CN117105838A - Synthesis method of beta-lactam - Google Patents

Synthesis method of beta-lactam Download PDF

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CN117105838A
CN117105838A CN202310262908.9A CN202310262908A CN117105838A CN 117105838 A CN117105838 A CN 117105838A CN 202310262908 A CN202310262908 A CN 202310262908A CN 117105838 A CN117105838 A CN 117105838A
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compound
reaction
beta
lactam
mmol
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智英
赵坤
姚庆强
孙皓熠
李华杰
丁天地
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Shandong First Medical University and Shandong Academy of Medical Sciences
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Shandong First Medical University and Shandong Academy of Medical Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by 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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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Abstract

The invention relates to a method for synthesizing beta-lactam, which comprises the specific synthesis steps of taking trans-nitrostyrene and 2- (methoxyl) malononitrile as raw materials, taking Catalyst A as a Catalyst and taking methylene dichloride as a solvent for reaction to obtain an intermediate 3; reacting the compound 3 with an acid and water to obtain a compound 4; reducing the compound 4 by hydrogen to obtain a compound 5; the compound 5 is subjected to condensation reaction to obtain a final product 6; the synthesis method has the advantages of simple and easily obtained raw materials, mild conditions, no use of metal catalyst, short synthesis route, no harsh reaction operation conditions, low cost, low toxicity, greenness and no pollution, and can be suitable for synthesizing a large amount of beta-lactam molecules with high efficiency and widely exploring the biological activity of the beta-lactam parent nucleus.

Description

Synthesis method of beta-lactam
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of beta-lactam.
Background
Beta-lactams, also known as azetidin-2-ones, are core structures of many drugs that exert pharmacological actions, exhibiting various pharmacological activities such as anticancer activity, cholesterol absorption inhibitory activity, anti-inflammatory, antidiabetic, etc. In addition, beta-lactam can be used as an intermediate of organic synthesis, is considered to be one of the most ideal synthesis intermediates, and chiral beta-lactam is used as a synthetic building block in asymmetric and racemic synthesis.
The synthesis of beta-lactams from beta-amino acids is a class of classical and efficient methods in common use, and some literature reports on the synthesis of beta-amino acids.
Karl Anker Jorgensen et al in Copper-Catalyzed Enatioselective Henry Reactions of alpha-Keto Esters An Easy Entry to OpticallyActive beta-Nitro-alpha-hydroxy Esters and beta-Amino-alpha-hydroxy Esters [ J ]]The method comprises the steps of carrying out a first treatment on the surface of the Journal of Organic Chemistry, 2002 reports a synthesis method of beta-amino-alpha-hydroxycarboxylic acid esters, which comprises the following specific routes: cu (OTf) was added to the burned Schlenk tube 2 (0.100 mmol) and 2,2' -isopropylidenebis [ (4. S) -4-tert-butyl-2-oxazoline](0.105 mmol); stirring for 2 hours under nitrogen protection, adding dry freshly distilled MeNO 2 (2 mL), after stirring for 1 hour, α -ketoester (0.5 mmol) was added followed by triethylamine (0.1 mmol); after 16 hours of reaction, the reaction solution is filtered by a truncated silica gel column, the filtrate is collected and the solvent is spin-dried, the obtained product is separated by fast column chromatography to obtain beta-nitro-alpha-hydroxy carboxylic ester, and the compound is obtained by Raney nickel catalytic hydrogenationTo beta-amino-alpha-hydroxycarboxylic acid esters. The method uses a Cu catalyst, so that the reaction has a restriction on application: on one hand, the use of heavy metal Cu can cause damage to the environment; on the other hand, cu is easy to oxidize so that the catalyst is deactivated, and especially when the humidity in the environment is high, cu is more easy to oxidize, so that the reaction needs to be carried out under anhydrous and anaerobic conditions, and the reaction conditions are severe.
