CN111233857B - Synthetic method for continuously producing pexidininib - Google Patents
Synthetic method for continuously producing pexidininib Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 8
- 239000002994 raw material Substances 0.000 claims abstract description 88
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 21
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to the technical field of chemical synthesis, and particularly discloses a synthesis method for continuously producing pexidartinib, which takes 5-chloro-7-azaindole and 2-chloro-5-chloromethylpyridine as starting raw materials, and obtains an alkylated intermediate through alkylation reaction of 5-chloro-7-azaindole at high yield, wherein the intermediate does not need to be purified, and directly and continuously goes to a next reaction unit to perform amino substitution reaction with 3-aminomethyl-6- (trifluoromethyl) pyridine to obtain the target product pexidartinib. The invention firstly provides a synthetic route for continuously producing the pexidartinib in two steps, is particularly suitable for commercial mass production, and can prepare the pexidartinib with low cost, high yield, high purity and high environmental protection.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method for continuously producing Pexidinib.
Background
Pexidinib (PLX-3397) (structure shown in formula I) is effective, has oral activity, and selective ATP-competitive colony stimulating factor 1(CSF1R or M-CSFR) and c-Kit inhibitor, and has antitumor activity. Approved by the FDA in 2019 for the treatment of tenosynostocytoma (TGCT). Giant cell tumor of the tendon sheath (TGCT) is a rare disabling tumor. Pexidaltinib was the first and only approved therapy for treatment of TGCT.
TGCT is a rare non-malignant tumor that may be locally invasive. It affects the synovial lining joints, bursa and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility of the affected joints or limbs. The current primary therapy for TGCT is resection of the tumor by surgery. However, in patients with recurrent, refractory or diffuse tumors, the tumor is more difficult to remove and surgical therapy does not necessarily improve symptoms. Multiple surgeries on severe patients can result in severe damage to joints, disabling functional impairment, reduced patient quality of life and even the need for amputation.
Although pexidaltinib (PLX-3397) has been approved by FDA for marketing, its synthesis method is very few, and there are only the following three methods:
(1) the route reported by Daiichi Sankyo Company is shown in the following equation 1. This route has the following problems: the starting compound 3 is very expensive. ② the synthesis of compound 5 from compound 4 requires low temperature of-78 ℃, and uses very dangerous reagent butyl lithium, which is not suitable for mass production. ③ the yield of the compound 8 is lower. Purification of the product in multiple steps in the whole route requires chromatographic columns, which are very expensive and waste solvent.
Reaction scheme 1
(2) A new synthetic route was reported in WO2016179412a1 in 2016, as shown in equation 2. This route provides a more economical route than the first route. The steps are shorter, and the yield is higher. However, the following problems still remain: the starting compounds 3, 7 and 9 are very expensive, and particularly the compound 9 is very difficult to be commercially available, resulting in a very high production cost. Secondly, a large amount of trifluoroacetic acid is used in two steps of the route, and a large amount of waste acid is generated, so that the method is not beneficial to environmental protection.
Reaction formula 2
(3) Recently, a new synthetic route has been reported in Synthesis, as shown in equation 3. The route has 4 steps in total, and the total yield can reach 49 percent. Although this method is a great improvement over the two methods described above, the following disadvantages remain: the synthesis of compound 13 requires the use of vinylmagnesium bromide (compound 14), which is a relatively dangerous reagent. ② the synthesis of the compound 18 needs expensive palladium catalyst, which causes high production cost and very easy heavy metal palladium residue, in order to meet the requirements of raw material medicine, the palladium removing process needs to be carried out, and the production cost is increased.
Reaction formula 3
In order to solve the above problems, the present invention aims to propose a novel synthetic route to produce pexidininib with low cost, high yield, high purity and high environmental protection.
