CN116693441A - Preparation method of 3CL protease inhibitor pyrrolidone cut block - Google Patents

Preparation method of 3CL protease inhibitor pyrrolidone cut block Download PDF

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Publication number
CN116693441A
CN116693441A CN202210184012.9A CN202210184012A CN116693441A CN 116693441 A CN116693441 A CN 116693441A CN 202210184012 A CN202210184012 A CN 202210184012A CN 116693441 A CN116693441 A CN 116693441A
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compound
protease inhibitor
pyrrolidone
group
reaction
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张凌霄
蔡刚华
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Hangzhou Zhenzhi Biotechnology Co ltd
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Hangzhou Zhenzhi Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The application relates to the field of organic synthesis, in particular to a preparation method of 3CL protease inhibitor pyrrolidone cut blocks, which comprises the following steps: s1, preparing a compound II through zinc metal and the compound I; s2, reacting the compound II with one of a compound III or a compound IV to obtain a compound V, S3, and deprotecting the compound V to obtain a target product compound VI; the integral reaction formula is shown in the formula I;wherein R is 1 And R is 2 R is a protecting group 3 Is any one of formate group, protected methanol group, formaldehyde group or cyano group, X is bromine or iodine, and the base used in the step S2 is organolithium. By adopting the technical scheme, the large-scale production of the preparation method of the 3CL protease inhibitor pyrrolidone dicing in fewer steps can be realized, and the method has good yield and excellent industrial application prospect.

Description

Preparation method of 3CL protease inhibitor pyrrolidone cut block
Technical Field
The application relates to the field of organic synthesis, in particular to a preparation method of a 3CL protease inhibitor pyrrolidone dicing.
Background
The 3CL protease inhibitor is a compound with a pyrrolidone structure and has wide application in the fields of medicine and veterinary medicine antiviral. J.org.chem.2021,86,13104-13110 describes the use of 3CL protease inhibitors in the field of antiviral medicine as follows:
the above related compounds all have a common intermediate:
for the compound, the current synthesis method path is shown as a formula II.
The whole process of the scheme is overlong, and the number of production steps is large, so that the requirements on equipment cost and site cost are large in the process of mass production of enterprises, and the production scale is not easily enlarged by the aid of the route.
Disclosure of Invention
In order to reduce the reaction steps and further obtain a reaction path suitable for mass production of the intermediate in enterprises, the application provides a preparation method of 3CL protease inhibitor pyrrolidone cutting blocks.
The preparation method of the 3CL protease inhibitor pyrrolidone dicing provided by the application comprises the following steps:
s1, preparing a compound II through zinc metal and the compound I;
s2, reacting the compound II with one of a compound III or a compound IV to obtain a compound V,
s3, deprotecting the compound V to obtain a target product compound VI;
the integral reaction formula is shown in the formula I;
wherein R is 1 And R is 2 R is a protecting group 3 Is any one of formate group, protected methanol group, formaldehyde group or cyano group, X is bromine or iodine, and the base used in the step S2 is organolithium.
In the technical scheme, the compound I is used as a raw material, and a target product is finally obtained through three steps of halogen activation, coupling and deprotection. The reaction steps are smaller, the raw materials are easy to obtain, the yield is good, and the method is suitable for industrial production.
In the production steps, the compound I is of a protected pyrrolidone structure, and the amide can be prepared by using the pyrrolidone and the anhydride, so that the effect of protecting the amino group from subsequent reaction is achieved.
In the compound IV and the compound V, R 3 And R is 3 ' can be independently selected, R in the absence of other steps 3 And R is 3 ' are the same substituents. R can also be modified to a certain extent 3 Further modification and reaction to obtain R 3 ’。
In step S1, zinc may be activated with trichloromethylchlorosilane to improve the reaction effect.
The reaction in the step S2 can be carried out at the temperature of-100 to 0 ℃, and the solvent can be tetrahydrofuran, dioxane or other aprotic solvents which can better dissolve the whole system.
The reaction steps are fewer, the intermediate reaction is simpler, and the yield is higher. The whole system can be simply carried out by a continuous flow reactor, and is suitable for industrial mass production.
Alternatively, X is bromine.
