CN108586465B - Preparation method of barretinib - Google Patents
Preparation method of barretinib Download PDFInfo
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Abstract
The invention discloses a preparation method of barretinib, belonging to the technical field of medicine preparation, wherein 4-chloropyrrolopyrimidine is used as an initial raw material, amino protection is firstly carried out, and then the amino protection, hydrazine hydrate and acrolein are substituted and ring-closed by a one-pot method to obtain a middle 4. Condensing starting raw materials 1, 3-dibromoacetone and ethylene glycol to obtain an intermediate 5, condensing the intermediate 5 and ethyl sulfonamide to obtain an intermediate 6, reacting the intermediate 6 and diethyl cyanomethyl phosphate under strong alkali to prepare an intermediate 7, and carrying out addition reaction and deprotection on the intermediate 4 and the intermediate 7 under the action of a catalyst to obtain a target product 1. The process has mild reaction conditions, simple and feasible intermediate purification method, high total yield of 40-55 percent and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of a selective JAK1 and JAK2 inhibitor britinib.
Technical Field
Baricitinib (Baricitinib) has a chemical name of 1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2, 3-D ] pyrimidin-4-yl) -1H-pyrazol-1-yl ] -3-azetidine acetonitrile, is a selective oral JAK1/JAK2 inhibitor developed by American Gift pharmaceutical company and Incyte pharmaceutical company, can inhibit intracellular signal conduction of various inflammatory cytokines such as IL-6, IL-23 and the like, and can be used for treating moderate-to-severe rheumatoid arthritis. In a study involving more than 1300 patients, barretinib (Baricitinib), taken daily by both lieus and Incyte compared to placebo, significantly improved RA symptoms after 12 weeks, meeting primary endpoint requirements. For two common clinical indexes of RA, the medicine is proved to be superior to adalimumab (Humira), achieves the secondary target of the research, and the recent clinical research result shows that the curative effect is obvious. Phase 3 clinical studies are currently conducted in a number of countries including china, the united states, making Baricitinib (Baricitinib) the first oral therapeutic to outperform standard injection therapies, including Humira and Enbrel. The structural formula is as follows:
the current technology for preparing baricitinib is less, and mainly comprises a patent CN105294699 and a PCT patent WO2009114512 (corresponding Chinese patent CN102026999A or CN 102026999B).
The method for preparing barretinib in CN105294699 is as follows:
the method comprises the steps of taking 4-pyrazole boronic acid pinacol ester and 3- (cyanomethylene) azetidine-1-tert-butyl formate as starting raw materials, carrying out Michael addition reaction to obtain a compound 9, and carrying out catalytic coupling reaction on the compound 9 and a starting raw material compound 10 to obtain an intermediate 11; removing two molecules of tert-butyl formate from the intermediate 11 to obtain an intermediate 12; and (3) carrying out sulfonylation amination reaction on the intermediate 12 and ethylsulfonyl chloride in an organic solvent to obtain a final product, namely barretinib (compound 1). The starting materials, compound 7 and compound 8, are difficult to purchase in the route, and the last step in the invention contains two amino groups with better activity, so that the bi-substitution is easy to occur when reacting with ethylsulfonyl chloride or the ethylsulfonyl chloride is easy to react with the amino group on the pyrrole ring, so that the side products are more in the step. In addition, the noble metal palladium is used in the reaction, the total cost is relatively high, and the method is not suitable for industrial production.
The process for the preparation of brigatinib in PCT patent WO2009114512 (corresponding chinese patent CN102026999A or CN102026999B) is as follows:
the method comprises the steps of taking 4-chloropyrrolopyrimidine as a raw material, firstly protecting with 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) to obtain SEM protected 4-chloropyrrolopyrimidine, then carrying out Suzuki coupling reaction on the SEM protected 4-chloropyrrolopyrimidine and a boric acid ester compound 17 to obtain a compound 18, then carrying out 1-ethoxyethyl protection removal on the compound 18 through a hydrochloric acid aqueous solution to obtain a pyrazole compound 19, carrying out Michael addition reaction on the prepared compound 6 and the compound 19 under the catalysis of DBU to obtain a compound 20, and finally carrying out LIBF on the compound 204And NH4And carrying out two-step deprotection on OH to obtain a final product of the balitinib. The reaction route is too long, the total yield is low, the operation is complicated, palladium is used twice in the reaction, the finished product is relatively high, and the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects, the invention provides a preparation method of barretinib, which has the advantages of easily obtained raw materials, easy operation and lower finished product.
The invention uses 4-chlorine pyrrolo pyrimidine as a starting material, firstly carries out amino protection, directly or after solvent is removed by evaporation, and the amino protection, hydrazine hydrate and acrolein are substituted and closed by a one-pot method to obtain the intermediate 4. Condensing 1, 3-dibromoacetone serving as a starting material and ethylene glycol to obtain an intermediate 5, condensing the intermediate 5 and ethyl sulfonamide to obtain an intermediate 6, eliminating the intermediate 6 and diethyl cyanomethyl phosphate under strong alkali to obtain an intermediate 7, carrying out addition reaction on the intermediate 4 and the intermediate 7 under the action of a catalyst, and carrying out deprotection to obtain a target product, wherein the total yield is 40-55%. The defects that the conventional preparation method has overlong route and complicated operation, or raw materials are not easy to obtain, or the cost is high due to the adoption of precious metal palladium for Michael addition are overcome.