Disclosure of Invention
The invention solves the technical problem of providing a synthetic method for continuously producing the pexidininib, and the method has the advantages of cheap and easily obtained raw materials, convenient production, environmental protection, safety and easy purification.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method for continuously producing Pexidininib has a reaction equation as follows:
wherein:
s1: firstly, in a reaction solvent, raw materials 1 and 2 are subjected to alkylation reaction under the action of an additive and a catalyst to generate an alkylation intermediate; and the number of the first and second groups,
s2: in a reaction solvent, the alkylation intermediate obtained in the step S1 and the raw material 3 are subjected to an amino substitution reaction under the action of a base to generate the pexidinib.
Preferably, the reaction solvent in step S1 is one or more of tetrahydrofuran, 1, 4-dioxane or methyl tetrahydrofuran, the additive is cuprous oxide, silver oxide or silver carbonate, and the catalyst is sodium iodide or potassium iodide; in the step S2, the reaction solvent is one or a mixture of several of tetrahydrofuran, 1, 4-dioxane or methyl tetrahydrofuran, and the base is sodium carbonate, potassium carbonate or triethylamine.
More preferably, the reaction solvent in step S1 is one or a mixture of more of 1, 4-dioxane and methyl tetrahydrofuran, the additive is cuprous oxide or silver oxide, the catalyst is sodium iodide or potassium iodide, the molar ratio of the catalyst to the raw material 1 is 0.1: 1.0-0.3: 1.0, the molar ratio of the raw material 2 to the raw material 1 is 1.0: 1.0-3.0: 1.0, the molar ratio of the additive to the raw material 1 is 1.0: 1.0-1.5: 1.0, and the reaction temperature is 60-120 ℃, preferably 80-110 ℃; the reaction solvent in the step S2 is one or a mixture of more of 1, 4-dioxane and methyl tetrahydrofuran, the alkali is sodium carbonate or potassium carbonate, the molar ratio of the raw material 3 to the raw material 1 is 0.9: 1.0-1.5: 1.0, the molar ratio of the alkali to the raw material 1 is 1.0: 1.0-2.5: 1.0, and the reaction temperature is 60-120 ℃, preferably 80-120 ℃.
More preferably, in step S1, the molar ratio of the catalyst to the raw material 1 is 0.2: 1.0-0.3: 1.0, the molar ratio of the raw material 2 to the raw material 1 is 1.0: 1.0-1.5: 1.0, the molar ratio of the additive to the raw material 1 is 1.0: 1.0-1.2: 1.0, and the reaction temperature is 100 ℃.
More preferably, in step S2, the molar ratio of raw material 3 to raw material 1 is 1.2: 1.0-1.5: 1.0, the molar ratio of base to raw material 1 is 1.2: 1.0-2.0: 1.0, and the reaction temperature is 120 ℃.
The invention provides a specific synthetic method for continuously producing Pexidinib, which comprises the following steps:
step S1: under the protection of inert gas, dissolving a raw material 1 into a reaction solvent 1, 4-dioxane, sequentially adding potassium iodide and silver oxide, heating the reaction solution to 100 ℃ under the atmosphere of nitrogen, dissolving a raw material 2 into the 1, 4-dioxane, dropwise adding the mixture into a reaction system for 1 hour, and reacting for 6-8 hours; detecting the reaction completion by HPLC, and then directly using the reaction liquid for the next reaction; wherein the equivalent ratio of each reactant is as follows: raw material 1: raw material 2: potassium iodide: silver oxide 1.0:1.1:0.2: 1.2;
step S2: dissolving a raw material 3 in 1, 4-dioxane, dissolving potassium carbonate in water, heating a reaction liquid obtained by the reaction in the step S1 to 120 ℃, then simultaneously dropwise adding the raw material 3 and a potassium carbonate aqueous solution into the reaction liquid for 0.5-2 hours, stirring and reacting for 4-6 hours after dropwise adding, filtering the reaction liquid after detecting that an alkylation intermediate disappears by HPLC, then distilling the filtrate under reduced pressure, recovering the 1, 4-dioxane, adding ethyl acetate into the concentrated reaction liquid, separating an organic phase obtained after layering, drying and spin-drying the organic phase, wherein the spin-dried substance is ethanol: recrystallizing with a solvent with water being 1:2 to obtain the product of Pexidintinib, wherein the equivalent ratio of each reactant is as follows: raw material 3: potassium carbonate: raw material 1: 1.2:1.5: 1.0.
