A process for the preparation of 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride

Abstract

This invention provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, the method comprising the following steps: (1) reacting chloroacetone with N-tert-butoxycarbonylglycine ethyl ester, a catalyst, and a base to obtain compound 1; (2) reacting compound 1 with a base to obtain compound 2; (3) reacting compound 2 with a reducing agent to obtain compound 3; (4) reacting compound 3 with a phosphorus ligand and an azodicarbonate ester to obtain compound 4, followed by hydrochloric acid treatment to obtain the 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride. The preparation method provided by this invention requires only five steps to prepare 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, with fewer synthesis steps, lower raw material costs, and higher overall reaction yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, and more particularly to a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride with fewer preparation steps and higher yield. Background Technology

[0002] 6-Oxa-3-azabicyclo[3.1.1]heptane hydrochloride is a key fragment of a drug containing an oxabridged ring. The conventional method is to react 4-methoxybenzaldehyde with ammonia to generate an imine, then ring-opening epichlorohydrin, chloroacetylation of the amino group, two consecutive ring-closings, borane reduction, and hydrogenation to form the hydrochloride in eight steps.

[0003]

[0004] However, the above steps are lengthy and not conducive to large-scale production, and the low overall yield leads to high unit costs. Therefore, how to provide an alternative method for synthesizing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloric acid with high yield, low cost and fewer reaction steps has become an urgent problem to be solved. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, and more particularly, a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride with fewer steps and higher yield. The preparation method provided by the present invention requires only five reaction steps to achieve the preparation of 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, with fewer synthesis steps, lower raw material costs, and higher overall reaction yield.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] This invention provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, the method comprising the following steps:

[0008] (1) Compound 1 was obtained by reacting chloroacetone with N-tert-butoxycarbonylglycine ethyl ester, catalyst and base;

[0009] (2) Compound 1 is reacted with a base to obtain compound 2;

[0010] (3) Compound 2 was mixed with a reducing agent and reacted to obtain compound 3;

[0011] (4) Compound 3 was mixed with phosphorus ligand and azodicarbonate to obtain compound 4, which was then hydrolyzed to obtain the 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride.

[0012] The reaction route is as follows:

[0013]

[0014] The above reaction starts with chloroacetone, reacts with N-tert-butoxycarbonylglycine ethyl ester under the action of a base, and then obtains the ring-closed product in a one-pot reaction under the action of a base. After reduction and photoelongation reactions, a bridged ring compound is obtained, and then deBoc is removed and salt is formed. Only five steps are needed to prepare 6-oxa-3-azabicyclic [3.1.1]heptane hydrochloride. The overall process is simple. At the same time, the one-pot synthesis can effectively reduce the number of steps required for preparation, improve the overall yield, and the raw materials are cheap and readily available, which reduces the production cost.

[0015] Preferably, the molar ratio of chloroacetone to N-tert-butoxycarbonylglycine ethyl ester, catalyst, and base in step (1) is (1-1.5):1:(0.08-0.12):(1-1.5), wherein the amount of chloroacetone can be 1, 1.1, 1.2, 1.3, 1.4, or 1.5, etc., the amount of catalyst can be 0.08, 0.09, 0.1, 0.11, or 0.12, etc., and the amount of base can be 1, 1.1, 1.2, 1.3, 1.4, or 1.5, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0016] Preferably, the catalyst in step (1) comprises any one or a combination of at least two of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate (TBAB), trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride, with tetrabutylammonium bromide being the most preferred.

[0017] Preferably, the reaction temperature in step (1) is 10-20℃ and the time is 1-5h. The temperature can be 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃ or 20℃, etc., and the time can be 1h, 2h, 3h, 4h or 5h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0018] Preferably, the reaction temperature in step (2) is 0-10℃ and the time is 1-5h. The temperature can be 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃ or 10℃, etc., and the time can be 1h, 2h, 3h, 4h or 5h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0019] Preferably, the alkali includes any one or a combination of at least two of sodium hydride, sodium tert-butoxide, or potassium tert-butoxide.

