CN117720542A - Preparation method of adefovir intermediate GS-441524 - Google Patents

Abstract

The invention relates to the technical field of drug synthesis, and discloses a preparation method of a adefovir intermediate GS-441524, which comprises the following steps: the method takes pyrrole [2,1-F ] [1,2,4] triazine-4-amine and D-ribose as raw materials, the reaction is carried out to obtain an intermediate II, and then the intermediate II is subjected to a hydroxyl protecting group reaction, a cyanation reaction and a hydroxyl deprotecting group reaction to obtain GS-441524.

Description

Preparation method of adefovir intermediate GS-441524

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a adefovir intermediate GS-441524.

Background

New coronavirus (COVID-19), which is caused by severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), has caused infection in more than 10 hundred million people. The COVID-19 has a great influence on the economic development of China and the world.

Remdesivir (Remdesivir), which belongs to an RNA-dependent RNA polymerase (RdRp) inhibitor, can achieve the antiviral purpose by inhibiting viral nucleic acid replication, and is the earliest drug for treating SARS-CoV-2 infection in epidemic outbreaks. Despite its good clinical efficacy, the synthesis of adefovir is cumbersome due to its relatively complex prodrug form, long synthesis steps (j.med. Chem.2017,60, 1648-1661), and in particular intermediate GS-441524, resulting in limited applicability and accessibility of adefovir.

GS-441524 has a structure shown in formula I and chemical name: (2R, 3R,4S, 5R) -2- (4-aminopyrrolo [2,1-F ] [1,2,4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile, having the Cas number: 1191237-69-0.

GS-441524 structure

At present, jide science company reports a synthesis route of Rede Sivir (formula 1). The synthetic route is to obtain a compound GS-441524 from 7-iodopyrrole [2,1-F ] [1,2,4] triazine-4-amine and 2,3, 5-tribenzyloxy-D-ribonucleotide-1, 4-lactone through metal lithium halogen exchange, asymmetric cyanation conversion and debenzylation. The route uses strong alkali, ultralow temperature environment and the protection and deprotection of hydroxyl groups of ribose, which is very complicated and is not beneficial to industrialization.

GS-441524 synthetic route of science company 1 Ji Lide

In 2021, german List group published a more concise method (formula 2) in Angew.chem.int.ed.2022,61, e202114619.

2List minor group into GS-441524 route

Pyrrole [2,1-F ] [1,2,4] triazine-4-amine is directly subjected to affinity addition with D-ribose, then acetyl is used for protecting hydroxyl, and finally GS-441524 is synthesized through Mn-catalyzed C-H oxidation and deoxidization. However, the catalyst synthesis is complicated by Mn-catalyzed C-H oxidation in this route. The added PhIO is difficult to post-treat, and the extremely toxic benzene is not friendly to the environment as a solvent.

Disclosure of Invention

Therefore, a preparation method of the adefovir intermediate GS-441524 is needed to solve the problems of long synthesis process route, low yield and inapplicability to mass production of the adefovir intermediate GS-441524 in the prior art.

In order to achieve the above purpose, the invention provides a preparation method of a adefovir intermediate GS-441524, which comprises the following steps:

(1) Pyrrole [2,1-F ] [1,2,4] triazine-4-amine and D-ribose are used as raw materials to react to obtain an intermediate II, wherein the reaction formula is as follows:

(2) The intermediate II is subjected to a reaction of protecting groups on hydroxyl groups to obtain an intermediate III, and the structural formula of the intermediate III is as follows:

III, PG, protecting group

(3) The intermediate III is subjected to cyanation reaction to obtain an intermediate IV, and the structural formula of the intermediate IV is as follows:

(4) The intermediate IV undergoes a hydroxy deprotection reaction to give GS-441524.

Further, in step (1), the intermediate II is prepared by catalytic reaction using a first catalyst and reaction in a first solvent,

further, the first catalyst is selected from one of trimethyl silyl triflate, triethyl silyl triflate and trimethyl silicon-based methane sulfonate; and/or

The first solvent is selected from one or more of N, O-bis (trimethylsilyl) trifluoroacetamide, acetamide, N-dimethylacetamide and N, N-dimethylformamide.

Preferably, the reaction solvent is selected from the group consisting of N, O-bis (trimethylsilyl) trifluoroacetamides.

Preferably, the catalyst is selected from the group consisting of trimethylsilyl triflate.

Preferably, in step (1), the reaction temperature is from 0℃to 100 ℃.

Preferably, the feeding amount of the pyrrole [2,1-F ] [1,2,4] triazine-4-amine and the D-ribose is 1:1 to 1.5:1.

further, in step (2), intermediate II and a hydroxyl protecting reagent are reacted under the action of a first base and a second catalyst to obtain intermediate III having a hydroxyl protecting group.

