CN116143676B - Preparation method of pyrrolidin-2-yl (hydroxy) methyl compound - Google Patents
Preparation method of pyrrolidin-2-yl (hydroxy) methyl compound Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- -1 pyrrolidin-2-yl (hydroxy) methyl compound Chemical class 0.000 title abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 239000002904 solvent Substances 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000012973 diazabicyclooctane Substances 0.000 claims abstract description 27
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims abstract description 27
- 230000035484 reaction time Effects 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000004593 Epoxy Substances 0.000 claims description 8
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000000967 suction filtration Methods 0.000 description 25
- 239000003480 eluent Substances 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 17
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- GCTPMLUUWLLESL-UHFFFAOYSA-N benzyl prop-2-enoate Chemical compound C=CC(=O)OCC1=CC=CC=C1 GCTPMLUUWLLESL-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- WRAQQYDMVSCOTE-UHFFFAOYSA-N phenyl prop-2-enoate Chemical compound C=CC(=O)OC1=CC=CC=C1 WRAQQYDMVSCOTE-UHFFFAOYSA-N 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000000126 substance Substances 0.000 description 10
- 238000005292 vacuum distillation Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- 229940043375 1,5-pentanediol Drugs 0.000 description 4
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000013341 scale-up 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a preparation method of a pyrrolidin-2-yl (hydroxy) methyl compound, and provides a preparation method of a compound shown in a formula III, which comprises the following steps of reacting the compound shown in the formula I with the compound shown in the formula II and DABCO under the condition of no solvent to obtain the compound shown in the formula III. The preparation method has simple reaction conditions and short reaction time, and is favorable for industrialized mass production.
Description
Technical Field
The invention relates to a preparation method of a pyrrolidine-2-yl (hydroxy) methyl compound, in particular to a preparation method of phenyl 2- ((S) -1-tert-butyloxycarbonyl pyrrolidine-2-yl (hydroxy) methyl) acrylate and benzyl ester.
Background
2- ((S) -1-t-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) methyl) acrylate is an important key intermediate for the synthesis of polypeptide drugs, such as dolastatin. However, relatively few processes are reported for the synthesis of such compounds.
The literature adopts N-Boc-L-prolyl and phenyl acrylate to be condensed under the catalysis of DABCO and ultrasonic condition to obtain 2- ((S) -1-tert-butyloxycarbonyl pyrrolidin-2-yl (hydroxy) methyl) phenyl acrylate. (Almeida W.P., et al tetrahedron letters,2003,44 (5): 937-940) but this method uses ultrasonic catalysis, which has long reaction times and is not conducive to industrial scale-up.
Disclosure of Invention
In order to find a method for preparing phenyl 2- ((S) -1-tert-butyloxycarbonyl pyrrolidin-2-yl (hydroxy) methyl) acrylate and benzyl ester which can be applied to the preparation of the pyrrolidin-2-yl (hydroxy) methyl compound without ultrasonic conditions, the invention provides a preparation method of the pyrrolidin-2-yl (hydroxy) methyl compound. The preparation method can achieve one or more of the following advantages, and has the advantages of mild reaction conditions, short reaction time and higher yield.
The preparation method has the technical problems that the reaction condition is simple, the reaction time is short, and the preparation method is favorable for industrialized amplified production.
The invention solves the technical problems through the following technical proposal.
The invention provides a preparation method of a compound shown in a formula III, which comprises the following steps that the compound shown in the formula I, the compound shown in the formula II and DABCO react under the condition of no solvent to obtain the compound shown in the formula III;
in the process for the preparation of the compound indicated as III, the reaction temperature of the reaction may be in the range from 10 to 50℃and preferably in the range from 20 to 25℃as is conventional for such reactions.
In the preparation method of the compound shown in the III, the compound shown in the formula I, the compound shown in the formula II and DABCO are mixed in sequence.
