CN115536517A - Preparation method of 4-hydroxymethyl phenylacetic acid - Google Patents
Preparation method of 4-hydroxymethyl phenylacetic acid Download PDFInfo
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- CN115536517A CN115536517A CN202211401384.9A CN202211401384A CN115536517A CN 115536517 A CN115536517 A CN 115536517A CN 202211401384 A CN202211401384 A CN 202211401384A CN 115536517 A CN115536517 A CN 115536517A
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- Prior art keywords
- acid
- reaction
- phenylacetic acid
- acetohydroxy
- methyl ester
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- FWZBPBKAANKOJQ-UHFFFAOYSA-N 2-[4-(hydroxymethyl)phenyl]acetic acid Chemical compound OCC1=CC=C(CC(O)=O)C=C1 FWZBPBKAANKOJQ-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims abstract description 53
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- WCOCCXZFEJGHTC-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(CBr)C=C1 WCOCCXZFEJGHTC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003279 phenylacetic acid Substances 0.000 claims abstract description 24
- 229960003424 phenylacetic acid Drugs 0.000 claims abstract description 24
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 19
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 15
- 239000001632 sodium acetate Substances 0.000 claims abstract description 14
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 14
- -1 phenylacetic acid ester Chemical class 0.000 claims abstract description 13
- GXXXUZIRGXYDFP-UHFFFAOYSA-N 2-(4-methylphenyl)acetic acid Chemical compound CC1=CC=C(CC(O)=O)C=C1 GXXXUZIRGXYDFP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000005886 esterification reaction Methods 0.000 claims abstract description 11
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims abstract description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 44
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 239000003999 initiator Substances 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 14
- 229940049953 phenylacetate Drugs 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 7
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- UICXTANXZJJIBC-UHFFFAOYSA-N 1-(1-hydroperoxycyclohexyl)peroxycyclohexan-1-ol Chemical compound C1CCCCC1(O)OOC1(OO)CCCCC1 UICXTANXZJJIBC-UHFFFAOYSA-N 0.000 claims description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 11
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012752 auxiliary agent Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 1
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic 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
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 4-hydroxymethyl phenylacetic acid, which comprises the following steps: step S1, reacting 4-methylphenylacetic acid with N-bromosuccinimide to generate 4-bromomethylphenylacetic acid; the preparation method comprises the following steps of S2, reacting the 4-bromomethyl phenylacetic acid with sodium acetate to generate 2- (4- (acetohydroxy methyl ester) phenylacetic acid, S3, carrying out esterification reaction on the 2- (4- (acetohydroxy methyl ester) phenylacetic acid and alcohol to obtain 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester, and S4, hydrolyzing the 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester under an alkaline condition to obtain the 4-hydroxymethylphenylacetic acid.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-hydroxymethyl phenylacetic acid.
Background
4-hydroxymethyl phenylacetic acid is an important organic drug intermediate, is a potential chiral ligand, and can be used for inducing and synthesizing a chiral compound. 4-hydroxymethyl phenylacetic acid is mainly applied to the synthesis of rock kinase and a norepinephrine transporter inhibitor, namely, nertadiol dimesylate. The prior method for synthesizing the neratide dimesylate is generally a method for separating by a chiral column, the chiral separation method has high cost and low yield, and the operation becomes simple and the cost is reduced since 4-hydroxymethylphenylacetic acid is used as a chiral ligand for synthesizing the neratide dimesylate in a chiral induction manner. In addition, because carboxyl and hydroxyl are very active functional groups, both ends can be connected with active drugs to synthesize potential drugs, so that 4-hydroxymethylphenylacetic acid is a new biological connecting agent. P-hydroxymethylphenylacetic acid has received considerable attention from those in the medical community since the last decade due to its highly potent reactivity.
As regards the synthesis of 4-hydroxymethylphenylacetic acid, the earliest patents (US 9643927/2017B 1) reported the synthesis of 4-bromomethylphenylacetic acid with 4-methylphenylacetic acid in the first step and the direct hydrolysis of 4-bromomethylphenylacetic acid in the second step. Wherein, in the first step, the yield can reach about 75 percent under the condition of using toxic carbon tetrachloride, and the yield is generally about 50 to 60 percent when replacing the solvent which is suitable for industrial use. However, the inventor researches and discovers that the amount of the hydrolysis solvent used in the second hydrolysis reaction is very large, the side reactions are more, the product is mixed, and the loss of purification and recrystallization is large. Therefore, the method has low industrial production efficiency, the total yield of two steps is only 20-25%, and impurities with the wavelength of 254nm, which cannot be removed in the current market, appear in the product.