Volkmar Wendisch et al Stereoselective Michael addition of trimethyl aluminium to nitro acrylates: a route to2-methyl-3-amino propionic acid [ J ]; tetrahedron: asymmetry,2003 reports a synthesis method of beta-amino-alpha-hydroxycarboxylic acid ester, which has the specific route: 30 mg copper (II) trifluoromethane sulfonate and 94 mg Feringa's BINAP are dissolved in 30 mL diethyl ether, stirred under nitrogen for 1 hour, and then 0.3 mL diethyl zinc solution (1N in hexane) is added; the orange solution obtained was cooled to a prescribed temperature and trialkylaluminum was added dropwise via syringe. After stirring at this temperature for 30 minutes, nitroacrylate (0.0083 mol) in 10mL diethyl ether was added and stirring continued for 60 minutes; the solution was quenched with 30 mL of 2m hydrochloric acid, then warmed to room temperature, the organic layer was separated, washed twice with water, dried, the solvent was spun dry, and column chromatography was performed to give the target product. In the method, besides the Cu catalyst, an aluminum reagent is needed, and the use of a metal reagent is not friendly to the environment, so that the method is one of adverse reasons for restricting the use of the reaction; in addition, aluminum alkyls are extremely reactive and improperly used, especially when exposed to moisture, can produce severe exothermic phenomena, thus imposing stringent requirements on the reaction conditions and operation.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of beta-lactam, which does not use a metal catalyst, has a short synthesis route and constructs a beta-lactam skeleton by efficiently synthesizing beta-amino acid.
In the synthesis provided by the present invention, a MAC reagent, i.e. protected hydroxymalononitrile, also known as masked acyl cyanide, is used, a versatile polarity reversing synthon. Beta-nitroolefin 1a and MAC reagent 2 are used as template substrates to react to obtain an intermediate 3a, the compound is treated by acid to generate equivalent nucleophilic acyl anions, the anions can react with water to obtain corresponding carboxylic acid 4, the compound 4 is reduced by hydrogen to obtain a compound 5, and the compound 5 is subjected to condensation reaction to obtain a final product 6.
In order to achieve the above purpose, we have screened the synthesis conditions of the key intermediate 3, and found that the target product 3a can be obtained in high yield under the room temperature condition by using trans-nitrostyrene 1a,2- (methoxyl methoxy) malononitrile as a raw material 2 and an amino acid derived thiourea difunctional compound Catalyst A (called CatA for short) as a Catalyst and methylene dichloride as a solvent.
In addition, in order to synthesize chiral beta-lactam skeleton, the reaction was screened under chiral conditions, and the ee value of the compound 3a was 83% and the yield was 80% at 0 ℃ by using amino acid-derived square amide bifunctional compound Catalyst E as a Catalyst. If the chiral compound 3a' is subjected to subsequent reaction, a chiral beta-lactam compound can be obtained.
。
The invention has the following beneficial effects:
1. the method takes trans-nitrostyrene and 2- (methoxyl) malononitrile as raw materials, cat A as a catalyst and methylene dichloride as a key intermediate 3 of solvent reaction, the raw materials of the reaction are simple and easy to obtain, the condition is mild, a metal catalyst is not used in the method, the synthetic route is shorter, the reaction operation condition is not harsh, and the method is cheaper, low in toxicity, green and pollution-free.
2. The method can be suitable for synthesizing the beta-lactam molecules in large quantity and high efficiency, and is used for widely exploring the biological activity of the beta-lactam parent nucleus. On the one hand, because of the various pharmacological activities shown by the beta-lactam derivative, various unknown medicaments with pharmacological activities can be synthesized by molecular hybridization or other methods based on the beta-lactam, so that experiments of late pharmacology, toxicology, pharmacokinetics effect kinetics and the like can be carried out, the safety, stability and effectiveness of the medicaments are researched, and further, new medicaments for treating diseases are developed. On the other hand, for some known drugs which have been widely used clinically, it may act as a precursor in the total synthesis of the drug, such as the anticancer drug taxol analog. In addition, the application of beta-lactam in organic synthesis is very wide, and the beta-lactam can be used for ring opening to form various heterocyclic compounds and amino compounds and can also be used as a substrate for a plurality of reactions.
