Preparation method of chiral tertiary alcohol benzo-fused bicyclo [m.3. 0] alkanone compound

A benzo-fused compound technology, which is applied in the field of preparation of chiral tertiary alcohol benzo-fused bicyclo[m. Excellent chemical selectivity, strong group tolerance, and wide application range

Pending Publication Date: 2022-07-22
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the asymmetric reductive desymmetry of 1,3-diketones was developed by an engineered carbonyl reductase as a biocatalyst, and although some progress has been made, due to the lack of efficient chiral catalytic systems to achieve good enantio Selective, enantioselective desymmetry of haloaryl-substituted 1,3-diketones via intramolecular aryl addition remains challenging and unresolved

Method used

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  • Preparation method of chiral tertiary alcohol benzo-fused bicyclo [m.3. 0] alkanone compound
  • Preparation method of chiral tertiary alcohol benzo-fused bicyclo [m.3. 0] alkanone compound
  • Preparation method of chiral tertiary alcohol benzo-fused bicyclo [m.3. 0] alkanone compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Catalyst Pd(R-DTBM-SEGPHOS)I 2 [i.e. Pd(L3)I 2 ] preparation

[0053] PdCl 2 +R-DTBM-segphos+2Kl=Pd(R-DTBM-segphos)l 2 +2KCl

[0054] Under nitrogen protection, the PdCl 2 (195mg, 1.1mmol, 1.1eq), (R)-DTBM-SEGPHOS (L3, 1.179g, 1.0mmol, 1.0eq), KI (1.66g, 10mmol, 10.0eq) and DMF (10mL) were added to the dried 25mL Schlenk tube. The reaction mixture was stirred at room temperature for 5 hours; the solution was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain Pd(L3)I 2 1.46 g, 95% yield, as a dark purple solid. 1 H NMR (400MHz, Chloroform-d)δ8.65(s,1H),7.56(d,J=12.7Hz,4H),7.00(s,1H),6.69-6.59(m,2H),6.46-6.40( m, 2H), 5.71(d, J=1.3Hz, 2H), 5.63(d, J=1.2Hz, 2H), 3.69(s, 6H), 3.67(s, 6H), 1.38(s, 72H).

[0055] 13 C NMR (100MHz, Chloroform-d) δ162.5,161.7,149.5,146.3,143.9,142.8,142.7,133.8,129.6,128.9,128.9,119.6,119.1,13,7.4,117.2,107.8,107.7,100.31.8,64 , 32.1.

[0056] 31 P NMR (162MHz, Chlorofor...

Embodiment 14

[0078] 2-(2-Bromobenzyl)-2-methylcyclohexane-1,3-dione (Ia) was prepared with reference to Example 1

[0079] Preparation of (4aR,9aR)-4a-hydroxy-9a-methyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-1-one (IIa) (gram scale preparation)

[0080]

[0081] Under argon protection, compound Ia (1.0 g, 3.4 mmol, 1.0 eq), Pd(L3)I 2 (261.5mg, 0.17mmol, 0.05eq), L3 (40mg, 0.034mmol, 0.01eq), Et 3 N (1.2 g, 11.9 mmol, 3.5 eq) and dry DMSO (34 mL) were added to a dry Schlenk tube. The resulting reaction mixture was raised to 80 °C, and the reaction was stirred for 48 h. Then the reaction solution was cooled to room temperature, and 60 mL of H was added. 2 O. The aqueous phase obtained by separation was extracted with DCM (15 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and desolubilized. The residue was purified by silica gel column chromatography to obtain 504.2 mg of compound IIa as a white solid, yield 69%, 95% ee. [α] D ...

Embodiment 15

[0084] (4aR,9aR)-4a-hydroxy-6-methoxy-7,9a-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-1-one (IIb) preparation

[0085]

[0086] The preparation was carried out with reference to Example 1, and 40.5 mg of white solid IIb was obtained, with a yield of 78% and 98% ee.

[0087] 1 H NMR(500MHz, Chloroform-d)δ7.01(d,J=1.0Hz,1H),6.72(s,1H),3.82(s,3H),3.49(d,J=15.2Hz,1H),2.59 (d, J=15.5Hz, 1H), 2.55–2.47 (m, 1H), 2.32–2.24 (m, 2H), 2.20–2.11 (m, 1H), 2.18 (s, 3H), 1.98–1.89 (m ,1H),1.70(br s,1H),1.50–1.39(m,1H),1.32(s,3H).

[0088] 13 C NMR (126MHz, Chloroform-d) δ213.5, 157.3, 143.3, 133.8, 127.8, 127.4, 103.6, 85.2, 62.5, 55.5, 38.1, 37.6, 32.0, 20.0, 17.9, 16.5.

[0089] ATR-FTIR (cm -1 ): 3447, 2935, 1699, 1943, 1295, 1201, 1001.

[0090] HRMS m / z(ESI): calcd for C 16 H 20 NaO 3 + (M+Na) + 283.1305, found 283.1310.

[0091] [α] D 25 = 12.4 (c = 1.40, CHCl 3 ).

[0092] HPLC (hexane / isopropanol=80:20, flow rate=1.0mL / min, uv-vis detection atλ=254nm)t R =6.8min...

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Abstract

The invention discloses a preparation method of a chiral tertiary alcohol benzo-fused bicyclo [m.3.0] alkanone compound, which is carried out according to the following reaction formula: (1) under the protection of inert gas, mixing a compound as shown in a general formula (I), a catalyst, a ligand, an additive and a solvent to prepare a mixture; (2) heating the mixture obtained in the step (1) to 25-100 DEG C to react for 0.5-72 hours, then cooling to room temperature, adding water to dilute, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, desolventizing under negative pressure, and purifying the obtained residue to obtain the compound as shown in the general formula (II); the preparation method is simple and convenient to operate, high in group tolerance, wide in application range and excellent in enantioselectivity, and is expected to become a powerful tool for candidate drug development in the drug development field.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for preparing a chiral tertiary alcohol benzo-fused bicyclic [m.3.0] alkanone compound Background technique [0002] Benzo-fused rings containing four-membered carbon stereocenters, as a class of complex polycyclic structures, are widely present in natural products and pharmaceutical molecules, with various desirable biological properties, such as 2-azabicyclo[3.3.0]octane Derivatives are antagonists of the somatostatin receptor type 5 (SSTR5) with potential to treat type 2 diabetes and obesity; two 2-azabicyclo-[3.3.0]octane and 3-azabicyclo[ 3.3.0] Octane derivatives have been identified as orexin receptor antagonists and have potential for the treatment of alcoholism; bicyclic cyanothiazolidines are inhibitors of dipeptidyl peptidase 4 (D PP4), which are similar to existing Inhibition of DPP4 in the treatment of diabetes has the adva...

Claims

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Application Information

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IPC IPC(8): C07C45/68C07C49/697C07C45/64C07C49/747C07C49/755C07C319/12C07C323/22C07B53/00B01J31/24
CPCC07C45/68C07C45/64C07C319/12C07B53/00B01J31/2452B01J31/2409C07B2200/07C07C2603/18C07C2601/14C07C2603/06B01J2531/824C07C49/697C07C49/747C07C49/755C07C323/22
Inventor 王治国郦荣浩罗春艳严德斌刘宝平
Owner 上海毕得医药科技股份有限公司
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