Further, the protecting group on the intermediate III is one selected from acetyl, trifluoroacetyl, a fluorene methoxycarbonyl, an allyl, an allyloxycarbonyl, a tert-butoxycarbonyl, a trimethylsilylethoxymethyl and a benzyloxycarbonyl.

Preferably, the protecting group is selected from acetyl, trifluoroacetyl or a benzyloxycarbonyl group; more preferably, the protecting group is selected from acetyl.

Further, in step (2), the first base is selected from one or more of triethylamine, pyridine, morpholine; and/or

In step (2), the second catalyst is selected from 4-dimethylaminopyridine.

Preferably, in step (2), the temperature of the reaction is from 0℃to 150 ℃.

Further, in step (3), intermediate III and trimethylcyanosilane are reacted in a second solvent under the combined action of a third catalyst, a ligand and an oxidizing agent to give intermediate IV.

Further, the third catalyst is selected from one or more of cuprous acetate, cuprous iodide, cuprous triflate, cuprous bromide, cuprous chloride, cupric acetate, cupric iodide, cupric triflate, cupric bromide, and cupric chloride; and/or

In step (3), the ligand is selected from one of (3 as,3'as,8ar,8' ar) -2,2 '-cyclopentylenebis [3a,8 a-dihydro-8H-indeno [1,2-D ] oxazole, (3 ar,3' ar,8as,8 'as) -2,2' -isopropylidenebis [3a,8 a-dihydro-8H-indeno [1,2-D ] oxazole ], (4 r,4 'r) -2,2' -cyclopentylenebis [4, 5-dihydro-4-benzyl ] oxazole, (4 s, 4's) -2,2' -cyclopentylenebis [ 4-tert-butyl-4, 5-dihydrooxazole ]; and/or

In the step (3), the oxidant is selected from one or more of N-fluoro-bis-benzene sulfonamide, potassium monopersulfate composite salt, peroxybenzoic acid and tert-butyl peroxide; and/or

In step (3), the second solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, diethylene glycol dimethyl ether, toluene, xylene, and methylene chloride.

Preferably, the third catalyst is selected from cuprous acetate or oxone iodide.

Preferably, in step (3), the temperature of the reaction is 20℃to 200 ℃.

Further, in step (4), intermediate IV and the second base are reacted in a third solvent to give GS-441524.

Further, in step (4), the third solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, and acetonitrile; and/or

In step (4), the second base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium carbonate, cesium carbonate and sodium hydride.

Preferably, in step (4), the temperature of the reaction is from 10℃to 150 ℃.

The technical scheme has the following beneficial effects:

in the preparation step 1, pyrrole [2,1-F ] [1,2,4] triazine-4-amine and D-ribose are directly reacted to obtain an intermediate II, the reaction process is simple, a metal catalyst is not needed, the intermediate II is protected by a protecting group and then is cyanated, and finally the protecting group is removed to obtain a Ruidexivir intermediate GS-441524, so that the whole synthesis process route is short, the synthesis yield of the Ruidexivir intermediate GS-441524 is effectively improved, the process condition is mild, the raw material cost is low, and the method is suitable for large-scale production.

Drawings

Fig. 1 is a synthetic route diagram of adefovir intermediate GS-441524 according to an embodiment.

Detailed Description

In order to describe the technical content, constructional features, achieved objects and effects of the technical solution in detail, the following description is made in connection with the specific embodiments in conjunction with the accompanying drawings.

The synthesis route diagram of the adefovir intermediate GS-441524 in the invention is shown in figure 1.

EXAMPLE 1 preparation of intermediate of formula II

Trimethylsilicone triflate (6.8 mL,37.5 mmol), pyrrolo [2,1-F ] [1,2,4] triazin-4-amine (24.1 g,180 mmol), D-ribose (22.5 g,150 mmol), and N, O-bis (trimethylsilyl) trifluoroacetamide (400 mL,1500 mmol) were sequentially added to a 2000mL three-necked flask and reacted at 50℃for 72 hours. After the reaction was completed, hydrochloric acid solution (1500 mL,4M 1, 4-dioxane, 6000 mmol) was added to the system to continue the reaction for 24 hours, the mixture was filtered, and the solid was washed with 300mL of methyl t-butyl ether and dried to give 35.9g of an off-white solid product, i.e., intermediate II, having a purity of 93% and a yield of 90%. The obtained product is confirmed by mass spectrum, and the result is that: MS (ESI) [ M+H ] +267.10.

