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Preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid

A technology of -5-R-5-, -5-boc-5-, applied in the field of medicinal chemistry, can solve the problems of reducing the total yield and achieve the effect of increasing the yield and reducing the cost

Active Publication Date: 2015-04-01
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method uses chiral resolution, although the target intermediate can be obtained smoothly, but chiral resolution is required, and the yield of the resolution step is only 33%, which greatly reduces the total yield

Method used

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  • Preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid
  • Preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid
  • Preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1 prepares compound 3

[0052]

[0053] At 0°C, compound 2a (22.3 g, 105 mmol) and 2 (31.5 g, 100 mmol) in DMAc (40 ml) were added dropwise to NaH (12 g, 300 mmol) in DMAc (110 ml). After dropping, the reaction solution was stirred at this temperature for 6 hours. After HPLC showed that less than 0.5% of compound 2 remained, 230 ml of 2N HCl was added dropwise at the same temperature. After the drop was completed, the temperature was raised to room temperature, and after stirring for 4 hours, 300 ml of ethyl acetate was added to the reaction solution for liquid separation. Saturated Na 2 CO 3 The pH of the solution was adjusted to alkaline. 300 ml of n-heptane was added thereto, and the liquid was separated. The aqueous phase was extracted with 200ml of n-heptane, the organic phases were combined, dried, and concentrated under reduced pressure to obtain 13g of oily substance, yield: 75%, enantiomeric excess (ee) was 99.2%.

[0054] 1 H NMR (400MHz, C...

Embodiment 2

[0055] Embodiment 2 prepares compound 4

[0056]

[0057] At 0°C, potassium carbonate powder (20.7g, 150mmol) was added to compound 3 (13g, 75mmol) in DCM (100ml), and after stirring at this temperature for 30min, di-tert-butyl dicarbonate (35ml, 150mmol) was added dropwise. After the drop, the temperature was raised to room temperature and stirred for 2 hours. After HPLC showed that the remaining compound 3 was less than 0.5%, 100ml of water was added to separate the organic phase. The organic phase was washed twice with 70ml of saturated saline, dried over anhydrous sodium sulfate, and spin-dried to obtain Light gray solid 19.3g, yield: 94%.

[0058] 1 H NMR (400MHz, CDCl 3 ):δ8.10(s,1H),4.09(t,4.8Hz,1H),3.68(s,3H),3.54(d,J=6.8Hz,1H),3.23(d,J=6.8Hz,1H ),2.03(dd,J=8.4Hz,4.8Hz,1H),1.92(d,J=8.4Hz,4.8Hz,1H),1.42(s,9H),0.55(m,2H),0.45(m, 2H) ppm.

Embodiment 3

[0059] The preparation of embodiment 3 compound 5

[0060]

[0061] At 0°C, PBr was slowly added dropwise to a solution of compound 4 (19.1g, 70mmol) in 60ml of dichloromethane (150ml) 3 (37.8g, 140mmol), after dropping, stirred overnight at room temperature. Wash with saturated potassium carbonate solution (100ml) and dry over anhydrous sodium sulfate to obtain 22.5g of light yellow solid, yield: 97%.

[0062] 1 H NMR (400MHz, CDCl 3 ):δ8.10(s,1H),4.09(t,4.8Hz,1H),3.68(s,3H),3.24(d,J=6.8Hz,1H),2.94(d,J=6.8Hz,1H ),2.03(dd,J=8.4Hz,4.8Hz,1H),1.92(d,J=8.4Hz,4.8Hz,1H),1.42(s,9H),0.55(m,2H),0.45(m, 2H) ppm.

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Abstract

The invention relates to a preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid which is a compound as shown in a formula (III). The preparation method comprises the following steps: dissolving a compound 5 in an inert solvent and adding alkali to perform reaction (5), wherein LG is a leaving group and R is an amino-protecting group. The reaction provided by the invention can be performed by chiral synthesis, the yield is above 75% and the total yield is about 50%. The high performance liquid chromatography (HPLC) purity of the product is above 99%, the ee is more than 98%, chiral separation is not required, the yield is greatly improved and the cost is reduced.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of (S)-5-R-5-azaspiro[2,4]heptane-6-carboxylic acid. Background technique [0002] Ledipasvir, also known as GS5885, has a structure as shown in formula (I), and Ledipasvir is an inhibitor of hepatitis C virus NS5A protein. Clinical phase III studies have shown that it has a good therapeutic effect on various types of hepatitis C, and will be the drug of choice for hepatitis C treatment in the next few years [0003] [0004] PCT applications WO2013184698 and WO2013184702 reported the synthetic route of ledipasvir, wherein (S)-5-Boc-5-azaspiro[2.4]heptane-6-carboxylic acid formula (IIIa) or its potassium salt is in the route The key intermediates: [0005] [0006] PCT application WO2013184702 reports the preparation method of the compound represented by formula (IIIa), the reaction process of which is shown in Scheme 1: [0007] Route 1 [0008] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/54C07C227/18C07C229/28C07C269/06C07C271/22
CPCY02P20/55C07D209/54C07C227/18C07C229/28C07C269/06C07C271/22C07C2601/02
Inventor 申燕王功金李荣疆
Owner SUNSHINE LAKE PHARM CO LTD
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