CN115806471A - Preparation method for preparing substituted propargyl alcohol by catalyzing paraformaldehyde and alkyne with alkali - Google Patents
Preparation method for preparing substituted propargyl alcohol by catalyzing paraformaldehyde and alkyne with alkali Download PDFInfo
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- 229930040373 Paraformaldehyde Natural products 0.000 title claims abstract description 19
- 229920002866 paraformaldehyde Polymers 0.000 title claims abstract description 19
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical class OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003513 alkali Substances 0.000 title claims description 17
- 150000001345 alkine derivatives Chemical class 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000010438 heat treatment Methods 0.000 claims description 16
- -1 phenylacetylene compound Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 claims description 4
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 10
- 238000000926 separation method Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000011261 inert gas Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 230000003321 amplification Effects 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- NITUNGCLDSFVDL-UHFFFAOYSA-N 3-phenylprop-2-yn-1-ol Chemical compound OCC#CC1=CC=CC=C1 NITUNGCLDSFVDL-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 description 1
- ZNTJVJSUNSUMPP-UHFFFAOYSA-N 1-ethyl-4-ethynylbenzene Chemical group CCC1=CC=C(C#C)C=C1 ZNTJVJSUNSUMPP-UHFFFAOYSA-N 0.000 description 1
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 description 1
- IIEJGTQVBJHMDL-UHFFFAOYSA-N 2-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-[2-oxo-2-[3-(sulfamoylamino)pyrrolidin-1-yl]ethyl]-1,3,4-oxadiazole Chemical compound C1CN(CC1NS(=O)(=O)N)C(=O)CC2=NN=C(O2)C3=CN=C(N=C3)NC4CC5=CC=CC=C5C4 IIEJGTQVBJHMDL-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- AARLJMFYTTUPGP-UHFFFAOYSA-N 3-(4-chlorophenyl)prop-2-yn-1-ol Chemical compound OCC#CC1=CC=C(Cl)C=C1 AARLJMFYTTUPGP-UHFFFAOYSA-N 0.000 description 1
- FLMHMSDRESJOIB-UHFFFAOYSA-N 3-(4-ethylphenyl)prop-2-yn-1-ol Chemical compound CCC1=CC=C(C#CCO)C=C1 FLMHMSDRESJOIB-UHFFFAOYSA-N 0.000 description 1
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
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Abstract
The invention provides a high-efficiency preparation method for preparing substituted propargyl alcohol by using phenylacetylene compounds and paraformaldehyde under the action of a base catalyst. The preparation synthesis method is simple and effective to operate, mild in reaction conditions and high in yield, and can well solve the technical problem that the existing preparation route for substituting the propargyl alcohol intermediate is high in cost.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical intermediates, and particularly relates to a synthetic method for efficiently preparing substituted propargyl alcohol by base catalysis.
Background
Substituted propargyl alcohol is an important organic and medical intermediate, and can perform various chemical conversion reactions. The main aryl propargyl alcohol in the market at present has fewer types and high price, and the situation is not beneficial to the further healthy development of the organic chemistry and medicine fields. Conventional methods for preparing substituted propargyl alcohols are generally of two types: (1) an equivalent of a base or strong base-promoted addition reaction; (2) by a palladium-catalyzed Sonogashira coupling reaction. In the two methods, the problems of easy ignition due to the use of equivalent alkali or organic metal strong alkali, expensive palladium catalyst and the like exist, the preparation method has the problems of potential safety hazard, high cost and the like, does not meet the green chemical requirements, and is not beneficial to the amplification production of the reaction. Therefore, the development of a relatively green and efficient synthesis method of substituted propargyl alcohol is needed, and the method is simple to operate, easy to amplify, and good in safety and reliability, so as to solve the unfavorable situation that different substituted propargyl alcohols, which are important medical intermediates, are seriously short and expensive in the market.
Disclosure of Invention
Aiming at the defects and shortcomings in the prior art, experiments and researches show that under mild conditions, some alkali can catalyze the efficient addition reaction of paraformaldehyde and alkyne and can be smoothly converted into substituted propargyl alcohol compounds, so that the efficient synthesis method for preparing substituted propargyl alcohol by catalyzing paraformaldehyde and alkyne with alkali is provided, a more green synthesis technical route is developed, and the method uses catalytic amount of alkali, is simple to operate, has mild reaction conditions, is safe and reliable and is easy to amplify.