Disclosure of Invention
In view of the above, the invention provides a preparation method of 4-hydroxymethylphenylacetic acid, which is easy to purify, has high yield and is suitable for industrial production.
In order to solve the technical problem, the invention adopts the following technical scheme:
the preparation method of 4-hydroxyphenylacetic acid according to the embodiment of the invention comprises the following steps:
step S1, reacting 4-methylphenylacetic acid with N-bromosuccinimide to generate 4-bromomethylphenylacetic acid;
step S2, reacting the 4-bromomethyl phenylacetic acid with sodium acetate to generate 2- (4- (acetyl hydroxymethyl) phenylacetic acid;
step S3, carrying out esterification reaction on the 2- (4- (acetohydroxy methyl ester) phenylacetic acid and alcohol to obtain 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester;
step S4, hydrolyzing the 2- (4- (acetohydroxy methyl ester) phenylacetate under alkaline conditions to obtain the 4-hydroxymethyl phenylacetic acid.
Further, in the step S1, the reaction is performed under the action of a radical initiator, wherein the ratio of 4-methylphenylacetic acid: n-bromosuccinimide: the molar ratio of the free radical initiator is 1 (1-1.2): (0.05-0.2), the reaction temperature is 20-80 ℃, and the reaction time is 5-16 hours.
Still further, the free radical initiator is selected from any one or more of oxide initiator and azo initiator, wherein the oxide initiator comprises cyclohexanone peroxide, dibenzoyl peroxide and tert-butyl hydroperoxide, and the oxide initiator comprises azodiisobutyronitrile and azodiisoheptonitrile.
Further, the step S2 includes:
heating and refluxing the 4-bromomethyl phenylacetic acid and sodium acetate in a solvent for 5-20 hours to generate the 2- (4- (acetohydroxy methyl ester) phenylacetic acid, wherein the solvent is any one or more of toluene, acetic acid and DMF.
Further, the molar ratio of the 4-bromomethylphenylacetic acid to the sodium acetate is 1.0: (1.5-5.0), and the reaction temperature range is 20-120 ℃.
Further, in step S3, the esterification reaction is performed under the action of an acid auxiliary agent, the acid auxiliary agent is selected from any one or more of sulfuric acid, p-toluenesulfonic acid, thionyl chloride and oxalyl chloride, and the alcohol includes methanol, ethanol, n-propanol, isopropanol, or a mixture thereof.
Still further, the acidic adjuvant is thionyl chloride, and the thionyl chloride is 1 to 2.5 equivalents relative to the 2- (4- (acetohydroxy methyl ester) phenylacetic acid.
Further, in step S4, the alkali used in the hydrolysis reaction is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
Further, the amount of the base used in the hydrolysis reaction is 1.0 to 4.0 equivalents.
Further, after the reaction in the step S1 is finished, after solid-liquid separation, the solid is pulped with dichloromethane and then used in the step S2, after the reaction in the step S2 is finished, the solid is concentrated, extracted with ethyl acetate and dried and then used in the step S3, after the reaction in the step S3 is finished, the solid is concentrated and distilled under reduced pressure and then used in the step S4, and after the reaction in the step S4 is finished, the solid is concentrated and dried to obtain the 4-hydroxymethylphenylacetic acid.
The technical scheme of the invention at least has one of the following beneficial effects:
according to the preparation method of 4-hydroxy phenylacetic acid, 4-methyl phenylacetic acid is used as a starting material, the starting material reacts with N-bromosuccinimide (NBS) under the action of a free radical initiator to generate an intermediate 4-bromomethyl phenylacetic acid, the intermediate reacts with sodium acetate to generate 2- (4- (acetohydroxy methyl ester) phenylacetic acid, the intermediate reacts with alcohol to generate an important intermediate 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester, and the intermediate is hydrolyzed to obtain a high-purity target product 4-hydroxy methyl phenylacetic acid, so that compared with the existing two-step synthesis method, the hydrolysis is carried out without using solvent which is dozens of times of solvent, the cost is reduced, and three wastes are reduced;
in addition, reduced pressure distillation purification can be carried out in the previous step of hydrolysis, so that purification is not needed in the last step of hydrolysis, and the loss caused by purification is reduced;
according to the preparation method provided by the embodiment of the invention, the yield is improved, and the problem that the purity of the impurity product with the wavelength of 254nm, which cannot be removed in the current market, is greatly improved is solved;
according to the method provided by the embodiment of the invention, the production cost can be reduced, the operation is convenient, and the method is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It should be apparent that the described embodiments are only some of the embodiments of the present invention, and not all of them. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
The following first describes a method for synthesizing 4-hydroxymethylphenylacetic acid according to an embodiment of the present invention.