The synthesis method for continuously producing the pexidininib provided by the invention comprises the following two steps:
the first step is as follows: in a reaction solvent, raw materials 1 and 2 are subjected to alkylation reaction under the action of an additive and a catalyst to generate an alkylation intermediate.
Further, the reaction solvent is one or a mixture of several of tetrahydrofuran, 1, 4-dioxane or methyl tetrahydrofuran, the additive is cuprous oxide, silver oxide or silver carbonate, and the catalyst is sodium iodide or potassium iodide.
Preferably, the reaction solvent is one or a mixture of more of 1, 4-dioxane and methyl tetrahydrofuran, the additive is cuprous oxide or silver oxide, the catalyst is sodium iodide or potassium iodide, the molar ratio of the catalyst to the raw material 1 is 0.1: 1.0-0.3: 1.0, the molar ratio of the raw material 2 to the raw material 1 is 1.0: 1.0-3.0: 1.0, the molar ratio of the additive to the raw material 1 is 1.0: 1.0-1.5: 1.0, and the reaction temperature is 60-120 ℃, preferably 80-110 ℃.
More preferably, the molar ratio of the catalyst to the raw material 1 is 0.2: 1.0-0.3: 1.0, the molar ratio of the raw material 2 to the raw material 1 is 1.0: 1.0-1.5: 1.0, the molar ratio of the additive to the raw material 1 is 1.0: 1.0-1.2: 1.0, and the reaction temperature is 100 ℃.
Most preferably, under the protection of inert gases such as nitrogen, the raw material 1 is dissolved in a reaction solvent 1, 4-dioxane, potassium iodide and silver oxide are sequentially added, the reaction solution is heated to 100 ℃ under the atmosphere of nitrogen, then the raw material 2 is dissolved in a proper amount of 1, 4-dioxane and is dropwise added into the reaction system, the dropwise adding time is 1 hour, and the reaction lasts for 6-8 hours; detecting the reaction completion by HPLC, and then directly using the reaction liquid in the next reaction unit; wherein the equivalent ratio of each reactant is as follows: raw material 1: raw material 2: potassium iodide: silver oxide ═ 1.0:1.1:0.2: 1.2.
The second step is that: in a reaction solvent, the alkylation intermediate directly reacts with the raw material 3 under the action of alkali to generate amino substitution reaction to generate the pexidinib.
Further, the reaction solvent is one or a mixture of more of tetrahydrofuran, 1, 4-dioxane or methyl tetrahydrofuran, and the alkali is sodium carbonate, potassium carbonate or triethylamine.
Preferably, the reaction solvent is one or a mixture of more of 1, 4-dioxane and methyl tetrahydrofuran, the alkali is sodium carbonate or potassium carbonate, the molar ratio of the raw material 3 to the raw material 1 is 0.9: 1.0-1.5: 1.0, the molar ratio of the alkali to the raw material 1 is 1.0: 1.0-2.5: 1.0, and the reaction temperature is 60-120 ℃, preferably 80-120 ℃.
More preferably, the molar ratio of the raw material 3 to the raw material 1 is 1.2:1.0 to 1.5:1.0, the molar ratio of the base to the raw material 1 is 1.2:1.0 to 2.0:1.0, and the reaction temperature is 120 ℃.
