Spirocyclic compound and application thereof

Abstract

The application provides a kind of spiro compound and its application, the structure of the spiro compound is as shown in formula I or formula II, the spiro compound is used for the preparation of spiro compound, and the preparation method comprises the following steps: (1) compound I is subjected to alkylation reaction to obtain compound II;(2) compound II is reacted with benzylamine compound to obtain compound III;(3) compound III is reduced to obtain compound IV;(4) compound IV is mixed with debenzyl reagent to obtain compound V, and then chiral resolution obtains the target spiro compound.The preparation method provided by the application is simple in process operation, raw materials are cheap and easy to obtain, the yield is high, and the process avoids the use of hydrogen and metal catalyst in the debenzyl process through specific process design, greatly reduces the safety and environmental problems, and also reduces the production cost.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically designing a spirocyclic compound and its application. Background Technology

[0002] Spirocyclic compounds are organic compounds consisting of two bicyclic rings linked by a single atom. Some spirocyclic compounds exhibit axial chirality and are important fragments in the synthesis of many new drugs. Therefore, various synthetic methods have been developed for the preparation of spirocyclic compounds. Taking α-azaspirocyclic compounds as an example, starting with protected proline methyl ester, a multi-step reaction process yields the target compound (J. Med. chem., 1990, 33, 2270). This route includes steps such as linking bromoacetonitrile, reduction, and ring closure, but the overall yield is only 7%, greatly limiting its application.

[0003]

[0004] CN 106883238 A describes a route that obtains the target compound from protected proline through steps such as substitution, reduction, oxidation, reductive amination, cyclization, and debenzylation. This route is simple in terms of the types of reactions involved, but it is relatively long, the oxidation products are difficult to control, and the cost is high, which limits its application.

[0005]

[0006] Furthermore, obtaining the target product via the aforementioned route requires ring closure and deprotection processes, and the metal-catalyzed removal method used in this process is costly. Therefore, providing a low-cost, high-yield method for preparing spirocyclic compounds has become an urgent problem to be solved. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a spirocyclic compound and its applications. The spirocyclic compound provided by the present invention is used for the preparation of spirocyclic compounds. The preparation method is simple to operate, uses inexpensive and readily available raw materials, and has a high yield. Furthermore, this process, through specific flow design, avoids the use of hydrogen and metal catalysts during the debenzylation process, greatly reducing safety and environmental issues, while also lowering production costs.

[0008] To achieve this objective, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides a spirocyclic compound, the structure of which is shown in Formula I or Formula II:

[0010]

[0011] In the formula, R is selected from benzylamine compounds.

[0012] The spirocyclic compounds with the above-mentioned specific structures can be used in the preparation of spirocyclic compounds, which can avoid the use of hydrogen and metal catalysts in the debenzylation process and effectively reduce costs.

[0013] Preferably, the benzylamine compound group includes benzyl or 4-methoxybenzyl.

[0014] In a second aspect, the present invention provides the application of the spirocyclic compounds described above in the preparation of spirocyclic compounds.

[0015] Thirdly, the present invention also provides a method for preparing spirocyclic compounds, the method comprising the following steps:

[0016] (1) Compound I was alkylated to obtain compound II;

[0017] (2) Compound II was reacted with a benzylamine compound to obtain compound III;

[0018] (3) Compound III was reduced to obtain compound IV;

[0019] (4) Compound IV was mixed with a debenzylating agent to obtain compound V, which was then chirally resolved to obtain the target spirocyclic compound;

[0020] The reaction route is as follows:

[0021]

[0022] Wherein, X1 is selected from bromine or iodine, X2 is selected from chlorine or bromine, and X1 and X2 are different;

[0023] R has the same scope as described above.

[0024] The above preparation method is simple to operate, uses cheap and readily available raw materials, and has a high yield. Furthermore, the process avoids the use of metal catalysts during the debenzylation process through a specific process design, which greatly reduces costs.

[0025] Preferably, the alkylation in step (1) is carried out in the presence of an alkaline reagent, which includes any one or a combination of at least two of n-BuLi, LDA, or LiHMDS.

[0026] Preferably, the temperature of the alkylation reaction in step (1) is -65 to 0°C, for example -65°C, -60°C, -55°C, -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, or 0°C, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0027] Preferably, the benzylamine compound in step (2) includes 4-methoxybenzylamine and / or benzylamine.

