CN116621756A - Preparation method of 3, 3-difluoro-gamma-lactam compound - Google Patents

Preparation method of 3, 3-difluoro-gamma-lactam compound Download PDF

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CN116621756A
CN116621756A CN202310595622.2A CN202310595622A CN116621756A CN 116621756 A CN116621756 A CN 116621756A CN 202310595622 A CN202310595622 A CN 202310595622A CN 116621756 A CN116621756 A CN 116621756A
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difluoro
nmr
gamma
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刘小卒
刘培均
张艺菲
江斌
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Zunyi Medical University
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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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The application discloses a preparation method of a 3, 3-difluoro-gamma-lactam compound in the field of organic synthesis chemistry, which takes vinyl azide and ethyl difluoroiodoacetate as raw materials and uses Et as a raw material 2 In the presence of Zn, in anhydrous acetonitrile, reacting for 3 hours at the temperature of minus 10 ℃ to synthesize a series of 3, 3-difluoro-gamma-lactam compounds containing C-5 quaternary carbon centers, wherein the reaction formula is as follows:

Description

Preparation method of 3, 3-difluoro-gamma-lactam compound
Technical Field
The application belongs to the field of organic synthetic chemistry, and particularly relates to a preparation method of a 3, 3-difluoro-gamma-lactam compound.
Background
The introduction of fluorine atoms or fluorine-containing groups, etc., into the organic compound will greatly improve the biological activity and physicochemical properties of the parent molecule. Wherein difluoromethylene (-CF) 2 ) As a representative fluorine-containing groupIt is considered a metabolically stable bioisostere of hydroxyl, thiol and carbonyl groups, and thus its introduction into target molecules is of continued interest to pharmaceutical chemists and synthetic chemists. Gamma-lactams are an important building block, are widely found in many natural products and drug molecules, and exhibit good antibacterial, antifungal and antitumor biological activities. The synthesis method of 3, 3-difluoro-gamma-lactam compound mainly comprises two types of intramolecular free radical cyclization reaction and free radical addition/intramolecular cyclization reaction. The method is characterized in that N-allyl bromodifluoroacetamide is used as a raw material, and 3, 3-difluoro-gamma-lactam compound is prepared through intramolecular free radical cyclization reaction under the catalysis of transition metal or the induction of visible light; the other is catalyst or oxidant Na of olefin and halogenated difluoro acetamide in transition metal 2 S 2 O 4 Under the action, amino difluoro alkylation of olefin is realized through intermolecular free radical addition/cyclization reaction, and the target 3, 3-difluoro-gamma-lactam compound is obtained.
1) Intramolecular radical cyclization reaction
2) Intermolecular radical addition/cyclization reaction
However, the above methods lack wide substrate versatility and synthetic practicality, have limitations for the preparation of complex derivatives, and are difficult to apply to the structural modification of drug molecules.
Disclosure of Invention
The application designs a preparation method of a 3, 3-difluoro-gamma-lactam compound aiming at the defects of the prior art.
An object of the present application is to provide a process for producing a 3, 3-difluoro-gamma-lactam compound from vinyl azide and ethyl difluoroiodoacetate as starting materials in Et 2 Zn presenceThen, a series of 3, 3-difluoro-gamma-lactam compounds containing C-5 quaternary carbon centers are synthesized by reacting for 3 hours at minus 10 ℃ in anhydrous acetonitrile, wherein the reaction formula is as follows:
wherein R is one of a substituted or unsubstituted aryl group and a substituted or unsubstituted alkyl group.
The aryl is phenyl, biphenyl, naphthyl, thienyl or furyl.
The alkyl is C1-C10 alkyl. Further C3-C6 alkyl.
Further, "substituted" in the "substituted or unsubstituted" means that at least one hydrogen atom on the group is substituted with a group selected from the group consisting of: hydrogen atom, halogen atom, methyl, ethyl, propyl, butyl, methoxy, acetyl, acetoxy, methoxycarbonyl, benzoyloxymethyl, tert-butyl, benzoyloxy.