The technical scheme provided by the invention is as follows:
a preparation method for preparing substituted propargyl alcohol by catalyzing paraformaldehyde and alkyne with alkali is characterized by comprising the following steps: the method comprises the following steps:
1) Mixing phenylacetylene compounds and paraformaldehyde according to a molar ratio of 1:1.5 adding the mixture into a corresponding solvent DMSO to ensure that the solute concentration of the phenylacetylene compound reaches 0.5mol/L;
2) Under the condition of stirring, adding a basic catalyst, wherein the dosage of the basic catalyst is 10% of the molar dosage of the phenylacetylene compound according to the equivalent of the alkali which can be provided by the basic catalyst;
3) Heating to 25-60 ℃, reacting for 2-24 hours, and adding water to quench the reaction;
4) Extracting with ethyl acetate, separating, drying, concentrating, and purifying to obtain product;
the reaction formula for preparing the substituted propargyl alcohol from the phenylacetylene compound and paraformaldehyde is as follows:
wherein the number of R substituents may be 0-5.
Preferably, the R substituent group can be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3 、NO 2 C1-8 alkyl, C1-8 alkoxy, et, n-Pr, i-Pr, bu, CH 2 = one or more of CH, OMe, OEt and OPr; further, the R substituent can be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3、 NO 2 One or more of the components; or further, the R substituent can be selected from Me, et, n-Pr, i-Pr, bu and CH 2 And (3) one or more of CH, OMe, OEt and OPr.
Preferably, the stirring speed of the step 2) is 200-500r/min, and further, the stirring speed of the step 2) is 300r/min.
Preferably, the heating temperature in the step 3) is 40-60 ℃, and further, the heating temperature in the step 4) can be 40 ℃ or 60 ℃.
Preferably, the alkaline catalyst can be selected from KOH, naOH and K 2 CO 3、 Cs 2 CO 3、 Tetrabutylammonium hydroxide (TBA-OH), tetraethylammonium hydroxide (TEA-OH), tetramethylammonium hydroxide (TMA-OH), and further TBA-OH may be selected.
The preparation method of the substituted propargyl alcohol provided by the invention has the following beneficial effects:
1. greatly reduces the using amount of the alkaline catalyst in the traditional method for preparing the substituted propargyl alcohol and overcomes the defect of high cost caused by the need of using a palladium catalyst.
2. The method has the advantages of mild reaction conditions, low heating temperature, simple synthesis steps, less side reactions, good product yield, short time consumption, simple and convenient operation, easy amplification, good safety and reliability, and can greatly reduce the technical cost for preparing the substituted propargyl alcohol medical intermediate in industrial production.
Drawings
FIG. 1 is nuclear magnetic hydrogen spectrum of product 3aa of example 1 1 H-NMR(400MHz in CDCl 3 )
FIG. 2 is nuclear magnetic carbon spectrum of product 3aa of example 1 13 C-NMR(400MHz in CDCl 3 )
FIG. 3 is nuclear magnetic hydrogen spectrum of product 3ab of example 2 1 H-NMR(400MHz in CDCl 3 )
FIG. 4 NMR spectra of product 3ab of example 2 13 C-NMR(400MHz in CDCl 3 )
FIG. 5 is the nuclear magnetic hydrogen spectrum of product 3ac from example 3 1 H-NMR(400MHz in CDCl 3 )
FIG. 6 nuclear magnetic carbon spectra of product 3ac from example 3 13 C-NMR(400MHz in CDCl 3 )
FIG. 7 is the nuclear magnetic hydrogen spectrum of product 3ad of example 4 1 H-NMR(400MHz in CDCl 3 )
FIG. 8 is nuclear magnetic carbon spectrum of product 3ad of example 4 13 C-NMR(400MHz in CDCl 3 )
FIG. 9 is the nuclear magnetic hydrogen spectrum of product 3ae of example 5 1 H-NMR(400MHz in CDCl 3 )
FIG. 10 nuclear magnetic carbon spectrum of product 3ae of example 5 13 C-NMR(400MHz in CDCl 3 )
FIG. 11 is the nuclear magnetic hydrogen spectrum of the product 3af of example 6 1 H-NMR(400MHz in CDCl 3 )
FIG. 12 NMR spectra of product 3af of example 6 13 C-NMR(400MHz in CDCl 3 )
FIG. 13 shows the experiment conducted to adjust the heating temperature in the case of the amplification reaction of example 1-1
Detailed Description
The reaction parameters and conditions of examples 1-6 given in the present invention were selected by setting different types of bases, solvent conditions and heating temperatures based on the reactant materials of example 1, and searching for comparison, as shown in Table 1. The separation yield of the examples 1-6 is higher than 60%, which shows that the synthesis method for preparing the substituted propargyl alcohol by using the base to catalyze the paraformaldehyde and the phenylacetylene compound, which is obtained by the invention, is very efficient and has very commercial value.
