CN113480512B - Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone - Google Patents
Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- -1 [1,3] dioxol-4-yl Chemical group 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 10
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 95
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 22
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 19
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 9
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 8
- 239000012346 acetyl chloride Substances 0.000 claims description 8
- 238000006138 lithiation reaction Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000003999 initiator Substances 0.000 abstract description 2
- 235000002566 Capsicum Nutrition 0.000 abstract 1
- 239000006002 Pepper Substances 0.000 abstract 1
- 235000016761 Piper aduncum Nutrition 0.000 abstract 1
- 235000017804 Piper guineense Nutrition 0.000 abstract 1
- 244000203593 Piper nigrum Species 0.000 abstract 1
- 235000008184 Piper nigrum Nutrition 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000004321 preservation Methods 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 229960005235 piperonyl butoxide Drugs 0.000 description 5
- 238000010791 quenching Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000001979 organolithium group Chemical group 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
Abstract
The application relates to the technical field of organic synthesis, and particularly discloses a preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one, which comprises the steps of using a pepper ring as an initiator, and sequentially carrying out an acylation reaction, a carbonyl protection reaction, a bromination reaction and a carbonyl deprotection reaction to obtain the 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one. The method simplifies the synthetic route and improves the yield and purity.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one.
Background
1- (7-Bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one (CAS: 1892297-18-6) is an important intermediate in pharmaceutical synthesis, for example: chronic hepatitis C therapeutic drug-cloperavir Hydrochloride (Clopavir Hydrochloride).
However, the synthesis route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one in the related art is long, the yield is low, and the product purity is low.
Disclosure of Invention
In order to simplify the synthetic route and improve the yield and purity, the application provides a preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone, which adopts the following technical scheme:
a preparation method of a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one shown as a formula (V) comprises the following steps:
preparation of a Compound of formula (II): carrying out lithiation reaction on the compound shown in the formula (I) and n-butyllithium, and then carrying out acylation reaction on the compound and acetyl chloride to obtain a compound shown in a formula (II); the molar ratio of the compound shown in the formula (I), n-butyl lithium and acetyl chloride is 1 (1.8-2.0) to 1.1-1.2;
preparation of a Compound of formula (III): carrying out carbonyl protection reaction on the compound shown in the formula (II) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (III); the molar ratio of the compound shown in the formula (II), the glycol and the catalyst is 1 (1.1-1.2) to 0.08-0.10; preparation of a Compound of formula (V): carrying out lithiation reaction on a compound shown in a formula (III) and lithium diisopropylamide, and then carrying out bromination reaction on the compound shown in the formula (III) and bromine to obtain a compound shown in a formula (IV), wherein the molar ratio of the compound shown in the formula (III) to the lithium diisopropylamide to the bromine is (1.4-1.6) to (0.9-1.0); and (3) carrying out carbonyl deprotection reaction on the compound shown in the formula (IV) to obtain the compound shown in the formula (V).
Optionally, in the step of preparing the compound represented by the formula (II), the condition of the lithiation reaction is that the reaction temperature is-80 to-70 ℃.
Optionally, in the preparation of the compound represented by the formula (II) in the step (II), the acylation reaction is performed at a reaction temperature of 20 to 30 ℃.
Optionally, in the step of preparing the compound shown in the formula (III), the catalyst is p-toluenesulfonic acid.
Optionally, in the preparation of the compound shown in the step (III), the carbonyl protection reaction is performed at a reaction temperature of 65-75 ℃.
Optionally, in the step of preparing the compound represented by the formula (IV), the lithiation reaction is carried out under the condition that the reaction temperature is-70 to-80 ℃.
Optionally, in the preparation of the compound shown in the step (IV), the bromination reaction is performed under the condition that the reaction temperature is 20-30 ℃.
Optionally, in the step of preparing the compound represented by the formula (IV), the solvent used for recrystallization is ethyl acetate.
In summary, the present application has the following beneficial effects:
the application not only simplifies the synthetic route of the 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, but also improves the yield and the purity.
Drawings
FIG. 1 is a synthetic scheme of a process for the preparation of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one of the present application.
Detailed Description
The present application will be described in further detail with reference to examples.
The synthetic route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one is shown in FIG. 1.
The compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone shown in the formula (V) is obtained by using a compound piperonyl shown in the formula (I) as an initiator and sequentially carrying out acylation reaction, carbonyl protection reaction, bromination reaction and carbonyl deprotection reaction.