[0020] Preferably, the reducing agent in step (3) includes sodium borohydride or potassium borohydride.

[0021] Preferably, the molar ratio of compound 3 in step (4) to phosphorus ligand and azodicarbonate is 1:(1-1.2):(1-1.2), wherein the amount of phosphorus ligand can be 1, 1.05, 1.1, 1.15 or 1.2, etc., and the amount of azodicarbonate can be 1, 1.05, 1.1, 1.15 or 1.2, etc., but is not limited to the values ​​listed above. Other values ​​not listed in the above range are also applicable.

[0022] Preferably, the phosphorus ligand in step (4) comprises triphenylphosphine.

[0023] Preferably, the azodicarbonate in step (4) includes any one or a combination of at least two of diisopropyl azodicarbonate, dimethyl azodicarbonate or diethyl azodicarbonate, with diisopropyl azodicarbonate being the most preferred.

[0024] Preferably, the reaction temperature in step (4) is 10-30℃ and the time is 8-16h. The temperature can be 10℃, 15℃, 20℃, 25℃ or 30℃, etc., and the time can be 8h, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃ or 16℃, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] This invention provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, which can be prepared by only five steps. The overall process is simple, and the one-pot synthesis can effectively reduce the number of steps required for preparation and improve the overall yield. At the same time, the raw materials are cheap and readily available, which reduces the production cost. Detailed Implementation

[0027] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0028] Example 1

[0029] This embodiment provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, the specific steps of which are as follows:

[0030] (1) Add 2.2L of tetrahydrofuran to a 5L reactor, then add ethyl N-tert-butyloxycarbonylglycine (296g, 1.46mol), then add tetrabutylammonium bromide (47g, 0.146mol). In an ice bath, add sodium hydride (65g, 1.62mol, in 60% mineral oil) in portions. Stir for 30 minutes, then add chloroacetone (150g, 16.2mol) dropwise, maintaining the temperature between 15-20℃. After the addition is complete, maintain the temperature for 3 hours. Then, cool to 0℃, and under nitrogen atmosphere, add sodium tert-butoxide (156g, 1.62mol) in portions, maintaining the temperature between 5-10℃. After the addition is complete, maintain the temperature for 3 hours. Then, add methyl tert-butyl ether (1.5L), add 100mL of water dropwise, and stir overnight. Filter, wash the filter cake with a small amount of cold methyl tert-butyl ether, and dry to obtain a crude yellow sodium salt. The crude product was dissolved in 1 L of water, and the insoluble matter was filtered off. The pH of the filtrate was adjusted to 4-5 with 0.5 M hydrochloric acid, cooled to 0-5 °C, and stirred overnight. The mixture was then filtered, the filter cake was washed with a small amount of water, and the solid was dried to obtain 288.7 g of yellow powder, with a yield of 93%.

[0031] (2) Dissolve 180g (0.844mol) of the product from the previous step in 2.5L of methanol. In an ice bath, add sodium borohydride (35.2g, 0.92mol) in portions, maintaining the temperature between 5-10°C. Allow to rise naturally to 25°C and stir for 4 hours. Then cool to 0°C and add 200mL of saturated ammonium chloride solution dropwise, stirring for 30 minutes. Concentrate to dryness, add 1L of water, and extract three times using DCM. Combine the organic phases, dry, and concentrate to obtain 165g of product, with a yield of 90%.

[0032] (3) The product from the previous step (65g, 300mmol) was dissolved in 2L of dichloromethane, and triphenylphosphine (80g, 305mmol) was added. Then, diisopropyl azodicarbonate (61.7g, 305mmol) was added dropwise. After the addition was complete, the mixture was stirred at 20℃ for 12h. Anhydrous zinc chloride (42g, 310mol) was added, the temperature was raised to 30℃, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated to dryness. The filtrate was then dissolved in 500mL of isopropyl ether, and the insoluble matter was filtered off. The filtrate was placed in an ice bath, and 4M isopropyl chloride hydrochloride solution was added dropwise. The intermediate temperature was controlled between 5-10℃. The mixture was then filtered, and the filter cake was washed with isopropyl ether. The filter cake was then placed in 300mL of acetone and stirred, filtered, and dried under vacuum to obtain 30.5g of a white powder, with a yield of 75%. The characterization data are as follows:

[0033] 1H NMR (500MHz, DMSO-d6): δ10.1(s,2H),4.57(d,2H),3.29-3.41(m,4H),3.14-3.20(q,1H),2.25-2.28(d,1H).

