CN113788741B - Method for preparing 2-cyclopropyl phenol derivative - Google Patents
Method for preparing 2-cyclopropyl phenol derivative Download PDFInfo
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- CN113788741B CN113788741B CN202111145996.1A CN202111145996A CN113788741B CN 113788741 B CN113788741 B CN 113788741B CN 202111145996 A CN202111145996 A CN 202111145996A CN 113788741 B CN113788741 B CN 113788741B
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- 238000000034 method Methods 0.000 title claims abstract description 21
- VKTBILBRBSALKI-UHFFFAOYSA-N 2-cyclopropylphenol Chemical class OC1=CC=CC=C1C1CC1 VKTBILBRBSALKI-UHFFFAOYSA-N 0.000 title claims abstract description 15
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229940015043 glyoxal Drugs 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 15
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 14
- 235000019270 ammonium chloride Nutrition 0.000 claims description 13
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 9
- VJAPTORLZMDPGU-UHFFFAOYSA-N thiolane 1,1-dioxide;toluene Chemical compound CC1=CC=CC=C1.O=S1(=O)CCCC1 VJAPTORLZMDPGU-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- BKBMACKZOSMMGT-UHFFFAOYSA-N methanol;toluene Chemical compound OC.CC1=CC=CC=C1 BKBMACKZOSMMGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000001276 controlling effect Effects 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 abstract description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 abstract 2
- 150000002596 lactones Chemical class 0.000 abstract 2
- 230000003247 decreasing effect Effects 0.000 description 7
- PRQKVXNVZPBESR-UHFFFAOYSA-N 2-cyclopropyl-6-methylphenol Chemical compound CC1=CC=CC(C2CC2)=C1O PRQKVXNVZPBESR-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000006138 lithiation reaction Methods 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- IWKQMRRGGSDCBA-UHFFFAOYSA-N 3-phenoxy-1h-pyridazin-4-one Chemical class OC1=CC=NN=C1OC1=CC=CC=C1 IWKQMRRGGSDCBA-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- -1 allyl halide Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- AUNNTHNQWVSPPP-UHFFFAOYSA-N cyclopropyloxyboronic acid Chemical compound OB(O)OC1CC1 AUNNTHNQWVSPPP-UHFFFAOYSA-N 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000007037 hydroformylation reaction Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/64—Preparation of O-metal compounds with O-metal group bound to a carbon atom belonging to a six-membered aromatic ring
- C07C37/66—Preparation of O-metal compounds with O-metal group bound to a carbon atom belonging to a six-membered aromatic ring by conversion of hydroxy groups to O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/74—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by distillation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing a 2-cyclopropyl phenol derivative, belonging to the field of organic chemistry. The method of the invention comprises the following steps: (1) taking a phenol derivative as a raw material, and performing cyclization reaction with glyoxal to generate a lactone intermediate 1; (2) the lactone intermediate 1 and dibromoethane are subjected to cyclization reaction to generate a cyclopropyl intermediate 2; (3) decarboxylation of cyclopropyl intermediate 2 to produce the 2-cyclopropylphenol derivative. The raw materials used by the method are low in cost and easy to obtain, and are safe and environment-friendly.
Description
Technical Field
The invention relates to a method for preparing a 2-cyclopropyl phenol derivative, belonging to the field of organic chemistry.
Background
2-cyclopropylphenol derivatives have a wide range of applications in the pesticide field, for example: it can be used as an important intermediate for the herbicide 3-phenoxy-4-pyridazinol derivative (see: CN 102510857).
The methods reported in the prior literature for synthesizing 2-cyclopropylphenol derivatives mainly comprise the following steps:
1) Patent CN101151234 reports that phenol derivatives are used as raw materials, undergo ortho-hydroformylation reaction with paraformaldehyde, then undergo addition reaction with vinyl magnesium chloride, then undergo dibromo with hydrogen bromide, then undergo grignard cyclization reaction with magnesium, and finally undergo deprotection to obtain the target product. The method has more steps, two steps of the method involve Grignard reaction, and the amount of waste is large.