Example 1
The specific preparation method of the compound 3-Phenyl-2-Propyn-1-ol (3-Phenyl-2-propyl-1-ol) (3 aa) is as follows:
adding phenylacetylene (1.0 mmol) and paraformaldehyde (1.5 mmol) into a corresponding solvent DMSO (0.5 mol/L), adding tetrabutylammonium hydroxide (TBA-OH) (0.1 equivalent) as a base under stirring to catalyze the reaction, keeping 60 ℃ under air without inert gas protection, heating for 10 hours, checking by TLC until the reaction is complete, adding 10mL of water to quench the reaction, extracting with ethyl acetate (10mL x 3), separating, drying and concentrating to obtain a crude product. The crude product was taken up in 1.0ml of CDCl 3 After dissolution, ethylene glycol dimethyl ether was quantitatively added as an internal standard, and the nuclear magnetic yield of 3aa was determined to be 99%, and the column chromatography separation yield was determined to be 93%.
The structural formula is as follows:
the 3aa nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 -d) δ 7.55-7.37 (m, 2H), 7.36-7.22 (m, 3H), 4.49 (s, 2H), 2.96 (s, 1H) ppm as shown in fig. 1; 13 C NMR(100MHz,CDCl 3 -d) delta 131.80,128.59,128.58,122.67,87.47,85.64,51.51ppm; as shown in fig. 2.
Example 1-1 (amplification reaction)
The compound 3-Phenyl-2-Propyn-1-ol (3-Phenyl-2-propyl-1-ol) (3 aa) is subjected to amplification reaction, and the specific preparation method is as follows:
phenylacetylene (200 mmol) and paraformaldehyde (300 mmol) are added into a corresponding solvent DMSO (0.5 mol/L), a base tetrabutylammonium hydroxide (TBA-OH) (0.1 equivalent) is added under stirring to catalyze the reaction, the reaction is kept at 60 ℃ under air without protection of inert gas and is heated for 10 hours, as shown in figure 13, after TLC detection is carried out until the reaction is completed, 200mL of water is added for quenching the reaction, ethyl acetate is used for extraction (150mL of 3), liquid separation is carried out, drying and concentration are carried out to obtain a crude product, and the crude product is separated by column chromatography to obtain a product 3aa (22.47 g, the isolated yield is 85%).
Example 2
The specific preparation method of the compound 3- (4-chlorphenyl) -2-propyne-1-ol (3- (4-chlorophenylyl) prop-2-yn-1-ol) (3 ab) is as follows:
adding 1.0mmol of 4-chlorophenylacetylene and paraformaldehyde (1.5 mmol) into a corresponding solvent DMSO (0.5 mol/L), adding alkali TBA-OH (0.1 equivalent) under stirring to catalyze the reaction, keeping the temperature of 60 ℃ under the air without inert gas protection, heating for reaction for 10 hours, checking by TLC until the reaction is complete, adding 10mL of water to quench the reaction, extracting with ethyl acetate (10mL x 3), separating, drying, concentrating, and separating by column chromatography to obtain a pure product 3ab, wherein the separation yield is 68%.
The 3ab nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 -d) δ 7.37-7.32 (m, 2H), 7.29-7.25 (m, 2H), 4.48 (s, 2H) ppm, as shown in fig. 3; 13 C NMR(100MHz,CDCl 3 d) delta 134.66,133.01,128.78,121.07,88.21,84.70,51.68ppm as shown in FIG. 4.
Example 3
The specific preparation method of the compound 3- (4-fluorophenyl) -2-propyn-1-ol (3- (4-fluorophenyl) prop-2-yn-1-ol) (3 ac) is as follows:
adding 1.0mmol of 4-fluoroacetylene and 1.5mmol of paraformaldehyde into a corresponding solvent DMSO (0.5 mol/L), adding alkali TBA-OH (0.1 equivalent) to catalyze the reaction under stirring, keeping 60 ℃ under the air without protection of inert gas, heating and reacting for 10 hours, detecting by TLC until the reaction is complete, adding 10mL of water to quench the reaction, extracting with ethyl acetate (10mL of 3), separating, drying, concentrating, and separating by column chromatography to obtain a pure product 3ac, wherein the separation yield is 81%.
