CN111333543B - Synthesis method of rilpivirine intermediate - Google Patents
Synthesis method of rilpivirine intermediate Download PDFInfo
- Publication number
- CN111333543B CN111333543B CN202010303642.4A CN202010303642A CN111333543B CN 111333543 B CN111333543 B CN 111333543B CN 202010303642 A CN202010303642 A CN 202010303642A CN 111333543 B CN111333543 B CN 111333543B
- Authority
- CN
- China
- Prior art keywords
- amino
- reaction
- dimethylphenyl
- rilpivirine
- rilpivirine intermediate
- 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
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
- C07C223/06—Compounds containing amino and —CHO groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention provides a synthesis method of rilpivirine intermediate, which takes 2,4, 6-trimethylaniline as raw material to react with 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) in dilute hydrochloric acid solution to obtain 4-amino-3, 5-dimethylbenzaldehyde, then the aldehyde and cyanoacetic acid generate Knoevenagel reaction under the condition of taking organic base as catalyst to obtain 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate, and an intermediate (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile is obtained through decarboxylation reaction, the used raw material in the whole synthesis process is cheap and easy to obtain, the utilization rate of the raw material is high, the synthesis process is simple, the reaction conditions are mild, the yield of the intermediate is high, is suitable for the requirement of industrial mass production. Moreover, compared with the reagent in the original synthesis route, the reagent used in the invention has low toxicity and better environmental protection benefit.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a rilpivirine intermediate.
Background
Rilpivrine (rilpivrine) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Tibotec corporation of america, is used for treating aids, and has the characteristics of easy synthesis, strong antiviral activity, high oral bioavailability, good safety and the like. The chemical name is as follows: [ [4- [ [4- [ (1E) -2-cyanoethenyl ] -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile. The chemical structure is as follows:
according to the literature report, rilpivirine is mainly synthesized by two key intermediates, namely an intermediate (1): (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile and intermediate (2): 4 ((4-amino-2 pyrimidinyl) amino) benzonitrile, salifying the intermediate (1), and carrying out N-alkylation reaction with the intermediate (2) to obtain the target product rilpivirine, wherein the chemical structure is as follows:
among them, the intermediate (1) is mainly synthesized by a Heck reaction or a method using a phosphine ligand. The intermediate (1) can be obtained by the above method, but the following problems occur in the synthesis: the synthesis route has high energy consumption, the palladium catalyst used in the reaction process is expensive, the synthesis cost is high, the used reagents are harmful to people and easy to cause environmental pollution, and some reagents belong to highly toxic controlled medicines and are not suitable for industrial mass production.
Disclosure of Invention
In view of the above, the invention aims to provide a synthesis method of a rilpivirine intermediate, so as to solve the problems that the synthesis energy consumption and cost of the rilpivirine intermediate are high and environmental pollution is easily caused in the prior art.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a synthesis method of rilpivirine intermediate comprises the following steps:
1) under the condition of a solvent, enabling mesitylene to react with 2, 3-dichloro-5, 6-dicyano benzoquinone to obtain 4-amino-3, 5-dimethylbenzaldehyde;
2) reacting the 4-amino-3, 5-dimethylbenzaldehyde with cyanoacetic acid in a Knoevenagel reaction under the condition of organic base to obtain 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate;
3) under the conditions of a catalyst and a solvent, the 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate is heated to carry out decarboxylation reaction, and then the rilpivirine intermediate (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile is obtained.
Optionally, the solvent in step 1) is one or more of diluted hydrochloric acid, water, 1, 4-dioxane and acetic acid.
Optionally, the mol ratio of the mesitylene and the 2, 3-dichloro-5, 6-dicyanobenzoquinone in the step 1) is 1 to (1.5-4).
Optionally, the reaction temperature of the reaction between the mesitylene and the 2, 3-dichloro-5, 6-dicyanobenzoquinone in the step 1) is 0-40 ℃, and the reaction time is 1-4 hours.
Optionally, the molar ratio of the 4-amino-3, 5-dimethylbenzaldehyde to the cyanoacetic acid to the organic base in the step 2) is 1: 1-2: 0.5-4.
Optionally, the reaction temperature of the Knoevenagel reaction in the step 2) is 0-40 ℃, and the reaction time is 2-8 h.