Drawings
FIG. 1 is a racemization HPLC profile of Compound 3 a;
FIG. 2 is a chiral HPLC profile of compound 3 a'.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent.
Preparation of intermediate 3
Trans-nitrostyrene, 2- (methoxyl) malononitrile are used as raw materials, cat A is used as a catalyst, and methylene dichloride is used as a solvent for reaction to obtain a key intermediate 3.
The reaction general formula is as follows:
。
example 1
Beta-trans nitroolefin 1a (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat a (0.05 mmol, 10 mol%) and solvent (2.5 mL) were added to a 10mL reaction tube, followed by the addition of a magneton. Stirring the reaction solution at normal temperature for reactionStopping the reaction after 12 hours, and concentrating the obtained crude product in vacuum; the crude product was purified by column chromatography to give intermediate 3a as a white solid in a yield of 98% as 135 mg. The racemization HPLC profile of Compound 3a of FIG. 1. ESI-HRMS m/z C 13 H 14 N 3 O 4 (M+H) + Calculated 276.0984, measured 276.0980. 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 – 7.39 (m, 5H), 5.09 (dd,J= 13.2, 8.8 Hz, 1H), 5.06 (s, 2H,), 4.95 (dd,J= 13.2, 5.6 Hz, 1H), 4.31 (dd,J= 8.8, 5.6 Hz, 1H), 3.50 (d,J= 1.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 130.4, 130.0, 129.5 (2C), 129.3 (2C), 111.6, 111.2, 96.9, 74.2, 68.6, 57.7,51.5 ppm。
Example 2
To a 10mL reaction tube were added compound 1b (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), followed by addition of a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give product 3b as a white solid in a yield of 96% and 148% mg. ESI-HRMS m/z C 13 H 13 ClN 3 O 4 (M+H) + Calculated 310.0595, measured 310.0592. 1 H NMR (600 MHz, CDCl 3 ) δ 7.55 (dd,J= 7.2, 1.8 Hz, 2H), 7.44 – 7.36 (m, 2H), 5.23 (dd,J= 9.0, 5.4 Hz, 1H), 5.16 – 5.06 (m, 3H), 4.94 (dd,J= 13.8, 9.0 Hz, 1H), 3.54 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 136.3, 131.4, 131.0, 128.4, 128.4, 127.8, 111.2, 111.0, 96.9, 74.2, 67.4, 57.8, 46.2 ppm。
Example 3
To a 10mL reaction tube were added compound 1c (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), followed by addition of a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product obtained was purified by column chromatography to give 3c as a white solid in 168mg in 95% yield. ESI-HRMS m/z C 13 H 13 BrN 3 O 4 (M+H) + Calculated 354.0089, measured 354.0092. 1 H NMR (600 MHz, CDCl 3 ) δ 7.73 (dd,J= 8.0, 1.3 Hz, 1H), 7.54 (dd,J= 7.8, 1.6 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.35 – 7.30 (m, 1H), 5.24 (dd,J= 9.0, 5.4 Hz, 1H), 5.12 – 5.08 (m, 3H), 4.94 (dd,J= 13.8, 9.0 Hz, 1H), 3.54 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 134.4, 131.6, 130.1, 128.5, 128.4, 127.3, 111.2, 111.0, 96.9, 74.3, 67.4, 57.8, 48.8 ppm。
Example 4
To a 10mL reaction tube were added compound 1d (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), followed by addition of a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product obtained was purified by column chromatography to give 3c as a white solid, which was 147mg in 93% yield. ESI-HRMS m/z C 13 H 13 N 4 O 6 (M+H) + Calculated 321.0835, measured 321.0833. 1 H NMR (600 MHz, CDCl 3 ) δ 8.11 (dd,J= 8.4, 1.2 Hz, 1H), 7.77 – 7.72 (m, 2H), 7.68 – 7.64 (m, 1H), 5.16 – 5.04 (m, 5H), 3.52(s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 150.5, 133.9, 131.2, 128.5, 126.5, 125.5, 111.1, 111.1, 97.0, 73.8, 67.1, 57.9, 44.0ppm。
