A method for preparing 2-oxa-6-aza-spiro[3,3]heptane

Abstract

The invention belongs to the technical field of organic synthesis, and specifically discloses a method for preparing 2-oxa-6-aza-spiro[3,3]heptane. The invention provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, using the compound tribromoneopentyl alcohol as a starting material, closing the ring under alkaline conditions to obtain 6-toluenesulfonyl-protected 2-oxa-6-aza-spiro[3,3]heptane, using by-product hydrogen and alkali in the process of preparing active Raney nickel, efficiently removing the protecting group, and then separating and distilling to obtain a high-purity free product 2-oxa-6-aza-spiro[3,3]heptane.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing 2-oxa-6-aza-spiro[3,3]heptane. Background Art

[0002] 2-oxa-6-azaspiro[3,3]heptane is an organic compound with the appearance of a transparent oily liquid. It is mainly used as an organic synthesis intermediate and a pharmaceutical intermediate.

[0003] The literature Angew.Chem.Int.Ed., 2008, 47, 4512, and the literature Eur.J.Med.Chem., 122(2016)475 reported similar preparations of 2-oxa-6-aza-spiro[3,3]heptane oxalate, see the following formula I.

[0004]

[0005] It can be seen from the above synthetic route that the preparation of 2-oxa-6-aza-spiro[3,3]heptane oxalate is usually based on the compound tribromoneopentyl alcohol as the starting material, which is cyclized with p-toluenesulfonamide under alkaline conditions to obtain the intermediate 6-p-toluenesulfonyl-2-oxa-6-aza-spiro[3,3]heptane, followed by methanol as the solvent system to dissolve the intermediate, and then magnesium chips are added in batches to reduce the hydrogen released by the reaction, remove the protecting group p-toluenesulfonyl, filter the magnesium salt several times, and extract to obtain the crude product 2-oxa-6-aza-spiro[3,3]heptane. Then, the oxalate is formed to obtain the pure product. In the actual operation process, the total yield is between 30-40%. The main reason is that the content of the product 2-oxa-6-aza-spiro[3,3]heptane is difficult to determine, and it is also difficult to control whether the oxalate is precipitated as hemioxalate or oxalate. The actual situation is a mixture of hemioxalate, oxalate, and excess oxalic acid. There are also patents that have been improved to acetates, such as the invention patent CN102746312A, which discloses a novel method for preparing 2-oxa-6-aza-spiro[3,3]heptane oxalate and its acetate, which is improved to acetate. In actual operation, it was found that the product was not very stable to acid, and the four-membered ring ether was easier to open. After opening, impurities can also form acetate or oxalate, which makes post-processing crystallization and purification very difficult. In addition, the literature method requires special equipment and uses low-boiling ether solvents. It is also very dangerous to enlarge the solvent loss, which is not suitable for large-scale preparation. Summary of the invention

[0006] The object of the present invention is to overcome the above problems existing in the prior art and provide a method for preparing 2-oxa-6-aza-spiro[3,3]heptane. The compound tribromoneopentyl alcohol is used as a starting material, and a ring is closed under alkaline conditions to obtain 6-toluenesulfonyl-protected 2-oxa-6-aza-spiro[3,3]heptane. The by-product hydrogen and base produced in the process of preparing active Raney nickel are used to efficiently remove the protecting group, and then a high-purity free product 2-oxa-6-aza-spiro[3,3]heptane is obtained through separation and distillation.

[0007] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0008] A method for preparing 2-oxa-6-aza-spiro[3,3]heptane, the method comprising the following steps:

[0009] S1: Under alkaline conditions, tribromoneopentyl alcohol is used as the starting material, and then cyclized with p-toluenesulfonamide to obtain compound 2;

[0010] S2: At room temperature and alkaline conditions, compound 2 is added to a mixed solvent, and then a reducing metal is added in batches to react to obtain 2-oxa-6-aza-spiro[3,3]heptane.

[0011] Furthermore, the reaction formula of the preparation method is shown in Formula II:

[0012]

[0013] In formula II, 1 is tribromoneopentyl alcohol and 2 is compound 2.

[0014] Furthermore, the reaction in step S1 is carried out under alkaline conditions in an organic solvent;

[0015] The organic solvent used is any one or more of methanol, ethanol, and isopropanol;

[0016] The reaction time used is 30-100h.