Most preferably, the raw material 3 is dissolved in a small amount of 1, 4-dioxane, potassium carbonate is dissolved in a proper amount of water, then the reaction system in the previous step is heated to 120 ℃, meanwhile, the raw material 3 and the potassium carbonate aqueous solution are dropwise added, the dropwise adding time is 0.5-2 hours, after the dropwise adding is finished, stirring is carried out for 4-6 hours, after the alkylated intermediate disappears through HPLC detection, the reaction liquid is firstly filtered, then the filtrate is subjected to reduced pressure distillation, most of 1, 4-dioxane is recycled and used, ethyl acetate is added into the concentrated reaction liquid, and the organic phase is dried and spin-dried, and is treated with ethanol: recrystallizing with water at a ratio of 1:2 to obtain the product of Pexidintinib, wherein the equivalent ratio of each reactant is as follows: raw material 3: potassium carbonate: raw material 1: 1.2:1.5: 1.0.
According to the invention, through a large number of experiments and mechanism researches, 5-chloro-7-azaindole and 2-chloro-5-chloromethyl pyridine which are cheap and easy to obtain in the market are selected as starting raw materials, an alkylation reaction of the 5-chloro-7-azaindole is carried out, an alkylation intermediate is obtained with high yield, the intermediate does not need to be purified, and is directly and continuously carried out to a next reaction unit, and the intermediate and another 3-aminomethyl-6- (trifluoromethyl) pyridine which is cheap and easy to obtain in the market are subjected to an amino substitution reaction, so that the target product pexidintinib is obtained. The invention firstly invents a two-step continuous production method, and realizes the synthesis of the pexidininib with low cost, high yield, high purity and high environmental protection by the process with the total yield of 78.8%. The method adopted by the invention has mild conditions and easy control, and the reaction solvent can be recycled, thereby greatly reducing the environmental pollution and the production cost and having important significance for the industrial production of the pexidininib medicine.
Detailed Description
The technical solution of the present invention will be described in detail by examples.
Example 1
The structural formula of the pexidininib is as follows:
the reaction equation is:
synthesized by the following method:
under the protection of inert gases such as nitrogen, dissolving a raw material 1(15.2g, 1.0eq) into a reaction solvent 1, 4-dioxane of 120mL, sequentially adding potassium iodide (3.32g, 0.2eq) and silver oxide (27.7g, 1.2eq), heating the reaction solution to 100 ℃ under the atmosphere of nitrogen, dissolving a raw material 2(17.8g, 1.1eq) into 30mL of 1, 4-dioxane, and dropwise adding the mixture into the reaction system for 1 hour to react for 8 hours; the reaction was complete by HPLC and the reaction was used directly in the next reaction unit.
Dissolving raw material 3(21.1g, 1.2eq) into 30mL of 1, 4-dioxane, dissolving potassium carbonate (20.6g, 1.5eq) into 30mL of water, heating the reaction system in the previous step to 120 ℃, simultaneously dropwise adding the raw material 3 solution and the potassium carbonate aqueous solution for 2 hours, stirring and reacting for 6 hours after dropwise adding, filtering the reaction solution while the reaction solution is hot after detecting the disappearance of an alkylated intermediate by HPLC (high performance liquid chromatography), then distilling the filtrate under reduced pressure, recycling and using most of 1, 4-dioxane (150mL), adding 200mL of ethyl acetate into the concentrated reaction solution, washing once with saturated saline solution, drying and spin-drying an organic phase, and using ethanol: recrystallization with water at a ratio of 1:2 gave the product, pexidinib, 32.5g, in 78% yield.1H NMR(400MHz，DMSO-d6):δ＝11.62(s,1H),8.71(s,1H),8.15(d,J＝2.0Hz,1H),7.96-7.94(m,3H),7.83(d,J＝8.0Hz,1H),7.33(d,J＝1.6Hz,1H),7.31(dd,J＝8.4,2.4Hz,1H),7.11(t,J＝6.0Hz,1H),6.48(d,J＝8.8Hz,1H),4.55(d,J＝6.0Hz,2H),3.82(s,2H)。
Example 2
The structural formula of the pexidininib is as follows:
the reaction equation is:
synthesized by the following method:
under the protection of inert gases such as nitrogen, dissolving a raw material 1(15.2g, 1.0eq) into a reaction solvent 1, 4-dioxane of 120mL, sequentially adding sodium iodide (4.5g, 0.3eq) and silver oxide (27.7g, 1.2eq), heating the reaction solution to 100 ℃ under the atmosphere of nitrogen, dissolving a raw material 2(17.0g, 1.05eq) into 30mL of 1, 4-dioxane, and dropwise adding the mixture into the reaction system for 1 hour to react for 8 hours; the reaction was complete by HPLC and the reaction was used directly in the next reaction unit.
