CN110713491A - Synthetic method of entecavir intermediate - Google Patents

Abstract

The invention relates to a method for synthesizing an entecavir intermediate. In particular, the invention relates to the use of TiCl₄And Ti (OiPr)₄The compound of formula N7 was synthesized as a Lewis acid.

Description

Synthetic method of entecavir intermediate

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of an entecavir intermediate.

Background

Nucleotide analogs have gained wide attention as an important class of compounds in the field of pharmaceutical chemistry. The research related thereto has led to a large number of drugs of great significance, especially in the field of antiviral drugs. A considerable number of anti-aids drugs and anti-hepatitis b drugs benefit from intensive research in this field.

There are 3.5 to 4.0 million Hepatitis B Virus (HBV) infected persons worldwide, and nearly 100 million patients die each year from cirrhosis and liver cancer caused by HBV infection. More than 1.2 hundred million HBV infected persons in China account for more than 1/3 of the total number of the world, and live in the 1 st position in the world, and 3000 ten thousand chronic hepatitis B (hepatitis B) patients exist, and the number is on the rise at present. Chronic hepatitis b virus infection has not been completely cured to date and patients require long-term or in most cases life-long viral suppression. Clinical guidelines recommend a treatment course of at least one year. The market share of nucleoside drugs in the existing hepatitis B treatment drugs exceeds 80 percent. Among nucleoside drugs, entecavir has replaced lamivudine as a first-line anti-hepatitis b virus drug since 2007 due to its remarkable therapeutic effect and good anti-drug resistance. Entecavir was developed by the united states company entitled "Baishi Guibao", and approved for marketing by the FDA in the united states on day 29/3 of 2005. The approval of China food and drug administration for marketing is obtained in 2005, 11 months and 15 days. The drug patent is expired in 2008, but because of the great difficulty in synthesis, the active ingredient (API) is high in market price at present and few manufacturers.

The entecavir bulk drug draws wide attention in the scientific community because of the great synthesis difficulty. Research on the synthesis methodology of entecavir has also been intensively developed. A representative synthetic route is described in detail in Entecavir route scheme (journal of Chinese medicine industry, 2007, No. 38, No. 10, No. 749, No. 752) by Shenmen et al and the literature cited therein.

For a key intermediate N7 in the entecavir synthesis process, TiCl is applied by most of the current patents and manufacturers₄+ Nysted reaction conditions. TiCl (titanium dioxide)₄The yield of Lewis acid is low and TiCl is used₄The use amount of the catalyst is large, so that a large amount of waste solids are generated in the post-treatment, the post-treatment operation is complicated, the atom utilization rate is low, the environmental pollution is serious, and the catalyst is not suitable for industrial production.

Therefore, a new synthesis method of entecavir intermediate N7 is needed.

Disclosure of Invention

The invention provides a method for synthesizing a compound of formula N7. The preparation method of the invention has less solid waste and higher product yield. Good atomic economy, environment-friendly and suitable for industrial production.

Specifically, the compound of formula N6 is used as a raw material in the synthesis method of the invention, and TiCl is used₄And Ti (OiPr)₄As Lewis acid and Nysted reagent was used.

In one embodiment, TiCl₄And Ti (OiPr)₄Is 1:1 to 6:1, preferably 3.5:1 to 4.5:1, more preferably 4: 1.

In one embodiment, TiCl₄And Ti (OiPr)₄Is 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, or 6:1, or any range therebetween.

In one embodiment, the synthesis method of the present invention is performed under nitrogen blanket.

In one embodiment, the synthesis method of the present invention is carried out in a suitable reaction solvent selected from tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, methyltetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or dioxane, preferably dichloromethane and tetrahydrofuran.

In one embodiment, the reaction time of the synthesis method of the present invention is 1 to 48 hours, preferably 1 to 8 hours.

In one embodiment, the reaction temperature of the synthesis process of the invention is from-78 ℃ to 25 ℃, preferably from-78 ℃ to-40 ℃.

In one embodiment, the volume of reaction solvent for the synthesis process of the present invention is selected to be 1-20V, preferably 1-10V.

Detailed Description

The present invention will be further described with reference to the following examples. It should be understood, however, that these examples are for the purpose of illustrating the invention in more detail only and are not to be construed as limiting the invention in any way.

The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is 10 deg.C to 30 deg.C, preferably 20 deg.C to 25 deg.C; the allowable error of the melting point is +/-1%; the yield is mass percent.

The unit of the solvent volume is V, for example 2V means 2 times the amount of solvent of the raw material.

Experimental methods

High Performance Liquid Chromatography (HPLC) detection

Detection was performed using an Agilent 1260HPLC or Waters 2695HPLC with PDA detector under the following chromatographic conditions:

examples

The following examples are intended to illustrate specific embodiments of the present invention, but are not intended to limit the invention in any way.

Ti (OiPr) used in the examples₄Purchased from the national drug group, lot number 20151209; TiCl (titanium dioxide)₄Purchased from the national pharmacy group, lot number 20170720; nysted reagent was purchased from adamas, lot number P1296447; n6 Compound was made in house as batch No. LXSH-00495-085-03.

