CN112010810B - Method for preparing high-purity rilpivirine intermediate by one-pot method - Google Patents

Method for preparing high-purity rilpivirine intermediate by one-pot method Download PDF

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CN112010810B
CN112010810B CN202010941599.4A CN202010941599A CN112010810B CN 112010810 B CN112010810 B CN 112010810B CN 202010941599 A CN202010941599 A CN 202010941599A CN 112010810 B CN112010810 B CN 112010810B
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compound
purity
rilpivirine
reaction
sodium
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CN112010810A (en
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苗得足
胡清文
张小伟
赵磊
王向华
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Reyoung Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Abstract

The invention relates to the technical field of chemical medicines, in particular to a method for preparing a high-purity rilpivirine intermediate by a one-pot method. The method for preparing the high-purity rilpivirine intermediate by the one-pot method comprises the following steps of: (1) Carrying out substitution reaction on the compound I and the compound II to obtain a reaction solution of a compound III; (2) Adding acrylamide into the III reaction solution of the compound, and obtaining a reaction solution of the compound IV under Heck reaction conditions; (3) Adding active carbon into the reaction liquid of the compound IV to perform decoloring treatment, and then adding a poor solvent to perform crystallization to obtain a white compound IV, namely a rilpivirine intermediate. The method for preparing the high-purity rilpivirine intermediate by the one-pot method is scientific, reasonable, simple and feasible, improves the purity and the yield of the product, and is suitable for large-scale production.

Description

Method for preparing high-purity rilpivirine intermediate by one-pot method
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a method for preparing a high-purity rilpivirine intermediate by a one-pot method.
Background
Rilpivirine hydrochloride (rilpivrine hydrochloride) is a novel non-nucleoside reverse transcriptase inhibitor (non-nucleoside reverse transcriptase inhibitor, NNRTI) developed by tibole (Tibotec Therapeutics) subordinate to the strong company in united states of america, is used for treating aids, has the commodity name of Edurant, is approved by the FDA in united states at 20 months 5 in 2011, and has the characteristics of easy synthesis, strong antiviral activity, high oral bioavailability, good safety and the like. Rilpivirine has the structural formula shown in formula 1:
according to the structural formula inverse analysis of the API, the API is mainly composed of three parts, as shown in the following figure:
the corresponding structural fragments are three important compounds, namely 4- [ (4-chloro-2-pyrimidinyl) amino ] benzonitrile (CAS: 244768-32-9), 4-bromo-2, 6-dimethylaniline (CAS: 24596-19-8) and acrylonitrile (CAS: 107-13-1), and the three compounds react in a certain order to form salts to obtain the rilpivirine hydrochloride. Various synthetic methods of rilpivirine hydrochloride have been described in the literature (rilpivirine synthesis route scheme [ J ]. Journal of the chinese medical industry, 2016,47 (03): 352-354.) in which the problem of difficulty in removal of Z isomer inevitably occurs in a route using acrylonitrile as a starting material, and since the acrylonitrile used is a B-class organic highly toxic product, toxicity is large, and industrial mass production is limited by the public security department, acrylamide (CAS: 79-06-1) is selected instead of acrylonitrile for industrial production of rilpivirine hydrochloride.
In the chemical reaction process, more or less side reactions and insufficient raw materials are generated along with the generation of main components, and in the actual production process, the problem to be solved by post-treatment is always solved for the purpose of cost control and operation simplification, so that the selection of a proper post-reaction treatment mode is particularly important.
Disclosure of Invention
The invention aims to provide a method for preparing a high-purity rilpivirine intermediate by a one-pot method, which is scientific, reasonable, simple and feasible, improves the purity and yield of the product, and is suitable for large-scale production.
