CN114790161B - Synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal and intermediate thereof - Google Patents
Synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal and intermediate thereof Download PDFInfo
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- PLBQLIFDSMCQBT-UHFFFAOYSA-N methyl 3-(5-formyl-4-methyl-1h-pyrrol-3-yl)propanoate Chemical compound COC(=O)CCC1=CNC(C=O)=C1C PLBQLIFDSMCQBT-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- -1 porphyrin compounds Chemical class 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 230000002194 synthesizing effect Effects 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 11
- 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 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 229930002875 chlorophyll Natural products 0.000 abstract description 2
- 235000019804 chlorophyll Nutrition 0.000 abstract description 2
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 abstract 1
- 239000003809 bile pigment Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 244000186140 Asperula odorata Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000008526 Galium odoratum Nutrition 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000003756 stirring Methods 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
- 206010004542 Bezoar Diseases 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000002585 base 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
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 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
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005292 vacuum distillation 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
- C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—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
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal and an intermediate thereof, wherein the structural formula of the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is shown as formula 1, the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is prepared from a compound shown as formula 2, and the reaction formula of the compound shown as formula 2 for preparing the compound shown as formula 1 is shown as follows:
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal and an intermediate thereof.
Background
4-methoxycarbonylethyl-3-methyl-2-pyrrolal is an important structural fragment (so-called B-and C-rings) of pharmaceutical and food additives such as bilirubin, biliverdin, phycocyanin, chlorophyll, heme and the like. Bilirubin is the main active ingredient of natural bezoar.
The Chinese patent publication No. CN112592356A 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 synthetic methods for B-ring or C-ring of Guan Dan pigments (including bilirubin) are reported. Among them, U.S. chemist Woodward synthesized the B ring using 15 multi-step reactions (Tetrahedron, 1995, vol.46, #22, p.7599-7659), and Lightner synthesized the B ring using sulfuryl chloride (Tetrahedron, 1993, vol.49, #11, p.2185-2255). However, these two methods have the problems of three wastes caused by sulfuryl chloride, and the preparation process requires special equipment such as high vacuum, so that the industrial value is not provided. In addition, both methods are based on the synthesis of compound 1 with compound 6:
the synthesis of compound 1 by this route is accompanied by the generation of impurities (isomer compound 5), and in addition, the preparation of compound 6 requires high temperature (175 ℃) decarboxylation followed by high vacuum (1 mmHg) distillation, and after high temperature high vacuum distillation, there is about 35% of black pot remaining solid (high molecular polymer), which is difficult to clean with common solvents and acid and base, and this process route is difficult to industrialize.
We prepared compound 3 according to literature (Lightner, journal of Heterocyclic Chemistry,2551, vol.38, #2, p.527-535), followed by debenzylation to give 2, high vacuum decarboxylation at 175℃to give low yield (35%) of 6, prepared the target compound 1 according to Woodward literature method (6 to 1 yield 45%, two step yield 12%), tried literature methods (J.Labelled. Com. & radio arm.1994, vol.34, no.3,263-274) to give 6 with the carboxyl groups of p-toluenesulfonic acid off 2, found that no reaction was carried out at 5℃and that a brownish black polymer was mainly obtained at 15 ℃.
Therefore, the development of a shorter synthetic route and the preparation of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal without column chromatography have great theoretical and industrial values.
Disclosure of Invention
The present invention aims to solve, at least to some extent, the technical problems existing in the prior art. Thus, in a first aspect of the present invention, the present invention provides a synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal, wherein the structural formula of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is shown in formula 1, the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal 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 1 is shown as follows:
in one or more embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 3, and the reaction formula of the compound of formula 3 to prepare the compound of formula 2 is as follows:
in other embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 4, and the reaction formula for preparing the compound of formula 2 from the compound of formula 4 is as follows:
in one or more embodiments of the present invention, in the process of preparing the compound represented by formula 1 from the compound represented by formula 2, trifluoroacetic acid is added, wherein the molar ratio of the trifluoroacetic acid to the compound represented by formula 2 is (4 to 11): 1, preferably (6 to 11): 1, more preferably (8 to 9): 1.
in one or more embodiments of the present invention, trimethyl orthoformate is added to the reaction system during the preparation of the compound of formula 1 from the compound of formula 2, and preferably, the reaction dropping speed is controlled to be 5-6 mmol/min.
