CN118027027A - Preparation method of non-neridrone - Google Patents

Preparation method of non-neridrone Download PDF

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Publication number
CN118027027A
CN118027027A CN202410151357.3A CN202410151357A CN118027027A CN 118027027 A CN118027027 A CN 118027027A CN 202410151357 A CN202410151357 A CN 202410151357A CN 118027027 A CN118027027 A CN 118027027A
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compound
substituted
acid
benzyl
cyano
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朱富强
黄建
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Shandong Fuchang Pharmaceutical Co ltd
Topharman Shandong Co Ltd
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Shandong Fuchang Pharmaceutical Co ltd
Topharman Shandong Co Ltd
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Abstract

The invention discloses a preparation method of non-nereirenone. The method has mild reaction conditions, is suitable for industrial production, can realize one-time resolution to realize the ee value of more than 99 percent, and can more easily reach the API quality requirement through purification.

Description

Preparation method of non-neridrone
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of non-neridrone.
Background
Non-nerlidone is a non-steroidal selective mineralocorticoid receptor antagonist, and is approved by the U.S. food and drug administration FDA and the national drug administration NMPA for the treatment of Chronic Kidney Disease (CKD) in adult patients with combined type 2 diabetes (T2D) on day 7, 9, 2022, 6, 28, respectively.
Various processes for the preparation of non-nelidane are reported in the prior art, for example:
CN101641352B discloses the following preparation method 1, but is costly due to the chiral column chromatography separation used therein.
Method 1:
CN107849043B discloses a preparation method 2 in which 4-formyl-3-methoxybenzonitrile is used as a raw material to prepare non-nelidane, which is also costly due to the use of chiral column chromatography.
Method 2:
the bayer company has successively reported methods of resolving intermediates and end products using tartrate-based resolving agents, CN114667284A discloses the following method 3, CN114698375A discloses the following method 4 and CN112041318A discloses the following method 5.
Method 3:
Method 4:
method 5:
However, the above methods 3 to 5 have a common problem in that the resolution efficiency is not high, the enantiomeric excess (ee value) can reach 97% -98% at the highest, and the requirement of API quality can be met by adopting secondary crystallization to make the enantiomeric excess (ee value) reach more than 99%.
Therefore, there is still a need to develop a more efficient resolution method for the enantiomers of non-nefarious ketones, which can obtain non-nefarious ketones with high ee values in one preparation.
Disclosure of Invention
In order to overcome the defects of the existing production method and process, the invention aims to provide the preparation method of the non-nefarious ketone, which has mild reaction conditions and is suitable for industrial production, and can realize one-time resolution to realize the ee value of more than 99 percent.
In order to achieve the above purpose, the invention adopts the following technical scheme:
In a first aspect, the present invention provides a process for the preparation of non-nelidane,
The preparation method comprises the following steps:
(5) Reacting the compound VI with a compound IX to obtain a compound VII;
(6) Reacting the compound VII with an alkalizing agent to obtain a compound (S) -VI;
(7) Reacting the compound (S) -VI with an acid to obtain a compound non-nelidanone;
Wherein R 1 is selected from the group consisting of C 1-C10 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in the substituted benzyl group means that the benzyl group may have 1 to 4 substituents thereon selected from the group consisting of C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano, and C 1-C6 alkyl;
Preferably, R 1 is selected from C 1-C6 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in substituted benzyl means that the benzyl group may have 1 to 4 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
More preferably, R 1 is selected from tert-butyl, p-methoxybenzyl, 2, 4-dimethoxybenzyl or 3, 4-dimethylbenzyl;
Ar is a substituted or unsubstituted C 6-C14 -to 8-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S, wherein said "substituted" means that the C 6-C14 aromatic or 5-to 8-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S may have 1 to 4 substituents on the 5-to 8-membered heteroaromatic group selected from C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano or C 1-C6 alkyl;
Preferably, ar is a substituted or unsubstituted C 6-C10 -to 6-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S, wherein said "substituted" means that C 6-C10 aromatic or 5-to 6-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S may have 1 or 2 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
more preferably, ar is preferably selected from p-tolyl, phenyl or p-methoxyphenyl.
Preferably, in the step (5), the compound IX is selected from one or more of D- (+) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid and D- (+) -di-p-methoxydibenzoyl tartaric acid; the reaction is carried out in a solvent selected from one or more of methanol, ethanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane.
Preferably, in step (6), the alkalizing agent is selected from one or more of sodium phosphate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate; the dissociation reaction is carried out in a solvent, wherein the solvent is one or more selected from ethanol, water, tetrahydrofuran and 2-methyltetrahydrofuran.
Preferably, in step (7), the acid is selected from one or more of trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, more preferably a mixed acid of trifluoromethanesulfonic acid and trifluoroacetic acid; the reaction is carried out with or without a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, N-methylpyrrolidone (NMP), N-dimethylacetamide (DMAc).
Preferably, in step (5), the solvent is preferably a mixed solvent of ethanol and water in a volume ratio of ethanol/water
The ratio of ethanol/water=1 to 15:1, particularly preferably ethanol/water=3 to 15:1; the feeding mole ratio of the compound VI to the compound IX is 1:0.6-1.6, preferably 1:1.0; the reaction temperature is 10-70 ℃, preferably 25-50 ℃; the reaction time is 6-24 h, preferably 10-18 h;
Preferably, in step (6), the solvent is preferably a mixed solvent of ethanol and water in a volume ratio of ethanol/water
A mixture of =1:3; the reaction temperature is 0-40 ℃, preferably 0-30 ℃; the reaction time is 2 to 6 hours, preferably 2 to 4 hours.