The method for preparing the high-purity rilpivirine intermediate by the one-pot method comprises the following steps of:
(1) Carrying out substitution reaction on the compound I and the compound II to obtain a reaction solution of a compound III;
(2) Adding acrylamide into the III reaction solution of the compound, and obtaining a reaction solution of the compound IV under Heck reaction conditions;
(3) Adding active carbon into the reaction liquid of the compound IV to perform decoloring treatment, and then adding a poor solvent to perform crystallization to obtain a white compound IV, namely a rilpivirine intermediate;
the chemical reaction formula is as follows:
compound I is 4-bromo-2, 6-dimethylaniline;
compound II is 4- [ (4-chloro-2-pyrimidinyl) amino ] benzonitrile;
compound III is 4- [ [4- [ (4-bromo-2, 6-dimethylphenyl) amino ] -2-pyrimidine ] amino ] -benzonitrile;
compound IV is 3- {4- [2- (4-cyano-phenylamino) -pyrimidin-4-ylamino ] -3, 5-dimethyl-phenyl } -acrylamide (E).
In the step (1), the substitution reaction is carried out under the condition of no acid binding agent or alkali, wherein the alkali is one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amyl alcohol, potassium tert-amyl alcohol, liHMDS, potassium acetate, sodium acetate, potassium fluoride, cesium carbonate, potassium carbonate and sodium carbonate.
The molar ratio of base to compound I is 1-2:1, preferably 1-1.5:1.
In the step (1), the substitution reaction is carried out in a polar aprotic solvent, wherein the polar aprotic solvent is one of acetonitrile, tetrahydrofuran, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide; preferably N-methylpyrrolidone or N, N-dimethylformamide; more preferably N-methylpyrrolidone.
The volume to weight ratio of polar aprotic solvent to compound I was (5-10) mL 1g.
In the step (1), the molar ratio of the compound I to the compound II is 1:0.95-1.
In the step (1), the substitution reaction temperature is 80-100 ℃.
In the step (2), heck reaction conditions are as follows:
the palladium source is one of tetra (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride and 1,1' -bis (di-tert-butylphosphine) ferrocene palladium dichloride;
the alkali is one of sodium methoxide, sodium acetate, sodium tert-butoxide, sodium tert-amyl alcohol, potassium tert-amyl alcohol, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine and N, N-diisopropylethylamine; preferably sodium acetate, sodium carbonate, triethylamine, N-diisopropylethylamine; more preferably N, N-diisopropylethylamine.
Wherein the molar ratio of the palladium source to the compound I is 0.005-0.01:1; the molar ratio of base to compound I is 1-2:1, preferably 1-1.5:1.
In the step (2), the molar ratio of the acrylamide to the compound I is 1-1.5:1.
In the step (2), the Heck reaction temperature is 100-110 ℃.
In the step (3), the decoloring temperature is 80-100 ℃, and the crystallization temperature is-10-10 ℃.
In the step (3), the poor solvent is one of water, ethyl acetate, isopropyl acetate, methanol, ethanol and isopropanol.
The chemical reaction flow of the intermediate IV to continuously participate in the reaction to synthesize rilpivirine is as follows:
in the reaction process of the step (1), a lot of impurities are generated, and due to the fact that the similarity of the structures of raw materials and products often causes the characteristics that the impurities, the raw materials and the products are difficult to separate, a post-treatment method of column chromatography is generally adopted in the prior art, the disadvantages of the amplification production of the column chromatography are obvious, and a large amount of organic solvents are generated in the operation process. The invention discovers that the problems can be effectively solved by adopting a one-pot method through the research on the route.
Compared with the prior art, the invention has the following beneficial effects:
(1) According to the invention, a one-pot method is adopted to prepare the rilpivirine Lin Zhongjian body, and reactants are only required to be added sequentially, so that a target intermediate does not need to be separated, and the yield and purity of the product are greatly improved;
(2) The invention uses acrylamide to replace acrylonitrile to carry out industrial production of rilpivirine hydrochloride, avoids the problem that Z-type isomer generated in the route of adopting acrylonitrile as a starting material is difficult to clear, has scientific and reasonable preparation method and low production cost, and is suitable for large-scale production.