Example 5
To a 10mL reaction tube were added compound 1e (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), followed by addition of a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product obtained was purified by column chromatography to give 3e as a white solid, which was 143mg in 94% yield. ESI-HRMS m/z C 14 H 16 N 3 O 5 (M+H) + Calculated 306.1090, measured 306.1094. 1 H NMR (600 MHz, CDCl 3 ) δ 7.36 (t,J= 7.8 Hz, 1H), 7.04 – 7.01 (m, 1H), 7.00 – 6.96 (m, 2H), 5.11 – 5.06 (m, 3H), 4.94 (dd,J= 13.8, 8.4 Hz, 1H), 4.30 (dd,J= 8.4, 5.4 Hz, 1H), 3.83 (s, 3H), 3.53 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 160.1, 131.4, 130.6, 121.3, 115.6, 115.3, 111.7, 111.2, 96.9, 74.3, 68.6, 57.8, 55.4, 51.5 ppm。
Example 6
To a 10mL reaction tube were added compound 1f (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally the magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; purifying and separating the crude product by column chromatography to obtainProduct 3f was a white solid, 140 mg in 96% yield. ESI-HRMS m/z C 13 H 13 FN 3 O 4 (M+H) + Calculated 294.0890, measured 294.0887. 1 H NMR (600 MHz, CDCl 3 ) δ 7.47 – 7.43 (m, 2H), 7.18 – 7.13 (m, 2H), 5.11 – 5.07 (m, 3H), 4.94 (dd,J= 13.2, 9.0 Hz, 1H), 4.33 (dd,J= 9.0, 5.4 Hz, 1H), 3.52 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 163.5 (d,J= 340.1 Hz), 131.3(d,J= 8.6 Hz, 2C), 125.8, 116.8(d,J= 21.6 Hz, 2C), 111.6, 111.1, 97.0, 74.2, 68.4, 57.8, 50.9 ppm。
Example 7
To a 10mL reaction tube were added 1g (0.5 mmol, 1.0 equiv) of the compound, 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), the amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and the solvent (2.5 mL), and finally the magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give 3g of a white solid product in a yield of 97% as 150 g mg. ESI-HRMS m/z C 13 H 13 ClN 3 O 4 (M+H) + Calculated 310.0595, measured 310.0591. 1 H NMR (600 MHz, CDCl 3 ) δ 7.46 – 7.42 (m, 2H), 7.41 – 7.38 (m, 2H), 5.11 – 5.06 (m, 3H), 4.94 (dd,J= 13.8, 9.0 Hz, 1H), 4.31 (dd,J= 9.0, 5.4 Hz, 1H), 3.52 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 136.8, 130.7 (2C), 129.8(2C), 128.4, 111.5, 111.0, 97.0, 74.0, 68.2, 57.8, 51.0 ppm。
Example 8
A10 mL reaction tube was charged with compound 1h (05mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), the amino acid-derived thiourea difunctional compound Cat a (0.05 mmol, 10 mol%) and the solvent (2.5 mL), finally the magneton was added. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give a white solid product, 3h, 154 mg in 96% yield. ESI-HRMS m/z C 13 H 13 N 4 O 6 (M+H) + Calculated 321.0835, measured 321.0835. 1 H NMR (600 MHz, CDCl 3 ) δ 8.36 – 8.30 (m, 2H), 7.72 – 7.66 (m, 2H), 5.17 – 5.13 (m, 1H), 5.12 – 5.07 (m, 2H), 5.05 – 5.00 (m, 1H),4.52 – 4.43 (m, 1H), 3.53 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 149.1, 136.9, 130.7 (2C), 124.5 (2C), 111.3, 110.8, 97.2, 73.6, 67.5, 58.0,51.1 ppm。
Example 9
