CN116023347A - Method for preparing carfilzomib side chain isomer - Google Patents

Method for preparing carfilzomib side chain isomer Download PDF

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CN116023347A
CN116023347A CN202211224789.XA CN202211224789A CN116023347A CN 116023347 A CN116023347 A CN 116023347A CN 202211224789 A CN202211224789 A CN 202211224789A CN 116023347 A CN116023347 A CN 116023347A
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carfilzomib
leucine
boc
reaction
isomers
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奚红亮
孟电力
杨金月
刘丹
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Wuxi Yew Pharmaceutical Co ltd
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a method for preparing isomers of carfilzomib side chains, wherein the side chain isomers are a compound A and a compound B, and the method comprises the following steps: (1) The Boc-D-leucine is activated by pivaloyl chloride and condensed with morpholine under the action of N-methylmorpholine to obtain an intermediate I; (2) reacting the intermediate I with a Grignard reagent to obtain an intermediate II; (3) The intermediate II is oxidized by MCPBA to obtain a compound A and a compound B. The method can obtain the isomer with higher purity, and the purity can meet the requirements of structure identification, impurity spectrum research and methodology verification. Has important significance for quality research and quality control of the carfilzomib key side chain compound I and finished carfilzomib.

Description

Method for preparing carfilzomib side chain isomer
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a method for preparing isomers of carfilzomib side chains.
Background
Carfilzomib, a proteasome inhibitor, is useful for treating patients with multiple myeloma. Multiple Myeloma (MM) is a malignancy derived from a B cell line, characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, causing fractures and bone marrow failure, the second most common hematological tumor worldwide, which cannot be cured by traditional chemotherapy regimens. Bortezomib (brotezomib) is the first proteasome inhibitor, and, due to its strong resistance and continued research on its resistance mechanism, carfilzomib (carfilzomib) is approved by the FDA as a second proteasome inhibitor following bortezomib for use in patients with multiple myeloma who received at least 2 drugs prior to treatment, including bortezomib and immunomodulator treatment.
Carfilzomib is a specific, irreversible targeted inhibitor, originally developed by Proteolix corporation, produced by the pharmaceutical company of aonix (Onyx), approved by the FDA for marketing in 7 months and 20 days 2012. The carfilzomib has a structure of a compound K, and a structural formula is shown in a formula 1:
Figure SMS_1
Figure SMS_2
the carfilzomib structure contains 5 chiral carbon molecules, so that the prepared isomer compound has important significance for quality research and control of a carfilzomib intermediate compound and a carfilzomib bulk drug.
In the synthesis process of carfilzomib, a key side chain, namely a compound I, is needed, and the structure is shown as formula 2:
Figure SMS_3
during the synthesis of the key side chain compound I, a chiral center is introduced into the starting materials, 1 chiral center is constructed, the intermediate product is mixed with isomer impurities, and during the synthesis, 2 isomers, namely compounds A and B, are found, wherein the compound A is shown as formula 3 and the compound B is shown as formula 4:
Figure SMS_4
if the content of the isomer compound A and the compound B in the side chain compound I is relatively high, the isomer compound A and the compound B are derived into isomer impurities in the subsequent synthesis of the bulk drug carfilzomib, and the derived isomer impurities are difficult to remove in the bulk drug. The isomer research of the bulk drug carfilzomib is important, the quality control of a side chain is an important link in the process of drug development, and a certain amount of reference substances are required for establishing quality standards, so that the preparation method development of the isomer is an important task of drug research. The method has great significance for relevant research of the carfilzomib isomers, and can be used for qualitative and quantitative analysis of impurities in production of carfilzomib side chains, so that the quality standard of the carfilzomib can be improved, and important guiding significance is provided for safe medication of people.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for preparing the isomer of the carfilzomib side chain, which has the advantages of direct reaction route, high reaction yield, high purity of target products, mild reaction conditions in each step, simple operation, reduced preparation cost and suitability for industrial production.