3ac Nuclear magnetic data as follows: 1 H NMR(400MHz,CDCl 3 -d) δ 7.44-7.30 (m, 2H), 7.01-6.87 (m, 2H), 4.46 (s, 2H), 3.38 (s, 1H) ppm, as shown in FIG. 5; 13 C NMR(101MHz,CDCl 3 -d) δ 162.63 (d, J =250.8 Hz), 133.68 (d, J =8.1 Hz), 118.70 (d, J =4.0 Hz), 115.78 (d, J =22.1 Hz), 87.09 (d, J =1.0 Hz), 84.56,51.32ppm; as shown in fig. 6.
Example 4
The specific preparation method of the compound 3- (4-methoxyphenyl) -2-propyn-1-ol (3- (4-methoxyphenyl) prop-2-yn-1-ol) (3 ad) is as follows:
adding 4-methoxyphenylacetylene (1.0 mmol) and paraformaldehyde (1.5 mmol) into a corresponding solvent DMSO (0.5 mol/L), adding alkali TBA-OH (0.1 equivalent) under stirring to catalyze the reaction, keeping 60 ℃ under the air without inert gas protection, heating and reacting for 10 hours, detecting by TLC until the reaction is complete, adding 10mL of water to quench the reaction, extracting with ethyl acetate (10mL of 3), separating, drying, concentrating, and separating by column chromatography to obtain a pure product 3ad with the separation yield of 64%.
3ad Nuclear magnetic data as follows: 1 H NMR(400MHz,CDCl 3 d) δ 7.34 (d, J =8.8hz, 2h), 6.79 (d, J =8.8hz, 2h), 4.46 (s, 2H), 3.75 (s, 3H), 2.86 (s, 1H) ppm, as shown in fig. 7; 13 C NMR(100MHz,CDCl 3 d) delta 159.72,133.28,114.77,114.02,86.14,85.55,55.36,51.56ppm, as shown in FIG. 8.
Example 5
The specific preparation method of the compound 3- (p-tolyl) -2-propyne-1-ol (3- (p-tolyl) prop-2-yn-1-ol) (3 ae) is as follows:
adding 4-methyl phenylacetylene 1a (1.0 mmol) and paraformaldehyde (1.5 mmol) into a corresponding solvent DMSO (0.5 mol/L), adding alkali TBA-OH (0.1 equivalent) under stirring to catalyze the reaction, keeping 60 ℃ under air without inert gas protection, heating and reacting for 10 hours, quenching the reaction by adding 10mL of water after TLC (thin layer chromatography) detects that the reaction is complete, extracting by ethyl acetate (10mL x 3), separating liquid, drying, concentrating, and separating by column chromatography to obtain a pure product 3ae, wherein the separation yield is 78%.
3ae nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 -d) δ 7.33 (d, J =8.1hz, 2h), 7.09 (d, J =8.4hz, 2h), 4.49 (s, 2H), 2.96 (s, 1H), 2.33 (s, 3H) ppm; as shown in fig. 9; 13 C NMR(100MHz,CDCl 3 d) delta 138.69,131.72,129.19,119.61,86.79,85.78,51.55,21.57ppm, as shown in FIG. 10.
Example 6
The specific preparation method of the compound 3- (4-phenylethyl) -2-propyn-1-ol (3- (4-ethylphenyl) prop-2-yn-1-ol) (3 af) is as follows:
adding 4-ethyl phenylacetylene 1a (1.0 mmol) and paraformaldehyde 2a (1.5 mmol) into a corresponding solvent DMSO (0.5 mol/L), adding alkali TBA-OH (0.1 equivalent) under stirring to catalyze the reaction, keeping 60 ℃ under air without protection of inert gas, heating and reacting for 10 hours, detecting by TLC until the reaction is complete, adding 10mL of water to quench the reaction, extracting with ethyl acetate (10mL of 3), separating liquid, drying, concentrating, separating by column chromatography to obtain a pure product 3af, wherein the separation yield is 62%.
The structural formula is as follows:
the 3af nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 -d) δ 7.36 (d, J =8.2hz, 2h), 7.12 (d, J =7.9hz, 2h), 4.49 (s, 2H), 2.67 (s, 1H), 2.63 (q, J =7.6hz, 2h), 1.21 (t, J =7.5hz, 3h) ppm; as shown in FIG. 11； 13 C NMR(100MHz,CDCl 3 D) delta 144.98,131.81,127.99,119.82,86.73,85.86,51.63,28.89,15.43ppm, as shown in FIG. 12.