Preferably, the ee value of the product compound (S) -VI obtained in step (6) is greater than 99%.
Preferably, in the step (7), the feeding mole ratio of the compound (S) -VI, the trifluoromethanesulfonic acid and the trifluoroacetic acid is 1:0.5-20.0:10.0-30.0, preferably 1:0.5-15.0:15.0-30.0; the reaction temperature is 25-70 ℃, preferably 30-50 ℃; the reaction time is 4 to 20 hours, preferably 4 to 12 hours.
In some embodiments, the preparation method employs the following specific steps:
(5) Mixing the compound VI, the solvent and the compound IX, controlling the temperature for reaction, cooling, filtering, washing and drying under reduced pressure after the reaction is finished to obtain a compound of a formula VII;
(6) Mixing a compound VII, a solvent and an alkalizing agent, performing temperature control reaction, filtering, washing and drying under reduced pressure after the reaction is finished to obtain a compound of the formula (S) -VI;
(7) And (3) mixing the compound (S) -VI, a solvent and an acid, performing a temperature-controlled reaction, concentrating, neutralizing, filtering, drying and recrystallizing after the reaction is finished to obtain the non-nereirenone.
In a second aspect, the present invention provides a compound represented by formula VI:
wherein the substituents R 1 are as defined above.
In a third aspect, the present invention provides a process for the preparation of a compound of formula VI:
The preparation method comprises the following steps:
(1) Reacting the compound I with a compound II to obtain a compound III;
(2) Reacting the compound III with the compound IV to obtain a compound V;
(3) Reacting the compound V with an ethylation reagent to obtain a compound VI;
wherein the substituents R 1 are as defined above.
Preferably, the step (1) is carried out in a catalyst and a solvent, wherein the catalyst is piperidine and acetic acid; the solvent is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and toluene.
Preferably, step (2) is performed in a solvent selected from one or more of isopropanol, N-butanol, 2-butanol, N-pentanol, ethylene glycol monomethyl ether, N-methylpyrrolidone, N-dimethylacetamide, chlorobenzene, butyl acetate, benzyl alcohol, sulfolane, dimethyl sulfoxide.
Preferably, step (3) is carried out in a catalyst and a solvent, wherein the catalyst is an acid, and the acid is selected from one of concentrated sulfuric acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid; the solvent is selected from one of N, N-dimethylacetamide and N-methylpyrrolidone; the ethylation reagent is selected from one of triethyl orthoacetate, triethyl orthoformate, triethyl orthopropionate and tetraethyl orthocarbonate.
Preferably, in the step (1), the feeding mole ratio of the compound I to the compound II to the acetic acid to the piperidine is 1:1.0-1.5:0.05-0.2: 0.05 to 0.2, preferably 1:1.1:0.1:0.1; the reaction temperature is 25-70 ℃, preferably 30-50 ℃; the reaction time is 2 to 20 hours, preferably 6 to 16 hours.
Preferably, in the step (2), the feeding molar ratio of the compound II I to the compound IV is 1:0.7-1.0, preferably 1:0.8; the reaction temperature is 100-150 ℃, preferably 120-140 ℃; the reaction time is 16 to 40 hours, preferably 16 to 30 hours.
Preferably, in step (3), the catalyst is 0.1 to 0.7 equivalents of acid, preferably 0.3 to 0.55 equivalents of concentrated sulfuric acid; the feeding mole ratio of the compound V to the concentrated sulfuric acid to the triethyl orthoacetate is 1:0.1-0.7:3-7, preferably 1:0.5:6; the reaction temperature is 100-150 ℃, preferably 110-125 ℃; the reaction time is 0.5 to 4 hours, preferably 1 to 2 hours.
Preferably, the preparation method comprises the following specific steps:
(1) Mixing a compound I, a solvent, a catalyst and a compound II, heating for reaction, cooling after the reaction is finished, filtering and drying to obtain a compound of a formula III;
(2) Mixing the compound III, the solvent and the compound IV, heating for reaction, concentrating after the reaction is finished, washing, and filtering to obtain a compound of a formula V;
(3) Mixing the compound V, a solvent, an ethylation reagent and a catalyst, heating for reaction, cooling after the reaction is finished, adding water for dilution, extracting, combining organic phases, washing, drying, filtering, concentrating and purifying by column chromatography to obtain the compound of the formula VI.
In a fourth aspect, the present invention provides a process for the preparation of a compound of formula VI:
The preparation method comprises the following steps:
(4) Reacting the compound VIII with a substituted amine compound to obtain a compound VI;
wherein the substituents R 1 are as defined above.
Preferably, step (4) is carried out in a condensing agent, which is oxalyl chloride, thionyl chloride, N, N '-Carbonyldiimidazole (CDI), N, N, N', one or more of N '-tetramethyl chloroformyl amine hexafluorophosphate (TCFH), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), 2- (7-azabenzotriazol) -N, N' -tetramethyl urea Hexafluorophosphate (HATU); the base is selected from one or more of imidazole, triethylamine, N-methylimidazole (NMI), N-diisopropylethylamine, 4-Dimethylaminopyridine (DMAP), pyridine and N-methylmorpholine; the solvent is selected from one or more of tetrahydrofuran, dichloromethane and acetonitrile.
Preferably, in the step (4), the molar ratio of the compound VIII, the condensing agent, the substituted amine compound and the alkali is 1:1.0-1.5:1.2-2.0: 1.4 to 3.0, preferably 1:1.2 to 1.5:1.2 to 1.8:2.0 to 3.0; the reaction temperature is 25-70 ℃, preferably 25-50 ℃; the reaction time is 2 to 16 hours, preferably 6 to 10 hours.