The technical aim of the invention is realized by the following technical scheme:
a method for preparing an isomer of a carfilzomib side chain, comprising the steps of:
step S1: dissolving Boc-D-leucine in dichloromethane, reacting with low Wen Dijia pivaloyl chloride and N-methylmorpholine at a high temperature to prepare mixed anhydride, cooling after the reaction is finished, dropwise adding dimethylhydroxylamine hydrochloride solution, and carrying out acid washing, alkali washing, water washing and concentration after the reaction is finished to obtain an intermediate I;
s2: dissolving the intermediate I in tetrahydrofuran, replacing nitrogen in a container, dropwise adding isopropenyl magnesium bromide solution under the conditions of no water and no oxygen at low temperature, heating to react, quenching an ammonium chloride aqueous solution, washing with purified water, saturated sodium bicarbonate solution and saturated saline, and concentrating an organic phase to obtain an intermediate II;
s3: dissolving the intermediate II in pyridine, adding MCPBA, quenching a sodium thiosulfate solution, extracting with n-heptane, concentrating an organic phase, and separating by column chromatography to obtain a compound A and a compound B;
the reaction process comprises the following steps:
Figure SMS_5
further, in the step S1, the molar ratio of pivaloyl chloride to Boc-D-leucine is 1-1.5:1; the molar ratio of the N-methylmorpholine to the Boc-D-leucine is 1-1.5:1; the molar ratio of the methylmorpholine to the Boc-D-leucine is 1-1.5:1; the weight ratio of the dichloromethane to the Boc-D-leucine is 5-20:1.
Further, in step S1, the molar ratio of pivaloyl chloride to Boc-D-leucine is 1.1:1; the molar ratio of N-methylmorpholine to Boc-D-leucine is 1.1:1; the molar ratio of the methylmorpholine to the Boc-D-leucine is 1.1:1; the weight ratio of dichloromethane to Boc-D-leucine was 10:1.
Further, in the step S1, the reaction temperature range after the dropwise addition of N-methylmorpholine is-10-30 ℃, and the reaction time range after the dropwise addition of N-methylmorpholine is 1-5 h.
Further, in step S2, the molar ratio of isopropenylmagnesium bromide to intermediate I is 1-5:1, and the weight ratio of tetrahydrofuran to intermediate I is 3-10:1.
Further, in step S2, the molar ratio of isopropenylmagnesium bromide to intermediate I is 1-5:1, and the weight ratio of tetrahydrofuran to intermediate I is 3-10:1.
Further, in step S3, the molar ratio of MCPBA to intermediate II is 1-5:1, and the weight ratio of pyridine to intermediate II is 10-20:1.
Further, in step S3, the molar ratio of MCPBA to intermediate II is 3:1 and the weight ratio of pyridine to intermediate II is 15:1.
Further, in step S3, the reaction temperature is in the range of-15 to 20 ℃.
Further, in step S3, the reaction time is in the range of 1 to 3 hours.
By adopting the technical scheme.
In summary, the invention has the following beneficial effects:
the Boc-D-leucine is activated by using pivaloyl chloride, so that the chain structure of the Boc-D-leucine is opened, then N-methylmorpholine is introduced, the Boc-D-leucine and the morpholine are condensed to obtain an intermediate I, the intermediate I reacts with a Grignard reagent to obtain an intermediate II, and then the intermediate II is subjected to oxidation reaction with MCPBA to obtain a target compound A and a target compound B, wherein the reaction route is direct, the reaction condition is mild, and the obtained target product has high isomer content and high purity.
2. In the step S1, since the flash point of the N-methylmorpholine is 14 ℃, the flash fire and the immediate combustion easily occur when the mixture is formed with the outside air and is contacted with flame, the dropping temperature of the pivaloyl chloride and the N-methylmorpholine is strictly controlled, and the condensation reaction temperature after the dropping temperature is strictly controlled, so that the maximum condensation of Boc-D-leucine and morpholine is ensured.
