CN113292479A

CN113292479A - Preparation method of 5-azaspiro [2.4] heptane and salt thereof

Info

Publication number: CN113292479A
Application number: CN202110584864.2A
Authority: CN
Inventors: 潘国骏; 陈书林; 郏如雪
Original assignee: Nanjing Heju Pharmaceutical Co ltd
Current assignee: Nanjing Heju Pharmaceutical Co ltd
Priority date: 2021-05-27
Filing date: 2021-05-27
Publication date: 2021-08-24
Anticipated expiration: 2041-05-27
Also published as: CN113292479B

Abstract

The invention discloses a preparation method of 5-azaspiro [2.4] heptane and salts thereof, which comprises the following steps: cyclopropyl nitrile reacts with ethylene oxide under strong alkaline conditions to obtain 1- (2-hydroxy-ethyl) -cyclopropane carbonitrile; reducing the 1- (2-hydroxy-ethyl) -cyclopropanecarbonitrile to obtain 2- (1-aminomethyl-cyclopropyl) -ethanol; 2- (1-aminomethyl-cyclopropyl) -ethanol is subjected to a ring closure reaction to obtain protected 5- (R-) azaspiro [2.4] heptane; deprotection of the protected 5- (R-) azaspiro [2.4] heptane affords 5-azaspiro [2.4] heptane or a salt thereof. The method has the advantages of cheap and easily obtained raw materials, low toxicity, few synthesis process steps, simple and convenient reaction operation, high yield and suitability for large-scale production.

Description

Preparation method of 5-azaspiro [2.4] heptane and salt thereof

Technical Field

The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of 5-azaspiro [2.4] heptane and salts thereof.

Background

5-azaspiro [2.4] heptane (I) as the homologue of pyrrolidine has wide application in drug development. For example, US2007167470a1 reports that (I) can be used to synthesize a class of spiro tyrosine kinase inhibitors, which have important applications in the treatment of cancers associated with protein tyrosine kinases, especially cancers associated with Epidermal Growth Factor (EGF) and Vascular Endothelial Growth Factor (VEGF). Patent WO2014170197a1 reports that (I) can be used to synthesize a class of ACC inhibitors for the treatment of metabolic diseases, such as obesity or diabetes, etc. Therefore, the (I) market prospect is very wide.

The existing synthesis process of 5-azaspiro [2.4] heptane (I) is as follows:

patent US2007167470a1 reports a process for the synthesis of 5-azaspiro [2.4] heptane from ethyl acetoacetate:

reagents and conditions: a) BrCH₂CH₂Br；b)aq.NaOH；c)Isobutyl chloroformate,then BnNH₂；d)HOCH₂CH₂OH；e)Br₂；f)NaH；g)LiAlH₄；h)H⁺；i)H₂NNH₂；j)H₂。

The process route is long and the process is complex. Ethylacetoacetate is used as a raw material, and 10 steps of reaction are totally needed to prepare the compound I. In addition, this route requires the use of highly corrosive, highly toxic reagents such as liquid bromine, hydrazine hydrate, and the like. Therefore, the process is not suitable for large-scale preparation of I.

Chinese patent application No. CN201280029101.0 reports a process for the synthesis of 5-azaspiro [2.4] heptane trifluoroacetate from tert-butyl (3-oxopyrrolidin-1-yl) acetate:

reagents and conditions: a) ph₃PCH₃Br,t-BuOK,THF,88％；b)Et₂Zn,CH₂I₂,CH₂Cl₂,87.8％；c)CF₃COOH,CH₂Cl₂,98％.

Chinese patent application No. CN201810024836.3 reports a process for preparing 5-azaspiro [2.4] heptane hydrobromide from benzyl 3-oxopyrrolidine-1-carboxylate:

reagents and conditions: a) ph₃PCH₃Br,t-BuOK,THF,58％；b)Et₂Zn,CH₂I₂,CH₂Cl₂,60％；c)HBr,AcOH,94％.

Both the two processes need to use diethyl zinc and diiodomethane for reaction to construct a three-membered ring, and the diethyl zinc is expensive and has high danger when being used in large quantity. In addition, both of the above processes require the use of column chromatography for purification. Therefore, the above two processes are also not suitable for the preparation of I or its salt in large quantities.