In the two cases of bromine and iodine, generally, iodine has better reaction performance, and can improve the conversion rate to a certain extent, but the advantage of the reaction performance is not obvious compared with bromine, and the advantages of the reaction performance are obvious in the dimensions of controlling cost, treating reaction byproducts and the like, so that the X is selected as bromine, and the method has better effect in practical production and application.
Alternatively, R 2 Is a formate group.
In the technical scheme, the methyl formate group has higher yield in the reaction, and different intermediate products can be obtained through further reaction and modification of the methyl formate group, so that the method has a larger application range in industrial production.
Alternatively, R 3 ' is any of cyano or formaldehyde; also included between step S2 and step S3 is step S2-2, converting methyl formate groups to either cyano or formaldehyde groups.
In the technical scheme, the methyl formate group can be modified to obtain the compound with cyano or formaldehyde group, so that the loss of the group with strong activity in the preparation process is reduced, and the method has a good prospect of large-scale application.
In the scheme, the conversion of methyl formate group into formaldehyde group can be obtained by reducing methyl formate group into methanol group and then oxidizing the methanol group into formaldehyde group; the cyano group can be obtained by transesterification of methyl formate to obtain formamide, and then dehydrated by a dehydrator such as phosphorus oxychloride to obtain the cyano group. The reaction can expand the applicable process of the synthesis method under the condition of limited raw materials, the reaction process can be continuously carried out with other reactions, the whole process is not greatly influenced, and the method has good practicability in the industrial production process.
Optionally, in step S2, lithium diisopropylethylamide is used as the base.
The lithium diisopropylethylamide is adopted for catalytic reaction, the reaction yield is higher, the generated impurities can be removed easily, and the effects of simplifying steps and reducing cost can be achieved in industrial production.
Optionally, the mass ratio of the compound I, the compound III or the compound IV to the alkali is 1 (1.2-4) to 2-3.
In the proportion range, the mode of excessive compound III or compound IV is adopted, so that the conversion rate of the compound II is improved, and the excessive compound III and compound IV are easy to separate. Because the compound II is easy to form a complex system with alkali in the reaction process, excessive compound III or compound IV is adopted, thereby being beneficial to improving the reaction yield and the raw material utilization rate and further reducing the production cost of enterprises.
Alternatively, the amount of the substances of compound I, compound III or compound IV and the base is in a ratio of 1:2:2.2.
The reaction is carried out by adopting the material proportion, so that the waste of raw materials can be reduced, the reaction yield and the conversion rate of the raw materials are improved, the method belongs to the selection with the lowest comprehensive cost, and the method has obvious advantages compared with other material proportion formulas.
Optionally, the reaction temperature in the step S2 is-80 to-20 ℃.
In the above reaction temperature range, the reaction efficiency is better, and the requirements on equipment are basically conventional. The temperature is lower, the side reaction is less, the conversion rate of the raw materials is higher, but the requirements on equipment and the consumption of energy are correspondingly increased, so that the control temperature is more suitable in the range.
Optionally, step S2 is performed using tetrahydrofuran as a solvent.
Tetrahydrofuran is used as a solvent for reaction, the overall reaction efficiency is high, and the solvent has good solubility, and meanwhile, the boiling point is low, so that the solvent is easy to separate and recycle in the whole process, and the production cost of enterprises is reduced.
Optionally, in step S3, deprotection catalysis is performed with trifluoroacetic acid.
The trifluoroacetic acid is adopted for deprotection, the reaction rate is high, and meanwhile, impurities are easy to remove from the system, so that the method has a good application prospect in industrial production.
In summary, the present application comprises at least one of the following beneficial effects:
1. in the application, the preparation of the 3CL protease inhibitor pyrrolidone cut block can be realized through three steps of halogen metal activation, coupling and deprotection, the steps of the preparation process are few, the raw materials are simple and easy to obtain, the reaction conditions are mild, the yield is high, and the preparation method is suitable for industrial mass production.
2. In the further arrangement of the application, the amounts of the substances of the compound II, the compound III or the compound IV and the alkali are limited, so that better reaction results are obtained, and the waste of raw materials is reduced.
3. In some embodiments of the application, R may be measured after the European step 3 The groups are further modified and modified, so that different derivatives can be obtained, and the derivative has good propertiesGood industrial application prospect.
Detailed Description
The application is further described in detail below in conjunction with and examples.
