CN114805168B - Pyrrolinones and synthesis method thereof - Google Patents
Pyrrolinones and synthesis method thereof Download PDFInfo
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- CN114805168B CN114805168B CN202210336473.3A CN202210336473A CN114805168B CN 114805168 B CN114805168 B CN 114805168B CN 202210336473 A CN202210336473 A CN 202210336473A CN 114805168 B CN114805168 B CN 114805168B
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- HMXQIFUGFZEJEO-UHFFFAOYSA-N 1,2-dihydropyrrol-3-one Chemical class O=C1CNC=C1 HMXQIFUGFZEJEO-UHFFFAOYSA-N 0.000 title claims description 27
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- -1 pyrrolinones compound Chemical class 0.000 claims abstract description 49
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 13
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 13
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 133
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 19
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 8
- 239000001257 hydrogen Substances 0.000 abstract description 8
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract description 5
- 239000003809 bile pigment Substances 0.000 abstract description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 231100000614 poison Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000009987 spinning Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000003172 aldehyde group Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 206010004542 Bezoar Diseases 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- FGWYWKIOMUZSQF-UHFFFAOYSA-N 1,1,1-triethoxypropane Chemical compound CCOC(CC)(OCC)OCC FGWYWKIOMUZSQF-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- 238000006418 Brown reaction Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- GWZYPXHJIZCRAJ-UHFFFAOYSA-N Biliverdin Natural products CC1=C(C=C)C(=C/C2=NC(=Cc3[nH]c(C=C/4NC(=O)C(=C4C)C=C)c(C)c3CCC(=O)O)C(=C2C)CCC(=O)O)NC1=O GWZYPXHJIZCRAJ-UHFFFAOYSA-N 0.000 description 1
- RCNSAJSGRJSBKK-NSQVQWHSSA-N Biliverdin IX Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(\C=C/2C(=C(C)C(=C/C=3C(=C(C=C)C(=O)N=3)C)/N\2)CCC(O)=O)N1 RCNSAJSGRJSBKK-NSQVQWHSSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 108010053210 Phycocyanin Proteins 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QBUVFDKTZJNUPP-UHFFFAOYSA-N biliverdin-IXalpha Natural products N1C(=O)C(C)=C(C=C)C1=CC1=C(C)C(CCC(O)=O)=C(C=C2C(=C(C)C(C=C3C(=C(C=C)C(=O)N3)C)=N2)CCC(O)=O)N1 QBUVFDKTZJNUPP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- KFZUDNZQQCWGKF-UHFFFAOYSA-M sodium;4-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=C(S([O-])=O)C=C1 KFZUDNZQQCWGKF-UHFFFAOYSA-M 0.000 description 1
- PVGBHEUCHKGFQP-UHFFFAOYSA-N sodium;n-[5-amino-2-(4-aminophenyl)sulfonylphenyl]sulfonylacetamide Chemical compound [Na+].CC(=O)NS(=O)(=O)C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 PVGBHEUCHKGFQP-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen 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
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen 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 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Abstract
The invention provides a pyrrolinones compound and a synthesis method thereof, the structural formula of the pyrrolinones compound is shown as a formula 1,the method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 1 Is C1-C12 alkyl; r is R 2 One of hydrogen, benzyl and substituted benzyl; preferably, R 1 Is vinyl or alpha-p-toluenesulfonylethyl, R 2 Is hydrogen, benzyl or p-methoxybenzyl, which can be used as an intermediate of drugs, in particular as an intermediate (A ring) of bile pigments (including bilirubin). The invention also provides a synthesis method of the pyrrolinones compound and the intermediate thereof, which has the advantages of short synthesis route, low cost, mild synthesis condition, no use of extremely toxic substances such as sodium cyanide and environmental friendliness.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of pyrrolinones.
Background
Pyrrolinones are important structural fragments of drugs and food additives such as bilirubin (structural formula shown below), biliverdin, phycocyanin, and the like, and in bilirubin, both the A ring and the D ring are pyrrolinones.