The 5-azaspiro [2.4] heptane and its salt have wide application in new medicine research and development, simple operation, short path, high yield and suitability for large-scale production.

Disclosure of Invention

Therefore, the invention aims to overcome the defects of complex production process, high raw material cost, use of high-risk reagents and unsuitability for large-scale production of 5-azaspiro [2.4] heptane and salts thereof in the prior art, and provides a preparation method of 5-azaspiro [2.4] heptane and salts thereof, wherein the raw materials used in the method are cheap and easy to obtain, the reaction operation is simple and convenient, the yield is high, and the method is suitable for large-scale production.

Therefore, the invention provides a preparation method of 5-azaspiro [2.4] heptane and salts thereof, which comprises the following steps:

(1) dissolving cyclopropyl nitrile in a first solvent, adding ethylene oxide, and reacting under a strong alkaline condition to obtain 1- (2-hydroxy-ethyl) -cyclopropane carbonitrile;

(2) dissolving 1- (2-hydroxy-ethyl) -cyclopropanecarbonitrile in a second solvent, adding a reducing agent, and reacting to obtain 2- (1-aminomethyl-cyclopropyl) -ethanol;

(3) dissolving 2- (1-aminomethyl-cyclopropyl) -ethanol in a third solvent, and adding a protective reagent under an alkaline condition to react to obtain 5- (R-) azaspiro [2.4] heptane;

(4) dissolving 5- (R-) azaspiro [2.4] heptane in a fourth solvent, adding a deprotection reagent, and then adding a basic reagent to obtain 5-azaspiro [2.4] heptane or a salt thereof:

wherein

X ═ HCl, HBr or CF₃CO₂H。

Preferably, the first solvent in step (1) is one of diethyl ether or tetrahydrofuran; the reaction temperature in the step (1) is-90-100 ℃, and is preferably-78-30 ℃; the reaction time is 6-8 h; the strong base in the step (1) is Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (LiHMDS), sodium bis (trimethylsilyl) amide (NaHMDS), potassium hexamethyldisilazane salt (KHMDS) or lithium 2,2,6, 6-tetramethylpiperidine (LiTMP); the molar ratio of cyclopropanecarbonitrile to strong base is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 2.0.

preferably, the molar ratio of the cyclopropylnitrile to the ethylene oxide in step (1) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 2.0-1.0: 4.0.

preferably, the second solvent in step (2) is one of tetrahydrofuran, diethyl ether or 1, 4-dioxane; the reaction temperature in the step (2) is 0-30 ℃, and the reaction time is 8-12 h; the reducing agent in the step (2) is LiAlH₄，Red-Al，NaBH₄At least one of borane dimethylsulfide or borane tetrahydrofuran.

Preferably, the molar ratio of 1- (2-hydroxy-ethyl) -cyclopropanecarbonitrile to reducing agent in step (2) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 2.0.

preferably, the third solvent in the step (3) is acetonitrile (CH)₃CN), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); the protective reagent is at least one of 2-nitrobenzene sulfonyl chloride, 4-nitrobenzene sulfonyl chloride or 2, 4-dinitrobenzene sulfonyl chloride;

preferably, the molar ratio of the 2- (1-aminomethyl-cyclopropyl) -ethanol and the protective agent in the step (3) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 2.0-1.0: 4.0;

preferably, the base in step (3) is triethylamine or N, N-Diisopropylethylamine (DIPEA); the molar ratio of 2- (1-aminomethyl-cyclopropyl) -ethanol to base is 1.0: 0.2-1.0: 10.0, preferably 1.0: 3.0-1.0: 5.0.

preferably, the deprotection reagent in the step (4) is a thiol-containing compound; the alkaline reagent in the step (4) is NaOH, KOH, LiOH and Na₂CO₃、K₂CO₃、Li₂CO₃、Cs₂CO₃Or 1, 8-diazacyclo [5,4,0 ]]At least one of undecene-7 (DBU).