In the following examples and comparative examples, yields refer to yields relative to compound i.
The preparation method of the protease inhibitor pyrrolidone cut blocks of examples 1 to 10 and comparative examples 1 to 3,3CL specifically comprises the following steps:
s1, under the protection of nitrogen, adding 13.1g (0.2 mol) of zinc powder and 0.03mol of trimethylchlorosilane into 50ml of tetrahydrofuran, stirring for 30min at room temperature, controlling the temperature to be 30+/-5 ℃, continuously reacting for 30min in t liquid (namely the compound I), and naturally cooling to the room temperature to obtain a first mixed system containing the compound II; the reaction formula of the step is shown as a formula III;
s2, cooling the first mixed system to-60 ℃, then dropwise adding 110mL of tetrahydrofuran solution containing 22.4g of lithium diisopropylamide (0.22 mol) into the first mixed system in 1h, and continuing to keep the temperature and stir for 60min after the dropwise addition is finished. Then 200mL of tetrahydrofuran solution containing 0.2mol of compound II is prepared and added dropwise into the system within 2h, the reaction is continued until TLC tracking reaction is finished (the reaction time is 2 h), then 100mL of methanol and 100mL of glacial acetic acid are added, the temperature is slowly raised to room temperature, 200mL of saturated sodium chloride solution is added, stirring is carried out for 1h, standing is carried out until the mixture is layered, an organic phase is separated, an aqueous phase is extracted by ethyl acetate, anhydrous sodium sulfate is dried after the organic phase is combined, and the solvent is distilled under reduced pressure, so that the compound IV is obtained.
S3, dissolving the reaction product (namely the compound V) in the step S2 in a mixed system of 100mL of trifluoroacetic acid and 100mL of dichloromethane, stirring for 2h at room temperature, and concentrating under reduced pressure after stirring is finishedTo 20mL, 100mL of dichloromethane was then added, followed by saturated sodium bicarbonate solution until the organic phase was neutral in pH. After the organic phase was separated, 100mL of 37% by mass hydrochloric acid was added dropwise to the organic phase over 30min, followed by stirring for 10 hours. And then decompressing and distilling the solvent and drying to obtain the target product, wherein the specific reaction is shown in a formula V.
In the above embodiment, between step S2 and step S3, there is no pair R 3 Modifications were made so that in the above examples R 3 And R is R 3 ' is the same group.
The difference between examples 1 to 10 and comparative examples 1 to 3 is that R 3 And X are adjusted so that the yields are slightly different. Specifically, the results are shown in Table 1.
Table 1, examples 1 to 10 and comparative examples 1 to 3
According to the experimental data, in the application, when X is bromine or iodine, the method has good yield and purity, the reaction process condition is mild and not harsh, the energy consumption is low, and the solvent can be recycled, so that the method has good application in mass production of enterprises. Wherein, when X is iodine, the reaction yield has weak advantages, but is not obvious, and when X is iodine, the overall raw material cost is higher, so that the method for selecting X as bromine is more suitable for industrial mass production. When X is chlorine, the reaction yield is low, and the method is not suitable for large-scale production.
Taking example 1 as an example, the nuclear magnetic resonance hydrogen spectrum of the final product is as follows: 1H NMR (400 MHz, d 6-DMSO): delta 8.72 (s, 3H), 7.97 (s, 1H), 4.13-4.24 (m, 1H), 3.76 (s, 3H), 3.12-3.24 (m, 2H), 2.54-2.65 (m, 1H), 2.23-2.34 (m, 1H), 2.01-2.10 (m, 1H), 1.83-1.92 (m, 1H), 1.62-1.73 (m, 1H).
Examples 11 to 20 and comparative examples 4 to 6 differ from examples 1 to 10 and comparative examples 1 to 3 in that a different compound II was used, and the specific reaction of step S2 in examples 11 to 20 and comparative examples 4 to 6 is shown in formula VI.
Table 1, examples 1 to 10 and comparative examples 1 to 3
The compound IV is adopted to participate in the synthesis step, and compared with the process of carrying out the reaction of the compound III, the yield is slightly reduced, but the method can be suitable for industrial mass production in the range of most of the compounds. Compared with the prior art, the reduction of steps brings about the reduction of equipment cost, and is still a scheme beneficial to enterprise production.
