷试剂和亲核试剂的存在下与邻苯二甲酰亚胺反应，得到化合物III，
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.

在本发明的一些实施方案中，所述磷试剂为烷基磷试剂或芳基磷试剂，优选地为三丁基磷或三苯基膦；In some embodiments of the present invention, the phosphorus reagent is an alkyl phosphorus reagent or an aryl phosphorus reagent, preferably tributylphosphine or triphenylphosphine;

在本发明的一些实施方案中，所述亲核试剂为偶氮二羧酸二异丙酯、偶氮二甲酸二乙酯、 偶氮二甲酸二甲酯、偶氮二甲酸二叔丁酯、偶氮二甲酸二苄酯中的一种或多种，优选地为偶氮二甲酸二异丙酯；In some embodiments of the present invention, the nucleophilic agent is diisopropyl azodicarboxylate, diethyl azodicarboxylate, One or more of dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, dibenzyl azodicarboxylate, preferably diisopropyl azodicarboxylate;

在本发明的一些实施方案中，所述磷试剂的用量为化合物Ⅱ的1～1.5摩尔当量，优选为1.0～1.1摩尔当量；所述亲核试剂的用量为化合物Ⅱ的1～1.5摩尔当量，优选为1.0～1.1摩尔当量；In some embodiments of the present invention, the phosphorus reagent is used in an amount of 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents; the nucleophilic reagent is used in an amount of 1 to 1.5 molar equivalents of compound II, preferably 1.0 to 1.1 molar equivalents;

在本发明的一些实施方案中，将化合物II、有机磷试剂和邻苯二甲酰亚胺溶解于有机溶剂中，降低反应液温度至-5℃～0℃，滴加亲核试剂，并控制内温不超过5℃，滴加完毕，保温反应，再升至室温反应，待反应结束后浓缩反应溶剂，纯化，得到化合物III。In some embodiments of the present invention, compound II, an organophosphorus reagent and phthalimide are dissolved in an organic solvent, the temperature of the reaction solution 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 temperature is kept for reaction, and then the temperature is raised to room temperature for reaction. After the reaction is completed, the reaction solvent is concentrated and purified to obtain compound III.

在本发明的一些实施方案中，步骤c中，所述有机溶剂为THF，化合物II和所述有机溶剂的摩尔体积比为0.1～1mol/L,优选0.5～0.6mol/L。在一些实施方案中，所述化合物III为化合物III-3，其制备包含以下步骤i：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:

步骤i：N-丙炔基邻苯二甲酰亚胺在碱的存在下，在重水中与氘代试剂反应，得到化合物III，
Step i: N-propynylphthalimide reacts with a deuterated reagent in heavy water in the presence of a base to obtain compound III.

在本发明的一些实施方案中，所述氘代试剂为氘代醇类试剂，优选地为氘代甲醇；In some embodiments of the present invention, the deuterated reagent is a deuterated alcohol reagent, preferably deuterated methanol;

在本发明的一些实施方案中，所述氘代试剂和重水的体积比为1:1；In some embodiments of the present invention, the volume ratio of the deuterated reagent to heavy water is 1:1;

在本发明的一些实施方案中，所述碱为NaOD或KOD；In some embodiments of the invention, the base is NaOD or KOD;

在本发明的一些实施方案中，所述碱的用量为N-丙炔基邻苯二甲酰亚胺的0.05～2摩尔当量，优选地为0.05～0.20摩尔当量；In some embodiments of the present invention, the base is used in an amount of 0.05 to 2 molar equivalents of N-propynylphthalimide, preferably 0.05 to 0.20 molar equivalents;

在本发明的一些实施方案中，所述N-丙炔基邻苯二甲酰亚胺和氘代试剂的重量体积比为1:5～1:20g/mL，优选1:5～1:10g/mL。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.

本发明第三方面提供一种化合物V的制备方法，包含以下步骤：The third aspect of the present invention provides a method for preparing compound V, comprising the following steps:

步骤g)化合物Ⅱ磺酰化后得到化合物Ⅳ，Step g) Compound II is sulfonylated to obtain compound IV,

步骤h)化合物Ⅳ再与胺化剂进行氨解反应得到化合物Ⅴ，Step h) Compound IV is then subjected to an aminolysis reaction with an aminating agent to obtain Compound V,

其中R3为任选取代的磺酰基，所述取代的取代基为烷基(例如甲基、乙基)或芳基(例如苯基、甲苯基)；优选地，R3为甲磺酰基、乙磺酰基、苯磺酰基、对甲苯磺酰基、三甲基苯磺酰基或硝基苯磺酰基，
wherein R 3 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, R 3 is a methanesulfonyl group, an ethylsulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a trimethylbenzenesulfonyl group or a nitrobenzenesulfonyl group,

R1为-H、-D、三甲基硅基或三甲基锗基。 R1 is -H, -D, trimethylsilyl or trimethylgermanyl.

在本发明的一些实施方案中，所述磺酰化的试剂为甲磺酰氯、甲磺酸酐、对甲苯磺酰氯或对甲磺酸酐；In some embodiments of the present invention, the sulfonylation reagent is methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or p-methanesulfonic anhydride;

在本发明的一些实施方案中，R3为甲磺酰基，所述磺酰化的试剂为甲磺酰氯或甲磺酸酐。In some embodiments of the present invention, R 3 is a methanesulfonyl group, and the sulfonylation reagent is methanesulfonyl chloride or methanesulfonic anhydride.

在本发明的一些实施方案中，R3为对甲苯磺酰基，所述磺酰化的试剂为对甲苯磺酰氯或对甲磺酸酐。In some embodiments of the present invention, R 3 is p-toluenesulfonyl, and the sulfonylation reagent is p-toluenesulfonyl chloride or p-methanesulfonic anhydride.

在本发明的一些实施方案中，所述磺酰化的试剂用量为化合物Ⅱ的1.0～1.5摩尔当量，优选为1.0～1.1摩尔当量；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;

在本发明的一些实施方案中，所述胺化剂为氨水；所述氨水的用量为化合物Ⅳ的1～5摩尔当量，优选为1～2摩尔当量。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.

在本发明的一些实施方案中，所述胺化剂为苯甲胺；所述苯甲胺的用量为化合物Ⅳ的1～5摩尔当量，优选为1～2摩尔当量。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.

在本发明的一些实施方案中，所述氨解反应的温度为0～5℃。In some embodiments of the present invention, the temperature of the aminolysis reaction is 0-5°C.

在本发明的一些实施方案中，所述化合物II的制备方法包含以下步骤：In some embodiments of the present invention, the method for preparing compound II comprises the following steps:

步骤a)有机溶剂中，化合物Ⅰ在LiAlD4作用下，生成化合物Ⅱ，R2为任选取代的-C1-C6烷基，所述取代的取代基为H、苯基；优选地，R2为C1-C3烷基或苄基；更优选地，R2为甲基或乙基，
Step a) Compound I is reacted with LiAlD 4 in an organic solvent to generate Compound II, wherein R 2 is an optionally substituted -C 1 -C 6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R 2 is a C 1 -C 3 alkyl group or a benzyl group; more preferably, R 2 is a methyl group or an ethyl group.