2) The literature bioorg.med.chem.2008,16,762 reports that o-bromophenol is used as a raw material, firstly, allyl halide and phenolic hydroxyl are subjected to etherification reaction, then tertiary butyl lithium is used for lithiation under the low-temperature condition, and further migration occurs to obtain a target product. Although this method has few steps, the low temperature conditions required for lithiation are too severe and tertiary butyl lithium must be used with great care. If mass produced, there are large limitations, both in terms of raw material costs and safety.
3) Patent CN110041253 reports that o-bromophenol is used as a raw material and is subjected to a coupling reaction with cyclopropylboric acid under the catalysis of palladium to obtain a target product. The method has few steps, but the cost of the cyclopropylboronic acid and the palladium catalyst is high, and the mass production is not possible.
Therefore, it is necessary to find a method which is low in raw material cost, safe and environment-friendly and is more suitable for industrial scale-up.
Disclosure of Invention
The invention synthesizes the 2-cyclopropyl phenol derivative by a novel method, and solves the problems.
The invention provides a method for preparing a 2-cyclopropyl phenol derivative, which comprises the following steps:
(1) taking a general formula I as a raw material, and performing cyclization reaction with glyoxal to generate a general formula II;
wherein R in the general formula I is H or CH 3 ；
(2) The general formula II and dibromoethane are subjected to cyclization reaction to generate a general formula III;
(3) decarboxylating the general formula III to generate a general formula IV;
the step (1) is preferably: takes general formula I and glyoxal as raw materials, and takes cyclization reaction in acetic acid aqueous solution in the presence of ammonium chloride to generate general formula II.
The invention preferably provides that the molar ratio of the general formula I, glyoxal, ammonium chloride and acetic acid in the step (1) is 1.0:1.0-1.5:0.05-0.15:2.0-4.0.
The step (1) is preferably: mixing the general formula I with acetic acid, heating to 50-60 ℃, synchronously dropwise adding glyoxal solution and ammonium chloride solution, wherein the concentration of glyoxal solution is 40wt% and the concentration of ammonium chloride solution is 30wt%, dropwise adding for 1h, controlling the temperature to be 50-60 ℃, then reacting for 2-5h at 50-60 ℃, cooling to 5-10 ℃ after the reaction, filtering to obtain wet cakes of the general formula II, and drying to obtain the general formula II.
The step (2) is preferably as follows: the general formula II and dibromoethane are used as raw materials, and in the presence of potassium carbonate, sulfolane and toluene mixed solution undergo a cyclization reaction to produce the general formula III.
The invention preferably comprises the following steps of (2) wherein the molar ratio of the general formula II to dibromoethane to potassium carbonate to sulfolane is 1.0:1.0-1.5:2.0-3.0:2.0 to 3.0, the mass ratio of sulfolane to toluene is 1.0:0.5-2.0 meshes of potassium carbonate with the mesh number of 200-300 meshes.
The step (2) is preferably as follows: sequentially adding potassium carbonate, sulfolane, toluene and dibromoethane into the general formula II, reacting for 4-12 hours at 90-110 ℃, cooling to room temperature after the reaction, and filtering to remove salt to obtain sulfolane toluene mixed solution of the general formula III.
The step (3) is preferably: the preparation method comprises the steps of taking sulfolane toluene mixed solution of a general formula III as a raw material, heating to 100-105 ℃, dropwise adding sodium methoxide methanol solution, azeotropically removing the toluene methanol mixed solution, reacting for 1-6 hours at 100-105 ℃, cooling to room temperature after the reaction, filtering to obtain sodium salt of the general formula IV, adding water for dissolving, regulating the pH value to 11-12, separating out an organic layer, and distilling under reduced pressure to obtain the general formula IV.
The molar ratio of the general formula III to the sodium methoxide in the step (3) is preferably 1.0:1.0-1.5, and the concentration of the sodium methoxide methanol solution is 30wt%.
The beneficial effects of the invention are as follows:
the raw materials used in the method are low in cost and easy to obtain, and are safe and environment-friendly;
the method has few steps, is simple to operate, and is more suitable for industrial amplification.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way.