Preferably, the preparation method comprises the following specific steps:
(4) Mixing the compound VIII, a solvent, a condensing agent, alkali and a substituted amine compound, performing temperature control reaction, adding water for dilution after the reaction is finished, extracting, filtering, concentrating, and purifying by column chromatography to obtain the compound of the formula VI.
In a fifth aspect, the present invention provides the use of a compound of formula VI in a process for the preparation of non-nelidane.
Advantageous effects
The preparation method provided by the invention has mild reaction conditions, is suitable for industrial production, can realize one-time resolution to obtain the ee value of more than 99%, and can more easily reach the API quality requirement through purification.
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.
In this document, the terms "comprising," "including," "having," "containing," or any other similar term are all open ended terms that are intended to cover a non-exclusive inclusion. For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed, and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….
All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.
In the field of pharmaceutical applications, certain chiral compounds often have pharmaceutical value, as do the corresponding isomers thereof, such as non-nelidamide. In pharmaceutical applications, high purity enantiomers are required, for example, ee values of over 99% are required. At present, the enantiomer resolution can only reach 97-98% ee at a time, and the subsequent crystallization and purification are needed to improve the enantiomer purity, but the yield is greatly lost. And increasing by 1% again is also quite difficult or significantly costly.
The inventor of the application discovers that when an amino protecting group is properly adopted in the resolution of a racemate of non-nefarious ketone, the amide group is firstly protected, and then the enantiomer resolution is carried out, so that the resolution efficiency can be more efficient, and the ee value of more than 99% can be obtained by one-time resolution. Based on such findings, the inventors developed the technique of the present application.
The following examples are merely illustrative of embodiments of the present invention and are not intended to limit the invention in any way, and those skilled in the art will appreciate that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.
Example 1
Preparation of Compound II-1 (N- (4-methoxybenzyl) -3-oxobutanamide)
P-methoxybenzylamine (46 g,0.335 mol) was added to tetrahydrofuran (273 mL), followed by further addition of diketene (31 g,0.369 mol), stirred at room temperature for 6 hours, concentrated under reduced pressure, added with ethyl acetate (27 mL), petroleum ether (273 mL), stirred for 1 hour, filtered, rinsed with a mixture of 10mL petroleum ether and 1mL ethyl acetate, and dried under reduced pressure to give 71g of the compound of formula II-1 in yield 96％.1H NMR(400MHz,CDCl3)δ:7.21(d,J＝8.0Hz,2H),6.86(d,J＝8.0Hz,2H),4.40(d,J＝4.0Hz,2H),3.55(s,3H),3.44(s,2H),2.26(s,3H).
(1) Preparation of 2- (4-cyano-2-methoxybenzylidene) -N- (4-methoxybenzyl) -3-oxobutanamide
4-Formyl-3-methoxybenzonitrile (44.25 g,0.275 mol) was added to isopropanol (260 mL), piperidine (2.34 g,27.5 mmol) and glacial acetic acid (1.65 g,27.5 mmol) were added, then compound II-1 (70 g,0.316 mol) was added, the temperature was raised to 30℃and stirred for 16 hours, cooled to 0-5℃and stirred for 0.5 hours, filtered, washed with cold isopropanol (50 mLx 2), and dried under reduced pressure to give 85g of the compound of formula III-1 in 85% yield. The product being a mixture of cis-trans configuration .1H NMR(400MHz,CDCl3)δ:8.17and 7.78(s,1H),7.52(d,J＝8.0Hz,1H),7.22-7.28(m,1H),7.05-7.12(m,3H),6.77-6.90(m,2H),6.12(brs,1H),4.46and 4.39(d,J＝8.0Hz,2H),3.89and 3.87(s,3H),3.80and 3.79(s,3H),2.46and 2.06(s,3H).
(2) Preparation of 4- (4-cyano-2-methoxyphenyl) -N- (4-methoxybenzyl) -2, 8-dimethyl-5-oxo-1, 4,5, 6-tetrahydro-1, 6-naphthyridine-3-carboxamide
Adding a compound (30 g,82.4 mmol) of formula III-1 into a glycol monomethyl ether (360 mL) solution, adding a compound (8.2 g,65.9 mmol) of formula IV, heating to 125 ℃ under the protection of nitrogen for reaction for 20 hours, concentrating to obtain a crude product, adding isopropanol (90 mL) for washing, filtering to obtain a compound of formula V-1, 25.1g, yield 81％.1H NMR(400MHz,DMSO-d6)δ:10.66(s,1H),7.84(t,J＝8.0Hz,1H),7.57(s,1H),7.22-7.31(m,2H),7.09(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,2H),6.93(s,1H),6.81(d,J＝12.0Hz,2H),5.27(s,1H),4.07-4.19(m,2H),3.73(s,3H),3.64(s,3H),2.05(s,3H),2.02(s,3H).
(3) Preparation of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula V-1 (9.4 g,20 mmol) was added to a solution of N, N-dimethylacetamide (56 mL), triethylorthoacetate (19.5 g,120 mmol) and concentrated sulfuric acid (0.98 g,10 mmol) were further added, the mixture was heated to 115℃under nitrogen protection, reacted for 2 hours, cooled, diluted with 50mL of water, extracted with ethyl acetate (70 mL x 4), the organic phases were combined, the organic phases were successively washed with 10% saline (100 mL) and saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give 7.9g of the compound of formula VI-1 in yield 80％.1H NMR(400MHz,DMSO-d6)δ:7.72(t,J＝8.0Hz,1H),7.64(s,1H),7.55(s,1H),7.22-7.34(m,2H),7.13(d,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,2H),6.79(d,J＝8.0Hz,2H),5.42(s,1H),4.10-4.23(m,2H),3.93-4.03(m,2H),3.73(s,3H),3.66(s,3H),2.13(s,3H),2.12(s,3H),1.01(t,J＝8.0Hz,3H).