Optionally, the organic base in step 2) is one or more of pyrrolidine, piperidine, pyridine, morpholine, triethylamine, triethanolamine, and triethylene diamine.
Optionally, the molar ratio of the 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate to the catalyst in the step 3) is 1 to (0.01-0.1).
Optionally, the reaction temperature of the decarboxylation reaction in the step 3) is 50-150 ℃, and the reaction time is 2-18 h.
Optionally, in the step 3), the catalyst is one or more of copper, copper oxide, cuprous oxide, copper bromide and copper iodide, and the solvent is one or more of dimethyl sulfoxide, tetrahydrofuran, ethanol, methanol, triethylamine and toluene.
Compared with the prior art, the synthesis method of the rilpivirine intermediate has the following advantages:
the method takes 2,4, 6-trimethylaniline as a raw material, reacts with 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) in a dilute hydrochloric acid solution to obtain 4-amino-3, 5-dimethylbenzaldehyde, then the aldehyde and cyanoacetic acid undergo Knoevenagel reaction under the condition that organic base is used as a catalyst to obtain 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate, and an intermediate (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile is obtained through decarboxylation reaction. Moreover, compared with the original synthetic route, the reagent used in the invention has low toxicity and better environmental protection benefit.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
The present invention will be described in detail with reference to examples.
Example 1
A synthesis process of a rilpivirine intermediate specifically comprises the following steps:
1) synthesis of 4-amino-3, 5-dimethylbenzaldehyde: adding 13.5g (0.1mol) of 2,4, 6-trimethylaniline (mesitylene), 250mL of 5% hydrochloric acid solution and 56.75g (0.25mol) of 2, 3-dichloro-5, 6-dicyanobenzoquinone into a round bottom flask with mechanical stirring, stirring to mix thoroughly, heating to 25 ℃, reacting for 2h, treating the reaction solution with 250mL of 10% sodium hydroxide solution after the reaction is finished, extracting the mixed solution with 50mL of ethyl acetate for four times, separating the solution, and using saturated NaHCO to the organic layer 3 The resulting residue was washed once with saturated brine, dried over anhydrous sodium sulfate, and finally distilled under reduced pressure to remove the solvent, whereby 14.3g of 4-amino-3, 5-dimethylbenzaldehyde was obtained as a waxy solid, and the yield was 95.97% by calculation and the NMR data thereof was found to be hydrogen spectra data of NMR 1 H-NMR(400MHz,CDCl 3 )δ9.72(s,1H),7.49(s,2H),4.17(s, 2H),2.22(s,6H);
2) Synthesis of 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate: 14.9g (0.1mol) of 4-amino-3, 5-dimethylbenzaldehyde, 100mL of absolute ethyl alcohol, 8.5g (0.1mol) of cyanoacetic acid and 14.2g (0.2mol) of pyrrolidine are added into a round bottom flask with mechanical stirring, the mixture is stirred to be fully mixed, the temperature is increased to 25 ℃, the reaction is carried out for 4 hours, after the reaction is finished, the solvent is distilled off under reduced pressure, 50mL of dichloromethane is used for dissolution, then, 20mL of water is added for beating and filtration, 13.1g of solid 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate is obtained, the yield is 60.65% by calculation, and the nuclear magnetic resonance hydrogen spectrum data is as follows by the nuclear magnetic resonance test: 1 H NMR(400MHz,DMSO-d 6 )δ13.17(s,1H),7.92(s,1H),7.62(s,2H), 6.12(s,2H),2.09(s,6H);
3) synthesis of (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile: adding 10.8g (0.05mol) of 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate, 0.5g (0.003mol) of cuprous oxide and 50mL of dimethyl sulfoxide into a round bottom flask with mechanical stirring, stirring to fully mix, heating to 120 ℃, reacting for 8 hours, filtering after the reaction is finished, distilling under reduced pressure to remove the solvent, recrystallizing the product in ethanol, and filtering to obtain 5.38g of solid (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile (rilpivirine intermediate (1)), wherein the yield is 62.56% by calculation and the nuclear magnetic resonance hydrogen spectrum data is that the yield is 62.56% by nuclear magnetic resonance test 1 H NMR(400MHz,CDCl 3 )δ7.42(d,1H),7.02(s,2H),6.12(d,1H),4.12(s, 2H),2.19(s,6H)。
The synthetic route of the rilpivirine intermediate (1) in the embodiment is as follows:
in the preparation process of the rilpivirine intermediate of the present invention, the solvent, catalyst, and the like in each step are not limited to the chemical substances in example 1, and a chemical substance that can realize the preparation of the rilpivirine intermediate of the present invention may be added as needed.