在本发明的一些实施方案中，化合物Ⅰ和LiAlD4的摩尔比为1:0.4～1，例如1:0.4、1:0.5、1:0.6、1:0.7、1:0.8或其间任意数值或范围。In some embodiments of the present invention, the molar ratio of compound I to LiAlD 4 is 1:0.4-1, such as 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or any value or range therebetween.

在本发明的一些实施方案中，所述化合物II的制备方法包含以下步骤：In some embodiments of the present invention, the method for preparing compound II comprises the following steps:

步骤b)化合物Ⅰ在金属试剂与氘代醇的作用下，生成化合物Ⅱ，R2为任选取代的-C1-C6烷基，所述取代的取代基为H、苯基；优选地，R2为C1-C3烷基或苄基；更优选地，R2为甲基或乙基，
Step b) Compound I is reacted with a metal reagent and a deuterated alcohol to generate Compound II, wherein R 2 is an optionally substituted -C 1 -C 6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R 2 is a C 1 -C 3 alkyl group or a benzyl group; more preferably, R 2 is a methyl group or an ethyl group.

在本发明的一些实施方案中，所述金属试剂为Na或K，所述氘代醇试剂为CH3OD或CH3CH2OD；所述化合物Ⅰ与金属试剂的摩尔比为1：0.5～5，优选为1：1～5，例如1:1、1:2、1:3、1:4、1:5或其间任意数值或范围；所述化合物Ⅰ与氘代醇试剂的摩尔比为1：0.5～5，优选为1：1～5，例如1:1、1:2、1:3、1:4、1:5或其间任意数值或范围。In some embodiments of the present invention, the metal reagent is Na or K, and the deuterated alcohol reagent is CH 3 OD or CH 3 CH 2 OD; 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.

在本发明的一些实施方案中，所述有机溶剂为四氢呋喃。In some embodiments of the present invention, the organic solvent is tetrahydrofuran.

在本发明的一些实施方案中，化合物Ⅰ在所述有机溶剂中的浓度为0.3～1.8mol/L。In some embodiments of the present invention, the concentration of Compound I in the organic solvent is 0.3-1.8 mol/L.

本发明第四方面提供一种化合物V-2的盐酸盐的制备方法，包括以下步骤：The fourth aspect of the present invention provides a method for preparing the hydrochloride of compound V-2, comprising the following steps:

步骤d：化合物Ⅲ-1以水合肼肼解，得到化合物Ⅴ-1：Step d: Compound III-1 is hydrazine-hydrated to give compound V-1:

步骤e：将化合物V-1溶于甲醇，加入K2CO3，室温下搅拌，反应结束后，过滤，得到的滤液中加入甲苯，得到化合物V-2的有机溶液；Step e: dissolving compound V-1 in methanol, adding K 2 CO 3 , stirring at room temperature, filtering after the reaction, adding toluene to the obtained filtrate to obtain an organic solution of compound V-2;

步骤f：将化合物V-2的有机溶液常压蒸馏，收集馏出液，酸化，得到化合物V-2的盐，
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.

优选地，化合物III-1通过步骤d、e、f一锅法制备得到化合物V-2的盐酸盐。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.

本发明第五方面提供一种化合物V-2的盐酸盐的制备方法，包括以下步骤：The fifth aspect of the present invention provides a method for preparing the hydrochloride of compound V-2, comprising the following steps:

步骤g：化合物Ⅱ-1磺酰化后得到化合物Ⅳ-1，Step g: Compound II-1 is sulfonylated to obtain compound IV-1.

步骤h：化合物Ⅳ-1再与胺化剂进行氨解反应得到化合物Ⅴ-1，Step h: Compound IV-1 is then subjected to an ammonolysis reaction with an aminating agent to obtain compound V-1.

步骤e：将化合物V-1溶于甲醇，加入K2CO3，室温下搅拌，反应结束后，过滤，得到的滤液中加入甲苯，得到化合物V-2的有机溶液；Step e: dissolving compound V-1 in methanol, adding K 2 CO 3 , stirring at room temperature, filtering after the reaction, adding toluene to the obtained filtrate to obtain an organic solution of compound V-2;

步骤f：将化合物V-2的有机溶液常压蒸馏，收集馏出液，酸化，得到化合物V-2的盐，

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.

其中，R3为甲磺酰基或对甲苯磺酰基；Wherein, R 3 is methanesulfonyl or p-toluenesulfonyl;

优选地，化合物II-1通过步骤g、h、e、f一锅法制备得到化合物V-2的盐酸盐。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.

本发明另一方面提供了一种化合物Ⅰ，其中R1为三甲基锗基，R2为-H、-C1-C3烷基或苄基，
Another aspect of the present invention provides a compound I, wherein R 1 is trimethylgermanyl, R 2 is -H, -C 1 -C 3 alkyl or benzyl,

本发明另一方面提供了一种化合物Ⅱ-2，
Another aspect of the present invention provides a compound II-2,

本发明另一方面提供了化合物Ⅲ-2、化合物III-3、化合物III-4，
Another aspect of the present invention provides compound III-2, compound III-3, compound III-4,

本发明再一方面提供了化合物Ⅳ-2、化合物IV-3、化合物IV-4，
In another aspect, the present invention provides compound IV-2, compound IV-3, and compound IV-4.

本发明再一方面提供了化合物Ⅴ-3、化合物V-4，
In another aspect, the present invention provides compound V-3 and compound V-4.

本发明再一方面提供了所述化合物Ⅰ、化合物Ⅱ-2、化合物Ⅲ-2、化合物III-3、化合物III-4、化合物Ⅳ-2、化合物IV-3、化合物IV-4、化合物Ⅴ-3或化合物V-4在制备氘代炔丙胺及其盐酸盐中的用途。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.

本发明制备得到的氘代炔丙胺可以通过本领域常规方法进一步制备成氘代炔丙胺盐酸盐。The deuterated propargylamine prepared in the present invention can be further prepared into deuterated propargylamine hydrochloride by conventional methods in the art.

有益效果：Beneficial effects:

1)本发明在的制备过程中，从化合物I-1出发，经过a、c～f共5步反应，以总收率61.3％得到1,1-二氘代-丙-2-炔-1-胺(1,1-d2-prop-2-yn-1-amine，化合物V-2)的盐酸盐，和现有技术相比，显著提高了反应的收率；并且本发明无需使用昂贵的NHBocPO(OEt)2，无需两轮Boc保护和脱保护的步骤，提高了原子经济性，简化了反应步骤，反应试剂价格更低，降低了生产成本，更有利于工业化生产。1) In the preparation process of the present invention, starting from compound I-1, after a, c to f, a total of 5 steps of reaction, 1,1-dideutero-prop-2-yn-1-amine (1,1-d2-prop-2-yn-1-amine, compound V-2) hydrochloride is obtained with a total yield of 61.3%, which significantly improves the yield of the reaction compared with the prior art; and the present invention does not need to use expensive NHBocPO(OEt) 2 , does not need two rounds of Boc protection and deprotection steps, improves atom economy, simplifies reaction steps, lowers the price of reaction reagents, reduces production costs, and is more conducive to industrial production.

2)在氘代炔丙胺(化合物V)的后处理过程中采用常压蒸馏，收集馏出液，无需在反应中引入保护基Boc，简化了制备步骤，后处理更为简单。2) In the post-treatment process of deuterated propargylamine (compound V), atmospheric distillation is adopted to collect the distillate, and there is no need to introduce the protecting group Boc in the reaction, which simplifies the preparation steps and makes the post-treatment simpler.

