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CN118871427A - Preparation method of lebol Lei Sheng and intermediate thereof - Google Patents

Preparation method of lebol Lei Sheng and intermediate thereof Download PDF

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Publication number
CN118871427A
CN118871427A CN202280090392.8A CN202280090392A CN118871427A CN 118871427 A CN118871427 A CN 118871427A CN 202280090392 A CN202280090392 A CN 202280090392A CN 118871427 A CN118871427 A CN 118871427A
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CN
China
Prior art keywords
compound
reaction
preparation
lei
sheng
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CN202280090392.8A
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Chinese (zh)
Inventor
沈冀钧
穆永乐
简正军
何先亮
黄鲁宁
陶安平
顾虹
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Shanghai Syncores Technologies Inc ltd
Zhejiang Huahai Pharmaceutical Co Ltd
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Shanghai Syncores Technologies Inc ltd
Zhejiang Huahai Pharmaceutical Co Ltd
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Publication of CN118871427A publication Critical patent/CN118871427A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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

Abstract

The invention provides a method for preparing a lebox Lei Sheng, which comprises the following steps: and (3) taking the compound II and the compound III as raw materials to react in a second reaction solvent to obtain the lebol Lei Sheng. The invention also provides a preparation method of the compound II, the compound II prepared by the method is an Oxyma active ester intermediate, has high reaction activity, is a safe and non-explosive auxiliary nucleophile, avoids using traditional HOBt, HOAt and other activators, and eliminates potential safety hazards; the preparation method of the lebol Lei Sheng is safer and more efficient in reaction, and the racemization rate of the obtained product is lower.

Description

Preparation method of lebol Lei Sheng and intermediate thereof Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a lebol Lei Sheng and an intermediate thereof.
Background
Insomnia refers to a subjective experience of a patient that does not meet sleep time and/or quality and affects daytime social functions. According to international diagnostic criteria for insomnia and epidemiological studies, at least 6% of the world's population suffers from insomnia and sleep disorders, lebol Lei Sheng is a dual inhibitor of orexin receptor 1 (OX 1) and orexin receptor 2 (OX 2), which inhibits orexin by competitively binding to the 2 subtypes of orexin receptors (OX 1 and OX 2), and lebol Lei Sheng can interfere with orexin-energy neurotransmission, purposely promoting the initiation and maintenance of sleep. Lebox Lei Sheng (Lemborexant) having the formula shown in formula I:
Disclosure of Invention
The first aspect of the present invention provides a preparation method of lebol Lei Sheng, which comprises the following steps:
B) Reacting the compound II with the compound III in a second reaction solvent to obtain the lebol Lei Sheng shown in the formula I;
In some embodiments of the first aspect of the present invention, the second reaction solvent is selected from the group consisting of organic solvents including, but not limited to, at least one of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate, tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
In some embodiments of the first aspect of the invention, the reaction temperature of the reaction is from-5 ℃ to 40 ℃, preferably from 10 ℃ to 35 ℃.
In some embodiments of the first aspect of the invention, the reaction time of the reaction is from 1h to 48h, preferably from 12 to 24h.
In a second aspect, the invention provides a compound of formula II:
In a third aspect, the present invention provides a process for the preparation of compound II comprising the steps of:
a) Reacting the compound IV, the compound V and the compound VI in a first reaction solvent to obtain a compound II;
In some embodiments of the third aspect of the present invention, the first reaction solvent is selected from an organic solvent including, but not limited to, at least one of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate, tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
In some embodiments of the third aspect of the invention, the reaction temperature of the reaction is from-15 ℃ to 10 ℃, preferably from-10 ℃ to 5 ℃.
In some embodiments of the third aspect of the invention, the reaction time of the reaction is from 1h to 48h, preferably from 4 to 24h.
In a fourth aspect, the present invention provides a process for the preparation of compound IV comprising the steps of:
A) Taking a compound VII as a raw material, and under the action of a catalyst and an oxidant, performing an oxidation reaction in a mixed solvent of tertiary butanol and water to generate a compound IV;
In some embodiments of the fourth aspect of the invention, the catalyst is selected from at least one of 2,6, -tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2, 6, -tetramethylpiperidine-1-oxyl.
In some embodiments of the fourth aspect of the invention, the catalyst is used in an amount of 1% to 25% of the molar amount of compound VII.
In some embodiments of the fourth aspect of the invention, the volume ratio of t-butanol to water in the mixed solvent is from 4:1 to 3:2.
In some embodiments of the fourth aspect of the invention, the oxidizing agent is sodium hypochlorite.
In some embodiments of the fourth aspect of the invention, the oxidizing agent is used in an amount of 2.0eq to 5.0eq of the molar amount of compound VII.
In some embodiments of the fourth aspect of the invention, the oxidation reaction has a pH in the range of 6 to 12.
In some embodiments of the fourth aspect of the present invention, sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent.
In some embodiments of the fourth aspect of the invention, the reaction temperature of the oxidation reaction is from-10 ℃ to 45 ℃, preferably from-3 ℃ to 3 ℃.
