Preparation method of 2-Boc-2, 7-diaza-spiro [4.4] nonane

Abstract

The invention discloses a preparation method of 2-Boc-2, 7-diaza-spiro [4.4] nonane, and belongs to the technical field of organic intermediates. The preparation method comprises the following steps: by taking spiro [3.3] heptane-2, 6-diketone as a raw material, reacting with hydroxylamine hydrochloride to generate spiro [3.3] heptane-2, 6-diketone dioxime; the preparation method comprises the following steps: firstly, preparing 2, 7-diazaspiro [4.4] nonane-3, 8-diketone, and then carrying out Beckmann rearrangement in the presence of an aluminum trichloride ionic liquid and a catalyst to generate 2, 7-diazaspiro [4.4] nonane-3, 8-diketone; then reducing the 2, 7-diazaspiro [4.4] nonane by sodium borohydride and iodine to generate 2, 7-diazaspiro [4.4] nonane; finally, the 2-Boc-2, 7-diazaspiro [4.4] nonane reacts with (Boc) 2O, and 2-Boc-2, 7-diazaspiro [4.4] nonane is generated. The preparation method comprises the following steps: carrying out Beckmann rearrangement on spiro [3.3] heptane-2, 6-diketone dioxime under the action of a catalyst, and constructing a 2, 7-diazaspiro [4.4] nonane-3, 8-diketone framework.

Description

Technical Field

[0001] The invention relates to a preparation method of 2-Boc-2,7-diaza-spiro[4.4]nonane, belonging to the technical field of organic intermediates. Background Art

[0002] 2-Boc-2,7-diazaspiro[4.4]nonane (CAS No.: 236406-49-8) is an important organic synthesis intermediate with wide applications in medicine, pesticides, photoelectric conversion materials, etc. In the field of organic catalysis and metal catalysis, the 2,7-diazaspiro[4.4]nonane skeleton is also an important structural unit.

[0003] There are few reports on the synthesis of 2,7-diazaspiro[4.4]nonane, and there are mainly two routes:

[0004] A. Patents and literature [WO200730061A; Journal of Organic Chemistry, 1981, 46, 2757] reported that diethyl 3,3-dicyanoglutarate was synthesized using malononitrile and ethyl 2-bromoacetate as raw materials under sodium hydride conditions, and then refluxed under concentrated sulfuric acid and glacial acetic acid conditions to generate 2,7-diazaspiro[4.4]nonane-1,3,6,8-tetraone, and then reduced with LiAlH4 to generate 2,7-diazaspiro[4.4]nonane.

[0005] B. The literature [Journal of Medicinal Chemistry, 1990, 33, 2270] reported that diethyl 3,3-dicyanoglutarate was synthesized using malononitrile and ethyl 2-bromoacetate as raw materials under sodium hydride conditions, and then 2,7-diazaspiro[4.4]nonane-3,8-dione was synthesized under Raney cobalt and hydrogen conditions, and then LiAlH4 was reduced to generate 2,7-diazaspiro[4.4]nonane.

[0006] In view of the shortcomings of the above routes, it is necessary to conduct in-depth research on the synthetic route of 2-Boc-2,7-diazaspiro[4.4]nonane to provide a better process route with cheaper and more readily available raw materials to meet the growing market demand. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing 2-Boc-2,7-diazaspiro[4.4]nonane. The method provided by the present invention uses spiro[3.3]heptane-2,6-dione as a raw material, reacts with hydroxylamine hydrochloride to generate spiro[3.3]heptane-2,6-dione dioxime; then, under the conditions of aluminum chloride ionic liquid and catalyst, Beckmann rearrangement is performed to generate 2,7-diazaspiro[4.4]nonane-3,8-dione; then, sodium borohydride and iodine are reduced to generate 2,7-diazaspiro[4.4]nonane; and finally, it reacts with (Boc)2O to generate 2-Boc-2,7-diazaspiro[4.4]nonane.