Into a 10mL reaction tube were charged compound 1i (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give product 3i as a white solid in a yield of 93% as 142, 142 mg. ESI-HRMS m/z C 14 H 16 N 3 O 5 (M+H) + Calculated 306.1090, measured 306.1092. 1 H NMR (600 MHz, CDCl 3 ) δ 7.39 – 7.35 (m, 2H), 6.98 – 6.93 (m, 2H), 5.10 – 5.04 (m, 3H), 4.92 (dd,J= 13.2, 8.4 Hz, 1H), 4.29 (dd,J= 8.4, 5.4 Hz, 1H), 3.82 (s, 3H), 3.52 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 161.0, 130.6 (2C), 121.6, 114.8 (2C), 111.8, 111.3, 96.9, 74.3, 68.8, 57.7, 55.3, 51.0 ppm。
Example 10
Into a 10mL reaction tube were charged compound 1j (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product obtained was purified by column chromatography to give 3j as a white solid, which was 157mg in 98% yield. ESI-HRMS m/z C 15 H 18 N 3 O 6 (M+H) + Calculated 336.1196, measured 336.1196. 1 H NMR (600 MHz, CDCl 3 ) δ 7.01 (dd,J= 8.4, 2.4 Hz, 1H), 6.94 – 6.88 (m, 2H), 5.10 – 5.05 (m, 3H), 4.93 (dd,J= 13.8, 8.4 Hz, 1H), 4.28 (dd,J= 8.4, 5.4 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H),3.53 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 150.6, 149.4, 121.9, 121.8, 112.2, 111.8, 111.5, 111.4, 96.9, 74.4, 68.9, 57.8, 56.1, 55.9,51.3 ppm。
Example 11
To a 10mL reaction tube were added compound 1k (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally the magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product obtained was purified by column chromatography to give 3k as a white solid, 150mg, in 94% yield. ESI-HRMS m/z C 14 H 14 N 3 O 6 (M+H) + Calculated 320.0883, measured values320.0880. 1 H NMR (600 MHz, CDCl 3 ) δ 6.94 – 6.89 (m, 2H), 6.85 (d,J= 8.4 Hz, 1H), 6.02 (s, 2H), 5.08 (s, 2H), 5.04 (dd,J= 13.2, 5.4 Hz, 1H), 4.89 (dd,J= 13.2, 9.0 Hz, 1H), 4.24 (dd,J= 9.0, 5.4 Hz, 1H), 3.53 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 149.4, 148.5, 123.6, 123.2, 111.7, 111.2, 109.1, 109.0, 101.8, 96.9, 74.4, 68.6, 57.8,51.4 ppm。
Example 12
To a 10mL reaction tube were added 1l (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), followed by addition of a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give 3l of a white solid product in a yield of 93% as 156, 156 mg. ESI-HRMS m/z C 13 H 13 N 4 O 6 (M+H) + Calculated 321.0835, measured 321.0837. 1 H NMR (600 MHz, CDCl 3 ) δ 8.39 – 8.34 (m, 2H), 7.82 (dt,J= 7.8, 1.4 Hz, 1H), 7.69 (t,J= 7.8 Hz, 1H), 5.17 – 5.04 (m, 4H), 4.46 (dd,J= 9.6, 4.8 Hz, 1H), 3.53 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 148.6, 135.6, 132.4, 130.7, 125.4, 124.3, 111.4, 110.8, 97.2, 73.7, 67.5, 57.9, 51.1 ppm。
Example 13
Into a 10mL reaction tube was charged compound 1m (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), and an amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%)) And solvent (2.5, mL), finally adding magnetons. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give 3m as a white solid in a yield of 90% as 126. 126 mg. ESI-HRMS m/z C 11 H 12 N 3 O 4 S (M+H) + Calculated 282.0549, measured 282.0549. 1 H NMR (600 MHz, CDCl 3 ) δ 7.43 (dd,J= 5.4, 1.2 Hz, 1H), 7.32 – 7.23 (m, 1H), 7.08 (dd,J= 5.4, 3.6 Hz, 1H), 5.10 – 5.05 (m, 3H), 4.88 (dd,J= 13.2, 9.0 Hz, 1H), 4.67 (dd,J= 9.0, 5.4 Hz, 1H), 3.55 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 131.1, 130.1, 128.3, 127.6, 111.6, 111.0, 97.1, 75.4, 68.3, 57.9, 47.7 ppm。
Example 14