In some embodiments of the fourth aspect of the invention, the oxidation reaction has a reaction time of from 1h to 96h, preferably from 1h to 24h.
The fifth aspect of the present invention provides a preparation method of a lebox Lei Sheng, which comprises the following steps:
A) The compound IV, the compound V and the compound VI are used as raw materials to react in a first reaction solvent to obtain a compound II;
b) And (3) carrying out condensation reaction on the compound II and the compound III in a second reaction solvent to obtain the lebol Lei Sheng shown in the formula I.
In some embodiments of the fifth aspect of the present invention, the compound IV is prepared by the step a) according to the fourth aspect of the present invention, that is, the compound VII is used as a raw material, and the compound IV is formed by performing an oxidation reaction in a mixed solvent of tert-butanol and water under the action of a catalyst and an oxidant.
In some embodiments of the fifth aspect of the invention, compound II prepared in step a) is used directly in step B) without isolation.
The beneficial effects are that:
Compared with the prior art, the method provided by the invention has the advantages that the method can safely and efficiently prepare the lebol Lei Sheng through preparing the Oxyma active ester intermediate, namely the compound II, and the obtained lebol Lei Shengguang has higher chemical purity, lower racemization rate and better application prospect. Meanwhile, the intermediate compound II is an Oxyma active ester intermediate, is a safe and non-explosive auxiliary nucleophile, and avoids the explosion potential safety hazard of traditional activators such as HOBt, HOAt and the like. In the preparation method of the intermediate compound IV, tertiary butanol and water are used as mixed solvents, ((1R, 2S) -2- (((2, 4-dimethylpyrimidin-5-yl) oxy) methyl) -2- (3-fluorophenyl) cyclopropyl) methanol is directly oxidized under the action of an oxidant and a catalyst to generate ((1R, 2S) -2- (((2, 4-dimethylpyrimidin-5-yl) oxy) methyl) -2- (3-fluorophenyl) cyclopropyl) formic acid, the yield is high, almost no waste gas is generated, a phosphorus-containing buffer solution is not used, no phosphorus-containing waste water is generated, and the method is environment-friendly, safe and simple in process and suitable for industrial production.
Drawings
FIG. 1 is a liquid chromatogram of a liquid chromatography-mass spectrometry (LC-MS) spectrum of a reaction liquid which is centrally controlled to reach a reaction end point in example 1 of the present invention.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum (1 H NMR) of the compound IV prepared in example 1 of the present invention.
FIG. 3 is a High Performance Liquid Chromatography (HPLC) purity profile of compound IV prepared in example 1 of the present invention.
FIG. 4 is a liquid chromatograph and an ion-flow chart in an LC-MS spectrum of the compound IV prepared in example 1 of the present invention; wherein 4a is a liquid chromatograph, and 4b is an ion flow graph.
FIG. 5 is a mass spectrum of the compound IV prepared in example 1 of the present invention in an LC-MS spectrum.
FIG. 6 is an optical purity profile of the compound IV prepared in example 1 of the present invention by HPLC.
FIG. 7 is an optical enantiomer chiral HPLC chart of compound IV prepared in example 1 of the present invention.
FIG. 8 is a liquid chromatogram in the LC-MS spectrum of the reaction liquid of example 2 of the present invention which was centrally controlled to reach the end of the reaction.
FIG. 9 is a liquid chromatogram in the LC-MS spectrum of the reaction liquid of comparative example 1 of the present invention which was centrally controlled to reach the reaction end point.
FIG. 10 is a liquid chromatogram in the LC-MS spectrum of the reaction liquid of comparative example 2 in which the reaction end point was reached by the center control of the present invention.
FIG. 11 is a liquid chromatogram in the LC-MS spectrum of a reaction solution of comparative example 3 in which the reaction end point was reached by the center control of the present invention.
FIG. 12 is a liquid chromatograph and an ion-flow chart in a liquid chromatograph mass spectrum (LC-MS) spectrum of the reaction liquid at the end of the reaction of the step A) in the embodiment 3 of the present invention; wherein 12a is a liquid chromatograph, and 12b is an ion flowsheet.
FIG. 13 is a mass spectrum of the compound II in the reaction liquid at the end of the reaction in the step A) in the example 3 of the present invention in the LC-MS spectrum.
FIG. 14 is a liquid chromatograph and ion-flow diagram in the LC-MS spectrum of the reaction liquid at the end of the reaction in step B) in example 3 of the present invention; wherein 14a is a liquid chromatograph, and 14b is an ion flowsheet.
FIG. 15 is a mass spectrum of the LC-MS spectrum of the reaction liquid at the end of the reaction in the step B) in the example 3 of the present invention; wherein 15a is the mass spectrum of the compound IV in the reaction liquid in the LC-MS spectrum, and 15b is the mass spectrum of the lebox Lei Sheng I in the reaction liquid in the LC-MS spectrum.
FIG. 16 is a nuclear magnetic resonance hydrogen spectrum (1 H NMR) of the preparation of Leibonum Lei Sheng I according to example 3 of the present invention (500 MHz).
FIG. 17 is an infrared spectrum of the lebox Lei Sheng I prepared in example 3 of the present invention.
