WO2023151188A1

WO2023151188A1 - Green synthesis method of antiviral drug intermediate

Info

Publication number: WO2023151188A1
Application number: PCT/CN2022/089006
Authority: WO
Inventors: 夏斌; 汪佳明; 张宪恕; 蔡伶俐; 王子坤; 曹铭; 杨绍波; 高强; 郑保富
Original assignee: 上海皓元医药股份有限公司
Priority date: 2022-02-08
Filing date: 2022-04-25
Publication date: 2023-08-17

Abstract

The present application provides a green synthesis method of an antiviral drug intermediate. The method comprises: in the presence of a catalyst, adding zinc powder into a compound as represented by a formula II and performing a cyclization reaction with dihaloalkane to generate a compound as represented by a formula I, zinc halide being not required to be added to the cyclization reaction, wherein R1 is selected from H or an amino-protecting group, and R2 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C14 aryl or substituted or unsubstituted C7-C14 aralkyl; R3 and R4 are each independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, and R3 and R4 can be connected to form a fatty ring containing 3-10 carbon atoms. The synthesis method is short in steps, dangerous and expensive materials are not used, a reaction conversion rate is high, reaction time is short, and operation is easy and convenient. Production costs and post-treatment costs are reduced, and a cost advantage is obvious. The method can be widely used for preparing antiviral drugs of nirmatrelvir, boceprevir or narlaprevir, and has good market prospects.

Description

A kind of green synthetic method of antiviral drug intermediate

This application is required to be submitted to the Chinese Patent Office on March 11, 2022. The application number is 202210239473.1. The Chinese patent application titled "A Green Synthesis Method for Antiviral Drug Intermediates" was submitted to the Chinese Patent Office on February 8, 2022. , The priority of the Chinese patent application with the application number 202210118686.9 and the title of the invention is "A Synthetic Method of Antiviral Drug Intermediate", the entire content of which is incorporated in this application by reference.

technical field

The application relates to the technical field of drug synthesis, in particular to a green synthesis method of an antiviral drug intermediate.

Background technique

(1R,2S,5S)-6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate or salt, is a synthetic antiviral drug nirmatrelvir , an important intermediate of boceprevir and narlaprevir, its structural formula is as follows:

WO2021250648A1 discloses the following preparation method, and the synthesis route is as follows:

The reaction mixture described in the preparation method needs to be stirred at room temperature for 5 days, and then filtered through diatomaceous earth and rinsed with tetrahydrofuran. Finally, a yellow oily product was obtained by extraction, washing, drying and concentration with a yield of 75%.

CN 114057627A discloses the following steps:

The preparation of compound V in the third step uses n-butyllithium and isopropyltriphenylphosphine iodide, which is costly, and the operation of n-butyllithium is relatively dangerous.

CN114057627A discloses a preparation method of hepatitis C and new crown drug intermediates and salts thereof. The method also generates catalyst reactions on-line, and the catalyst consumption is 0.1 times equivalent, using cobalt bromide and ligand 2,6-bis[1-(2 - tert-butylphenylimino) ethyl] pyridine as a catalyst; stirred at room temperature for 24 hours, and after the reaction, the crude product was purified by column chromatography to obtain a slightly oily compound, which was then removed in HCl/EA (ethyl acetate) Boc obtained the hydrochloride, and the yield reached 84.1%.

The prior art has problems such as high cost, low yield, long reaction time, and the use of dangerous reagents. Therefore, it is currently necessary to find a new (1R, 2S, 5S)-6,6-dimethyl-3-nitrogen A method for synthesizing heterobicyclo[3.1.0]hexane-2-carboxylate derivatives or salts thereof.

Contents of the invention

The present application is mainly to provide a green synthesis method of an antiviral drug intermediate, specifically a (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1. 0] A new synthetic method of hexane-2-carboxylate derivatives or salts (such as hydrochloride), the route is short, the yield is high, the cost is low, the reaction time is short, no need to use dangerous reagents, and it can meet the needs of industrialization Scale up production.