Into a 10mL reaction tube were charged compound 1n (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give product 3n as a white solid in 143 mg% yield 89%. ESI-HRMS m/z C 17 H 16 N 3 O 4 (M+H) + Calculated 326.1141, measured 326.1140. 1 H NMR (600 MHz, CDCl 3 ) δ 8.25 (d,J= 8.4 Hz, 1H), 7.99 – 7.91 (m, 2H), 7.75 – 7.67 (m, 2H), 7.61 – 7.52 (m, 2H), 5.45 (dd,J= 7.8, 6.0 Hz, 1H), 5.26 (dd,J= 13.8, 6.0 Hz, 1H), 5.16 – 5.01 (m, 3H), 3.53 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 134.2, 132.0, 131.1, 129.4, 127.6, 126.7, 126.6, 125.9, 125.1, 122.2, 111.6, 111.5,96.9, 75.2, 68.4, 57.8, 44.7 ppm。
Example 15
Into a 10mL reaction tube were added compound 1o (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally the magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give the product 3o as a white solid, 161 mg in 96% yield. ESI-HRMS m/z C 15 H 18 N 3 O 6 (M+H) + Calculated 336.1196, measured 336.1194. 1 H NMR (600 MHz, CDCl 3 ) δ 7.10 (td,J= 7.8, 1.2 Hz, 1H), 7.04 – 6.97 (m, 2H), 5.11 – 5.03 (m, 4H), 4.96 – 4.88 (m, 1H), 3.99 (s,3H), 3.88 (s, 3H), 3.52 (s, 3H) ppm. 13 C NMR (150 MHz, CDCl 3 ) δ 152.9, 148.3, 124.3, 123.8, 119.2, 114.3, 111.8, 111.4, 96.8, 74.6, 68.1,61.3, 57.7, 55.8, 43.7 ppm。
Example 16
To a 10mL reaction tube were added compound 1p (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived thiourea difunctional compound Cat A (0.05 mmol, 10 mol%) and solvent (2.5 mL), followed by addition of a magneton. Stirring the reaction solution at normal temperature for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product was purified by column chromatography to give 3p as a white solid in a yield of 95% as 159 mg. ESI-HRMS m/z C 15 H 18 N 3 O 6 (M+H) + Calculated 336.1196, measured 336.1196. 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (d,J= 1.6 Hz, 1H), 7.18 – 7.09 (m, 2H), 5.10 – 5.02 (m, 3H), 4.92 (dd,J= 13.6, 8.8 Hz, 1H), 4.70 (dd,J= 8.8, 5.6 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.53 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 136.6, 135.4, 131.7, 130.8, 128.6, 127.3, 111.7, 111.3, 96.8, 74.8, 68.1, 57.7, 46.0, 21.1,19.4 ppm。
Example 17
Synthesis of chiral compound 3 a':
to a 10mL reaction tube were added beta-trans nitroolefin 1a (0.5 mmol, 1.0 equiv), 2- (methoxymethoxy) malononitrile 2 (0.6 mmol, 1.2 equiv), amino acid-derived squarylium amide difunctional compound Catalyst E (0.05 mmol, 10 mol%) and solvent (2.5 mL), and finally the magneton. Stirring the reaction solution at 0 ℃ for reaction for 12 hours, stopping the reaction, and concentrating in vacuum to obtain a crude product; the crude product obtained was purified by column chromatography to give the product 3a' as a white solid, 129 mg in 94% yield. ESI-HRMS m/z C 13 H 14 N 3 O 4 (M+H) + Calculated 276.0984, measured 276.0984.HPLC:Chiralpak IC;n-heptane/EtOH = 95:5; flow rate 0.7 mL/min; T= 30 o C; retention time: 8.6 min (minor), 10.72 min (major), ee: 83%。
as shown in fig. 1, a racemization HPLC profile of compound 3a, as shown in fig. 2, a chiral HPLC profile of compound 3 a'. FIG. 1 shows that compound 3a is a racemate which is resolved using a chiral column (model Chiralpak IC) tonThe enantiomers were separated by elution with an equal gradient of heptane/EtOH (95/5) as eluent at a flow rate of 0.7 mL/min, peaking at 8.54 min and 10.78min, respectively. FIG. 2 shows that the product 3a' obtained by catalysis with the chiral catalyst is an optically active compound, and has a high isomer ratio with a peak time of 10.78min and an ee value of 83%.