In step 1), the solvent can be preferably one or more of dilute hydrochloric acid, water, 1, 4-dioxane and acetic acid except the dilute hydrochloric acid in example 1, and the mass fraction of the dilute hydrochloric acid can be preferably 3-15%;
in the step 2), the organic base may be preferably one or more of pyrrolidine, piperidine, pyridine, morpholine, triethylamine, triethanolamine and triethylene diamine, in addition to the pyrrolidine in the embodiment 1;
the catalyst in the step 3) can also be preferably one or more of copper, cupric oxide, cuprous oxide, cupric bromide and cupric iodide besides the cuprous oxide of the embodiment 1; the solvent may preferably be one or more selected from dimethylsulfoxide, tetrahydrofuran, ethanol, methanol, triethylamine, and toluene, in addition to dimethylsulfoxide in example 1.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A synthesis method of rilpivirine intermediate is characterized by comprising the following steps:
1) under the condition of a solvent, enabling mesitylene to react with 2, 3-dichloro-5, 6-dicyano benzoquinone to obtain 4-amino-3, 5-dimethylbenzaldehyde;
2) under the condition of organic base, the 4-amino-3, 5-dimethylbenzaldehyde and cyanoacetic acid are subjected to Knoevenagel reaction to obtain 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate; the organic alkali is one or more of pyrrolidine, piperidine, pyridine, morpholine, triethylamine, triethanolamine and triethylene diamine;
3) under the conditions of a catalyst and a solvent, heating the 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate to perform decarboxylation reaction to obtain a rilpivirine intermediate (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile; the catalyst is one or more of copper, cupric oxide, cuprous oxide, cupric bromide and cupric iodide, and the solvent is one or more of dimethyl sulfoxide, tetrahydrofuran, ethanol, methanol, triethylamine and toluene.
2. The method for synthesizing rilpivirine intermediate according to claim 1, wherein the solvent in step 1) is one or more of dilute hydrochloric acid, water, 1, 4-dioxane and acetic acid.
3. The method for synthesizing rilpivirine intermediate according to claim 1, wherein the molar ratio of mesitylene and 2, 3-dichloro-5, 6-dicyanobenzoquinone in step 1) is 1 to (1.5-4).
4. The method for synthesizing rilpivirine intermediate according to claim 1, wherein the reaction temperature of the reaction of mesitylene with 2, 3-dichloro-5, 6-dicyanobenzoquinone in step 1) is 0-40 ℃ and the reaction time is 1-4 h.
5. The method for synthesizing rilpivirine intermediate according to claim 1, wherein the molar ratio of the 4-amino-3, 5-dimethylbenzaldehyde, the cyanoacetic acid and the organic base in step 2) is 1: 1-2: 0.5-4.
6. The synthesis method of rilpivirine intermediate according to claim 1, wherein the reaction temperature of Knoevenagel reaction in step 2) is 0-40 ℃ and the reaction time is 2-8 h.
7. The method for synthesizing rilpivirine intermediate according to claim 1, wherein the molar ratio of the 3- (4-amino-3, 5-dimethylphenyl) 2-cyanoacrylate to the catalyst in the step 3) is 1 to (0.01-0.1).
