CN111793017A - Preparation method of lactam compound - Google Patents

Preparation method of lactam compound Download PDF

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CN111793017A
CN111793017A CN202010250827.3A CN202010250827A CN111793017A CN 111793017 A CN111793017 A CN 111793017A CN 202010250827 A CN202010250827 A CN 202010250827A CN 111793017 A CN111793017 A CN 111793017A
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compound
optionally substituted
benzyl
iii
reaction
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CN111793017B (en
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孙国栋
王仲清
罗忠华
林义操
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention relates to a preparation method of lactam compound, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of carrying out asymmetric hydrogenation reaction on raw materials under the action of a ruthenium catalyst and a hydrogen donor reagent, and then carrying out post-treatment to obtain a target compound. The product obtained by the method has high ee value, the method is simple and convenient, and the target compound can be conveniently and efficiently obtained.

Description

Preparation method of lactam compound
Technical Field
The invention relates to a preparation method of lactam compound, belonging to the technical field of pharmaceutical chemistry.
Background
The lactam compound shown as the following formula III is an intermediate in the preparation process of various medicaments, comprises 2 chiral centers, and how to simply obtain the compound III with a single configuration has important influence on the preparation process of medicaments which need to use the compound III as the intermediate,
Figure BDA0002435416430000011
in the prior art, a compound III is prepared, a mixture with different configurations is obtained through hydrogenation reduction reaction, and then a target compound with a single configuration is obtained through a separation process and other processes. Therefore, it is necessary to develop a simple and high-yield method for producing compound III.
Disclosure of Invention
The inventor develops a method for preparing the compound III through research, the method can simply obtain a product with more single configuration and high ee value, avoids using hydrogen, and is simple, convenient and safe to operate.
The invention provides a method for preparing a compound III, which comprises the following steps: the compound II is subjected to asymmetric hydrogenation reaction under the action of a ruthenium catalyst and a hydrogen donor reagent, and then is subjected to post-treatment to obtain a compound III,
Figure BDA0002435416430000012
wherein the content of the first and second substances,
n is 1, 2 or 3;
R1is optionally substituted linear or branched alkyl, ester, aryl, heteroaryl, or R1Is hydrogen;
R2is optionally substituted linear or branched alkyl, benzyl, aryl, heteroaryl, or R2Is hydrogen.
The alkyl group may be an optionally substituted C1-C6 (1C-6C) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like;
the ester group may be an optionally substituted C2-C12 (2-C12-C) ester group, such as a methyl formate group (COOMe), an ethyl formate group (COOC)2H5) Methyl acetate (CH)2COOMe), ethyl acetate group (CH)2COOC2H5) A phenol formate group (COOPh), etc.;
the aryl group may be an optionally substituted C6-C12 (6-C12-C) aryl group such as an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted naphthyl group, an optionally substituted naphthylmethyl group, etc.;
the heteroaryl is an optionally substituted five-or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, such as an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted furyl, an optionally substituted pyrimidinyl, an optionally substituted piperidyl, an optionally substituted piperazinyl and the like.
In some embodiments, the R is1Is an optionally substituted straight chain or branched chain C1-C6(1 carbon-6 carbon) alkyl group, a C2-C12(2 carbon-12 carbon) ester group, an optionally substituted C6-C12(6 carbon-12 carbon) aryl group, an optionally substituted five-or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or R1Is hydrogen.
In some embodiments, the R is2Is optionally substituted straight chain or branched chain C1-C6(1 carbon-6 carbon) alkyl, benzyl, optionally substituted C6-C12(6 carbon-12 carbon) aryl, optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur element, or R2Is hydrogen.
In some embodiments, R1Is an optionally substituted straight chain or branched chain C1-C6(1 carbon-6 carbon) alkyl group, a C2-C12(2 carbon-12 carbon) ester group, an optionally substituted C6-C12(6 carbon-12 carbon) aryl group, an optionally substituted five-or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or R1Is hydrogen; r2Is optionally substituted, linear or branchedC1-C6 (1C-6C) alkyl, benzyl, optionally substituted C6-C12 (6C-12C) aryl, optionally substituted five-or six-membered heterocyclic group containing nitrogen, oxygen or sulfur element, or R2Is hydrogen.
In some embodiments, n is 1, 2 or 3; r1Is an optionally substituted straight chain or branched chain C1-C6(1 carbon-6 carbon) alkyl group, a C2-C12(2 carbon-12 carbon) ester group, an optionally substituted C6-C12(6 carbon-12 carbon) aryl group, an optionally substituted five-or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or R1Is hydrogen; r2Is optionally substituted straight chain or branched chain C1-C6(1 carbon-6 carbon) alkyl, benzyl, optionally substituted C6-C12(6 carbon-12 carbon) aryl, optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur element, or R2Is hydrogen.