3)引入氘原子的反应中，优选氘化乙醇作为氘化试剂，可避免LiAlD4易燃、成本高、反应温度低、对设备要求高的缺点。3) In the reaction of introducing deuterium atoms, deuterated ethanol is preferably used as the deuteration reagent, which can avoid the shortcomings of LiAlD 4 , such as flammability, high cost, low reaction temperature and high equipment requirements.

具体实施方式DETAILED DESCRIPTION

术语和说明：Terms and description:

本发明中的术语，如无特别说明，具有如下含义：The terms in this invention, unless otherwise specified, have the following meanings:

本发明中术语“eq”是“equivalent”的缩写，指当量，是用作物质相互作用时的物质的量比值的称谓。The term "eq" in the present invention is an abbreviation of "equivalent", which means equivalent, and is a term used for the ratio of the amounts of substances when substances interact with each other.

氘代炔丙胺指炔丙胺上的一个或多个H被氘取代的化合物。包括但不限于：
Deuterated propargylamine refers to propargylamine Compounds in which one or more H on the molecule is replaced by deuterium. Including but not limited to:

本发明中术语“磺酰基”包括但不限于甲磺酰基、乙磺酰基、苯磺酰基或对甲苯磺酰基、三甲基苯磺酰基或硝基苯磺酰基。The term "sulfonyl" in the present invention includes, but is not limited to, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or p-toluenesulfonyl, trimethylbenzenesulfonyl or nitrobenzenesulfonyl.

本发明中术语“亲核试剂”包括但不限于偶氮二羧酸二异丙酯、偶氮二甲酸二乙酯、偶氮二甲酸二甲酯、偶氮二甲酸二叔丁酯或偶氮二甲酸二苄酯。 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.

本发明中术语“氨解反应”指含各种不同官能团的有机化合物在胺化剂的作用下生成胺类化合物的过程；胺化剂包括液氨、氨水、尿素、铵盐及有机胺。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; the aminating agent includes liquid ammonia, ammonia water, urea, ammonium salts and organic amines.

本发明中术语“-C1-C6烷基”包括包含1至6个碳原子的烷基,例如：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、仲戊基或正己基等；术语“-C1-C3烷基”包括包含1至3个碳原子的烷基,具体指甲基、乙基、正丙基及异丙基。In the present invention, the term "-C 1 -C 6 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 "-C 1 -C 3 alkyl" includes alkyl groups containing 1 to 3 carbon atoms, specifically methyl, ethyl, n-propyl and isopropyl.

本发明中术语“取代的”是指指定原子上的任何一个或多个氢原子被选自指定组的取代基取代,取代的结果是产生稳定的化合物。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 a designated group, and the result of the substitution is to produce a stable compound.

本发明中术语“有机溶剂”包括但不限于四氢呋喃、乙酸乙酯、二氯甲烷、甲醇、乙醇中任意一种或多种的组合。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.

本发明中术语“蒸馏”包括但不限于简单蒸馏、精馏、特殊精馏等。The term "distillation" in the present invention includes but is not limited to simple distillation, rectification, special distillation, etc.

本发明中“室温”指20～30℃。In the present invention, "room temperature" refers to 20 to 30°C.

本发明中“冰水浴”指-5～5℃。In the present invention, "ice water bath" refers to -5 to 5°C.

本发明中，氢质子核磁共振谱(1H NMR)通过Bruker AVANCE 400在400MHz测得。In the present invention, hydrogen proton nuclear magnetic resonance spectrum ( 1 H NMR) was measured by Bruker AVANCE 400 at 400 MHz.

本发明中，质谱(LC-MS)通过Agilent HPLC 1260InfinityⅡ及G6125C LC/MSD测得。In the present invention, mass spectrometry (LC-MS) was measured by Agilent HPLC 1260 InfinityⅡ and G6125C LC/MSD.

本发明部分缩写的含义：
Boc  叔丁氧羰基
TMS  三甲基硅基
DIAD  偶氮二甲酸二异丙酯
DEAD  偶氮二甲酸二乙酯
DIPEA  N,N-二异丙基乙胺
THF  四氢呋喃
LiAlD4  氘代氢化铝锂
Ph3P  三苯基膦
MsCl  甲基磺酰氯
TsCl  对甲苯磺酰氯
DCM  二氯甲烷The meanings of some abbreviations in this invention are:
Boc tert-Butyloxycarbonyl
TMS Trimethylsilyl
DIAD Diisopropyl azodicarboxylate
DEAD Diethyl azodicarboxylate
DIPEA N,N-Diisopropylethylamine
THF Tetrahydrofuran
LiAlD 4 -deuterated lithium aluminum hydride
Ph 3 P Triphenylphosphine
MsCl Methanesulfonyl chloride
TsCl p-Toluenesulfonyl chloride
DCM Dichloromethane

如无特别说明，本发明中，醇类溶剂为C1-C6烷基醇，优选地选自甲醇、乙醇、丙醇、异丙醇中的一种或多种，更优选地为甲醇或乙醇。If not otherwise specified, in the present invention, the alcohol solvent is a C 1 -C 6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, isopropanol, more preferably methanol or ethanol.

如无特别说明，本发明中，芳香烃类溶剂为苯、甲苯、二甲苯中的一种或多种，优选地为甲苯。 If not otherwise specified, in the present invention, the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene, preferably toluene.

如无特别说明，本发明中，酯类溶剂为乙酸乙酯或乙酸甲酯，优选地为乙酸乙酯。If not otherwise specified, in the present invention, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate.

为了使本发明所解决的技术问题、技术方案及有益效果更佳清楚明白，以下结合具体实施例，对本发明作进一步的说明，但应理解，实施例并非限制本申请的范围。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, but it should be understood that the embodiments do not limit the scope of the present application.

本发明中的试剂与溶剂通过商业来源购买，除非本申请另有说明，所有试剂与溶剂无需处理可供直接使用。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.

本发明中所用水合肼包括但不限于水合肼的水溶液，在一些实施方案中，溶液浓度为80％。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%.

实施例1：步骤a
Example 1: Step a

将LiAlD4(8.0g，0.54eq)加入瓶中，加入无水THF(600mL)，搅拌溶解，用干冰乙醇浴将反应液温度降至-70～-60℃，氮气置换三次，继续搅拌30分钟，控温滴加3-(三甲基硅基)丙炔酸乙酯(60g，0.35mol，1eq)的THF(200mL)溶液，约滴加1.5h，加毕保温反应1.5h，然后缓慢升温约1h至室温，在室温下继续反应至原料基本反应完全，反应液降温至0℃左右，滴加1N HCl(180mL)溶液淬灭反应，再加入水(600mL)和DCM(600mL)搅拌10min，用1N HCl(420mL)溶液调节体系pH至3～4左右，静置分层，水相用DCM(600ml)萃取1次，合并有机相，水洗2次，无水Na2SO4干燥，过滤，浓缩得到化合物II-1(110g)直接用于下一步反应，收率以100％计算。LiAlD 4 (8.0 g, 0.54 eq) was added to a bottle, and anhydrous THF (600 mL) was added, stirred to dissolve, and the reaction liquid temperature was lowered to -70 to -60°C with a dry ice ethanol bath, and nitrogen was replaced three times, and stirring was continued for 30 minutes. A solution of 3-(trimethylsilyl)propiolic acid ethyl ester (60 g, 0.35 mol, 1 eq) in THF (200 mL) was added dropwise at a 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 liquid was cooled to about 0°C, and a 1N HCl (180 mL) solution was added dropwise to quench the reaction. 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 layers were separated by standing. The aqueous phase was extracted once with DCM (600 ml), and 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%.