Preparation of Compound of formula (II)
Preparation example 1 of Compound represented by formula (II)
Adding a compound piperonyl (136.0g, 1.114mol) shown in the formula (I) and 200mL of tetrahydrofuran into a reactor, cooling to-78 ℃, dropwise adding n-butyllithium (135.0g, 2.107mol), and reacting at-79 ℃ for 1.5h with heat preservation; then, acetyl chloride (96.3g, 1.226mol) is dripped, the dripping temperature is kept below-79 ℃, then the temperature is slowly raised to 20-30 ℃, and the reaction is carried out for 1.5h under heat preservation. The reaction was quenched by dropping the reaction solution into 150mL of water while maintaining the quenching temperature below 35 ℃ and then sequentially taking 10% by weight of H 2 SO 4 The resulting mixture was washed once with 100mL of the aqueous solution, 200mL of saturated saline solution and 200mL of water, and the mixture was separated to give the compound represented by formula (II) (171.87g, 1.047mol, yield 93.97%).
Preparation example 2 of Compound represented by the formula (II)
Adding the compound piperonyl (136g, 1.114mol) shown in the formula (I) and 200mL of tetrahydrofuran into a reactor, cooling to-78 ℃, dropwise adding n-butyllithium (135g, 2.107mol), and reacting at-79 ℃ for 1.5 h. Acetyl chloride (104.8g, 1.336mol) is dripped, the dripping temperature is kept below-79 ℃, then the temperature is slowly raised to 20-30 ℃, and the reaction is carried out for 1.5h under heat preservation. Dropwise adding the reaction solution into 150mL of water for quenching, and keeping the quenching temperature below 35 ℃; then using H with the weight percentage concentration of 10 percent 2 SO 4 The resulting aqueous solution (100 mL), saturated saline (200 mL) and water (200 mL) were washed once and separated to give a compound represented by formula (II) (169.0g, 1.029mol, yield 92.40%).
Preparation example 3 of Compound represented by formula (II)
A compound, namely piperonyl (136g, 1.114mol) shown in the formula (I) and 200mL of tetrahydrofuran are added into a reactor, n-butyllithium (135g, 2.107mol) is added dropwise after the temperature is reduced to-78 ℃, and the reaction is carried out at-79 ℃ for 1.5 h. Dropwise adding acetyl chloride (96.2g, 1.225mol) and keeping the dropwise adding temperature below-79 ℃, then slowly heating to 20-30 ℃, and carrying out heat preservation reaction for 1.5 h. The reaction was quenched by adding droplets to 150ml of tap water and maintaining the quench temperature below 35 ℃. Then sequentially using H with the weight percentage concentration of 10 percent 2 SO 4 The resulting mixture was washed with 100mL of the aqueous solution, 200mL of saturated saline solution and 200mL of water, followed by separation to give a compound represented by formula (II) (163.67g, 0.997mol, yield 89.50%).
Preparation of Compound of formula (II) comparative example 1
Production comparative example 1 was conducted in contrast to production example 1 except that n-butyllithium (135.0g, 2.107mol) was replaced with lithium diisopropylamide (225.7g, 2.107mol) to obtain a compound represented by formula (II) (87.9g, 0.535mol, yield 68.68%).
Table 1: yield of the Compound of formula (II)
| Preparation of the Compound of formula (II) | Preparation example 1 | Preparation example 2 | Preparation example 3 | Preparation of comparative example 1 |
| Organic lithium | N-butyl lithium | N-butyl lithium | N-butyl lithium | Lithium diisopropylamide |
| Molar ratio of piperonyl, organolithium and acetyl chloride | 1:1.89:1.10 | 1:1.89:1.20 | 1:1.89:1.10 | 1:1.89:1.10 |
| Yield of | 93.97％ | 92.40％ | 89.50％ | 68.68％ |
As is clear from Table 1, the selection of the organolithium reagent has a great influence on the yield of the compound represented by the formula (II).
Preparation of the Compound of formula (III)
Preparation example 1 of Compound represented by formula (III)
A compound represented by the formula (II) (127.8g, 0.779mol), ethylene glycol (58g, 0.934mol), p-toluenesulfonic acid (13.8g, 0.080mol) and 300mL of toluene were charged into a reactor and heated to boiling (70 ℃ C.). After the reaction, the temperature is reduced to room temperature, 25g of anhydrous sodium sulfate is added for drying, the mixture is filtered, a filter cake is rinsed by a small amount of toluene, and the compound shown in the formula (III) is obtained after reduced pressure distillation (151.3g, 0.727mol, yield 93.32%).