Example 1
(1) O-cresol (108.1 g,1.0 mol) and acetic acid (180.1 g,3.0 mol) are mixed and heated to 50-60 ℃, glyoxal solution (174.1 g,1.2mol,40 wt%) and ammonium chloride solution (17.8 g,0.1mol,30 wt%) are synchronously added dropwise, the dropping process is 1h and the temperature is controlled between 50 and 60 ℃, then the reaction is carried out for 2h at 50 to 60 ℃, the temperature is reduced to 5 to 10 ℃ after the reaction, intermediate 1 wet cake is obtained after the filtration, and the vacuum drying is carried out at 40 to 50 ℃ to obtain light yellow solid 105.2g with the purity of 97 percent and the yield of 71 percent;
(2) to intermediate 1 (103.7 g,0.7mol, purity 97%) was added potassium carbonate (241.9 g,1.75mol,200-300 mesh), sulfolane (210.3 g,1.75 mol), toluene (210.3 g), dibromoethane (157.8 g,0.84 mol), reacted at 100℃for 5 hours, cooled to room temperature after the reaction, filtered to remove salt, thereby obtaining a sulfolane toluene mixed solution 531g of intermediate 2, purity 91%;
(3) the sulfolane toluene mixed solution (531 g,0.7 mol) of intermediate 2 was heated to 100-105℃and sodium methoxide methanol solution (138.7 g,0.77mol,30 wt%) was added dropwise thereto, the toluene methanol mixed solution was azeotropically removed, then reacted at 100-105℃for 1 hour, cooled to room temperature after the reaction, filtered to obtain the sodium salt of 2-cyclopropyl-6-methylphenol, 350g of water was added, pH was adjusted to 11-12 with 10wt% hydrochloric acid, an organic layer was separated, and distilled under reduced pressure (fraction at 81-83℃was collected, 5 mmHg) to obtain 88.2g of 2-cyclopropyl-6-methylphenol as a colorless liquid with a purity > 98% and a yield of 85%.
1H NMR(400MHz,CDCl3)δppm 7.01(d,1H),6.96(d,1H),6.76(t,1H),5.55(s,1H),2.26(s,3H),1.79-1.73(m,1H),0.99-0.94(m,2H),0.65-0.62(m,2H).
Example 2
(1) Mixing phenol (94.1 g,1.0 mol) with acetic acid (180.1 g,3.0 mol), heating to 50-60 ℃, then synchronously dropwise adding glyoxal solution (174.1 g,1.2mol,40 wt%) and ammonium chloride solution (17.8 g,0.1mol,30 wt%) for 1h at a controlled temperature of 50-60 ℃, then reacting for 2h at 50-60 ℃, cooling to 5-10 ℃ after the reaction, filtering to obtain an intermediate 1 wet cake, and vacuum drying at 40-50 ℃ to obtain light yellow solid 103.3g with purity of 96% and yield of 77%;
(2) to intermediate 1 (93.9 g,0.7mol, purity 96%) was added potassium carbonate (241.9 g,1.75mol,200-300 mesh), sulfolane (210.3 g,1.75 mol), toluene (210.3 g), dibromoethane (157.8 g,0.84 mol), reacted at 100℃for 4 hours, cooled to room temperature after the reaction, and filtered to remove salt to obtain 525g of sulfolane toluene mixed solution of intermediate 2;
(3) the sulfolane toluene mixed solution (525 g,0.7 mol) of the intermediate 2 is heated to 100-105 ℃, and sodium methoxide methanol solution (138.7 g,0.77mol,30 wt%) is added dropwise, the toluene methanol mixed solution is azeotropically removed, then the reaction is carried out for 1h at 100-105 ℃, the temperature is reduced to room temperature after the reaction, the sodium salt of 2-cyclopropylphenol is obtained by filtration, 350g of water is added, the pH is adjusted to 11-12 by 10wt% hydrochloric acid, the organic layer is separated out, the distillation is carried out under reduced pressure (the fraction at 75-77 ℃ is collected, 5 mmHg) to obtain 78.0g of colorless liquid 2-cyclopropylphenol with the purity more than 98% and the yield of 83%.