1H NMR(400MHz,CDCl3):δ＝0.17(9H)。 1 H NMR (400MHz, CDCl 3 ): δ = 0.17 (9H).

实施例2：步骤a
Example 2: Step a

将LiAlD4(0.2g，0.8eq)加入瓶中，加入无水THF(20mL)，搅拌溶解，用干冰乙醇浴将反应液温度降至-70～-60℃，氮气置换三次，继续搅拌30分钟，控温滴加3-(三甲基硅基)丙炔酸乙酯(1.0g，5.9mmol，1eq)的THF(10mL)溶液，约滴加0.5h，加毕保温反应1.5h，然后缓慢升温约1h至室温，在室温下继续反应至原料基本反应完全，反应液降温至0℃左右，滴加1N HCl(20mL)溶液淬灭反应，再加入水(20mL)和DCM(10mL)搅拌10min，用1N HCl(20mL)溶液调节体系pH至3～4左右，静置分层，水相用DCM(10ml) 萃取1次，合并有机相，水洗2次，无水Na2SO4干燥，过滤，浓缩得到II-1(0.9g)，直接用于下一步反应，收率以100％计算。LiAlD 4 (0.2 g, 0.8 eq) was added to a bottle, and anhydrous THF (20 mL) was added, stirred and dissolved, and the reaction liquid temperature was lowered to -70 to -60 ° C with a dry ice ethanol bath, and nitrogen was replaced three times, and stirring was continued for 30 minutes. A THF (10 mL) solution of 3-(trimethylsilyl)propiolic acid ethyl ester (1.0 g, 5.9 mmol, 1 eq) was added dropwise at a temperature control, and the addition was about 0.5 h. After the addition was completed, the reaction 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 liquid was cooled to about 0 ° C, and 1N HCl (20 mL) solution was added dropwise to quench the reaction. 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 Na 2 SO 4 , filter, and concentrate to obtain II-1 (0.9 g), which is directly used in the next reaction. The yield is calculated as 100%.

实施例3：步骤b
Example 3: Step b

将3-(三甲基硅基)丙炔酸乙酯(60g，0.35mol，1eq)加入瓶中，依次加入无水正庚烷(1L)，EtOD(74.15g，1.58mol，4.5eq)，冰水浴冷却，再加入钠分散体(质量分数40％，90.56g，1.58mol，4.5eq)，氮气保护下搅拌反应，反应温度缓慢升至室温，反应完全后，滴加1N HCl(1.6L)溶液淬灭反应，静置分层，有机相用无水Na2SO4干燥，过滤，浓缩得到II-1(45.6g)，直接用于下一步反应，收率以100％计算。Ethyl 3-(trimethylsilyl)propiolate (60 g, 0.35 mol, 1 eq) was added to a bottle, and anhydrous n-heptane (1 L) and EtOD (74.15 g, 1.58 mol, 4.5 eq) were added in sequence. The mixture was cooled in an ice-water bath, and sodium dispersion (mass fraction 40%, 90.56 g, 1.58 mol, 4.5 eq) was added. The mixture 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. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain II-1 (45.6 g), which was directly used in the next step reaction. The yield was calculated as 100%.

实施例4：步骤c
Example 4: Step c

将化合物II-1(45.9g，0.35mol，1eq)加入瓶中，加入无水THF(600mL)搅拌溶清，分别加入Ph3P(101.7g，1.1eq)和邻苯二甲酰亚胺(57g，1.1eq)，搅拌溶解，反应液降温至0℃左右，滴加DIAD(78.4g，1.1eq)并控制内温不超过5℃，滴加完毕，保温反应4h，再升至室温反应18h，浓缩反应溶剂，粗品经柱层析纯化，得到化合物III-1 65.3g，收率71.3％。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. Ph 3 P (101.7 g, 1.1 eq) and phthalimide (57 g, 1.1 eq) were added respectively and stirred to dissolve. The reaction solution was cooled to about 0°C, DIAD (78.4 g, 1.1 eq) was added dropwise and the internal temperature was controlled not to exceed 5°C. After the addition was completed, the reaction was kept warm for 4 h, and then the temperature was raised to room temperature for 18 h. 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%.

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

实施例5：步骤c
Example 5: Step c

将化合物II-2(58.08g，1mol，1eq)加入瓶中，加入无水THF(1.5L)搅拌溶清，分 别加入Ph3P(288.52g，1.1eq)和邻苯二甲酰亚胺(161.84g，1.1eq)，搅拌溶解，反应液降温至0℃左右，滴加DIAD(222.42g，1.1eq)并控制内温不超过5℃，滴加完毕，保温反应4h，再升至室温反应18h，浓缩反应溶剂，粗品经柱层析纯化，得到化合物III-2 149.75g，收率80％。Add compound II-2 (58.08 g, 1 mol, 1 eq) into a bottle, add anhydrous THF (1.5 L) and stir to dissolve. Ph 3 P (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 mixture was kept warm for 4 h and then heated to room temperature for 18 h. 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%.

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

实施例6：步骤d～f
Example 6: Steps d to f

步骤d：将化合物III-1(72g，0.28mol，1eq)加入瓶中，加入甲醇(800mL)搅拌溶解，缓慢滴加水合肼(35mL，3eq)溶液，约1h滴加完毕，继续搅拌约20h，过滤，滤饼用乙酸乙酯(300mL)淋洗，滤液即化合物V-1的有机溶液。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, the addition is completed in about 1 hour, and stirring is continued for about 20 hours. Filter, rinse the filter cake with ethyl acetate (300 mL), and the filtrate is the organic solution of compound V-1.

步骤e：浓缩滤液得化合物V-1。加入甲醇(210mL)至瓶中，搅拌溶清，加入无水K2CO3(55g，1.5eq)，室温搅拌3h，过滤，向滤液中加入100mL甲苯，得化合物V-2的有机溶液。Step e: Concentrate the filtrate to obtain compound V-1. Add methanol (210 mL) to the bottle, stir to dissolve, add anhydrous K 2 CO 3 (55 g, 1.5 eq), stir at room temperature for 3 h, filter, add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.

步骤f：常压蒸馏，收集馏出液。将所得馏出液冰水浴冷却，滴加HCl-乙酸乙酯溶液(2M，200mL)，缓慢析出固体，搅拌约2h，浓缩除去溶剂，再加入正庚烷(300mL)，搅拌约1h，过滤，滤饼用正庚烷(50mL)淋洗，滤饼烘干得到化合物V-2的盐酸盐22.4g，收率86％。Step f: atmospheric distillation, collect the distillate. The obtained distillate was cooled in an ice-water bath, HCl-ethyl acetate solution (2M, 200 mL) was added dropwise, solids were slowly precipitated, stirred for about 2 h, concentrated to remove the solvent, and then n-heptane (300 mL) was added, stirred for about 1 h, filtered, the filter cake was rinsed with n-heptane (50 mL), and the filter cake was dried to obtain 22.4 g of the hydrochloride of compound V-2, with a yield of 86%.