Example 1

Mixing Ti (OiPr)₄(0.2eq) TiCl was added slowly dropwise₄Adding the mixture into dichloromethane solution (2V) (0.2eq), and stirring and reacting at room temperature for 1h for later use; adding Nysted (4.0eq) tetrahydrofuran solution into a reaction bottle (under nitrogen protection), cooling to-75 ℃, slowly dropwise adding the Ti ligand mixed solution to be used into the system, keeping the system temperature not higher than-65 ℃, after adding, keeping the temperature for reaction for 4h, simultaneously dissolving N6(1.0eq) in tetrahydrofuran (2V), slowly dropwise adding into the system, keeping the system temperature at-65 ℃, after adding, under nitrogen protection, returning to room temperature for reaction till the reaction is finished, filtering with kieselguhr, extracting, combining filtrates, concentrating under reduced pressure to dry, and purifying by column chromatography to obtain the productThe target product N7 (HPLC: greater than 98.5%, yield: 67%).

1HNMR(400MHz,CDCl₃)：7.86(s,1H),7.41-7.31(m,20H),7.24-7.14(m,9H),6.79-6.77(d,2H),5.28(br,1H),5.09(s,1H),4.55-4.43(m,5H),3.97(s,1H),3.68(s,3H),3.52(br,1H),3.42(s,2H),2.93(br,1H),2.07-2.05(br,1H).

ESI-MS：820.4[M+H]⁺.

Example 2

Mixing Ti (OiPr)₄(0.2eq) TiCl was added slowly dropwise₄Adding the mixture into dichloromethane solution (6V) by 0.8eq, and stirring and reacting at room temperature for 2 hours for later use; adding a 4.0eq tetrahydrofuran solution into a reaction bottle (under nitrogen protection), cooling to-70 ℃, slowly dropwise adding the standby Ti ligand mixed solution into the system, keeping the system temperature at-60 ℃, keeping the temperature for 1h after adding, preserving the temperature for reaction for 1h, simultaneously dissolving N6(1.0eq) into tetrahydrofuran (4V), slowly dropwise adding into the system, keeping the system temperature at-60 ℃, keeping the temperature for adding until the reaction is finished, carrying out kieselguhr filtering, extracting, combining filtrates, concentrating under reduced pressure to dryness, and carrying out column chromatography purification to obtain a target product N7 (HPLC: more than 98.5%, yield: 90%).

1HNMR(400MHz,CDCl₃)：7.86(s,1H),7.41-7.31(m,20H),7.24-7.14(m,9H),6.79-6.77(d,2H),5.28(br,1H),5.09(s,1H),4.55-4.43(m,5H),3.97(s,1H),3.68(s,3H),3.52(br,1H),3.42(s,2H),2.93(br,1H),2.07-2.05(br,1H).

ESI-MS：820.4[M+H]⁺.

Example 3

Mixing Ti (OiPr)₄(0.2eq) TiCl was added slowly dropwise₄(1.2eq) in a dichloromethane solution (10V), and stirring and reacting at room temperature for 4h after the addition is finished; adding Nysted (4.0eq) tetrahydrofuran solution into a reaction bottle (under nitrogen protection), cooling to-70 ℃, slowly dropwise adding the Ti ligand mixed solution for later use into the system, keeping the system temperature at-70 ℃, after adding, keeping the temperature for reaction for 2h, simultaneously dissolving N6(1.0eq) in tetrahydrofuran (8V), slowly dropwise adding into the system, keeping the system temperature at-70 ℃, after adding, under nitrogen protection, returning to room temperature for reaction until the reaction is finished, filtering by using kieselguhr to filterAnd extracting, combining the filtrates, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain the target product N7 (HPLC: more than 98.5%, yield: 75%).

1HNMR(400MHz,CDCl₃)：7.86(s,1H),7.41-7.31(m,20H),7.24-7.14(m,9H),6.79-6.77(d,2H),5.28(br,1H),5.09(s,1H),4.55-4.43(m,5H),3.97(s,1H),3.68(s,3H),3.52(br,1H),3.42(s,2H),2.93(br,1H),2.07-2.05(br,1H).

ESI-MS：820.4[M+H]⁺.

It should be understood that the above examples are for illustrative purposes only and are not intended to limit the scope of the present invention, and that various insubstantial modifications and adaptations of the invention may be made by those skilled in the art in light of the above teachings.

Claims (10)

1. A process for the synthesis of a compound of formula N7 starting from a compound of formula N6 using TiCl₄And Ti (OiPr)₄As Lewis acid and Nysted reagent was used.

。

2. The process according to claim 1, wherein TiCl is used₄And Ti (OiPr)₄The equivalent ratio of (A) to (B) is 1:1-6: 1.

3. The process according to claim 2, wherein TiCl is used₄And Ti (OiPr)₄The equivalent ratio of (a) to (b) is preferably 4: 1.

4. The process of claim 1, wherein the process is conducted under a nitrogen blanket.

5. The process of claim 1, wherein the process is carried out in a reaction solvent selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, methyltetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and dioxane.

6. The process of claim 5, wherein the reaction solvent is dichloromethane or tetrahydrofuran.

7. The process of claim 5, wherein the volume of the reaction solvent is 1-20V.

8. The process of claim 1, wherein the reaction time of the process is from 1 to 48 hours.

9. The process of claim 1, wherein the process has a reaction temperature of-78 ℃ to 25 ℃.

10. The process of claim 9, wherein the process has a reaction temperature of-78 ℃ to-40 ℃.