Preparation example 2 of Compound represented by formula (III)
A compound represented by the formula (II) (125.7g, 0.766mol), ethylene glycol (57.1g, 0.920mol), p-toluenesulfonic acid (13.8g, 0.080mol) and 300mL of toluene were placed in a reactor and heated to boiling (70 ℃ C.). After the reaction, the temperature was reduced to room temperature, 25g of anhydrous sodium sulfate was added, the mixture was dried, filtered, the filter cake was rinsed with a small amount of toluene, and the resulting mixture was distilled under reduced pressure to obtain a compound represented by the formula (III) (149.7g, 0.719mol, yield 93.86%).
Preparation example 3 of Compound represented by formula (III)
300mL of the compound represented by the formula (II) (121.8g, 0.742mol), ethylene glycol (55.3g, 0.891mol), p-toluenesulfonic acid (12.2g, 0.071mol) and toluene were charged into a reactor and heated to boiling (70 ℃ C.). After the reaction, the temperature was reduced to room temperature, 25g of anhydrous sodium sulfate was added, the mixture was dried, filtered, the filter cake was rinsed with a small amount of toluene, and the resulting mixture was distilled under reduced pressure to obtain the compound represented by the formula (III) (148.1g, 0.711mol, yield 95.82%).
Table 2: yield of the Compound of formula (III)
| Preparation of the Compound of formula (III) | Preparation example 1 | Preparation example 2 | Preparation example 3 |
| The molar ratio of the compound represented by the formula (II), ethylene glycol and p-toluenesulfonic acid | 1:1.20:0.103 | 1:1.20:0.104 | 1:1.20:0.096 |
| Yield of | 93.32％ | 93.86％ | 95.82％ |
Preparation of Compound represented by the formula (V)
Preparation of Compound represented by formula (V) 1
Adding a compound (151.3g, 0.727mol) shown in the formula (III) and 200mL of tetrahydrofuran into a reactor, stirring and cooling to-78 ℃, dropwise adding lithium diisopropylamide (122.5g, 1.144mol) and keeping the dropwise adding temperature below-79 ℃, and preserving heat for reacting for 4 hours after dropwise adding; then adding bromine (116g, 0.726mol) dropwise and keeping the dropwise adding temperature below-79 ℃; after the dropwise addition, heating to 25-30 ℃, and carrying out heat preservation reaction for 2 hours. And (3) dropwise adding the reaction solution into a sodium thiosulfate aqueous solution, extracting with 200mL of ethyl acetate, separating, concentrating the organic phase under reduced pressure until crystals are precipitated, cooling, crystallizing and filtering to obtain the compound shown in the formula (IV).
The compound represented by the formula (IV) is dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid is added, the mixture is stirred, heated and refluxed for 2 hours, then the residue is dissolved in 100mL of ethyl acetate by evaporation under reduced pressure, the obtained solution is washed by water and saturated aqueous solution of sodium chloride in the same volume, finally the obtained solution is dried by magnesium sulfate and the solvent is evaporated to dryness, and the compound represented by the formula (V) is obtained (153.6g, 0.632mol, yield 86.93% and purity 99.2%).
Preparation of Compound of formula (V) 2
Adding the compound shown in the formula (III) (149.7g, 0.719mol) and 200mL of tetrahydrofuran into a reactor, stirring and cooling to-78 ℃, dropwise adding lithium diisopropylamide (115.1g, 1.074mol) and keeping the dropwise adding temperature below-79 ℃, and preserving heat for reacting for 4 hours after dropwise adding. Bromine (109g, 0.682mol) was then added dropwise while maintaining the addition temperature below-79 ℃. And heating the mixture to 25-30 ℃, and reacting for 2 hours under the condition of heat preservation. Adding the reaction solution into an aqueous solution of sodium thiosulfate dropwise, extracting with 200mL of ethyl acetate, separating, concentrating the organic phase under reduced pressure until crystals precipitate, cooling, and filtering to obtain the compound shown in the formula (IV).