The reaction route of the preparation method of 4-hydroxyphenylacetic acid according to the embodiment of the invention is shown as the following formula (1):
referring to the above formula (1), the method for preparing 4-hydroxyphenylacetic acid according to the embodiment of the invention comprises the following steps:
step S1, reacting 4-methylphenylacetic acid with N-bromosuccinimide to generate 4-bromomethylphenylacetic acid.
That is, in the first step, 4-bromomethylphenylacetic acid is prepared by reacting 4-methylphenylacetic acid, which is used as a starting material, with N-bromosuccinimide (NBS).
In some embodiments of the invention, in step S1, the reaction is performed under the action of a radical initiator, wherein the ratio of 4-methylphenylacetic acid: n-bromosuccinimide: the molar ratio of the free radical initiator is 1 (1-1.2): (0.05-0.2), the reaction temperature is 20-80 ℃, and the reaction time is 5-16 hours.
Still further, the free radical initiator is selected from any one or more of oxide initiator and azo initiator, wherein the oxide initiator comprises cyclohexanone peroxide, dibenzoyl peroxide and tert-butyl hydroperoxide, and the oxide initiator comprises azodiisobutyronitrile and azodiisoheptonitrile.
The reaction in step S1 may be performed in a solvent such as dichloromethane, chloroform, dichloroethane, chlorobenzene, and carbon tetrachloride.
After the reaction is finished, the reaction liquid is subjected to post-treatment and is pulped by dichloromethane, and the next reaction can be directly carried out.
And step S2, reacting the 4-bromomethyl phenylacetic acid with sodium acetate to generate 2- (4- (acetyl hydroxymethyl) phenylacetic acid.
That is, in contrast to the second direct hydrolysis step of the two-step process of the prior art, in the present invention, 4-bromomethylphenylacetic acid is first reacted with sodium acetate to produce the intermediate 2- (4- (acetohydroxymethyl) phenylacetic acid.
In order to improve the production efficiency and reduce the generation of byproducts, 4-bromomethylphenylacetic acid is firstly reacted with sodium acetate to generate 2- (4- (acetohydroxy methyl ester) phenylacetic acid, and then hydrolyzed, so that the problem of surprising solvent amount existing in the prior two-step method for directly hydrolyzing 4-bromomethylphenylacetic acid firstly can be effectively avoided, and the solvent amount can be reduced to a normal value.
In some embodiments of the invention, said step S2 comprises:
heating and refluxing the 4-bromomethyl phenylacetic acid and sodium acetate in a solvent for 5-20 hours to generate the 2- (4- (acetohydroxy methyl ester) phenylacetic acid, wherein the solvent is any one or more of toluene, acetic acid and DMF.
Further, the molar ratio of the 4-bromomethylphenylacetic acid to the sodium acetate is 1.0: (1.5-5.0), and the reaction temperature range is 20-120 ℃.
After the reaction is finished, the reaction solution is post-treated to obtain a crude product, and the crude product can be directly subjected to the next reaction.
And S3, carrying out esterification reaction on the 2- (4- (acetohydroxy methyl ester) phenylacetic acid and alcohol to obtain 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester.
That is, after obtaining 2- (4- (acetohydroxy methyl ester) phenylacetic acid as an intermediate, it was first esterified to produce 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester.
It should be noted that the reaction pathway type (1) shows the structural formula of methyl 2- (4- (acetohydroxymethyl) phenylacetate, but the esterified product obtained by the alcohol used is different, and for example, in the case of using ethanol, ethyl 2- (4- (acetohydroxymethyl) phenylacetate is produced, and the formula (1) is given only for convenience of understanding, and for example, propyl 2- (4- (acetohydroxymethyl) phenylacetate may be produced by using propanol, and the like, and the description thereof is not limited.