3. In the step S2, in order to avoid that the intermediate I is oxidized in advance to generate different isomers, the yield and the purity of a target product are improved, on the other hand, the boiling point of isopropenyl magnesium bromide is 67 ℃ and is easy to oxidize and deteriorate, the concentration of the isopropenyl magnesium bromide is strictly controlled, and accidents such as deflagration are avoided.
4. In step S3, the MCPBA and the intermediate II undergo an N-oxidation reaction to decompose the intermediate II to obtain the target isomer, thereby avoiding the method of liquid phase preparation and reducing intermediate byproducts.
5. The reaction steps are few, the raw material cost is low, and the cost of synthesizing the target substance is greatly reduced.
Drawings
FIG. 1 is a schematic illustration of the steps of a method for preparing isomers of carfilzomib side chains.
FIG. 2 is an HPLC detection pattern of Compound A.
FIG. 3 is an HPLC detection pattern of Compound B.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the solution according to the present invention will be given with reference to the accompanying drawings and the detailed description. The advantages and features of the present invention will become more apparent from the following description.
Example 1:
s1, preparation of an intermediate I:
adding 10g of Boc-D-leucine and 60g of dichloromethane into a reaction bottle, replacing with nitrogen, cooling to-10 ℃, slowly adding 4.97g of pivaloyl chloride into the system, stirring for 10min at-10 ℃, slowly adding 4.47g of N-methylmorpholine, heating to 15 ℃ for reaction, cooling to-10 ℃, slowly adding 3.85g of morpholine into the system, heating to 15 ℃ for reaction, ending the reaction, dropwise adding 8mL of 1M sulfuric acid solution into the reaction bottle, standing for separating liquid, adding sodium hydroxide solution into an organic phase, separating liquid, washing an organic phase with water and saturated saline sequentially, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 12.10g of intermediate I crude product, wherein the yield is 93.18%, and the purity is 90.13%;
s2, preparation of an intermediate II:
10g of intermediate I is dissolved in 100g of tetrahydrofuran, nitrogen protection is adopted, the temperature is reduced to below-15 ℃, 91mL of 1M isopropenyl magnesium bromide solution is added dropwise, the temperature is raised to 15 ℃ until the reaction is finished, the reaction solution is added into 30% citric acid aqueous solution (80 mL), the solution is separated, the organic phase is washed twice with water, dried with anhydrous sodium sulfate, concentrated under reduced pressure, the residue silica gel is stirred, the column chromatography is purified, and the ethyl acetate/petroleum ether (1/100) is eluted, so that 7.38g of intermediate II is obtained, the yield is 80.6%, and the purity is 98.60%.
S3, preparation of a compound A and a compound B:
adding 5.0g of intermediate II and 75g of pyridine solution into a reaction bottle, adding 9.4g of MCPBA in batches, controlling the temperature to minus 10 ℃ for reaction, adding 500mL of 13% sodium thiosulfate solution for quenching reaction after the reaction is finished, extracting an aqueous phase with 300mL of n-heptane, combining organic phases, washing with 200mL of water once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, stirring a sample of residue silica gel, purifying by column chromatography, eluting with petroleum ether ethyl acetate=50:1-40:1 to obtain 2.4g of compound A, wherein the yield is 45.2%, and the liquid phase purity is 96.85%; petroleum ether ethyl acetate=10:1 elution gives 1.0g of compound B in 18.8% yield, 99.21% purity.
And finally, carrying out HPLC detection on the prepared compound A, wherein the graph results are shown in figure 2.
The HPLC detection of compound B is performed, and the results of the spectrum are shown in FIG. 3.