(5) Preparation of diastereomeric salt VII-1 of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula VI-1 rac 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide (5 g,10 mmol) and compound D- (+) -di-p-methylbenzoyl tartaric acid of formula IX-1 (3.9 g,10 mmol) were suspended in a mixture of 150mL ethanol and 50mL water, warmed to 30℃and stirred for 2 hours, then stirred overnight at room temperature, filtered, washed twice with a mixture of 20mL ethanol/water (3 v:1 v) and dried under reduced pressure to give 4.1g of the compound of formula VII-1 in 46% yield.
(6) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of compound VII-1 (5.3 g,6 mmol) in 50mL of a mixture of water/ethanol (3 v:1 v), cooling to 0℃and then stepwise metering in a 20% aqueous sodium phosphate solution (over 1 hour) and adjusting the pH to pH 8-9, stirring at this temperature for a further 2 hours, filtration, washing twice with 10mL of a mixture of water/ethanol (3 v:1 v) (0 ℃) and drying under reduced pressure gives compound of formula (S) -VI-1 2.7g, yield 91％,99.2％ee.1H NMR(400MHz,DMSO-d6)δ:7.72(t,J＝8.0Hz,1H),7.64(s,1H),7.55(s,1H),7.22-7.34(m,2H),7.13(d,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,2H),6.79(d,J＝8.0Hz,2H),5.42(s,1H),4.10-4.23(m,2H),3.93-4.03(m,2H),3.73(s,3H),3.66(s,3H),2.13(s,3H),2.12(s,3H),1.01(t,J＝8.0Hz,3H).
(7) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Dissolving a compound (S) -VI-1 (2.5 g,5 mmol) in methylene dichloride (30 mL), sequentially adding trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (1 mL), heating to 40 ℃ and stirring for reaction for 4 hours, concentrating to remove most of the trifluoroacetic acid and methylene dichloride, adding sodium bicarbonate solution for neutralization to pH 9, filtering, washing with a small amount of water, drying the solid, and recrystallizing with ethanol (15 mL) to obtain a white solid, namely, 1.5g of non-nelidone, and obtaining the yield 79％.1H NMR(400MHz,DMSO-d6)δ:7.69(s,1H),7.55(s,1H),7.36(d,J＝1.5Hz,1H),7.27(dd,J＝8.0,1.5Hz,1H),7.15(d,J＝8.0Hz,1H),6.88-6.50(bs,2H),5.37(s,1H),4.08-3.95(m,2H),3.82(s,3H),2.18(s,3H),2.12(s,3H),1.05(t,J＝7.0Hz,3H).
Example 2
(1) Preparation of 2- (4-cyano-2-methoxybenzylidene) -N- (4-methoxybenzyl) -3-oxobutanamide
4-Formyl-3-methoxybenzonitrile (44.25 g,0.275 mol) was added to isopropanol (260 mL), piperidine (2.34 g,27.5 mmol) and glacial acetic acid (1.65 g,27.5 mmol) were added, then compound II-1 (70 g,0.316 mol) was added, the temperature was raised to 30℃and stirred for 16 hours, cooled to 0-5℃and stirred for 0.5 hours, filtered, washed with cold isopropanol (50 mLx 2), dried under reduced pressure to give 92g of the compound of formula III-1 in 92% yield. The product is a mixture of cis-trans configurations. Nuclear magnetic resonance data were the same as in example 1 (1).
(2) Preparation of 4- (4-cyano-2-methoxyphenyl) -N- (4-methoxybenzyl) -2, 8-dimethyl-5-oxo-1, 4,5, 6-tetrahydro-1, 6-naphthyridine-3-carboxamide
The compound of formula III-1 (30 g,82.4 mmol) was added to a solution of n-butanol (360 mL), then the compound of formula IV (8.2 g,65.9 mmol) was added thereto, the temperature was raised to 125℃under nitrogen protection for reaction for 20 hours, the crude product was obtained by concentration, isopropanol (90 mL) was added for washing, and filtration to obtain 24.2g of the compound of formula V-1 in 78% yield. Nuclear magnetic resonance data were the same as in example 1 (2).
(3) Preparation of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
A compound of formula V-1 (9.4 g,20 mmol) was added to a solution of N-methylpyrrolidone (56 mL), triethyl orthoacetate (19.44 g,120 mmol) and concentrated sulfuric acid (0.98 g,10 mmol) were added thereto, the mixture was heated to 115℃under nitrogen protection, reacted for 2 hours, cooled, diluted with 50mL of water, extracted with ethyl acetate (70 mL x 4), the organic phases were combined, the organic phases were successively washed with 10% saline (100 mL) and saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give 8.2g of the compound of formula VI-1 in 83% yield. Nuclear magnetic resonance data were the same as in example 1 (3).
(5) Preparation of diastereomeric salt VII-1-B of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula VI-1, racemic 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide (5 g,10 mmol) and compound of formula IX-2, D- (+) -dibenzoyltartaric acid (3.6 g,10 mmol) were suspended in a mixture of 100mL ethanol and 20mL water, warmed to 30℃and stirred for 2 hours. Then stirred overnight at room temperature, filtered, washed twice with 20mL of a mixture of ethanol/water (3 v:1 v) and dried under reduced pressure to give 3.8g of the compound of formula VII-1-B in 45% yield.