Optimized screening assay for reaction conditions
The experimental parameters were adjusted according to the experimental parameters shown in table 1 below to investigate the comparison data of nuclear magnetic yield under different alkali conditions, solvent conditions and heating temperature conditions, and the experimental results are as follows:
TABLE 1 comparison of the nuclear magnetic yields of 3-Phenyl-2-Propyn-1-ol (3-Phenyl-2-propyl-1-ol) (3 aa) under different test parameters
The test comparison result shows that the DMSO is selected as the solvent, the TBA-OH is selected as the base catalyst, the temperature is 60 ℃, and the product generation rate of the reaction is optimal under the reaction condition. From this experimental data, it is proved that the parameter setting in the synthesis method of the present invention can achieve the inventive purpose of the present invention without selecting the conventional base species, the conventional solvent, or setting the conventional temperature conditions.
It should be understood that although the present specification has been described in terms of embodiments, such descriptions are for clarity only and those skilled in the art will understand that the present specification as a whole may form other embodiments that will be apparent to those skilled in the art and also fall within the scope of the present invention.
Claims (10)
1. A preparation method for preparing substituted propargyl alcohol by catalyzing paraformaldehyde and alkyne with alkali is characterized by comprising the following steps: the method comprises the following steps:
1) Mixing phenylacetylene compounds and paraformaldehyde according to a molar ratio of 1:1.5 adding the mixture into a corresponding solvent DMSO to ensure that the solute concentration of the phenylacetylene compound reaches 0.5mol/L;
2) Under the condition of stirring, adding an alkaline catalyst, wherein the dosage of the alkaline catalyst is 10 percent of the molar dosage of the phenylacetylene compound according to the equivalent of the alkali provided by the alkaline catalyst;
3) Heating to 25-60 ℃, reacting for 2-24 hours, and adding water to quench the reaction;
4) Extracting with ethyl acetate, separating, drying, concentrating, and purifying to obtain product;
the reaction formula for preparing substituted propargyl alcohol from phenylacetylene compounds and paraformaldehyde is as follows:
wherein the number of R substituents may be 0-5.
2. The production method according to claim 1, characterized in that: the R substituent can be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3 、NO 2 C1-8 alkyl, C1-8 alkoxy, et, n-Pr, i-Pr, bu, CH 2 And (4) one or more of CH, OMe, OEt and OPr.
3. The method of claim 1, wherein: the alkaline catalyst in step 2) can be selected from KOH, naOH and K 2 CO 3， TBA-OH，Cs 2 CO 3 Tetrabutylammonium hydroxide (TBA-OH), tetraethylammonium hydroxide (TEA-OH), tetramethylammonium hydroxide (TMA-OH).
4. The production method according to claim 3, characterized in that: the base catalyst in the step 2) may preferably be tetrabutylammonium hydroxide (TBA-OH).
5. The method of claim 1, wherein: the stirring speed of the step 2) is 200-500r/min.
6. The production method according to claim 1, characterized in that: the stirring speed of the step 2) is 300r/min.
7. The method of claim 1, wherein: the heating temperature in the step 3) is 40-60 ℃.
8. The method of manufacturing according to claim 4, characterized in that: the heating temperature in the step 3) can be 40 ℃ or 60 ℃.
9. The method of claim 1, wherein: the R substituent can be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3、 NO 2 One or more of them.
10. The method of claim 1, wherein: the R substituent can be selected from Me, et, n-Pr, i-Pr, bu and CH 2 And (3) one or more of CH, OMe, OEt and OPr.
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| US5110966A (en) * | 1991-06-20 | 1992-05-05 | Merrell Dow Pharmaceuticals Inc. | New organoboron reagents for the preparation unsubstituted propargylic alcohols |
| US20020010377A1 (en) * | 2000-03-31 | 2002-01-24 | Takanori Aoki | Production process and use for propargyl alcohol and its intermediate |
| CN1460096A (en) * | 2001-03-21 | 2003-12-03 | 丸善石油化学株式会社 | Method for separation and recovery of propargyl alcohol |
| CN1984860A (en) * | 2004-02-26 | 2007-06-20 | 巴斯福股份公司 | Method for producing a propargyl alcohol and an allyl alcohol |
| CN108358749A (en) * | 2018-02-07 | 2018-08-03 | 重庆弛源化工有限公司 | A kind of production method of propargyl alcohol |
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2022
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5110966A (en) * | 1991-06-20 | 1992-05-05 | Merrell Dow Pharmaceuticals Inc. | New organoboron reagents for the preparation unsubstituted propargylic alcohols |
| US20020010377A1 (en) * | 2000-03-31 | 2002-01-24 | Takanori Aoki | Production process and use for propargyl alcohol and its intermediate |
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| CN1984860A (en) * | 2004-02-26 | 2007-06-20 | 巴斯福股份公司 | Method for producing a propargyl alcohol and an allyl alcohol |
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