EXAMPLE 2 preparation of intermediate of formula III

In a 500mL three-necked flask, 4-dimethylaminopyridine (1.8 g,15 mmol), triethylamine (220 mL,158 mmol), acetic anhydride (64 mL,677 mmol) and intermediate II (35.9 g,135 mmol) prepared in example 1 were sequentially added and reacted at 30℃for 20 hours. After the reaction, the reaction mixture was added to 500mL of ethyl acetate, then 500mL of water was added, the separated liquid was extracted, the residue obtained by rotary evaporation of the organic phase was added to 200mL of isopropyl ether, and a solid was precipitated, filtered and dried to obtain 50.6g of a white solid product, namely, intermediate formula III, having a purity of 90% and a yield of 86%. The obtained product is confirmed by mass spectrum, and the result is that: MS (ESI) [ M+H ] +435.15.

EXAMPLE 3 preparation of intermediate formula IV

In a 500mL three-necked flask, intermediate III (50.6 g,116 mmol) prepared in example 2, (3 AS,3' AS,8AR,8' AR) -2,2' -cyclopentylenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole (6.7 g,17.4 mmol), cuprous acetate (2.2 g,17.4 mmol), N-fluorobiphenyl sulfonamide (54.8 g,174 mmol), trimethylsilane (23.0 g,232 mmol) and toluene were sequentially added and reacted at 40℃for 20 hours. After the reaction is finished, 200mL of dilute acid solution is added into the system, the solution is separated, the organic phase is washed by 200mL of water, the solution is separated, the residue obtained by rotary evaporation of the organic phase is added into 200mL of a mixture of toluene and n-hexane, solids are separated out, the solid is filtered and dried, and 45.5g of white solid product, namely an intermediate formula IV, is obtained, the purity is 95%, and the yield is 85%. The obtained product is confirmed by mass spectrum, and the result is that: MS (ESI) [ M+H ] +460.15.

Example 4 preparation of intermediate formula IV

In a 500mL three-necked flask, preparation of intermediate III (50.6 g,116 mmol), (3 AS,3' AS,8AR,8' AR) -2,2' -cyclopentylenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole (6.7 g,17.4 mmol), cuprous iodide (3.3 g,17.4 mmol), N-fluorobiphenyl sulfonamide (54.8 g,174 mmol), trimethylsilane (23.0 g,232 mmol) and toluene (200 mL) were sequentially added and reacted at 40℃for 20 hours. After the reaction is finished, 200mL of dilute acid solution is added into the system, the solution is separated, the organic phase is washed by 200mL of water, the solution is separated, the residue obtained by rotary evaporation of the organic phase is added into 200mL of a mixture of toluene and n-hexane, solids are separated out, filtration and drying are carried out, and 42.8g of white solid product, namely an intermediate formula IV, is obtained, the purity is 93%, and the yield is 80%.

EXAMPLE 5 preparation of intermediate formula IV

In a 500mL three-necked flask, preparation of intermediate III (50.6 g,116 mmol), (3 AR,3' AR,8AS,8' AS) -2,2' -isopropylidenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole ] (6.2 g,17.4 mmol), cuprous acetate (2.2 g,17.4 mmol), N-fluorobiphenyl sulfonamide (54.8 g,174 mmol), trimethylsilane (23.0 g,232 mmol) and toluene 200mL were sequentially added and reacted at 40℃for 20 hours. After the reaction is finished, 200mL of dilute acid solution is added into the system, the solution is separated, the organic phase is washed by 200mL of water, the solution is separated, the residue obtained by rotary evaporation of the organic phase is added into 200mL of a mixture of toluene and n-hexane, solids are separated out, the solid is filtered and dried, and 41.8g of white solid product, namely an intermediate formula IV, is obtained, the purity is 90%, and the yield is 78%.

Example 6 preparation of intermediate GS-441524

The intermediate prepared in example 3, formula IV (45.5 g,99 mmoL), sodium methoxide (1.6 g,29.7 mmoL) and 200mL of methanol were introduced into a 500mL three-necked flask and reacted at 30℃for 5 hours. After the completion of the reaction, the mixture was filtered, and the solid was added to 100mL of a mixed solvent of methanol and n-hexane, after 20 hours, the mixture was filtered, and the solid was dried to obtain 26.5g of GS-441524, the purity was 96%, and the yield was 92%. The structure of the obtained product is confirmed by mass spectrum and nuclear magnetic resonance, and the result is that:

¹ H-NMR(600MHz,DMSO-d6)δ7.91(s,1H),7.89(s,2H),6.90(d,J＝4.5Hz,1H),6.88(d,J＝4.5Hz,1H),6.09(s,1H),5.19(d,J＝4.5Hz,1H),4.91(t,J＝5.7Hz,1H),4.64(d,J＝5.1Hz,1H),4.09–4.03(m,1H),3.96(d,J＝5.9Hz,1H),3.64(ddd,J＝12.2,5.1,3.4Hz,1H),3.51(ddd,J＝12.1,6.1,4.5Hz,1H).