(6) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of the compound of formula VII-1-B (5.1 g,6 mmol) in 50mL of a mixture of water/ethanol (3 v:1 v), cooling to 0℃and then stepwise metering in of a 20% aqueous sodium phosphate solution (over 1 hour) and adjusting the pH to pH 8-9, stirring at this temperature for a further 2 hours, filtration, washing twice with 10mL of a mixture of water/ethanol (3 v:1 v) (0 ℃) and drying under reduced pressure gives 2.7g of the compound of formula (S) -VI-1 in 91% yield, 99.1% ee. Nuclear magnetic resonance data were the same as in example 1 (6).
(7) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Compound (S) -VI-1 (2.5 g,5 mmol) of formula (I) was dissolved in tetrahydrofuran (30 mL), trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (1 mL) were added sequentially, the mixture was stirred and reacted at 40℃for 4 hours, most of the trifluoroacetic acid and tetrahydrofuran were concentrated and removed, sodium bicarbonate solution was added for neutralization to pH 9, filtration, washing with a small amount of water, drying of the solid, and recrystallization with ethanol (15 mL) was carried out to give 1.3g of a white solid, namely, non-nelidone, in 71% yield. Nuclear magnetic resonance data were the same as in example 1 (7).
Example 3
Preparation of Compound II-2 (N- (2, 4-dimethoxybenzyl) -3-oxobutanamide)
2, 4-Dimethoxybenzylamine (56 g,0.335 mol) was added to tetrahydrofuran (300 mL), followed by further addition of diketene (31 g,0.369 mol), stirred at room temperature for 6 hours, concentrated under reduced pressure, added with ethyl acetate (273 mL) and petroleum ether (27 mL), stirred for 1 hour, filtered, rinsed with a mixture of 10mL petroleum ether and 1mL ethyl acetate, and dried under reduced pressure to give 77g of the compound of formula II-2 in the yield 92％.1H NMR(400MHz,CDCl3)δ:7.21(d,J＝8.0Hz,1H),6.52-6.67(m,2H),4.36(d,J＝4.0Hz,2H),3.58(s,3H),3.47(s,3H),3.44(s,2H),2.24(s,3H).
(1) Preparation of 2- (4-cyano-2-methoxybenzylidene) -N- (2, 4-dimethoxybenzyl) -3-oxobutanamide
4-Formyl-3-methoxybenzonitrile (44.25 g,0.275 mol) was added to isopropanol (260 mL), piperidine (2.34 g,27.5 mmol) and glacial acetic acid (1.65 g,27.5 mmol) were added, then compound II-2 (79.4 g,0.316 mol) was added, the temperature was raised to 30℃and stirred for 16 hours, cooled to 0-5℃and stirred for 0.5 hours, filtered, washed with cold isopropanol (100 mLx 2), and dried under reduced pressure to give 99g of the compound of formula III-2 in 91% yield. The product being a mixture of cis-trans configuration .1H NMR(400MHz,CDCl3)δ:8.18and 7.80(s,1H),7.52(d,J＝8.0Hz,1H),7.05-7.12(m,3H),6.77-6.90(m,2H),6.12(brs,1H),4.46and 4.39(d,J＝8.0Hz,2H),3.89and 3.87(s,3H),3.80and 3.79(s,3H),3.72and 3.70(s,3H),2.46and 2.06(s,3H).
(2) Preparation of 4- (4-cyano-2-methoxyphenyl) -N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-5-oxo-1, 4,5, 6-tetrahydro-1, 6-naphthyridine-3-carboxamide
Adding a compound (11.8 g,30 mmol) of formula III-2 into a glycol monomethyl ether (130 mL) solution, adding a compound (3.0 g,24 mmol) of formula IV, heating to 125 ℃ under nitrogen protection, reacting for 20 hours, concentrating to obtain a crude product, adding isopropanol (36 mL) for washing, filtering to obtain a compound of formula V-2, 8.5g, yield 71％.1H NMR(400MHz,DMSO-d6)δ:10.62(s,1H),7.82(t,J＝8.0Hz,1H),7.55(s,1H),7.22-7.31(m,2H),7.09(d,J＝8.0Hz,1H),6.91-6.99(m,1H),6.93(s,1H),6.79-6.87(m,2H),5.27(s,1H),4.07-4.19(m,2H),3.73(s,3H),3.67(s,3H),3.64(s,3H),2.05(s,3H),2.02(s,3H).
(3) Preparation of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound (10 g,20 mmol) of formula V-2 is added into N, N-dimethylacetamide (56 mL) solution, triethyl orthoacetate (19.5 g,120 mmol) and concentrated sulfuric acid (0.98 g,10 mmol) are added, the mixture is heated to 115 ℃ under the protection of nitrogen and reacts for 2 hours, the mixture is cooled, 50mL of water is added for dilution, ethyl acetate (70 mLx 4) is used for extraction, organic phases are combined, the organic phases are sequentially washed by 10% saline (100 mL) and saturated saline (100 mL), anhydrous sodium sulfate is used for drying, filtration and concentration are carried out to obtain crude products, 8.4g of the compound of formula VI-2 is obtained after silica gel column chromatography purification (petroleum ether/ethyl acetate=1:1), the yield is obtained 79％.1H NMR(400MHz,DMSO-d6)δ:7.72(t,J＝8.0Hz,1H),7.64(s,1H),7.55(s,1H),7.22-7.34(m,2H),7.13(d,J＝8.0Hz,1H),6.91-6.99(m,1H),6.71-6.83(m,2H),5.42(s,1H),4.10-4.23(m,2H),3.93-4.03(m,2H),3.73(s,3H),3.67(s,3H),3.66(s,3H),2.13(s,3H),2.12(s,3H),1.00(t,J＝8.0Hz,3H).
