Preparation method of 4-oxa-7-azaspiro [2.5] octane

Abstract

The invention provides a preparation method of 4-oxa-7-azaspiro [2.5] octane and salt thereof, which is simple and convenient to operate, mild in condition, lower in equipment requirement, easily available in raw materials and higher in yield, and is suitable for industrial application. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemical synthesis, and in particular to a method for preparing 4-oxa-7-azaspiro[2.5]octane and a salt thereof. Background Art

[0002] 4-Oxa-7-azaspiro[2.5]octane or its salt is a widely used pharmaceutical intermediate. As recorded in the international patent publication with publication number WO2022003575A1, 4-oxa-7-azaspiro[2.5]octane hydrochloride can be used as an intermediate to prepare a compound with HER2 mutation inhibitory activity for treating abnormal cell growth (including cancer) and other diseases in subjects in need; as recorded in the Chinese patent publication with publication number CN106488919A, 4-oxa-7-azaspiro[2.5]octane can be used as an intermediate to prepare a compound with GPR43 receptor agonist activity for treating diseases such as diabetes, obesity and inflammatory bowel disease; in addition, there is also a Chinese patent publication with publication number W The international patent publication number WO2019148005A1 is recorded as an intermediate for preparing compounds that have the ability to inhibit the E3 enzyme Cbl-b in the ubiquitin-proteasome pathway, regulate the immune system, and treat diseases suitable for immune system regulation; the international patent publication number WO2016089797A1 is recorded as an intermediate for preparing compounds with isocitrate dehydrogenase (IDH) inhibitory activity; the international patent publication number WO2016130818A1 is recorded as an intermediate for preparing compounds with retinoic acid receptor-related orphan receptor γt (RORγt) inhibitory activity, etc.

[0003] Chinese patent CN108530375A1 discloses a method for preparing 4-oxa-7-azaspiro[2.5]octane:

[0004]

[0005] This process step 1 requires NaH, which is highly active. When heated or in contact with moisture or acids, it releases heat and hydrogen, causing combustion and explosion. This process has a great safety risk if it is carried out in large-scale production. Currently, 4-oxa-7-azaspiro[2.5]octane is widely used as an important intermediate in drug research for various targets, and the market demand is huge. Therefore, it is very necessary to develop a process that is simple to operate, mild in conditions, has low equipment requirements, is easy to obtain raw materials, has a high yield, and is suitable for industrial production. Summary of the invention

[0006] In view of the problem that the routes and preparation methods of 4-oxa-7-azaspiro[2.5]octane and its salts in the prior art require the use of highly active reagents and there are safety risks in large-scale production, the present invention provides a preparation method of 4-oxa-7-azaspiro[2.5]octane, which has cheap and easily available raw materials, is easy to operate, has mild conditions and low requirements on equipment, and is suitable for industrial production.

[0007] On the one hand, the present invention provides a method for preparing 4-oxa-7-azaspiro[2.5]octane, characterized in that it is prepared by the following route:

[0008]

[0009] Preferably, in the step of preparing compound VI from compound V, alkaline reagent 1 is selected from K2CO3, Na2CO3, Cs2CO3, NaHCO3 or TEA; the molar ratio of compound V, chloroacetyl chloride and alkaline reagent 1 is in the range of 1:1:1 to 1:2:3; and the reaction temperature is in the range of -20 to 25°C.

[0010] Preferably, in the step of preparing compound VII from compound VI, alkaline reagent 2 is selected from potassium tert-butoxide or sodium tert-butoxide; the molar ratio of compound VI to alkaline reagent 2 is in the range of 1:2 to 1:3; and the reaction temperature is in the range of -10 to 25°C.

[0011] Preferably, in the step of preparing compound I from compound VII, the reducing agent is selected from lithium aluminum tetrahydride, red aluminum, tetrahydrofuran borane or borane dimethyl sulfide; the molar ratio of compound VII and reducing agent 2 is in the range of 1:1 to 1:3; and the reaction temperature is in the range of 55 to 65°C.

[0012] On the other hand, the present invention provides a method for preparing 4-oxa-7-azaspiro[2.5]octane, characterized in that it is prepared by the following route:

[0013]

[0014] Preferably, in the step of preparing compound III from compound II, alkaline reagent 3 is selected from K2CO3, Na2CO3, Cs2CO3 or NaHCO3; the molar ratio of compound II, benzyl bromide and alkaline reagent 1 is in the range of 1:2:1.5 to 1:2.2:5; and the reaction temperature is in the range of 0 to 50°C.

