CN112321599B - Synthesis method of drug intermediate 7-oxo-2-azaspiro [3.5] nonane - Google Patents
Synthesis method of drug intermediate 7-oxo-2-azaspiro [3.5] nonane Download PDFInfo
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a method for synthesizing a drug intermediate 7-oxo-2-azaspiro [3.5] nonane, belonging to the technical field of drug synthesis. The specific synthetic operation steps are as follows: (1) Under the condition of an acid binding agent, carrying out a first cyclization reaction on a compound 1 and a compound 2 in N, N-dimethylformamide under the action of a phase transfer catalyst and an iodo metal salt to obtain a compound 3; the acid binding agent absorbs the acid in the reaction and prevents the formation of an alkane halide. (2) Carrying out a second cyclization reaction on the compound 3, lithium aluminum hydride and a reaction solvent to obtain 7-oxo-2-azaspiro [3.5] nonane; the main impurity of lithium aluminum hydride cyclization is olefin impurity of transition reduction. The invention realizes the synthesis of 7-oxo-2-azaspiro [3.5] nonane by a two-step method, solves the problem of ring opening of cyclic ether in the preparation process, has the preparation yield of more than 82 percent, shortens the production period and greatly reduces the production cost; the synthetic route has mild reaction conditions, convenient post-treatment of steps and easy mass production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a spiro medicine intermediate.
Background
7-oxo-2-azaspiro [3.5] nonane is an important segment in drug design, has very high biological activity, and derivatives thereof have various physiological activities such as Respiratory Syncytial Virus (RSV) inhibitors (WO 2017123884), irreversible inhibitors of Epidermal Growth Factor Receptor (EGFR) (Bioorganic and Medicinal Chemistry,2014, vol.22, #7, p.2366-2378) and the like, and in recent years, drug screening by linking 7-oxo-2-azaspiro [3.5] nonane with a specific structure has become one of hot spots of research in drug discovery phase, so 7-oxo-2-azaspiro [3.5] nonane is a very promising drug intermediate.
No complete synthesis method report is found by searching 7-oxo-2-azaspiro [3.5] nonane.
The synthesis of similar compound 2-azaspiro [3.5] nonane, the new synthesis of journal 3,3- (spiro) substituted azacyclic compounds, is reported to prepare compound I by nucleophilic substitution, protection and cyclization using compound 1 as a starting material, with the following reaction schemes:
the document reports that the synthesis of compound 2 in the route involves a lithium diisobutylamine reagent, a strictly anhydrous and anaerobic reaction at ultralow temperature of-80 ℃; the second step has the problem of low yield in the process of protecting the hydroxyl group by using Ts, and the yield is only 38%.
The synthesis of 4- (hydroxymethyl) tetrahydro-2H-pyran-4-cyano, the world patent (phenyl heteroaromatic amine compound and application thereof) takes bis (2-bromoethyl) ether as a raw material, and a compound intermediate is prepared by nucleophilic substitution and reduction, the nucleophilic substitution yield is only 68 percent, and the reaction process is as follows:
in summary of the above analysis, no literature reports on a complete and definite synthetic method of 7-oxo-2-azaspiro [3.5] nonane exists, and at present, two synthetic routes are provided, and the synthetic products of the synthetic method do not have the pharmaceutical activity of 7-oxo-2-azaspiro [3.5] nonane, do not have the characteristics of new drug screening building blocks, and have complicated route operation and low yield.
Disclosure of Invention
In view of the above, the invention needs to provide a method for synthesizing a drug intermediate 7-oxo-2-azaspiro [3.5] nonane, which has the advantages of short steps, simple process, convenient operation, high total yield, low requirements on equipment and environmental protection, and solves the technical problems of high synthesis difficulty and low total yield in the prior art.
The synthetic route of the drug intermediate 7-oxo-2-azaspiro [3.5] nonane is as follows:
the specific synthetic operation steps are as follows:
(1) Preparation of Compound 3
Under the condition of an acid binding agent, carrying out a first cyclization reaction on a compound 1 and a compound 2 in N, N-dimethylformamide under the action of a phase transfer catalyst and an iodo metal salt, wherein the reaction temperature is 70-100 ℃ and the reaction time is 10-24 hours, so as to obtain a compound 3;
the compound 1 is bis (2-chloroethyl) ether, bis (2-bromoethyl) ether or bis (2-iodoethyl) ether;
the compound 2 is cyanoacetaldehyde diethyl acetal;
the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium bisulfate:
the iodized metal salt is potassium iodide or sodium iodide;
the molar ratio of the compound 1 to the compound 2 to the acid-binding agent is 1.0:1.1:1.2-1.0:1.1:2.0, and the molar ratio of the compound 1 to the phase transfer catalyst to the iodo metal salt is 1.00:0.05:0.05-1.00:0.15:0.15;
(2) Preparation of Compound I
Carrying out a second cyclization reaction on the compound 3, lithium aluminum hydride and a reaction solvent, wherein the reaction temperature is-50-50 ℃ to obtain a compound I;
the molar ratio of the compound 3 to the lithium aluminum hydride is 1.0:1.1-1.0:3.0.
The further defined technical scheme is as follows:
the acid binding agent is anhydrous potassium carbonate, sodium carbonate and sodium bicarbonate.
In step (1), 720ml to 1600ml of N, N-dimethylformamide is added to the reactor, 71.5g to 163g of bis (2-chloroethyl) ether is added thereto, 78.8g of cyanoacetaldehyde diethyl acetal, 50.4g to 138.2g of an acid binding agent, 8.1g to 25.5g of a phase transfer catalyst and 3.7g to 12.5g of an iodometal salt are added with stirring; quickly heating to 70-100 ℃ for reaction for 12-24 hours, cooling the reaction liquid to 0 ℃, adding 200-800 ml of purified water and 400ml of ethyl acetate, stirring, standing for layering, collecting an upper organic phase, adding 100-200 ml of 10% sodium bicarbonate solution for washing, collecting the organic phase, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining 76.8-106.5 g of crude product of the compound 3.
In the step (2), 770ml-1000ml of tetrahydrofuran is added into a reactor, 76.8g-106.5g of crude compound 3 is added, nitrogen is substituted, the temperature is reduced to minus 10-10 ℃, 15.2g-56.9g of lithium aluminum hydride is added in 10 equal parts in sequence in one hour, stirring reaction is carried out for 4-8 hours, 15ml-57ml of purified water is slowly added, 15ml-57ml of 15% sodium hydroxide solution is slowly added, 45ml-188ml of purified water is added, filtration and filtrate concentration are carried out, crude compound I is obtained, and the crude compound I is purified by passing neutral alumina through a column, thus obtaining 35.8g-52.9g of refined compound I, and the total yield is 56.3% -82.6%.
The beneficial technical effects of the invention are as follows:
(1) The invention realizes the synthesis of 7-oxo-2-azaspiro [3.5] nonane by a two-step method, solves the problem of ring opening of cyclic ether in the preparation process, has the preparation yield of more than 82 percent, shortens the production period and greatly reduces the production cost; the synthetic route has mild reaction conditions, convenient post-treatment of steps and easy mass production.
(2) In the first-step cyclization reaction, a phase transfer catalyst and iodized metal salt are added, the iodized metal salt is potassium iodide or sodium iodide, and the potassium iodide or sodium iodide serves as a catalyst chloride or bromide to make the chloride or bromide easier to leave, and the catalyst promotes the reaction conversion to take the role of a key catalyst, the phase transfer catalyst improves the solubility of inorganic matters in a solvent, so that a poorly soluble acid-binding agent and iodized metal salt are more soluble in the reaction solvent, and meanwhile, iodine ions are introduced to catalyze the cyclization reaction, so that the cyclization conversion rate is improved. Acid-binding agents commonly used in the art are potassium carbonate, sodium carbonate and sodium bicarbonate, which can be used in the technical scheme of the invention, and the acid-binding agent has the functions of absorbing acid in the reaction, accelerating the speed of substitution reaction and preventing the generation of halogenated alkane.
(3) The reaction temperature in the second-step cyclization reaction has larger influence on the reaction, and main impurities are olefin impurities generated by transition reduction of lithium aluminum hydride and ring-opening impurities degraded by exothermic addition, and the destructive test proves that a large amount of residual raw materials or byproduct impurities are rapidly increased, so that the generation of the ring-opening impurities and the olefin impurities can be greatly reduced at the same time by controlling the reaction temperature, the refining difficulty is reduced, and the yield of the step is improved.