The first aspect of the present application provides a (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate derivative represented by formula I or The synthesis method of its salt comprises: in the presence of a catalyst, adding zinc powder and a dihaloalkane to the compound shown in formula II for cyclization reaction to generate the compound shown in formula I; the cyclization reaction does not need to add zinc halide ;

in:

R ^is selected from H or an amino protecting group selected from Cbz, 2-chloro-Cbz, 2-fluoro-Cbz, 2,4-dichloro-Cbz, 4-bromo-Cbz, methoxymethyl Benzyl, benzyloxymethyl, benzyloxycarbonyl, trityl, pivaloyloxymethyl, benzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, triphenyl phenylmethyl, (p-methoxyphenyl) diphenylmethyl, diphenylphosphinyl, phenylsulfinyl, methoxycarbonyl, ethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1-methyl-1-phenylethoxycarbonyl, tert-butoxycarbonyl, cyclobutoxycarbonyl, 1-methylcyclobutoxycarbonyl, adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, cinnamyl Oxycarbonyl, 8-quinolyloxycarbonyl, 4,5-diphenyl-3-oxazolidin-2-onyl, 9-anthracenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, diphenyl Methoxycarbonyl, S-benzyloxycarbonyl or CY ₃ CO-, wherein Y is selected from halogen;

R ² is selected from substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted C ₇ -C ₁₄ aralkyl; said C ₁ -C The substituents of ₁₀ alkyl groups are each independently selected from halogen, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₆ -C ₁₀ aryl or C ₃ -C ₁₀ heteroaryl, the C ₁ -C ₆ heteroalkyl or the heteroatoms on the C ₃ -C ₁₀ heteroaryl are each independently selected from O, S or N; the C ₆ -C ₁₄ The substituents of aryl are independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, -CF ₃ or -NO ₂ , the substituents of said C ₆ -C ₁₄ aryl The number is 0-3; the substituted or unsubstituted C ₇ -C ₁₄ aralkyl is selected from benzyl, p-nitrobenzyl, 1-phenethyl, 2-phenethyl, 1-naphthyl Methyl or 2-naphthylmethyl;

R ³ and R ⁴ are each independently selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl groups, and the R ³ and the R ⁴ can be connected to form an aliphatic ring containing 3-10 carbon atoms; The substituents of the C ₁ -C ₁₀ alkyl are each independently selected from fluorine or cyclopropyl.

Cbz described in this application refers to benzyl ester group, also known as benzyloxycarbonyl; 9-fluorenylmethoxycarbonyl described in this application, also known as Fmoc; tert-butoxycarbonyl described in this application, also known as Boc .

The aralkyl group described in the present application refers to an aryl-alkyl group; in the C ₇ -C ₁₄ aralkyl group described in the present application, the aryl group has 7-14 C atoms.

The C ₁ -C ₆ haloalkyl mentioned in the present application means that the hydrogens on the C ₁ -C ₆ alkyl are independently replaced by halogen.

The halogen described in this application refers to F, Cl, Br or I.

The synthesis method provided by this application has short steps, does not use zinc halide reagents such as zinc bromide, and can obtain the target compound with high yield and high purity after one-step reaction, and the yield is all above 90%, more preferably up to 95%, and There is no need for column treatment, which reduces production costs and post-processing costs; no dangerous and expensive materials are used, and there is no special requirement for equipment during the reaction, the reaction time is short, the overall reaction cost is low, and the operation is simple; it can well realize industrialized large-scale production , has good economic benefits.

In some embodiments of the present application, (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate derivatives shown in formula I In or its salt, in the R ¹ , the amino protecting group is selected from tert-butoxycarbonyl, Cbz, benzyl, 9-fluorenylmethoxycarbonyl or 2-chloro-Cbz;

In the R ² , the substituted or unsubstituted C ₁ -C ₁₀ alkyl group is selected from heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl, cyclopropylmethyl or C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl; the substituted or unsubstituted C ₆ -C ₁₄ aryl is selected from C ₆ -C ₁₀ aromatic monocyclic ring system or C ₆ -C ₁₀ aromatic polycyclic ring system, preferably selected from phenyl or p-fluorophenyl; the substituted or unsubstituted C ₇ - C _Aralkyl is selected from benzyl, p-nitrobenzyl, 2-phenethyl, 1-naphthylmethyl or 2-naphthylmethyl;

In said R ³ and said R ⁴ , said C ₁ -C ₁₀ alkyl groups are each independently selected from C ₁ -C ₆ alkyl groups, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl; the aliphatic ring containing 3-10 carbon atoms is selected from cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl.

In some embodiments of the present application, the catalyst is selected from catalysts prepared from ligand compounds represented by formula III and cobalt halides;

Wherein, R ^is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

The catalyst ligand used in the present application is cheap, the catalyst is easy to prepare, and the catalyst can effectively catalyze the cyclization reaction, which is economical and efficient.