[0034] Example 2

[0035] This embodiment provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride. Except for step (1) as follows, the specific steps are the same as in Example 1:

[0036] (1) Add 2.2L of tetrahydrofuran to a 5L reactor, then add ethyl N-tert-butyloxycarbonylglycine (296g, 1.46mol), and tetrabutylammonium hydrogen sulfate (49.5g, 0.146mol). In an ice bath, add sodium hydride (65g, 1.62mol, in 60% mineral oil) in portions. Stir for 30 minutes, then add chloroacetone (150g, 16.2mol) dropwise, maintaining the temperature between 15-20℃. After the addition is complete, maintain the temperature for 3 hours. Then, cool to 0℃, and under nitrogen atmosphere, add sodium tert-butoxide (156g, 1.62mol) in portions, maintaining the temperature between 5-10℃. After the addition is complete, maintain the temperature for 3 hours. Then, add methyl tert-butyl ether (1.5L), add 100mL of water dropwise, and stir overnight. Filter, wash the filter cake with a small amount of cold methyl tert-butyl ether, and dry to obtain a crude yellow sodium salt. The crude product was dissolved in 1 L of water, and the insoluble matter was filtered off. The pH of the filtrate was adjusted to 4-5 with 0.5 M hydrochloric acid, and the solution was cooled to 0-5 °C and stirred overnight. The solution was then filtered, the filter cake was washed with a small amount of water, and the solid was dried to obtain 273 g of yellow powder, with a yield of 88%.

[0037] Example 3

[0038] This embodiment provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride. Except for step (1) as follows, the specific steps are the same as in Example 1:

[0039] (1) Add 2.2L of tetrahydrofuran to a 5L reactor, then add ethyl N-tert-butoxycarbonylglycine (296g, 1.46mol), and dodecyltrimethylammonium chloride (83.4g, 0.146mol). In an ice bath, add sodium hydride (65g, 1.62mol, in 60% mineral oil) in portions. Stir for 30 minutes, then add chloroacetone (150g, 16.2mol) dropwise, maintaining the temperature between 15-20℃. After the addition is complete, maintain the temperature for 3 hours. Then, cool to 0℃, and under nitrogen atmosphere, add sodium tert-butoxide (156g, 1.62mol) in portions, maintaining the temperature between 5-10℃. After the addition is complete, maintain the temperature for 3 hours. Then, add methyl tert-butyl ether (1.5L), add 100mL of water dropwise, and stir overnight. Filter, wash the filter cake with a small amount of cold methyl tert-butyl ether, and dry to obtain a crude yellow sodium salt. The crude product was dissolved in 1 L of water, and the insoluble matter was filtered off. The pH of the filtrate was adjusted to between 4 and 5 with 0.5 M hydrochloric acid, and the solution was cooled to 0-5 °C and stirred overnight. The solution was then filtered, the filter cake was washed with a small amount of water, and the solid was dried to obtain 254.6 g of yellow powder, with a yield of 82%.