1H NMR(400MHz,DMSO-d6):δ＝8.55(3H),3.58(1H)。 1 H NMR (400MHz, DMSO-d 6 ): δ = 8.55 (3H), 3.58 (1H).

实施例7：步骤d，f
Example 7: Steps d, f

步骤d：将化合物III-2(46.80g，0.25mol，1eq)加入瓶中，加入甲醇(800mL)搅拌溶解，缓慢滴加水合肼(32mL，3eq)溶液，约1h滴加完毕，继续搅拌约20h，过滤，滤饼用乙酸乙酯(300mL)淋洗，滤液即化合物V-2的有机溶液。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, the addition is completed in about 1 hour, and stirring is continued for about 20 hours. Filter, rinse the filter cake with ethyl acetate (300 mL), and the filtrate is the organic solution of compound V-2.

步骤f：常压精馏，收集馏出液，得化合物V-2 14.28g。将所得化合物V-2溶于乙酸乙酯(100mL)，冰水浴冷却，滴加HCl乙酸乙酯溶液(2M，200mL)，缓慢析出固体，搅拌约2h， 浓缩除去溶剂，再加入正庚烷(300mL)，搅拌约1h，过滤，滤饼用正庚烷(50mL)淋洗，滤饼烘干得到化合物V-2的盐酸盐23.40g，收率90％。Step f: Normal pressure distillation, collect the distillate, and obtain 14.28 g of compound V-2. Dissolve the obtained compound V-2 in ethyl acetate (100 mL), cool in an ice-water bath, add HCl ethyl acetate solution (2M, 200 mL) dropwise, slowly precipitate solid, stir for about 2 hours, The solvent was removed by concentration, and n-heptane (300 mL) was added, stirred for about 1 h, filtered, and the filter cake was rinsed with n-heptane (50 mL). The filter cake was dried to obtain 23.40 g of the hydrochloride of compound V-2 with a yield of 90%.

实施例8：步骤g
Example 8: Step g

步骤g：将化合物II-1(13.03g，0.1mol，1eq)加入瓶中，分别加入二氯甲烷(200mL)，三乙胺(15.18g，1.5eq)，搅拌溶解，反应液降温至0℃左右，滴加MsCl(12.60g，1.1eq)并控制内温不超过5℃，滴加完毕后保温反应2h。Step g: Add compound II-1 (13.03 g, 0.1 mol, 1 eq) into 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 and control the internal temperature not to exceed 5°C. After the addition is complete, keep the reaction warm for 2 hours.

步骤h:再向反应液中缓慢滴加氨水(13.60g，2eq)溶液，滴加完毕后继续搅拌约2h。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.

步骤e：浓缩除去溶剂，加入甲醇(150mL)至瓶中，搅拌溶清，加入无水K2CO3(20.73g，1.5eq)，室温搅拌3h，过滤，向滤液中加入100mL甲苯，得化合物V-2的有机溶液。Step e: Concentrate to remove the solvent, add methanol (150 mL) to the bottle, stir to dissolve, add anhydrous K 2 CO 3 (20.73 g, 1.5 eq), stir at room temperature for 3 h, filter, add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.

步骤f：常压蒸馏，收集馏出液，将所得馏出液冰水浴冷却，滴加HCl乙酸乙酯溶液(2M，100mL)，缓慢析出固体，搅拌约2h，浓缩除去溶剂，再加入正庚烷(100mL)，搅拌约1h，过滤，滤饼用正庚烷(20mL)淋洗，滤饼烘干得到化合物V-2的盐酸盐3.26g，收率35％。Step f: distill under normal pressure, collect the distillate, cool the obtained distillate in an ice-water bath, add HCl ethyl acetate solution (2M, 100 mL) dropwise, slowly precipitate solid, stir for about 2 hours, concentrate to remove the solvent, add n-heptane (100 mL), stir for about 1 hour, filter, rinse the filter cake with n-heptane (20 mL), and dry the filter cake to obtain 3.26 g of the hydrochloride salt of compound V-2, with a yield of 35%.

实施例9
Embodiment 9

步骤g：将化合物II-1(13.03g，0.1mol，1eq)加入瓶中，分别加入二氯甲烷(200mL)，三乙胺(15.18g，1.5eq)，搅拌溶解，反应液降温至0℃左右，滴加TsCl(20.97g，1.1eq)二氯甲烷溶液并控制内温不超过5℃，滴加完毕后保温反应2h。Step g: Add compound II-1 (13.03 g, 0.1 mol, 1 eq) into 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 and control the internal temperature not to exceed 5°C. After the addition is complete, keep the reaction warm for 2 hours.

步骤h：再向反应液中缓慢滴加氨水(13.60g，2eq)溶液，滴加完毕后继续搅拌约2h。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.

步骤e：浓缩除去溶剂，加入甲醇(150mL)至瓶中，搅拌溶清，加入无水K2CO3(20.73g，1.5eq)，室温搅拌3h，过滤，向滤液中加入100mL甲苯，得化合物V-2的有机溶液。Step e: Concentrate to remove the solvent, add methanol (150 mL) to the bottle, stir to dissolve, add anhydrous K 2 CO 3 (20.73 g, 1.5 eq), stir at room temperature for 3 h, filter, add 100 mL of toluene to the filtrate to obtain an organic solution of compound V-2.

步骤f：常压蒸馏，收集馏出液。将所得馏出液冰水浴冷却，滴加HCl乙酸乙酯溶液(2M，100mL)，缓慢析出固体，搅拌约2h，浓缩除去溶剂，再加入正庚烷(100mL)，搅拌约1h，过滤，滤饼用正庚烷(20mL)淋洗，滤饼烘干得到化合物V-2的盐酸盐2.58g，收率28％。Step f: atmospheric distillation, collect the distillate. The obtained distillate was cooled in an ice-water bath, HCl ethyl acetate solution (2M, 100 mL) was added dropwise, solids were slowly precipitated, stirred for about 2 hours, concentrated to remove the solvent, and then n-heptane (100 mL) was added, stirred for about 1 hour, filtered, the filter cake was rinsed with n-heptane (20 mL), and the filter cake was dried to obtain 2.58 g of the hydrochloride of compound V-2, with a yield of 28%.

实施例10
Example 10

步骤i：将N-丙炔基邻苯二甲酰亚胺(10g，54mmol，1eq)加入瓶中，加入氘代甲醇(100mL)和重水(100mL)搅拌溶解，再加入NaOD溶液(5.4mmol，0.1eq)，搅拌约24h，加入稀盐酸溶液(约6mmol，0.11eq)，继续搅拌约15分钟，浓缩反应液得化合物III-3。Step i: Add N-propynylphthalimide (10 g, 54 mmol, 1 eq) into 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.

步骤d：向上述固体中加入甲醇(100mL)，缓慢滴加水合肼(8mL，3eq)溶液，约1h滴加完毕，继续搅拌约20h，过滤，滤饼用乙酸乙酯(100mL)淋洗，滤液即化合物V-3的有机溶液。Step d: Add methanol (100 mL) to the above solid, slowly add hydrazine hydrate (8 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 (100 mL). The filtrate is the organic solution of compound V-3.

