Preparation method of N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative

Abstract

The present application provides a method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative, and relates to the pharmaceutical field. The preparation method includes: adding hexamethyldisilazane solution to a reaction vessel under a protective atmosphere, dropping n-butyl lithium after cooling to a first temperature, heating to a second temperature after completion of the dropwise addition for a first reaction, then dropping N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester solution, dropping 2-bromo-1,1-dimethoxyethane solution or 2-bromomethyl-1,3-dioxolane solution after a second reaction, and then performing a third reaction and a first post-treatment to obtain a first intermediate; the first intermediate is subjected to a second reaction with hydroxylamine hydrochloride, and then a second post-treatment is performed to obtain a second intermediate; the second intermediate is subjected to a dehydration reaction, and then a third post-treatment is performed. The method does not use halogen-substituted acetonitrile, and provides a new preparation idea.

Description

Technical Field

[0001] The present application relates to the pharmaceutical field, and in particular to a method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative. Background Art

[0002] (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester, CAS#328086-57-3, is a derivative of N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester, which can be used to produce (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionic acid methyl ester, CAS#328086-60-8, which is a key intermediate of nematevir, a drug for the treatment of the new coronavirus. The specific structural formula is as follows:

[0003] ,

[0004] ,

[0005] (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester, CAS#328086-57-3, is usually synthesized using N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester and bromoacetonitrile. The relevant technical patents are as follows:

[0006] The claims of CN115073347 clearly state that N-tert-butoxycarbonyl-L-glutamate dimethyl ester reacts with bromoacetonitrile to obtain (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester; patents using the same method include: CN114149415 (page 74); CN114456211 (page 7); CN110354248 (page 8); CN114230504 still uses the same raw materials, but changes the synthesis method to use continuous flow technology.

[0007] It has become an urgent problem to study a new method for preparing dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate to avoid using halogen-substituted acetonitrile such as bromoacetonitrile, chloroacetonitrile, and iodoacetonitrile as raw materials. Summary of the invention

[0008] The purpose of the present application is to provide a method for preparing N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivatives to solve the above problems.

[0009] To achieve the above objectives, this application adopts the following technical solutions:

[0010] A method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative, comprising:

[0011] Add a hexamethyldisilazane solution to a reaction container under a protective atmosphere, drop n-butyl lithium after cooling to a first temperature, heat to a second temperature after the addition is complete, perform a first reaction, drop N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester solution, drop 2-bromo-1,1-dimethoxyethane solution or 2-bromomethyl-1,3-dioxolane solution after a second reaction, and then perform a third reaction and a first post-treatment to obtain a first intermediate;

[0012] The first intermediate is subjected to a second reaction with hydroxylamine hydrochloride, and then subjected to a second post-treatment to obtain a second intermediate;

[0013] The second intermediate is subjected to a dehydration reaction and then subjected to a third post-treatment to obtain dimethyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)glutarate.

[0014] Preferably, the first temperature is -45°C to -35°C, the second temperature is 5-15°C, and the reaction time of the first reaction is 0.5-2h.

[0015] Preferably, the time of the second reaction and the third reaction is independently 1-3 hours.

[0016] Preferably, the first post-processing comprises:

[0017] The reaction system was cooled to 0°C, and aqueous hydrochloric acid was added dropwise for quenching. The organic phase was separated, concentrated, and dried to obtain the first intermediate.

[0018] Preferably, the solvents of the hexamethyldisilazane solution, the N-tert-butyloxycarbonyl-L-glutamate dimethyl ester solution, the 2-bromo-1,1-dimethoxyethane solution, and the 2-bromomethyl-1,3-dioxolane solution are all tetrahydrofuran.

[0019] Preferably, the first intermediate and the hydroxylamine hydrochloride are reacted in the presence of methanol, and sodium hydroxide is added in batches before the second reaction is carried out.

[0020] Preferably, the temperature of the second reaction is 20-30°C and the time is 5-10h.

[0021] Preferably, the second post-processing comprises:

[0022] The reaction system is mixed with an ice-water mixture, stirred to precipitate the product, and the solid-liquid separation and drying are performed to obtain the second intermediate.

[0023] Preferably, the dehydration reaction comprises:

[0024] The second intermediate is mixed with acetic anhydride, and the temperature is gradually raised to 125-135° C., the by-product acetic acid is continuously removed, and the reaction is carried out for 2-4 hours.

[0025] Preferably, the third post-processing comprises:

[0026] The reaction system was cooled to 20-30° C., and then mixed with an ice-water mixture. After the solid was precipitated, the solid-liquid separation and drying were performed, and then recrystallization was performed using a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:10.