The application does not specifically limit the preparation method of the catalyst ligand, as long as the purpose of the invention of the application can be realized, for example, in an organic solvent (such as toluene), under the presence of a catalyst (such as p-toluenesulfonic acid), the 2, 6-diacetylpyridine reacts with any substituted aniline (such as aniline substituted by methyl, ethyl, n-propyl, isopropyl or n-butyl) and heats it under reflux for 20-30 hours, then concentrates under reduced pressure to obtain a solid, Purification may be optionally performed.

In some embodiments of the present application, the cobalt halide is selected from cobalt iodide, cobalt bromide or cobalt chloride.

In some embodiments of the present application, the catalyst is selected from in-situ generated catalysts or pre-prepared catalysts.

The catalyst used in the present application can be generated in situ, that is, the ligand compound shown in formula III and cobalt halide can be directly added to the reaction raw materials; it can also be directly inserted into the reaction system after pre-preparing the catalyst, so that the yield and product quality There is obvious improvement, and the time required for the reaction is shorter, which not only saves the reaction time, but also reduces the cost to a large extent.

In some embodiments of the present application, the cyclization reaction is carried out in an organic solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, tert-butyl methyl ether, 1,2 - at least one of dimethoxyethane and toluene.

In some embodiments of the present application, the halo in the dihaloalkane is independently selected from fluoro, chloro, bromo or iodo; the alkyl group in the dihaloalkane is selected from C ₁ -C ₆ aliphatic alkyl or C ₃ -C ₁₀ cycloalkyl.

The halo in the dihaloalkanes described in this application are each independently selected from fluoro, chloro, bromo or iodo, which means that the dihaloalkanes may include two identical halogen substitutions, or may include two different halogen substitutions. halogen substitution.

In some embodiments of the present application, the dihaloalkane is selected from dihalomethane, dihaloethane, dihalogenated n-propane, dihalogenated isopropane, dihalogenated n-butane, dihalogenated tertiary Butane, dihalo-n-pentane, dihalocyclopropane, dihalocyclobutane, dihalocyclopentane or dihalocyclohexane.

In some embodiments of the present application, the dihaloalkane is selected from 2,2-dichloropropane, 2,2-dibromopropane, 2,2-diiodopropane, 2,2-bromochloropropane, 2, 2-bromoiodopropane, dibromomethane, bromochloromethane, 1,1-dichlorocyclohexane, 1,1-dichlorocyclopentane or 1,1-dibromocyclopropane.

In some embodiments of the present application, the molar ratio of the catalyst to the compound represented by the formula II is 1: (1-100), preferably 1: (10-30); The molar ratio of the compound shown in the formula II is (1-5): 1, preferably (1.2-3): 1; the molar ratio of the zinc powder to the compound shown in the formula II is (2-5 ):1.

In some embodiments of the present application, the reaction temperature of the cyclization reaction is 10-30° C., and the reaction time is 0.5-28 hours, preferably 1-3 hours.

In some embodiments of the present application, the product obtained by the cyclization reaction can be selectively purified, and the purified solvent is selected from water, diethyl ether, petroleum ether, methyl tert-butyl ether, n-hexane, n-heptane , cyclohexane, methanol, ethanol, acetone and ethyl acetate at least one.

The present application does not specifically limit the purification method of the product obtained by the cyclization reaction, as long as the purpose of the present application can be achieved, for example, a purification solvent can be added for beating, followed by filtration and concentration.

The second aspect of the present application provides a method for preparing the antiviral drug nematevir, boceprevir or neraprevir, which comprises the synthesis method described in the first aspect of the present application.

Synthesis of (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate derivatives or salts thereof shown in formula I provided by the application The method can be widely used for preparing antiviral drugs nirmatrelvir, boceprevir and narlaprevir, and has a good market prospect.

(1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate derivatives or salts (such as hydrochloride) provided by the application are brand new The synthesis method has short steps, no dangerous and expensive materials are used, the reaction conversion rate is high, there is no special requirement for equipment during the reaction, the reaction time is short, and the operation is simple; the target compound with high yield and high purity can be obtained through one-step reaction, and the The yields are all above 90% and more preferably up to 95%, and there is no need for column treatment, the catalyst ligand is more economical, and the overall reaction cost is low; it can well realize industrialized large-scale production and has good economic benefits.

Description of drawings

Figure 1 is the H NMR spectrum of the final product prepared in Example 2 of the present application.

Detailed ways

Yield calculation: Yield=actual synthetic product mass/theoretical synthetic product mass×100%.