The Chinese patent publication No. CN112592306A discloses a pyrrolinones compound and a synthesis method thereof, and the patent is a synthesis method of bilirubin D ring. In the prior art, few routes have been reported in the literature for synthesizing the A ring of Guan Dan pigments (including bilirubin). Of these, the German chemist Plaienter synthesized the vinyl A ring in 10 steps [ Liebigs Ann. Chem.723,149-158 (1969) ] and Gossauer synthesized the A-ring precursor (3-methyl-4-acetoxypyrrolinone) under pressurized conditions using sodium cyanide, however, in yields of only 10% [ HELVETICCAH IMICACTA-Vol.72,518 (1989) ]. Bilirubin is the main active ingredient of bezoar (including natural bezoar and in vitro cultured bezoar), and the A ring is a key intermediate for synthesizing bile pigment (including bilirubin).
Therefore, a short synthetic route for preparing pyrrolinones, in particular 4-vinyl pyrrolinones (A ring), is developed, and has great theoretical and industrial values.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent, and in a first aspect of the present invention, the present invention provides a pyrrolinone compound, the structural formula of which is shown in formula 1,
wherein R is 1 Is C1-C12 alkyl; r is R 2 One of hydrogen, benzyl and substituted benzyl; preferablyGround, R 1 Is vinyl or alpha-p-toluenesulfonylethyl, R 2 Is hydrogen or p-methoxybenzyl or benzyl.
In a second aspect of the invention, the invention provides a pyrrolinone compound intermediate, the structural formula of which is shown in a formula 6,
；
wherein R is 2 Is selected from one of hydrogen, benzyl and substituted benzyl, R 3 From vinyl or CH 3 CH，R 4 Taken from hydroxy-substituted methyl or aldehyde groups; preferably, R 2 Is p-methoxybenzyl or benzyl.
In a third aspect of the present invention, the present invention provides a method for preparing a pyrrolinones compound according to the first aspect of the present invention, wherein the pyrrolinones compound is shown in formula 1a, the pyrrolinones compound shown in formula 1a is prepared from a compound shown in formula 1b, and a reaction formula of the compound shown in formula 1b for preparing the compound shown in formula 1a is as follows:
wherein R is 2 One of benzyl and substituted benzyl; preferably, R 2 Is p-methoxybenzyl or benzyl.
In a fourth aspect of the present invention, there is provided a process for producing another pyrrolinones according to the first aspect of the present invention, wherein the compound of formula 1 is produced from the compound of formula 4, and the compound of formula 4 is produced
The reaction formula of the compound shown in formula 1 is as follows:
wherein R is 2 Is taken fromOne of benzyl and substituted benzyl, R 1 Is C1-C12 alkyl; preferably, R 2 R is p-methoxybenzyl or benzyl 1 Is vinyl or alpha-p-toluenesulfonylethyl.
In one or more embodiments of the present invention, the compound of formula 4 is prepared from the compound of formula 3, and the reaction formula of the compound of formula 3 to prepare the compound of formula 4 is as follows:
in one or more embodiments of the present invention, the compound of formula 3 is prepared from the compound of formula 2, and the reaction formula of the compound of formula 2 to prepare the compound of formula 3 is as follows:
。
in one or more embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 5, and the reaction formula of the compound of formula 5 to prepare the compound of formula 2 is as follows:
。
in a fifth aspect of the present invention, there is provided a process for the preparation of an intermediate for pyrrolinones as described in the second aspect of the present invention, when R 3 Is CH 3 CH，R 4 When the pyrrolinones are aldehyde groups, namely, the pyrrolinones are compounds shown in a formula 4, the compounds shown in the formula 4 are prepared from compounds shown in a formula 3, and the reaction formula of the compounds shown in the formula 3 for preparing the compounds shown in the formula 4 is as follows:
。
in the sixth aspect of the inventionIn a second aspect, the present invention provides a process for the preparation of an intermediate for pyrrolinones as described in the second aspect of the present invention, when R 3 Is vinyl, R 4 When the compound is hydroxyl substituted methyl, namely, the pyrrolinones compound is a compound shown in a formula 3, the compound shown in the formula 3 is prepared from a compound shown in a formula 2, and the reaction formula of the compound shown in the formula 2 for preparing the compound shown in the formula 3 is as follows:
。
in one or more embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 5, and the reaction formula of the compound of formula 5 to prepare the compound of formula 2 is as follows:
。
compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention provides a pyrrolinones compound and an intermediate thereof, which can be used as a drug intermediate, in particular to an intermediate (A ring) of bile pigment (including bilirubin).