(5) Preparation of diastereomeric salt VII-2 of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula VI-2 racemic 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide (5.3 g,10 mmol) and the compound of formula IX-1D- (+) -di-p-methylbenzoyl tartaric acid (3.9 g,10 mmol) were suspended in a mixture of 150mL ethanol and 10mL water, and the reaction was stirred at 30℃for 2 hours. Then stirred overnight at room temperature, filtered, washed twice with 20mL of a mixture of ethanol/water (3 v:1 v) and dried under reduced pressure to give 4.0g of the compound of formula VII-2 in 44% yield.
(6) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of compound VII-2 (5.5 g,6 mmol) in 50mL of a mixture of water/ethanol (3 v:1 v), cooling to 0℃and then stepwise metering in a 20% aqueous sodium phosphate solution (over 1 hour) and adjusting the pH to pH 8-9, stirring at this temperature for a further 2 hours, filtration, washing twice with 10mL of a mixture of water/ethanol (3 v:1 v) (0 ℃) and drying under reduced pressure gives compound of formula (S) -VI-2 2.8g, yield 88％,99.4％ee.1H NMR(400MHz,DMSO-d6)δ:7.72(t,J＝8.0Hz,1H),7.64(s,1H),7.55(s,1H),7.22-7.34(m,2H),7.13(d,J＝8.0Hz,1H),6.91-6.99(m,1H),6.71-6.83(m,2H),5.42(s,1H),4.10-4.23(m,2H),3.93-4.03(m,2H),3.73(s,3H),3.67(s,3H),3.66(s,3H),2.13(s,3H),2.12(s,3H),1.00(t,J＝8.0Hz,3H).
(7) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Compound (S) -VI-2 (2.6 g,5 mmol) of formula (I) was dissolved in methylene chloride (30 mL), trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (0.3 mL) were added in sequence, the mixture was stirred and reacted for 4 hours at 40℃and concentrated to remove most of the trifluoroacetic acid and methylene chloride, sodium bicarbonate solution was added for neutralization to pH 9, filtration, washing with a small amount of water, drying the solid, and recrystallization with ethanol (15 mL) was carried out to obtain 1.6g of a white solid, namely, non-nelidone, in 85% yield. Nuclear magnetic resonance data were the same as in example 1 (7).
Example 4
(4) Preparation of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula VIII (7.6 g,20 mmol) was added to a solution of THF (80 mL) under nitrogen protection, CDI (4.5 g,28 mmol), imidazole (3.4 g,50 mmol) and DMAP (244 mg,2 mmol) were added, stirred at room temperature for 16 hours, then p-methoxybenzylamine (4.11 g,30 mmol) was added, stirred at 40℃for 6 hours, cooled, 50mL of water was added for dilution, extracted with ethyl acetate (70 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give 8.2g of the compound of formula VI-1 in 82% yield. Nuclear magnetic resonance data were the same as in example 1 (3).
(5) Preparation of diastereomeric salt VII-1 of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of compound VI-1 of formula (5 g,10 mmol) and compound D- (+) -di-p-methylbenzoyl tartaric acid of formula IX-1 (3.9 g,10 mmol) in a mixture of 150mL ethanol and 50mL water and stirring at 30℃for 2 hours, then stirring at room temperature overnight, filtering, washing twice with a mixture of 20mL ethanol/water (3 v:1 v) and drying under reduced pressure gave 4.1g of compound VII-1 in 46% yield.
(6) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of compound VII-1 (5.3 g,6 mmol) in 50mL of a mixture of water/ethanol (3 v:1 v), cooling to 0℃and then stepwise metering in of a 20% aqueous sodium phosphate solution (over 1 hour) and adjusting the pH to pH 8-9, stirring at this temperature being continued for 2 hours, filtration, washing twice with 10mL of a mixture of water/ethanol (3 v:1 v) (0 ℃) and drying under reduced pressure gives compound of formula (S) -VI-1 2.7g, yield 91%,99.2% ee. Nuclear magnetic resonance data were the same as in example 1 (6).
(7) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Compound (S) -VI-1 (2.5 g,5 mmol) of formula (I) is dissolved in methylene dichloride (30 mL), trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (1 mL) are sequentially added, the temperature is raised to 40 ℃ and the mixture is stirred for reaction for 4 hours, most of the trifluoroacetic acid and methylene dichloride are concentrated and removed, sodium bicarbonate solution is added for neutralization until the pH value is 9, filtration, washing with a small amount of water, drying the solid, and recrystallizing with ethanol (15 mL) to obtain white solid, namely, 1.75g of non-nelidone with the yield of 92%. Nuclear magnetic resonance data were the same as in example 1 (7).
Example 5
(4) Preparation of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula VIII (7.6 g,20 mmol) was added to a mixed solution of THF (40 mL), CH 3 CN (40 mL), TCFH (6.7 g,24 mmol) and NMI (4.9 g,60 mmol) under nitrogen, stirred at room temperature for 16 hours, then p-methoxybenzylamine (4.11 g,30 mmol) was added, stirred at 40 ℃ for 6 hours, the reaction solution was cooled, 50mL of water was added for dilution, extraction with ethyl acetate (70 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give the compound of formula VI-1 8.8g, yield 88%. Nuclear magnetic resonance data were the same as in example 1 (3).