Purity: The purity of the product was detected by high performance liquid chromatography (HPLC).

Embodiment 1: preparation catalyst

1. Preparation of Ligands

2,6-Diacetylpyridine and any substituted aniline are reacted in an organic solvent (such as toluene) and heated to reflux for 24 hours, concentrated under reduced pressure to obtain a solid, which can be optionally purified to obtain a ligand represented by the following formula III compound;

^R is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

For example the preparation of catalyst 2,6-bis[1-[2-(ethylphenyl)imino]ethyl]pyridine may include:

2,6-Diacetylpyridine (16.3g, 0.1mol) and 2-ethylaniline (24.3g, 0.2mol) were successively added to a three-necked flask containing 200mL of toluene, and a catalytic amount of p-toluenesulfonic acid (1.72g , 0.01mol), stirred and mixed, and the reaction solution was heated to reflux for 24h. The reaction solution was directly concentrated to dryness under reduced pressure to obtain a yellow solid. Add 150 mL of methanol to the crude yellow solid, stir at room temperature for 1 hour, filter, and dry the filter cake to obtain a yellow solid, which is 2,6-bis[1-[2-(ethylphenyl)imino]ethane Base] pyridine, yield 85%.

2. Preparation of catalyst

Under nitrogen protection, 2,6-bis[1-[2-(ethylphenyl)imino]ethyl]pyridine (4.01g, 10mmol), anhydrous cobalt dibromide were successively added to a 100mL three-necked flask (2.18g, 10mmol) and 100mL of anhydrous tetrahydrofuran, and the reaction solution was stirred at room temperature for 24h. The reaction solution was concentrated under reduced pressure to obtain a tan solid, namely [2,6-bis[1-[2-(ethylphenyl)imino]ethyl]pyridine]cobalt dibromide, with a yield of 100%.

Other catalyzers of the present application all can select suitable raw material to synthesize according to the thinking of above-mentioned synthetic compound 2,6-two [1-[2-(ethylphenyl) imino] ethyl] pyridine] cobalt dibromide, Any other suitable methods and raw materials can also be selected for synthesis.

Example 2

1. Reference Example 1 prepares methyl ligand L1, gets methyl ligand L1 and CoBr ₂ and prepares catalyst solid;

2. Add 24.6g of the above-mentioned catalyst solid and 100g of the substrate N-Boc-3,4-dehydro-L-proline, dissolve it in a three-necked flask with 1000mL of anhydrous THF (tetrahydrofuran), replace it with nitrogen, and prepare anhydrous Oxygen operation, mechanical stirring;

3. Add 57.2g of zinc powder into the reaction bottle at room temperature and stir mechanically;

4. Stir at room temperature for 20 minutes, at this time the reduced cobalt catalyst in the solution presents a dark purple color;

5. Then add 235g of 2,2-dibromopropane, and continue to stir and react at room temperature for 3 hours;

6. After the reaction is finished, the reaction solution is directly concentrated under reduced pressure to obtain the crude product;

7. The crude product was dispersed by adding 10 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain a light yellow oily product with a yield of 93% and a purity of 99.25%; the obtained final product

The H NMR spectrum is shown in Figure 1. ¹ HNMR (CDCl ₃ , 400Hz): δ0.95and 0.96(3H,s+s), 1.02(3H,s), 1.36(2H,m), 1.38and 1.41(9H,s+s), 3.43(1H, m), 3.64(1H,m), 3.73(3H,s), 4.19 and 4.07(1H,s+s).[M+H] ⁺ 270.1627.

Example 3

2. Add the above catalyst solid (246mg, 0.44mmol), the substrate N-Boc-3,4-dehydro-L-proline (1.0g, 4.4mmol), and dissolve it in 25mL of three ports with 10mL of anhydrous THF In the bottle, nitrogen replacement, anaerobic operation, magnetic stirring;

3. Add zinc powder (572mg, 8.8mmol) into the reaction flask at room temperature, and magnetically stir;

4. Stir at room temperature for 15 minutes, at this time, the reduced cobalt catalyst in the solution presents a dark purple color;

5. Then add 2,2-dibromopropane (2.4g, 8.8mmol), and continue to stir and react at room temperature for 1 hour;

7. The crude product was dispersed by adding 10 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain a light yellow oily product, the final product

The yield was 93%.