The ruthenium catalyst can be a compound of formula CAT-A or CAT-B:
Figure BDA0002435416430000021
wherein A is oxygen, alkylene or absent; q is hydrogen or alkyl; ar is benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; r3Is optionally substituted straight or branched chain C1-C6 (1C-6C) alkyl, or optionally substituted phenyl, including without limitation, phenyl optionally substituted with straight or branched chain C1-C6 alkyl, phenyl optionally substituted with halogen, phenyl optionally substituted with C1-C6 (1C-6C) haloalkyl, and the like.
In some embodiments, a is oxygen, methylene, or absent.
In some embodiments, Q is a linear or branched C1-C6(1 carbon-6 carbon) alkyl.
In some embodiments, R3Is methyl, trifluoromethyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, or perfluorobutyl.
In some embodiments, a is oxygen, methylene, or absent; q is a linear or branched C1-C6 (1)Carbon-6 carbon) alkyl; r3Is methyl, trifluoromethyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, or perfluorobutyl.
In some embodiments, a is oxygen and Q is methyl. In some embodiments, a is oxygen and Q is hydrogen. In some embodiments, a is alkylene and Q is hydrogen or methyl. In some embodiments, a is methylene and Q is hydrogen or methyl. In some embodiments, a is absent and Q is hydrogen or methyl.
In some embodiments, A is oxygen, Q is methyl, R3Is p-methylphenyl. In some embodiments, A is absent, Q is hydrogen, R is hydrogen3Is p-methylphenyl.
In some embodiments, Ar is benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; r3Is methyl, trifluoromethyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, or perfluorobutyl.
In some embodiments, Ar is 4-methylisopropylbenzene, R3Is trifluoromethyl.
In some embodiments, the ruthenium catalyst is selected from at least one compound represented by the following formula (R, R) -Ts-DENEB, formula (R, R) -Teth-TsDpen, formula (R, R) -CAT 01-formula (R, R) -CAT07, wherein i-Pr represents an isopropyl group, Ph represents a phenyl group, and Ts represents a p-toluenesulfonyl group:
Figure BDA0002435416430000031
Figure BDA0002435416430000041
in some embodiments, the ruthenium catalyst is (R, R) -Ts-DENEB, which facilitates reaction performance and product availability. In some embodiments, the ruthenium catalyst is of the formula (R, R) -Teth-TsDpen, facilitating reaction and product acquisition.
The amount of the ruthenium catalyst can be any suitable amount of the catalyst; for example, the ruthenium catalyst may be used in an amount of 0.0001 to 0.1 mole relative to 1 mole of the compound II. In some embodiments, the molar ratio of the ruthenium catalyst to compound II feed is 0.0001:1 to 0.05: 1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II feed is from 0.0005:1 to 0.05: 1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II feed is from 0.001:1 to 0.02: 1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II feed is from 0.008:1 to 0.015: 1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II feed is 0.005:1 to 0.01:1, which facilitates better reaction.
The hydrogen donor agent can be any suitable hydrogen donor agent.
In some embodiments, the hydrogen donor reagent is formic acid and an organic amine selected from at least one of diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, N-diisopropylethylamine. In some embodiments, the hydrogen donor agent is formate, which may be sodium formate, potassium formate, or a combination thereof.
The hydrogen donor agent may be used in any suitable amount.
In some embodiments, the molar ratio of hydrogen donor reagent to compound II fed, calculated as formic acid or formate salt, is from 1:1 to 4: 1. In some embodiments, the molar ratio of hydrogen donor reagent to compound II fed, calculated as the amount of formic acid used, is from 1:1 to 2: 1.
The organic amine may be used in any suitable amount. In some embodiments, the charged molar ratio of the organic amine to compound II is from 10:1 to 1: 1. In some embodiments, the organic amine is fed to compound II in a molar ratio of 8:1 to 1: 1. In some embodiments, the organic amine is fed to compound II in a molar ratio of 5:1 to 1: 1. In some embodiments, the feeding molar ratio of the organic amine to the compound II is 4:1-1:1, which is beneficial for better reaction.
The temperature of the asymmetric hydrogenation reaction can be 0-100 ℃. In some embodiments, the asymmetric hydrogenation reaction is at a temperature of 15 ℃, 25 ℃, 30 ℃, 35 ℃, 55 ℃, 65 ℃, or 80 ℃. In some embodiments, the asymmetric hydrogenation reaction is carried out at a temperature of 20 ℃ to 45 ℃ to facilitate the obtaining of the reaction product.
The reaction solvent for the asymmetric hydrogenation reaction may be any suitable solvent. In some embodiments, the reaction solvent for the asymmetric hydrogenation reaction may be at least one of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. In some embodiments, the reaction solvent is dichloromethane, which facilitates the reaction process.
The reaction of the present invention can be monitored by using methods such as High Performance Liquid Chromatography (HPLC), and the reaction is considered to be completed when the HPLC content of the compound represented by formula II is less than or equal to 5%, and the reaction time is usually 10 to 80 hours depending on the substrate, the catalyst, and the reaction conditions.