Example 18
Synthesis of compound 4 a:
in a dry reaction flask were added compound 3a (1.5 mmol), D-camphorsulfonic acid (0.75 mmol) and a volume ratio of 1:1 AcOH/H 2 O (5 mL), heat to 60 ℃. After 15 hours the reaction was completed and the reaction solution was cooled to room temperature, at which point a white solid began to precipitate. The mixture was extracted 3 times with dichloromethane and the organic phase was collected and dried over anhydrous sodium sulfate. After the solvent was dried by spin-drying, compound 4a was obtained as an off-white solid by flash column chromatography in 263 mg with a yield of 93%. ESI-HRMS m/z C 9 H 10 NO 4 (M+H) + Calculated 196.0610, measured 196.0607. 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 – 7.30 (m, 4H), 7.29 – 7.24 (m, 1H), 5.06 (dd,J= 13.6, 5.6 Hz, 1H), 4.90 (dd,J= 13.6, 8.8 Hz, 1H), 4.06 (dd,J= 8.8, 5.6 Hz, 1H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 175.1, 134.9, 130.1 (2C), 129.0 (2C), 127.6, 77.3, 49.5 ppm。
3b-3p→4b-4p and 3a '→4a' are synthesized as above.
Example 19
The synthesis of compound 5a is:
compound 4a (1.35 mmol) and palladium on charcoal (10%, 10% w/w) were dissolved in 10mL methanol and reacted for 12 hours with hydrogen. The reaction solution was filtered through celite, and the filtrate was collected and the solvent was dried to give compound 5a as 189, 189 mg in 85% yield, which was directly used in the next reaction. ESI-HRMSm/z C 9 H 12 NO 2 (M+H) + Calculated 166.0868, measured 166.0868. 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 – 7.24 (m, 5H), 4.02 (dd,J= 8.8, 5.6 Hz, 1H), 3.72-3.68 (m, 1H),3.34 – 3.14 (m, 1H), 2.14 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 177.4, 137.3, 129.0 (2C), 128.3 (2C), 127.7, 50.6, 44.9 ppm。
The synthetic route of 4b-4 p- & gt 5b-5p and 4a '& gt 5a' is the same.
Example 20
The synthetic formula of compound 6 a:
sodium bicarbonate (4 mmol) and compound 5a (1 mmol) were dissolved in 20mL anhydrous acetonitrile under nitrogen, and trifluoromethanesulfonyl chloride (1.1 mmol) was slowly added dropwise with stirring, and then the mixture was stirred in an oil bath at 80 ℃ for further 19 hours. After cooling in an ice bath for 1 hour, the reaction solution was filtered, washed 3 times with anhydrous acetonitrile, the organic phases were combined and the solvent was spin-dried on a rotary evaporator at 35 ℃. Flash column chromatography of the resulting material afforded compound 6a as a white solid in a yield of 52% as 80 mg. ESI-HRMS m/z C 9 H 10 NO (M+H) + Calculated 148.0762, measured 148.0762. 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 – 7.20 (m, 5H), 6.50 (bs, 1H), 4.06 (dd,J= 8.8, 5.6 Hz, 1H), 3.84-3.81 (m, 1H),3.56 – 3.52 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 172.7, 137.9, 128.9 (2C), 128.3 (2C), 127.6, 46.7, 42.8 ppm。
5b-5 p.fwdarw.6b-6 p and 5a '. Fwdarw.6a' are synthesized as above.