[0017] Furthermore, in step S1, the reaction time used is 70 hours.

[0018] Furthermore, in step S1, the molar ratio of tribromoneopentyl alcohol to p-toluenesulfonamide is 1:(1-1.5).

[0019] Furthermore, the base used under alkaline conditions in step S1 and the base used under alkaline conditions in step S2 are independently selected from any one of potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate.

[0020] Furthermore, the alkali used under alkaline conditions in step S1 is potassium hydroxide, and the alkali used under alkaline conditions in step S2 is sodium hydroxide.

[0021] Furthermore, the mixed solvent is a mixture of alcohols and deionized water.

[0022] Furthermore, the alcohol is any one or more of methanol, ethanol, and isopropanol.

[0023] Furthermore, the alcohol is ethanol.

[0024] Furthermore, in step S2, the reducing metal is any one or more of metal magnesium, metal sodium, metal zinc, and nickel-aluminum alloy.

[0025] Furthermore, the reducing metal is a nickel-aluminum alloy.

[0026] Furthermore, in the nickel-aluminum alloy, the mass percentage of nickel is 45-60%.

[0027] Furthermore, in step S2, the molar ratio of compound 2 to reducing metal is 1:(1.5-2.5).

[0028] Furthermore, in step S2, the time interval for adding the reducing metal in batches is 5-20 minutes, and the number of batches is 7-25 times.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which comprises taking tribromoneopentyl alcohol as a starting material, performing ring closure under alkaline conditions to obtain 6-toluenesulfonyl-protected 2-oxa-6-aza-spiro[3,3]heptane, using by-product hydrogen gas and a base in the process of preparing active Raney nickel to efficiently remove the protecting group, and then separating and distilling to obtain a high-purity free product 2-oxa-6-aza-spiro[3,3]heptane.

[0031] 2. In the present invention, in step S2, ethanol and water are selected as a mixed solvent, and the reducing metal is a nickel-aluminum alloy. The nickel-aluminum alloy is added in batches at room temperature to control the heat release and gas production, so that the reaction process is mild and controllable, and the conditions are greatly simplified, so that it can be applied to the large-scale preparation of 2-oxa-6-aza-spiro[3,3]heptane.

[0032] 3. In the present invention, in step S2, since nickel-aluminum alloy is used, after most of the aluminum is consumed during the reaction, the nickel particles produced are easy to separate the solid and liquid by means of suction filtration or pressure filtration, and the solid catalyst nickel can be used as a catalyst after fully washing the organic matter; specifically, ethanol is used for sufficient elution, and then the ethanol and water mixture is distilled to finally produce a liquid product. Since the product has a boiling range of 165.7°C-170°C / 760mmHg, it can be better separated from the low-boiling point ethanol azeotrope; in the present invention, since the final prepared 2-oxa-6-aza-spiro[3,3]heptane product has a high purity, in order to facilitate storage and use, it can be more conveniently quantified into oxalate in anhydrous methanol or acetate in ethyl acetate. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] A method for preparing 2-oxa-6-aza-spiro[3,3]heptane, the method comprising the following steps:

[0035] S1: Under alkaline conditions, tribromoneopentyl alcohol is used as the starting material, and then cyclized with p-toluenesulfonamide to obtain compound 2;

[0036] Specifically, step S1 comprises the following steps: under alkaline conditions, dissolving tribromoneopentyl alcohol and p-toluenesulfonamide in solvent A, heating and refluxing the reaction, concentrating the obtained product, adding it into alkaline solution and stirring, and finally filtering, washing with water, and drying to obtain compound 2;

[0037] Specifically, the heating reflux reaction time is 30-100h, the heating reflux reaction time is preferably 70-96h, and the heating reflux reaction time is more preferably 70h;

[0038] Wherein, the molar ratio of tribromoneopentyl alcohol to p-toluenesulfonamide is 1:(1-1.5), and specifically, the molar ratio of tribromoneopentyl alcohol to p-toluenesulfonamide may be preferably 1:1.2;

[0039] The alkali in the alkali solution is any one of potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and the alkali in the alkali solution is preferably potassium hydroxide;