Based on the method, the invention provides a preparation method of barretinib.
The technical scheme for realizing the purpose is as follows:
a preparation method of barretinib comprises the following steps:
(1) 4-chloro-pyrrolopyrimidine is taken as a raw material, amino protection is carried out on the raw material and an amino protecting group to obtain an intermediate compound 3, and then the intermediate compound, hydrazine hydrate and acrolein are substituted, cyclized and recrystallized in a certain proportion by a one-pot method under oxygen and in an organic solvent to obtain a compound 4; the structural formula of the compound 4 is as follows:
r is an amino protecting compound such as alkoxycarbonyl including di-tert-butyl dicarbonate, ((Boc)2O), fluorenylmethoxycarbonylcarbonyl chloride (Fmoc-Cl), benzylcarbonyl (Cbz-Cl); acyl groups including p-toluenesulfonyl chloride (TS-Cl), trifluoroacetyl chloride (Tfa-Cl); alkyl groups, including chlorotritylmethane (Trt-Cl), p-methoxybenzyl bromide (or chloride) (PMB-Br, or PMB-Cl)
R' is a protecting group corresponding to R, such as tert-butyloxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fomc), benzylcarbonyl (Cbz), p-methanesulfonyl (TS), trifluoroacetyl chloride (Tfa), chlorotritylmethane (Trt), p-methoxybenzyl (PMB)
(2) 1, 3-dibromoacetone and ethylene glycol are used as raw materials and condensed under the catalysis of strong acid to obtain a carbonyl protective compound 5; the structural formula of the compound 5 is as follows:
(3) heating the compound 5 obtained in the step (2) and ethyl sulfonamide to perform cyclization under the action of alkali to obtain a compound 6; the structural formula of the compound 6 is as follows:
(4) eliminating raw materials of diethyl cyanomethyl phosphate and the compound 6 in the step (3) under strong alkali to obtain a compound 7; the structural formula of the compound 7 is as follows:
(5) and (3) carrying out addition and deamination protecting groups on the compound 4 obtained in the step (1) and the compound 7 obtained in the step (4) in an organic solvent under the action of a catalyst to obtain the barretinib.
In some of the embodiments, the organic solvent in step (1) is one of tetrahydrofuran, toluene, xylene, and o-dichlorobenzene;
in some of these embodiments, the molar ratio of 4-chloropyrrolopyrimidine, hydrazine hydrate, acrolein in step (1) is 1: 1: 1-1: 4: 4.
in some of the embodiments, the strong acid catalyst in step (2) is one of p-toluenesulfonic acid and sulfuric acid.
In some of the embodiments, the base in step (3) is one of potassium carbonate, sodium carbonate, cesium carbonate, preferably cesium carbonate; the reaction temperature is 50-80 DEG C
In some of these embodiments, the base in step (3) is cesium carbonate and the reaction temperature is 65 ℃;
in some embodiments, the strong base in step (4) is one of sodium hydride, potassium hydride, sodium methoxide, and sodium ethoxide; the reaction temperature is 10-40 ℃.
In some of these embodiments, the catalyst described in step (5) is one of DBU, TBAB, TEBA; the reaction temperature is 40-70 ℃.
Has the advantages that:
(1) the method avoids the problem of high cost caused by using metal palladium in a Suzuki coupling reaction in the traditional synthetic method of the Baritinib;
(2) the invention skillfully uses the amino protecting group, avoids the amino in the pyrrole ring from participating in the reaction, reduces the possibility of generating byproducts, and improves the quality and the total yield of intermediates and finished products;
(3) after the amino protection of the compound 2, the solvent is directly distilled off, and then the compound is substituted and closed with ammonia water and acrolein by a one-pot method to obtain an intermediate 4, so that the operation steps are simplified;
(4) the invention adopts cheap and easily obtained starting raw materials, has much shorter reaction route than the traditional route and mild reaction condition, and is suitable for industrial production.
Drawings
FIG. 1 hydrogen spectrum of example 1 Baritinib
FIG. 2 liquid chromatogram of example 1 Baratinib
Detailed Description
Example 1
Synthesis of Compound 4
15.4g (0.1mol) of Compound 2, 11.4g (0.05mol) of dipotassium hydrogenphosphate, 26.2g (0.12mol) of di-tert-butyl dicarbonate, 300g of tetrahydrofuran and 70g of water were put into a 1L reaction flask, stirred at room temperature for 12 hours, then subjected to neutralization, the reaction of the raw materials was completed, separated, the aqueous layer was extracted with 200g of tetrahydrofuran, and the organic layers were combined and used in the next step as they were.