Further, R is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-acetylphenyl, 4-acetoxyphenyl, 4-methoxycarbonylphenyl, 4-benzoyloxymethylphenyl, 4-t-butylphenyl, biphenyl, 3-methylphenyl, 3-bromophenyl; 3-thienyl, 5-benzofuranyl, cyclohexyl, n-hexyl, 4-methoxycarbonyl n-butyl or 3-benzoyloxy n-propyl.
Further, the above reaction was carried out under argon.
Further, after the reaction is finished, concentrating under vacuum; eluting with petroleum ether/ethyl acetate, and separating with silica gel column to obtain 3, 3-difluoro-gamma-lactam compound.
Further, the molar ratio of ethyl difluoroiodoacetate to vinyl azide is 1.2:1.
Further, the Et 2 The molar ratio of Zn to vinyl azide was 0.5:1.
Further, the solvent anhydrous acetonitrile was added in an amount 200 times that of the vinyl azide compound.
The application has the beneficial effects that: the application mainly provides a synthesis method of the 3, 3-difluoro-gamma-lactam compound, which has the advantages of mild reaction conditions, high step economy, high atom economy, short reaction time, good substrate universality, easily obtained raw materials, environmental friendliness and the like.
The second object of the present application is to provide a series of compounds shown in 1 a-1 n, which are novel compounds, and since 3, 3-difluoro-gamma-lactam compounds are an important type of framework structure, they have wide application in the fields of organic synthesis and pharmaceutical chemistry.
Drawings
FIG. 1 is a 1H-NMR chart of compound 1 a.
FIG. 2 is a 13C-NMR chart of compound 1 a.
FIG. 3 is a 1H-NMR chart of compound 1 b.
FIG. 4 is a 13C-NMR chart of compound 1 b.
FIG. 5 is a 1H-NMR chart of compound 1 c.
FIG. 6 is a 13C-NMR chart of compound 1C.
FIG. 7 is a 1H-NMR chart of compound 1 d.
FIG. 8 is a 13C-NMR chart of compound 1 d.
FIG. 9 is a 1H-NMR chart of compound 1 e.
FIG. 10 is a 13C-NMR chart of compound 1 e.
FIG. 11 is a 1H-NMR chart of compound 1 f.
FIG. 12 is a 1H-NMR chart of compound 1 g.
FIG. 13 is a 1H-NMR chart of compound 1H.
FIG. 14 is a 1H-NMR chart of compound 1 i.
FIG. 15 is a 1H-NMR chart of compound 1 j.
FIG. 16 is a 1H-NMR chart of compound 1 k.
FIG. 17 is a 1H-NMR chart of compound 1 l.
FIG. 18 is a 1H-NMR chart of compound 1 m.
FIG. 19 is a 1H-NMR chart of compound 1 n.
Detailed Description
The following is a further detailed description of the embodiments:
example 1: synthesis of methyl 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzoate (1 a)
Methyl 4- (1-azido vinyl) benzoate (101.5 mg,0.5 mmol) was added to a dry 25mL reaction tube under argon, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added with stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a reaction bath with stirring at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:5) to give methyl 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzoate (1 a) as a yellow solid (99.8 mg, 67%), m.p.137.4-138.3 ℃. 1 H NMR(400MHz,Chloroform-d)δ8.73(s,1H),8.10(d,J＝8.6Hz,2H),7.53(d,J＝8.6Hz,2H),3.94(s,3H),3.47–3.41(m,1H),3.29–3.22(m,1H),3.04(td,J＝16.1,4.9Hz,1H),2.59(q,J＝16.1Hz,1H),1.22(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ167.6(t,J＝31.2Hz),166.3,144.3(d,J＝2.2Hz),130.9,130.5,125.4,116.7(t,J＝251.8Hz),88.6(dd,J＝8.7,2.0Hz),59.3,52.4(d,J＝2.6Hz),47.0(t,J＝21.5Hz),15.0. 19 F NMR(376MHz,Chloroform-d)δ-103.1(dt,J＝281.5,16.5Hz,1F),-106.53(d,J＝275.1Hz,1F).HRMS(ESI)calcad for C 14 H 15 F 2 NNaO 4 + ([M+Na] + ):322.0861,found 322.0872.
