CN113929689B - Synthetic method of key intermediate of Lukapari - Google Patents
Synthetic method of key intermediate of Lukapari Download PDFInfo
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- CN113929689B CN113929689B CN202111288254.4A CN202111288254A CN113929689B CN 113929689 B CN113929689 B CN 113929689B CN 202111288254 A CN202111288254 A CN 202111288254A CN 113929689 B CN113929689 B CN 113929689B
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the field of synthesis of medical intermediates, and relates to a synthesis method of a key intermediate of Lucarpari, which comprises the following steps: reacting 3-amino-5-fluorobenzoic acid methyl ester with pyruvic acid in the presence of a catalyst A to obtain an indole compound 2; the indole compound 2 and the compound 3 react in the presence of a catalyst B to obtain a compound 4; and (3) reacting the compound 4 with ammonia gas, adjusting the pH value to 6-7, carrying out solid-liquid separation, washing and drying to obtain the compound. The reaction steps are shortened to three steps, the operation is simpler, the three wastes are less, the yield and the product quality are guaranteed, and the method is more suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a novel poly (adenosine diphosphate ribose) polymerase (parp) inhibitor, which can prevent gene mutation of cancer cells spreading in the whole body and is used for treating advanced ovarian cancer associated with brca gene mutation and treated by two-line or more-line chemotherapy.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Polyadenyldiphosphoribose polymerase (PARP) is a family of ribozymes responsible for ADP-ribosylation, where poly ADP-ribosyltransferases transfer ADP-ribose moieties from NAD to specific amino acid side chains in nuclear target protein repair enzymes or to previously attached ADP-ribose units, and the PARP family in humans includes 17 enzymes, of which PARP-1 is best characterized.
The Rukapari, also known as Rukaparib and Rukapabru in Chinese and English, is named Rucaparib in trade name of Rubraca, is a novel poly-adenosine diphosphate ribose polymerase (parp) inhibitor, can prevent gene mutation of cancer cells in the whole body, and is used for treating advanced ovarian cancer which is treated by two-line or more-line chemotherapy and is associated with brca gene mutation.
The drug was first discovered by the university of n.kazall, then purchased by fevereire, sold to clovis corporation 2011, entitled breakthrough therapy for treating ovarian cancer by the U.S. food and drug administration (fda) at month 2015 4, and marketed as a monotherapy for refractory advanced ovarian cancer patients at month 2016 at 12.
For this drug, the literature reports two synthetic routes:
route one: 5-fluoro-2-methyl-3-nitrobenzoic acid is used as a starting material, 2 is obtained by nitration and esterification, 2, 3 is obtained by reaction of DMFDMA under catalysis of triethylamine, indole of 4 is obtained by hydrogenation reduction, the indole of 4 is reacted with 1-dimethylamino-2-nitroethylene under catalysis of trifluoroacetic acid, double bond reaction is reduced by sodium borohydride to obtain 6,6 is subjected to hydrogenation reduction and ring closure to obtain 7 lactam target compound.
The six-step reaction of the route, the route is longer, the operation is complicated, firstly, the nitration reaction of the first step needs to use excessive sulfuric acid and nitric acid, produce a large amount of acid waste water, be unfavorable for environmental protection, the temperature is higher when the second step reacts with DMFDMA, and be accompanied with the process of violent heat release, it is a big potential safety hazard, and the aftertreatment produces a large amount of black waste water that ammonia nitrogen is too high and have ammonia smell, be unfavorable for environmental protection problem under the present form too, secondly, palladium carbon that hydrogenation reduction used, with higher costs, palladium carbon does not inactivate after the reaction, the hidden danger of catching fire easily takes place to strain futilely, so from the safety, environmental protection, be unfavorable for the industrial amplification production in operation.
And a second route:
the indole ring of 4 is synthesized in the first three steps of the route, the same as the route I, 8N- (2, 2-dimethoxyethyl) phthalimide is hydrolyzed into aldehyde, and then the amino group is protected and deprotected under the catalysis of trifluoroacetic acid, so that the lactam compound of 7 is obtained.
The route also faces a large amount of acidic wastewater and environmental protection problems, and during deprotection, the generated N-hydroxyethyl phthalimide impurity seriously exceeds the standard and is difficult to remove, so that the quality requirement cannot be met, and the method is not beneficial to large-scale production.
The following technical routes are disclosed in U.S. patents filed by the company pfeiri and in chinese family patents:
the route adopts cheap and easily obtained 5-fluorosalicylic acid as a raw material, the problem of environmental protection wastewater is also involved through nitration and esterification, expensive dichlorobis (triphenylphosphine) palladium is used during Sonogashira coupling, oxygen-free control is strictly needed in the reaction process, a palladium-containing catalyst cannot be completely removed after the reaction is finished, the possibility of heavy metal exceeding is existed, and the industrial amplification is not facilitated.