[0027] Compared with the prior art, the beneficial effects of this application include:

[0028] The preparation method of N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester derivative provided in the present application uses N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester as a raw material, reacts with 2-bromo-1,1-dimethoxyethane, then reacts with hydroxylamine hydrochloride, and finally performs a dehydration reaction to synthesize (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester. Halogen-substituted acetonitrile such as bromoacetonitrile, chloroacetonitrile, and iodoacetonitrile is not used as a raw material. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope of the present application.

[0030] Figure 1 This is the hydrogen spectrum of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate obtained in Example 1. DETAILED DESCRIPTION

[0031] As used herein:

[0032] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0033] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0034] When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0035] In these examples, parts and percentages are by mass unless otherwise indicated.

[0036] "Mass parts" refers to the basic unit of measurement for expressing the mass ratio of multiple components. 1 part can represent any unit mass, such as 1g or 2.689g. If we say that the mass parts of component A are a parts and the mass parts of component B are b parts, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it means that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number, indicating a multiple factor). It should not be misunderstood that, unlike the mass parts, the sum of the mass parts of all components is not limited to 100 parts.

[0037] "And / or" is used to indicate that one or both of the stated situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0038] A method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative, comprising:

[0039] Add a hexamethyldisilazane solution to a reaction container under a protective atmosphere, drop n-butyl lithium after cooling to a first temperature, heat to a second temperature after the addition is complete, perform a first reaction, drop N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester solution, drop 2-bromo-1,1-dimethoxyethane solution or 2-bromomethyl-1,3-dioxolane solution after a second reaction, and then perform a third reaction and a first post-treatment to obtain a first intermediate;

[0040] The first intermediate is subjected to a second reaction with hydroxylamine hydrochloride, and then subjected to a second post-treatment to obtain a second intermediate;

[0041] The second intermediate is subjected to a dehydration reaction and then subjected to a third post-treatment to obtain dimethyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)glutarate.

[0042] The reaction equation is as follows:

[0043] .

[0044] In an optional embodiment, the first temperature is -45°C to -35°C, the second temperature is 5-15°C, and the reaction time of the first reaction is 0.5-2h.

[0045] Optionally, the first temperature can be -45°C, -40°C, -35°C or any value between -45°C and -35°C, the second temperature can be 5°C, 10°C, 15°C or any value between 5-15°C, and the reaction time of the first reaction can be 0.5h, 1h, 1.5h, 2h or any value between 0.5-2h.

[0046] In an optional embodiment, the time of the second reaction and the third reaction is independently 1-3 hours.

[0047] Optionally, the time of the second reaction and the third reaction can be independently 1 h, 2 h, 3 h or any value between 1-3 h.

[0048] In an optional embodiment, the first post-processing includes:

[0049] The reaction system was cooled to 0°C, and aqueous hydrochloric acid was added dropwise for quenching. The organic phase was separated, concentrated, and dried to obtain the first intermediate.

[0050] In an optional embodiment, the solvents of the hexamethyldisilazane solution, the N-tert-butyloxycarbonyl-L-glutamate dimethyl ester solution, the 2-bromo-1,1-dimethoxyethane solution, and the 2-bromomethyl-1,3-dioxolane solution are all tetrahydrofuran.

[0051] In an optional embodiment, the first intermediate and the hydroxylamine hydrochloride are reacted in the presence of methanol, and sodium hydroxide is added in batches to carry out the second reaction.

[0052] In an optional embodiment, the temperature of the second reaction is 20-30°C and the time is 5-10 hours.

[0053] Optionally, the temperature of the second reaction can be 20°C, 25°C, 30°C or any value between 20-30°C, and the time can be 5h, 6h, 7h, 8h, 9h, 10h or any value between 5-10h.

[0054] In an optional embodiment, the second post-processing comprises:

[0055] The reaction system is mixed with an ice-water mixture, stirred to precipitate the product, and the solid-liquid separation and drying are performed to obtain the second intermediate.

[0056] In an optional embodiment, the dehydration reaction comprises:

[0057] The second intermediate is mixed with acetic anhydride, and the temperature is gradually raised to 125-135° C., the by-product acetic acid is continuously removed, and the reaction is carried out for 2-4 hours.

[0058] Optionally, the endpoint temperature of the gradual heating can be 125°C, 130°C, 135°C or any value between 125-135°C, and the reaction time can be 2h, 3h, 4h or any value between 2-4h.