[0028] Preferably, the molar ratio of compound 2 to benzylamine compound in step (2) is 1:(2-4), such as 1:2, 1:2.5, 1:3, 1:3.5 or 1:4, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0029] Preferably, the reducing agent in step (3) includes any one of lithium aluminum hydride, sodium borohydride, or borane.

[0030] Preferably, the reduction temperature in step (3) is 30-60℃, such as 30℃, 35℃, 40℃, 45℃, 50℃, 55℃ or 60℃, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0031] Preferably, the debenzylidene reagent in step (4) includes any one or a combination of at least two of chloroethyl chloroformate, chloromethyl chloroformate or chlorophenyl chloroformate, with chloroethyl chloroformate being preferred.

[0032] The aforementioned specific debenzylidene reagents can more effectively remove protecting groups and improve reaction yield; at the same time, they avoid the use of metal debenzylidene reagents, effectively reducing costs.

[0033] Preferably, the molar ratio of compound IV to the debenzylidene reagent in step (4) is 1:(1-2), such as 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or 1:2, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0034] Preferably, the reaction temperature in step (4) is 40-60°C, such as 40°C, 45°C, 50°C, 55°C or 60°C, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0035] Preferably, the solvent for the reaction in step (4) includes any one or a combination of at least two of dichloromethane, toluene, or acetonitrile, with dichloromethane being the most preferred.

[0036] Preferably, the chiral resolving agent in step (4) includes any one or a combination of at least two of tartaric acid, glutamic acid, or lysine, with tartaric acid being preferred.

[0037] The aforementioned specific resolving agent can effectively separate products with different chiralities to obtain the target product, thereby effectively improving the product yield.

[0038] Preferably, the molar ratio of compound V to the resolving agent is 1:(0.7-1), such as 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95 or 1:1, but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0039] On the other hand, the present invention also provides the application of the preparation method of spirocyclic compounds as described above in the preparation of chiral spirocyclic compounds.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] This invention provides a method for preparing spirocyclic compounds. The method is simple to operate, uses inexpensive and readily available raw materials, and has a high yield. Furthermore, the process avoids the use of metal catalysts during the debenzylation process through a specific process design, which greatly reduces costs. Detailed Implementation

[0042] 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.

[0043] Example 1

[0044] This embodiment provides a method for preparing spirocyclic compounds, and the reaction route is as follows:

[0045]

[0046] The preparation method is as follows:

[0047] (1) 5 g (21.8 mmol) of compound I was placed in a 50 mL flask and dissolved in 12 g of tetrahydrofuran. 12 g of 1 mol / L diisopropylaminolithium was added at -65 °C. After the reaction was completed, 37.4 g (28.34 mmol) of bromochloroethane was added dropwise. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction. 10 g of ethyl acetate was added to extract the aqueous phase and the organic phase was concentrated to dryness to obtain 6.5 g of compound II with a purity of 90% and a yield of 92%.

[0048] (2) 5 g (20 mmol) of compound II and 5.5 g (40 mmol) of 4-methoxybenzylamine were placed in a 50 mL flask and heated to 130 °C for 8 h. After the reaction was completed, the pH was adjusted to between 2 and 3. After stirring thoroughly, EA was added and the mixture was separated. The organic phase was concentrated to dryness to obtain 6.9 g of compound III with a purity of 93% and a yield of 90%.

[0049] Ms: 361.2(M+H); Ms: 305.2(M-55);

[0050] 1 HNMR (400MHz, CDCl3) δ7.15–7.06 (m, 2H), 6.82–6.72 (m, 2H), 4.74 (d, J=14.4Hz, 0.5H), 4.59 (d, J=14.6 Hz, 0.5H), 4.15 (d, J=14.6Hz, 0.5H), 3.89 (d, J=14.4Hz, 0.5H), 3.72 (d, J=1.3Hz, 3H), 3.53–3.38 (m, 2H ), 3.21(td, J=9.6, 2.3Hz, 0.5H), 3.12(td, J=9.8, 1.9Hz, 0.5H), 3.06–2.92(m, 1H), 2.52(ddd, J=12.5, 9.7, 8.2Hz, 0.5H), 2.43–2.28 (m, 0.5H), 2.14–1.87 (m, 2H), 1.79–1.70 (m, 3H), 1.35 (d, J=30.5Hz, 9H).