8. The synthesis method of rilpivirine intermediate according to claim 1, wherein the decarboxylation in step 3) is carried out at 50-150 ℃ for 2-18 h.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010303642.4A CN111333543B (en) | 2020-04-17 | 2020-04-17 | Synthesis method of rilpivirine intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010303642.4A CN111333543B (en) | 2020-04-17 | 2020-04-17 | Synthesis method of rilpivirine intermediate |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111333543A CN111333543A (en) | 2020-06-26 |
CN111333543B true CN111333543B (en) | 2022-09-16 |
Family
ID=71179152
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010303642.4A Active CN111333543B (en) | 2020-04-17 | 2020-04-17 | Synthesis method of rilpivirine intermediate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111333543B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112592289B (en) * | 2020-12-15 | 2022-09-20 | 内蒙古永太化学有限公司 | Preparation method of gabapentin intermediate |
CN115819158A (en) * | 2022-11-25 | 2023-03-21 | 湖北航天化学技术研究所 | Aniline speed reducer with anti-aging effect, preparation method and solid propellant |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1747941A (en) * | 2003-02-07 | 2006-03-15 | 詹森药业有限公司 | HIV inhibiting 1,2,4-triazines |
CN105566162A (en) * | 2016-02-23 | 2016-05-11 | 苏州莱克施德药业有限公司 | Rilpivirine midbody preparing technology |
CN106749203A (en) * | 2016-11-28 | 2017-05-31 | 洛阳聚慧医药科技有限公司 | A kind of pyrimidine heterocyclic compounds, miazines heterocyclic compound salts and preparation method and application |
-
2020
- 2020-04-17 CN CN202010303642.4A patent/CN111333543B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1747941A (en) * | 2003-02-07 | 2006-03-15 | 詹森药业有限公司 | HIV inhibiting 1,2,4-triazines |
CN105566162A (en) * | 2016-02-23 | 2016-05-11 | 苏州莱克施德药业有限公司 | Rilpivirine midbody preparing technology |
CN106749203A (en) * | 2016-11-28 | 2017-05-31 | 洛阳聚慧医药科技有限公司 | A kind of pyrimidine heterocyclic compounds, miazines heterocyclic compound salts and preparation method and application |
Non-Patent Citations (1)
Title |
---|
Regiospecific oxidation of an alkyl group of aromatic amine to carbonyl group by DDQ in aq. medium;Madhav S. Mane 等;《Chinese Chemical Letters》;20110625;第22卷;第1039-1042页 * |
Also Published As
Publication number | Publication date |
---|---|
CN111333543A (en) | 2020-06-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111333543B (en) | Synthesis method of rilpivirine intermediate | |
CN111646922B (en) | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid | |
CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
EP1873151B1 (en) | Improved process for producing moxonidine | |
WO2005044805A1 (en) | A novel process for preparing donepezil and its derivatives | |
WO2005012264A1 (en) | Process for producing 6,7-bis(2-methoxyethoxy)-quinazolin-4-one | |
CN111233745B (en) | (E)1- (9-alkyl-carbazole-3-) -acrylic acid and preparation method thereof | |
CN111039858B (en) | Preparation method of fluazuron | |
CN103992278A (en) | Synthesis method of cytosine | |
CA3022444C (en) | Method for preparing azoxystrobin | |
CN109694335B (en) | Solvent-free preparation method of disubstituted p-nitrophenylacetonitrile derivative | |
CN108727179B (en) | Synthetic method of alpha-allyl substituted alpha, beta-unsaturated ketone, ester or nitrile compound | |
CN113717085A (en) | Accurate-sequence poly-monothioacetal and preparation method thereof | |
CN108658826B (en) | Method for preparing vildagliptin | |
CN107954872B (en) | Method for synthesizing malonate type compound | |
CN113087667A (en) | Synthesis method of imidazolidinone derivative | |
JPH0269457A (en) | Pyrrole derivative and production thereof | |
CN106748725B (en) | preparation method of 4-chloro-2-fluoro-phenylpropionic acid | |
CN111454217A (en) | Preparation method of apltinib intermediate | |
CN105153039A (en) | Preparation method for rosuvastatin calcium intermediate impurity | |
CN109438422A (en) | It is a kind of difficult to understand uncommon for Buddhist nun's impurity and preparation method thereof | |
CN110590641B (en) | Green preparation method of 3-hydroxyisoindole-1-ketone series compounds | |
CN112979563B (en) | Preparation method of medical intermediate 2, 3-diaryl-2, 3-dihydroquinazoline-4 [1H ] -ketone | |
CN103073498A (en) | Novel preparation method for (R)-Alpha-amino-e-caprolactam | |
CN107353217A (en) | A kind of preparation method of Anthranilate and amides compound |
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 |