¹³ C-NMR(151MHz,DMSO-d6)δ155.6,147.9,123.9,117.3,116.5,110.8,100.8,85.4,78.5,74.2,70.1,60.9.

HRMS(ESI+)calculated for C ₁₂ H ₁₄ N ₅ O ₄ [M+H]+292.1040,found292.1039.

EXAMPLE 7 preparation of intermediate of formula III

In a 500mL three-necked flask, 4-dimethylaminopyridine (1.8 g,15 mmol), triethylamine (220 mL,158 mmol), trifluoroacetic anhydride (70 mL,677 mmol) and intermediate II (35.9 g,135 mmol) prepared in example 1 were successively added and reacted at 30℃for 20 hours. After the reaction, the reaction mixture was added to 500mL of ethyl acetate, then 500mL of water was added, the separated liquid was extracted, the residue obtained by rotary evaporation of the organic phase was added to 200mL of isopropyl ether, and a solid was precipitated, filtered and dried to obtain 74.7g of a white solid product, i.e., intermediate formula III, having a purity of 89% and a yield of 85%. The obtained product is confirmed by mass spectrum, and the result is that: MS (ESI) [ M+H ] +651.10.

EXAMPLE 8 preparation of intermediate formula IV

In a 500mL three-necked flask, intermediate III (74.7 g,115 mmol) prepared in example 7, (3 AS,3' AS,8AR,8' AR) -2,2' -cyclopentylenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole (6.7 g,17.4 mmol), cuprous acetate (2.2 g,17.4 mmol), N-fluorobiphenyl sulfonamide (54.8 g,174 mmol), trimethylsilane (23.0 g,232 mmol) and toluene (200 mL) were sequentially added and reacted at 40℃for 20 hours. After the reaction is finished, 200mL of dilute acid solution is added into the system, the solution is separated, the organic phase is washed by 200mL of water, the solution is separated, the residue obtained by rotary evaporation of the organic phase is added into 200mL of a mixture of toluene and n-hexane, solids are separated out, filtration and drying are carried out, and 65.3g of white solid product, namely the intermediate formula IV, is obtained, the purity is 92%, and the yield is 84%. The obtained product is confirmed by mass spectrum, and the result is that: MS (ESI) [ M+H ] +676.16.

Example 9 preparation of GS-441524

The intermediate prepared in example 8, formula IV (65.3 g,96.6 mmoL), sodium methoxide (1.6 g,29.7 mmoL) and 200mL of methanol were introduced into a 500mL three-necked flask and reacted at 30℃for 5 hours. After the completion of the reaction, the mixture was filtered, and the solid was added to 100mL of a mixed solvent of methanol and n-hexane, after 20 hours, the mixture was filtered and dried to obtain 25.3g of GS-441524 with a purity of 94% and a yield of 90%.

Example 10 preparation of intermediate of formula II

Unlike example 1, intermediate formula II was prepared in a purity of 90% and a yield of 87% using triethylsilyl triflate as a catalyst and trifluoroacetamide as a solvent.

EXAMPLE 11 preparation of intermediate of formula II

Unlike example 1, intermediate formula II was prepared in a purity of 91% and a yield of 85% using trimethylsilyl methane sulfonate as a catalyst and N, O-bis (trimethylsilyl) trifluoroacetamide as a solvent.

EXAMPLE 12 preparation of intermediate of formula II

Unlike example 1, intermediate formula II was prepared in a purity of 87% and a yield of 83% using trimethylsilyl methane sulfonate as a catalyst and N, O-bis (trimethylsilyl) trifluoroacetamide as a solvent.

EXAMPLE 13 preparation of intermediate of formula II

Unlike example 1, the reaction charge was: pyrrole [2,1-F ] [1,2,4] triazin-4-amine (150 mmol) and D-ribose (150 mmol), molar ratio 1:1, the intermediate formula II is prepared, the purity is 89%, and the yield is 82%.

EXAMPLE 14 preparation of intermediate of formula II

Unlike example 1, the reaction charge was: pyrrole [2,1-F ] [1,2,4] triazin-4-amine (225 mmol) and D-ribose (150 mmol), molar ratio 1.5:1, the intermediate formula II is prepared, the purity is 88%, and the yield is 92%.