The post-processing may include: after the reaction, the reaction solution was washed with water, and the solvent was removed by distillation under reduced pressure to obtain a crude compound III. To further enhance the purity of compound III, the crude product may be purified by any suitable method that increases or enhances the purity of the desired product, including without limitation, decolorization, adsorption, washing, crystallization, recrystallization, and the like.
In some embodiments, n is 1; r1Is methyl, n-propyl, isopropyl, ester, naphthylmethyl, benzyl, or substituted benzyl; r2Is methyl, isopropyl, n-butyl, benzyl or p-methoxybenzyl.
In some embodiments, n is 2; r1Is methyl, n-propyl, isopropyl, ester, naphthylmethyl, benzyl, or substituted benzyl; r2Is methyl, isopropyl, n-butyl, benzyl or p-methoxybenzyl.
In some embodiments, n is 1 and R is1Is methyl, R2Is benzyl.
In some embodiments, n is 2 and R1Is methyl, R2Is benzyl.
In some embodiments, compound III may be of any one of formulas III-1 to III-19 below, wherein Bn represents benzyl, PMB represents p-methoxyphenyl, and Me represents methyl:
Figure BDA0002435416430000051
Figure BDA0002435416430000061
in some embodiments, compound III is represented by formula III-a or III-b below, wherein Bn represents benzyl:
Figure BDA0002435416430000062
the compound III can be used as an intermediate for preparing medicaments in the medicament preparation process, the compound shown as the formula III-a can be used for preparing medicament Tofacitinib (English name: Tofacitinib) after reduction carbonyl reaction,
Figure BDA0002435416430000063
the compound II can be obtained by adopting a known method or prepared by carrying out cyclization reaction on the compound I under certain conditions:
Figure BDA0002435416430000064
wherein R is1，R2N is as defined above; r0Is cyano, or an ester group.
In some embodiments, a compound of formula I-A is reacted to provide a compound of formula II-A, and then prepared to provide compound II, wherein R is1，R2N is as defined above:
Figure BDA0002435416430000071
the method provided by the invention does not need to use hydrogen, and the ee value of the obtained compound III can reach 99% or more.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the invention, g: g; mL: ml; mol: molar ratio; DEG C: c, centigrade degree; h: hours; min: the method comprises the following steps of (1) taking minutes; DEG C: c, centigrade degree; LCMS or LC-MS represents liquid chromatography-mass spectrometry; GC-MS represents gas chromatography-mass spectrometry; DCM represents dichloromethane; TLC indicated thin layer chromatography.
dr (diastereometric ratio) value calculation method: dr ═ (RR + SS)/(RS + SR); ee (enantiomeric excess) value calculation method: ee ═ 100% (RR ] - [ SS ])/([ RR ] + [ SS ]), in the present invention, the main product is the cis-configured product (i.e., the RR or SS configured product), so only the ee value of the main product is calculated; wherein RR represents RR configuration product content, SS represents SS configuration product content, RS represents RS configuration product content, and SR represents SR configuration product content.
In the invention, the room temperature refers to the ambient temperature and is 0-30 ℃, or 0-25 ℃ or 15-25 ℃.
Example 1
Preparation of Compound I-1:
Figure BDA0002435416430000072
benzylamine (10.12g, 1.00eq), methyl acrylate (8.13g, 1.0eq) were added to a reaction flask, the reaction was stirred at room temperature for 30h, the reaction was monitored by gas chromatography, and after completion of the reaction, the reaction solution was concentrated to give a transparent oil: compound I-1, 18.03g, assay LC-MS: m + H+＝194.2。
Preparation of Compound I-2:
Figure BDA0002435416430000073
adding p-benzylamine (14.13g, 1.10eq), methyl methacrylate (12.00g, 1.0eq) and lithium perchlorate (12.75g, 1.00eq) into a reaction bottle, stirring at room temperature for 26h for reaction, adding DCM (150mL) for dilution, filtering, concentrating the filtrate to obtain a crude product of the compound I-2, and purifying the crude product by silica gel column chromatography (ethyl acetate: n-hexane: 1:2, volume ratio) to obtain a compound I-2: 11.91g of a clear oil; detection, LC-MS: m + H+＝208.2。
Example 2
Preparation of Compound II-A1:
Figure BDA0002435416430000081
adding a compound I-1(18.00g, 1.0eq), dimethyl oxalate (13.20g, 1.20eq) and a 30% sodium methoxide solution (20.13g, 1.20eq) into a reaction bottle, heating up and refluxing for 6h, controlling the reaction in TLC to be finished, concentrating to remove methanol, adding 200ml of water into the residual liquid, stirring for 5min, dropwise adding an HCl solution to adjust the pH value to 6, stirring for 30min, performing suction filtration to obtain a crude filter cake product of 19.2g, adding 200ml of methanol into the crude product, heating up to reflux and pulping for 1h, cooling to room temperature, and performing suction filtration to obtain a compound II-A1: 16.8g of a white solid, yield 88.37%, found LC-MS, M + H+＝248.2。