Example 2: synthesis of 5-ethoxy-3, 3-difluoro-5- (4-fluorophenyl) pyrrolidin-2-one (1 b)
1- (1-azidoethyl) -4-fluorobenzene (81.5 mg,0.5 mmol) was added to a dry 25mL reaction tube under argon, anhydrous MeCN (5 mL) was added with stirringEthyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added thereto, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a reaction bath with stirring at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:8) to give 5-ethoxy-3, 3-difluoro-5- (4-fluorophenyl) pyrrolidin-2-one (1 b) as a white solid (92.9 mg, 71%), m.p.136.3-137.1 ℃. 1 H NMR(400MHz,Chloroform-d)δ9.19(s,1H),7.43(dd,J＝8.7,5.2Hz,2H),7.13(t,J＝8.6Hz,2H),3.45–3.38(m,1H),3.29–3.21(m,1H),3.02(td,J＝16.3,4.9Hz,1H),2.58(q,J＝16.1Hz,1H),1.20(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Acetone-d 6 )δ165.6(t,J＝30.6Hz),162.8(d,J＝245.8Hz),136.5(d,J＝2.7Hz),127.9(d,J＝8.6Hz),117.3(t,J＝249.9Hz),115.5(d,J＝21.8Hz),88.0(dd,J＝9.5,2.1Hz),58.5,46.8(t,J＝21.4Hz),14.6. 19 F NMR(376MHz,Chloroform-d)δ-103.2(dt,J＝275.8,13.3Hz,1F),-106.7(dt,J＝274.6,15.6Hz,1F),-112.4(s,1F).HRMS(ESI)calcad for C 12 H 12 F 3 NNaO 2 + ([M+Na] + ):282.0712,found 282.0721.
Example 3: synthesis of phenyl 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) acetate (1 c)
Into a dry 25mL reaction tube under argon, phenyl 4- (1-azido vinyl) acetate (101.5 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a reaction bath with stirring at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:6) to give phenyl 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) acetate (1 c) as a white solid (94.6 mg, 64%), m.p.105.2-105.9 ℃. 1 H NMR(400MHz,Chloroform-d)δ8.96(s,1H),7.45(d,J＝8.6Hz,2H),7.15(d,J＝8.6Hz,2H),3.45–3.37(m,1H),3.30–3.22(m,1H),3.01(td,J＝16.3,4.5Hz,1H),2.60(q,J＝16.0Hz,1H),2.31(s,3H),1.19(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ169.3,167.5(t,J＝31.0Hz),151.1,137.0(d,J＝2.2Hz),126.5,122.3,116.8(t,J＝252.3Hz),88.5(dd,J＝9.0,1.9Hz),59.1,47.2(t,J＝21.6Hz),21.1,15.0. 19 F NMR(376MHz,Chloroform-d)δ-103.1(dt,J＝276.2,17.1Hz,1F),-106.6(dd,J＝274.7,11.8Hz,1F).HRMS(ESI)calcad for C 14 H 15 F 2 NNaO 4 + ([M+Na] + ):322.0861,found 322.0872.
