CN113354700B

CN113354700B - Preparation method of sofosbuvir intermediate

Info

Publication number: CN113354700B
Application number: CN202110490805.9A
Authority: CN
Inventors: 石利平; 陈本顺; 叶金星; 李大伟; 江涛; 钱若灿; 张维冰; 杨武林; 邱磊; 于娜娜
Original assignee: Jiangsu Alpha Pharmaceutical Co ltd
Current assignee: Jiangsu Alpha Pharmaceutical Co ltd
Priority date: 2021-05-06
Filing date: 2021-05-06
Publication date: 2022-11-11
Anticipated expiration: 2041-05-06
Also published as: CN113354700A

Abstract

The invention relates to the technical field of biological pharmacy, in particular to a preparation method of a sofosbuvir intermediate, and more particularly relates to a preparation method of a sofosbuvir intermediate ((2R, 3R, 4R) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methyl benzoate. The preparation process has simple reaction conditions, easy operation and low cost; the operation of hydrolysis is reduced in the post-treatment process of the chlorination stage, so that the amount of waste water is reduced, and the method is more environment-friendly; the preparation process has the advantages of high yield, high product purity and more stable product, and is suitable for large-scale production.

Description

Preparation method of sofosbuvir intermediate

Technical Field

The invention relates to the field of pharmacy, in particular to a preparation method of a sofosbuvir intermediate, and more particularly relates to a preparation method of a sofosbuvir intermediate ((2R, 3R, 4R) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methyl benzoate.

Background

Sofosbuvir (Sofosbuvir), chemical name (2S) -isopropyl-2- ((((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid ethyl ester, CAS number 1190307-88-0, its structural formula is as follows:

sofosbuvir is a Hepatitis C Virus (HCV) nucleotide analog NS5B polymerase inhibitor useful as a combination component in a combination antiviral treatment regimen for the treatment of Chronic Hepatitis C (CHC) infection. The composition is a new drug developed by the Gilidder company for treating chronic hepatitis C, is approved to be on the market in the United states by the U.S. Food and Drug Administration (FDA) in 12-month and 6-month in 2013 and is approved to be on the market in European Union countries by the European drug administration (EMEA) in 1-month and 16-month in 2014. In the production process, it is usually produced using (2R) -2-deoxy-2-fluoro-2-methyl-D-ribofuranosyl chloride or the like as an intermediate, and more usually ((2R, 3R, 4R) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methylbenzoate as an intermediate.

Therefore ((2R, 3R, 4R) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methylbenzoate is an important intermediate compound for the preparation of sofosbuvir. At present, a plurality of preparation researches for the intermediate compound are carried out at home and abroad. For example, US2013/0324709A1 discloses a method for synthesizing the compound, which comprises the following steps:

in view of the above synthetic method, this reaction is disclosed in chinese patent application CN 109438537A. The modified red aluminum and the passivating agent trifluoroethanol used in the process have poor selectivity to the reaction, are easy to reduce excessively, generate byproducts and further bring inconvenience to subsequent reactions. Also, it is further disclosed in the patent that morphine is a deactivator of red aluminum, so that the generation of by-products can be reduced. It can be seen that modification of red aluminum in the preparation of ((2R, 3R, 4R) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methylbenzoate, a key intermediate, is one of the hotspots and difficulties studied by those skilled in the art.

In addition, in the preparation process of ((2r,3r,4r) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methylbenzoate, controlling the reaction conditions and thus controlling impurities in the reaction is also a research focus of those skilled in the art, for example, chinese patent application CN106310515A controls the generation of impurities by improving the raw materials of the chlorination reaction, etc., and chinese patent application CN109422781A improves the reaction yield and quality by changing the chlorination reagent and using organic amine to perform the chlorination reaction with triphosgene in a small molecular polar solvent.

It follows that although ((2r, 3r, 4r) -3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methylbenzoate has had much prior research work in the art as a key intermediate in the preparation of sofosbuvir. However, improving the purity of the product, reducing the production cost, and simplifying the preparation process parameters and conditions are still the key points of research by those skilled in the art.

Disclosure of Invention

The invention discloses a preparation method of a sofosbuvir intermediate, which comprises the steps of reacting a compound shown in a formula a with modified red aluminum to obtain a compound shown in a formula b, carrying out chlorination reaction on the compound shown in the formula b in an oxalyl chloride/chlorobenzene solution to obtain a compound shown in a formula c, and finally reacting the compound with a compound shown in a formula e to obtain a target compound shown in a formula d. In the process of preparing the compound with the structure shown in the formula c by using the method, byproducts which are difficult to treat are not generated, so that other reagents are not required to be added for hydrolysis and washing, and the generation of a large amount of waste water is avoided. The technical scheme of the invention can simplify the process flow, reduce the production cost, improve the product purity, produce less wastewater in the production process and improve the environmental friendliness. The reaction formula of the preparation method is as follows:

wherein R is phenyl or C _1-4 Alkyl groups of (a);

further preferably, C _1-4 The alkyl group of (2) is one of phenyl, methyl, ethyl, isopropyl and tert-butyl.

