Preparation method of optical N-acyl fused indoline-piperidine derivative

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a preparation method of an optical N-acyl fused indoline-piperidine derivative, which is further characterized in that a compound shown as a formula (I) is subjected to asymmetric hydrogenation under the action of a ligand L7 and Ir metal precursor complex catalyst and trifluoroacetic acid to obtain a compound shown as a formula (II). Through the action of the ligand L7, the Ir metal precursor complex catalyst and the trifluoroacetic acid, compared with the previous synthesis mode, the pressure required by hydrogenation is reduced, the equipment investment in the step is remarkably reduced, and the method is safer compared with the previous method.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and specifically discloses a method for preparing an optically active N-acyl fused indoline-piperidine derivative. Background Art

[0002] N-acyl fused indoline-piperidine compound, the structure is as follows:

[0003]

[0004] Derivatives with this compound as the parent core have broad applications. For example, patent CN 114105980 B discloses a method of using a ligand (S, RFc)-ZhaoPhos and [Ir(COD)Cl]2 complex as a catalyst, adding p-toluenesulfonic acid in a dichloromethane solvent, and asymmetric chiral catalysis of compound 5d (CAS: 688029-28-9) to obtain compound 6d (CAS: 1059630-20-4), as follows:

[0005]

[0006] Compound 6d (CAS: 1059630-20-4) is a synthetic intermediate of the indole ketone drug Lumateperone (CAS: 313368-91-1), and the structural formula of the drug is shown below:

[0007]

[0008] It is mainly used to treat schizophrenia, and has shown good efficacy and safety during the treatment process. It can significantly improve the positive and negative symptoms of schizophrenia patients in a relatively short period of time and help patients return to normal life faster. Most patients can tolerate lumepirone treatment well and rarely experience adverse reactions that require discontinuation of medication.

[0009] In patent CN 114105980 B, the synthesis of compound 6d (CAS: 1059630-20-4) from compound 5d (CAS: 688029-28-9) in the presence of ligand (S, RFc)-ZhaoPhos and [Ir(COD)Cl]2 complex requires pressurization to 50 to 65 atm. This pressure requirement increases the safety risk and investment in production equipment. Practice has shown that during the scale-up process of this step, thicker wall thickness and higher strength materials are required to ensure that no deformation or cracking occurs under high pressure, such as titanium alloy. The difficulty and cost of design and manufacturing increase accordingly, exceeding expectations. Summary of the invention

[0010] In view of the problems existing in the prior art, the first aspect of the present invention provides a method for preparing an optically active N-acyl-fused indoline-piperidine derivative, comprising:

[0011]

[0012] In an organic solvent, the compound of formula (I) is asymmetrically hydrogenated under the action of an Ir metal precursor and a ligand L7 complex catalyst to obtain a compound of formula (II), wherein R is selected from halogen, and R' is selected from alkoxy.

[0013] It is characterized in that

[0014] The ligand L is Trifluoroacetic acid is added into the organic solvent.

[0015] In some specific embodiments of the first aspect of the present invention, the halogen is selected from F, Cl, Br or I.

[0016] In some specific embodiments of the first aspect of the present invention, the alkoxy group is selected from methoxy and ethoxy.

[0017] In some specific embodiments of the first aspect of the present invention, the ee value of the compound of formula (II) is >85%.

[0018] In some specific embodiments of the first aspect of the present invention, the pressure of the hydrogenation is less than 65 atm, preferably less than 30 atm.

[0019] In some specific embodiments of the first aspect of the present invention, the organic solvent is selected from methanol, ethanol, N,N-dimethylformamide, toluene, tetrahydrofuran, and dichloromethane.

[0020] In some specific embodiments of the first aspect of the present invention, the Ir metal precursor is selected from [Ir(COD)Cl]2, [Ir(NBD)2]BF4, [Ir(NBD)2]X; [Ir(NBD)Cl]2; Ir(acac)(CO)2; [Ir(COD)Cl]2; Ir(ethylene)2(acac); [Ir(ethylene)2Cl]2; [Ir(COD)2]X,

[0021] The X is a negative anion, such as Cl-, Br - ,I-,BF4 - , ClO4 - , SbF6 - , PF6 - , TfO - ,B(Ar)4 - .

[0022] In some specific embodiments of the first aspect of the present invention, the molar ratio of the Ir metal precursor to the ligand is 5:10.5.

[0023] In some specific embodiments of the first aspect of the present invention, the molar ratio of the compound of formula (I) to trifluoroacetic acid is 1:3.

[0024] The second aspect of the present invention provides a method for synthesizing the compound of formula (I) described in the first aspect.