Drawings
FIG. 1 is an HPLC chart of compound IV prepared in example 1 of the present invention;
FIG. 2 is a mass spectrum of compound IV prepared in example 1 of the present invention;
FIG. 3 is an HPLC chart of compound V prepared in example 3 of the present invention;
FIG. 4 is an HPLC plot of the API prepared in example 4 of the present invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the compound IV prepared in example 1 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Modifications of the preparation method and the apparatus used may be made by those skilled in the art within the scope of the claims, and such modifications should also be considered as the scope of the invention.
In the following examples, compound I is 4-bromo-2, 6-dimethylaniline;
compound II is 4- [ (4-chloro-2-pyrimidinyl) amino ] benzonitrile;
compound III is 4- [ [4- [ (4-bromo-2, 6-dimethylphenyl) amino ] -2-pyrimidine ] amino ] -benzonitrile;
compound IV is 3- {4- [2- (4-cyano-phenylamino) -pyrimidin-4-ylamino ] -3, 5-dimethyl-phenyl } -acrylamide (E);
compound V is 4- [ [4- [ [4- (2-cyanoethyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E);
wherein compounds I and II are obtained by commercially available methods.
Example 1
Synthesis of rilpivirine intermediate Compound VI:
(1)N 2 under the protection condition, adding the compound I (80.36 g,40.16 mmol) and the compound II (92.63 g,40.16 mmol) into a 300mL three-port bottle at one time, heating 750mL N-methylpyrrolidone in an oil bath to the internal temperature of 90 ℃ for heat preservation reaction, and obtaining a reaction solution of the compound III when TLC tracks that the residue of the compound II is unchanged;
(2) N, N-diisopropylethylamine (12.92 g,100.4 mmol) and acrylamide (3.43 g,48.19 mmol) were added to the reaction mixture of the compound III under heat-retaining conditions, the internal temperature was lowered, and Pd (dppf) Cl was added at once when the internal temperature was raised again to about 100 ℃ 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (2.93 g,4 mmol), continuing to keep the temperature and stir for 1h, tracking the residue of the compound III by TLC, and cooling the reaction after the residue is unchanged to obtain a reaction solution of the compound IV;
(3) When the internal temperature of the reaction liquid of the compound IV is reduced to 80 ℃, 0.8g of active carbon is added, the mixture is heated and decolored for 2 hours, then the mixture is filtered while the mixture is hot, the filtrate is transferred to a clean 3L three-mouth bottle, 1.5L of purified water is added under the condition of mechanical stirring, the internal temperature is controlled to be not lower than 20 ℃ in the adding process, the system is white paste after the addition is completed, the temperature is reduced to 5-10 ℃, the mixture is continuously stirred for 1 hour, and after the mixture is subjected to suction filtration and the filter cake is leached by 500ml of methanol, 12.5g of white solid powder is obtained after drying, and the yield of the compound IV is 81.0 percent (calculated by the compound I).
The purity of the compound IV detected by HPLC is 98.5%, and the maximum single impurity is the debrominated reduction product of the compound III.