(5) Preparation of diastereomeric salt VII-1-B of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The racemic 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide of formula VI-1 (5 g,10 mmol) and the compound D- (+) -dibenzoyltartaric acid of formula IX-2 (3.6 g,10 mmol) were suspended in a mixture of 100mL ethanol and 30mL water and stirred at 30℃for 2 hours, then stirred overnight at room temperature, filtered, washed twice with a mixture of 20mL ethanol/water (3 v:1 v) and dried under reduced pressure to give the compound of formula VII-1-B3.8 g in 45% yield.
(6) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (4-methoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of the compound of formula VII-1-B (5.1 g,6 mmol) in 50mL of a mixture of water/ethanol (3 v:1 v), cooling to 0℃and then stepwise metering in of a 20% aqueous sodium phosphate solution (over 1 hour) and adjusting the pH to pH 8-9, stirring at this temperature for a further 2 hours, filtration, washing twice with 10mL of a mixture of water/ethanol (3 v:1 v) (0 ℃) and drying under reduced pressure gives 2.7g of the compound of formula (S) -VI-1 in 91% yield, 99.1% ee. Nuclear magnetic resonance data were the same as in example 1 (6).
(7) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Compound (S) -VI-1 (2.5 g,5 mmol) of formula (I) is dissolved in tetrahydrofuran (30 mL), trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (1 mL) are sequentially added, the temperature is raised to 40 ℃ and the mixture is stirred and reacted for 4 hours, most of the trifluoroacetic acid and tetrahydrofuran are concentrated and removed, sodium bicarbonate solution is added for neutralization to pH 9, filtration, washing with a small amount of water, drying the solid, and recrystallization is carried out with ethanol (15 mL) to obtain white solid, namely, 1.7g of non-nelidone with a yield of 90%. Nuclear magnetic resonance data were the same as in example 1 (7).
Example 6
(4) Preparation of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Under nitrogen protection, the compound of formula VIII (7.6 g,20 mmol) was added to a solution of THF (80 mL), CDI (4.5 g,28 mmol), imidazole (3.4 g,50 mmol) and DMAP (244 mg,2 mmol) were added, stirred at room temperature for 16 hours, then 2, 4-dimethoxybenzylamine (5.01 g,30 mmol) was added, stirred at 40℃for 6 hours, cooled, diluted with 50mL of water, extracted with ethyl acetate (70 mLx 2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give 9.4g of the compound of formula VI-2 in 89% yield. Nuclear magnetic resonance data were the same as in example 3 (3).
(5) Preparation of diastereomeric salt VII-2 of 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
The compound of formula VI-2 rac 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide (5.3 g,10 mmol) and compound of formula IX-1D- (+) -di-p-methylbenzoyl tartaric acid (3.9 g,10 mmol) were suspended in a mixture of 150mL ethanol and 10mL water, warmed to 30℃and stirred for 2 hours, then stirred overnight at room temperature, filtered and washed twice with a mixture of 20mL ethanol/water (3 v:1 v) and dried under reduced pressure to give 4.1g of compound of formula VII-2 in 45% yield.
(6) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-N- (2, 4-dimethoxybenzyl) -2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Suspension of compound VII-2 (5.5 g,6 mmol) in 50mL of a mixture of water/ethanol (3 v:1 v), cooling to 0℃and then stepwise metering in of a 20% aqueous sodium phosphate solution (over 1 hour) and adjusting the pH to pH 8-9, stirring at this temperature for 2 hours, filtration, washing twice with 10mL of a mixture of water/ethanol (3 v:1 v) (0 ℃) and drying under reduced pressure gives 3.0g of compound of formula (S) -VI-2 in 95% yield, 99.4% ee. Nuclear magnetic resonance data were the same as in example 3 (6).
(7) Preparation of (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide
Compound (S) -VI-2 (2.6 g,5 mmol) of formula (I) was dissolved in methylene chloride (30 mL), trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (0.3 mL) were added in sequence, the mixture was stirred and reacted for 4 hours at 40℃and concentrated to remove most of the trifluoroacetic acid and methylene chloride, sodium bicarbonate solution was added for neutralization to pH 9, filtration, washing with a small amount of water, drying the solid, and recrystallization with ethanol (15 mL) was carried out to obtain 1.6g of a white solid, namely, non-nelidone, in 85% yield. Nuclear magnetic resonance data were the same as in example 1 (7).
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A method for preparing non-neridrone,
The preparation method comprises the following steps:
(5) Reacting the compound VI with a compound IX to obtain a compound VII;
(6) Reacting the compound VII with an alkalizing agent to obtain a compound (S) -VI;
(7) Reacting the compound (S) -VI with an acid to obtain a compound non-nelidanone;
Wherein R 1 is selected from the group consisting of C 1-C10 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in the substituted benzyl group means that the benzyl group may have 1 to 4 substituents thereon selected from the group consisting of C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano, and C 1-C6 alkyl;
Ar is a substituted or unsubstituted C 6-C14 -to 8-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S, wherein said "substituted" means that the C 6-C14 aromatic or 5-to 8-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S may have 1 to 4 substituents on the C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano or C 1-C6 alkyl.