The compound represented by the formula (IV) is dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid is added, the mixture is stirred, heated and refluxed for 2 hours, then the residue is dissolved in 100mL of ethyl acetate by evaporation under reduced pressure, the obtained solution is washed by water and saturated aqueous solution of sodium chloride in the same volume, finally the obtained solution is dried by magnesium sulfate and the solvent is evaporated to dryness, and the compound represented by the formula (V) is obtained (148.1g, 0.609mol, the yield is 84.70%, and the purity is 99.3%).
Preparation of Compound represented by the formula (V) 3
Adding the compound (148.1g, 0.711mol) shown in the formula (III) and 200mL of tetrahydrofuran into a reactor, stirring and cooling to-78 ℃, slowly dropwise adding lithium diisopropylamide (119.9g, 1.119mol) while keeping the dropwise adding temperature below-79 ℃, and preserving heat for reacting for 4 hours after dropwise adding. Bromine (110.1g, 0.689mol) was then added dropwise while maintaining the dropping temperature below-79 ℃. The mixture is heated to 25-30 ℃ and the reaction is carried out for 2 hours under the condition of heat preservation. Adding the reaction solution into sodium thiosulfate aqueous solution dropwise, extracting with 200ml ethyl acetate, separating, concentrating the organic phase under reduced pressure until crystals precipitate, cooling, and filtering to obtain the compound shown in formula (IV).
The compound represented by the formula (IV) is dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid is added, the mixture is stirred, heated and refluxed for 2 hours, then the residue is dissolved in 100mL of ethyl acetate by evaporation under reduced pressure, the obtained solution is washed by water and saturated aqueous solution of sodium chloride in the same volume, finally the obtained solution is dried by magnesium sulfate and the solvent is evaporated to dryness, and the compound represented by the formula (V) is obtained (152.6g, 0.628mol, yield 88.33% and purity 99.2%).
Preparation of Compound of formula (V) comparative example 1
Production comparative example 1 was conducted in contrast to production example 1 except that lithium diisopropylamide (122.5g, 1.144mol) was replaced with n-butyllithium (73.3g, 1.144mol) to obtain a compound represented by formula (V) (90.2g, 0.371mol, yield 51.03%, purity 97.5%).
Confirmation of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one represented by formula (V):
1 H-NMR(300MHz,DMSO-d 6 )：δ7.47(d,1H),7.133(d,1H),6.07(s,2H),2.62(s,3H)；
MZ：m/z:241.96。
table 3: yield of the Compound of formula (V)
As is clear from table 3, in the production step of the compound represented by formula (V), the kind of the organolithium reagent has a great influence on both the yield and the purity of the compound represented by formula (V).
As can be seen from the yields in tables 1-3, the total yield of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one synthesized by the preparation method provided by the application can reach 87.28% at most, and the purity is more than 99%.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (6)
1. A preparation method of a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one shown as a formula (V) is characterized by comprising the following steps:
Preparation of a Compound of formula (II): carrying out lithiation reaction on a compound shown in a formula (I) and n-butyllithium, and then carrying out acylation reaction on the compound and acetyl chloride to obtain a compound shown in a formula (II); the molar ratio of the compound shown in the formula (I), n-butyl lithium and acetyl chloride is 1 (1.8-2.0) to 1.1-1.2;
preparation of a Compound of formula (III): carrying out carbonyl protection reaction on the compound shown in the formula (II) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (III); the molar ratio of the compound shown in the formula (II), the glycol and the catalyst is 1 (1.1-1.2) to 0.08-0.10;
preparation of a Compound of formula (V): carrying out lithiation reaction on the compound shown in the formula (III) and lithium diisopropylamide, and carrying out bromination reaction on the compound shown in the formula (III) and bromine to obtain a compound shown in a formula (IV), wherein the molar ratio of the compound shown in the formula (III) to the lithium diisopropylamide to the bromine is 1 (1.4-1.6) to 0.9-1.0; carrying out carbonyl deprotection reaction on the compound shown in the formula (IV) to obtain a compound shown in a formula (V);
in the preparation of the compound shown in the step (III), the catalyst is p-toluenesulfonic acid.
2. The method according to claim 1, wherein the lithiation reaction is carried out at a reaction temperature of-80 to-70 ℃ in the preparation of the compound represented by the formula (II).
3. The method according to claim 1, wherein the acylation reaction is carried out at a temperature of 20 to 30 ℃ in the preparation of the compound represented by the formula (II).
4. The method according to claim 1, wherein the carbonyl protection reaction is carried out at a reaction temperature of 65-75 ℃ in the preparation of the compound represented by the formula (III).