[0051] (3) 6.9 g (18 mmol) of compound III was dissolved in 13 g of tetrahydrofuran and placed in a 50 mL flask. 45 mL (45 mmol) of BH3·THF was slowly added dropwise at room temperature. After the addition was complete, the mixture was kept at 30 °C for 10 h. The reaction was quenched with methanol after completion. The mixture was extracted three times with EA and the organic phase was concentrated to obtain 6.8 g of compound IV with a purity of 85% and a yield of 93%.

[0052] Ms: 347.3 (M+H).

[0053] (4) 6.8 g (16 mmol) of compound IV was mixed with 21 g of dichloromethane, and 2.6 g (18 mmol) of chloroethyl chloroformate was slowly added dropwise at 20 °C. After the addition was complete, the mixture was kept at this temperature for 1 h, and then heated to 40 °C and refluxed for 6 h. After the reaction was completed, the mixture was concentrated to remove DCM, and 5 g of methanol was added and refluxed for 4 h. After the reaction was completed, the pH was adjusted to between 10 and 12 with NaOH, and the mixture was extracted three times with EA. The organic phases were combined and concentrated to dryness to obtain 3 g of compound V with a purity of 92% and a yield of 82%.

[0054] (5) Mix 3g (13mmol) of compound VII with 2g L-tartaric acid (13mmol), add 21g acetonitrile and 4g water, stir at 20℃ for 12h, filter out the solid, release the solid with 5wt% NaOH aqueous solution, and extract with EA to obtain the chiral target compound, concentrate to obtain 1.1g product with a purity of 99.8%, a yield of 38%, and an ee value of 99.4.

[0055] Example 2

[0056] This embodiment provides a method for preparing spirocyclic compounds, and the reaction route is as follows:

[0057]

[0058] The preparation method is as follows:

[0059] (1) 0.5 kg (2.18 mol) of compound I was placed in a 5 L four-necked flask and dissolved in 1.2 kg of tetrahydrofuran. 2.834 L of 1 mol / L bis(trimethylsilyl)aminolithium was added dropwise at -65 °C. After the reaction was completed, 0.374 kg (2.834 mol) of bromochloroethane was added dropwise. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction. After stirring thoroughly, the mixture was allowed to stand and separated. The aqueous phase was extracted with 1 kg of ethyl acetate. The organic phases were combined and concentrated to dryness to obtain 0.643 kg of compound II with a purity of 89% and a yield of 90%.

[0060] (2) 0.643 kg (1.962 mol) of compound II and 0.420 kg (3.924 mol) of benzylamine were placed in a 2L four-necked flask and heated to 130℃ for 8 hours. After the reaction was completed, the pH was adjusted to between 2 and 3. After stirring thoroughly, EA was added and the mixture was separated. The organic phase was concentrated to dryness to obtain 0.648 kg of compound III with a purity of 90% and a yield of 90%. 1 H NMR (400MHz, DMSO-d6) δ7.39–7.17(m, 5H), 4.67(d, J=14.7Hz, 0.5H), 4.39(d, J=6.9Hz, 0.5H), 4.15–3.95( m, 1H), 3.58–3.25 (m, 4H), 2.34 (ddt, J=38.6, 12.8, 9.5Hz, 1H), 2.01–1.65 (m, 5H), 1.34 (dt, J=47.7Hz, 9H).

[0061] (3) 0.648 kg (1.766 mol) of compound III was dissolved in 1.27 kg of tetrahydrofuran and placed in a 1 L four-necked flask. 1.059 L (2.649 mol) of lithium aluminum hydride (2.5 mol / L) was slowly added dropwise at room temperature. After the addition was complete, the mixture was kept at 40 °C for 10 h. The reaction was quenched with methanol after completion. The mixture was extracted three times with EA, and the organic phase was concentrated to obtain 0.565 kg of compound IV with a purity of 88% and a yield of 89%.

[0062] 1HNMR (400MHz, CDCl3) δ7.33–7.06 (m, 5H), 3.63 (dd, J=13.0, 8.1Hz, 1H), 3.49 (d, J=13.0 Hz, 1H), 3.43–3.11 (m, 2H), 2.91–2.37 (m, 4H), 2.18–1.45 (m, 6H), 1.38 (d, J=3.3Hz, 9H).