2. The process for preparing non-nelidane according to claim 1, wherein,
Preferably, R 1 is selected from C 1-C6 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in substituted benzyl means that the benzyl group may have 1 to 4 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
More preferably, R 1 is selected from tert-butyl, p-methoxybenzyl, 2, 4-dimethoxybenzyl or 3, 4-dimethylbenzyl;
Preferably, ar is a substituted or unsubstituted C 6-C10 -to 6-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S, wherein said "substituted" means that C 6-C10 aromatic or 5-to 6-membered heteroaromatic group containing 1 to 3 heteroatoms selected from N, O, S may have 1 or 2 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
more preferably, ar is preferably selected from p-tolyl, phenyl or p-methoxyphenyl.
3. The process for preparing non-nelidane according to claim 1 or 2, wherein,
Preferably, in the step (5), the compound IX is selected from one or more of D- (+) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid and D- (+) -di-p-methoxydibenzoyl tartaric acid; the reaction is carried out in a solvent, wherein the solvent is selected from one or more of methanol, ethanol, water, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;
Preferably, in step (6), the alkalizing agent is selected from one or more of sodium phosphate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate; the dissociation reaction is carried out in a solvent, wherein the solvent is selected from one or more of ethanol, water, tetrahydrofuran and 2-methyltetrahydrofuran;
Preferably, in step (7), the acid is selected from one or more of trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, more preferably a mixed acid of trifluoromethanesulfonic acid and trifluoroacetic acid; the reaction is carried out with or without a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, N-methylpyrrolidone (NMP), N-dimethylacetamide (DMAc).
4. A compound represented by formula VI:
Wherein the substituent R 1 is selected from the group consisting of C 1-C10 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in the substituted benzyl group means that the benzyl group may have 1 to 4 substituents thereon selected from the group consisting of C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano, and C 1-C6 alkyl;
Preferably, R 1 is selected from C 1-C6 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in substituted benzyl means that the benzyl group may have 1 to 4 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
More preferably, R 1 is selected from tert-butyl, p-methoxybenzyl, 2, 4-dimethoxybenzyl or 3, 4-dimethylbenzyl.
5. A process for the preparation of a compound of formula VI,
The preparation method comprises the following steps:
(1) Reacting the compound I with a compound II to obtain a compound III;
(2) Reacting the compound III with the compound IV to obtain a compound V;
(3) Reacting the compound V with an ethylation reagent to obtain a compound VI;
Wherein the substituent R 1 is selected from the group consisting of C 1-C10 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in the substituted benzyl means that the benzyl group may have 1 to 4 substituents thereon selected from the group consisting of C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano, and C 1-C6 alkyl.
6. The process according to claim 5, wherein,
Preferably, R 1 is selected from C 1-C6 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in substituted benzyl means that the benzyl group may have 1 to 4 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
More preferably, R 1 is selected from tert-butyl, p-methoxybenzyl, 2, 4-dimethoxybenzyl or 3, 4-dimethylbenzyl.
7. A process according to claim 5 or 6, characterized in that,
Preferably, the step (1) is carried out in a catalyst and a solvent, wherein the catalyst is piperidine and acetic acid; the solvent is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and toluene;
Preferably, step (2) is performed in a solvent selected from one or more of isopropanol, N-butanol, 2-butanol, N-pentanol, ethylene glycol monomethyl ether, N-methylpyrrolidone, N-dimethylacetamide, chlorobenzene, butyl acetate, benzyl alcohol, sulfolane, dimethyl sulfoxide;
Preferably, step (3) is carried out in a catalyst and a solvent, wherein the catalyst is an acid, and the acid is selected from one of concentrated sulfuric acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid; the solvent is selected from one of N, N-dimethylacetamide and N-methylpyrrolidone; the ethylation reagent is selected from one of triethyl orthoacetate, triethyl orthoformate, triethyl orthopropionate and tetraethyl orthocarbonate.
8. A process for the preparation of a compound of formula VI:
The preparation method comprises the following steps:
(4) Reacting the compound VIII with a substituted amine compound to obtain a compound VI;
Wherein the substituent R 1 is selected from the group consisting of C 1-C10 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in the substituted benzyl group means that the benzyl group may have 1 to 4 substituents thereon selected from the group consisting of C 1-C6 alkoxy, halogen, hydroxy, nitro, cyano, and C 1-C6 alkyl;
Preferably, R 1 is selected from C 1-C6 alkyl, substituted or unsubstituted benzyl, wherein the "substituted" in substituted benzyl means that the benzyl group may have 1 to 4 substituents selected from methoxy, ethoxy, halogen, hydroxy, nitro, cyano, methyl, ethyl, propyl or butyl;
More preferably, R 1 is selected from tert-butyl, p-methoxybenzyl, 2, 4-dimethoxybenzyl or 3, 4-dimethylbenzyl.
9. The method according to claim 8, wherein,
Step (4) is performed in condensing agent, alkali and solvent, wherein the condensing agent is one or more of oxalyl chloride, thionyl chloride, N, N ' -Carbonyl Diimidazole (CDI), N, N, N ', N ' -tetramethyl chloroformyl amine hexafluorophosphate (TCFH), 1-ethyl- (3-dimethyl amino propyl) carbonyl diimine hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt) and 2- (7-aza-benzotriazole) -N, N, N ', N ' -tetramethyl urea Hexafluorophosphate (HATU); the base is selected from one or more of imidazole, triethylamine, N-methylimidazole (NMI), N-diisopropylethylamine, 4-Dimethylaminopyridine (DMAP), pyridine and N-methylmorpholine; the solvent is selected from one or more of tetrahydrofuran, dichloromethane and acetonitrile.
10. Use of a compound of formula VI in a process for the preparation of non-nelidane.
CN202410151357.3A 2024-02-02 2024-02-02 Preparation method of non-neridrone Pending CN118027027A (en)

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