Example 4: synthesis of 5-methoxy-5- (4-ethylphenyl) -3, 3-difluoropyrrolidin-2-one (1 d)
1- (1-azidoethyl) -4-ethylbenzene (86.6 mg,0.5 mmol) was added to a dry 25mL reaction tube under argon, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring at-10 ℃ Drop-down Et 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was maintained at-10 in a low temperature constant temperature stirred reaction bath ℃ The reaction was continued for 3h and the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:10) to give 5-methoxy-5- (4-ethylphenyl) -3, 3-difluoropyrrolidin-2-one (1 d) as a brown oily liquid (85.0 mg, 63%). 1 H NMR(400MHz,Chloroform-d)δ8.51(s,1H),7.33(d,J＝8.2Hz,2H),7.26(d,J＝8.2Hz,2H),3.43–3.36(m,1H),3.31–3.24(m,1H),3.06–2.97(m,1H),2.70–2.54(m,3H),1.26–1.19(m,6H). 13 C NMR(101MHz,Chloroform-d)δ167.6(t,J＝31.2Hz),145.3,136.6(d,J＝2.1Hz),128.6,125.1,117.0(t,J＝252.4Hz),88.8(dd,J＝8.8,2.2Hz),59.0,47.3(t,J＝21.3Hz),28.5,15.4,15.1. 19 F NMR(376MHz,Chloroform-d)δ-103.1(dt,J＝275.1,16.8Hz,1F),-106.73(dd,J＝274.9,16.5Hz,1F).HRMS(ESI)calcad for C 14 H 17 F 2 NNaO 2 + ([M+Na] + ):292.1120,found 292.1118.
Example 5: synthesis of 5- (3-bromophenyl) -5-ethoxy-3, 3-difluoropyrrolidin-2-one (1 e)
1- (1-azidoethyl) -3-bromobenzene (111.5 mg,0.5 mmol) was added to a dry 25mL reaction tube under argon, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added with stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10deg.C in a reaction bath with stirring at a low temperature and constant temperature for further reaction for 3 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column (ethyl acetate/petroleum ether=1:10) to give 5- (3-bromophenyl) -5-ethoxy-3, 3-difluoropyrrolidin-2-one (1 e) as a white solid (105.5 mg, 66%), m.p.131.9-132.6deg.C. 1 H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.59(s,1H),7.53(d,J＝8.1Hz,1H),7.38(d,J＝7.9Hz,1H),7.32(t,J＝7.8Hz,1H),3.48–3.40(m,1H),3.31–3.23(m,1H),3.01(td,J＝16.2,4.9Hz,1H),2.59(q,J＝16.2Hz,1H),1.22(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Acetone-d 6 )δ166.4(t,J＝30.7Hz),143.9(d,J＝2.4Hz),132.7,131.7,129.6,125.5,123.3,118.1(t,J＝250.1Hz),88.6(dd,J＝9.5,2.2Hz),59.5,47.3(t,J＝21.7Hz),15.4. 19 F NMR(376MHz,Chloroform-d)δ-103.1(dt,J＝275.8,17.1Hz,1F),-106.6(dd,J＝275.8,16.5Hz,1F).HRMS(ESI)calcad for C 12 H 12 BrF 2 NNaO 2 + ([M+Na] + ):341.9920,found 341.9912.
Example 6: synthesis of benzyl 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzoate (1 f)
Benzyl 4- (1-azido vinyl) benzoate (139.6 mg,0.5 mmol) was added to a dry 25mL reaction tube under argon, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added with stirring, and the mixture was stirred at room temperatureEt is added dropwise at 10 DEG C 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a reaction bath with stirring at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:7) to give benzyl 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzoate (1 f), a white solid (118.6 mg, 63%), m.p.119.1-119.5 ℃. 1 H NMR(400MHz,Chloroform-d)δ8.54(s,1H),8.17–7.94(m,2H),7.58(t,J＝7.4Hz,1H),7.52(d,J＝8.2Hz,2H),7.47–7.43(m,4H),5.38(s,2H),3.46–3.39(m,1H),3.32–3.24(m,1H),3.03(td,J＝16.4,4.7Hz,1H),2.60(q,J＝16.1Hz,1H),1.22(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ167.6(t,J＝31.1Hz),166.4,139.5(d,J＝2.2Hz),137.2,133.2,129.8,129.7,128.9,128.4,125.5,116.9(d,J＝251.3Hz),88.6(dd,J＝8.7,2.0Hz),65.9,59.1,47.2(t,J＝21.6Hz),15.1. 19 F NMR(376MHz,Chloroform-d)δ-99.96(dt,J＝275.4,17.1Hz,1F),-103.49(dd,J＝275.5,16.1Hz,1F).HRMS(ESI)calcad for C 20 H 19 F 2 NNaO 4 + ([M+Na] + ):398.1174,found 398.1184.