Preparation of Compound II-A2:
Figure BDA0002435416430000082
adding a compound I-2(11.91g, 1.0eq), diethyl oxalate (10.08g, 1.2eq) and 20% sodium ethoxide solution (23.46g, 1.20eq) into a reaction bottle, heating and refluxing for 6h, controlling the reaction by TLC (thin layer chromatography), concentrating to remove ethanol, adding 100ml of water into the residual liquid, stirring for 5min, dropwise adding HCl solution to adjust the pH to 6, stirring for 30min, performing suction filtration, and performing silica gel column chromatography on a filter cake crude product to obtain a compound II-A2: 6.12g of white solid, yield 52.66%; detection, LC-MS: m + H+＝204.2。
Preparation of Compound II-A3:
Figure BDA0002435416430000083
adding 17.0g of methyl 5-chloropentanoate, 14.7g (2eq) of sodium azide and 68mL of N, N-dimethylformamide into a 250mL single-neck bottle, reacting at 60 ℃ for 24 hours, stopping the reaction, and cooling to room temperature; adding 200mL of water, extracting with dichloromethane (100mL by 3), spin-drying the organic phase at 40 ℃ to obtain 14.00g of light yellow oily matter, detecting by GC-MS, wherein M is 157.1, and the compound is the compound I-3-02;
dissolving 12g of compound I-3-02 and 13.75g of methyl formate (3eq) in 100mL of dichloromethane, cooling the system to 0 ℃, dropwise adding 31.9g of titanium tetrachloride (2.2eq), maintaining the temperature of 0-10 ℃ after dropwise adding, dropwise adding 20g of triethylamine (2.6eq), reacting at0 ℃ for 2 hours after adding, stopping the reaction, slowly adding 100mL of water, extracting with ethyl acetate (100mL x 3), and spin-drying the organic phase at 40 ℃ to obtain compound I-3-03, 11.8g and yield of 83%;
dissolving 5.0g of compound I-3-03 and 2.89g of benzylamine (1.0eq) in 30mL of acetic acid, adding 6.18g of sodium cyanoborohydride (4.5eq) in portions at room temperature, reacting at room temperature for 2 hours after the addition, stopping the reaction, removing acetic acid by spinning at 50 ℃, adding 100mL of ethyl acetate, washing with 1mol/L sodium hydroxide solution (100 mL. multidot.2), and washing with water once (100 mL); the resulting organic phase was dried over anhydrous sodium sulfate and then spin dried at 40 ℃ to give compound I-3: 4.5g of oil, LC-MS: m + H+＝277.3。
Figure BDA0002435416430000091
Adding a compound I-3(0.3g, 1.0eq), diethyl oxalate (0.19g, 1.2eq) and 20% sodium ethoxide solution (0.44g, 1.20eq) into a reaction bottle, heating and refluxing for reaction for 3h, controlling by TLC, finishing the reaction, concentrating to remove ethanol, adding 20ml of water into the residual liquid, stirring for 5min, dropwise adding an HCl solution to adjust the pH to 6, stirring for 30min, performing suction filtration, and performing silica gel column chromatography on a filter cake crude product (EA: n-hexane: 1:10, volume ratio) to obtain a compound II-A3: 0.12g of white solid, yield 40%; detection, LC-MS: m + H+＝273.3。
Preparation of Compound II-B1:
Figure BDA0002435416430000092
adding 50ml of compound II-A1(5.00g, 1.0eq), benzaldehyde (2.03g, 1.00eq) and 20% HCl aqueous solution (mass fraction) into a reaction bottle, heating to 80 ℃ for reaction for 6h, controlling the reaction in TLC, concentrating to remove ethanol, adding 100ml of water into the residual liquid, stirring for 5min, extracting with DCM for three times, combining organic phases, concentrating and drying to obtain 5.00g of crude solid, recrystallizing the crude solid with 95% ethanol to obtain 3.96g of pure product, wherein the yield is 79.2%; adding the obtained intermediate (0.96g, 1.00eq) and 10% palladium carbon (50mg) into 50ml of methanol, reacting at room temperature for 16h under normal pressure and hydrogen pressure, monitoring by HPLC (high performance liquid chromatography), filtering off the palladium carbon, concentrating the filtrate to obtain a crude product II-B1, and recrystallizing the crude product with absolute ethyl alcohol to obtain a compound II-B1: 0.48g white solid, yield: 50%, detection, LC-MS: m + H+＝280.3。
Preparation of Compound II-B2:
Figure BDA0002435416430000101
adding 140mL of compound II-A1(7.00g, 1.0eq), 4-chlorobenzaldehyde (3.77g g, 1.00eq) and 20% HCl aqueous solution (mass fraction) into a reaction bottle, heating to 100 ℃ for reaction for 6h, carrying out TLC (thin layer chromatography) controlled reaction, cooling to 0 ℃ after the reaction is finished, carrying out suction filtration, washing a filter cake with 50mL of water, and carrying out vacuum drying at 50 ℃ to obtain 6.0g of solid.