5.1g (0.1mol) of hydrazine hydrate and 5.6g (0.1mol) of acrolein were added to the above system, and the mixture was refluxed for 8 hours under an oxygen atmosphere. And (3) stopping heating after the medium-control raw materials completely react, cooling the system to room temperature, pouring the system into 100g of ice water while stirring, layering after stirring for 10min, drying and filtering an organic layer, carrying out rotary evaporation on filtrate to obtain a crude sticky substance, and recrystallizing the crude product with methyl tert-butyl ether and n-hexane to obtain a compound 4 of about 24.9g, wherein the yield is as follows: 87.2 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 5
Adding 500g of toluene into a 2L reaction bottle, adding 43.2g (0.2mol) of 1, 3-dibromoacetone, 24.3g (0.4mol) of ethylene glycol and 0.3g of p-toluenesulfonic acid while stirring, heating the system to 110 ℃, refluxing, separating generated water by using a water separator in the refluxing process, performing heat preservation reaction for 12 hours, performing reduced pressure evaporation on the toluene, adding 450g of ethyl acetate into the system after no liquid drips out, and washing the system twice by using 450g of water and drying an organic layer. Drying, passing the organic layer through fiber activated carbon, then passing through diatomite, distilling the obtained filtrate to remove an ethyl acetate layer, and finally obtaining colorless transparent liquid 41.9g, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0 percent, and the yield is as follows: 80.7 percent.1HNMR(400MHz，CDCl3)，δppm3.61(s，4H)，4.14(s，4H)。
Synthesis of Compound 6
500g of 1, 4-dioxane, 39.0g (0.15mol) of compound 5, 97.7g (0.3mol) of cesium carbonate and 18.0g (0.17mol) of ethylsulfonamide are added into a 2L reaction bottle, the system is heated to 80 ℃, the reaction is carried out for 20 hours under the condition of heat preservation, the control is carried out, and the reaction of the raw material compound 5 is basically completed. The reaction was stopped, the system was cooled to room temperature, 500g of water and 500g of ethyl acetate were added to the system, stirring and layering were performed, the aqueous layer was extracted with 300g of x2 ethyl acetate, the organic layers were combined, and the organic layer was washed with 500g of water. The organic layer was then placed in a 2L clean reaction flask and 30.4g of concentrated hydrochloric acid was added dropwise with stirring at room temperature. After dripping, stirring for 1h, layering, washing an organic layer with 500g of water, drying, filtering, concentrating half of filtrate, adding 300g of n-heptane, cooling the system to 0-10 ℃, preserving heat, pulping for 2h, filtering, drying a filter cake until the chemical combination is about 22.6g, and obtaining the yield: 92.4 percent and HPLC is more than or equal to 98.0 percent.
m/z＝164.1(M+1)，1HNMR(300MHz,CDCl3):δ4.08(d,J＝2.4Hz,2H),3.94(d,J＝2.6Hz,2H),3.35-3.10(m,2H),1.40-1.20(m,3H)ppm。
Synthesis of Compound 7
Adding 450g of tetrahydrofuran and 21.3g (0.12mol) of diethyl cyanomethylphosphonate into a 2L reaction bottle, cooling the system to-5-5 ℃, adding 5.3g (0.13mol) of sodium hydride (with the content of 60%) in batches under the protection of nitrogen, and gradually heating the system to 20 ℃ after 30min of addition. Stirring for 45 min. A solution of 16.3g (0.1mol) of Compound 6 and 80g of tetrahydrofuran was further added dropwise to the system. After dripping within 1h, stirring at room temperature for reaction for 12h, and basically completely reacting the controlled raw materials. After the temperature of the system was reduced to 0 ℃, 500g of ethyl acetate and 300g of saturated saline were added, and the mixture was stirred for 5min and then separated into layers. The aqueous layer was extracted with 300g of X3 ethyl acetate and the organic layers were combined. The organic layer was washed with 500g of water. The organic layer was dried, filtered, and the filtrate was concentrated to give crude compound 7, which was rinsed with a small amount of n-hexane and dried to give 15.2g of compound 7, yield: 88.2 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of target product 1
200g of acetonitrile and 14.3g (0.05mol) of the compound 4 are added into a 1L reaction bottle, 6.9g (0.05mol) of potassium carbonate is added under stirring, the mixture is stirred at room temperature for 30min, 9.3g (0.05mol) of the compound 7 and 8.1g (0.025mol) of TBAB are added, the system is heated to 40 ℃ to react for 8h, the reaction is controlled, the raw materials are completely reacted, and the reaction is stopped. Evaporating under reduced pressure to remove solvent, adding 100g of water into the system, quenching, reacting, adding 200g of ethyl acetate, stirring, layering, extracting a water layer with 100g of X3 ethyl acetate, combining organic layers obtained by extraction, adding 10.2g of concentrated hydrochloric acid at room temperature, stirring for 30min, filtering, adding 300g of fresh ethyl acetate into a filter cake, adjusting pH to be neutral by using 10% potassium carbonate solution under stirring, layering, drying the organic layer, filtering, drying the filter cake to obtain 16.6g of white solid, wherein HPLC (HPLC: 99.82%) is more than or equal to 99.0%, and the yield: 89.3 percent. The hydrogen spectrum of the target product 1 is shown in FIG. 1.
Example 2
Synthesis of Compound 4
15.4g (0.1mol) of compound 2, 11.4g (0.05mol) of dipotassium hydrogen phosphate, 31.0g (0.12mol) of fluorenylmethoxycarbonyl chloride and 400g of dichloromethane are put into a 1L reaction bottle, stirred at room temperature for 12 hours, then subjected to central control, completely reacted, filtered, added with 300g of ice water into filtrate, stirred for 10 minutes, separated, the water layer is extracted by 200g, the organic layers are combined and dried in a spinning mode, and the obtained system is directly used for the next reaction.