Example 7: synthesis of 5-ethoxy-3, 3-difluoro-5- (thiophen-3-yl) pyrrolidin-2-one (1 g)
Under the protection of argon, 3- (1-azidoethyl) thiophene (75.5 mg,0.5 mmol) was added to a dry 25mL reaction tube, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10deg.C in a reaction bath with stirring at a low temperature and constant temperature for further reaction for 3 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column (ethyl acetate/petroleum ether=1:10) to give 5-ethoxy-3, 3-difluoro-5- (thiophen-3-yl) pyrrolidin-2-one (1 g), as a white solid (82.2 mg, 67%), m.p.110.7-111.4deg.C. 1 H NMR(400MHz,Chloroform-d)δ8.71(s,1H),7.40(dd,J＝5.0,3.0Hz,1H),7.34(dd,J＝2.9,1.3Hz,1H),7.07(dd,J＝5.0,1.2Hz,1H),3.46–3.38(m,1H),3.34–3.26(m,1H),3.07–2.98(m,1H),2.75–2.64(m,1H),1.19(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ167.4(t,J＝31.1Hz),141.2(d,J＝2.4Hz),127.9,125.0,122.7,116.9(dd,J＝252.5,251.1Hz),86.7(dd,J＝8.8,2.5Hz),59.2,46.4(t,J＝21.6Hz),15.1. 19 F NMR(376MHz,Chloroform-d)δ-102.8(d,J＝275.5Hz,1F),-106.4(d,J＝275.5Hz,1F).HRMS(ESI)calcad for C 10 H 11 F 2 NNaO 2 S + ([M+Na] + ):270.0381,found 270.0371.
Example 8: synthesis of propyl 3- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzoate (1 h)
Into a dry 25mL reaction tube under argon protection, 4-azidopent-4-en-1-yl benzoate (115.6 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring, et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a stirred reaction bath at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:4) to give propyl 3- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzoate (1 h), a white solid (108.3 mg, 66%), m.p.64.4-65.1 ℃. 1 H NMR(400MHz,Chloroform-d)δ8.03(d,J＝7.3Hz,2H),7.67(s,1H),7.57(t,J＝7.4Hz,1H),7.45(t,J＝7.7Hz,2H),4.36(t,J＝6.0Hz,2H),3.48–3.37(m,2H),2.77–2.66(m,1H),2.60–2.48(m,1H),2.08–1.86(m,4H),1.19(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ166.5,166.0(t,J＝30.5Hz),133.1,129.9,129.5,128.4,117.0(dd,J＝251.7,250.3Hz),87.3(dd,J＝7.0,3.2Hz),64.1,57.6,41.0(t,J＝21.9Hz),36.4(d,J＝2.0Hz),22.8,15.1. 19 F NMR(376MHz,Chloroform-d)δ-102.8(dd,J＝276.8,12.9Hz,1F),-104.6(dd,J＝276.3,10.0Hz,1F).HRMS(ESI)calcad for C 16 H 19 F 2 NNaO 4 + ([M+Na] + ):350.1174,found 350.1178.