Example 4 to Example 23

The different reaction conditions shown in the following table 1, embodiment 4-embodiment 23 are prepared with reference to the above-mentioned embodiment 3, and the variable parameters are the type of catalyst ligand R5 substituent, the type and amount of cobalt halide, the amount of zinc powder, reaction time and reaction temperature and the type and amount of dihaloalkane; ligand preparation and catalyst preparation refer to the method described in Example 1 above.

^R is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

The amount of ligand used is the same as the amount of cobalt halide. The amount of feed in the following table 1 is the substrate N-Boc-3, 4-dehydro-L-proline multiple equivalent feed, for example, 2eq means the substrate N-Boc-3 , 4-dehydro-L-proline molar weight 2 times feed intake; wherein substrate N-Boc-3, 4-dehydro-L-proline input amount in embodiment 4-embodiment 23 is 1.0 g, namely 4.4mmol; the final product prepared is

Table 1 Different reaction conditions and yields

Example 24

1. Methyl ligand L1 (144mg, 0.44mmol), CoBr ₂ (96mg, 0.44mmol) was prepared in reference example 1 to obtain a solid catalyst, and the solid catalyst (246mg, 0.44mmol), substrate N-Cbz-3, 4-Dehydro-L-proline (1.15g, 4.4mmol), dissolved in 10mL of anhydrous THF in a 25mL three-neck flask, nitrogen replacement, anaerobic operation, magnetic stirring;

2. Add zinc powder (572mg, 8.8mmol) into the reaction flask at room temperature, and magnetically stir;

3. Stir at room temperature for 15 minutes, at this time, the reduced cobalt catalyst in the solution presents a dark purple color;

4. Then add 2,2-dibromopropane (2.4g, 8.8mmol), and continue to stir and react at room temperature for 2h;

5. After the reaction is finished, the reaction solution is directly concentrated under reduced pressure to obtain the crude product;

6. The crude product was dispersed by adding 10 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain a light yellow oily product, the final product

The yield is 90%. ¹ HNMR (CDCl ₃ , 400Hz): δ0.88 (3H, d, 1.6Hz); 0.96 (3H, s); 1.34 (2H, m); 3.44 (1H, dd, 11.2Hz, 10.8Hz); 3.53 ( 1.5H, s); 3.65(1H, m); 3.68(1.5H, s); 4.17(1H, d, 23.6Hz); 5.05(2H, m); 7.23(5H, m).[M+H] +304.1471.

Example 25

1. Methyl ligand L1 (144mg, 0.44mmol) and CoBr ₂ (96mg, 0.44mmol) were prepared by referring to Example 1 to obtain a solid catalyst (246mg, 0.44mmol). Take the solid catalyst and substrate N-Fmoc-3, 4-Dehydro-L-proline (1.54g, 4.4mmol), dissolved in 10mL of anhydrous THF in a 25mL three-neck flask, nitrogen replacement, anaerobic operation, magnetic stirring;

4. Then add 2,2-dibromopropane (2.4g, 8.8mmol), and continue to stir and react at room temperature for 4h;

The yield was 91%. ¹ HNMR (CDCl ₃ , 400Hz): δ0.94(3H,d,11.6Hz); 1.05(3H,d,5.6Hz); 1.27(1H,m); 1.43(1H,m); 3.51(1H,m );3.68(1.5H,s);3.74(1H,m);3.77(1.5H,s);4.13(1H,m);4.26(1H,t);4.41(2H,m);7.30(2H, m); 7.39(2H,m); 7.57(2H,m); 7.76(2H,m).[M+H]+392.4596.

Example 26

1. Methyl ligand L1 (144mg, 0.44mmol), CoBr ₂ (96mg, 0.44mmol) was prepared in reference example 1 to obtain a solid catalyst, and the solid catalyst (246mg, 0.44mmol), the substrate N-trityl -3,4-Dehydro-L-proline (1.62g, 4.4mmol), dissolved in 10mL of anhydrous THF in a 25mL three-neck flask, nitrogen replacement, anaerobic operation, magnetic stirring;

4. Then add 2,2-dibromopropane (2.4g, 8.8mmol), and continue to stir and react at room temperature for 1h;

The yield was 92%. ¹ HNMR (CDCl ₃ , 400Hz): δ0.27(3H,s); 0.84(3H,s); 1.35(2H,m); 2.57(1H,m); 3.27(3H,s); d,2.0Hz); 3.63(1H,m); 7.12(3H,t); 7.24(6H,m); 7.56(6H,d,7.2Hz).[M+H]+412.2198.