To the above system were added 10.2g (0.2mol) of hydrazine hydrate, 500g of toluene and 11.2g (0.2mol) of acrolein, and the mixture was refluxed for 8 hours under an oxygen atmosphere. And (3) stopping heating after the medium-control raw materials completely react, cooling the system to room temperature, pouring the system into 100g of ice water while stirring, layering after stirring for 10min, filtering after drying an organic layer, carrying out rotary evaporation on the filtrate to obtain a crude sticky substance, and recrystallizing the crude product with methyl tert-butyl ether and n-hexane to obtain a compound 4 of about 41.7g, wherein the yield is as follows: 80.5 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 5
Adding 500g of toluene into a 2L reaction bottle, adding 43.2g (0.2mol) of 1, 3-dibromoacetone, 24.3g (0.4mol) of ethylene glycol and 2.0g of concentrated sulfuric acid while stirring, heating the system to 110 ℃, refluxing, separating generated water by a water separator in the refluxing process, performing heat preservation reaction for 12 hours, evaporating toluene under reduced pressure, adding 450g of ethyl acetate into the system after no liquid drips out, washing the system with 450g of water twice, and drying an organic layer. Drying, passing the organic layer through fiber activated carbon, passing through diatomite, distilling the obtained filtrate to remove an ethyl acetate layer, and finally obtaining colorless transparent liquid 42.1g, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0 percent, and the yield is as follows: 81.1 percent.
Synthesis of Compound 6
500g of 1, 4-dioxane, 39.0g (0.15mol) of compound 5, 41.5g (0.3mol) of potassium carbonate and 18.0g (0.17mol) of ethylsulfonamide are added into a 2L reaction bottle, the system is heated to 70 ℃, the reaction is carried out for 20 hours under the condition of heat preservation, the control is carried out, and the reaction of the raw material compound 5 is basically completed. The reaction was stopped, the system was cooled to room temperature, 500g of water and 500g of ethyl acetate were added to the system, stirring and layering were performed, the aqueous layer was extracted with 300g of x2 ethyl acetate, the organic layers were combined, and the organic layer was washed with 500g of water. The organic layer was then placed in a 2L clean reaction flask and 30.4g of concentrated hydrochloric acid was added dropwise with stirring at room temperature. After dripping, stirring for 1h, layering, washing an organic layer with 500g of water, drying, filtering, concentrating half of filtrate, adding 300g of n-heptane, cooling the system to 0-10 ℃, preserving heat, pulping for 2h, filtering, drying a filter cake until the chemical combination is about 22.8g, and obtaining the yield: 93.1 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 7
Adding 450g of tetrahydrofuran and 21.3g (0.12mol) of diethyl cyanomethylphosphonate into a 2L reaction bottle, cooling the system to 10 ℃, adding 7.0g (0.13mol) of sodium methoxide under the protection of nitrogen, and gradually heating the system to 20 ℃ after the addition is finished. Stirring for 45 min. A solution of 16.3g (0.1mol) of Compound 6 and 80g of tetrahydrofuran was further added dropwise to the system. After dripping within 1h, stirring and reacting at 30 ℃ for 10h, and basically completely reacting the central control raw materials. After the temperature of the system was reduced to 10 ℃, 500g of ethyl acetate and 300g of saturated saline were added, and the mixture was stirred for 5min and then separated into layers. The aqueous layer was extracted with 300g of X3 ethyl acetate and the organic layers were combined. The organic layer was washed with 500g of water. The organic layer was dried, filtered, and the filtrate was concentrated to give crude compound 7, which was rinsed with a small amount of n-hexane and dried to give 16.6g of compound 7, yield: 96.4 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of target product 1
200g of acetonitrile and 20.4g (0.05mol) of compound 4 are added into a 1L reaction bottle, 6.9g (0.05mol) of potassium carbonate is added under stirring, 9.3g (0.05mol) of compound 7 and 8g (0.05mol) of DBU are added after stirring for 30min at room temperature, the system is heated to 40 ℃ and reacts for 8h, the reaction is controlled, the raw materials completely react, and the reaction is stopped. And (2) after the solvent is evaporated under reduced pressure, adding 100g of water into the system, quenching, reacting, adding 200g of ethyl acetate, stirring for 30min, filtering, rinsing the filter cake with 100g of fresh ethyl acetate, drying the filter cake to obtain 17.0g of white solid, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0%, and the yield is as follows: 91.2 percent.
Example 3
Synthesis of Compound 4
15.4g (0.1mol) of compound 2, 27.6g (0.2mol) of potassium carbonate, 19.1g (0.1mol) of paratoluensulfonyl chloride and 500g of acetonitrile are put into a 1L reaction bottle, stirred for 8 hours at room temperature and then subjected to central control, the raw materials are reacted completely, filtered, and the filtrate is decompressed and dried in a rotary manner and is directly used in the next step.