[0040] In step S1, under alkaline conditions, tribromoneopentyl alcohol and p-toluenesulfonamide are dissolved in solvent A; specifically, tribromoneopentyl alcohol and p-toluenesulfonamide react in solvent A in the presence of a base; specifically, the base is any one of potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, and the base is preferably potassium hydroxide; solvent A is any one or more of methanol, ethanol, and isopropanol, and solvent A is preferably anhydrous ethanol;

[0041] S2: Add compound 2 to a mixed solvent at room temperature and alkaline conditions, and then add reducing metal in batches to react to obtain 2-oxa-6-aza-spiro[3,3]heptane;

[0042] Specifically, step S2 comprises the following steps: adding compound 2 to a mixed solvent at room temperature and alkaline conditions, and then adding reducing metals in batches to react, cooling after the reaction is complete, filtering, rinsing with ethanol, and concentrating, and then adding sodium sulfate decahydrate and ethanol, filtering, concentrating, and distilling under reduced pressure, collecting the product at 80-85° C., and obtaining 2-oxa-6-aza-spiro[3,3]heptane;

[0043] In step S2, adding compound 2 to a mixed solvent under alkaline conditions at room temperature means adding compound 2 to a mixed solvent in the presence of a base; specifically, the base is any one of potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, and the base is preferably sodium hydroxide;

[0044] The mixed solvent is a mixture of alcohols and deionized water, the alcohol is any one or more of methanol, ethanol, and isopropanol, and the alcohol is preferably ethanol; more specifically, in the mixed solvent, the volume mass ratio of deionized water to ethanol is 1:(1-2) in mL / g, and the volume mass ratio of deionized water to ethanol is preferably 1:1 in mL / g;

[0045] In step S2, the reducing metal is any one or more of metal magnesium, metal sodium, metal zinc, and nickel-aluminum alloy, preferably nickel-aluminum alloy; specifically, the mass percentage of nickel in the nickel-aluminum alloy is 45-60%, and the mass percentage of nickel in the nickel-aluminum alloy is preferably 50%;

[0046] In step S2, the molar ratio of compound 2 to the reducing metal is 1:(1.5-2.5). Specifically, in step S2, the molar ratio of compound 2 to the reducing metal is 1:(1.5-2.0). More specifically, in step S2, the molar ratio of compound 2 to the reducing metal may preferably be 1:1.8.

[0047] In step S2, the reducing metal is added in batches at a time interval of 5-20 minutes, and the number of batches is 7-25 times;

[0048] In addition, the reaction formula of the preparation method is as follows:

[0049]

[0050] In the reaction formula, 1 is tribromoneopentyl alcohol, 2 is compound 2, i.e. 6-toluenesulfonyl-protected 2-oxa-6-aza-spiro[3,3]heptane, i.e. 6-toluenesulfonyl-2-oxa-6-aza-spiro[3,3]heptane, 3 is free 2-oxa-6-aza-spiro[3,3]heptane, and 4 is high-purity 2-oxa-6-aza-spiro[3,3]heptane.

[0051] In the present invention, in step S2, through process improvement, that is, using alcohols and water as mixed solvents, adding reducing metals in batches at room temperature, controlling heat release and gas production, the reaction process is mild and controllable, the conditions are greatly simplified, and the reaction can be applied to the large-scale preparation of 2-oxa-6-aza-spiro[3,3]heptane.

[0052] In the present invention, the reducing metal is preferably a nickel-aluminum alloy (in the nickel-aluminum alloy, the mass percentage of nickel is 50%). After most of the aluminum is consumed, the generated nickel particles are very easy to separate the solid and liquid by means of suction filtration or pressure filtration.

[0053] The following are specific examples. In the following examples, unless otherwise specified, all raw materials can be obtained from commercial sources.

[0054] In the following examples and comparative examples, the mass percentage of nickel in the nickel-aluminum alloy is 50%.