In the preparation method of the compound shown in the III, the molar ratio of the compound shown in the formula I to the compound shown in the formula II is 1:1-2:1, preferably 1:1.
In the preparation method of the compound shown in the III, the molar ratio of DABCO to the compound shown in the formula II is 1:0.5-1:2, preferably 1:1.
In the reaction, the progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically at the end of the reaction when the compound of formula II is lost or no longer reacted. The reaction time is preferably 15 to 30 hours, more preferably 15 to 20 hours, and still more preferably 15 hours.
The preparation method can further comprise the following post-treatment steps: suction filtration, washing, reduced pressure distillation and column chromatography.
In the preparation method, the washed solvent is dichloromethane.
In the preparation method, the eluent used in the column chromatography is ethyl acetate, petroleum ether=20:1, 15:1, 10:1 and 5:1 gradient elution.
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps that the compound shown in the formula I, the compound shown in the formula V and DABCO react in the presence of a protic solvent to obtain the compound shown in the formula IV;
in the process for the preparation of the compounds indicated in IV, the reaction temperature of the reaction may be conventional reaction temperatures for such reactions, for example 20 to 25 ℃.
In the preparation method of the compound shown in IV, the compound shown in the formula I, the compound shown in the formula V and DABCO are mixed in sequence.
In the preparation method of the compound shown in IV, the molar ratio of the compound shown in the formula I to the compound shown in the formula V is 1:1-2:1, for example, 1:1.
in the preparation method of the compound shown in IV, the molar ratio of DABCO to the compound shown in the formula V is 1 (0.5-2), preferably 1 (0.8-2), for example 1:1.
in the preparation method of the compound shown in IV, the protic solvent can be a conventional protic solvent in the reaction, preferably an alcohol solvent or a mixed solvent of an epoxy solvent and water. The alcohol solvent is methanol, ethanol, isopropanol or 1, 5-pentanediol, preferably methanol or 1, 5-pentanediol. The epoxy solvent is preferably a mixed solution of 1, 4-dioxane and water. In the mixed solution of the epoxy solvent and water, the volume ratio of the epoxy solvent to the water can be 4:1-0.5:1, for example, 1:1.
In the preparation of the compound of formula IV, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically by taking the compound of formula V as the end point of the reaction when it disappears or no longer reacts. The reaction time is preferably 15 to 30 hours, more preferably 15 to 20 hours, and still more preferably 15 hours.
In the preparation method of the compound shown in IV, the mass volume ratio of the compound shown in the formula V to the protic solvent is (1:0.1-2) g/mL, for example (1:0.82) g/mL.
The preparation method of the compound shown in IV can further comprise the following post-treatment steps: suction filtration, washing, reduced pressure distillation and column chromatography.
In the preparation method of the compound shown in IV, the washed organic solvent is dichloromethane.
In the preparation method of the compound shown in IV, the eluent used in the column chromatography is ethyl acetate, petroleum ether=20:1, 10:1 and 5:1 gradient elution.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method of the phenyl 2- ((S) -1-tert-butyloxycarbonyl pyrrolidin-2-yl (hydroxy) methyl) acrylate and benzyl ester can achieve one or more of the following beneficial effects, and has the advantages of mild reaction conditions, short reaction time and higher yield.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 12 Synthesis of phenyl- ((S) -1-t-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (13.4 g,1.0 eq), phenyl acrylate (10.0 g,1.0 eq) and DABCO (7.5 g,1.0 eq) were added to a 100mL three-necked flask, stirred magnetically, reacted in a water bath at 20-25℃for 15 hours, and the reaction of the raw material phenyl acrylate was completed by TLC. Adding 20mL of ethanol, carrying out suction filtration through a suction filtration funnel paved with 40.0g of silica gel, adding 800mL of dichloromethane, and washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent, petroleum ether=20:1, 15:1, 10:1,5:1 gradient, and distilling the eluent at 50deg.C under reduced pressure to remove solvent to obtain yellow oily substance 19.4g, with a yield of 82.9%. 1 H NMR(400MHz,CDCl 3 ,ppm):δ＝1.35(s,9H),1.67-1.94(m,4H),3.20-3.62(m,2H),3.95-4.13(m,1H),4.57-4.87(m,1H),5.91-6.20(m,1H),6.45(s,1H),7.05-7.12(m,3H),7.25-7.28(m,2H)。
MS(ESI):m/z[M+H] + Calculated value C 19 H 26 NO 5 348.17; actual value 348.30.