Example 27

1. The ethyl ligand L2 (150mg, 0.46mmol), CoBr ₂ (100mg, 0.46mmol) was prepared in reference example 1 to obtain a solid catalyst, and the solid catalyst (270mg, 0.46mmol), the substrate N-Bn-3, 4-Dehydro-L-proline (1.0g, 4.6mmol), dissolved in 10mL of anhydrous THF in a 25mL three-neck flask, nitrogen replacement, anaerobic operation, magnetic stirring;

2. Add zinc powder (598mg, 9.2mmol) into the reaction flask at room temperature, and magnetically stir;

4. Then add 2,2-dibromopropane (2.5g, 8.8mmol), and continue to stir and react at room temperature for 3h;

6. The crude product was dispersed by adding 10 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain the product, the final product

The yield is 90%. ¹ HNMR (CDCl ₃ , 400Hz): δ1.00(3H,s); 1.17(3H,s); 1.32(2H,m); 2.69(1H,d,9.2Hz); 3.16(1H,dd,5.2Hz ), 3.52 (1H, s), 3.68 (3H, s), 3.73 (2H, d, J=2.4Hz), 7.25 (5H, m). [M+H]+260.3434.

Example 28

1. The methyl ligand L1 (144mg, 0.44mmol), CoBr ₂ (96mg, 0.44mmol) was prepared as a solid catalyst in reference example 1, and the solid catalyst (246mg, 0.44mmol), the substrate (S)-N- Boc-2,3-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1.0g, 4.4mmol), dissolved in a 25mL three-necked flask with 10mL of anhydrous THF, nitrogen replacement, anaerobic operation, magnetic stir;

4. Add dibromomethane (2.4g, 8.8mmol) and continue stirring for 2h at room temperature;

The yield was 93%.

Example 29

1. The methyl ligand L1 (144mg, 0.44mmol), CoBr ₂ (96mg, 0.44mmol) was prepared as a solid catalyst with reference to Example 1, and the solid catalyst (246mg, 0.44mmol) was added to the substrate N-Boc- 3,4-Dehydro-L-proline (1.0g, 4.4mmol), dissolved in 10mL of anhydrous THF in a 25mL three-neck flask, nitrogen replacement, anaerobic operation, magnetic stirring;

4. Then add bromochloromethane (2.4g, 8.8mmol), and continue to stir and react at room temperature for 2h;

The yield was 91%.

Example 30

1. The methyl ligand L1 (144mg, 0.44mmol, 0.1eq), CoBr ₂ (96mg, 0.44mmol, 0.1eq) was prepared with reference to Example 1 to obtain a solid catalyst, and the solid catalyst (246mg, 0.44mmol), the substrate N-Boc-3,4-dehydro-L-proline (1.0g, 4.4mmol, 1.0eq), dissolved in 10mL of anhydrous THF in a 25mL three-necked flask, replaced with nitrogen, and performed anaerobic operation, Magnetic stirring;

2. Add zinc powder (572mg, 8.8mmol, 2eq) into the reaction flask at room temperature, and magnetically stir;

4. Then add 1,1-dichlorocyclohexane (2.4g, 8.8mmol, 2eq), and continue to stir and react at room temperature for 4h;

6. The crude product was dispersed by adding 7 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain the product, the final product

The yield is 90%.

Example 31

4. Then add 1,1-dichlorocyclopentane (2.4g, 8.8mmol, 2eq), and continue to stir and react at room temperature for 3h;

6. The crude product is dispersed by adding 8 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain the product, the final product

The yield was 92%.

Example 32

1. The methyl ligand L1 (144mg, 0.44mmol, 0.1eq), CoBr ₂ (96mg, 0.44mmol, 0.1eq) was prepared with reference to Example 1 to obtain a solid catalyst, and the solid catalyst (246mg, 0.44mmol), the substrate (S)-N-Boc-2,3-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1.0g, 4.4mmol, 1.0eq), was dissolved in a 25mL three-necked flask with 10mL of ultra-dry THF, nitrogen Replacement, good anaerobic operation, magnetic stirring;

4. Then add 1,1-dibromocyclopropane (2.4g, 8.8mmol, 2eq), and continue to stir and react at room temperature for 6h;

6. The crude product was dispersed by adding 12 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain the product, the final product

The yield was 93%.