1 H NMR(600MHz,DMSO-d 6 )δ9.63(s,1H),8.95(s,1H),8.06(s,1H),7.73(s,2H),7.61(s,1H),7.54-7.33(m,4H),7.23(s,1H),6.70(d,J＝15.9Hz,1H),6.40(s,1H),5.41(s,1H),2.22(s,6H)。
13 C NMR(151MHz,DMSO-d 6 ):δ167.29,162.25,159.65,157.41,156.12,145.99,139.35,138.20,136.76,133.28,133.83,127.59,122.32,120.13,118.30,101.74,99.18,99.54,18.78。
m/z:calcd.for C 22 H 20 N 6 O(M+H) + :385.2,386.2,Found:385.1,386.1。
Example 2
Synthesis of rilpivirine intermediate Compound VI:
(1)N 2 under the protection condition, compound I (80.36 g,40.16 mmol), compound II (92.63 g,40.16 mmol) and 750mL of N, N-dimethylformamide are added into a 300mL three-port bottle at one time, the reaction is carried out under the condition that the temperature is kept at 100 ℃ when an oil bath is heated to the internal temperature, and when the TLC tracks that the residue of the compound II is unchanged, the reaction is carried outThe reaction liquid is the reaction liquid of the compound III;
(2) N, N-diisopropylethylamine (12.92 g,100.4 mmol) and acrylamide (3.43 g,48.19 mmol) were added to the reaction mixture of the compound III under heat-retaining conditions, the internal temperature was lowered, and Pd (dtbpf) Cl was added at once when the internal temperature was raised again to about 100 ℃ 2 :1,1' -bis (di-tert-butylphosphine) ferrocene palladium dichloride (2.61 g,4 mmol), continuously preserving heat and stirring for 1h, and after TLC tracking the residue of the compound III unchanged, starting to cool the reaction to obtain a reaction solution of the compound IV;
(3) When the internal temperature of the reaction liquid of the compound IV is reduced to 80 ℃, adding 1.0g of active carbon, preserving heat and decoloring for 2 hours, filtering while the reaction liquid is hot, transferring the filtrate to a clean 3L three-port bottle, adding 1.5L of methanol under the condition of mechanical stirring, controlling the internal temperature to be not lower than 20 ℃ in the adding process, cooling to 5-10 ℃ after the adding system is a white paste, continuing stirring for 1 hour, filtering, leaching the filter cake by using 500ml of methanol, and drying to obtain 11.9g of white solid powder, namely the compound IV, wherein the yield is 77.1 percent (calculated by the compound I).
The purity of the compound IV detected by HPLC is 99.70%, and the maximum single impurity is the debrominated reduction product of the compound III.
Mass spectrometry was performed on the product obtained in example 2, and mass spectrometry data were identical to those in example 1.
Example 3
Synthesis of Compound V:
compound VI (10.00 g,26.0 mmol) and 80mL phosphorus oxychloride are sequentially added into a 500mL three-port bottle, the mixture is stirred for 2 to 3 hours at 20 to 30 ℃ and then heated to reflux reaction for 3 hours, TLC is tracked until the residue of the compound VI is unchanged, the temperature is reduced to 5 to 10 ℃, the mixture is continuously stirred for 1 hour, and then the mixture is filtered and dried by suction to obtain 9.05g of pale yellow solid, namely a crude product of the compound V, wherein the yield is 95.0%.
Adding all the pale yellow solid into a 500ml three-mouth bottle containing 300ml of acetone, heating to dissolve, then adding 0.8g of active carbon, keeping the temperature and stirring for 1h, filtering while hot, and spin-drying the filtrate to obtain 8.50g of white solid, namely the pure product of the compound V, wherein the purity is 99.74%, and the yield is 93.9%.
Example 4
The composition API:
sequentially adding 50ml glacial acetic acid, 8.00g of compound V, heating to 90-95deg.C, dissolving, filtering, adding concentrated hydrochloric acid dropwise into the filtrate, and slowly adding 50ml H 2 O, controlling the internal temperature to be more than or equal to 70 ℃ in the adding process, adding Bi Tidu to cool to 20-25 ℃, continuously stirring for 0.5H, and then carrying out suction filtration, and using 10ml of H 2 O is leached for two times, the filter cake is dried to constant weight by a vacuum drying oven at 50-55 ℃ to obtain white crystal solid powder API 7.92g, the yield is 90.0%, and the HPLC purity is 99.82%.