[0059] In an optional embodiment, the third post-processing includes:

[0060] The reaction system was cooled to 20-30° C., and then mixed with an ice-water mixture. After the solid was precipitated, the solid-liquid separation and drying were performed, and then recrystallization was performed using a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:10.

[0061] The end point temperature of the cooling can be 20°C, 25°C, 30°C or any value between 20-30°C.

[0062] The embodiments of the present application will be described in detail below in conjunction with specific examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. If specific conditions are not specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0063] Example 1

[0064] This embodiment provides a method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative, which specifically comprises the following steps:

[0065] 1. Preparation of Intermediate-1:

[0066] Disperse 27.53 g of N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester (0.1 mol) in 200 mL of tetrahydrofuran, disperse 16.9 g of 2-bromo-1,1-dimethoxyethane in 100 mL of tetrahydrofuran, add 200 mL of 1.2 mol / L tetrahydrofuran solution of hexamethyldisilazane to the reactor under a nitrogen atmosphere, cool to -40°C and mix evenly, add 14 g of n-butyl lithium (0.22 mol) dropwise, raise the temperature to 10°C after the addition is complete, continue to react for 1 hour, add N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester dropwise in tetrahydrofuran solution, react for 2 hours, add 2-bromo-1,1-dimethoxyethane dropwise in tetrahydrofuran solution, and continue to react for 2 hours. The reaction solution was cooled to 0°C and quenched by adding 0.1 mol / L aqueous hydrochloric acid solution. The organic phase was separated, concentrated and dried to obtain intermediate-1 with a yield of 91.2%.

[0067] The analysis results of intermediate-1 are as follows:

[0068] MS:[M+1] + =318.15, 1 H-NMR, 300MHz, CDCl3, δ 9.71(1H,t), 4.42(1H,t), 3.67(6H,s), 2.88-2.54(3H,brs), 2.25(2H,m), 1.39(9H,s).

[0069] 2. Preparation of Intermediate-2:

[0070] 31.7 g of intermediate-1 (0.1 mol), 300 mL of methanol, and 7 g of hydroxylamine hydrochloride (0.11 mol) were added to the reactor. 4 g of sodium hydroxide (0.1 mol) was added in batches at 5 °C. The temperature was raised to 25 °C and the reaction was completed for 8 hours. The reaction solution was poured into 1000 g of ice-water mixture and stirred for half an hour. The product precipitated and was filtered and dried to obtain intermediate-2 with a yield of 95.4%.

[0071] The analysis results of intermediate-2 are as follows:

[0072] MS:[M+1] + =333.16, 1 H-NMR, 300MHz, CDCl3, δ 7.35(1H,t), 4.42(1H,t), 3.67(6H,s), 2.31-2.24(3H,brs), 1.85(2H,m), 1.39(9H,s).

[0073] 3. Preparation of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)glutarate:

[0074] 31.4 g of intermediate-2 (0.1 mol) and 180 g of acetic anhydride were added to the reactor, and the reaction mixture was slowly heated to 130°C. During this period, by-product acetic acid was continuously generated and should be evaporated in time. The reaction was completed after 3 hours. The reaction solution was cooled to 25°C and poured into 1000 g of ice-water mixture. The precipitated solid was filtered, dried, and recrystallized with ethyl acetate: n-heptane = 1:10 (volume ratio) to obtain the product (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester with a yield of 79.6%.

[0075] The product analysis results are as follows:

[0076] MS:[M+1] + =315.16, H-NMR (400 MHz, CDCl3) δ 5.18 (d,1H), 4.33–4.41 (m,1H), 3.75 (s, 3H), 3.74 (s, 3H), 2.83–2.89 (m, 1H), 2.74–2.80 (m, 2H), 2.13–2.23 (m, 2H), 1.43 (s, 9H) (e.g. Figure 1 as shown).

[0077] Example 2

[0078] This embodiment provides a method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative, which specifically comprises the following steps:

[0079] 1. Preparation of Intermediate-1:

[0080] Disperse 27.53 g of N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester (0.1 mol) in 200 mL of tetrahydrofuran, disperse 16.9 g of 2-bromomethyl-1,3-dioxolane in 100 mL of tetrahydrofuran, add 200 mL of 1.2 mol / L tetrahydrofuran solution of hexamethyldisilazane to the reactor under a nitrogen atmosphere, cool to -40°C and mix evenly, add 14 g of n-butyl lithium (0.22 mol) dropwise, raise the temperature to 10°C after the addition is complete, continue to react for 1 hour, add N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester in tetrahydrofuran solution dropwise, react for 2 hours, add 2-bromomethyl-1,3-dioxolane in tetrahydrofuran solution dropwise, and continue to react for 2 hours. The reaction solution was cooled to 0°C and quenched by adding 0.1 mol / L aqueous hydrochloric acid solution. The organic phase was separated, concentrated and dried to obtain intermediate-1 with a yield of 92.1%.