1H NMR(400MHz,CDCl3)δppm 7.06-7.16(m,2H),6.82-6.88(m,2H),5.46(s,1H),1.74-1.86(m,1H),0.91-1.02(m,2H),0.59-0.69(m,2H).
Example 3
Step (1): referring to the procedure of step (1) of example 1, the results of Table 1 were obtained after changing the reaction conditions.
TABLE 1
Increasing the addition amount of glyoxal solution compared to example 1 affects the purity and yield of intermediate 1, and decreasing the addition amount of glyoxal solution compared to example 1 affects less the purity and yield of intermediate 1;
increasing the amount of ammonium chloride solution added compared to example 1 affects the purity and yield of intermediate 1, and decreasing the amount of ammonium chloride solution added compared to example 1 affects less the purity and yield of intermediate 1;
decreasing the amount of acetic acid added compared to example 1 affects the purity and yield of intermediate 1, and increasing the amount of acetic acid compared to example 1 does not affect the purity and yield of intermediate 1 much;
when the mode of dropping glyoxal solution and ammonium chloride solution is not simultaneous dropping, both the purity and yield of intermediate 1 are lower than those of example 1.
Step (2): referring to the procedure of step (2) of example 1, the results of Table 2 were obtained after changing the reaction conditions.
TABLE 2
Increasing the amount of dibromoethane as compared with example 1 has little effect on the purity of intermediate 2, and decreasing the amount of dibromoethane as compared with example 1 has effect on the purity of intermediate 2;
increasing or decreasing the amount of potassium carbonate added compared to example 1 had little effect on the purity of intermediate 2;
the lower addition of sulfolane compared to example 1 affects the purity of intermediate 2, while the higher addition of sulfolane compared to example 1 affects less the purity of intermediate 2;
increasing the amount of toluene added compared to example 1 has little effect on the purity of intermediate 2, and decreasing the amount of toluene added compared to example 1 affects the purity of intermediate 2;
lowering the reaction temperature compared to example 1 affects the purity of intermediate 2, and raising the reaction temperature compared to example 1 does not affect the purity of intermediate 2 much.
Step (3): referring to the procedure of step (3) of example 1, the results of Table 3 were obtained after changing the reaction conditions.
TABLE 3 Table 3
Increasing or decreasing sodium methoxide compared to example 1 had little effect on the yield of 2-cyclopropyl-6-methylphenol;
pouring sodium methoxide methanol solution at a time compared with example 1 affects the yield of 2-cyclopropyl-6-methylphenol;
increasing the reaction temperature compared with example 1 affects the yield of 2-cyclopropyl-6-methylphenol.
Claims (4)
1. A process for preparing a 2-cyclopropylphenol derivative, characterized by: the method comprises the following steps:
(1) taking general formula I and glyoxal as raw materials, and carrying out cyclization reaction in acetic acid aqueous solution in the presence of ammonium chloride to generate general formula II, wherein the specific steps are as follows: mixing the general formula I with acetic acid, heating to 50-60 ℃, synchronously dropwise adding glyoxal solution and ammonium chloride solution, wherein the concentration of the glyoxal solution is 40wt% and the concentration of the ammonium chloride solution is 30wt%, dropwise adding for 1h, controlling the temperature to be 50-60 ℃, then reacting for 2-5h at 50-60 ℃, cooling to 5-10 ℃ after the reaction, filtering to obtain wet cakes of the general formula II, and drying to obtain the general formula II;
wherein R in the general formula I is H or CH 3 ；
(2) Taking general formula II and dibromoethane as raw materials, and carrying out cyclization reaction in a sulfolane and toluene mixed solution in the presence of potassium carbonate to generate general formula III, wherein the specific steps are as follows: sequentially adding potassium carbonate, sulfolane, toluene and dibromoethane into a general formula II, reacting for 4-12 hours at 90-110 ℃, cooling to room temperature after the reaction, and filtering to remove salt to obtain a sulfolane toluene mixed solution of the general formula III;
(3) decarboxylation reaction of the general formula III to generate the general formula IV, which comprises the following specific steps: heating sulfolane toluene mixed solution of a general formula III as a raw material to 100-105 ℃, dropwise adding sodium methoxide methanol solution, azeotropically removing the toluene methanol mixed solution, then reacting for 1-6 hours at 100-105 ℃, cooling to room temperature after the reaction, filtering to obtain sodium salt of the general formula IV, adding water for dissolving, regulating the pH value to 11-12, separating out an organic layer, and distilling under reduced pressure to obtain the general formula IV;
2. the process for preparing 2-cyclopropylphenol derivatives as claimed in claim 1, wherein: the molar ratio of the general formula I, glyoxal, ammonium chloride and acetic acid in the step (1) is 1.0:1.0-1.5:0.05-0.15:2.0-4.0.