[0055] Example 1

[0056] This embodiment provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which comprises the following steps:

[0057] Step 1, add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (6.32kg, 37.0mol), and 5.52kg (98.6mol) of potassium hydroxide into a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added into 30L, 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (5.3kg, 20.9mol), i.e., compound 2, with a yield of 67.8%; the nuclear magnetic resonance hydrogen spectrum of compound 2 is measured, and the hydrogen spectrum is analyzed: H NMR (CDCl3) δ7.69 (d, 2H, J = 8.4Hz), 7.47 (d, 2H, J = 8.4Hz), 4.42 (s, 4H), 3.85 (s, 4H), 2.41 (s, 3H);

[0058] Step 2, 1000ML reaction flask was added with 166.5ml of water, sodium hydroxide (28.08g, 0.70mol), dissolved and cooled to about 20°C, then ethanol (166.5g) was added, 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol) was added, and the temperature was continued to be cooled to about 15°C, and then nickel-aluminum alloy (39g, 0.45mol) was added in batches, and heat was released during the period, and the temperature was controlled below 30°C, and the time interval of adding the reducing metal in batches was 10min, and the number of times in batches was 13 times, and the nickel-aluminum alloy was added, and the reaction was complete. The reaction system was cooled to about 0°C, carefully filtered, and a small amount of ethanol was rinsed to obtain the catalyst Raney nickel, and the mother liquor was concentrated to obtain a viscous solid, and then 100 grams of sodium sulfate decahydrate were added, and 200 milliliters of anhydrous ethanol were stirred and filtered. Ethanol was concentrated again to obtain a viscous liquid, which was then distilled under reduced pressure. A small portion of low-boiling fractions was collected first, and then the product at about 82°C (19.8 g, 0.20 mol, yield 80%) was collected, namely 2-oxa-6-aza-spiro[3,3]heptane. The prepared 2-oxa-6-aza-spiro[3,3]heptane was measured by hydrogen nuclear magnetic resonance spectrum, and the hydrogen spectrum was analyzed: H NMR (CDCl3) δ 4.77 (s, 4H), 3.79 (s, 4H).

[0059] Example 2

[0060] This embodiment provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which comprises the following steps:

[0061] Step 1: Add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (6.32kg, 37.0mol), and 5.52kg (98.6mol) of potassium hydroxide to a 100L reactor. After adding, heat and reflux for 4 days (about 96h). The reaction solution is concentrated and dried, added to 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (4.8kg, 18.9mol), i.e., compound 2, with a yield of 61.4%;

[0062] Step 2, 1000ML reaction bottle is added with water 166.5ml, sodium hydroxide (28.08g, 0.70mol), after dissolving, cool to about 20 ℃, then add ethanol (166.5g), add 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol), continue to cool to about 0 ℃, then add nickel aluminum alloy (39g, 0.45mol) in batches, during heat release, temperature control below 5 ℃, add reducing metal in batches at a time interval of 5min, batch number of times is 25 times, add nickel aluminum alloy, after reaction is complete. Cool the reaction system to about 0 ℃, carefully filter, rinse with a small amount of ethanol to obtain catalyst Raney nickel, concentrate the mother liquor to obtain a viscous solid, add 100 grams of sodium sulfate decahydrate, add 200 milliliters of anhydrous ethanol and stir, filter with suction. The ethanol was then concentrated to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 80°C (17.8 g, 0.18 mol, yield 72%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0063] Example 3

[0064] This embodiment provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which comprises the following steps:

[0065] Step 1: Add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (7.90kg, 46.2mol), and 5.52kg (98.6mol) of potassium hydroxide to a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added to 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (3.8kg, 15.2mol), namely compound 2, with a yield of 49.3%;

[0066] Step 2, 1000ML reaction flask was added with 166.5ml of water, sodium hydroxide (28.08g, 0.70mol), dissolved and cooled to about 20°C, then ethanol (333g) was added, 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol) was added, and the temperature was continued to be cooled to about 15°C, and then nickel-aluminum alloy (39g, 0.45mol) was added in batches, and heat was released during the period, and the temperature was controlled below 30°C. The time interval of adding the reducing metal in batches was 20min, and the number of times in batches was 7 times, and the nickel-aluminum alloy was added, and the reaction was complete. The reaction system was cooled to about 0°C, carefully filtered, and a small amount of ethanol was rinsed to obtain the catalyst Raney nickel, and the mother liquor was concentrated to obtain a viscous solid, and then 100 grams of sodium sulfate decahydrate were added, and 200 milliliters of anhydrous ethanol were stirred and filtered. The ethanol was then concentrated to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 85°C (18.8 g, 0.19 mol, yield 76%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0067] Example 4

[0068] This embodiment provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which comprises the following steps:

[0069] Step 1: Add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (6.32kg, 37.0mol), and 6.90kg (123.2mol) of potassium hydroxide into a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added into 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (4.1kg, 15.9mol), i.e., compound 2, with a yield of 52%.