Example 9: synthesis of 5-cyclohexyl-5-ethoxy-3, 3-difluoropyrrolidin-2-one (1 i)
Under the protection of argon, in a dry 25mL reaction tube, (1-azido vinyl) cyclohexane (75.6 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring, et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10deg.C in a reaction bath with stirring at a low temperature and constant temperature for further reaction for 3 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column (ethyl acetate/petroleum ether=1:10) to give 5-cyclohexyl-5-ethoxy-3, 3-difluoropyrrolidin-2-one (1 i) as a white solid (64.2 mg, 52%), m.p.71.3-71.9 ℃. 1 H NMR(400MHz,Chloroform-d)δ7.74(s,1H),3.44–3.32(m,2H),2.65–2.45(m,2H),1.80(d,J＝11.5Hz,3H),1.72–1.66(m,3H),1.28–0.99(m,8H). 13 C NMR(101MHz,Chloroform-d)δ166.1(t,J＝30.9Hz),117.2(t,J＝250.6Hz),89.9(dd,J＝7.3,2.8Hz),57.1,45.6(d,J＝1.8Hz),38.2(t,J＝21.9Hz),26.7,26.3,26.1,25.81,25.80,15.1. 19 F NMR(376MHz,Chloroform-d)δ-101.8–-102.6(m,1F),-104.4–-105.2(m,1F).HRMS(ESI)calcad for C 12 H 19 F 2 NNaO 2 + ([M+Na] + ):270.1276,found 270.1280.
Example 10: synthesis of methyl 5- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) pentanoate (1 j)
Under the protection of argon, in a dry 25mL reaction tube, (1-azido vinyl) cyclohexane (91.6 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring, et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was maintained at-10℃in a stirred reaction bath at a low temperatureThe reaction was continued for 3h, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:4) to give methyl 5- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) pentanoate (1 j) as a yellow oily liquid (71.5 mg, 57%). 1 H NMR(400MHz,Chloroform-d)δ7.63(s,1H),3.65(s,3H),3.43–3.32(m,2H),2.69–2.59(m,1H),2.53–2.41(m,1H),2.32(t,J＝7.3Hz,2H),1.90–1.82(m,1H),1.78–1.72(m,1H),1.68–1.60(m,2H),1.44–1.36(m,2H),1.15(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ173.8,165.9(t,J＝30.9Hz),117.1(t,J＝250.2Hz),87.4(dd,J＝7.1,3.1Hz),57.5,51.6,41.0(t,J＝21.7Hz),39.1(d,J＝2.2Hz),33.6,24.5,22.6,15.1. 19 F NMR(376MHz,Chloroform-d)δ-103.1(dd,J＝275.2,15.4Hz,1F),-105.4(d,J＝276.1Hz,1F).HRMS(ESI)calcad for C 12 H 19 F 2 NNaO 4 + ([M+Na] + ):302.1174,found 302.1179.
Example 11: synthesis of 5-ethoxy-3, 3-difluoro-5-hexylpyrrolidin-2-one (1 k)
Into a dry 25mL reaction tube under argon, 2-azidooctan-1-ene (76.6 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added under stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a stirred reaction bath at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:8) to give 5-ethoxy-3, 3-difluoro-5-hexylpyrrolidin-2-one (1 k) as a colorless oily liquid (59.5 mg, 58%). 1 H NMR(400MHz,Chloroform-d)δ7.48(s,1H),3.45–3.34(m,2H),2.71–2.61(m,1H),2.56–2.44(m,1H),1.90–1.83(m,1H),1.75–1.68(m,1H),1.37–1.28(m,8H),1.18(t,J＝7.0Hz,3H),0.88(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ166.2(t,J＝31.5Hz),117.3(t,J＝250.7Hz),87.7(dd,J＝7.2,2.8Hz),57.5,41.2(t,J＝21.7Hz),39.1,31.5,29.0,23.1,22.5,15.2,14.0. 19 F NMR(376MHz,Chloroform-d)δ-103.0(dt,J＝275.7,15.9Hz,1F),-105.0–-105.8(m,1F).HRMS(ESI)calcad for C 12 H 21 F 2 NNaO 2 + ([M+Na] + ):272.1433,found 272.1441.