FIG. 18 is a High Performance Liquid Chromatography (HPLC) purity profile of lebsiella Lei Sheng I prepared in example 3 of the present invention.
FIG. 19 is a chiral HPLC chart of Leibo Lei Sheng I prepared in example 3 of the present invention.
FIG. 20 is a chiral HPLC profile of the enantiomer of Leibo Lei Sheng I according to example 3 of the present invention.
Detailed Description
Terminology and definition:
oxyma: ethyl 2-oxime cyanoacetate, also known as ethyl 2-cyano-2- (hydroxy imine) acetate.
Oxyma active ester intermediates refer to O-acylisourea (O-acylisourea) intermediates formed by rapid reaction of an acid with Oxyma. In some embodiments of the invention, the Oxyma active ester intermediate is compound II.
The first aspect of the present invention provides a preparation method of lebol Lei Sheng, which comprises the following steps:
b) Reacting the compound II with the compound III in a second reaction solvent to obtain the lebol Lei Sheng shown in the formula I;
The inventor has intensively studied and found that by using the method, the preparation of the lebox Lei Sheng can be performed more safely and efficiently than the prior art.
In some embodiments of the first aspect of the present invention, the second reaction solvent is selected from the group consisting of organic solvents including, but not limited to, at least one of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate, tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
The inventors have found that the use of the second reaction solvent can sufficiently dissolve the raw materials, thereby producing the lebsiella Lei Sheng more safely and efficiently.
In some embodiments of the first aspect of the present invention, the reaction temperature of the above reaction is referred to as a second reaction temperature, which is from-5 ℃ to 40 ℃, preferably from 10 ℃ to 35 ℃. For example, the reaction temperature may be-5 ℃,0 ℃, 12 ℃,20 ℃,25 ℃, 40 ℃ or any range therebetween, and the inventors have studied and found that by controlling the second reaction temperature of the above reaction within the above range, the raw materials can be sufficiently reacted with each other, thereby producing lebsiella Lei Sheng more safely and efficiently.
In some embodiments of the first aspect of the invention, the above reaction is referred to as a second reaction time, which is from 1h to 48h, preferably from 12 to 24h. For example, the second reaction time may be 1h, 4h, 8h, 10h, 12h, 18h, 24h, 48h or any range therebetween, and the inventors have found that by controlling the second reaction time of the above reaction within the above range, the raw materials can be sufficiently reacted in the second reaction solvent, thereby producing lebo Lei Sheng more safely and efficiently.
In the present invention, the molar ratio of the compound II to the compound III is not particularly limited, and for example, the molar ratio of the compound II to the compound III may be 1:1, 1:5, 1:10, 10:1, 5:1 or any range therebetween.
In a second aspect, the invention provides a compound of formula II:
In a third aspect, the present invention provides a process for the preparation of compound II comprising the steps of:
reacting the compound IV, the compound V and the compound VI in a first reaction solvent to obtain a compound II;
The inventor has found through intensive research that the compound shown in the formula II prepared by the method is an Oxyma active ester intermediate, and can avoid using traditional activators HOBt and HOAt with explosion danger when being applied to the preparation process of the lebol Lei Sheng, so that the preparation method of the lebol Lei Sheng is safer and more efficient.
In some embodiments of the third aspect of the present invention, the first reaction solvent is selected from organic solvents including, but not limited to, at least one of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate, tetrahydrofuran, preferably tetrahydrofuran or acetonitrile. The inventor finds that the raw materials can be fully dissolved by using the first reaction solvent to prepare the compound II, so that the reaction is more efficient, and the prepared compound II is further applied to the preparation process of the lebol Lei Sheng, so that the preparation process of the lebol Lei Sheng is safer and more efficient.
In some embodiments of the present invention, the reaction temperature of the above reaction is referred to as a first reaction temperature, which is-15 ℃ to 10 ℃, preferably-10 ℃ to 5 ℃, for example, the first reaction temperature may be-15 ℃, -5 ℃,0 ℃,5 ℃,10 ℃ or any range therebetween, and the inventors have found that by controlling the first reaction temperature of the above reaction within the above range, the reaction between raw materials can be made sufficient, the reaction can be made more efficient, and further the prepared compound II can be applied to the preparation process of lebol Lei Sheng, making the preparation process of lebol Lei Sheng more safe and efficient.
In some embodiments of the third aspect of the invention, the reaction time of the above reaction is referred to as the first reaction time, which is from 1h to 48h, preferably from 4 to 24h. For example, the first reaction time may be 1h, 14h, 28h, 42h, 48h or any range therebetween, and the inventors have found that by controlling the first reaction time of the above reaction within the above range, the reaction can be made more efficient, and further the prepared compound II can be applied to the preparation process of lebol Lei Sheng, so that the preparation process of lebol Lei Sheng is made more safe and efficient.
In the present invention, the feed molar ratio of compound IV, compound V and compound VI is not particularly limited, and for example, the feed molar ratio may be 1:1:1, 1:5:1, 1:10:1, 1:1:5, 1:1:10, 5:1:1, 10:1:1 or any range therebetween.