[0025] In alcohol solution, formula (III) Compound and formula (IV) The reaction obtains the compound of formula (I)

[0026] The compound of formula (I) is used as a substrate and asymmetric hydrogenation is performed under the action of an Ir metal precursor and a ligand L7 complex catalyst to obtain a compound of formula (II).

[0027] The R is selected from halogen, and the R' is selected from alkoxy.

[0028] In some specific embodiments of the second aspect, the alcohol solution is selected from ethanol, methanol or isopropanol.

[0029] In some specific embodiments of the second aspect, the reaction temperature is 80-100°C, and in some specific preferred embodiments of the second aspect, the reaction temperature is 90°C.

[0030] "Room temperature" means 40°C to 10°C in some embodiments, 35°C to 15°C in some embodiments, 30°C to 20°C in some embodiments, 25°C to 20°C in some embodiments, and 25°C in other embodiments.

[0031] The reagents used in the present invention are purchased from the open legal market, such as Aladdin, Xilong, Sigma, and McLean, with a purity of AR or GR or HPLC, and have not been further processed, such as purification.

[0032] The advantages of the present invention are:

[0033] The present invention discloses a method for preparing an optically active N-acyl fused indoline-piperidine derivative, further comprising asymmetric hydrogenation of a compound of formula (I) under the action of a ligand L7, an Ir metal precursor complex catalyst and trifluoroacetic acid to obtain a compound of formula (II). The present invention reduces the pressure required for hydrogenation compared to previous synthesis methods through the action of a ligand L7, an Ir metal precursor complex catalyst and trifluoroacetic acid, synthesizes some compounds not mentioned in the prior art, significantly reduces the equipment investment in this step, and is safer than previous methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Chiral HPLC test chart of compound 6d';

[0035] Figure 2 Chiral HPLC test chart of compound 6d;

[0036] Figure 3 Chiral HPLC test chart of compound 6b';

[0037] Figure 4 Chiral HPLC test chart of compound 6b;

[0038] Figure 5 Chiral HPLC test chart of compound 6a';

[0039] Figure 6 Chiral HPLC test chart of compound 6a; DETAILED DESCRIPTION

[0040] Through the following further detailed description of the embodiments of the present invention in combination with the accompanying drawings and specific implementation methods, those skilled in the art will more clearly and thoroughly understand the further features, advantages and effects of the present invention.

[0041] Example 1: Synthesis of Compound 5

[0042]

[0043] In a 100mL dry three-necked flask equipped with a stirring magnet, phenyl hydrochloride 3 (20mmol, 1.0equiv.) was added, and then a reflux tube was installed on the three-necked flask. The three-necked flask was replaced with gas three times under an argon atmosphere, and then anhydrous ethanol (35ml) was added to the reaction flask through a syringe. Piperidone 4 (20mmol, 1.0equiv.) was added to the flask through a syringe under stirring. Then the reaction tube was transferred to 90°C and kept at this temperature for one day until white solid turbidity appeared in the reaction flask. The reaction was cooled to room temperature and water was slowly added to quench the reaction. After the reaction was quenched, it was directly washed with anhydrous ethanol solution and filtered to obtain a white solid. After washing the white solid with n-hexane, the organic phase was concentrated under vacuum, and then petroleum ether and ethyl acetate were used as mobile phases for column chromatography separation and purification. The results are shown in Table 1:

[0044]

[0045] Example 2: Synthesis of Compound 6a

[0046]

[0047] Using dichloromethane as solvent, compound 5a (1.0 equivalent) as template substrate, 0.5 mol% 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2) as metal catalyst, 1.05 mol% 4-F-Ph-ZhaoPhos as ligand, 3.0 equivalents of trifluoroacetic acid (TFA) were added, and the reaction was carried out at room temperature under 30 atmospheres of hydrogen for 24 hours. After the reaction was completed, the gas valve of the high-pressure reactor was slowly opened, and the high-pressure hydrogen in the system was carefully released. After the pressure gauge pointer returned to zero, the reactor was opened and the ampoule containing the reactants was taken out.

[0048] The reaction was quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate or dichloromethane, and then dried over anhydrous sodium sulfate. The organic phase was concentrated by rotary evaporator, and then diluted hydrochloric acid was added to the concentrated organic phase for pickling. The product was easily salted in the hydrochloric acid solution. After pickling, the aqueous phase was transferred, sodium hydroxide solution or saturated sodium bicarbonate solution was added to adjust the pH value of the system to alkaline, and the aqueous phase was extracted with ethyl acetate or dichloromethane. After concentrating the organic phase, compound 6a (99% yield, 87.9% ee) was obtained.