[0040] Example 4

[0041] This embodiment provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride. Except for step (3) as follows, the specific steps are the same as in Example 1:

[0042] (3) The product from the previous step (65g, 300mmol) was dissolved in 2L of dichloromethane, and triphenylphosphine (80g, 305mmol) was added, followed by the dropwise addition of dimethyl azodicarbonate (305mmol). After the addition was complete, the mixture was stirred at 20°C for 12 hours. Anhydrous zinc chloride (42g, 310mol) was added, the temperature was raised to 30°C, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated to dryness. It was then dissolved in 500mL of isopropyl ether, and the insoluble matter was filtered off. The filtrate was placed in an ice bath, and 4M isopropyl chloride hydrochloride solution was added dropwise. The intermediate temperature was controlled between 5-10°C. The mixture was then filtered, and the filter cake was washed with isopropyl ether. The filter cake was then placed in 300mL of acetone and stirred to form a slurry. The mixture was then filtered, dried under vacuum, and 28g of a white powder was obtained, with a yield of 69%.

[0043] Example 5

[0044] This embodiment provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride. Except for step (3) as follows, the specific steps are the same as in Example 1:

[0045] (3) The product from the previous step (65g, 300mmol) was dissolved in 2L of dichloromethane, and triphenylphosphine (80g, 305mmol) was added, followed by the dropwise addition of diethyl azodicarbonate (305mmol). After the addition was complete, the mixture was stirred at 20°C for 12 hours. Anhydrous zinc chloride (42g, 310mol) was added, the temperature was raised to 30°C, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated to dryness. It was then dissolved in 500mL of isopropyl ether, and the insoluble matter was filtered off. The filtrate was placed in an ice bath, and 4M isopropyl chloride solution was added dropwise. The intermediate temperature was controlled between 5-10°C. The mixture was then filtered, and the filter cake was washed with isopropyl ether. The filter cake was then placed in 300mL of acetone and stirred, filtered, and dried under vacuum to obtain 26.8g of a white powder, with a yield of 66%.

[0046] Comparative Example 1

[0047] This comparative example provides a method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, the specific steps of which are as follows:

[0048]

[0049] (1) Add 56.3 g (413.5 mol) of 4-methoxybenzaldehyde to 500 mL of MTBE (methyl tert-butyl ether), then add 47 mL of 30% ammonia water and 36.5 mL of epichlorohydrin. React at 20 °C for 18 hours. Continue to add 28 mL of 30% ammonia water and 23 mL of epichlorohydrin, and the reaction is completed after 4 hours. After the reaction is complete, allow the mixture to stand and separate into layers. Dry and concentrate the organic layer to obtain an oily product. Add 300 mL of n-hexane to crystallize, and obtain 80 g of white solid, yield 85%.

[0050] (2) Add (80g, 351.4mmol) of the product from step (1) to 800mL of methanol, cool to 0℃, add sodium borohydride (20g, 527mmol) in portions, react for one hour after addition, quench with 1M hydrochloric acid and adjust pH to 8, concentrate to 200mL, adjust pH to 14 with 6M sodium hydroxide, extract twice with 200mL dichloromethane, combine the organic layers, dry with anhydrous magnesium sulfate, concentrate, and obtain 62g of white solid, yield 77%.

[0051] (3) Add 60 g (261.2 mmol) of the product from step (2) and 300 mL of 1 M sodium hydroxide solution to 600 mL of dichloromethane, cool to 0 °C, and add 30.4 g (269 mmol) of chloroacetyl chloride dropwise. After the addition is complete, react at 0 °C for 1 hour, raise the temperature to 20 °C, add 195 mL of 10 M sodium hydroxide solution, react at 20 °C for 4 hours, add 300 mL of water, separate the layers, extract the aqueous layer once with 150 mL of dichloromethane, combine the organic layers, wash once with 200 mL of saturated brine, dry with anhydrous magnesium sulfate, concentrate, and obtain 57 g of product, yield 81%.

[0052] (4) Add 50 g (185.37 mmol) of the product from step (3) to 500 mL of tetrahydrofuran, cool to 0 °C, and add dropwise a tetrahydrofuran solution of LDA (diisopropylaminolithium) (2.1 eq). After the addition is complete, keep the reaction at 0 °C for 2 hours, quench in 300 mL of saturated ammonium chloride solution, filter to remove the solid, extract the aqueous layer twice with 200 mL of ethyl acetate, combine the organic layers, dry to anhydrous magnesium sulfate, concentrate under reduced pressure to obtain 18 g of product, yield 42%.