Adding the obtained intermediate (6.0g, 1.00eq) and 10% palladium carbon (1.2g) into 600ml tetrahydrofuran, reacting at room temperature for 16h under normal pressure of hydrogen, monitoring by HPLC to finish the reaction, filtering off the palladium carbon, concentrating the filtrate to dryness to obtain a crude product II-B2, and recrystallizing the crude product with absolute ethyl alcohol to obtain a compound II-B2: 5.0g white solid, yield 83%, assay, LC-MS: m + H+＝314.1。
Preparation of Compound II-B3:
Figure BDA0002435416430000102
adding compound II-A1(10g, 1.0eq), 4-chlorobenzaldehyde (4.29g, 1.00eq) and 200mL of 20% HCl aqueous solution (mass fraction) into a reaction bottle, heating to 100 ℃ for reaction for 4h, carrying out TLC (thin layer chromatography) center control, cooling to 0 ℃ after the reaction is finished, carrying out suction filtration, washing a filter cake with 50mL of water, and carrying out vacuum drying at 50 ℃ to obtain 6.8g of a solid intermediate.
Adding the obtained intermediate (6.8g, 1.00eq) and 10% palladium carbon (6.8g) into 150ml of methanol, reacting at room temperature for 16h under normal pressure and hydrogen pressure, monitoring by HPLC to finish the reaction, filtering off the palladium carbon, concentrating the filtrate to dryness to obtain a crude product II-B3, and recrystallizing the crude product with absolute ethyl alcohol to obtain a compound II-B3: 5.2g white solid, yield: 76.5 percent. Detection, LC-MS: m + H+＝285.2。
Preparation of Compound II-C1:
Figure BDA0002435416430000103
adding 5.9g N-benzyl-4-methylpiperidine, 150ml tetrahydrofuran and 0.5ml water into a 250ml single-mouth bottle, slowly adding 15.8g of iodine under stirring in a water bath, and slowly adding iodobenzene diacetate (20g, 2.0eq) after the addition is finished; transferring the added materials to an oil bath at 25 ℃ for heat preservation, after reacting for 30min, adding iodobenzene diacetate (10g, 1.0eq), continuing to react for 1 hour, sampling for LCMS detection, adding saturated sodium thiosulfate (200ml) into the reaction solution after the reaction is completed, extracting with DCM (100 ml. times.4), combining organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a crude product II-C1; and purifying the crude product by gradient column chromatography with an eluent n-hexane and ethyl acetate which are 10:1 → 8:1 → 6:1 → 4:1 → 2:1 (volume ratio) to obtain a compound II-C1: 7.14g of a yellow solid, yield 83.4%; detection, LC-MS: m + H+＝218.2。
Example 3
Catalyst screening experiments:
Figure BDA0002435416430000111
dissolving a compound II-A2(2mmol, 1.00eq), a ruthenium catalyst (0.02mmol, 1% eq) and triethylamine (6.5mmol, 3.25eq) in 6ml of dichloromethane, slowly adding formic acid (2.60mmol, 1.30eq) at room temperature, heating to reflux reaction for 16h, monitoring the reaction by HPLC, washing the reaction solution for three times after the reaction is finished, performing rotary evaporation, concentration and drying to obtain a crude product, feeding the crude product to a sample, detecting the content of an isomer by normal phase HPLC, and performing silica gel column chromatography to obtain III-1: 364mg of white solid with the yield of 88.76 percent, and the content of the isomers is detected by normal phase HPLC, and the ee value and the dr value are calculated.
The results obtained by carrying out the reaction under the same conditions and in the same operation as above except that the catalyst conditions were different are shown in the following Table 1, wherein the catalyst number 10 was 0.01mmol, 0.5% eq and the catalyst number was 0.02mmol, 1% eq; the conversion data were determined by HPLC measurements, the isomer contents were determined by normal phase HPLC measurements, and the ee and dr values were calculated from the normal phase HPLC data.
Table 1: reaction results of different catalysts
Figure BDA0002435416430000112
Figure BDA0002435416430000121
As can be seen from Table 1, the reaction results of different catalysts are slightly different, the catalyst dosage is from 1% eq to 0.5% eq, the conversion of the raw materials is still complete, and the isomer content is basically unchanged.