Disclosure of Invention
The technical problem to be solved by the invention is mainly to overcome the defects in the prior art, and provide a new synthetic route, so that the reaction steps are shortened to three steps, the operation is simpler, the three wastes are less, the yield and the product quality are guaranteed, and the method is more suitable for industrial large-scale production.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a method for preparing a key intermediate of lucaparil, comprising:
reacting 3-amino-5-fluorobenzoic acid methyl ester with pyruvic acid in the presence of a catalyst A to obtain an indole compound 2;
the indole compound 2 and the compound 3 react in the presence of a catalyst B to obtain a compound 4;
and (3) reacting the compound 4 with ammonia gas, adjusting the pH value to 6-7, carrying out solid-liquid separation, washing and drying to obtain the compound.
The specific reaction formula is as follows:
in a second aspect of the invention, there is provided a key intermediate of lucaparil prepared by the above process.
In a third aspect of the present invention, an application of the key intermediate of rukapari in the preparation of an anti-cancer drug is provided, preferably, the anti-cancer drug is a poly (adenosine diphosphate ribose) polymerase inhibitor.
The invention has the beneficial effects that:
the synthetic route of the invention shortens the reaction steps to three steps, has simpler operation, less three wastes and guaranteed yield and product quality, and is more suitable for industrial scale-up production.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
A preparation method of a key intermediate of Lucaper comprises the following steps:
reacting 3-amino-5-fluorobenzoic acid methyl ester with pyruvic acid in the presence of a catalyst A to obtain an indole compound 2;
reacting the indole compound 2 with the compound 3 in the presence of a catalyst B to obtain a compound 4;
and (3) reacting the compound 4 with ammonia gas, adjusting the pH value to 6-7, carrying out solid-liquid separation, washing and drying to obtain the compound.
In some embodiments, the catalyst a is p-toluenesulfonic acid.
In some embodiments, the process for preparing indole compound 2 further comprises: cooling, crystallizing and carrying out solid-liquid separation treatment.
In some embodiments, the methyl 3-amino-5-fluorobenzoate is dissolved in methanol.
In some embodiments, the catalyst B is trifluoroacetic acid.
In some embodiments, the process for preparing compound 4 further comprises: desolventizing, cooling, crystallizing and carrying out solid-liquid separation treatment.
In some embodiments, the ammonia gas has a concentration of 15 wt% to 20 wt%.
In some embodiments, the compound 4 is reacted with ammonia gas at 25-30 ℃ for 4-6 h.
In some embodiments, the dried compound 4 is added into a methanol system, certain ammonia gas is introduced into the system at low temperature, when the mass fraction of the ammonia gas reaches 15-20% of the system, the ammonia and the ammonia are stopped, and the temperature is raised to the room temperature of 25-30 ℃ for reaction.
The present invention is described in further detail below with reference to specific examples, which are intended to be illustrative of the invention and not limiting.
Example 1:
the novel method for synthesizing the Rukapari key intermediate comprises the following specific steps:
step A) using cheap and easily-obtained solid 3-amino-5-fluorobenzoic acid methyl ester as a starting material, using methanol as a solvent, carrying out rearrangement and deacidification reaction under the catalysis of protonic acid p-toluenesulfonic acid and pyruvic acid under a reflux condition, and carrying out cooling crystallization, filtration or centrifugation to obtain an indole compound of a solid 2, wherein the specific steps are as follows: adding 338g of 3-amino-5-methyl fluorobenzoate (169g, 1mol) pyruvic acid (105.6g, 1.2mol) solvent methanol into a four-mouth reaction bottle with a mechanical stirring thermometer 1L, adding 3.38g of p-toluenesulfonic acid with a catalytic amount under stirring, heating an oil bath to 70 ℃, refluxing for 4h, monitoring the reaction by TLC, cooling to 10-15 ℃ after the reaction is finished, crystallizing for 2h, filtering to obtain 185g of a wet heavy solid 2 compound, drying, and obtaining 168.8g, wherein the yield is as follows: 87.5% δ H (400MHz, DMSO-d6),3.87(s,3H),6.9(dd,1H, J ═ 0.8,3.1Hz),7.43-7.49(m,2H),7.51(d,1H, J ═ 3.1Hz),11.47(s, br, 1H); δ C (100MHz, DMSOd6)51.85,102.05,102.78(d, J ═ 25.8Hz),109.49(d, J ═ 25.8Hz),120.79(d, J ═ 9.2Hz),123.96,128.49(d, J ═ 3.3Hz),136.73(d, J ═ 12.4Hz),157.33(J ═ 234.4Hz),166.21(J ═ 3.2 Hz); anal. Calcd for C10H8FNO2 requires C62.18; h4.17; f9.83; n7.25 Found C62.08; h4.21; f9.85; and (7) N7.27.