Most preferably, R is phenyl.

Further preferably, the preparation method of the modified Red aluminum (Red-Al) comprises the following steps: under the protection of nitrogen, HMDS/toluene solution is dripped into the mixture of toluene with the temperature of-15 to-20 ℃ and 70 percent of red aluminum, and the modified red aluminum is prepared by stirring at controlled temperature.

Further preferably, the 70% red aluminum is a 70% red aluminum/toluene solution with a red aluminum mass fraction.

In another preferred technical scheme, the mass fraction of HMDS in the HMDS/toluene solution is 30-60%, and is preferably 41%.

Further, the invention also discloses a specific step for preparing the compound shown in the formula b from the compound shown in the formula a, wherein the specific step is as follows: adding the compound with the structure shown in the formula a into dry DCM under the stirring condition, cooling, using nitrogen as protective gas, and dropwise adding a reducing agent to modify red aluminum to obtain a reduction product reaction solution; and (3) putting the reaction solution into hydrochloric acid under the stirring condition, extracting, washing and drying to obtain the compound shown in the formula b.

Further, the mass ratio of DCM to the compound represented by formula a is 5.

Further, the feeding molar ratio of the compound shown in the formula a, HMDS and red aluminum is 1: (0.9-1.8): (0.9-2.2), preferably 1.

Further preferably, the invention also discloses a specific step of carrying out chlorination reaction on the compound shown in the formula b in an oxalyl chloride/chlorobenzene solution to obtain the compound shown in the formula c, wherein the specific step is as follows: adding chlorobenzene into a reaction bottle, using nitrogen as protective gas, adding DMF, cooling to-10-0 ℃, dropwise adding oxalyl chloride/chlorobenzene solution, and stirring at controlled temperature; the temperature of the reaction system is recovered to about 15 ℃, a compound with the structure shown in the formula b/chlorobenzene solution is dripped, the internal temperature is maintained to carry out the first reaction, and the reaction temperature is raised to carry out the second reaction when a small amount of residual is monitored by TLC (thin layer chromatography) until the raw materials disappear; and adding a hydrochloric acid aqueous solution into the system, stirring, separating liquid, washing and drying to obtain the compound with the structure of the formula c.

Further preferably, the dropping temperature of the compound with the structure of the formula b/chlorobenzene solution is 10-30 ℃, and preferably 20 ℃; the first reaction time is 0.5-3 h, preferably 1h.

Further, the feeding molar ratio of the compound with the structure of the formula b, oxalyl chloride and DMF is 1: (0.8-1.5):

(0.8 to 1.5), preferably 1.15.

Further, the temperature of the second reaction is 20 ℃ to 50 ℃, and more preferably 40 ℃; the time of the second reaction is 0.5 h-3 h, and 1h is preferred.

Further, the ratio of the compound with the structure of the formula b to chlorobenzene is 1: (5-20) g/mL, preferably 1.

The specific steps of reacting the compound shown in the formula c with the compound shown in the formula e to prepare the target compound shown in the formula d are as follows: under the condition of controlling the internal temperature, adding a chlorobenzene solution of the compound shown as the formula e into the compound shown as the formula c, stirring for 10-40 min, heating to 48-52 ℃, dropwise adding stannic chloride, controlling the temperature to be below 55 ℃, and heating for reaction; dropwise adding hydrochloric acid, controlling the temperature to be 5-10 ℃, stirring, carrying out suction filtration, pulping, combining organic phases, washing, controlling the system temperature to be 10-15 ℃, distilling, carrying out reduced pressure concentration, cooling, adjusting the pH value to be 6-7, recrystallizing and synthesizing the target compound shown in the formula d.

Further preferably, the internal temperature is controlled to 10 to 30 ℃ and preferably 23 ℃.

Further preferably, the feeding molar ratio of the compound with the structure shown in the formula c to the compound with the structure shown in the formula e to the stannic chloride is 1: (0.6-2): (1.4 to 2.5), preferably 1.5.

Further preferably, the reaction temperature is 55-65 ℃, preferably 60 ℃; the reaction time is 13 to 24 hours, preferably 18 hours.