In addition, on the basis of example 1, step S2-2 was added between step S2 and step S3 to give R 3 Modification of the radicals to R 3 The following examples can be obtained.
Example 21 differs from example 1 in that after step S2 is completed, step S2-2 is performed, and step S2-2 is specifically as follows:
s2-2, adding the compound obtained in the step S2 into 50mL of ethanol, adding 0.2mol of sodium borohydride in batches, stirring at room temperature for 2 hours, adding 50mL of saturated sodium chloride solution after the reaction is completed, concentrating and evaporating, extracting with dichloromethane, adding a dessert-martin oxidant (0.1 mol) and sodium bicarbonate solid (0.1 mol) into the mixture, stirring at room temperature until no raw material point is detected by TLC, carrying out suction filtration on the system, washing and extracting with saturated sodium bicarbonate solution for three times, carrying out back extraction with dichloromethane, removing the solvent, and keeping the mixture for the next step for standby.
In example 21, the specific reaction schemes of steps S2, S2-2 and S3 are shown in formula VII.
The total yield of this example was 59.1%, slightly higher than that of the synthesis directly using the raw material containing aldehyde groups, and the reaction process was not complicated.
Example 22 differs from example 1 in that after step S2 is completed, step S2-2 is performed, and step S2-2 is specifically as follows:
s2-2, mixing the compound obtained in the step S2 with a methanol solution of ammonia (100 mL, ammonia concentration 7M), heating to 80 ℃ in a sealed system, reacting for 12h, then distilling under reduced pressure to remove the solvent, dissolving the solid with 200mL of dichloromethane, adding Burgess reagent (0.25 mol), stirring for 4h at room temperature under the protection of nitrogen, blowing the solvent with nitrogen, separating by column chromatography, and leaving the obtained product for the next reaction.
In example 22, the specific reaction schemes of steps S2, S2-2 and S3 are shown in formula IX.
The final product yield of this example was 56.1% and was also higher than in examples 7 and 17 where the reaction was carried out directly with cyano compounds.
Further, on the basis of example 1, some of the parameters were adjusted to obtain the following examples.
Examples 23 to 27 are different from example 1 in that the amount of the base and the solvent in step S2 were adjusted, and the specific results are shown in table 3.
Table 3, results of experiments in examples 23 to 27
According to the experimental data, in the application, the dioxane and the tetrahydrofuran can be adopted to complete the reaction, the yield is better, and the three types of organolithium can realize better reaction effects, but a system of lithium diisopropylethylamide and tetrahydrofuran is selected, the reaction yield is higher, the boiling point of tetrahydrofuran is lower, the tetrahydrofuran is easy to separate in the system, and the tetrahydrofuran solution of lithium diisopropylethylamide can be directly purchased in the market, so that the tetrahydrofuran and lithium diisopropylethylamide are adopted to have more superior reaction conditions in actual production.
Examples 28 to 32, the ratio of the amounts of the compounds II, III and the base was adjusted in step S2, and the experimental results are shown in Table 4.
Table 4, results of experiments in examples 28 to 32
From the above experimental data, it is found that in the present application, when the amount of the base or the compound III is too large, the improvement of the yield is small, but the final purity is affected to some extent, and the waste of the material is caused. When the amount of compound III or base is small, the conversion of compound I is affected. In addition, the reaction using the compound IV has similar effects through experiments, and is not described in detail in the present application.
Examples 33 to 37, the reaction temperature in step S2 was adjusted based on example 1, and the reaction time was determined according to the TLC trace result, and the reaction was terminated until the starting point of Compound II had completely disappeared, and the results are shown in Table 5.
Table 5, results of experiments in examples 33 to 37
In the above experimental data, it can be seen that the lower the temperature, the higher the yield of the final product compared to compound i. However, the reaction time is prolonged due to the low temperature, so that the reaction is generally controlled at-80 to-20 ℃, and the method has a better effect on cost control.
In addition, the following examples were obtained by conducting a large-scale reaction experiment in a continuous flow reactor on the basis of examples 1 and 11.
