CN116396299B - Method for preparing Wu Pa tenib intermediate - Google Patents

Method for preparing Wu Pa tenib intermediate Download PDF

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CN116396299B
CN116396299B CN202310661690.4A CN202310661690A CN116396299B CN 116396299 B CN116396299 B CN 116396299B CN 202310661690 A CN202310661690 A CN 202310661690A CN 116396299 B CN116396299 B CN 116396299B
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CN116396299A (en
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李文森
陆超
孙云龙
周惠宏
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Heading Nanjing Pharmtechnologies Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • 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

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Abstract

The invention belongs to the technical field of chemical synthesis, and provides a method for preparing a Martinib intermediate. In the method, 3-aminopyrazine-2-carboxylic acid methyl ester is taken as a starting material, and the target product is prepared through 7 steps of reactions including reduction, oxidation, bromination, wittig reaction, ring closure reaction, protection of amino group by Tos and coupling reaction. The invention provides an effective and economic synthetic route, and solves the problem of large treatment capacity of three wastes caused by using a large amount of bromine in the original grinding process. The total yield of the synthetic route of the method of the invention is 40% and the purity of the final product is more than 99%. The method has simple process in the amplifying process, is easy to operate and is suitable for industrial application.

Description

Method for preparing Wu Pa tenib intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a Wupattinib intermediate.
Background
Wu Pati Nib (Upadacitinib) is a novel JAK1 inhibitor developed by Abovine. In month 8 2019, lapatinib was first approved worldwide in the united states for the treatment of moderate to severe active Rheumatoid Arthritis (RA) adult patients who have poor or intolerant responses to Methotrexate (MTX).
In 12 months 2019, lapatinib has gained approval from the european union for the treatment of moderate to severe RA adult patients who have poor or intolerant response to disease-modifying antirheumatic drugs (DMARDs).
In 2022, as well as 2 months, the drug administration of the chinese country has approved for refractory, moderately severe atopic dermatitis patients in adults and teenagers aged 12 years and older who do not respond well to or are not suitable for other systemic treatments (e.g. hormones or biological agents). In month 2022, the drug administration of the state of the art was approved by the glatirib for the treatment of adult patients with moderate to severe active rheumatoid arthritis who responded poorly or intolerantly to one or more TNF inhibitors (tumor necrosis factor inhibitors) and adult patients with active psoriatic arthritis (PsA) who had poor or intolerant efficacy to one or more DMARDs. The sustained release tablet of lapatinib was approved by the national drug administration for the treatment of adult patients with moderate to severe active ulcerative colitis who responded poorly or were intolerant or contraindicated to one or more TNF inhibitors, day 2, 2023.
The structure of Wu Pati Ni compound is as follows:
one key intermediate for the preparation of Wu Pati Ni is tert-butyl 5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamate, which has the following structure:
。
there are currently few synthetic literature to make this key intermediate. The original patent US2015118229 reports the use of PdC1 in (trimethylsilyl) acetylene, cuI, triethylamine systems starting from 3, 5-dibromopyrazin-2-amine 2 (PPh 3 ) 2 Catalytic coupling, then closing the ring under basic conditions and protecting the amino group with Tos (p-toluenesulfonyl). The synthetic route is as follows:
the overall yield of this synthetic route was 18%. However, in the actual synthesis process, it was found that the suppliers of starting material compound 1 were few, and that additional dibromo by 2-aminopyrazine was required to prepare compound 1. In addition, in the preparation of compound 2, the catalyst PdC1 used 2 (PPh 3 ) 2 The amount of (c) depends on the quality of the starting compound 1, otherwise the reaction is not guaranteed to be complete. In the ring closing reaction of the step b, a strong alkali sodium hydrogen and DMF system is needed to construct the pyrazinopyrrole ring, the conditions are harsh, and the yield is low. In addition, in industrial production, the use of sodium hydrogen has a great potential safety hazard.
Patent application CN110156791a reports a preparation method of 5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamic acid tert-butyl ester, the synthetic route is as follows:
in the process of this patent application, pyrazine-2, 5-diamine is used as a starting material and the target compound is obtained through a series of reactions. However, the patent application does not give data about the yield and the like of each step, and the process uses sodium nitrite for diazotization reaction, so that great potential safety hazards exist in industrial production.
The existing technology is difficult to meet the requirement of industrial production, so a new method for preparing the key intermediate (5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamic acid tert-butyl ester) of the Martinib needs to be developed.