[0015] Preferably, in the step of preparing compound IV from compound III, the molar ratio of compound III, ethyl magnesium bromide and tetraisopropyl titanate is in the range of 1:2:0.2 to 1:5:2; and the reaction temperature is in the range of -20 to 20°C.

[0016] Preferably, in the step of preparing compound V from compound IV, the catalyst is Pd / C or Pd(OH)2 / C; the reaction temperature ranges from 20 to 60°C

[0017] The preparation route and method of 4-oxa-7-azaspiro[2.5]octane of the present invention are ingeniously designed, simple to operate, mild under mild conditions, low requirements on equipment, easy to obtain raw materials and high yield, and are suitable for industrial applications. DETAILED DESCRIPTION

[0018] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0019] Unless otherwise specified, the reagents or starting materials used in the following examples were obtained from commercial sources.

[0020] Example 1

[0021]

[0022] Preparation of compounds of formula III:

[0023] The compound of formula II (1200.0 g, 9.56 mol, 1 eq.) and MeCN (12000 mL) were added to a four-necked bottle (20 L), and then K2CO3 (2.64 kg, 19.12 mol, 2.0 eq.) was added, cooled to 10°C, and then BnBr (3.27 kg, 19.12 mol, 2.0 eq.) was slowly added dropwise, and the temperature was naturally raised to 25°C for 12 hours. TLC showed that the raw material disappeared and the reaction was complete. The reaction solution was filtered and the filtrate was dried to obtain the compound of formula III (2350 g, 8.73 mol, yield 91.29%), which was directly used in the next step without further purification.

[0024] Preparation of compound of formula IV:

[0025] The compound of formula III (2350 g, 8.73 mol, 1 eq.), tetraisopropyl titanate (743.96 g, 2.62 mol, 0.3 eq.) and THF (10 L) were added to a four-necked bottle (20 L), and then slowly dripped into EtMgBr ether solution (21.81 mol, 3.0 M, 7.27 L, 2.5 eq.) at -10 ° C, and the temperature was raised to 10 ° C for 3 hours. TLC showed that the raw material disappeared and the reaction was complete. Saturated NH4Cl (2 L) was added to quench the reaction, and then filtered, and the filtrate was spin-dried to obtain the compound of formula IV (2250 g, 8.42 mol, yield 96.45%).

[0026] Preparation of compounds of formula V:

[0027] The compound of formula IV (2000.0 g, 7.480 mol, 1 eq.), methanol (15 L), and 20% Pd(OH)2 / C (400.0 g) were added to an autoclave (20 L) and reacted at 20°C for 48 hours under a 2 MPa hydrogen atmosphere. TLC showed that the raw material disappeared and the reaction was complete. The reaction solution was filtered and dried to obtain the compound of formula V (640.0 g, 7.346 mol, yield 98.21%).

[0028] Preparation of compound of formula VI:

[0029] The compound of formula V (480.0 g, 5.510 mol, 1 eq.), methanol (400 mL), tetrahydrofuran (2600 mL) and potassium carbonate (912.5 g, 6.612 mol, 1.2 eq.) were added to a four-necked flask (10 L), and then chloroacetyl chloride (622.27 g, 5.510 mol, 1 eq.) was slowly added dropwise at 0°C, and the temperature was naturally raised to 20°C for reaction for 16 hours. TLC showed that the raw material disappeared and the reaction was complete. The reaction solution was filtered, the filtrate was spin-dried, and n-heptane (2 L) was added and stirred for 10 minutes, and the liquid was separated. The lower layer was continuously added with n-heptane (2 L) and stirred for 10 minutes, and the lower layer liquid was separated, and a light yellow oil was obtained by spin-drying. After cooling, a light yellow solid compound VI (560.0 g, 3.423 mol, yield 62.13%) was obtained.

[0030] Preparation of compound of formula VII:

[0031] Add isopropanol (7L) into a four-necked flask (20L), then slowly add t-BuOK (768.178g, 6.846mol, 2.0eq.) at 5-10°C, stir to dissolve, then slowly drip a solution of compound VI (560.0g, 3.423mol, 1eq) dissolved in DCM (4000mL) into the reaction solution at 0-5°C, naturally raise the temperature to 20°C and react for 16 hours.

[0032] TLC showed that the raw material disappeared and the reaction was complete. The reaction solution was adjusted to pH = 7 with 6N hydrochloric acid, filtered, and the filtrate was spin-dried. The concentrate was added with methyl tert-butyl ether (1.5L), and the temperature was controlled at 0-5 degrees Celsius for 3 hours. The slurry was filtered, and the filter cake was washed with a mixed solution of methyl tert-butyl ether: n-heptane = 1:1 (1L), and the filter cake was dried to obtain a pure product. The slurry mother liquor was concentrated to dryness, and the pure product was obtained by wet loading on a column (n-heptane: EA = 1:2), and the Ⅶ compound (260.0g, 2.046mol, yield 60%) was obtained.