Preferably, the mercapto-containing compound is at least one of thiophenol, 4-bromophenylthiophenol, 4-ethylthiophenol, 4-tert-butylphenol, mercaptoethanol, mercaptoacetic acid, n-dodecylmercaptan, methyl thioglycolate or ethyl thioglycolate; the molar ratio of the 5- (R-) azaspiro [2.4] heptane to the mercapto-containing compound is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 2.0; the molar ratio of the 5- (R-) azaspiro [2.4] heptane to the alkaline reagent in the step (4) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 3.0.

the technical scheme of the invention has the following advantages:

1. the preparation method of the 5-azaspiro [2.4] heptane and the salt thereof has the advantages of cheap and easily obtained raw materials, low toxicity, few synthesis process steps, simple and convenient reaction operation, high yield and suitability for large-scale production;

2. according to the preparation method of the 5-azaspiro [2.4] heptane and the salt thereof, the reaction intermediate or the product can be purified by distillation or recrystallization, column chromatography is not needed, the process requirement is reduced, and the preparation method is suitable for large-scale production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is a hydrogen spectrum of compound III of example 1 of the present invention;

FIG. 2 is a hydrogen spectrum of compound V-1 in example 1 of the present invention;

FIG. 3 is a carbon spectrum of compound V-1 in example 1 of the present invention;

FIG. 4 is a hydrogen spectrum of Compound I of example 1 of the present invention;

FIG. 5 is a hydrogen spectrum of Compound I-1 in example 2 of the present invention;

FIG. 6 is a hydrogen spectrum of compound V-2 in example 3 of the present invention;

FIG. 7 is a hydrogen spectrum of Compound I-2 of example 3 of the present invention;

FIG. 8 is a hydrogen spectrum of compound V-3 in example 4 of the present invention;

FIG. 9 is a hydrogen spectrum of Compound I-3 of example 4 of the present invention.

Detailed Description

The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.

The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.

Example 1

Synthesis of Compound III:

under the protection of nitrogen, n-BuLi (2.5M in n-hexane, 390mL, 0.975mol, 1.3equiv.) was added dropwise to a diethyl ether (1.5L) solution of diisopropylamine (101.8g, 1.01mol, 1.36equiv.) to react for half an hour at-78 ℃ to obtain an LDA solution, and then cyclopropylnitrile (II) (50.0g, 0.745mol, 1.0equiv.) was added dropwise slowly to react at-78 ℃ for 1 hour. Ethylene oxide (98.45g, 2.235mol, 3.0equiv.) was slowly added dropwise to react at-78 ℃ for 3 hours, and then the temperature was naturally raised to room temperature to react overnight. TLC showed complete reaction of starting material, 600mL of 2N HCl was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL. times.4), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 69.78g of a red oil, yield: 84.3 percent.

¹H NMR(400M Hz，CDCl₃)：δ(ppm)3.90(dd,J＝11.48,5.96Hz,2H),1.81(t,J＝5.00Hz,1H),1.73(dd,J＝12.80,6.4Hz,2H),1.26(dd,J＝7.36,5.04Hz,2H),0.90(dd,J＝7.20,4.84Hz,2H)。

Synthesis of compound IV:

1- (2-hydroxy-ethyl) -cyclopropanecarbonitrile (III) above (69.78g, 0.628mol,1.0equiv.) was dissolved in THF (300mL), cooled to 0 deg.C, and lithium aluminum hydride (LiAlH H) was added in portions₄23.80g, 0.628mol,1.0equiv.), stirring overnight at room temperature. 24mL of water, 24mL of 15% NaOH, and 72mL of water were added in this order, the mixture was stirred at room temperature for 1 hour, filtered by suction, and the filter cake was washed with 100mL of ethyl acetate by 2. The filtrate was concentrated under reduced pressure and oil-dried by oil pump to give 68.70g of oil which was used directly in the next reaction.

Synthesis of Compound V-1:

2- (1-aminomethyl-cyclopropyl) -ethanol (IV) (34.35g,0.298mol,1.0equiv.) described above was dissolved in 500mL CH at room temperature₃In the step (CN), the first step of the method,triethylamine (90.45g, 0.894mol,3.0equiv.) and 2-nitrobenzenesulfonyl chloride (132.08g,0.596mol,2.0equiv.) were added and reacted at room temperature for 24h, TLC showed completion of the reaction, and most of the solvent was removed by concentration under reduced pressure. The system was added with ethyl acetate 400mL, washed with 1N HCl (400 mL. times.2) and saturated brine (200 mL. times.2) in this order, and dried over anhydrous Na₂SO₄Drying, filtering, concentrating under reduced pressure, and pulping with petroleum ether to obtain 60.70g of white solid with yield of 68.5% in two steps.