In the prior art, the synthesis method of the compound IV comprises the following steps: ((1R, 2S) -2- (((2, 4-dimethylpyrimidin-5-yl) oxy) methyl) -2- (3-fluorophenyl) cyclopropyl) methanol (VII) is oxidized by sodium hypochlorite and under the catalysis of 2, 6-tetramethyl piperidine-nitrogen-oxide (TEMPO) to generate corresponding aldehyde (compound VIII), and is further oxidized by sodium chlorite to generate ((1R, 2S) -2- (((2, 4-dimethylpyrimidin-5-yl) oxy) methyl) -2- (3-fluorophenyl) cyclopropyl) formic acid.
The preparation method adopts chlorine-containing oxidizing agent for oxidation twice and uses phosphorus-containing compound to prepare buffer solution, so that a large amount of waste gas and phosphorus-containing wastewater containing chlorine dioxide can be generated in the production process.
In a fourth aspect, the present invention provides a process for the preparation of compound IV comprising the steps of:
A) Taking a compound VII as a raw material, and under the action of a catalyst and an oxidant, performing an oxidation reaction in a mixed solvent of tertiary butanol and water to generate a compound IV;
The inventors have conducted intensive studies to find that the method of directly oxidizing an alcohol to an acid in a mixed solvent using a mixed solvent of t-butanol and water as a reaction solvent is simple and efficient and the post-treatment step is simple, and not limited to any theory, the inventors believe that since t-butanol is used as a solvent, part of t-butanol is oxidized to a peroxide during the reaction, the generated peroxide further catalyzes the above oxidation reaction to directly oxidize an alcohol to an acid.
In some embodiments of the fourth aspect of the invention, the catalyst is selected from at least one of 2,6, -tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2, 6, -tetramethylpiperidine-1-oxyl. The inventors have found that the oxidation reaction can be made more efficient by using the above catalyst in conjunction with a mixed solvent.
In some embodiments of the fourth aspect of the invention, the catalyst is used in an amount of 1% to 25% of the molar amount of compound VII. In the present invention, the amount of the catalyst is not particularly limited, and may be an amount well known to those skilled in the art, and the amount of the catalyst may be selected from, but not limited to, 1% to 25%, based on the molar amount of the reaction raw material compound II, for example, the amount of the catalyst may be 1%, 2%, 6%, 14%, 25%, or any range therebetween.
In some embodiments of the fourth aspect of the invention, the volume ratio of t-butanol to water in the mixed solvent is from 4:1 to 3:2, such as 4:1,3:1,2:1,1.7:1,1.6:1,3:2; the inventors have found that the oxidation reaction is more efficient when the volume ratio of t-butanol to water meets the above relationship.
In some embodiments of the fourth aspect of the invention, the oxidizing agent is sodium hypochlorite. The inventor finds that only sodium hypochlorite is used as an oxidant, and compared with the combination of sodium hypochlorite and sodium chlorite in the prior art, the method has the advantages that almost no chlorine-containing waste gas is generated in the oxidation reaction process, and sodium chlorite is a flammable chemical, so that the preparation method is more green, safer and more efficient.
In some embodiments of the fourth aspect of the invention, the oxidizing agent is used in an amount of 2.0eq to 5.0eq of the molar amount of compound VII. In the present invention, the amount of the oxidizing agent is not particularly limited, and may be selected from, but not limited to, 2.0eq to 5.0eq, for example, 2.0eq, 2.8eq, 3.4eq, 4.6eq, 5.0eq, or any range therebetween, based on the molar amount of the reaction raw material compound II.
In some embodiments of the fourth aspect of the invention, the oxidation reaction has a pH in the range of 6 to 12, such as: 6. 7, 8, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12 or any range therebetween. The inventors have found that the oxidation reaction can be made more efficient by controlling the pH of the oxidation reaction within the above-described range.
In some embodiments of the fourth aspect of the present invention, sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent. The inventor finds that by using sodium bicarbonate and/or sodium carbonate as a buffer solution, compared with the prior art that sodium dihydrogen phosphate and disodium hydrogen phosphate are used as buffer solvents, the preparation method provided by the invention does not generate phosphorus-containing wastewater and is environment-friendly. And when sodium carbonate and sodium bicarbonate are added into the mixed solvent, the synergistic effect of the sodium carbonate and the sodium bicarbonate can realize a better buffering effect.
In some embodiments of the fourth aspect of the invention, the reaction temperature of the oxidation reaction is from-10 ℃ to 45 ℃, preferably from-3 ℃ to 3 ℃, for example, the reaction temperature may be from-10 ℃,5 ℃,0 ℃, 15 ℃, 30 ℃, 45 ℃ or any range therebetween. The inventors have found that by controlling the reaction temperature of the oxidation reaction within the above range, the reaction between the raw materials can be made sufficient, and the oxidation reaction can be made more efficient.
In some embodiments of the fourth aspect of the invention, the oxidation reaction has a reaction time of from 1h to 96h, preferably from 1h to 24h, for example, the reaction time may be from 1h, 5h, 16h, 29h, 42h, 55h, 68h, 81h, 96h or any range therebetween. The inventors have found that by controlling the reaction time of the oxidation reaction within the above range, the oxidation reaction can be made more efficient.