Detailed Description
In order that the invention may be readily understood, a more particular description of the invention will be rendered by reference to specific embodiments that are illustrated below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the following examples, the materials and reagents used were commercially available and were mainly purchased from Shanghai Bi medical science and technology Co., ltd.
Example 1
The synthetic operation steps of the drug intermediate 7-oxo-2-azaspiro [3.5] nonane are as follows:
(1) Preparation of compound 3:
to the reactor was added 720ml of N, N-dimethylformamide, to which was added 71.5g (0.50 mol) of bis (2-chloroethyl) ether, and 78.8g (0.55 mol) of cyanoacetaldehyde diethyl acetal, 82.9g (0.60 mol) of anhydrous potassium carbonate, 8.1g (0.025 mol) of tetrabutylammonium bromide and 4.2g (0.025 mol) of potassium iodide with stirring. Then the temperature is quickly raised to 70 ℃ for reaction for 12 hours, the reaction solution is cooled to 0 ℃, 300ml of purified water and 400ml of ethyl acetate are added, stirring, standing and layering are carried out, an upper organic phase is collected, 200ml of 10% sodium bicarbonate solution is added for washing, an organic phase is collected, anhydrous magnesium sulfate is dried, filtration and reduced pressure concentration are carried out until the mixture is dried, and 76.8g of crude product of the compound 3 is obtained. The next step is directly.
The mol ratio of the compound 1 to the compound 2 to the acid binding agent in the structural formula is 1.0:1.1:1.2;
the molar ratio of compound 1, phase transfer catalyst and iodo metal salt in the structural formula is 1.00:0.05:0.05.
(2): preparation of Compound I:
770ml of tetrahydrofuran is added into a reactor, 76.8g (0.36 mol) of crude compound 3 is added, nitrogen is replaced, the temperature is reduced to-10 ℃, 15.2g (0.40 mol) of lithium aluminum hydride is added in 10 equal parts in sequence within one hour, stirring is carried out for 4 hours, 15ml of purified water is slowly added, 15ml of 15% sodium hydroxide solution is slowly added, 45ml of purified water is then added, filtration and concentration of filtrate are carried out, thus obtaining crude compound I, and the crude compound I is purified by passing neutral alumina through a column, thus obtaining 35.8g of refined compound I with the total yield of 56.3%.
The molar ratio of the compound 3 and lithium aluminum hydride in the structural formula is 1.0:1.1.
The nuclear magnetic resonance test result is 1 H NMR(400MHz，CDCl 3 )δ(ppm)3.56(d，4H)，3.38(s，4H)，1.82(s,1H)，1.74(d,4H)。
Example 2
The first step: preparation of compound 3:
1200ml of N, N-dimethylformamide was added to the reactor, and 116.0g (0.50 mol) of bis (2-bromoethyl) ether, 78.8g (0.55 mol) of cyanoacetaldehyde diethyl acetal, 50.4g (0.60 mol) of sodium hydrogencarbonate, 8.5g (0.025 mol) of tetrabutylammonium hydrogen sulfate and 3.7g (0.025 mol) of sodium iodide were added thereto with stirring. Then quickly heating to 90 ℃ for reaction for 24 hours, cooling the reaction liquid to 0 ℃, adding 600ml of purified water and 400ml of ethyl acetate, stirring, standing and layering, collecting an upper organic phase, adding 200ml of 10% sodium bicarbonate solution for washing, collecting an organic phase, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining 106.1g of crude compound 3, and directly performing the next step.
The mol ratio of the compound 1 in the structural formula to the compound 2 in the structural formula to the acid binding agent is 1.0:1.1:1.2;
the molar ratio of compound 1, phase transfer catalyst and iodo metal salt in the structural formula is 1.00:0.05:0.05.