[0008] The preparation method of 2-Boc-2,7-diazaspiro[4.4]nonane of the present invention is achieved by the following technical scheme, and the reaction equation is expressed as follows:

[0009]

[0010] The steps include:

[0011] A. mixing spiro[3.3]heptane-2,6-dione, hydroxylamine hydrochloride and a base in methanol and reacting them under reflux to generate spiro[3.3]heptane-2,6-dione dioxime;

[0012] B. mixing spiro[3.3]heptane-2,6-dione dioxime, ionic liquid and catalyst in hexafluoroisopropanol and reacting them at elevated temperature to generate 2,7-diazaspiro[4.4]nonane-3,8-dione;

[0013] C. Mix 2,7-diazaspiro[4.4]nonane-3,8-dione, sodium borohydride and iodine in THF and react under reflux; then cool to room temperature, add methanol and (Boc)2O to generate 2-Boc-2,7-diazaspiro[4.4]nonane;

[0014] Preferably, in step A of the above technical solution, the base is selected from sodium acetate or sodium carbonate.

[0015] Preferably, in step A of the above technical solution, the molar ratio of spiro[3.3]heptane-2,6-dione, hydroxylamine hydrochloride and base is 1:2-2.5:3-3.5.

[0016] Preferably, in step B of the above technical solution, the ionic liquid is selected from 1-butyl-3-methylimidazolium ferric chloride, 1-butyl-3-methylimidazolium zinc chloride or 1-butyl-3-methylimidazolium aluminum chloride.

[0017] Preferably, in step B of the above technical solution, the temperature rising condition is 40-50°C.

[0018] Preferably, in step B of the above technical solution, the catalyst is selected from cyanuric chloride or hexachlorocyclotriphosphazene.

[0019] Preferably, in step B of the above technical solution, the molar ratio of spiro[3.3]heptane-2,6-dione dioxime, ionic liquid and catalyst is 1:0.01-0.05:0.001-0.003.

[0020] Preferably, in step C of the above technical scheme, the molar ratio of 2,7-diazaspiro[4.4]nonane-3,8-dione, sodium borohydride, iodine and (Boc)2O is 1:3-3.5:2-3:1-1.1.

[0021] Beneficial effects of the present invention

[0022] A. The present invention uses spiro[3.3]heptane-2,6-dione dioxime to carry out Beckmann rearrangement under the action of a catalyst to construct a 2,7-diazaspiro[4.4]nonane-3,8-dione framework. The route is novel and feasible, and provides a new route reference for the synthesis of 2,7-diazaspiro[4.4]nonane compounds.

[0023] B. The 2,7-diazaspiro[4.4]nonane-3,8-dione of the present invention uses sodium borohydride and iodine to reduce amide, the excess sodium borohydride is quenched with methanol, and the remaining iodine directly catalyzes the (Boc)2O reaction to synthesize 2-Boc-2,7-diazaspiro[4.4]nonane, which reduces the operation steps and improves the yield. A route reference is provided for the synthesis of such compounds. Specific embodiments

[0024] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

[0025] Example 1

[0026]

[0027] Under nitrogen protection, 12.4 g (0.1 mol) of spiro[3.3]heptane-2,6-dione, 15.3 g (0.22 mol) of hydroxylamine hydrochloride and 26.2 g (0.32 mol) of sodium acetate were mixed in 250 mL of methanol, reacted for 3 hours under reflux conditions, cooled to room temperature, filtered, concentrated, and the crude product was slurried with 100 ml of deionized water, filtered, and dried to obtain spiro[3.3]heptane-2,6-dione dioxime, 13.8 g, yield 90%, GC 98.7%. 1 HNMR (400MHz, DMSO-d6): 8.62 (s, 1H), 3.10 (m, 4H).

[0028] Example 2

[0029]

[0030] Under nitrogen protection, 15.4 g (0.1 mol) of spiro[3.3]heptane-2,6-dione dioxime, 0.62 g (0.002 mol) of 1-butyl-3-methylimidazole zinc chloride and 0.052 g (0.15 mmol) of hexachlorocyclotriphosphazene were mixed in 80 mL of hexafluoroisopropanol, heated to 40-50 ° C, reacted for 2 hours, cooled to room temperature, concentrated, and the crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v = 1 / 1-2) to obtain 2,7-diazaspiro[4.4]nonane-3,8-dione, 12.6 g, with a yield of 82%, and GC 99%. 1 HNMR(400MHz, DMSO-d6):7.53(s,2H),3.15(s,4H),2.2(s,4H).