步骤f：常压精馏，收集馏出液，得化合物V-3 2.88g。将所得化合物V-3溶于乙酸乙酯(20mL)，冰水浴冷却，滴加HCl乙酸乙酯溶液(2M，25mL)，缓慢析出固体，搅拌约2h，浓缩除去溶剂，再加入正庚烷(50mL)，搅拌约1h，过滤，滤饼用正庚烷(50mL)淋洗，滤饼烘干得到化合物V-3的盐酸盐4.70g，收率92％。Step f: distillation at normal pressure, collect the distillate, and 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 solids. 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, filtered, and the filter cake was rinsed with n-heptane (50 mL). The filter cake was dried to obtain 4.70 g of the hydrochloride of compound V-3, with a yield of 92%.

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

Claims (20)

一种化合物Ⅴ的盐的制备方法，其特征在于，包括以下步骤f：A method for preparing a salt of compound V, characterized in that it comprises the following steps f: 步骤f：将化合物V的有机溶液常压蒸馏，收集馏出液，酸化，得到化合物V的盐，所述化合物V的有机溶液的选自醇类溶剂、酯类溶剂或芳香烃类溶剂中的一种或多种，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, 其中R1为-H、-D、三甲基硅基或三甲基锗基，优选地R1为-H、-D。 Wherein R 1 is -H, -D, trimethylsilyl or trimethylgermanyl, preferably R 1 is -H or -D. 根据权利要求1所述的制备方法，其特征在于，所述化合物V的盐为化合物V的无机酸盐或有机酸盐，优选地为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐，更优选地为盐酸盐；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; 优选地所述酸化为：将馏出液冷却至0～10℃，滴加酸的乙酸乙酯溶液，缓慢析出固体，更优选地，所述酸化后还包含加入正庚烷重结晶的步骤；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; 优选地所述酸为盐酸、氢溴酸、硫酸、磷酸，更优选地为盐酸；Preferably, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, more preferably hydrochloric acid; 优选地，所述醇类溶剂为C1-C6烷基醇，优选地选自甲醇、乙醇、丙醇、异丙醇中的一种或多种，更优选地为甲醇或乙醇。Preferably, the alcohol solvent is a C 1 -C 6 alkyl alcohol, preferably one or more selected from methanol, ethanol, propanol, isopropanol, more preferably methanol or ethanol. 优选地，所述芳香烃类溶剂选自苯、甲苯、二甲苯中的一种或多种，更优选地为甲苯。Preferably, the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene and xylene, more preferably toluene. 优选地，所述酯类溶剂为乙酸乙酯或乙酸甲酯，更优选地为乙酸乙酯。Preferably, the ester solvent is ethyl acetate or methyl acetate, more preferably ethyl acetate. 根据权利要求1所述的制备方法，其特征在于，所述化合物V的制备方法，包含以下步骤d：The preparation method according to claim 1, characterized in that the preparation method of compound V comprises the following steps d: 步骤d：化合物Ⅲ肼解，得到化合物ⅤStep d: Compound III is subjected to hydrazinolysis to obtain compound V 其中R1为-H、-D、三甲基硅基或三甲基锗基。 Wherein R 1 is -H, -D, trimethylsilyl or trimethylgermanyl. 根据权利要求3所述的制备方法，其特征在于，所述化合物V为化合物V-2，所述化合物V-2的有机溶液通过以下步骤e制备得到：The preparation method according to claim 3, characterized in that the compound V is compound V-2, and the organic solution of the compound V-2 is prepared by the following steps e: 步骤e：将化合物V-1溶于醇类溶剂，加入碱，室温下搅拌，反应结束后，过滤，得到的滤液中加入芳香烃类溶剂，即为所述化合物V-2的有机溶液，
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.
进一步地，所述醇类溶剂和所述芳香烃类溶剂的体积比为1:0.2～2，优选为1:0.4～1；Furthermore, the volume ratio of the alcohol solvent to the aromatic hydrocarbon solvent is 1:0.2-2, preferably 1:0.4-1; 所述碱为碳酸钾、碳酸钠、氢氧化钠、氢氧化钾中的一种或多种；The base is one or more of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; 所述碱与化合物V-1的摩尔比为1:1～3；The molar ratio of the base to the compound V-1 is 1:1 to 3; 所述醇类溶剂为甲醇、乙醇、丙醇、异丙醇中的一种或多种，优选地为甲醇或乙醇；The alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol; 所述芳香烃类溶剂选自苯、甲苯、二甲苯中的一种或多种，优选地为甲苯。The aromatic hydrocarbon solvent is selected from one or more of benzene, toluene and xylene, preferably toluene. 一种化合物Ⅴ的制备方法，其特征在于，包含以下步骤d：A method for preparing compound V, characterized in that it comprises the following steps d: 步骤d：化合物Ⅲ肼解，得到化合物Ⅴ，其中R1为-H、-D或三甲基锗基，
Step d: Compound III is subjected to hydrazinolysis to obtain compound V, wherein R1 is -H, -D or trimethylgermanium,
根据权利要求3或5所述的制备方法，其特征在于，步骤d中，所述肼解的试剂为水合肼；The preparation method according to claim 3 or 5, characterized in that in step d, the reagent for hydrazine hydrolysis is hydrazine hydrate; 步骤d中，所述水合肼的用量为化合物Ⅲ的2～5摩尔当量，优选为3摩尔当量；In step d, the amount of hydrazine hydrate used is 2 to 5 molar equivalents of compound III, preferably 3 molar equivalents; 步骤d中，所述肼解的反应温度为0～30℃；In step d, the reaction temperature of the hydrazinolysis is 0 to 30°C; 步骤d中，将化合物III溶解于醇类溶剂中，缓慢滴加水合肼溶液，滴加完毕继续搅拌反应，过滤，滤饼用酯类溶剂淋洗，得到化合物Ⅴ的有机溶液。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. 进一步地，步骤d中，所述醇类溶剂为甲醇、乙醇、丙醇、异丙醇中的一种或多种，优选地为甲醇或乙醇，更优选地为甲醇；Further, in step d, the alcohol solvent is one or more of methanol, ethanol, propanol, and isopropanol, preferably methanol or ethanol, more preferably methanol; 步骤d中，所述酯类溶剂为乙酸乙酯或乙酸甲酯，优选地为乙酸乙酯。In step d, the ester solvent is ethyl acetate or methyl acetate, preferably ethyl acetate. 根据权利要求6所述的制备方法，其特征在于，所述化合物III的制备包含以下步骤c：The preparation method according to claim 6, characterized in that the preparation of compound III comprises the following steps c: 步骤c：有机溶剂中，化合物II在磷试剂和亲核试剂的存在下与邻苯二甲酰亚胺反应，得到化合物III，
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.
进一步地，所述磷试剂为烷基磷试剂或芳基磷试剂，优选地为三丁基磷或三苯基膦；Further, the phosphorus reagent is an alkyl phosphorus reagent or an aryl phosphorus reagent, preferably tributylphosphine or triphenylphosphine; 所述亲核试剂为偶氮二羧酸二异丙酯、偶氮二甲酸二乙酯、偶氮二甲酸二甲酯、偶氮二甲酸二叔丁酯、偶氮二甲酸二苄酯中的一种或多种，优选地为偶氮二甲酸二异丙酯；The nucleophilic agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, and dibenzyl azodicarboxylate, preferably diisopropyl azodicarboxylate; 所述磷试剂的用量为化合物Ⅱ的1～1.5摩尔当量，优选为1.0～1.1摩尔当量；所述亲核试剂的用量为化合物Ⅱ的1～1.5摩尔当量，优选为1.0～1.1摩尔当量；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; 优选地，所述步骤c包含以下步骤：将化合物II、有机磷试剂和邻苯二甲酰亚胺溶解于有机溶剂中，降低反应液温度至-5℃～0℃，滴加亲核试剂，并控制内温不超过5℃，滴加完毕，保温反应，再升至室温反应，待反应结束后浓缩反应溶剂，纯化，得到化合物III；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; 优选地，所述有机溶剂为THF，化合物II和有机溶剂的摩尔体积比为0.1～1mol/L,更优选0.5～0.6mol/L。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. 根据权利要求6所述的制备方法，其特征在于，所述化合物III为化合物III-3，其制备包含以下步骤i：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: 步骤i：N-丙炔基邻苯二甲酰亚胺在碱的存在下，在重水中与氘代试剂反应，得到化合物III，