And a second step of: preparation of Compound I:
1000ml of diethyl ether is added into a reactor, 106.1g (0.50 mol) of compound 3 is added, nitrogen is replaced, the temperature is reduced to minus 50 to minus 30 ℃, 28.4g (0.75 mol) of lithium aluminum hydride is added into 10 equal parts of the reactor in sequence within one hour, the mixture is stirred for 4 hours to react, 28ml of purified water is slowly added, then 28ml of 15% sodium hydroxide solution is slowly added, 84ml of purified water is added, filtration is carried out after the filtrate is concentrated, a crude product of the compound I is obtained, and the crude product is purified by passing neutral alumina through a column, thus obtaining 52.5g of refined product of the compound I, and the total yield is 82.5%.
The molar ratio of the compound 3 and lithium aluminum hydride in the structural formula is 1.0:1.5.
The nuclear magnetic resonance test result is 1 H NMR(400MHz，CDCl 3 )δ(ppm)3.55～3.57(d，4H)，3.38(s，4H)，1.82(s,1H)，1.74～1.77(d,4H)。
Example 3
The first step: preparation of compound 3:
1600ml of N, N-dimethylformamide was added to the reactor, and thereto was added 163.0g (0.50 mol) of bis (2-iodoethyl) ether, 78.8g (0.55 mol) of cyanoacetaldehyde diethyl acetal, 79.5g (0.75 mol) of anhydrous sodium carbonate, 13.9g (0.05 mol) of tetrabutylammonium chloride and 8.3g (0.05 mol) of potassium iodide with stirring. Then quickly heating to 100 ℃ for reaction for 12 hours, cooling the reaction liquid to 0 ℃, adding 800ml of purified water and 400ml of ethyl acetate, stirring, standing and layering, collecting an upper organic phase, adding 200ml of 10% sodium bicarbonate solution for washing, collecting an organic phase, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining 105.2g of crude compound 3, and directly carrying out the next step.
The mol ratio of the compound 1 in the structural formula to the compound 2 in the structural formula to the acid binding agent is 1.0:1.1:1.5;
the molar ratio of compound 1, phase transfer catalyst and iodo metal salt in the structural formula is 1.00:0.10:0.10.
And a second step of: preparation of Compound I:
1000ml of methyltetrahydrofuran is added into a reactor, 105.2g (0.49 mol) of compound 3 is added, nitrogen is replaced, the temperature is reduced to minus 30 to minus 10 ℃, 28.1g (0.74 mol) of lithium aluminum hydride is added into 10 parts in sequence within one hour, the mixture is stirred for 8 hours for reaction, 28ml of purified water is slowly added, then 28ml of 15% sodium hydroxide solution with concentration is slowly added, 84ml of purified water is added, filtration is carried out after the addition of 84ml of purified water, the filtrate is concentrated to obtain a crude product of the compound I, and 50.6g of refined product of the compound I is obtained after passing through a neutral alumina column for purification, and the total yield is 79.6%.
The molar ratio of the compound 3 and lithium aluminum hydride in the structural formula is 1.0:1.5.
Example 4
The first step: preparation of compound 3:
800ml of N, N-dimethylformamide was added to the reactor, and 71.5g (0.50 mol) of bis (2-chloroethyl) ether, 78.8g (0.55 mol) of cyanoacetaldehyde diethyl acetal, 138.2g (1.00 mol) of anhydrous potassium carbonate, 24.2g (0.075 mol) of tetrabutylammonium bromide and 11.2g (0.075 mol) of sodium iodide were added thereto with stirring. Then quickly heating to 90 ℃ for reaction for 12 hours, cooling the reaction liquid to 0 ℃, adding 400ml of purified water and 400ml of ethyl acetate, stirring, standing and layering, collecting an upper organic phase, adding 200ml of 10% sodium bicarbonate solution for washing, collecting an organic phase, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining 102.4g of crude compound 3, and directly carrying out the next step.
The mol ratio of the compound 1 in the structural formula to the compound 2 in the structural formula to the acid binding agent is 1.0:1.1:2.0;
the molar ratio of compound 1, phase transfer catalyst and iodo metal salt in the structural formula is 1.00:0.15:0.15.