[0031] Comparative Example 2

[0032] Under nitrogen protection, 15.4 g (0.1 mol) of spiro[3.3]heptane-2,6-dione dioxime, 0.62 g (0.002 mol) of 1-butyl-3-methylimidazole aluminum chloride and 0.052 g (0.15 mmol) of hexachlorocyclotriphosphazene were mixed in 80 mL of hexafluoroisopropanol, heated to 60-70 ° C, reacted for 2 hours, cooled to room temperature, concentrated, and the crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v = 1 / 1-2) to obtain 2,7-diazaspiro[4.4]nonane-3,8-dione, 10.9 g, with a yield of 71%, and GC 98.5%.

[0033] Example 3

[0034]

[0035] Under nitrogen protection, 15.4 g (0.1 mol) of 2,7-diazaspiro[4.4]nonane-3,8-dione and 12.1 g (0.32 mol) of sodium borohydride were mixed in 80 mL of THF and the temperature was lowered to 0-10°C. 56 g (0.22 mol) of iodine was mixed with 200 mL of THF and slowly added dropwise to the above reaction solution. After the addition was completed, the temperature was raised to reflux and the reaction was carried out for 5 hours. The temperature was then lowered to room temperature, 50 mL of methanol was added, and then 1.8 g (0.1 mol) of (Boc)2O2 was added and stirred at room temperature for 1 hour. After the reaction was completed, 100 mL of ammonia water (5%) was added, the layers were separated, and the aqueous layer was extracted twice with 50 mL of diisopropyl ether. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v=1 / 6-10) to obtain 2-Boc-2,7-diazaspiro[4.4]nonane, 15.4 g, with a yield of 68% and a GC of 99%. 1 HNMR (400MHz, DMSO-d6): 3.48-3.28(m,4H), 3.03(m,2H), 2.88-2.78(m,2H), 1.92(m,1H), 1.87-1.73(m,4H), 1.48(s,9H).

[0036] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane, characterized in that: The steps include: A. mixing spiro[3.3]heptane-2,6-dione, hydroxylamine hydrochloride and a base in methanol and reacting them under reflux to generate spiro[3.3]heptane-2,6-dione dioxime; B. mixing spiro[3.3]heptane-2,6-dione dioxime, ionic liquid and catalyst in hexafluoroisopropanol and reacting them at elevated temperature to generate 2,7-diazaspiro[4.4]nonane-3,8-dione; C. Mix 2,7-diazaspiro[4.4]nonane-3,8-dione, sodium borohydride and iodine in THF and react under reflux; then cool to room temperature, add methanol and (Boc)2O to generate 2-Boc-2,7-diazaspiro[4.4]nonane.

2. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step A, the base is selected from sodium acetate or sodium carbonate.

3. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step A, the molar ratio of spiro[3.3]heptane-2,6-dione, hydroxylamine hydrochloride and base is 1:2-2.5:3-3.

5.

4. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step B, the ionic liquid is selected from 1-butyl-3-methylimidazolium ferric chloride, 1-butyl-3-methylimidazolium zinc chloride or 1-butyl-3-methylimidazolium aluminum chloride.

5. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step B, the temperature is raised to 40-50°C.

6. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step B, the catalyst is selected from cyanuric chloride or hexachlorocyclotriphosphazene.

7. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step B, the molar ratio of spiro[3.3]heptane-2,6-dione dioxime, ionic liquid and catalyst is 1:0.01-0.05:0.001-0.

003.

8. The method for preparing 2-Boc-2,7-diaza-spiro[4.4]nonane according to claim 1, characterized in that: In step C, the molar ratio of 2,7-diazaspiro[4.4]nonane-3,8-dione, sodium borohydride, iodine and (Boc)2O is 1:3-3.5:2-3:1-1.1.

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