[0070] Step 2, add 166.5ml of water and sodium hydroxide (0.70mol) to a 1000ML reaction bottle, cool to about 20°C after dissolving, add ethanol (166.5g), add 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol), continue to cool to about 15°C, then add nickel-aluminum alloy (0.5mol) in batches, exothermic during the period, control the temperature below 30°C, add the reducing metal in batches at a time interval of 10min, the number of batches is 13 times, add the nickel-aluminum alloy, and react completely. Cool the reaction system to about 5°C, carefully filter, rinse with a small amount of ethanol to obtain the catalyst Raney nickel, concentrate the mother liquor to obtain a viscous solid, add 100 grams of sodium sulfate decahydrate, add 500 milliliters of anhydrous ethanol, stir, and filter. The ethanol was then concentrated to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 81°C (18.81 g, 0.19 mol, yield 76%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0071] Example 5

[0072] This embodiment provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which comprises the following steps:

[0073] Step 1: Add 120L of anhydrous ethanol, tribromoneopentyl alcohol (30.8mol), p-toluenesulfonamide (37.0mol), and 5.52kg of potassium hydroxide to a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added to 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (5.0kg, 19.7mol), namely compound 2, with a yield of 64%;

[0074] Step 2, add 166.5ml of water and sodium hydroxide (0.70mol) to a 1000ML reaction bottle, cool to about 20°C after dissolving, add ethanol (166.5g), add 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol), continue to cool to about 15°C, then add nickel-aluminum alloy (0.38mol) in batches, exothermic during the period, control the temperature below 30°C, add the reducing metal in batches at a time interval of 10min, the number of batches is 13 times, add the nickel-aluminum alloy, and react completely. Cool the reaction system to about 5°C, carefully filter, rinse with a small amount of ethanol to obtain the catalyst Raney nickel, concentrate the mother liquor to obtain a viscous solid, add 100 grams of sodium sulfate decahydrate, add 500 ml of anhydrous ethanol, stir, and filter. The ethanol was concentrated again to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 84°C (17.8 g, 0.18 mol, yield 72%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0075] Comparative Example 1

[0076] This comparative example provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which is different from Example 1 in that in this comparative example, the nickel-aluminum alloy is added all at once, as follows:

[0077] Step 1: Add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (6.32kg, 37.0mol), and 5.52kg of potassium hydroxide to a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added to 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (5.3kg, 20.9mol), i.e., compound 2, with a yield of 67.8%;

[0078] Step 2, add 166.5ml of water, sodium hydroxide (28.08g, 0.70mol) in the 1000ML reaction bottle, cool to about 20°C after dissolving, add ethanol (166.5g), add 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol), continue to cool to about 15°C, then add nickel-aluminum alloy (26g, 0.30mol) in batches, exothermic during, temperature control below 30°C, add reducing metal in batches at a time interval of 10min, batchwise number of times is 13 times, add nickel-aluminum alloy, after the reaction is complete. The reaction system is cooled to about 0°C, carefully filtered, a small amount of ethanol rinses to obtain the catalyst Raney nickel, and after concentrating the mother liquor, a viscous solid is obtained, and after adding 100 grams of sodium sulfate decahydrate, 200 milliliters of anhydrous ethanol are added and stirred, and filtered. The ethanol was concentrated again to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 80-85°C (5.45 g, 0.055 mol, yield 22%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0079] Comparative Example 2

[0080] This comparative example provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which is different from Example 1 in that in this comparative example, the reducing metal is a Raney nickel catalyst, as follows:

[0081] Step 1: Add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (6.32kg, 37.0mol), and 5.52kg of potassium hydroxide to a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added to 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (5.3kg, 20.9mol), i.e., compound 2, with a yield of 67.8%;

