CN114195834A

CN114195834A - Preparation method of impurity of prophenoltenofovir lactose

Info

Publication number: CN114195834A
Application number: CN202111634651.2A
Authority: CN
Inventors: 杨志龙; 王少宾; 翟家豪; 巩洪举; 冯雅慧; 周玉; 谷杰
Original assignee: Shijiazhuang Lonzeal Pharmaceutical Co ltd
Current assignee: Shijiazhuang Lonzeal Pharmaceutical Co ltd
Priority date: 2021-12-29
Filing date: 2021-12-29
Publication date: 2022-03-18

Abstract

The invention relates to the technical field of preparation of medicinal impurities, and provides a preparation method of a propionofovir lactose impurity, wherein the propionofovir lactose impurity is N6- [2, 3-dihydroxy-5-hydroxymethyl-4- (3,4, 5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -tetrahydro-pyran-2-yl ] -9- { (R) -2- [ ((S) - { [ (S) -1- (isopropoxycarbonyl) ethyl ] amino } -phenoxyphosphinyl) methoxy ] propyl } adenine, and the preparation method comprises the following steps: s1, dissolving the propofol tenofovir in an organic solvent; s2, heating, and distilling with lactose to remove organic solvent through condensation reaction to obtain a crude product; s3, purifying the crude product to obtain the impurity of the prophenoltenofovir lactose. By adopting the technical scheme, the quality of the standard tenofovir disoproxil fumarate is improved.

Description

Preparation method of impurity of prophenoltenofovir lactose

Technical Field

The invention relates to the field of preparation of pharmaceutical impurities, in particular to a preparation method of a prophenoltenofovir lactose impurity.

Background

The medicine is characterized in that the medicine is prepared from Tenofovir disoproxil Fumarate, an English name Tenofovir Alafenamide Fumarate (TAF), a nucleic acid reverse transcriptase inhibitor, developed by the American Gilidard scientific company, and a single-component product with the trade name Virlide, wherein the single-component product is obtained in 2018 and approved by NMPA for marketing, and is clinically used for treating chronic hepatitis B; the compound variety Bituwei is approved by NMPA in 2019 and is clinically used for treating AIDS virus (HIV) infection. The time of Bituwei to be put into the market is less than two years, the sales volume reaches $ 72.59 billion in 2020, and a single-medicine sales record of the AIDS medicine is created.

TAF and the most commonly used hepatitis B drug, namely Tenofovir Disoproxil Fumarate (TDF), are prodrugs of Tenofovir (TFV), and TAF can generate an antiviral effect equivalent to TDF only by one tenth of dosage, so that the risk of nephrotoxicity and osteoporosis is greatly reduced, and the safety and the tolerance are higher.

The molecular structure of TAF is shown below:

it is known that primary and secondary amines react with lactose via condensation reactions to form lactose bound impurities (Maillard L.R., complexes Rends, 1912; 154(2): 66; Colaco C., Collett M., Roser B., Chem Oggi, 1996; 14:32), but there is no literature reporting a method for the preparation of TAF lactose bound impurities.

Disclosure of Invention

The invention provides a preparation method of a Propofol and Tenofovir lactose impurity, which is used for obtaining TAF lactose combined impurity with purity of more than 90% and improving the quality of a Propofol and Tenofovir fumarate standard substance.

The technical scheme of the invention is as follows:

a process for the preparation of a propionofovir lactose impurity which is N6- [2, 3-dihydroxy-5-hydroxymethyl-4- (3,4, 5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -tetrahydro-pyran-2-yl ] -9- { (R) -2- [ ((S) - { [ (S) -1- (isopropoxycarbonyl) ethyl ] amino } -phenoxyphosphinyl) methoxy ] propyl } adenine, said process comprising the steps of:

s1, dissolving the propofol tenofovir in an organic solvent;

s2, heating, and distilling with lactose to remove organic solvent through condensation reaction to obtain a crude product;

s3, purifying the crude product to obtain the impurity of the prophenoltenofovir lactose.

As a further technical scheme, the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide.

Preferably, the organic solvent is dimethyl sulfoxide.

As a further technical scheme, the mass-volume ratio of the propofol tenofovir to the organic solvent is 1g (1-1.2 mL).

As a further technical scheme, the water content of the organic solvent is less than 0.1 percent.

As a further technical scheme, the molar ratio of the propofol tenofovir to the lactose is 1: 4

As a further technical scheme, in the step S2, the temperature is 50-100 ℃, and the reaction time is 25-40 h.

As a further technical scheme, the temperature is 90-95 ℃, and the reaction time is 35-40 h.

As a further technical scheme, in the step S3, the crude product is purified by taking octadecyl bonded silica gel as a stationary phase, a mobile phase a as an ammonium bicarbonate solution, and a mobile phase B as acetonitrile, and then freeze-drying after gradient elution.

The application of the impurity of the Propofovir lactose prepared by the preparation method of the impurity of the Propofovir lactose in the quality control of the Propofovir.

The invention has the beneficial effects that:

the invention provides a preparation method of a Propofovir lactose impurity (N6- [2, 3-dihydroxy-5-hydroxymethyl-4- (3,4, 5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -tetrahydro-pyran-2-yl ] -9- { (R) -2- [ ((S) - { [ (S) -1- (isopropoxycarbonyl) ethyl ] amino } -phenoxyphosphinyl) methoxy ] propyl } adenine), which takes Propofovir as a reactant to obtain a TAF lactose combined impurity through a condensation reaction, has simple synthesis method and convenient operation, can obtain TAF lactose combined impurities with the purity of more than 90 percent, and improves the quality of the Propofovir fumarate standard substance.

