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Intermediate compound of medicine LB80380 and preparing method and application thereof

A technology of LB80380 and compound, which is applied to the intermediate compound of LB80380 medicine and the fields of its preparation and use, and can solve problems such as potential safety hazards

Active Publication Date: 2017-02-22
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, this route needs to use extremely explosive reagent sodium azide (NaN 3 ), the azide compound (14) is an explosive reagent, which is potentially dangerous and brings serious safety hazards to the preparation process, post-processing and future industrial production

Method used

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  • Intermediate compound of medicine LB80380 and preparing method and application thereof
  • Intermediate compound of medicine LB80380 and preparing method and application thereof
  • Intermediate compound of medicine LB80380 and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Embodiment 1: the preparation of intermediate compound I-1

[0190] step 1. Preparation of ethyl 2-(dibenzylamino)acetate (IV-1)

[0191]

[0192] Dibenzylamine (VI-1) (4.7g, 23.9mmol) was dissolved in dichloromethane (10ml), and ethyl bromoacetate (V-1) (2.0g, 12mmol) was added under stirring at 25°C, and the addition was completed , a white solid precipitated out. Stirring was continued for about 16h, TLC monitored the completion of the reaction, filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated under reduced pressure to obtain a crude solid, which was recrystallized from petroleum ether / ethyl acetate (100:1) to obtain 3.3 g of a white solid, yield was 97.3%.

[0193] HNMR (400MHz, CDCl 3 )δ7.26-7.42 (m, 10H), 4.17 (q, 2H), 3.83 (s, 4H), 3.30 (s, 2H), 1.28 (t, 3H).

[0194] Step 2. Preparation of 1-(dibenzylamino)methylcyclopropanol (II-1)

[0195]

[0196] Under nitrogen protection, ethyl 2-(dibenzylamino)acetate ...

Embodiment 2

[0202] Embodiment 2: Preparation of LB80380 compound

[0203] step 1. Preparation of 1-(aminomethyl)cyclopropoxymethylphosphonic acid diethyl ester (VII-1)

[0204]

[0205] Add 1-(dibenzylamino)methylcyclopropyloxymethylphosphonic acid diethyl ester (I-1) (80.0g, 0.2mol) and methanol (1.2L) into the autoclave, add 5%Pd / C (8.0g), catalytic hydrogenation after gas replacement (pressure 0.3MPa, temperature 25°C). The completion of the reaction was monitored by TLC, filtered, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography (dichloromethane:methanol=5:1) to obtain an oily substance, a total of 41.36g, with a yield of 91%.

[0206] HNMR (400MHz, CDCl 3 )δ4.10-4.17(m,4H),3.78(d,2H),2.78(s,2H),2.70(brs,2H),1.31(t,6H),0.88(t,2H),0.53(t ,2H).

[0207] Step 2. Diethyl (1-(2,5-diamino-6-chloropyrimidine-4-amino)methyl)cyclopropoxymethylphosphonate Preparation of (VIII-1)

[0208]

[0209] Diethyl 1-(aminomethyl)cyclop...

Embodiment 3

[0227] Embodiment 3: the preparation of intermediate compound I-1

[0228] step 1. Preparation of ethyl 2-(dibenzylamino)acetate (IV-1)

[0229]

[0230] Dissolve ethyl glycine (10.3g, 0.1mol) in dichloromethane (50ml), add triethylamine (20.2g, 0.2mol) at 25°C, and add benzyl chloride (25.32g, 0.2mol) under stirring , After the addition, a white solid precipitated out. Continue to stir, TLC monitors that the reaction is complete, filter, the filter cake is washed with dichloromethane (20ml), the combined filtrate is washed with water (100ml), the organic layer is dried over anhydrous sodium sulfate, filtered, concentrated to obtain a solid, and washed with petroleum ether / ethyl acetate (100:1) recrystallization to obtain 27.21 g of white solid with a yield of 96.03%.

[0231] HNMR is the same as that in Step 1 of Example 1.

[0232] Step 2. Preparation of 1-(dibenzylamino)methylcyclopropanol (II-1)

[0233] Prepare with reference to step 2 of Example 1.

[0234] S...

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Abstract

The invention provides an LB80380 intermediate compound (as shown in formula I in the specification). In the LB80380 intermediate compound, R1, R2, R3 and R4 are chosen from linear chain or branched chain alkyl group, benzyl group which is replaced by one or five R5, or R5CO independently, wherein the R1, the R1, the R3 and the R4 are identical or different; R5 is chosen from hydrogen, C1-C4 alkoxy which is replaced or not replaced, C3-C7 alkenyl alkoxy, or benzyloxy- which is replaced or not replaced. The invention also provides a preparing method and an application of the compound in the formula I. When the compound in formula I is used for preparing a compound (specific chemical formula is in the specification), reaction route raw materials and intermediate materials are low in price and easy to get, cost is low, safety is good, and thus the LB80380 intermediate compound in formula I is applicable to industrial production.

Description

technical field [0001] The invention relates to an intermediate compound of LB80380 medicine, a preparation method and application thereof. Background technique [0002] Nucleoside phosphonate derivative LB80380 (shown in formula A) is a new drug with obvious antiviral activity (especially anti-hepatitis B virus) developed by South Korea LG Life Science Company. Clinical trials have shown that the derivative (1) inhibits HBV activity 100 times more than adefovir dipivoxil, and has good safety without obvious adverse reactions. [0003] [0004] Regarding the preparation of this compound, three synthetic routes have been disclosed at present: [0005] Route 1 (patent document CN1487949A): [0006] [0007] In this route, in the process of synthesizing compound (6) by starting material compound (2), the hydroxyl protection reagent that adopts is tert-butyl (diphenyl) silyl chloride (TBDPSCl), and this reagent is expensive, causes cost In addition, in the process of pr...

Claims

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Application Information

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IPC IPC(8): C07F9/40C07F9/6561
Inventor 赵富录王琦王银虎李森王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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