3. The process for preparing 2-cyclopropylphenol derivatives as claimed in claim 1, wherein: the molar ratio of the general formula II, dibromoethane, potassium carbonate and sulfolane in the step (2) is 1.0:1.0-1.5:2.0-3.0:2.0 to 3.0, the mass ratio of sulfolane to toluene is 1.0:0.5-2.0 meshes of potassium carbonate with the mesh number of 200-300 meshes.
4. The process for preparing 2-cyclopropylphenol derivatives as claimed in claim 1, wherein: the molar ratio of the general formula III to the sodium methoxide in the step (3) is 1.0:1.0-1.5, and the concentration of the sodium methoxide methanol solution is 30wt%.
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Citations (7)
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|---|---|---|---|---|
| CN103467292A (en) * | 2012-06-08 | 2013-12-25 | 上海力田化学品有限公司 | 4-carbonyl diethyl pimelate synthesis method |
| CN105016984A (en) * | 2015-07-02 | 2015-11-04 | 成都丽凯手性技术有限公司 | Industrial preparation method of 2-(2-ethoxyphenoxy)bromic ether |
| CN105555780A (en) * | 2013-07-31 | 2016-05-04 | 吉利德科学公司 | Syk inhibitors |
| CN106083542A (en) * | 2016-07-05 | 2016-11-09 | 盐城辉煌化工有限公司 | A kind of synthetic method of SAN-619F intermediate |
| CN108472288A (en) * | 2015-12-10 | 2018-08-31 | 奥提芙尼治疗学有限公司 | The conditioning agent in the channels KV3 is for treating pain |
| CN110498733A (en) * | 2019-09-17 | 2019-11-26 | 西安近代化学研究所 | A kind of 1-(2- chlorphenyl) -2-(1- chlorine cyclopropyl) -3- diazanyl -2- propanol hydrochloride synthetic method |
| CN110734364A (en) * | 2019-12-04 | 2020-01-31 | 上海生农生化制品股份有限公司 | Synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone |
-
2021
- 2021-09-28 CN CN202111145996.1A patent/CN113788741B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467292A (en) * | 2012-06-08 | 2013-12-25 | 上海力田化学品有限公司 | 4-carbonyl diethyl pimelate synthesis method |
| CN105555780A (en) * | 2013-07-31 | 2016-05-04 | 吉利德科学公司 | Syk inhibitors |
| CN105016984A (en) * | 2015-07-02 | 2015-11-04 | 成都丽凯手性技术有限公司 | Industrial preparation method of 2-(2-ethoxyphenoxy)bromic ether |
| CN108472288A (en) * | 2015-12-10 | 2018-08-31 | 奥提芙尼治疗学有限公司 | The conditioning agent in the channels KV3 is for treating pain |
| CN106083542A (en) * | 2016-07-05 | 2016-11-09 | 盐城辉煌化工有限公司 | A kind of synthetic method of SAN-619F intermediate |
| CN110498733A (en) * | 2019-09-17 | 2019-11-26 | 西安近代化学研究所 | A kind of 1-(2- chlorphenyl) -2-(1- chlorine cyclopropyl) -3- diazanyl -2- propanol hydrochloride synthetic method |
| CN110734364A (en) * | 2019-12-04 | 2020-01-31 | 上海生农生化制品股份有限公司 | Synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone |
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