And a second step of: preparation of Compound I:
800ml of diethyl ether is added into a reactor, 102.4g (0.48 mol) of compound 3 is added, nitrogen is replaced, the temperature is reduced to-10 ℃, 47.4g (1.25 mol) of lithium aluminum hydride is added into the reactor in turn in 10 equal parts within one hour, the mixture is stirred for 4 hours, 48ml of purified water is slowly added, then 48ml of 15% sodium hydroxide solution is slowly added, 184ml of purified water is added, filtration is carried out after the filtrate is layered, crude products are obtained after concentration, and 50.6g of refined products of the compound I are obtained after purification by passing neutral alumina through a column, and the total yield is 79.6%.
The molar ratio of the compound 3 and lithium aluminum hydride in the structural formula is 1.0:2.6.
Example 5
The first step: preparation of compound 3:
to the reactor was added 1000ml of N, N-dimethylformamide, 116.0g (0.50 mol) of bis (2-bromoethyl) ether, and 78.8g (0.55 mol) of cyanoacetaldehyde diethyl acetal, 106.0g (1.00 mol) of anhydrous sodium carbonate, 13.9g (0.05 mol) of tetrabutylammonium chloride and 8.3g (0.05 mol) of potassium iodide were added with stirring. Then quickly heating to 80 ℃ for reaction for 12 hours, cooling the reaction liquid to 0 ℃, adding 500ml of purified water and 400ml of ethyl acetate, stirring, standing and layering, collecting an upper organic phase, adding 200ml of 10% sodium bicarbonate solution for washing, collecting an organic phase, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining 106.5g of crude compound 3, and directly carrying out the next step.
The mol ratio of the compound 1 in the structural formula to the compound 2 in the structural formula to the acid binding agent is 1.0:1.1:2.0;
the molar ratio of compound 1, phase transfer catalyst and iodo metal salt in the structural formula is 1.00:0.10:0.10.
And a second step of: preparation of Compound I:
1000ml of diethyl ether is added into a reactor, 106.5g (0.50 mol) of compound 3 is added, nitrogen is replaced, the temperature is reduced to minus 50 to minus 30 ℃, 56.9g (1.50 mol) of lithium aluminum hydride is added into 10 equal parts in sequence within one hour, the mixture is stirred for 4 hours to react, 57ml of purified water is slowly added, 57ml of 15% sodium hydroxide solution is slowly added, 171ml of purified water is added, filtration is carried out after the filtration, the filtrate is layered and concentrated to obtain a crude product of the compound I, and the crude product of the compound I is purified by a neutral alumina column, thus obtaining 46.1g of refined product of the compound I, and the total yield is 72.5%.
The molar ratio of the compound 3 and lithium aluminum hydride in the structural formula is 1.0:3.0.
Example 6
The first step: preparation of compound 3:
1000ml of N, N-dimethylformamide was added to the reactor, and thereto was added 163.0g (0.50 mol) of bis (2-iodoethyl) ether, 78.8g (0.55 mol) of cyanoacetaldehyde diethyl acetal, 138.2g (0.60 mol) of anhydrous potassium carbonate, 25.5g (0.075 mol) of tetrabutylammonium hydrogen sulfate and 12.5g (0.075 mol) of potassium iodide with stirring. Then, after the temperature is quickly raised to 70 ℃ for reaction for 12 hours, the reaction solution is cooled to 0 ℃, 200ml of purified water and 300ml of ethyl acetate are added, stirring, standing and layering are carried out, an upper organic phase is collected, 100ml of 10% sodium bicarbonate solution is added for washing, an organic phase is collected, anhydrous magnesium sulfate is dried, and then, filtration and decompression concentration are carried out until the dried product is dried, thus 105.4g of crude product of the compound 3 is obtained, and the next step is directly carried out.
The mol ratio of the compound 1 in the structural formula to the compound 2 in the structural formula to the acid binding agent is 1.0:1.1:1.2;
the molar ratio of compound 1, phase transfer catalyst and iodo metal salt in the structural formula is 1.00:0.15:0.15.
And a second step of: preparation of Compound I:
800ml of tetrahydrofuran is added into a reactor, 105.4g (0.49 mol) of compound 3 is added, nitrogen is replaced, the temperature is reduced to minus 30 to minus 10 ℃, 47.4g (1.25 mol) of lithium aluminum hydride is added into 10 equal parts in sequence within one hour, the mixture is stirred for 4 hours to react, 47ml of purified water is slowly added, 47ml of 15% sodium hydroxide solution is slowly added, 188ml of purified water is added, water layer is removed from the filtrate, the filtrate is concentrated to obtain a crude product of the compound I, and the crude product is purified by a neutral alumina column to obtain 52.9g of refined product of the compound I, and the yield is 82.6%.