[0049] 1 H NMR(600MHz,Chloroform-d)δ7.17(d,J=7.5Hz,1H),7.03(d,J=7.2Hz,1H),6.64(t,J=7.6Hz,1H),4.07-3.97(m,2H),3.94-3.73(m,1H),3.69( s,3H),3.59(s,1H),3.43(ddd,J=13.3,9.8,3.6Hz,1H),3.32(d,J=41.4Hz,2H),1.92(t,J=11.9Hz,1H),1.80(dtd,J=14.2,5.3,3.7Hz,1H)ppm. 13 C NMR (151MHz, Chloroform-d) δ 155.6, 149.3, 131.4 (d, J = 18.9Hz), 130.5, 123.0, 120.1, 103.7, 57.3, 52.6, 43.7, 41.5, 39.7, 27.8ppm.

[0050] Example 3: Synthesis of Compound 6b

[0051]

[0052] Using dichloromethane as solvent, compound 5b (1.0 equivalent) as template substrate, 0.5 mol% 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2) as metal catalyst, 1.05 mol% 4-F-Ph-ZhaoPhos as ligand, 3.0 equivalents of trifluoroacetic acid (TFA) were added, and the reaction was carried out at room temperature under 30 atmospheres of hydrogen for 24 hours. After the reaction was completed, the gas valve of the high-pressure reactor was slowly opened, and the high-pressure hydrogen in the system was carefully released. After the pressure gauge pointer returned to zero, the reactor was opened and the ampoule containing the reactants was taken out.

[0053] The reaction was quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate or dichloromethane, and then dried with anhydrous sodium sulfate. The organic phase was concentrated by rotary evaporator, and then diluted hydrochloric acid was added to the concentrated organic phase for pickling. The product was easily salted in the hydrochloric acid solution. After pickling, the aqueous phase was transferred, sodium hydroxide solution or saturated sodium bicarbonate solution was added to adjust the pH value of the system to alkaline, and the aqueous phase was extracted with ethyl acetate or dichloromethane. After concentrating the organic phase, compound 6b (90% yield, 86% ee) was obtained.

[0054] Example 4: Synthesis of Compound 6c

[0055]

[0056] Using dichloromethane as solvent, compound 5b (1.0 equivalent) as template substrate, 0.5 mol% 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2) as metal catalyst, 1.05 mol% 4-F-Ph-ZhaoPhos as ligand, 3.0 equivalents of trifluoroacetic acid (TFA) were added, and the reaction was carried out at room temperature under 30 atmospheres of hydrogen for 24 hours. After the reaction was completed, the gas valve of the high-pressure reactor was slowly opened, and the high-pressure hydrogen in the system was carefully released. After the pressure gauge pointer returned to zero, the reactor was opened and the ampoule containing the reactants was taken out.

[0057] The reaction was quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate or dichloromethane, and then dried over anhydrous sodium sulfate. The organic phase was concentrated by rotary evaporator, and then diluted hydrochloric acid was added to the concentrated organic phase for pickling. The product was easily salted in the hydrochloric acid solution. After pickling, the aqueous phase was transferred, sodium hydroxide solution or saturated sodium bicarbonate solution was added to adjust the pH value of the system to alkaline, and the aqueous phase was extracted with ethyl acetate or dichloromethane, and the organic phase was concentrated to obtain compound 6c. (99% yield, 88% ee).

[0058] 1H NMR(600MHz,Chloroform-d)δ7.05(d,J=8.1Hz,1H),7.00(s,1H),6.66(t,J=7.6Hz,1H),4.07-

[0059] 3.97(m,2H),3.94-3.73(m,1H),3.69(s,3H),3.59(s,1H),3.43(ddd,J=13.3,9.8,3.6Hz,1 H), 3.32 (d, J = 41.4Hz, 2H), 1.92 (t, J = 11.9Hz, 1H), 1.80 (dtd, J = 14.2, 5.3, 3.7Hz, 1H) ppm.

[0060] 13 C NMR (151MHz, Chloroform-d) δ156.0, 147.8, 131.6 (d, J = 13.9Hz), 127.8, 122.4 (d, J = 28. 5Hz), 119.8, 115.4, 57.3 (d, J = 18.1Hz), 52.6, 43.7, 41.5, 39.7, 27.8 (d, J = 31.2Hz) ppm.

[0061] The enantiomeric excess was determined by HPLC analysis using a Daicel Chiralpak OD-3 column (0.46×25 cm), n-hexane:isopropanol=85:15, flow rate=0.8 mL / min, λ=254 nm, tR: 12.939 min (S, R), 17.334 min (R, S).

