Method for preparing oxaspirocycle derivative, and intermediate thereof

Abstract

A method for preparing an oxaspirocycle derivative and an intermediate thereof are described. The method reduces reaction steps, improves reaction yield, is simple and easy to operate, and is favorable for industrial large-scale production.

Claims

1. A method for preparing a compound represented by formula D1 or a salt thereof, ##STR00066## comprising separating optical isomers of a compound represented by formula D or a salt thereof, by a chemical resolution method: ##STR00067## wherein, R is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, oxo, alkenyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR.sup.3, C(O)R.sup.3, C(O)OR.sup.3, S(O).sub.mR.sup.3 and NR.sup.4R.sup.5; R.sup.3 is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; each of R.sup.4 and R.sup.5 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, carboxylic ester group, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, amino, carboxylic ester group, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and m is 0, 1 or 2; wherein a resolving agent is used in the chemical resolution method, and the resolving agent is a basic chiral resolving agent selected from the group consisting of S-phenylethylamine, quinidine, cinchonidine and arginine.

2. The method according to claim 1, further comprising preparing the compound represented by formula D from a compound represented by formula E by basic hydrolysis; ##STR00068##

3. The method according to claim 1, wherein the compound represented by formula D1 is a compound represented by formula D2: ##STR00069##

4. The method according to claim 1, wherein the method comprises: ##STR00070## 1) mixing the compound represented by formula D with S-phenylethylamine thereby to obtain a compound represented by formula D1-1; and 2) cleaving the compound represented by formula D1-1 to obtain the compound represented by formula D1.

5. A compound represented by formula D1 or a salt thereof, ##STR00071## wherein, R is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected front the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, oxo, alkenyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR.sup.3, C(O)R.sup.3, C(O)OR.sup.3, S(O).sub.mR.sup.3 and NR.sup.4R.sup.5; R.sup.3 is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; each of R.sup.4 and R.sup.5 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, carboxylic ester group, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, amino, carboxylic ester group, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and m is 0, 1 or 2; and wherein the compound has an enantiomeric excess (ee) value of more than 99%.

6. The compound according to claim 5, wherein the compound is a compound represented by formula D2: ##STR00072##

7. The compound according to claim 5, wherein the salt of the compound is a compound represented by formula D1-1: ##STR00073## wherein M is selected from the group consisting of S-phenylethylamine, quinidine, cinchonidine and arginine.

8. The method of claim 1, ##STR00074## further comprising preparing a compound represented by formula B or a stereoisomer thereof from the compound represented by formula D or a stereoisomer thereof via an one-step reaction or a reaction of more than one step: ##STR00075##

9. The method according to claim 8, wherein the method comprises: ##STR00076## 1) converting the compound represented by formula D to obtain a compound represented by formula C; and 2) reducing the compound represented by formula C thereby to obtain the compound represented by formula B: wherein, R is ##STR00077##

10. The method according to claim 8, wherein the compound represented by formula B is a compound represented by formula B2: ##STR00078##

11. The method according to claim 8, further comprising hydrolyzing a compound represented by formula E thereby to obtain the compound represented by formula D: ##STR00079##

12. The method of claim 1, further comprising: reacting a compound represented by formula D or a stereoisomer thereof to prepare a compound represented by formula B or a stereoisomer thereof, and reacting the compound represented by formula B or a stereoisomer thereof with a compound represented by formula A or a stereoisomer thereof to obtain a compound represented by formula I, ##STR00080## wherein, R.sup.1 is a hydrogen or an alkyl; R.sup.2 is an optionally substituted aryl or heteroaryl, the substituent is selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, amino, nitro, cyano, oxo, alkenyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR.sup.3, —C(O)R.sup.3, —C(O)OR.sup.3, —S(O)mR.sup.3 and —NR.sup.4R.sup.5, wherein the alkyl, alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and n is 0, 1, 2 or 3.

13. The method according to claim 12, wherein the compound represented by formula B is prepared by a method comprising: ##STR00081## 1) converting the compound represented by formula D to obtain a compound represented by formula C; and 2) reducing the compound represented by formula C thereby to obtain the compound represented by formula B.

14. The method according to claim 12, wherein the compound represented by formula I is a compound represented by formula III: ##STR00082##

15. The method according to claim 12, wherein the compound represented by formula I is a compound represented by formula IV: ##STR00083##

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(1) The following embodiments further illustrate the present disclosure, but the present disclosure is not limited thereto.