Example 4
Preparation of Compound III-1
Figure BDA0002435416430000122
Adding the compound II-A2(406mg, 1.00eq), the catalyst (R, R) -Ts-DENEB (7mg, 0.5% eq) and triethylamine (657mg, 3.25eq) into 6ml of DCM solvent, then slowly adding formic acid (120mg, 2.60eq), and heating to reflux reaction; after the reaction is finished for 16h through HPLC (high performance liquid chromatography) central control reaction, washing the reaction solution for three times by using water, concentrating and drying to obtain a crude product, and performing silica gel column chromatography on the crude product to obtain a compound III-1: 364mg of white solid, inspectionAnd (3) measurement: yield 88.76%, chiral purity by normal phase HPLC: ee value 98.7% and dr value 98: 2; melting point: 70.8 ℃; specific rotation degree
Figure BDA0002435416430000124
LC-MS，M+H+：206.11；
1H NMR(600MHz,CDCl3)7.34(q,J＝7.2Hz,2H),7.30(dd,J＝12.6,5.3Hz,1H),7.24(d,J＝7.2Hz,2H),4.53(d,J＝14.6Hz,1H),4.41(dd,J＝13.8,11.2Hz,2H),3.34(dd,J＝9.9,6.3Hz,1H),2.87(dd,J＝9.9,1.9Hz,1H),2.62-2.54(m,1H),1.01(d,J＝7.0Hz,3H)；
13C NMR(101MHz,CDCl3)174.42(s),135.84(s),128.74(s),128.18(s),127.75(s),72.17(s),50.70(s),46.94(s),32.09(s),12.46(s)；
HRMS[M+H]+：C12H15NO2And calculating: 206.1176, actually measuring: 206.1187.
example 5
Figure BDA0002435416430000123
Figure BDA0002435416430000134
With reference to the previous procedure, compound III-2 was prepared: white solid, yield 95.7%, ee value: 96.2%, dr value: 97: 3; melting point: 117.1 ℃; specific rotation degree
Figure BDA0002435416430000135
1H NMR(400MHz,CDCl3)7.34–7.23(m,3H),7.22–7.16(m,2H),7.14–7.03(m,3H),6.77(d,J＝6.9Hz,2H),4.59(d,J＝14.5Hz,1H),4.40(d,J＝5.1Hz,1H),4.12(d,J＝14.4Hz,1H),3.87(s,1H),3.05–3.00(m,1H),2.99(d,J＝4.0Hz,1H),2.87(dd,J＝10.3,2.5Hz,1H),2.66–2.55(m,1H),2.13(dd,J＝13.5,11.6Hz,1H)；
13C NMR(101MHz,CDCl3)174.23(s),139.65(s),135.88(s),129.05(s),128.84(s),128.57(s),128.40(s),127.91(s),126.12(s),71.95(s),46.94(s),46.85(s),39.71(s),31.91(s)；
HRMS[M+H]+：C18H19NO2And calculating: 282.1489, found 282.1491.
Example 6
Figure BDA0002435416430000131
Compound III-3 was prepared according to the previous procedure to give a white solid in 89.5% yield, ee: 99.1%, dr value: 92: 8; melting point: 152.9 deg.C; specific rotation degree
Figure BDA0002435416430000132
1H NMR(600MHz,CDCl3)7.41–7.32(m,3H),7.26(t,J＝3.0Hz,3H),7.13(d,J＝8.3Hz,2H),6.71(d,J＝8.3Hz,2H),4.71(t,J＝14.1Hz,1H),4.43(dd,J＝7.0,1.7Hz,1H),4.12(d,J＝14.4Hz,1H),3.15(d,J＝2.1Hz,1H),3.09(dd,J＝10.3,6.0Hz,1H),2.99(dd,J＝14.0,4.7Hz,1H),2.87(dd,J＝10.4,2.4Hz,1H),2.69–2.60(m,1H),2.11(dd,J＝14.0,11.1Hz,1H)；
13C NMR(101MHz,CDCl3)173.64(s),137.92(s),135.80(s),132.01(s),130.35(s),128.91(s),128.68(s),128.51(s),128.01(s),71.86(s),46.81(s),46.41(s),39.62(s),31.20(s)；
HRMS[M+H]+：C18H18ClNO2And calculating: 316.1099, respectively; 316.1106 are measured.
Example 7
Figure BDA0002435416430000133
Figure BDA0002435416430000141
Compound III-4 was prepared as a dark oil in 76.6% yield, ee value: 98.5%, dr value: 98: 2;specific rotation
Figure BDA0002435416430000142
1H NMR(400MHz,CDCl3)7.41–7.30(m,3H),7.24(d,J＝7.0Hz,2H),4.55–4.41(m,2H),4.39(d,J＝6.8Hz,1H),4.19(s,1H),3.34–3.18(m,3H),3.01(dd,J＝10.0,4.5Hz,1H),2.39(dq,J＝13.6,6.9Hz,1H),1.83–1.71(m,1H),1.68–1.46(m,2H),1.32(ddd,J＝15.8,9.5,4.7Hz,2H)；
13C NMR(101MHz,CDCl3)174.45(s),135.68(s),128.81(s),128.19(s),127.86(s),71.49(s),51.46(s),49.03(s),46.84(s),37.17(s),26.79(s),23.98(s)；
HRMS[M+H]+：C14H18N4O2And calculating: 275.1503, respectively; 275.1492 are measured.