Comparative example 1

1. Reference Example 1 prepares tert-butyl ligand L3, gets tert-butyl ligand L3 and CoBr Prepare _catalyst solid;

2. Add the above catalyst solid (246mg, 0.44mmol), substrate N-Boc-3, 4-dehydro-L-proline (1.0g, 4.4mmol), dissolve in 10mL of anhydrous THF (tetrahydrofuran) In a 25mL three-necked flask, replace with nitrogen, perform anaerobic operation, and stir magnetically;

3. Add zinc powder (572mg, 8.8mmol) into the above reaction three-necked flask at room temperature, and magnetically stir;

The yield is 75%.

Comparative example 2

3. Add zinc powder (572mg, 8.8mmol) and zinc bromide (991mg, 4.4mmol) into the above reaction three-necked flask at room temperature, and magnetically stir;

The yield was 82%.

Comparative example 3

The yield was 76%.

Comparative example 4

1. Reference Example 1 prepares tert-butyl ligand L3, gets tert-butyl ligand L3 and CoBr Prepare catalyst _solid ;

2. Add the above-mentioned catalyst solid (246mg, 0.44mmol), substrate N-Boc-3,4-dehydro-L-proline (1.0g, 4.4mmol), dissolve in 10mL of anhydrous THF (tetrahydrofuran) In a 25mL three-neck flask, replace with nitrogen, perform anaerobic operation, and stir magnetically;

5. Then add 2,2-dichloropropane (1g, 8.8mmol), and continue to stir and react at room temperature for 5 days;

7. The crude product was dispersed by adding 10 times the volume of methyl tert-butyl ether, filtered to remove the solid, and concentrated to obtain 0.9 g of a light yellow oily product. The final product

The yield is 75%.

According to Example 3 and Comparative Example 1, the catalyst ligand compound

change to

After that, the yield of the final product dropped from 93% to 75%; it can be seen that the catalyst ligand compound

Compare

The catalytic effect has been significantly improved.

According to embodiment 3 and comparative example 2, by adding zinc bromide reagent, the yield of final product drops to 82% by 93%; It can be seen that, do not add zinc bromide reagent in the reaction system, can significantly improve final product yield. Rate.

According to embodiment 3 and comparative example 3, comparative example 4 can know, by adding zinc bromide reagent, and catalyst ligand compound

change to

The yield of the final product dropped from 93% to 76%; even in Comparative Example 4, the yield of the final product was 75% without improvement even after 5 days of reaction. It can be seen that the catalyst ligand compound

Compare

The catalytic effect of the catalyst is significantly improved, and no zinc bromide reagent is added to the reaction system, which can significantly increase the yield of the final product.

As can be seen from the foregoing examples, the (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate derivatives provided by the application or their The synthesis method of the salt has short steps, no zinc bromide reagent is used, and the target compound with high yield and high purity can be obtained after one-step reaction. The production cost and post-processing cost are reduced; dangerous and expensive materials are not used, and there are no special requirements for equipment during the reaction, the reaction time is short, the overall reaction cost is low, and the operation is simple; it can well realize industrialized large-scale production and has a good economic benefits.

The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Claims

A synthetic method of (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate derivatives or salts thereof shown in formula I, It is characterized in that it includes: in the presence of a catalyst, adding zinc powder and dihaloalkane to the compound represented by the formula II to carry out the cyclization reaction to generate the compound represented by the formula I; the cyclization reaction does not need to add zinc halide;

in:

R is selected from H or an amino protecting group selected from Cbz, 2-chloro-Cbz, 2-fluoro-Cbz, 2,4-dichloro-Cbz, 4-bromo-Cbz, methoxymethyl Benzyl, benzyloxymethyl, benzyloxycarbonyl, trityl, pivaloyloxymethyl, benzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, triphenyl phenylmethyl, (p-methoxyphenyl) diphenylmethyl, diphenylphosphinyl, phenylsulfinyl, methoxycarbonyl, ethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1-methyl-1-phenylethoxycarbonyl, tert-butoxycarbonyl, cyclobutoxycarbonyl, 1-methylcyclobutoxycarbonyl, adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, cinnamyl Oxycarbonyl, 8-quinolyloxycarbonyl, 4,5-diphenyl-3-oxazolidin-2-onyl, 9-anthracenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, diphenyl Methoxycarbonyl, S-benzyloxycarbonyl or CY 3 CO-, wherein Y is selected from halogen;