Disclosure of Invention
In view of the problems of the prior art, the present invention provides a process for preparing a lapatinib intermediate compound 5 (5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamic acid tert-butyl ester), comprising the following synthetic routes:
the method comprises the following steps:
(1) Reducing compound 8 to compound 9 using a reducing agent;
(2) Oxidizing compound 9 to compound 10 using an oxidizing agent;
(3) Brominating compound 10 with a brominating agent to produce compound 11;
(4) Reacting the compound 11 with (methoxymethyl) triphenyl phosphorus chloride, and performing a Wittig reaction to generate a compound 12;
(5) Cyclizing compound 12 under acidic conditions to form compound 3;
(6) Under alkaline conditions, adopting Tos protecting groups to carry out amino protection on the compound 3 to obtain a compound 4;
(7) Compound 4 was reacted with tert-butyl carbamate to give compound 5.
According to one embodiment of the method of the present invention, in step (1), the reducing agent is selected from at least one of sodium borohydride, lithium aluminum hydride. Further, in the step (1), a lewis acid is added, wherein the lewis acid is at least one selected from calcium chloride, zinc chloride and aluminum trichloride. The addition of the lewis acid can improve the reducibility of the reducing agent.
According to one embodiment of the method of the present invention, in step (2), the oxidizing agent is selected from at least one of manganese dioxide, PCC (pyridine chlorochromate), jones reagent (Jones reagent). For the oxidation of piperazinylmethanol, an oxidant with moderate oxidation capacity is required to avoid the formation of acids or other impurities due to oxidation that does not occur or that is excessive.
According to one embodiment of the method of the present invention, in step (3), the brominating agent is selected from the group consisting of bromine, NBS (N-bromosuccinimide), pyridinium tribromide. The type and amount of brominating agent can be selected by one skilled in the art according to the particular circumstances.
According to one embodiment of the process of the present invention, in step (4), the Wittig reaction is carried out under alkaline conditions provided by potassium tert-butoxide. Potassium tert-butoxide provides a moderately alkaline environment for the Wittig reaction. Combining reactivity, reaction rate, reaction conditions and impurity profile, potassium t-butoxide is a preferred alkaline reagent in the present process. The amount of potassium tert-butoxide added can be determined by the person skilled in the art based on the particular case of the Wittig reaction. The potassium t-butoxide is preferably added in an amount of 2.0 to 2.5 equivalents based on the compound 11.
According to one embodiment of the method of the present invention, in step (5), the acidic condition is provided by at least one acid of hydrochloric acid, sulfuric acid, nitric acid, acetic acid. In addition, other organic or inorganic acids are contemplated as long as the acidic conditions provided by these acids promote the reaction and do not react with the reaction substrate.
According to one embodiment of the method of the present invention, in step (6), the alkaline conditions are provided by at least one base of potassium hydroxide, sodium hydroxide, lithium hydroxide. In this step, a basic substance having a strong basicity is used to promote completion of the reaction in view of the progress of the reaction and the yield. Other organic or inorganic bases other than potassium hydroxide, sodium hydroxide, lithium hydroxide are contemplated as long as the alkaline conditions provided by these bases promote the reaction and do not react with the reaction substrate. For the amino protection, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride may be used. From the viewpoint of operability of the reaction, p-toluenesulfonyl chloride is preferable.
According to one embodiment of the process according to the invention, in step (7), the reaction of compound 4 with tert-butyl carbamate is carried out under catalysis of Xantphos and palladium acetate, and the amount of Xantphos added is 2-5% and the amount of palladium acetate added is 1-5% based on the mass of compound 4. The amount of Xantphos and palladium acetate added can be determined by the person skilled in the art according to the particular case. The amount of Xantphos is preferably 2-5% and the amount of palladium acetate is preferably 1-5% within the applicable range.
The beneficial effects of the invention are that
In the method, 3-aminopyrazine-2-carboxylic acid methyl ester is used as a starting raw material, and is subjected to reduction, oxidation, bromination, wittig reaction, ring closure reaction and amino protection by Tos, and a coupling reaction totaling 7 steps to prepare Wu Pati-Ni intermediate 5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamic acid tert-butyl ester. The method provided by the invention has the advantages that the adopted starting raw materials are cheap and easy to obtain, the Pd/Cu catalysis is not needed for carrying out Sonogashim cross coupling, and the risk of catalyst poisoning is avoided. In addition, in the method of the invention, the ring closing step is realized without using high-risk sodium hydrogen, thereby providing more favorable conditions for industrialization. The total yield of the synthetic route of the method is 40%, and the purity of the obtained target product (5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamic acid tert-butyl ester) is more than 99%. The method has simple process in the amplifying process, is easy to operate and is suitable for industrial application.