2. The invention provides a synthesis method of pyrrolinones and intermediates thereof, in particular to a synthesis method of 3-methyl-4-vinyl pyrrolinones, which has the advantages of short synthesis route, low cost and mild synthesis condition, and is suitable for industrialization.
3. The synthesis method of the pyrrolinones compound and the intermediate thereof provided by the invention avoids the use of sodium cyanide and other extremely toxic substances and is environment-friendly.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The methods used are conventional methods known in the art unless otherwise specified, and the consumables and reagents used are commercially available unless otherwise specified. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any method or material similar or equivalent to those described may be used in the present invention. NMR was measured with a Bruker-AMX600 NMR apparatus; ESI-MS was determined using a Finnigan-MAT-95 mass spectrometer; all reagents were analytically pure.
The invention provides pyrrolinones, pyrrolinones intermediates and methods of making the same
Pyrrolinones
The invention provides a pyrrolinones compound, the structural formula of which is shown as formula 1,
；
wherein R is 1 Is C1-C12 alkyl; r is R 2 One of hydrogen, benzyl and substituted benzyl; preferably, R 1 Is vinyl or alpha-p-toluenesulfonylethyl, R 2 Is hydrogen or p-methoxybenzyl or benzyl.
Pyrrolinones intermediates
In a second aspect of the invention, the invention provides a pyrrolinone compound intermediate, the structural formula of which is shown in a formula 6,
wherein R is 2 Is selected from one of hydrogen, benzyl and substituted benzyl, R 3 From vinyl or CH 3 CH，R 4 Taken from hydroxy-substituted methyl or aldehyde groups; preferably, R 2 Is p-methoxybenzyl or benzyl.
Preparation method of pyrrolinones
In a third aspect of the present invention, the present invention provides a preparation method of a pyrrolinone compound, where the pyrrolinone compound is shown in formula 1a, the pyrrolinone compound shown in formula 1a is prepared from a compound shown in formula 1b, and a reaction formula of the compound shown in formula 1b to prepare the compound shown in formula 1a is as follows:
wherein R is 2 One of benzyl and substituted benzyl; preferably, R 2 Is p-methoxybenzyl or benzyl.
Preferably, the compound shown in the formula 1b is reacted with p-toluenesulfonic acid, and purified to obtain the compound shown in the formula 1a, and the reaction temperature is preferably controlled to be 100-120 ℃.
In a fourth aspect of the present invention, the present invention provides a method for preparing another pyrrolinones according to the first aspect of the present invention, wherein the compound of formula 1 is prepared from the compound of formula 4, and the reaction formula for preparing the compound of formula 1 from the compound of formula 4 is as follows:
wherein R is 2 From one of benzyl, substituted benzyl, R 1 Is C1-C12 alkyl; preferably, R 2 R is p-methoxybenzyl or benzyl 1 Is vinyl or alpha-p-toluenesulfonylethyl.
Preferably, the reaction formula for preparing the compound represented by formula 1 from the compound represented by formula 4 is as follows:
wherein R is 2 Is p-methoxybenzyl or benzyl.
Specifically, the compound shown in formula 4 is reacted with acetic acid and purified to obtain the compound shown in formula 1b, and preferably, the reaction temperature is controlled to be 100-120 ℃.
In other embodiments, the reaction of the compound of formula 4 to prepare the compound of formula 1 is as follows:
wherein R is 2 Is p-methoxybenzyl or benzyl.
Specifically, the compound shown in the formula 4, sodium paratoluenesulfinate and acetic acid react and are purified to obtain the compound shown in the formula 1c, and the reaction temperature is preferably controlled to be 50-70 ℃.
In one or more embodiments of the present invention, the compound of formula 4 is prepared from the compound of formula 3, and the reaction formula of the compound of formula 3 to prepare the compound of formula 4 is as follows:
specifically, the compound shown in the formula 3 reacts with triethylamine to obtain the compound shown in the formula 4, preferably, the reaction temperature is controlled to be 15-35 ℃, and preferably, the solvent used in the reaction is a mixed solvent of DMSO and dichloromethane.
In one or more embodiments of the present invention, the compound of formula 3 is prepared from the compound of formula 2, and the reaction formula of the compound of formula 2 to prepare the compound of formula 3 is as follows:
。
specifically, the compound shown in the formula 2 reacts with 4-methoxybenzylamine or benzylamine, and is purified to obtain the compound shown in the formula 3.