Dissolving raw material 3(21.1g, 1.2eq) into 30mL of 1, 4-dioxane, dissolving sodium carbonate (26.5g, 2.5eq) into 50mL of water, heating the reaction system in the previous step to 120 ℃, simultaneously dropwise adding the raw material 3 solution and a potassium carbonate aqueous solution for 2 hours, stirring and reacting for 6 hours after dropwise adding, filtering the reaction solution while the reaction solution is hot after detecting the disappearance of an alkylated intermediate by HPLC (high performance liquid chromatography), then distilling the filtrate under reduced pressure, recycling and using most of 1, 4-dioxane (150mL), adding 200mL of ethyl acetate into the concentrated reaction solution, washing once with saturated saline water, drying and spin-drying an organic phase, and using ethanol: recrystallizing with water at a ratio of 1:2 to obtain the product of Pexidininib, 29.7g, with a yield of 71.2%.
Example 3
The structural formula of the pexidininib is as follows:
the reaction equation is:
synthesized by the following method:
under the protection of inert gases such as nitrogen, dissolving 1.52Kg of raw material 1, 0eq into a reaction solvent 1, 4-dioxane by 12L, sequentially adding potassium iodide (332g, 0.2eq) and silver oxide (2.77Kg, 1.2eq), heating the reaction solution to 100 ℃ under the atmosphere of nitrogen, dissolving 2(1.78Kg, 1.1eq) of raw material into 3L of 1, 4-dioxane, and dropwise adding the mixture into the reaction system for 1 hour to react for 8 hours; the reaction was complete by HPLC and the reaction was used directly in the next reaction unit.
Dissolving raw material 3(2.11Kg, 1.2eq) into 3L of 1, 4-dioxane, dissolving potassium carbonate (2.06Kg, 1.5eq) in 3L of water, heating the reaction system in the previous step to 120 ℃, simultaneously dropwise adding the raw material 3 solution and the potassium carbonate aqueous solution for 2 hours, stirring and reacting for 5 hours after dropwise adding, filtering the reaction solution while the reaction solution is hot after detecting the disappearance of an alkylated intermediate by HPLC (high performance liquid chromatography), then distilling the filtrate under reduced pressure, recycling and mechanically using most of 1, 4-dioxane (15L), adding 20L of ethyl acetate into the concentrated reaction solution, washing with saturated salt water once, drying and spin-drying an organic phase, and using ethanol: recrystallizing with water at a ratio of 1:2 to obtain the product of Pexidininib, 3.3Kg, with yield of 78.8% and HPLC purity of 99.8%.
The above description is only an example of the present invention, and is not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or other related fields directly or indirectly are included in the scope of the present invention.
Claims (5)
1. A synthetic method for continuously producing Pexidinib is characterized in that a reaction equation is as follows:
wherein:
s1: firstly, in a reaction solvent, raw materials 1 and 2 are subjected to alkylation reaction under the action of an additive and a catalyst to generate an alkylation intermediate; and the number of the first and second groups,
s2: in a reaction solvent, the alkylation intermediate obtained in the step S1 and a raw material 3 are subjected to an amino substitution reaction under the action of alkali to generate pexidinib;
in the step S1, the reaction solvent is one or a mixture of tetrahydrofuran, 1, 4-dioxane or methyl tetrahydrofuran, the additive is cuprous oxide, silver oxide or silver carbonate, and the catalyst is sodium iodide or potassium iodide; in the step S2, the reaction solvent is one or a mixture of several of tetrahydrofuran, 1, 4-dioxane or methyl tetrahydrofuran, and the base is sodium carbonate, potassium carbonate or triethylamine.