Drawings
FIG. 1 is a diagram of Compound 9 obtained in example 1 of the present invention 1 H NMR spectrum.
FIG. 2 is an HPLC chart of compound 10 obtained in example 2 of the present invention.
FIG. 3 is an HPLC chart of Compound 11 obtained in example 3 of the present invention.
FIG. 4 is an HPLC chart of Compound 12 obtained in example 4 of the present invention.
FIG. 5 is a diagram of Compound 3 obtained in example 5 of the present invention 1 H NMR spectrum.
FIG. 6 is an HPLC chart of Compound 4 obtained in example 6 of the present invention.
FIG. 7 is a diagram of Compound 5 obtained in example 7 of the present invention 1 H NMR spectrum.
FIG. 8 is a mass spectrum of compound 5 obtained in example 7 of the present invention.
FIG. 9 is an HPLC chart of Compound 5 obtained in example 7 of the present invention.
Detailed Description
The invention is further illustrated by the following specific examples.
The synthetic route of the method of the invention is as follows:
。
in general, the method comprises the steps of:
(1) Reducing compound 8 to compound 9 using a reducing agent;
(2) Oxidizing compound 9 to compound 10 using an oxidizing agent;
(3) Brominating compound 10 with a brominating agent to produce compound 11;
(4) Reacting the compound 11 with (methoxymethyl) triphenyl phosphorus chloride, and performing a Wittig reaction to generate a compound 12;
(5) Cyclizing compound 12 under acidic conditions to form compound 3;
(6) Under alkaline conditions, adopting Tos protecting groups to carry out amino protection on the compound 3 to obtain a compound 4;
(7) Compound 4 was reacted with tert-butyl carbamate to give compound 5.
For each step in the process of the invention, a different synthetic route may be employed to prepare the corresponding compound. Thus, these different synthetic pathways can be combined to construct numerous embodiments. The synthesis of each intermediate is described in detail below by means of specific examples.
Example 1
Synthesis of Compound 9
The synthetic route for compound 9 is as follows:
table 1 shows the material data for this example (calcium chloride may be replaced with zinc chloride, aluminum trichloride).
TABLE 1
Synthesis procedure for compound 9:
3000 ml of THF, 200g of compound 8 and 74.5g of sodium borohydride are sequentially added into a 5L three-necked flask, the temperature is reduced to 0-5 ℃ in an ice bath, and then 600ml of methanol is slowly added dropwise. After the methanol is added, the temperature of the reaction system is raised to 50-55 ℃ and the reaction is continued for 3 hours. Detection by TLC showed complete reaction of starting material.
Post-treatment: the reaction system was cooled to about 10℃and 300ml of 2N diluted hydrochloric acid was added dropwise, followed by stirring at room temperature for 30 minutes after the completion of the dropwise addition. THF and methanol were removed by concentration under reduced pressure, the residue was dissolved in Dichloromethane (DCM), the pH of the system was adjusted to around 9 with aqueous ammonia and the salt solids were removed by filtration. Rinsing the filter cake with DCM for 2 times, mixing the organic phases, washing with saturated saline water for 1 time, washing with water for 1 time, collecting the organic phase, and concentrating to obtain crude product of the compound 9 [ (]160g, yield 98%), taking a small amount, purifying, performing nuclear magnetic detection, 1 the H NMR spectrum is shown in FIG. 1. The crude product is directly put into the next reaction step.
Example 2
Synthesis of Compound 10
The synthetic route for compound 10 is as follows:
table 2 shows the material data for this example (the oxidant manganese dioxide could also be replaced with PCC, jones reagent).
TABLE 2
The operation process comprises the following steps:
160g of compound 9, 1600ml of THF and 224g of manganese dioxide are added into a 2L three-port reaction bottle, and the temperature is raised to 40-45 ℃ after the addition, so that the reaction is carried out for 20 hours. TLC detection showed complete reaction of starting material.
Post-treatment: filtering to remove manganese dioxide (MnO) 2 ) The filter cake was rinsed with 100ml of THF, the THF phases were combined and concentrated to give 165g of crude product. 1000ml of 20% sodium bisulphite solution and 300ml of methyl tertiary butyl ether are added into the crude product, and the mixture is stirred for 0.5h at room temperature after the addition. The mixture was allowed to stand to separate, the aqueous phase was adjusted to pH 9 by adding sodium hydroxide solution, then extracted 2 times with DCM, and the organic phases were combined and concentrated under reduced pressure to give 143g of Compound 10 in a purity of 97.1% by HPLC (see FIG. 2) in 91% yield.