20.4g (0.4mol) of hydrazine hydrate, 450g of o-dichlorobenzene and 22.4g (0.4mol) of acrolein were added to the above system, and the mixture was refluxed for 4 hours under an oxygen atmosphere. And (3) stopping heating after the medium-control raw materials completely react, cooling the system to room temperature, pouring the system into 100g of ice water while stirring, layering after stirring for 10min, drying and filtering an organic layer, carrying out rotary evaporation on the filtrate to obtain a crude sticky substance, and recrystallizing the crude product with methyl tert-butyl ether and n-hexane to obtain a compound 4 of about 27.7g, wherein the yield is as follows: 81.6 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 5
500g of toluene was charged into a 2L reaction vessel, and 43.2g (0.2mol) of 1, 3-dibromoacetone and 24.3g of toluene were added thereto with stirring
(0.4mol) of ethylene glycol and 0.3g of p-toluenesulfonic acid, heating the system to 110 ℃ for reflux, separating out generated water by using a water separator in the reflux process, performing heat preservation reaction for 12 hours, performing reduced pressure evaporation on toluene, adding 450g of ethyl acetate into the system after no liquid is dripped out, washing the system with 450g of water twice, and drying an organic layer. Drying, passing the organic layer through fiber activated carbon, then passing through diatomite, distilling the obtained filtrate to remove an ethyl acetate layer, and finally obtaining colorless transparent liquid 42.6g, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0 percent, and the yield is as follows: 82.0 percent.1HNMR(400MHz，CDCl3)，δppm3.61(s，4H)，4.14(s，4H)。
Synthesis of Compound 6
500g of 1, 4-dioxane, 39.0g (0.15mol) of compound 5, 31.8g (0.3mol) of sodium carbonate and 18.0g (0.17mol) of ethyl sulfonamide are added into a 2L reaction bottle, the temperature of the system is raised to 65 ℃, the reaction is kept for 16 hours, and the reaction is controlled to be almost complete when the raw material compound 5 is reacted. The reaction was stopped, the system was cooled to room temperature, 500g of water and 500g of ethyl acetate were added to the system, stirring and layering were performed, the aqueous layer was extracted with 300g of x2 ethyl acetate, the organic layers were combined, and the organic layer was washed with 500g of water. The organic layer was then placed in a 2L clean reaction flask and 30.4g of concentrated hydrochloric acid was added dropwise with stirring at room temperature. After dripping, stirring for 1h, layering, washing an organic layer with 500g of water, drying, filtering, concentrating half of filtrate, adding 300g of n-heptane, cooling the system to 0-10 ℃, preserving heat, pulping for 2h, filtering, drying a filter cake until the chemical combination is about 23.0g, and obtaining the yield: 94.1 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 7
Adding 450g of tetrahydrofuran and 21.3g (0.12mol) of diethyl cyanomethylphosphonate into a 2L reaction bottle, cooling the system to 10 ℃, adding 10.2g (0.15mol) of sodium ethoxide under the protection of nitrogen, and gradually heating the system to 20 ℃ after the addition is finished. Stirring for 45 min. A solution of 16.3g (0.1mol) of Compound 6 and 80g of tetrahydrofuran was further added dropwise to the system. After dripping within 1h, stirring and reacting at 40 ℃ for 10h, and basically completely reacting the central control raw materials. After the temperature of the system was reduced to 10 ℃, 500g of ethyl acetate and 300g of saturated saline were added, and the mixture was stirred for 5min and then separated into layers. The aqueous layer was extracted with 300g of X3 ethyl acetate and the organic layers were combined. The organic layer was washed with 500g of water. The organic layer was dried, filtered, and the filtrate was concentrated to give crude compound 7, which was rinsed with a small amount of n-hexane and dried to give 16.3g of compound 7, yield: 94.3 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of target product 1
200g of acetonitrile and 17.0g (0.05mol) of the compound 4 are added into a 1L reaction bottle, 6.9g (0.05mol) of potassium carbonate is added under stirring, 9.3g (0.05mol) of the compound 7 and 5.7g (0.025mol) of TEBA are added after stirring for 30min at room temperature, the system is heated to 70 ℃ to react for 6h, the reaction is controlled, the raw materials are reacted completely, and the reaction is stopped. After the solvent is removed by reduced pressure evaporation, 100g of water is added into the system to quench the reaction, 400g of acetone is added, 9.8g (0.1mol) of concentrated sulfuric acid is dropwise added at room temperature, the mixture is stirred at 40 ℃ for 1h, then the temperature is reduced to 0 ℃ for filtration, a filter cake is rinsed by 50g of acetone, the filtrate is reduced pressure and is rotary evaporated to dryness, 300g of ethyl acetate is added, the mixture is stirred at room temperature for 2h and is filtered, the filter cake is dried to obtain 16.0g of white solid, HPLC (high performance liquid chromatography) is more than or equal to: 85.9 percent.
Example 4
Synthesis of Compound 4
15.4g (0.1mol) of Compound 2, 20.2g (0.2mol) of triethylamine, 27.9g (0.1mol) of triphenylchloromethyl chloride and 600g of acetonitrile were put into a 1L reaction flask, and after stirring at room temperature for 4 hours, the reaction was controlled to completion. Filtering, and spin-drying the filtrate under reduced pressure for direct use in the next step.