5. The process according to claim 1, wherein the lithiation reaction is carried out at a reaction temperature of-70 to-80 ℃ in the production of the compound represented by the formula (V).
6. The preparation method according to claim 1, wherein in the preparation of the compound represented by the formula (V), the bromination reaction is carried out at a reaction temperature of 20-30 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110839803.6A CN113480512B (en) | 2021-07-23 | 2021-07-23 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1659144A (en) * | 2002-04-02 | 2005-08-24 | 舍林股份公司 | Quinoline and isoquinoline derivatives, a process for their production and their use as inflammation inhibitors |
| CN101157679A (en) * | 2007-11-15 | 2008-04-09 | 上海化学试剂研究所 | Method for preparing N- ethyl-3,4-(methylenedioxy) aniline |
| WO2009064251A1 (en) * | 2007-11-15 | 2009-05-22 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 066 |
| CN108675998A (en) * | 2018-06-28 | 2018-10-19 | 北京凯因科技股份有限公司 | A kind of crystallinity methyl carbamate class compound |
| CN108904496A (en) * | 2018-06-28 | 2018-11-30 | 北京凯因科技股份有限公司 | For treating the pharmaceutical composition of hepatitis C infection |
| CN109419806A (en) * | 2017-08-23 | 2019-03-05 | 南京圣和药业股份有限公司 | Antiviral composition and its application |
| WO2019200005A1 (en) * | 2018-04-10 | 2019-10-17 | Atea Pharmaceuticals, Inc. | Treatment of hcv infected patients with cirrhosis |
| CN111072625A (en) * | 2019-12-06 | 2020-04-28 | 浙江理工大学 | Preparation method of 3, 4-methylenedioxyacetophenone |
| WO2020117966A1 (en) * | 2018-12-05 | 2020-06-11 | Atea Pharmaceuticals, Inc. | Highly active drug combination for treatment of hepatitis c virus |
| CN112358462A (en) * | 2020-11-10 | 2021-02-12 | 成都伊诺达博医药科技有限公司 | Synthetic method of piperonyl derivatives |
| CN113603670A (en) * | 2021-07-23 | 2021-11-05 | 阜阳欣奕华制药科技有限公司 | Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one |
-
2021
- 2021-07-23 CN CN202110839803.6A patent/CN113480512B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1659144A (en) * | 2002-04-02 | 2005-08-24 | 舍林股份公司 | Quinoline and isoquinoline derivatives, a process for their production and their use as inflammation inhibitors |
| CN101157679A (en) * | 2007-11-15 | 2008-04-09 | 上海化学试剂研究所 | Method for preparing N- ethyl-3,4-(methylenedioxy) aniline |
| WO2009064251A1 (en) * | 2007-11-15 | 2009-05-22 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 066 |
| CN109419806A (en) * | 2017-08-23 | 2019-03-05 | 南京圣和药业股份有限公司 | Antiviral composition and its application |
| WO2019200005A1 (en) * | 2018-04-10 | 2019-10-17 | Atea Pharmaceuticals, Inc. | Treatment of hcv infected patients with cirrhosis |
| CN108675998A (en) * | 2018-06-28 | 2018-10-19 | 北京凯因科技股份有限公司 | A kind of crystallinity methyl carbamate class compound |
| CN108904496A (en) * | 2018-06-28 | 2018-11-30 | 北京凯因科技股份有限公司 | For treating the pharmaceutical composition of hepatitis C infection |
| WO2020001089A1 (en) * | 2018-06-28 | 2020-01-02 | 北京凯因格领生物技术有限公司 | Crystalline methyl carbamate compound |
| WO2020117966A1 (en) * | 2018-12-05 | 2020-06-11 | Atea Pharmaceuticals, Inc. | Highly active drug combination for treatment of hepatitis c virus |
| CN111072625A (en) * | 2019-12-06 | 2020-04-28 | 浙江理工大学 | Preparation method of 3, 4-methylenedioxyacetophenone |
| CN112358462A (en) * | 2020-11-10 | 2021-02-12 | 成都伊诺达博医药科技有限公司 | Synthetic method of piperonyl derivatives |
| CN113603670A (en) * | 2021-07-23 | 2021-11-05 | 阜阳欣奕华制药科技有限公司 | Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸可洛派韦在HCV感染者中的耐受性和药代动力学;娄金凤等;《临床肝胆病杂志》;20210630;第37卷(第6期);第1304-1308页 * |
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