[0053] (5) Add 18 g (77.2 mmol) of the product from step (4) to 200 mL of tetrahydrofuran solution, cool to 0 °C under nitrogen protection, and add 1 M borane tetrahydrofuran solution (11 mL) dropwise. After the addition is complete, allow the temperature to rise naturally to 20 °C overnight. Quench the product by adding 50 mL of methanol dropwise, stir at 20 °C for 30 min, and concentrate under reduced pressure to obtain 15.2 g of oily product, with a yield of 90%.

[0054] (6) Add 15g (68.4mmol) of the product from step (5) and 2g of 10% palladium on carbon to 150mL of methanol. Replace with hydrogen three times, heat to 50℃, hydrogenate overnight in a hydrogen balloon until the raw material reaction is complete, filter, concentrate under pressure, add 50mL of tetrahydrofuran, add 30mL of 4M HCl isopropyl ether solution dropwise, stir for half an hour, filter, wash with isopropyl ether, and obtain 7.2g of white solid, yield 78%.

[0055] Test case

[0056] The overall yields of the preparation methods provided in Examples 1-5 and Comparative Example 1 were calculated, and the results are as follows:

[0057] Group Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Overall yield (%) 62.7％ 59.4％ 55.3％ 57.7％ 55.2％ 15.6％

[0058] The data in the table above shows that the preparation method provided by the present invention has significantly fewer reaction steps and processes compared with the prior art (Comparative Example 1), the overall process is simpler, and the total yield is higher. Comparing Examples 1-5, it can be found that the present invention can further improve the total yield of the reaction by selecting specific catalysts and azodicarbonate.

[0059] The applicant declares that the present invention illustrates the preparation method of 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0060] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0061] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride, characterized in that, The preparation method includes the following steps: (1) Compound 1 was obtained by reacting chloroacetone with N-tert-butoxycarbonylglycine ethyl ester, catalyst and base; (2) Compound 1 is reacted with a base to obtain compound 2; (3) Compound 2 was mixed with a reducing agent and reacted to obtain compound 3; (4) Compound 3 was mixed with phosphorus ligand and azodicarbonate to obtain compound 4, which was then hydrolyzed to obtain the 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride; The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that, The molar ratio of chloroacetone to N-tert-butoxycarbonylglycine ethyl ester, catalyst, and base in step (1) is (1-1.5):1:(0.08-0.12):(1-1.5).

3. The preparation method according to claim 1, characterized in that, The catalyst in step (1) is any one or a combination of at least two of the following: tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, or tetradecyltrimethylammonium chloride.

4. The preparation method according to claim 1, characterized in that, The catalyst in step (1) is tetrabutylammonium bromide.

5. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out at a temperature of 10-20℃ for 1-5 hours.

6. The preparation method according to claim 1, characterized in that, The reaction in step (2) is carried out at a temperature of 0-10℃ for 1-5 hours.

7. The preparation method according to claim 1, characterized in that, The alkali is any one or a combination of at least two of sodium hydride, sodium tert-butoxide, or potassium tert-butoxide.

8. The preparation method according to claim 1, characterized in that, The reducing agent in step (3) is sodium borohydride or potassium borohydride.

9. The preparation method according to claim 1, characterized in that, The molar ratio of compound 3 in step (4) to phosphorus ligand and azodicarbonate is 1:(1-1.2):(1-1.2).

10. The preparation method according to claim 1, characterized in that, The phosphorus ligand in step (4) is triphenylphosphine.

11. The preparation method according to claim 1, characterized in that, The azodicarbonate in step (4) is any one or a combination of at least two of diisopropyl azodicarbonate, dimethyl azodicarbonate or diethyl azodicarbonate.

12. The preparation method according to claim 11, characterized in that, The azodicarbonate ester mentioned in step (4) is diisopropyl azodicarbonate.

13. The preparation method according to claim 1, characterized in that, The reaction in step (4) is carried out at a temperature of 10-30℃ for 8-16 hours.

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