CN114790161A - 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 18
- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
- 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
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 15
- 239000002904 solvent Substances 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 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 2
- 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 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 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
- -1 porphyrin compounds Chemical class 0.000 abstract description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 238000004821 distillation Methods 0.000 description 4
- 239000000203 mixture Substances 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 244000186140 Asperula odorata Species 0.000 description 2
- 235000008526 Galium odoratum Nutrition 0.000 description 2
- 239000003809 bile pigment Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 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
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920000642 polymer Polymers 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
- 150000007513 acids Chemical class 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
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry 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
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 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-pyrrole aldehyde and an intermediate thereof, wherein the structural formula of 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is shown as a formula 1, the 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is prepared from a compound shown as a formula 2, and the reaction formula for preparing the compound shown as the formula 1 from the compound shown as the formula 2 is as follows:
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthetic method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal and an intermediate thereof.
Background
4-methoxycarbonylethyl-3-methyl-2-pyrroldehyde is an important structural fragment (so-called B ring and C ring) of medicaments and food additives such as bile pigment (including bilirubin and biliverdin), phycocyanin, chlorophyll and heme. Bilirubin is the major active ingredient of natural bezoar.
Chinese patent publication No. CN112592356A discloses a pyrrolinone compound and a synthesis method thereof, which is a synthesis method of bilirubin D ring. In the prior art, few literature reports exist about methods for synthesizing B-ring or C-ring of bile pigments (including bilirubin). Among them, Woodward, the U.S. chemist, synthesizes B-rings in 15 steps (Tetrahedron,1995, vol.46, #22, p.7599-7659), and Lightner synthesizes B-rings with sulfuryl chloride (Tetrahedron,1993, vol.49, #11, p.2185-2255). However, the two methods have too long route, the three wastes problem caused by sulfuryl chloride exists, and special equipment such as high vacuum is needed in the preparation process, so that the two methods have no industrial value. In addition, both methods are based on the synthesis of compound 1 with compound 6:
the synthesis of compound 1 through this route is accompanied by the production of impurities (isomer compound 5), and in addition, the preparation of compound 6 requires high temperature (175 ℃) decarboxylation followed by high vacuum (1mmHg) distillation, after which there is about 35% of black kettle residual solid (high molecular polymer), which is difficult to clean with common solvents and acids and bases, and this process route is difficult to industrialize.
We prepared compound 3 in the literature (Lightner, Journal of Heterocyclic Chemistry,2551, vol.38, #2, p.527-535) and then debenzylated to 2, 2 to decarboxylate at 175 ℃ under high vacuum to give 6 in low yield (35%), prepared target compound 1 by the literature method of Woodward (6 to 1 yield 45%, two step yield 12%), attempted to prepare 6 by the literature method (J.laboratory Com. & radiopharm.1994, Vol.34, No.3, 263-274) using the carboxy group of p-toluenesulfonic acid debenzolized 2, and found to be unreactive at 5 ℃ and predominantly a brownish black polymer at 15 ℃.
Therefore, the research and development of a shorter synthetic route and the preparation of the 4-methoxycarbonylethyl-3-methyl-2-pyrrolal without column chromatography have larger theoretical and industrial values.
Disclosure of Invention
The present invention aims to solve, at least to some extent, the technical problems of the prior art. Accordingly, in a first aspect of the present invention, the present invention provides a method for synthesizing 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 for preparing the compound shown in formula 1 from the compound shown in formula 2 is as follows:
in one or more embodiments of the present invention, the compound represented by formula 2 is prepared from a compound represented by formula 3, and the reaction formula for preparing the compound represented by formula 2 from the compound represented by formula 3 is as follows:
in other embodiments of the present invention, the compound of formula 2 is prepared from a 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 invention, during the preparation of the compound shown in the formula 1 from the compound shown in the formula 2, trifluoroacetic acid is added, wherein the molar ratio of the trifluoroacetic acid to the compound shown in the formula 2 is (4-11): 1, preferably (6-11): 1, more preferably (8-9): 1.
in one or more embodiments of the present invention, during the preparation of the compound represented by formula 1 from the compound represented by formula 2, trimethyl orthoformate is added, and the trimethyl orthoformate is dropped into the reaction system, preferably, the reaction dropping speed is controlled to be 5-6 mmol/min.
In one or more embodiments of the invention, the reaction temperature is controlled to be-5-35 ℃ in the process of preparing the compound shown in the formula 1 from the compound shown in the 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 invention, the temperature of the sodium bicarbonate solution treatment reaction liquid 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 invention, during the preparation of the compound of formula 2 from the compound of formula 3, triethylamine is added; preferably, the molar ratio of triethylamine to the compound shown in the formula 3 is controlled to be (1-2): 1, and preferably (1.5-2): 1.