Claims (8)

1. The synthesis method of the beta-lactam is characterized by comprising the following specific steps:
trans-nitrostyrene, 2- (methoxyl) malononitrile as a raw material and Cat as a catalyst are reacted by using methylene dichloride as a solvent to obtain an intermediate 3;
reacting the compound 3 with an acid and water to obtain a compound 4;
reducing the compound 4 by hydrogen to obtain a compound 5;
the compound 5 is subjected to condensation reaction to obtain a final product 6;
the synthetic route is as follows:
2. the method for synthesizing beta-lactam according to claim 1, wherein in the step 1), the structural formula of trans-nitrostyrene is any one of the following 1a-1 p:
3. the method for synthesizing beta-lactam according to claim 1 or 2, wherein in the step 1), when Cat is Catalyst a, the reaction yields intermediate 3 corresponding to 3a-3p;
wherein, catalyst A formula is:
the structural formulas of 3a-3p are respectively as follows:
4. the method for synthesizing beta-lactam according to claim 1 or 2, wherein in the step 1), when Cat is Catalyst E, the intermediate 3 obtained by the reaction is a chiral compound 3a';
wherein, the Catalyst E structure is:
the chiral compound 3a' has the structure:
5. the method for synthesizing beta-lactam according to claim 1, wherein the step 1) is specifically:
0.5mmol of trans-nitrostyrene, 0.6mmol of 2- (methoxyl) malononitrile, 0.05mmol of 10mol percent Cat and 2.5mL of dichloromethane are added into a 10mL reaction tube, and finally magneton is added, the reaction solution is stirred at normal temperature for reaction for 12 hours, then the reaction is stopped, and a crude product is obtained by vacuum concentration; the crude product is purified and separated by column chromatography to obtain an intermediate 3.
6. The method for synthesizing beta-lactam according to claim 1, wherein the step 2) is specifically: into a dry reaction flask were charged 1.5mmol of intermediate 3, 0.75mmol of D-camphorsulfonic acid and 5ml of AcOH/H in a volume ratio of 1:1 2 O, heating to 60 ℃, reacting for 15 hours, cooling to room temperature, at the moment, separating out white solid, extracting with dichloromethane for 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, spin-drying a solvent, and obtaining an off-white solid compound 4 through flash column chromatography.
7. The method for synthesizing beta-lactam according to claim 1, wherein the step 3) specifically comprises: 1.35mmol of compound 4 and 10% w/w palladium on charcoal are dissolved in 10mL of methanol, hydrogen is introduced to react for 12 hours, the reaction solution is filtered by diatomite, and the filtrate is collected and the solvent is dried by spin to obtain compound 5; wherein the mass ratio of the compound 4 to the palladium on charcoal of 10% w/w is 9:1.
8. The method for synthesizing beta-lactam according to claim 1, wherein the step 4) is specifically: under the protection of nitrogen, 4mmol of hydrogen carbonate and 1mmol of compound 5 are dissolved in 20mL of anhydrous acetonitrile, 1.1mmol of trifluoromethanesulfonyl chloride is dropwise added under stirring, then the mixture is continuously stirred in an oil bath at 80 ℃ for 19 hours, then the mixture is cooled in the ice bath for 1 hour, the reaction solution is filtered, the mixture is washed 3 times with the anhydrous acetonitrile, the organic phases are combined, the solvent is dried by spinning at 35 ℃, and the obtained product can be obtained by flash column chromatography.
CN202310262908.9A 2023-03-17 2023-03-17 Synthesis method of beta-lactam Pending CN117105838A (en)

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