[0062] Example 5: Synthesis of Compound 6d

[0063]

[0064] Using dichloromethane as solvent, compound 5d (1.0 equivalent) as template substrate, 0.5 mol% 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2) as metal catalyst, 1.05 mol% 4-F-Ph-ZhaoPhos as ligand, 3.0 equivalents of trifluoroacetic acid (TFA) were added, and the reaction was carried out at room temperature under 30 atmospheres of hydrogen for 24 hours. After the reaction was completed, the gas valve of the high-pressure reactor was slowly opened, and the high-pressure hydrogen in the system was carefully released. After the pressure gauge pointer returned to zero, the reactor was opened and the ampoule containing the reactants was taken out.

[0065] The reaction was quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate or dichloromethane, and then dried with anhydrous sodium sulfate. The organic phase was concentrated by rotary evaporator, and then diluted hydrochloric acid was added to the concentrated organic phase for pickling. The product was easily salted in the hydrochloric acid solution. After pickling, the aqueous phase was transferred, sodium hydroxide solution or saturated sodium bicarbonate solution was added to adjust the pH value of the system to alkaline, and then the aqueous phase was extracted with ethyl acetate or dichloromethane. After concentrating the organic phase, compound 6d was obtained (87% yield, 88% ee).

[0066] Comparative Example 1: (Synthesis of racemate)

[0067] Compound 1 (0.2 mmol, 1.0 equiv.) was added to a 25 mL dry Shrek reaction tube equipped with a stirring magnet, and then the reaction tube was replaced with gas three times under an argon atmosphere, 1.0 mL of dichloromethane was added to the reaction tube through a syringe, and then trifluoroacetic acid (2 mmol, 10.0 equiv.) was slowly added to the reaction tube through a syringe, and after stirring until the raw material was completely dissolved, triethylsilane (0.6 mmol, 3.0 equiv.) was added to the reaction tube through a micro syringe, and the reaction tube was placed at room temperature for 12 hours. After the reaction was completed, the trifluoroacetic acid in the reaction tube was neutralized with a saturated sodium bicarbonate aqueous solution, the organic phase was extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate. After the organic phase was concentrated by rotary evaporation, petroleum ether and ethyl acetate were used as mobile phases for column chromatography separation (PE / EtOAc v / v=5:1) to purify the racemic products 6a'-6d'.

[0068] entry Product (racemate) Conv.(%) ee(%) 5a 6a’ 92.1 1.00 5b 6b’ 91.8 0.51 5c 6c’ 94.3 1.07 5d 6d’ 92.6 1.17

[0069] Comparative Example 2:

[0070]

[0071] Using dichloromethane as solvent, compound 5d (1.0 equivalent, 1 mol / L) as template substrate, 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2, 0.5 mol%) as metal catalyst, any one of L1 to L9 (1.05 mol%) as ligand, 3.0 equivalents of trifluoroacetic acid (TFA) or 1.05 equivalents of p-toluenesulfonic acid were added, and the reaction was carried out at room temperature for 24 hours under a hydrogen atmosphere of 30 to 65 atmospheres P.

[0072] After the reaction is completed, slowly open the valve of the high-pressure reactor, carefully release the high-pressure hydrogen in the system, and after the pressure gauge pointer returns to zero, open the reactor and take out the ampoule containing the reactants. Add saturated sodium bicarbonate solution to quench the reaction, extract with ethyl acetate or dichloromethane, and then dry with anhydrous sodium sulfate. Concentrate the organic phase by rotary evaporator, then add dilute hydrochloric acid to the concentrated organic phase for pickling, transfer the aqueous phase after pickling, add sodium hydroxide solution or saturated sodium bicarbonate solution to adjust the pH value of the system to alkaline, and then extract the aqueous phase with ethyl acetate or dichloromethane. After concentrating the organic phase, the product is obtained, and the product yield (%) and enantiomer (%) are measured.

[0073] entry Acid P(atm) Yield(%) ee(%) L1 Trifluoroacetic acid 30 ND —— L2 Trifluoroacetic acid 30 ND —— L3 Trifluoroacetic acid 30 ND —— L4 Trifluoroacetic acid 30 8.1 61.1 L4 p-Toluenesulfonic acid 30 12.1 94.3 L4 p-Toluenesulfonic acid 50 87.3 99.6 L5 Trifluoroacetic acid 30 25.3 33.4 L6 Trifluoroacetic acid 30 ND —— L7 Trifluoroacetic acid 30 87.2 88.6 L7 p-Toluenesulfonic acid 30 10.1 44.3 L7 Trifluoromethanesulfonic acid 30 12.5 57.2 L8 Trifluoroacetic acid 30 47.7 86.7 L9 Trifluoroacetic acid 30 trace ——

[0074] The present invention improves CN 114105980 A, successfully reduces the synthesis reaction pressure by combining trifluoroacetic acid with a specific structural ligand L7, and develops a compound not mentioned in the prior art.