Wherein, preferably, the alcohol comprises methanol, ethanol, n-propanol, isopropanol, or a mixture thereof. Further preferably, the alcohol is methanol or ethanol. Since the corresponding esters of methanol and ethanol are methyl 2- (4- (acetohydroxy methyl) phenylacetate and ethyl 2- (4- (acetohydroxy methyl) phenylacetate, which are both liquid and have relatively low boiling points, impurities can be easily removed by distillation.
Further, in the step S3, the esterification reaction is performed under the action of an acid auxiliary agent, and the acid auxiliary agent is selected from any one or more of sulfuric acid, p-toluenesulfonic acid, thionyl chloride and oxalyl chloride. Preferably, for example, thionyl chloride is used as an acid auxiliary,
wherein the sulfoxide chloride is 1 to 2.5 equivalents relative to the 2- (4- (acetohydroxy methyl ester) phenylacetic acid.
In this case, firstly, thionyl chloride and 2- (4- (acetohydroxy methyl ester) phenylacetic acid are first subjected to acylchlorination to give 2- (4- (acetohydroxy methyl ester) phenylacetyl chloride, and thereafter, active 2- (4- (acetohydroxy methyl ester) phenylacetyl chloride is subjected to esterification with alcohol to give 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester, whereby esterification becomes easier and the yield can be close to theoretical.
It should be noted that the thionyl chloride and the alcohol may be added in one step or may be added in steps (i.e., the thionyl chloride is added first, and the alcohol is added after the one-step reaction is completed).
The inventors have found that some impurities are present during the esterification reaction. Therefore, the inventor further finds that methyl 2- (4- (acetohydroxy methyl ester) phenylacetate and ethyl 2- (4- (acetohydroxy methyl ester) phenylacetate are liquid, reaction liquid is directly subjected to reduced pressure distillation after being concentrated to obtain a pure product with the purity of more than 98%, and the pure product is hydrolyzed to obtain a crude product with the purity of more than 99%.
Step S4, hydrolyzing the 2- (4- (acetohydroxy methyl ester) phenylacetate under alkaline conditions to obtain the 4-hydroxymethyl phenylacetic acid.
That is, after esterification to obtain 2- (4- (acetohydroxy methyl ester) phenylacetate, the target product 4-hydroxymethyl phenylacetic acid can be obtained only by hydrolyzing the 2- (4- (acetohydroxy methyl ester) phenylacetate under alkaline conditions.
In some embodiments of the invention, the base used in the hydrolysis reaction is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide.
Further, the amount of the base used in the hydrolysis reaction is 1.0 to 4.0 equivalents.
And (4) carrying out post-treatment on the reaction solution, wherein the crude product is qualified without purification. The operation condition is mild and simple, the kettle rate and the yield are improved, and the method is suitable for industrial production.
In some embodiments of the present invention, after the reaction in step S1 is completed, solid-liquid separation is performed, the solid is slurried with dichloromethane and then used in step S2, after the reaction in step S2 is completed, the solid is concentrated, extracted with ethyl acetate, and dried and then used in step S3, after the reaction in step S3 is completed, the solid is concentrated and distilled under reduced pressure and then used in step S4, and after the reaction in step S4 is completed, the solid is concentrated and dried to obtain the 4-hydroxymethylphenylacetic acid.
As can be seen from the above description, according to the preparation method of 4-hydroxymethylphenylacetic acid of the embodiment of the present invention, 4-methylphenylacetic acid is used as a starting material, and reacts with N-bromosuccinimide (NBS) under the action of a radical initiator to generate an intermediate 4-bromomethylphenylacetic acid, the intermediate reacts with sodium acetate to generate 2- (4- (acetohydroxymethyl) phenylacetic acid, and then the 2- (4- (acetohydroxymethyl) phenylacetic acid is esterified to generate an important intermediate, which is 2- (4- (acetohydroxymethyl) phenylacetic acid ester, and finally the intermediate is hydrolyzed to obtain a high-purity target product 4-hydroxymethylphenylacetic acid.
In addition, the hydrolysis can be purified by distillation under reduced pressure in the previous step, so that the hydrolysis in the last step does not need purification, and the loss caused by purification is reduced.