[0063] (4) Mix 0.565 kg (1.571 mol) of compound IV with 2.1 kg of dichloromethane, and slowly add 0.488 kg (3.142 mol) of ethyl chloroformate dropwise at 20 °C. After the addition is complete, maintain the temperature for 1 h, then raise the temperature to 40 °C and reflux for 6 h. After the reaction of the starting material is complete, concentrate to remove DCM, add 0.5 kg of methanol and reflux for 4 h. After the reaction of the intermediate is complete, adjust the pH to between 10 and 12 with NaOH. Extract three times with EA, combine the organic phases and concentrate to dryness to obtain 0.316 kg of compound V with a purity of 90% and a yield of 80%.

[0064] (5) Mix 0.316 kg (1.257 mol) of compound VII with 0.188 kg L-tartaric acid (0.880 mol), add 2.1 kg acetonitrile and 0.4 kg water, stir at 20 °C for 12 h, filter out the solid, release the solid with 5 wt% NaOH aqueous solution, and extract with EA to obtain the chiral target compound, concentrate to obtain 94.8 g of product with a purity of 99.2%, a yield of 30%, and an ee value of 99.0.

[0065] 1 H NMR (400MHz, CDCl3) δ3.48–3.16 (m, 3H), 2.65–2.46 (m, 4H), 2.14 (dt, J=12.5, 9.2Hz , 1H), 1.86–1.65 (m, 4H), 1.56 (ddd, J=12.5, 6.9, 2.8Hz, 1H), 1.40 (d, J=22.6Hz, 9H).

[0066] Example 3

[0067] This embodiment provides a method for preparing spirocyclic compounds, and the reaction route is as follows:

[0068]

[0069] The preparation method is as follows:

[0070] (1) 5 g (21.8 mmol) of compound I was placed in a 50 mL flask and dissolved in 12 g of tetrahydrofuran. 28 mL of 1 mol / L lithium diisopropylamino was added at 0 °C. After the reaction was completed, 3.7 g (2.834 mmol) of bromochloroethane was added dropwise. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction. After stirring thoroughly, the mixture was allowed to stand and separated. The organic phase was concentrated to dryness to obtain 6.5 g of compound II with a purity of 89% and a yield of 92%.

[0071] (2) 6.5 g (20 mmol) of compound II and 11 g (80 mmol) of 4-methoxybenzylamine were placed in a 50 ml flask and heated to 130 °C for 8 h. After the reaction was completed, the pH was adjusted to between 2 and 3. After stirring thoroughly, EA was added and the mixture was separated. The organic phase was concentrated to dryness to obtain 6.9 g of compound III with a purity of 91% and a yield of 88%.

[0072] (3) 6.9 g (17 mmol) of compound III was dissolved in 13 g of tetrahydrofuran and placed in a 50 mL flask. 53 mL (53 mmol) of BH3·THF (1 mol / L) was slowly added dropwise at room temperature. After the addition was complete, the mixture was kept at 60 °C for 10 h. The reaction was quenched with methanol after completion, extracted three times with EA, and the organic phase was concentrated to obtain 6.1 g of compound IV with a purity of 84% and a yield of 85%.

[0073] (4) 6.1 g (15 mmol) of compound IV was mixed with 21 g of toluene, and 2.1 g (15 mmol) of ethyl chloroformate was slowly added dropwise at 20 °C. After the addition was complete, the mixture was kept at this temperature for 1 h, then the temperature was raised to 60 °C and kept at this temperature for 6 h. After the reaction of the starting material was completed, the mixture was concentrated to remove toluene, and 5 g of methanol was added and refluxed for 4 h. After the reaction of the intermediate was completed, the pH was adjusted to between 10 and 12 with NaOH. The mixture was extracted three times with EA, and the organic phases were combined and concentrated to dryness to obtain 2.9 g of compound V with a purity of 90% and a yield of 78%.

[0074] (5) 2.9 g (11 mmol) of compound VII was mixed with 1.7 g L-tartaric acid (11 mmol), 21 g acetone and 4 g water were added, and the mixture was stirred at 20 °C for 12 h. The solid was filtered out, and the solid was freed with 5 wt% NaOH aqueous solution and extracted with EA to obtain the chiral target compound. The product was concentrated to obtain 0.8 g of product with a purity of 99.0%, a yield of 32%, and an ee value of 99.0.