¹H NMR(400M Hz，CDCl₃)：δ(ppm)8.02(m,1H),7.84(m,2H),7.62(m,1H),3.60(t,J＝6.76Hz,2H),3.33(s,2H),1.84(t,J＝6.80Hz,2H),0.61-0.58(m,4H)。

¹³C NMR(101M Hz，CDCl₃)：δ(ppm)148.31,133.42,132.16,131.47,130.63,123.98,55.15,48.41,34.27,22.04,10.59。

Synthesis of Compound I:

5- (2-Nitrophenylsulphonyl) -5-aza-spiro [2.4] heptane (V-1) (10.00g,0.035mol,1.0equiv.) was dissolved in 50mL DMF, 4-bromophenylthiol (11.90g,0.063mol,1.8equiv.) was added under ice bath, lithium hydroxide (1.70g,0.071mol,2.0equiv.) was added in portions, stirring was carried out at room temperature for 10h, TLC showed completion of the reaction, 1NHCl was added to the system, the pH was adjusted to 3, and 50mL of 3 was extracted with ethyl acetate. The aqueous phase was adjusted to pH 10 with 1n naoh water, 30mL 4 was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product 5-azaspiro [2.4] heptane (I) as a pale yellow oil 2.20g (20 Wt% EtOAc in) 51.7% yield.

¹H NMR(400M Hz，CDCl₃)：δ(ppm)3.09(t,J＝6.96Hz,2H),3.08(s,2H),1.72(t,J＝6.96Hz,2H),0.58-0.55(m,4H)。

Example 2

The synthesis of compounds III, IV and V-1 was the same as in example 1.

Synthesis of Compound I-1:

5- (2-Nitrobenzenesulfonyl) -5-aza-spiro [2.4] heptane (V-1) (15.00g,0.053mol,1.0equiv.) was dissolved in 80mL EtOAc, cooled in an ice bath, 4-tert-butylthiophenol (26.40g,0.159mol,3.0equiv.), DBU (24.20g,0.159mol,3.0equiv.) were added, and after completion of stirring at room temperature for 3h, TLC indicated complete reaction of the starting materials. 1N HCl was added, the pH was adjusted to 3 and the organic phase was separated. The aqueous phase was extracted with 50mL x 2 of ethyl acetate. The aqueous phase was adjusted to pH 10 with 1n naoh water, 60mL _ 3 was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and added with 70mL of 1N HCl/ethyl acetate, followed by stirring thoroughly and concentration under reduced pressure to give the product (I-1) as a white solid (6.54 g, yield 92.3%).

¹H NMR(400M Hz，D₂O)：δ(ppm)3.46(t,J＝7.40Hz,2H),3.17(s,2H),1.96(t,J＝7.44Hz,2H),0.74-0.72(m,4H)。

Example 3

Synthesis of Compound III:

cyclopropyl nitrile (II) (20.0g, 0.298mol,1.0equiv.) was dissolved in anhydrous THF (100mL) solution, cooled to-78 ℃ under nitrogen protection, KHMDS (1.0M in tetrahydrofuran, 0.358L, 0.358mol, 1.2equiv.) was slowly added dropwise, reacted for one hour, ethylene oxide (19.70g, 0.447mol, 1.5equiv.) was slowly added dropwise, reacted for 5 hours at-78 ℃ and then naturally warmed to room temperature. 200mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (80 mL. times.4), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 17.95g of red oil (III) in 54.3% yield.

Synthesis of compound IV:

1- (2-hydroxy-ethyl) -cyclopropanecarbonitrile (III) (8.00g, 0.072mol,1.0equiv.) was dissolved in diethyl ether 50mL at room temperature, and LiAlH was added in portions₄(5.46g, 0.144mol,2.0equiv.), and stirred at room temperature overnight. 5.5mL of water, 5.5mL of 15% NaOH, and 16.5mL of water were added in this order, and the mixture was stirred at room temperature for 1 hour, filtered with suction, and the filter cake was washed with 30mL of 2 with ethyl acetate. The filtrate was concentrated under reduced pressure and oil-dried to give 7.90g of oil which was used directly in the next reaction.