20.4g (0.4mol) of hydrazine hydrate, 450g of o-dichlorobenzene and 22.4g (0.4mol) of acrolein were added to the above system, and the mixture was refluxed for 4 hours under an oxygen atmosphere. And (3) stopping heating after the medium-control raw materials completely react, cooling the system to room temperature, pouring the system into 100g of ice water while stirring, layering after stirring for 10min, drying and filtering an organic layer, carrying out rotary evaporation on the filtrate to obtain a crude product sticky substance, and recrystallizing the crude product with diethyl ether and n-hexane to obtain a compound 4 of about 35.6g, wherein the yield is as follows: 83.2 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 5
Adding 500g of toluene into a 2L reaction bottle, adding 43.2g (0.2mol) of 1, 3-dibromoacetone, 24.3g (0.4mol) of ethylene glycol and 0.3g of p-toluenesulfonic acid while stirring, heating the system to 110 ℃, refluxing, separating generated water by using a water separator in the refluxing process, performing heat preservation reaction for 12 hours, performing reduced pressure evaporation on the toluene, adding 450g of ethyl acetate into the system after no liquid drips out, and washing the system twice by using 450g of water and drying an organic layer. Drying, passing the organic layer through fiber activated carbon, then passing through diatomite, distilling the obtained filtrate to remove an ethyl acetate layer, and finally obtaining colorless transparent liquid 42.6g, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0 percent, and the yield is as follows: 82.0 percent.
Synthesis of Compound 6
500g of 1, 4-dioxane, 39.0g (0.15mol) of compound 5, 31.8g (0.3mol) of sodium carbonate and 18.0g (0.17mol) of ethyl sulfonamide are added into a 2L reaction bottle, the temperature of the system is raised to 50 ℃, the reaction is kept for 16 hours, and the reaction is controlled to be almost complete when the raw material compound 5 is reacted. The reaction was stopped, the system was cooled to room temperature, 500g of water and 500g of ethyl acetate were added to the system, stirring and layering were performed, the aqueous layer was extracted with 300g of x2 ethyl acetate, the organic layers were combined, and the organic layer was washed with 500g of water. The organic layer was then placed in a 2L clean reaction flask and 30.4g of concentrated hydrochloric acid was added dropwise with stirring at room temperature. After dripping, stirring for 1h, layering, washing an organic layer with 500g of water, drying, filtering, concentrating half of filtrate, adding 300g of n-heptane, cooling the system to 0-10 ℃, preserving heat, pulping for 2h, filtering, drying a filter cake until the chemical combination is about 22.1g, and obtaining the yield: 90.2 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 7
Adding 450g of tetrahydrofuran and 21.3g (0.12mol) of diethyl cyanomethylphosphonate into a 2L reaction bottle, cooling the system to 10 ℃, adding 10.2g (0.15mol) of sodium ethoxide under the protection of nitrogen, and gradually heating the system to 20 ℃ after the addition is finished. Stirring for 45 min. A solution of 16.3g (0.1mol) of Compound 6 and 80g of tetrahydrofuran was further added dropwise to the system. After dripping within 1h, stirring and reacting at 40 ℃ for 10h, and basically completely reacting the central control raw materials. After the temperature of the system was reduced to 10 ℃, 500g of ethyl acetate and 300g of saturated saline were added, and the mixture was stirred for 5min and then separated into layers. The aqueous layer was extracted with 300g of X3 ethyl acetate and the organic layers were combined. The organic layer was washed with 500g of water. The organic layer was dried, filtered, and the filtrate was concentrated to give crude compound 7, which was rinsed with a small amount of n-hexane and dried to give 16.3g of compound 7, yield: 94.3 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of target product 1
400g of acetonitrile and 21.4g (0.05mol) of compound 4 are added into a 1L reaction bottle, 6.9g (0.05mol) of potassium carbonate is added under stirring, 9.3g (0.05mol) of compound 7 and 5.7g (0.025mol) of TEBA are added after stirring for 30min at room temperature, the system is heated to 70 ℃ to react for 6h, the reaction is controlled, the raw materials are reacted completely, and the reaction is stopped. After removing the solvent by reduced pressure evaporation, adding 100g of water into the system, quenching, reacting, then adding 400g of acetone, dropwise adding 19.6g (0.2mol) of concentrated sulfuric acid at room temperature, stirring for 1h at 40 ℃, then cooling to 0 ℃, preserving heat, stirring for 1-2h, then filtering, rinsing the filter cake with 50g of acetone, carrying out reduced pressure rotary evaporation on the filtrate until the filtrate is dry, adding 300g of ethyl acetate, stirring for 2h at room temperature, then filtering, drying the filter cake to obtain 16.7g of white solid, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0%, and the yield is as follows: 89.6 percent.
Example 5
Synthesis of Compound 4
15.4g (0.1mol) of compound 2, 20.2g (0.2mol) of potassium carbonate, 24.1g (0.12mol) of 4-methoxybenzyl bromide and 500g of acetonitrile are put into a 1L reaction flask, stirred at room temperature for 6 hours, then the reaction is controlled, and the reaction of the raw materials is completed. Filtering, and spin-drying the filtrate under reduced pressure for direct use in the next step.
20.4g (0.4mol) of hydrazine hydrate, 450g of o-dichlorobenzene and 22.4g (0.4mol) of acrolein were added to the above system, and the mixture was refluxed for 4 hours under an oxygen atmosphere. And (3) stopping heating after the medium-control raw materials completely react, cooling the system to room temperature, pouring the system into 100g of ice water while stirring, layering after stirring for 10min, drying and filtering an organic layer, carrying out rotary evaporation on the filtrate to obtain a crude product sticky substance, and recrystallizing the crude product with methyl tert-butyl ether and n-hexane to obtain a compound 4 of about 24.6g, wherein the yield is as follows: 80.5 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 5
Adding 500g of toluene into a 2L reaction bottle, adding 43.2g (0.2mol) of 1, 3-dibromoacetone, 24.3g (0.4mol) of ethylene glycol and 0.3g of p-toluenesulfonic acid while stirring, heating the system to 110 ℃, refluxing, separating generated water by using a water separator in the refluxing process, performing heat preservation reaction for 12 hours, performing reduced pressure evaporation on the toluene, adding 450g of ethyl acetate into the system after no liquid drips out, and washing the system twice by using 450g of water and drying an organic layer. Drying, passing the organic layer through fiber activated carbon, then passing through diatomite, distilling the obtained filtrate to remove an ethyl acetate layer, and finally obtaining colorless transparent liquid 42.6g, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0 percent, and the yield is as follows: 82.0 percent.
