A kind of preparation method of rucaparib intermediate of medicine for treating ovarian cancer

An intermediate, ovarian cancer technology, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of long reaction time, complex process, harsh conditions, etc., and achieve the effects of shortening the reaction period, readily available raw materials, and mild and easily controllable reaction conditions.

Active Publication Date: 2021-04-16
JIANGSU SKYRUN PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Purpose of the invention: the purpose of the present invention is to provide a drug for the treatment of ovarian cancer in view of the defects of harsh conditions, complicated process, long reaction time and low yield in the preparation method of Rucaparib intermediate (intermediate V) in the prior art The preparation method of Rucaparib intermediate

Method used

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  • A kind of preparation method of rucaparib intermediate of medicine for treating ovarian cancer
  • A kind of preparation method of rucaparib intermediate of medicine for treating ovarian cancer
  • A kind of preparation method of rucaparib intermediate of medicine for treating ovarian cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] a) 6-fluoro-4-cyano-1H-indole

[0059]

[0060] The compound of formula I (460g), cuprous cyanide (290g) and N,N-dimethylformamide (2.3L) were mixed, replaced with nitrogen three times, heated to 150°C and stirred for 6 hours. After the reaction was completed, it was cooled to room temperature.

[0061] Water (7L) and ethyl acetate (2L) were added to the reaction solution, filtered through diatomaceous earth, the filtrate was extracted twice with ethyl acetate (2L*2), the organic layer was dried with anhydrous sodium sulfate, decolorized with activated carbon, Concentrate to dryness to obtain 310 g of gray solid (compound of formula II), purity: 97.51%, yield: 90%.

[0062] The HNMR spectrogram of formula II compound sees attached figure 1 .

[0063] HNMR (400MHz, CDCl 3 ): δ9.38(br s,1H),7.25(t,J=4.0Hz,1H),7.15(dd,J=8.0,4.0Hz,1H),7.08(d,J=8.0Hz,1H), 6.59 (t, J=4.0Hz, 1H).

[0064] b) 6-fluoro-4-carboxy-1H-indole

[0065]

[0066] Compound of formula II (29...

Embodiment 2

[0082] a) 6-fluoro-4-cyano-1H-indole

[0083]

[0084] Compound of formula I (360g), zinc cyanide (400g) and dimethylsulfoxide (1.8L) were mixed, and Pd(dppf)Cl was added 2 (18 g), nitrogen replacement 3 times. Heat to 120°C and stir for 8 hours. After the reaction was completed, it was cooled to room temperature.

[0085] Water (5.4L) and ethyl acetate (2L) were added to the reaction solution, filtered through diatomaceous earth, the filtrate was extracted twice with ethyl acetate (2L*2), the organic layer was dried with anhydrous sodium sulfate, decolorized with activated carbon, Concentrate to dryness to obtain 250 g of gray solid (compound of formula II), purity: 95.87%, yield: 93%.

[0086] b) 6-fluoro-4-carboxy-1H-indole

[0087]

[0088] The compound of formula II (240 g) and concentrated hydrochloric acid (1.2 L) were added into a pressure reactor, heated to 120° C. and stirred for 10 hours. After the reaction was completed, it was cooled to room temperature...

Embodiment 3

[0098] a) 6-fluoro-4-cyano-1H-indole

[0099]

[0100] The compound of formula I (750g), cuprous cyanide (377g), potassium iodide (872g) and N,N'-dimethylformamide (3.7L) were mixed, and replaced with nitrogen three times. Heat to reflux and stir for 16 hours. Cool to room temperature.

[0101] Add water (11L) and ethyl acetate (3L) to the reaction kettle, filter through diatomaceous earth, extract the filtrate twice with ethyl acetate (3L*2), dry the organic layer with anhydrous sodium sulfate, decolorize with activated carbon, Concentrate to dryness to obtain 455 g of gray solid (compound of formula II), purity: 98.01%, yield: 81%.

[0102] b) 6-fluoro-4-carboxy-1H-indole

[0103]

[0104] Compound of formula II (510 g), potassium hydroxide (893 g), ethylene glycol (1.2 L) and 2.4 L of water were mixed, heated to 120° C. and stirred for 20 hours. After the reaction was completed, it was cooled to room temperature.

[0105] Water (7 L) was added to the reaction ket...

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Abstract

The invention discloses a method for preparing an intermediate of Rucaparib, a drug for treating ovarian cancer, which comprises the following steps: a compound of formula III undergoes a condensation reaction with an aminoacetaldehyde acetal compound under the action of a condensing agent or a carboxylic acid activator to obtain a compound of formula IV; The compound of formula IV is subjected to the action of acid and reducing agent to obtain the compound of formula V, which is the intermediate of the drug Rucaparib. The preparation method of the present invention has a reasonable route design, avoids nitration reaction, avoids the use of a large amount of strong acid, ensures safe production, is safe and environmentally friendly; the reaction conditions are mild and easy to control, effectively shortens the reaction route, shortens the reaction cycle, and reduces production costs. in industrial production.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, in particular to a method for preparing an intermediate of Rucaparib, a medicine for treating ovarian cancer. Background technique [0002] Rucaparib (Recaparib) is a polyadenosine diphosphate-ribose polymerase (PARP) inhibitor used as a monotherapy for advanced ovarian cancer with BRCA (breast cancer susceptibility gene mutation). [0003] Rucaparib chemical name: 8-fluoro-2-{4-[(methylamino)methyl)]phenyl}-1,3,4,5-tetrahydro-6H-azepine [5, 4,3 -cd] indol-6-one phosphate, molecular formula: C 19 h 18 FN 3 O·H 3 PO 4 , CAS: 459868-92-9, its structural formula is as follows: [0004] [0005] Literature (OPRD, 16, 12, (2012), p.1897–1904) reported the synthesis method of Rucaparib, and the synthesis route is as follows: [0006] [0007] Among them, intermediate V (chemical name: 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3 ,2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/06
CPCC07D487/06
Inventor 燕立波邓海存任聪金永华刘宇
Owner JIANGSU SKYRUN PHARMA CO LTD
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