Example 3
Synthesis of Compound 11
The synthetic route for compound 11 is as follows:
table 3 shows the material data for this example (brominating agent can also be replaced with bromine or NBS).
TABLE 3 Table 3
The operation process comprises the following steps:
120g of compound 10 and 720ml of DCM were placed in a 2L three-necked flask, the temperature of the system was lowered to 5℃and a solution of 343g of pyridinium tribromide in 720ml of DCM was added dropwise, the temperature of the reaction system was controlled at 15℃and the reaction was continued for 2 hours at the end of the dropwise addition. TLC showed complete reaction of starting material.
Post-treatment: the mixture was quenched by dropwise addition of saturated aqueous sodium thiosulfate, the layers separated, the aqueous phase extracted 1 more time with 240ml of DCM, and the DCMs combined. The organic phase was washed once with saturated brine, concentrated to yield 198g of crude product, slurried with 800ml of ethanol for 1h, filtered and dried to yield 167g of solid with an HPLC purity of 97.9% (see FIG. 3) in 85% yield.
Example 4
Synthesis of Compound 12
The synthetic route for compound 12 is as follows:
table 4 shows the reaction mass data of this example.
TABLE 4 Table 4
The operation process comprises the following steps:
143g of (methoxymethyl) triphenylphosphine chloride and 1000ml of THF are introduced into a 2L three-necked flask, the reaction system is cooled to 0℃and then 90.2g of potassium tert-butoxide are introduced. After the addition of potassium tert-butoxide is completed, the system is controlled at 0-5 ℃, 65g of 300ml of THF solution of the compound 11 is dropwise added, the dropwise addition is completed for about 1 hour, the reaction is kept for 3 hours, and TLC (thin layer chromatography) detects that the raw materials are reacted completely.
Post-treatment: water and Ethyl Acetate (EA) were added to the reaction system, the layers were stirred and separated, the aqueous phase was extracted 2 more times with EA, and the organic phases were combined and concentrated under reduced pressure to give 210g of an oil. To the oil was added 5wt% phosphoric acid solution and methyl tert-butyl ether (MTBE), stirred for 0.5h, and allowed to stand for delamination. The aqueous phase was extracted 1 more time with MTBE, the organic phase was separated off, the pH of the aqueous phase was adjusted to about 9 with sodium hydroxide, then extracted 3 times with EA, the EA phases were combined and concentrated to 60.5g with an HPLC purity of 97.1% (FIG. 4) in 82% yield.
Example 5
Synthesis of Compound 3
The synthetic route for compound 3 is as follows:
table 5 shows the reaction mass data of this example.
TABLE 5
The operation process comprises the following steps:
23g of compound 12, 115ml of ethanol and 100ml of 3N hydrochloric acid are added into a 500ml reaction bottle, the temperature is raised to 75 ℃ for reaction for 4 hours, and TLC detection shows that the reaction of the raw materials is complete.
Post-treatment: the reaction system was cooled to 0 ℃, at this time, solid precipitation was observed, stirring was continued for 2 hours, filtration was continued, and the obtained solid was dried to obtain 17g of solid, with an HPLC purity of 99.4% and a yield of 86%. Compound 3 1 The H NMR spectrum is shown in FIG. 5.
Example 6
Synthesis of Compound 4
The synthetic route for compound 4 is as follows:
table 6 shows the material data of this example.
TABLE 6
The operation process comprises the following steps:
in a 250ml reaction flask, 10g of Compound 3, 30ml of DMF and 8.5g of potassium hydroxide were added, 10.1g of p-toluenesulfonyl chloride was added in portions at room temperature, and the reaction was continued for 3h after the addition was completed, and TLC detection showed complete reaction of the starting material.
Post-treatment: and controlling the temperature of the reaction system to 10-20 ℃ by using an ice bath, adding 100ml of water, stirring for 1h, cooling to 0 ℃, adding EA for extraction for 3 times, and merging EA phases. The organic phase was washed 1 time with saturated sodium chloride solution, the organic phase was added with 3g of activated carbon, stirred at room temperature for 1h, filtered, and the filtrate was concentrated to give 16.9g of solid, compound 4, 99.4% pure by hplc (fig. 6) in 95% yield.