[0075] Comparative Example 3:

[0076]

[0077] Using dichloromethane as solvent, compound 5e (1.0 equivalent, 1 mol / L) as template substrate, 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2, 0.5 mol%) as metal catalyst, any one of L1 to L3, L6, L9 (1.05 mol%) as ligand, 3.0 equivalents of trifluoroacetic acid (TFA) were added, and the reaction was carried out at room temperature for 24 hours under a hydrogen atmosphere of 30 atmospheres P.

[0078] After the reaction is completed, slowly open the valve of the high-pressure reactor, carefully release the high-pressure hydrogen in the system, and after the pressure gauge pointer returns to zero, open the reactor and take out the ampoule containing the reactants. Add saturated sodium bicarbonate solution to quench the reaction, extract with ethyl acetate or dichloromethane, and then dry with anhydrous sodium sulfate. Concentrate the organic phase by rotary evaporator, then add dilute hydrochloric acid to the concentrated organic phase for pickling, transfer the aqueous phase after pickling, add sodium hydroxide solution or saturated sodium bicarbonate solution to adjust the pH value of the system to alkaline, and then extract the aqueous phase with ethyl acetate or dichloromethane. After concentrating the organic phase, the product is obtained, and the yield (%) and enantiomer (%) of the product 6e are measured.

[0079] entry Acid P(atm) Yield(%) ee(%) L1 Trifluoroacetic acid 30 ND —— L2 Trifluoroacetic acid 30 ND —— L3 Trifluoroacetic acid 30 ND —— L6 Trifluoroacetic acid 30 ND —— L9 Trifluoroacetic acid 30 trace ——

[0080] The embodiments described above are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. Such modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present application, and should all be included in the protection scope of the present application.

Claims

1. A method for preparing an optically active N-acyl-fused indoline-piperidine derivative, comprising: In an organic solvent, the compound of formula (I) is asymmetrically hydrogenated under the action of an Ir metal precursor and a ligand L7 complex catalyst to obtain a compound of formula (II), wherein R is selected from halogen, and R' is selected from alkoxy. It is characterized in that The ligand L7 is Trifluoroacetic acid is added into the organic solvent.

2. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to claim 1, characterized in that: The halogen is selected from F, Cl, Br or I, and / or the alkoxy is selected from methoxy and ethoxy.

3. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to any one of claims 1 or 2, characterized in that: The organic solvent is selected from methanol, ethanol, N,N-dimethylformamide, toluene, tetrahydrofuran, and dichloromethane.

4. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to any one of claims 1 to 3, characterized in that: The ee value of the compound of formula (II) is >85%.

5. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to any one of claims 1 to 4, characterized in that: The hydrogenation pressure is less than 65 atm, preferably less than 30 atm.

6. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to any one of claims 1 to 5, characterized in that: The Ir metal precursor is selected from [Ir(COD)Cl]2, [Ir(NBD)2]BF4, [Ir(NBD)2]X, [Ir(NBD)Cl]2, Ir(acac)(CO)2, [Ir(COD)Cl]2, Ir(ethylene)2(acac), [Ir(ethylene)2Cl]2 or [Ir(COD)2]X; The X is a negative anion, such as Cl - ,Br - , I - , BF4 - , ClO4 - , SbF6 - , PF6 - , TfO - ,B(Ar)4 - . .

7. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to any one of claims 1 to 6, characterized in that: The molar ratio of the Ir metal precursor to the ligand is 5:10.

5.

8. The method for preparing the optically active N-acyl-fused indoline-piperidine derivative according to any one of claims 1 to 7, characterized in that: The molar ratio of the compound of formula (I) to trifluoroacetic acid is 1:

3.

9. The method for synthesizing an optically active N-acyl-fused indoline-piperidine derivative according to claim 1, characterized in that: In alcohol solution, formula (III) Compound and formula (IV) The reaction yields a compound of formula (I) The compound of formula (I) is used as a substrate and asymmetric hydrogenation is performed under the action of an Ir metal precursor and a ligand L7 complex catalyst to obtain a compound of formula (II). The R is selected from halogen, and the R' is selected from alkoxy.

10. The method for synthesizing an optically active N-acyl-fused indoline-piperidine derivative according to claim 9, characterized in that: The alcohol solution is selected from ethanol, methanol or isopropanol, and / or the reaction temperature is 80-100°C, preferably 90°C.

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