In one or more embodiments of the present invention, the reaction temperature is controlled to be-5 to 35 ℃ during the preparation of the compound represented by formula 1 from the compound represented by formula 2.
In one or more embodiments of the present invention, the preparation of the compound of formula 1 from the compound of formula 2 further comprises a purification step comprising: adding the reaction solution into saturated sodium bicarbonate solution, extracting with dichloromethane, washing with water to neutrality, removing solvent, recrystallizing with organic solvent, and drying.
In one or more embodiments of the present invention, the temperature of the sodium bicarbonate solution treatment reaction solution is controlled to be 5 ℃; preferably, the organic solvent is a mixed solvent of ethyl acetate and petroleum ether, and more preferably, the volume ratio of the ethyl acetate to the petroleum ether is 1:4.
In one or more embodiments of the present invention, triethylamine is added during the preparation of the compound represented by formula 2 from the compound represented by formula 3; preferably, the molar ratio of triethylamine to the compound represented by formula 3 is controlled to be (1-2): 1, and preferably (1.5-2): 1.
In one or more embodiments of the present invention, pd/C is added during the preparation of the compound of formula 2 from the compound of formula 3; preferably, the preparation of the compound of formula 2 from the compound of formula 3 further comprises a purification step comprising: filtering, rotary evaporating to remove solvent, adding ethyl acetate, regulating pH to 3-4, water washing, rotary evaporating to remove solvent, recrystallizing and drying.
In a second aspect of the invention, the invention provides an intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal, wherein the structural formula of the intermediate is shown in formula 2:
compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention provides a method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal, which has the advantages of short synthetic route, high yield, high purity, low cost and mild synthesis condition, and is suitable for industrialization.
2. The synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal provided by the invention can effectively avoid using substances such as sulfuryl chloride and is environment-friendly.
3. The invention provides an intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal, which has a short route for preparing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal.
Detailed Description
The invention provides a method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal, and provides an intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal.
Synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal
The structural formula of the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is shown as formula 1, the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is prepared from a compound shown as formula 2, and the reaction formula of the compound shown as formula 2 for preparing the compound shown as formula 1 is shown as follows:
in one or more embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 3, the reaction formula of the compound of formula 3 to prepare the compound of formula 2 is shown below,
in other embodiments of the present invention, the compound of formula 2 is prepared from the compound of formula 4, and the reaction formula for preparing the compound of formula 2 from the compound of formula 4 is as follows:
in one or more embodiments of the present invention, in the process of preparing the compound represented by formula 1 from the compound represented by formula 2, trifluoroacetic acid is added, wherein the molar ratio of the trifluoroacetic acid to the compound represented by formula 2 is (4 to 11): 1, preferably (6 to 11): 1, more preferably (8 to 9): 1.
in one or more embodiments of the present invention, trimethyl orthoformate is added to the reaction system during the preparation of the compound of formula 1 from the compound of formula 2, and preferably, the reaction dropping speed is controlled to be 5-6 mmol/min.
In one or more embodiments of the present invention, the reaction temperature is controlled to be-5 to 35 ℃ during the preparation of the compound represented by formula 1 from the compound represented by formula 2.
In one or more embodiments of the present invention, the preparation of the compound of formula 1 from the compound of formula 2 further comprises a purification step comprising: adding the reaction solution into saturated sodium bicarbonate solution, extracting with dichloromethane, washing with water to neutrality, removing solvent, recrystallizing with organic solvent, and drying.
In one or more embodiments of the present invention, the temperature of the sodium bicarbonate solution treatment reaction solution is controlled to be 5 ℃; preferably, the organic solvent is a mixed solvent of ethyl acetate and petroleum ether; more preferably, the volume ratio of ethyl acetate to petroleum ether is 1:4.
In one or more embodiments of the present invention, triethylamine is added during the preparation of the compound represented by formula 2 from the compound represented by formula 3; preferably, the molar ratio of triethylamine to the compound represented by formula 3 is controlled to be (1-2): 1, and preferably (1.5-2): 1.
In one or more embodiments of the present invention, pd/C is added during the preparation of the compound of formula 2 from the compound of formula 3; preferably, the preparation of the compound of formula 2 from the compound of formula 3 further comprises a purification step comprising: filtering, rotary evaporating to remove solvent, adding ethyl acetate, regulating pH to 3-4, water washing, rotary evaporating to remove solvent, recrystallizing and drying.
Intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal
The invention provides an intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal, which has a structural formula shown in formula 2:
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 using a Bruker-AMX655 NMR apparatus; ESI-MS was determined using a Finnigan-MAT-95 mass spectrometer; all reagents were analytically pure.
The present invention provides a process for the preparation of 4-methoxycarbonylethyl-3-methyl-2-pyrrolidinone, starting material compound 3 is prepared in the literature (Lightner, journal of Heterocyclic Chemistry,2551, vol.38, #2, p.527-535). Compound 4 was prepared by hydrolysis of the corresponding dimethyl ester.
Example 1: synthesis of Compound 2
The reaction formula is as follows:
the preparation process comprises the following steps: into a 255ml reaction flask, 15.68 g of Compound 3 (35.4 mmol), 85 ml of methanol, 6.96 g (68.78 mmol) of triethylamine, 5% Pd/C2.8 g (water content 55%, baojirayleigh Co.) were charged with hydrogen at room temperature and normal pressure, and after the completion of the reaction, the reaction was filtered, the solvent was distilled off by rotation, ethyl acetate was added, the pH was adjusted to 3 to 4 with 15% acetic acid, the mixture was washed with water, and the solvent was distilled off by rotation, and ethyl acetate was used in a ratio of 1:4: petroleum ether is recrystallized, phosphorus pentoxide is dried in vacuum to obtain 3.82 g of off-white solid, namely the compound 2. P.135-137 deg.c (partial decomposition). The yield was 51.5% (mother liquor recovery was not counted). 1 H NMR(DMSO)δ12.55(s,1H),11.11(s,1H),6.65(s,1H),3.55(s,1H),2.65(t,2H),2.49(t,2H),2.15(s,3H).MS m/z 252.5916(M + +1).
Compound 2 was unstable to room temperature in light and slightly brown-grey in color after storage in a 3 degree celsius refrigerator, with obvious origin impurities found by TLC (1:1:5.1 ea: pe: acoh). The compound 2 was dried with phosphorus pentoxide under vacuum and stored in a-15 ℃ freezer.
EXAMPLE 2 Synthesis of Compound 1
The reaction formula is as follows:
the preparation process comprises the following steps: to a 255mL bottle, 9.5mL trifluoroacetic acid (125 mmol,8.4 eqv.) and 3.55g of Compound 2 (14.2 mmol) were added, cooled to-5℃and nitrogen-protected, 4.52g of trimethyl orthoformate (42.6 mmol) was added dropwise to the reaction mixture, stirring was continued for 1 hour at 15-35℃after the TLC monitoring was completed, 65 mL of dichloromethane was added, saturated sodium bicarbonate solution was added under cooling, water was washed to neutrality, and the solvent was removed by rotary distillation using 1:4 ethyl acetate: petroleum ether is recrystallized, phosphorus pentoxide is dried in vacuum to obtain 1.65 g of pale yellow solid, namely the compound 1. Yield 57.7% (mother liquor recovery not counted), mp: 75-77 ℃ (document 76-77 ℃). Compound 1 was unstable in room temperature light and phosphorus pentoxide was vacuum dried and stored in a-15 ℃ freezer.
Other reaction conditions were unchanged, and the reaction conditions were screened for the effect of the amount of trifluoroacetic acid on the reaction, and the screening conditions and results are shown in table 1.
TABLE 1 list of aldehyde group reactions on trifluoroacetic acid (TFA)
Wherein, HPLC conditions: chromatography column, irinotec 18 (4.6 mm. Times.255 mm,5 μm), column temperature 25 ℃, flow rate 1.5mL/min, detection wavelength 254nm, mobile phase ACN: h 2 O: TFA = 75%:35%:5.1%, and the sample injection amount is 25 mu L.
Example 3: reaction of Compound 4 with trifluoroacetic acid, trimethyl orthoformate.