In one or more embodiments of the 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, removing the solvent by rotary evaporation, adding ethyl acetate, adjusting the pH to 3-4, washing with water, removing the solvent by rotary evaporation, recrystallizing and drying.
In a second aspect of the present invention, the present invention provides an intermediate for the synthesis of 4-methoxycarbonylethyl-3-methyl-2-pyrrolealdehyde, said intermediate having a structural formula shown in formula 2:
compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention provides a synthesis method of 4-methoxycarbonyl ethyl-3-methyl-2-pyrrole aldehyde, which has the advantages of short synthesis route, high yield, high purity, low cost and mild synthesis conditions, and is suitable for industrialization.
2. The synthesis method of 4-methoxycarbonyl ethyl-3-methyl-2-pyrrole aldehyde provided by the invention can effectively avoid using sulfuryl chloride and other substances, 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-pyrrole aldehyde and an intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde.
Synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde
The structural formula of 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is shown as formula 1, the 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is prepared from a compound shown as formula 2, and the reaction formula for preparing the compound shown as formula 1 from the compound shown as formula 2 is as follows:
in one or more embodiments of the invention, the compound of formula 2 is prepared from a compound of formula 3, the reaction formula for preparing the compound of formula 2 from the compound of formula 3 is shown below,
in other embodiments of the present invention, the compound of formula 2 is prepared from a 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 invention, during the preparation of the compound shown in the formula 1 from the compound shown in the formula 2, trifluoroacetic acid is added, wherein the molar ratio of the trifluoroacetic acid to the compound shown in the formula 2 is (4-11): 1, preferably (6-11): 1, more preferably (8-9): 1.
in one or more embodiments of the invention, during the preparation of the compound shown in formula 1 from the compound shown in formula 2, trimethyl orthoformate is added, and the trimethyl orthoformate is dropped into the reaction system, preferably, the reaction dropping speed is controlled to be 5-6 mmol/min.
In one or more embodiments of the invention, the reaction temperature is controlled to be-5 to 35 ℃ in the process of preparing the compound shown in the formula 1 from the compound shown in the 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 invention, the temperature of the sodium bicarbonate solution treatment reaction liquid 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 invention, during the preparation of the compound of formula 2 from the compound of formula 3, triethylamine is added; preferably, the molar ratio of triethylamine to the compound shown in the formula 3 is controlled to be (1-2): 1, and preferably (1.5-2): 1.
In one or more embodiments of the 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, removing the solvent by rotary evaporation, adding ethyl acetate, adjusting the pH to 3-4, washing with water, removing the solvent by rotary evaporation, recrystallizing and drying.
Intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde
The invention provides an intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde, wherein the structural formula of the intermediate is shown as a formula 2:
the scheme of the invention will be explained with reference to the following examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. 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, technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to those described herein can also be used in the present invention. NMR was measured using a Bruker-AMX655 NMR spectrometer; ESI-MS with 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-pyrrolcarbaldehyde starting material compound 3 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 shown as follows:
the preparation method comprises the following specific steps: a 255ml reaction bottle is filled with 15.68 g of compound 3(35.4mmol), 85 ml of methanol, 6.96 g of triethylamine (68.78mmol), 5% Pd/C2.8 g (55% water, Baojiruike corporation), hydrogen is introduced at room temperature and normal pressure, after the reaction is monitored by TLC, the solution is filtered, the solvent is removed by rotary distillation, ethyl acetate is added, the pH is adjusted to 3-4 by 15% acetic acid, the solution is washed by water, the solvent is removed by rotary distillation, and the mixture is treated by 1:4 ethyl acetate: recrystallizing with petroleum ether, and vacuum drying phosphorus pentoxide to obtain 3.82 g of white solid, namely compound 2. M.p.135-137 deg.c (partial decomposition). Yield 51.5% (mother liquor recovery is 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 is not stable to light at room temperature, changes color to brown-gray after being stored in a refrigerator at 3 ℃ for one week, and TLC (1:1:5.1EA: PE: AcOH) finds that there is an obvious original impurity. The compound 2 was dried in vacuum with phosphorus pentoxide and stored in a freezer at-15 ℃.