Example 2 2 Synthesis of phenyl- ((S) -1-t-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (13.4 g,1.0 eq), phenyl acrylate (10.0 g,1.0 eq) and DABCO (6.0 g,0.8 eq) were added into a 100mL three-necked flask, stirred magnetically, reacted in a water bath at 20-25℃for 15 hours, and the reaction of the raw material phenyl acrylate was completed by TLC detection. Adding 20mL of ethanol, carrying out suction filtration through a suction filtration funnel paved with 40.0g of silica gel, adding 800mL of dichloromethane, and washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent, petroleum ether=20:1, 15:1, 10:1,5:1 gradient, and distillation of the eluent at 50deg.C under reduced pressure to remove solvent, gave 17.1g of yellow oil, 73.2% yield.
Example 32 Synthesis of phenyl- ((S) -1-t-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (13.4 g,1.0 eq), phenyl acrylate (10.0 g,1.0 eq) and DABCO (11.3 g,1.5 eq) were added into a 100mL three-necked flask, stirred magnetically, reacted in a water bath at 20-25℃for 15 hours, and the reaction of the raw material phenyl acrylate was completed by TLC. Adding 20mL of ethanol, carrying out suction filtration through a suction filtration funnel paved with 40.0g of silica gel, adding 800mL of dichloromethane, and washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent, petroleum ether=20:1, 15:1, 10:1,5:1 gradient, and distilling the eluent at 50deg.C under reduced pressure to remove solvent to obtain yellow oily substance 19.3g, with a yield of 82.6%.
Example 42 Synthesis of phenyl- ((S) -1-t-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (13.4 g,1.0 eq), phenyl acrylate (10.0 g,1.0 eq) and DABCO (15.0 g,2.0 eq) were added into a 100mL three-necked flask, stirred magnetically, reacted in a water bath at 20-25℃for 15 hours, and the reaction of the raw material phenyl acrylate was detected by TLC. Adding 20mL of ethanol, carrying out suction filtration through a suction filtration funnel paved with 40.0g of silica gel, adding 800mL of dichloromethane, and washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent, petroleum ether=20:1, 15:1, 10:1,5:1 gradient, and distilling the eluent at 50deg.C under reduced pressure to remove solvent to obtain yellow oily substance 19.3g, with a yield of 82.6%.
Example 5
N-BOC-L-prolyl (III) (5.0 g,1.0 eq), phenyl acrylate (3.7 g,1.0 eq), DABCO (2.8 g,1.0 eq) and methylene chloride (25 mL, 5.0V) are added into a 50mL three-necked flask, magnetically stirred, reacted for 48h in a water bath at 20-25 ℃, and the TLC detection of the reaction of the raw material phenyl acrylate is completed. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent, petroleum ether=20:1, 15:1, 10:1,5:1 gradient, and vacuum distillation of the eluent at 50deg.C to remove solvent, gave (I) as yellow oil 1.7g in 19.5% yield.
Example 6
N-BOC-L-prolyl aldehyde (5.0 g,1.0 eq), phenyl acrylate (3.7 g,1.0 eq), DABCO (2.8 g,1.0 eq) and 1, 5-pentanediol (5 mL, 1.0V) are added into a 50mL three-necked flask, magnetically stirred, and reacted for 15 hours at 20-25 ℃ in a water bath, and the TLC detects that the reaction of the raw material phenyl acrylate is completed. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent, petroleum ether=20:1, 15:1, 10:1,5:1 gradient, and vacuum distillation of the eluent at 50deg.C to remove solvent, gave (I) as yellow oil 3.7g in 42.5% yield.