A25 mL reaction flask was taken, compound 4 (1.55 g,5.57 mmol), meOH 15mL, and CF was added with magnetic stirring under nitrogen 3 COOH 5.188mL (2.53 mmol), no exotherm, light-protected reaction overnight at 15℃with the addition of 5.188mL (2.53 mmol) of trifluoroacetic acid, the reaction mixture being bluish violet, then 5.694 g of trimethyl orthoformate (6.5 mmol,1.29 eqv) were added, stirring overnight at 15℃, the reaction mixture darkening, spin-removing the solvent, EA extraction, sodium bicarbonate washing, saturated sodium chloride washing, then column chromatography gave 5.65 g of an off-white solid in 61% yield. Melting point, HPLC, NMR were the same as the product debenzylated from compound 3.
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 (13)
1. The structural formula of the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is shown as formula 1, and the method is characterized in that the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal is prepared from a compound shown as formula 2, and the reaction formula of the compound shown as formula 2 for preparing the compound shown as formula 1 is shown as follows:
in the process of preparing the compound shown in the formula 2 and the compound shown in the formula 1, trifluoroacetic acid is added, and the molar ratio of the trifluoroacetic acid to the compound shown in the formula 2 is (8-9): 1.
2. the method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein the compound of formula 2 is prepared from the compound of formula 3, and the reaction formula of the compound of formula 3 for preparing the compound of formula 2 is as follows:
3. the method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein the compound of formula 2 is prepared from the compound of formula 4, and the reaction formula of the compound of formula 4 for preparing the compound of formula 2 is as follows:
4. the method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein trimethyl orthoformate is added in the process of preparing the compound represented by formula 1 from the compound represented by formula 2, and the trimethyl orthoformate is dropped into the reaction system.
5. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 4, wherein the reaction dropping speed is controlled to be 5-6 mmol/min.
6. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 4, wherein the reaction temperature is controlled at-5 to 30 ℃.
7. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein the preparation of the compound represented by formula 1 from the compound represented by formula 2 further comprises a purification step comprising: adding the reaction solution into saturated sodium bicarbonate solution, extracting with dichloromethane, washing with water to neutrality, removing solvent, recrystallizing with organic solvent, and drying.
8. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 7, wherein the saturated sodium bicarbonate solution temperature is controlled to be 0 ℃.
9. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 7, wherein the organic solvent is a mixed solvent of ethyl acetate and petroleum ether.
10. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 9, wherein the volume ratio of ethyl acetate to petroleum ether is 1:4.
11. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 2, wherein triethylamine is added in the process of preparing the compound represented by formula 2 from the compound represented by formula 3, and the molar ratio of triethylamine to the compound represented by formula 3 is controlled to be (1-2): 1.
12. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 2, wherein Pd/C is added during the preparation of the compound of formula 2 from the compound of formula 3.
13. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 12, wherein the preparation of the compound represented by formula 2 from the compound represented by formula 3 further comprises a purification step comprising: filtering, rotary evaporating to remove solvent, adding ethyl acetate, regulating pH to 3-4, water washing, rotary evaporating to remove solvent, recrystallizing and drying.
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| US5599928A (en) * | 1994-02-15 | 1997-02-04 | Pharmacyclics, Inc. | Texaphyrin compounds having improved functionalization |
| CN101657420A (en) * | 2007-03-30 | 2010-02-24 | 赛诺菲巴斯德有限公司 | Preparation derivatives of porphyrin, for example method of protoporphyrin (IX) and synthetic intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5599928A (en) * | 1994-02-15 | 1997-02-04 | Pharmacyclics, Inc. | Texaphyrin compounds having improved functionalization |
| CN101657420A (en) * | 2007-03-30 | 2010-02-24 | 赛诺菲巴斯德有限公司 | Preparation derivatives of porphyrin, for example method of protoporphyrin (IX) and synthetic intermediate |
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| Synthesis and anticancer activity of prodigiosenes bearing C-ring esters and amides;Kate-lyn A. R. Lund等;《RSC Adv.》;第7卷;第18617-18627页 * |
| The total synthesis of chlorophyll a;Woodward, Robert Burns等;《Tetrahedron》;第46卷(第22期);第7641页 * |
| Total Syntheses of 8-Formyl-8-demethylprotoporphyrinI X, 8-(Hydroxymethyl)-8-demethylprotoporphyrin IX, and 8-Fluoromethyl Analogues of Protoporphyrin IX;Kevin M. Snow，Kevin M. Smith;《J. Org. Chem.》;第54卷(第14期);第3274页Scheme V，第3279页右栏最后1段，第3280页左栏第1段 * |
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