Example 38,3CL preparation of a protease inhibitor pyrrolidone block comprising the steps of:
s1, presetting 13.1kg of zinc powder and 3.5kg of trichloromethyl silane in a first reaction kettle, then adding 30L of tetrahydrofuran, stirring for 30min, controlling the temperature at 33 ℃, slowly injecting 100L of tetrahydrofuran solution containing 26.4kg of N-Boc-3-bromopyrrolidone solution (namely the compound I) in 2h, continuously stirring for 30min, and pumping into a second reaction kettle for standby;
s2, the second reaction kettle is cooled to the temperature of minus 60 ℃ in advance, and a commercial 2M LDA tetrahydrofuran solution (containing 22.4kg of LDA) is added in 1h, and then the mixture is stirred at the temperature for 60min. Then 80L of tetrahydrofuran solution containing 40.2kg of N-Boc-2-methyl formate-aza tricyclic is injected in 1h, the temperature is controlled to react for 2h, the reaction is finished, the reaction is transferred into extraction equipment for extraction, the extractant is methanol, glacial acetic acid and saturated sodium chloride solution with the volume ratio of 1:1:1, water is reversely extracted for three times, and an organic phase is discharged after the extraction and distilled under reduced pressure, and the solvent is recovered.
S3, dissolving the reduced pressure distillation product in the step S2 in a mixed system of trifluoroacetic acid and methylene dichloride with the volume ratio of 1:1, reacting for 2 hours at room temperature and normal pressure in a reaction kettle, then concentrating under pressure until solid is separated out (generally 10% of the initial volume), adding 50L of methylene dichloride, adding saturated solution of sodium bicarbonate, transferring into extraction equipment to separate an organic phase, back-extracting for three times, adding 100L of commercial concentrated hydrochloric acid after the organic phase is combined, continuously stirring for 10 hours, and then distilling under reduced pressure to remove the solvent to obtain the target product.
After amplification to kilogram level, the three steps total yield was 58.9% and the final product purity was 99.0%.
Example 39,3CL the protease inhibitor pyrrolidone was cut into pieces and the difference from example 38 was that in step S2, the following compound was substituted for the N-Boc-2-methyl formate-azatricyclic ring in the amounts of the same substances.
In this example, the yield was 52.5% and the final product purity was 98.9%.
The present embodiment is only for explanation of the present application and is not to be construed as limiting the present application, and modifications to the present embodiment, which may not creatively contribute to the present application as required by those skilled in the art after reading the present specification, are all protected by patent laws within the scope of claims of the present application.

Claims (10)

1.3 preparation method of pyrrolidone cut block of CL protease inhibitor, characterized by comprising the following steps:
s1, preparing a compound II through zinc metal and the compound I;
s2, reacting the compound II with one of a compound III or a compound IV to obtain a compound V,
s3, deprotecting the compound V to obtain a target product compound VI;
the integral reaction formula is shown in the formula I;
wherein R is 1 And R is 2 R is a protecting group 3 Is any one of formate group, protected methanol group, formaldehyde group or cyano group, X is bromine or iodine, and the base used in the step S2 is organolithium.
2. The method for preparing a 3CL protease inhibitor pyrrolidone block according to claim 1, wherein X is bromine.
3. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 1, wherein R 2 Is a formate group.
4. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 3, wherein R 3 ' is any of cyano or formaldehyde; also included between step S2 and step S3 is step S2-2, converting methyl formate groups to either cyano or formaldehyde groups.
5. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 1, wherein in step S2, lithium diisopropylacetamido is used as a base.
6. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 5, wherein the ratio of the amounts of the substances of compound I, compound III or compound IV and the base is 1 (1.2-4) to (2-3).
7. The method for preparing 3CL protease inhibitor pyrrolidone piece according to claim 6, wherein the ratio of the amounts of the substances of compound I, compound III or compound IV and the base is 1:2:2.2.
8. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 1, wherein the reaction temperature of step S2 is-80 to-20 ℃.
9. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 8, wherein step S2 is performed using tetrahydrofuran as a solvent.
10. The method for preparing 3CL protease inhibitor pyrrolidone block according to claim 1, wherein in step S3, deprotection catalysis is performed with trifluoroacetic acid.
CN202210184012.9A 2022-02-26 2022-02-26 Preparation method of 3CL protease inhibitor pyrrolidone cut block Pending CN116693441A (en)

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Application Number Priority Date Filing Date Title
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