Example 7 2 Synthesis of benzyl- ((S) -1-tert-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (20.0 g,1.0 eq), benzyl acrylate (16.3 g,1.0 eq) and DABCO (11.3 g,1.0 eq) were added to a 250mL three-necked flask, stirred magnetically, 1, 4-dioxane/water solution (1, 4-dioxane: water=1:1) (20 mL, 1.0V) was added, and the reaction was carried out in a water bath at 20-25℃for 15 hours, whereupon TLC detected that the starting benzyl acrylate was reacted. Filtering by a suction filtration funnel paved with 40.0g of silica gel, and washing by 1000mL of dichloromethane; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 32.8g, with a yield of 90.4%.
MS(ESI):m/z[M+H] + Calculated value C 20 H 28 NO 5 362.19; actual value 362.03.
Example 82 Synthesis of benzyl- ((S) -1-tert-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (5.0 g,1.0 eq), benzyl acrylate (4.1 g,1.0 eq) and DABCO (2.8 g,1.0 eq) were added to a 50mL three-necked flask, stirred magnetically, reacted in a water bath at 20-25℃for 7 days, and the reaction of the raw material benzyl acrylate was detected by TLC. 15mL of ethanol is added, the mixture is filtered by a suction filter funnel paved with 20.0g of silica gel, and the mixture is washed by 300mL of dichloromethane; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 7.4g with a yield of 81.3%.
Example 9 2 Synthesis of benzyl- ((S) -1-tert-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (5.0 g,1.0 eq), benzyl acrylate (4.1 g,1.0 eq) and DABCO (2.8 g,1.0 eq) were added to a 50mL three-necked flask, stirred magnetically, methanol (5 mL, 1.0V) was added, and reacted in a water bath at 20-25℃for 15 hours to complete the reaction of the starting benzyl acrylate by TLC detection. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 7.7g with a yield of 84.6%.
EXAMPLE 10 Synthesis of benzyl 2- ((S) -1-tert-Butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (5.0 g,1.0 eq), benzyl acrylate (4.1 g,1.0 eq) and DABCO (2.8 g,1.0 eq) were added to a 50mL three-necked flask, stirred magnetically, 1, 5-pentanediol (5 mL, 1.0V) was added, and the reaction was carried out in a water bath at 20-25℃for 15 hours, after which the TLC detection of the completion of the reaction of the starting benzyl acrylate. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 7.2g with yield of 79.1%.
EXAMPLE 11 Synthesis of benzyl 2- ((S) -1-tert-butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (5.0 g,1.0 eq), benzyl acrylate (4.1 g,1.0 eq), DABCO (2.3 g,0.8 eq) were added to a 50mL three-necked flask, stirred magnetically, 1, 4-dioxane/water solution (1, 4-dioxane: water=1:1) (5 mL, 1.0V) was added, and the reaction was carried out in a water bath at 20-25℃for 30 hours, whereupon TLC detected that the starting benzyl acrylate was reacted. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 7.3g with a yield of 80.2%.
EXAMPLE 12 Synthesis of benzyl 2- ((S) -1-tert-butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (5.0 g,1.0 eq), benzyl acrylate (4.1 g,1.0 eq), DABCO (4.2 g,1.5 eq) were added to a 50mL three-necked flask, stirred magnetically, 1, 4-dioxane/water solution (1, 4-dioxane: water=1:1) (5 mL, 1.0V) was added, and the reaction was carried out in a water bath at 20-25℃for 15 hours, whereupon TLC detected that the starting benzyl acrylate was reacted. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 8.2g with a yield of 90.1%.