[0082] Step 2, 1000ML reaction flask was added with 166.5ml of water, sodium hydroxide (28.08g, 0.70mol), dissolved and cooled to about 20°C, then ethanol (166.5g) was added, 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol) was added, and the temperature continued to be cooled to about 0°C, and then catalyst Raney nickel (0.45mol) was added in batches, and heat was released during the period, and the temperature was controlled below 30°C. The time interval of adding the reducing metal in batches was 10min, and the number of times in batches was 13 times, and metallic nickel was added, and the reaction was complete. The reaction system was cooled to about 0°C, carefully filtered, rinsed with a small amount of ethanol, and a thick solid was obtained after concentrating the mother liquor, and then 100 grams of sodium sulfate decahydrate were added, and 200 milliliters of anhydrous ethanol were stirred and filtered with suction. The ethanol was concentrated again to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 80-85°C (2.48 g, 0.025 mol, yield 10%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0083] Comparative Example 3

[0084] This comparative example provides a method for preparing 2-oxa-6-aza-spiro[3,3]heptane, which is different from Example 1 in that, in this comparative example, the mixed solvent (a mixture of ethanol and water) in Example 1 is replaced with 90% ethanol, as follows:

[0085] Step 1: Add 80L of anhydrous ethanol, tribromoneopentyl alcohol (10.0kg, 30.8mol), p-toluenesulfonamide (6.32kg, 37.0mol), and 5.52kg of potassium hydroxide to a 100L reactor. After adding, heat and reflux for 3 days (about 70h). The reaction solution is concentrated and dried, added to 30L of 1M potassium hydroxide aqueous solution, stirred for 2 hours, filtered, washed with water, and dried to obtain a white solid (5.3kg, 20.9mol), i.e., compound 2, with a yield of 67.8%;

[0086] Step 2, 90% ethanol (333.0g) was added to a 1000ML reaction bottle, followed by 6-p-methylbenzenesulfonyl-2-oxo-assorted-spiro [3,3] heptane (63.37g, 0.25mol), sodium hydroxide (28.08g, 0.70mol), and the temperature was continued to be lowered to about 15°C, and then nickel-aluminum alloy (39g, 0.45mol) was added in batches, during which heat was released, the temperature was controlled below 30°C, and the time interval for adding the reducing metal in batches was 10min, and the number of batches was 13 times, and the nickel-aluminum alloy was added, and the reaction was complete. The reaction system was cooled to about 0°C, carefully filtered, and a small amount of ethanol was rinsed to obtain the catalyst Raney nickel. After concentrating the mother liquor, a viscous solid was obtained, and then 100 grams of sodium sulfate decahydrate were added, and 200 milliliters of anhydrous ethanol were added, stirred, and filtered. The ethanol was then concentrated to obtain a viscous liquid, which was then distilled under reduced pressure. A small amount of low-boiling fractions were collected first, and then the product at about 82°C (8.42 g, 0.085 mol, yield 34%) was collected, which was 2-oxa-6-aza-spiro[3,3]heptane.

[0087] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0088] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for preparing 2-oxa-6-aza-spiro[3,3]heptane, characterized in that: The preparation method comprises the following steps: S1: Under alkaline conditions, tribromoneopentyl alcohol is used as the starting material, and then cyclized with p-toluenesulfonamide to obtain compound 2; S2: At room temperature and alkaline conditions, compound 2 is added to a mixed solvent, and then a reducing metal is added in batches to react to obtain 2-oxa-6-aza-spiro[3,3]heptane.

2. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: The reaction in step S1 is carried out under alkaline conditions in an organic solvent; The organic solvent used is any one or more of methanol, ethanol, and isopropanol; The reaction time used is 30-100h.

3. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: In step S1, the molar ratio of tribromoneopentyl alcohol to p-toluenesulfonamide is 1:(1-1.5).

4. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: The base used under alkaline conditions in step S1 and the base used under alkaline conditions in step S2 are independently selected from any one of potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate.

5. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: The mixed solvent is a mixture of alcohols and deionized water.

6. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 5, characterized in that: The alcohol is any one or more of methanol, ethanol and isopropanol.

7. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: In step S2, the reducing metal is any one or more of metal magnesium, metal sodium, metal zinc, and nickel-aluminum alloy.

8. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 7, characterized in that: The reducing metal is a nickel-aluminum alloy; In the nickel-aluminum alloy, the mass percentage of nickel is 45-60%.

9. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: In step S2, the molar ratio of compound 2 to reducing metal is 1:(1.5-2.5).

10. The method for preparing 2-oxa-6-aza-spiro[3,3]heptane according to claim 1, characterized in that: In step S2, the time interval for adding the reducing metal in batches is 5-20 minutes, and the number of batches is 7-25 times.

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