In one or more embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 5, and the reaction formula of the compound of formula 5 to prepare the compound of formula 2 is as follows:
。
specifically, the compound shown in the formula 5 reacts with triethyl orthopropionate, and is purified to obtain the compound shown in the formula 2. Preferably, the reaction temperature is controlled to be 90-160 ℃.
Preparation method of pyrrolinones compound intermediate
In a fifth aspect of the present invention, there is provided a process for the preparation of an intermediate for pyrrolinones as described in the second aspect of the present invention, when R 3 Is CH 3 CH，R 4 When the pyrrolinones are aldehyde groups, namely, the pyrrolinones are compounds shown in a formula 4, the compounds shown in the formula 4 are prepared from compounds shown in a formula 3, and the reaction formula of the compounds shown in the formula 3 for preparing the compounds shown in the formula 4 is as follows:
。
in a sixth aspect of the present invention, there is provided a process for the preparation of an intermediate for pyrrolinones as described in the second aspect of the present invention, when R 3 Is vinyl, R 4 When the compound is hydroxyl substituted methyl, namely, the pyrrolinones compound is a compound shown in a formula 3, the compound shown in the formula 3 is prepared from a compound shown in a formula 2, and the reaction formula of the compound shown in the formula 2 for preparing the compound shown in the formula 3 is as follows:
in one or more embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 5, and the reaction formula of the compound of formula 5 to prepare the compound of formula 2 is as follows:
example 1: synthesis of Compound 2
The reaction formula is as follows:
the preparation process comprises the following steps: into a 2000 ml three-port flask, 409 g (4.64 mol) of maleic glycol (compound shown in formula 5) and 900 g (5.11 mol) of triethyl orthopropionate were put, heated and stirred for 9 hours, the temperature was raised from 100 to 155 degrees, ethanol was distilled off continuously until no liquid was distilled off, cooled to 75 degrees, a glass bead packed rectifying column 15cm high was connected, and a fraction of bp 75 ℃ (11 mmHg) was collected to obtain 552 g of a product (colorless liquid), namely, the compound shown in formula 2 in 94% yield.
EXAMPLE 2 Synthesis of the Compound N- [ 4-methoxyphenylmethyl ] -2-methyl-3-hydroxymethyl-4-pentenamide (Compound represented by formula 3)
The reaction formula is as follows:
wherein R is 2 Is p-methoxybenzyl.
The preparation process comprises the following steps: 50.0 g (0.397 mol) of the compound represented by formula 2 and 4-methoxybenzylamine (217.3 g, 1.58 mol) were heated and stirred under nitrogen for 20 hours, excess benzylamine was recovered by distillation under reduced pressure (oil bath temperature 95 ℃ C., pump vacuum), 127 ml of ethyl acetate and 90 ml of petroleum ether were added, stirred for one hour at 15 to 35 ℃ C., a large amount of solids were precipitated, and filtered, and 1:1EA: PE washing and phosphorus pentoxide vacuum drying to obtain a white solid, 71.8 g, which is the compound of formula 3, yield 68.7%, mp: 80-82 ℃, 1 H NMR(CDCl 3 )δ7.22(d,2H),6.88(d,2H)，5.99(s,1H),5.74(m,1H),5.20(m,2H),4.39(m,2H),3.82(s,3H),3.64(m,2H),2.45(m,1H),2.37(m,1H),1.19(d,1H).MS m/z 263(M + ).
EXAMPLE 3 Synthesis of the Compound N-benzyl-2-methyl-3-hydroxymethyl-4-pentenamide
The reaction formula is as follows:
wherein R is 2 Is benzyl.
The preparation process comprises the following steps: 21.6 g (0.171 mol) of the compound represented by formula 2 and benzylamine (36.7 g, 0.349mol, 2eq v) were stirred under nitrogen for 20 hours under heating, and excess benzylamine was recovered by distillation under reduced pressure (oil bath temperature 95 ℃ C., vacuum pumped by a water pump), ethyl acetate and petroleum ether were added to obtain 17.7 g of a white solid after recrystallization, namely, the compound represented by formula 3, with a yield of 44.3%.
EXAMPLE 4 Synthesis of the Compound N- [ 4-methoxyphenylmethyl ] -2-methyl-3-oxomethyl-4-pentenamide (Compound represented by formula 4)
The reaction formula is as follows:
wherein R is 2 Is p-methoxybenzyl.