The fifth aspect of the present invention provides a preparation method of a lebox Lei Sheng, which comprises the following steps:
a) The compound IV, the compound V and the compound VI react in a first reaction solvent to obtain a compound II,
B) And (3) carrying out condensation reaction on the compound (II) and the compound (III) in a second reaction solvent to generate the lebol Lei Sheng shown in the formula I.
In some embodiments of the fifth aspect of the present invention, the compound IV is prepared by the step a) according to the fourth aspect of the present invention, that is, the compound VII is used as a raw material, and the compound IV is formed by performing an oxidation reaction in a mixed solvent of tert-butanol and water under the action of a catalyst and an oxidant.
In some embodiments of the fifth aspect of the invention, compound II prepared in step a) is used directly in step B) without isolation.
In the present invention, the first reaction solvent and the second reaction solvent may be the same or different, and are preferably the same.
In the invention, the synthesis of the lebol Lei Sheng can be directly carried out by a one-pot method without separating the compound II after the synthesis step of the compound II is finished, and the inventor finds that the one-pot method can simplify the process steps and reduce the production cost.
In the process of synthesizing the lebol Lei Sheng by the one-pot method, the reaction time and the temperature for synthesizing the intermediate compound II are the same as the selection range of the reaction time and the temperature in the preparation method of the compound II in the third aspect of the invention; the reaction time and temperature for synthesizing lebol Lei Sheng are the same as the reaction time and temperature in the preparation method of lebol Lei Sheng according to the first aspect of the invention.
Examples
Hereinafter, embodiments of the present application will be described more specifically with reference to examples. The various tests and evaluations were carried out according to the following methods.
HPLC method:
The reaction progress is monitored by High Performance Liquid Chromatography (HPLC) or the purity of the product is analyzed in the examples. High Performance Liquid Chromatography (HPLC) uses liquid as mobile phase, adopts a high pressure transfusion system, pumps single solvent with different polarities or mixed solvent with different proportions, buffer solution and other mobile phases into a chromatographic column filled with stationary phase, after each component in the column is separated, enters a detector for detection, and realizes analysis of sample components, and chromatographic detection conditions are shown in the following table 1:
TABLE 1
In the present invention, the method of nuclear magnetic resonance hydrogen spectrum test (1 H NMR), liquid chromatography-mass spectrometry (LC-MS) test, and infrared test is not particularly limited, and may be performed by methods known to those skilled in the art, wherein the deuterated reagent used in nuclear magnetic resonance hydrogen spectrum test is commercially available deuterated dimethyl sulfoxide (DMSO).
Ee value measurement:
In the examples, two enantiomers of chiral molecules of the product each rotated plane polarized light to an angle, the values of which were identical but opposite, this property was referred to as optical activity. The enantiomeric composition of a product is described in terms of "enantiomeric excess (enantiomeric excess)" or "ee value" and represents the excess of one enantiomer over the other, usually expressed as a percentage.
The ee value of the product was measured by High Performance Liquid Chromatography (HPLC) in the examples.
The starting materials and reagents of the invention are commercially available, compound III being commercially available as 2-amino-5-fluoropyridine from Funew Jin Telai, inc., unless otherwise specified; compound V (2-oxime ethyl cyanoacetate) and compound VI (diisopropylcarbodiimide) were purchased from Shanghai Bi De medical technology.
Example 1
In a reaction flask, 302g of Compound VII was dissolved in a mixed solvent of 2000mL of t-butanol and 1200mL of water, and 150g of sodium hydrogencarbonate, 15g of sodium carbonate and 7.5g of 2, 6-tetramethylpiperidine-nitrogen-oxide (TEMPO) were added thereto and stirred well. The temperature outside the reaction flask was reduced to-10 ℃. Aqueous sodium hypochlorite (2.2 eq,2200 ml) was added dropwise, the pH of the aqueous phase=9, and the temperature of the reaction system was kept at-3 to 3 ℃. After the completion of the dropwise addition, the mixture was reacted at 0℃for 12 hours. HPLC monitored compound VII content less than 0.2% at the end of the reaction, at which point the aqueous phase ph=9.2. The reaction end point was monitored by LC-MS test to obtain LC-MS spectrum of the reaction solution having the central control reaching the reaction end point (as shown in fig. 1, wherein the peak of 5 # is the peak corresponding to the target compound IV, and the content of the compound IV in the reaction solution is 98.7%).