Synthesis of Compound 6
500g of 1, 4-dioxane, 39.0g (0.15mol) of compound 5, 31.8g (0.3mol) of sodium carbonate and 18.0g (0.17mol) of ethyl sulfonamide are added into a 2L reaction bottle, the temperature of the system is raised to 60 ℃, the reaction is kept for 16 hours, and the reaction is controlled to be almost complete when the raw material compound 5 is reacted. The reaction was stopped, the system was cooled to room temperature, 500g of water and 500g of ethyl acetate were added to the system, stirring and layering were performed, the aqueous layer was extracted with 300g of x2 ethyl acetate, the organic layers were combined, and the organic layer was washed with 500g of water. The organic layer was then placed in a 2L clean reaction flask and 30.4g of concentrated hydrochloric acid was added dropwise with stirring at room temperature. After dripping, stirring for 1h, layering, washing an organic layer with 500g of water, drying, filtering, concentrating half of filtrate, adding 300g of n-heptane, cooling the system to 0-10 ℃, preserving heat, pulping for 2h, filtering, drying a filter cake until the chemical combination is 6.5 g, and obtaining the yield: 93.4 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of Compound 7
Adding 450g of tetrahydrofuran and 21.3g (0.12mol) of diethyl cyanomethylphosphonate into a 2L reaction bottle, cooling the system to 10 ℃, adding 10.2g (0.15mol) of sodium ethoxide under the protection of nitrogen, and gradually heating the system to 20 ℃ after the addition is finished. Stirring for 45 min. A solution of 16.3g (0.1mol) of Compound 6 and 80g of tetrahydrofuran was further added dropwise to the system. After dripping within 1h, stirring and reacting at 40 ℃ for 10h, and basically completely reacting the central control raw materials. After the temperature of the system was reduced to 10 ℃, 500g of ethyl acetate and 300g of saturated saline were added, and the mixture was stirred for 5min and then separated into layers. The aqueous layer was extracted with 300g of X3 ethyl acetate and the organic layers were combined. The organic layer was washed with 500g of water. The organic layer was dried, filtered, and the filtrate was concentrated to give crude compound 7, which was rinsed with a small amount of n-hexane and dried to give 16.3g of compound 7, yield: 94.3 percent and HPLC is more than or equal to 98.0 percent.
Synthesis of target product 1
400g of acetonitrile and 15.3g (0.05mol) of the compound 4 are added into a 1L reaction bottle, 6.9g (0.05mol) of potassium carbonate is added under stirring, 9.3g (0.05mol) of the compound 7 and 5.7g (0.025mol) of TEBA are added after stirring for 30min at room temperature, the system is heated to 70 ℃ to react for 6h, the reaction is controlled, the raw materials are reacted completely, and the reaction is stopped. Evaporating under reduced pressure to remove a solvent, adding 100g of water into the system, quenching, reacting, adding 400g of ethanol, cooling the system to 0-10 ℃, dropwise adding 17.1g (0.15mol) of trifluoroacetic acid under heat preservation, stirring at room temperature for 1h, cooling to 0 ℃, preserving heat, stirring for 1-2h, filtering, rinsing a filter cake with 50g of ethanol, adding 400g of dichloromethane into the system, cooling to 0-10 ℃, stirring for 2h, filtering, drying the filter cake to obtain 15.2g of white solid, wherein HPLC (high performance liquid chromatography) is more than or equal to 99.0%, and the yield is as follows: 81.8 percent.
Claims (9)
1. A preparation method of barretinib is characterized by comprising the following steps:
the reaction steps are as follows:
(1) 4-chloro-pyrrolopyrimidine is taken as a raw material, and is subjected to amino protection with an amino protection compound R to obtain an intermediate compound 3, and then is subjected to substitution, cyclization and recrystallization with hydrazine hydrate and acrolein in an organic solvent under oxygen to obtain a compound 4;
wherein the amino protecting compound R is di-tert-butyl dicarbonate ((Boc)2O), fluorenylmethoxycarbonylcarbonyl chloride (Fmoc-Cl), benzylcarbonyl (Cbz-Cl); p-toluenesulfonyl chloride (TS-Cl), trifluoroacetyl chloride (Tfa-Cl); chlorotrityl methane (Trt-Cl), p-methoxybenzyl bromide (PMB-Br) or p-methoxybenzyl chloride (PMB-Cl);
r' is a protective group corresponding to R and is tert-butyloxycarbonyl (Boc), fluorenyl methoxycarbonyl (Fomc), benzylcarbonyl (Cbz), p-Toluenesulfonyl (TS), trifluoroacetyl (Tfa), trityl (Trt) or p-methoxybenzyl (PMB);
(2) 1, 3-dibromoacetone and ethylene glycol are used as raw materials and condensed under the catalysis of strong acid to obtain a carbonyl protective compound 5;
(3) heating the compound 5 obtained in the step (2) and ethyl sulfonamide to perform cyclization under the action of alkali to obtain a compound 6;
(4) eliminating raw materials of diethyl cyanomethyl phosphate and the compound 6 in the step (3) under strong alkali to obtain a compound 7;
(5) and (3) carrying out addition and deamination protecting groups on the compound 4 obtained in the step (1) and the compound 7 obtained in the step (4) in an organic solvent under the action of a catalyst to obtain the barretinib.