Example 7
Synthesis of Compound 5
The synthetic route for compound 5 is as follows:
table 7 shows the material data of this example.
TABLE 7
The operation process comprises the following steps:
into a 250ml reaction flask were charged 10g of Compound 4, 0.41g of Xantphos (4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, 2.5 wt%), 0.08g of palladium acetate (1.25 wt%), 4g of tert-butyl carbamate, 100ml of 1, 4-dioxane, 13.7g of potassium carbonate, and the mixture was purged with nitrogen to give a sufficient displacement protection. And heating the reaction system to the internal temperature of 65-70 ℃, stirring for 20h, and displaying complete reaction by TLC.
Post-treatment: cooling the reaction system to about 40 ℃, filtering, concentrating the filtrate to remove 1, 4-dioxane, adding 2-methyltetrahydrofuran, L-cysteine and saturated sodium bicarbonate solution, stirring for 1h at room temperature, standing and layering. The organic phase is washed and layered with a half-saturated sodium bicarbonate solution and a half-saturated saline solution in sequence, and the organic phase is collected for subtractionConcentrating under pressure to obtain a solid crude product. Adding 50ml of acetonitrile into the crude product, heating to dissolve, slowly dripping 30ml of water, and slowly cooling to 10 ℃ for crystallization for 1h after dripping. The crystals were filtered, and the filter cake was rinsed once with a 1:1 acetonitrile/water mixture, air-blown and dried to give 8.9g of solid in 81% yield. The chemical structure of the product is that 1 H NMR spectrum (FIG. 7) and mass spectrum (FIG. 8) confirmed that the solid was 5-tosyl-5H-pyrrolo [2,3-B ] as a target intermediate of Wu Pati Ni]Pyrazine-2-carbamic acid tert-butyl ester (compound 5). HPLC purity was 99.5% (see fig. 9).
The method of the invention is described above by means of specific examples. In the method, 3-aminopyrazine-2-carboxylic acid methyl ester is used as a starting material, and the target intermediate, namely 5-tosyl-5H-pyrrolo [2,3-B ] pyrazine-2-carbamic acid tert-butyl ester is prepared through 7 steps of reactions. The route of the invention has cheap and easily obtained starting materials, does not need Pd/Cu catalyzed Sonogashim cross coupling, avoids the risk of catalyst poisoning, and does not need dangerous NaH. The total yield of the synthetic route of the method is 40%, and the purity of the obtained target product is more than 99%, so that the method is suitable for industrial application.

Claims (7)

1. A process for preparing a lapatinib intermediate, comprising the following synthetic route:
；
the method comprises the following steps:
(1) Reducing compound 8 to compound 9 using a reducing agent; the reducing agent is at least one selected from sodium borohydride, lithium borohydride and lithium aluminum hydride;
(2) Oxidizing compound 9 to compound 10 using an oxidizing agent; the oxidant is at least one selected from manganese dioxide, PCC and Jones reagent;
(3) Brominating compound 10 with a brominating agent to produce compound 11; the brominating agent is at least one selected from bromine, NBS and pyridinium tribromide;
(4) Reacting the compound 11 with (methoxymethyl) triphenyl phosphorus chloride, and performing a Wittig reaction to generate a compound 12;
(5) Cyclizing compound 12 under acidic conditions to form compound 3;
(6) Under alkaline conditions, adopting Tos protecting groups to carry out amino protection on the compound 3 to obtain a compound 4;
(7) Compound 4 was reacted with tert-butyl carbamate to give compound 5.
2. The method of claim 1, further comprising adding a lewis acid selected from at least one of calcium chloride, zinc chloride, aluminum trichloride in step (1).
3. The process of claim 1, wherein in step (4), the Wittig reaction is conducted under alkaline conditions provided by potassium t-butoxide.
4. The method of claim 1, wherein in step (5), the acidic condition is provided by at least one acid of hydrochloric acid, sulfuric acid, nitric acid, acetic acid.
5. The method of claim 1, wherein in step (6), the alkaline condition is provided by at least one base selected from the group consisting of potassium hydroxide, sodium hydroxide, and lithium hydroxide.
6. The method according to claim 1, wherein in step (6), the amino protection is achieved by reacting compound 3 with p-toluenesulfonyl chloride.
7. The process according to claim 1, wherein in step (7), the reaction of compound 4 with t-butyl carbamate is carried out under the catalysis of Xantphos and palladium acetate, and Xantphos is added in an amount of 2 to 5% and palladium acetate is added in an amount of 1 to 5% based on the mass of compound 4.
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