Example 2 Synthesis of Compound 1
The reaction formula is shown as follows:
the preparation process comprises the following steps: to a 255mL bottle, 9.5mL of trifluoroacetic acid (125mmol,8.4eqv.), 3.55g of compound 2(14.2mmol) were added, the mixture was cooled to-5 ℃ under nitrogen, 4.52g of trimethyl orthoformate (42.6mmol) was added dropwise to the reaction mixture, the mixture was stirred at 15 to 35 ℃ for 1 hour, 65 mL of dichloromethane was added after TLC monitoring reaction, a saturated sodium bicarbonate solution was added under cooling, the mixture was washed with water to neutrality, the solvent was removed by rotary distillation, and 1:4 ethyl acetate: recrystallizing with petroleum ether, and vacuum drying phosphorus pentoxide to obtain 1.65 g of light yellow solid, namely compound 1. Yield 57.7% (mother liquor recovered not), mp: 75 to 77 ℃ (76 to 77 ℃ in the document). Compound 1 is unstable to light at room temperature, and is stored in a freezer at-15 deg.C after vacuum drying of phosphorus pentoxide.
Other reaction conditions were not changed, 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 aldehyde group reaction on trifluoroacetic acid (TFA) summary Table
Wherein, HPLC conditions are as follows: chromatography column Erit C18(4.6mm 255mm, 5 μm), column temperature 25 deg.C, flow rate 1.5mL/min, detection wavelength 254nm, mobile phase ACN: h 2 O: TFA 75%: 35 percent: 5.1%, sample size 25. mu.L.
Example 3: and (3) reacting the compound 4 with trifluoroacetic acid and trimethyl orthoformate.
A25 mL reaction flask was charged with Compound 4(1.55g, 5.57mmol), MeOH 15mL, and under nitrogen, the solution was dissolved by magnetic stirring, and CF was added 3 5.188mL (2.53mmol) of COOH, no heat release, light-shielding reaction at 15 ℃ overnight, supplementing 5.188mL (2.53mmol) of trifluoroacetic acid, enabling the reaction solution to be bluish purple, adding 5.694 g of trimethyl orthoformate (6.5mmol,1.29eqv), stirring at 15 ℃ overnight, deepening the color of the reaction solution, rotationally removing the solvent, extracting EA, washing with sodium bicarbonate and saturated sodium chloride, and performing column chromatography to obtain 5.65 g of off-white solid with the yield of 61%. Melting Point, HPLC, NMR is the same as the product debenzylated from Compound 3.
Although embodiments of the present invention have been shown and described, it should be understood that the above embodiments are illustrative and not restrictive, and that various changes, modifications, substitutions, combinations, and simplifications may be made without departing from the spirit and principles of the invention and are intended to be included within the scope of the invention.
Claims (10)
1. A synthetic method of 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is disclosed, wherein the structural formula of 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is shown in formula 1, and is characterized in that the 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is prepared from a compound shown in formula 2, and the reaction formula for preparing the compound shown in formula 1 from the compound shown in formula 2 is shown as follows:
2. the method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein the compound represented by formula 2 is prepared from a compound represented by formula 3, and the reaction formula for preparing the compound represented by formula 2 from the compound represented by formula 3 is as follows:
3. the method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein the compound represented by formula 2 is prepared from a compound represented by formula 4, and the reaction formula for preparing the compound represented by formula 2 from the compound represented by formula 4 is as follows:
4. the method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal according to claim 1, wherein during the preparation of the compound represented by formula 1 from the compound represented by formula 2, trifluoroacetic acid is added, and the molar ratio of the trifluoroacetic acid to the compound represented by formula 2 is (4-11): 1, preferably (6-11): 1, more preferably (8-9): 1.
5. the synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde according to claim 1, wherein trimethyl orthoformate is added in the process of preparing the compound shown in formula 1 from the compound shown in formula 2, and the trimethyl orthoformate is dripped into a reaction system, preferably, the reaction dripping speed is controlled to be 5-6 mmol/min; preferably, the reaction temperature is controlled to be-5-30 ℃.
6. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal as claimed in claim 1, wherein 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.
7. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolal as claimed in claim 6, wherein the temperature of the saturated sodium bicarbonate solution is controlled to be 0 ℃; 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.
8. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolealdehyde 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; preferably, the molar ratio of triethylamine to the compound shown in the formula 3 is controlled to be (1-2): 1.
9. The method for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrolealdehyde according to claim 2, wherein in the process of preparing the compound represented by formula 2 from the compound represented by formula 3, Pd/C is added; preferably, the preparation of the compound of formula 2 from the compound of formula 3 further comprises a purification step comprising: filtering, removing the solvent by rotary evaporation, adding ethyl acetate, adjusting the pH value to 3-4, washing with water, removing the solvent by rotary evaporation, recrystallizing and drying.
10. An intermediate for synthesizing 4-methoxycarbonylethyl-3-methyl-2-pyrrole aldehyde is characterized in that the structural formula of the intermediate is shown as formula 2:
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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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| KATE-LYN A. R. LUND等: "Synthesis and anticancer activity of prodigiosenes bearing C-ring esters and amides", 《RSC ADV.》, vol. 7, pages 18617 - 18627 * |
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