After the technical scheme disclosed by the invention is adopted, the following beneficial effects are achieved:

1) The modified red aluminum is prepared by the HMDS/toluene solution, and the modified red aluminum with better selectivity can be obtained by controlling the modification conditions of the red aluminum, so that the generation of byproducts can be reduced, and the product purity is improved.

2) The invention improves chlorination reaction, thereby not only improving the purity of the product, but also not needing hydrolysis operation, thereby greatly reducing the amount of industrial waste water, being more environment-friendly and meeting the requirements of modern industry.

3) The preparation process has the advantages of high yield, high product purity and more stable product, and is suitable for large-scale production.

Detailed Description

In order that the invention may be better understood, it will now be further described with reference to specific examples.

Unless otherwise specified, the reagents used in the examples of the present invention are all common commercial products.

The abbreviations referred to in the present invention have the following meanings:

HMDS-hexamethyldisilane

DMF-N, N-dimethylformamide

NCS-N-chlorosuccinimide

DCM-dichloromethane

SOCl ₂ -thionyl chloride

Example 1R is phenyl (conditions are preferred parameters)

(1) The compound a-1 reacts with the modified red aluminum to prepare a compound b-1, and the chemical reaction formula is as follows:

(1) adding 17.4g of toluene and 23.3g (80.7 mmol of red aluminum) of 70% red aluminum into a reaction bottle, cooling to-18 ℃, using nitrogen as a protective gas, dropwise adding an HMDS/toluene solution, wherein the mass of the HMDS and the mass of the toluene in the solution are respectively 13.9g (86.1 mmol) and 20g, and stirring for 1h at controlled temperature to obtain modified red aluminum;

(2) adding 200g of dried DCM into a reaction bottle, adding 20g of compound a-1 (53.7 mmol) under the condition of stirring, cooling to-18 ℃, using nitrogen as protective gas, dropwise adding a reducing agent to modify red aluminum when the system becomes turbid and solids appear, gradually reducing the solids of the system in the dropwise adding process, and finally dissolving the materials to be clear, wherein TLC shows that the raw materials disappear. After the raw materials disappear, reaction liquid is obtained;

(3) and (2) putting the reaction solution into 100mL 4mol/L hydrochloric acid under a stirring state, separating the solution after stirring, washing the organic phase twice by using the 100mL 4mol/L hydrochloric acid, extracting the combined aqueous phase by using DCM, washing the combined organic phase to be neutral by using saturated sodium bicarbonate, concentrating the filtrate at 63 ℃ under reduced pressure to be dry, drying the filtrate by using 20ml chlorobenzene each time, and carrying the filtrate for 3 times to obtain a light yellow oily substance, namely the compound b-1. The purity of the compound b-1 was found to be 98% or more by high performance liquid chromatography.

(2) The compound b-1 is subjected to chlorination reaction to prepare a compound c-1, and the chemical reaction formula is as follows:

(1) adding 300mL of chlorobenzene into a reaction bottle, using nitrogen as protective gas, adding 10.8g (147.4 mmol) of DMF (dimethyl formamide), cooling to-8 ℃, dropwise adding an oxalyl chloride/chlorobenzene solution, wherein the mass of oxalyl chloride and the mass of chlorobenzene in the solution are respectively 19.6g (154 mmol) and 100g, and stirring at a controlled temperature for 0.5h;

(2) the temperature of the reaction system is restored to about 15 ℃, a compound b-1/chlorobenzene solution is dripped, the amount of the compound b-1 and the chlorobenzene in the solution are respectively 50g (134 mmol) and 100mL, the reaction is carried out for 1h by maintaining the internal temperature at 20 ℃, and when 3 percent of the internal temperature is remained by monitoring by TLC, the reaction temperature is raised to 40 ℃ for 1h until the raw material disappears;

(3) after the raw materials completely react, adding 200g of aqueous solution of 2mol/L hydrochloric acid into the system, stirring for 0.5h for liquid separation, washing an organic phase with 200ml of clear water for 2 times, drying a product with anhydrous sodium sulfate, concentrating a filtrate at 63 ℃ under reduced pressure until the filtrate is dried to obtain a compound c-1, and analyzing by using a high performance liquid chromatography to obtain the compound c-1 with the purity of about 97%. The compound c-1 prepared by the method does not generate byproducts which are difficult to treat, so that other reagents do not need to be added for hydrolysis and water washing, and the generation of a large amount of waste water is avoided.