Claims (9)

1. A method for preparing a high-purity rilpivirine intermediate by a one-pot method is characterized by comprising the following steps of: the method comprises the following steps:
(1) Carrying out substitution reaction on the compound I and the compound II to obtain a reaction solution of a compound III;
(2) Adding acrylamide into the III reaction solution of the compound, and obtaining a reaction solution of the compound IV under Heck reaction conditions;
(3) Adding active carbon into the reaction liquid of the compound IV to perform decoloring treatment, and then adding a poor solvent to perform crystallization to obtain a white compound IV, namely a rilpivirine intermediate;
in the step (1), the substitution reaction is carried out in a polar aprotic solvent, wherein the polar aprotic solvent is one of N-methylpyrrolidone and N, N-dimethylformamide;
in the step (3), the poor solvent is one of water and methanol;
the chemical reaction formula is as follows:
compound I is 4-bromo-2, 6-dimethylaniline;
compound II is 4- [ (4-chloro-2-pyrimidinyl) amino ] benzonitrile;
compound III is 4- [ [4- [ (4-bromo-2, 6-dimethylphenyl) amino ] -2-pyrimidine ] amino ] -benzonitrile;
compound IV is 3- {4- [2- (4-cyano-phenylamino) -pyrimidin-4-ylamino ] -3, 5-dimethyl-phenyl } -acrylamide (E).
2. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (1), the substitution reaction is carried out under the condition of no acid binding agent or alkali, wherein the alkali is one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amyl alcohol, potassium tert-amyl alcohol, liHMDS, potassium acetate, sodium acetate, potassium fluoride, cesium carbonate, potassium carbonate and sodium carbonate; the molar ratio of base to compound I is 1-2:1.
3. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (1), the volume weight ratio of the polar aprotic solvent to the compound I is (5-10) mL/1 g.
4. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (1), the substitution reaction temperature is 80-100 ℃.
5. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (1), the molar ratio of the compound I to the compound II is 1:0.95-1.
6. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (2), heck reaction conditions are as follows:
the palladium source is one of tetra (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride and 1,1' -bis (di-tert-butylphosphine) ferrocene palladium dichloride; the molar ratio of the palladium source to the compound I is 0.005-0.01:1;
the alkali is one of sodium methoxide, sodium acetate, sodium tert-butoxide, sodium tert-amyl alcohol, potassium tert-amyl alcohol, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine and N, N-diisopropylethylamine; the molar ratio of base to compound I is 1-2:1.
7. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (2), the molar ratio of the acrylamide to the compound I is 1-1.5:1.
8. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (2), the Heck reaction temperature is 100-110 ℃.
9. The method for preparing high-purity rilpivirine intermediate by one-pot method according to claim 1, characterized in that: in the step (3), the decoloring temperature is 80-100 ℃, and the crystallization temperature is-10-10 ℃.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1541215A (en) * 2001-08-13 2004-10-27 ղɭҩҵ���޹�˾ HIV inhibiting pyrimidines derivatives
CN1681774A (en) * 2002-08-09 2005-10-12 詹森药业有限公司 Processes for the preparation of 4- 4- 4-(2 -cyanoethenyl)-2,6-dimethylphenyl )amino) -2-pyrimidinyl)amino benzonitrile
CN1720027A (en) * 2002-11-29 2006-01-11 詹森药业有限公司 Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base
CN106008366A (en) * 2016-05-25 2016-10-12 山东大学 Preparation method of rilpivirine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1541215A (en) * 2001-08-13 2004-10-27 ղɭҩҵ���޹�˾ HIV inhibiting pyrimidines derivatives
CN1681774A (en) * 2002-08-09 2005-10-12 詹森药业有限公司 Processes for the preparation of 4- 4- 4-(2 -cyanoethenyl)-2,6-dimethylphenyl )amino) -2-pyrimidinyl)amino benzonitrile
CN1720027A (en) * 2002-11-29 2006-01-11 詹森药业有限公司 Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base
CN106008366A (en) * 2016-05-25 2016-10-12 山东大学 Preparation method of rilpivirine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1;Jerome Guillemont等;J. Med. Chem.;第48卷;2072-2079 *
利匹韦林合成路线图解;张衡 等;中国医药工业杂志;第47卷(第3期);352-354 *

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