Quenching agent (280 g sodium sulfite and 150g sodium hydroxide are dissolved in 1500mL water) is added dropwise, the temperature is not higher than 25 ℃ when the dropwise addition is finished, the temperature is raised to 60 ℃ after the dropwise addition is finished, the solution is clear, and the pH of the water phase is=9.5. After standing, separating the solution to remove the water phase. Concentrating the organic phase to about 800mL volume, adding 1L of sodium hydroxide aqueous solution (concentration is 10%), regulating pH to be more than 13.5, extracting the aqueous phase with tert-butyl methyl ether, separating to remove the organic phase, controlling the temperature of the aqueous phase to be not more than 10 ℃, adding 3.1L of concentrated hydrochloric acid (mass fraction to be more than 20%), regulating pH to be 1.5-2.5, filtering to remove most of water to obtain a viscous solid, dissolving the solid in 800mL of dichloromethane, separating to remove a small amount of water. The organic phase was concentrated and stripped with dichloromethane to a moisture content of less than 0.05% to give an off-white powdered solid. 400mL of isopropyl ether was added, heated to reflux with vigorous stirring and hot-slurried, cooled and filtered to yield 295g of compound IV as a white solid (1 H NMR characterization shown in FIG. 2). LC-MS spectra of compound IV are shown in fig. 4 and 5 (theoretical value of compound IV C 17H 17FN 2O 3 m+h is 317.13, found 317.1 in fig. 5). Purity was 99.5% (as shown in fig. 3), yield was 93%, and ee value was 99.99% (as shown in fig. 6 and 7).
Example 2
The procedure of example 1 was repeated except that 2000mL of t-butanol and 1000mL of water were included in the mixed solvent, and the catalyst was 4-hydroxy-2, 6, -tetramethylpiperidine-1-oxyl and the catalyst amount was 6.7 g. The reaction endpoint was monitored by LC-MS testing, and the LC-MS characterization of the reaction solution obtained to the reaction endpoint was shown in fig. 8, wherein the 11 # peak was the peak corresponding to the target compound IV, and the contents of compound IV, compound VII, and compound VIII in the reaction solution were shown in table 2.
Comparative example 1
The procedure of example 1 was repeated except that a toluene-water mixed solvent was used as the mixed solvent during the reaction, and the volume ratio of toluene to water was 2:1.2. The reaction endpoint was monitored by LC-MS testing, and the LC-MS characterization of the reaction solution obtained to the reaction endpoint was shown in fig. 9, wherein the 5 # peak was the peak corresponding to the target compound IV, and the contents of compound IV, compound VII, and compound VIII in the reaction solution were shown in table 2.
Comparative example 2
The reaction endpoint was monitored by LC-MS test, and the LC-MS characterization of the reaction solution obtained to the reaction endpoint was shown in fig. 10, wherein the 5 # peak was the peak corresponding to the target compound IV, and the contents of compound IV, compound VII, and compound VIII in the reaction solution were shown in table 2, as in example 1, except that the mixed solvent was acetonitrile-water mixed solvent, and the volume ratio of acetonitrile to water was 2:1.2, during the reaction.
Comparative example 3
The procedure of comparative example 2 was repeated except that 0.3% of t-butyl hydroperoxide was added to the mixed solvent based on the total volume of the mixed solvent. Without being bound by any theory, the inventors believe that it is possible that the tertiary butanol is partially oxidized to peroxide as a solvent, and the peroxide formed catalyzes the oxidation reaction so that it can be directly oxidized to acid. Therefore, the reaction conversion rate is greatly improved compared with that of comparative example 2 by further adding tert-butyl hydroperoxide into acetonitrile on the basis of comparative example 2. The reaction endpoint was monitored by LC-MS testing, and the LC-MS characterization of the reaction solution obtained to the reaction endpoint was shown in fig. 11, wherein the 2 # peak was the peak corresponding to the target compound IV, and the contents of compound IV, compound VII, and compound VIII in the reaction solution were shown in table 2.
TABLE 2
As can be seen from example 1, and comparative examples 1 and 2 (solvents described in original patent CN 104114524B), different solvents have a great influence on the reaction, toluene is used as a solvent to mainly produce aldehyde, so that the original patent CN104114524B uses sodium chlorite for further oxidation, and the mixed solvent of the present invention is used as a reaction solvent to directly prepare acid; meanwhile, the method of the original patent CN104114524B can generate a large amount of waste gas containing chlorine dioxide and phosphorus-containing wastewater polluting the environment, which does not meet the requirements of the green industry. The preparation method of the invention can not produce toxic and harmful waste gas and phosphorus-containing wastewater, is environment-friendly and has simple process. As can be seen from comparative examples 2 and 3, the addition of a trace amount of t-butyl hydroperoxide significantly improved the reaction, and not limited to any theory, the inventors believe that it is possible because t-butanol is partially oxidized as a solvent to peroxide, and the resulting peroxide catalyzes the oxidation reaction so that it can be directly oxidized to an acid. However, the reaction result of comparative example 3 is far less good than that of example 1, and it can be seen that the preparation method of the invention for preparing the intermediate of lebol Lei Sheng has simple reaction process and is environment-friendly.
