New process for synthesizing tenofovir disoproxil fumarate

A technology of tenofovir dipivoxil and a new process, which is applied in the field of preparation of antiviral drug tenofovir dipivoxil, can solve the problems of not reaching clinical drug use, unstable yield of chiral enrichment treatment, etc.

Inactive Publication Date: 2010-02-17
广东京豪生物制药有限公司
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  • Abstract
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Problems solved by technology

[0015] This route is comparatively brief, but this document (US5935946A1, 1999-08-10) points out simultaneously: the optical purity of the obtained target object is only 90-94%, does not reach the requirement of clinical medicine; Optical purity, but the literature data show that the yield of chiral enrichment treatment is very unstable

Method used

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  • New process for synthesizing tenofovir disoproxil fumarate
  • New process for synthesizing tenofovir disoproxil fumarate
  • New process for synthesizing tenofovir disoproxil fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of 2-O-(diisopropyloxy-phosphono-methyl)-(R)-lactate methyl ester (III)

[0026] 1.1 Synthesis of diisopropyl p-toluenesulfonyloxyphosphonate

[0027] The synthetic route is as follows:

[0028] PCl 3 +(CH 3 ) 2 CHOH→HPO[OCH(CH 3 ) 2 ] 2

[0029] (HCHO) n +HPO[OCH(CH 3 ) 2 ] 2 →HOCH 2 PO[OCH(CH 3 ) 2 ] 2

[0030]

[0031] Under ice bath, 787g (5.73mol) PCl 3 Slowly added dropwise to 1033g (17.2mol) of isopropanol, the dropwise addition was completed in 2 hours, and continued stirring under ice bath for 30 minutes. The ice bath was removed and stirred at room temperature for 3 hours. The low-boiling point solvent was evaporated by rotary evaporation, fractionated under reduced pressure, and the components at 70°C / 2mmHg were collected to obtain 450 g of diisopropyl phosphonite.

[0032] Add 12ml of toluene, 80g (0.48mol) of diisopropyl phosphite, 22g of paraformaldehyde and 6g of triethylamine in a nitrogen-filled reaction vesse...

Embodiment 2

[0035] Example 2 Preparation of 2-O-(diisopropyloxy-phosphono-methyl)-(R)-propanol (IV)

[0036] Add 14.2g (50.3mmol) of compound III to 840ml of anhydrous THF, under stirring in an ice bath, add 4.53g (120mmol) of NaBH in batches 4 , reacted in an ice bath for 15 minutes, removed the ice bath, and continued to react at room temperature for 8 hours (determining the reaction situation by TLC detection), until the end of the reaction.

[0037] Filtration, the filtrate was rotary evaporated to remove the solvent, extracted with ethyl acetate, anhydrous Na 2 SO 4 Dry overnight, filter, remove the solvent by rotary evaporation, use ethyl acetate as the eluent, and separate by column chromatography to obtain 6.82 g of light yellow oily liquid of IV, with a yield of 53.3%. H-NMR (DMSO, δppm): 4.583-4.640 (m, 2H); 3.761-3.783 (d, 2H); 3.492-3.507 (m, 1H); 3.383-3.396, 3.298-3.345 (m, 2H); 1.237-1.253 (m, 12H); 1.047-1.062 (dd, 3H).

Embodiment 3

[0038] Example 3 Preparation of 2-O-(diisopropyloxy-phosphono-methyl)-(R)-propyl p-toluenesulfonate (V)

[0039]In a 500ml three-neck flask, 110ml of pyridine, 13g (51mmol) of compound IV and 0.7ml of dimethylaminopyridine were added successively, and cooled in an ice bath. A solution of 36 g (188.8 mmol) of TsCl dissolved in 60 ml of pyridine was slowly added dropwise under stirring, and reacted overnight in an ice bath. Distilled water was added, the solvent was removed by rotary evaporation, extracted with ethyl acetate, washed with water, then acidified with 1M HCl, again with water, saturated NaHCO 3 , wash. The organic layer was separated and washed with anhydrous MgSO 4 dry. After filtration, the filtrate was rotary evaporated to remove the solvent to obtain 13.8 g of V as a yellow oily liquid, 66.25%. H-NMR (CDCl 3 , δppm): 7.783-7.804 (d, 2H); 7.274-7.367 (d, 2H), 4.712-4.731 (m, 2H); 3.960 (d, 2H); 3.776-3.822 (m, 2H); 3.697-3.753 (m, 2H); 2.456 (s, 3H); 1.296-...

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Abstract

The invention discloses a new process for sysnthesizing tenofovir disoproxil fumarate as an antiviral medicament. The invention greatly reforms the preparation process of tenofovir disoproxil as a keyintermediate for synthesizing the tenofovir disoproxil fumarate and establishes a new process suitable for industrial production. The new process includes the following steps: firstly (R)-methyl lactate and diisopropyl-p-ethyl methyl-phosphonate are condensed so that diisopropyl oxygroup- phosphonyl-methyl is introduced and the condensate can be used as a protection group of hydroxyl, and then the reaction step is shortened; secondly, carboxylic ester can be selectively reduced into alcohol by NaBH4 without affecting the phosphonate; and thirdly, adenine and 2-O-( diisopropyl oxygroup- phosphonyl-methyl)-(R)- isopropyl p-toluenesulfonic acid are condensed. Through hydrolysis, the enofovir disoproxil (II) as the key intermediate can be conveniently obtained, and the optical purity can reach more than 98%.

Description

technical field [0001] The invention relates to a new synthesis process for preparing antiviral drug tenofovir dipivoxil. technical background [0002] Tenofovir dipivoxil (I) chemical name: 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphono]methoxy]propyl]adenine , is an acyclic nucleoside phosphonate compound with anti-HIV and anti-HBV activities, and its fumarate is clinically used. Tenofovir dipivoxil is a prodrug of tenofovir (II) (chemical name: (R)-9-(2-phosphonomethoxypropyl) adenine), which will be hydrolyzed to release Tylenol soon after entering the body Fovir, produces antiviral effect. [0003] The chemical structures of tenofovir dipivoxil and tenofovir are shown below: [0004] [0005] Tenofovir is the key intermediate of synthesizing tenofovir dipivoxil, and the synthetic method of tenofovir reported in literature mainly contains two kinds. [0006] Synthetic method 1 (Holy A, Masojidkova M., Collect Czech Chem Commun, 1995, 60: 1196~1212): usi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07F9/40A61P31/12
CPCY02P20/55
Inventor 陈文彪
Owner 广东京豪生物制药有限公司
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