Step i: N-propynylphthalimide reacts with a deuterated reagent in heavy water in the presence of a base to obtain compound III.
优选地，所述氘代试剂为氘代醇类试剂，优选地为氘代甲醇；Preferably, the deuterated reagent is a deuterated alcohol reagent, preferably deuterated methanol; 所述氘代试剂和重水的体积比为1:1～1:2；The volume ratio of the deuterated reagent to heavy water is 1:1 to 1:2; 所述碱为NaOD或KOD；The base is NaOD or KOD; 所述碱的用量为N-丙炔基邻苯二甲酰亚胺的0.05～2摩尔当量，优选地为0.05～0.20摩尔当量，所述N-丙炔基邻苯二甲酰亚胺和氘代试剂的重量体积比为1:5～1:20g/mL，优选1:5～1:10g/mL。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. 一种化合物V的制备方法，其特征在于，包含以下步骤：A method for preparing compound V, characterized in that it comprises the following steps: 步骤g)化合物Ⅱ磺酰化后得到化合物Ⅳ，Step g) Compound II is sulfonylated to obtain compound IV, 步骤h)化合物Ⅳ再与胺化剂进行氨解反应得到化合物Ⅴ， Step h) Compound IV is then subjected to an ammonolysis reaction with an aminating agent to obtain compound V, 其中R3为任选取代的磺酰基，所述取代的取代基为烷基或芳基；优选地，R3为甲磺酰基、乙磺酰基、苯磺酰基、对甲苯磺酰基、三甲基苯磺酰基或硝基苯磺酰基，更优选地R3为甲磺酰基或对甲苯磺酰基，
wherein R 3 is an optionally substituted sulfonyl group, wherein the substituted substituent is an alkyl group or an aryl group; preferably, R 3 is a methanesulfonyl group, an ethanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a trimethylbenzenesulfonyl group or a nitrobenzenesulfonyl group, more preferably, R 3 is a methanesulfonyl group or a p-toluenesulfonyl group,
R1为-H、-D、三甲基硅基或三甲基锗基。 R1 is -H, -D, trimethylsilyl or trimethylgermanyl. 根据权利要求9所述的制备方法，其特征在于，所述磺酰化的试剂为甲磺酰氯、甲磺酸酐、对甲苯磺酰氯或对甲磺酸酐；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; 所述磺酰化的试剂用量为化合物Ⅱ的1.0～1.5摩尔当量，优选为1.0～1.1摩尔当量；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; 所述胺化剂为氨水；所述氨水的用量为化合物Ⅳ的1～5摩尔当量，优选为1～2摩尔当量；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; 所述胺化剂为苯甲胺；所述苯甲胺的用量为化合物Ⅳ的1～5摩尔当量，优选为1～2摩尔当量；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; 所述氨解反应的温度为0～5℃。The temperature of the ammonolysis reaction is 0-5°C. 根据权利要求7、9或10中任一项所述的制备方法，其特征在于，所述化合物II的制备方法包含以下步骤a：The preparation method according to any one of claims 7, 9 or 10, characterized in that the preparation method of compound II comprises the following steps a: 步骤a：有机溶剂中，化合物Ⅰ在LiAlD4作用下，生成化合物Ⅱ，R2为任选取代的-C1-C6烷基，所述取代的取代基为H、苯基；优选地，R2为C1-C3烷基或苄基；更优选地，R2为甲基或乙基，
Step a: In an organic solvent, compound I is reacted with LiAlD 4 to generate compound II, wherein R 2 is an optionally substituted -C 1 -C 6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R 2 is a C 1 -C 3 alkyl group or a benzyl group; more preferably, R 2 is a methyl group or an ethyl group.
优选地，化合物Ⅰ和LiAlD4的摩尔比为1:0.4～1。Preferably, the molar ratio of compound I to LiAlD 4 is 1:0.4-1. 根据权利要求7、9或10中任一项所述的制备方法，其特征在于，所述化合物II的制备方法包含以下步骤b：The preparation method according to any one of claims 7, 9 or 10, characterized in that the preparation method of compound II comprises the following steps b: 步骤b：化合物Ⅰ在金属试剂与氘代醇的作用下，生成化合物Ⅱ，R2为任选取代的-C1-C6烷基，所述取代的取代基为H、苯基；优选地，R2为C1-C3烷基或苄基；更优选地，R2为甲基或乙基，
Step b: Compound I is reacted with a metal reagent and a deuterated alcohol to generate Compound II, wherein R 2 is an optionally substituted -C 1 -C 6 alkyl group, wherein the substituted substituent is H or phenyl; preferably, R 2 is a C 1 -C 3 alkyl group or a benzyl group; more preferably, R 2 is a methyl group or an ethyl group.
优选地，所述金属试剂为Na或K，所述氘代醇试剂为CH3OD或CH3CH2OD；所述化合物Ⅰ与金属试剂的摩尔比为1：0.5～5，优选为1：1～5；Preferably, the metal reagent is Na or K, the deuterated alcohol reagent is CH 3 OD or CH 3 CH 2 OD; the molar ratio of the compound I to the metal reagent is 1:0.5-5, preferably 1:1-5; 优选地，所述有机溶剂为四氢呋喃。Preferably, the organic solvent is tetrahydrofuran. 优选地，化合物Ⅰ在所述有机溶剂中的浓度为0.3～1.8mol/L。Preferably, the concentration of compound I in the organic solvent is 0.3-1.8 mol/L. 一种化合物V-2的盐酸盐的制备方法，其特征在于，包括以下步骤：A method for preparing the hydrochloride of compound V-2, characterized in that it comprises the following steps: 步骤d：化合物Ⅲ-1以水合肼肼解，得到化合物Ⅴ-1：Step d: Compound III-1 is hydrazine-hydrated to give compound V-1: 步骤e：将化合物V-1溶于甲醇，加入K2CO3，室温下搅拌，反应结束后，过滤，得到的滤液中加入甲苯，得到化合物V-2的有机溶液；Step e: dissolving compound V-1 in methanol, adding K 2 CO 3 , stirring at room temperature, filtering after the reaction, adding toluene to the obtained filtrate to obtain an organic solution of compound V-2; 步骤f：将化合物V-2的有机溶液常压蒸馏，收集馏出液，酸化，得到化合物V-2的盐，
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.
优选地，化合物III-1通过步骤d、e、f一锅法制备得到化合物V-2的盐酸盐。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. 一种化合物V-2的盐酸盐的制备方法，其特征在于，包括以下步骤：A method for preparing the hydrochloride of compound V-2, characterized in that it comprises the following steps: 步骤g：化合物Ⅱ-1磺酰化后得到化合物Ⅳ-1，Step g: Compound II-1 is sulfonylated to obtain compound IV-1. 步骤h：化合物Ⅳ-1再与胺化剂进行氨解反应得到化合物Ⅴ-1，Step h: Compound IV-1 is then subjected to an ammonolysis reaction with an aminating agent to obtain compound V-1. 步骤e：将化合物V-1溶于甲醇，加入K2CO3，室温下搅拌，反应结束后，过滤，得到的滤液中加入甲苯，得到化合物V-2的有机溶液；Step e: dissolving compound V-1 in methanol, adding K 2 CO 3 , stirring at room temperature, filtering after the reaction is completed, adding toluene to the obtained filtrate to obtain an organic solution of compound V-2; 步骤f：将化合物V-2的有机溶液常压蒸馏，收集馏出液，酸化，得到化合物V-2的盐，