EXAMPLE 13 Synthesis of benzyl 2- ((S) -1-tert-butoxycarbonyl pyrrolidin-2-yl (hydroxy) meth) acrylate
N-Boc-L-prolyl aldehyde (5.0 g,1.0 eq), benzyl acrylate (4.1 g,1.0 eq) and DABCO (5.6 g,2.0 eq) were added to a 50mL three-necked flask, stirred magnetically, 1, 4-dioxane/water solution (1, 4-dioxane: water=1:1) (5 mL, 1.0V) was added, and the reaction was carried out in a water bath at 20-25℃for 15 hours, whereupon TLC detected that the starting benzyl acrylate was reacted. Suction filtration is carried out through a suction filtration funnel paved with 20.0g of silica gel, and 300mL of dichloromethane is used for washing; distilling the filtrate at 40 ℃ under reduced pressure to remove the solvent, thus obtaining yellow oily matter; column chromatography purification, eluting with ethyl acetate as eluent (petroleum ether=20:1, 10:1, 5:1) gradient, and vacuum distillation at 50deg.C to remove solvent to obtain yellow oily substance 8.2g with a yield of 90.1%.
Claims (7)
1. A process for the preparation of a compound of formula III comprising the steps of: the compound shown in the formula I, the compound shown in the formula II and DABCO react under the condition of no solvent to obtain the compound shown in the formula III;
the molar ratio of the compound shown in the formula I to the compound shown in the formula II is 1:1;
the molar ratio of the compound shown in the formula II to the DABCO is 1:1-1:2.
2. The process for producing a compound of formula III according to claim 1, wherein the temperature of the reaction is 10 to 50 ℃.
3. The method of preparing a compound of formula III according to claim 2, wherein the molar ratio of the compound of formula II to DABCO is 1:1;
and/or the temperature of the reaction is 20-25 ℃.
4. A process for the preparation of a compound of formula III according to any one of claims 1 to 3, wherein the reaction time is 15 to 30 hours.
5. The preparation method of the compound shown in the formula IV is characterized by comprising the following steps of reacting the compound shown in the formula I with the compound shown in the formula V and DABCO in the presence of a protic solvent to obtain the compound shown in the formula IV;
the proton solvent is an alcohol solvent or a mixed solvent of an epoxy solvent and water; the alcohol solvent is methanol; the epoxy solvent is 1, 4-dioxane;
in the mixed solution of the epoxy solvent and the water, the volume ratio of the epoxy solvent to the water is 1:1;
the molar ratio of the compound shown in the formula I to the compound shown in the formula V is 1:1;
the molar ratio of DABCO to the compound shown in the formula V is 1 (0.5-1).
6. The method for preparing a compound of formula IV according to claim 5, wherein the temperature of the reaction is 10 to 50 ℃;
and/or the reaction time is 15-30 h.
7. The method for preparing a compound of formula IV according to claim 5, wherein the temperature of the reaction is 20 to 25 ℃;
and/or, the reaction time is 15h;
and/or the mol ratio of the compound shown in the formula V to DABCO is 1:1.
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Non-Patent Citations (4)
| Title |
|---|
| An asymmetric substrate-controlled MoritaeBayliseHillman reaction as approach for the synthesis of pyrrolizidinones and pyrrolizidines;Kristerson R. Luna-Freire等;《Tetrahedron》;第70卷;第3319-3326页 * |
| An easy and stereoselective synthesis of N-Boc-dolaproine via the Baylis–Hillman reaction;Wanda P. Almeida等;《Tetrahedron Letters》;第44卷(第5期);第937-940 * |
| Chiral, cyclic amino aldehydes in the Baylis-Hillman reaction - a route to sphingosine analogs;Drewes, Siegfried E.等;《Synthetic Communications》;第23卷(第2期);第183-188页 * |
| Formation of Unusual Seven-Membered Heterocycles Incorporating Nitrogen and Sulfur by Intramolecular Conjugate Displacement;Zhenhua Chen等;《J. Org. Chem.》;第75卷;第7014-7017页 * |
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