[0081] 2. Preparation of Intermediate-2:

[0082] 31.7 g of intermediate-1 (0.1 mol), 300 mL of methanol, and 7 g of hydroxylamine hydrochloride (0.11 mol) were added to the reactor. 4 g of sodium hydroxide (0.1 mol) was added in batches at 5 °C. The temperature was raised to 25 °C and the reaction was completed for 8 hours. The reaction solution was poured into 1000 g of ice-water mixture and stirred for half an hour. The product precipitated and was filtered and dried to obtain intermediate-2 with a yield of 93.8%.

[0083] 3. Preparation of dimethyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)glutarate:

[0084] 31.4 g of intermediate-2 (0.1 mol) and 180 g of acetic anhydride were added to the reactor, and the reaction mixture was slowly heated to 130°C. During this period, by-product acetic acid was continuously generated and should be evaporated in time. The reaction was completed after 3 hours. The reaction solution was cooled to 25°C and poured into 1000 g of ice-water mixture. The precipitated solid was filtered, dried, and recrystallized with ethyl acetate: n-heptane = 1:10 (volume ratio) to obtain the product (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester with a yield of 82.1%.

[0085] Comparative Example 1

[0086] CN115073347 was used as a control.

[0087] Compared with Comparative Example 1, the core advantage of the method for preparing N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivatives provided in the present application is that halogen-substituted acetonitrile such as bromoacetonitrile, chloroacetonitrile, and iodoacetonitrile is not used as a raw material.

[0088] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

[0089] In addition, those skilled in the art will appreciate that, although some embodiments herein include certain features included in other embodiments but not other features, the combination of features of different embodiments is meant to be within the scope of the present application and form different embodiments. For example, in the above claims, any one of the claimed embodiments may be used in any combination. The information disclosed in this background technology section is intended only to deepen the understanding of the overall background technology of the present application and should not be regarded as an admission or in any form of implication that the information constitutes prior art known to those skilled in the art.

Claims

1. A method for preparing a N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative, characterized in that: include: Add a hexamethyldisilazane solution to a reaction container under a protective atmosphere, drop n-butyl lithium after cooling to a first temperature, heat to a second temperature after the addition is complete, perform a first reaction, drop N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester solution, drop 2-bromo-1,1-dimethoxyethane solution or 2-bromomethyl-1,3-dioxolane solution after a second reaction, and then perform a third reaction and a first post-treatment to obtain a first intermediate; The first intermediate is reacted with hydroxylamine hydrochloride in a second stage, and then subjected to a second post-treatment to obtain a second intermediate; The second intermediate is subjected to a dehydration reaction and then subjected to a third post-treatment to obtain dimethyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)glutarate.

2. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The first temperature is -45°C to -35°C, the second temperature is 5-15°C, and the reaction time of the first reaction is 0.5-2h.

3. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The time of the second reaction and the third reaction is independently 1-3h.

4. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The first post-processing comprises: The reaction system was cooled to 0°C, and aqueous hydrochloric acid was added dropwise for quenching. The organic phase was separated, concentrated, and dried to obtain the first intermediate.

5. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The solvents of the hexamethyldisilazane solution, the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester solution, the 2-bromo-1,1-dimethoxyethane solution and the 2-bromomethyl-1,3-dioxolane solution are all tetrahydrofuran.

6. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The first intermediate and the hydroxylamine hydrochloride are reacted in the presence of methanol, and sodium hydroxide is added in batches to carry out the second stage reaction.

7. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The temperature of the second stage reaction is 20-30°C and the reaction time is 5-10h.

8. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The second post-processing comprises: The reaction system is mixed with an ice-water mixture, stirred to precipitate the product, and the solid-liquid separation and drying are performed to obtain the second intermediate.

9. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to claim 1, characterized in that: The dehydration reaction comprises: The second intermediate is mixed with acetic anhydride, and the temperature is gradually raised to 125-135° C., the by-product acetic acid is continuously removed, and the reaction is carried out for 2-4 hours.

10. The method for preparing the N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester derivative according to any one of claims 1 to 9, characterized in that: The third post-processing comprises: The reaction system was cooled to 20-30° C., and then mixed with an ice-water mixture. After the solid was precipitated, the solid-liquid separation and drying were performed, and then recrystallization was performed using a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:10.

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