Example 8
Figure BDA0002435416430000143
Compound III-5 was prepared as a white solid in 88.1% yield, ee value: 100%, dr value: 93: 7; melting point: 99.6 ℃; specific rotation degree
Figure BDA0002435416430000144
1H NMR(400MHz,CDCl3)7.42–7.32(m,3H),7.31–7.23(m,2H),7.11(d,J＝5.0Hz,1H),6.89–6.83(m,1H),6.49(d,J＝2.8Hz,1H),4.63(d,J＝14.5Hz,1H),4.50(dd,J＝7.0,2.2Hz,1H),4.30(d,J＝14.5Hz,1H),3.74(d,J＝2.4Hz,1H),3.30–3.18(m,2H),3.06(dd,J＝10.3,2.6Hz,1H),2.79–2.69(m,1H),2.58(dd,J＝14.8,10.9Hz,1H)；
13C NMR(101MHz,CDCl3)173.93(s),142.00(s),135.77(s),128.85(s),128.39(s),127.91(s),126.81(s),125.67(s),123.77(s),71.66(s),47.36(s),46.87(s),39.84(s),26.51(s)；
HRMS[M+H]+：C16H17NO2S, calculating: 288.1053, respectively; 288.1044 are measured.
Example 9
Figure BDA0002435416430000145
Referring to the previous procedure, compound III-6 was prepared as a white solid in 88.3% yield, ee: 100%, dr value: 98: 2; melting point: 135.9 ℃; specific rotation degree
Figure BDA0002435416430000151
1H NMR(400MHz,CDCl3)7.31–7.21(m,3H),7.18(d,J＝7.6Hz,2H),4.52(dd,J＝7.6,4.1Hz,1H),4.49–4.37(m,2H),4.00(d,J＝3.4Hz,1H),3.63(s,3H),3.49(dd,J＝9.9,3.5Hz,1H),3.32(td,J＝7.5,3.6Hz,1H),3.26(dd,J＝9.7,7.5Hz,1H)；
13C NMR(101MHz,CDCl3)172.23(s),170.60(s),135.26(s),128.77(s),128.23(s),127.89(s),70.60(s),52.18(s),46.97(s),45.70(s),42.93(s)；
HRMS[M+H]+：C13H15NO4And calculating: 250.1074, respectively; 250.1059 are measured.
Example 10
Figure BDA0002435416430000152
Compound III-7 was prepared as a colorless transparent oil in 82% yield, ee value: 97.8%, dr value: 98: 2; specific rotation degree
Figure BDA0002435416430000153
1H NMR(400MHz,CDCl3)4.32(t,J＝11.2Hz,1H),3.91(d,J＝15.2Hz,1H),3.43(dt,J＝15.5,7.7Hz,1H),3.28(t,J＝7.3Hz,2H),2.95(dt,J＝9.6,4.8Hz,1H),2.59(hd,J＝7.0,2.5Hz,1H),1.55–1.45(m,2H),1.32(dt,J＝14.9,7.4Hz,2H),1.05(d,J＝7.1Hz,3H),0.93(t,J＝7.3Hz,3H)；
13C NMR(101MHz,CDCl3)174.23(s),72.18(s),51.23(s),42.59(s),32.21(s),29.14(s),19.95(s),13.69(s),12.63(s)；
HRMS[M+H]+：C9H17NO2And calculating: 172.1332, respectively; 172.1346 are measured.
Example 11
Figure BDA0002435416430000154
Referring to the previous procedure, compound III-a was prepared as a clear oil in 83% yield, ee: 99.8%, dr value: 93:7, specific rotation
Figure BDA0002435416430000155
Figure BDA0002435416430000156
1H NMR(400MHz,CDCl3)7.33(dd,J＝13.7,6.4Hz,2H),7.27(t,J＝6.9Hz,3H),4.69–4.61(m,1H),4.51(d,J＝14.5Hz,1H),4.18(d,J＝5.3Hz,1H),3.81(s,1H),3.31–3.21(m,1H),3.20–3.11(m,1H),2.48–2.36(m,1H),2.07–1.95(m,1H),1.77–1.70(m,1H),0.95(d,J＝7.0Hz,3H)；
13C NMR(151MHz,CDCl3)172.21(s),136.58(s),128.71(s),128.19(s),127.68(s),70.85(s),50.44(s),43.59(s),30.78(s),26.17(s),11.79(s)；
HRMS[M+H]+：C13H17NO2And calculating: 220.1332, respectively; 220.1314 are measured.