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.

其中，R3为甲磺酰基或对甲苯磺酰基；Wherein, R 3 is methanesulfonyl or p-toluenesulfonyl; 优选地，化合物II-1通过步骤g、h、e、f一锅法制备得到化合物V-2的盐酸盐。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. 一种化合物Ⅰ，其中R1为三甲基锗基，R2为-H、-C1-C3烷基或苄基，
A compound I, wherein R 1 is trimethylgermanyl, R 2 is -H, -C 1 -C 3 alkyl or benzyl,
一种化合物Ⅱ-2，
A compound II-2,
化合物Ⅲ-2、化合物III-3、化合物III-4，
Compound III-2, Compound III-3, Compound III-4,
化合物Ⅳ-2、化合物IV-3、化合物IV-4，
Compound IV-2, Compound IV-3, Compound IV-4,
化合物Ⅴ-3、化合物V-4，
Compound V-3, Compound V-4,
化合物Ⅰ、化合物Ⅱ-2、化合物Ⅲ-2、化合物III-3、化合物III-4、化合物Ⅳ-2、化合物IV-3、化合物IV-4、化合物Ⅴ-3或化合物V-4在制备氘代炔丙胺及其盐酸盐中的用途。 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.
PCT/CN2024/121032 2023-09-25 2024-09-25 Preparation method for deuterated propargylamine hydrochloride, intermediate thereof, and use Pending WO2025067218A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202311236472.2 2023-09-25
CN202311236472 2023-09-25

Publications (1)

Publication Number Publication Date
WO2025067218A1 true WO2025067218A1 (en) 2025-04-03

Family

ID=95203687

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/121032 Pending WO2025067218A1 (en) 2023-09-25 2024-09-25 Preparation method for deuterated propargylamine hydrochloride, intermediate thereof, and use

Country Status (1)

Country Link
WO (1) WO2025067218A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020206034A1 (en) * 2019-04-01 2020-10-08 G1 Therapeutics, Inc. Cell cycle inhibiting compounds for the treatment of medical disorders
CN112673014A (en) * 2018-07-26 2021-04-16 中生医药股份有限公司 17 beta-heterocyclyl-digitalis compounds for the treatment of heart failure
WO2023131677A1 (en) * 2022-01-07 2023-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Compounds containing a hydroxyphenyl moiety and their use
WO2024002210A1 (en) * 2022-06-30 2024-01-04 上海喆邺生物科技有限公司 Aromatic amide derivative and use thereof in antitumor drugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112673014A (en) * 2018-07-26 2021-04-16 中生医药股份有限公司 17 beta-heterocyclyl-digitalis compounds for the treatment of heart failure
WO2020206034A1 (en) * 2019-04-01 2020-10-08 G1 Therapeutics, Inc. Cell cycle inhibiting compounds for the treatment of medical disorders
WO2023131677A1 (en) * 2022-01-07 2023-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Compounds containing a hydroxyphenyl moiety and their use
WO2024002210A1 (en) * 2022-06-30 2024-01-04 上海喆邺生物科技有限公司 Aromatic amide derivative and use thereof in antitumor drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MONS ELMA, KIM ROBBERT Q, VAN DOODEWAERD BJORN R, VAN VEELEN PETER A, MULDER MONIQUE, OVAA HUIB: "Exploring the Versatility of the Covalent Thiol–Alkyne Reaction with Substituted Propargyl Warheads: A Deciding Role for the Cysteine Protease", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ACS PUBLICATIONS, vol. 143, no. 17, 1 May 2021 (2021-05-01), pages 6423 - 6433, XP093296267, ISSN: 0002-7863, DOI: 10.1021/jacs.0c10513 *

Similar Documents

Publication Publication Date Title
TW474934B (en) Process for synthesizing COX-2 inhibitors
CN102143964A (en) The method for preparing adenine compound
CN101065379B (en) Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
AU2024201119A1 (en) Methods of preparing cytotoxic benzodiazepine derivatives
CN114805308A (en) Method for synthesizing aminopyrimidine FAK inhibitor compound
TWI485136B (en) Method for synthesizing ferrocene fluoroquine by convergent reductive amination reaction
JP2002505322A (en) Method for producing protected-4-aminomethyl-pyrrolidin-3-one
CN110072851B (en) Picolinic acid derivatives and their use as intermediates
CN103601645B (en) The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt
WO2025067218A1 (en) Preparation method for deuterated propargylamine hydrochloride, intermediate thereof, and use
CN103664816B (en) The one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds
RU2552350C2 (en) Method of biphenylimidazole compounds
CN118580191A (en) Intermediates for the preparation of imidazo[1,2-b]pyridazine compounds
CN110526855B (en) A kind of preparation method of 3-nitroso-substituted indole derivatives
CN110997139B (en) Catalyst, method for forming amide bond, and method for producing amide compound
CN114573496B (en) Preparation method of 4-chloroindole-3-acetic acid
CN100457711C (en) Prepn of 2-methyl-3-nitrophenylalkylamine derivative or its salt
CN113416139B (en) A kind of 4-fluoro-substituted arylamine compound and its synthesis method
CA2661737C (en) Process and intermediates for the synthesis of (3-alkyl-5-piperidin-1-yl-3,3a-dihydro-pyrazolo[1,5-a]pyrimidin-7-yl)-amino derivatives and intermediates
CN119768394A (en) Intermediate of di-parallel ring inhibitor and preparation method thereof
WO2024011450A1 (en) Synthetic methods for preparing a pyridinecarboxamide compound
WO2024212883A1 (en) Preparation method for aryl methoxy isoindoline derivative
WO2025237354A1 (en) Method for preparing mirogabalin besilate
CN114891005A (en) Preparation process of laparis p-toluenesulfonate
JPS6317850A (en) Production of 3-phenoxycatechols

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24870762

Country of ref document: EP

Kind code of ref document: A1