The preparation process comprises the following steps: 26.3 g (100 mmol) of the compound represented by the formula 3, 40.4 g of triethylamine (400 mmol), and a solution (260 ml) of DMSO (156.3 g, 2000 mmol) in methylene chloride were stirred at 15-35 ℃ for 15 minutes, and a sulfur trioxide pyridine complex (48.0 g, 301 mmol) was added to give a brown reaction solution, which was further stirred at 15-35 ℃ for one hour, then quenched by adding 900 ml of 4N hydrochloric acid, extracted with DCM, washed with water, then washed with sodium bicarbonate, washed with brine, dried over sodium sulfate, and the solvent was removed by rotary evaporation to give 24.1 g of a pale yellow oil, which was the compound represented by the formula 4, in 92.3% yield. 1 H NMR(CDCl 3 )δ9.34(s,1H),7.17(d,2H),6.86(d,2H),6.72(q,1H),6.07(s,1H),4.35(m,2H),3.80(s,3H),3.72(q,1H),2.09(d,3H),1.38(d,3H).
EXAMPLE 5 Synthesis of Compound N-benzyl-2-methyl-3-oxomethyl-4-pentenamide (Compound represented by formula 4)
The reaction formula is as follows:
wherein R is 2 Is benzyl.
The preparation process comprises the following steps: a solution of the compound of formula 3 in 2.00 g (8.58 mmol), 3.46 g triethylamine (34.3 mmol) and DMSO (13.38 g, 171.6 mmol) in dichloromethane (20 mL) was added with stirring at 15-35℃for 15 min to give a brown reaction solution, which was further stirred at 15-35℃for one hour and then quenched with 80 mL of 4N hydrochloric acid, extracted with DCM, washed with water, then washed with sodium bicarbonate, washed with brine, dried over sodium sulfate and the solvent was removed by rotary evaporation to give 1.9 g of a pale yellow oil, which was the compound of formula 4 in 95.8% yield.
EXAMPLE 6 Synthesis of Compound N- [ 4-methoxyphenylmethyl ] -3-methyl-4-vinyl-1, 5 dihydro-2H-pyrrolin-2-one (Compound represented by formula 1 b)
The reaction formula is as follows:
wherein R is 2 Is p-methoxybenzyl.
The preparation process comprises the following steps: 4.1 g of the compound of formula 4 (15.7 mmol) and 40 ml of acetic acid are stirred under nitrogen at 110℃for 20 hours, the acetic acid is distilled off by spinning, the EA-dissolved residue is washed with water, then with sodium hydrogencarbonate, with brine, dried over sodium sulfate, and the solvent is distilled off by spinning to give a pale yellow oil, which is obtained by spinning with EA: PE 2:1 was recrystallized to give 2.6 g of a pale yellow solid, which is a compound of formula 1b, mp: 58-60 ℃ and 68% of yield. 1 H NMR(CDCl 3 )δ1.80(s,3H),3.76(s,3H),3.84(s,2H),4.58(s,2H),5.27～5.33(m,2H),6.66～6.71(m,1H),6.85(m,2H),7.19(m,2H)。
EXAMPLE 7 Synthesis of Compound N-benzyl-3-methyl-4-vinyl-1, 5 dihydro-2H-pyrrolin-2-one (Compound of formula 1 b)
The reaction formula is as follows:
wherein R is 2 Is benzyl.
The preparation process comprises the following steps: 1.0 g of the compound of formula 4 (4.3 mmol) and 10 ml of acetic acid are stirred under nitrogen at 110℃for 2 hours, the acetic acid is distilled off by spinning, the EA-dissolved residue is washed with water, then with sodium hydrogencarbonate, with brine, dried over sodium sulfate, and the solvent is distilled off by spinning to give a pale yellow oil, which is obtained by spinning with EA: PE 4:1 column chromatography gave 0.33 g of an oil, which is a compound of formula 1b, yield 35.8%. 1 H NMR(CDCl 3 )δ1.90(s，3H)，3.87(m,2H),4.65(s,2H),5.30(m,2H),6.69(m,1H),7.26(m,5H).MS m/z 214(M + +1).
EXAMPLE 8 Synthesis of Compound 3-methyl-4-vinyl-1, 5 dihydro-2H-pyrrolin-2-one (Compound of formula 1 a)
The reaction formula is as follows:
wherein R is 2 Is p-methoxybenzyl.