Drawings

The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.

FIG. 1 is a graph showing the hydrogen spectrum of impurities obtained in example 1 of the present invention;

FIG. 2 is a carbon spectrum of impurities obtained in example 1 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive step, are intended to be within the scope of the present invention.

Example 1

Propofol tenofovir (30g) and dimethyl sulfoxide (315mL, water content 0.05%) were put into a 500mL reaction flask, and lactose (86g) was added with stirring and reacted at 90-95 ℃ for 35 hours. And (3) distilling the reaction liquid under reduced pressure to remove dimethyl sulfoxide to obtain a crude product, and purifying the crude product by using a preparation column under the following preparation conditions:

octadecyl bonded silica gel is used as a stationary phase, a mobile phase A is ammonium bicarbonate solution, and a mobile phase B is acetonitrile. The gradient elution conditions were as follows:

Time(min)	mobile phase A	Mobile phase B
			0	70％	30％
21	50％	50％
			21.5	5％	95％
26	5％	95％
			26.5	90％	10％
30.5	90％	10％

The resulting preparation was freeze dried to yield the TAF lactose bound impurity in HPLC purity 97.2%.

Analysis of TAF lactose binding impurity structure confirmation data:

HR-ESI(m/z)：[M+H]⁺＝801.3184；[2M+H]⁺＝1601.5817

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.308(s，H)，8.221(s，H)，7.703(d，H，J＝6.0Hz)，7.287(t，2H，J＝7.6Hz)，7.127(t，H，J＝7.6Hz)，7.042(d，2H，J＝7.6Hz)，6.180(m，H)，5.630(t，H，J＝11.2Hz)，5.268(d，H，J＝4.8Hz)，5.093(d，H，J＝3.2Hz)，4.850(sep，H，J＝6.4Hz)，4.809(d，H，J＝2.0Hz)，4.743(t，H，J＝4.8Hz)，4.701(brs，H)，4.551(d，H，J＝4.0Hz)，4.508(t，H，J＝5.6Hz)，4.332(dd，H，J＝14.4Hz,2.8Hz)，4.274(d，H，J＝6.4Hz)，4.192(dd，H，J＝14.4Hz,6.4Hz)，3.839～4.009(overlap，4H)，3.780(dd，H，J＝13.2Hz,9.6Hz)，3.484～3.654(overlap，8H)，3.415(m,H)，3.350(m，2H)，1.153(d，9H,J＝6.4Hz)，1.084(d，3H,J＝6.0Hz)。

¹³C-NMR(400MHz,DMSO-d6)δ(ppm):17.08，20.78，21.85，21.89，47.42，49.54，60.77，60.91，64.53，68.41，68.65，70.93，71.16，71.41，71.62，73.75，75.90，75.95，78.32，80.97，103.99，119.42，120.93，124.85，129.98，142.63，150.62，150.71，152.48，154.93，173.36。

example 2

Adding propionofovir (20g) and N, N-dimethylformamide (200mL, the water content is 0.02%) into a reaction bottle, stirring, adding lactose (57g), reacting at the temperature of 90-95 ℃ for 40 hours, and distilling the reaction liquid under reduced pressure to remove the N, N-dimethylformamide to obtain a crude product.

The crude product was purified using a preparative column under the same conditions as in example 1, and the resulting stock solution was lyophilized to give the TAF lactose bound impurity in 95.6% HPLC purity.

The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A process for the preparation of a propionofovir lactose impurity which is N6- [2, 3-dihydroxy-5-hydroxymethyl-4- (3,4, 5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -tetrahydro-pyran-2-yl ] -9- { (R) -2- [ ((S) - { [ (S) -1- (isopropoxycarbonyl) ethyl ] amino } -phenoxyphosphinyl) methoxy ] propyl } adenine, said process comprising the steps of:

s1, dissolving the propofol tenofovir in an organic solvent;

2. The method of claim 1, wherein the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide.

3. The preparation method of the impurity Propofovir lactose as claimed in claim 1, wherein the mass volume ratio of Propofovir to the organic solvent is 1g (1-1.2 mL).

4. The method of claim 1, wherein the organic solvent has a water content of less than 0.1%.

5. The method of claim 1, wherein the molar ratio of the Propofovir to the lactose is 1: 4.

6. the method for preparing the impurity Propofovir lactose as claimed in claim 1, wherein in the step S2, the temperature is 50-100 ℃ and the reaction time is 25-40 h.

7. The method for preparing the impurity Propofovir lactose as claimed in claim 6, wherein the temperature is 90-95 ℃ and the reaction time is 35-40 h.

8. The method for preparing the impurity Propofovir lactose as claimed in claim 1, wherein in step S3, the crude product is purified by gradient elution with octadecyl bonded silica gel as stationary phase, mobile phase A as ammonium bicarbonate solution and mobile phase B as acetonitrile, and then freeze-dried.

9. Use of the tenofovir lactose impurity prepared by the method of preparation of the tenofovir lactose impurity according to any of claims 1-8 for the quality control of tenofovir.