Example 12
Figure BDA0002435416430000161
Adding lithium aluminum hydride (281mg, 2.50eq) into 6ml tetrahydrofuran for suspension, replacing nitrogen, protecting nitrogen, and stirring at0 ℃; dissolving a compound III-a (650mg, 1.00eq) in 10ml tetrahydrofuran, dropwise adding into a reaction bottle by a syringe, continuously stirring for 30min after 15min of dropwise adding is finished, then heating to reflux reaction, after 15h of reaction, monitoring the reaction by thin layer chromatography, stirring at0 ℃, adding 6Quenching and stirring by using ml of ethyl acetate; pouring the reaction solution into 200ml of saturated sodium citrate, stirring for 30min, adding 50ml of ethyl acetate, stirring, combining organic phases, filtering a layer of diatomite, separating the filtrate, extracting the aqueous phase EA twice, combining all the organic phases, and drying with anhydrous sodium sulfate; filtration and concentration of the filtrate to dryness gave 800mg of clear oil III-a 1: (3R,4R) -1-benzyl-4-methylpiperidin-3-ol, clear oil, yield 74%; specific rotation degree
Figure BDA0002435416430000162
Figure BDA0002435416430000163
1H NMR(400MHz,CDCl3)7.37–7.24(m,5H),3.59(s,1H),3.53(s,2H),3.03–2.92(m,1H),2.83(dd,J＝11.0,1.7Hz,1H),2.53(s,1H),2.17(d,J＝11.2Hz,1H),2.00(td,J＝11.4,3.0Hz,1H),1.59–1.39(m,3H),1.01(d,J＝6.0Hz,3H)；
13C NMR(151MHz,CDCl3)138.32,128.97,128.29,127.12,69.36,62.65,60.09,53.30,34.88,28.38,17.84；
HRMS[M+H]+：C13H19NO, calculation: 206.1539, respectively; 206.1570 are measured.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (13)

1. A process for preparing compound III comprising: the compound II is subjected to asymmetric hydrogenation reaction under the action of a ruthenium catalyst and a hydrogen donor reagent, and then is subjected to post-treatment to prepare a compound III,
Figure FDA0002435416420000011
wherein the content of the first and second substances,
n is 1, 2 or 3;
R1is optionally substituted linear or branched alkyl, ester, aryl, heteroaryl, or R1Is a hydrogen atom;
R2is optionally substituted linear or branched alkyl, benzyl, aryl, heteroaryl, or R2Is a hydrogen atom.
2. The process according to claim 1, wherein the molar ratio of the ruthenium catalyst to the compound II is from 0.0001:1 to 0.05: 1.
3. The method of claim 1, the hydrogen donor reagent being formic acid and an organic amine selected from at least one of diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, N-diisopropylethylamine; or the hydrogen donor agent is formate selected from sodium formate, potassium formate, or a combination thereof.
4. The method of claim 3, wherein the charged molar ratio of organic amine to compound II is 10:1 to 1: 1.
5. The process according to claim 3, wherein the molar ratio of formic acid or formate salt to compound II is from 1:1 to 4: 1.
6. The process according to claim 1, wherein the asymmetric hydrogenation is carried out at a temperature of 0 to 100 ℃.
7. The method of claim 1, wherein the reaction solvent for the asymmetric hydrogenation reaction is at least one of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran.
8. The method of claim 1, the post-processing comprising: after the reaction, the reaction mixture was washed with water, and the solvent was distilled off under reduced pressure to obtain compound III.
9. The process of claim 1, wherein the ruthenium catalyst is a compound of formula CAT-a or formula CAT-B:
Figure FDA0002435416420000012
wherein the content of the first and second substances,
a is oxygen, alkylene or absent;
q is hydrogen or alkyl;
ar is benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene;
R3is optionally substituted straight chain or branched chain C1-C6 alkyl or optionally substituted phenyl.
10. The method of claim 1, wherein R1Is an optionally substituted straight chain or branched chain C1-C6 alkyl group, a C2-C12 ester group, an optionally substituted C6-C12 aryl group, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or R1Is hydrogen; r2Is optionally substituted straight chain or branched chain C1-C6 alkyl, benzyl, optionally substituted C6-C12 aryl, optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur element, or R2Is hydrogen.
11. The method of claim 1, wherein n is 1 and R is1Is methyl, n-propyl, isopropyl, ester, naphthylmethyl, benzyl, or substituted benzyl, R2Is methyl, isopropyl, n-butyl, benzyl or p-methoxybenzyl; or n is 2, R1Is methyl, n-propyl, isopropyl, ester, naphthylmethyl, benzyl, or substituted benzyl, R2Is methyl, isopropyl, n-butyl, benzyl or p-methoxybenzyl or n is 1, R1Is methyl, R2Is benzyl; or n is 2, R1Is methyl, R2Is benzyl.
12. The process according to claim 1 or 9, wherein the ruthenium catalyst is at least one selected from the group consisting of compounds represented by the following formula (R, R) -Ts-DENEB, formula (R, R) -Teth-TsDpen, formula (R, R) -CAT 01-formula (R, R) -CAT07, i-Pr represents an isopropyl group, Ph represents a phenyl group, Ts represents a p-toluenesulfonyl group:
Figure FDA0002435416420000021
Figure FDA0002435416420000031
13. a compound having the structure of formula III:
Figure FDA0002435416420000032
wherein n is 1, formula III is shown as formulas III-4 to III-6 or III-16 or III-17:
Figure FDA0002435416420000033
Figure FDA0002435416420000034
or n is 2, formula III is shown as formula III-a or formula III-b below:
Figure FDA0002435416420000035
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