Example 2:
s1, preparation of an intermediate I:
adding 10g of Boc-D-leucine and 150g of dichloromethane into a reaction bottle, replacing with nitrogen, cooling to 0 ℃, slowly adding 6.25g of pivaloyl chloride into the system, stirring for 10min at-10 ℃, slowly adding 5.25g of N-methylmorpholine, heating to 20 ℃ for reaction, cooling to-5 ℃, slowly adding 4.50g of morpholine into the system, heating to 20 ℃ for reaction, ending the reaction, dropwise adding 8mL of 1M sulfuric acid solution into the reaction bottle, standing for liquid separation, adding sodium hydroxide solution into an organic phase, liquid separation, washing an organic phase with water and saturated saline sequentially, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 10.80g of intermediate I, wherein the yield is 83.16% and the purity is 88.9%;
s2, preparation of an intermediate II:
10g of intermediate I is dissolved in 100g of tetrahydrofuran, nitrogen protection is adopted, the temperature is reduced to below-12 ℃, 120mL of 1M isopropenyl magnesium bromide solution is dripped, the temperature is raised to 20 ℃ until the reaction is finished, the reaction solution is added into 30% citric acid aqueous solution (80 mL), the solution is separated, the organic phase is washed twice with water, dried by anhydrous sodium sulfate, decompressed and concentrated, the residue silica gel is stirred, the column chromatography is purified, and the ethyl acetate/petroleum ether (1/100) is eluted, so that 7.08g of intermediate II is obtained, the yield is 77.32%, and the purity is 98.50%.
S3, preparation of a compound A and a compound B:
adding 5.0g of intermediate II and 75g of pyridine solution into a reaction bottle, adding 10.5g of MCPBA in batches, controlling the temperature to minus 5 ℃ for reaction, adding 500mL of 13% sodium thiosulfate solution for quenching reaction after the reaction is finished, extracting an aqueous phase with 300mL of n-heptane, combining organic phases, washing with 200mL of water once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, stirring a sample of residue silica gel, purifying by column chromatography, eluting with petroleum ether ethyl acetate=50:1-40:1 to obtain 2.2g of compound A, wherein the yield is 41.4%, and the liquid phase purity is 96.20%; petroleum ether ethyl acetate=10:1 elution gives 1.2g of compound B, 22.56% yield, 99.0% purity.
Example 3:
s1, preparation of an intermediate I:
adding 10g of Boc-D-leucine and 60g of dichloromethane into a reaction bottle, replacing with nitrogen, cooling to 0 ℃, slowly adding 7.50g of pivaloyl chloride into the system, stirring for 10min at 0 ℃, slowly adding 6.50g of N-methylmorpholine, heating to 25 ℃ for reaction, cooling to-10-0 ℃, slowly adding 5.65g of morpholine into the system, heating to 25 ℃ for reaction, ending the reaction, dropwise adding 8mL of 1M sulfuric acid solution into the reaction bottle, standing for separating liquid, adding sodium hydroxide solution into an organic phase, separating liquid, washing an organic phase with water and saturated saline water sequentially, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 11.4g of intermediate I, wherein the yield is 87.79%, and the purity is 85.3%;
s2, preparation of an intermediate II:
10g of intermediate I is dissolved in 100g of tetrahydrofuran, nitrogen protection is adopted, the temperature is reduced to below minus 10 ℃, 150mL of 1M isopropenyl magnesium bromide solution is dripped, the temperature is raised to 25 ℃ until the reaction is finished, the reaction solution is added into 30% citric acid aqueous solution (80 mL), the solution is separated, the organic phase is washed twice by water, dried by anhydrous sodium sulfate, decompressed and concentrated, the residue silica gel is stirred, the column chromatography is purified, and the ethyl acetate/petroleum ether (1/100) is eluted, thus 6.90g of intermediate II is obtained, the yield is 75.35%, and the purity is 98.2%.