(3) Preparing a target compound d-1 by using the compound c-1 as a substrate, wherein the chemical reaction formula is as follows:

controlling the inner temperature to be 23 ℃, adding a solution containing 11.0g (38.3 mmol) of the compound e-1 and 100mL of chlorobenzene into 10g (25.5 mmol) of the compound with the structure of the formula c-1, stirring for 15min, heating to 50 ℃, dropwise adding 12.6g (48.5 mmol) of stannic chloride, and controlling the temperature to be below 55 ℃; raising the temperature to 60 ℃ for reaction for 18h; after the reaction is completed, 100mL of 2mol/L hydrochloric acid is dripped, the temperature is controlled to be 8 ℃, the stirring is continued for 1h, and the filtration is carried out; heating the filter cake to 58 ℃ by using 3 times of chlorobenzene for pulping; and combining organic phases, washing with 80ml of 2mol/L diluted hydrochloric acid, controlling the system temperature to be 13 ℃, combining the organic phases, pumping the combined organic phases into a distillation kettle for distillation when no product exists in the hydrochloric acid phase, concentrating under reduced pressure, cooling to 23 ℃, dropwise adding triethylamine, adjusting the pH value to be 6-7, recrystallizing and synthesizing the target compound shown in the formula d-1. The total yield is 72.5%, and the product purity is 99.2%.

Examples 2 to 5

The procedure disclosed in example 1 was followed except that the charge ratio of compound a-1 to 70% of red aluminum in the preparation of compound b-1 from compound a-1 was changed, respectively, and the results are shown in Table 1.

Table 1 different reaction conditions and results

Examples	n _a-1 ：n _{Red aluminium}	m _{70% Red aluminium} /g	Total yield/%)	Purity of the product/%)
					1	1:1.5	23.3	72.5	99.2
2	1:2.2	34.1	66.8	97.5
					3	1:0.9	14.0	60.5	98.3
4	1:2.5	38.8	30.2	91.6
					5	1:0.7	10.9	31.9	90.4

Examples 6 to 16

The chlorinating reagent, the charge ratio of compound b-1 to the chlorinating reagent, and the reaction temperature were varied in the manner disclosed in example 1 except that the chlorinating reaction of compound b-1 to produce compound c-1 was carried out, respectively, and the results are shown in Table 2.

Note: the white spots in the table indicate the same parameters as in example 1.

Table 2 different reaction conditions and results

Examples 17 to 24

The procedure of example 1 was followed except for changing the charge ratios of the compounds c-1 and e-1 and the reaction temperature in the preparation of the objective compound d-1 using the compound c-1 as a substrate, respectively, and the results are shown in Table 3.

Note: the white space in the table indicates that the parameters are the same as in example 1.

Table 3 different reaction conditions and results

Examples 25 to 26

The results are shown in Table 4, in the manner disclosed in example 1, except that the R groups in each material are different.

TABLE 4 reaction conditions and results for varying R groups

Examples	R radical	Total yield/%	Purity of the product/%)
				1	Phenyl radical	72.5	99.2
25	Methyl radical	70.6	99.2
				26	Isopropyl group	70.9	98.3

What has been described above is a specific embodiment of the present invention. It should be noted that modifications and adaptations can be made by those skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.

Claims

1. A preparation method of a sofosbuvir intermediate is characterized by comprising the following steps: the preparation method comprises the steps of reacting a compound shown in a formula a with modified red aluminum to obtain a compound shown in a formula b, carrying out chlorination reaction on the compound shown in the formula b in an oxalyl chloride/chlorobenzene solution to obtain a compound shown in a formula c, and finally reacting the compound with a structural compound shown in a formula e to synthesize a target compound shown in a formula d, wherein the reaction formula of the preparation method is as follows:

，

wherein R is phenyl or C _1-4 Alkyl groups of (a);

the preparation method of the modified red aluminum comprises the following steps: under the protection of nitrogen, HMDS/toluene solution is dripped into the mixture of toluene with the temperature of-15 to-20 ℃ and 70 percent of red aluminum, and the modified red aluminum is prepared by stirring at controlled temperature.

2. The preparation method of sofosbuvir intermediate as claimed in claim 1, wherein C is _1-4 The alkyl group of (2) is one of phenyl, methyl, ethyl, isopropyl and tert-butyl.

3. The preparation method of sofosbuvir intermediate as claimed in claim 1, wherein R is phenyl.

4. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein the 70% of the red aluminum in the preparation method of the modified red aluminum is a 70% red aluminum/toluene solution with a red aluminum mass fraction.

5. The preparation method of the sofosbuvir intermediate as claimed in claim 4, wherein the mass fraction of the solute HMDS in the HMDS/toluene solution is 30-60%.

6. The preparation method of sofosbuvir intermediate as claimed in claim 5, wherein the mass fraction of solute HMDS in the HMDS/toluene solution is 41%.

7. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein the specific steps for preparing the compound represented by the formula b from the compound represented by the formula a are as follows: adding the compound with the structure shown in the formula a into dry DCM under the stirring condition, cooling, using nitrogen as protective gas, and dropwise adding a reducing agent to modify red aluminum to obtain a reduction product reaction solution; and (3) putting the reaction solution into hydrochloric acid under the stirring condition, extracting, washing and drying to obtain the compound shown in the formula b.

8. The preparation method of sofosbuvir intermediate as claimed in claim 7, characterized by selecting any one of the following reaction conditions:

the mass ratio of DCM to the compound shown in the formula a is 5;

b. the feeding molar ratio of the compound shown in the formula a to HMDS to red aluminum is 1: (0.9-1.8): (0.9-2.2).

9. The preparation method of the sofosbuvir intermediate as claimed in claim 8, wherein the feeding molar ratio of the compound of formula a, HMDS and red aluminum is 1.6.

10. The preparation method of the sofosbuvir intermediate as claimed in claim 8, wherein the mass ratio of DCM to the compound represented by formula a is 10.

11. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein the step of chlorinating the compound represented by the formula b in oxalyl chloride/chlorobenzene solution to obtain the compound represented by the formula c comprises the following steps: adding chlorobenzene into a reaction bottle, using nitrogen as protective gas, adding DMF, cooling, dropwise adding oxalyl chloride/chlorobenzene solution, and stirring at controlled temperature; the temperature of the reaction system is recovered to about 15 ℃, a compound/chlorobenzene solution with the structure shown in the formula b is dripped, the internal temperature is maintained to carry out the first reaction, and the reaction temperature is increased to carry out the second reaction when a small amount of residual compound is monitored by TLC (thin-layer chromatography) until the raw materials disappear; and adding a hydrochloric acid aqueous solution into the system, stirring, separating liquid, washing and drying to obtain the compound with the structure of the formula c.

12. The preparation method of the sofosbuvir intermediate as claimed in claim 11, wherein the feeding molar ratio of the compound with the structure represented by the formula b, oxalyl chloride and DMF is 1: (0.8-1.5): (0.8-1.5).

13. The preparation method of the sofosbuvir intermediate as claimed in claim 12, wherein the feeding molar ratio of the compound of the formula b, oxalyl chloride and DMF is 1.15.

14. The preparation method of sofosbuvir intermediate as claimed in claim 11, wherein the reaction conditions are selected from any one or more of the following:

a. the dripping temperature of the compound with the structure of the formula b/chlorobenzene solution is 10-30 ℃, and the first reaction time is 0.5-3 h;

b. the temperature of the second reaction is 20-50 ℃; the time of the second reaction is 0.5 to 3 hours;

c. the ratio of the compound of formula b to chlorobenzene was 1: (5-20) g/mL.

15. The preparation method of sofosbuvir intermediate as claimed in claim 14, characterized by selecting any one or several reaction conditions selected from the group consisting of:

a. the dropping temperature of the compound with the structure of the formula b/chlorobenzene solution is 20 ℃; the first reaction time is 1h;

b. the temperature of the second reaction is 40 ℃; the time of the second reaction is 1h;

c. the ratio of the compound with the structure of the formula b to chlorobenzene was 1:10g/mL.

16. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein the step of reacting the compound represented by the formula c with the compound represented by the formula e to obtain the target compound represented by the formula d comprises the following specific steps: under the condition of controlling the internal temperature, adding a chlorobenzene solution of the compound shown in the formula e into the compound shown in the formula c, stirring, heating, dropwise adding stannic chloride, controlling the temperature to be below 55 ℃, and heating for reaction; dropwise adding hydrochloric acid, controlling the temperature to be 5-10 ℃, stirring, carrying out suction filtration, pulping, combining organic phases, washing, controlling the system temperature to be 10-15 ℃, distilling, carrying out reduced pressure concentration, cooling, adjusting the pH value to be 6-7, recrystallizing and synthesizing the target compound shown in the formula d.

17. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein the internal temperature is controlled to be 10 to 30 ℃; the feeding molar ratio of the compound with the structure shown in the formula c to the compound with the structure shown in the formula e to the stannic chloride is 1: (0.6-2): (1.4-2.5); the reaction temperature is 55-65 ℃; the reaction time is 13-24 h.

18. The preparation method of the sofosbuvir intermediate as claimed in claim 17, wherein the internal temperature is controlled to be 23 ℃; the feeding molar ratio of the compound with the structure shown in the formula c to the compound with the structure shown in the formula e to the stannic chloride is 1.5; the reaction temperature is 60 ℃; the reaction time was 18h.