Synthesis of Compound V-2:

dissolving the raw material IV (7.90g,0.068mol,1.0equiv.) in 80mL of DMF, sequentially adding DIPEA (35.16g, 0.272mol,4.0equiv.), 4-nitrobenzenesulfonyl chloride (45.21g,0.204mol,3.0equiv.), reacting for 10H at room temperature, TLC showing complete reaction, and adding H into the system₂O500 mL, stirring for 2h, CH₂Cl₂Extract 50mL x 3 and combine the organic phases. The organic phase was washed successively with 1N HCl (50mL), saturated brine (50 mL). Anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressure to obtain 15.60g of light yellow solid (V-2) with the yield of two steps of 76.8 percent.

¹H NMR(400M Hz，CDCl₃)：δ(ppm)8.40(dd,J＝6.84,2.00,2H),8.03(dd,J＝6.84,2.04Hz,2H),3.47(t,J＝6.84Hz,2H),3.19(s,2H),1.73(t,J＝6.84Hz,2H),0.51-0.49(m,4H)。

Synthesis of Compound I-2:

compound V-2(15.00g,0.053mol,1.0equiv.) is dissolved in THF/H₂50mL of O (V/V5: 1), n-dodecyl mercaptan (12.87g,0.064mol,1.2equiv.), K₂CO₃(11.00g,0.080mol,1.5equiv.), stirred at room temperature for 24 deg.C, TLC indicated complete reaction of starting materials. 1N HCl is added into the system, the pH is adjusted to 3, and the organic phase is separated. The aqueous phase was extracted with ethyl acetate to give 40mL of 2. The aqueous phase was adjusted to pH 10 with 1n naoh water, 20mL _ 3 was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, added with 12mL of 40% HBr solution, fully stirred and concentrated under reduced pressure, taken with water in ethanol, 30mL 3, concentrated to dryness under reduced pressure to give the product (I-2) 7.85g, white solid, yield 83.2%.

¹H NMR(400M Hz，CDCl₃)：δ(ppm)3.43(t,J＝7.44Hz,2H),3.14(s,2H),1.93(t,J＝7.44Hz,2H),0.70-0.69(m,4H)。

Example 4

The synthesis of compounds III, IV was the same as in example 3.

Synthesis of Compound V-3:

2- (1-aminomethyl-cyclopropyl) -ethanol (IV) (10g,0.087mol,1.0equiv.) was dissolved in 100mL DMSO at room temperature, triethylamine (30.80g, 0.304mol,3.5equiv.) and 2, 4-dinitrobenzenesulfonyl chloride (58.00g,0.218mol,2.5equiv.) were added and the reaction was allowed to proceed for 24h at room temperature, and TLC indicated completion. Addition of H₂O400 mL, stirring for 2 h. CH (CH)₂Cl₂Extract 100mL x 3 and combine the organic phases. The organic phase was washed successively with 1N HCl (100mL), saturated brine (100 mL). Anhydrous Na₂SO₄Drying, filtering, concentrating under reduced pressure, and performing silica gel column chromatography (eluent: petroleum ether/ethyl acetate 5:1) to obtain 24.40g of pale yellow solid (V-3) with yield of 85.8%.

¹H NMR(400M Hz，CDCl₃)：δ(ppm)8.50(dd,J＝8.56,2.24Hz,1H),8.46(d,J＝2.24Hz,1H),8.24(d,J＝8.56Hz,1H),3.63(t,J＝6.80Hz,2H),3.36(s,2H),1.87(t,J＝6.76Hz,2H),0.64-0.62(m,4H)。

Synthesis of Compound I-3:

compound V-3(13.10g,0.040mol,1.0 equ) was added at room temperatureiv.) and mercaptoethanol (3.13g,0.040mol,1.0equiv.) in 50mL CH₃CN and 10mL H₂O, adding Cs₂CO₃(15.64g,0.048mol,1.2equiv.), stirred at room temperature for 24h, TLC showed complete reaction of starting material. The system was put into ice water, 1NHCl adjusted pH to 3, EA extracted 40mL x 3. Adding saturated Na into the water phase₂CO₃Solution 50mL, CH₂Cl₂Extraction (50mL x 3), combining the organic phases, washing the organic phase with saturated brine, anhydrous Na₂SO₄Drying and filtering. 6mL of CF was added to the filtrate₃CO₂H, stirring fully and spin-drying to obtain 5.76g of light yellow oily matter (I-3) with the yield of 68.2%.