R 2 is selected from substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted C 7 -C 14 aralkyl; said C 1 -C The substituents of 10 alkyl groups are each independently selected from halogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 6 -C 10 aryl or C 3 -C 10 heteroaryl, the C 1 -C 6 heteroalkyl or the heteroatoms on the C 3 -C 10 heteroaryl are each independently selected from O, S or N; the C 6 -C 14 The substituents of aryl are independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, -CF 3 or -NO 2 , the substituents of said C 6 -C 14 aryl The number is 0-3; the substituents of the substituted or unsubstituted C 7 -C 14 aralkyl are independently selected from benzyl, p-nitrobenzyl, 1-phenethyl, 2-phenethyl Base, 1-naphthylmethyl or 2-naphthylmethyl;

R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1 -C 10 alkyl groups, and the R 3 and the R 4 can be connected to form an aliphatic ring containing 3-10 carbon atoms; The substituents of the C 1 -C 10 alkyl are each independently selected from fluorine or cyclopropyl.
synthetic method according to claim 1, is characterized in that:

In the R , the amino protecting group is selected from tert-butoxycarbonyl, Cbz, benzyl, 9-fluorenylmethoxycarbonyl or 2-chloro-Cbz;

In the R 2 , the substituted or unsubstituted C 1 -C 10 alkyl group is selected from heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl, cyclopropylmethyl or C 1 -C 6 alkyl, the C 1 -C 6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl; the substituted or unsubstituted C 6 -C 14 aryl is selected from C 6 -C 10 aromatic monocyclic ring system or C 6 -C 10 aromatic polycyclic ring system, preferably selected from phenyl or p-fluorophenyl; the substituted or unsubstituted C 7 - C Aralkyl is selected from benzyl, p-nitrobenzyl, 2-phenethyl, 1-naphthylmethyl or 2-naphthylmethyl;

In said R 3 and said R 4 , said C 1 -C 10 alkyl groups are each independently selected from C 1 -C 6 alkyl groups, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl; the aliphatic ring containing 3-10 carbon atoms is selected from cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl.
The synthesis method according to claim 1 or 2, characterized in that: the catalyst is selected from catalysts prepared from ligand compounds shown in formula III and cobalt halides;

Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.
The synthesis method according to claim 3, characterized in that: the cobalt halide is selected from cobalt iodide, cobalt bromide or cobalt chloride.
The synthesis method according to claim 1 or 2, characterized in that: the catalyst is selected from catalysts generated in situ or pre-prepared catalysts.
The synthetic method according to claim 1 or 2, characterized in that: the cyclization reaction is carried out in an organic solvent, and the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, At least one of tert-butyl methyl ether, 1,2-dimethoxyethane and toluene.
The synthetic method according to claim 1 or 2, characterized in that: the halo in the dihaloalkane is independently selected from fluoro, chloro, bromo or iodo; the alkane in the dihaloalkane The group is selected from C 1 -C 6 aliphatic alkyl or C 3 -C 10 cycloalkyl.
The synthetic method according to claim 7, characterized in that: said dihalogenated alkane is selected from dihalomethane, dihalogenated ethane, dihalogenated n-propane, dihalogenated isopropane, dihalogenated n-butane , dihalogenated tert-butane, dihalogenated n-pentane, dihalogenated cyclopropane, dihalogenated cyclobutane, dihalogenated cyclopentane or dihalogenated cyclohexane.
The synthetic method according to claim 7 or 8, characterized in that: the dihaloalkane is selected from 2,2-dichloropropane, 2,2-dibromopropane, 2,2-diiodopropane, 2,2 - Bromochloropropane, 2,2-bromoiodopropane, dibromomethane, bromochloromethane, 1,1-dichlorocyclohexane, 1,1-dichlorocyclopentane or 1,1-dibromocyclopropane.
The synthesis method according to claim 1 or 2, characterized in that: the molar ratio of the catalyst to the compound represented by the formula II is 1: (1-100), preferably 1: (10-30);

The molar ratio of the dihaloalkane to the compound represented by the formula II is (1-5):1, preferably (1.2-3):1;

The molar ratio of the zinc powder to the compound represented by the formula II is (2-5):1.
The synthesis method according to claim 1 or 2, characterized in that: the reaction temperature of the cyclization reaction is 10-30° C., and the reaction time is 0.5-28 hours, preferably 1-3 hours.
The synthetic method according to claim 1 or 2, characterized in that: the product obtained by the cyclization reaction can be selectively purified, and the purified solvent is selected from water, diethyl ether, petroleum ether, methyl tert-butyl ether , at least one of n-hexane, n-heptane, cyclohexane, methanol, ethanol, acetone and ethyl acetate.
A method for preparing antiviral drugs Namatevir, Boceprevir or Naraprevir, characterized in that it comprises the synthesis method described in any one of claims 1-12.