[0033] Preparation of compounds of formula I:

[0034] Add THF (1500mL) into a four-necked flask (10L), then slowly add LiAlH4 (89.64g, 2.360mol, 1.5eq), heat to 60°C, then slowly drip compound VII (200.0g, 1.573mol, 1eq.) dissolved in THF (1500mL) into the reaction solution, heat to 65°C and react for 1 hour. TLC shows that the raw material disappears and the reaction is complete. Cool to 0-5°C, add water (90mL), 15% NaOH solution (90mL), and water (90mL) to quench the reaction, filter the reaction solution, spin dry the filtrate, then add 4mol / L HCl / EA to adjust pH=4, spin dry the reaction solution, precipitate a large amount of solid, add EA (200mL) for pulping, and obtain the compound of formula I (207.60g, 1.388mol, yield 88.21%). Purity: 99.4%, 1 HNMR (400MHz, DMSO-d6) δ (ppm) 9.57 (Br, 2H), 3.82-3.80 (m, 2H), 3.10 (s, 4H), 0.80-0.69 (m, 4H).

[0035] Although the above describes the specific implementation methods of the present invention, it is not intended to limit the scope of protection of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing 4-oxa-7-azaspiro[2.5]octane, characterized in that Prepared by the following route:

2. The preparation method according to claim 1, characterized in that In the step of preparing compound VI from compound V, alkaline reagent 1 is selected from K2CO3, Na2CO3, Cs2CO3, NaHCO3 or TEA; the molar ratio of compound V, chloroacetyl chloride and alkaline reagent 1 is in the range of 1:1:1 to 1:2:3; and the reaction temperature is in the range of -20 to 25°C.

3. The preparation method according to claim 1, characterized in that In the step of preparing compound VII from compound VI, alkaline reagent 2 is selected from potassium tert-butoxide or sodium tert-butoxide; the molar ratio of compound VI to alkaline reagent 2 is in the range of 1:2 to 1:3; The reaction temperature ranges from -10 to 25°C.

4. The preparation method according to claim 1, characterized in that In the step of preparing compound I from compound VII, the reducing agent is selected from lithium aluminum tetrahydride, red aluminum, tetrahydrofuran borane or borane dimethyl sulfide; the molar ratio of compound VII and reducing agent 2 is in the range of 1:1 to 1:3; and the reaction temperature is in the range of 55 to 65°C.

5. A method for preparing 4-oxa-7-azaspiro[2.5]octane, characterized in that Prepared by the following route:

6. The preparation method according to claim 5, characterized in that: In the step of preparing compound III from compound II, the alkaline reagent 3 is selected from K2CO3, Na2CO3, Cs2CO3 or NaHCO3; the molar ratio of compound II, benzyl bromide and alkaline reagent 1 is in the range of 1:2:1.5 to 1:2.2:5; and the reaction temperature is in the range of 0 to 50°C.

7. The preparation method according to claim 5, characterized in that: In the step of preparing compound IV from compound III, the molar ratio of compound III, ethyl magnesium bromide and tetraisopropyl titanate is in the range of 1:2:0.2 to 1:5:2; and the reaction temperature is in the range of -20 to 20°C.

8. The preparation method according to claim 5, characterized in that: In the step of preparing compound V from compound IV, the catalyst is Pd / C or Pd(OH)2 / C; and the reaction temperature ranges from 20 to 60°C.

9. The preparation method according to claim 5, characterized in that: In the step of preparing compound VI from compound V, alkaline reagent 1 is selected from K2CO3, Na2CO3, Cs2CO3, NaHCO3 or TEA; the molar ratio of compound V, chloroacetyl chloride and alkaline reagent 1 is in the range of 1:1:1 to 1:2:3; the reaction temperature is in the range of -20 to 25°C; In the step of preparing compound VII from compound VI, alkaline reagent 2 is selected from potassium tert-butoxide or sodium tert-butoxide; the molar ratio of compound VI to alkaline reagent 2 is in the range of 1:2 to 1:3; and the reaction temperature is in the range of -10 to 25°C; In the step of preparing compound I from compound VII, the reducing agent is selected from lithium aluminum tetrahydride, red aluminum, tetrahydrofuran borane or borane dimethyl sulfide; the molar ratio of compound VII and reducing agent 2 is in the range of 1:1 to 1:3; and the reaction temperature is in the range of 55 to 65°C.

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