S3, preparation of a compound A and a compound B:
adding 5.0g of intermediate II and 75g of pyridine solution into a reaction bottle, adding 12g of MCPBA in batches, controlling the temperature to be 0 ℃ for reaction, adding 500mL of 13% sodium thiosulfate solution for quenching reaction after the reaction is finished, extracting water phase with 300mL of n-heptane, combining organic phases, washing with 200mL of water once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, mixing a residual silica gel sample, purifying by column chromatography, eluting with petroleum ether ethyl acetate=50:1-40:1 to obtain 2.3g of compound A, wherein the yield is 43.31%, and the liquid phase purity is 95.3%; petroleum ether ethyl acetate=10:1 elution gives 1.0g of compound B in 18.8% yield with 99.0% purity.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (10)

1. A method for preparing an isomer of a carfilzomib side chain, which is characterized by comprising the following steps:
step S1: dissolving Boc-D-leucine in dichloromethane, reacting with low Wen Dijia pivaloyl chloride and N-methylmorpholine at a high temperature to prepare mixed anhydride, cooling after the reaction is finished, dropwise adding dimethylhydroxylamine hydrochloride solution, and carrying out acid washing, alkali washing, water washing and concentration after the reaction is finished to obtain an intermediate I;
s2: dissolving the intermediate I in tetrahydrofuran, replacing nitrogen in a container, dropwise adding isopropenyl magnesium bromide solution under the conditions of no water and no oxygen at low temperature, heating to react, quenching an ammonium chloride aqueous solution, washing with purified water, saturated sodium bicarbonate solution and saturated saline, and concentrating an organic phase to obtain an intermediate II;
s3: dissolving the intermediate II in pyridine, adding MCPBA, quenching a sodium thiosulfate solution, extracting with n-heptane, concentrating an organic phase, and separating by column chromatography to obtain a compound A and a compound B;
the reaction process comprises the following steps:
Figure FDA0003879232700000011
2. a process for the preparation of isomers of carfilzomib side chains according to claim 1, characterized in that: in the step S1, the mol ratio of pivaloyl chloride to Boc-D-leucine is 1-1.5:1; the molar ratio of the N-methylmorpholine to the Boc-D-leucine is 1-1.5:1; the molar ratio of the methylmorpholine to the Boc-D-leucine is 1-1.5:1; the weight ratio of the dichloromethane to the Boc-D-leucine is 5-20:1.
3. A process for the preparation of isomers of carfilzomib side chains according to claim 2, characterized in that: in step S1, the molar ratio of pivaloyl chloride to Boc-D-leucine is 1.1:1; the molar ratio of N-methylmorpholine to Boc-D-leucine is 1.1:1; the molar ratio of the methylmorpholine to the Boc-D-leucine is 1.1:1; the weight ratio of dichloromethane to Boc-D-leucine was 10:1.
4. A process for the preparation of isomers of carfilzomib side chains according to claim 1, characterized in that: in the step S1, the reaction temperature range after the dropwise addition of the N-methylmorpholine is-10-30 ℃, and the reaction time range after the dropwise addition of the N-methylmorpholine is 1-5 h.
5. A process for the preparation of isomers of carfilzomib side chains according to claim 1, characterized in that: in the step S2, the concentration of isopropenyl magnesium bromide is 1M, the mol ratio of isopropenyl magnesium bromide to the intermediate I is 1-5:1, and the weight ratio of tetrahydrofuran to the intermediate I is 3-10:1
6. The method for preparing the isomer of carfilzomib side chain of claim 5, wherein the method comprises the following steps: in the step S2, the mol ratio of isopropenyl magnesium bromide to the intermediate I is 1-5:1, and the weight ratio of tetrahydrofuran to the intermediate I is 3-10:1.
7. A process for the preparation of isomers of carfilzomib side chains according to claim 1, characterized in that: in step S3, the molar ratio of MCPBA to intermediate II is 1-5:1, and the weight ratio of pyridine to intermediate II is 10-20:1.
8. A process for the preparation of isomers of carfilzomib side chains according to claim 7, characterized in that: in step S3, the molar ratio of MCPBA to intermediate II was 3:1 and the weight ratio of pyridine to intermediate II was 15:1.
9. A process for the preparation of isomers of carfilzomib side chains according to claim 8, characterized in that: in step S3, the reaction temperature is in the range of-15 to 20 ℃.
10. A process for the preparation of isomers of carfilzomib side chains according to claim 9, characterized in that: in step S3, the reaction time ranges from 1 to 3 hours.
CN202211224789.XA 2022-10-09 2022-10-09 Method for preparing carfilzomib side chain isomer Pending CN116023347A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114276412A (en) * 2021-12-28 2022-04-05 南京格亚医药科技有限公司 Preparation method of carfilzomib oxide impurities

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