Fig. 1 shows a liquid chromatogram in an LC-MS spectrum of a reaction liquid reaching a reaction end point in example 1 of the present invention, wherein data of the liquid chromatogram are reported in table 3 below:
TABLE 3 Table 3
Fig. 3 shows HPLC purity profile of compound IV prepared in example 1 of the present invention, wherein data of HPLC purity profile are reported in table 4 below:
TABLE 4 Table 4
Fig. 5 shows mass spectra of compound IV prepared in the examples of the present invention in LC-MS spectra, wherein data of LC-MS spectra are reported in table 5 below:
TABLE 5
Retention time (MS) MS area M/z of MS
15.045 57833156 318.10
317.10
Fig. 6 shows an HPLC optical purity profile of the compound IV prepared in example 1 of the present invention, wherein data of the HPLC optical purity profile is reported in table 6 below:
TABLE 6
Fig. 8 shows a liquid chromatogram in a centrally controlled LC-MS spectrum in example 2 of the present invention, wherein the data of the liquid chromatogram are reported in table 7 below:
TABLE 7
Fig. 9 shows a liquid chromatogram in the LC-MS spectrum of the center control in comparative example 1 of the present invention, wherein data of the liquid chromatogram are reported in table 8 below:
TABLE 8
Fig. 10 shows a liquid chromatogram in the LC-MS spectrum of the center control in comparative example 2 of the present invention, wherein data of the liquid chromatogram are reported in table 9 below:
TABLE 9
Fig. 11 shows a liquid chromatogram in the LC-MS spectrum of the center control in comparative example 3 of the present invention, in which data of the liquid chromatogram are reported in the following table 10:
Table 10
Example 3
A) (1R, 2S) -2- (((2, 4-dimethylpyrimidin-5-yl) oxy) methyl) -2- (3-fluorophenyl) cyclopropane-carboxylic acid (compound IV) (1.0 eq,316 g) and ethyl 2-cyano-2-hydroxyiminoacetate (compound V) (1.05 eq,149 g) were dissolved in 10V tetrahydrofuran (first reaction solvent) and stirred, and cooled to-10 ℃. Diisopropylcarbodiimide (compound VI) (1.5 eq,189 g) was added in three portions, 63g each, 20min apart. After the completion of the addition, the reaction was carried out once at 0℃overnight, the LC-MS spectra of the reaction solution were shown in FIG. 12 and FIG. 13, the retention time of the ion flow peak of Compound II in 12b in FIG. 12 was=22.113 min, the theoretical value of M+H + was 441.15[ M+1] +, the content of Compound IV was less than 1%, which was regarded as the end of the reaction, corresponding to the actual value of 441.1[ M+1] + in the mass spectrum in FIG. 13, and the first reaction time was 18 hours.
B) Further, 2-amino-5-fluoropyridine (compound III) (1.03 eq,115 g) (the second reaction solvent of step B), i.e., the first reaction solvent of step a)) was added to the reaction system, and the reaction was allowed to proceed to a secondary reaction at 15 ℃ (the second reaction temperature) and after a lapse of time, the LC-MS spectra of the reaction mixture was monitored as shown in fig. 14 and 15 (retention time of the ion flow peak of compound I at 14B in fig. 14=18.261 min, theoretical value of m+h + was 411.16[ m+1] +, corresponding to the actual measurement value of 411.1[ m+1] + in the mass spectrum of 15B in fig. 15), and the content of intermediate compound II was less than 3%, which was regarded as the end of the reaction, and the reaction time was 4h (second reaction time). The reaction solution was poured into 3 liters of an ice-water mixture, and extracted 1 time with 3 liters and 1.5 liters of isopropyl acetate, respectively. The organic phase is washed once with 500 ml of 1mol/L aqueous sodium carbonate solution. 200 ml of a 0.3mol/L aqueous hydrochloric acid solution was washed once. The organic phase was concentrated and spin-dried with isopropanol. 1L of isopropanol is added to be heated to reflux, 600 ml of n-heptane is added dropwise, the mixture is placed into a low-temperature cold circulation system to be cooled to 55 ℃ in 2h, the mixture is kept at 55 ℃ for 1 hour, and the mixture is further cooled to 0 ℃ in 5 h. Incubation at 0deg.C for 10h, filtration gave 307g of compound I in 75% yield, 99.86% purity (as shown in FIG. 16), 100% ee (as shown in FIGS. 19 and 20), and structural characterization of compound I as shown in FIGS. 17 and 18.
Compared with the prior art, the method provided by the invention has the advantages that the method can safely and efficiently prepare the lebol Lei Sheng through preparing the Oxyma active ester intermediate, namely the compound II, and the obtained lebol Lei Shengguang has higher chemical purity, lower racemization rate and better application prospect. Meanwhile, the intermediate compound II of the invention is an Oxyma active ester intermediate, which is a safe and non-explosive auxiliary nucleophile, and avoids the explosion safety hazards of traditional activators such as HOBt, HOAt and the like (see Fernando Albericio et al in chem. Eur. J.2009,15,9394-9403 for evaluation of the safety of Oxyma).
Fig. 16 shows HPLC purity profile of compound I prepared in example 3 of the present application, wherein data of HPLC purity profile is reported in table 11:
TABLE 11
Fig. 19 shows a chiral HPLC profile of compound I prepared in example 3 of the present application, wherein the data of the chiral HPLC profile are reported in table 12:
Table 12
Examples 4 to 8
Examples 4 to 8 refer to step A) in example 3, which differs in the first reaction solvent, the first reaction temperature and/or the first reaction time, as detailed in Table 13.
In examples 4 to 8, after 18 hours of reaction (first reaction time) in step A), the content of the relevant substances in the reaction liquid was examined, and the results are shown in Table 13.