2. The method for preparing brigatinib according to claim 1, wherein the organic solvent in step (1) is one of tetrahydrofuran, toluene, xylene and o-dichlorobenzene.
3. The method for preparing barretinib according to claim 1, wherein the molar ratio of 4-chloropyrrolopyrimidine, hydrazine hydrate to acrolein in step (1) is 1: 1: 1 or 1: 4: 4.
4. a method for preparing brigatinib according to claim 1, wherein the recrystallization solvent used in step (1) is methyl tert-butyl ether/n-hexane, methyl tert-butyl ether/n-heptane, ethyl ether/n-hexane or ethyl ether/n-heptane.
5. The method for preparing barretinib according to claim 1, wherein the strong acid catalyst in step (2) is one of p-toluenesulfonic acid and sulfuric acid.
6. The method for preparing barretinib according to claim 1, wherein the base in step (3) is one of potassium carbonate, sodium carbonate and cesium carbonate; the reaction temperature is 50-80 ℃.
7. The process for preparing brigatinib according to claim 6, wherein the base used in the step (3) is cesium carbonate and the reaction temperature is 65 ℃.
8. The process for preparing barretinib according to claim 1, wherein the strong base in step (4) is one of sodium hydride, potassium hydride, sodium methoxide, and sodium ethoxide; the reaction temperature is 10-40 ℃.
9. The process for preparing barretinib according to claim 1, wherein the catalyst in step (5) is one of DBU, TBAB and TEBA; the reaction temperature is 40-70 ℃.
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| AU2018102141A AU2018102141A4 (en) | 2017-12-13 | 2018-07-03 | Method for preparing Baricitinib |
| PCT/CN2018/094160 WO2019114258A1 (en) | 2017-12-13 | 2018-07-03 | Method for preparing baricitinib |
| AU2018366342A AU2018366342A1 (en) | 2017-12-13 | 2018-07-03 | Method for preparing Baricitinib |
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| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
| WO2021053690A1 (en) * | 2019-09-17 | 2021-03-25 | Natco Pharma Limited | An improved process for the preparation of baricitinib |
| CN111362853A (en) * | 2020-04-27 | 2020-07-03 | 安徽大学 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
| CN112898306B (en) * | 2021-02-02 | 2022-04-08 | 山东四环药业股份有限公司 | Preparation method of barretinib |
| CN115124537A (en) * | 2022-07-13 | 2022-09-30 | 山东大学 | Preparation method of JAK inhibitor britinib |
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| DE3035395A1 (en) * | 1980-09-19 | 1982-05-06 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING PYRAZOLE |
| CN101631792B (en) * | 2007-02-28 | 2013-05-01 | 利奥制药有限公司 | Novel phosphodi esterase inhibitors |
| AU2009223640B2 (en) * | 2008-03-11 | 2013-07-04 | Incyte Holdings Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
| EP3227298A4 (en) * | 2014-12-05 | 2018-05-23 | Sun Pharmaceutical Industries Ltd | Process for the preparation of baricitinib and an intermediate thereof |
| WO2016125080A2 (en) * | 2015-02-02 | 2016-08-11 | Sun Pharmaceutical Industries Limited | Process for the preparation of baricitinib and an intermediate thereof |
| AR104918A1 (en) * | 2015-06-19 | 2017-08-23 | Lilly Co Eli | PROCESSES AND INTERMEDIARIES FOR THE PREPARATION OF {1- (ETILSULFONIL) -3- [4- (7H-PIRROLO [2,3-D] PIRIMIDIN-4-IL) -1H-PIRAZOL-1-IL] AZETIDIN-3-IL } ACETONITRILE |
| CN105294699B (en) * | 2015-12-04 | 2019-06-11 | 上海勋和医药科技有限公司 | Ba Rui replaces the preparation method of Buddhist nun |
| CN105541891B (en) * | 2016-02-04 | 2017-11-28 | 东南大学 | Ba Rui prepares methods of the Ba Rui for Buddhist nun for intermediate of Buddhist nun and preparation method thereof and by the intermediate |
| CN106496195B (en) * | 2016-10-18 | 2019-03-08 | 杭州科巢生物科技有限公司 | Ba Rui is for Buddhist nun and its synthetic method of intermediate |
| CN106946917B (en) * | 2017-03-20 | 2019-06-11 | 杭州科巢生物科技有限公司 | A kind of JAK inhibitor Ba Rui replaces the novel synthesis of Buddhist nun and its intermediate |
| CN107176955B (en) * | 2017-03-24 | 2019-04-09 | 南京优科制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
| CN107739328B (en) * | 2017-11-22 | 2020-03-20 | 海化生命(厦门)科技有限公司 | Preparation method of key intermediate 1 for synthesizing barretinib |
| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
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| AU2018366342A1 (en) | 2019-07-04 |
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