Example 12: synthesis of 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzyl 4- (N, N-di-N-propylamine sulfonyl) benzoate (1 l)
Into a dry 25mL reaction tube under argon, 4- (1-azidoethyl) benzyl 4- (N, N-di-N-propylaminosulfonyl) benzoate (221.1 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added with stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane), kept at-10℃in a reaction bath with stirring at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:4) to give 4- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) benzyl 4- (N, N-di-N-propylaminosulfonyl) benzoate (1L), colorless oily liquid (181.9 mg, 68%). 1 H NMR(400MHz,Chloroform-d)δ8.79(s,1H),8.19(d,J＝8.6Hz,2H),7.88(d,J＝8.6Hz,2H),7.52(d,J＝8.3Hz,2H),7.47(d,J＝8.4Hz,2H),5.40(s,2H),3.46–3.39(m,1H),3.31–3.23(m,1H),3.11–2.98(m,5H),2.60(q,J＝16.2Hz,1H),1.58–1.49(m,4H),1.21(t,J＝7.0Hz,3H),0.86(t,J＝7.4Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ167.7(t,J＝29.6Hz),165.0,144.3,139.8,136.5,133.1,130.3,129.1,127.0,125.6,116.9(t,J＝252.1Hz),88.6(dd,J＝8.7,1.8Hz),66.5,59.1,49.8,47.1(t,J＝21.6Hz),21.8,15.0,11.1. 19 F NMR(376MHz,Chloroform-d)δ-103.6(dt,J＝275.4,17.0Hz,1F),-107.1(dd,J＝275.2,16.4Hz,1F).HRMS(ESI)calcad for C 26 H 32 F 2 N 2 NaO 6 S + ([M+Na] + ):561.1846,found 561.1841.
Example 13: synthesis of 5- ((3, 5-dimethylphenoxy) methyl) -3- (3- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) propyl) oxazolidin-2-one (1 m)
Into a dry 25mL reaction tube under argon, 3- (4-azidopent-4-en-1-yl) -5- ((3, 5-dimethylphenoxy) methyl) oxazolidin-2-one (165.1 mg,0.5 mmol) was added, anhydrous MeCN (5 mL) was added, ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) was added with stirring, and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10℃in a stirred reaction bath at a low temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (ethyl acetate/petroleum ether=1:3) to give 5- ((3, 5-dimethylphenoxy) methyl) -3- (3- (2-ethoxy-4, 4-difluoro-5-oxopyrrolidin-2-yl) propyl) oxazolidin-2-one (1 m) as a white solid (111.2 mg, 52%), m.p.103.6-104.8 ℃. 1 H NMR(500MHz,Chloroform-d)δ7.40(s,1H),6.64(s,1H),6.52(s,2H),4.86–4.80(m,1H),4.13–4.07(m,2H),3.70(t,J＝8.8Hz,1H),3.56(dd,J＝8.6,5.8Hz,1H),3.42–3.27(m,4H),2.70–2.62(m,1H),2.54–2.44(m,1H),2.28(s,6H),1.90–1.81(m,2H),1.72–1.64(m,2H),1.16(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ165.6(t,J＝30.7Hz),158.0,157.9,139.4,123.3,117.0(t,J＝250.0Hz),112.2,87.1(dd,J＝5.9,3.1Hz),71.0,67.9,57.5,46.3,43.5,40.8(t,J＝21.4Hz),36.2,21.3,21.2,15.1. 19 F NMR(376MHz,Chloroform-d)δ-102.8(d,J＝275.1Hz,1F),-104.3–-105.1(m,1F).HRMS(ESI)calcad for C 21 H 28 F 2 N 2 NaO 5 + ([M+Na] + ):449.1858,found 449.1868.