TABLE 13
Examples First reaction solvent First reaction temperature Content of Compound IV Content of Compound II
Example 4 Tetrahydrofuran (THF) 45℃ 90％ 2％
Example 5 Tetrahydrofuran (THF) 25℃ 55％ 38％
Example 6 Tetrahydrofuran (THF) -5℃ 0.2％ 97％
Example 7 Toluene (toluene) -5℃ 43％ 51％
Example 8 Acetonitrile -5℃ 4％ 93％
Examples 9 to 13
Examples 9 to 13 refer to step B) of example 1, wherein example 9 is the subsequent reaction of example 4, example 10 is the subsequent reaction of example 5, example 11 is the subsequent reaction of example 6, example 12 is the subsequent reaction of example 7, and example 13 is the subsequent reaction of example 8; the difference is in the second reaction solvent, the second reaction temperature and/or the second reaction time in step B), as detailed in Table 14.
In examples 9 to 13, the content of the relevant substances in the reaction liquid was measured 24 hours after the reaction in the step B) (second reaction time), and the results are shown in Table 14.
TABLE 14
Examples Second reaction solvent Second reaction temperature Content of Compound IV Content of Compound II Content of Compound I
Example 9 Tetrahydrofuran (THF) -5℃ 7％ 22％ 66％
Example 10 Tetrahydrofuran (THF) 10℃ 5％ 2％ 87％
Example 11 Tetrahydrofuran (THF) 35℃ 14％ 0.1％ 75％
Example 12 Toluene (toluene) 10℃ 68％ 5％ 16％
Example 13 Acetonitrile 10℃ 12％ 1％ 79％
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby 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.

Claims (22)

  1. The preparation method of the lebo Lei Sheng is characterized by comprising the following steps:
    B) Reacting the compound II with the compound III in a second reaction solvent to obtain the lebol Lei Sheng shown in the formula I;
  2. The preparation method according to claim 1, characterized in that the second reaction solvent is selected from the group consisting of at least one of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate, tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
  3. The preparation process according to claim 1 or 2, characterized in that the reaction temperature of the reaction is-5 ℃ to 40 ℃, preferably 10 ℃ to 35 ℃.
  4. A preparation process according to any one of claims 1-3, characterized in that the reaction time of the reaction is 1h-48h, preferably 12-24h.
  5. A compound of formula II:
  6. A process for the preparation of compound II, characterized by comprising the steps of:
    a) Reacting the compound IV, the compound V and the compound VI in a first reaction solvent to obtain a compound II;
  7. The method according to claim 6, wherein the first reaction solvent is selected from the group consisting of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate, and tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
  8. The preparation process according to claim 6 or 7, characterized in that the reaction temperature of the reaction is-15 ℃ to 10 ℃, preferably-10 ℃ to 5 ℃.
  9. The preparation method according to any one of claims 6 to 8, characterized in that the reaction time of the reaction is 1h to 48h, preferably 4 to 24h.
  10. A process for the preparation of compound IV, characterized by comprising the steps of:
    A) Taking a compound VII as a raw material, and under the action of a catalyst and an oxidant, performing an oxidation reaction in a mixed solvent of tertiary butanol and water to generate a compound IV;
  11. The preparation method according to claim 10, characterized in that the catalyst is selected from at least one of 2,6, -tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2, 6, -tetramethylpiperidine-1-oxyl radical.
  12. The process according to claim 10, wherein the catalyst is used in an amount of 1% to 25% of the molar amount of compound VII.
  13. The method according to claim 10, wherein the volume ratio of t-butanol to water in the mixed solvent is 4:1 to 3:2.
  14. The method of claim 10, wherein the oxidizing agent is sodium hypochlorite.
  15. The process according to claim 10, wherein the oxidizing agent is used in an amount of 2.0eq to 5.0eq based on the molar amount of compound VII.
  16. The method according to claim 10, wherein the oxidation reaction has a pH in the range of 6 to 12.
  17. The preparation method according to claim 10, characterized in that sodium bicarbonate and/or sodium carbonate are/is added to the mixed solvent.
  18. The preparation method according to claim 10, characterized in that the reaction temperature of the oxidation reaction is-10 ℃ to 45 ℃, preferably-3 ℃ to 3 ℃.
  19. The preparation method according to claim 10, characterized in that the reaction time of the oxidation reaction is 1h-96h, preferably 1h-24h.
  20. The preparation method of the lebo Lei Sheng is characterized by comprising the following steps:
    Compound II prepared by step a) according to any one of claims 6 to 9;
    preparing a lebox Lei Sheng of formula I by a process according to any one of claims 1 to 4 in step B);
  21. The process according to claim 20, characterized in that compound IV is prepared by step a) according to any one of claims 10 to 19.
  22. The preparation method according to claim 20 or 21, characterized by comprising the steps of:
    the compound II prepared in step A) is used directly in step B) without isolation.
CN202280090392.8A 2022-03-25 2022-03-25 Preparation method of lebol Lei Sheng and intermediate thereof Pending CN118871427A (en)

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