2. The method for continuously synthesizing Pexidinib according to claim 1, wherein the reaction solvent in step S1 is one or more of 1, 4-dioxane and methyltetrahydrofuran, the additive is cuprous oxide or silver oxide, the catalyst is sodium iodide or potassium iodide, the molar ratio of the catalyst to the raw material 1 is 0.1: 1.0-0.3: 1.0, the molar ratio of the raw material 2 to the raw material 1 is 1.0: 1.0-3.0: 1.0, the molar ratio of the additive to the raw material 1 is 1.0: 1.0-1.5: 1.0, and the reaction temperature is 60-120 ℃; the reaction solvent in the step S2 is one or a mixture of more of 1, 4-dioxane and methyl tetrahydrofuran, the alkali is sodium carbonate or potassium carbonate, the molar ratio of the raw material 3 to the raw material 1 is 0.9: 1.0-1.5: 1.0, the molar ratio of the alkali to the raw material 1 is 1.0: 1.0-2.5: 1.0, and the reaction temperature is 60-120 ℃.
3. The method for continuously synthesizing Pexidinib according to claim 2, wherein in step S1, the molar ratio of the catalyst to the raw material 1 is 0.2: 1.0-0.3: 1.0, the molar ratio of the raw material 2 to the raw material 1 is 1.0: 1.0-1.5: 1.0, the molar ratio of the additive to the raw material 1 is 1.0: 1.0-1.2: 1.0, and the reaction temperature is 100 ℃.
4. The method for continuously synthesizing Pexidinib according to claim 2, wherein in step S2, the molar ratio of raw material 3 to raw material 1 is 1.2: 1.0-1.5: 1.0, the molar ratio of alkali to raw material 1 is 1.2: 1.0-2.0: 1.0, and the reaction temperature is 120 ℃.
5. The synthetic method for continuously producing Pesiccatinib as claimed in claim 2, wherein step S1: under the protection of inert gas, dissolving a raw material 1 into a reaction solvent 1, 4-dioxane, sequentially adding potassium iodide and silver oxide, heating the reaction solution to 100 ℃ under the atmosphere of nitrogen, dissolving a raw material 2 into the 1, 4-dioxane, dropwise adding the mixture into a reaction system for 1 hour, and reacting for 6-8 hours; detecting the reaction completion by HPLC, and then directly using the reaction liquid for the next reaction; wherein the equivalent ratio of each reactant is as follows: raw material 1: raw material 2: potassium iodide: silver oxide 1.0:1.1:0.2: 1.2;
step S2: dissolving a raw material 3 in 1, 4-dioxane, dissolving potassium carbonate in water, heating a reaction liquid obtained by the reaction in the step S1 to 120 ℃, then simultaneously dropwise adding the raw material 3 and a potassium carbonate aqueous solution into the reaction liquid for 0.5-2 hours, stirring and reacting for 4-6 hours after dropwise adding, filtering the reaction liquid after detecting that an alkylation intermediate disappears by HPLC, then distilling the filtrate under reduced pressure, recovering the 1, 4-dioxane, adding ethyl acetate into the concentrated reaction liquid, separating an organic phase obtained after layering, drying and spin-drying the organic phase, wherein the spin-dried substance is ethanol: recrystallizing with a solvent with water being 1:2 to obtain the product of Pexidintinib, wherein the equivalent ratio of each reactant is as follows: raw material 3: potassium carbonate: raw material 1: 1.2:1.5: 1.0.
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