Step B), the solid 2 compound does not need to be dried, trifluoroacetic acid is used for catalyzing and carrying out condensation reaction on a compound 3(2- (2, 5-dioxopyrrolidine-1-yl) acetaldehyde, Cas:676558-37-5) to generate a compound 4 under the condition of taking methanol as a solvent, desolventizing, cooling, crystallizing, filtering or centrifuging to obtain a solid product 4, and the compound 4 needs to be dried by an oven or a bipyramid, wherein the specific steps are as follows: 96.5g of solid compound 2 which is converted into dry weight and 0.5mol of solid compound 2 are added into a 1L four-mouth bottle provided with a mechanical stirring thermometer, 482.5g of methanol and 84.6g of compound 3 are added, the stirring is carried out at room temperature to uniformly mix the system, 4.8g of trifluoroacetic acid with catalytic amount is added, the oil bath is heated to 68 ℃ for reflux, the system is dissolved and cleared, the reaction is carried out for 5h, the TLC monitors the reaction, the methanol is removed under normal pressure when the reaction is finished, the internal temperature is removed to 85 ℃, the temperature is reduced to 10-15 ℃, the crystallization is carried out for 2h, the mixture is filtered and dried by a gulf drying oven to obtain 132.6g of compound 4, and the yield is 83.4%.
And C) adding the dried compound 4 in a methanol system, introducing certain ammonia gas into the system at low temperature, stopping reacting with ammonia when the mass fraction of the system reaches 15%, heating to room temperature and 25 ℃ for 4h, monitoring the reaction by TLC, adjusting the pH to 6-7 by using 10% dilute hydrochloric acid when the reaction is finished, filtering or centrifuging, pulping and washing the solid twice by using water, and drying by using an oven or a bipyramid to obtain the target product yield of 5: 82% δ H (400MHz, DMSO-d6)2.86-2.88(m,2H),3.37(q,2H, J ═ 5.6Hz),7.22(s, br,1H),7.30(dd,1H, J ═ 2.4,9.3Hz),7.37(dd,1H, J ═ 2.4,9.3Hz),8.11(t, br, J ═ 5.6Hz),11.13(s, br, 1H); delta C (100MHz, DMSO-d6)
27.91,42.06,100.82(d,J＝25.8Hz),109.12(d,J＝25.8Hz),114.40,121.87,123.72(d,J＝3.3Hz),125.48(d,J＝8.7Hz),136.71(d,J＝12.4Hz),158.21(d,J＝233.6Hz),168.39.
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and the present invention is not limited thereto, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or equivalents thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A preparation method of a key intermediate of Lucaper is characterized by comprising the following steps:
reacting 3-amino-5-fluorobenzoic acid methyl ester with pyruvic acid in the presence of a catalyst A to obtain an indole compound 2;
reacting the indole compound 2 with the compound 3 in the presence of a catalyst B to obtain a compound 4;
reacting the compound 4 with ammonia gas, adjusting the pH value to 6-7, carrying out solid-liquid separation, washing and drying to obtain the compound;
the catalyst A is p-toluenesulfonic acid;
the catalyst B is trifluoroacetic acid;
the structural formula of the indole compound 2 is as follows:
the structural formula of the compound 3 is as follows:
the structural formula of the compound 4 is as follows:
the structural formula of the Rukapari key intermediate is as follows:
2. the process for the preparation of key intermediates of rukapari according to claim 1, wherein the process for the preparation of indole compound 2 further comprises: cooling, crystallizing and carrying out solid-liquid separation treatment.
3. The process for the preparation of lucapali key intermediate as claimed in claim 1, wherein said methyl 3-amino-5-fluorobenzoate is dissolved in methanol.
4. The process for the preparation of key intermediates of rukapari according to claim 1, wherein the process for the preparation of compound 4 further comprises: desolventizing, cooling, crystallizing and carrying out solid-liquid separation treatment.
5. The method of preparing a key intermediate of rukaphaline as recited in claim 1, wherein the concentration of ammonia gas is 15 wt% to 20 wt%.
6. The preparation method of the Rukapari key intermediate as claimed in claim 1, wherein the reaction condition of the compound 4 and ammonia gas is that the reaction lasts for 4-6 h at 25-30 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102741222A (en) * | 2009-10-27 | 2012-10-17 | 拜尔农作物科学股份公司 | Halogenalkyl-substituted amides used as insecticides and acaricides |
| CN108348503A (en) * | 2015-09-16 | 2018-07-31 | 爱欧梅特制药公司 | Medical compounds |
| CN110869359A (en) * | 2017-07-06 | 2020-03-06 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of fibrosis |
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| CN109651376B (en) * | 2017-10-12 | 2022-06-03 | 江苏创诺制药有限公司 | Synthetic method of azepino [5,4,3-cd ] indol-6-one compound |
| CN108752353B (en) * | 2018-04-28 | 2020-05-08 | 程春晓 | Preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib |
| CN111217818A (en) * | 2018-11-27 | 2020-06-02 | 台耀化学股份有限公司 | Crystal of lucapanib camphorsulfonate, and method for producing tricyclic compound, lucapanib and its camphorsulfonate crystal |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102741222A (en) * | 2009-10-27 | 2012-10-17 | 拜尔农作物科学股份公司 | Halogenalkyl-substituted amides used as insecticides and acaricides |
| CN108348503A (en) * | 2015-09-16 | 2018-07-31 | 爱欧梅特制药公司 | Medical compounds |
| CN110869359A (en) * | 2017-07-06 | 2020-03-06 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of fibrosis |
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