The preparation process comprises the following steps: the compound of formula 1b (2.00 g, 8.2 mmol), 6.25 g (32.9 mmol) of p-toluenesulfonic acid monohydrate and 40 ml of toluene were heated and stirred for 5 hours at 110℃under nitrogen, cooled to 15-35℃and washed with water, then washed with sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed by rotary evaporation to give a pale yellow oil, which was purified by EA: recrystallization of PE 1:3 afforded 0.66 g of a pale yellow solid, which was a compound of formula 1a, mp: 85-87 ℃ (literature 86-88 ℃) and yield 65%, MS M/z 123 (M) + ) Nuclear magnetism is consistent with literature.
EXAMPLE 9 Synthesis of the Compound N- [ 4-methoxyphenylmethyl ] -3-methyl-4- (1-p-methylbenzenesulfonylethyl) -1,5 dihydro-2H-pyrrolin-2-one (1 c)
Wherein R is 2 Is p-methoxybenzyl.
The preparation process comprises the following steps: a mixture of 8.53 g (32.6 mmol) of the compound represented by formula 4, 5.81 g (32.6 mmol) of sodium p-toluene sulfinate, 2.94 g of acetic acid (49.0 mmol), 240 ml of ethanol and 40 ml of water was heated and stirred at 60℃under nitrogen for 4 hours, the solvent was distilled off, the residue was dissolved with ethyl acetate, washed with water, then washed with sodium hydrogen carbonate, brine, dried over sodium sulfate and the solvent was distilled off by spin distillation to give a yellow paste, which was obtained by 1:2EA: PE is recrystallized to obtain 5.45 g of off-white solid, namely the compound shown in the formula 1c, and the yield is 43%. 1 H NMR(CDCl 3 )δ7.57(d,2H),7.29(d,2H),7.16(d,2H),6.87(d,2H),4.59(d,J＝14.80Hz,1H),4.52(d,J＝14.80Hz,1H),4.21(q,J＝7.2Hz,1H),3.99(d,J＝19.2Hz,1H),3.81(s,3H),3.67(d,J＝19.2Hz,1H),2.43(s,3H),1.57(d,J＝7.2Hz,3H),1.34(s,3H).MS m/z 399(M + ).
While embodiments of the invention have been illustrated and described, it will be understood that the above embodiments are illustrative, and not restrictive, and that all changes, modifications, substitutions, combinations, and simplifications that come within the spirit and scope of the invention are desired to be protected.
Claims (4)
1. The preparation method of the pyrrolinones is characterized in that the pyrrolinones are compounds shown in a formula 1, the compounds shown in the formula 1 are prepared from compounds shown in a formula 4, and the reaction formula of the compounds shown in the formula 4 for preparing the compounds shown in the formula 1 is as follows:
wherein R is 2 R is p-methoxybenzyl or benzyl 1 Is vinyl or alpha-p-toluenesulfonylethyl.
2. The preparation method of the pyrrolinones according to claim 1, wherein the compound shown in formula 4 is prepared from a compound shown in formula 3, and the reaction formula of the compound shown in formula 3 for preparing the compound shown in formula 4 is as follows:
3. the preparation method of the pyrrolinones according to claim 2, wherein the compound shown in formula 3 is prepared from a compound shown in formula 2, and the reaction formula of the compound shown in formula 2 for preparing the compound shown in formula 3 is as follows:
。
4. the method for preparing pyrrolinones according to claim 3, wherein the compound of formula 2 is prepared from the compound of formula 5, and the reaction formula of the compound of formula 5 for preparing the compound of formula 2 is as follows:
。
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| Bile pigments. VI. Synthesis of vinyl-substituted pyrrolinone derivatives;Plieninger, Hans等;《Justus Liebigs Annalen der Chemie》(第9期);第1523页、第1527页 * |
| Plieninger, Hans等.Bile pigments. VI. Synthesis of vinyl-substituted pyrrolinone derivatives.《Justus Liebigs Annalen der Chemie》.1974,(第9期),第1523页、第1527页. * |
| Subhash P. Chavan等.Scalable Synthesis of 3-Ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one:An Important Building Block of the Antidiabetic Drug Glimepiride.《Synthesis》.2020,第52卷第B页Scheme 2. * |
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