¹H NMR(400M Hz，D₂O)：δ(ppm)3.38(t,J＝7.44Hz,2H),3.09(s,2H),1.87(t,J＝7.44Hz,2H),0.64(m,4H)。

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims

1. A method for preparing 5-azaspiro [2.4] heptane and salts thereof is characterized by comprising the following steps:

wherein

X ═ HCl, HBr or CF₃CO₂H。

2. The process for the preparation of 5-azaspiro [2.4] heptane and salts thereof, as claimed in claim 1, wherein the first solvent in step (1) is one of diethyl ether or tetrahydrofuran;

the reaction temperature in the step (1) is-90-100 ℃, and is preferably-78-30 ℃; the reaction time is 6-8 h;

the strong base in the step (1) is at least one of LDA, LiHMD, NaHMDS, KHMDS or LiTMP;

the molar ratio of cyclopropanecarbonitrile to strong base is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 2.0.

3. the process for the preparation of 5-azaspiro [2.4] heptane and its salts according to claim 1 or 2, characterized in that the molar ratio of cyclopropylnitrile and ethylene oxide in step (1) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 2.0-1.0: 4.0.

4. the process for the preparation of 5-azaspiro [2.4] heptane and its salts as claimed in claim 1, wherein the second solvent in step (2) is one of tetrahydrofuran, diethyl ether or 1, 4-dioxane;

the reaction temperature in the step (2) is 0-30 ℃, and the reaction time is 8-12 h;

the reducing agent in the step (2) is LiAlH₄，Red-Al，NaBH₄At least one of borane dimethylsulfide or borane tetrahydrofuran.

5. A process for the preparation of 5-azaspiro [2.4] heptane and its salts as claimed in claim 1 or 4, characterized in that the molar ratio of 1- (2-hydroxy-ethyl) -cyclopropanecarbonitrile to the reducing agent in step (2) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 2.0.

6. the process for the preparation of 5-azaspiro [2.4] heptane and its salts as claimed in claim 1, wherein the third solvent in step (3) is one of acetonitrile, N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone;

the protective reagent is at least one of 2-nitrobenzene sulfonyl chloride, 4-nitrobenzene sulfonyl chloride or 2, 4-dinitrobenzene sulfonyl chloride.

7. A process for the preparation of 5-azaspiro [2.4] heptane and its salts as claimed in claim 1 or 6, wherein the molar ratio of 2- (1-aminomethyl-cyclopropyl) -ethanol and protecting agent in step (3) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 2.0-1.0: 4.0.

8. the process for the preparation of 5-azaspiro [2.4] heptane and salts thereof according to claim 7, characterized in that the base in step (3) is triethylamine or N, N-diisopropylethylamine;

the molar ratio of 2- (1-aminomethyl-cyclopropyl) -ethanol to base is 1.0: 0.2-1.0: 10.0, preferably 1.0: 3.0-1.0: 5.0.

9. the process for the preparation of 5-azaspiro [2.4] heptane and its salts as claimed in claim 1, characterized in that the deprotecting reagent in step (4) is a mercapto group-containing compound;

the alkaline reagent in the step (4) is NaOH, KOH, LiOH and Na₂CO₃、K₂CO₃、Li₂CO₃、Cs₂CO₃Or a DBU.

10. The process for the preparation of 5-azaspiro [2.4] heptane and its salts, as claimed in claim 9, wherein the mercapto group-containing compound is at least one of thiophenol, 4-bromophenylthiophenol, 4-ethylthiophenol, 4-tert-butylphenol, mercaptoethanol, mercaptoacetic acid, n-dodecylmercaptan, methyl thioglycolate or ethyl thioglycolate;

the molar ratio of the 5- (R-) azaspiro [2.4] heptane to the mercapto-containing compound is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 2.0;

the molar ratio of the 5- (R-) azaspiro [2.4] heptane to the alkaline reagent in the step (4) is 1.0: 0.2-1.0: 10.0, preferably 1.0: 0.8-1.0: 3.0.