According to the preparation method provided by the embodiment of the invention, the total yield can reach 49%, in addition, the yield is improved, and the problem that the purity of the impurity product with the wavelength of 254nm, which cannot be removed in the current market, is greatly improved is solved. Compared with the traditional two-step method, the method has the advantages that although the steps are increased by two steps, the yield is improved by nearly one time, the kettle rate is improved by tens of times, and the method is suitable for industrial large-scale production.
According to the method provided by the embodiment of the invention, the production cost can be reduced, the operation is convenient, and the method is suitable for industrial production.
Hereinafter, the synthesis method of 4-hydroxymethylphenylacetic acid according to the present invention is described in further detail by way of specific examples.
Example 1
(1) Synthesis of 4-bromomethylphenylacetic acid
4-Methylphenylacetic acid (1Kg, 6.66mol), DCE and azobisisobutyronitrile (10.94g, 0.07mol) were charged into a 10L reactor, NBS (1.3 Kg, 7.33mol) was added in portions, and after the addition, the mixture was refluxed for 8 to 10 hours, and the plate was stopped until the starting material disappeared.
Stopping reaction, cooling, suction filtering, adding water and dichloromethane respectively, pulping, drying to obtain white solid (0.915Kg, 60% yield), melting point 178.8-180.3 ℃.
1 H NMR(400MHz,DMSO):δ＝3.49(s,2H,CH 2 COOH),4.56(s,2H,BrCH 2 ),6.94(m,4H,ArH),11.23(s,1H,COOH)。
(2) Synthesis of 2- (4- (acetohydroxy-methyl) phenylacetic acid
Anhydrous sodium acetate (656 g,8.0 mol), 4-bromomethylphenylacetic acid (915g, 4.0 mol) and acetic acid are respectively added into a 10L reaction kettle, and after the addition is finished, the reaction liquid is heated and refluxed for 5-8h. The reaction was completed as detected by TLC spot plate.
Post-treatment, concentrating acetic acid, adjusting pH to 2-3 with hydrochloric acid, extracting with ethyl acetate, drying, filtering, and concentrating to obtain crude 2- (4- (acetohydroxy methyl ester) phenylacetic acid (802.6 g,96.5% yield).
1 H NMR(400MHz,CDCl 3 ):δ＝2.01(s,3H,CH 3 ),3.48(s,2H,CH 2 COOH),5.34(s,2H,OCH 2 ),6.96-6.99(m,2H,ArH),7.05-7.08(m,2H,ArH),11.24(s,1H,COOH)。
(3) Synthesis of methyl 2- (4- (acetohydroxy-methyl) phenylacetate
2- (4- (acetohydroxy methyl ester) phenylacetic acid (802g, 3.85mol) and methanol are respectively added into a 10L reaction kettle, thionyl chloride (549.64g, 4.62mol) is dripped into the reaction kettle at room temperature, after the addition, the temperature of reaction liquid is raised, the reflux reaction is carried out for 4 to 8h, the detection reaction is finished by a TLC point plate, the post-treatment is carried out, the methanol is concentrated, and the crude product is distilled under reduced pressure, so that the pure product of 2- (4- (acetohydroxy methyl ester) phenylacetic acid methyl ester (753g, 88 percent yield) is colorless liquid.
1 H NMR(400MHz,CDCl 3 ):δ＝2.01(s,3H,CH 3 ),3.51(s,2H,CH 2 COOH),3.68(s,3H,CH 3 ),5.35(s,2H,OCH 2 ) 6.97-6.99 (m, 2H, arH), 7.06-7.08 (m, 2H, arH). (4) Synthesis of 4-hydroxymethylphenylacetic acid
A10L reaction kettle is added with ice bath for cooling, sodium hydroxide (339g, 8.46mol) and water are added into the reaction kettle, the temperature is controlled below 25 ℃, methyl 2- (4- (acetyl hydroxyl methyl ester) phenylacetate (752g, 3.38mol) is dripped into the reaction kettle, and the reaction kettle reacts for 2 to 3 hours at room temperature after the dripping is finished.
The reaction was completed by TLC plate detection. Stopping the reaction, performing post-treatment, adjusting pH of the reaction solution to =2-3 with hydrochloric acid, extracting with ethyl acetate (2L × 3), combining organic phases, washing with water, washing with saturated saline, and anhydrous Na 2 SO 4 Drying, filtering, concentrating, and oven drying to obtain white solid (540g, 96% yield), liquid phase 99.7%, melting point 131.4-133.3 deg.C.
1 H NMR(400MHz,DMSO):δ＝3.54(s,2H,CH 2 COOH),4.43(s,2H,OCH 2 ),5.13(s,1H,OH),7.22-7.27(m,4H,ArH),11.27(s,1H,COOH)。
While the foregoing is directed to the preferred embodiment of the present invention, it will be appreciated by those skilled in the art that various changes and modifications may be made therein without departing from the principles of the invention as set forth in the appended claims.
Claims (10)
1. A preparation method of 4-hydroxymethylphenylacetic acid is characterized by comprising the following steps:
step S1, reacting 4-methylphenylacetic acid with N-bromosuccinimide to generate 4-bromomethylphenylacetic acid;
step S2, reacting the 4-bromomethyl phenylacetic acid with sodium acetate to generate 2- (4- (acetyl hydroxyl methyl ester) phenylacetic acid;
step S3, carrying out esterification reaction on the 2- (4- (acetohydroxy methyl ester) phenylacetic acid and alcohol to obtain 2- (4- (acetohydroxy methyl ester) phenylacetic acid ester;
step S4, hydrolyzing the 2- (4- (acetohydroxy-methyl ester) phenylacetate under alkaline conditions to obtain the 4-hydroxymethyl phenylacetic acid.
2. The method according to claim 1, wherein in step S1, the reaction is carried out under the action of a radical initiator, wherein the ratio of 4-methylphenylacetic acid: n-bromosuccinimide: the molar ratio of the free radical initiator is 1 (1-1.2): (0.05-0.2), the reaction temperature is 20-80 ℃, and the reaction time is 5-16 hours.
3. The method of claim 2, wherein the free radical initiator is selected from any one or more of oxide initiator and azo initiator, wherein the oxide initiator comprises cyclohexanone peroxide, dibenzoyl peroxide and tert-butyl hydroperoxide, and the oxide initiator comprises azobisisobutyronitrile and azobisisoheptonitrile.
4. The method according to claim 1, wherein the step S2 comprises:
heating and refluxing the 4-bromomethyl phenylacetic acid and sodium acetate in a solvent for 5-20 hours to generate the 2- (4- (acetohydroxy methyl ester) phenylacetic acid, wherein the solvent is any one or more of toluene, acetic acid and DMF.
5. The method of claim 4, wherein the molar ratio of 4-bromomethylphenylacetic acid to sodium acetate is 1.0: (1.5-5.0), and the reaction temperature range is 20-120 ℃.
6. The method according to claim 1, wherein in step S3, the esterification reaction is performed under the action of an acid promoter, the acid promoter is selected from any one or more of sulfuric acid, p-toluenesulfonic acid, thionyl chloride and oxalyl chloride, and the alcohol comprises methanol, ethanol, n-propanol, isopropanol or a mixture thereof.
7. The process of claim 6, wherein the acidic adjuvant is thionyl chloride, and the thionyl chloride is 1 to 2.5 equivalents relative to the 2- (4- (acetohydroxy-methyl ester) phenylacetic acid.
8. The method according to claim 1, wherein in step S4, the base used in the hydrolysis reaction is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
9. The method of claim 8, wherein the base is used in an amount of 1.0 to 4.0 equivalents in the hydrolysis reaction.
10. The method of claim 1,
after the reaction in the step S1 is finished, after solid-liquid separation, pulping the solid by dichloromethane and then using the solid in the step S2,
after the reaction in the step S2 is finished, concentrating, extracting with ethyl acetate, drying, and then using in the step S3,
after the reaction in the step S3 is finished, the reaction mixture is concentrated and distilled under reduced pressure, and then is used in the step S4,
and after the reaction in the step S4 is finished, concentrating and drying to obtain the 4-hydroxymethylphenylacetic acid.
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| CN113121436A (en) * | 2019-12-31 | 2021-07-16 | 江苏艾立康医药科技有限公司 | Preparation method of nertadalal dimethyl sulfonate |
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| WO2008149110A1 (en) * | 2007-06-08 | 2008-12-11 | Argenta Discovery Limited | Bicyclor [2.2.1] hept-7-ylamine derivatives and their use in the treatment of diseases and conditions in which m3 muscarinic receptor activity and beta-adrenergic activity are implicated |
| CN113121436A (en) * | 2019-12-31 | 2021-07-16 | 江苏艾立康医药科技有限公司 | Preparation method of nertadalal dimethyl sulfonate |
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