CN113024399B - Pharmaceutical intermediate compound and preparation method and application thereof - Google Patents
Pharmaceutical intermediate compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN113024399B CN113024399B CN202110266484.4A CN202110266484A CN113024399B CN 113024399 B CN113024399 B CN 113024399B CN 202110266484 A CN202110266484 A CN 202110266484A CN 113024399 B CN113024399 B CN 113024399B
- Authority
- CN
- China
- Prior art keywords
- trifluoroacetic acid
- preparation
- intermediate compound
- water
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a pharmaceutical intermediate compound, and the compoundThe compound is N- (4-formyl-2-methylphenyl) trimethyl acetamide, and the structural formula of the compound is as follows:
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a medicinal intermediate compound and a preparation method and application thereof.
Background
N- (4-formyl-2-methylphenyl) trimethyl acetamide (1) does not have CAS number at present, can be used for preparing antihypertensive drug telmisartan with molecular formula C 12 H 17 ON of the formula
In the prior art, two methods are available for synthesizing formyl on a benzene ring, generally Blanc chloromethylation and then Sommelet oxidation preparation, but the steps are too long, the yield is low, and the post-treatment is troublesome. The other method is to adopt Viserier reaction, and introduce formyl on a benzene ring by DMF under the action of phosphorus oxychloride, so that the method has the disadvantages of great pollution and troublesome post-treatment.
Disclosure of Invention
The invention aims to overcome the problem of introduction of formyl on a benzene ring in the prior art, and provides a pharmaceutical intermediate compound, and a preparation method and application thereof.
The invention provides a drug intermediate compound, which is N- (4-formyl-2-methylphenyl) trimethyl acetamide (1), and has the following structural formula:
the drug intermediate compound is a novel substance, and currently, no CAS number exists.
The invention also provides a preparation method of the drug intermediate compound (1), which comprises the following steps: n- (o-tolyl) trimethylacetamide N- (4-formyl-2-methylphenyl) trimethylacetamide was obtained by the Duff reaction.
Preferably, the preparation method comprises the following steps: sequentially adding N- (o-tolyl) trimethyl acetamide, trifluoroacetic acid and urotropine, reacting at a preset temperature, adding water, refluxing for 1-2 h, cooling to room temperature, adding toluene for extraction, separating liquid, retaining an organic layer, extracting a water layer for one or more times, combining the organic layers, washing with water to be neutral, namely pH being 7.0, enabling the water layer to be colorless, drying an organic phase, performing suction filtration, and performing rotary evaporation on a filtrate to obtain the drug intermediate compound (1).
The specific route of the preparation method is as follows:
preferably, the reaction at the predetermined temperature is specifically: reacting for 1-10 h at the temperature of 80-160 ℃.
Preferably, the reaction at the predetermined temperature is specifically: reacting for 2-3 h at the temperature of 120-125 ℃.
Preferably, the dosage of the trifluoroacetic acid is 5 to 20 eq; the dosage of the urotropine is 1-5 eq; the water dosage is 1-10 times of the volume of the trifluoroacetic acid.
Preferably, the dosage of the trifluoroacetic acid is 14-16 eq, and preferably not less than 15 eq; the dosage of the urotropine is 2-3 eq; the amount of water is 2 times of the volume of the trifluoroacetic acid.
In the above synthetic route, the number of toluene extractions is preferably not more than 3.
The invention also provides application of the pharmaceutical intermediate compound (1) in preparing telmisartan which is a hypotensive drug, for example, telmisartan can be prepared based on the compound (1) of the invention through the following routes:
based on the preparation method of benzimidazole reported in reference 1 (the improvement of the synthesis process of telmisartan key intermediate, China journal of pharmaceutical chemistry 2020, 30 (3): 149-152.), the compound (3) is prepared from the pharmaceutical intermediate compound (1) prepared by the invention; based on reference 2(Synthesis and Structure-activity relationships of series of sub-specified 2- (1H-furo [2, 3-g)]indazol-1-yl)ethylamine derivatives as 5-HT 2C Amidolytic method reported in receiver aginsts.bioorg Med chem.2008,16,1966-1982.) Compound (3) is prepared as an intermediate (4) of telmisartan, a hypotensive drug which has been disclosed; the telmisartan intermediate (4) is prepared into telmisartan as a blood pressure lowering drug based on the methods in reference 3 (benzimidazole compound and a preparation method thereof: CN107434786A) and reference 4 (6-neutralized benzamidozoles as new non-Substituted peptides and receptors II receptors: synthesis, biological activity, and structure-activity relationships, J.Med.Chem.1993,36, 4040-.