(2) 2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile (represented by formula (E1)) was prepared according to the method disclosed in patent application WO2012129495A1 (publication date 2012 Sep. 27),

(3) ##STR00062##

Embodiment 1: Preparation of (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine

(4) ##STR00063## ##STR00064##

Step One: Synthesis of Intermediate (D-1)

(5) The compound represented by the formula (E1) (25 g), potassium hydroxide (22.4 g) and ethylene glycol (150 mL) were mixed and the resulting mixture was stirred at 150° C. for 16 hours, and then the reaction was stopped. The reaction solution was cooled to room temperature, diluted with water (150 mL) and extracted with dichloromethane (150 mL×2). The aqueous phase was adjusted to pH=6-7 with 3M hydrochloric acid and extracted with dichloromethane (200 mL×4). The combined organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (26.1 g, pale yellow oil) with a yield of 97.4% and a HPLC purity of 92%.

Step Two: Synthesis of Intermediate (D2-1)

(6) The compound represented by the formula (D-1) (28 g) was dissolved in anhydrous ethanol (100 mL) and the temperature was raised to 50° C. The resolving agent S-phenylethylamine (6.2 g) was dissolved in anhydrous ethanol (100 mL) and the resulting S-phenylethylamine solution was added dropwise into the above solution at 50° C. The mixture was heated to reflux and stirred for 2 hours. Then the mixture was allowed to cool to 10° C. naturally, and solid was precipitated. The mixture was filtered, and the filter cake was washed to give the product (13 g, solid) with an enantiomeric excess (ee) value of 96.7%;

(7) recrystallization: the obtained 13 g solid product was added to anhydrous ethanol (80 mL), heated to reflux and stirred for 6 hours. Then the mixture was naturally cooled to 10° C. and solid was precipitated. The mixture was filtered, the filter cake was washed and dried to give the product (10.6 g) with an ee value of 99.0%.

Step Three: Synthesis of Intermediate (D2)

(8) KOH (2.18 g) was dissolved in water (120 mL), and then the compound represented by formula (D2-1) was dissolved in the solution. The mixture was extracted with dichloromethane (100 mL×3). The aqueous phase was adjusted to pH=6-7 with IN HCl solution and then extracted with dichloromethane (150 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (7 g) with a yield of 50% and an ee value of 99.4%.

(9) MS m/z (ESI): 276.71 [M+H].sup.+, 298.68 [M+Na].sup.+.

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.50-8.51 (m, 1H), 7.73-7.77 (m, 1H), 7.51-7.53 (d, 1H), 7.21-7.24 (m, 1H), 3.73-3.84 (m, 2H), 2.78-2.81 (d, 1H), 2.58-2.63 (m, 1H), 2.53-2.56 (d, 1H), 2.39-2.43 (m, 1H), 1.98-2.02 (d, 1H), 1.87-1.94 (m, 1H), 1.76-1.80 (m, 1H), 1.61-1.65 (m, 1H), 1.39-1.58 (m, 4H), 1.14-1.19 (m, 1H), (m, 1H), (m, 1H).

Step Four: Synthesis of Intermediate (C2)

(11) Dichloromethane (8.5 kg) was added to a reaction flask, and then the raw material (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetic acid (350 g), N,O-dimethylhydroxylamine hydrochloride (148.8 g), EDCI (292.3 g) and DMAP (15.5 g) were added under stirring. After the resulting mixture was stirred for 15-25 minutes, DIPEA (492.4 g) was added. Then the mixture was stirred under argon protection at room temperature for 16-18 hours. A saturated ammonium chloride aqueous solution (2.8 kg) was added to the reaction solution, and the resulting mixture was stirred for 5-10 minutes and partitioned. The organic phase was washed with saturated ammonium chloride aqueous solution (2.8 kg×2) and saturated brine (2.7 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then dichloromethane (2.5 kg) was added. The mixture was concentrated to dryness under reduced pressure to give an oil (372.03 g) with a yield of 92.0%.

(12) MS m/z (ESI): 319.1 [M+H].sup.+, 341.3 [M+Na].sup.+.

(13) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.50-8.51 (m, 1H), 7.66-7.71 (m, 1H), 7.43-7.45 (d, 1H), 7.15-7.18 (m, 1H), 3.63-3.66 (m, 2H), 3.47 (s, 3H), 2.86-2.88 (d, 3H), 2.62-2.65 (d, 1H), 2.50-2.57 (m, 1H), 2.36-2.39 (d, 1H), 1.96-2.00 (d, 1H), 1.80-1.86 (m, 1H), 1.68-1.72 (m, 1H), 1.48-1.55 (m, 1H), 1.31-1.46 (m, 4H), 1.03-1.07 (m, 1H), 0.63-0.71 (m, 1H).

Step Five: Synthesis of Intermediate (B2)

(14) The compound represented by formula (C2) (334.4 g) was dissolved in toluene (2.2 kg) in a reaction flask. The solution was cooled to −45° C. to −35° C. and purged with argon, and then red aluminum (348.76 g) was added dropwise while maintaining the temperature between −45° C. to −35° C. After completion of the addition, the reaction solution was stirred at −45° C. to −35° C. for 3-4 hours, and then 10% citric acid aqueous solution (1 kg) was added to the reaction solution at −45° C. to −35° C. Then concentrated hydrochloric acid solution was added to adjust the pH to 2-3, followed by addition of ethyl acetate (1.8 kg). The mixture was stirred and allowed to stand to partition. The aqueous phase was adjusted to pH=11-13 with 5N sodium hydroxide solution, and then extracted with dichloromethane (3.3 kg×2). The combined dichloromethane phase was washed with saturated sodium chloride solution (2.7 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then dichloromethane (3.3 kg) was added. The mixture was concentrated again under reduced pressure to give a pale red oil, which was directly used in the next step.

Step Six: Synthesis of the Compound Represented by Formula (III)

(15) The above oil was added to a reaction flask, followed by addition of dichloromethane (8.5 kg) and the compound represented by formula (A1) (134.56 g). The resulting mixture was stirred for 2-3 hours, followed by addition of sodium triacetoxyborohydride (373.86 g). The mixture was stirred at room temperature for 16-18 hours, followed by addition of saturated sodium carbonate solution (2.66 kg). Then the mixture was adjusted to pH=11-13 by addition of 5N sodium hydroxide aqueous solution and partitioned. The organic phase was washed with saturated ammonium chloride aqueous solution (2.83 kg) and saturated sodium chloride aqueous solution (2.74 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and then acetonitrile (120 g) was added. The mixture was stirred at room temperature for 16-18 hours to crystallize, and then filtered. The filter cake was dried to give the product (206.87 g) with a yield of 68.0%.

(16) MS m/z (ESI): 435.3 [M+H].sup.+.

(17) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.74 (d, 1H), 9.58 (d, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 7.94 (d, 1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.47 (t, 1H), 4.46-4.49 (m, 1H), 4.30-4.33 (m, 1H), 3.84-3.87 (m, 1H), 3.66-3.70 (m, 2H), 3.53-3.56 (m, 2H), 2.82-2.85 (d, 2H), 2.67 (s, 2H), 2.39-2.41 (m, 4H), 2.30-2.33 (m, 4H), 1.85 (s, 2H), 1.48-1.52 (m, 6H), 1.27 (m, 3H).

Embodiment 2

(18) ##STR00065##

Step One: Synthesis of Intermediate (D-1)

(19) The compound represented by the formula (E1) (13.5 kg, 1.0 eq), potassium hydroxide (2.6 kg, 2.0 eq) and ethylene glycol (135 L, 10 vol) were mixed, and the mixture was heated to 110° C. and stirred for 24 hours, and then the reaction was stopped. The resulting mixture was concentrated under reduced pressure to remove ethanol, then dichloromethane (26 L) was added to the residue and the mixture was stirred for dissolution. The mixture was washed twice with saturated sodium chloride solution (5 L), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (13 kg, yellow oil) with a yield of 90% and a HPLC purity of 95%.

Step Two: Synthesis of Intermediate (D2-1)

(20) The product obtained from previous step (13 kg) was dissolved in ethylene glycol (65 L, 5 vol) and the temperature was raised to 50° C. The resolving agent S-phenylethylamine (5.7 kg, 1.0 eq) was dissolved in ethylene glycol (1 L) and the resulting S-phenylethylamine solution was added dropwise into the above solution at 50° C. The mixture was heated to reflux and stirred for 3 hours. Then the resulting mixture was allowed to cool to room temperature naturally, and solid was precipitated. The mixture was filtered, and the filter cake was washed to give the product (6600 g, solid);

(21) recrystallization: the 6600 g solid was added into ethylene glycol (3 L), heated to reflux and stirred for 6 hours. Then the resulting mixture was naturally cooled to room temperature and solid was precipitated. The mixture was filtered, the filter cake was washed and dried to give the product (4700 g) with an ee value of 99.0%.

Step Three: Synthesis of Intermediate (D2)

(22) The 4700 g solid was dissolved in water, and then 1.2 eq of potassium hydroxide was added and the resulting mixture was stirred for dissolution. The mixture was extracted with dichloromethane (DCM) (30 L×3). The organic phase was isolated, and the aqueous phase was adjusted to pH=6-7 with hydrochloric acid. Then the aqueous phase was extracted with DCM (30 L×5). The combined organic phase was dried and concentrated to give 200 g product with an ee value of 99.42% and a purity of 99%.

(23) Although specific embodiments of the present disclosure are described above, those skilled in the art should understand that these are only examples for illustration, various modifications and changes can be made to the embodiments without departing from the principle and substance of the present disclosure. Thus the scope of the present disclosure is as defined in the claims attached herein.