The molar ratio of the compound 3 and lithium aluminum hydride in the structural formula is 1.0:2.6.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (4)
1. A method for synthesizing a pharmaceutical intermediate 7-oxo-2-azaspiro [3.5] nonane is characterized in that: the synthetic route is as follows:
the specific synthetic operation steps are as follows:
(1) Preparation of Compound 3
Under the condition of an acid binding agent, carrying out a first cyclization reaction on a compound 1 and a compound 2 in N, N-dimethylformamide under the action of a phase transfer catalyst and an iodo metal salt, wherein the reaction temperature is 70-100 ℃ and the reaction time is 10-24 hours, so as to obtain a compound 3;
the compound 1 is bis (2-chloroethyl) ether, bis (2-bromoethyl) ether or bis (2-iodoethyl) ether;
the compound 2 is cyanoacetaldehyde diethyl acetal;
the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium bisulfate:
the iodized metal salt is potassium iodide or sodium iodide;
the molar ratio of the compound 1 to the compound 2 to the acid-binding agent is 1.0:1.1:1.2-1.0:1.1:2.0, and the molar ratio of the compound 1 to the phase transfer catalyst to the iodo metal salt is 1.00:0.05:0.05-1.00:0.15:0.15;
(2) Preparation of Compound I
Carrying out a second cyclization reaction on the compound 3, lithium aluminum hydride and a reaction solvent, wherein the reaction temperature is-50-10 ℃ to obtain a compound I; the total yield of the refined product of the compound I is 56.3-82.6%;
the molar ratio of the compound 3 to the lithium aluminum hydride is 1.0:1.1-1.0:3.0.
2. A process for the synthesis of the pharmaceutical intermediate 7-oxo-2-azaspiro [3.5] nonane according to claim 1, characterized in that: in step (1), 720ml to 1600ml of N, N-dimethylformamide is added to the reactor, and 71.5g to 163 and g of bis (2-chloroethyl) ether or bis (2-iodoethyl) ether or bis (2-bromoethyl) ether, 78.8 to g of cyanoacetaldehyde diethyl acetal, 50.4g to 138.2 to g of an acid-binding agent, 8.1g to 25.5 to g of a phase transfer catalyst and 3.7g to 12.5 to g of an iodometal salt are added thereto with stirring; quickly heating to 70-100 ℃ for reaction for 12-24 hours, cooling the reaction liquid to 0 ℃, adding 200ml-800ml purified water and 400ml ethyl acetate, stirring, standing for layering, collecting an upper organic phase, adding 100ml-200ml concentration 10% sodium bicarbonate solution for washing, collecting the organic phase, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining a crude product of the compound 3 of 76.8g-106.5 g.
3. A process for the synthesis of the pharmaceutical intermediate 7-oxo-2-azaspiro [3.5] nonane according to claim 1, characterized in that: in the step (2), 770ml-1000ml of tetrahydrofuran is added into a reactor, 76.8g-106.5g crude compound 3 is added, nitrogen is replaced, the temperature is reduced to minus 10-10 ℃, 15.2g g-56.9g of lithium aluminum hydride are added into the reactor in turn in 10 equal parts in one hour, stirring reaction is carried out for 4-8 hours, 15ml-57ml of purified water is slowly added, 15ml-57ml of 15% sodium hydroxide solution is slowly added, 45ml-188ml of purified water is then added, filtration and concentration of filtrate are carried out, thus obtaining a crude compound I, and the crude compound I is purified by passing neutral alumina through a column, thus obtaining 35.8g-52.9g of refined compound I, and the total yield is 56.3% -82.6%.
4. A process for the synthesis of the pharmaceutical intermediate 7-oxo-2-azaspiro [3.5] nonane according to claim 1, characterized in that: in the step (1) or the step (2), the acid binding agent is anhydrous potassium carbonate, anhydrous sodium carbonate and sodium bicarbonate.
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