Example 14: synthesis of 5- (benzofuran-5-yl) -5-ethoxy-3, 3-difluoropyrrolidin-2-one (1 n)
Under the protection of argon, adding into a dry 25mL reaction tube5- (1-azidoethyl) benzofuran (92.5 mg,0.5 mmol), anhydrous MeCN (5 mL) and ethyl difluoroiodoacetate (77.0. Mu.L, 0.6 mmol) were added with stirring and Et was added dropwise at-10 ℃ 2 Zn (0.25 mL,0.25mmol,1.0mol/L in hexane) was kept at-10deg.C in a reaction bath with stirring at a low temperature and constant temperature for further reaction for 3 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column (ethyl acetate/petroleum ether=1:8) to give 5- (benzofuran-5-yl) -5-ethoxy-3, 3-difluoropyrrolidin-2-one (1 n), as a white solid (91.7 mg, 65%), m.p.113.9-114.7deg.C. 1 H NMR(400MHz,Chloroform-d)δ8.87(s,1H),7.69(d,J＝2.0Hz,2H),7.56(d,J＝8.7Hz,1H),7.38(dd,J＝8.7,1.9Hz,1H),6.82(d,J＝2.1Hz,1H),3.48–3.40(m,1H),3.33–3.26(m,1H),3.13–3.03(m,1H),2.72–2.60(m,1H),1.22(t,J＝7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ167.8(t,J＝31.2Hz),154.9,146.2,134.2(d,J＝2.0Hz),127.9,121.5,118.2,117.1(dd,J＝253.4,251.0Hz),112.2,106.8,89.1(dd,J＝8.8,2.2Hz),59.1,47.7(t,J＝21.3Hz),15.1. 19 F NMR(376MHz,Chloroform-d)δ-103.1(dt,J＝275.3,16.2Hz,1F),-106.6(dd,J＝275.5,16.1Hz,1F).HRMS(ESI)calcad for C 14 H 13 F 2 NNaO 3 + ([M+Na] + ):304.0756,found 304.0764.
The foregoing is merely exemplary embodiments of the present application, and specific structures and features that are well known in the art are not described in detail herein. It should be noted that modifications and improvements can be made by those skilled in the art without departing from the structure of the present application, and these should also be considered as the scope of the present application, which does not affect the effect of the implementation of the present application and the utility of the patent. The protection scope of the present application is subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.

Claims (8)

1. A process for preparing 3, 3-difluoro-gamma-lactam compound features that vinyl azide and ethyl difluoroiodoacetate are used as raw materials and are used in Et 2 In the presence of Zn, in anhydrous acetonitrile at-10 deg.c for 3 hr to synthesize a series of C-5 quaternary carbon centers3, 3-difluoro-gamma-lactam compound of formula:
wherein R is one of a substituted or unsubstituted aryl group and a substituted or unsubstituted alkyl group.
2. The method of manufacturing according to claim 1, characterized in that: the "substitution" in the "substituted or unsubstituted" means that at least one hydrogen atom on the group is substituted with a group selected from the group consisting of: hydrogen atom, halogen atom, methyl, ethyl, propyl, butyl, methoxy, acetyl, acetoxy, methoxycarbonyl, benzoyloxymethyl, tert-butyl, benzoyloxy.
3. The method of manufacturing according to claim 1, characterized in that: r is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-acetylphenyl, 4-acetoxyphenyl, 4-methoxycarbonylphenyl, 4-benzoyloxymethylphenyl, 4-tert-butylphenyl, biphenyl, 3-methylphenyl, 3-bromophenyl; 3-thienyl, 5-benzofuranyl, R is selected from cyclohexyl, n-hexyl, 4-methoxycarbonyl n-butyl or 3-benzoyloxy n-propyl.
4. A process according to any one of claims 1 to 3, characterized in that: the above reaction was carried out under argon.
5. The method of manufacturing according to claim 4, wherein: concentrating under vacuum after the reaction is finished; eluting with petroleum ether/ethyl acetate, and separating with silica gel column to obtain 3, 3-difluoro-gamma-lactam compound.
6. The method of manufacturing according to claim 5, wherein: the molar ratio of the ethyl difluoroiodoacetate to the vinyl azide is 1.2:1.
7. The method of manufacturing according to claim 6, wherein: said Et 2 The molar ratio of Zn to vinyl azide was 0.5:1.
8. The method of manufacturing according to claim 7, wherein: the addition amount of the anhydrous acetonitrile is 200 times that of the vinyl azide.
CN202310595622.2A 2023-05-24 2023-05-24 Preparation method of 3, 3-difluoro-gamma-lactam compound Pending CN116621756A (en)

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