According to the preparation route provided by the invention, N- (o-tolyl) trimethyl acetamide and urotropine are adopted to prepare N- (4-formyl-2-methylphenyl) trimethyl acetamide in trifluoroacetic acid through Duff reaction in one step, the raw materials are easy to obtain, the safety is high, the product purity is high, the side reaction is less, the total yield is higher, the preparation route is environment-friendly, the operation is simple and convenient, and the preparation method is suitable for industrial production.
Detailed Description
In order to more clearly describe the technical contents of the present invention, the following further description is given in conjunction with specific embodiments.
Example 1:
taking a 2L three-neck flask, sequentially adding 38.23g (0.2mol) of N- (o-tolyl) trimethyl acetamide and 345.45g (3mol) of trifluoroacetic acid, stirring for 0.5h, slowly adding 56.64g (0.4mol) of urotropine, reacting for 2.5h at 120-125 ℃, detecting a point plate until the raw materials are basically reacted, adding 700mL of water, hydrolyzing at 90-95 ℃ for 2h, stopping heating, cooling, adding 200mL of water and 400mL of toluene, pouring into a separating funnel, retaining an organic layer, continuously extracting the water layer twice with 100mL of toluene, combining the organic layers, adding acid into the water layer, and distilling under normal pressure to recover the aqueous trifluoroacetic acid. And washing the organic layer once, adjusting the pH value of the water layer to 6.0-7.0 by using a 5% sodium carbonate solution, enabling the organic layer to be colorless, adding anhydrous magnesium sulfate, drying, filtering after 1h, and washing. Rotary evaporating at 50 deg.c and-0.1 mpa for 2 hr to obtain white solid 35.93g in 82% yield and measured melting point 44.3-46.2 deg.c.
Example 2:
taking a 2L three-neck flask, sequentially adding 38.23g (0.2mol) of N- (o-tolyl) trimethyl acetamide and 345.45g (3mol) of trifluoroacetic acid, stirring for 0.5h, slowly adding 84.96g (0.6mol) of urotropine, reacting for 3h at 120-125 ℃, detecting a point plate until the raw materials are basically reacted, adding 700mL of water, carrying out hydrolysis reaction for 1.5h at 90-95 ℃, stopping heating, cooling, adding 200mL of water and 400mL of toluene, pouring into a separating funnel, retaining an organic layer, continuously extracting a water layer twice with 100mL of toluene, combining the organic layer, adding acid into the water layer, and distilling under normal pressure to recover the aqueous trifluoroacetic acid. And washing the organic layer once, adjusting the pH value of the water layer to 6.0-7.0 by using a 5% sodium carbonate solution, enabling the organic layer to be colorless, adding anhydrous magnesium sulfate, drying, filtering after 1h, and washing. Rotary evaporating at 50 deg.c and-0.1 mpa for 2 hr to obtain white solid 35.05g in 80% yield and melting point 43.3-45.4 deg.c.
1 H NMR(400MHz,CDCl 3 )δ9.83(s,1H),8.28(d,J＝8.4Hz,1H),7.66(dd,J＝10.6,2.0Hz,2H),7.49(br,s,1H),2.27(s,3H),1.29(s,9H).
13 C NMR(600MHz,CDCl 3 )δ191.43,176.71,141.92,132.25,131.17,129.99,127.27,120.98,40.31,27.72,17.57.
ESI-MS:242.1(M+Na) +
In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.