[0075] Example 4

[0076] This embodiment provides a method for preparing spirocyclic compounds. The specific steps are the same as in Example 1, except that chloroethyl chloroformate in step (4) is replaced with an equal amount of chloromethyl chloroformate.

[0077] Example 5

[0078] This embodiment provides a method for preparing spirocyclic compounds. The specific steps are the same as in Example 1, except that chloroethyl chloroformate in step (4) is replaced with an equal amount of chlorophenyl chloroformate.

[0079] Example 6

[0080] This embodiment provides a method for preparing spirocyclic compounds. The specific steps are the same as in Example 1, except that L-tartaric acid in step (5) is replaced with an equal amount of L-glutamic acid.

[0081] Example 7

[0082] This embodiment provides a method for preparing spirocyclic compounds. The specific steps are the same as in Example 1, except that L-tartaric acid in step (5) is replaced with an equal amount of L-lysine.

[0083] Comparison of effects:

[0084] The overall yield of the methods in Examples 1-7 was calculated, and the results are as follows:

[0085] Group Overall yield (%) Example 1 23.9 Example 2 17.3 Example 3 17.2 Example 4 18.7 Example 5 17.8 Example 6 15.7 Example 7 12.5

[0086] As can be seen from the above, the preparation method provided by the present invention is simple to operate, the raw materials are cheap and readily available, and the use of metal catalysts in the debenzylation process is avoided through the design of a specific process route, which greatly reduces the cost. Comparing Examples 1 and 4-7, it can be found that the present invention can further improve the product yield by selecting specific debenzylation reagents and chiral resolving agents, thereby improving the overall total yield.

[0087] The applicant declares that the above embodiments illustrate the spirocyclic compounds and their applications, 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 product 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.

[0088] 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.

[0089] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A spirocyclic compound, characterized in that, The structure of the spirocyclic compound is shown in Formula I or Formula II: In the formula, R is selected from benzylamine compounds.

2. The spirocyclic compound according to claim 1, characterized in that, The benzylamine compounds include benzyl or 4-methoxybenzyl groups.

3. The application of a spirocyclic compound according to claim 1 or 2 in the preparation of spirocyclic compounds.

4. A method for preparing a spirocyclic compound, characterized in that, The preparation method includes the following steps: (1) Compound I was alkylated to obtain compound II; (2) Compound II was reacted with a benzylamine compound to obtain compound III; (3) Compound III was reduced to obtain compound IV; (4) Compound IV was mixed with a debenzylating agent to obtain compound V, which was then chirally resolved to obtain the target spirocyclic compound; The reaction route is as follows: Wherein, X1 is selected from bromine or iodine, X2 is selected from chlorine or bromine, and X1 and X2 are different; R has the same scope as claim 1 or 2.

5. The method for preparing spirocyclic compounds according to claim 4, characterized in that, The alkylation in step (1) is carried out in the presence of a basic reagent, which includes any one or a combination of at least two of n-BuLi, LDA or LiHMDS; Preferably, the temperature of the alkylation reaction in step (1) is -65 to 0°C; Preferably, the benzylamine compound in step (2) includes 4-methoxybenzylamine and / or benzylamine; Preferably, the molar ratio of compound 2 to benzylamine in step (2) is 1:(2-4); Preferably, the reducing agent in step (3) includes any one of lithium aluminum hydride, sodium borohydride, or borane; Preferably, the reduction temperature in step (3) is 30-60℃.

6. The method for preparing spirocyclic compounds according to claim 4 or 5, characterized in that, The debenzylidene reagent in step (4) includes any one or a combination of at least two of chloroethyl chloroformate, chloromethyl chloroformate or chlorophenyl chloroformate, preferably chloroethyl chloroformate.

7. The method for preparing the spirocyclic compound according to any one of claims 4-6, characterized in that, The molar ratio of compound IV to the debenzylidene reagent in step (4) is 1:(1-2).

8. The method for preparing the spirocyclic compound according to any one of claims 4-7, characterized in that, The reaction temperature in step (4) is 40-60℃.

9. The method for preparing the spirocyclic compound according to any one of claims 4-8, characterized in that, The chiral resolving agent in step (4) includes any one or a combination of at least two of tartaric acid, glutamic acid, or lysine, preferably tartaric acid.

10. The method for preparing spirocyclic compounds according to claim 9, characterized in that, The molar ratio of compound V to the resolving agent is 1:(0.7-1).

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