It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the statement "comprising … …" or "comprising … …" does not exclude the presence of additional elements in a process, method, article or terminal device comprising the element. Further, herein, "greater than," "less than," "exceeding," and the like are understood to not include the present number; "above", "below", "within" and the like are understood to include this number.

While the embodiments have been described above, other variations and modifications will occur to those skilled in the art once the basic inventive concepts are known, and it is therefore intended that the foregoing description and drawings illustrate only embodiments of the invention and not limit the scope of the invention, and it is therefore intended that the invention not be limited to the specific embodiments described, but that the invention may be practiced with their equivalent structures or with their equivalent processes or with their use directly or indirectly in other related fields.

Claims (10)

1. A preparation method of a adefovir intermediate GS-441524, which is characterized by comprising the following steps:

(1) Taking pyrrole [2,1-F ] [1,2,4] triazine-4-amine and D-ribose as raw materials, and reacting to obtain an intermediate II;

(2) The intermediate II reacts with a protective group on hydroxyl to obtain an intermediate III;

(3) The intermediate III is subjected to cyanation reaction to obtain an intermediate IV;

(4) The intermediate IV is subjected to hydroxyl deprotection reaction to obtain GS-441524,

the reaction formula is as follows:

2. the process for the preparation of adefovir intermediate GS-441524 according to claim 1, wherein in step (1) intermediate II is prepared by a catalytic reaction using a first catalyst in a first solvent.

3. The process for the preparation of adefovir intermediate GS-441524 as claimed in claim 2, wherein in step (1), the first catalyst is selected from one of trimethyl silyl triflate, triethyl silyl triflate and trimethylsilyl methane sulfonate; and/or

The first solvent is selected from one or more of N, O-bis (trimethylsilyl) trifluoroacetamide, acetamide, N-dimethylacetamide and N, N-dimethylformamide.

4. The process for the preparation of adefovir intermediate GS-441524 according to claim 1, wherein in step (2) intermediate II is reacted with a hydroxy protecting reagent in the presence of a first base and a second catalyst to give intermediate III having a hydroxy protecting group.

5. The process for preparing adefovir intermediate GS-441524 of claim 4, wherein the hydroxy protecting group on intermediate III is one selected from the group consisting of acetyl, trifluoroacetyl, methoxycarbonyl, allyl, allyloxycarbonyl, t-butoxycarbonyl, trimethylsilylethoxymethyl, and benzyloxycarbonyl.

6. The process for the preparation of adefovir intermediate GS-441524 according to claim 4, wherein in step (2) the first base is selected from one or more of triethylamine, pyridine, morpholine; and/or

In step (2), the second catalyst is selected from 4-dimethylaminopyridine.

7. The process for the preparation of adefovir intermediate GS-441524 according to claim 1, wherein in step (3) intermediate III is reacted with trimethylcyanosilane in a second solvent under the combined action of a third catalyst, a ligand and an oxidizing agent to give intermediate IV.

8. The process for the preparation of adefovir intermediate GS-441524 of claim 7, wherein in step (3) the third catalyst is selected from one or more of cuprous acetate, cuprous iodide, cuprous triflate, cuprous bromide, cuprous chloride, cupric acetate, cupric iodide, cupric triflate, cupric bromide and cupric chloride; and/or

In step (3), the ligand is selected from one of (3 as,3'as,8ar,8' ar) -2,2 '-cyclopentylenebis [3a,8 a-dihydro-8H-indeno [1,2-D ] oxazole, (3 ar,3' ar,8as,8 'as) -2,2' -isopropylidenebis [3a,8 a-dihydro-8H-indeno [1,2-D ] oxazole ], (4 r,4 'r) -2,2' -cyclopentylenebis [4, 5-dihydro-4-benzyl ] oxazole, (4 s, 4's) -2,2' -cyclopentylenebis [ 4-tert-butyl-4, 5-dihydrooxazole ]; and/or

In the step (3), the oxidant is selected from one or more of N-fluoro-bis-benzene sulfonamide, potassium monopersulfate composite salt, peroxybenzoic acid and tert-butyl peroxide; and/or

In step (3), the second solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, diethylene glycol dimethyl ether, toluene, xylene, and methylene chloride.

9. The process for the preparation of adefovir intermediate GS-441524 according to claim 1, wherein in step (4) intermediate IV is reacted with a second base in a third solvent to yield GS-441524.

10. The process for the preparation of adefovir intermediate GS-441524 according to claim 9, wherein in step (4) the third solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane and acetonitrile; and/or

In step (4), the second base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium carbonate, cesium carbonate and sodium hydride.