Claims (3)
1. A method for preparing a pharmaceutical intermediate compound, wherein the compound is N- (4-formyl-2-methylphenyl) trimethylacetamide, and the structural formula of the compound is as follows:
the preparation method of the compound comprises the following steps: the N- (o-tolyl) trimethyl acetamide is obtained through a Duff reaction to obtain the N- (4-formyl-2-methylphenyl) trimethyl acetamide, wherein the Duff reaction specifically comprises the following steps: sequentially adding N- (o-tolyl) trimethyl acetamide, trifluoroacetic acid and urotropine, reacting at a preset temperature, adding water, refluxing for 1-2 h, cooling to room temperature, adding toluene for extraction, separating liquid, retaining an organic layer, extracting a water layer for one or more times, combining the organic layers, washing with water to neutrality, drying an organic phase, performing suction filtration, and performing rotary evaporation on a filtrate to obtain the drug intermediate compound;
the reaction at the preset temperature specifically comprises the following steps: reacting for 1-10 h at the temperature of 80-160 ℃;
the dosage of the trifluoroacetic acid is 5-20 eq; the dosage of the urotropine is 1-5 eq; the amount of water is 1-10 times of the volume of trifluoroacetic acid.
2. The method for preparing a pharmaceutical intermediate compound according to claim 1, wherein the reaction at the predetermined temperature is specifically: reacting for 2-3 h at the temperature of 120-125 ℃.
3. The method for preparing a pharmaceutical intermediate compound according to claim 1, wherein the amount of trifluoroacetic acid is 14 to 16 eq; the dosage of the urotropin is 2-3 eq; the amount of water used was 2 times the volume of trifluoroacetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110266484.4A CN113024399B (en) | 2021-03-11 | 2021-03-11 | Pharmaceutical intermediate compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110266484.4A CN113024399B (en) | 2021-03-11 | 2021-03-11 | Pharmaceutical intermediate compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113024399A CN113024399A (en) | 2021-06-25 |
| CN113024399B true CN113024399B (en) | 2022-09-09 |
Family
ID=76469898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110266484.4A Active CN113024399B (en) | 2021-03-11 | 2021-03-11 | Pharmaceutical intermediate compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113024399B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113024469A (en) * | 2021-03-12 | 2021-06-25 | 华东理工大学 | Synthesis method of telmisartan intermediate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220016124A (en) * | 2019-05-31 | 2022-02-08 | 우베 고산 가부시키가이샤 | Benzotriazole derivatives |
| CN111423382B (en) * | 2020-04-03 | 2022-03-15 | 南京国星生物技术研究院有限公司 | Preparation method of telmisartan key intermediate |
-
2021
- 2021-03-11 CN CN202110266484.4A patent/CN113024399B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113024399A (en) | 2021-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108623456B (en) | Preparation method of butylphthalide and pharmaceutical intermediate thereof | |
| CN113024399B (en) | Pharmaceutical intermediate compound and preparation method and application thereof | |
| CN108341804A (en) | The preparation method of high-purity olmesartan medoxomil | |
| CN114292231A (en) | 2-methyl-8-substituent-quinoline and preparation method thereof | |
| CN111825612B (en) | Preparation method of 2, 3-quinoxaline dimethanol-1, 4-dioxide | |
| CN106883175A (en) | A kind of preparation method of tolvaptan | |
| CN104649970A (en) | Method for directly synthesizing organic luminous material, namely 8-hydroxyquinoline zinc | |
| CN105566257B (en) | A kind of industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran | |
| CN105820174B (en) | A kind of preparation method of polysubstituted thiophene diindyl derivative | |
| CN107098855A (en) | A kind of method for preparing the quinolinone of 7 hydroxyl 2 | |
| CN108101860B (en) | Preparation method of cis-2, 6-dimethyl morpholine | |
| CN109721552B (en) | Preparation method of gefitinib | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN103373956B (en) | Method for preparing clevidipine butyrate | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN108129414B (en) | Preparation method of mosapride citrate intermediate | |
| CN112645901A (en) | Preparation method of 1-cyclohexyl piperazine | |
| CN105777539B (en) | One kind 2 [2（2,4 difluorophenyls）Pi-allyl] 1,3 diethyl malonates synthetic method | |
| CN112125889A (en) | Preparation method of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline | |
| CN105732613B (en) | A kind of synthetic method of 9 demethyl (+) α dihydrotetrabenazineins | |
| CN111484460A (en) | Synthetic method of olanzapine related substance compound I and compound II | |
| CN101747343B (en) | Sulbactam pivoxil preparation method | |
| CN104910113A (en) | Preparation method of hydroxy benzene anhydride | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN101613317B (en) | Mozavaptan synthesis technology for treating congestive heart failure (CHF) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |